BIOMEDICAL SIDE EFFECTS OF DOPING Biomedical Side Effects

Transcription

2007
Congress Manual:
"Biomedical Side Effects of Doping" is the summary of the scientiﬁc outcomes based on an international symposium organised by the Institute
of Public Health Research at the Technische Universität München (TUM)
in October 2006. The chapters of the manual take a critical look into the
different doping issues, preventive actions and knowledges of the public
on these topics. Furthermore, a detailed analysis is given how various
doping substances can affect health of the different body systems.
Free Copy
[email protected]
www.doping-prevention.sp.tum.de
International Symposium October 21st, 2006
Munich, Germany
Biomedical Side Effects of Doping
Medical University of Plovdiv, Department of Physiology, Bulgaria
Aristotle University of Thessaloniki, Lab of Sports Medicine, Greece
Institute of Sport, Department of Antidoping Research, Poland
University of Extremadura, Department of Physiology, Spain
TU München, Institute of Public Health Research, Germany
BIOMEDICAL SIDE EFFECTS
OF DOPING
edited by:
Hande Sarikaya
Christiane Peters
Thorsten Schulz
Martin Schönfelder
Horst Michna
"Harmonising the knowledge about
biomedical side effects of doping"
Project of the European Union
Congress Manual:
BIOMEDICAL SIDE EFFECTS OF DOPING
International Symposium October 21st, 2006
Munich, Germany
edited by:
Hande Sarikaya
Christiane Peters
Thorsten Schulz
Martin Schönfelder
Horst Michna
Project of the European Union
Editors:
Hande Sarikaya, Christiane Peters, Thorsten Schulz, Martin Schönfelder, Horst Michna
Cover Designer:
Christina Loibl, graduate designer (FH), [email protected]
Printer:
Uni-Druck OHG, 82319 Starnberg, Germany
All rights reserved.
"This project was developed with financial support from the Commission of the European
Communities. The contents of the project results are the responsibility of and reflect the views of the
beneficiaries. The European Commission is not liable for any use that may be made of the
information developed through this project."
First Edition, 2007
ISBN 978-3-00-022081-4
Printed in Germany
This manual is available for free under the ordering address:
Institute of Public Health Research, Technische Universität München
Connollystr. 32, 80809 München, Germany
Preface
Addressing health effects related to doping in sports is an important priority for
the European Union and its Member States. While the EC Treaty does not
include a specific legal basis to fight doping in sports, in the field of public
health, the Community takes action to complement Member States’ activities in
reducing drugs-related health damage, including information and prevention.
In 1999, the Commission adopted a Community support plan to combat doping
in sports. In parallel, we have been able to support the project on biomedical
side effects of doping coordinated by the “Technische Universität” Munich from
the Public Health Programme 2003-2008.
Recent international sports events were a reminder of the need to keep up the
struggle against doping. Although controls, laboratory analysis and related
activities have expanded, a lack of knowledge regarding the side effects of
doping remains among the general public, the athletes and the sporting world.
Greater knowledge of the immediate and the long-term physical and
psychological effects of doping are essential among trainers and athletes,
particularly young athletes, to resist the lure of doping.
Combining licit and illicit substances in doping leads to complex health effects,
which are difficult to manage in particular in adolescence. Through this project
financially supported by the Commission, the current level of scientific
knowledge on biomedical side effects caused by doping is being coordinated.
I trust that the work of the “Technische Universität” of Munich will contribute
considerably to harmonising knowledge about the biomedical side effects of
doping and I congratulate the “Technische Universität” of Munich for the
production of this manual.
Markos Kyprianou
European Commissioner for Health
Preface
One new doping scandal after the other is shattering the foundations of sport,
for drug abuse and doping methods are not only serious dangers to the life and
health of the sportspersons themselves, but are just as dangerous for sport as a
whole, where the first rule should be fairness. If the public gains the impression,
that manipulation has become a basic component of competitive sports, then
sport’s role as a model of behaviour for the young will also be lost, resulting in
the loss of the essential legitimation for state sponsorship of sport.
This goes to show that the campaign against doping is basically all about sport.
Because of its deep social roots in our society, this matters a great deal! This is
why the Bavarian Free State took the initiative of introducing an anti-doping law,
which should improve the methods of prevention as well as the means of
penalising and, as a result, should supplement the rules and regulations already
available in the world of sport itself.
With the common aim of effectively fighting drug abuse, the State and sports
authorities have, however, to rely entirely on highly qualified scientists, who
have set themselves the same targets. This is why it is a great pleasure for me
to welcome you all here to Munich, to the international symposium “Biomedical
Side Effects of Doping”. In this regard, I would like to express my thanks to the
TU Munich for organising this symposium, providing proof once again of why it
belongs to the league of top universities.
I would like to wish all participants deep, lively discussions in their fields and
rewarding insights, as well as good, lasting memories of Munich, of the city and
its sights and of Bavarian hospitality.
Siegfried Schneider
Bavarian Minister of Culture
Preamble
Sport connects people, promotes health as well as personality development and
in the meanwhile it is a substantial component of leisure activities worldwide.
The practice and pursuit of a fair and drug-free sport are matters of public
interest. More particularly, it reflects the common interest of athletes, coaches,
sport facilities and governments all over the world.
The public community is hardly informed about the issue of drug abuse in sports
and the health hazards which may occur. In some European countries the issue
of doping is completely negated. Therefore, the aim of the present project,
financially supported by the European Commission in the field ob public health,
is to harmonise the scientific state of knowledge about the biomedical side
effects of drug abuse in sports throughout Europe and to make the information
available for the general public of all European countries.
During an international symposium with the topic “Biomedical Side Effects of
Doping” situated in Munich in October 2006 the actual state of knowledge
concerning doping related issues and health hazards was presented to the
public by well known international experts. Reacting to the increasing incidence
of doping violations in sport that has been evident in recent years, the
international community has established some new prevention strategies and
programs that grab this problem at grass-roots level. Doping related problems
as well as possible prevention strategies were discussed with scientists,
coaches, physicians, politicians and further interested guests from 22 nations.
As one major outcome the scientific results presented during this symposium
are summarized within the present manual accompanied by further important
doping related topics. The chapters take a critical look into the different doping
issues, preventive actions and knowledges of the public. Furthermore, a
detailed analysis is given how various doping substances can affect health of
the different body systems.
Further part of the whole European project will be the development of an
interactive internet platform containing versatile information concerning doping
related issues including teaching material in several European languages to
improve doping prevention on an international European level.
Project partners
Project Partners
Medical University of Plovdiv, Department of Physiology, Bulgaria
Katerina N. Georgieva, Nenko Nenkov
Institute of Sport, Department of Antidoping Research, Poland
Ryszard Grucza, Dorota Kwiatkowska
Aristotle University of Thessaloniki, Lab of Sports Medicine, Greece
Asterios Deligiannis, Nikolaos Koutlianos
University of Extremadura, Department of Physiology, Faculty of Science, Spain
Eduardo Ortega Rincón, Ma Dolores Hinchado, Esther Giraldo Reboloso
Technische Universität München, Institute of Public Health Research, Germany
Horst Michna, Hande Sarikaya, Christiane Peters, Thorsten Schulz, Martin
Schönfelder, Peter Selg
Contents
1
INTERNATIONAL CONVENTION AGAINST DOPING IN SPORT .............................. 1
Paul Marriott-Lloyd
2
THE DOPING ISSUE...................................................................................... 16
Barrie Houlihan
3
HEALTH SIDE EFFECTS OF DOPING SUBSTANCES
3.1
Supporting Apparatus and Musculoskeletal System............. 34
Hande Sarikaya, Horst Michna
3.2
Cardiovascular System ............................................................. 45
Asterios Deligiannis, Evangelia Kouidi
3.3
Respiratory System ................................................................... 55
Katerina N. Georgieva
3.4
Gastrointestinal Tract and Liver............................................... 66
Carl Müller-Platz, Tsuyuki Nishino, Hande Sarikaya
3.5
Reproductive and Endocrine System ...................................... 89
3.6
Renal Disorders and Electrolyte Metabolism........................ 112
Nikolaos Koutlianos, Evangelia Kouidi
3.7
Immune System and Skin:
The Importance of Studying this Problem ............................ 119
Eduardo Ortega, Mª Dolores Hinchado, Esther Giraldo
3.8
Psychological Effects and Addiction including CNS........... 135
Ryszard Grucza
4
ACTUAL TOPICS OF INTEREST
4.1
Nutritional Supplements – Creatine....................................... 154
Martin Schönfelder
4.2
Gene Doping............................................................................. 186
Thorsten Schulz
4.3
Narcotics................................................................................... 209
Ryszard Grucza, Andrzej Pokrywka, Dorota Kwiatkowska
4.4
Cannabinoids ........................................................................... 223
Peter Van Eenoo, Frans T. Delbeke
5
THE KNOWLEDGE OF DIFFERENT TARGET GROUPS IN THE
FIGHT AGAINST DOPING ............................................................................ 231
Christiane Peters
6
DOPING IN HANDICAPPED SPORT ............................................................... 245
Christiane Peters
7
PREVENTION STRATEGIES
7.1
Overview About the Actual Status Quo in Europe ............... 250
Hande Sarikaya, Jezabel Ohanian, Asterios Deligiannis, Katerina
N. Georgieva, Esther Giraldo, Ryszard Grucza , Mª Dolores
Hinchado, Nikolaos Koutlianos, Dorota Kwiatkowska, Eduardo
Ortega, Christiane Peters
7.2
Drug Prevention and Health Promotion for
High School Athletes:
A Summary of the ATLAS and ATHENA Programs.............. 262
Melissa B. Durham, Linn Goldberg
8
POSTER ABSTRACTS................................................................................. 278
9
SYMPOSIUM PROGRAM.............................................................................. 306
International Convention against Doping in Sport
1
1
INTERNATIONAL CONVENTION AGAINST DOPING IN SPORT
Paul Marriott-Lloyd1
On 1 February 2007, the International Convention against Doping in Sport
entered into force. This landmark occasion signified the most successful
international convention in the history of the United Nations Educational,
Scientific and Cultural Organization (UNESCO) in terms of the speed of its
development and entry into force. Important as this achievement might be, the
enactment of the Convention is of greater significance to the future of sport.
Never before have global anti-doping efforts been stronger and more focused
on providing an honest and equitable playing environment for athletes. The
Convention provides the hitherto absent legal framework with which all
governments can address the growing prevalence and increasingly insidious
use of performance-enhancing substances and methods in sport. This is
significant because there are specific areas where only governments can
progress anti-doping efforts. It is no coincidence that all of the major doping
scandals, for example Festina in 1998, BALCO in 2003 or the ongoing
Operation Puerto, were uncovered by government agencies. Further action is
required to target athlete support personnel, to curtail trafficking and to regulate
dietary or nutritional supplements which all fall under the aegis of governments.
The Convention also helps ensure coordination of testing and the development
of education, training and research programmes. This chapter discusses the
development of the Convention, outlines the obligations it imposes on
governments and examines why doping in sport has become relevant to the
international system.
A
Rationale for Action
It was natural for UNESCO, an organisation that stands on principles of equality
and justice, to have facilitated the development of the Convention, particularly
given its education and sport mandate. UNESCO was deeply concerned about
the erosion of ethics and the gross inequity created by the use of performance___________________
1
Paul Marriott-Lloyd, BA (Hons), PGCHS, MIR is the Anti-Doping Programme Specialist at UNESCO. He is
responsible for the International Convention against Doping in Sport, the development of anti-doping education
programmes and the provision of anti-doping policy advice to Member States. Previously he was the Chief Policy
Advisor for Sport and Recreation New Zealand. He has published a number of articles on drug policy issues and
has held senior roles with the Office of the Commissioner of the New Zealand Police and the New Zealand
Ministry of Health.
2
Paul Marriott-Lloyd
enhancing drugs by athletes. Doping poses one of the biggest threats to sport
today. It harms athletes, destroys fair play and equitable competition and does
irreparable damage to the credibility of sport. However, the impact of doping
goes far beyond the athletes concerned or sport itself. It is a problem that
affects all of society by undermining the intrinsic value of sport.
Sport can be a powerful vehicle for peace by forging social ties and networks,
mutual respect and understanding between peoples. Sport contributes to
development, drawing individuals together, providing facilities and access to
community services. It is also an important learning tool for young people.
During the playing of games and sport children learn about fair play, teamwork
and cooperation. These lessons help to shape attitudes and values, and provide
models of good conduct that last a lifetime. “That is why the United Nations is
turning more and more often to the world of sport for help in our work for peace
and our efforts to achieve the Millennium Development Goals.” [1] It also
explains why the unanimous adoption of the Convention by the UNESCO
General Conference in 2005 was considered one of the triumphs of the
International Year for Sport and Physical Education.
Doping seriously threatens the ethics and values upon which sport is based.
These principles are embodied in the 1978 International Charter of Physical
Education, which was amended in 1991 to make reference to the doping
problem:
“No effort must be spared to highlight the harmful affects of doping, which is
both injurious to health and contrary to the sporting ethic, or to protect the
physical and mental health of athletes, the virtues of fair play and
competition, the integrity of the sporting community and the rights of people
participating in it at any level whatsoever.” [2]
Anti-doping programmes, therefore, seek to preserve the essence of sport
characterised by values such as honesty, fairness, respect, courage,
commitment and solidarity.
The potential for athletes to act as role models should not be underestimated.
Sportspersons are held in high regard in modern society. Young people in
particular are fascinated by athletes and often seek to emulate their deeds.
Perhaps this helps to explain why 6.1 percent of American teenagers have
taken steroids without a prescription one or more times during their lifetime [3].
Research in other countries also indicates growing use of doping substances,
perhaps for image enhancing purposes, across society but particularly among
the young [4].
3
The harm caused by the use of performance-enhancing drugs and methods is a
compelling rationale for action. The contributors to this publication provide
scientific evidence about the biomedical side effects of doping on the
cardiovascular, musculoskeletal, reproductive, endocrine, immune and
respiratory systems. Examination of the impacts on the gastrointestinal tract,
liver, kidneys and electrolyte metabolism as well as psychological effects are
also presented. This research is vital because anti-doping efforts must be
underpinned by a solid evidence base. One of the three criteria for the inclusion
of a substance or method on the Prohibited List maintained by the World AntiDoping Agency (WADA) is “medical or other scientific evidence,
pharmacological effect, or experience that the use of the substance or method
represents an actual or potential health risk to the athlete.” [5]
Competitiveness and the fixation on records in elite sport incite doping. Drug
use may help to deliver results as a complement to dedicated training
programmes and natural sporting prowess. For an athlete attuned to continual
improvement (stronger, higher, faster), performance-enhancing drugs allow for
an extension of the physical strength ceiling and greater adaptation [6]. The use
of ergogenic agents can therefore mean the difference between a first place
finish, where lucrative prizes and endorsements accrue to the winners, or
otherwise. While some athletes are willing to take considerable risks to achieve
sporting fame and fortune, this practice constrains the choice of others to
remain drug free. Use by one athlete often forces others to follow in order to
remain competitive, resulting in a form of sporting brinksmanship. The impact of
doping is therefore not only limited to the athletes that consume the substances.
B
International Response
In developing the Convention, UNESCO responded to calls from the
international community. Concern was expressed at the dearth of ethical values
in sport, manifested by doping, by the Third International Conference of
Ministers and Senior Officials Responsible for Physical Education and Sport
(MINEPS III) in 1999. Countries were urged to take concerted action. Sports
Ministers also endorsed the outcomes of the World Conference on Doping in
Sport convened by the International Olympic Committee, which led to the
establishment of WADA. This unique organisation, a partnership between
governments and the sport movement which enshrines cooperation and
collaboration, is charged with the elimination of doping in sport.
Doping was a key item during the UNESCO-initiated Round Table of Ministers
and Senior Officials Responsible for Physical Education and Sport in 2003. The
4
Paul Marriott-Lloyd
final communiqué, issued on behalf of 103 Member States and 20
intergovernmental and non-governmental organisations, highlighted the danger
posed by doping in sport, not only as a breach of sporting ethics but also as a
danger to public health. The participants committed to the preparation of an
international convention focused on education, information, research, controls
and sanctions before the 2004 Summer Olympic Games and no later than the
2006 Winter Olympic Games.
A critical juncture was the adoption of the World Anti-Doping Code (the Code)
on 5 March 2003 during the 2nd World Conference on Doping in Sport. This
document provides a comprehensive framework to protect the fundamental right
of athletes to participate in doping-free sport and to ensure harmonised,
coordinated and effective anti-doping programmes at the international and
national levels with regard to the detection, deterrence and prevention of doping
[5]. While a large number of sporting organisations signed the Code and ensure
its global application through a series of cascading relationships, it is not legally
binding for governments. In fact, governments cannot be direct parties to the
Code because of its legal status and that of WADA under whose authority it was
elaborated. The Code is a non-governmental document that operates in the
realm of private or contractual law and WADA, despite equal governmental
involvement in its funding and management, was established as a private
foundation. Therefore, governments could only give a moral commitment to the
Code by signing the Copenhagen Declaration on Anti-Doping and Sport. Only
an international convention can create binding obligations on governments.
These developments culminated in the decision by the UNESCO General
Conference in 2003 to develop an international convention to remove doping
from sport. The Convention was developed after extensive drafting and
consultation meetings involving representatives from over 95 countries. It was
the product of three meetings of an experts group and three intergovernmental
meetings between 2004 and 2005. Further, the Fourth International Conference
of Ministers and Senior Officials Responsible for Physical Education and Sport
(MINEPS IV) considered the draft Convention and helped to resolve a number
of outstanding issues. The final Convention, adopted on 19 October 2005, met
the objectives of providing an internationally recognised legal framework to: (1)
ensure that governments take actions against doping in sport that are
complementary to those already being taken by the sporting movement,
including anti-doping activities at the national level, international cooperation,
education and training, and research; (2) provide support for the Code and for
other international standards developed by WADA, recognising the importance
of these documents in harmonising policy and practice worldwide.
5
The Convention was also drafted to keep pace with changes in the international
anti-doping environment. There is a mechanism that allows the Conference of
Parties, the sovereign body of the Convention, to approve changes made to the
Prohibited List and the Standards for Granting Therapeutic Use Exemptions
(TUE). Both documents are integral parts of the Convention because they are
fundamental to international harmonisation. It is essential to establish a single
Prohibited List based on the latest scientific knowledge so that athletes and
athlete support personnel are fully aware of the substances or methods
prohibited in-competition, out-of-competition and by particular sports. Universal
acceptance of therapeutic use exemptions is important so that athletes may be
prescribed medicines contained on the Prohibited List for legitimate medical
purposes. Any changes made by WADA to these two standards can be rapidly
incorporated into Convention following approval by the Conference of Parties
either in session or via written procedure. In this way the Convention can be
seen as a living document.
C
Complying with the Convention
The purpose of the Convention is to promote the prevention of and the fight
against doping in sport, with a view to its elimination. It has been designed to
coordinate and compel government action in specific areas beyond the domain
of the sports movement. Where the Code only applies to members of sports
6
Paul Marriott-Lloyd
organisations, the reach of governments allows a systemic approach to antidoping encompassing a broad range of actors.
The Convention outlines clear obligations required of governments. States
Parties undertake to: (1) adopt appropriate measures at the national and
international level consistent with the principles of the Code; (2) encourage all
forms of international cooperation aimed at protecting athletes and ethics in
sport and sharing the results of research; (3) foster international cooperation
between States Parties and with WADA in particular. However, the Convention
is a permissive document and it provides flexibility in the approach governments
can take to implementation, either by way of legislation, regulation, policies or
administrative practices.
Availability of performance-enhancing drugs
The first problem the Convention seeks to address is the availability of
performance- enhancing drugs. Under Article 8 of the Convention, governments
are obliged to limit the availability of prohibited substances and methods in
order to restrict their use in sport. These include measures against production,
movement, importation, distribution, sale and trafficking. At the same time there
is the need to ensure that these measures do not impede the general
availability of medicines or therapeutic products for legitimate purposes or to
prevent their use by athletes who obtain therapeutic use exemptions. This
balance can be achieved by separating use and possession from issues of
supply.
The Code, Prohibited List and TUE Standard provide the framework to restrict
the use of performance-enhancing substances and methods in a sporting
context. It is an anti-doping rule violation to use, attempt to use, possess,
administer or traffic substances or methods contained on the Prohibited List
without a TUE. Governments are encouraged to reinforce these provisions. One
such means is medicines-control legislation, which makes listed drugs
prescription-only medicines to be dispensed by licensed medical practitioners
for therapeutic purposes. Within this clinical setting athletes can also document
legitimate medical conditions as the first step towards obtaining a TUE.
The issues of supply, trafficking (if a specific legal prohibition exists) and
manufacture are more complicated and pressing. It makes a mockery of antidoping efforts when an athlete incurs a two-year to lifetime ban, while those
manufacturing and supplying the very same substances escape serious
punishment. The BALCO and Operation Puerto investigations confirmed what
7
had long been suspected - there are business networks operating on the
margins of the law with the express purpose of furnishing athletes with
performance-enhancing substances and methods. Moreover, these businesses
are well frequented by athletes and derive substantial financial gains from this
trade.
There is an expectation that governments will introduce concrete measures
under the Convention to curtail the supply of performance-enhancing
substances and methods. Tangible actions include the imposition of border
controls and criminal penalties and for this matter to be afforded priority by
enforcement agencies. Italy, France and more recently Spain, within their antidoping legislation, have created criminal offences for the unauthorised or illicit
supply of performance-enhancing drugs or methods. The Australian Customs
Service has successfully instituted border controls to stop trafficking, most
notably prior to the 1998 FINA World Swimming Championships. Finally, the
United States, having amended the penalties for offences involving anabolic
steroids under the Anabolic Steroid Control Act in 2006, recently arrested a
number of individuals involved in a steroid and prescription drug manufacturing
operation. Further arrests and prosecutions are expected from increased
government involvement in anti-doping.
Athlete support personnel
The Convention seeks to target all those who are complicit in the doping
violations of athletes. Previously, it was difficult to deal with the coaches who
used their privileged relationship with athletes to encourage the use
performance-enhancing drugs or methods. For example, Kelli White has spoken
publicly of the influence of her coach Remi Korchemny in her decision to take a
range of drugs, including modafinil and tetrahydrogestrinone supplied by
BALCO [7]. This is not an isolated case. Behind every anti-doping rule violation
committed by an athlete there are those who facilitated the doping. Some might
play an intermediary role introducing the suppliers of ergogenic substances to
athletes. Not to mention disreputable doctors that are willing to give blood
transfusions or apply their knowledge of the pharmacopoeia - those who forget
the Hippocratic Oath and put profit or prizes ahead of the health of the athlete.
Anti-doping efforts had been constrained up until this point by the fact that these
people could not be held accountable or penalised for their actions because
they were not actual members of sporting organisations. This is one of the
obvious limitations arising from the contractual basis on which the Code
operates.
8
Paul Marriott-Lloyd
Under Article 9 of the Convention governments are obliged to adopt measures
aimed at ‘athlete support personnel’. This term is broadly constructed to refer to
all persons involved in sport, working with or treating athletes. It includes
coaches, trainers, managers, team support staff, agents, administrators,
officials, and medical or paramedical practitioners. Governments may need to
extend those legislative changes outlined in the previous section to target those
complicit athlete support personnel. Other approaches depend on the amount of
leverage governments have over these persons, however, medical
professionals present an obvious target. Their licences or practicing certificates
should be revoked if they are found to be complicit in doping.
Nutritional supplements
Measures are required to deal with dietary or nutritional supplements (Article
10), a key area of concern for the anti-doping movement. Questionable
business practices abound in this highly unregulated industry. Products often
vary between batches, are mislabelled, contaminated or contain prohibited
substances in a deliberate attempt to circumvent food or drug legislation.
Several recent studies have shown that common supplements available in a
number of countries contain banned substances, including stimulants,
hormones, pro-hormones (for example, nandrolone or testosterone) and
anabolic androgenic steroids. It is estimated that 10-20 percent of these
products may be contaminated [8]. This situation is problematic if we take into
account the high prevalence of supplement use by athletes. Putting aside
questions about the safety and efficacy of these products, their use by athletes
poses significant risks to their careers. Taking a tainted supplement could result
in a two-year or lifetime ban. This is because anti-doping violations under the
Code are based on strict liability. The mere presence of a prohibited substance
in a blood or urine sample provided by an athlete constitutes an anti-doping rule
violation. The manner in which the substance was ingested by the athlete,
inadvertently or otherwise, might only impact on the length of the sanction
imposed if no significant fault or negligence can be demonstrated.
Article 10 of the Convention attempts to deal with the problems concerning
supplements. Governments are obliged to encourage producers and distributors
of dietary or nutritional supplements to establish marketing best practices,
including information regarding the analytic composition of their products and
quality assurance. Effectively, this means self-regulation or the development of
a certification scheme to improve labelling and production. It is doubtful if this
alone l provides sufficient certainty for athletes and the possibility of further
9
government intervention remains. However, some anti-doping organisations
have also taken to testing to determine the constituents of supplements. They
are then in a position to provide assurances or to issue warnings if the products
contain banned substances. Others strongly warn athletes against the use of
any supplements.
Doping control
International efforts will be at their strongest if athletes can be drug tested
anywhere in the world at anytime. Under Article 11 of the Convention, State
Parties shall support or provide testing programmes. All doping controls shall be
consistent with the Code and include no-advance notice, out-of-competition and
in-competition testing (Article 12). Further, international cooperation between
anti-doping organisations, public authorities and sports organisations is
encouraged. Through coordination, the costly and unnecessary duplication of
doping controls, not to mention the inconvenience for athletes, can be avoided.
It is fair to say that doping controls are the most developed and well-known
aspects of the world anti-doping programme. In 2005, the WADA accredited
laboratories analysed 183,337 blood or urine samples of athletes, which
represented an 8.4 percent increase on the previous year [9]. Having said that,
there are still many countries were athletes are not tested at all. In order to
expand the network of countries that undertake regular drug testing and to build
capacity, WADA has developed Regional Anti-Doping Organisations (RADOs)
composed of government and sport representatives. Their purpose is to
establish effective anti-doping programmes among countries in a distinct
geographical region through the coordination of testing as well as the training
and funding of doping control officers. RADOs are also responsible for results
management and appeals, as well as the dissemination of education and
information materials. These regional organisations allow small or less
developed countries to develop testing programmes whilst maximising
economies of scale and the sharing of expertise and costs. To date, 10 RADOs
have been established across 91 countries, while five others involving a further
31 countries will be launched during 2007. The result is that there should be no
place to hide from the all-essential drug testing.
The emphasis placed on out-of-competition testing is important. It is often at
international competitions that athletes are tested for the first time. By then it
may be too late. Many of those using performance-enhancing drugs would have
long since completed their cycles, ceasing their use well in advance of
competition to allow these drugs and their telltale metabolites to clear their
10
Paul Marriott-Lloyd
system. As one commentator suggested, only stupid or careless athletes ever
get caught during in-competition drug screens [10]. Out-of-competition testing is
a more constant threat to would-be cheats and the latest talk is of ‘intelligent
testing’. This refers to doping controls when the risk of doping may be
increased, for example during training or immediately following an injury.
Financial leverage
As highlighted above, there is a clear expectation that all States Parties institute
effective national testing programmes. Under the Convention, governments
shall, where appropriate, provide funding to support a national testing
programme across all sports or assist sports organisations and anti-doping
organisations in financing doping controls. The Convention also seeks to
maximise the leverage that governments have through the power of their
financial contributions. This is considerable given that sport does not typically
exist without some level of government funding, direct or indirect. Governments
are required to withhold financial support to athletes and prevent their access to
sporting facilities upon conviction of an anti-doping rule violation for the period
of their ban. Clearly cheats should not prosper. Governments should also
withhold financial or other support from sports organisations not in compliance
with the Code. The public interest is not served by propping up those sporting
organisations that do not commit to, or meet their obligations, in the fight
against doping in sport.
Education and training
The Convention requires governments to support, devise or implement antidoping education and training programmes (Article 19-23). Athletes are the
primary audience and at a minimum, should be informed of their rights and
obligations, and made aware of prohibited substances and methods, doping
control procedures and relevant aspects of Code. Education on the potential
risks posed by the use of nutritional supplements is specifically listed. For the
sporting community, these programmes should provide accurate and up-to-date
information on the ethical or health consequences of doping. Moreover, all
members of sports organisations, athletes and athlete support personnel should
participate in ongoing education programmes. For this latter group, the
Convention also calls for the establishment of professional codes of conduct
based on best practice and ethics.
11
Prevention will be best achieved through the education of athletes and the wider
sporting community. It is also important to sensitise the general public to the
harm caused by doping. What place would it have if all spectators, participants,
administrators and sponsors demand doping-free sport?
While the need for anti-doping education may be self-evident, it does not attract
a commensurate level of attention or resourcing as is currently allocated to
intervention. An increasing number of doping controls are being undertaken
across the world, but truly effective education programmes remain sparse. A
step in the right direction would be to make Article 18 of the Code dealing with
education to become mandatory, backed by government programmes under the
Convention. However, before embarking on particular activities it is important to
re-conceptualise education. It is much more than mere distribution of
information resources; true education is lasting knowledge and the application
of values. Education requires commitment, investment, constant reinforcement
and time to take effect. While the provision of value and skill-based education
programmes remains the mandate of governments, it should be informed and
supported by the sports movement. A seamless application of anti-doping
education from the classroom to the sports field is required.
Research
Finally, the promotion of research on anti-doping is another central component
of the Convention (Articles 24-27). States Parties are encouraged to undertake,
within their means, to encourage and promote anti-doping research. Specific
areas of focus are articulated. Clearly research is needed to close the gap
between those who seek to avoid detection and the methods at the disposal of
the anti-doping movement. Research into prevention, behavioural and social
aspects of doping and health consequences are also highlighted, as is sports
science research that is consistent with the principles of the Code.
All research should conform to ethical practices and avoid the administration of
performance-enhancing drugs or methods to athletes. Adequate precautions
need to be taken to ensure that research results are not applied for doping
purposes. It is an unfortunate fact that those who facilitate or partake in doping
are well read. The latest scientific literature is scanned for any developments
that might improve performance or increase the training load athletes can
sustain, while the considerable evidence of harm is selectively ignored. Some
athletes even appear willing to trial drugs in the very early stages of
development with no thought of contraindications.
12
D
Paul Marriott-Lloyd
Implementation of the Convention
As of 15 March 2007, 48 governments have become States Parties to the
Convention [11]. The rapid pace at which governments have adhered to this
international instrument is without precedent. Lengthy constitutional processes
involving a thorough treaty examination, consultation, parliamentary or
presidential approval and in some cases, enactment of legislation need to be
concluded before governments can ratify, approve, accept of accede to an
international convention. The fact that so many have done so, allowing the
Convention to enter in force in accordance with its Article 37 only sixteen
months after the negotiations concluded, demonstrates a steadfast commitment
to anti-doping.
The first session of the Conference of Parties, responsible for implementation of
the Convention, was held at UNESCO Headquarters in Paris from 5 to 7
February 2007. This meeting was attended by delegations representing all but
four States Parties and over fifty Member States of UNESCO participated as
observers. A number of administrative items were resolved, including the
adoption of rules of procedure and the election of a six-person bureau which will
remain in place until the next conference in 2009. The Conference also made
decisions concerning the monitoring framework for the Convention, however
further work is required to harmonise reporting requirements with those under
the Code and the 1989 Anti-Doping Convention articulated by the Council of
Europe, and to explore the possibility of establishing a joint electronic
monitoring tool. Of greater significance was the unanimous approval of the 2007
Prohibited List and for Annex I of the Convention to be amended accordingly.
Effectively this means that governments and sport are united in applying the
same list of prohibited substances and methods, critical to international
harmonisation.
The entry into force of the Convention marks the point at which UNESCO’s
attention will shift from normative development towards the challenges of
implementation. In this regard, dedicated funding has been set aside to assist
States Parties establish effective anti-doping programmes. UNESCO seeks to
build capacity around the world through the application of the Fund for the
Elimination of Doping in Sport established under the Convention. This Fund,
made up of contributions, gifts or bequests from Member States, private or
public bodies and individuals, recognises the fact that anti-doping programs
across the world are at different stages of development and that the fight
against doping in sport will be best served by building a global network of
capable governments.
13
The Conference of Parties identified three areas for the investment of the Fund.
The highest priority was attached to education projects focusing on youth and
sports organisations. Secondly, States Parties can apply for assistance with the
development of legislation, regulation, policies and administrative practices for
the purposes of complying with the Convention. Thirdly, funding was earmarked
for mentoring and capacity development programmes, particularly among least
developed or low income States Parties. At the same time, the governments of
Canada, China, Denmark, Greece, Luxembourg, Netherlands, Norway, Russian
Federation, South Africa, Spain and Sweden announced substantial financial
contributions which will allow the first projects to be initiated in 2007.
UNESCO’s intent in developing the Convention was much greater than simply
filling a normative void; it was an opportunity to focus renewed attention on
ethics, personal responsibility and integrity. This objective, combined with the
organization’s mandate and considerable experience in the development and
implementation of education programmes, should help to redefine anti-doping
efforts. It is important to build on the momentum behind the Convention to raise
public awareness and to invest in prevention through education programmes.
Ultimately, one of the keys to success will be providing quality advice to young
people and building resilience among the next generation of athletes by
fostering strong values and promoting sport ethics.
UNESCO is currently working with WADA and a range of partners to develop a
school-based education programme for young people. This follows on from a
number of workshops and youth fora and the production of educational
materials which introduce young people to the issue of doping in sport in a
positive and empowering manner. It is important to educate young people about
the harm doping does to sport as well as to the individuals concerned. That
harm is not just physical or psychological, it is also ethical. If the values of fair
play can be effectively instilled, it is hoped that they will have a lasting impact.
E
Conclusion
The development and entry into force of the Convention is a significant step in
the fight against doping in sport. It represents the first time that governments
around the world have collectively decided to focus their considerable powers
and resources on tackling the doping problem. The Convention was needed to
complement the actions taken by the sporting movement under the Code and to
address particular limitations that have impeded progress. A series of measures
for governments to avert or eliminate doping in sport and to foster cooperation
are outlined. Specific actions include restricting the availability of prohibited
14
Paul Marriott-Lloyd
substances and methods, targeting those that facilitate doping, funding doping
controls, addressing problems associated with nutritional supplements and
promoting education as the central tool in prevention. All of these provisions,
and those engaged in their implementation across the globe, share a single
purpose - that future generations are able to enjoy and excel in doping-free
sport.
F
1.
References
United Nations. Report on the International Year of Sport and Physical
Education. Geneva: United Nations Publishing Service, 2006.
2. UNESCO. International Charter of Physical Education and Sport. Paris:
UNESCO, 1978.
3. National Centers for Disease Control and Prevention. National Youth Risk
Behaviour Survey http://www.cdc.gov/yrbb , 2003.
4. P. Laure. ‘Drug abuse, doping behaviour’, Biomedical Side Effects of
Doping: Harmonising the Knowledge, Munich, 21 October 2006
5. WADA. World Anti-Doping Code. Montreal: WADA, 2003.
6. D. Sale. ‘Neutral adaptation to strength training’ in Komi, P. (ed.) Strength
and Power in Sport, pp. 249-265, Oxford: Blackwell Scientific Publications,
1992.
7. K. White. Personal Communication. Play the Game Conference,
Copenhagen, 6-10 November 2005.
8. W. Schanzer. Analysis of Non-Hormonal Nutritional Supplements for
Anabolic-Androgenic Steroids - An International Study, 2002 and H.
Geyer. ‘Analysis of non-hormonal nutritional supplements for anabolicandrogenic steroids – Results of an international study', International
Journal of Sport Medicine, 25: 124-129, 2004.
9. WADA. 2005 Adverse Analytical Finding reported by Accredited
Laboratories. Montreal: WADA, 2006.
10. C. Yesalis, M. Bahrke. ‘The epidemiology of doping in sport’ in Peters, C.,
Schulz T. & Michna, H. (eds.) Biomedical Side Effects of Doping. Köln:
Sport und Buch Straub, 2001.
11. Albania, Algeria, Argentina, Australia, Bahamas, Barbados, Bolivia,
Bulgaria, Canada, China, Cook Islands, Denmark, Finland, France,
Ghana, Greece, Iceland, Jamaica, Japan, Latvia, Lithuania, Luxembourg,
Malaysia, Mauritius, Monaco, Mozambique, Namibia, Nauru, Netherlands,
New Zealand, Niger, Nigeria, Norway, Peru, Poland, Republic of Korea,
Romania, Russian Federation, Seychelles, Slovakia, South Africa, Spain,
15
Sweden, Thailand, Trinidad and Tobago, Tunisia, Ukraine, United
Kingdom of Great Britain and Northern Ireland.
Correspondence
Paul
Marriott-Lloyd,
Programme
SHS/SRP/YSPE, Room Bonvin
[email protected]
Specialist:
Anti-doping,
UNESCO
2.31, www.unesco.org/en/antidoping,
16
2
Barrie Houlihan
THE DOPING ISSUE
Barrie Houlihan
A
The Doping Issue
It is extremely difficult to establish a clear picture about the extent of doping in
sport and whether current anti-doping efforts are having an impact on the
prevalence of doping. In the six months between August 2006 and February
2007 the following incidents were reported in the media. In August 2006 Finnish
customs authorities seized 24,800 vials of human growth hormone and 11.8
million tablets of anabolic steroids which were in two vans crossing the border
into Russia. The doping agents had entered Finland from China via Denmark. In
the same year a leading German cyclist was reputed to have spent €35,000 in
one twelve month period on performance-enhancing drugs and a court enquiry
into drug-taking within the Cofidis cycling team heard that between 2001 and
2003 €37,000 a year was spent on drugs which allegedly included anabolic
steroids, hormones, amphetamines and diuretics.1 In August 2006 Christine
Ohuruogo, one of Britain’s most promising runners, was suspended from
competition because she missed three drug tests. In mid 2006 nine Iranian
weightlifters (out of a team of eleven) tested positive for excessive levels of
testosterone prior to a competition in the Dominican Republic. Finally, in early
2007 it was reported in a television documentary that 250 German athletes,
including track and field athletes, cyclists and swimmers, refused about 400
unannounced drug tests and received no penalty from the national anti-doping
organisation.
Large scale smuggling, continuing problems with sports such as weight-lifting
and road cycling, high profile athletes violating anti-doping rules and
weaknesses in the application of anti-doping procedures and penalties provide
ample evidence of both the scale and the persistence of the challenge facing
anti-doping authorities. However, it is easy to let reports such as these obscure
the achievements of the last few years and the progress in making doping in
sport increasingly difficult. Of particular significance is the development of a
global anti-doping regime centred on the World Anti-Doping Agency (WADA).
A policy regime may be defined as 'principles, norms, rules and decisionmaking procedures around which actor expectations converge in a given issuearea' [1]. According to Krasner (1983), 'Principles are beliefs of fact, causation,
and rectitude. Norms are standards of behavior defined in terms of rights and
___________________
1
Guardian Unlimited (http://sport.guardian.co.uk/print/0,,329620370-108653,00.html) accessed 07.11.06
The Doping Issue
17
obligations. Rules are specific prescriptions or proscriptions for action. Decisionmaking procedures are prevailing practices for making and implementing
collective choice' [1]. The main features of the more effective policy regimes
are: first, significant degree of stability in the pattern of relations between core
actors; second, a process by which some interests (sports organisations and
governments for example) emerge as core actors and others are marginalised;
and third, the fulfilment of key functions of regime maintenance, such as
information exchange, policy review and the monitoring, verification and, in
some regimes, the enforcement of compliance [2-5]. Prior to the establishment
of WADA the global anti-doping effort was characterised by organisational
fragmentation, mutual suspicion and under-resourcing. Although the
International Olympic Committee (IOC) was considered to be the lead
international agency on doping issues its capacity to lead effectively was
hampered by its lack of a direct relationship with athletes, its lack of leverage
with governments (many of whom, such as the Soviet Union, were major
instigators of elite-level doping) and its unwillingness to devote adequate
resources to tackling the problem. Consequently, while there was a degree of
stability in relations between key policy actors the links were weak and irregular.
Key policy actors such as the IOC, the major Olympic international federations
(IFs), the Council of Europe and a small number of activist governments tended
to operate in relative isolation. The deep suspicion and mutual distrust between
the IOC and the International Federations and between the IOC and the IFs on
the one hand and governments on the other tended to stymie attempts to build
more cooperative working. Consequently, the IOC, many of the major IFs and
most governments were content, up until the late 1980s at least, to adopt a
passive or minimalist role within the nascent policy regime consequently leaving
centre stage free for a relatively small group of enthusiastic, but underresourced and politically weak, actors such as the Council of Europe and a few
'activist' governments.
The third common feature of successful regimes is that key functions of regime
maintenance, such as information exchange, policy review, monitoring,
verification and, in some regimes, the enforcement of compliance, are fulfilled.
Within the anti-doping regime the maintenance function was poorly fulfilled. In
the absence of a permanent secretariat or an agreed division of labour regime
maintenance was erratic with information exchange and debate, such as it was,
confined to a relatively closed groups of actors – the IOC, IFs and activist
governments – which tended to take a very narrow views of their
responsibilities. Some regular forums, e.g. the Council of Europe Anti-doping
Convention Monitoring Group and the IOC Medical Commission did give a
18
Barrie Houlihan
degree of stability and continuity to policy discussions, but membership tended
to be limited to either state or sport actors. Overall, the anti-doping regime prior
to 1999 was characterised by fragmentation of effort, a general lack of
momentum and a severe lack of resources.
The establishment of WADA in November 1999 did much to strengthen the
organisational infrastructure of the regime. The mission of the Agency is 'to
promote and co-ordinate at international level the fight against doping in sport in
all its forms. The Agency's principal task will be to co-ordinate a comprehensive
anti-doping programme at international level, laying down common, effective,
minimum standards, compatible with those in internationally recognised quality
standards for doping controls [6]. The Board of the Agency draws fifty percent of
its membership from public authorities with the remainder coming from a variety
of sports stakeholders including the IOC, the IFs, national Olympic committees
and athletes. The Agency, headquartered in Montreal, has a significant staff
complement, a relatively secure, if not overly generous, funding base, and an
expanding network of working groups and standing committees. However,
WADA's most significant contribution to the anti-doping regime has been the
successful implementation of the World Anti-Doping Code. The draft Code
emerged against a background of increasing litigiousness among athletes found
guilty of doping violations with many of the challenges based either on
arguments relating to the poor management of the process of sample collection
and laboratory analysis, or on the lack of consistency between the rules of the
sample collection agency, the domestic federation of the athlete, and the
relevant international federation. Vrijman (1995), Siekmann (1999) and
Siekmann & Soek (2000) [7-9] confirm that many domestic and international
federations had poorly drafted, and frequently out of date, regulations covering
doping. It is not only in the areas of harmonising the management of doping
control processes and the treatment of positive results that the Code has had
an impact it has also resolved many of the problems arising from overlapping
and multiple jurisdictions
The World Anti-Doping Code has been an extremely successful document
which not only introduced a considerable degree of harmonisation of policy and
practice in anti-doping but also established a framework for continuing and
closer cooperation between governments and their domestic federations. The
acceptance of the Code by international sports federations, for both able-bodied
and disability sport, is almost universal and all 203 national Olympic committees
affiliated to the IOC are signatories. In total over 570 international sports
organisations have indicated their acceptance of the Code. Although the Code
is the obvious symbol of the success of WADA the Agency has been active is a
The Doping Issue
19
broad range of other important areas including developing athlete education
programmes, providing independent observers to monitor the efficacy and
fairness of doping control programmes at major sports events, and
commissioning research. However, although WADA’s establishment made a
major change to the international anti-doping policy regime other significant
contributions have been made by the Court of Arbitration for Sport (CAS), the
European Union (EU) and the United Nations Educational, Scientific and
Cultural Organisation (UNESCO).
The Court of Arbitration for Sport (CAS) has emerged in recent years as an
increasingly important arbitration body in international sport and is intended to
fulfil a crucial appeal function in relation to the operation of the World AntiDoping Code. CAS has been formally independent of the IOC since 1994 and
deals with two types of disputes – commercial and disciplinary. A substantial
proportion of the disciplinary disputes is doping-related and arrives at CAS on
appeal. The Code notes the exclusive right of CAS to hear appeals from
international level athletes on doping issues [10]. Since 2003 CAS has proved
itself to be a robust and independent organisation which has steadily won the
respect of both athletes and their international federations. Not only does CAS
provide relatively cheap and quick decisions but it has contributed to the
establishment of an important body of case law which has increased the
sensitivity of the Code to the wide variety of circumstances in which doping
violations take place.
The role of CAS in a successful anti-doping regime is crucial as there has to be
some concern that the athlete will always be at a disadvantage in appeals
against convictions for doping violations as s/he is facing the combined might of
WADA, their IF and possibly also their national anti-doping organisation. Foster
(2001) expresses this concern succinctly by arguing that 'The power
relationship between a powerful global international federation, exercising a
monopoly over competitive opportunities in the sport, and a single athlete is so
unbalanced. Rather like the employment contract, a formal equality disguises a
substantive inequality and a reciprocal form belies an asymmetrical relationship'
[11]. However, Foster’s concern is counter-balanced by a series of opinions
which suggest that CAS has shown itself capable of protecting the interests of
the weaker party in anti-doping appeals and delivering a fair decision. McLaren
(1998) [12], for example, notes that in a number of cases 'CAS has
endeavoured to maintain a balance in the doping offences by not literally
applying the strict liability concept in some cases requiring a degree of fault
before upholding the imposition of a sanction' and Nafziger (1999) notes that in
reaching its decisions 'principles of equity seem to play a role' [13]. CAS has
20
Barrie Houlihan
also asserted its independence of both major international federations and the
IOC in finding in favour of the athlete. McLaren (1998) is confident that the
growing popularity of CAS as an appellate body is due to its 'jurisprudence
approach' and its lack of timidity in overruling or modifying IF or IOC decisions
on doping violations. However, while taking an appeal to CAS is undoubtedly
cheaper than progress through domestic courts it is not cost free and may well
prove prohibitively expensive for individual athletes. Burger (2000) also notes
the lack of capacity within CAS to award compensation as 'the principle
deficiency' [14]. Thus the athlete who successfully establishes that a sports
organisation has wronged him or her in a doping case has no means through
CAS of seeking compensation for their loss. These concerns notwithstanding
CAS complements the work of WADA and is an important element in the global
anti-doping infrastructure.
In the past a central concern regarding anti-doping activity was the tendency for
initiatives to be led by sports organisations, most notably the IOC and the
International Association of Athletic Federations, or clusters of governments, for
example the International Anti-Doping Agreement2, but rarely jointly by both.
However, not only has WADA brought together governments and international
sports organisations in its Board, but it has also been instrumental in
encouraging greater involvement by the European Union and UNESCO. While
the European Union has no formal responsibility in relation to sport it has used
its more general responsibility for public health to intervene on anti-doping
issues and to support research and has sought to coordinate the work of
NADOs in member states. According to Wolfgang Schaeuble, the German
Interior Minister, ‘The network [of NADOs] will in particular improve informationsharing and the coordination of NADOs regarding EU-related issues. It will also
make it easier to initiate and coordinate EU-wide campaigns in the field of antidoping policy’3. More significantly, the involvement of UNESCO has dramatically
strengthened the international anti-doping effort.
In October 2005 UNESCO adopted unanimously the International Convention
against Doping in Sport. The Convention entered into force at the beginning of
February 2007 and by the end of March 2007 the Convention had been ratified
by forty-nine countries, including a number of major ‘sports powers’ such as
Russia, France, Japan and China. The purpose of the Convention is to ‘promote
the prevention of and the fight against doping in sport’ and as such the
___________________
2
Formerly the Memorandum of Understanding Group which comprises included Australia, Canada, New Zealand,
Norway, Sweden and the United Kingdom.
3
Online edition of ‘The European Weekly’. http://www.neurope.eu/print_news.php?id=71649
The Doping Issue
21
Convention is intended to provide governments ‘with the means … to back the
efforts of the sporting movement … [and] to give effect to the World Anti-Doping
Code, creating an obligation on nations to take steps in accordance with its
principles’ [15]. The Convention is designed in such a way that it can
incorporate changes made to the WAD Code without the necessity for fresh
ratification.
Ratification by so many countries in such a relatively short period of time is a
considerable achievement and indicates a substantial level of support from
governments. Clearly there are more ratifications yet to be announced due to
the slower pace of the process of approval in some countries. However, at this
stage there are still twelve EU members who have not yet ratified the
Convention, including Belgium, Italy and Portugal and also five countries who
finished in the top fifteen places on the medals table at the Athens Olympic
Games who have yet to ratify, including Italy, Germany and Cuba. It should also
be remembered that 186 countries signed the Copenhagen Declaration on AntiDoping in Sport (the governments’ expression of support for the World AntiDoping Code) which means that there are still 137 countries yet to ratify the
UNESCO Convention.
The evidence of increased government support has been matched by a similar
trend among the international federations for the more commercial sports. For
many years golf, tennis, football and rugby were, at best, weak supporters of a
robust anti-doping policy. In general, these sports tended to deny that they had
a doping problem and when they introduced drug testing it was done with
obvious reluctance and with a very lenient attitude towards positive test results.
Due mainly to the pressure to adopt and implement the WAD Code these sports
have slowly come into line with the practices of the main Olympic sports.
B
Continuing Challenges and Concerns
Despite the considerable progress that has been made since 1999 substantial
challenges remain if momentum in anti-doping is to be maintained. It is one of
the truisms of policy implementation and of political life generally that a long
term perspective, persistence and policy innovation are rare attributes among
policy-makers who are under considerable pressure to deliver rapid and
immediately visible results. In discussions about doping in sport one of the most
dangerous, but unfortunately common assumptions, is that doping in sport can
be eliminated. However, drug free sport is about as likely as crime-free society.
Anti-doping policy-makers are involved not only in a long term confrontation with
doping, but are, or at least should be, working towards objectives that are
22
Barrie Houlihan
specified in terms of doping reduction rather than doping elimination. With this
caveat in mind it is possible to identify a number of challenges that face WADA
and other anti-doping policy makers. The discussion which follows concentrates
on a series of political and organisational challenges.
C
Political Challenges
Governments: Active, inactive and the ineffective
Governments can be divided into two categories – the active and the ineffective.
The ‘active’ category includes the Scandinavian countries, the Netherlands,
France, Australia and Canada who have a relatively long history of involvement
in anti-doping policy at both the domestic and international levels. The
membership of this group has hardly altered since the early 1990s. More
problematic is the second category - the ‘ineffective’ – a group that would
include many former communist countries in central and eastern Europe where
there is nominal compliance with the WAD Code but an insufficient allocation of
resources to ensure effective compliance. Other countries in this category
would include the United States which has made dramatic strides to improve its
previously appalling record on anti-doping, but still has much to do. Although
WADA has recently identified the US as an example of a country taking
effective action against the manufacture and distribution of drugs it is also the
country with one of the poorest records for dealing with doping in professional
sports.
Substantial doubts still surround certain sports in China especially (women’s)
swimming and middle and long distance running. While China has done much
to establish an anti-doping capacity it has been accused by Australian and
American swimming federations of not presenting its strongest teams in
international competition fuelling the suspicion that it is keeping it strongest
swimmers secure against out-of-competition testing in the period before the
Beijing Olympic Games. Moreover, Zhou Ming, former head coach who was
banned for eight years in 1998 for involvement in doping is now back coaching.
However, the fact that China won no gold medals at the Sydney Olympic
Games and only one gold medal at Athens might indicate a more effective
approach to combating doping in swimming. More ambiguous evidence comes
from the recent raid by Chinese anti-doping officials on an athletics school in
Anshan Province where 141 bottles of steroids were found in a refrigerator in
the head teacher’s office. The fact that the raid took place is an indication of
effective policing of the problem but the lack of any action to date against the
staff at the school is a cause for concern. In a generally positive assessment of
The Doping Issue
23
the progress that China had made in improving its anti-doping efforts Dick
Pound nevertheless drew attention to the fact that China’s 7000 tests each year
compared poorly with the 8000 undertaken by Australia with its much smaller
population.
In India, a country with clear Olympic ambitions, the anti-doping system is, at
best, basic. India has experienced a number of positive drug tests among its
elite athletes, but it has yet to establish an effective national anti-doping
organisation and there is very little evidence of serious consideration of the
issue of doping within the Indian Olympic Association (IOA) and the major
Olympic federations. While the IOA does conduct in-competition testing there is
no evidence of a capacity to conduct, the far more important, out-of-competition
testing. Nor is there evidence of a capacity to maintain a database of athletes’
whereabouts which is a requirement of the WAD Code. India’s record on the
implementation of the World Anti-Doping Code is, to date at least, extremely
poor. Even Germany, which for many years has been seen as an ‘activist’
country with a strong record on doping, was embarrassed by the disclosure that
over 200 athletes had refused unannounced tests without any apparent
sanction. Of 4418 planned tests there were 385 ‘no-shows’ involving 201
athletes indicating that a number of athletes had refused tests more than once.
Although the national anti-doping organisation was aware of the missed tests it
did not pass the information on to the respective domestic sports federations.
International federations: The reluctant few
While formal acceptance of the WAD Code was unproblematic for most Olympic
and non-Olympic International Federations some, mainly the more commercial,
have experienced serious problems demonstrating compliance. Cycling
provides the clearest example of an international federation struggling to come
to terms with doping. The UCI is an interesting federation as it has been
involved in anti-doping policy efforts since the 1960s yet, in the words of Dick
Pound, WADA Chairman, ‘Whatever has been done to date has been sadly
lacking’ (quoted in Cycling News, 14th August 2006). Pound’s view is confirmed
by the fact that the winner of the 2006 Tour de France and the riders who came
second, third and fourth in the 2005 Tour have all been accused of doping
violations. Furthermore, the investigation of doping initiated by the Spanish
police, Operation Puerto, provided evidence that blood-boosting drugs with a
value of over £1m had been sold in Spain and south-west France each year
since 2002.
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Barrie Houlihan
Professional tennis has long remained aloof from global anti-doping debates,
partly because of the weakness of the International Tennis Federation in
relation to the Association of Tennis Professionals and the Women’s Tennis
Association which effectively manage most of the major tour events. It was only
in late 2006 that the ITF finally reached agreement with the ATP and WTA to
coordinate anti-doping testing on their behalf. Cricket has also struggled to cope
with the positive test results for two Pakistani cricketers, Shoaib Akhtar and
Mohammed Asif. The decision by the Pakistan Cricket Board (PCB) to ban the
players for two years and one year respectively was overturned by a PCB
appeal panel much to the annoyance of the International Cricket Council (the
sport’s international federation) and of WADA which is to challenge the decision
at the Court of Arbitration for Sport.
Other highly commercialised sports like golf are also proving to be extremely
slow to embrace the requirements of the WAD Code despite the fact that in
France, where testing has been in operation since 2001, 13% of elite golfers
produced positive test results for drugs including cocaine, and sambutamol. In
Britain, however, the domestic governing body, the Royal and Ancient Golf
Club, has published an anti-doping policy, but has declared it to be only
‘advisory’. In the United States the US Golf Association has the following
memorably insouciant statement ‘The Committee may require in the Conditions
of Competition that players comply with an anti-doping policy’4 while the US
Professional Golfers’ Association still maintains that there is no drug problem in
golf. Finally, football spent two years from 2004 attempting to be selective about
the parts of the WAD Code that it would accept. Despite a ruling from the Court
of Arbitration for Sport in April 2006 that FIFA was not compliant on eight points
(including the Federation’s unwillingness to accept the automatic imposition of a
two year suspension for a serious doping offence) FIFA remains, at best, a
reluctant signatory to the Code. The commitment of these federations must
remain open to question and await more comprehensive evidence of sustained
compliance.
___________________
4
US Golf Association Rule Book 2006: http://www.usga.org/playing/rules/books/rules/appendix_I.html (accessed
4th April 2007)
The Doping Issue
D
25
Organisational and Management Challenges
Whereabouts information and missed tests
When the British runner, Christine Ohuruogo, missed three unannounced tests
and was subsequently suspended from competition it was also revealed that an
additional 70 track and field athletes had also missed one or two tests. At
present all athletes have to notify their federation of their whereabouts so that
unannounced tests can be conducted. Unfortunately, there seems to be little
consistency between national anti-doping organisations regarding what
whereabouts information is required, how that information is collected and
stored, and what are the consequences for a failure to be available for a test on
three occasions. The consequence of the lack of uniformity is considerable
frustration among athletes. In the revisions to the WAD Code currently under
discussion it is proposed to give much clearer guidance to national anti-doping
organisations. In the draft of the new Code athletes will have to provide details
of their whereabouts every quarter and identify an hour in every day of the week
when they will be available. More importantly the range of penalties available
has been narrowed from three months to two years to between twelve months
to two years.
Penalties for doping violations
The Code requires a two year suspensions for a first violation followed by a life
ban for a second violation. While allowing an athlete a second chance to
compete without drugs is widely accepted the significance of the two year ban
needs to be seen in relation to the competition structure and career 'lifeexpectancy' within particular sports. In some gymnastic events, for example, the
length of time an athlete could normally expect to remain competing at the
highest level is far shorter than that for a rower or middle-distance runner.
Equally significantly there may only be one competition for the gymnast, usually
the Olympic Games, which offers global media exposure and prestige. There
might also be a lack of other means of indicating relative ability, for example the
opportunity to set world, continental or national records. For the runner the IAAF
World Championships have a status close to that of the Olympic Games and
even for athletes who under-perform at both the Olympics and the World
Championships there is always the possibility of setting a new record at other
IAAF recognised events.
It is, at the very least, debatable whether the gymnast who, due to the
imposition of a two year ban, misses possibly his/her only chance to compete in
26
Barrie Houlihan
the Olympic Games is being treated in an equitable fashion when compared to
the 5000m runner who has a far greater likelihood of competing in a future
Olympic Games as well as having the possibility of a high media profile world
championships or securing his/her place in sporting history through recordsetting. While a standard period of ineligibility might be administratively
convenient it is inequitable and can be justified, if at all, only as an interim
arrangement until such time as a sanction tariff can be introduced which is more
sensitive to the characteristics of the athlete's sport and working conditions.
However, there seems to be no move to introduce variable or sports-specific
penalties as current debates on revisions to the Code, led by the IAAF and the
IOC, are focused on increasing the penalty for a first offence to a minimum of
four years and a life ban from Olympic competition.
The location of NADOs
According to WADA, best practice in anti-doping requires that not only should
each country establish a national anti-doping organisation (NADO) but that ‘the
NADO should be independent in decisions and actions from the sports
organisations. The principle of independence from elite athlete development
underpins anti-doping programs world-wide, and ensures the integrity of antidoping work’ (WADA, 2004, Introduction). The justification for this
recommendation was: first, that grant giving (a supportive function) and antidoping (an adversarial function) were incompatible and created the potential for
unethical behaviour; second, that co-location often lacked transparency and
accountability; and third, that leading countries in anti-doping, such as Canada,
Australia and the United States, had independent NADOs.
The recommendation for an independent NADO presented a number of
countries with a dilemma due to the frequency with which doping control and
the talent identification and development process were the responsibility of the
same organisation – usually either a government agency (as in Canada,
Australia and the UK) or the national sports confederation (as in Sweden and
Norway). The response of many countries was to establish a new and
independent organisation to oversee anti-doping activity.
While a new and independent NADO may be a requirement if the previous
system was tainted by scandal or inefficiency there are strong arguments for
maintaining an organisational link between elite development and anti-doping.
First, the concept of independence is dubious in relation to NADOs. In
examining the concept of organisational independence it is possible to identify
four central dimensions: legal, financial, administrative and political. Given that
The Doping Issue
27
in many countries the legislature is dominated by the executive, legal
independence is always qualified and contingent and rarely provides an
effective barrier to ministerial interference. The potential for funding
arrangements, the second dimension, to confer independence is similarly
qualified. While it is possible for NADOs to generate some income through the
sale of drug testing services to commercial sports, most of their work relies on
public subsidy as ‘public interest’ is the primary justification for drug testing. The
third dimension, administrative independence, suggests not only separate
central services (personnel, financial, IT etc) but also a geographically separate
location intended to segregate personnel. The final dimension, political
independence, is the most important dimension as financial, administrative and
even legal independence can be easily undermined or circumvented if there is
no commitment to political independence. However, it is by far the most difficult
dimension to specify. One formulation of political independence implies the
acceptance of a set of values according to which intervention is normatively
unacceptable. An additional/alternative view of political independence is one
which requires a degree of transparency regarding NADO operations such that
any undue political influence would be readily apparent. A third possibility is that
the NADO is ‘patrolled’ by a cluster of stakeholder interest groups, for example
for athletes, national federations and event organisers who would counterbalance not only the political influence of the government, but also the influence
of each other.
The problems with an independent NADO include: the potential isolation of
NADO staff from information about developments in elite training practices; the
exclusion of NADO staff from policy discussions in WADA, Council of Europe
and other government-based international organisations; uncertainty about the
role and status of the organisation in the eyes of athletes; and the risk that the
NADO develops, over time, its own norms and values which deviate from those
in the broader international anti-doping regime. There are also strong
arguments for locating the NADO within government which include: first, that
the government grant giving (and withholding) powers in relation to elite sport
reinforce the work of the NADO; second, that where independent NADOs have
been established it has usually been as a result of a crisis prompted by scandal
(Australia and Canada), anti-doping policy failure (USA), or previous location
within the national sports confederation (Norway); third, that the cost of running
an independent NADO would add between 10-15% to the cost of anti-doping
activity (Houlihan & Preece 2007). Rather than focus on the dubious concept of
independence WADA should ensure that NADOs are located within a clear
framework of accountability and operates in a transparent manner.
28
Barrie Houlihan
Policy instruments and focus
Understandably the predominant focus of anti-doping policy since the
establishment of WADA has been on the athlete and on detection, the
management of doping violations and the education of the athlete. There is an
increasing need to expand the scope of anti-doping activity to encompass not
only the athlete’s entourage but only the rapidly growing industry that
manufactures and supplies drugs to athletes. As regards the athlete’s
entourage there has been an increasing concern to impose penalties on those
coaches, doctors and others who contribute to and support an athlete’s drug
use. However, while there has been a steady increase in the number of
coaches suspended from involvement in sport the process by which a member
of an athlete’s entourage can be excluded from sport is more complex and
potentially expensive as guilt cannot be simply determined on the basis of strict
liability and necessitates a more traditional adversarial or investigative process.
However, the significance of some coaches and trainers in encouraging the use
of drugs requires that anti-doping activity adapt and continues to extend
sanctions beyond the athlete.
The BALCO affair in the United States provided ample evidence of the extent to
which the manufacture and supply of drugs to athletes has become a major
industry estimated by Donati (2007) to be providing performance enhancing
drugs to an estimated 31m users world-wide [16]. While the WAD Code already
allows for the punishment of those who supply drugs to athletes the
punishments are confined to involvement in sport. However, the ability of
NADOs to prosecute successfully drug suppliers requires close cooperation
with law enforcement agencies and assumes that NADOs have resources to
collect evidence to allow successful prosecution. At present there are
discussions which would allow a reduction in the penalty imposed on athletes if
they provided evidence leading to the prosecution of suppliers. Consideration is
also being given to changes in the Code to make it an offence to fail to
cooperate with an investigation and to make it an offence to lie to an
investigator [17]. Australia is one of the few countries that has adopted a more
aggressive approach to pursuing suppliers and reports that around 25% of its
recent doping violations were uncovered due to Australian Sport Anti-Doping
Agency’s new investigative powers. However, while there are clear advantages
to a more robust investigative role for NADOs there are substantial cost
implications and the most promising amendment to the Code might be to put
give the athlete strong incentives (such as reduced suspensions) to reveal
information about their suppliers and about other drug users.
The Doping Issue
29
Monitoring compliance with the WAD Code
The gap between formal acceptance of the WAD Code and compliance can
often be substantial. Consequently, the procedures identified to monitor
compliance are crucial for establishing and maintaining confidence in the antidoping effort. However, monitoring compliance is resource intensive, particularly
when dealing with a complex document such as the Code. WADA’s compliance
procedures are weak as they rely too heavily on self-reporting by individual
countries. At present signatories report in alternate years on their compliance by
means of the completion of an on-line structured questionnaire. Apart from the
general weaknesses of structured questionnaires many of the questions allow
too much scope for subjective interpretation. For example one question asks,
‘Do you apply the currently enforced WADA prohibited list?’. Respondents
choose between: ‘Yes, without any changes’; ‘Yes, without any substantive
changes’; ‘Yes, but with a few significant changes’; ‘No’; and ‘Do not know’.
How the respondent decides whether changes are ‘substantive’ or ‘significant’ is
unclear. Without doubt the reliance on self-reporting is a consequence of the
cost of alternatives, but it would certainly be preferable if WADA were to
augment self-reporting by occasional external inspections as is the practice
adopted by the Council of Europe in monitoring compliance with its own AntiDoping Convention.
American professional sports
It is tempting to ignore the four major American sports of American football,
baseball, ice hockey and basketball, on the grounds that the very few other
countries play the first two and neither is an Olympic sport and also to ignore
the last two on the grounds that it is only in the US that these sports are so
intensely commercial. However, to allow them to assume exceptional status
would be a serious mistake as these sports are in the vanguard of the steadily
accelerating commercialisation and commodification sport and their
intransigence on doping control has set an example which golf, football and
tennis have all sought to emulate. To its credit WADA has kept the spotlight on
these sports and has aided the efforts of US Congress members to try to force
them into line with the WAD Code.
The National Hockey League for example introduced testing in 2006 and
conducted 1406 tests. However, the programme lacks transparency as it is not
clear who is administering the tests, under what circumstances, to which
players and at what times. More importantly it is not clear whether the
programme tests for the full range of banned substances on the WADA list. In
30
Barrie Houlihan
mid 2006 the NHL announced that none of the 1406 tests had been positive
prompting Bill Daly, deputy commissioner, to claim, rather disingenuously, that
the results showed that ‘doping is not a problem in our sport’.5 The National
Basketball Association has had a drug policy since 1984 (to test for cocaine and
heroin), but only started to test for steroids and marijuana in 1999. Only three
players have been suspended for doping offences since 1999. Not only is there
a similar lack of transparency within basketball as in ice hockey, but its
sanctions are weak (suspension for 10 games for a first offence by comparison
to WADA’s two year suspension). Major League Baseball has long been
reluctant to address the issue of doping. Like American Football many baseball
team owners see drug use as having boosted spectator numbers due to the
greater prevalence of offensive play – more attacking play in football and more
home runs in baseball. Not surprisingly positive tests results, when they are
made public, result in negligible sanctions. For example Shawne Merriman, the
San Diego Chargers linebacker, who breached the NFL’s steroid policy, was
given a four game suspension.
E
Conclusion
As this review has illustrated that the short period since 2003 has witnessed
considerable strengthening of the global effort to combat doping in sport. The
infrastructure of the anti-doping policy regime is firmly in place with WADA, CAS
and UNESCO at its heart and with the WAD Code a key policy instrument. The
review of the Code that began in 2006 provides an insight into two important
aspects of the work of WADA: first, the modest scale of proposals for
amendment is indicative of the extent to which the Code has generated support
across a range of countries and sports and among athletes as well as sports
organisations; and second, the commitment to regular reviews of the Code
indicate the extent to which it is seen as a living document seeking to adapt
itself to changes in what is clearly a dynamic policy environment.
However, the review also makes clear that many substantial challenges remain
and that combating doping in sport is going to be a permanent feature of sport
at the highest levels. Perhaps the most important challenge facing the policy
regime is building the capacity among poorer and less politically committed
countries. Government commitment is the essential first step in ensuring
commitment by national federations. Nowhere is this better illustrated than in
___________________
5
News story from the Globe and Mail: www.theglobeandmail.com/servlet/story/RTGAM.20060613.wpound13/
The Doping Issue
31
the United States where the absence of doping from the mainstream political
agenda allowed a deep cynicism and corruption to establish itself across a
broad range of Olympic and commercial sports. The change of priorities in the
late 1990s, signalled by General Barry McCaffrey’s appointment as Director of
the Office for National Drug Control Policy under Bill Clinton and his strong lead
on doping in sport, has had a dramatic impact on one of the most corrupt sports
systems outside the former communist bloc countries. Unfortunately, as was
made clear in the earlier discussion, much still remains to be done to bring the
United States into line with the leading countries on anti-doping policy.
Moreover, there is a long list of countries which still deserve scepticism towards
their anti-doping activities including most of the countries of the European
former communist bloc, a large number of countries in the Middle East, India
and China.
The fundamental challenge facing all policy actors concerned with anti-doping
policy is to be able to maintain, over the next twenty to thirty years, political
commitment and the legislative, financial and administrative resources that
follow from that political commitment. However, the achievement s of the last
five years are considerable and provide a strong foundation for establishing a
sustained and well resourced commitment to combating doping in sport over the
medium to long term.
F
References
1.
S. Krasner. Structural causes and regime consequences: Regimes as
intervening variables. In: S. Krasner (ed.) International regimes. Cornell
University Press, Ithaca, NY, pp 1-21, 1983.
S. Haggard and B.A. Simmons. Theories of international regimes,
International Organisation 41: pp 491-517, 1987.
M.A. Levy, O.R. Young and M. Zurn. The study of international relations.
European Journal of International Relations 1: pp 267-330, 1995.
R.B. Mitchell. Regime design matters: International oil pollution and treaty
compliance, International Organisation 48: pp 425-458, 1994.
O.R. Young. The politics of regime formation: Managing national resources
and the environment. In F. Kratochwil & E.D. Mansfield (eds.) International
Organisation: A reader, New York: Harper-Collins, 1994.
WADA. Mission statement, Lausanne, WADA, 1999.
E.N. Vrijman. Harmonisation: Can it Ever Really be Achieved? Strasbourg:
Council of Europe, 1995.
2.
3.
4.
5.
6.
7.
32
Barrie Houlihan
8.
R.R.C. Siekmann, J. Soek and A. Bellani. (eds.) Doping rules of
international sports organisations, The Hague: TMC Asser/Kluwer, 1999.
R.R.C. Siekmann and J. Soek. (eds.) Arbitral and disciplinary rules of
international sports organisations, The Hague: TMC Asser/Kluwer, 2000.
WADA. The World Anti-doping Code, Montreal: WADA, 2003.
F. Foster. Is there a global sports law? Paper, International Sports Law
seminar, Anglia Polytechnic University, p 11, 2001.
R. McLaren. 'A new order: Athlete's rights and the Court of Arbitration at
the Olympic Games'. Olympika 7: 1-24, 1998.
J.A.R. Nafziger. 'Globalizing sports law'. Marquette Sports Law Journal
9.2: 225-238, 1999.
C.J. Burger. “Taking sport out of the courts”: Alternative dispute resolution
and the international Court of Arbitration for Sport. Journal of Legal
Aspects of Sport 10.2: 123-128, 2000.
UNESCO. International Convention against Doping in Sport. Paris, 2005.
A. Donati. Report on Trafficking, Montreal, WADA, 2007.
D. Howman. The way forward. In: Play True, Issue 1, Montreal. WADA,
2007.
9.
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17.
Correspondence
Barrie Houlihan, Institute of Sport and Leisure Policy, School of Sport and
Exercise Sciences, Loughborough University, Leicestershire LE11 3TU, UK,
[email protected]
Health Side Effects of Doping Substances
3
33
HEALTH SIDE EFFECTS OF DOPING SUBSTANCES
Speculations shadow peak performances in sport since it is known that there
exist an unlimited number of substances which enhance physical performance:
Did this bodybuilder win that contest without abusing androgenic anabolic
substances? Did Tour de France Champions abuse EPO? Are all present world
records in sport achieved illegally? What are the consequences of using
forbidden substances in suprapharmacological doses and what side effects will
cause modern gene doping? Finally, a lot of high level sport athletes suffer or
even die from biomedical side effects of doping during or after their career.
One major problem is that at the height of steroid development in the 1960`s
and 70`s pharmaceutical companies researched dozens of potential drugs and
picked the one that worked best in trials. Therefore, there are thousands of
abandoned steroid projects that could be easily converted to the next
Nandrolone, Desoxymethyltestosterone or Tetrahydrogestrinone concerning
androgenic anabolic steroids. Similar undesirable progression may happen in all
substance classes and methods used illegally in high level sports to say nothing
of upcoming gene doping.
Doping issues have also become a social problem just as illegal narcotics
already are. All-purpose drugs for all imaginable use are available on the streets
while most peoples/customers don't know if they are harmful to health or illegal.
The conclusion is that it is most important to highlight the perilous potential of
such abused substances not only among high level athletes but also in public
especially if used for performance enhancement typically in suprapharmacological doses.
34
3.1
Hande Sarikaya
SUPPORTING APPARATUS AND MUSCULOSKELETAL SYSTEM
Hande Sarikaya, Horst Michna
A
Introduction
Athletes may be tempted to use a range of different hormones for a variety of
reasons. But as sports does not automatically include a course on
pharmacology, most athletes have only a poor knowledge regarding these
substances especially concerning their adverse health effects. The application
of additional hormones or drugs to a healthy person modifies the normal
hormonal balance of the body, which attempts to redress this balance. The
warnings concerning these impacts and potential dangers are often neglected.
The athletes self-administering ergogenic aids to increase their competitive
edge continue to be a problem. But the gap of knowledge applies not solely to
professional athletes. Recreational sportsmen and coaches are not proficient in
the field of health side effects of ergogenic aids, too. It is thus essential that
athletes, both recreationals and professionals, and coaches etc. learn and
understand that the careless abuse of illicit drugs has severe consequences on
health. In this context, this review focuses on the adverse health effects and the
problems connected with the use of illicit drugs on the supporting apparatus and
musculoskeletal system.
The human musculoskeletal system consists of the skeleton, made by bones
attached to other bones with joints, and the skeletal muscle attached to the
skeleton by tendons. Understanding the structures and functions of human
muscles has long occupied scientists. As muscles do not replicate throughout
life, the human body is endowed with the capacities to induce muscle repair and
to prevent cell death. Whether the individual is young or old, muscle bulk can
only be increased through the hypertrophy of existing individual fibres that
results from the creation of new myofibrils. This fact is just one reason why this
organ system is relevant to discuss in the context of sport, doping and health
side effects.
B
Anabolic Androgenic Agents
The use of doping agents, and in this case anabolic androgenic steroids (AAS),
is not limited to competitive sports. It has already spread to leisure sports
including the fitness and bodybuilding area [1]. In spite of numerous reports on
health risks associated with the use of AAS it still remains a widely abused drug
and its popularity persists. AAS, synthetic derivatives of testosterone, produce
Supporting Apparatus and Musculoskeletal System
35
anabolic and androgenic effects. The androgenic effect pertains mainly to the
development of male characteristics (virilisation) and the anabolic effect
includes the stimulation of protein synthesis and inhibition of protein breakdown
[2]. The proposed mechanisms of action being attractive in relation to athletic
performance are the increase in skeletal muscle protein synthesis and skeletal
muscle hypertrophy and the decrease in the rate of protein breakdown [3-6]. But
as AAS are often used in supraphysiological doses the adverse effects cannot
be neglected. The main adverse effects can be seen in the hepatic,
cardiovascular, reproductive and endocrine, dermatological, and psychiatric
systems (see specific chapters). But there are also some adverse effects
reported in the musculoskeletal system, e.g. causing bone fractures, tendon
pathology and rhabdomyolysis [7].
If applicated in young athletes at children age, AAS induce a premature closure
of the epiphysis resulting in growth retardation. Furthermore, a premature
closure of the growth centres of long bones in adolescents can occur, which
may result in the stunting of the linear growth [8,9].
The steroids, as well as having generalized effects, cause changes in the
tendon structure itself, and this is compounded by intense exercise. This has
been demonstrated earlier in animal models [10-13]. AAS appear to induce
reversible changes in the biomechanical properties of tendon producing a stiff,
less elastic tendon. The ultimate strength of the tendon is unaffected [12,14].
Although AAS increase tendon stiffness no AAS-induced structural or
biochemical alterations have been found. Therefore, a strict distinction should
be made between the loss of elasticity and an actual tendon rupture [12,14]. It is
possible that the rapid strength adaptations being produced by AAS in skeletal
muscle are not simultaneously accompanied by slower adapting, less vascular
tendon structures, making tendons the weakest link in the chain [15].
The reports of tendon damage mostly occur among weight lifters, although
ligament ruptures may be due to the excessive loads. The use of AAS
concomitantly with exercise may lead to dysplasia of collagen fibrils, which can
decrease the tensile strength of tendon. Changes in tendon's crimp morphology
have been shown to occur as well. They may alter the rupturing strain of tendon
and the normal biomechanics of the extremities. Altered arrangement and
contractility of myofibrils and collagen fibres may lead to deterioration in
plasticity [16]. In this context, a case of spontaneous rupture of the anterior
cruciate ligament is reported in a bodybuilder taking steroids [17]. A current
case report of a 29-year-old professional footballer abusing AAS for 3 years,
showed a rupture of the patellar tendon and of both Achilles tendons within 18
months. After a ligament reconstruction with a semitendinosus tendon graft with
36
Hande Sarikaya
subsequent infection, the tendon and reserve traction apparatus were lost.
Repeated warnings of impaired healing if anabolic use is continued had been
neglected completely [18].
Rhabdomyolysis, or acute skeletal muscle destruction may occur after intake of
anabolic androgenic steroids in combination with weight-training programmes
[19,20], too. Taking the supraphysiological doses of steroids consumed by
some athletes into account, these athletes are at a significant risk to exert a
destructive effect to the integrity of their tissue.
C
Hormones and Related Substances
The most important substances in this field associated with the supporting
apparatus and the musculoskeletal system are the human growth hormone
(hGH), the insulin-like growth factor (IGF-1), the gonadotrophins, and the
corticotrophins.
The hGH is a peptide hormone secreted by the anterior pituitary gland and. It
acts by binding to a specific growth hormone receptor, which is expressed by
almost all human body cells [21]. The belief that hGH and thus IGF-1 can
enhance performance led to the idea of abusing these substances in sports.
The abuse by athletes and amateurs is based on the stimulation of the protein
synthesis and thus the hypertrophy in muscle fibres. The effects of hGH intake
described in controlled studies are often less impressive than anabolic effects
reported by those who misuse this substance [22-24]. HGH activates tissues
and liver cells to produce IGF-1 [25-28], thus the side effects occur through the
actions of either hGH and IGF-1. The clinical version of an oversecretion of
hGH in the pituitary gland is known as acromegaly [29]. The adverse effects
seen in adults abusing hGH are the same as those of the clinical symptoms of
acromegaly. The visible changes of bone and cartilage are amongst others the
enlargement of hands and feet, nose, chin, tongue and ears. High hGH levels in
the adult lead to hypertrophy and bone protuberances, sometimes irreversible,
arthritis and induces acromegaly. The same side effects are noticed in children,
but in addition gigantism can occur due to the increase in the linear growth of
bone tissue. Reduced hGH levels in children result in dwarfism. Bone growth
can be enhanced by hGH and IGF-1 as well as normal body growth and it can
lead to osteoarthritis. For athletes, usually having normal levels of hGH,
treatment with hGH essentially aims to raise blood levels above the normal
value. This artificially creates a condition of hGH excess and leads to the above
mentioned effects [25-31]. It is difficult to completely dissociate the biological
37
effects of hGH from those mediated through its target growth factor IGF-I.
Therefore the adverse effects have to be seen as combined effects.
D
Beta-2-Agonists
Although beta-2-agonists were traditionally used for the treatment for respiratory
ailments, their abuse became prevalent for the purpose of enhancing
performance. The ability to increase skeletal muscle mass and decrease body
fat led to a high attractiveness among sportsmen [32,33]. Animal data reveal
that 14 consecutive days of ingesting clenbuterol increases contractile strength
of skeletal muscle. However, expressed per gram of muscle, power output was
similar between animals receiving the beta-agonist clenbuterol and those
receiving placebo. The authors, Dodd and colleagues, concluded that
clenbuterol increased muscle strength and muscle size due to hypertrophy of
both slow-twitch and fast-twitch fibres [34]. The respiratory agents have some
adverse effects on the musculoskeletal function that shall be discussed briefly.
They are based on a cascade of beta-agonists binding to beta-adrenoreceptors,
which influence several metabolic and physiological processes in the skeletal
muscle [35].
For instance, negative effects on the bone architecture of salbutamol-treated
rats could be observed [36]. Bone loss occurred independently of a salbutamolinduced anabolic effect on muscle mass and was equally severe in sedentary
and exercising rats. These results undermined the deleterious effect of beta-2agonists on bone mass and bone mineral density during chronic treatment.
Additionally, these effects were investigated on ovariectomized rats, i.e. rats
with an estrogen deficiency. The negative effects on bone quality (femoral
trabecula thickness) and quantity (femoral bone mineral density) were most
significant in trained and ovariectomized rats and may indicate potential
complications in doping female athletes with exercise-induced amenorrhea [37].
Furthermore, the effects of salbutamol and clenbuterol on bone were tested
separately in female rats. The salbutamol and clenbuterol treated animals
displayed lower bone mineral contents, femoral length and cortical width than
the control animals. Clenbuterol treatment further reduced bone mineral density
and the bone microarchitecture was clearly altered by clenbuterol. This was
evidenced by lower trabecular number, connectivity and trabecular bone
volume, leading to lower ultimate force. Both beta-2-agonists increased the
bone resorption marker without any change of a bone formation marker. These
results confirm again the deleterious effect of beta-2-agonists on bone mass
38
Hande Sarikaya
and show the negative
microarchitecture. [38].
effects
of
clenbuterol
on
trabecular
bone
Excessive intake of beta-2-agonists can also lead to symptoms of muscle
tremor and muscle cramps, especially observed with clenbuterol [33,39]. These
effects are intensified by the simultaneous intake of diuretics, which is common
among bodybuilders being near to a competition. Therefore, bodybuilder
platforms recommend a potassium supplementation to improve the electrolyte
balance and reduce the muscle cramping.
E
Diuretics
The intention of abusing diuretics in sports is not because of an expected effect
in performance enhancement but rather the control or loss of body weight.
Bodybuilders for example use diuretics to achieve a better muscle definition due
to the loss of water [40]. Furthermore, diuretics can be abused to dilute urine so
that other abused doping substances cannot be detected. Common among all
diuretics is hypohydration, which has been shown to have a variety of effects on
performance, including impaired strength, power and endurance [41,42]. The
adverse effects of diuretics on the musculoskeletal system are often secondary
effects. Thus, effects like muscle cramps and pain are related to alterations of
the resting electrical potentials in nerves and muscle membranes and their
subsequent effects on the conduction of neuromuscular impulses. They are
mostly based on the hypokalemia caused by the diuretics [43]. The potassium
concentration levels in the serum can be correlated with specific clinical
symptoms [41]:
3.0–2.6 mmol/l
tenderness or pain in muscles, occasional cramps
< 2.5 mmol/l
muscle breakdown
< 2.0 mmol/l
muscle cell death
Another potential risk of diuretic abuse by athletes is a deteriorated
thermoregulation, based on the potentiated hypohydration effect of diuretics and
sweat loss during exercise [44]. The increase in the body heat storage during
exercise, due to a reduced sweating and skin blood flow coupled with
electrolyte imbalances, especially potassium, can lead to serious health
problems.
F
39
Glucocorticosteroids
Glucocorticosteroids (GCs) are among the most potent and effective antiinflammatory agents, with an unusually wide spectrum of activity. They are
prominent in the treatment of a variety of acute and chronic inflammatory
conditions, what makes them attractive for sports medicine. GCs are often
administered locally by musculoskeletal problems as they can be injected in
joints and around tendons ad ligaments [45]. Corticosteroid injections are one of
the most commonly used treatments for chronic tendon disorders as they lead
to a rapid improvement of the symptoms [46,47]. But it is also discussed that
this feeling of improvement can result in a premature exposure of the tendon. In
the worst case this can imply the risk of a total tendon rupture [48,49].
The adverse effects of GCs can be compared to those of the anabolic steroids
due to the affiliation of GCs to catabolic hormones. For instance, long-term
abuse of glucocorticoids is associated with loss of bone and muscle mass [50].
Corticosteroids are the principal cause of secondary osteoporosis after a
therapy. Doses of more than 5 mg daily and periods of treatment lasting more
than 3 months increase the risk of osteoporosis and fragility fractures [51,52].
The trigger of this effects is a inhibited bone metabolism. Adverse effects like
atrophies of tendon and ligaments were also reported in animal studies and
case studies of humans [53-55]. Therefore, controversial opinions about the use
of local corticosteroid injections for the treatment of Achilles tendonitis are
existent. Some recommend the use of GCs based on efficacy in accelerating
the healing process of Achilles tendonitis; others believe the associated side
effects should preclude their use altogether. The decreased tendon strength
seen upon intratendinous injections in animal studies suggests that rupture may
be a potential complication for several weeks following injection and athletes
should comply with a period of restricted training and sporting activity. In
summary, GCs present severe side effects and risks on muscles, tendons and
ligaments: starting with osteoporosis and the increased risk of fractures and a
delayed bone repair up to a decrease in muscle nutrition and a severe risk of
muscle atrophy.
G
Beta-Blockers
Beta-blockers, also known as beta-adrenergic antagonists, are used to treat a
variety of conditions, such as hypertension, tremor, anxiety and migraines. They
bind to the surface of adrenergic receptors found throughout the whole body
[56]. The main reason that beta-blockers are abused in sports is their effect to
reduce anxiety and the associated increase in heart rate and skeletal muscle
40
Hande Sarikaya
tremor. Therefore, the abuse is located in the field of sports requiring precision
like shooting events [57]. The beta-blocker metoprolol improved the pistol
shooting performance by 13.4% compared with placebo refered to a decreased
hand tremor [57]. The positive effects of beta-blockers in competition
performance have also been detected in ski jumping, flying, motor car racing,
parachute jumping and bob running [58]. Adverse effects of beta-blockers can
be observed at an overdose or an abuse in healthy persons mainly located in
the cardiovascular system. An adverse effect concerning the skeletal muscle
can be seen in glycogenolysis, which is mediated by epinephrine via stimulation
of beta-2 receptors. During submaximal exercise muscle glycogenolysis is
unaffected, but the maximal glycogenolytic rate at high exercise intensities is
decreased. [59].
H
Conclusion
The reviewed scientific works show that some doping substances can seriously
affect the musculoskeletal system and the supporting appartus. These adverse
effects are mainly located in bones, muscles, tendons, and ligaments and
sometimes with irreversible effects. Every way of distribution of the above
mentioned drugs to athletes with a non-medical intent has to be considered as
unethical and irresponsible alike the abuse of these substances for doping
purposes.
I
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Correspondence
Hande Sarikaya, Technische Universität München, Institute of Public Health
Research, Connollystr. 32, 80809 Munich, Germany, [email protected]
Cardiovascular System
3.2
45
CARDIOVASCULAR SYSTEM
Asterios Deligiannis, Evangelia Kouidi
A
Introduction
The abuse of doping substances has numerous cardiovascular side effects,
which are deleterious for athletes’ health. The problem is that most of the
athletes are using a variety of prohibited substances, in huge doses and for a
long period of time. Therefore, it is difficult to isolate and specify the disorders
that the abuse of a unique prohibited substance may cause. Additionally, the
majority of the athletes refuse to admit that they are users and most of the side
effects are not listed. Some of the prohibited drugs cause acute side-effects and
may lead to sudden cardiac death, while others are associated with chronic
adverse effects. The common cardiac side-effects of the most known
substances are shown in table 1 [1], while the last WADA doping list of drugs
affecting cardiovascular system is presented at the end of the article in table 2 .
B
Substances and Methods Prohibited at all Times
Androgenic-anabolic steroids (AASs)
Athletes usually use AASs to enhance athletic performance or to improve
appearance. The side effects of AAS are many but unclear, mainly because it is
difficult to isolate the side effects of the drugs used. Several cardiovascular
adverse effects have been reported. Myocardial infarction and sudden cardiac
death are the most serious complications of the abuse of anabolic steroids.
Other common cardiovascular disorders are arterial hypertension, heart failure,
cardiomyopathy, arrhythmias, thrombosis etc. [2-4].
According to Melchert and Welder there are four hypothetical models of
anabolic-induced adverse cardiovascular effects [5]:
An “atherogenic” model involving the effects of AASs on lipoprotein
concentrations.
A “thrombogenic” model involving the effects of AASs on clotting factors and
platelets.
A “vasospasm” model involving the effects of AASs on the vascular nitric
oxide system.
A “direct myocardial injury” model involving the effects of AASs on
myocardial cells.
46
Asterios Deligiannis
Table 1. Cardiac side effects of prohibited substances (adapted from A. Deligiannis et
al. [1]). LVH: Left Ventricular Hypertrophy, CAD: Coronary Artery Disease, MI:
Myocardial Infarction, HF: Heart Failure, SCD: Sudden Cardiac Death, AAS: AndrogenicAnabolic Steroids, hGH: Human Growth Hormone, EPO: Erythropoietin
AAS
Hypertension
Arrhythmias
LVH
CAD
MI
HF
SCD
+
+
+
+
+
+
+
+
+
+
+
hGH
EPO
+
+
Beta 2-Agonists
+
Diuretics
+
+
+
+
+
+
+
+
+
Amphetamines
+
+
Cocaine
+
+
+
+
Ephedrine
+
+
+
+
+
+
Narcotics
+
Cannabinoids
+
Alcohol
+
+
+
+
+
+
+
+
+ indicates effect on parameter
Many studies have demonstrated that AAS abuse in combination with
resistance training cause concentric hypertrophy of left ventricular wall. The
long-term use of AASs is found to cause an increase in myocardial mass and
end-diastolic volume [6, 7]. However not only contractile but also non-contractile
elements are increased. Generalized and focal fibrosis and myofibrillar disarray
are also found in autopsy of athletes consuming large amounts of AAS [8, 9]. It
is reported that AASs use does not improve left ventricular systolic function and
may lead to diastolic dysfunction [6, 7]. There is evidence that AASs can
generate dysrhythmias [5, 10]. AASs are found to affect the cardiac sympathetic
nervous system and also electrolyte concentrations, which may lead to atrial or
ventricular fibrillation [1, 11]. Sudden cardiac arrest related to adrenergic stress
and documented by an extensive myocardial necrosis is also found in young
athletes abusing AAS [4].
47
Use of AASs is found to lead to a significant decrease in high density lipoprotein
(HDL) cholesterol and an increase in low-density lipoprotein (LDL) cholesterol
[12]. However, AAS abuse may cause a beneficial effect on Lp(a) levels [12].
The duration of AAS intake seems to affect the lipids level, rather than the
dosages [12]. Decreased fibrinolytic activity and increased clotting factors have
been reported after AAS abuse causing thrombotic phenomena [13].
Bodybuilding is found to be associated with impaired vascular reactivity and
increased arterial thickening regardless of AAS use [14]. It is also supported
that AAS and particularly androgens may increase either systolic or diastolic
blood pressure [15].
Peptide hormones, mimetics and analogues
Growth hormone (hGH) appear direct anabolic effects, it increases insulin
levels, which exerts an antiproteolytic effect, possibly leading to short-term
increase of physical performance [16]. However, long-term use of hGH is found
to cause cardiomyopathy, and increase the incidence of arrhythmias [17].
Erythropoietin (rHuEPO) is mainly used by endurance athletes, in order to
increase their aerobic capacity. Treatment with rHuEPO leads to a dosedependent increase in hematological parameters. It increases red blood cell
mass and can also elevate the levels of Hb and Hct, when it is repeatedly
administered [18]. High levels of Hct may cause increased viscosity of the
blood, which elevates the risk of thrombosis and embolisms [19]. Moreover,
arterial hypertension and seizures may be observed [20]. A significant decrease
in maximum heart rate is also been reported [18].
Beta-2 agonists
Beta-2 agonists such as clenbuterol and salbutamol, may increase muscle
mass and decrease fat. Clenbuterol leads to increased heart rate, cardiac
output and cardiac oxygen demands. Beta-2 agonists abuse may lead to
arrhythmias, myocardial ischemia, congestive heart failure, prolonged QT
interval and sudden cardiac death [21].
Diuretics
Athletes usually use diuretics either to reduce body weight or to mask drug
contents in the urine. The intake of diuretics may cause electrolytic imbalance
48
and particularly hypokalaemia. Hypotension, prolonged QT and arrhythmias are
also observed after administration of diuretics [22].
C
Substances and Methods Prohibited only in Competition
Stimulants
There may be an improvement of exercise performance when taking
amphetamines, due to their ability to mask fatigue. Amphetamine abuse may
lead to arterial hypertension, cardiac arrhythmias, acute myocardial infarction,
cardiogenic shock and sudden cardiac death [23].
Cocaine doesn’t seem to affect athletic performance. However, its use causes
myocardial ischemia and coronary artery thrombosis and myocardial infarction.
These disorders are the result of vasoconstriction and stimulation of areceptors, as well as of increased myocardial oxygen demand, decreased
oxygen supply and ingressive thrombogenesis [24,25]. Other cardiovascular
side effects of cocaine use include infective endocarditis, ruptured aortic
aneurysm, vascular thrombosis, coronary vasospasm, arterial hypertension and
stroke [24,25]. Moreover, cocaine may cause myocarditis and dilated
cardiomyopathy. Chronic cocaine abuse leads to myofibrial necrosis, interstitial
fibrosis and congestive heart failure [26]. Cocaine abuse may cause prolonged
QT and PR intervals and A-V conduction disorders. It increases the cardiac
sympathetic activity by stimulating the β-receptors and inhibits the cardiac ion
channels acting as local anesthetic. Sudden cardiac death may occur due to
adrenergic overactivity and lethal arrhythmias [27].
Ephedrine-containing preparations may increase energy levels, produce
euphoria, aid to weight loss and improvement of muscle mass. Bodybuilders
show a high incidence rate for ephedrine abuse. There is evidence that
ephedrines cause cardiac stimulation and an increase of systolic and diastolic
blood pressure [28]. Other cardiovascular adverse effects of its use are cardiac
arrhythmias, acute myocardial infarction and sudden cardiac death [29].
Constriction of coronary arteries and vasospasm are thought to be the
mechanisms of myocarditis and myocardial infarction after ephedrine
administration. They may also cause ischemic stroke as a result of
vasoconstriction of cerebral arteries and hemorrhagic stroke following the
hypertensive action of ephedrine [29].
49
Narcotics
The use of narcotics is not ergogenic. Especially narcotic analgesics use can be
harmful when an injured athlete participates in a sport activity. The use of
morphine, heroin or codeine may affect blood pressure and cause acute
pulmonary edema, coma and death [30].
Cannabinoids
Cannabinoids can reduce anxiety, but do not have an ergogenic effect. They
possibly cause a parasympathetic blockade. Moreover, they produce βadrenergical stimulation leading to increased heart rate and decreased cardiac
output [31]. Its use may increase the myocardial oxygen demand, as well as
decrease oxygen delivery, as a result of arterial vasospasm. These alterations
lead to myocardial ischemia, arrhythmias, and sudden cardiac death [31].
Cannabis may also cause changes in ST-segment, T-wave and flattering of Pwave. There are also published cases of stroke after smoking cannabis [31].
Arterial hypertension is the most serious side effect of high doses and
prolonged intake of glucocorticosteroids [32]. Oral or parenteral administration
of glucocorticoids is found to be a significant risk factor for hypokalaemic events
[33]. Other side-effect is dydlipidemia, caused by increased plasma insulin
levels and disorders of lipid metabolism.
D
Substances Prohibited in Particular Sports
Alcohol
Alcohol does not have an ergogenic effect. Long-term alcohol consumption may
lead to arterial hypertension, cardiac arrhythmias, ischemic heart disease,
dilated cardiomyopathy, stroke and sudden cardiac death [25,34]. Moderate
alcohol consumption is a common cause of secondary hypertension, more often
systolic than diastolic. Alcohol use causes increased cardiac sympathetic
activity, leading to tachycardia and increasing the risk for ischemic heart
disease and artrial, mainly, arrhythmias. However, moderate drinkers may have
low LDL and high HDL levels, which decreases the incidence of coronary
atherosclerosis.
50
Beta-blockers
B-blockers are mainly used in sports that require accuracy, since they are found
to reduce anxiety and tremor. However, they are found to decrease physical
capacity. Their use may cause demonstrable reduction of heart rate and blood
pressure [35].
E
Prohibited Methods
In the prohibited methods, the following categories are included: Enhancement
of oxygen transfer, pharmacological, chemical and physical manipulation and
gene doping. From these methods, only blood doping is reported to cause
adverse cardiovascular effects.
Blood doping leads to increased red blood cell mass and thus to increased
physical capacity. Increasing the heart rate and the cardiac afterload may cause
arterial hypertension, myocardial infarction and heart failure [20].
F
Combination of Prohibited Substances
In practice, most of the athletes use a combination of the above mentioned
substances or methods, which usually have synergic action.
There is a report of a bodybuilder taking AASs, amphetamines, diuretics and
potassium supplements and collapsed with a run of ventricular tachycardia and
myocardial infarction [10].
Combination of ephedrine and caffeine, which are mainly used in herbal dietary
supplements are found to produce significant cardiovascular, metabolic and
hormonal responses and cause seizures, strokes and death [36]. They produce
both chronotropic and vasopressor responses and increase both blood pressure
and heart rate. Increased cardiac sympathetic activity may lead to myocardial
ischemia and induce cardiac arrhythmias. Their effects seem to be a result of
pharmacodynamic interactions [36].
Historically, 102 different substances were detected in the body of Brigit
Dressel, who died due to an anaphylactic shock in 1987 and a huge number of
prohibited substances were found in the personal diary of Andreas Münzer,
whose death was also due to doping substances abuse.
Finally, the cardiovascular side effects of prohibited substances and methods
depend on the amount and combination of the consumed drug, the duration of
use and the counteractions of each athlete.
51
Table 2. WADA doping list of drugs with cardiac side effects (adapted from A.
Deligiannis et al. [1])
Prohibited in
competitive sports
Prohibited in certain
competitive sports
Stimulants:
Beta Blockers:
amphetamine
cocaine
ephedrine
fencamfamin
modafinil
nikethamide
Narcotics:
morphine
pethidine
Beta-2-agonists:
reproterol
isoprenaline
Masking Drugs (Diuretics):
amiloride
chlortalidon
etacrynic acid
furosemide
Anabolic Steroids:
testosterone
nandrolone
stanozolol
metandienone
Glucocorticosteroids:
betamethason
triamcinolon
Peptide Hormones:
human growth hormone
erythropoietin
atenolol
bisoprolol
carvedilol
esmolol
labetolol
metoprolol
pindolol
propranolol
sotalol
52
G
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Correspondence
Asterios Deligiannis, Prof. of Sports Medicine, Aristotle University of
Thessaloniki, 26 Agias Sophias Str., 54622 Thessaloniki, Greece,
[email protected]
Respiratory System
3.3
55
RESPIRATORY SYSTEM
A
Anabolic Androgenic Steroids
Misuse of the synthetic derivatives of the testosterone, the anabolic androgenic
steroids (AAS), causes serious side effects on several functional systems of
athletes [1]. Little data are available about the side effects of AAS use on
respiratory system. Some studies associate androgen administration with a
higher risk of occurrence or exacerbation of the sleep apnea syndrome [2- 4]. In
general, sleep apnea is a phenomenon of recurrent cessation or decrease of
airflow to the lungs during sleep. Sleep apnea, considered to be at least 5
episodes of apnea/hypopnea lasting at least 10 sec of every sleep hour, is
classified as either central, due to cessation of respiratory movements, or
obstructive due to narrowing of the upper respiratory airways [5,6]. A
combinations of these two conditions leads to mixed sleep apnea. The repetitive
episodes of apnea occurring during the sleep are associated with severe
intermittent hypoxia and sleep fragmentation. The symptoms include morning
headaches, fatigue and in more advanced cases – clinical picture of respiratory
failure. Sleep apnea is a common cause of snoring, daytime sleepiness,
impaired cognitive performance and road traffic accidents. It also has been
shown to predispose to ischemic heart disease, arterial hypertension and
cerebrovascular accidents [5,7]. The sleep apnea syndrome is more common in
men than in women and testosterone is thought to play a role in the
pathogenesis of the sleep apnea. Recent data suggest that endogenous
testosterone affects the ventilatory response to chemoreceptor stimulation
during wakefulness and sleep in young healthy males [8].
Androgen administration may induce or exacerbate obstructive sleep apnea in
some men [2], women [3] and children [4]. Consistent with these observations
are recent results demonstrating a reduction in total sleep time, longer hypoxic
episodes and increases in the respiratory disturbance index (the number of
apneas and hypopneas per hour) in healthy older men exposed to high doses of
testosterone esters [6]. Increased endogenous testosterone production as a
result of testosterone-producing tumor also may induce obstructive sleep apnea
in women [9]. The possible mechanisms of this effect of androgens are
associated with an increase in the upper airway collapsibility and influence on
the neuromuscular control of upper airway patency during sleep, [4] as well as
to a reduction in upper airway dimension following the anabolic effect on the
structural configurations of the oropharynx, especially in women [3].
56
B
Growth hormone and Insulin-like growth factor-1
Growth hormone (GH) is used in sport because of its anabolic and lipolytic
effects [10]. While its effectiveness in enhancing physical performance is still
not proved, recent data show that high doses of GH given to healthy subjects
and endurance athletes lead to glucose intolerance and insulin resistance,
significant alterations in iodine-containing thyroid hormones levels, and
increased insulin-like growth factor-1 (IGF-1) concentrations [11,12]. The longterm health effects of GH use in athletes are not well known but acromegalic
patients with chronic endogenous GH excess may serve as the most accurate
model for an athlete supplementing an already normal hormone level [10].
Prolonged exposure to elevated endogenous levels of GH and IGF-1 results in
both direct structural and functional tissue damage and the development of
secondary systemic disorders. The clinical manifestations of acromegaly range
from subtle signs of acral overgrowth, soft-tissue swelling, arthralgias, and
fasting hyperglycemia to florid osteoarthritis, diabetes mellitus, goiter,
hypertension, and cardiac and respiratory failure [13,14].
Patients with acromegaly develop several respiratory alterations as a
consequence of the hypertrophic action of GH and IGF-1 on craniofacial bones
and soft tissue, respiratory mucosa/cartilages, lung volumes and activity of
respiratory muscles (Tab. 1.) This range of abnormalities results in sleep apnea
and impaired respiratory functions. In the upper airways, remodeling of bones
and soft tissues results in the impairment of normal pharyngeal patency during
sleep and is a key to the onset of obstructive sleep apnea, the prominent type of
sleep breathing disorder in acromegaly. Chronic GH excess causes several
alterations which may contribute to impairing the intrapharyngeal balance during
inspiration and thus increase pharynx collapsibility during sleep [14,16]. About
one third of acromegalic patients develop mixed sleep apnea [18]. Sleep apnea
may affect as many as 80% of acromegalic patients and is apparently more
frequent and severe in case of elevated GH/IGR-1 levels and male gender [14].
Respiratory System
57
Table 1. Chronic GH excess induced morphological and functional alterations related to
respiratory system dysfunction [13, 14, 15, 16, 17].
Site
Pathological findings
Craniofacial region
Macroglossia
and upper
Swelling of the soft palate
Impaired airflow transit
respiratory airways
Swelling/collapse of the
pharyngeal walls
Obstructive sleep apnea
Thickening of vocal cords
Overgrowth and protrusion of
mandible, overgrowth of maxilla
Clinical disorder
Nocturnal snoring
Fragmented sleep
Daytime somnolence
Thyroid overgrowth
Thoracic cage,
Small airway narrowing
lower respiratory
airways
Derangement of respiratory
muscles
and lungs
Enlargement of vertebral
bodies
Elongation and divergence of
the ribs
Lung overgrowth
Increased lung volume
Increased lung compliance
Impaired airflow transit
Stiffened rib cage
Impaired breathing
movement
Respiratory muscle
impairment
Short inspiratory time
Emphysema
Bronchiectasis
Impaired respiratory function originates from the alterations involving the bone,
muscle structure of the chest and in lung volume and elasticity. In the lungs
proliferations of pneumocytes and smooth muscles cells is reflected in the
overgrowth of pulmonary epithelium and thickening of interstitial tissue. This
alteration decreases pulmonary elasticity, whereas lung volumes are increased
due to alveoli overgrowth [14,15]. This process leads to respiratory dysfunction;
the ventilatory response on effort is frequently inadequate in the face of a
greater effort as well as the sense of physical exhaustion. Respiratory mortality
appears to be 3-fold higher in acromegalic patients than in normal subjects [14].
C
Stimulants
Central nervous system stimulants, such as amphetamines and cocaine, are
usually used by athletes to improve performance on the day of competition. The
58
beneficial effects of amphetamines on exercise performance appear to result
from masking pain and/or fatigue. Cocaine increases tolerance to intense
exercise, but most of its chronic effects on energy metabolism are negative.
Amphetamine misuse may carry significant risk for the athletes as evidenced by
several amphetamine-linked deaths in sport. A number of dramatic fatalities
have also occurred in athletes misusing cocaine [19]. Acute and chronic abuse
of these stimulants may result in significant neurologic, cardiac, psychiatric,
obstetric and respiratory complications. The severity and variability of stimulantinduced pulmonary toxic reactions appears to depend on the compound used,
the dosage and the route of administration [20,21].
Cocaine
Acute pulmonary symptoms of smoking cocaine include cough, black sputum,
hemoptysis and pleuritic chest pain. Smokers of crack cocaine with chest pain
have higher carboxyhemoglobin levels and this may play a role in nonpleuritic
cocaine-related chest pain [22]. The use of freebase cocaine has been
associated with barotraumas. Pneumothorax, pneumopericardium and
pneumomediastinum are the common manifestations of cocaine-induced
barotraumas. Smoking of cocaine is also associated with asthma-like
symptoms, exacerbation of asthma and various airway complications including
sinusitis, epiglottitis, bronchitis, and obliterative bronchiolitis. In addition, hot
cocaine vapours may cause thermal burns of the respiratory tract [20,23].
Research has found decreased diffusion capacity of the lungs reflecting
reduced alveolar-capillary interface that lasts weeks to months after cocaine
exposure. The proposed mechanism of this reduction is vascular abnormalities
[20]. Crack use is associated with the syndrome of “crack-lung”, characterized
by diffuse alveolar infiltrates, pulmonary and systemic eosinophilia, fever and
respiratory failure. It occurs within 1 to 48 hours after heavy cocaine smoking.
Pulmonary alveolar hemorrhage, hemoptysis with and without pulmonary
infarction are frequently reported with cocaine abuse. Cocaine use also induces
acute noncardiogenic pulmonary edema [20,23,24]. Possible mechanisms
include local cellular toxic reactions and microvascular pulmonary effects.
Stimulation of the central nervous system to induce noncardiogenic or
neurogenic pulmonary edema is also postulated. Stimulants generally cause
respiratory stimulation, but severe overdose may lead to respiratory depression.
Animal models of cocaine poisoning suggest that postictal respiratory
depression or, in the absence of seizures, direct respiratory depression plays a
major role in the mechanisms of cocaine-induced death [25,26]. Chronic
cocaine use can induce foreign body granulomas, interstitial pneumonitis and
Respiratory System
59
fibrosis, and pulmonary hypertension. It is suggested that prenatal exposure of
cocaine increases the risk of sudden infant death syndrome [20].
Amphetamines
The effects of amphetamine intoxication on respiratory system include dyspnea,
asthma exacerbation, bronchitis, and acute noncardiogenic pulmonary edema
[20,21]. Panlobular emphysema with granulomas is observed in intravenous
abusers of methylphenidate [27]. Pulmonary hypertension has long been
reported in amphetamine users. Contaminants have been suggested as the
cause of pulmonary hypertension after methamphetamine inhalation, although a
direct role of the stimulant is not excluded [21].
D
Narcotics
Narcotics are naturally occurring, semisynthetic or synthetic drugs which bind to
opioid receptors to produce physiological effects and which are antagonized by
naloxane. The main use of opioids in medical practice is in the treatment of
moderate-to-severe pain. Most of the current available opioid analgesics exert
their analgesic and adverse effects primarily through the opioid mu-receptors.
The clinical use of the opioids is limited by serious side effects such as
respiratory depression, development of tolerance, and psychological and
physical dependence. Excessive dosing of opioids may results in significant
toxicity. The toxic and lethal doses depend greatly on the individual's tolerance
to the drug, thus the usual dose for an addict is dangerous for a nonuser or may
be dangerous for the same addict after several days of abstinence because of
the rapid diminution in tolerance. The main toxic effects are respiratory
depression, coma and death [28-30].
The respiratory system is the commonest site of complications of opioid
overdosage. The effects include respiratory depression, acute pulmonary
edema, bronchospasm, aspiration of vomit and aspiration pneumonia. Death
from opioid overdose is usually due to respiratory failure [31]. Respiration is
controlled through medullary respiratory centers with peripheral input from
chemoreceptors and other sources. Opioid administration leads to respiratory
depression because it produces inhibition at the chemoreceptors via mu-opioid
receptors and in the medulla via mu- and delta-receptors [29]. Reduction in the
ventilation (at end-tidal Pco2), increase in the resting and tidal CO2, and a rise in
the CO2 threshold are observed in healthy subjects after opioid administration
[32, 33]. The effect on respiration depends on the type of the opioid agonist. For
60
example, in opioid-naïve volunteers morphine and fentanyl (pure agonists)
produce dose-dependent depression of minute ventilation with apnea at high
dose levels, but buprenorphine (partial agonist) causes dose-independent
respiratory depression with a ceiling effect at higher doses [34, 35].
Independent of the type of the opioid, the opioid–induced respiratory depression
leading to hypoventilation and hypoxemia may produce irreversible neurologic
injury and this combined with the central nervous system depression may result
in death [36]. Concurrent use of opioids with alcohol or benzodiazepines
increases the risk of respiratory arrest. Glutamate and gamma-aminobutyric
acid (GABA) are the major excitatory and inhibitory neurotransmitters,
respectively, that mediate the control of respiration. This explains the potential
for interaction of opioids with benzodiazepines and alcohol. Both
benzodiazepines and alcohol facilitate the inhibitory effect of GABA, while
alcohol also decreases the excitatory effect of glutamate on respiration [29].
Opioid overdose may also induce noncardiogenic pulmonary edema and
bronchospasm. Pulmonary edema is almost universal occurrence in fatal
overdose. Direct toxic effects or anaphylactoid reactions have been suggested
as possible mechanisms of the opioid-induced noncardiogenic pulmonary
edema [37, 38, 39]. Opioids have a histamine-releasing effect, which can also
cause constriction of bronchial smooth muscles and induce bronchospasm and
asthma exacerbation [40, 41]. In addition, opioids can cross the placenta and
can be found in breast milk. Therefore, neonatal respiratory depression can
occur in babies born to mothers addicted to opioids.
E
Cannabinoids
Cannabis preparations contain more than 60 cannabinoids, but the major
psychoactive component of cannabis is tetrahydrocannabinol (THC). Some of
the most serious adverse effects of cannabis (marijuana) smoking are on the
respiratory system. For the adverse effects of cannabis smoke on the lungs,
effects of THC are perhaps of less importance than the numerous products of
combustion to which smokers are exposed. Evidence suggests that the range of
adverse effects on the lungs exerted by smoking cannabis is similar to those
induced by tobacco smoking. Both the gaseous and the particulate phases of
tobacco and cannabis smoke contain a similar range of harmful chemicals (“tar
content”, carcinogens). However, the pulmonary consequences of cannabis
smoking may be magnified by the greater deposition of smoke particulates in
the lung due to the differing manner in which cannabis is smoked. Smokers
typically inhale deeply and hold their breath to ensure maximum absorption of
THC [42]. Studies demonstrate that airway inflammation develops even after
Respiratory System
61
limited exposure to cannabis smoke. While THC causes modest short-term
bronchodilation, cannabis smoke produces a number of long-term pulmonary
changes including histopathological evidence of acute and chronic bronchitis.
Symptoms of chronic cough and sputum production, and exercise-related
dyspnea are common in cannabis smokers [43]. Habitual marijuana smoking is
associated with abnormalities in the structure and function of alveolar
macrophages potentially predisposing to pulmonary infection [44].
Cannabis smoke is carcinogenic in vitro and in vivo and is a possible cause of
respiratory cancers in regular cannabis smokers. The same histopathological
and mutagenic changes thought to be precursors of lung carcinoma have been
found in the lungs of chronic cannabis smokers. Case reports have also
documented cancers of the upper aerodigestive tract (mouth, tongue, and
esophagus) in young adults who have been chronic cannabis smokers, but
evidence from epidemiological studies is inconsistent [45].
F
Beta–Blockers
Beta-blockers block the action of catecholamines on beta-adrenergic receptors.
Asthma is a disease which is characterised by recurrent episodes of
bronchospasm with periods of essentially normal lung function. Inhaled or
injected beta-agonists cause bronchodilation (via beta 2-adrenergic receptors)
and are used in the management of asthma. Therefore, use of (nonselective)
beta-blockers may exacerbate or trigger bronchospasm in athletes/patients with
asthma or pulmonary disease associated with hyper-reactive airways [46].
G
Conclusion
There are little data available about the side effects of doping substances on the
respiratory system of athletes. Anabolic androgenic steroids and GH/IGF-1 can
provoke and/or exacerbate the obstructuve sleep apnea, which can be partially
attributed to their anabolic action. The airways and lungs can be seriously
impaired by cocaine and cannabis smoking. Overdosage of stimulants and
narcotics leads to respiratory depression, pulmonary edema and
bronchospasms which may often have lethal outcome. On the basis of the
research we reviewed we can conclude that some doping substances can exert
serious life-threatening side effects on the respiratory system of athletes.
62
H
1.
2.
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46. P. Lama. Systemic adverse effects of beta-adrenergic blockers: an
evidence-based assessment. Am J Ophtalmol 134 (5): 749-760, 2002.
Correspondence
Katerina N. Georgieva, Department of Physiology, Medical University - Plovdiv,
15A Vasil Aprilov Blvd., 4000 Plovdiv, Bulgaria, [email protected],
[email protected]
66
3.4
Carl Müller-Platz
GASTROINTESTINAL TRACT AND LIVER
Carl Müller-Platz, Tsuyuki Nishino, Hande Sarikaya
A
Introduction
The digestive system is the organ to absorb and utilize food and also to egest
indigestible substances. Digestive system disorders affect quality of life and
decrease performance in and out of competition. Gastrointestinal diseases are
often tedious due to constant stress of this organ.
B
The Digestive System
The digestive system is a mucosa lined passage in which the ingested food will
be broken up and subjected to mechanical and chemical processes. The
nutrients will be resorbed, the indigestible residues will be egested as faeces.
Morphologically, the digestive system is regarded as a hose-like antrum, which
is encircled by the mucosa with cells of different types and functions. In profile,
connective tissue including capillaries and adenoids surrounds the tract while
the longitudinal and circular musculature defines the outer boundary.
The directed transport of the food through the tract results from coordinated
movements of the muscular layers, the peristalsis. The digestive system can be
divided into different functional sections.
The upper digestive part
After ingestion, the food will be hackled by the teeths and prepared for further
transport by saliva. The enzyme ptyaline, which is already present in the saliva,
breaks down carbohydrates into smaller components. The mucosa around the
oral cavity is able to resorb different substances. This fact is also used in the
medical therapy. Through the oral cavity and the pharynx the mechanically
hackled food reaches the esophagus. With the swallowing the volitional control
ends and the digestive apparatus is subjected by autonomous nervous
systems. The esophagus itself carries the food by strong peristaltic movements
into the stomach. A further processing of the food does not take part in this
section of the upper digestive tract. A ring-shaped muscle at the end of the
esophagus causes the food intake into the stomach in portions.
In the stomach the food is further digested chemically by hydrochloric acid and
biochemically by enzymes. Different cells of the stomach mucosa secrete
Gastrointestinal Tract and Liver
67
gastric juice, parietal cells hydrochloric acid, chief cells pepsinogen and mucous
neck cells mucus. In the musculature of the stomach a wavelike contraction will
be initiated by the so-called Cajal cells.
Figure 1. The gastrointestinal tract and main innervations, ENS: Enteric Nervous
System, ANS: Autonomic Nervous System .
The small intestine
From the stomach the chyme reaches the duodenum through the pylorus. The
bile duct and the excretory duct of the exocrine part of the pancreas also
discharge into the duodenum. The exocrine part of the pancreas secretes
digestive enzymes. From the gall bladder the biles coming from the liver will be
stored and delivered. The jejunum and the ileum follow the duodenum. In these
parts of the bowel enzymes and neuroactive substances are released.
Enterochromaffin cells, which liberate the transmitter serotonine, are important
for the control of the musculature and the secretion. Other cells secrete
digestive enzymes. Additionally, intracellular enzymes are liberated by stalled
upper mucosa cells.
The food is mixed by contraction of the bowel muscle layers, while contact with
the mucosa is optimized and the chyme is transported along by peristaltic
movements. The nutrients are resorbed by the mucosa and get into the
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Carl Müller-Platz
bloodstream and the lymphatic channels. The non absorbable parts of the food
and the dietary fiber remain in the bowel.
Figure 2. The cross section of the small (a) and large (b)intestine
The colon
Below the junction of the small intestine the colon closes with a blind ended
tube, the vermiform appendix. Above the junction the ascending colon travels
up mostly along the right side of the body. The next section of the colon is
termed the transverse colon due to it running across the body horizontally.
Then, the descending colon turns downward and becomes sigmoid, which
transports the indigestible rest of the food into the rectum. In the rectum the
excrements will be collected and rectal tenesmus will be activated. The rectal
tenesmus is controlled by the voluntary motor function. The most important task
of the colon is the absorbtion of water and electrolytes and the increase of
slippage of the indigestible rests.
Liver, gall bladder and exocrine pancreas
The liver is the most important organ for the metabolism and detoxication. The
gall bladder is attached to it. The liver is a highly perfused organ, which cells are
arranged to have intensively contact to the bloodstream. During metabolic
processes the liver produces bile, which is important for the fat digestion. Main
types of the liver cells are the parenchyma cells of the metabolic tissue, the
stromal cells as supporting connective tissue and the so-called Kupffer cells for
phagocytosing extraneous particles.
69
Furthermore, amino-acids are metabolized in the liver, glycogen is formed and it
is the central organ for fat metabolism. The liver produces clotting factors and
regulates the acid-base balance, vitamins and trace elements.
In the gall bladder the bile is stored, which is mainly produced by the
hepatocytes of the liver, and then delivered into the duodenum. There is a
feedback on the composition of the chymus via chemoreceptors which
regulates the released amount of biles.
Liver and gall bladder are controlled differently. While the liver is controlled
sympathetically and parasympathetically [1], the gall bladder is controlled by the
enteric nervous system (ENS). The ENS also controls the exocrine part of the
pancreas. The pancreas is divided into an exocrine, digestive orientated and an
endocrine metabolism orientated part. The exocrine pancreas releases through
the ductus pancreaticus further digestive enzymes (e.g. chymotrypsin) into the
lumen of the duodenum. With its hormones insulin and glucagon the endocrine
part mainly controls the glucose metabolism.
The enteric nervous system (ENS)
In the year 1897 Dogiel discovered neurons in the abdominal cavity, which he
divided into three types according to their structure. He placed the cadre for the
ENS which is comparable in its dimensions with the spinal cord. This nervous
system controls the intestinal motility, secretion and absorption [2]. The
ganglions are located in the intestinal wall. The Plexus Myentericus (Auerbach)
is situated between the longitudinal and circular layers of muscle in the Tunica
Muscularis and exerts control over the muscle tonicity and the intestinal motility.
The Plexus Submucosus (Meissner) controls the secretory sequences and is
located in the submucous coat of the intestine and contains ganglia from which
nerve fibers pass to the mucous membrane. The high number of receptors
consisting of afferent, sensoric and efferent pathways is responsible for often
unspecific biomedical side effects on the digestive system.
The signal conduction of the ENS is similar to the vegetative nervous system
(VNS), mainly working via acetylcholin and noradrenalin. The release of these
neurotransmitters is modulated via several co-transmitters which react mostly at
presynaptic located receptors [3]. Substances docking at these receptors are for
example kinines, substance P or serotonine [4,5]. The VNS exerts direct
influence up to the stomach and from the colon on. In animal experiments
alpha- and beta-adrenergic receptors were detected in different densities based
on the sections [6].
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Carl Müller-Platz
Since ghrelin was detected in the stomach of rats the knowledge on the food
intake control mechanisms and energy balance has improved dramatically.
Ghrelin causes with other mediators the appetite which leads to food intake. In
fasting state and after food intake, the effect patterns between intestinal motility
and secretion in the particular parts of the digestive tracts can be identified and
assigned. Ghrelin also stimulates the excretion of human growth hormone via
gastric afferent parasympathetic nervous pathways. Using the neuropeptide Y it
stimulates the food intake [7]. In animal studies, the motor activity of the
duodenum in saturated animals after application of ghrelin shows similar
patterns like conditions before food intake [8].
Currently, 20 neuronal transmitters and other hormone-like substances are
identified, whose interactions are under investigation in this system.
C
Biomedical Side Effects of Doping Substances
The ENS reacts on many stimuli from the intestinal tract (mechanical and
chemical receptors). Co-transmitters affect and modulate the signal
transmission pre- and postsynaptically. In addition, further indirect influences of
the sympathetic and parasympathetic nervous system have to be added.
Systemic health side effects of doping active substances on the digestive tract
are to be expected always then, when the active substance has an effect on this
ENS, on the lymphatic or the circulatory system. Besides, it can lead to
hormonal effects in target cells of the mucous membrane and the smooth
musculature.
Actually, doping substances are drugs and thus developed for the therapy of
illnesses. Besides desired therapeutic effects, undesirable side effects occur,
whose appearance and frequency is investigated within the scope of the clinical
test to healthy volunteers. These data, which would be especially appropriate
for the consideration of the abuse by competitive athletes, are seldom available.
After the commercial launch as a pharmacological drug of different galenics
further messages about side effects emerge. This spectrum of side effects is
dependent on the description and on the respective clinical picture of the
treated patient. Just in the digestive tract side effects are mainly unspecific and
appear often already as a concomitant of the illness, from incompatibility or,
however, from other cause. In the end, psychosomatic influence has to be taken
into consideration. Indeed, the side effects which are to be announced within
the scope of the drug vigilance within the therapeutic application are taken up in
their frequency, nevertheless, about the origin there are only very seldom
investigations.
71
Hence, in the following consideration such side effects are only mentioned if
their frequency lies in the percent area and, hence, a causal connection with the
active substance can be supposed.
Side effects of the liver originate almost exclusively in cytotoxic mechanisms.
The liver cells are overtaxed, die or the functional cellular tissue alters itself
degenerative into connective tissue, inclusions or cancer cells.
In the clinical picture changes in the metabolism and linked illness symptoms
are detected. A special importance comes up with the origin of liver damages to
the so-called oxydative stress. This process leads to increased emission of free
radicals, which can attack the cell at different places and lead to damages up to
cell death. Signs of liver tissue damage are the increases of the concentration
of hepatocyte specific enzymes in blood, hepatitis and icterus.
The health side effects of the active substances from the list of prohibited
substances and methods are demonstrated in the following, according to the
systematics of the 2007 WADA list.
S1. Anabolic active substances
Here, two kinds of substances are distinguished, anabolic androgenic steroids
and other anabolic active substances using other mechanisms.
The androgenic-anabolic steroids (AAS)
The AAS are derivatives of the male gender hormone testosterone. The
development of derivatives served the improvement of the pharmacokinetics
and the change of the active spectrum for the amplification of one of the always
together appearing androgenic and anabolic effect. Many derivatives have not
overcome the hurdle of the bioassays for the clinical test, nevertheless, are to
be purchased from different, mostly forbidden sources. Their specific side
effects on the gastrointestinal tract are not known, presumably they may be like
those of the admitted preparations.
In many investigations, mostly as surveys in fitness studios [9] admit between
10-40% of the interviewees the abuse of anabolic steroids. In a survey with 253
fitness studio customers 6% complained about diarrhea, 4% have declared
changed faeces. About 30% of the drug abusing candidates reported an
increased appetite during the intake cycles, which is probably released central
nervously and hormonal, as the protein buildup requires additional nutrients.
This symptom reverses beyond the intake cycles by 25% of the interviewed
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Carl Müller-Platz
persons in a loss of appetite and is accompanied in about 10% by feeling of
nausea.
The effect of anabolic steroids on the gastrointestinal tract can be explained
partly by the metabolic ways. Thus, the oversupply of anabolics leads to a partly
conversion of those in estradiol by the enzyme aromatase. In animal
experiments estradiol has a detectable influence on the intestinal functions,
already in low concentrations. The threshold of these effects is increased by the
pressure receptors, which initiate the peristaltic movement [10], and the
defaecation of the intestine delays [11].
Anabolic steroids have an affinity to the androgen receptors whose stimulation
causes a momentary hyperglycemia which leads to motility disturbances in the
whole intestinal area. Acute effects from testosterone on the gastrointestinal
tract are often nausea and vomiting, as well as loss of appetite and diarrhea. An
oral application with longer whereabouts of the preparation in the oral space
local inflammations are also reported what probably allows suggesting more on
an allergenic reaction. Contact of testosterone with the skin can also cause
irritations. In some cases severe side effects like stomach bleeding or bleeding
of existing esophagus varices are reported. The latter has probably to be seen
in close connection with other side effects like liver toxicity and blood pressure
increase. With testosterone undecanoate side effects like indigestion and
diarrhea are also described.
Nandrolone and oxandrolone are similar in their structure, stanozolol and
danazol however not. Nevertheless, the side effects of this four AAS are
comparable. Often the intake leads to nausea and vomiting as well as to a sore
tongue, feeling to be stuffed and failure. Oxymetholone is also reported with a
nausea, vomiting and diarrhea. These side effects appear very frequently by
fluoxymesterone intake. However, the mechanisms of the side effects are not
known in detail.
AAS are known in particular for their damage potential to the liver. The
alkylation in the C-17 atom should endure the anabolic effectiveness during the
first liver passage, indeed to the detriment of the liver tissue. In a survey nearly
30% of the interviewees know about these liver damaging effects of the
AAS [12]. About 5% of the persons abusing high doses of AAS, like it is known
for building up of muscles, declare liver problems but without a closer
description [13].
There are many medical investigations about side effects of anabolic steroids
on the liver available. The first sign of a liver damage is the increase of the
concentration of the hepatocyte specific enzymes in the blood. The liver cell
73
damages can also lead to congestions of the small excretory ducts for bilious
secretion, which can disturb the bilious outflow. Thus it can result in a more or
less distinctive jaundice. If after longer-termed and strong abuse the abusers
are forced to attend medical treatment because of acute illnesses, mostly
further serious side effects appear.
By long-term overloading of the liver tissue it seems to come to development of
carcinomas as late damage. Although the mechanisms of the origin of different
cancer forms are not understood yet in all details, the epidemiological data
show at least a clear connection. Different forms are described among them:
hepatocellulare adenoma, focal nodular hyperplasia and hepatocellulare
carcinoma [14]. Another dangerous late effect is the Peliosis hepatis, whose
mechanism of origin is also not known yet. The Peliosis hepatis is usually poor
in symptoms, so that their appearance is seldom noted. In a late stage it leads
to life-menacing liver failure and in some cases it is ascertained only with an
autopsy.
The liver tumors which appear in connection with the abuse of anabolic steroids
are very strong vasculated, so that also here in a later stage, like the Peliosis
hepatis, quite life-menacing bleeding can appear. In the end, deaths are also
reported in particular from the circles of the bodybuilders with excessive
medicinal supported building up of muscles. In these cases, the autopsies give
other hints to the whole damage potential [15] in different organs.
Other anabolic substances
A chemical relationship between these so-called other anabolic working
substances do not always exist. Their commonness is the anabolic side effect
at least in higher concentrations. Clenbuterol and zilpaterol present the group of
the beta-2 agonists, zeranol and tibolon the group of estrogen active
substances. The anabolic trenbolon also belongs to the latter group. Some of
the active substances originate from the animal mast, however, are approved
only in few states beyond Europe. Clenbuterol, a beta-sympathomimetic, is a
stimulant of the sympathetic nervous system and unfolds in larger quantities
also an anabolic side effect. It has only one indirect influence on the
gastrointestinal tract. Possible nausea and vomiting are probably of centralnervous origin. Zilpaterol has an effect like clenbuterol on the sympathetic
nervous system and in this regard a high toxicity is discussed. However, the
investigations limit themselves to toxicological considerations as remains in the
animal food. Hence, there is no information available concerning the side
effects in the digestive tract.
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Carl Müller-Platz
Tibolon is an estrogen- and progesterone-active steroid with low androgenic
effect. Nausea is often described as a side effect after intake.
Zeranol is a toxin which is formed by molds of the type Fusaria. It works like a
slight active estrogen. In some states it is permitted for mast of farm animals,
but not in Europe. But zeranol is not permitted for human application. Hence,
data about intake levels and side effects are not available. The substance is
merely scientifically discussed in connection with long time toxicity and tolerable
daily intake levels with the food.
S2. Hormones and related substances
The substance group of hormones itemized in the list of banned substances
and methods is very heterogeneous concerning its effects on the organism.
These substances which are mostly converted from preliminary stages in few
metabolism steps to the active hormone intervene in different hormonal
regulatory mechanisms. Because the effects are involved in very different
regulatory mechanisms, the side effects of these substances have to be
discussed individually.
Side effects of the growth hormone IGF-I (Increlex®) and somatorelin can be
summarized in one group. IGF-1 supports the hGH effect, somatorelin releases
hGH from the anterior pituitary gland. A brief application is generally free of side
effects on the digestive tract, if some single reports after the market launch are
neglected. Longer-term abuse of suprapharmacological doses leads to a
general organ growth, thus also of the liver including functional disturbances.
Epidemiological studies of the long-term therapy point to an increased risk of
the development of a colorectale carcinoma [16]. The modes of action for this
are not cleared up in detail.
Erythropoietin is considered as a well tolerated substance in general. Side
effects on the digestive system are barely described. The appearance of
nausea, vomiting and diarrhea usually appears on patients, treated with
Erythropoetin as a therapy for their disease, before their treatment than under
the treatment with Epoetin-alpha [17]. The disease itself seems to have stronger
effects on the digestive system.
The application of insulin does not lead to side effects in the digestive system,
neither with brief nor even with long-term therapy. However, it is discussed
whether it is involved in the genesis of colon cancer.
75
Human choriongonadotropin is therapeutically used for women with insufficient
oogenesis to fulfil the desire for children. In return it can stimulate the natural
testosterone production of men. But most investigations were carried out on
women. However, it can be supposed that the unspecific side effects like
nausea and vomiting also occur with the substance abuse for testosterone
stimulation in men.
Gonadorelin stimulates the formation of the luteotropic hormone. On a therapy
with this releasing factor nausea and vomiting are frequently reported,
additionally abdominal pain appears. Nevertheless, these side effects are not
very intensive and quickly fade away.
The luteotropic hormone (LH) leads to a release of estrogen. Concerning the
side effects in the gastrointestinal tract animal experiments showed that
estrogen but not testosterone delays the stomach emptying [18] and raises the
threshold of the pressure charm for the release of peristaltic movements [9].
Women under therapy often report unspecific nausea. The follicle-stimulating
hormone (FSH) unfolds unspecific nausea, vomiting, feeling of fullness and
diarrhea in the digestive tract. In rare cases FSH is also used for men and then
frequently leads to an increase in weight.
S3. Beta-2 agonists
The beta-2 agonists have to be assigned to the group of stimulants. Their
characteristic is the mostly selective and at least predominant effect on the
beta-2 receptors in the sympathetic, adrenergic system. Especially these
receptors can be numerously found in the bronchial tract.
The application of these agents is considered to be safe. Nevertheless, side
effects in the digestive tract are to be expected, as the enterochromaffin cells of
the small intestine liberate serotonin itself, due to the cholinergic effect of these
cells. Furthermore, serotonin intervenes actively in the control of the gastric
motility in the cholinergic system and on the other hand, raises the secretion of
the mucosa cells. Like in other areas different receptor sub-groups were found
for the serotonin, which are proved either in the same species in different areas
of the ENS or in different forms in different species [19].
The side effects of beta-2 agonists can be explained by the generally known
impact pattern of sympathetic activation. It has to be taken into account, that an
inhalational application can anyhow affect the upper digestive tract up to the
stomach due to the swallowing of considerable quantums of inhalants [20].
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Carl Müller-Platz
Occasionally, isoetharine leads to xerostomia, a typical sympathetic effect, and
to taste disturbances (dysgeusia), like reported for formoterol or salmeterol. As
an unspecific and rare allergic reaction irritation of the oral cavity and pharynx
or the swell of the lips have to be assessed. In particular after inhalational
application irritations in the oral and cervical cavity can appear. Such side
effects are reported for formoterol, isoetharine and orciprenaline.
However, pyrosis, like it occurs with clenbuterol, terbutaline, tolbuterol or
fenoterol, is a sympathetic effect of the stomach. As orciprenaline
(Metaproterenol) has not only beta-agonistic effects, nausea is a further
frequent side effect. A study with more than 700 patients ingesting pirbuterol
ascertained frequent side effects in the the gastrointestinal tract like nausea and
vomiting [20].
S4. Substances with antiestrogenic effect
This group of agents can be divided into steroidal and non-steroidal aromatase
blockers, selective estrogen receptor modulators and "blockers of the 3rd
generation". Investigations to the appearance and frequencies of side effects of
this substance group refer in the essentials to women with estrogen-sensitive
tumors of the breast, which are treated with aromatase blockers. However,
aromatase blockers are in particular also abused by men who abuse anabolics
and want to prevent the metabolism of anabolic steroids in estrogen.
Anastrozol [21] and letrozol are non-steroidal aromatase blockers. In a phase I
study with a non-steroidal aromatase blocker tested on healthy male volunteers
a significant increase in LH and FSH blood concentration appeared and side
effects like nausea, indisposition and dizziness [22] could be observed.
However, results do not exclude that the nausea was caused by the dizziness.
Another phase I study with letrozol [23] tested on postmenopausal women
points out to the fact that no side effects on a significant level appear in this
case. The same study using exemestane on postmenopausal women showed
only few side effects, mainly in the gastrointestinal tract, like light gastritis,
flatulence and diarrhea [24]. About the steroidal aromatase blockers like
aminogluthedimide, exemestane, formestane and testolactone the loss of
appetite, nausea also with vomiting and gastrointestinal discomfort are reported.
Testolactone seems to have a high potential of releasing an unspecific allergic
reaction, which process is not very severe.
77
Estrogen receptor modulators
The selective receptor modulators (SERM) [25] inhibit the estrogenic activity of
the receptor so that the biochemical active cascade is missing. Nevertheless,
estrogen remains in the bloodstream and can still release unspecific effects in
the digestive tract.
The intake of tamoxifene leads to gastrointestinal disturbances, often expressed
by nausea and vomiting. In a P-1 NSABP study [26] constipation was observed
with a lower incidence. The similar agent toremifene [27] often releases nausea
and vomiting, too. It is noteworthy, that clinical tests performed in the USA
generally show a higher frequency of the prementioned side effects compared
to European studies. The group of the other antiestrogen active substances are
probably planned as "collecting ponds" for newer developments like tyrosinekinase-inhibitors (Gefitinib®). Clomiphene [28], for instance, stimulates LH and
is now and then accompanied by lower abdomen discomfort and flatulence and
more seldom with nausea and vomiting. Cyclofenil releases in a case collection
in 10 out of 30 women nausea and vomiting. The common choice criterion for
those cases was a diagnosed impairment of liver function caused by a longterm intake of cyclofenil. The liver damages healed after discontinuing the
medication [29]. Fulvestrant [30] releases very often nausea, vomiting,
constipation or diarrhea and abdominal pain. Frequently, a loss of appetite
appears, too. It has to be taken into account that all side effects can
sporadically reach a severe level.
S5. Diuretics and other masking agents
Diuretics
The diuretics [30] are divided into different categories which induce forced urine
excretion (diuresis) indeed, but with different mechanisms or acting at different
places of the Nephrons. The loop-diuretics lead to rapid diuresis including
electrolyte loss, in particular of potassium ions [31]. Therefore, potassiumsaving diuretics were developed.
The benzothiadiazine derivatives work prior long lasting as well as the
aldosterone antagonists, which are suitable for the long time therapy, whereas,
the osmotic diuretics have a very narrow range of application.
The spectrum of side effects can be ascribed decisively on changes in the
electrolyte balance. Thus, thiazides cause a sodium and calcium lack and loopdiuretics a potassium and calcium lack. The osmotic diuretics lead to a sodium
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Carl Müller-Platz
lack, too. Potassium-saving diuretics and aldosterone antagonists cause, like
the name expresses, a potassium profit. In summary, sodium, potassium and
calcium levels are the decisive factors which determine the side effect
spectrum. While sodium lack releases a strong thirst feeling, which disturbs
sensations of taste and can release cramps also in the upper abdomen, a
potassium lack leads to inertness of the intestinal musculature. Calcium lack
can also cause indigestion. Calcium has a pivotal function for the transfer of the
electrical impulses in the ENS.
The dryness of mouth via abuse of diuretics can be traced back to the reduced
reflexive salivary flow rate [32]. It is a fact, that the application of diuretics can
cause a thiamine deficiency, which excites symptoms in the nervous system
and can also lead to a loss of appetite [33]. Gastrointestinal discomfort like
diarrhea and constipation are apparently opposite symptoms. Nevertheless,
they can be explained by reduced water resorption out of the intestinal lumen
on the one hand and by the disturbance of the intestinal peristaltics caused by
the potassium loss on the other hand. The latter can also lead to abdominal
pain.
Thiazides lead to a temporary hyperglycemia [34]. The increased blood sugar
level inhibits the motility of the whole intestinal tract [35]. This explains at least
partially the gastrointestinal disturbances. Thiazides are also associated with
the appearance of cholecystitis. An epidemiological study about thiazide use
showed an increased relative risk of 2.4 compared with a control group
presenting a relative risk of 1.9 [36].
Generally, trouble and incidental bleeding of stomach indicates, just like
inflammatory processes and ulceration, to cell damages caused by the contact
with the drug. In this context, potassium salts play the essential role as they are
added to the diuretics for potassium substitution. Such inflammatory processes
can continue up to the small intestine.
Furosemide is first-pass metabolized to a very small proportion in the liver [37].
Animal experiments showed that the bioavailability of furosemide is strongly
raised by vitamin C [38], what has to be taken into account while application.
With etacrynic acid the gastrointestinal disturbances appear more frequently
and run severe, what is expressed through watery diarrhea and gastrointestinal
bleeding. The side effects of the potassium-sparing canrenone (Spironolactone)
contain often gastrointestinal disturbances like abdominal pain and diarrhea.
Epidemiological studies on the side effects of Spironolactone strongly allude to
the incidence of ulcers with stomach bleeding caused by the decreased healing
process of the mucous membrane, which is generally induced by aldosterone,
79
and in this case decreased by the antagonist [39]. Also the induction of cancer
is supposed.
Masking agents
Probenecide is classed in the fight against doping as a masking agent. Its side
effect spectrum on the digestive system is limited to the upper area. As general
pathology nausea, feeling of fullness and also the loss of appetite can appear. It
is also under suspicion to be liver-toxic and to cause necrosis. In clinical tests
no appreciable side effects were ascertained for finasteride [40] and dutasteride
[41].
The application of infusions is known to be applied to healthy but exhausted top
athletes. In sports this act is attached very tightly to the therapeutic need. Any
other intended application is evaluated as a prohibited method. However,
infusion solutions can also develop side effects. The priority has to be given to
the unspecific symptoms like nausea and vomiting, which can appear with the
infusion of albumine- and dextrane-containing solutions. This can possibly be
explained by the pressure change of the vascular wall of the precapillary
arterioles, whose pressure receptors release transmitters that cause the enteral
sensoric nausea. Hydroxyethyl starch (HES) infusions can lead to an
enlargement of the salivary glands, whereas after application of albuminecontaining infusions increased salivation can be released.
S6. Stimulants
The stimulants work as agonists directly on the alpha- and beta-receptors,
which are on account of their different effects partitioned into these subgroups.
Side effects of beta-2 agonists have been described in a former chapter.
The therapeutic application field for stimulants decreased during the last years.
In particular as a central-nervously active appetite suppressant their application
is judged very critically. Amphetamine and amphetamine derivatives belong ab
initio the list of banned substances and methods to the group of stimulants and
are known to have a high addiction potential. Amphetamines are indirect
sympathomimetics and act as stimulants also on the liver and digestive tract,
but indirectly by modulation of the ENS. However, especially one of the general
injurious effects has to be followed in the context of sports, the deregulation of
the body temperature at high physical exertion and thus the overheating of the
body and its organs. In one study the following causes of death were
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Carl Müller-Platz
ascertained at 87 deaths by an involvement of amphetamines: overheating
(34.5%), unknown causes (25.3%), accident (14.3%), hyponatremia (10.3%),
heart-circulatory failure (9.2%), and liver failure (4.6%) [42].
Amphetamines and derivatives are metabolized by the cytochrome P450
oxydase system. This system is known for hereditary changes. This could
probably be the reason why people react differently sensitive to this drug.
Mostly, the affected persons are not in the knowledge of this idiosyncrasy. In
this respect, the abuse of amphetamines and related substances can lead in
worst case to acute liver failure. This results from the oxidative stress of the liver
cells which causes the cell death. Light forms of hepatitis, mostly accompanied
by jaundice and an increased bleeding inclination, are frequent [43]. The reason
for this kind of jaundice is the disturbed removal of bile from the cystic ducts of
the liver.
Preparations and active substances, which promise a selective fat combustion
as for example Ma Huang, behave in a similar way. The extracts of this plant
contain ephedrine and derivatives like Pseudoephedrine and also alkaloids in
an extraction-dependent composition. Such preparations rescue the danger of
direct liver cell damages as they contain liver-toxic materials and can strengthen
and aggravate an existing, possibly not recognized liver pre-disease,
respectively. In general the sympathomimetic symptoms are distinctive. The
sympathetic innervation with direct effect on the stomach causes the side
effects already described with the beta-mimetics. The enterochromaffin cells of
the intestinal mucous membrane present adrenergic receptors. This allows the
release of serotonin, which activates presynaptic the intestinal motility. In
addition, the secretion into the intestinal lumen is increased. This sympathetic
excitation results in an increase of the tonus of the sphincter ani and leads to a
sluggish action of the bowels at the rectum sphincters.
Strychnine is no longer used for medication, as it really has a low therapeutic
index and thus the application is problematic. It is toxic, tastes very bitter and
causes reflectory oversecretion in the stomach [44] and vomiting [45].
S7. Narcotics
Central nervously acting analgesics of the morphine type belong to this closed
group of active substances. The substances of this group have a high addiction
potential. As mentioned before, their analgesic property is located central
nervous, just like their side effects. But the side effects can also be of peripheral
origin.
81
The frequent side effect of central nervous origin is nausea, often accompanied
by unique or repeated vomiting. This is closely connected with the opiates
working at the µ-receptor. The subjective perception of nausea is distinctive and
also depending on the administered dose [46]. However, these symptoms occur
significantly more often in women than in men [47]. The vomiting center is
located in the brain stem between the extended spinal cord and interbrain, area
postrema, Nucleus tractus solitarii and Formatio reticularis and is controlled by
the neurotransmitters dopamine and serotonine.
It is also reported that morphine therapy can cause upper abdomen discomfort
due to the fact that the general receptor linked tonicity-raising effect on the
smooth musculature is transmitted as tension pain by the peripheral pain
receptors [48]. This increased tonus affects also the sphincter between
esophagus and stomach as well as the sphincter between stomach and
duodenum. Tonus increase further leads to the reduction of the peristalsis, the
directed aboral transport of the food mash. The inhibiting effect pertains the
secretion of the salivary glands and the gastric juice secretion, too. Thereby, the
food remains longer in the upper digestive tract and the lowering of the bowel
peristalsis results in constipation of varying duration. This is supported by a
strong dehydration of the faeces in the large intestine and spastic states of the
sphincter ani.
In particular, µ-receptors were detected also in the presynaptic ganglia of the
bowel. This is evidenced as the side effects in the bowel released by µagonists, e.g. constipation, are avoided by µ-antagonists that cannot pass the
blood brain barrier. These antagonists do not affect the analgesic effect of the
narcotics [49].
A retrospective study in a pain clinic about side effects of morphine on the
digestive tract with patients less than 65 years old showed the following effects
(sorted by frequency) [50]: Dry mouth (xerostomia), constipation, nausea,
dysphagia, vomiting and diarrhea. Indeed, xerostomia is explicable by the
anticholinergic effect of the narcotics. The precise mechanism itself is not
cleared up to now. Probably, the authors describe the frequency of dry mouth
too frequently, because dry mouth can have the most different causes. An
evaluation of various scientific works about Pethidine set the appearance of
side effects in relation to the concentration of the active substance in the
plasma. At a blood concentration of already 0.15 mg/l dry mouth appeared;
nausea occurred at a concentration above 0.25 mg/l [51]. A frequent loss of
appetite is reported in this context with fentanyl, but cannot be assigned to this
painkiller causally.
82
Carl Müller-Platz
Animal experiments show that the liver is subjected to oxydative stress by
morphine application [52]. This fact can probably be transferred to human liver
cells. According to the spastic effect on the bile ducts in the liver and the
contraction of the sphincter oddi biliary colics can also appear. Morphine inhibits
the cholinergic stimulus transference in animal experiments and thus the
secretion of enzymes in the exocrine pancreas [53]. Spastic effects after
morphine application can also be detected in the smooth muscle cells of the
exocrine part of the pancreas and their execretory ducts. This contributes to the
upper abdomen complaints.
S8. Cannabis
Cannabis has evolved into a party drug. According to different investigations
approximately one quarter of the population between 15 and 58 years already
tried cannabis once in their life. As frequent side effects on the digestive system
nausea and vomiting are reported.
Today it is known that cannabis receptors (CB 1 and CB 2) are present in the
digestive system, in particular in the area of the small intestine, whose
stimulation unfolds a protective effect on the intestinal mucous membrane.
Animal experiments show, that agonists of the CB 1 receptor located in the
stomach lead also to a protective effect by lesions of the mucosa. On the other
hand, this activation of CB 1 results in a worsening of pancreatitis induced by
Coeruleine [54].
S9. Glucocorticosteroids
The glucocorticosteroids form a row of side effects and also some in the
digestive tract [55]. The side effects mentioned here refer basically to the active
substances Cortisone, Prednisone, Prednisolone and Dexamethasone.
Glucocorticosteroids are known for their anti-inflammatory effect. It is also a
fact, that a systemic application regulates the metabolism into a catabolic state.
This results in proteolysis and reduced cell proliferation. To what extent the
intestinal mucosa and musculature are affected is not known yet, although
intestinal disturbances are reported during the therapy. A development of ulcers
in the stomach with long time therapy can be ascribed to the stimulation of the
gastric acid secretion. Glucocorticoid receptors can be found in the large as well
as in the small intestine. Especially in the small intestine they play a decisive
role in the regulation of the electrolyte transport [56]. Due to the catabolic
83
metabolism effects a long-term overstraining of the liver and pancreas cannot
be excluded, which comments then paradoxically in inflammatory processes.
Furthermore, glucocorticosteroids lead to passing hyperglycemia, which inhibits
in turn the intestine motility. This can also be expressed through health side
effects in the digestive system.
P2. Beta-blockers
Therapeutically, beta-blockers prior serve the regulation of high blood pressure.
As antagonists of the beta-sympathomimetics they control the opposite
mechanisms of action in the ENS. Thus they block the secretion of serotonin in
the enterochromaffin cells. Reduced secretion and a decrease in the tonicity of
the smooth muscle cells of the intestinal wall are the result. Nevertheless, this
has no influence on the passage of the chymus of a healthy person [57].
In the metabolism some substances of this material group work restraining on
the fat oxidation [58] and lipolysis. For instance, this effect appears with
Propanolole in healthy athletes during physical exercise [59]. Generally, betablockers decrease the liver blood flow what can possibly lead to light liver
damages and Propanolole, in particular, decreases the enzymatic activity [60].
D
Summary
Many mechanisms of the side effects of pharmaceuticals appearing in the
digestive system are not understood yet, as the feedback control system of the
ENS needs lots of additional scientific investigations. Side effects of doping
related active substances on the digestive system are always given, however
they are seldom severe or life-threatening. They fit into the general side effect
spectrum, which is already summarized by Peters and coworkers [61].
In particular, polymedication, as it is known from the leisure and recreational
sports [11], affects the digestive system by the appearance of not predictable
side effects resulting from e.g. delayed or quickened resorption. Side effects in
the liver also change the metabolism of the respective doping substance. To
comment about possible late damages further investigations and
epidemiological studies are essential.
84
Carl Müller-Platz
E
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Correspondence
Carl Müller-Platz, Bundesinstitut für Sportwissenschaft (BISp), Postfach
170377, 53029 Bonn, Germany, [email protected]
Reproductive and Endocrine System
3.5
89
REPRODUCTIVE AND ENDOCRINE SYSTEM
A
Introduction
Many of the doping substances are hormones, their structural analogues,
precursors of hormones or agonists/antagonists of their receptors. For this
reason if used by healthy people they can cause endocrine imbalance and a
number of other hazardous effects on the reproductive and endocrine systems.
This review surveys the side effects caused by doping substances in athletes
and healthy subjects but where is appropriate or data are unavailable studies on
patients and animal studies have also been included.
B
Anabolic Androgenic Steroids and Testosterone Prohormones
Androgens play a pivotal role in male reproductive and sexual function. They
are required for the developing and maintaining masculine sexual
characteristics – from the sexual differentiation in utero, through secondary
sexual development during puberty to the establishment and the maintenance
of adult sexual function and fertility. Testosterone, produced by the Leydig cells
in the testes is the primary male sex hormone and is responsible for androgenic
and anabolic effects observed during male adolescence and adulthood.
Anabolic androgenic steroids (AAS) are synthetic derivatives of the testosterone
and have similar biological effects [1]. Dehydroepiandrosterone (DHEA) and
androstenedione are steroids in the sex hormone biosynthesis pathway and are
precursors in the endogenous production of testosterone and estrogens. These
steroid precursors are weak androgens secreted primarily by adrenal glands in
both sexes. They provide a pool of circulating steroids that can be converted to
active androgens and estrogens in the peripheral tissues. Adrenal androgens
exert very little masculinizing and anabolic effects when secreted in normal
amounts [2,3]. Testosterone, or its analogs, can act directly on target cells, or it
can be converted to dihydrotestosterone (DHT) by the enzymes 5α-reductase or
to estradiol by the enzyme aromatase in the peripheral tissues [1].
AAS are used in various sports for their anabolic (anticatabolic) effects to
increase muscle mass, enhance athletic performance and physical appearance.
Usually, these substances are used by athletes in dosages exceeding
physiological replacement levels by 10 to 50 times or more [4]. This leads to
hyperandrogenic conditions in the organism and results in anabolic steroid-
90
induced endocrine imbalance and impairment of the male and female
reproductive functions.
Anabolic androgenic steroids and male reproductive system
The secretory and gametogenic functions of the testis are both dependent upon
the secretion of gonadotrophin-releasing hormone (GnRH) from the
hypothalamus, which stimulates the secretion of the anterior pituitary
gonadotrophins, luteinizing hormone (LH) and follicle-stimulating hormone
(FSH). FSH helps maintain the spermatogenic epithelium by stimulating the
Sertoli cells in the testes and LH stimulates the testosterone production by the
Leydig cells. The production of testosterone provides the high local
concentration of androgen to the Sertoli cells that is necessary for normal
spermatogenesis. Although upon maturation the responsiveness for FSH of the
Sertoli cells diminishes and switches to an increased responsiveness for
androgens, a dual action of both FSH and intratesticular testosterone is
necessary for complete quantitative and qualitative spermatogenesis [5].
As derivatives of testosterone, AAS have pronounced effects on the male
hypothalamic-pituitary-gonadal axis and their use results in the clinical
syndrome of hypogonadotrophic hypogonadism. This steroid-induced
hypogonadal state is characterized by decreased serum concentrations of FSH
and LH, low endogenous testosterone production, impaired spermatogenesis
and testicular atrophy [6-8]. These effects stem from the negative feedback of
anabolic steroids on the hypothalamic-pituitary axis and possibly from the local
suppressive effects of excess androgens on the testes [6,9]. The administration
of AAS mimics an enhanced level of circulating endogenous testosterone. High
testosterone levels, as well as AAS, inhibit LH secretion by acting directly on the
anterior pituitary and by inhibiting the secretion of GnRH from the
hypothalamus. This in turn causes a corresponding decrease in secretion of
both LH and FSH and the decrease in LH reduces the production of
endogenous testosterone. Serum testosterone concentrations also decrease,
except when exogenous testosterone is administered [5,10,11].
Administration of high doses testosterone induces supraphysiological levels of
serum total and free testosterone. Serum concentrations of estradiol,
androstenedione and DHT also increase because of peripheral conversion of
AAS. In athletes on stacking regimen of androgens, plasma estradiol levels can
rise as much as 7-fold to levels comparable to those normally seen in ovulating
women. The AAS use reduces sex hormone-binding globulin (SHBG) levels
[10-12].
91
High levels of testosterone are needed inside the testis for normal
spermatogenesis and this can never be accomplished by oral or parenteral
administration of AAS [5]. AAS use does not raise the androgen level in the
testes to as great a degree, but inhibits LH and FSH secretion. Consequently,
the net effect of AAS use is impaired spermatogenesis. With the impaired
sperm production semen quality decreases, and infertility, manifested as
oligospermia or azoospermia, along with abnormalities of sperm motility and
morphology, often results. Due to these changes testicular atrophy (testicular
shrinkage) is usually observed in male AAS users [7,8,13].
Recent animal studies have shown that high doses of AAS also reduce the
length of seminiferous tubules [14] as well as suppress steroidogenic capacity
(Fig. 1) and increase apoptotic tendency in Leydig cells (Fig. 2) [15,16]. These
effects of AAS on the Leydig cells correspond to the suppression of serum
testosterone concentrations after anabolic steroid use.
A
B
Figure 1. Activity of the key steroidogenic enzyme 3β hydroxysteroid dehydrogenase in
Leydig cells (LC) of endurance trained rats treated with placebo (A) or nandrolone
decanoate (B) x 200. The suppression is significant (P<0.001).
The anabolic steroid-induced state of hypogonadotrophic hypogonadism in
male athletes is usually reversible after steroid withdrawal, but the time needed
for full recovery of the hypothalamic-pituitary-gonadal axis and reproductive
function is not exactly known [6]. After long-term AAS abuse spontaneous
recovery may take up to 4-20 months [10,17]. Case reports indicate that
problems may persist for up to 3 years and that recovery does not always occur
[13,18]. Human chorionic gonadotrophin is sometimes used by athletes
concurrently with anabolic steroids to prevent testicular atrophy or afterwards to
promote quicker resumption of testosterone production by the testes. Data
show that concomitant abuse of AAS and human chorionic gonadotrophin
cause impairment on semen quality, although it seems that sperm count could
be maintained with this regimen [19].
92
Gynaecomastia is another adverse effect observed as a result of AAS use [20].
Gynaecomastia is a benign enlargement of the male breast resulting from an
altered estrogen-androgen balance. It is associated with the peripheral
conversion of AAS to estrogens, due to the huge amounts of administered
aromatizable androgens [6]. Rarely, a small amount of clear fluid is secreted
[21]. A common practice among AAS users is to take aromatase inhibitors or
selective estrogen receptor modulators such as tamoxifen to minimize side
effects of estrogen and for the prevention of gynaecomastia. Once
gynaecomastia is diagnosed cosmetic surgery is often needed to correct the
problem.
Intensity (RU)
250
*
200
150
***
100
##
**#
50
0
C
TP
group
Bcl-2
TND
Bax
Figure 2. Intensity of antiapoptotic Bcl-2 and proapoptotic Bax factors expression in
Leydig cells of endurance trained rats treated with placebo (TP), trained rats treated with
nandrolone decanoate (TND) and controls (C). *P<0.05, **P<0.01, ***P<0.001 (in
#
##
comparison with C); P<0.01, P<0.001 (in comparison with TP). AAS treatment
decreases Bcl-2/Bax ratio in TND group in comparison with C and TP (P<0.01), which is
a marker of increased apoptotic tendency.
Changes in libido appear to be a common adverse event reported by AAS
abusers [20]. Although some data suggest that supraphysiological doses of
exogenous testosterone do not increase sexual interest in healthy men [22],
other studies have reported enhanced sexual desire, higher frequency of sexual
behaviors as well as higher incidence of erectile difficulties in male athletes
during AAS cycle in comparison with nonusers [21,23]. Reports indicate that
towards the end of an androgen cycle some men may experience loss of libido
probably related to the anabolic steroid-induced hypogonadism and low serum
levels of androgens after cessation of AAS abuse [20]. Changes in libido do
93
appear to normalize once baseline endogenous testosterone concentrations
return [21].
In adult men, DHT mediates several effects of androgens including prostate
hypertrophy and balding. Androgens play a permissive role in the development
of prostate cancer and benign prostate hyperplasia and some data suggest that
AAS use may increase prostatic disease risk [1]. AAS abuse can induce
increased prostatic volume with decreased urinary flow rate [24] as well as
adenocarcinoma of the prostate gland [25]. Androgenetic alopecia (male pattern
hair loss) is accelerated in male AAS users who have inherited a tendency for
baldness [21].
Anabolic androgenic steroids and female reproductive system
AAS have been associated with a number of adverse effects on female
reproductive system, some of which are not reversible upon discontinuation of
steroid use. Many of the differences in sexual characteristics between men and
women are determined by testosterone. Therefore, it is not surprising that
women who take AAS, too, gradually develop masculine secondary sex
characteristics.
The secretory and gametogenic functions of the ovaries are both dependent
upon the hypothalamic pulsatile secretion of GnRH, which stimulates the
anterior pituitary to secrete gonadotrophins. FSH stimulates the early growth of
ovarian follicles, and FSH and LH together are responsible for their final
maturation and estrogen secretion from them. LH is responsible for ovulation,
the formation of the corpus luteum, and secretion of estrogen and progesterone
from the corpus luteum.
In the normal female body small amounts of testosterone are produced, and as
in males, artificially increasing levels by administration of AAS will affect the
hypothalamic-pituitary-gonadal axis. The increase in circulating androgens will
suppress the hypothalamic-pituitary axis, resulting in a suppression of ovarian
function, disturbances in menstrual cycle and infertility [1]. AAS administration
decreases serum levels of LH, FSH, progesterone, and SHBG in women [2628]. Female athletes using exogenous testosterone also have dramatically
elevated serum testosterone levels [28,29].
Anabolic steroid use can result in inhibition of follicle growth and ovulation, and
irregularities of menstrual cycle [21,27,30]. The observed menstrual
abnormalities include dysmenorrhea, oligomenorrhea or amenorrhea [28,31].
Although these changes are generally more pronounced in younger women,
94
large inter-individual responsiveness to anabolic steroids exists. The effects are
similar to the effects in patients treated with anabolic steroids. It is accepted that
steroid-induced endocrine imbalance that results in disturbances of menstrual
function and infertility is reversible [1].
The effects of AAS dosages, as generally used in sport on the hypothalamicpituitary-gonadal axis in females are little studied [28]. Androgen-induced
amenorrhea and more severe changes such as ovarian cyst formation
(polycystic ovarian syndrome) with recurrent inflammation is reported as
frequent damaging effects of AAS administration in female athletes from former
East Germany [31]. Menopause also may be reached sooner in women who
have a long history of anabolic steroid use [21]. In addition, animal studies show
that high doses of AAS cause alterations in the uterus that are associated with a
suppression of the reproductive capacity [32].
Other side effects of anabolic steroid use on female reproductive system are
enlargement of the clitoris, decreased breast size and atrophy of the uterus
[21,29,31]. Increased sexual desire is also reported in female AAS users.
Changes in libido do appear to normalize after discontinuation of steroid use
[21].
Additional masculinizing effects of AAS in women are lowering of the voice, hair
loss and excessive hair growth on the face and body [21,31,33]. Virilization of
the female’s voice is characterized by a lower fundamental frequency during
speech, a loss of high frequencies and an increase in voice instability. These
alterations can be explained by changes in the vocal cords as a result of AAS
use [34]. The breast atrophy, hypertrophy of the clitoris, deepening of the voice,
hirsutism and alopecia are generally irreversible.
Anabolic steroid use by pregnant women may lead to vaginal bleeding as well
as to pseudohermaphroditism or to growth retardation of the female fetus [1].
Female pseudohermaphroditism is characterized by several grades of
reproductive organs virilization of genetically female fetus as a result of
excessive amount of circulating anabolic steroids during intrauterine life. The
degree of prenatal masculinization is related to androgen concentration and to
the embryonic development stage at the time of exposure. Other side effects in
children born to mothers that have used AAS during pregnancy are skin
challenge type of allergy, asthma-type problems with breath and damage of
heart structures [31]. Animal studies show that prenatal testosterone propionate
exposure reduces body weight of male and female offspring as well as induces
dose-dependent malformations in reproductive organs and occurrence of
prostatic tissue and seminal vesicles in females [35].
95
Anabolic androgenic steroids and reproductive system of children and
adolescents
Anabolic steroids administered to growing children and adolescent athletes
cause more side effects than they do in adults both qualitatively and
quantitatively [31]. In pre- and peripubertal children side effects include
development of pubic hair, clitoral/phallic enlargement and other signs of
virilization or precocious puberty [3,36]. Gynaecomastia is more pronounced in
children who are given androgens, possibly due to a greater capacity for
extraglandular aromatization [1]. The side effects of AAS use are generally
more pronounced in adolescent girls than in women and the atrophy of the
uterus is a typical side effect in girls. Reduction of female breast and
amenorrhea are common. The decision to undergo a sex transformation taken
by a former East German female athlete suggests that long lasting AAS intake
during puberty could lead to sexual identity disturbances in women [31].
Other endocrine effects of anabolic androgenic steroids
AAS abuse could lead to impairment of thyroid function in male and female
athletes. In male athletes, administration of AAS has been found to decrease
serum concentrations of the iodine-containing hormones secreted by the thyroid
gland – triiodothyronine (T3) and thyroxine (T4). Thyroid binding globulin (TBG)
is also reduced [11,37,38]. The reports of serum thyroid stimulating hormone
(TSH) changes found after AAS administration are controversial. Increased
serum TSH after short-term AAS treatment [38] and reduction or no differences
in TSH levels after a prolonged AAS use have been observed [11,37]. The TSH
response of pituitary after thyrotrophin-releasing hormone stimulation is
increased in male bodybuilders using high doses of AAS [37]. In female weight
lifters administration of AAS decreases serum concentrations of T4 and thyroid
binding proteins, and increases the TSH levels [28]. The mechanisms of these
effects of anabolic steroids on the thyroid function are still not entirely clear. The
changes reverse within weeks after discontinuation of AAS use [11].
Anabolic steroid use may induce insulin resistance and diminished glucose
tolerance. These changes mimic type 2 diabetes and are observed in patients
treated with 17-alkylated oral androgens [1] and in male athletes using AAS
over a long period of time (3-7 years) [39]. Although there has been no
documented diabetes mellitus in athletes using anabolic steroids, these
changes are associated with increased cardiovascular risk.
96
AAS abuse can decrease serum corticotrophin (adrenocorticotrophic hormone,
ACTH) concentrations. An initial and transient decrease in cortisol is also
observed. The suppression of ACTH is reversible after steroid withdrawal [10].
Recent data suggest that long lasting AAS abuse may enhance tissue activity of
the renin-angiotensin-aldosterone system in bodybuilders, which can also
increase the risk of cardiovascular disease in athletes [40].
Side effects of testosterone precursors
DHEA, androstenedione and androstenediol are produced by adrenal, gonadal
and peripheral steroidogenic pathways as part of the normal sexual and
reproductive hormonal milieu in both genders. Athletes use DHEA and various
forms of androstenedione and androstenediol as testosterone prohormones in
an attempt to elevate testosterone levels. Research indicates that the use of
prohormones supplements does not produce either anabolic or ergogenic
effects in healthy men but can lead to endocrine imbalance and other side
effects similar to those induced by synthetic AAS [2,3].
DHEA administration increases serum DHEA and androstenedione
concentrations in men. Serum estradiol is also elevated in older men [2].
Prolonged androstenedione and androstenediol intake in men does not
uniformly increase serum testosterone, but increases serum androstenedione,
DHT and estrogen (estrone and estradiol) concentrations [3]. The
characteristics of the enzymes involved in the interconversion of
androstenedione suggest that, although larger doses of androstenedione may
increase serum testosterone concentrations, still larger increases would occur
in serum estrogens and DHT. The data about the effect of androstenedione on
serum testosterone levels in men are controversial – the effect seems to
depend on the dose, the age and the basal serum testosterone concentrations.
In healthy men a moderate and transient increase of serum testosterone
concentrations can be seen only after high doses (200-300 mg) of
androstenedione, but no differences with controls can be found after long-term
use [2,41]. Some data suggest that prolonged (12 weeks, 200 mg•d-1)
androstenedione use may downregulate endogenous testosterone production
by lower serum LH levels [41]. Undoubtedly, many users consume daily doses
substantially higher than those used in these studies and for a longer time
period [3]. Case reports indicate that in young male bodybuilders long lasting (1
year) androstenedione use can cause priapism [42] as well as suppression of
the hypothalamic-pituitary-gonadal axis resulting in very low serum total and
free testosterone levels, severe oligospermia, testicular atrophy and loss of
97
libido [43]. The long-term health effects of prohormones supplementation are
unknown. The altered hormonal milieu caused by prohormones intake (elevated
serum androstenedione, DHT and estradiol concentrations) is similar to the
hormonal profile observed in men with gynaecomastia, prostate cancer,
testicular cancer and pancreatic cancer [2]. In addition, animal studies have
found resultant hyperplastic prostatic changes with androstenedione use [44].
There are no data available on the effects of DHEA administration in young
women. In older women chronic intake of DHEA increases serum DHEA,
androstenedione, testosterone, DHT and estrogen levels, decreases serum LH
and FSH concentrations and causes adverse virilizing effects, impaired insulin
sensitivity and glucose tolerance [2,3,45]. Androstenedione intake in women
causes a large increase in serum androstenedione and testosterone
concentrations. In women, 50-100 mg of androstenedione intake does not
change serum estradiol, but a significant, acute increase is seen in estradiol
levels after intake of 300 mg [2,3]. Although there are no available data on the
effects of prolonged androstenedione or androstenediol administration in
women, the change in the hormonal milieu resulting from prohormones use may
cause masculinizing effects along with other negative effects similar to those
observed after DHEA and AAS use.
C
Growth Hormone and Insulin-like growth factor-1
Growth hormone (GH) is a peptide hormone secreted by the anterior pituitary.
GH’s major action is to stimulate protein synthesis. GH also mobilizes fat by
direct lipolytic action and has a hyperglycemic effect. GH stimulates the
synthesis of insulin-like growth factor I (IGF-I) in all tissue. In most tissues IGF-1
has local actions, but liver secretes it into the circulation. IGF-1 also stimulates
protein synthesis, but it has a weaker lipolytic action and hypoglycemic effect
[46,47]. The long-term risks of high doses GH use in athletes are not well
known. Patients who have acromegaly with chronic endogenous GH excess
(consequence of somatotroph pituitary adenoma) may be the most accurate
model for an athlete who supplements an already normal hormone level.
Growth hormone and reproductive system
The impairment of gonadal function is a common clinical finding of acromegaly
in both sexes, but its pathogenesis remains unclear. Recent data suggest that
not only FSH/LH deficiency (caused by the tumor mass effect) and/or
98
hyperprolactinemia, but also GH excess per se could be responsible for these
effects in at least some of these patients [48].
Menstrual irregularity (amenorrhea, oligomenorrhea, polymenorrhea) is
common in women with acromegaly in reproductive age. Compared to patients
with normal cycles, patients with menstrual abnormalities are more hirsute,
have lower serum estradiol and SHBG concentrations, but similar testosterone
levels.
Gonadotrophin
deficiency
with
or
without
concomitant
hyperprolactinemia appears to be the major cause of the menstrual irregularity
in women with amenorrhea and larger tumors. However, some women with
oligomenorrhea and also those with regular cycles show many of the clinical
and biochemical characteristics of polycystic ovarian syndrome. Recent data
suggest that elevated GH levels per se are responsible for the high prevalence
of signs of hyperandrogenism in women with chronic GH excess, either directly
or via the effects of the induced hyperinsulinemia leading to reduced SHBG
levels. This, in turn, may lead to menstrual abnormalities [48].
Most men with acromegaly have hypogonadism associated with a reduced
sperm number and considerably reduced sperm motility. Serum FSH,
testosterone and DHT concentrations are lower, whereas estradiol levels are
higher in acromegalic patients than in controls [49]. The mechanisms of these
effects are not well understood but the data of an animal study has shown that
administration of very high doses of GH induces reduction of testes and
prostate weights, germ cells degenerations, and notable reduction of LH and
testosterone levels [50]. At partial variance with these experimental findings in
dogs, men with chronic GH excess have prostate enlargement with a high
prevalence of prostate abnormalities [51].
Other endocrine effects of growth hormone
It is well established that GH counteracts the effects of insulin on glucose and
lipid metabolism, although it shares anabolic properties on protein metabolism
with insulin. GH is a diabetogenic hormone and the anti-insulin or
counterregulatory effect of GH is characterized by decreased glucose uptake
into skeletal muscles, increased hepatic glucose production, rising blood
glucose levels and increased insulin secretion. There is increasing evidence
that this effect may occur secondary to the lipolytic effect of GH. Exposure to
supraphysiological doses of growth hormone in the pathophysiological model of
acromegaly leads to insulin resistance, impaired glucose tolerance, and
clinically overt diabetes mellitus [51]. Similar effects have been observed in
healthy men after GH administration. High doses of GH increase fasting insulin
99
and insulin resistance in endurance trained athletes [52] and glucose
intolerance or diabetes develop significantly more often in healthy aged men
after GH treatment than in controls [53].
GH use could lead to impairment of thyroid function. GH administration
stimulates extrathyroidal conversion of T4 to T3 in a dose-dependent manner
and suppresses circadian TSH levels in GH-deficient adults [54]. Administration
of high doses GH to endurance trained athletes increase free T3 into
supraphysiological range and reduce free T4 [52]. The long term effect of high
doses GH use on thyroid function in athletes is unclear, but GH and IGF-1
excess cause thyroid overgrowth, which is a common phenomenon in
acromegaly. Chronic GH excess is frequently associated with the presence of
nodular or diffuse goiter [51].
Other consequences of chronic GH excess are hyperparathyroidism and
increased risk of neoplastic complications [51]. Several lines of evidence show
a relationship between the GH/IGF-1 system and cancer development. IGF-1
could increase epithelial cell proliferations and prevent apoptosis. GH
administration increase serum IGF-1 concentrations [53] and epidemiological
studies show that high-normal IGF-1 levels in healthy adult subjects may be
associated with an increased risk of breast, prostatic and colorectal cancer. In
addition, the mortality from cancer-related complications is increased in
acromegalic patients [51].
D
Gonadotrophins
LH is secreted by the pituitary gland. It stimulates ovulation and luteinization of
ovarian follicles in women and the testosterone production by the Leydig cells in
men. Human chorionic gonadotrophin (hCG) is secreted during pregnancy and
stimulates testosterone secretion by the fetal testis. hCG has almost the same
effects on the reproductive system as LH. hCG is used by athletes to increase
the endogenous testosterone production. Administration of hCG may result in
ovarian hyperstimulation syndrome in women [55] and may induce
gynaecomastia in men [13]. The concomitant abuse of hCG and AAS causes
impairment to semen quality in male athletes. A significant positive correlation
has been found between the hCG dose during the AAS cycle and the relative
amount of morphologically abnormal spermatozoa [19].
100
E
Insulin
Insulin is secreted by the beta cells of the islets of Langerhans in the pancreas.
Insulin stimulates lipogenesis and has an inhibitory effect on lipolysis,
proteolysis, glycolysis, gluconeogenesis and ketogenesis. Insulin stimulates the
translocation of glucose transporters from the cytoplasm of muscle and adipose
tissue to the cell membrane and increases the rate of glucose uptake. Insulin
thus lowers blood glucose concentrations through inhibiting hepatic glucose
production and through accelerating glucose uptake [46].
Abuse of insulin by athletes as performance-enhancing agent may result in
hypoglycemia and hypoglycemic coma [56]. The risk of hypoglycemic coma is
increased in overdosing and using insulin during increased physical activity
and/or inadequate diet. Physical exercise increases the insulin sensitivity of the
skeletal muscles by causing an insulin-independent increase in the number of
the glucose transporters in cell membranes. Exercise can precipitate
hypoglycemia not only because of the increase in glucose uptake but also
because absorption of injected insulin is more rapid during exercise. The
symptoms of hypoglycemia include sweating, anxiety, hunger, tremor, cognitive
abnormalities, convulsions, lethargy, etc. Unless treated promptly
hyperglycemia may result in coma and death.
F
ACTH and Glucocorticosteroids
Glucocorticosteroids are steroid hormones secreted by the adrenal cortex.
Glucocorticosteroids have catabolic, lipolytic and hyperglycemic effects. They
are essential for the response to stress. Under the effects of various stressors
hypothalamus secretes corticotrophin-releasing hormone (CRH), which
stimulates the anterior pituitary to secrete ACTH. ACTH increases the synthesis
and the release of glucocorticosteroids (and adrenal androgens) from the
adrenal gland. In clinical practice glucocorticosteroids are used mainly for their
anti-inflammatory and immunosuppressive effects. The long-term use of
glucocorticosteroids is associated with serious and sometimes irreversible side
effects [57].
Glucocorticosteroids and reproductive system
Administration of glucocorticosteroids reduces testosterone levels in men [58].
Data from animal studies suggest that one of the possible mechanisms of this
effect is impairment of LH signal transduction and steroidogenesis in the Leydig
101
cells [59]. Estrogen is reduced in women after glucocorticosteroid treatment and
menstrual irregularities and amenorrhea can occur. Delayed puberty can also
be observed. Corticosteroid use during pregnancy may cause intrauterine
growth retardation and adrenal suppression in the baby [58].
Other endocrine effects of glucocorticosteroids
Typically, the side effects of long-term glucocorticosteroid administration on the
endocrine system include iatrogenic Cushing’s syndrome, diabetes mellitus,
adrenal atrophy and growth retardation [57]. The Cushing’s syndrome is
characterized by a moon face, buffalo hump, central obesity, glucose
intolerance, osteoporosis, etc. The reason for the cushingoid habitus is not
clearly understood but one hypothesis is that truncal and peripheral adipocytes
vary in sensitivity to the glucocorticosteroid facilitated lipolytic effect [57,58].
Glucocorticosteroids elevate blood glucose and produce a diabetic type of
glucose tolerance curve. The major diabetogenic effect of glucocorticosteroids
is an increase in protein catabolism with increased gluconeogenesis.
Glucocorticosteroid excess causes decreased glucose tolerance and insulin
resistance and one fifth of patients may develop overt diabetes. Upon
discontinuation of the steroids, the diabetes normally disappears [57,58].
Glucocorticosteroid administration suppresses hypothalamic-pituitary-adrenal
axis. Glucocorticosteroids inhibit ACTH secretion by acting directly on the
anterior pituitary and by inhibiting the secretion of CRH from the hypothalamus.
The suppression of ACTH levels leads to atrophy of the adrenal cortex and
secondary adrenal insufficiency with low serum cortisol concentrations. This
adrenal insufficiency becomes clinically relevant if exogenous therapy is
withdrawn too rapidly (hypotonia) or in the case of stressful situations when
higher glucocorticosteroid levels may be required. The frequent use of
glucocorticosteroids by athletes necessitates testing for adrenal insufficiency
because of the risk of death in cases of associated severe stress (trauma,
infection, surgery) [60]. In addition, it is not only the synthesis of endogenous
glucocorticosteroids that is depressed but also the synthesis of the adrenal
androgens. In females, this way may lead to nullification of androgen-dependent
anabolism, e.g. of the bones [57]. Glucocorticosteroids can inhibit linear growth.
The mechanism is unknown but may involve a combination of reduced GH
production and a direct inhibitory effect on bone and connective tissue. Growth
failure is commonly experienced by children receiving prolong
glucocorticosteroid therapy [58].
102
Endocrine effects of ACTH
ACTH increases the secretion of glucocorticosteroids and adrenal androgens
from the adrenal cortex. The artificially increasing levels of ACTH caused by
ACTH misuse in healthy subjects may mimic excess hormone secretion
observed in patients with some pituitary tumors resulting in ACTH-dependent
Cushing’s syndrome (Cushing’s disease). Besides the other signs of the
Cushing’s syndrome, the level of the weak mineralcorticoid deoxycorticosterone
may be elevated by ACTH leading to salt and water retention. The secretion of
adrenal androgens will be also elevated and may result in masculinizing effects
(hirsutism, acne) in women.
G
Stimulants
Central nervous system stimulants, such as amphetamines and cocaine, may
be used by athletes to reduce tiredness and increase alertness,
competitiveness, and aggression. They are more likely to be used in
competition but may be also used during training to increase the intensity of the
training session [61]. Amphetamines and cocaine are powerful addictive
stimulants; they have high potential for abuse and produce intense physiological
and psychological side effects including also effects on the reproductive system.
Amphetamine use during pregnancy is associated with increased risk of
maternal, fetal and infant death, fetal growth restriction and birth defects [62,
63]. Causes of maternal deaths include intracerebral hemorrhage,
cardiovascular collapse and amniotic fluid embolism [63]. Cocaine
administration decreases serum estradiol concentration and disrupts menstrual
cyclicity and folliculogenesis in female animals [64]. Cocaine use during
pregnancy can cause spontaneous abortion, placental abruption, fetal growth
restriction, preterm labour, low birth weight and variety of congenital
malformations (cardiac abnormalities, genito-urinary and gastro-intestinal tract
defects) [62,65]. Some data suggest that fetal malformations related to maternal
cocaine administration are the result of vasoactive effects of cocaine leading to
hemorrhage, oedema and hypoxia [70]. In men, chronic cocaine use is
associated with loss of libido [61] and increased risk of priapism [66].
H
Narcotics
Narcotics are naturally occurring or synthetic drugs which bind to opioid
receptors to produce physiological effects. In medical practice narcotics are
used in the management of severe acute pain and moderate or severe chronic
103
pain. Long term administration of narcotics may result in endocrine side effects
as opioid receptors (and endogenous opiates) are involved in the regulation of
some hormones. In humans, the acute administration of opioids in healthy men
increase prolactin, GH, TSH and ACTH secretion but inhibits LH release [67].
Chronic intrathecal administration of opioids has been found to induce central
hypocorticism in 15%, GH deficiency in 15% and hypogonadotrophic
hypogonadism in almost all patients. Decreased LH, estradiol and progesterone
levels, menstrual irregularities including amenorrhea and decreased libido are
observed in women receiving intrathecal opioids [68]. It appears that the impact
of opioids on testosterone production depends on the route of administration.
Significantly lower testosterone and LH levels are observed after intrathecal
administration [68] but modest or no changes in testosterone have been
reported in heroin addicts [69]. However, decreased libido and impairment of
spermatogenesis have been observed in men receiving intrathecal opioids as
well as in heroin addicts [68,69].
I
Cannabinoids
Cannabinoids are isolated from Cannabis sativa and Cannabis indica plants. Of
the natural phytocannabinoids, tetrahydrocannabinol (THC) is the main source
of the effects caused by the consumption of cannabis [70]. Cannabinoids exert
their effects through the activation of two specific receptors located on the
surface of the target cells. Recent evidence suggests that multiple
endocannabinoid ligands may also play an important role in the maintenance
and regulation of early pregnancy and fertility. Furthermore, endocannabinoids
are involved in the anterior pituitary and hypothalamic control of sex hormones
[71]. Marijuana, THC, and other exogenous cannabinoids exert potent effects
on this homeostasis. Thus, they have the potential to produce pronounced
adverse effects on male and female reproductive systems [72].
Cannabinoids and male reproductive system
In males, cannabis smoking decreases serum LH concentrations. In some
studies chronic marijuana use has been shown to be associated with decreased
plasma testosterone levels, but other studies have failed to reproduce these
findings. Reduced sperm counts in males have been more consistently seen.
Animal studies indicate that acute and chronic THC exposure decreases
testicular weight and depresses testosterone synthesis probably by reducing
104
gonadotrophin levels. High doses of THC causes an increase in abnormally
formed sperm in rodents [72].
Cannabinoids and female reproductive system
In women, acute administration of THC suppresses the secretion of LH in the
luteal phase. In chronic users, it shortens the menstrual cycle, the effect being
predominately a short luteal phase leading to menstrual irregularities and
anovulation [71]. Animal studies show that THC produces dose-related
inhibition of pulsatile LH release and preovulatory LH surge. Some data suggest
that the decreased release of hypothalamic GnRH into the pituitary is
responsible for the suppressed level of LH. The possible mechanism of this
effect of THC is modulation of neuronal systems known to inhibit GnRH
secretion. Cannabinoids have also an inhibitory effect on prolactin release in
female animals [71,72].
Several experimental and clinical studies have shown adverse effects of
marijuana exposure on embryo development and in early pregnancy. In women
cannabis use during pregnancy is correlated with low birth weight, prematurity,
intrauterine growth retardation, presence of congenital abnormalities, perinatal
death and delayed time to commencement of respiration [72,73,62]. THC exert
a potent direct relaxant effect on human pregnant myometrium and these
findings rise the possibility that regular use after term might delay the onset of
labor and therefore increase stillbirth rates, as shown in animal studies [74].
THC exposure results in increased miscarriage, fetal deaths, stillbirths and
neonatal deaths in animals [73]. It is reported that THC-exposed male mouse
fetuses have significantly reduced testosterone concentrations and testis weight
[72].
J
Beta–Blockers
Beta-blockers block the action of catecholamines on β-adrenergic receptors.
Their chronic use in clinical practice is associated with detrimental effects on
insulin sensitivity, glycaemic control and the incidence of type 2 diabetes
mellitus. Research has shown that most beta-blockers significantly decrease
insulin sensitivity and increase the risk for development of new-onset diabetes.
The mechanisms of this effect are not fully understood, but several possibilities
have been put forward: body weight gain, decrease in insulin secretion, and
probably most important, reduced blood flow to muscles and subsequent
reduced insulin-stimulated glucose uptake [75]. Recent data suggests that beta-
105
blockers induce a worsening of sexual activity and a reduction of plasma
testosterone concentrations in male hypertensive patients [76].
K
Conclusion
These data clearly suggest that most doping substances disrupt the hormonal
balance of human body exerting serious side effects on the endocrine and/or
male and female reproductive systems. Some of these effects persist long after
the substances have been discontinued and may become irreversible. Their
severity depends on the gender and age of user, the specific substance and
dosage used, and the duration of intake. The bodies of adolescent girls and
boys are especially susceptible to the side effects described above. Many
athletes use several doping substances either simultaneously or in various
regimens, in which case the harm done to the body can be severer and the
consequences quite unpredictable. In some cases the artificially induced
hormone imbalance may increase the risk of development of neoplastic
conditions and/or is potentially lethal.
L
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Correspondence
Katerina N. Georgieva, Department of Physiology, Medical University - Plovdiv,
15A Vasil Aprilov Blvd., 4000 Plovdiv, Bulgaria, [email protected],
[email protected]
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Nikolaos Koutlianos
3.6
RENAL DISORDERS AND ELECTROLYTE METABOLISM
Nikolaos Koutlianos, Evangelia Kouidi
A
Introduction
The abuse of banned substances and/or methods in sports for the
enhancement of physical performance may cause numerous health disorders.
One should keep in mind that firstly all drugs have side effects, secondly too
large a dose increases the risk of undesirable effects and thirdly the effect of
some drugs can be altered markedly by the administration of other substances agents. Athletes using excessive amounts of drugs have an increase likelihood
of impaired renal excretion of drugs and nephrotoxicity, since the drugs are
excreted from the kidneys. Although rare, adverse renal effects have been
reported, leading mostly to renal failure or even Wilms’ tumors in isolated cases
(especially in body-builders using anabolic steroids) [1]. The major renal, urinary
and electrolyte side effects of prohibited substances abuse in sports are
presented in table 1.
Table 1. Possible adverse renal effects and electrolytic disorders of banned drugs
abuse.
AAS
Acute renal failure
+
Chronic renal failure
+
Interstitial nephritis
+
Rhabdomyloytic complications
+
Renal cell carcinoma
+
Wilm’s tumor
+
Hypokalaemia
+
Hyperkalaemia
+
Elevated blood urine nitrogen
+
Elevated creatinine
+
Renal overfunction
Diuretics
+
+
Renal Disorders and Electrolyte Metabolism
113
The functions of the kidney can be divided into two major groups: secretion of
hormones and extracellular homeostasis. The kidney preserves the extracellular
homeostasis by maintaining a balance in several substances such as: water,
glucose, amino acids, urea, bicarbonate, protons, sodium, chloride, potassium,
calcium, magnesium and phosphate. Furthermore, the renal function is
responsible for retaining a stable balance of sodium and water in the body. The
major homeostatic control point for maintaining this equilibrium is renal
excretion. Abnormal ranges of the fractional excretion of sodium can imply
acute tubular necrosis or glomerular dysfunction [2].
B
Renal Side Effects
Androgenic-anabolic steroids (AAS) are the most popular drugs among
athletes, but their chronic abuse is associated with a lot of side effects in almost
all systems, as reproductive, cardiovascular, endocrine etc. [3]. Zeier et al.
reported that the magnitude of renal risks in adults depend on gender and may
be presumably mediated via sex hormones [4]. Testosterone renal receptors
probably play a crucial role and they may set the stage for accelerated
progression of renal disease in the athlete exposed to male sex hormones.
The accelerating effect of high protein consumption in the process of chronic
renal failure has been well known for many years. Bodybuilders usually prefer a
high-protein and creatine-supplemented diet in order to achieve maximal
morphological adaptations in skeletal muscles. Weightlifters often experience a
rise in serum creatinine as a result of increased skeletal muscle mass. On the
other hand, AAS use may elevate serum creatinine levels, blood urine nitrogen
and uric acid. These values often return to normal once the drugs are
discontinued [5, 6]. The combination of AAS and creatine supplement that has
been currently abused by body builders may also cause severe renal damage.
Revai et al. reported a case of severe nephrotic syndrome with diffuse
membranoproliferative glomerulonephritis in an athlete using AAs and creatine
for a long time [7].
Wilm’s tumor, uncommon in adults has been reported in several athletes using
AAS [8]. There is evidence suggesting that steroids are weak carcinogens that
can initiate tumor growth or promote such growth in the presence of other
carcinogens [9, 10]. It is suggested that the long-term use of AAS should be at
least considered as etiologic factor for renal cell carcinoma occurrence [11, 12].
There are only a few studies indicating a potential linkage between the use of
AAS and acute renal failure (ARF). Abuse of stanozolol was found to cause
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Nikolaos Koutlianos
severe cholestasis and ARF [13]. The renal biopsy findings were consistent with
resolving acute tubular necrosis white light or electron microscopy revealed no
glomerular changes. ARF as a complication of rhabdomyolysis in a body builder
using AAS has also been reported [14]. Furthermore, attention should also be
paid to the possibility of interstitial nephritis as an adverse effect of AAS abuse.
Chronic hypovolaemia, which is frequently found among athletes using AAS,
may magnify renal damage processes or electrolytic disorders. These side
effects are often exacerbated by diuretics as well.
Renal failure due to even intermittent consumption of increased doses of betaadrenergic substances and/or AAS should be recognized in general. Hartung et
al. studied a 27-year-old male body-builder referred for azotaemia who had
regularly taken testosterone as well as clenbuterol tablets for 18 months [15].
The combined use of clenbuterol and AAS seems to increase the risk of renal
failure especially in pre-existing kidney diseases. The renal biopsy revealed
nephrosclerosis with pronounced obstructive lesions of preglomerular vessels,
hypertension-like vascular damage, global glomerulosclerosis and diffuse
chronic tubulo-interstitial damage. Beta-adrenergic substances may lead to
acceleration of a hypertensive renal damage process. High to toxic doses of
clenbuterol are found to cause a remarkable beta-adrenergic receptor downregulation in rats [16]. An additional adverse effect of clenbuterol may be
intestitial nephritis and hypertensive nephrosclerosis [15].
Diuretics have the ability to increase urine production and secretion and are
frequently used by athletes either to excrete the banned drug or to lose weight
rapidly [17]. However, urinary tract fluid losses caused by drug-induced diuresis
may lead to intravascular volume depletion sufficient to cause ARF. Excessive
diuretic therapy in combination with increased ephidrosis, usually lead to
dehydration and hypovolemia, which is one of the major causes of
hypokalaemia [18].
Athletes using ephedrine are at increased risk of rhabdomyolysis [19].
Rhabdomyolysis and myoglobinuric ARF may occur with cocaine overdose,
alcoholism and excessive exercise, while ARF due to hemolysis is also seen
following blood transfusion reactions. Moreover, alcohol is a diuretic and
contributes to a state of dehydration. Therefore, attention should be paid
particularly by athletes performing in the heat.
Nutritional supplements such as cobalt may be frequently abused in sports.
Cobalt is an element which presents properties similar to those of iron and
nickel, leading to a significant and stable polycythemic response through a more
efficient transcription of the erythropoietin gene [20]. However, renal adverse
115
side effects may be produced by cobalt salts administration since cobalt
accumulates especially in kidney, promoting organ damage and renal
dysfunction due to enhanced oxidative stress, even at low dosage below of 34
mg/kg [21].
C
Electrolyte Metabolism Disorders
Doping-triggered disorders in electrolyte homeostasis are concomitantly linked
to renal function. It is well known that kidneys regulate the amount of water,
sodium, potassium and other electrolytes in the body. Diuretics are justifiably
considered as the major category of banned drugs in sports, which is mostly
linked to disturbed electrolyte metabolism.
Unlike medical patients, athletes do not retain excess water, thus the use of
diuretics results in an abnormal and dangerous loss of water and electrolytes.
Athletes with diuretic-induced dehydration, performing in heat, are more
susceptible to heat exhaustion. Hypotension can be particularly troublesome
sometimes. Use of diuretics commonly leads to low levels of body potassium.
However, severe symptomatic hypokalaemia is rare, while moderate levels of
hypokalaemia are common [18]. Hypokalaemia mainly causes disturbed
neurological functioning and cardiac arrhythmias, even heart failure.
Additionally, symptoms as muscle weakness and muscle cramps are common.
On the other hand, overuse of diuretics such as spironolactone, triamterene and
amiloride may lead to extremely high potassium concentration in the blood.
Hyperkalaemia may lead to malignant arrhythmias. Appleby et al. reported a
case of a 31-year-old body-builder with serum potassium 6.7 mmol/l, which
caused a run of sustained ventricular tachycardia [22]. Furthermore, most
diuretics disturb the metabolism of uric acid and this can precipitate a painful
attack of gout. Nevertheless, anabolic agents also influence electrolyte
concentrations. AAS use may lead to increased levels of potassium, sodium,
calcium and phosphate, which can ultimately result in atrial and ventricular
fibrillation [23].
Oral or parenteral abuse of glucocorticoids may also lead to electrolyte
disorders. Widmer et al., reported that the administration of prednisone (5 to
2000 mg/d) was a significant risk factor for hypokalaemic events in various
patients [24]. However, these findings are not yet confirmed in athletes abusing
glucocorticoids for doping.
Additionally, sodium’s levels are frequently found increased in athletes mainly
due to supplements’ abuse. Indeed, numerous athletes intake sodium
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Nikolaos Koutlianos
bicarbonate or sodium citrate in an attempt to enhance their athletic
performance, especially, in activities of high intensity and involving large
muscular groups (e.g. 400 m running). However, elevated sodium levels may
lead to gastrointestinal disturbances and they are often accompanied by
diarrhea especially for sodium bicarbonate supplement [25].
D
Conclusion
Banned substances users should be aware that many of the adverse effects
might be present without obvious warning signs. This statement seems to be
valid also for renal side effects. AAS and diuretics abuse, often combined with
high-protein diet can result in severe renal failure and electrolyte imbalancetriggered side effects such as malignant arrhythmias. Much of our knowledge
about these potentially severe but usually limited side effects is confounded by
the concomitant use of various substances. With the knowledge about the
effects and side effects physicians should adequately counsel and educate
athletes, parents and coaches to avoid doping.
E
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Correspondence
Asterios Deligiannis, Aristotle University of Thessaloniki, Sports Medicine
Laboratory, 20 Stratigou Makriyianni Str., 54635 Thessaloniki, Greece,
[email protected]
Immune System and Skin
3.7
119
IMMUNE SYSTEM AND SKIN:
THE IMPORTANCE OF STUDYING THIS PROBLEM
Eduardo Ortega, Mª Dolores Hinchado, Esther Giraldo
Today there is still a big lack of information about the scientific knowledge of the
side effects of doping in both competitive sports and recreational ones. In
addition this knowledge is not always unified, and it is very important to
harmonise in Europe the scientific information about the biomedical side effects
of doping, in order to get chance for preventing this practise.
Most of the information about the side effects of the different doping substances
is available on the respiratory and cardiovascular systems as well as the brain.
However, little information is currently examined about the side effects of doping
substances on the immune system. Today, it is clearly known that exercise
modulates the immune system, and while moderate exercise stimulates most of
the immune responses, intense exercise can be dangerous for the adaptative
response mechanisms. In addition, the exercise-induced changes are mediated
by different hormones released during the exercise, mainly the so called “stress
hormones”. Then, a modification of the neuroendocrine balance by hormones
intake during exercise practise modify the feed-back of neuroimmune
mechanisms, and may seriously affect the normal function of the immune
system, damaging sportspeople’s health.
However, although there are a lot of investigations about different substances
(i.e. anabolic steroids, stimulants, narcotics, diuretics, nutritional
supplements…) related to doping, and about these substances on immune
system at pharmacological concentration; nothing is known about the
biomedical side effects of these doping substances (at raised blood
concentrations) on the immune system during exercise, an special physiological
situation.
The purpose of this communication is to emphasize the importance of studying
the biomedical side effects of doping substances on the immune system, above
all during exercise practise, as well as to show the lack of information at this
respect.
120
A
Eduardo Ortega
Introduction
In order to improve the performance in high competition sports, day after day
new methods are developed to try to overcome the physiological limits.
Therefore athletes have resorted to take substances, which not only are
forbidden because they increase performance, but also they are a risk for
health. These substances cause an artificial increase of the sports performance,
but destabilize the physiological functions of the organism, impairing health.
Although doping is limited to sports, the intake of drugs to improve performance
is also extended to many other fields, since humans in order to overcome their
physical and mental limitations, resort to external substances. In Spanish
society the use of medicines is spread, not only to fight against diseases, but
also for anxiety, depression, tiredness, stress, pain, insomnia, etc. In the same
way sportspeople take these substances to improve their performance, increase
their muscular mass, improve their concentration, etc. Maybe they turn to these
methods because they are under the pressure of their own ambition, coaches,
federations, media and sponsors who look for greater performances in order to
get higher benefits. In amateur sports there is also a big incidence of doping,
they are tempted with drugs with the hope to get better results and the
professional appreciation. From this social scope, it is normally forgotten or
hidden the risks of these practices at short and long term. From a scientific
view, nowadays the side effects of most of these drugs are known, but the
studies on the matter are mainly focused in the effects on cardiovascular and
nervous systems, since the aim of these studies is to know if the use of these
substances can lead to death. However, little research is done about the side
effects of doping substances on the immune system.
The immune system is a system of self-recognition and maintaining
homeostasis. It is an extremely complex network that extends throughout the
body, and it is capable of recognizing and defending the organism against
pathogens. Cellular and soluble constituents of the immune system have to
work in close coordination. Classically the immune system has been divided
into: the innate (non-specific) response and the adaptative (specific) response.
The innate response consists of macrophages and neutrophils, along with NK
cells, complement and defensins, and constitutes the first line of defence. All its
constituents need a basic capacity to distinguish between self and foreign. By
picking up, processing and presenting antigens, macrophages form the critical
link to the specific branch of the specific immune system which mainly consists
in the lymphocytes and their products.
121
It is well known that exercise alters many immunophysiological parameters.
Thus some studies have shown, that excessive exhaustive exercise is
associated with symptoms of transient immunosuppression [1-10] leading to
increased susceptibility to infection. Reductions in lymphocyte function include a
decreased capability to produce cytokines have been observed after this type of
exercise. This is particular true for athletes in a competitive setting. Since an
infection would decrease athletes’ performance, and athletes are susceptible to
infections, we consider it is important to know the effects of doping substances
on the immune system, as well as the magnitude of these effects during training
periods and competition settings. The side effects of doping substances on the
immune system could be greater taking into account that most of the exerciseinduced changes on this physiological system are mediated by stress hormones
that can be unbalanced by the use of doping substances.
B
The Immune System
In order to know the studies in this field, we did a bibliography search in the
scientific database “pubmed”. We chose as keywords each prohibited
substance (anabolics, narcotics, hormones and related substances, diuretics or
nutritional supplements) and we match them in the following way:
Substance + doping
Substance + immune system
Substance + immune system + doping
Substance + exercise + doping
The results are shown in Figure 1. There are a lot of studies done on these
substances, but it is hard to find studies which test the side effects of doping
substances on the immune system.
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Eduardo Ortega
Anabolic Steroids
Anabolic Steroids + IS + Exercise
6
Anabolic Steroids + IS + doping
2
Anabolic Steroids + IS
143
Anabolic Steroids + Doping
390
0
100
200
300
400
500
Diuretics
Diuretics + IS + Exercise
4
Diuretics + IS + doping
0
923
Diuretics + IS
90
Diuretics + Doping
0
200
400
600
800
1000
Nutritional Supplements
Nutritional Supplements + IS + Exercise
42
Nutritional Supplements + IS + Doping
1
Nutritional Supplements + IS
774
Nutritional Supplements + Doping
99
0
500
1000
Stimulants
Stimulants + IS + Exercise
7
Stimulants + IS + doping
0
Stimulants + IS
776
Stimulants + Doping
16
0
500
1000
Narcotics
Narcotics+ IS + Exercise
6
Narcotics + IS + Doping
0
Narcotics + IS
1013
Narcotics + Doping
63
0
500
1000
1500
Figure 1. Bibliography search in the scientific database “pubmed”. IS= Immune system
123
Stimulants
The use of stimulants has a long history in society as well as in sports. Doping
has not only been used for sports, Russian astronauts and military used
stimulants as bromatan as an immune and psycho stimulant. In sports,
stimulants are usually used in basketball, boxing, cycling, football, swimming
and water polo. Some of the prohibited stimulants are: amphetamine, cocaine
and related analogues. The effects of amphetamines and cocaine on the central
nervous system are mediated through dopamine, noradrenaline and serotonine,
which are all closely involved in the regulation of behaviour. Together to the
psychological effects and dependence, it is known that stimulants can cause
cardiovascular, respiratory, gastrointestinal and musculoskeletal diseases; but
only few studies have tested the effects of these drugs on the immune system.
Some of these works have observed that chronic treatment with amphetamines
decreases in vitro and in vivo phagocytosis [11]. It has also been observed that
cocaine induces suppression of thymus dependent T-lymphocyte response as
well as increases IFN-γ production [12]. These drugs also affect the
neuroendocrine system which is linked to the immune system, so alterations on
the hypothalamic-pituitary-adrenal (HPA) axis would also affect the immune
response, because many changes on the immune response are mediated by
catecholamines and glucocorticoids. Some studies have evaluated the effects
of cocaine and heroine on the HPA activation and immune response, including
the release of pro-inflammatory cytokines as TNF-α. These studies showed that
the immunomodulatory effects of drugs abuse, such as cocaine and opiates,
affect the immune system directly as well as indirectly by also affecting the
neurologic system [13].
Narcotics
Narcotics are well known drugs that are usually used in fight sports. Some
examples of these substances are: morphine, methadone, buprenorphine,
oxycodone, etc. There are used to relieve pain when there is an injury or postsurgical pain. The intake of narcotics to reduce pain can aggravate an injury
because these drugs disguise pain so the athlete feels more self-confident and
ignore the problem. Narcotics can be divided into 3 groups:
Pure agonists on opioid-receptors (morphine, methadone)
Partly agonists on opioid-receptors (buprenorphine)
Mixed agonists/antagonists on opioid-receptors (pentazocine)
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It is well known that narcotic abuse causes addiction and other psychological
and physical effects such as depression, slight respiratory or nausea. In
addition, opioids receptors participate in the function of immune cells due to
opioid receptors have been found on the surface of different immune cells.
Several evidences suggest that opioids modulate both innate and acquired
immune responses. Two possible mechanisms of opiate actions have to be
considered. The first one represents a direct action of the opiates through the
opioid receptors on immune cells; the second mechanism would be mediated
by the nervous system [14]. Thus, opioid modulation of the immune response is
mediated, in part, directly through the interaction with opioid receptors
expressed by one or more populations of immune cells, but the influence of
opioids on the immune response is also the result of the effects of these drugs
on both the central nervous system and the hypothalamic-pituitary-adrenal axis
[15]. Some studies have observed that the capacity of both peritoneal
macrophages and neutrophils to phagocytose the yeast Candida albicans is
inhibited following in vivo administration of morphine [15-18]. These effects may
be particularly dangerous for athletes during exercise, because in this situation
the stimulation of innate immune responses can be crucial for preventing the
entry and the maintenance of microorganism in the body [10,19]. In fact, it has
been reported that exercise stimulates phagocytosis and killing of C. albicans
by macrophages and neutrophils and this stimulation of phagocytes is mediated
through glucocorticoids and catecholamines [20-23], this fact could be affected
at the same time by narcotics. The administration of morphine in vivo also
results in an atrophy of hematopoietic cells and in a reduced capacity of
lymphoid cells to generate antibody in response to tetanus toxoid [15,24], which
suggest that narcotics can also inhibit the adaptative response mechanism.
Anabolic agents
Anabolic steroids are usually synthetical derivates of testosterone. Anabolic
steroids are the most used substances to increase performance and/or to
improve physical appearance. These substances are usually used in athletics,
bodybuilding, cycling or weight-lifting. The existence of “illegal” users and
dealers of these substances, involve health risks and it makes necessary to
control their toxic effects. Since 1950 till today 120 of these compounds have
been synthesised, being available in the market. However, only 12 of them are
used in human therapy, whereas the rest are mainly used as anabolic agents by
sportspeople. The sale and use of steroid has drastically increased as a
consequence of the abusive intake by athletes and by young people who take
these drugs in order to improve their physical appearance. Even in the internet
125
you can find websites which explain how to take steroids and where to buy
them.
Steroids increase protein synthesis and they can be useful in medicine, but
there are so many side effects that some countries as Sweden have prohibited
anabolic steroids even for therapeutic use.
There are not many studies which test the side effects of steroids on the
immune system at doping concentrations. Some studies have observed that the
administration of nandrolone at 10 mg/kg body weight in rats inhibited
lymphocyte activity in vitro, particularly in thymus-derived cells. In this study the
authors concluded that the administration of suprapharmacological doses of
anabolic steroids during prolonged periods of time impairs the in vitro
functionality of thymus and spleen lymphocytes [25]. Other study also observed
that nandrolone and oxymethelone induced production of inflammatory
cytokines, such as IL-1β and TNF-α, from human peripheral blood lymphocytes
[26]. To gain a deeper insight into the effects of anabolic steroids on the
immune system, further experiments are necessary to characterize other effects
on cell-mediated and humoral responses.
Hormones and related substances
Some examples of this type of substances are erythropoietin (EPO), growth
hormone, gonadothrophins, insulin or corticotrophins. They are used in
basketball, cycling, bodybuilding, triathlon or volleyball. This type of substances
has got a clear therapeutically use in many diseases, but have also been used
by sportspeople to improve their performance, in spite of their side effects.
Maximal oxygen intake is the major performance limiting factor in endurance
sports. In the last years, many recombinant EPOs have been developed. The
side effects of EPO on the immune system are not still clear. Some authors
suggest that artificial oxygen carriers can impair the immune system [27] or may
cause severe side effects [28]. On the other hand Tu et al., [29] showed that
premature rats with lower levels of red blood cell, presented a decrease in
immune function, such as T cell responsiveness and TNF-α production,
compared with mature rats. After the administration of recombinant human
EPO, premature rats had an improved immune response.
Growth hormone (GH) has been described in general as immunosupermissive
hormones [10,30]. Exogenously administrated GH is protective in many models
of infection in which macrophages play important effector roles [31]. There are
studies about physiological role of GH in the immune response and the
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Eduardo Ortega
variations of this hormone following exercise, but there are no studies which link
the administration of this hormone as a doping resource and its effects on the
immune system. GH mediates the acute effects of exercise on neutrophils [32].
Intravenous GH injection induces a marked neutrophilia [33]. In addition an
increased respiratory burst immediately after maximal exercise performed by
cross-country skiers was found in parallel with increased serum GH levels [34].
However, although changes in the concentration of GH may also contribute to
changes in the respiratory burst of neutrophils over repeated exercise bouts or
in response to training, the results are confusing [10,35].
Diuretics
Diuretics increases diuresis. They are any substance which its chemical
structure or effects are similar to those of the following substance:
acetazolamide, etacrynic acid, metolazone, thiazides, triamterene, etc. Diuretics
at high doses can cause loose of weight that can lead to dehydration and
looses of potassium, that can cause arrhythmia even death if the lost of
potassium is too high. They can also cause nausea, fatigue, fever, kidney
diseases or confusion. Diuretics are usually used by bodybuilders, boxers,
weight-lifters or judokas. Other athletes take these substances to disguise other
prohibited substance since diuretics help to eliminate the trace of other drugs.
Some diuretics such as furosemide or spironolactone are potent inhibitors of
leukocyte migration through endothelial cell monolayers [36].
The intake of nutritional supplements is widespread in sports. The main problem
of these substances is that usually they are sold as innocuous herbal derivates
and in most cases they are contaminated with prohormones or other prohibited
substances such as ephredines. It is, for example, the case of Ma Huang which
contains ephredines that stimulate the central nervous system in the same way
as amphetamines. These compounds sometimes are sold through internet,
without sanitary supervision or right labelling.
The literature suggests that a heavy schedule of training and competition leads
to immunosuppression in athletes, so they would be more susceptible to
opportunistic infection. There are many factors which influence exerciseinduced immunosuppression, and nutrition undoubtedly plays a critical role.
Furthermore, inadequate or inapropiate nutrition can compound the negative
127
influence of heavy exertion on immunocompetence. Dietary deficiencies of
protein and specific micronutrients (iron,zinc, vitamins) have long been
associated with immune dysfunction and, on the contrary excess intakes of
some micronutrients can also impair immune function and have adverse effects
on health [37]. As we have explained in the introduction athletes, due to
strenuous bouts of prolonged exercise and heavy training, can present a
depressed immune cell function. For this reason they take immunoestimulants
which prevent from tissue damage caused by the exercise-induced stress.
Sometimes the containers of these products do not reflect their real
composition. Moreover the so called “herbal products” have sometimes
immunosupressive effects. Immunosuppressive drugs have been developed
from natural products, such as soil and fungi, which are also sources of some
commonly, used herbal products. However, the effect of herbal products on
immune response has not yet been well investigated. Wilasrusmee et al. [38]
studied the effects of some substances on lymphocyte proliferation. They
observed that ginger and green tea have an immunosuppressive effect, and this
effect was mediated through a decrease in IL-2 production. On the other hand,
Dong quai and milk thistle increased alloresponsiveness in mixed lymphocyte
culture. Other nutritional supplement frecuently used is L-carnitine. It is an
essential nutrient with a major role in the cellular energy production. At high
doses, L-carnitine might mimic some of the biological activities of
glucocorticoids, especially immunomodulation [39].
In sum, athletes may need to take some nutritional supplements in order to
complement their diet, but these supplements must be supervised by physicians
who also control their effects. Moreover, athletes must be cautious when they
take “natural” compounds, because they can be danger to health as far as
these compound can be contaminates with other harmful substances that do
not appear in the label.
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Table 1. Side effects of doping substances on the immune system
Substance
Examples
Side effects on Immune
System
Anabolics
Testosterone
Inhibits antibody production
Nandrolone and other
steroids
↑ proinflammatory cytokines
(IL-1β and TNF-α)
GH
↑ inflammatory cytokines and
free radicals production by
macrophages
Peptide Hormones
EPO
Stimulants
Amphetamines
↓ Resistance to pathogens
Cocaine
↑ Susceptibility of infection
Caffeine
↓ Phagocytosis
Suppression of T-lymphocyte
response
Narcotics
Morphine
↓ Lymphocytes proliferation
Methadone
↑ proinflammatory cytokines
Inhibits antibody response
Inhibits macrophages and
neutrophils phagocytosis
Diuretics
Triamterene
Not clear
Thiazides
Nutritional
Supplements
Carnitine
Ma Huang Gingsen
Can hide other prohibited
substances as anabolics or
stimulants
Some herbal products are
immunosupressive
C
129
The Skin
On the other hand, some of the side effects of these drugs on the immune
system affect the skin too, as the result of an alteration of the inflammatory
response. Because of this reason we will explain briefly some of the side effects
of these substances on the skin.
Human skin is permanently exposed to microorganisms, but rarely infected.
One reason for this natural resistance might be the existence of a 'chemical
barrier' consisting in constitutively and inducible produced antimicrobial peptides
and proteins [40]. Several compounds listed as illicit doping agents can express
some effects on the skin. The cutaneous signs are diverse. The clue of the
intake of such compounds can be supported by objective non-invasive
biometrological assessments. However, such evaluations do not bring the
irrefutable proof. The skin can also present unwanted reactions indicating
intolerance to the doping agent. Such physiopathological manifestations are not
limited to the sport competition, but can also affect some groups of the
population searching for a look reminiscent of the ideal young and performing
athlete [41].
A good example about how doping substances affect skin are narcotis as
morphine, that frequently causes side effects such as hyperhydrosis and facial
flushing, but serious cutaneous adverse drug reactions are seldom observed.
Best known are urticaria, erythema, and pruritus; sometimes pseudoallergic
anaphylactoid reactions and blisters are reported [42]. Morphine also has other
side effects on skin as the inhibition of nociceptors of skin under inflammation
conditions [43].
In connection with AAS abuse, acne may develop as the skin’s contents of
cholesterol, tallow, and certain bacterial increase.
In AAS abusers, acne often spreads characteristically over shoulders and chest.
A steroid pimple is usually distinguishable from a normal adolescent pimple by
being larger and often sanguineous. It can also cause great pain.
When the abuse has stopped, acne will often subside but may persist for a
while. More over anabolic steroids as B12 increases fulminans acne [44].
Another side effect of taking doping substances is the stretch marks. They are
probably caused by hormonal changes in the skin and are seldom present in
non-AAS abusers but very frequently in AAS abusers. They often occur
between the large pectoral muscle and the biceps (biceps-pectoral groove), but
it has been reported of their spreading on the back, thighs, and in the face.
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Eduardo Ortega
They will remain throughout life but may fade somewhat in time. There is no
effective treatment till today.
The use of ACTH or corticotrophin may cause allergic reaction, in particular in
people who have a predisposition towards asthma, urticaria, eczema, etc. The
non steroid anti-inflammatory drugs (NSAIDs) have common side effects that
include skin eruptions and edemas. Codeine, opiates and other derivatives can
affect pruritus and Erythropoietin can cause in some cases skin reactions,
allergy-like edema at the site of injection. The associated dangers’ chorionic
gonadtropin (hCG) depend on dosage and according to sex, but en hombres
puede mostrar allergic manifestations. The probenecid may cause dermatitis
and others skin irritations.
D
Conclusion
Athletes seem to suffer infections during and after high intensity training
periods. Many research groups are studying the effects of exercise on the
immune system. On the other hand there are also studies about side effects of
substances which are used for doping. But there are very few studies which link
the use of these substances as a doping strategy (at high concentrations and
with no therapeutically purpose) and their effects on the immune system. The
doping substances may impair the immune system both directly, affecting the
function of immune cell, and indirectly, through the neuroendocrine system,
because many of the exercise-induced changes on the immune system are
mediated by neuroendocrine factors released following stress. So, the studies
focused on the side effects of doping substances on the immune system are
particularly important in the context of exercise-induced neuroimmunoendocrine
changes. Finally, to indicate that the fact that doping substances affect the skin
shows that these drugs may induce immunological reactions, however, further
studies are needed.
E
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lymphocyte transformation test. J. Am Acad Dermatol. 55: 21-23, 2006.
43. H.N. Wenk, J.D. Brederson and C.N. Honda. Morphine directly inhibits
nociceptors in inflamed skin. J Neurophysiol. 95:2083-2097, 2006.
44. W. Mayerhausen and B. Riebel. Acne fulminans following use of anabolic
steroids. Z. Hautkr. 64: 875-876, 1989.
134
Eduardo Ortega
Other information resources
45. www.dopingjouren.se
46. www.uci.ch: Rivier L., Saugy M., Mangin P. Principal doping substances
and their side effects.
47. www.fulp.ulpgc.es: Socas Hernandez L. Efectos adversos para la salud
inducidos por los esteroides anabolizantes en un grupo controlado de
fisioculturistas.
Correspondence
Eduardo Ortega, Dpt. Fisiología, Facultad de Ciencias, Universidad de
Extremadura. Av. De Elvas s/n. 06071, Spain, [email protected]
Psychological Effects and Addiction
3.8
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PSYCHOLOGICAL EFFECTS AND ADDICTION INCLUDING CNS
Ryszard Grucza
A
Motives of Doping Use by Athletes
From the beginning of human history most of the form of the rivalry has been
performed with all possible means. Many events in development of human
society brought clear evidence for such statement [1]. As far as sport is
concerned, wherever and whenever the outcome of sporting competition has
involved status, money or other similar rewards, attempts have been made to
seek an advantage through doping.
Development of doping methods and substances in second half of the last
century enlarged the problem of doping use in sport. Coincidence of high
pharmacological technology with professionalism and commercialism in sport,
rivalry of two former political systems and finally limits of human organism to
drive sports results higher, created enormous pressure on athletes for better
preparation for sports events and for better scientific support during training and
performance. Better scientific support could also mean, for some athletes, the
use of forbidden substances.
Theory of human behaviour bases on changes in social identity and individual
personality in relation to understanding of current situation [2, 3]. In accordance
with the theory some athletes could feel that use of banned substance would be
desired or even necessary. The rush for best result and for success seems to
be the main reason for using forbidden substances. Also the risk-attitude
characterized for sport personality favours to accept the risk connected with
doping [4]. The risk is natural and immanent part of sport and doping might be
considered by an athlete as a normal cost of sport engagement.
Athletes face enormous pressure to excel in competition. Some social factors
and stressing influence of sport environment can play an important role in
choosing doping as a way to achieve the success. The set of “sport values”,
enabling individual and social tolerance of doping, and steel acceptable by
some athletes, coaches and sport managers, are presented in Figure 1.
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Doping is
necessary to win
Win for any price
Financial rewards
DOPING
To be the best in
the world
Tolerance of
doping by sport
authorities
All athletes take
drugs
Winning is an
ultimate aim of
sport
Figure 1. Some “sport values” favouring acceptance of doping by athletes.
B
Physiological Mechanisms of Behaviour and Emotion
Structures of the brain
Among the brain’s four external lobes the frontal lobe has a great meaning in
development of emotions and individual character of a person. Frontal lobe is
involved in planning, organizing, problem solving, selective attention,
personality and a variety of "higher cognitive functions" including behaviour and
emotions. The anterior portion of the frontal lobe (prefrontal cortex) is very
important for the "higher cognitive functions" and determination of the
personality.
The limbic system controls inborn and acquired behaviour and is a localization
of instinctive behaviour, emotions and motivation. It controls the expression of
emotions conveying important signals to the environment (e.g. fear, anger,
discomfort, joy, happiness, etc.). Inversely, signals from the environment are
closely associated to behaviour [5].
The amygdale, part of the limbic system, is a structure essential for decoding
emotions, and in particular for stimuli that are threatening to the organism. The
other parts of brain also project their connections to the amygdale (Figure 2).
137
Sensory cortex
Prefrontal
cortex
Thalamus
AMYDGALE
Septum
Brainstem
Hypothalamus
Hippocampus
EMOTIONAL RESPONSE
Figure 2. Structures of the brain participating in behavioural emotions.
The role of neurotransmitters
Neurotransmitters are chemicals that are used to relay, amplify and modulate
electrical signals from one nerve cell to another. This occurs at a specialized
cellular structure known as the synapse. The neurotransmitters diffuse across
the synaptic cleft to bind to receptors which, to large extent, decide on final
effect. Neurotransmitters may cause either excitatory or inhibitory post-synaptic
potentials. The basic neurotransmitters and their action are presented in
Table 1.
Noradrenaline, dopamine, serotonin and GABA are involved in the control of
many of emotional and mental states. Most of the psychoactive drugs work by
changing either their metabolism or receptor sensitivity to these
neurotransmitters [6].
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Table 1. Basic neurotransmitters and their action
Neurotransmitter
Action
Acetylcholin
voluntary movement of the muscles
Gamma aminobutyric
acid (GABA)
motor behaviour
Glycine
spinal reflexes and motor behaviour
Glutamate
memory
Dopamine
voluntary movement and emotional
arousal
Noradrenaline
wakefulness or arousal
Serotonin
memory, emotions, wakefulness, sleep
and temperature regulation
Noradrenaline activates nervous and motor systems. Amphetamines cause
the release of noradrenaline and other catecholamine neurotransmitters.
Dopamine has an inhibitory effect on other neurons and is strongly
associated with reward mechanisms in the brain. Drugs like cocaine, opium,
heroin, and alcohol increase the levels of dopamine. The nicotine brings a
similar effect.
Serotonin is involved in emotion and mood. Low level of serotonin may lead
to depression, trouble sleeping and problems with anger control.
Hallucinogens, such as LSD, probably act by inhibition of activity of the
serotonin neurons. Antidepressant drugs help to keep a normal level of
serotonin by preventing its removal from the synaptic cleft.
GABA (gamma aminobutyric acid) exhibits inhibitory effects on excitatory
neurotransmitters that lead to anxiety. Benzodiazepines enhance the effects
of GABA.
Figure 3 shows a schematic model of the influence of noradrenaline, dopamine,
serotonin and GABA on cognitive function, mood and emotions in man.
139
GABA
NORADRENALINE
Motivations
Anxiety,
irritability
Cognitive function,
mood, emotions
SEROTONIN
Appetite, sex,
aggression
Pleasure
DOPAMINE
Figure 3. Influence of some neurotransmitters on psychical state of an organism.
The mechanisms by which the neurotransmitters elicit responses in both presynaptic and post-synaptic neurons are diverse. Once the molecules of
neurotransmitter are released from a cell, as the result of the firing of an action
potential, they bind to specific receptors on the surface of the postsynaptic cell.
There are numerous subtypes of receptor for any given neurotransmitter.
Dopamine receptors play an important role in psychical state, behaviour and
personality. Some studies indicate that D2-receptor may be involved in
pleasure-seeking behaviour influencing the brain rewarding system. On the
other hand, adventure-seeking personality, characterized by an impulsive and
aggressive activity, could be attributed to type of D4-dopamine receptor [7].
Neuromodulators represent a special type of neurotransmitters, which are not
reabsorbed by the pre-synaptic neuron or broken down into metabolite.
Because of their longer activity in cerebrospinal fluid they can enhance or damp
the overall activity level of the brain. These neuromodulators are called
endogenous opioids because of they opium-like activity. The endogenous
opioids include endorphins, enkephalins and dynorphins.
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The reward-punishment mechanisms
Studies investigating possible mechanisms of pleasure-seeking behaviour
revealed that there are some structures in the brain activated when the state of
satisfaction is finally obtained be an organism. These structures work in a
reward mechanism consisting of ventral tegmental area and the nucleus
accumbens with cooperation of septum, amygdale, prefrontal cortex, and
certain parts of the thalamus. It might be inferred that the increased dopamine
release is a physiological source of satisfaction in man under sexual arousal,
gambling, sport performance, etc., without any drug application [8].
Negative stimuli activate brain punishment mechanism, provoking “fight or flight”
response to cope with unpleasant situation. It includes various brain structures,
hypothalamus, thalamus, amygdale and hippocampus. The system functions by
means of acetylcholine, which stimulates the secretion of adrenal cortico-trophic
hormone (ACTH). ACTH in turn stimulates the adrenal glands to release
adrenaline to prepare an organism for fight or flight response. Stimulation of the
punishment mechanism can inhibit the reward mechanism [9].
There is also a third mechanism activated when both fight and flight seem
impossible and the only remaining option is to behave passively. The
mechanism bases on the same brain structures as for punishment mechanism
with serotonin as a responsible neurotransmitter.
Fear, anxiety, aggression and pain
Fear is a strong, intense emotion experienced in the presence of a real,
immediate threat, pain or danger. The neural center for fear is amygdale with
influence of sensory cortex. It originates in a system that detects dangers and
triggers a sequence of defensive behaviour.
Anxiety is a vague, unpleasant emotion that reflects apprehensive anticipation
of future danger or misfortune accompanied by a feeling of dysphoria and some
somatic symptoms. It can also result from imagining situations that do not really
exist. The anxiety, originating in cortex, can be relieved by medications such as
benzodiazepines, which increase the effect of GABA. Chronic anxiety can lead
to pathological conditions.
Aggression is a form of behaviour characterized by physical or verbal attack.
According to Moyer (1968) aggression has been defined as "overt behaviour
with the intention of inflicting damage or other unpleasantness upon another
individual" [10]. It should be noted that some aggressive behaviours can be
141
normal and adaptive. Most form of sport aggression may be described as an
instrumental aggression which occurs in the quest of some non-aggressive goal
[11].
The leading role in development of aggression has been attributed to
testosterone, a male sex hormone. It is also possible, however, that some forms
of human aggression, particularly violent episodic rage, may have its origin in
limbic system [10]. Despite of the difference in sex hormones the neural
systems modulating defensive aggression act in similar way in both males and
females. This could lead to the conclusion that human aggression might have
biological roots in the defensive aggression of non-primate mammals and not in
hormone-dependent aggression based on testosterone [12].
Pain is a sensory modality protecting body from permanent damage. It is
defined as an unpleasant sensory and emotional experience associated with
actual or potential tissue damage. Pain is an independent sensation with its own
specialized neural sensors (nociceptors), conduction pathways and centers.
The most effective pharmacological way to treat the pain is application of
narcotic analgesics in which the oldest representative is morphine, a constituent
of opium.
C
Drugs Actions
The reward mechanism and drugs
As it has been already mentioned, the pleasure centers in the brain favour
behaviours that are helpful for survival. But, on the other hand, this mechanism
drives people for seeking euphoria, also by using the psychoactive substances.
Thus, to seek-pleasure and avoid-pain would be the mechanism responsible for
taking drugs and, eventually, for the drug addiction. The risks associated with
consuming a drug vary with its nature, the vulnerability of the person consuming
it, the dose of drug and the time of application. For most people, abusing
psychoactive substances is a learned behaviour designed to cope with some
form of stress.
It is generally believed that all substances triggering dependencies in human
beings increase the release of dopamine in the nucleus accumbens. The actual
level of dopamine would decide, therefore, on experience pleasure, satisfaction
or craving.
Different drugs increase dopamine levels in the brain in different way, either
directly or indirectly. Some substances imitate natural neurotransmitters and
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take place on their receptors (e.g. morphine binds to the receptors for
endorphin, while nicotine binds to the receptors for acetylcholine). Other
substances increase the secretion of natural neurotransmitters (e.g. cocaine
mainly increases the amount of dopamine in the synapses, while ecstasy mainly
increases the amount of serotonin). Still other substances block natural
neurotransmitters (e.g. alcohol blocks the NMDA receptors) [9].
Drugs dependency and addiction
Use of substances for non-medical purpose causes a various sequence of
events including psychological, physiological, pharmacological, neurobiological,
social and political consequences. From the individual perspective, the flexibility
and adaptability of the brain structure in response to drugs application may
cause tolerance, dependency, addiction or withdrawal effects. Tolerance is one
of the brain compensating mechanisms that gradually reduce the effects of
drugs by change the number, or sensitivity, of the specific receptors leading to a
new threshold of effective dosage. The tolerance can be associated with drug
dependency defined as a persistent drug intake to prevent or diminish the
physical or psychological disturbances of withdrawal (abstinence syndrome)
[13]. However, the tolerance is neither a necessary nor a sufficient condition to
trigger a dependency.
Physical dependency occurs when the body is deprived of drugs. Such
deprivation leads to physical symptoms that vary with the drug: pain (opiates),
severe tremors (alcohol), and convulsions (barbiturates and benzodiazepines).
Psychological dependency can last far longer than physical dependency. It is
based more on the individual’s traits (habits, affective states, lifestyle) than on
the substance itself. Reward system plays important role in development of
psychological dependence. Cocaine and amphetamines could be good
examples of substances with high psychological and low physical dependency.
Addiction to drug is a compulsive use and impaired control of intake of a drug
despite of its adverse consequences [13]. The most addictive drugs are opiates,
cocaine, amphetamines, alcohol and nicotine acting on reward system in the
brain.
D
Psychological Effects of Doping Substances
Contemporary medicine, physiology, biochemistry, genetics and pharmacology
bring enormous possibilities to enhance sport performance. Although, drugs are
143
primarily designated to cure people suffering from different illnesses they are
also misuse by healthy sportsmen to get an extra advantage over other
competitors despite of possible short- and long-lasting negative side effects.
Stimulants
Stimulants (sympathomimetics) are the drugs activating central nervous system
by catecholamine (adrenaline and noradrenaline) actions. Direct
sympathomimetics mimic the actions of the naturally occuring catecholamines.
Indirect sympathomimetics elevate the concentration of noradrenaline at
neuroeffector junctions, because they either inhibit re-uptake (cocaine), facilitate
release, or slow breakdown by monoamine oxidase (MAO), or exert all three of
theses effects (amphetamine, methamphetamine).
Stimulants are group of substances able to increase the mood and arousal,
eliminate or decrease feeling of fatigue and, possibly, to enhance physical
performance. In fact, the performance enhancing effects of stimulants are
difficult to demonstrate. Some reports indicate that stimulants exhibit a
moderate effect on performance and only when a high dose of these
substances were applied. On the other hand, in contemporary sports,
performance improvements amounting to less than 1% may make the
difference between the gold medal and a bronze [14]. The most popular
stimulants uses for doping purpose are: cocaine, amphetamine, ecstasy and
methylphenidate (Ritalin). The nicotine and caffeine are also frequently used as
stimulants.
Cocaine acts by blocking the re-uptake of dopamine, noradrenalin and
serotonin. As a result, the natural effect of dopamine on the post-synaptic
neurons is amplified. The group of such modified neurons brings a euphoria
(from dopamine), feelings of confidence (from serotonin), and energy (from
noradrenalin). Dependency on cocaine is closely related to its effect on the
reward system. The ergogenic effects of cocaine are similar to those of
amphetamines and caffeine.
Amphetamines (amphetamine and methamphetamine) are similar in structure to
dopamine and act mainly by an increase in concentration of dopamine in the
synaptic gap, by reducing the re-uptake of dopamine, and by excitation of
dopamine sensitive neurons. Amphetamines has often been used for military
and sport purposes to combat fatigue enabling sustaining attention over
prolonged periods of time. Amphetamines became the drugs of choice for
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athletes, particularly in sports such as cycling where these drug effects were
perceived to be beneficial in enhancing sporting performance [15].
Ecstasy (MDMA) is a synthetic drug which acts simultaneously as a stimulant
and as hallucinogen because of its similarity to both amphetamines and LSD.
Like amphetamines and cocaine, ecstasy blocks the re-uptake of certain
neurotransmitters increasing the effect of noradrenaline and dopamine. The
person may then experience increased energy and euphoria.
Nicotine and caffeine are also stimulants. Nicotine is an agonist of nicotine
receptors, located in the central nervous system and in neural-muscle junctions.
Stimulation of nicotine receptors in ventral tegmental area enhances dopamine
secretion in the nucleus accumbens. In result, the higher concentration of
dopamine in the reward system contributes to development of nicotine
dependency. Nicotine affects the brain quickly, like other inhalants, producing
feelings of pleasure, like cocaine, and is highly addictive, like heroin.
Stimulatory effect of caffeine comes from its action on adenosine receptors,
adenosine-receptor antagonist and on pituitary gland to secrete hormones
enabling release of more adrenaline and driving the level of alertness. Like
other stimulants, caffeine increases the production of dopamine in the brain’s
rewarding system. The performance enhancing effects of caffeine has not been
clearly proved. Despite of its effect on the central nervous system there are,
supposedly, other mechanisms including metabolic improvement and direct
stimulatory action on the skeletal muscle [14].
Narcotics
Narcotics are substances causing pain relief and mood alteration in wide range
from sleep and total immobilization of the body up to euphoria and overexcitation. In popular meaning the narcotics include all substances and drugs
which are able to change psychical and physical status of an organism.
However, in medicine the meaning of the word narcotics is limited to analgesic
narcotics (opioids) which refer to all natural, semi-synthetic and synthetic
substances that behave pharmacologically like morphine. Morphine, as other
natural opiates, is an alkaloid derived from opium, dried juice of immature fruit
capsule of Papaver somniferum. The primary medical application of morphine is
to decrease the pain. The opioids, however, exert a powerful action against
stress, depression and psychosis [6].
The use of pain killers is frequent in sports, especially among athletes engaged
in violent activities (such as boxing for instance). Increased threshold for pain
145
tolerance, adjusted by narcotics application, allows for better sport performance.
Additionally, narcotic analgesic may reduce anxiety, possibly enhancing
performance in sport events in which excess anxiety could adversely affect fine
motor control, such as pistol shooting and archery [16].
Opioids work trough endogenous opioids (endorphins), enkephalins and
dynorphin, modulating reactions of central nervous system to the pain stimuli.
Heroin and morphine bind to the same receptors as those endogenous opioids
which lead to reduced excitability of neurons, the likely source of the euphoric
effect. The euphoric effect can be enlarged by involvement of GABA-inhibitory
neurons of the ventral tegmental area influencing on increase of dopamine
release.
It has been reported that some people with inclination to depressive mood are
seeking psychological improvement trough the sport. They are especially
susceptible for narcotics, mainly heroin, which give a pleasure which is
incomparably stronger than that obtained trough intensive sports. Such
psychological mechanism could lead to high risk of addiction in this group of
people [17].
Beta-2 agonists
Activation of the sympathetic nervous system is associated with release of
adrenaline and noradrenaline. These powerful neurotransmitters acts trough
specific receptors, called beta adrenergic receptors, located in various tissues
including skeletal muscle and adipose tissue. Beta adrenergic receptors can be
divided into two categories (α- and β- receptors) according to their specific
response to sympathetic stimuli. Generally, the α-receptors are involved in
intestinal relaxation whereas the β-receptors participate in myocardial
stimulation, vasodilution and inhibition of bronchial smooth muscle. The βreceptors can be further divided to subgroups of β1 and β2, based on the
receptor affinity for certain compounds.
A β-agonist can be described as a substance that stimulates the β-receptors.
The most prominent representative of the β-receptor agonists are clenbuterol
and salbutamol (both β2-agonists) used primarily for treatment of asthma and
related bronchospasm [14]. The problem with upper respiratory airways is very
common for athletes of endurance sports. This is partly due to exercise-induced
bronchoconstriction related to the water and heat loss from the respiratory
airways. Considering the fact that about 10-15% of Olympic athletes exhibit
asthma syndromes the use of β-2 agonists is relatively high [18]. Among many
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negative side effects of β-agonists application the tachycardia, nervousness,
insomnia, increased blood pressure and body temperature as well as muscle
tremor are most commonly observed in the users.
Cannabinoids
Cannabinoids are substances able to elicit psychic changes like those
manifested in the course of psychosis. These substances are called as
psychotomimetics, or psychedelics, or hallucinogens. Chemical structure of
cannabinoids, substances obtained from Cannabis sativa (hashish and
marihuana), are different comparing to natural, biogenic amines. When
cannabinoids are introduced into the body, its active ingredient, delta-9tetrahydrocannabinol (THC) modifies the function of the brain.
THC acts on the cannabinoid receptors in the brain bringing sensation of
euphoria, relaxation and amplified sensory perception. The information
concerning the presence of THC in the brain has been transmitted by an
endogenous molecule – anandamide – bound to the cannabinoid receptors.
Anandamide is involved in regulation of mood, appetite, pain, cognition and
emotions.THC increases dopamine realising by compensation of inhibitory
effect of GABA neurons. Chronic consumption of cannabinoids could lead to
destruction of some neuron receptors in the brain (CB1) resulting in attention
deficits, memory loss and impaired learning ability.
Cannabis is widely used for its altering mood and relaxation properties also in
sport. Lack of scientific evidence for performance enhancing of cannabis is
associated with the strong evidence of its adverse effects on psychomotor
performance and cognitive function in the user. There is a growing number of
young athletes using cannabinoids despite of the discipline of sport. This fact
suggests that cannabinoids are not used for doping purpose but rather for social
reasons [19]. However, it seems that competitors of extreme and combat sports
are more susceptible for cannabinoids use than other athletes.
Hallucinogens and inhalants
LSD (lysergic acid diethylamide) is derived from ergot, a sugary excretion of the
fungus Claviceps purpurea, which grows on rye and other grains. Recreational
use of LSD became pandemic during the 1960s. LSD modifies serotonin
neurotransmission by complex interaction with the 5-HT receptors. Selective
serotonin re-uptake inhibitors are also reported to be involved in hallucinatory
147
episodes. The exact mode of action that accounts for the peripheral, cognitive,
and affective distortions remains unknown. LSD causes complex physiological
changes including tremor, dizziness, headache, hypertension, tachycardia,
vomiting, hyperthermia, paralysis and hyperglycemia. Among psychological and
psychiatric effects the most important are: restlessness, anxiety, panic,
depression, paranoia, perceptual distortions, delusions, hallucinations, visual
illusions, flashbacks and prolonged psychotic reactions [20].
All inhalants can be toxic. Sniffed inhalants, such as glue, gasoline, solvents,
kerosene, butyl nitrate, paint thinner, etc. exhibit almost immediate effect on the
brain. Repeated use of the inhalants leads to destruction of fatty tissues
protecting the nerve cells in the brain slowing down or even stops some neural
transmissions. In effect a complex of physical and psychological symptoms
appear among which the most typical are: muscle weakness, abdominal pain,
liver, lung and kidney damage, decreases in heart and respiratory rates,
nausea, nose bleeding, fatigue, headache, severe mood swings and violent
behaviour, lack of coordination, mental confusion, emotional excitement and
memory impairment.
Hallucinogens and inhalants are not popular doping substances because of lack
of enhancing performance properties and strong psychical side effects.
CNS depressants
Drugs inhibiting activity of the central nervous system (CNS) are accidentally
used in sport. The purpose of its application is calming, relaxation and good
sleep. The most popular CNS depressants are benzodiazepines and alcohol.
Benzodiazepines, such as diazepam (Valium), are anxiolytics that can also
have hypnotic or amnesia-inducing effects. Like alcohol, these drugs increase
the efficiency of synaptic transmission of GABA. Benzodiazepines can cause a
drug dependency even in therapeutic doses. Some athletes use anxiolytics to
help avoid the risk of performance impairment due to lack of sufficient sleep.
Alcohol influences on membranes, ion channels, enzymes, and receptors of
neurons in the central nervous system. It also binds directly to the receptors for
acetylcholine, serotonin, GABA and the NMDA receptors for glutamate. In
result, alcohol helps to increase the release of dopamine. In sport, the alcohol
may be consumed for its potential positive effects on psychological well-being
or for its tension-reduction properties. Frequent alcohol intoxication and
involvement in power sports appear to be a good predictor for future anabolicandrogenic steroid abuse by an athlete [21].
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Anabolic androgenic steroids
Testosterone, the male sex hormone, acts on central and peripheral nervous
system and produces both anabolic (tissue building) and androgenic
(masculinisation) effects. Anabolic-androgenic steroids are derivatives of
testosterone. Applied initially for a treatment of hypogonadism, anemia and
certain psychiatric disorders anabolic androgenic steroids has been widely used
by elite and recreational athletes to gain strength and muscle mass, to increase
the protein synthesis and the red blood cells as well as to decrease the body
fat. The steroids are especially attractive in such discipline of sport like
professional football, weight lifting, power lifting, bodybuilding and track and
field.
Although, the application of anabolic steroids by competitive athletes has been
well documented the greatest abuse of anabolic steroids has been observed in
non-competitive sportsmen who take those steroids for fashionable muscular
physique [22, 23]. The exact physiological mechanism of anabolic androgenic
steroids enabling enhance of athletic performance has not been yet well
documented and brought conflicting results [24, 25, 26].
A pattern of association between the use of anabolic-androgenic steroids and
increased levels of irritability, aggression, personality disturbances and
psychiatric diagnoses has been revealed in several reports [14, 27, 28].
Anabolic steroids have also been used with other harmful drugs, including
tobacco, alcohol and cocaine [29]. The increased arousal and aggression may
enable some athletes to train and perform more intensely. However, the high
level of aggressiveness and lack of control could bring some devastating effects
[30]. Some case reports indicate that using steroids with combination of
amphetamine and marihuana can lead even to murder and suicide [31, 32, 33].
It should be noted that literature review on human aggression in relation to
anabolic steroids misuse gives some conflicting results. Müller and Müller-Platz
(2002) suggested that possible connection between anabolic steroids and
aggressiveness could be restricted to “weak aggressiveness” like readiness and
eagerness to compete [28, 34]. Violence and harm to others would be,
therefore, exceptional. However, other reports still underlay the fact that
significant psychiatric symptoms including aggression, violence, mania,
psychosis and suicide have been associated with anabolic steroid abuse [32,
35].
Athletes often use other medications to hide anabolic steroids abuse or reduce
the associated side effects. Anti-estrogenic agents and human chorionic
gonadotropin (HCG) are usually applied to reduce gynecomastia, a potential
149
side effect of anabolic steroids misuse. Competitive athletes sometimes attempt
to dilute their urine by taking diuretics such as furosemid or probenecid.
It has long been accepted that anabolic androgenic steroids can cause
psychological dependence. The age at which sportsmen start to use steroids as
well as the dose and frequency of use might be some predisposing factors. Also
acceptance of alcohol, nicotine and other social drugs could favour the misuse
of anabolic androgenic steroids in sports.
E
Conclusion
It may be concluded that majority of doping substances used in sports cause a
complex, immediate and long-lasting, changes in the central nervous system
manifested by psychical and psychiatric symptoms (Tab. 2). These changes are
associated with other negative side effects occurring in the body which are
discussed in other chapters of the review.
It should be noted that, generally, sportsmen are not aware about the danger of
psychical consequences of doping misuse and possible addiction to the drugs
they apply. Also social environment with increasing acceptance of use of
“recreational drugs” may favour easier use of doping substances, especially by
young athletes. These facts strongly stress the needs for appropriate
informative and educational programs concerning psychical side effects of
doping abuse devoted to the athletes and their entourage.
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Table 2. Effects of doping substances on the central nervous system manifested by
psychical and psychiatric symptoms.
SUBSTANCE
EFFECTS ON CENTRAL NERVOUS SYSTEM
STIMULANTS
Amphetamine
Irritability, anxiety, paranoia, psychosis, depression, aggression,
convulsions, dizziness, insomnia.
Metamphetamine
Irritability, aggression, paranoia, psychosis, convulsions,
hallucinations, formication (the sensation of insects creeping on or
under skin).
Ecstasy (MDMA)
Panic, anxiety, depression, paranoia, hallucinations, insomnia.
Methylphenidate (Ritalin)
Paranoia, hallucinations, excessive repetition of movements,
headache, anxiety, delusions.
Cocaine
Irritability, euphoria, psychosis, anxiety, restlessness, insomnia.
Nicotine
Alertness, euphoria, reduction of fatigue.
Caffeine
Alertness, reduction of fatigue, anxiety, mild paranoia.
NARCOTICS
Morphine, Heroine
Pain relief, euphoria, lethargy, apathy, inability to concentrate,
slurred speech.
β-2 AGONISTS
(Clenbuterol)
Nervousness, migraine, psychosis, insomnia.
CANNABINOIDS
Tetrohydrocannabinol
(THC)
(Hashish, Marihuana)
INHALANTS
Euphoria, panic attacks, impaired comprehension, altered sense of
time, paranoia, anxiety, altered cognition, impaired learning,
memory, perception, and judgment, depersonalization, confusion,
amnesia, hallucinations.
Headache, severe mood swings and violent behaviour, lack of
coordination, mental confusion, emotional excitement and memory
impairment.
CNS DEPRESSANTS
Benzodiazepines
Sedation, decreased anxiety, amnesia
Alcohol
Dizziness, hangovers, slurred speech, disturbed sleep, violent
behavior, memory lapses, blackout.
ANABOLIC
ANDROGENIC STEROIDS
Aggression, depression, mood swing, impaired memory, insomnia.
HALLUCINOGENS
PCP
(phencyclidine)
Hallucinations, out-of-body experiences, pain resistance,
disorientation, fear, panic, aggressive behaviour, depression,
anxiety, paranoia, apathy.
LSD
(Lysergic Acid Diethylamide)
Sleeplessness, recurring hallucinations, panic, dizziness,
intellectual impairment, euphoria, paranoia, panic attacks,
depersonalization
Mushrooms
Hallucinations
151
F
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G. English. A theoretical explanation of why athletes choose to use
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K.E. Moyer. Kinds of aggression and their physiological basis.
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19. P. Van Eenoo, F.T. Delbeke. The Prevalence of Doping in Flanders in
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Correspondence
Ryszard Grucza, Institute of Sport, Department of Antidoping Research, Trylogii
2/16, 01-982 Warsaw, Poland, [email protected]
154
4
4.1
Martin Schönfelder
ACTUAL TOPICS OF INTEREST
NUTRITIONAL SUPPLEMENTS – CREATINE
Martin Schönfelder
A
Introduction
The use of dietary supplements is widespread in sport worldwide and it is not
limited exclusively to athletes competing at the highest level of competition.
Many of these supplements are also commonly used in popular sport as well.
The main reasons for using dietary supplements are to enhance physical
performance, to promote health, to reduce risk of getting sick and at least to
control body weight.
One of the main risk factors of dietary supplements alongside positive doping
testing by contaminated supplements [1-3] is the matter of fact that a lot of
sportsmen are using supplements without the knowledge of side effects and
recommended intake levels. In the face of the great market of nutritional
supplements (about 12 billion US$ in the USA in the year 2001) and the
tremendous selling of about 3 million kilograms of creatine (Cr) worldwide in the
year 2000, the edge between a recommended use and misuse is floating.
Although the ergogenic potential of this naturally occurring guanidine compound
was extensively studied beginning in the early 1990s [4], there are still open
questions concerning health risk of long term usage of creatine.
This chapter does not purport to be an exhaustive review containing all
published literature in extenso, however, this review should give a critical
overview about a dietary substance which has risen on top of shopping lists of
professional and popular sportsmen and which is presently not signed on the
list of banned substances by the International Olympic Committee.
B
Biochemistry of Creatine: From Synthesis to Storage
Cr itself was first isolated in 1832 by a French chemist named Michel Eugène
Chevreul. Another scientist - Lieberg - confirmed that Cr was a regular
constituent of flesh extracted from mammals. His extensive research in 1847
with wild foxes concluded that muscle work involves an accumulation of
creatine. Around this time, the researchers Heintz and Pettenkofer discovered a
substance in urine called creatinine (Crn). It was speculated that Crn originated
from the Cr stored in muscles.
Creatine
155
Nowadays it is known that Cr (methylguanidine acetic acid) is a derivate of
amino acids which is both endogenously synthesized in the liver, pancreas,
respectively the kidneys, and partly ingested by an omnivorous diet [4]. The
biosynthesis, which is integrated in the arginine metabolism [5], consists of a
two-step reaction which involves the amino acids glycine, arginine, and
methionine (Fig. 1).
Figure 1. Proposed interorgan pathway for creatine synthesis. GAA, guanidinoacetate;
SAM, S-adenosylmethionine; SAH, S-adenosylhomocysteine [5].
In the first reversible reaction, catalyzed be L-arginine:glycine
amidinotransferase (AGAT), arginine donates an amidino group to glycine to
form guanidinoacetate (GAA) and ornithine. In the second irreversible step,
catalyzed by the enzyme guanidinoacetate N-methyltransferase (GAMT), GAA
is methylated by S-adenosylmethionine (SAM) to form S-adenosylhomocysteine
(SAH) and Cr. The total body content of Cr is approximately 120 g for a 70 kg
man, most of which is present in muscles and brain. Cr, respectively
phosphocreatine (PCr), are liable to spontaneous, nonenzymatic cyclisation to
Crn at a rate corresponds of 1.7 % of total body Cr pool. In correspondence to
the total muscle mass an adult human excretes 1-2 g Crn/d.
If the source of Cr runs dry, PCr pools would be depleted in the muscle by the
continuous irreversible conversion of Cr into Crn, finally excreted by the
kidneys. Therefore, skeletal, cardiac and smooth muscle and brain would lose
an essential component of energy metabolism. Therefore among biosynthesis,
the estimated daily requirement of Cr for an average individual is about 1-2 g
Cr/d.
Independent of its origin, biosynthesis or ingestion, Cr is released into the blood
stream, from where it is taken up by cells, expressing the creatine transporter
(CrT). This saturable sodium- and chloride dependant transporter, belonging to
a transport gene family of neurotransmitters (GAT/NET), accomplish the Cr
156
Martin Schönfelder
transport against a concentration gradient in a variety of cell types [6,7]. The
presence of the CrT could be demonstrated for various species by protein- or
mRNA-analyses in different tissues: kidney, heart, skeletal muscle, testis, brain
and colon [8-18]. Further investigations indicating the existence of mRNA
transcripts in additional tissues, but the verification of its functional protein has
not been conducted [7]. In addition, a few studies have reported the existence
of two different mRNA transcripts and gene loci, whereby Iyer et al. have
postulated that one of the genes is exclusively expressed in the testes [19]. The
cellular localization of the CrT is predominantly in the plasma membrane
[15,20], but there are additional evidences that the CrT protein is also located in
the mitochondria. Walzel et al. showed by immunofluorescence a co-localization
of CrT protein with mitochondrial markers [21]. The regulation of the CrT activity
is possibly depending on the extracellular and intracellular Cr concentration,
briefly reviewed in [7]. Many studies indicating, that high extracellular Cr levels,
caused by a nutritional regimen, lead to an initial increase in Cr uptake and an
elevated intracellular Cr concentration. Over the time, this elevated Cr
concentration may feed back to inhibit the Cr uptake. Additionally, the total
intracellular Cr content could be increased by co-ingestion of other nutritional
ingredients, such as carbohydrates [22,23] or alpha-lipoic acid [24]; and could
vary between different muscle types [25]. Furthermore, the regulation of the CrT
possibly underlies certain regulatory proteins [26,27] and several hormones
such as insulin and catecholamines [28], increasing the electrochemical sodium
gradient across the cell membrane, which serves as the driving force of the Cr
transport.
C
Creatine: Metabolic Function and Physiological Mode of Action
Cr plays a key role in cellular energy metabolism and is found in metabolically
active cell types such as skeletal muscle and neurons. Therefore, Cr is
important for energy demand during exercise and physical activity as well as for
protein synthesis that may have health or sport performance implications.
In context of the energy metabolism, all cells use the ubiquitous energy rich
nucleotide ATP as predominant energy source. But according to the limited ATP
stores, ATP has to be recycled by other metabolic processes. Subject to the
intensity of the exercise and consequently to the energy demand,
phosphocreatine (PCr) stores, anaerobic glycolysis and at least oxidative
metabolism provide the regeneration of ATP [29,30]. However, it is well
established that PCr stores may be more important for short lasting intensive
exercise and that in most cases Cr supplementation increases total body Cr,
Creatine
157
PCr stores and PCr resynthesis [31-33]. Energy production and interconversion
of PCr and ATP is facilitated by the cellular enzyme creatine kinase CK [34]. For
cytoplasmic CKs there exit three different dimeric isoenzymes, which are
composed of two different monomeric subunits type M and type B: MM-CK in
the muscle, MB-CK in the heart and at least BB-CK in the brain. In addition, a
fourth CK isoenzyme is located in the mitochondrial membrane [35,36]. Under
conditions of high intensive exercise the resynthesis of PCr could be a limited
factor. The PCr pool is supposed to be an energy buffer which is involved in a
creatine phosphate shuttle concept coupling glycolysis and/or oxidative
processes in the mitochondria [37-39].
Figure 2. The phosphocreatine pathway for intracellular energy transport. ANT =
adenine nucleotide translocase; CKmito and CK = mitochondrial and myofibrillar creatine
kinases, correspondingly; PCr and Cr = phosphocreatine and creatine, respectively [39].
Beneath the energy demand during exercise, PCr, respectively Cr, is involved in
further processes which possibly could influence or may explain the
enhancement of physical performance:

Buffering hydrogen ions (H+): H+ +PCr + ADP – Cr + ATP. This
reaction may serve to attenuate the decline in pH levels during intense
exercise and may delay fatigue [71]

Metabolic regulation of mitochondrial respiration, possibly influencing
oxygen kinetics during exercise [39-43]
158
D
Martin Schönfelder

Alteration of gene expression of muscle myogenic factors in humans
such as myogenic regulatory factor 4 or myogenin [44,45]

Some authors postulate a possible stimulation of protein synthesis
and/or anticatabolic effects respectively [46], but some negate a
stimulatory effect [47,48]

Increased satellite cell mitotic activity [49]

Changes in myoplasmic ionic strength and total body water composition
[50-52]

Increasing glycogen stores in muscle cells [23,53-55]
Consumption and Knowledge of Creatine
In context of the tremendous selling of Cr worldwide it would be very interesting
which kind of sportsmen use Cr as a nutritional supplement or which kind of
sport shows the highest incidence of its use. Table 1 illustrates an overview
about studies which are engaged with the evaluation of Cr usage in different
kind of sports or populations.
Own results, generated by questionnaires with in a cohort of German freshman
students (n=238, mean value of age: male = 23.8y / female = 23.7), indicate
that there is a tremendous lack of knowledge about nutritional supplements
(Schoenfelder and Kieweg, unpublished). Only 27.7% of the asked students
think that Cr gains its postulated effects, whereby 11.5% say no and 57.4% do
not know anything about its effects. About 77% of all do not know the right
dosage of Cr and additional 48.9% do not know the natural source of Cr.
Furthermore 14.9% of the asked students think that vegetables (11.5%) or fruits
(3.4%) are the natural sources of Cr. Concerning to the question of the Cr
usage a sex specific distribution could be elucidated. Only 2.2% of the female
students reply that they use Cr irregularly (0% regular use). In contrast, 3.5% of
the male students use regularly and 10.4% use irregularly Cr as a nutritional
supplement. A comparable sex specific diversity has also been shown by other
authors [57,59,63,64,67].
Creatine
159
Table 1. Evaluation of the use of creatine and nutritional supplements by
questionnaires. N = responder sample sizes; NS = nutritional supplements; Cr =
creatine; F = female; M = male.
Reference
Population
N
Age (y)
NS use
Cr use
Comments
McGuine et al. [56]
high school athletes
4011
16.1±1.2
-
All: 16.6%
F: 3.9%
M: 25.3%
Ray et al. [57]
674
15.9 (13-19)
-
All: 16%
F: 2%
M: 23%
creatine use in all high school
grades; usage increase with age
high encouragement for Cr use by
friends, coach and parents
26% of creatine users indicate side
effects; creatine use in all high
school grades; usage increase with
age
coach
Jonnalagada et al. [58]
18.2±0.5
42%
M: 36%
Metzl et al. [59]
Male freshman football 31
players
1103
Morrison et al. [60]
commercial gym
222
84.7%
All: 5.6%
F: 1.8%
M: 8.8%
All: 33%
grades
usage increase with age
Cr usage decrease with age
Kristiansen et al. [61]
varsity athletes
211
98.6%
M: 9.2%
no Cr use in females
controls
91
Huang et al. [62]
Canadian athletes
(Atlanta)
Canadian athletes
(Sydney)
adolescents from high
school
elite athletes
not asked
94.3%
M: 3.3%
257
18-30; 3145; 46+
f: 20.7±1.6
m: 21.3±2
f: 21.9±2.8
m: 22.7±4.5
-
69%
All: 14.4%
300
-
74%
All: 11./%
333
15.4±1.1
-
1222
f: 21.4±4.6
m: 23.2±4.7
F: 2.2%
M: 7.7%
F: 3%
M: 12%
controls
1203
f: 24.6±6.5
m: 25.2±6.2
Greenwood et al. [65]
Division I collegiate
athletes
219
-
All: 53%
F: 54%
M: 51%
All: 42%
F: 52%
M: 32%
-
Juhn et al. [66]
LaBotz [67]
collegiate athletes
varsity athletes
52
806
-
-
Mason et al. [68]
Male football players
495
-
Female volleyball
players
High school football
players
407
-
All: 5%
M: 8%
F: 2%
All: 75%
All: 28%
F: 4%
M: 48%
All: 3%
M: 6%
F: >1%
1349
-
-
M: 30%
78
328
11-18
14-18
-
5,2%
All: 8.2%
Bell et al. [63]
Sundgot-Borgen et al. [64]
McGuine et al. [56]
O´Dea [69]
Smith & Duhn [70]
High school athletes
High school athletes
F: 0%
M: 2%
All: 41%
89% describe positive, 38%
negative and 11% no effects by Cr
use
friends and team mates
grades
usage increase with age
Cr use in small schools 41%, in
large schools 29%
78% of the Cr users are male
football players; age of Cr users is
significant higher than non users;
friends; 67% of Cr users consume
other supplements
160
Martin Schönfelder
E
Effects and Side Effects of Creatine Supplementation
In 1999 Williams et al. [71] published an exhaustive summary on Cr
supplementation and its various effects on physical performance. For 80
studies, focused effects on anaerobic power, they conclude that 50 studies
showed an ergogenic effect and 42 reported nonergogenic effects and
numerous studies showed both. In addition, most of the significant results were
obtained in a laboratory environment but only a few field studies showed
significant ergogenic results. In the context of an enhancement in prolonged
(>30 to <150 sec) high-intensity tasks 12 of 22 analysed studies reported
improvements in performance. Almost all reports on swim performance showed
a nonergogenic effect of Cr supplementation [71]. At least the minority of
studies indicate a support of efficacy of creatine in improving performance in
tasks greater than 150sec in duration. Additionally, recent studies may support
the opinion that Cr supplementation enhances performance in high-intensity,
short-duration single or repetitive aerobic exercise. Studies on aerobic cycling
exercise indicate that there exists no significant increasing in performance [7277]. Almost all authors report no beneficial effect by Cr supplementation on
blood lactate concentration, cardiovascular system or oxygen uptake. The only
enhancing or modulating effects which were described are:

lowering of plasma concentration of ammonia and hypoxanthine [72],

significant increase of individual lactate threshold [78],

reduced fall of blood glucose concentration during endurance exercise
[73],

Cr induced hyper-hydration can result in a more efficient
thermoregulatory response during prolonged exercise in the heat [79],

decrease in muscle inosine monophosphate [74],

increase in fat free mass [80],

decrease in submaximal VO2 and maximum heart rate [81].
According to the great variety of results it is necessary to perform criteria for the
execution of scientific research in this field. Additionally, it is indicated to
generate meta-analyses and systematic reviews to support the described
beneficial results of narrative reviews. To make up the summary of Williams et
al. for the years 2000 up to now in the context of power performance, an own
study was set up to quantify and effects sizes (ES) for the different variables of
body composition and the performance of different strength components
(Schönfelder and Loeppert, unpublished). The quality assessment of the
Creatine
161
included studies was examined on the basis of the following criteria:
randomization, (double) blinding, dropouts/withdrawals, population and
selection criteria, uninterpretable/intermediate results, execution of the tests,
training and supplementation with their results (see Table 2). Small, but
significant (p=0.05) ES were reported for body composition components:
increase in body mass [BM] (0.17±0.08) and fat free mass [FFM] (0.31±0.17).
The ES of percent body fat [BF] (0.04±0.01) and fat mass [FM] (-0.04±0.16)
were not significantly greater than zero. ES was greater for change in BM
following a loading and maintenance regimen (0.37±0.15), compared to a
loading-only (0.05±0.11) or maintenance-only (0.19±0.18) regimen. There was
a significant (p=0.05) ES for one repetition maximum bench press performance
(0.41±0.17), but no significant ES for isometric strength of the knee extension
(0.23±0.19). There were no differences in body composition or strength
performance ES between males and females.
In the context of beneficial effects or no-effects of Cr supplementation the
question for the side effects has also to be posed. Based on questionnaire
studies (compare Chapter D) also negative effects of Cr are evident. Although
most side effects are anecdotal, their evidence should not be underestimated
because in context of long term usage of Cr in most cases scientific data are
missing. The most described adverse effects of which are mentioned in
questionnaire studies are: stomach and muscle cramps, diarrhea, nausea,
dizziness, increased thirst, gastrointestinal distress and dehydration
[57,65,66,118]. The fact that oral supplemented Cr reaches almost all organ
systems, this nitrogenious guanidino compound could have several metabolic
properties. On basis of the critical review of Juhn and Tranopolsky in 1998 [119]
table 3 will sum up Cr metabolism in various organ systems and concerns
regarding the effects of oral Cr supplementation.
Table 2: Alphabetical summary of studies in context Cr supplementation, body
composition and power performance in the years 2000 until now (see next page).
BC = Body Composition, IT = isotonic power work out, IM = isometric power work out,
IK = isokinetic power workout. RDBPK = randomized, double blinded, placebo controlled;
RSBPK = randomized, single blinded, placebo controlled; RDBPKX = randomized,
double blinded, placebo controlled, cross over
162
Martin Schönfelder
Table 2:
Creatin Supplementation
Loading
Reference
Year
n
ncr
Ahmun et al. [82]
2005
14
Arciero et al. [83]
2001
30
10
10
Ayoama et al. [84]
2003
26
7+6
7+6
Bemben et al. [85]
2001
25
9
8
Bemben et al. [86]
2001
19
11
8
8
8
Bennett et al. [87]
2001
16
Biwer et al. [88]
2003
15
Brose et al. [89]
2003
28
14
Burke et al. [90]
2003
24
Canete et al. [91]
2006
16
npl
nc
10
8
Maintain
Total
sex
Age
Population
Design
g/d
d
g/d
d
g
m
20,6
rugby
RDBPKX
20
5
-
-
100
Effect size
BC
m
21
unseasoned persons in
strength training
RDBPK
20
5
10
23
330
IT, BC
f
19,4
female softball players
RDBPK
20
7
3
14
182
IM, IK
m
19,2
NCAA Division I football
RDBPK
20
5
5
58
390
IK, IT, BC
m
20,4
untrained Sedentary
working students
RDBPK
20
5
5
5
125
IM, BC
IT, BC
m
25,6
soldiers
RDBPK
20
6
6
28
288
f/m
n.b.
soccer
RDBPKX
21,2
6
-
-
141
BC
14
f/m
68,6
healthy seniors
RDBPK
-
-
5
98
490
IM, IT, BC
12
12
f/m
32,5
recreational athletes
RDBPK
17,4
7
4,4
49
335
IT,IK,BC
10
6
f
67,5
healthy seniors
RSBPK
17,5
7
-
-
122,4
BC
Carter et al. [92]
2005
20
10
10
m
56,1
healthy seniors
RDBPK
7
3
5
45
246
IK
Chilibeck et al. [93]
2004
24
13
11
f/m
27,1
-
RDBPK
-
-
15,4
42
648,5
IT, BC
Chrusch et al. [94]
2001
30
16
14
m
70,8
Low active seniors
RDBPK
26,4
5
6,2
79
621,8
IT,IK,BC
Cornish et al. [95]
2006
17
9
8
m
19,4
ice hockey
RDBPK
23,3
5
-
-
116,7
IK
Eckerson et al. [96]
2004
10
f
22
moderate active and
unseasoned volunteers
in strength training
RDBPKX
20
5
-
-
100
BC
Eckerson et al. [97]
2005
61
20
20
f/m
21
Moderate active people
seasoned volunteers in
strength training
RDBPK
20
6
-
-
120
BC
Eijnde et al. [98]
2003
46
23
23
m
63,1
moderate active and
RDBPK
-
-
5
180
900
IM, BC
Falk et al. [99]
2003
28
15
13
m
22,3
strength training
RDBPK
-
-
5
56
280
IT, BC
Ferguson et Syrotuik
[100]
2006
26
13
13
f
24,6
strength training
RDBPK
19,7
7
1,97
63
261
IT, BC
Finn et al. [101]
2001
16
8
8
m
26,7
triathletes
RDBPK
20
5
-
-
100
BC
Glaister et al. [102]
2006
42
21
21
m
20
sport stundents
RDBPK
20
5
-
-
100
BC
Hoffman et al. [103]
2005
40
20
20
m
21,4
sportive active
volunteers
RDBPK
6
6
-
-
36
BC
20
Hoffman et al. [104]
2006
33
11
11
m
n.b.
college football players
RDBPK
-
-
10,5
70
735
IT, BC
Izquierdo et al. [105]
2002
19
9
10
m
22,2
handball
RDBPK
20
5
-
-
100
IT, BC
Kilduff et al. [106]
2002
32
21
11
m
24,5
strength training
RDBPK
20
5
-
-
100
IM, BC
2003
19
9
10
m
20,7
RDBPK
20
7
5
21
245
IT, IM, BC
2004
21
11
10
m
27,5
endurcance trained
volunteers
RDBPK
20
7
-
-
140
BC
Lehmkuhl et al. [109]
2003
29
10
9
Parise et al. [110]
2001
22
14
8
11
10
f/m
19,6
athletics
RDBPK
21,2
7
2,12
49
252,4
BC
f/m
23
sportive active
volunteers
RDBPK
20
5
5
4
120
BC
Pluim et al. [111]
2006
36
24
12
Selsby et al. [112]
2004
31
10
10
Stevenson et Dudley
[113]
2001
31
18
13
f/m
Volek et al. [114]
2001
20
10
10
m
Volek et al. [115]
2004
17
9
8
m
21
Watsford et al. [116]
2003
20
9
11
Willoughby et Rosene 2001
[117]
22
8
8
10
6
m
22,7
tennis
RDBPK
22,2
6
2,22
28
195
IM
m
20,4
strength training
RDBPK
2,5
10
-
-
25
IT
24
strength training
RDBPK
20
7
-
-
140
IM, IT
23
volunteers
RDBPK
24,6
7
-
-
172
BC
strength training
RDBPK
26,6
7
13,3
21
465,5
IT, BC
m
23,4
healthy adults
RDBPK
20
7
10
21
350
IM,BC
m
20,4
sportive inactive
volunteers
RDBPK
-
-
6
84
504
IT, BC
Creatine
163
Table 3. Cr metabolism in various organ systems and concerns regarding the effects of
oral Cr supplementation: an update with recent studies based on Juhn and Tranopolsky
[119].
Organ system /
effect
Comments
Cardiovascular
No changes in cardiac muscle Cr concentration in rats (7% Cr
weight); creatine feeding does not attenuate left ventricular
remodelling in rat hearts post-myocardial infarction [120,121]
No change in cardiac ejection fraction [122]
Cr supplementation and swimming exercise stress potentially
alters cardiac protein synthesis [123]
In heart, Cr transport is determined by the content of a plasma
membrane isoform of the CrT but not by the total cellular CrT
pool [124]
Dietary Cr increases cardiac muscle high energy phosphate
reserves and its oxidative potential [125]
Cr administration does not affect blood pressure neither in
men nor in women [126]
No changes in any of the echocardiographic or blood pressure
measurements [81]
Gastrointestinal
Diarrhoea and gastrointestinal pain are anecdotally reported,
but no direct relationship established.
No significant differences in the occurrence to Cr
supplementation were found in context to nausea,
gastrointestinal discomfort diarrhea in an 310 day trial [127].
Liver
Cr supplementation shows minimal or no liver enzyme
elevation [128].
Cr has no long-term detrimental effects on liver functions in
highly trained college athletes [129].
Musculoskeletal
Because of water retention in muscle cell, there is theoretical
concern about muscle cramps and tears, but causal
relationship is not established [130,131].
Neurologic
Cr is naturally found in brain tissue. The effect of oral Cr on
brain Cr concentration is unknown [132], but recent studies
could indicate possible beneficial effects:
Expression profiling showed an upregulation of genes
implicated in neuronal growth, neuroprotection, and learning
[133].
Cr supplementation appears to improve high-energy
phosphate turnover in healthy brain and can result in either a
decrease or an increase in high-energy phosphate
concentrations [134].
164
Martin Schönfelder
20g/d ingested Cr augmentation does not alter the magnetic
resonance visible Cr pool in the deep frontal cerebral white
matter of young active sportsmen [135].
Cr supplementation had a significant positive effect on both
working memory and intelligence in young, adult, vegetarian
subjects [136].
Excess consumption of Cr yields regionally dependent
increases of the total Cr concentration in human brain over
periods of several weeks [137].
Oncologic
Cr and PCr/Cr kinase system may influence cellular
oncogenesis. Long term studies would help to determine if oral
Cr is beneficial, detrimental, or has no effect on healthy
subjects in this regard. [138,139].
Cr ingestion does not lead to increased formation of the
carcinogen N-nitrososarcosine [140].
Anticancer effect of methylglyoxal was significantly augmented
by ascorbic acid and creatine [141].
Pediatric/adolescent
Theoretical concerns exist regarding extra load placed on
developing kidney/other organs and the effects of creatine on
muscle/bone junctions in the skeletal immature [59,142].
In context of high usage of Cr adolescent subjects [57]
physicians, athletic trainers, and coaches should disseminate
proper information and advise these adolescent athletes.
Renal
Urinary excretion of Cr increases up to 90-fold, though
glomerular filtration rate unchanged, at least during 5-day
loading phase. Elevation of serum and urinary creatinine also
occurs, but generally small in studies of <28 days. Concern
lies with unknown effects of longer term supplementation. The
results on long term effects are inconsistent.
Neither short-term, medium-term, nor long-term oral creatine
supplements induce detrimental effects on the kidney of
healthy individuals [129,143-145].
The use of creatine alone induced an important and significant
reduction of both renal perfusion and glomerular filtration rate
in rats [146].
Reproductive organs
Cr is normally synthesized in the testes by the Sertoli cells
with the seminiferous tubules. Cr and PCr are involved in
sperm metabolism, but no studies exist on the effect of oral
supplementation. As with liver, concern regarding reversibility
of the suppression of endogenous Cr synthesis.
In pregnant mice, exogenous application of Cr is effective in
neuroprotection. ATP as well as PCr concentrations were
increased during anoxia in pups of creatine fed mice [147].
However human system remains unstudied.
Creatine
165
Weight gain
Proven to occur in many studies. Initially caused by water
retention. With prolonged use, increased muscle synthesis
may also occur [148-150].
Dehydration
Intracellular fluid retention in the muscle cell may predispose
to dehydration, but studies are lacking. Proper hydration
during supplementation is encouraged [33].
Thermoregulation
Short-term supplementation has no adverse effect on
thermoregulatory responses during exercise in heat [151-158].
Cr and glycerol could be
hyperhydration
capable
of
cardiovascular responses [159].
an effective method of
reducing
thermal
and
Anti aging
Median healthy life span of Cr-fed mice was 9% higher than in
control mice. In brains of Cr-fed mice a trend of reduction of
reactive oxygen species and significantly lower accumulation
of the "aging pigment" lipofuscin; upregulation of genes
implicated in neuronal growth, neuroprotection, and learning
[160].
Long term effects
Unknown in any human organ system. Studies involving 12
months or more are needed, preferably with lager sample
sizes than previous studies.
Several studies have shown that continuous Cr intake for
three months or more can lead to a habituation in healthy
muscle [161].
In summary of possible side effects of Cr supplementation, at the moment there
is no scientific evidence that the short- or long-term use of Cr has any
detrimental effects on otherwise healthy individuals, with exception of weight
gain. This statement is also supported by several reviews recently published by
Terjung and colleagues [162], Poortmans and Fanrcaux [143] and at least
Bofrod and colleagues [163]. The latter formulated a position statement for the
International Society of Sports Nutrition which declares that Cr supplementation
“within the established guidelines is safe, effective, and ethical”. However,
athletes should be educated as to proper dosing or to take creatine under
medical supervision.
In this context of safety other questions arise which depends not directly on the
potential health risk of excess Cr supplementation itself. Next to the fact that
several nutritional supplements are contaminated with substances, e.g. nonlabelled anabolic agents [1-3] - potentially leading to positive doping testing recent reports of Benzi [164] and Yu and Deng [165] indicate additional
potential cytotoxic effects. Benzi [164] mentioned that the major point related to
the quality of Cr products used by humans is the amount of Cr ingested in
relation to the amount of the contaminants present in the consumer products.
166
Martin Schönfelder
During the industrial process of synthetic Cr production from sarcosine and
cyanamide, variable amounts of contaminants are generated; thereto belong
also dicyandiamides (derivative of the starting cyanamide), dihydrotriazines (byproducts of non-optimized creatine production), creatinine (by-product of
industrial Cr production) and ions (such as sodium and calcium). In some cases
the potential risk factors of these by-products are not clarified in detail,
especially for long-term administration to human beings. Therefore, it has to be
defined what is the maximal tolerable content of these substances in
commercial products.
Yu and Deng [165] showed in there recent study that Cr is metabolized to
methylamine, which is further converted to formaldehyde (Fig. 3) by
semicarbazide-sensitive amine oxidase (SSAO). Formaldehyde is well known to
cross-link proteins and DNAs. SSAO-mediated production of toxic aldehydes
has been recently proposed to be related to pathological conditions such as
vascular damage, diabetic complications, nephropathy, etc. [167,168].
Therefore long-term supplementation of large quantities of Cr products can
increase the production of formaldehyde, which may potentially cause serious
unwanted side effects.
Creatine
167
Figure 3. Pathway of creatine metabolism by Persky and Brazeau [166]. Catalyzed by
AGAT (1), catalyzed by GAMT (2), catalyzed by creatine kinase (CK) (3), spontaneous
(4), catalyzed by creatine amidohydrolase (5), catalyzed by glycine oxidase (6), and
catalyzed by semicarbazide-sensitive amine oxidase (SSAO) (7). Dotted pathway
indicates recently hypothesized toxic formation of formaldehyde by Yu and Deng [165].
168
F
Martin Schönfelder
Creatine in the Context of Ethics and Doping
As manifold the described effects and potential side effects of Cr
supplementation, as diverse are the opinions about Cr in context to ethics and
doping. Several authors postulate that Cr supplementation is safe, effective and
ethical [163]. In most case of high intensive and short duration exercise it is
indisputable that Cr supplementation may bring out an increase in physical
performance. But there still exist unanswered questions on health and
psychological long-term effects, possible impacts on human growth, and at least
the question looking forward to the “gateway theory” which is possibly related to
adolescence supplement and other drug use [169]; or is it more appropriate to
ask whether the Cr supplementation is “save as steak” [170]? The depicted
literature suggests that oral Cr supplementation may increase muscle levels of
Cr/CrP and enhance performance. But in most cases a high dose
supplementation regime – approximate 20-30 g Cr per day - is necessary to
gain the requested aim. Beneath commercially available Cr supplements the
best natural dietary source of Cr is meat and fish. To displace just a common
daily dose of 5 g Cr, for example during a maintenance regime, it is needed to
eat about 1 kilogram of uncooked meat or fish; additionally Cr is unstable in
heat, so cooking additively reduces the natural Cr content [171,172]. Although
Cr is a naturally occurring compound and is therefore not foreign to the human
body, an intake of about 30 g would appear to contravene the doping law
because the amount consumed may be abnormal in comparison to normal
dietary intakes and may be taken with the primary intent of enhancing
performance. But currently Cr supplementation is not banned by any athletic
organization, although the NCAA, the largest collegiate athletic organization in
the world, enacted the ban in the year 2000 to its associated institutions that
they were not allowed to provide Cr or other “muscle increasing” supplements to
their athletes. Additionally, in January 2001 the France's Food Safety Agency
banned the use of Cr because of potential carcinogenic risk in context of longterm supplementation. The international Olympic Committee (IOC) considered
these arguments and ruled that there is no need to ban Cr supplements since
Cr readily available in naturally sources. Furthermore, the IOC depict that there
is still no valid test to determine whether an athlete using Cr supplements or Cr
is of naturally origin [163]. In contrast to this argumentation on valid test
systems, in the year 2002 Cartigny and co-workers from France published a
study to discriminate between naturally ingested Cr and artificial supplements of
Cr. On basis of 1H nuclear magnetic resonance (NMR) spectroscopy they
presented an easy urine test as an effective tool to detect Cr supplementation
[173]. Their work documented that Cr can be analysed and quantified by 1H
Creatine
169
NMR without any pretreatment of urine samples, except for pH 5 adjustment.
The results indicated that it is possible to separate between natural and artificial
Cr within 24 hours after supplementation.
And if we mindfully read the “story of creatine”, we inevitably find the publication
of Kalinski [174] on state-sponsored research on Cr supplementation in elite
soviet sport. The countries of the former Soviet Union have a long history of
research in exercise biochemistry but, because of inaccessibility of soviet
journals, lack of familiarity with the language, and the secrecy surroundings this
research is not well known in the West. On basis of the research of Palladin and
Volkov the Central Institute of Physical Culture in Moscow initiated a long-tem
research program to characterize the role of Cr in muscular performance. So it
could be shown that routinely given Cr led to an improvement of about 1% in
100-meter dash and 1.7% in 200m-meter sprint [174]. Of course, this was not
only the practise in the former Soviet Union, but the ideology of enhancing
performance by artificial substances is still evident. And we have to ask: "Is this
a case of doping or is it possibly comparable to carbo loading?" And as long as
it is impossible to fill up Cr stores with natural dietary sources like it works with
“artificial” supplements, Cr should not be labelled as save and ethical.
G
Conclusion
In today’s literature, most but not all studies depict a positive effect on shortterm (less than 2 months) oral Cr supplementation on muscle in both healthy an
ill humans. Additionally, Cr is indisputable one of the most used nutritional
supplements in serious and popular sports, and especially adolescents may
regard the use of performance-enhancing substances as an easy way to gain
self-esteem through improved body appearance and athletic performance.
Although many side effects are anecdotal and short-term supplementation of
creatine has not been associated with major health risks, there are still existing
open questions on safety and in particular the use of performance-enhancing
supplements by adolescents is troubling because of the lacking safety data. On
the other hand, the phenomenon of a possible habituation in healthy muscle to
Cr supplementation for three months or more requires a systematic and
intermitted regime of intake leaving a slight mark of “doping”. In addition, if it is
not possible to fill up Cr/CrP stores with natural Cr sources, like it works with
artificial Cr supplements, the question for “doping or not” is also still
unanswered. Therefore, it is recommended that in this context of further studies
have to clarify long-term effects under the maxim to elucidate health risk, to
evaluate basis data on urinary Cr concentration in sportsmen concerning Cr
170
Martin Schönfelder
intake, and to prove and/or validate alternative techniques such as NMR
spectroscopy as a tool to discriminate natural and artificial produced Cr in urine
samples.
H
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Thermoneutral Environment. J. Athl. Train. 39 (39): 50-55, 2004.
157. T. Bennett, G. Bathalon, D. Armstrong, III, B. Martin, R. Coll, R. Beck, T.
Barkdull, K. O'Brien, and P. A. Deuster . Effect of creatine on performance
of militarily relevant tasks and soldier health. Mil. Med. 166 (166): 9961002, 2001.
158. J. S. Volek, S. A. Mazzetti, W. B. Farquhar, B. R. Barnes, A. L. Gomez,
and W. J. Kraemer . Physiological responses to short-term exercise in the
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supplementation
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cardiovascular,
metabolic,
and
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160.
161.
162.
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164.
165.
166.
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168.
169.
170.
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A. Bender, J. Beckers, I. Schneider, S. M. Holter, T. Haack, T. Ruthsatz,
D. M. Vogt-Weisenhorn, L. Becker, J. Genius, D. Rujescu, M. Irmler, T.
Mijalski, M. Mader, L. Quintanilla-Martinez, H. Fuchs, V. Gailus-Durner, M.
H. de Angelis, W. Wurst, J. Schmidt, and T. Klopstock . Creatine improves
health and survival of mice. Neurobiol. Aging, 2007.
W. Derave, B. O. Eijnde, and P. Hespel . Creatine supplementation in
health and disease: what is the evidence for long-term efficacy? Mol Cell
Biochem. 244 (244): 49-55, 2003.
R. L. Terjung, P. Clarkson, E. R. Eichner, P. L. Greenhaff, P. J. Hespel, R.
G. Israel, W. J. Kraemer, R. A. Meyer, L. L. Spriet, M. A. Tarnopolsky, A. J.
Wagenmakers, and M. H. Williams . American College of Sports Medicine
roundtable. The physiological and health effects of oral creatine
supplementation. Med. Sci. Sports Exerc. 32 (32): 706-717, 2000.
T. W. Buford, R. B. Kreider, J. R. Stout, M. Greenwood, B. Campbell, M.
Spano, T. Ziegenfuss, H. Lopez, J. Landis, and J. Antonio . International
Society of Sports Nutrition position stand: creatine supplementation and
exercise. J. Int. Soc. Sports Nutr. 4 (4): 6-, 2007.
G. Benzi . Is there a rationale for the use of creatine either as nutritional
supplementation or drug administration in humans participating in a sport?
Pharmacol. Res. 41 (41): 255-264, 2000.
P. H. Yu and Y. Deng . Potential cytotoxic effect of chronic administration
of creatine, a nutrition supplement to augment athletic performance. Med.
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A. M. Persky and G. A. Brazeau . Clinical pharmacology of the dietary
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H. Kinemuchi, H. Sugimoto, T. Obata, N. Satoh, and S. Ueda . Selective
inhibitors of membrane-bound semicarbazide-sensitive amine oxidase
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Correspondence
Martin Schönfelder, Technische Universität München, Institute of Public Health
186
4.2
Thorsten Schulz
GENE DOPING
Thorsten Schulz
A
Introduction
In the last decades the progress in gene technology has become a real
possibility not only to treat serious diseases but also to enhance athletic
performance. For this reason gene doping was included in the list of banned
substances and methods of the WADA in 2003. The new prohibited list of the
WADA 2008 defines gene doping as "The non-therapeutic use of cells, genes,
genetic elements, or of the modulation of gene expression, having the capacity
to enhance athletic performance [1]". Independent of the exigency of a gene
doping definition, this definition shows a great dilemma, because every
physiological and morphological adaptation in the development of organisms is
based on the modulation of gene expression. Despite this all existing training
methods and models include the adaptation of the body and the mind to most
non-natural environmental forces in order to enhance athletic performance.
Also, all ingestion (of nutrition) compromises cells, e.g. probiotics are microorganisms to enhance the colon activity or to limit the degree of exerciseinduced immune depression. Creatine is able to modulate gene expression, for
example of the glucose transporter 4 (see also chapter 4.1), zinc as a nutritional
supplementation will influence zinc-sensitive genes and therefore the
expression of these genes – is this gene doping? Strictly speaking, does this
definition of gene doping lead finally to the end of the supplementation of
minerals and trace-elements, the training and professional sports?
Gene expression contains the way from the gene to the protein. This includes
the process of the transcription and the translation of the genes in form of the
RNA and furthermore, the posttranslational modification of the protein. All these
transcription and (post)translation processes incorporate manipulation factors:
the question in the detection of gene doping is therefore not only if a gene is
manipulated or if genetic elements are used. It is of course furthermore the way
how long or often a sequence on the DNA is accessible for a DNA-polymerase,
or how long a transcript is stabile and how often the translation of the transcript
occurs in order to build proteins is manipulated. The effects of many of the
forbidden methods and substances on the prohibited list base also on the
modulation of gene expression: this includes the action of the (anti-)hormones,
SARMS, blocking antibodies and so on. Another question therefore is if we
have a double definition for some manipulation factors?
Gene Doping
187
Anyway, even if the definition is debateable, fact is that there is a great potency
for gene doping, not only in future. In the following, this review will focus on
discussed principles of gene doping, the status quo of the science in this area
and major identified candidate genes which may enhance athletic performance
through gene doping.
B
Gene Technology: The Basis of Gene Doping
The definition of gene doping is based on the specific modulation of the genetic
information and the expression of genes. To study, identify or modify the genes
of living organisms, bio- and gene technology is used, a term that refers to a
whole range of tools and techniques. This includes also techniques to transfer
genetic material like DNA or RNA in order to supply possible absent
components or to compensate abnormal genes. Further techniques are the
sequencing of the DNA, the cloning technology, gene marker technology,
transgenic techniques, and gene silencing or gene therapy. All this techniques
were used by a lot of scientists like (molecular)biologists, (bio-)chemists,
geneticists or medical doctors.
In broad public, gene doping is strictly associated with gene therapy, but it is
more, it is the consequent appliance of gene technology. This runs from the use
of specific antibodies to modify (stimulate or inhibit) gene expression to a
selective modification of a cell, a gene or the modulation of a receptor to the
specific regulation of gene expression after gene transfer.
Therefore, strategies to detect gene doping must have more than one focus: on
the one hand it has to detect if a performance enhancement gene itself or a
gene modulating construct is transferred into the body and on the other hand, if
important target genes for physical performance were switched on or off with
special substances.
C
From Gene Transfer to Gene Doping
Athletic performance enhancement is not the intent of molecular geneticists and
biochemists. There are a lot of common diseases underlying a genetic cause: a
lot of cancer diseases as well as Duchenne Muscular Dystrophy (DMD),
Alzheimer and Parkinson have genetic reasons. DMD, for example, is a muscledestroying disorder that affects 1 in 3,500 young boys and typically limits their
lifespan to no more than 30 years. In order to heal such disorders the idea of
the “adjustment” of the dysfunctional or deleted genes was born, the gene
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Thorsten Schulz
therapy. In short words gene therapy can be defined as an experimental
technique that uses modified genes to treat or prevent disease. The most
common form of the gene therapy is to insert a normal gene in a nonspecific
location of the genome to replace an abnormal gene. Further approaches
include
swapping of an abnormal gene for a normal one through homologous
recombination,
repairing of an abnormal gene through selective reverse mutation, which
returns the gene to its normal function,
and altering the regulation to which a gene is turned on or off (antisense
therapy).
Since 1989 more than 1300 gene therapy clinical trials have been approved
world wide, most of them, 869, in the US. But only about 2.5% of those studies
were clinical phase III trials, in which more than 200 subjects were tested for a
therapeutic effect. John Wiley refers the gene types transferred in clinical trials
as follows [2]:
Marker
4,1%
Oncolytic virus
2,1%
Hormone
0,3%
Porins, ion
channels,
transporters
0,7%
Receptor
5,1%
Replication
inhibitor
3,7%
siRNA
0,8%
Suicide
8,2%
Growth factor
8,2%
Transcription factor
1,4%
Deficiency
7,9%
Cytokine
18,9%
Cell
protection/Drug
resistance
1,2%
Ribozyme
0,5%
Tumor suppressor
12,0%
Cell cycle
0,2%
Antisense
1,0%
Antigen
20,4%
Unknown
2,9%
Others
0,2%
Figure 1. Gene types transfered in clinical trials [2]
To transfer the modified genes into the genome, different methods and
transporters – the so-called vectors – are used. Virus-mediated gene delivery
systems were differentiated from non-virus mediated gene delivery systems.
Gene Doping
189
Furthermore ex vivo gene transfer, removed through special target cells,
transfected and then transplanted back into the body and in vivo methods,
which describe the transduction of the gene through carriers into the cells of the
body were differentiated. Most common virus vectors in clinical trials are
adenoviruses (AV) and retroviruses (RV) or the recombinant forms (rAV, rRV).
The different viral vector systems have several unique advantages and
disadvantages and therefore have special applications for which they are best
suited [3]. Non-virus systems contain the injection of naked DNA in form of a
plasmid or the lipofection, the injection of liposomes which carries the DNA,
further the electroporation or nucleofection – the direct injection of DNA in the
cell nucleus. All the non-viral vectors are relatively easy to manufacture, less
costly, and have a lower toxicity as compared to viral vectors [4].
Table 1. Vectors used in gene therapy clinical trials [2]
Vector
Gene Therapy Clinical Trials
Number
%
Adeno-associated virus (AAV)
48
3,6
Adenovirus (AD)
331
24,6
Herpes simplex virus (HSV)
43
3,2
Lipofection
102
7,6
Naked/Plasmid DNA (pDNA)
241
18,0
Poxvirus
86
6,4
Retrovirus (RV)
305
22,8
RNA transfer
17
1,3
Vaccinia virus
91
6,8
Other categories
36
2,7
Unknown
40
3,0
1340
100
Total
Although there is much hope for gene therapy, it is still experimental. And there
are still some problems which kept gene therapy from becoming an effective
treatment for genetic disease. In 1999, 18-year-old Jesse Gelsinger participated
in a gene therapy trial for ornithine transcarboxylase deficiency (OTCD). It is
believed that the adenoviral gene delivery triggered a severe immune response
and at the end he died from multiple organ failures 4 days after starting the
treatment. In January 2003 two children treated in a French gene therapy trial
190
Thorsten Schulz
using retroviral vectors in blood stem cells had developed a leukemia-like
condition. So the FDA stopped temporarily all gene therapy trials. In conclusion
problems are:
Short-lived nature of gene therapy: the therapeutic DNA introduced
into target cells must remain functional and the cells containing the
therapeutic DNA must be long-lived and stable. There are still some
problems with integrating therapeutic DNA into the genome to achieve
any long-term benefits.
Immune response: the possibility of stimulating the immune system in a
way that reduces gene therapy effectiveness is always a potential risk.
Problems with viral vectors: they include toxicity, immune and
inflammatory responses, gene control and targeting issues. Furthermore,
the viral vector itself may recover its ability to cause disease.
Multigene disorders: they are caused by the combined effects of
variations in many genes, therefore multigene or multifactorial disorders
would be difficult to treat effectively using gene therapy.
Independent of the common problems of gene therapy in clinical trials and the
occurrence of perilous long-term side effects, at the latest of the BALCO affair
and the use of Tetrahydrogestrinone (THG) it is well known, that sportsmen use
not clinically proofed substances or a pharmacological or clinical trial failed
product in order to enhance performance. For this reason not only the problem
of the misuse of gene therapy with the intention of doping is given, more over
the use of gene technology in terms of gene doping.
D
Genes and Physical Performance: Does it Work?
In recent years, evidence is growing that physical performance is determined by
genetics variants (polymorphisms). The working group around Claude Bouchard
shows yearly an update of the human gene map for physical performance and
health-related fitness phenotypes. A lot of possible genes are identified to
influence physical performance. 2005 the gene map included 165 autosomal
entries, five X chromosome assignments, and 17 mitochondrial DNA markers
[5]. But in general, it seems that only a few polymorphisms (e.g. angiotensin
converting enzyme ACE I/D polymorphism) or genes have the potential to really
enhance performance and it is more likely that any single gene polymorphism or
variant that may offer physical improvement influences the fine-tuning of
performance rather than simply conferring success or failure [6].
Gene Doping
191
Anyway, phenotypes of mice, cattle and humans with a special mutation in
genes like myostatin, follistatin or erythropoietin receptor (EPOR) and the high
performance in endurance or power of these phenotypes confirm genetic
advantages. Schuelke et al. identified a myostatin mutation in a child in Berlin:
at 4.5 years of age, the child had increased muscle development and strength,
and was able to hold two 3-kg dumbbells with his arms extended in horizontal
suspension [7]. In 1993, de la Chapelle investigated 97 members of a family
with a mutation in the C-terminal part of the EPOR gene. One of the probands,
Ero Mäntyranta, was one of the best crosscountry skiers in the world, winner of
three Olympic gold medals and two world championships. He had a Hb level of
200 g/liter or greater since childhood and 236 g/l in the last measurement. Both,
the Berlin child and Mäntyranta showed no or only harmful side effects: the
motor and mental development of the myostatin mutation child has been normal
and also Mäntyrantas family showed only a marked erythrocytosis with no or
slight clinical implications.
E
Gene Manipulation and Sports
Independent of the function of modulated genes, one of the most important
considerations of the gene transfer is the cell specific gene delivery and the
specific regulation of the genes in order to build the relevant protein.
Nowadays, there are several regulatory systems which for example control the
transferred gene by gene promoters containing specific responsive elements.
Those elements were induced by hormones (e.g. the antiprogestin mifepristone
(RU486), the prohormone ecdysone), antibiotics (tetracycline (Tet),
docyxycline), immunosupressives (rapamycine), heat shock or heavy metal ions
[8; 9].
On the basis of the different transferred genes in the clinical trials, it is likely that
gene transfer in sports will be used for increasing physical endurance capacity,
enhancing muscle size, supporting regeneration after training and reducing the
recovery for the fast resumption of training. Furthermore, training and
competition associated pain and disorders will be reduced. Indeed, it is useful to
cluster candidate genes for selective gene doping, but because of the complex
biological function, most of the regulated genes have more than one effect.
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Thorsten Schulz
Endurance genes
Endurance performance is strongly related to optimal tissue oxygenation and
allocation of energy. This implicates an enhancement of the oxygen delivering
system, e.g. the blood himself or the blood flow or the improvement of
hormones regulating and proteins which modulate the energy metabolism.
Targets of a gene-transfer or gene-modulation in this area include the hormonal
axis e.g. erythropoietin (EPO), mitochondrial genes or receptors like
peroxisome proliferator-activated receptors (PPARs), angiotensin I-converting
enzyme (ACE), or hypoxia-inducible factors (HIF) and other angiogenic growth
factors like VEGF or FGF.
ACE
Several studies have shown an association between ACE genotypes and
athlete performance [10]. Montgomery et al. (1998) found in the first case
control-study in this area an enhanced aerobic endurance performance in
correlation with ACE I-alleles in British mountaineers [11]. Furthermore, the
ACE D-allele is associated with impaired strength increase in the quadriceps
muscle as an answer to training [12], elevated fast-twitch (FT) muscle fiber ratio
[13], and better anaerobic performance [14].
Even if the present data of the polymorphisms in the ACE-allele on the athlete
performance are controversial [15], there is evidence that controlling ACE is
related to performance. Onden et al. reported a positive association between
use of ACE inhibitors and muscle strength and walking speed in elderly women
[16]. The use of ACE inhibitors in aged rats lowered the age-related decrease in
physical performance and was accompanied with a reduction in total body fat
mass [17]. It is known that ACE inhibitors block the production of angiotensin II,
an effective inhibitor of insulin-like growth factor 1 (IGF-1) synthesis. Long term
treatment with ACE inhibitors increased serum levels of IGF-1 in the elderly
[18].
ACE inhibitors and angiotensin II type I receptor blockers (ARBs) are effective
therapeutic agents in the treatment of hypertension. Therefore genetic
manipulation of this system in principle, might be an ideal method to attempt a
genetic cure for this disease. In vivo rat models show that the use of an
antisense mRNA technique successfully down-regulates transcription of the
ACE and/or the angiotensin I receptor (AT1R) [19]. Already in 1999, retroviral
vectors containing ACE sense and ACE antisense sequences were constructed
and used in rat pulmonary artery endothelial cells. The infection of the cells
Gene Doping
193
resulted in a robust expression of transcripts corresponding to ACE sense and
ACE antisense. The expression of ACE-AS but not of ACE-S was associated
with a permanent decrease of about 70% to 75% in ACE expression [20].
EPO
The effects of erythropoietin administration to stimulate erythropoiesis for
patients [21] as well as for athletes [22] or rats [23; 24], are well documented.
But dependent on the achieved hematocrit level, there are diverse effects on
performance. Heinicke et al. used a transgenic mouse line (tg6) which reaches
hematocrit levels up to 89% to study effects of excessive erythrocytosis. In
conclusion the animals had a reduced lifespan, the exercise performance during
a 120s swim test was decreased, and at age of 7 month, some animals
revealed spastic contractions of the hind limb. Nerve and muscle fiber
degeneration was also shown as degenerative processes in liver and kidney
[25]. Eliopoulos et al. found an enhanced performance in anaemic chronic renal
failure (CRF). Mice after implantation of bone marrow stromal cells (MSCs)
genetically engineered to secrete pharmacologic amounts of EPO. Even if the
treated animals reached a hematocrit level of about 55% that means to normal
values, the animals did not reach the swimming duration of the normal control
mice. In humans recombinant human EPO (rHuEPO) treatment 3 times a week
for 7 weeks (20-40 IU/kg BW) improves VO2max and running times to
exhaustion with an increase in hematocrit from 44% to 49% [24]. Anyway, it is
likely, that since rHuEPO became available as a performance enhancing drug, it
has been misused by athletes in aerobic sports.
In anaemic patients, the EPO gene therapy is a smart option for the treatment
of erythropoietic drugs: if gene therapy is able to gain balanced protein
expression in vivo, on the one hand frequent injections can be eliminated and
on the other hand, producing recombinant protein is not absolutely necessary
any more. In vivo and ex vivo techniques for EPO gene transfer have been
used. Main focus in EPO gene therapy is the regulation of EPO release in
correlation to the blood haemoglobin concentration [26]. Several different
methods have been used to transfer the EPO gene in order to produce the
protein in the aimed tissue. In in vivo animal studies pDNA or AAV vectors were
injected intramuscular or rAAV-EPO or rLV-EPO were given subcutaneous in
mice and primates. Rivera et al. describes in primates after a intramuscular
injection of different single AAV vectors a long term regulated gene expression
of more than 6 years for EPO [27]. The system was controlled by a rapamycin
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Thorsten Schulz
analogue for 26 cycles. In ex vivo gene delivery studies modified myoblasts,
fibroblasts, smooth muscle cells or marrow stromal cells were used.
Electroporation-based gene transfer (electro gene transfer, EGT) is another
new strategy in gene delivery. Some studies indicate that EGT is able to
transfer DNA to cells through electric pulses very effectively both in vitro and in
vivo [28]. In particular cells with a long lifetime e.g. muscle fibers, are of interest
for a long-term expression of transferred genes. Hojman et al. could show that
EGT transfer of EPO to the m. tibialis cranialis in mice led to a significant
hemoglobin elevation. Furthermore, a preset level of EPO expression could be
achieved by controlling the dose of inducer (doxycycline) [29].
Peroxisome proliferator-activated receptors (PPARs)
Recent studies could show that alterations in the PPARδ gene is associated
with exercise training-induced enhancement in cardiorespiratory fitness levels in
athletes [30] as well in sedentary healthy men [31]. These findings may provide
evidence that PPARs are involved in physical performance. PPARs are
transcription factors belonging to the nuclear receptor superfamily. Together
with co-activators, they are involved in anabolic/catabolic pathways. E.g.
PPARα and PPARβ/δ induce primarily genes encoding enzymes involved in
fatty acid oxidation, whereas PPARγ activates genes involved in lipogenesis
[32] and also plays an essential role in insulin sensitivity and adipocyte
differentiation. Furthermore PPARδ is a regulatory factor responsible for muscle
development.
Transgenic studies show that PPARs are possibilities for gene doping. A
transgenic mouse line overexpressing wild-type PPARδ in skeletal muscle
showed both development and metabolism capability of muscles by increasing
fibres with oxidative metabolic capabilities. The raise was related to both
hyperplasia and shifts from glycolytic to oxidative fibres and was similar of that
aided by endurance training [33]. Wang et al. engineered a transgenic mouse
able to run up to twice the distance of a wild-type littermate. This was achieved
by a constitutively activated form of PPARδ in skeletal muscle, which promoted
a switch to form high numbers of type I muscle fibers [34]. While all the
described studies used transgenic mice expressing the transgene during the
whole development, Lunde et al. showed with an in vivo transfection in normally
active adult fibres that the somatic gene transfer tripled the number of I/IIa
muscle fibre hybrids of a skeletal muscle, IIa fibres nearly doubled, and IIb
fibres decreased [35]. Furthermore, the enzyme activity of succinate
dehydrogenase was enhanced in these fibres. Even if Lunde et al. has not
Gene Doping
195
evaluated these findings in a running test to show performance enhancement,
he was able to show in the absence of general exercise that altering PPARδ
can change muscle fibre composition, oxidative enzymes and size in muscle
cells.
Further, several animal and human studies indicate that the peroxisome
proliferator-activated receptor-γ coactivator 1α (PPARGC1A) gene product is
also associated with endurance capacity. The PPARGC1A gene coactivates the
OXPHOS genes which control oxidative phosphorylation and therefore plays a
role in the development of maximal oxygen uptake (VO2max). Anyway, Lucia et
al. found that PPARGC1A genotype (Gly482Ser) predicts exceptional
endurance capacity in European men [36].
Hypoxia-inducible factors (HIFs)
Members of the hypoxia-inducible factor (HIF) family are key mediators of
genes involved in the hypoxic response. Three HIF-α subunits (HIF1-α, HIF2-α
and HIF3-α) and a HIF-β subunit (with several splice variants) were identified.
Only the α-subunit is in contrast to the β-subunit under control in response to
changing oxygen levels [37]. However, to date more than 70 target genes
involved in the response to hypoxia have been identified that are regulated by
HIF-binding to hypoxia response elements (HRE) [26]. The regulated genes
including those encoding for oxygen supply (e.g. EPO, vascular endothelial
growth factor (VEGF), nitric oxide synthase (NOS)), HIF control, transcription,
cellular metabolism (e.g. the glucose transporters GLUT1 and GLUT3), cell
growth (e.g. IGFBP1, TGF-β3) and cell death. Even though HIF-1 was identified
to bind to the EPO gene via the HRE and to induce the transcription and
therewith the amount of EPO, it is also interesting for misuse in sports
competition because of the multitude functions in angiogenesis and glucose
metabolism.
Pajusola et al. investigated the effects of VEGF vs. a stabilized form of hypoxiainducible factor 1-α (HIF1-α) by transferring the genes via AAV gene delivery to
a mouse skeletal muscle. Stabilized HIF-1α increased capillary sprouting and
proliferation, the vascular perfusion in the HIF1-α treated muscles was
significantly enhanced [38]. Both are factors for a better oxygen delivery and
therefore performance. But independent of the HIF1-α gene delivery,
administration of some drugs which activates HIF-1 may enhance physical
performance as well: e.g. K-11706 inhibits GATA (a negative regulator of the
EPO gene expression) binding activity, but enhances HIF-1 binding activity to
the EPO enhancer. Imagawa et al. reported after administration of 3 mg/kg K-
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Thorsten Schulz
11706 for five or eight days significantly an increased erythropoietin
concentration, elevated hemoglobin concentrations, hematocrit and endurance
performance in mice [39].
Because the degradation of HIF-1 is induced via hydroxylation by HIF-prolyl
hydroxylases (HIF-PH), HIF-PH inhibitors (HIF-PHI) may increase EPO and red
blood cell production. FibroGen has recently developed FG-2216, a HIF-PHI.
Hsieh et al. reviewed that several HIF-PHI induced EPO expression in vitro and
in mice, with peak EPO expression ranging from 5.6 to 207 fold above control
animals [40]. In his study, chronic oral dosing of FG-2216 in male rhesus
macaques was well tolerated and significantly increased erythropoeisis.
In a latest publication another gene in regard to glucose metabolism and
performance
enhancement
was
described:
overexpressing
phosphoenolpyruvate carboxykinase (PEPCK-C) led to a higher exercise
performance in mice [41]. PEPCK-C is expressed in a number of mammalian
tissues. It is involved in gluconeogenesis and the main expression occurs in
white and brown adipose tissue, kidney cortex and the liver [42]. Hakimi et al.
generated a transgenic mouse model, in which the PEPCK-C was expressed in
skeletal muscle by linking cDNA for PEPCK-C to the α-skeletal actin gene
promoter [41]. One of the results showed that PEPCK-Cmus mice were 7 times
more active than the control animals. In detail they ran longer distances, were
faster and had a up to 40% higher VO2max. Furthermore, they had more
mitochondria than the control animals and lived longer.
Muscle performance enhancement via hypertrophy, hyperplasia and better
regeneration
Performance enhancement in sport is strictly addicted to adaptations of the
skeletal muscle and therefore the remodeling of the myofibers. Responses of
the myofibers to training include activation of intracellular signaling pathways
and genetic reprogramming via endocrine mechanisms, growth factors [43] and
mechanical stimuli [44] which lead as a consequence to alterations of muscle
mass, contractile properties, and metabolic states [45]. Therefore, modeling
hormonal status and growth factors is a target for gene therapy for people with
degenerative muscle conditions. This includes for example hormones like
androgens, growth hormone, insulin or growth factors like MGF, IGF, myostatin
(GDF-8), TGF-ß and follistatin. Also influencing factors which block or induce
muscle related hormones and growth factors are relevant, e.g. decorin or IL-6
and TNFα, and therefore candidates for gene doping.
Gene Doping
197
MGF/IGF/IGFBP
A key regulator in muscle mass is the growth hormone (GH) / insulin-like growth
factor I (IGF-1) axis. Beside the systemic control of muscle growth by the IGFs
a local one was discovered as well. Goldspink named this cryptic splice variant
of IGF in the muscle, mechano growth factor (MGF) because of it’s expression
in response to mechanical stimulation and the different carboxy peptide
sequence to the liver type of IGF-I [46]. However, both play a role in muscle
development and regeneration and show tremendous effects after alterations
[46; 47]. There is evidence that in vivo both MGF and IGF-I enhance the rate of
muscle protein synthesis in muscle fibers and increase proliferation of satellite
cells. In different transgenic studies with naked DNA or AAV-vectors MGF
cDNA and also the IGF-I liver type cDNA were inserted into muscle of normal
and dystrophic mice. An increase of 15% in muscle mass and an enhancement
of strength after duration of 4 months was investigated after IGF transfer. The
direct MGF peptide transfer respectively injecting naked DNA intramuscular
lead after a duration of 3 weeks to an increase in strength: 25% in normal and
35% in dystrophic muscle [46; 48].
Early, Scherzer et al. showed that inhibition of IGF binding proteins (IGFBPs) which are able to bind up to 99% of IGF-I in the circulation - could lead to an
increased rate of functional repair in fast-twitch muscles, evidenced by an
enhanced maximum force producing capacity at 10 days after injury [49].
Growth Hormone (GH)
Doping with growth hormone has become an increasing problem since the early
1990s. Even though some studies indicate that the effectiveness of GH abuse
respectively treatment in regard to performance enhancement in athletes as
well as in healthy people has to be discussed [50; 51; 52]. However, GH acts
through its well-known anabolic, lipolytic and antinatriuretic role, demonstrated
in patients with GH deficiency or in GH deficient animal models. Besides the
direct effect of GH on the peripheral tissues, there is an indirect action e.g. via
the secretion of IGF-I, mostly from the liver. Anyway, it seems that only little is
known about the direct action of GH on muscle and performance, e.g. GH giant
transgenic mice develop large muscle fibres, GHA and GHR –/– mice build
smaller muscle fibres [47]. But if those big fibres have more strength abilities is
not known.
There are several gene therapy studies with animal models for the treatment of
GH deficiency but till now treatment had not reached clinical phase [53].
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Thorsten Schulz
Nevertheless, the animal models showed successful results [54], in transferring
the GH gene. The GH gene delivery studies include in vivo and ex vivo models
with e.g. either rAD or rAAV or naked DNA transfer techniques including the
regulation of GH expression for example with rapamycine as well as ex vivo
transfected myoblasts. In a latest report GH expression after hydrodynamic
gene transfer affects different organs differently so that GH gene studies require
further investigations [55].
Furthermore, increased GH secretion could be reached directly via GH
releasing hormone (GHRH) or GH secretagogues e.g. the cytokine like
hormone ghrelin or indirectly via leptin [56]. Khan et al. examined and discussed
the effects of GHRH plasmid administration on various animal species with the
presumption that this technology will reach human applications in the near
future [57]. Some of the performance effects of GHRH transfer are treating
anaemia, enhance immune function as well as body composition [58].
Myostatin (GDF-8) and other members of the TGF-β superfamily
Myostatin is a member of the transforming growth factor-β (TGF-β) family
specifically expressed in skeletal muscle and is a negative muscle growth
regulator. In 1997, McPherron et al. could show for the first time that
modulations in the myostatin gene correlated with a phenotype of exaggerated
muscle hypertrophy [59]. Several genetic studies revealed that GDF-8
mutations are responsible for the so-called ‘double muscling’ phenotype; a
phenomenon almost described 200 years ago for cattle. Today, mutations for
mice, sheep, cattle, dogs and humans are described [60]. Myostatin signals
through activin type I and type II receptors (Alk4 and Alk5, ActR2A and ActR2B)
[61]. Moreover and important in the field of doping, some endogenous peptides
(see below) bind and therefore inhibit the action of myostatin. Therefore, new
strategies to modulate myostatin expression or signalling could have on the one
hand the possibility for treating human muscle diseases and on the other hand
cheating.
Mosher et al. reported that the mutations in the myostatin gene increase muscle
mass and enhances racing performances in heterozygote dogs [62]. The
highest racing grade was found for 67% of the heterozygous dogs and the one
homozygous mutant in contrast to 16% of the wild type dogs performed at this
level. In conclusion, mutations in the myostatin alleles of these dogs showed a
competitive advantage for a sprint race. Currently, only one young boy in
Germany homozygote for the myostatin mutation is known. The child is
unusually strong for his age; interestingly his mother is heterozygous for the
Gene Doping
199
myostatin mutation and was a professional sprinter [7]! In a first transgenic
GDF-8 null-mice study, animals showed a 2-3 times higher muscle weight for
individual muscles via a combination of hypertrophy and hyperplasia [59].
Beside the transgenic modulation, blocking of myostatin seems a useful tool of
enhancing muscle growth. Bartoli et al. tested the inhibition of myostatin by
AAV-mediated expression of a mutated propeptide in two animal models of two
limb-girdle muscular dystrophies: In the used calpain 3-deficient mice increased
muscle mass and an enhanced force was obtained [63].
MYO-029 is a recombinant human anti-myostatin monoclonal antibody to
blockade myostatin activity. It is in a clinical phase I/II trial in patients with
muscular dystrophy in the USA “Evaluating MYO-029 in Adult Muscular
Dystrophy”, but results are not published yet. In fact, antibody-mediated
myostatin blockade in mdx mice lead to enhanced muscle mass and strength
[64; 65].
Acceleron Pharma's had developed a myostatin inhibitor: ACE-031. ACE-031 is
a biotherapeutic based on the activin receptor type IIB (ActRIIB) and an
antibody molecule that allows ACE-031 to circulate freely throughout the body.
The “antibody” acts as a decoy receptor and binds myostatin before it is able to
bind with ActRIIB on the surface of muscle cells. Preclinical studies with ACE031 demonstrated that the drug directly enhances muscle mass and strength
models of neuromuscular diseases. Acceleron Pharma expects to enter clinical
trials with ACE-031 in early 2008 [66]! Another new approach are ALK7 decoys,
which may inhibit myostatin.
Several studies concerning the administration or modulation of myostatin
inhibitors like follistatin, myostatin propeptide, follistatin related protein (FLRG),
Gasp-1, Titin cap, hSGT, protein ACE-031 or decorin do correlate with
increased strength. Furthermore, other TGF-ß superfamily related ligands
normally work together with myostatin to inhibit muscle growth so that the ability
for increasing muscle growth by modulating the TGF-ß signalling pathway
seems to be much bigger than appreciated [60]. But the effects of follistatin are
controversial.
Gene ablation of follistatin could lead to skeletal and cutaneous abnormalities
because activins are also members of the TGF-superfamily, affects many
tissues and are inhibited by follistatin as well. Therefore, follistatin affects a lot
of different tissues not only skeletal muscle [67]. Anyway recently, Nakatani et
al. developed a myostatin inhibitor derived from follistatin, which does not affect
activin signalling. Transgenic dystrophin-deficient mdx mice (genetic orthologue
of Duchenne and Becker muscular dystrophies) with FS I-Inhibitor (FS I-I) were
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Thorsten Schulz
generated by standard pronuclear microinjection techniques. This FS I-I
transgenic mice did not show any behavioural abnormalities and reproduced
normally. FS I-I transgenic mice had higher endurance capabilities than control
mice up to 30% and up to 35% in strength.
Regeneration Genes
Injuries are the most common factors in competitive sports to reduce the
training forces and the training processes. The need of fast and exact
regeneration for skeletal muscle, ligaments, bone and cartilage is therefore
obviously. Particularly, skeletal muscles are affected.
Decorin, a small leucine-rich proteoglycan, was shown to block TGF-ß1 to
improve muscle healing after injury and prevent fibrous scar formation. In
decorin-treated muscles, an enhancement of muscle regeneration could be
observed via histological examination [68]. Moreover, decorin may be able to
up-regulate the expression of follistatin, an antagonist of myostatin (see above)
[69], and may enhance expression of peroxisome-proliferator-activated
receptor-gamma co-activator-1alpha (PGC-1alpha), p21, and the myogenic
genes, and down-regulates TGF-ß1 and myostatin. A decorin gene transfer in
vivo promoted skeletal muscle regeneration and accelerated muscle healing
after injury [68], suggesting that however decorin improves muscle regeneration
and repair.
Usas and Huard reviewed methods with muscle-derived stem cells, which were
shown to posses high myogenic capacity, regenerate both skeletal and cardiac
muscle and genetically modified can differentiate into osteogenic and
chondrogenic lineages to promote the repair of cartilage and bone. They report
that isolated muscle-derived cells (MDCs) tolerate ex vivo manipulation well,
and can be easily transduced with a variety of viral vectors [70].
A lot of growth factors are described in promoting bone healing: e.g. fibroblast
growth factor (FGF), insulin-like growth factor (IGF-I, -II), platelet derived growth
factor (PDGF-AA, -AB, -BB), transforming growth factor-β (TGF-β), bone
morphogenetic protein (BMP), vascular endothelial growth factor (VEGF-A, -B, E) etc. Different gene delivery systems were tested both non viral and viral; for
the last system also tetracycline-based and rapamicine-based promoters
regulated viral expression systems were used [4]. Anyway, the literature
demonstrates the forward progress in using gene therapy for bone tissue
engineering applications.
Gene Doping
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201
Possible Detection of Gene Doping
The discussion if gene doping is detectable exists since the debate of gene
doping. Therefore, a lot of efforts were founded by the WADA to be aware of
gene doping in future [1]. In 2004, the French scientific group around Lasne
reported “Genetic doping with erythropoietin cDNA in primate muscle is
detectable”. Anyway, a real convincing test in gene doping analytics does not
exist at the moment, even if there are ambitious efforts in creating test systems
on the basis of following promising strategies [71]:
1.
2.
3.
4.
G
Modifications of proteins encoded by transgenes: analysis of minor
structural differences between the recombinant proteins expressed by
the transgenes and their endogenous counterparts, possibly due to
different post-translational modifications in different cells.
Investigation of probable immune response to gene vectors:
because viral vectors are the most common method for gene targeting
and therefore probably in gene doping as well. One possible method
might be the detection of the specific immune response to viral vectors.
DNA microarrays and expression profiles and molecular
fingerprints: analysis of expression profiles of endogenous genes
altered by the expression of transferred or modulated genes by
molecular techniques which will become more and more useful in
identifying gene doping, e.g. different real time PCRs, proteomic or
transcriptomic techniques and microarrays.
DNA barcodes: Manufactures may add a unique short oligonucleotide
sequence to each transgene and/or viral vectors in order to detect gene
doping easily. However, this approach will be based on the cooperation
of all companies and scientists in the area of gene delivery and will
include database maintenance with all barcodes!
Conclusion
In conclusion to this time point gene doping is – of course – not something an
athlete could do in his garage; the athlete would need a lot of scientific or
medical help. However, in our days, a lot of money could be earned in sports,
and as the BALCO scandal taught us, there are a lot of persons who will
participate in undergoing the ethical and juristic border in order to earn money
or to celebrate a pharmacological or medical victory. The reviewed potential of
gene doping and the today available prospects show that gene doping is not
only science fiction any more.
202
H
1.
Thorsten Schulz
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65. L.A. Whittemore, K. Song, X. Li, J. Aghajanian, M. Davies, S. Girgenrath,
J.J. Hill, M. Jalenak, P. Kelley, A. Knight, R. Maylor, D. O´Hara, A.
Pearson, A. Quazi, S. Ryerson, X.Y. Tan, K.N. Tomkinson, G.M. Veldman,
A. Widom, J.F. Wright, S. Wudyka, L. Zhao, N.M. Wolfman. Inhibition of
myostatin in adult mice increases skeletal muscle mass and strength.
Biochem Biophys Res Commun 300: 965–971, 2003.
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06.12.2007
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Hasegawa, T. Murakami, A. Uezumi, S. Takeda, S. Noji, Y. Sunada, K.
Tsuchida. Transgenic expression of a myostatin inhibitor derived from
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pathology in mdx mice. FASEB J. 24: Epub ahead of print, 2007
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68. Y. Li, J. Li, J. Zhu, B. Sun, M. Branca, Y. Tang, W. Foster, X. Xiao, J.
Huard. Decorin gene transfer promotes muscle cell differentiation and
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Branca, J. Huard. Relationships between Transforming Growth Factor-β1,
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technology: challenges for doping control. Analyst 132: 951-957, 2007.
Correspondence
Thorsten Schulz, Technische Universität München, Institute of Public Health
Narcotics
4.3
209
NARCOTICS
Ryszard Grucza, Andrzej Pokrywka, Dorota Kwiatkowska
A
Introduction
The word “narcotic” has a different meaning in different societies and brings
some misunderstanding when clear description of the drug is necessary. In
popular meaning the narcotics include all substances and drugs which are able
to change psychical and physical status of an organism. These changes can
generally vary in effects beginning from sleep and total immobilization of the
body up to euphoria and over excitation. At this same time unusual feelings and
imaginations can appear altering, positively or negatively, the psychical state of
a person after narcotic application. This popular understanding of the word
narcotic is, therefore, more related to the symptoms observed than to the
specific action of narcotic substances. In science, the narcotic effects of
different substances are defined more precisely basing on their chemical
structure and biological mechanisms involved in the provoked changes in
human organism.
Analgesic narcotic is an addictive drug that reduces pain, induces sleep and
may alter mood or behavior. The word was derived from the Greek word
narkotikos, meaning "benumbing or deadening", and originally referred to a
variety of substances that induce sleep (such state can be called narcosis). In
some countries, narcotic refers to opium, opium derivatives, and their semisynthetic or fully synthetic substitutes as well as cocaine and coca leaves,
which, although classified as "narcotics", are chemically not narcotics. Because
the term is often used broadly, inaccurately or pejoratively outside medical
contexts, most medical professionals prefer the more precise term opioid, which
refers to all natural, semi-synthetic and synthetic substances that behave
pharmacologically like morphine, the primary constituent of natural opium. The
opioids are classified on the WADA List as narcotics (Tab. 1).
The second group of substances, which are inappropriately described as
narcotics, are sympathomimetics. These are generally the drugs activating the
central nervous system by catecholamine (adrenaline and noradrenaline)
actions. Adrenoreceptors are differentially distributed in tissues of the body and
agonists at adrenoreceptors (direct sympathomimetics) mimic the actions of the
naturally occurring catecholamines, and are used for various therapeutic
effects. Indirect sympathomimetics are agents that elevate the concentration of
noradrenaline at neuroeffector junctions, because they either inhibit re-uptake
(cocaine), facilitate release, or slow breakdown by monoamine oxidase (MAO),
210
Ryszard Grucza
or exert all three of theses effects (amphetamine, methamphetamine). The
popular psychostimulant, methylenedioxymetamphetamine (MDMA or
“ecstasy”) acutely increases neuronal dopamine and noradrenaline release
bringing, as a delayed effect, a degeneration of serotonine nerve endings [1].
The substances activating the sympathetic part of the human nervous system
are classified on the WADA List of prohibited substances and methods as
stimulants (Tab. 1).
Table 1. Stimulants, narcotics and cannabinoids prohibited in-competition by World
Anti-Doping Agency in 2007.
SUBSTANCES AND METHODS PROHIBITED IN-COMPETITION
In addition to the categories S1 to S5 and M1 to M3 defined above, the following
categories are prohibited in competition
S6. STIMULANTS
All stimulants (including both their (D- & L-) optical isomers where relevant) are
prohibited, except imidazole derivatives for topical use and those stimulants included
in the 2007 Monitoring Program.
Stimulants include:
Adrafinil, adrenaline, amfepramone, amiphenazole, amphetamine, amphetaminil,
benzphetamine, benzylpiperazine, bromantan, cathine, clobenzorex, cocaine,
cropropamide, crotetamide, cyclazodone, dimethylamphetamine, ephedrine, etamivan,
etilamphetamine, etilefrine, famprofazone, fenbutrazate, fencamfamin, fencamine,
fenetylline, fenfluramine, fenproporex, furfenorex, heptaminol, isometheptene,
levmethamfetamine, meclofenoxate, mefenorex, mephentermine, mesocarb,
methamphetamine, methylenedioxyamphetamine, methylenedioxymethamphetamine,
p-methylamphetamine, methylephedrine, methylphenidate, modafinil, nikethamide,
norfenefrine,
norfenfluramine,
octopamine,
ortetamine,
oxilofrine,
parahydroxyamphetamine, pemoline, pentetrazol, phendimetrazine, phenmetrazine,
phenpromethamine, phentermine, 4-phenylpiracetam (carphedon), prolintane,
propylhexedrine, selegiline, sibutramine, strychnine, tuaminoheptane and other
substances with a similar chemical structure or similar biological effect(s).
S7. NARCOTICS
The following narcotics are prohibited:
buprenorphine, dextromoramide, diamorphine (heroin), fentanyl and its derivatives,
hydromorphone, methadone, morphine, oxycodone, oxymorphone, pentazocine,
pethidine.
S8. CANNABINOIDS
Cannabinoids (e.g. hashish, marijuana) are prohibited.
Narcotics
211
The third group constitutes substances able to elicit psychic changes like those
manifested in the course of psychosis. These substances are called
psychotomimetics or psychedelics or hallucinogens. Since different
psychotomimetics exhibit different actions on the central nervous system the
mechanism of the psychotogenic effects remains unclear. Some hallucinogens
such as LSD, psilocin, bufotenin, and mescaline bear a structural resemblance
to serotonine, natural biogenic amine playing a neuromediator function in the
central nervous system. Conversely, the structure of other substances such as
tetrahydrocannabinol from Cannabis sativa (hashish and marihuana), muscimol
or phencyclidine is different comparing to biogenic amines. Among the
psychotomimetics only the cannabinoids were located on the WADA list of
prohibited substances and methods as a separated group of substances (Tab.
1).
B
Analgesic Narcotics (Opioids)
Background
Ideographs of the ancient Sumerians suggest that psychological effects of
opium may have been known around 4000 B.C. The Egyptians described the
medicinal value of the opium poppy in 1552 B.C. However, the first reference to
the actual juice of the poppy appeared in the 3rd century B.C. writings of
Theophrastus. The term opium is derived from the Greek word for juice and
refers to the juice of the poppy capsule. Opium appeared in Western Europe in
XI and XII centuries. In XVI century Paracelsus composed laudanum – a
mixture of opium, wine and spices. The laudanum is still used today to treat a
variety of ailments [2].
Periodic reports describing the use by athletes of caffeine, strychnine, opium,
ether and alcohol appeared between the middle of the nineteenth century and
the advent of the Second World War [3]. However, the main applications of
substances considered today as doping agents were exercised during
numerous military conflicts between different countries. The opioids were
especially popular in XIX century in USA and Germany where they were widely
used by soldiers and brought some social problems after the wars (Tab. 2).
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Table 2. Doping use for military purpose.
Year
War
Substance or
Method
Purpose
Country
1718
Norway-Sweden
Amanita
muscaria
Stimulation
Norway
Sweden
1863
Civil War
Morphine
USA
1883
Germany-France
Heroine
Germany
1939-1945
World War II
Amphetamine
(“Benzendrine”)
Stimulation
(over 72 mln
“energy tablet”)
Great Britain
USA
1939-1945
World War II
Ephedrine,
methamphetamie
(“Pervitin”)
Stimulation
Germany
1939-1945
World War II
Testosterone
Aggressiveness
Germany
1939-1945
World War II
Blood transfusion
Adaptation to high
attitude in pilots
Germany
Even that the opium was widely used during the recent four centuries for its
hypnotic and analgesic properties the pure morphine was extracted in 1803 by
the German pharmacist Friedrich Wilhelm Sertürner. The codeine, another
alkaloid derived from opium, was discovered 29 years later by Pierre Jean
Robiquet. Codeine will be discussed in contrast to morphine since this is a drug
exhibiting a low level of addiction when applied to patients. From this reason
codeine is widely used in medicine and has not been banned in sport. Morphine
is a main alkaloid derived from opium, dried juice of the immature fruit capsule
of Papaver somniferum, and used as an analgesic narcotic drug [4]. Codeine is
another opium alkaloid applied as a antitussive and analgesic drug. Codeine is
classified as a relatively mild analgesic. It is frequently used clinically in
combination with other analgesic and as a cough suppressant [5]. The chemical
structure of both morphine and codeine is presented in Figure 1.
N CH3
H
H
N CH3
H
H
HO
O
OH
CH3O
Morphine
Figure 1. Chemical structure of morphine and codeine.
O
Codeine
OH
Narcotics
213
The primary medical application of morphine is to decrease the pain. Based on
the theory of Beckett (1957) it has been experimentally proved that a specific
opioid receptors exists, located in some structures of the brain. These receptors
differ in pharmacological properties, localization and in specific responses to
different opioid peptides (Tab. 3).
Table 3. Some receptors of the central nervous system with specific reactivity to opioid
peptides.
Receptor
Effect
Endogenous opioids
μ
Analgesic, respiratory depression,
constipation, euphoria
Endorphin
δ
Analgesic
Enkephalin
κ
Dysphoria
Dynorphin
Morphine and codeine are the natural fenantren alkaloids present in opium and,
as remaining about 20 other alkaloids, are derived from a premature poppy
capsule (Papaver somniferum). The content of opium in the poppy capsule
depends on the climatic conditions and on the form of the poppy cultivation. It
usually varies between 3-23% (10% on average) for morphine and between 06% (0.2% on average) for codeine. The content of izochinoline alkaloids varies
from 1.5% to 12% (10% on average) for noscapine (narcotine) and from 0.1% to
4.5% (5% on average) for papaverine. In general, the fenantren derivatives of
opium exhibit analgesic properties while the isochinoline derivatives exhibit
spasmolytic properties [6].
The opiate receptors are located in both the central nervous system and the
periphery [5]. However, the predominant effect of opioids is the partial
modification of the activity of the central nervous system. The peripheral action
of analgesic narcotics is partly related to the effects of histamine release
following the narcotics application (Tab. 4).
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Table 4. Central and peripheral action of analgesic narcotics.
CENTRAL
Comment
Pain relief (analgesia)
All sorts of pain
Calming
Drowsiness, decreased concentration, mental
clouding
Dysphoria
(at the beginning of application)
Decreased physical activity, lethargy
Euphoria
Respiratory depression
Prolonged pauses between breaths, periodic
breathing; after opioid overdose – death due to
respiratory arrest
Anti caught action
Decreased volume of urine
Modification of hormonal activity in hypophysealhypothalamic axis
Decreased body temperature
Depressing action on hypothalamus
Nausea and vomiting
(at the beginning of application)
Activation of vomiting centre
Decreased tremor level of
muscles
Augmenting activity of inhibitory neurons mediated
by benzodiazepine receptors (GABA)
Narrowing the pupils
Bradycardia
Effect on vagal nerve
Physical and psychical
dependence
PERIPHERAL
Comment
Peristalsis, constipation, biliary
colic, urinary tract obstruction
Increased tension of smooth muscles
Bronchial spasm
Effect of histamine release
Hypotension
Vasodilatation – effect of histamine release
Inhibiting of uterus muscles
tension
Birth process prolongation – effect of histamine
release
Narcotics
C
215
Clinical, Pharmacological and Biological Function of Analgesic
Narcotics
Clinical application
The drugs based on opium act only symptomatically. The main, medical reason
of its application is analgesic (pain killing). When applied, the balance of
positive and negative effects of the opioids on an organism should be
considered.
Form of application
Morphine is primarily applied by injection. Oral use of morphine causes a
decreased biological availability because of its elimination by liver immediately
after absorption. The analgesic effect of morphine taken orally is about of onetenth of the effect produced by subcutaneous injection.
Pharmacokinetics
With a standard dose of 10 mg of morphine a maximum analgesic effect is
observed after 20-30 min of intravenous injection and after 60-90 min of
intramuscular injection. The anti-pain effect lasts 3-4 h and 4-5 h, respectively.
Body distribution
Morphine penetrates the central nervous system moderately. Derivatives of
morphine are easier accepted by CNS (i.e. monoacetylmorphine – MAM) than
pure morphine. Greater concentration of morphine can be found in kidneys,
liver, lungs and spleen.
Metabolism
Morphine does not cumulate in the organism. It appears in the urine during 30
min after application. About 50 % of the dose is excreted during 8 h. After 24 h
over 90 % of the morphine dose is removed from the organism. The main
metabolic process (about 70 %) is taking place in liver and consists of the
junction of morphine and its metabolites with glucuronid acid.
Symptoms of acute intoxication by opioids
Intoxication by opioids is associated with following symptoms: narrowing the
pupils, drowsiness, coma, dry and cool skin, breathing disturbances (CheyneStokes breathing) up to the inhibition of respiration, decreased heart rate, blood
pressure and body temperature. Death can appear in result of respiratory and
cardiovascular insufficiency immediately after intravenous injection of morphine
or during 2-4 h after oral application of morphine.
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Opioids addiction
Opioids are the drugs with a great potential of physical and psychical
dependence. Tolerance to morphine develops quickly. However, heroine
(diacetylmorphine) penetrates into the central nervous system much faster than
morphine, developing dependence in a very short time. In contrast to heroine,
codeine, generally, does not cause physical or psychical dependence. There is
a long list of adverse effects of opioid addiction. The most important ones are:

damage of soft tissues (mainly liver)

hormonal deregulation (especially water balance control)

disturbances in immunological function

organism devastation

inflammatory changes in skin, and in venous and lymph tubes

needle sharing (infection, hepatitis B, HIV)

sexual problems

constipation
Mechanism of opioids addiction
Some studies indicate that opioids, cannabinoids and cocaine may affect the
same reward centers in the central nervous system systems as alcohol and
nicotine. The dependence syndrome occurs with heavy chronic use in
individuals who report problems in controlling their use and who continue to use
the drug despite experiencing adverse personal consequences. Estimated risk
of dependence development is about 32 % for nicotine, 23 % for opioids, 15 %
for alcohol and over 10% for cannabinoids [7].
Abstention syndrome
Sudden withdrawal of opioid drugs or application of opioid antagonists causes a
withdrawal syndrome in an addicted person. The withdrawal syndrome can
appear just after 8 h and last 7-10 days. The maximum of negative symptoms is
observed during 2-3 day of abstention. Opioid hunger is hardly tolerated by
patients who can exhibit the following symptoms:

increase in heart rate, blood pressure and body temperature

sweating, heat flashes

muscle tremor, spasm and pain

piloerection

sleeplessness, dizziness, restlessness
Narcotics
D
217

nausea, vomiting, diarrhea

yawning

drug-seeking behaviour
Narcotics and Sport
Narcotics were indicated on the first list of banned substances in sport prepared
by the International Olympic Committee (IOC) in 1967. Currently, as it has been
mentioned above (Tab. 1), the World Anti-Doping Agency (WADA) located
narcotics in categories of substances prohibited in competition only. The
number of prohibited substances in this category is closed and restricted to the
substances directly mentioned on the list. The concept of the doping list is the
prohibition of substances and methods which can positively affect athletic
performance, which might have a negative impact on health, and which are
contrary to the spirit of sport [8].
Narcotics are often treated as non ergogenic drugs nor the drugs enhancing
physical performance. This is a controversial attitude towards narcotics because
their potential use in sports might be of some importance allowing athletes to
perform competitively despite of various musculoskeletal injuries [2, 9]. As
shown in Figure 2, the increased pain threshold, adjusted by narcotics
application, allows for better both pain tolerance and exercise performance. In
result of the decreased inhibitory effect of pain the greater effort exerted by the
athlete could lead to some injuries and damages in the athlete organism. The
described mechanism fully complies with all elements of the concept of doping.
Figure 2. Simplified representation of the basic mechanism of enhancing performance
with increased tolerance to pain by analgesic narcotics, which can lead to damage in the
athlete organism.
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Ryszard Grucza
The use of pain killers is frequent in sports, especially among athletes engaged
in violent activities (such as boxing for instance). Often, the fear of losing a
place or not fulfilling a contractual obligation leads to an obsession to keep the
fight in spite of any type of wound or handicap. The most common effect of this
class of substances is sedation, providing that habitual doses are used [10].
Additionally, narcotic analgesic may reduce anxiety, possibly enhancing
performance in sport events in which excess anxiety could adversely affect fine
motor control, such as pistol shooting and archery [11].
These drugs are banned both to limit the potential abuses that may lead to
career ending injuries and to reduce the risk for tragic addictions. The death of
Baltimore Colts great “Big Daddy” Lipscomb, caused by heroin addiction in
1963, still serves as one of the most infamous examples of a narcotic related
tragedy [12]. Also Poli Diaz, an eight time European Lightweight Champion,
ended his professional career hooked on heroin. Recently, former French cyclist
Laurent Roux was convicted of supplying a drug mix known as “the Belgian pot”
reported to include cocaine, heroin and amphetamines to cyclist.
It has been found that there exists a significant association between doping
agents using and acceptance of narcotics. In the study of Pedersen (2001)
8.3% of doping users used also amphetamines, 14.2% MDMA, and 30.3%
heroin [13]. Thus, it might be concluded that some people exhibit a psychical
susceptibility to accept all sort of external drivers beginning from tobacco and
alcohol and ending on doping agents and narcotics.
The presence of narcotics and cannabinoids on the WADA list of prohibited
substances is a subject of some controversy. According to Kindermann (2004)
the use of illegal drugs like heroin and cannabinoids should better be addressed
as "unsportsmanlike" behaviour and punished on the basis of regulations
separate from the doping list [8]. The Netherlands Anti-Doping Organization
presented similar opinion in comments on the proposed WADA Prohibited List
for 2005. In their opinion, the entire group of narcotics should not be part of the
prohibited list. The inclusion of this group in the prohibited list is far more likely
to do harm to the anti-doping efforts than the chances that it will protect fair play
and the health of athletes. Similarly, cannabis use, however objectionable it
might be, should not be regarded as doping use [14].
Contrary to cannabinoids the analgesic narcotics are not often used by athletes
and whenever they are misused, it is rather a case of malpractice than intended
doping application. In the period 2001-2005 opioids were detected only in 0.1%
of total samples analyzed in all IOC and WADA accredited laboratories. At the
Narcotics
219
same time the relative contribution of positive samples with cannabinoids was
0.27 % (Tab. 5).
Table 5. Narcotics and cannabinoids detected in IOC and WADA accredited
laboratories [AL] in the years 2001-2005.
Year
AL
Samples
2001
25
125,701
29
0.02
298
0.24
2002
26
131,373
13
0.01
347
0.26
2003
31
151,210
26
0.02
378
0.25
2004
32
169,187
15
0.01
518
0.31
2005
33
183,337
17
0.01
503
0.27
760,808
100
0.01
2,044
0.27
Years 2001-2005
Narcotics % Narcotics Cannabinoids % Cannabinoids
The majority (81%) of the 100 examined samples with different narcotics
contained morphine. The other substances were pethidine (6%), methadone
(5%), hydromorphone (3%), oxycodone (2%), buprenorphine, dextromoramide
and hydrocodone (each by 1%).
It should be noted that, according to the WADA regulations, out-of-competition
samples are not tested for narcotics and cannabinoids. This type of samples
account for approximately of 50% of the total number of samples. Thus, it might
infer that the real number of samples containing opioids and cannabinoids can
be much greater than that reported by IOC and WADA accredited laboratories.
Among 9061 urine samples tested in the Department of Anti-doping Research
in Warsaw during the years 2001 to 2005, only 4 cases with analgesic narcotics
were found (Tab. 6). At the same time 102 samples containing cannabinoids
(carboxy-THC > 15 ng/ml) were detected.
Table 6. Analgesic narcotics detected in urine samples in the Department of Antidoping Research, Institute of Sport Warsaw during recent 5 years.
Year
2001
Substance
Morphine >1μg/ml
Nandrolone 4.9 ng/ml
Gender
Age
Sport
Male
26
Water motor sports
2001
Morphine >1μg/ml
Male
21
Cycling
2001
Morphine >1μg/ml
Female
20
Fencing
2005
Hydromorphone
Female
18
Cycling
220
Ryszard Grucza
Poppy seeds consumption and doping detection
Poppy seeds are popular ingredients of some cakes in many countries.
However, consumption of such a cake may cause morphine appearance in the
body. As it has been shown by Thevis et al. (2003) consumption of typical cake
containing poppy seeds or baking mixtures brought in result morphine
concentrations in urine greater than 1 µg/ml, with a peak value of about 10
µg/ml [15]. Similar effects of morphine concentration in urine were observed by
Van Thuyne et al. (2002) after administration of two Papaveris fructus
containing herbal teas to five male volunteers. Maximum morphine
concentrations, 4.3 and 7.4 µg/ml, respectively, were obtained 4-6 h after
administration [16]. Under such circumstances the established cutoff limit for
morphine concentrations in human urine equal to 1 µg/ml is disputable since the
poppy seeds consumption may lead to an unintentional doping case.
Codeine and doping detection
Some studies indicated also a possible occurrence of morphine in human
organism caused by metabolism of allowed medicines containing codeine.
Codeine, after oral administration, is metabolized in the liver to morphine,
norcodeine and its conjugates. Results of investigations performed by Delbeke
and Debackere (1991) clearly showed that application of antitussive drugs
(tablets or syrups) may result in appearance of morphine concentrations in urine
greater than 1 µg/ml, thus to provoke an adverse analytical finding in antidoping laboratory [17].
E
Conclusion
Analgesic narcotic is a highly addictive drug that reduces pain, alters mood or
behavior and causes various health effects. Furthermore it exhibits a potential
to enhance performance by increased tolerance to pain and reduced anxiety.
This damped physiological reactivity to increased pain can lead to damages in
athlete organism during strenuous exercise. But the number of doping cases by
analgesic narcotics is relatively small. Excessively so, there is a higher risk of
unintentional doping by consumption of poppy cakes or application of allowed
medicines containing codeine. Therefore, the cutoff limit for morphine
concentrations in human urine equal to 1 µg/ml should be revised.
Narcotics
221
F
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16. W. Van Thuyne and F.T. Delbeke. Morphine and other painkillers in
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Correspondence
Ryszard Grucza, Institute of Sport, Department of Antidoping Research, Trylogii
2/16, 01-982 Warsaw, Poland, [email protected]
Cannabinoids
4.4
223
CANNABINOIDS
Peter Van Eenoo, Frans T. Delbeke
A
Introduction
Cannabinoids are a group of active substances present in the plant Cannabis
sativa L. There are mainly two types of this plant, Cannabis sativa sativa
(regular hemp) and Cannabis sativa indica (Indian hemp). For use as a narcotic
Cannabis sativa indica is of outmost interest. The resin, flowers, leaves and
other parts of this plant contain a high amount of psychoactive substances. The
most active ingredient is tetrahydrocannabinol (THC), although more than 20
other constituents have been identified. The other ingredients of the plant
resemble those of tobacco leaves [1]
The main routes of consumption of cannabis products are smoking and eating.
The minimum effective dose of THC is 2 mg. If cannabis is taken orally a five
fold higher dose is needed to have similar effects, predominantly due to a firstpass effect in the liver [1].
The in-competition use of cannabinoids is prohibited in sports by the World AntiDoping Agency (WADA) [2] when the urinary concentration of 11-nor-Δ9tetrahydrocannabinol 9 carboxylic acid, the major urinary metabolite of
tetrahydrocannabinol (THC), exceeds 15 ng/ml [3].
B
The Prevalence of Cannabis in Sport
DoCoLab of the Ghent University in Belgium is the laboratory with the longest
tradition in doping controls, starting in the sixties in horse doping and since
1973 also in human doping control. DoCoLab is one of the 34 laboratories
world-wide that are accredited by the World Anti-Doping Agency and in 2005,
51 out of 5378 samples tested at DoCoLab tested positive for cannabinoids
(0.95 %).
World-wide, 183.370 samples were analyzed in WADA-accredited laboratories
in 2005. This led to 503 adverse analytical findings for cannabinoids (0.27 %)
[4]. An overview on the prevalence of adverse analytical findings at DoCoLab
and world-wide for the period 1998-2005 is given in Fig. 1. From these results it
is clear that there is a statistically higher prevalence of adverse analytical
findings at DoCoLab compared to the mean of all laboratories. Indeed, although
DoCoLab only analysed ca. 3% of all samples, it is responsible for more than
10% of all cannabis cases. Moreover, in 2005, cannabis was the fourth most
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Peter Van Eenoo
detected substance in doping control laboratories world-wide and accounted for
11.8% of all adverse analytical findings [4].
2
1,8
1,6
1,4
1,2
DoCoLab
1
IOC/WADA
0,8
0,6
0,4
0,2
0
1998
1999
2000
2001
2002
2003
2004
2005
Figure 1. Prevalence (%) of positive samples for cannabis at DoCoLab and in all
laboratories accredited by the International Olympic Committee (IOC) or World AntiDoping Agency (WADA) world-wide
Since there is a threshold level of 15 ng/ml for the main metabolite of cannabis
and all laboratories included in this statistics are accredited by the World AntiDoping Agency and ISO17025 guidelines, this deviation can not be caused by
the individual performance of our lab. Indeed, three factors play an important
role in the high percentage of cannabis positives in DoCoLab. Firstly, the fact
that cannabis is only prohibited in-competition and while on an average only 1
out of 2 samples world-wide is an in competition sample, this percentage is
approximately 90 percent in our laboratory. Secondly, the samples collected by
the Flemish and French Community of Belgium are deriving from low level as
well as top level competitions, while many national doping organisations and
federations primarily focus on top level athletes. Lastly, the fact that the
samples analyzed in our lab are predominantly originating from Belgium and the
Netherlands, two countries that are characterized by a society and legislation
which are very tolerant towards the use of cannabis.
Cannabinoids
C
225
Rationale for Prohibition
Cannabinoids are prohibited for three reasons:
1. performance enhancement,
2. health risks and
3. the detrimental effects of cannabis use to the image of sports.
D
Performance Enhancement
Generally, performance enhancement is associated with stimulating or growth
promoting properties of a substance. However, performance enhancement is
not only restricted to changes in physical capabilities. Psychological effects
should also be taken into account.
Cannabinoids can be useful to relax, e.g. the night before a competition and a
good nights’ rest will be beneficial at an event [55]. Cannabis can reduce the
effects of anxiety. In certain sports, beta-blockers are also prohibited for this
performance enhancing effect. Increased confidence [6] is associated with
cannabis use and for high level athletes' psychology can play a role in making
great achievements.
For sports where fear might influence the outcome, cannabis might reduce
these feelings [7] and allow the athlete to take greater risks. This can become
especially beneficial in high risk sports (e.g. snowboarding, down hill
moutainbiking or bob sleighing).
E
Image of Sports
Elite-level athletes serve as a role model in today's society. Although in Europe,
most people do not really object to personal use of cannabis in a restricted
environment, even the most liberal minds do agree that smoking cannabis
should not be promoted [8,9].
Today's society does not even like famous athletes to use other, socially more
accepted drugs including alcohol and nicotine. This attitude has led to a
European ban on advertisements for tobacco products for sponsors of sport
events or teams [10], while in the fifties some brands even stated that they sold
the cigarettes for the ”true” athlete.
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Peter Van Eenoo
Taking into account that children are a particularly vulnerable group for imitating
habits of their favourite sportsmen several sports federations have taken steps
in order to dissuade athletes from using cannabis, by putting it on the list.
F
Health Risks
Acute health risks for cannabis users are fairly small and therefore, it can be
perceived that cannabis use is not harmful. Indeed, cannabis has very low
toxicity, in the sense that there are no reports of deaths caused exclusively by
cannabis [1]. Nevertheless, several types of health risks can be distinguished:
Involvement in (traffic) accidents
Numerous studies have been performed to assess the effects of cannabis use
on driving and flying skills [1,11,12]. It can now be concluded above any
reasonable doubt that the use of cannabis leads to a clear but modest
impairment of these skills and evidence exists that use of cannabis in
combination with alcohol or other drugs aggravates these effects greatly. It is
extremely worrisome that in most cases the test subjects were unaware of this
reduction in skills [1]. These experiments have also shown that there was a
significant decrease in attention and in the ability to react to sudden unexpected
emergencies and several studies have shown that the use of cannabis leads to
a distortion of spatial perception and speed [1,11,12]. Such a distortion can be
dangerous in contact sports and in sports where physical contacts are possible.
One could imagine for example the effects of a distorted perception of speed
and distance on a tackle in soccer. Within the framework of doping control, it is
also clear that smoking cannabis by for example a rally driver could have
detrimental effects for a great number of persons, including the athlete himself,
his co-pilot and fans along the itinerary. Population statistics of injured people
after traffic accidents seem to confirm the results of the mentioned experiments.
It should however be noted that in these population studies several other cofactors are involved, including the use of alcohol and other drugs. These cofactors make it difficult to attribute the increased risk for traffic accidents solely
to the exclusive use of cannabis [11].
Respiratory diseases
It has been clearly and unequivocally demonstrated that cannabis produces
chronic inflammation of the respiratory tract in regular users [1,11,13]. This
Cannabinoids
227
effect is manifested as chronic cough, wheezing and phlegm. Recently severe
indications have also been found that regular use of cannabis can lead to the
development of chronic obstructive pulmonary disease although no conclusive
evidence is available so far, since in the population studies most of the subjects
used tobacco concurrently with cannabis [1313].
It is estimated that smoking a cannabis cigarette leads to a threefold increase of
inhaled tar as compared to smoking a tobacco cigarette, predominantly due to
the way a cannabis cigarette is smoked, namely with a deep and prolonged
inhalation and without a filter [1, 13]. Moreover tar from a cannabis cigarette
contains higher concentrations of benzanthracenes and benzpyrenes than
tobacco and both substances are well known tumour promoters and
carcinogens [1, 1313].
Mental health and brain effects
Several effects on the brain and mental health of cannabis users have been
described in literature. The acute responses such as panic, anxiety, depression
or psychosis that can be associated with the use of cannabis are generally quite
rare and are associated with an excess consumption of the drug. Therefore,
according to Johns, they might be classified as toxic effects [14]. Other temporal
toxic effects described in literature are confusion and disorientation. Unless the
user has a history of psychiatric problems, these symptoms only last for a
maximum of a few days [11,14,15,16].
Besides the toxic short duration effects, cannabis use can also lead to the
precipitation of clinically overt schizophrenia or to the relapse of previously well
compensated schizophrenics [14,15,16]. Indeed, several studies have
confirmed these negative effects on the clinical course of schizophrenia and it
seems that besides the frequency of use and the average dose, also the age at
which the use of cannabis started is a critical factor. These studies have shown
a far greater incidence in the development of schizophrenia in people that
started the use before the age of 18 years [11,14,15,16].
Cannabis also affects the progression of schizophrenic psychoses and worsens
the prognosis. Recently, a large-scale study in New-Zealand has shown that
there is a serious link between the risks for depression and suicide attempts
when cannabis is frequently used [17].
An American study even provided evidence that there was a positive correlation
between the increase in use of cannabis and the level of depression [18].
Nevertheless, data on this subject is still relatively scarce and several more
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Peter Van Eenoo
longitudinal studies with standardized questions will be needed before drawing
definitive conclusions [1111].
Until the mid-seventies it was believed that cannabis use did not lead to
tolerance and that there were no withdrawal effects, but these views have
changed and indeed it has been proved that after regular use, the dose of
cannabis needs to be increased to experience similar effects. Withdrawal
effects are generally observed during the first week of abstinence and lead to
behavioural effects as well as insomnia and increased appetite. As an effect of
dependency, the need to purchase and use cannabis can lead to criminal
behaviour like theft [11].
Other health effects
Nevertheless, one of the well-known acute effects of cannabis is an increase in
heart rate and in blood pressure. This results in an increase of workload for the
heart and in oxygen demand. Hence, if there is already a pre-existing disease
that impairs the heart muscle function, the additional use of cannabis can have
fatal consequences [1, 11].
Several cases have been reported of transient cerebral attacks in heavy users
after smoking cannabis. These cerebral attacks are recognized precursors of
strokes. It should however be noted that these attacks probably would not have
occurred in the absence of pre-existing obstructive disease of the cerebral
arteries [19].
Although the clinical significance is not clear so far, it should be noted that
cannabis also has immunosuppressant and endocrine effects. Chronic use of
cannabis appears to generate reproductive risks both to the mother during
pregnancy and birth, as well as to the foetus [1].
G
General Remark
Finally, following observations and concerns should be mentioned:
It seems indeed that the acute health side-effects of cannabis are minimal,
however only a few studies have been performed so far on the long term
health risks of chronic cannabis use.
Much of the work on the health effects of cannabis so far has been done
during the seventies or with relatively low doses of cannabis. Indeed, the
quality of the cannabis products, to use the terminology of the consumers, or
Cannabinoids
229
the quantity of tetrahydrocannabinol, in scientific terms, has increased
tremendously over the last decades [20].
This should be taken into account when assessing risks and effects.
H
References
1.
C.H. Ashton. Pharmacology and effects of cannabis: a brief review. British
Journal of Psychiatry, 178: 101-106, 2001.
WADA. The 2006 Prohibited List – International Standard.
http://www.wada-ama.org
WADA. Technical Document WADA TD2004MRPL. Minimum required
performance
limits
for
detection
of
prohibited
substances.
http://www.wada-ama.org
WADA. 2005 Adverse analytical findings reported by accredited
laboratories. Overview of results. http://www.wada-ama.org
P. Mura, R. Trouvé, G. Mauco. Le cannabis est-il un produit dopant ? [Is
cannabis a doping substance?] Annales de Toxicologie Analytique, 12: 4348, 2000.
A. Johns. Psychiatric effects of cannabis. Pharmacology and effects of
cannabis: a brief review. British Journal of Psychiatry, 178: 116-122, 2001.
P. Robson. Therapeutic aspects of cannabis and cannabinoids. British
journal of psychiatry, 178: 107-115, 2001.
P. Van Eenoo , F.T. Delbeke. Cannabis and doping issues. In: Schänzer
W, Delbeke F, Deligiannis A, Gmeiner G, Maughan R, Mester J (Eds):
Proceedings of the International Symposium Health and Doping Risks of
nutritional supplements and social drugs, 37-42, 2002.
P.H.H.M. Lemmens, HFL Garretsen. Unstable pragmatism: Dutch drug
policy under national and international pressure. Addiction, 93: 157-162,
1998.
Anonymous, European Union, Directive 2003/33/EC.
H. Kalant. Adverse effects of cannabis on health: an update of the
literature since 1996. Progress in Neuro-Psychopharmacology & Biological
Psychiatry, 28: 849-863, 2004.
H. Kalant, W.A. Corrigall, W. Hall, R.G. Smaret (Eds). The health effects of
cannabis. ARF Books, Toronto, pp. 1-526, 1999.
M. Hashibe, K. Straif, D.P. Tashkin, H. Morgenstern, S. Greenland, Z-F
Zhang. Epidemiologic review of marijuana use and cancer risk. Alcohol,
35: 265-275, 2005.
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3.
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5.
6.
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8.
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13.
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14. A. Johns. Psychiatric effects of cannabis. British Journal of Psychiatry,
178: 116-122, 2001.
15. W. Hall. Cannabis and Psychosis. Drug and Alcohol Review, 17: 433-444,
1998.
16. M. Drewe, J. Drewe, A. Reichle-Rössler. Cannabis and risk of psychosis.
Swiss Medical Weekly, 134: 659-663, 2004.
17. A.L. Beautrais, P.R. Joyce, R.T. Mulder. Cannabis abuse and serious
suicide attempts. Addiction, 94: 1155-1164, 1999.
18. C.Y. Chen, F.A. Wagner, J.C. Anthony. Marijuana use and the risk for
major depressive episode. Epidemeologic evidence from the United States
National Comorbidity Survey. Soc. Psychiatry Psychiatr. Epidemiol., 37:
199-206, 2002.
19. M. Moussouttas. Cannabis use and cerebrovascular disease. Neurologist,
10: 47-53, 2004.
20. M. Licata, P. Verri, G. Beduschi. Delta9 THC content in illicit cannabis
products over the period 1997-2004 (first four months). Ann 1st Super
Sanità, 41 (4): 483-485, 2005.
Acknowledgements
The authors would like to thank the Flemish Ministry of Culture, Youth, Sport
and Media for the financial support.
Correspondence
Peter van Eenoo, DoCoLab – UGent, Technologiepark 30, B-9052 Zwijnaarde,
http://www.docolab.ugent.be/ , [email protected]
Knowledge of Different Target Groups
5
231
THE KNOWLEDGE OF DIFFERENT TARGET GROUPS IN THE FIGHT
AGAINST DOPING
Christiane Peters
A
Introduction
The public’s impression of the prevalence of doping in sports is mainly based on
the attention paid to individual cases by the media. The image an elite athlete
projects may be very powerful, yet he probably only belongs to what is the most
visible group of performance enhancing drug abusers. The larger group of socalled “sportsmen” consists of individuals doing lower-level recreational sports,
who have other reasons for using drugs, mostly to improve their physical
appearance [1]. In addition to the statistical analysis of all doping samples
worldwide [2], results from scientific surveys confirm a high amount of drug
abuse in competition as well as in recreational and fitness sports [3-5].
Furthermore, performance enhancing drug abuse is not just a problem in sports;
lifestyle drug abuse as well as using drugs with the intention of improving one’s
performance at one’s occupation [6] makes this matter into a new public health
problem worldwide [7].
While performance enhancing drug abuse in sport is clearly defined by the list
of prohibited substances and methods, and the procedures for doping controls
as well as analytical methods have been prescribed in detail [8], comparatively
speaking, doping prevention is as yet poorly defined. Up to now it has been
regarded as a small negligible sector in the fight against doping, mainly
consisting of controls and punishment.
In our highly competitive society, performance enhancing drug abuse can be
observed in a large number of persons, not solely among those participating in
sport activities. Therefore, the fight against doping must focus on individual
responsibility and prevention [9]. The word prevention has its roots in the Latin
word ‘praeventum’, and means taking all measures which shall hinder the
occurrence of aberrant and conspicuous acts in terms of prophylaxis [10]. To be
effective, doping prevention should therefore be about primary prevention with
the aim of reducing the present risk factors and building up resources for
doping-free sport before sportspersons actually get involved with drugs [11].
The main aim of doping prevention is the reduction and control of doping
offences to create drug-free sport. This could be achieved by influencing the
individuals themselves and their environment [11]. Therefore, the measures
used for prevention should mainly support the individual’s competence to make
an adequate analysis of the demands made by the social environment.
232
B
Christiane Peters
The Importance of the Sporting Environment
The most important points in the fight against doping are measures such as
supplying information, education and bringing about changes in the individual’s
consciousness. But these measures can only be effective if they take the main
motives for performance enhancing drug abuse in sport into consideration. With
regard to the sporting orientation, the motives can be very different indeed.
While bodybuilders wish to have lean mass and less fat, weightlifters want to lift
the maximum amount of weight, whereas runners, for example, want to be the
fastest or to carry out long-duration workouts without a physical breakdown
[1,4]. In addition, the main motives for doping misuse among Germany’s elite
athletes are sporting success and financial aspects [12]. The top priorities
among male pupils at school, however, are generally to become more attractive
physically, to develop larger muscles or to enhance their performance in sport,
while some pupils point out that it is fun to try drugs or maintain their friends do
so [13]. Therefore, Laure [3] divided the motives for doping into two categories:
physiological considerations, such as reducing fatigue and compensating lack
of training, and psycho-social factors including e.g. economic factors, the
influence of the mass media and the desire for social recognition.
Although the motives for performance enhancing drug abuse may be
heterogeneous in different abuser groups, the athletes, the sporting
environment and the general public are fully aware of the importance of the
doping problem and the potential health risks. Public awareness of performance
enhancing drug abuse was confirmed by a Swiss telephone survey, in which
interviewees perceived doping as a serious problem for elite and recreational
sports [14]. Furthermore, three out of four German elite athletes stated they had
already thought about the doping problem in general [15]. When questioned,
most of them replied they would discuss a possible abuse of doping substances
with the coach, indicating that coaches are regarded as pivotal, reliable persons
in the athletes’ sporting environment. Additionally, the team doctor is a very
popular source of advice, if information on a substance or product is required
[16]. This reveals that the physician plays a key role, being the person athletes
may turn to for reliable, objective information when contemplating doping [17].
But also parents, team members, partners or friends may be involved in
discussions about doping due to the bond of trust [15]. Therefore, for the
success of doping prevention measures, it is important not only to focus on the
individual responsibility of the athlete but also to generate positive modes of
behaviour and attitudes. The sporting and social environment including
coaches, physicians, therapists, parents as well as the sports clubs and schools
should be involved in implementing educational programs. Because people who
233
use doping substances may also use recreational drugs for a non-recreational
purpose [18], one has to keep in mind that drug abuse prevention programs
among adolescent athletes cannot solely be limited to the list of banned
substances and methods, but must include all other unhealthy forms of
behaviour like smoking.
C
The Athlete
Many athletes believe that banned substances and methods have performance
enhancing effects [19,20]. Forbidden use of drugs implies that the drug
enhances performance, which is not necessarily the case [21]. In sporting
circles there is insufficient information concerning the effects of the banned
substances on exercise performance, and many athletes are unaware, that
some of the banned substances lack any performance enhancing effect [22].
Knowledge about the potential health risks of performance enhancing
substances as well as information concerning permitted medicines in case of
illness seems to be a very important factor when dealing with the doping
problem. General knowledge scores about doping in general are low [23, 24]
and the potential health risk associated with performance enhancing drug abuse
is frequently underestimated: Of 1459 French high school students interviewed,
7% were of the opinion that doping is not always dangerous for the human body
and 27% stated that doping prescribed by a physician could be used without
any health risk [19]. Furthermore, boys seemed to be more careless than girls.
In addition, those subjects who regarded doping as a minor health risk seemed
to be more often associated with drug abusers than those regarding doping as a
significant health risk [20]. In contrast, many top-level athletes used only those
medicines containing no IOC banned sympathomimetic drugs, in case of upper
respiratory tract infections. Those athletes competing at the higher level of sport
were found to be the most knowledgeable in terms of banned over-the-counter
medicines and were most in favour of their prohibition [25].
Although the prevalence of doping seems to be around 3-5% in children and
may be estimated at 5-15% among adults, whatever the age, the prevalence of
performance enhancing drug abuse is always higher in men than in women [3].
According to a telephone survey of pharmacists and general practitioners in
Switzerland, requests for testosterone and peptide hormones were
predominantly made by 20 to 40-year-old men, who were either top athletes or
body-builders [26,27]. Stimulants and anabolic steroids seem to be the most
frequently used drugs, followed by narcotics (cocaine, marijuana) and
analgesics. Anabolic androgenic steroids were often abused in team sports like
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Christiane Peters
football, baseball, basketball and rugby as well as in athletics or swimming, with
the highest prevalence in weight-lifting and body-building [3]. Actual findings
made by Alaranta and co-workers [20] indicate that the risk of performance
enhancing drugs being used appears to be highest in speed and power sports
and lowest in motor-skills sports.
Furthermore, many athletes may attempt to gain a performance advantage with
the use of a variety of dietary supplements [28] in order to compensate for any
exercise dependent higher consumption of energy, and mineral requirements.
For athletes competing in an event this includes the risk of taking contaminated
supplements on the one hand. On the other hand it may reduce the individual
inhibition threshold to taking substances like pills, capsules and powders rather
than a balanced nutrition, so as to be prepared for any exercise-induced
demands of the human body [29]. Moreover, it has been pointed out that there
are some athletes in top level sport who personally know others who use
banned substances [20]. For those athletes it becomes more difficult to believe
in sports ethics, being aware of the disadvantage in competition, so sometimes
it may be hard to keep steadfast and continue to refuse doping.
Although distribution of performance enhancing substances in sport is
prohibited, according to athletes, the three main networks for the sources of
supply are [6,19,30]:
the medical sector including a doctor, mostly a general practitioner or a
pharmacist with a medical prescription,
the black market, mostly for narcotics such as cannabis or cocaine (from
traditional dealer sources) and other substances available on prescription
only,
their own social network including other participants, but mainly friends, a
coach, other team members, or relatives.
This has been confirmed by Striegel and co-workers for the fitness sector,
where the health care system supplies each second anabolic ergogenic
substance user with their substances, frequently monitored by a physician [31].
Health reasons and the possible biomedical side effects of doping are
mentioned in the first place by those athletes refusing to use doping [15].
Most of the athletes do not generally show any active personal engagement in
order to get information about how to prevent doping, but get passive
information from others (Peters et al., unpublished data). For doping-sensitive
topics, the first contact person for athletes is the coach. The rising generation of
German elite athletes frequently confers with the coach when thinking about
235
doping. Three out of four athletes confirmed that they had already thought about
doping in general and half of them confirmed that doping associated topics, like
general information about the list of prohibited substances and methods, doping
controls etc. were discussed during team courses [15]. This corresponds with
results from a UK survey in which elite athletes confirmed that they had
received a doping educational update within the pervious 6 months, but they
would like to get reminders more often [16]. Education in this field requires the
coach to be well informed about doping related issues, including health risks, so
as to be an adequate adviser, giving knowledgeable answers on all doping
related questions. A presentation of his anti-doping views, with adequate
alternatives for healthy and balanced nutrition in combination with a harmonized
training program, would give him the opportunity to influence his athletes in
many respects, including their doping mentality.
From the athletes` point of view, improved detection methods would be the best
way to fight against doping. Furthermore, the anti-doping policy should include
more supervision. While all athletes demanded severe punishments,
significantly more female athletes recommended better education about health
risks than male athletes [12].
D
The Coach
One of the most important figures in an athlete’s environment is the coach. He
plays a significant role as model, especially for young people. Many athletes
accept his ideas, attitudes and ideals and grant everything he says great
importance. His influence increases when training becomes more intensive and
takes up more time. In exceptional cases, the coach becomes a kind of
substitute parent, who is frequently consulted on private matters. This occurs
more frequently among girls and women [11,32].
On the one hand the coach must aim for the maximum performance in sport; on
the other hand he has to take care of the personality development of his
protégés and should exemplify ethical principles [11]. The coach’s work can be
very good, but only if the athlete is successful, will the output of his coaching
become visible [33]. Therefore, the success of an athlete is just as important for
the coach as it is for the athlete himself, sometimes even of existential,
occupational relevance.
The question whether a coach is able to transmit his attitude on doping to his
protégés was confirmed by an American survey done among football players 10
years ago, where a great number of athletes agreed that they would get in
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Christiane Peters
trouble with the coach if they were taken by surprise when using anabolic
steroids [34].
Many coaches take a doubtful look at the performance development in some
special top level sport disciplines. The majority of French coaches, when
replying to a written survey, considered the improvement of numerous records
only possible with the support of performance enhancing drugs. Despite clearly
negative attitudes towards doping, one third of the coaches responded to
believe that athletes who object to doping would not be successful [35].
Therefore, many coaches would like to have doping controls amplified in the
athletes´ environment [36].
In their daily work, coaches are frequently forced to give some thought to
doping issues. In addition to the health related aspects, doping controls as well
as the question of fairness in sport appear to be the front issues (Peters et al.,
unpublished data). Furthermore, doping related issues have been discussed
between athletes and coaches much more often in the last few years. While in a
French survey one out of six coaches stated that he had been confronted by a
request concerning information about doping related issues during the previous
12 months [35], in a German survey every second coach confirmed he had
been asked regularly for advice with regard to doping and doping prevention
(Peters et al., unpublished data). In both surveys the coaches were asked about
their attitudes and their opinion on the use of performance enhancing drugs.
Additionally, information about the list of prohibited substances and methods as
well as doping control procedures or health hazards were topics of
conversation. During such discussions, most of the coaches did not feel
educated enough for this task (Peters et al., unpublished data). More than 80%
of the interviewed French coaches consider themselves badly trained for coping
with the prevention of doping and less than 50% had a copy of the actual list of
prohibited substances and methods or knew the World Anti-Doping Code [35,
Peters et al., unpublished data].
Despite their lack of knowledge, only a few coaches actively seek more
information. Yet the majority want to get it from their respective associations.
Furthermore, they are interested in taking part in special educational programs
(Peters et al., unpublished data). In contrast, personal engagement in support of
others actively fighting against doping was poor. Only one out of ten coaches
organized special measures for doping prevention or took part in such [35]. On
the one hand, a possible explanation for this lack of engagement may be the
feeling of not being properly prepared for this duty, although they assume they
have a high influence on the athletes they coach. On the other hand, one has to
keep in mind that coaches themselves confirmed having taken performance
237
enhancing drugs during the previous 12 months or during their sports career
[35]. Therefore, a strong anti-doping policy on the part of the sports association
and the national government would seem to be very important.
In order to use the coaches′ support on doping prevention more efficiently in
future, it would be necessary to increase their knowledge on doping problems,
then they would be able to influence their athletes positively on the matter. From
to the coaches′ point of view, doping prevention should start at the age of 10 to
15 (Peters et al., unpublished data). Therefore, it would be important to start
educational programs, not only for those coaches working in elite sports, but
also for coaches working at a lower level of education, because they are in
close contact with younger athletes and would be in a position to develop an
anti-doping attitude among them.
E
The Sports Physician
Due to their field of expertise, physicians, especially those with an additional
training in sports medicine, are persons of trust regarding health specific issues
and are frequently contacted by both elite and recreational athletes. While only
one in four German elite athletes stated that in a case of performance
enhancing drug abuse they would contact their general practitioner, every
second athlete would consult a sports physician [15]. In their daily work a lot of
sports physicians are responsive to doping issues put to them by athletes,
mostly in search of information and education [29,30,37-40]. Most demands
concern nutritional supplements and if certain medicines conform to the list of
prohibited substances and methods. But in some cases questions concerning
performance enhancement and biomedical side effects were also asked [40].
Other physicians confirmed that they were contacted as a source of supply for
prohibited supplements [26,29,40,41] and according to some athletes, the
physician in some individual cases knowingly prescribed prohibited substances
during routine consultation [30].
Due to their relationship of trust to athletes and patients, sports physicians are
frequently confronted with doping issues. Therefore, they would be in a position
to play a decisive role in doping prevention, but they do not feel informed
enough for this task. Results from an English survey of 400 general
practitioners showed that only one in three practitioners knew that the doping
regulations can be found in the British National Formulary. Furthermore, 12% of
the responding practitioners believed that they were allowed to prescribe
steroids for non-medical reasons [41].
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Christiane Peters
Many practitioners do not feel well prepared for an active role in the fight
against doping. In a survey done in the Netherlands, more than 70% of the
interviewed general practitioners indicated the need to improve their knowledge
concerning doping related issues, because they were not familiar with the
substances prohibited in sports and their respective health side effects [38].
Poor knowledge about doping related issues was confirmed by French, British
and German physicians [40-42], indicating that the doping prevention policy
should be improved in several countries. Some authors noticed a difference in
knowledge between general practitioners and sports physicians: While sports
physicians working actively in the consultation and treatment of athletes
deemed their doping related knowledge mostly as “good” or “very good”, only
15 - 25% of the general practitioners confirmed this statement. Therefore,
nearly all sports physicians feel themselves able to give competent answers to
doping related questions. But more than every second general practitioner had
to deny this [40]. This stands in contrast to results obtained in a study of the
Senegalese Association of Sports Medicine, where only 18% knew the
definition of doping and only 15% could cite any class of doping products [39].
Nevertheless, all practitioners, whether active or non-active in the field of sport,
would like to get more education concerning doping related issues [26,40].
There is a great uncertainty concerning the use of medicine in sport because of
changes in the list of prohibited substances and methods and the complexity of
the anti-doping policy [43].
In the sporting environment of recreational and elite athletes, the sports
physician is an important member of the team. Because of his close contact to
the athletes, a sports physician well informed on doping prevention would be in
a good position to support the fight against doping. But a lot of them neither
received any detailed information about doping during their course of studies,
nor during their course in sports and exercise medicine. Therefore, they feel
they have not enough knowledge and do not feel well enough prepared to take
an active part in doping prevention. In addition, they fear being used as a
source of supply for prohibited substances with or without their own awareness.
Furthermore, unwilling to violate laws but under the obligation to take care of
their patient’s health, a physician may at times get into moral conflict when
supervising athletes who medicate themselves [44]. Therefore, they should
have so much detailed knowledge of these problems, that the athletes who
contact them may be properly informed about potential risks and about the fact
that for the majority of people, proper advice on training and diet will bring the
desired effect in physical performance without any need of doping substances.
And finally, sufficient information about performance enhancing drug abuse
239
might act as a kind of protection for the physicians themselves, to prevent their
being utilized unawareness as a source of supply.
F
The Athletes´ Environment
To be effective, doping prevention measures should not only focus on athletes,
coaches and physicians but also on the sporting environment. Therefore, the
European Convention against Doping ascribed importance to the athlete’s
environment. The involvement of the sporting (coach, carer, club members), the
social (friends, family, etc.) and the medical environment (general practitioner,
masseur, physiotherapist, etc.) of young and ambitious athletes in active doping
prevention would assume an anti-doping attitude on their part as well as some
doping related knowledge about potential effects and health risks among the
target group.
For young people who are members of a peer group, it is important to be
educated within the respective social environment, because the motivation to
use performance enhancing drugs may arise under peer-group pressure, with
the desire for social recognition, or to feel “cool”, or because friends do so [13].
This implies, that doping prevention measures for young people should not be
organised on an individual basis but in the peer-groups, clubs, teams or grades
of schools to make sure that all members of the group are involved, that they all
get the information about the possible health risks and receive information
about alternatives for diet and training, so as to achieve performance
enhancement naturally. Otherwise it could be very difficult if one individual
demonstrated an anti-doping attitude contrary to that of the others in the group.
G
Prevention Campaigns
In the fight against doping, it is the responsibility of the scientific community to
spread scientific knowledge and to take part in the education of athletes,
coaches and others involved in sports [22]. Because some older training
programs seemed to be inefficient [42], special anti-doping prevention programs
should be developed.
An easy and frequently used alternative source of information concerning any
detail on doping or on doping in general is the internet. The National AntiDoping Agencies of several countries as well as the websites of different sports
are offering a lot of general information. However, these websites should not
only provide the list of prohibited substances and methods, but also regularly
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Christiane Peters
update lists of acceptable medicines as well as recommendations on healthy
nutrition and efficient training. Access to the internet in addition to promotion of
specially prepared websites could be a good method of improving general
knowledge, but this in itself is also too limited. What happens if there are any
individual questions [16]? For those people looking for objective information an
anti-doping hotline could be an easy and anonymous way to get information on
detailed questions. Sweden’s anonymous Anti-Doping Hotline, where 3.500
callers per year searched for information concerning doping showed that such a
service would actually be used. While most callers were non-abusers, 17%
stated they had had doping experience. Men called more frequently than
women, with the dominant group aged between 17 and 30. Commonly asked
questions were, firstly, on specific drugs and, secondly, regarding information
about doping in general [7].
In contrast to these singular contact measures, complex educational programs
can be carried out for several weeks: Within the American anti-doping programs
ATHENA and ATLAS, young female and male students were taught about the
consequences of using substances and other unhealthy behaviour, and the
beneficial effects of appropriate sport nutrition and effective exercise training.
Courses were organised in weekly sessions, with small learning squads under a
squad leader over a period of several weeks. The programs were accompanied
by special teaching material in terms of guides on sport nutrition and training.
The efficacy of both programs was evaluated by a control protocol using
confidential questionnaires prior to and following the sport season, indicating
enhanced healthy behaviour and including less new use of performance
enhancing substances, and among the girls less ongoing and new abuse of diet
pills in the experimental group. Furthermore, positive changes were observed in
other non-sport related but health-harming actions, for example less driving with
an alcohol-consuming driver, or illicit use of marijuana and other drugs [45-47].
Similar results were obtained in a controlled French study, where a specific
educational intervention showed a reduction in the intent to abuse drugs among
adolescent top-class athletes [48] and in a controlled American 10-week study
with student athletes, where participating athletes confirmed that drug education
can be effective in preventing drug abuse [49].
H
Conclusion
Most of the older concepts on doping prevention measures are generally used
keeping the negative consequences of drug abuse in mind and are based on
241
the deterrent factor. Concluding from the athletes’ statements, this however did
not prevent the use of prohibited substances [15].
Some newer concepts make us hopeful that prevention programs can be
effective in the fight against doping and social drug abuse, but they have to be
carried out in a wide area and implemented within existing structures such as
schools, clubs or sport associations, to make sure that each adolescent will be
involved automatically in such programs. Therefore, programs like those
described in the available literature would not only require excellent concepts
and clear, organisational structures but also teaching material, educated
personnel, time and money in order to be carried through effectively in future.
To be effective, doping prevention measures must not only focus on athletes
but must involve their sporting, social and medical environment.
I
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11. Singler and G. Treutlein. Doping – von der Analyse zur Prävention.
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Correspondence
Christiane Peters, Technische Universität München, Institute of Public Health
Doping in Handicapped Sport
6
245
DOPING IN HANDICAPPED SPORT
Christiane Peters
A
Historical Overview
Due to professionalizing of training and coaching in sport for athletes with a
disability as well as high technical development of sport equipment exercise
performance rapidly increased over the last years. In parallel, rising attention of
mass media during international events like the Paralympic Games draws
successful athletes into the focus of the public. Therefore, the uncompromising
will to win combined with a possible financial incentive and social approval may
be reasons for a considerable increase of doping in sport for the disabled.
Although negative-tested urine samples for doping analysis were taken for the
first time in 1984 during Paralympic wheelchair events in Stoke Mandeville,
official doping controls were started 1988 in Seoul/Korea during the Summer
Paralympic Games and 1992 in Tignes-Albertville/France during the Winter
Paralympic Games [1].
The continuously increasing number of doping controls reached an amount of
643 in the Sydney-Games 2000, when the first tests were found to be positive
according to the World Anti Doping Code. From the 14 positive-tested urine
samples three contained documented substances with medical justification. Ten
of the remaining eleven official doping offences were found in power lifting, and
one in athletics. Nine of the power lifters were convicted by the use of training
controls. The tenth power lifter as well as the short distance runner have been
under the group of medallists of their finals, but were found to be positive after
their obligatory in-competition controls. On the one hand they had to return
medals to the International Paralympic Committee; on the other hand, all
convicted athletes received the obligatory suspension. The first positive doping
control during Paralympic Winter Games was found in Salt Lake City 2002,
where the anabolic steroid Methenolone was detected in the urine sample of an
athlete with an amputation of the upper extremity in Nordic skiing. At
International Championships of different Sports Federations or at Paralympic
Games several doping controls of athletes with a disability were found to be
positive during the 21st century. Due to repeated doping offence three power
lifters were suspended for lifetime since the Paralympic Games 2004 in Athens.
Because performance determining factors in sport are mostly independent of a
disability, in general, the kinds of sport or sports disciplines as well as the
abused substances were comparable to those found in sport for athletes without
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Christiane Peters
a disability. Therefore, most of the substances detected in urine samples were
anabolic steroids, less frequently stimulants, glucocorticosteroids or diuretics.
These substances have the same potential to induce the already known
biomedical side effects in athletes with a disability in comparison to those
athletes without. Therefore, in the fight against doping in sport for athletes with
a disability and in conformity with the general principles of the World AntiDoping Code the IPC Anti-Doping Code was established in 2004 with the main
aim to preserve the spirit of fair play in sport for athletes with a disability.
But in comparison to non-handicapped adult persons two additional facts have
to be kept in mind: On the one hand there are some disabilities, whereby
athletes become reliant on guides or carers such as visually impaired athletes.
This dependency in activities of everyday life including nutritional intake may
bear an increased risk of becoming a doping victim due to contaminated food
provided, for example, by rivalling athletes or teams. Furthermore, special
attention must be given to the procedure of taking urine samples, which e.g. can
not be controlled by blind athletes. On the other hand a significant number of
athletes with a disability, competing in top-level sport, need to take some kind of
medication. Under these circumstances additional doping may bear an
increased health risk due to the combination of several medications for a
special disability with regard to possible multiplying effects.
Nowadays, in-competition controls are the norm during International
Championships and Paralympic Games, while out-of competition controls just
take place on the verge of International competitions, indicating that a close
control network is not a rule in top-level sport for the disabled. Beyond the
handicap-specific problems in doping prevention and sampling of doping
controls there is a risk of doping related health side effects in sports for this
athletes. In addition to the potential health risks and hazards, already mentioned
in literature regarding the able-bodies athletes, there are important handicapspecific aspects explained in the next chapter.
B
Health Side Effects
Due to their individual disability some athletes may have conditions requiring
them to take specific medications which are mentioned on the official WADA-list
of prohibited substances and methods in sport. Under these special conditions
they are allowed to use those substances for medical reasons but in agreement
with the Anti-Doping rules they have to declare this in advance showing a
therapeutic use exemption.
247
Beyond the well-known doping practices in top-level sport for people without a
disability, there is a special doping method unique in disabled sport, which is
called “boosting”. Boosting is a deliberate attempt to cause or provoke
autonomic dysreflexia (AD), an abnormal sympathetic reflex which is up to an
overactivity of the autonomic nervous system [2].
Because some quadriplegic athletes had noticed that the rate of perceived
exertion was reduced under AD conditions and faster top speeds could be
achieved in wheelchair racing, this state becomes interesting to deliberately
enhance exercise performance in competitions [3]. Comments of quadriplegic
athletes are e.g. “If I cannot sweat, I am not able to reach my best
performance”. A significantly enhanced peak performance, higher maximal
heart rate, and peak oxygen consumption were observed under experimental
conditions for high level spinal cord injured athletes under AD and confirm these
subjective impressions [4]. Therefore, due to the performance enhancement of
AD connected with an increased health risk in spinal cord injured athletes, in
1994 the IPC deemed boosting to be a banned method [2].
AD is a state; people with a cervical or high thoracic spinal cord injury most
often at or above the sixth vertebrae can suffer from. Anatomical explanation for
this phenomenon is the absence of cerebral control over reflex sympathetic
activity because of the transduction of the cord [3,5]. With regard to
competitions in sport, it is important that persons with a high level spinal cord
injury have a limited potential for improvements of the cardiopulmonary system
under exercise conditions. The loss of sympathetic cardiac innervations results
in a restriction of the maximum heart rate for quadriplegic and high paraplegic
persons causing a limitation in the cardiac output and maximal oxygen uptake.
This is accompanied by a reduced catecholamine response to exercise, and in
addition, by a loss of the muscular venous pump in the lower limbs, a limitation
of their performance [3].
The AD-reflex may occur spontaneously or may be provoked deliberately by
distension or irritation of the urinary bladder e.g. following clamping of the
urinary catheter or by distension of the bowel. Although boosting techniques do
not cause any pain to athletes with paralysis, any peripheral afferent and painful
stimuli to the lower part of the body may trigger AD, resulting in a rapid rise in
blood pressure [3,5-7]. With regard to a generally increased risk of arterial
hypertension in spinal cord injured persons, episodic increases of blood
pressure following AD may additionally enhance this risk for cardiac and
circulatory dysfunction [6]. Upon leg extension exercise in combination with
electrical stimulation an immediate increase in systolic blood pressure was
observed, giving their body a feeling of some kind of stimulation [8]. This is in
248
Christiane Peters
agreement with findings from others observing a lower heart rate at rest in the
boosted state, as well as the ability of the athletes to achieve levels in excess of
the normal maximum during exercise. In association with AD state elevated
catecholamine levels were observed in quadriplegic athletes under boosting
conditions, mostly due to a rise in norepinephrine, while peak lactate at the
point of exhaustion was comparable with and without AD [4,5,6,9].
In addition to the blood pressure rise other symptoms like headache, sweating
or gooseflesh may occur under AD. Most dangerous complications may be
cardiac arrhythmia, cerebral haemorrhage, and even death [3,10]. Due to the
possible health hazards AD has been regarded as a medical emergency and
the IPC forbids competition in this state. Therefore, controls of the systolic blood
pressure in competition for athletes with a high spinal cord injury are in
progress: If in two consecutive examinations with a 10 min break it is 180 mm
Hg or above, withdrawal from competition will be determined [1]. Because AD
occurs spontaneously in people with a high level spinal cord injury, it is nearly
impossible to catch an athlete provoking this reflex deliberately. Therefore,
withdrawal of an athlete in an AD state is comparable to the protective
suspension of health reasons in cross-country skiing for the able-bodied
athletes.
Spinal cord injured persons have trophic, vascular and neurogene
particularities, which may predispose the development of thromboembolic
disorders [11]. Therefore, well-known doping substances and methods already
abused in the able-bodied athletes to increase oxygen transport capability, like
EPO or blood doping, may additionally increase the risk of circulatory
disturbances in wheelchair-dependent athletes.
C
Conclusions
With regard to biomedical side effects similar reactions of the able-bodied
athletes to most of the abused substances and methods can be expected in
athletes with a disability. But there are only few documented projects dealing
with doping in sport for the disabled, mainly with regard to autonomic
dysreflexia. Beyond the already described facts, further studies have to
investigate whether the knowledge concerning health side effects of doping in
athletes without a disability can be easily transferred to those with a disability or
whether the dimensions of health hazards are different.
D
249
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1.
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2006.
2. A.D. Webborn. "Boosting" performance in disability sport. Br J Sports Med
33 (2):74-75, 1999.
3. B.Y. Lee, M.G. Karmakar, B.L. Herz and R.A. Sturgill. Autonomic
dysreflexia revisited. J Spinal Cord Med 18 (2): 75-87, 1995.
4. A. Schmid, A. Schmidt-Trucksäss, M. Huonker, D. König, I. Eisenbarth, H.
Sauerwein, C. Brunner, M.J. Storch, M. Lehmann and J. Keul.
Catecholamines response of high performance wheelchair athletes at rest
and during exercise with autonomic dysreflexia. Int J Sports Med 22 (1): 27, 2001.
5. Y. Bhambhani. Physiology of wheelchair racing in athletes with spinal cord
injury. Sports Med 32 (1): 23-51, 2002.
6. A. Cavigelli. Kardiovaskuläre Störungen bei querschnittgelähmten
Patienten. Schweiz Med Wochenschr 130: 837-843, 2000.
7. J. Blackmer. Rehabilitation medicine: 1. Autonomic dysreflexia. CMAJ 169
(9): 931-935, 2003.
8. E.A. Ashley, J.J. Laskin, L.M. Olenik, R. Burnham, R.D. Steadward, D.C.
Cumming and G.D. Wheeler. Evidence of autonomic dysreflexia during
functional electrical stimulation in individuals with spinal cord injuries.
Paraplegia 31 (9): 593-605, 1993.
9. G. Wheeler, D. Cumming, R. Burnham, I. Maclean, B.D. Sloley, Y.
Bhambhani and R.D. Steadward. Testosterone, cortisol and catecholamine
responses to exercise stress and autonomic dysreflexia in elite
quadriplegic athletes. Paraplegia 32 (5):292-299, 1994.
10. M.G. Ziegler, P. Ruiz-Ramon and M.H. Shapiro. Abnormal stress
responses in patients with diseases affecting the sympathetic nervous
system. Psychosom Med 55 (4):339-346, 1993.
11. G.A. Zäch and H.G. Koch. Thrombose und Embolie – Pathophysiologie
der Blutgerinnung. In: Zäch GA, Koch HG (Hrsg): Paraplegie Ganzheitliche Rehabilitation. Basel, Karger 2006, pp 115-124.
Correspondence
Christiane Peters, Technische Universität München, Institute of Public Health
250
7
7.1
Hande Sarikaya
PREVENTION STRATEGIES
OVERVIEW ABOUT THE ACTUAL STATUS QUO IN EUROPE
Hande Sarikaya, Jezabel Ohanian, Asterios Deligiannis, Katerina N. Georgieva,
Esther Giraldo, Ryszard Grucza , Mª Dolores Hinchado, Nikolaos Koutlianos,
Dorota Kwiatkowska, Eduardo Ortega, Christiane Peters
A
Introduction
One of the main subjects of any health system is prevention. Unfortunately in
the fight against doping activities are focused on the development of new
techniques for drug identification and controls and less in prevention. Antidoping controls must be considered as a way to guarantee a competition free of
drugs and prohibited methods. But the better way to beat doping is through
education, information and with the correct medical assistance. Usually most of
the efforts try to discover the culprits, while other actions are neglected.
Sportspeople are encouraged to win at any price while the prestige of the team,
school, locality, nation they represent are at stake. On the other hand we forget
that the problem is bigger at amateur or recreational levels, where most of the
users are not checked medically and more often they resort to ergogenic drug
abuse.
Not all states deal identically with the issue of doping in sport. In Europe for
example, six countries pioneered in taking the legislative route to define the
juridical framework of the fight against doping. Their concepts, measures and
sanctions developed through the years, although some countries still present
gaps concerning the topic of doping and few years ago only five countries had
specific legislation on doping. As it is stated in the report “Harmonisation of
Methods and Measurements in the Fight against Doping” by Merode and
Schamasch [1]:
"Doping is not a concern only of high-level athletes. It affects amateurs and
people who practise sport as a leisure activity. Fighting the problem effectively
clearly means putting a stop to the trafficking that feeds it. It is therefore
essential to develop cooperation between the sports world, on the one hand,
and the judicial, police and customs authorities, on the other."
The present review tries to emphasize the differences and similarities between
the strategies of prevention followed in the various countries of Europe.
Therefore, a questionnaire was created inquiring the actions in the different
countries in the field of doping prevention. This questionnaire was sent per mail
to the anti-doping agencies of all European countries or queried by phone.
Prevention Strategies in Europe
B
251
Structure of the questionnaire
The main purpose of the survey was to evaluate the engagement of European
anti-doping agencies in the realization and accomplishment of anti-doping and
prevention strategies. Therefore a simple questionnaire of four pages containing
four main chapters was distributed. 25 European Agencies were contacted and
the total reflux was 22, which are assessed as 100% in our statistical
calculations performed using SPSS (Statistical Product and Service Solutions).
The questionnaire is partitioned into the main chapters: (1) Hotlines, (2) Training
on doping prevention, (3) Doping prevention in schools/universities and (4)
Distribution of prevention strategies.
Chapter 1 (Hotlines) covers the following questions:
a)
Do you provide anti-doping hotlines?
b)
Who is in charge of the hotlines?
c)
Who is using the hotlines the most?
d)
What are the main topics / questions asked?
e)
What are the operating hours?
f)
Are the hotlines anonymous?
Chapter 2 (Training on doping prevention) covers the following questions:
a)
Do you offer training programs for specific target groups?
b)
Which institution provides the program?
c)
Who is teaching on the training program?
d)
What are the topics of these programs?
e)
How often does the training program take place?
f)
Is there a curriculum?
g)
Are there special materials for these programs?
Chapter 3 (Doping prevention in schools/universities) covers the following
questions:
a)
Do you address doping / doping prevention in schools?
b)
Do you address doping / doping prevention in universities?
Chapter 4 (Distribution of prevention strategies) covers the following questions:
a)
Do you hand out materials about doping and prevention?
b)
Do you / did you publish articles in scientific newspapers, journals etc.?
252
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Hande Sarikaya
Prevention in Europe
Chapter 1: Hotlines
Only 41% of the contacted agencies operate an anti-doping hotline. In 62.5% of
those cases the National Anti-Doping Agency (NADA) is in charge of the
hotlines. 12.5% are controlled by the National Olympic Committee. Remarkable
25% of the hotlines are controlled by other institutions not further defined here.
As expected, athletes for competitive sports are using the provided hotlines the
most with 87.5% followed by physicians 62.5%, coaches 37.5% and, still
remarkable, athletes for recreational sports 25.0% (Fig. 1). The main topics
issued on phone are downward drugs & medications, nutritional supplements,
prescription, doping testing, legal basis, side effects, prevention and finally
health hazards (Fig. 2). 62.5% of the hotlines are operated 24 hours a day.
37.5% are just operated during working hours. In most cases the advices are
given by physicians followed by trained personal, medical attendants and others
including nurses, pharmacists and secretaries. 37.5% of the hotline operators
claim to assure anonymity.
100%
90%
80%
70%
60%
no
59%
yes
41%
50%
40%
Athletes for
competitive sports
88%
Physicians
63%
30%
20%
10%
Athletes for
recreational sports
25%
Coaches
38%
0%
multiple answers possible
(total > 100%)
Figure 1. Do you provide any anti-doping hotlines and who is using them most?
253
100%
Drugs and medications
63%
50%
Prescription
Doping testing
25%
Legal basis
25%
Others
13%
Side effects
13%
Prevention
13%
Health hazards
13%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Figure 2. What are the main topics and questions asked?
According to scandinavian models, the major aim of anti-doping hotlines is to
decrease doping misuse and contemporaneously increase the knowledge and
awareness of the potential health risks and overall consequences of doping by
providing general information, education, development and actual research data
[2]. Thereby, the information is divided into 6 following main fields of action:
medical questions, prohibited substances, introduction of relevant
organisations, maintain up-to-date anti-doping knowledge, preserve data
anonymously, provide information about healthy ways of performance
enhancement. Such an attempt to organize a hotline was firstly emerged in
Sweden in 1993. This anonymous hotline was operated by trained nurses cooperating with clinical pharmacologists [2]. The success and acceptance of this
service is reflected by the number of 25,835 calls within 7 years.
Chapter 2: Training on doping prevention
86.4% of the anti-doping agencies offer training programs mainly for athletes
89.5%, coaches 84.2%, physicians 73.7%, medical attendants 57.9% and more
seldom for teachers 36.8% and for the open public 31.6% (Fig. 3). Happily,
these programs are offered by 47.1% of the questioned agencies to an extend
of approximately 12 hours and more. The NADA provide most (75%) of the
training programs and that for free followed by the National Olympic Committee
254
Hande Sarikaya
(12.5%). Program executives are trained personals 75%, physicians 37.5%,
medical attendants 25%, others (members of educational departments and
scientific assistants) 12.5%, coaches 12.5% and teachers with 6.0%
participation (Fig. 4). The main topics of the provided programs are in
decrescent order nutritional supplements, doping testing, prevention, side
effects, legal basis, health hazards, doping means and techniques (Fig. 5).
100%
90 %
90%
84 %
80%
74 %
70%
58 %
32 %
10%
Open public
20%
37 %
Teachers
30%
Medical attendant
40%
Physicians
50%
Coaches
Athletes
60%
yes
86%
no
14%
0%
(total > 100%)
Figure 3. Do you offer training programs and for whom?
Trained personal
75%
Physicians
38%
Medical attendants
25%
Other
13%
Coaches
13%
Teacher
6%
0%
10%
20%
30%
40%
50%
Figure 4. Who is teaching on the training program?
60%
70%
80%
90%
100%
255
100%
Doping testing
100%
Prevention
94%
Side effects
88%
Legal basis
88%
Helath hazards
88%
Doping means and techniques
88%
13%
Other
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Figure 5. What are the topics of the training programs?
The training programs are provided by the agencies once a year (33.3%), twice
a year (20%) and surprisingly also more than twice a year (26.7%). Other
performing strategies are used by 20%. A curriculum is mandatory for 76.9% of
the contacted agencies even if the curriculum is defined in a broad spectrum
e.g. including (so named by the agencies)

6 core modules on anti-doping,

variable, depending on target group,

doping means & techniques, prevention, health hazards, doping
testing, side effects, legal basis, nutritional supplements,

new things in anti-doping fights,

nutrition and doping control cheating,

educational materials.
71.4% claim to use specific materials for their sessions like advertising antidoping materials, lectures presented as articles in short (2 pages) or long
version (5-8 pages), brochures information materials, leaflets, DVDs, video
materials, websites, WADA list, anti-doping handbook (compilation of all antidoping legal acts and rules) etc. All the mentioned specified materials were
used in programs in similar parts around 5.0%.
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There are lot of different and well designed efforts and serious attempts for the
creation of doping prevention studies to fight against doping at its roots
worldwide. But there is still a need to align all differently designed studies to
compete doping in the same way worldwide. Besides biological and chemical
methods to detect doping, evaluations and studies also focus on the prevention
of illegal doping at all. One preventive laboratory method described e.g. is
based on a Fourier-transform infrared spectroscopy analyzing serum extracted
out of 50µl capillary blood [3]. The results of this measurements containing a
wide range of biological molecules in a single microsample provides a
„discriminatory biomolecular profile“ so that individuals can be differentiated on
the basis of their physiological status [3] and consequentially reflecting doping
misuse. This is the one active side of doping prevention. Another probably most
important side of doping prevention is the contacting of the main clientele and
also the main public including schools and universities. There are programmes
accomplished by United Kingdom Sport (UK Sport) like the 100% ME education
programme [4]. Other efforts are consultancy studies of the European
Commission like „Fight against Doping 2000-2001“ [5]. Under the title „Aren't we
all positive?“ the KPMG - Bureau voor Economische Argumentatie (Hoofddorp,
NL) provided a social and economic analysis of doping in elite sport. The
analysis consisted a social science and a legal part and recommended that antidoping policies should include legal and economic measures to counteract the
economic powers active in sport [5].
Chapter 3: Doping prevention in schools / university
Approximately half of the European anti-doping agencies address the topic
doping prevention in schools (45.5%) and in universities (50%) (Fig. 6). The age
of the students confronted with this topic in school ranges mostly between 1219 (80%) and more seldom at younger age. In the majority of cases this
informative school courses are arranged between the teachers and the
agencies and the attendance of the students is more or less obligatory.
As universities represent a diverse form of education the addressing is also
partly organized different, so that 45.5% of the courses held in universities are
voluntary and 36.4% are nonvoluntary (Fig.7). The numbers of hours equally
differ from 0.75 to 6 hours. The topics raised in university programs contain
besides doping means&techniques (20.0%), prevention strategies (20.0%)
health hazards (14.3%), doping testing (14.3%) also side effects (14.3%) and
the legal basis (11.4%).
257
no
55%
…schools
yes
45%
no
46%
…universities
0%
10%
20%
yes
50%
30%
40%
50%
60%
70%
n/a
4%
80%
90%
100%
Figure 6. Do you address doping prevention in...?
voluntary
37%
no
46%
yes
50%
not
voluntary
27%
n/a
36%
n/a
5%
Figure 7. Do you address doping prevention in universities and is it voluntary?
The US granted prevention studies ATLAS (Adolescents Training and Learning
to Avoid Steroids) and ATHENA (Athletes Targeting Healthy Exercise and
Nutrition Alternatives) present such possibilities of addressing doping
prevention to students. These programs were started in 1996 and 2006
respectively and are still very effective and successful [6-9]. One of the root
knowledges of such programs is the fact that in our society and preliminary in
elite sports an increasing tendency can be seen to enhance performance with
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Hande Sarikaya
the help of illegal drugs and methods. According to diverse European studies
accomplished with high school students and athletes this phenomenon covers
also children and youths using prohibited substances [10,11]. ATLAS´ objective
was to test a educational intervention designed to reduce adolescent athletes´
intention to use anabolic androgenic steroids (AAS). This AAS prevention
program enhanced healthy behaviors, reduced factors that encourage AAS use,
and lowered intention to use AAS [6,7]. The ATHENA intervention is a scripted,
coach-facilitated, peer teaching program, which was integrated into high school
athletic programs. The ATHENA program altered the targeted risk factors and
reduced ongoing and new use of diet pills and body-shaping substances [8,9].
These two programs show the importance of a structured process and a defined
curriculum content. Furthermore, the program´s positive results confirm the
potential to act as a vehicle to effectively prevent from health-harming
behaviors.
Baron et al. [12] review impressively the spread of doping to at-risk populations
and that developing education, prevention and treatment programs is the only
way to prevent the spread of this doping abuse especially in groups like the
youth.
Chapter 4: Distribution of prevention strategies
Most pleasant is the fact that at least 90.9% of the anti-doping agencies in
Europe hand out informational materials about doping and its prevention. The
doping prevention materials include brochures (36.4%), educational flyers
(34.1%), DVDs (18.2%) and CDs (11.4%) (Fig. 8). Such hand-outs are inter alia
advice cards on prohibited substances, testing procedure leaflets, medication
database promotional cards (www.didglobal.com) and outreach for events &
seminars. This listed material was equally distributed among National
Federations & Sports Clubs, Health National Centres, athletes, coaches, top
level/elite athletes, teachers, physicians and pharmacists. The informational
material was provided on request, using media, in doping control offices, during
sample collection or during competitions. Unfortunately, just 25.0% of the
agencies mail actively, while 75.0% act only on demand.
259
90%
80 %
80%
75 %
70%
40 %
40%
30%
25 %
CDs
20%
10%
Brochures
50%
DVDs
yes
91%
Educational flyers
60%
no
9%
0%
(total > 100%)
Figure 8. Do you hand out materials about doping prevention and if yes, what kind of
material?
The attempts towards using TV spots or radio shows for anti-doping prevention
activities is marginal. Only 31.8% of the European agencies use this tool of
information spreading. The major part of the agencies (68.2%) never thought
about reaching the public by TV or radio. 59.1% of the national anti-doping
agencies submitted scientific papers in journals or newspapers, presenting
their accomplished work in the field of anti-doping prevention activities [e.g. 1316].
D
Conclusions
Differences among the anti-doping strategies exist still between the European
countries, although they share the common points of prevention and
suppression. The methods used to attack the problem of doping are being
made progressively stricter, although this is not always well received by
everyone.
Such is the case of the well-known and controversial legal establishment of
official testers e.g. in France, Italy, Belgium, and Spain who can carry out their
work by surprise, i.e. coming unannounced at night into sportspeople's rooms or
into team facilities to determine whether there exist any doping materials. This
practice have yield fruit in France and Italy during the Tour de France or the
Giro d'Italia but they have also met with an indignant response from the
sportspeople who feel that it is an outrage to themselves as persons, and
unanimously consider that their fundamental rights have been violated.
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An important preventive action would be to accomplish that all people linked
actively or inactively to sports participate in the various anti-doping actions. The
road to take is to alert these people to the health problems caused by doping
substances. Indeed, most of the countries studied in this review now view
doping in their laws and adjudications as a helping tool to arouse people on this
topic. As well as health messages all European campaigns should always
concomitantly aim to promote the ethical values of sport.
E
References
1.
P.A. de Merode and P. Schamasch. Harmonisation of methods and
measurements in the fight against doping. Technical Report Project SMT41998-6530. European Commission 17-18. 1999.
A.C. Eklöf, A.M. Thurelius, M. Garle, A. Rane and F. Sjöqvist. The antidoping hot-line, a means to capture the abuse of doping agents in the
Swedish society and a new service function in clinical pharmacology. Eur J
Clin Pharmacol 59 (8-9): 571-577, 2003.
C. Petibois, G. Déléris and G. Cazorla. Perspectives in the utilisation of
Fourier-transform infrared spectroscopy of serum in sports medicine:
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(6):387-396, 2000.
R. Langley. Athlete attitudes at the fore on 100% ME anniversary.
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nniversary/ access on 24.05.2007
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L. Goldberg, D.L. Elliot, G.N. Clarke, D.P. MacKinnon, L. Zoref, E. Moe, C.
Green and S.L. Wolf. The Adolescents Training and Learning to Avoid
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Green, S.L. Wolf, E. Greffrath, D.J. Miller and A. Lapin. Effects of a
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Correspondence
Hande Sarikaya, Technische Universität München, Institute of Public Health
262
7.2
Melissa Durham
DRUG PREVENTION AND HEALTH PROMOTION FOR HIGH SCHOOL
ATHLETES: A SUMMARY OF THE ATLAS AND ATHENA PROGRAMS
Melissa B. Durham, Linn Goldberg
This article summarizes the information provided at the EU Symposium in
Munich, Germany regarding the need for effective drug prevention and health
promotion education for adolescent athletes and descriptions of the ATLAS and
ATHENA interventions, two gender-specific, evidence-based programs for
adolescent athletes.
A
Background of Drug Use in Sport for Young Athletes:
Is there a problem?
Alcohol and drug use is the leading cause of adolescents’ injury and death in
the United States [1]. Adolescent illicit drug and alcohol use has stayed
relatively steady or slightly declined over the past five years, but current use
among youth ages 12-17 remains high [2]. During 2004, over 30% of 10th grade
students (32.8% males; 33.6% females) and approximately half of 12th grade
students (50.7% males; 43.3 % females) reported using alcohol [2, 3]. Over a
fifth of the 10th graders (23.8% males; 20.2% females) and of the 12th grade
students, 33.4% of male seniors and 22.7% of female seniors reported binge
drinking, while marijuana use among 10th and 12th graders was 16.7% males,
13.4% females and 23.6% males, 15.8% females, respectively [3].
Anabolic steroid use is linked to this drug and alcohol use among adolescents.
Most studies report that 3-12% of adolescent males admit to using an anabolic
androgenic steroid (AAS) at some time during their life [4]. According to the
United States Center for Disease Control survey in 2005, the percentage of 9th12th grade students who took steroid pills or shots without a doctor’s
prescription one or more times during their life was 4.8% (+/-0.8) for males and
3.2% (+/-0.5) for females [5]. However, this study included all students, not just
those participating in school sports, whose use of steroids is considered to be
higher. While steroid use is relatively low compared to some of the more
popular drugs, it has been a growing problem, especially among young women
[6]. With approximately 19.5 million adolescents in the United States, over 1.5
million in the United States have reported using steroids in 2005 [5, 7].
In the United States, high schools have school-sponsored sports programs and
more than 50% of the students participate [8]. Despite the potential health
benefits from participating in athletics, adolescent athletes, especially males,
ATLAS and ATHENA
263
may be at higher risk than their non-athlete peers for engaging in healthharming behaviors [9, 10]. Naylor (2001) and French (1995) discovered that
athletes are not protected from health-harming behaviors because of their
athletic participation [11, 12]. Multiple regional and national studies by Yesalis
(1993), Buckley (1988), Johnson (1989), and Johnston (1998) have reported
high school athletes use some illicit drugs at the same rate or more frequently
than their non-athlete peers [13, 14, 15, 16].
DuRant, Escobedo and Heath (1995) reported that adolescent athletes who use
anabolic steroids for improving their athletic potential often use a variety of other
illicit substances [17]. In a study among younger adolescent (6th, 7th and 8th
grade students) sports participants, as compared with non-sports participants,
significantly higher frequencies of weapon carrying, use of alcohol, and
experimentation with tobacco was found [18]. While anabolic steroid use is
more common among males, Becker (2002) and Byrne (2001) have shown that
young women high school athletes use diet pills and other body shaping
substances, including steroids, at higher rates than their non-athlete peers [19,
20].
B
Risk Factors for Anabolic Steroid Use, other Substance Use and
Disordered Eating Practices
There are associated behaviors for young steroid users that may underscore
the need for the critical elements in a steroid prevention program. In a study by
Bahrke, Yesalis, Kopstein, and Stephens (2000), adolescent AAS users were
significantly more likely to be males and to use other illicit drugs, alcohol and
tobacco [21]. Student athletes are also more likely than non-athletes to use
AAS; and American style football players, wrestlers, weightlifters and
bodybuilders have significantly higher prevalence rates than students not
engaged in these athletic activities. Anabolic steroid using males have been
found to have lower self-esteem and higher rates of depressed mood and
attempted suicide, poorer knowledge and attitudes about health, greater
participation in sports that emphasize weight and shape, report greater parental
concern about weight, and higher rates of disordered eating and substance use
[22].
Among female steroid users, a similar pattern of results emerged. Students in
grades 7-12 in the state of Nebraska were assessed for their anabolic steroid
use. Of the students who reported using anabolic steroids, 72.6% were sports
participants. Female steroid users had a greater likelihood of using alcohol,
264
Melissa Durham
tobacco, and other drugs than their non-steroid using counterparts. Also, these
anabolic steroid users were more likely than nonusers to report violent acts [23].
In Sweden, researchers attempted to assess the importance of risk factors such
as socio-demographics, sports activities, tobacco use, alcohol consumption,
use of certain psychotropic substances and violence in the use of doping agents
in adolescents. Their assessment was that the use of doping agents in Sweden
probably involves more than a desire to enhance appearance or sports
performance and had much in common with use of alcohol, tobacco and
psychotropic drugs [24].
Other adolescent drug and alcohol use is associated with the development of
disordered eating practices among young women. This may be due to the
finding that unhealthy behaviors have similar risk factors including, but not
limited to, depression, observation of role models, concerns about body image,
an emphasis of unattainable and unrealistic images of men and women in the
media, and peer influences [25, 26, 27].
C
Depression
Several authors have studied the relationship between depression and
substance use or abuse, along with disordered eating behaviors for
adolescents, but the causal pathway is unclear [28]. Alcohol use can lead to
depression and depression can lead to alcohol use and disordered eating
behaviors. Bukstein, Brent, and Kamainer (1989) found that the most common
precursors of substance use or abuse were depression in girls and antisocial
behavior in boys [29]. Khantzian (1985) discovered that adolescents who were
depressed began consuming alcohol as a way to self-medicate [30], while Teri
(1982) and Windle and Davies (1999) reported that adolescent females
experienced higher levels of depression than did males, but for all of the
depressed adolescent males and females, they engaged in heavier drinking
than their non-depressed peers [31, 32]. For young women, depression appears
to be a risk factor for both substance abuse and disordered eating behaviors
such as vomiting and fasting [27].
Other research suggests that the earlier misuse of alcohol begins, the greater
the likelihood that psychiatric problems, such as depression, will occur.
Buydens-Branchey, Branchey, and Noumair (1989) report that adults who had
started abusing alcohol in their teens were three times as likely to be depressed
as their non-abusing peers [33]. Likewise, Koenig & Wasserman’s (1995) study
ATLAS and ATHENA
265
found young adolescent women to more likely become depressed if they
experimented with disordered eating behaviors, such as dieting [34]:
As dieting is typically unsuccessful as a means of long-term weight control,
depression will result from the sense of failure and helplessness associated
with dieting failure. This depression then leads to increasingly maladaptive
eating behaviors that serve to assuage negative affect and regain control
over body appearance (p. 225).
D
Role Models
Role models, such as professional athletes, are also an influence on
adolescents’ use of drugs and alcohol. Professional Major League Baseball
players Mark McGwire and Rafael Palmeiro testified in March 2005 before the
United States Congress on the issue of doping in baseball [35]. Although
McGwire had previously admitted using androstenedione (a steroid precursor)
before it was banned by the U.S. Food and Drug Administration, he refused to
discuss any drug use during his testimony, repeatedly stating, “Like I said, I’m
not here to talk about the past.” Palmeiro’s testimony included this statement, “I
have never used steroids, period.” Five months later, after Palmeiro tested
positive for anabolic steroids, he rephrased his prior testimony by announcing, “I
have never intentionally used steroids” [35]. Their action may impact adolescent
behavior because of their athletic accomplishments and monetary rewards.
Some believe their steroid intake glamorizes use and promotes dishonesty [36].
Palmeiro and McGwire are not alone. Other professional athletes from different
sports have denied doping allegations, but some have been discovered and in
some cases, banned from competition for using steroids or tampering with their
drug test. Both Michelle “Smith” de Bruin, an Irish Olympic swimmer, and Justin
Gatlin, an American Olympic track athlete have been sanction for steroid use
(Gatlin) and specimen manipulation (de Bruin) [37, 38]. Soon, the results of
Floyd Landis’ appeal in court will assess his guilt or innocence regarding the
allegation and positive test for steroid doping. Landis had elevated ratios of
testosterone to epitestosterone during the 2006 Tour de France. If Landis'
appeal fails, he could be banned from cycling for two years [39].
E
Media
The media, including advertisements, covers of magazines, television, movies,
websites and more, play a powerfully influential role in shaping both adolescent
266
Melissa Durham
attitudes towards drug and alcohol use and their beliefs about what body types
are acceptable by society [36, 40]. Many companies use the phrase “on
steroids” to advertise bigger or more powerful products for sale. In this respect,
anabolic steroids have a positive connotation [36]. For example, the 3M
Corporation advertised the Post-it Easel Pad by stating, “Think of it as a Post-it
Note on Steroids” [41]. The word “steroids” is often displayed in a larger font
than the brand name of the product (e.g., advertisement for Saab motor
vehicles: Steroids vs. Saab). Often only the positive effects of steroids are
represented in the advertisement; getting bigger, faster, and more powerful.
Adolescent viewers of this type of imbalanced media presentation do not learn
that steroids are illegal, they can cause acne, shrunken testicles, baldness,
stunted height, multiple health problems, or that injecting steroids increases the
risk of developing AIDS [41, 42]. Imagine reading an ad for Saab engines that
said “This is a Saab on heroin.” Heroin has a negative connotation in the United
States and would not assist product sales; in part because of the well known
side effects that include exposure to disease from needle sharing, mood
disturbances, and cardiovascular problems [43].
F
Body Image
Kilbourne’s (2007) work has raised awareness about the media presentation of
young men and women for decades [44]. Covers of magazines often display
images of men that are very muscular, lean, and handsome. Images of women,
or parts of their bodies, have flawless skin, very thin physical frames with
skimpy clothing, enlarged breasts and perfect teeth. The images are digitally
enhanced and present an unattainable, unrealistic image to the public. Young
adolescent men and women are bombarded by these images, often using them
as a reference for comparison with their own bodies. Due to this exposure,
males desire a larger, more muscular frame and females typically want to lose
weight, purchase self-improvement products, and feel inadequate. This
unnecessary pressure on adolescents to look a certain way leads to healthharming behaviors [40, 44].
G
Peer Influence
Along with role models, the media and body image, the behavior and choices of
an adolescent’s peers are very influential. Buddeberg-Fischer and Reel (2001)
reported that adolescents are more likely to listen to their peers than any other
person, including a parent, a coach, or a teacher [45]. For those who are in a
ATLAS and ATHENA
267
peer group that is experimenting with drugs and alcohol, they are also more
likely to ride in a car with a drunk driver, wear their seatbelt less frequently,
engage in sexual activity more frequently, demonstrate antisocial behavior
including violent, aggressive behavior, and their academic performance is more
likely to decline [9, 10]. However, peer influence can also be a protective factor.
Adolescents who choose to abstain from substance use often attract friends
who share similar beliefs and make healthier choices [9, 10].
H
Female Athlete Triad
For young women athletes, the pressure to be thin and athletic can lead to
unhealthy eating habits such as fasting, vomiting, over-exercising or use of
body-shaping substances like steroids, laxatives or diet pills [46]. If left
untreated, a reduced level of estrogen in the bloodstream may cause
amenorrhea and weaker bones. Osteoporosis may develop from the imbalance
in hormones and lack of nutrients in the woman’s diet. This cyclical effect is
referred to as the Female Athlete Triad [46]. If young women practice these
unhealthy behaviors, they risk developing injuries and permanent harm.
Because eating behaviors and substance abuse have similar risk and protective
factors, substance abuse prevention programs for young women should
address unhealthy eating habits as well [10].
I
Protective Factors for Preventing Substance Use
Adolescent behaviors often cluster, meaning one health-harming choice may
lead or be associated with another [17]. The same may be true for positive
healthy behaviors. The National Institute on Drug Abuse (2003) summarized the
factors that protect adolescents from health-harming behaviors [47]. These
include positive social support, healthy peer attitudes, heightened perception of
risk, engaging in healthy activities, and having realistic beliefs about images in
the media. For example, adolescents are more likely to remain drug free if they
have a group of friends and a positive outlook on life, they believe
experimentation with drugs and alcohol is risky and they can entertain
themselves without it, and they are able to critically analyze what they see in the
media [36, 40, 47].
268
J
Melissa Durham
Why Programs Often Fail
Substance abuse prevention programs for adolescents are not effective at
changing behavior if they only rely on adult lectures, use scare tactics or
slogans, aim to be universal rather than gender-specific or only provide
knowledge [48]. Adult lectures lack the important influence that peers have on
one another, especially for adolescents, to improve behavior. Adolescents are
in a stage of life where they feel invincible, as if they can avoid being harmed
[49]. Adolescents can have difficulty imagining themselves getting older or
having any type of lasting effect from their present choices. For this reason,
scare tactics about drugs and alcohol and anabolic steroids are ineffective [50].
Often adolescents believe they are protected from experiencing negative side
effects [48, 49].
Successful prevention programs help adolescents build their skills through
practice and rehearsal [48]. For substance abuse prevention, adolescents must
learn to be able to refuse an offer for drugs or stand up to their peers when they
are engaging in unhealthy behaviors like excessive dieting or using diet pills.
Peer pressure is intense and unfortunately, refusing unhealthy behaviors
requires a more complex approach than the once used slogan in the United
States, “Just Say No”. Multifaceted prevention programs are required for
effective behavior change [9, 10, 48].
Adolescents prefer to talk about the changes their bodies are experiencing or
decisions they are trying to make in a homogenous environment [48]. Programs
that provide a comfortable environment where members of the opposite sex are
not present allow adolescents to discuss their thoughts and ask questions more
openly. An adolescent needs honest information about the benefits and
consequences of a decision, support from peers, and an incentive to change
their behavior [48]. The most successful prevention programs present balanced
information, allow peers to influence and teach each other, engage people in
activities, and allow adolescents to experience something new so there is an
incentive to make a change [9, 10, 48].
K
Two Effective Programs: ATLAS & ATHENA
ATLAS (Athletes Training & Learning to Avoid Steroids) and ATHENA (Athletes
Targeting Healthy Exercise & Nutrition Alternatives) are examples of two
evidence-based, gender-specific, drug prevention, and health promotion
programs for adolescent athletes. They were developed and researched
through two separate National Institute on Drug Abuse grants. To date, ATLAS
ATLAS and ATHENA
269
and ATHENA are the only substance abuse prevention programs for high
school athletes recommended by the United States legislation known as the
Anabolic Steroid Control Act of 2004 and signed into federal law in October
2004.
ATLAS and ATHENA incorporate the following principles of effective program
delivery: they are gender-specific, integrated into high school athletic programs,
rely on peer teaching and coach facilitation, are interactive and engaging,
scripted to enhance fidelity, and encourage students to create their own health
promoting messages, tailoring the communication to the intended audience.
L
Behavioral Theories Provide Foundation for Prevention Programs
Two behavioral change theories guided the development of the ATLAS and
ATHENA Programs. The Theory of Reasoned Action describes how behavior is
based on beliefs, attitudes and intentions [51]. For example, an athlete will
decide to use drugs if she believes that her peers are using drugs, they won’t
disapprove of her for using drugs and the drugs will improve her performance.
ATLAS and ATHENA change adolescents’ beliefs about societal norms;
students realize fewer peers are experimenting with unhealthy behaviors than
they previously thought. Together as teammates, they set goals to improve as
athletes with sports nutrition and strength training rather than cheating and
taking drugs. Bandura’s (1977) Social Learning Theory provided another
intervention model [52]. Social learning is a process that occurs as a function of
observing, retaining and replicating behavior observed in others [52]. In
addition, it is based on rewards and consequences from a social group and
reinforces the power of the environment in modeling behavior. A sports team
presents an opportunity for teammates to observe each other, build their skills
and understand the rules of engagement, learn how to achieve acceptance from
teammates, and behave in a supportive way to contribute to the team’s overall
goals [9, 10].
M
Specific Aims
ATLAS and ATHENA encourage athletes to work together to achieve improved
sports performance and health by understanding and practicing strength
training techniques and sports nutrition. Participants set weekly nutrition goals
and reinforce healthy behavior norms through the development and
presentation of public service announcements. The curricula for ATLAS and
ATHENA have unique components because males and females develop
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Melissa Durham
unhealthy behaviors for different reasons. ATLAS teaches young males how to
strength train and eat enough protein and calories to increase their muscle
mass. ATHENA emphasizes calcium intake for bone health and the importance
of eating protein to maintain and repair their muscles, but avoids discussion of
calories. Carter, Stewart, Dunn, & Fairburn, (1997) found that discussion of
calories by young women has been associated with the development of eating
disorders [53]. For this reason, calorie counting is not emphasized in the
ATHENA curriculum [10].
Because young women are at a higher risk of experiencing a low mood and
depression than young males, ATHENA provides a mood diary for young
women to keep track of their fun activities and observe how their mood relates
to their daily activities [27]. The mood diary is modeled after Clarke’s (1995)
effective depression prevention program for adolescents [54]. For young
women, ATHENA emphasizes team building activities to build social support
and positive attitudes. Alternatively, ATLAS addresses young males’ impulsivity
in decision making. ATLAS provides a balanced presentation of the benefits
and consequences associated with illicit substance use [10]. ATLAS training
strengthens athletes’ refusal skills, meaning their ability to resist an offer to use
drugs.
Both programs incorporate a media deconstruction activity so athletes attain a
more critical view of the images to which they are exposed. Young males
analyze advertisements from body-building magazines to uncover some of the
side effects of steroid use. Young women analyze alcohol, tobacco, and
nutrition supplement advertisements. Athletes discuss what actually occurs
when you engage in substance abuse and spend time remaking an ad to create
a more realistic image of the consequences of smoking, drinking or taking
unregulated supplements.
Both programs were rigorously evaluated by multi-year, randomized controlled
studies. The results have previously been published [9, 10]. A brief summary of
the results after one year of exposure to the ATLAS or ATHENA intervention is
listed below. Please refer to the publications for further explanation.
ATLAS and ATHENA
ATLAS Results
• New anabolic steroid use decreased
50%
• New alcohol and illicit drug use
271
ATHENA Results
• Less use of performance enhancing
substances (steroids, amphetamines,
supplements)
• Less new and ongoing use of diet pills
decreased 50%
• Occurrences of drinking and driving
• Improved nutrition practices
declined 24%
• Improved nutrition practices
• Less riding in a car with a drinking
driver
• Improved strength-training skills
• Less new sexual activity
• Reduced use of performance-
• Fewer injuries
enhancing supplements
• Students believed they were better
athletes
N
• One to three years following
graduation: improved nutrition and
reduced use of alcohol, marijuana and
diet pills
Training for Coaches or Program Instructors
The Center for Health Promotion Research (CHPR) team provides training for
effective implementation of the ATLAS and ATHENA programs. Training
participants learn the current trends in adolescent athlete substance abuse,
underpinnings of effective drug prevention and health promotion programs,
alternatives to drug use (sports nutrition and strength training) and the
background and outcomes of ATLAS and ATHENA. Coaches receive practical
experience learning to use the programs so they feel confident integrating the
program sessions into their usual team activities. Training is accomplished in
one day-long workshop. Ongoing technical assistance is available for all
participants through CHPR.
O
Program Materials
The ATLAS and ATHENA Programs provide gender-specific content, but the
information is presented in the same manner. The program materials consist of
a Coach or Instructor Manual, a Squad Leader Manual, a Team Workbook and
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Melissa Durham
an Athlete’s Guide. Each coach receives the Coach Manual containing
background information on sports nutrition, strength training, and drugs in sport.
The Coach Manual has a squad leader training guide, the curriculum sessions
(10 for ATLAS, 8 for ATHENA), and extra materials for the program. Selected
student-athlete leaders called Squad Leaders use their Squad Leader Manuals
to lead most of the activities within their small groups. The Squad Leader
Manuals have the same curriculum sessions that their coach has with the
answers. This way, they are the instructors for their groups. For every five
athletes, one is the designated Squad Leader. All other teammates need a
Team Workbook to participate in the activities. Team Workbooks contain the
curriculum sessions without the answers. All participants receive a pocket-sized
Athlete’s Guide containing information about sports nutrition, healthy choices at
fast food restaurants, strength training routines, drugs, vitamins, supplements,
and more.
P
ATLAS & ATHENA: Beyond Research and Development
Currently, over 30 states and Puerto Rico have high schools that have
incorporated ATLAS and ATHENA within their athletic programs. Further
research could verify whether ATLAS and ATHENA could be beneficial and
effective for adolescent athletes within other countries and cultures outside of
the USA.
Q
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Correspondence
Melissa B. Durham, MPH, Research Associate and Director of
Communications, Center for Health Promotion Research, Oregon Health &
Science University, Portland, Oregon, USA
Linn Goldberg, MD, FACSM, Head, Division of Health Promotion and Sports
Medicine, Oregon Health & Science University, Portland, Oregon, USA
278
8
Poster Abstracts
POSTER ABSTRACTS
P01 Hemoglobin and hematocrit in elite athletes - cross-sectional and
longitudinal aspects
Ulrich Hartmann*, Margot Niessen, Alois Mader
Against the background of erythropoietin-doping and its interpretation, the special
interest is focussed on the natural behaviour of hemoglobin (Hgb) and hematocrit (Hct)
[1, 2, 3]. The Hgb and Hct values collected over 15 years from male (n=210) and female
(n=84) elite athletes in track and field as well as rowing in the laboratory or in field testing
will be presented in cross and 12 weeks longitudinal sections, during rest and during
training. – The determination of both parameters was done in the laboratory using a semi
automatic hematology system (Sysmex F-800, DD-100, Fa. Toa, Japan) and during field
testing using a Hgb photometer following the principle of the cyanhemoglobin method
respectively a Hct-centrifuge. Mean values for Hgb were 16.5 ± 1.3 g/dl (max 22.2 g/dl)
in males and 14.7 ± 1.1 g/dl (max 18.3 g/dl) in females. The corresponding values for Hct
were 48.8±3.1 vol% (max. 60.0 vol%) and 44.6±3.3 vol% (max 59.0 vol%). Frequency
distributions show that 74 % (40 %) of all Hgb values in males are >16.0 g/dl (>17g/dl)
and 72 % (40 %) of all Hgb values in females are >14.0 g/dl (>15 g/dl) (2). Hct for 28 %
of men is > 50 vol% and for 30 % of women is > 45 vol% (3), whereby the longitudinal
variation is 5 % on average for the whole group and 8 % in individual cases; variation
over the day is up to 15 %.There was no erythropoietin substitution, i.e. all of the values
found resulted from environmental circumstances and training itself. The findings of this
study show that a reconsideration of the respective limit values is imperative.
1.
2.
3.
Luca Malcovati, Cristiana Pascutto and Mario Cazzola. Hematologic passport for
athletes competing in endurance sports: a feasibility study. Haematologica 88 (5):
570-581, 2003.
Ken Sharpe, Will Hopkins, Kerry R. Emslie, Chris Howe, Graham J. Trout, Rymantas
Kazlauskas, Michael J. Ashenden, Christopher J. Gore, Robin Parisotto and Allan G.
Hahn. Development of reference ranges in elite athletes for markers of altered
erythropoiesis. Haematologica 87 (12): 1248-1257, 2002.
Peter C. Vergouwen, Tonkie Collee, Joannes J. Marx. Haematocrit in elite athletes.
Int J Sports Med 20 (8): 538-541, 1999
Correspondence: Department for Theory and Practice in Sport, Technische Universität
München, Connollystr. 32, 80809 Munich, Germany, [email protected].
Poster Abstracts
279
P02 Health side effects of doping substances on the immune system: the
importance of study this problem.
Esther Giraldo*, M. Dolores Hinchado, Eduardo Ortega
Today there is still a big lack of information about the scientific knowledge of the side
effects of doping in both competitive sports and recreational ones. In addition this
knowledge are not always unified and in our opinion it is very important to harmonise in
Europe the scientific information about the biomedical side effects of doping, in order to
get chance for preventing this practise.
Most of the information about the side effects of the different doping substances is
available on the respiratory and cardiovascular systems as well as the brain. However,
little information is currently examined about the side effects of doping substances on the
immune system. Today it is clearly known that exercise modulates the immune system,
and while moderate exercise stimulates most of the immune responses, intense exercise
can be dangerous for the adaptative response mechanisms. In addition, the exerciseinduced changes are mediated by different hormones released during the exercise,
mainly the so called “stress hormones”. Then, a modification of the neuroendocrine
balance by hormones intake during the exercise practise modify the feed-back of the
neuroimmue mechanisms, and may seriously affect the normal function of the immune
system, damaging sportspeople’s health.
However, although there are a lot of investigation about different substances (i.e.
anabolic steroids, stimulants, narcotics, diuretics, nutritional supplements…) related to
doping, and about these substances on immune system at pharmacological
concentration; nothing is known about the biomedical side effects of these doping
substances (at raised blood concentrations) on the immune system during exercise, an
special physiological situation.
The purpose of this communication is to emphasize the importance of study the
biomedical side effects of doping substances on the immune system, above all during
exercise practise, as well as to show the lack of information at this respect.
Correspondence: Department of Physiology, Faculty of Sciences, University of
Extremadura, Avd. Elvas s/n 06071- Badajoz, Spain, [email protected].
280
Poster Abstracts
P03 The alteration of the urinary steroid profile under the stress
Agata Gronowska1, Dorota Kwiatkowska2, Andrzej Pokrywka2, Marcin Koteras1,
1
Miroslaw Szutowski *
In the second part of twentieth century anabolic-androgenic steroids were introduced in
doping practice and received continuously increasing significance. In order to prove the
usage of doping substances, the determination of steroid profile in the urine came into
practice. Several factors may be responsible for alterations in the normal steroid profile
for example age, sex and diet.
The aim of this paper was to find out, whether the psychological stress may cause
modifications in the indicators of the steroid profile.
The steroid profile was determined in the group of 34 students of pharmacy being in nonstress conditions and under stress immediately before the important university exam.
The intensity of stress was raeted by self-reported questionnaire. The intensity of stress
feeling was taken into account. The GC/MS method was applied to determine the steroid
profile in the urine samples.
The results of the experiment have shown that psychological stress may cause
significant changes in the steroid profile, especially in females. Physical activity,
independently of stress significantly modified the steroid profile.
The observed changes in the testosterone and epitestosterone levels did not influence
the T/Et ratio. In males higher level of stress caused the decrease in the T/Et ratio (from
1.28 to 0.53). Physical activity did not change significantly steroid profile in males.
In summary, psychological stress modifies the steroid profile in females and males but
the magnitude of the observed changes does not indicate the possibility of significant
modification of the results during doping analysis.
1
Correspondence: Department of Toxicology, Medical University of Warsaw, Banacha 1,
02-097 Warsaw, Poland, [email protected]. 2Department of AntiDoping Research, Institute of Sport, Trylogii 2/16, 01-982 Warsaw, Poland.
Poster Abstracts
281
P04 Cannabinoids in polish athletes
Andrzej Pokrywka1*, Zbigniew Obminski2, Ewa Turek-Lepa1, Dorota Kwiatkowska1,
1,2
Ryszard Grucza
The main biologically active component of cannabis, tetrahydrocannabinol (THC) has
sometimes been detected in athletes' urine samples that may suggest active or passive
marijuana smoking. Since THC has a narcotic property, its application is forbidden also
for athletes. However, cannabinoids are prohibited in sport in competition only.
According to the anti-doping rules maximum acceptable level of carboxy-THC (the main
THC metabolite) detected in urine athletes is equal to15 ng/ml [1, 2].
This study on THC content in urine was performed during the years 1998 - 2004. Urine
samples (n=13.631) were taking in-competition (n=8.490) and out-of-competition
(n=5.141), from polish male and female athletes engaged in different disciplines of sport.
The results were presented as a percentage of samples containing cannabinoids
(%THC) with respect to the appropriate subgroups. Carboxy-THC was detected in 1.95%
of total samples. The percentage of cannabinoids positive samples in females (0.21%)
was markedly lower than that in males (2.75%). Cannabinois were found in 1.7% of total
samples in competition and in 2.3% of those out of competition. The most frequent
(2.65%) usage of THC was revealed in athletes' age from 16 to 24y.
Relatively high numbers of positive samples with cannabinoids were found in rugby
(11.27%), figure skating (5.63%), boxing (4.91%), badminton (4.20%), speed skating
(3.44%) and bodybuilding (3.37%). Only sports for which more than 50 samples were
analyzed were taken into consideration.
In the year 2003, the percentage of samples of polish athletes found positive for
cannabinoids (carboxy-THC > 15 ng/ml) was 0.79% while in the all World IOC/WADA
accredited laboratories was on average 0.25%. The similar proportion was found in the
next year (0.81% in Poland and 0.31% in the other laboratories). For this period from
only laboratories in Gent and Paris reported higher relative number of positive
cannabinoids samples than Warsaw laboratory.
1.
2.
Peter Van Eenoo, Frans T. Delbeke. The Prevalence of Doping in Flanders in
Comparison to the Prevalence of Doping in International Sports. Int J Sports Med
2003 Nov, 24(8): 565-570.
Ute Mareck-Engelke, Hans Geyer, Wilhelm Schänzer. Cannabismissbrauch im
Hochleistungssport. Deutsche Zeitschrift für Sportmedizin 2001, 10: 280-284.
1
Correspondence: Department of Anti-Doping Research, Institute of Sport, Trylogii 2/16,
01-982 Warsaw, Poland, [email protected]. 2Department of Endocrinology,
Institute of Sport, Trylogii 2/16, 01-982 Warsaw, Poland.
282
Poster Abstracts
P05 Doping, drugs and drug abuse among adolescents in the state of
Thuringia. Prevalence, knowledge and attitudes
Berit Wanjek*1, Jenny Rosendahl2, Holger Gabriel1
Goal-directed measures to prevent doping and drug abuse in sports require empirical
data. In this connection a cross-sectional-analysis was carried out in 2004. The purpose
of the study on the one hand was to register reliable data of the current situation in
Thuringia, and on the other hand it was to give information on possible interventional
steps with scientific support. Within three months 2319 adolescents out of 16 Thuringian
schools (5 regular schools, 4 secondary schools, 3 sport schools and 4 vocational
schools) were surveyed.
346 (15.1%) students out of 2287 students (26 students without a statement) indicated
use of prohibited substances from the WADA - list in the previous year: 16 (0.7%)
anabolic-androgenic steroids (AAS), 10 (0.4%) growth hormones, 56 (2.4%) stimulants,
305 (13.2%) cannabis, 2 (0.1%) diuretics, 52 (2.2%) cocaine/heroin and 6 (0.3%)
erythropoeitin. Moreover, non-athletes (N = 490) reported a substance use that was
approximately 5.0% higher than that of recreational athletes (N = 1254) and nearly three
times as high as that of competitive athletes (497).
All three groups (non-athletes, recreational athletes and competitive athletes) performed
poorly on a knowledge test regarding doping in general with an average below 60% in
each case.
Another main aspect of the study was to determine factors influencing substance use in
sports. Besides the doping specific knowledge (Beta = 0.06, p < 0.05) age contributed
(Beta = 0.09, p < 0.05) as well as anti-doping attitude (Beta = -0.34, p < 0.05) to the
resulting variance. Gender, however, played no role.
The findings of the study point towards the need for improvement of specific knowledge
of doping among students, and that their attitude towards doping must be altered. The
goal in this case is to test the effectiveness of appropriate scientific intervention.
1
Correspondence: Department of Sports Medicine, Friedrich-Schiller-Universität Jena,
Wöllnitzer Str. 42, D-07749 Jena, Germany, [email protected]. 2University
Hospital Jena, Institute of Medical Psychology
Poster Abstracts
283
P06 Nandrolone decanoate affects mitochondrial apoptotic pathway in
myocardium
Slavi D. Delchev1*, Katerina N. Georgieva2, Yvetta A. Koeva1, Pepa K. Atanassova1
Anabolic androgenic steroid (AAS) abuse induces unfavorable cardiovascular events
and different models for these effects have been suggested (1, 2). It is still unclear to
what extent apoptosis takes place in these processes. In postmitotic tissues, like
myocardium, loss of myocytes would lead to functional failing and cardiac diseases (3).
Bcl-2 family proteins and mitochondria play a key role in the triggering of apoptotic
cascade (3, 4). A study demonstrated increased cardiomyocytes’ apoptosis after AAS
treatment in vitro (5). Up to now the effects of chronic AAS administration on the cardiac
apoptotic potential and heat shock protein (HSP) level have not been studied in vivo.
The aim of the study was to investigate the effects of AAS on aerobic capacity,
ultrastructure, inducible HSP72 and some apoptotic proteins in rat myocardium. Male
Wistar rats were divided into two groups (n=10). One group received 10 mg·kg-1.wk-1
nandrolone decanoate (ND) for 6 weeks and the other group - placebo (PL). At the end
of the experiment submaximal running endurance (SRE) and VO2max tests were
performed for all the rats. Samples from left ventricles were taken and
immunohistochemical reactions for HSP72, Bcl-2 and Bax were done, accompanied with
TEM study. Protein expression was assessed by specialized software. We found no
differences in SRE and VO2max between the groups. TEM analysis demonstrated that
most of the mitochondria of ND group were swelled with reduced and not well defined
cristae. In comparison with the controls HSP72 immunoreactivity was decreased in ND
rats (P<0.05). The expression of pro-apoptotic protein Bax was higher in the
cardiomyocytes and coronary endothelium of the steroid treated rats (P<0.05). Antiapoptotic protein Bcl-2 did not differ between groups. Bcl-2/Bax ratio was lower in ND
group than that in PL rats (P<0.01).
In conclusion, supraphysiological doses of ND do not improve SRE and VO2max but
attenuate the expression of cardioprotective HSP72 and increase apoptotic tendency in
myocardium of untrained rats. The disturbance of the inner mitochondrial membrane
integrity and decreasing of Bcl-2/Bax ratio reveal one of the potential mechanisms
through which ND treatment leads to loss of cardiomyocytes by apoptotic pathway.
Reduction of contractile cells and endothelial alterations could explain some of the
cardiovascular sequels of AAS abuse.
1.
2.
3.
John R. Payne, Paul J. Kotwinski and Hugh E. Montgomery. Cardiac effects of
anabolic steroids. Heart 90: 473-475, 2004.
Russell B. Melchert and Allison Welder. Cardiovascular effects of androgenicanabolic steroids. Med Sci Sports Exerc 27(9): 1252-1262, 1995.
Michael Pollack, Sharon Phaneuf, Amie Dirks and Christiaan Leeuwenburgh. The
role of apoptosis in the normal aging brain, skeletal muscle, and heart. Ann N Y
Acad Sci 959: 93-107, 2002.
284
4.
5.
Poster Abstracts
Bernd Mayer and Rainer Oberbauer. Mitochondrial regulation of apoptosis. News
Physiol Sci 18: 89-94, 2003.
Michael Zaugg, Nasir Z. Jamali, Eliana Lucchinetti et al. Anabolic-androgenic
steroids induce apoptotic cell death in adult rat ventricular myocytes. J Cell Physiol
187: 90-95, 2001.
1
2
Correspondence: Department of Anatomy, Histology and Embryology. Department of
Physiology, Medical University – Plovdiv, 15A V. Aprilov Blvd., 4000 Plovdiv, Bulgaria,
[email protected].
Poster Abstracts
285
P07 Gross cardiac pathology in medicolegally examined deceased users
of anabolic androgenic steroids
Ingemar Thiblin*, Hamid Mobini-Far
Anabolic androgenic steroids (AAS) represent a group of compounds that have been
connected with cardiac hypertrophy, arrhythmia, unfavourable blood lipid profiles and
myocardial infarction. However, scientific data of increased risk for cardiac death among
users of these compounds are at best questionable.
We have addressed this issue by retrospective mapping of the occurrence of diagnosed
coronary sclerosis with significant stenosis and cardiac hypertrophy and by exploring the
heart weights with consideration to the body weight among medico-legally examined
deceased users of AAS (n=92) employing subjects without suspected abuse of AAS or
illicit drugs and who died in traumatic accidents as controls (n=96). In order to control for
age, comparisons the AAS users and controls were divided into two age strata; those
who were 30-years-old or younger and those who were 31-years old or older. Use of
AAS was associated with a high prevalence of cardiac hypertrophy in both age groups
(35% and 36%, respectively) (AAS vs. contr 30-years-max: RR = 3.71, p<0.0001 and 31years-min: RR = 2.68, p=0.06). When body weight was taken into consideration, both the
AAS-users and the controls had a highly significant correlation between body weight and
heart weight. At the same time there was no difference with respect to the heart
weight/body weight ratio. The prevalence of coronary sclerosis was significantly higher
among the younger AAS using subjects (AAS: 14 % and controls: 2%, RR=9.1, p=0.01).
Among the older subjects this difference had levelled out (16% vs. 11%). Thus, it
appeared as if the diagnosed cardiac hypertrophy among several AAS users could be an
adaptation to the increased body weight that is a result of a generally increased muscle
mass. However, the increased heart size may still be pathological considering that the
increased muscle mass to a great part is dependent on long term supraphysiological
levels of testosterone resembling substances. Furthermore, our results indicate that use
of AAS may in deed accelerate the development of coronary sclerosis, although this
effect might be confined to certain predisposed individuals.
Correspondence: Department of Surgical Sciences, Forensic Medicine, Uppsala
University, Dag Hammarskjölds väg 17, SE-752 37 Uppsala, Sweden,
[email protected].
286
Poster Abstracts
P08 Scientific criteria to differentiate the nandrolone endogenous or
exogenous precedence
Marcos Maynar-Mariño1, A. Ballesteros-Meneses2, M. Maynar-Muñoz2, P. VizueteMuro2, A.F. Toribio-Delgado2, J.I. Maynar-Mariño2
Nowadays the world of sports analyses has suffered a great evolution. Just like this,
dopping technicals and methods used for these practices have suffered the same
evolution. One of the challenges, it is to be able to discern among the possible
endogenous or exogenous procedence of given substances (metabolites of nandrolone)
that appear in the list of products forbidden in sports. Two types of studies exist: direct
evaluations ((Gas-Isotopyc relation-MS Chromatography (GC-IRMS), hair analysis)); and
indirect evaluations (Hormonal valoration in serum, evaluation of the esteroideal profile
difference among sulfoconjugated and glucoconjugated fractions, test of stimulation with
hCG for the evaluation of a possible alteration of aromatase systems). In the case of the
nandrolone and its metabolites we present the obtained data when we applied the
variations of the relation Testosterone/β-Estradiol (T/βE) as scientific criteria.
We have used data from several subjects who were declarated positive in a doping
control and ten subjects who were injected with nandrolone. We took a sample of urine
from all of them. These samples were analysed by gas-mass Cromatography with the
Galán & cols’s technique.
With the results obtained in our investigation, we think that the relation testosterone/betaestradiol can be an interesting scoreboard for the differentiation endogenous or
exogenous of nandrolone´s metabolites.
1.
2.
3.
4.
Galán Marín A M & Cols Determination of nandrolone and metabolites in urine
samples from sedentary persons and sportsmen. Journal of Chromatograhy 761:
229-236, 2001.
Maynar Mariño M, Galán Martín AM, Caballero Loscos MJ, García de Tiedra MP,
Maynar Mariño JI. Endogenous production of nandrolone and his metabolites in
sportsmen. III Congress International of Soccer and the Sciences of Sports.
Organized for the Medical Center of the Real Madrid. Madrid, 2002.
Maynar Mariño M, Ballestero Meneses A, Olcina Camacho G, Timón Andrada R,
García de Tiedra MP, Maynar Mariño JI. Nandrolone and Sport: endogenous or
exogenous procedence. Journey Medicine and Soccer. Organized for Foundation
Recre and the RCR Huelva Medical Service. 29 and 30 of April, 2004.
Rivero Marabé JJ. Determination of anabolic steroids and corticosuprarrenales in
biological fluids. Doctoral Thesis. University of Extremadura, 2002.
1
Correspondence: Department of Physiology, University of Extremadura, Spain.
2
Department of Analytical Chemistry and Electrochemistry, University of Extremadura,
Spain, [email protected].
Poster Abstracts
287
P09 Recent results of Anti-doping actions
Christian Hirtreiter1, Tsuyuki Nishino2
Dopingagents are spreading out in all social areas. Besides sports and job affairs, even
in partner relations stimulating and activating substances are more and more in use.
What EPO is for the cyclists, is a variety of different compounds in other areas of social
life. Abusing physical relevant substances gets more and more common.
The poster describes the current situation and latest inventions in this field. In the last
decade it is more and more common to use so called brain-doping-substances e.g.
Ritalin, Ampakines, Donezepil and Modafinil. The adult-generation used dextrose and
caffeine as brain food, nowadays even the children use Ritalin and Donezepil in order to
stay more attentive in the lessons and to absorb more. Healthy persons avoided in
former days to take pills vice versa the new generation is used to take vitamins and other
tablets for various purposes. Although it is claimed from the pharmaceutical industries
that there is no adductive potential it is sure not only a miracle to enlarge the cognitive
abilities.
The effector-mechanisms and moieties of the mostly used substances are described and
it is also shown the result of a survey is shown. Recent results of different clinical studies
are evaluated. Many of the substances were created in order to heal diseases and the
long-term effects are not taken into account in every case. Therefore we compare the
chemical structures and draw conclusions why the substances might cause unforeseen
side effects especially during the adolescence. The results of questionnaires are stated,
where scientist which took caffeine in order to prolong there learning time during their
own study period report about their experiences 10 years ago and the effects on their
behaviour with caffeine nowadays.
1.
http://www.polizei.bayern.de/lka/ and personal communications
1
Correspondence: University of Regensburg, Universitätsstr. 31, 93053 Regensburg.
Institute of Public Health Research, Technische Universität München, Connollystr. 32,
80809 Munich, Germany, [email protected].
2
288
Poster Abstracts
P10 Anabolic androgenic steroids impact on testis
Yvetta Koeva1*, Katerina N. Georgieva2, Slavi Delchev1, Pepa Atanassova1
Anabolic androgenic steroids (AAS) supplementation leads to decreased serum
testosterone (TS) concentration and impaired spermatogenesis [1, 2]. Leydig cells (LC)
are the only cellular components that have the capacity to produce TS from cholesterol.
To date, little is known about the effect of AAS on the activity of the key steroidogenic
enzymes in the LC of trained and untrained individuals. It is also obscure whether AAS
treatment can provoke changes in the apoptotic proteins Bcl-2 and Bax levels in
testicular germinative and/or somatic elements. In this relation, the purpose of the
present work was to study the effect of AAS on the serum TS level in parallel with the
activity of LC 3β hydroxysteroid dehydrogenase (3βHSD), the NADH2 cytochrome-Creductase, as well as apoptotic markers Bcl-2 and Bax expression in testes of endurance
trained rats.
Twenty male Wistar rats were trained on treadmill with submaximal loading for 8 weeks.
Half of them received nandrolone decanoate (TND) and the other half - placebo (TP) for
the last 6 weeks of the experiment. Ten rats were sedentary and served as controls (C).
At the end of the experiment serum TS levels were measured and on testicular sections
enzymohistochemical and immunohistochemical reactions were performed.
Our results showed a decrease of 3βHSD (P<0.01; P<0.01) and NADH2 cytochrome-Creductase activities (P<0.001; P<0.001) in rat LC after treatment with AAS compared to
both C and TP groups. These results correspond with the established lower TS serum
levels in TND rats than those in C and TP rats (P<0.001; P<0.05). In TP animals
compared to the controls there were lower 3βHSD activity in parallel with decreased TS
level and higher NADH2 cytochrome-C-reductase staining (P<0.001; P<0.01; P<0.01). In
comparison with C and TP rats an increased Bax (P<0.05; P<0.05) and a decreased Bcl2 (P<0.001; P<0.001) expression in LC of TND group were observed. In contrast, in TP
group Bcl-2 intensity was stronger than the controls (P<0.01). The differences in Bcl-2
and Bax expression resulted in a lower Bcl-2/Bax ratio in the TND groups compared to C
and TP group (P<0.001; P<0.001).
In conclusion, AAS suppress the activity of key steroidogenic enzyme in LC of trained
rats which corresponds to the established serum TS decrease. The obtained results for
the first time demonstrate that AAS treatment of endurance trained rats decrease Bcl2/Bax ratio in the LC suggesting apoptotic tendency in these cells.
1.
2.
PJ Turek, LH Williams, JH Gilbaugh, LI Lipshultz. The eversibility of anabolic steroidinduced azoospermia. J Urology; 153: 1628-1630, 1995.
NP Bojadjiev, KN Georgieva, RI Massaldjieva, SI Guerguiev. Reversible
hypogonadism and azoospermia as a result of anabolic-abdrogenic steroid use in a
bodybuilder with personality disorder. J Sports Med Phys Fitness; 40: 1587-1590,
2000.
Poster Abstracts
289
Correspondence: 1Department of Anatomy, Histology and Embryology, 2Department of
Physiology, Medical University- Plovdiv, 15A V. Aprilov Blvd., BG-4000 Plovdiv, Bulgaria,
[email protected].
290
Poster Abstracts
P11 Health Complaints and Health related Consumer Behaviour in
International Theatres: A current Assessment
Pia - M. Wippert, Horst Michna
Due to the long training sessions and in part non-physiological postures, top
performance in dance and music places high demands on the human body. This abstract
reports a current assessment, regarding the consumption of medication and stimulants in
international theatres.
72 artists (45 dancers/27 musicians) from German and Swiss theatres took part in the
cross sectional study. The sum of bodily complaints was measured with a derived
version of Zerssen’s Complaint List. Responses to the extent of consumption of assistive
medication were assessed by direct questioning. The statistical analysis was carried out
with descriptive methods, as well as tests for differences.
Active dancers differed significantly to active musicians in the amount of complaints
(t(2,7)=-2,45, p<.05). Especially, they expressed more frequent pains of the
musculoskeletal system, gastro-intestinal problems, infections, depression and sleeping
disorders. They consumed more medication, stimulants, alcohol and tobacco, whereby
however, only tobacco consumption revealed a significant effect (Chi2(1)=4.37, p<.05).
With dancers, the average number of cigarettes per day was around 19 cigarettes and
for musicians around 13. Medication was used by only 21% of the dancers, of which
50% consumed strong pain killers and 38% consumed weak to medium strong pain
killers. The remaining 12% consumed anti-inflammatories. In the group of musicians,
11% express sole use of homeopathic medication and medicine against colds. In both
groups only caffeine is mentioned as a stimulant.
The groups under study come from elite, professional theatrical institutions with
consequent high levels of performance, making the consumption values stated seem far
too low- especially in comparison with findings from elite, professional sports. This refers
to both the dancers and musicians. Especially amongst the musicians many suffer from
symptoms related to their profession, such as tinnitus and problems of the fingers and
sinews, which pose an immense threat to their career. Amongst the dancers, the high
exertion afforded by the entire musculoskeletal system requires extended periods of rest.
The need to cope with constantly recurring stage-fear is an additional factor. Here, the
hidden numbers of those who deal with these problems using stimulants or tranquilisers
is high. Due to this, and in light of social desirability effects, the results must be
interpreted carefully.
1.
D. von Zerssen, D.-M. Koeller. Die Beschwerden-Liste. Klinische SelbstbeurteilungsSkalen (KSb-S) aus dem Münchener Psychiatrischen Informations-System. Beltz,
Weinheim 2000.
Correspondence: Institute of Public Health Research, Technische Universität München,
Connollystr. 32, 80809 Munich, Germany, [email protected].
Poster Abstracts
291
P12 Effect of Spirulina food supplement on blood morphological
parameters, biochemical composition and on the immune function of
sportsmen
Kazys Milasius*, Ruta Dadeliene
Of highest biological value are natural concentrates of optimally combined substances
produced by nature. One of food supplements of this kind is dietary Spirulina produced
by the Tianshi firm (China). It is a most rationally balanced food supplement of a high
biological value; it satisfies the needs of the whole body, including its immune system.
The aim of the current work was to assess the effect of the multicomponent natural food
supplement Spirulina on the physical development, blood morphological, biochemical
picture and immune function of sportsmen.
The study cohort comprised 12 sportsmen (age 20-22 years). They were using tablets of
Spirulina, a dietary product of the company Tianshi for 14 days. Physical development
was determined with the aid of standard methods. The general blood picture was
analyzed with the aid of a Micros-60 hematological analyzer (company ABX
DIAGNOSTICS, France). Lymphocytes and their subsets were analysed by flow
cytometery (FACSCalibur, Becton Dickinson Immunocytometry Systems (BDIS, USA)
and the absolute and percentage values were calculated. To evaluate immune function
lymphocyte blasttransformation response to mitogens was studied.
Investigations carried out on endurance-training sportsmen showed that a 14-d
administration of Spirulina exerted a positive effect on blood morphological composition
indices and its biochemical changes. The results of our study confirm the positive effect
of Spirulina food supplement on the quantitative parameters of immune system. Part of
the study cohort after weeks showed a tendency of normalizing CD3+, CD3+,
CD4+lympocite count: positive changes were still present two weeks following the
interruption of Spirulina intake.
Immediately following the 14-d period of Spirulina administration, parameter shifts in the
sportsmen’s blood composition showed positive changes. Under higher than medium
physical loads, the number of lymphocyte subtypes characteristic of specific immune
response, particularly CD3+ (T lymhocytes), CD3+CD4+ (T helpers/inductors) has a
tendency to decrease with increasing the number of CD3- CD16+ CD56+ (natural killer
cells). Lymphocyte response is enhanced by mitogen stimulation. The Spirulina food
supplement, based on microalgae, exerts a positive effect on the quantitative indices of
immune response: the number of T helpers/inductors.
1.
Milasius K, Peciukoniene M, Palaikiene Z. The use of biologically active substances
for better adaptation of athletes to physical loads. Acta Medica Lituanica. 4: 39-43,
1996.
292
2.
3.
Poster Abstracts
Lisheng L., et al. Inhibitive Effective and Mechanism of Polysaccharide of Spirulina
platensis on Transplanted Tumor cells in Mice, - Marine Science’s, Qindao China. 5:
33-38, 1991;.
Hyashi K. Enhancement of antiboly production in mice by dietary Spirulina platensis.
Nutrit Sci Vitaminol. 40: 431-441, 1994.
Correspondence: Vilnius Pedagogical University, Studentu st. 39, LT-08106, Vilnius,
Lithuania, [email protected].
Poster Abstracts
293
P13 General practitioners’ knowledge of and attitude to prohibited
substances in sport
Katerina N. Georgieva*, Raycho Rossejon
General practitioners (GPs) could be important participants in the doping prevention, but
it is reported that their knowledge and experience are insufficient to play this role [1, 2].
General medicine is a newly created speciality in Bulgarian Healthcare system and the
GPs’ Union is founded by physicians with heterogeneous medical majors and
professional experience. The level of Bulgarian GPs’ knowledge of and their attitude to
doping in sport as well as how often they have been confronted with doping problems in
their everyday practice is not known. The aim of the present study was to investigate the
GPs’ attitude, self-estimation of their knowledge and the frequency of their consultations
concerning doping. The sample of the study included 112 randomly selected GPs
(39.3% men), whose practices are situated in Plovdiv region, the second largest in
Bulgaria. The mean (SD) age of the participants was 42.7 (8.8) years and the mean
duration (SD) of their professional medical practice and GP practice were respectively
16.5 (8.6) and 4.8 (1.5) years. The participants completed a self-reported questionnaire.
From all the GPs 5.4% admitted to have consulted regarding doping in the last 12
months before the study and this percentage is lower than those reported in other
countries (1). However 9.8% reported that they have been asked to prescribe doping
agents. The most common substances determined by respondents as prohibited in sport
were amphetamines (100%), anabolic androgenic steroids (99.1%), diuretics (90.2%).
The majority of GPs rated their knowledge about doping as insufficient and almost all
(95.5%) indicated a need to improve it preferably by using an Internet site in Bulgarian
(83.2 %), courses, lectures (81.3%) and manuals (42%). The majority of GPs (90.2%)
considered doping usage as unacceptable at all and none of them would prescribe a
doping agent without a medical indication. Doping use was considered by most of the
respondents (64.2%) as a problem of all people practicing sport and a need of preventive
anti-doping programs in sport schools were determined by 67.9% and in all high schools
by 59.8% of GPs. In conclusion, most GPs considered that their knowledge about doping
is insufficient and would like to improve it. Our results show the need of doping
educational programs having been harmonized with the specific work of this target group
in Bulgaria
1.
2.
P. Laure, C. Binsinger, T. Lecerf. General practitioners and doping in sport: attitudes
and experience. Br J Sports Med 37:335-338, 2003.
P. Greenway, M. Greenway General practitioner knowledge of prohibited
substances in sport. Br J Sports Med 31:129-131, 1997.
Correspondence: Department of Physiology, Medical University – Plovdiv, 15A Vassil
Aprilov Blvd., 4000 Plovdiv, Bulgaria, [email protected].
294
Poster Abstracts
P14 Coaches and athletes and their role in doping prevention - empirical
data
Christiane Peters*1, Peter J. Selg1, Jezabel Ohanian1, Katharina Habermann1, Thorsten
Schulz1, Helmut Pabst2, Horst Michna1
The major aims of doping prevention are the athletes and the coaches. With regard to
doping there is just little data known about the coaches´ knowledge and their point of
view [1]. Therefore, we decided to set out a project (VF 0407/03/41/2003-2004,
supported by the BISP/Bonn/Germany) to examine doping related state of knowledge of
athletes and coaches from diverse sports associations as well as flow of information.
By means of a written survey, we asked 620 coaches of different levels (rate of return
41%) and 1757 high-level athletes (handicapped and non-handicapped; rate of return
46%) about several doping related aspects. One out of two coaches is regularily
confronted with doping issues by their athletes. Main topics are hereby biomedical side
effects (15%), nutritional supplements (16%), doping controls (12%) and fairplay (12%).
Despite this extensive confrontation with the topic the majority of the coaches (62%)
quote to be rather bad or well informed about doping. Just 50% of them owned the
current forbidden list and just 58% knew the World-Anti-Doping-Code. However, most
coaches are not proactive but want to be informed by their sports association. For over
90% of the coaches it is important to stop doping and to reach this goal they propose a
better information of the athletes (17%), a delivery of the current information flyer to all
squad members (14%) and the integration of the doping issue into the educational
trainings curricula of coaches.
Additionally, a lots of athletes claim to frequently think about doping related topics
whereas the coach is their main contact person. About a half of the athletes (52%) have
heard about doping issues at their squad meetings. The information was given by the
coaches in the most cases (45%) and in 19% of the cases by the physician. Three
quarter of the athletes are not proactive at all but were informed by colleagues or other
parties. Often national anti-doping associations, diverse flyers or internet information are
unknown by athletes. We conclude, that there are urgent needs to change the
information policy of sports associations, Olympic training centres, coaches and
physicians. Coaches need to use the current knowledge on doping to convince their
athletes (of all levels) of a doping-free sport.
1.
Laure P, Thouvenin F & Lecerf T. Attitudes of coaches toward doping. J Sports Med
Phys Fitness, 41, 132-136, 2001.
1
Correspondence: Institute of Public Health Research, Technische Universität München,
Connollystraße 32, 80809 Munich/Germany, [email protected]. 2Bavarian Association
of Sports Medicine, Georg-Brauchle-Ring 93, 80992 Munich/Germany.
Poster Abstracts
295
P15 Sports physicians and their role in doping prevention - empirical data
Peter J. Selg*1, Christiane Peters1, Thorsten Schulz1, Helmut Pabst2, Horst Michna1
Recent publications quoted the performance enhancing drug abuse as an increasing
problem of "public health" [1-3]. The physician plays hereby an important role, as he is
an important contact person, who could recognize biomedical side effects and take a
very important part of doping prevention. To characterize the opportunities of
advancement of the sports physicians trainings on doping issues we decided to set out
an empirical study of the knowledge and attitudes towards doping of the sports
physicians (VF 0407/03/41/2003-2004, supported by the BISP/Bonn/Germany).
A total number of 2667 physicians (all qualified in sports medicine) were included into the
survey and were divided into two subgroups: While the first group included all physicians
in the state of Bavaria (n=2404) running their own surgery the second one sums up all
German team physicians being members of a sports association (n=263). An
anonymous questionnaire about doping related knowledge, flow of information, observed
abuse by athletes as well as preventive strategies was forwarded.
Rate of return of the questionnaire was 18% (n=472) in total, 16% (n=392) among the
Bavarian physicians and of 30% (n=80) among the German team physicians. A general
demand on doping by athletes was affirmed by 62% of all physicians (57% physicians
vs. 81% team physicians). More than one third of the sports physicians evaluate (five
aries range of marks) their educational trainings (university, specialists, sports physician)
in concern of the extent of their teachings on doping related knowledge as insufficient.
The content of the prohibited list is quite well resp. well known for just 25% of the sports
physicians running their own surgery. Among the German team physicians more than
75% of counts are seen. At the same time all sports physicians see a quite high resp. a
high need for extended doping prevention in following sectors: coaches (86%), competitive sports (85%), students (49%) and even medical sector (66%). The sports physicians
show an extensive disaffection towards their educational train-ings concerning doping
related knowledge. This fact is accompanied by a heteroge-neous and limited knowledge
of the sports physicians, especially the physicians running their own surgery seems to be
less qualified. Therefore, doping prevention should be integrated much more into the
corresponding medical curricula.
1.
2.
3.
Laure P, Binsinger C & Lecerf T. General practitioners and doping in sport: attitudes
and experience. Br J Sports Med 37: 335-338, 2003.
Eklöf AC, Thurelius AM, Garle M, Rane A & Sjöqvist F. The anti-doping hot-line, a
means to capture the abuse of doping agents in the Swedish society and a new
service function in clinical pharmacology. Eur J Clin Pharmacol 59: 571-577, 2003.
Botrè F. Drugs of abuse and abuse of drugs in sportsmen: the role of in vitro models
to study effects and mechanisms. Toxicol In Vitro 17: 509-513, 2003.
296
Poster Abstracts
Correspondence: 1Institute of Public Health Research, Technische Universität München,
Connollystraße 32, 80809 Munich/Germany, [email protected]. 2Bavarian Association of
Sports Medicine, Georg-Brauchle-Ring 93, 80992 Munich/Germany.
Poster Abstracts
297
P16 Analysis of the mechnism of action of different anabolic agents in
bovine tissues to develope an expression pattern for drug screening
Martina Reiter, Vanessa M. Walf, Arne Christians, Michael W. Pfaffl, Heinrich H.D.
Meyer
In this study the effects of the anabolic agents melengestrol acetate (MGA), trenbolone
acetate and zeranol were analysed in different bovine tissues (liver, muscle, uterus).
Using quantitative RT-PCR, the gene expression of specific genes, influenced by the
anabolic agents, should be identified.
The selection of candidate genes varied between the different tissues because of the
different hormone induced pathways in every single organ. To identify influenced
pathways, all candidate genes were selected and seperated in functional groups:
angiogenesis, apoptosis, cell cycle, endocrine factors, energy metabolism, inflammatory
factors, muscle function, oncogenes, protein metabolism and transcription factors.
With the investigation of the regulation and possible function of anabolic sex steroids via
gene expression, a preparatory work for the development of an expression pattern for
drug screening, was made. Not only in veterinary drug screening but also in the human
doping analysis, this can be a promissing method to prove the abuse of illegal anabolic
agents.
1.
2.
H.H.D. Meyer. Biochemistry and physiology of anabolic hormones used for
improvement of meat production. – In: APMIS 109: 1-8 2001.
M.W. Pfaffl, I.G. Lange, H.H.D. Meyer. The gastrointestinal tract as target of steroid
hormone action: Quantification of steroid receptor mRNA expression (AR, ERalpha,
ERbeta and PR) in 10 bovine gastrointestinal tract compartments by kinetic RTPCR. – In: Journal of Steroid Biochemistry & Molecular Biology 84: 159-166, 2003.
Correspondence: Physiology Weihenstephan, Technical University Munich,
Weihenstephaner
Berg
3,
85354
Freising-Weihenstephan,
Germany,
[email protected].
298
Poster Abstracts
P17 Erythrocyte aminotransferase as an indirect marker for stimulated
erythropoiesis in athletes
Yohan Robinson*, Edgar Cristancho, Dieter Böning
Even though doping with erythropoietin (EPO) is an effective but illegal performance
enhancer, a simple and reliable screening-test is still unavailable. Most of the existing
direct and indirect detection methods are either too expensive or not sensitive enough.
Thus a new approach by estimating mean red blood cell (RBC) age by means of
erythrocyte aspartate aminotransferase activity (eAST) – an effective indicator of mean
RBC age - was developed.1,2 Previous investigations have shown that eAST was
capable to determine RBC rejuvenation in chronic hypoxia.3,4 This study was designed
to establish reference values and to evaluate the influence of training status on eAST.
201 female and 169 male individuals residing at low altitude were investigated for serum
EPO concentration (sEPO), haemoglobin concentration [Hb], and eAST.5 Furthermore
63 female and 42 male individuals residing and training at 2,600 m above sea level were
investigated for sEPO and eAST. Participants were subdivided into trained, moderately
trained and untrained. Additionally 22 female and 28 male patients with renal failure
receiving recombinant human EPO (rhEPO) were investigated for eAST levels.
For low altitude residents there was no difference in eAST among trained, moderately
trained and untrained subjects for either sex (Tab. 1); the distribution of values was
approximately normal (Fig. 1). Trained high-altitude residents had higher eAST than
untrained high-altitude residents (ANOVA, p<0.05) and male lowlanders (ANOVA,
p<0.05). sEPO did not differ between high and low altitude. Patients receiving rhEPO
had higher eAST with increasing weekly rhEPO-dose (r=0.25, p<0.05).
Since long-lasting training has no effect on eAST but rhEPO-therapy and high-altitude
residency have, eAST-elevation in lowlanders should indicate EPO-doping. eAST-values
above the 95% confidence interval (>3.3 U·gHb-1 for males, >4.1 U·gHb-1 for females)
are suspicious of EPO-doping.
1.
2.
3.
4.
5.
W. Schmidt, D. Böning, K. M. Braumann. Red cell age effects on metabolism and
oxygen affinity in humans. Respir. Physiol. 68:215-225, 1987.
Y. Robinson, E. Cristancho, D. Böning. Intravascular haemolysis and mean red
blood cell age in athletes. Med. Sci. Sports Exerc. 38:480-483, 2006.
D. Böning, J. Rojas, M. Serrato, C. Ulloa, L. Coy, M. Mora, J. Gomez, M. Hütler.
Hemoglobin mass and peak oxygen uptake in untrained and trained residents of
moderate altitude. Int. J. Sports Med. 22:572-578, 2001.
D. Böning, E. Cristancho, M. Serrato, O. Reyes, M. Mora, L. Coy, J. Rojas.
Hemoglobin mass and peak oxygen uptake in untrained and trained female altitude
residents. Int. J. Sports Med. 25:561-568, 2004.
Y. Robinson, E. Cristancho, D. Böning. An optimized method for the assay of the
mean red blood cell-age-related enzyme aspartate aminotransferase. Lab. Hematol.
10:144-146, 2004.
Poster Abstracts
299
Correspondence: Charité - Campus Benjamin Franklin, Klinik für Unfall- und
Wiederherstellungschirurgie,
Hindenburgdamm
30,
D-12200
Berlin,
[email protected].
300
Poster Abstracts
P18 Doping prevention strategies in Spain and the importance of social
alarm as preventive strategy
Maria Dolores Hinchado*, Esther Giraldo, Eduardo Ortega
The main subject of any sanitary system is prevention. Unfortunately in the fight against
doping all investments are focused in development of new techniques for drugs
identification and controls and there is not a lot of interest in prevention. Antidoping
controls must be considered as a way to guarantee a competition free of drugs and
prohibited methods. But the best way to beat doping is through education, information
and with the correct medical assistance. Usually most of the efforts try to discover the
culprits, but often we forget other actions. We encourage sportspeople to win at any
price, the prestige of the team, school, locality, nation which represents are at stake.
Therefore huge amounts of money are offered in order to win or to get better results. On
the other hand we forget the day-a-day sportsperson’s medical specialized assistance.
This problem gets bigger in amateur or recreational level, where most of the users are
not checked medically and more often they resort to exogenous stimulants.
The present study considers the prevention actions related to doping control developed
in Spain and also the new actions that we propose. Until few years ago, in our country
the law about doping was based on the sports field; unlike France, Italy or Belgium which
their actions against doping consider doping such as a criminal act. However, it is just
passed in Spain the new Law to protect health and to fight against doping in Sports. In
this law doping is considered for the first time as a health problem and people who
promote or practise doping attempt on public health. The new law promotes different
measures in order to prevent and improve sportspeople’s health. So, the fight against
doping in Spain is based on the need to inform, educate and to make aware
sportspeople about the harmful effects of doping, and moreover to show that the
sportspeople can improve their scores without doping.
Finally, in this presentation we also propose to stand out the need to generate social
alarm in relation to the side effects of doping on health and a prevention strategy, above
all for those who start practising sports.
Correspondence: Department of Physiology, Faculty of Sciences, University of
Extremadura. Avd. Elvas s/n. 06071Badajoz, Spain, [email protected].
Poster Abstracts
301
P19 Glucocorticosteroids in doping analysis
Radoslaw Jazwiec*, Andrzej Pokrywka, Dorota Kwiatkowska, Ryszard Grucza
Glucocorticosteroids (GCS) were considered, as doping agents by IOC Medical
Commission in 1975. But until September 2003, decision on banning them was in
authority of particular sport federation. In this year, WADA has set prohibition of this
group, as a mandatory rule for all in-competition samples. According to 2006 edition of
the WADA Prohibited List - all GCS administered locally are permitted. For drugs
administered by inhalations there is a special simplified procedure for obtaining TUE
(Therapeutic Use Exemptions) [1].
GCS as pharmacological group are defined by their pharmacodynamic similarity with
natural hormones: cortisol and cortison. As other steroid hormones - they migrate into
target cells, and act directly on the transcription of DNA. Their main metabolic action is
opposite to efect of insuline administration. In contemporary medicine they are used as
anti-inflammatory agents, and to prevent the rejection of the transplant by the patient's
immune system [2].
GCS effectiveness as doping agents is disputable. The doping efect is not adequate to
side effects connected with administration of high doses of GCS. It is also possible, that
most GCS positive samples were caused not by intentional doping, but by improper
medical use.
Because use of glucocorticosteroids is allowed in some cases, prohibited threshold of
30ng/ml has been set by WADA [3]. The same value for all GCS, caused considerable
controversies, because drugs of this group have very various strength of action. There is
a scientific project going on (founded by WADA), aimed to set appropriate thresholds for
substances of this group.
According to statistics presented by WADA for the years 2004 and 2005, the first year of
prohibition of glucocorticosteroids showed that GCS became the second ranking doping
agents, after anabolic steroids. In 2005 they were located on the fifth place. During that
year the polish laboratory found only three positive samples containing
glucocorticosteroids (over 30ng/ml). It is possible that lowering of GCS prohibited
threshold would increase the number of these positive samples.
1.
2.
A. Gotzmann, M. Thevis, U. Mareck, M. Bredehöft, S. Guddat, W. Schänzer. LCMS/MS analysis of glucocorticosteroids: first experiences with Therapeutic Use
Exemption in routine doping analysis. In: W. Schänzer, H. Geyer, A. Gotzmann, U.
Mareck (Eds.). Recent Advances in Doping Analysis (12). Sport und Buch Strauß,
Köln 2004, pp 55-64.
Władysław Traczyk. Physiology of human - with applied and clinical physiology
elements (in polish). PZWL, Warszawa 2004.
302
3.
Poster Abstracts
WADA Technical Document - TD2004MRPL. Minimum Required Performance Limits
for Detection of Prohibited Substances. Version no 1.0, January 15, 2004.
Correspondence: Department of Anti-Doping Research, Institute of Sport, Trylogii 2/16,
01-982 Warsaw, Poland, [email protected].
Poster Abstracts
303
P20 Resting blood hormones levels and weightlifting performance
Zbigniew Obminski*1, Dorota Kwiatkowska2, Andrzej Pokrywka2, Ryszard Grucza1,2
The goal of the present study was to examine weightlifting performance in relation to
resting blood endogenous hormones. Six male athletes preparing to the European
Championships (EC) and after that to the Olympic Games were subjected to the study
covering long-lasting training period. Levels of cortisol (C) and testosterone (T) were
measured in the blood sampled on the each day of six simulated competition and
additionally on the other 12 terms. The levels of performance were rated by outcomes of
snatch (S), clean and jerk (C&J), and total weight (TW) each of them expressed as
percentage of those reached later on the Olympic Game. Differences between changes
of the of blood parameters: C, T and T/C ratio, and of athletic performance were tested
by analysis of variance with repeated measures followed by the post-hoc test. The
results indicated two peaks performance reached during training period. The first one
was prior to EC and manifested itself as the best average, relative S (97.9±1.5%), C&J
(102.4±2.3%) and TW (100.1±1.4%) despite the lowest hormonal parameters such as
mean level of T (15.5±3.5 nmol/L) and index T/C (2.8±2.1). The second one was
reached three month after the first one, on the latest simulated competition when the
mean examined values were as follows: snatch - 95.5±1.4%, C&J - 102.5±1.5%, TW 99.2±0.6%, T - 31.3±11.7 nmol/L, and T/C ratio - 7.5±3.3. The best outcome on the
Olympic Games i.e. silver medal won the athlete exhibiting moderate T but the lowest
intra-subject variability of T during the whole preparatory training. Among 82
observations we noted 14 cases of episodic androgenic hyperactivity expressed as very
high T levels each of them exciding the upper level (41.6 nmol/L) and giving the mean
value amounting 51.8±9.7 nmol/L. Majority of these cases occurred after EC. These
findings may suggest that lower blood T allows to maintain excellent athletic
performance over only short-lasting period. Since the noted cases of hyperandrogenism
are hard to explain based on physiology, and generally doping with androgenic-anabolic
steroids among weightlifters are more frequent then among the other athletes [1] we may
suspect, that prolonged psycho-physical overloading forced some of weightlifters of
lower training tolerance to take anabolic steroids. However, that assumption might be
judged only by more advanced analysis.
1.
Dorota Kwiatkowska, Ryszard Grucza, Krzysztof Chrostowski, Jerzy Smorawiński.
Doping cases in polish athletes. Biol Sport 17:121-131, 2000.
1
Correspondence: Department of Endocrinology, Institute of Sport, Trylogii 2/16, 01-982
Warsaw, Poland, [email protected]. 2Department of Anti-Doping
Research, Institute of Sport, Trylogii 2/16, 01-982 Warsaw, Poland.
304
Poster Abstracts
P21 Searching the reasons for temporary abnormal hormonal status in the
healthy athletes. A case study.
Zbigniew Obminski*1, Dorota Kwiatkowska2, Andrzej Pokrywka2, Ryszard Grucza1,2
This communication presents cases of abnormal blood cortisolism and androgenism in
two endurance trained and six judokas. One male and one female, the modern
pentathlon athletes, have been regularly examined throughout 4-years period and
completed 13 exercise studies. The each study consisted of cortisol measures in four
blood samples taken in the morning, prior the exertion, and at 3 and 30 minutes of postexercise recovery. The mean blood cortisol levels in these samples calculated from 12
studies were as follows; in the male: 633±109, 530±131, 616±136 and 793±186, and in
the female: 506±177, 367±127, 374±138 and 499±150 nmol/L. However, during the one
exercise study, the male and the female athlete exhibited abnormal hormonal status. In
the blood taken from the male cortisol levels were: 1518, 1380, 1408 and 1435nmol/L,
and these results were associated with non-physiological testosterone levels reaching
almost two-fold the upper limit (41.6 nmol). In the female hormonal abnormality
manifested itself as very low levels of blood cortisol: 25, 26, 25, and 19 nmol/L, and very
low testosterone levels, on average 0.3nmol/L, while during the other studies it ranged
from 1.3 to 2.8. In the six judokas, 3 males and 3 females, morning blood cortisol and
testosterone levels were monitored during training camps. Cortisol levels ranged from
389 to 689nmol/L, until they had to stop their training activity, and had to be treated with
steroidal anti inflammatory agents. 24h followed by single into knee or elbow joints
injections of artificial steroids, endogenous cortisol strongly decreased to the range 2148 nmol/L. In response to treatment by steroids, blood testosterone levels decreased,
somewhat in the males, by 30%, and makcedly, 5-6 fold in the females. Some difficulties
appear with understanding of hormonal behavior in the pentathlon athletes. They did not
report to use any medication. Moreover, despite huge deficits of the endogenous
hormones observed in the female, similar to those in female judokas, her athletic
performances was quite good. That mentioned adrenal suppression was caused due to
negative feedback [1]. In the male athletes blood hypercortisolism and
hyperandrogenism were not ever report by others. In summary, for explanation such as
blood hormonal abnormality further investigations are required.
1.
R J Perry, C A Findlay, M D C Donaldson. Cushing syndrome, growth impairment,
and occult adrenal suppression associated with intranasal steroids. Arch Dis Child
87:45-48, 2002.
1
Correspondence: Department of Endocrinology, Institute of Sport, Trylogii 2/16, 01-982
Warsaw, Poland, [email protected]. 2Department of Anti-Doping
Research, Institute of Sport, Trylogii 2/16, 01-982 Warsaw, Poland.
306
9
Symposium Program
SYMPOSIUM PROGRAM
GREETINGS
09:00 – 09:20 a.m.
Welcome & Opening
Rudolf Schilling
Vice-President of TU Munich
Paul Marriott-Lloyd
Programme Specialist Anti-Doping, UNESCO
09:20 – 09:30 a.m.
The Project – Idea and Goal!
Horst Michna
Dean Faculty of Sports Science, GER
SESSION:
DOPING IN GENERAL
Chairs: Asterios Deligiannis and Paul Marriott-Lloyd
09:30 – 10:05 a.m.
The Doping Issue
Barrie Houlihan
School of Sport & Exercise Sciences, Loughborough
University, UK
10:05 – 10:40 a.m.
Drug Abuse and Doping Behaviour
Patrick Laure
DRDJS– Sports and Public Health, Saint-Max Cedex, F
SESSION:
HEALTH SIDE EFFECTS – PART I
Chairs: Katerina Georgieva and Martin Halle
11:10 – 11:45 a.m.
Nutritional Supplements
Christiane Ayotte
Doping Control Laboratory, INRS-Institute Armand
Frappier, CND
11:45 – 12:20 a.m.
Anabolic Steroids
Linn Goldberg
Human Performance Laboratory, Oregon Health &
Science University, USA
Symposium Program
SESSION:
307
HEALTH SIDE EFFECTS – PART II
Chairs: Eduardo Ortega Rincón and Hans-H. Dickhuth
01:50 – 02:25 p.m.
Narcotics
Ryszard Grucza
Department of Antidoping Research, Institute of Sport,
PL
02:25 – 03:00 p.m.
Cannabinoids
Peter Van Eenoo
Doping Control Laboratory, Ghent University, B
03:00 – 03:30 p.m.
Gene Doping
Odile Cohen-Haguenauer
LBPA, ENS-Cachan, F
Bernd Gänsbacher
Institute of Experimental Oncology, GER
SESSION:
DOPING PREVENTION STRATEGIES
Chairs: Roland Augustin and Carl Müller-Platz
04:00 – 04:30 p.m.
ATLAS & ATHENA
Melissa Durham
Center for Health Promotion Research, Oregon Health
& Science University, USA
04:30 – 05:00 p.m.
Prevention Strategies in Sweden
Bengt O. Eriksson
Swedish Doping Commission Goeteborg, SWE
05:00 – 05:15 p.m.
Conclusion & Closing
Horst Michna
ROUND TABLE: PERSPECTIVES OF PREVENTION
Chair and Moderator: Linn Goldberg
05:15 – 06:15 p.m.
Barrie Houlihan (UK)
Linn Goldberg (USA)
Hans-H. Dickhuth (GER)
Luis Horta (P)
Patrick Laure (F)
Thomas Kistler (GER)
Dedication
In memory of Horst Michna
a much valued colleague and good friend
and initiator of this project.
Thanks for your large commitment in the
fight against doping in sport and the possibility
that we could go a piece of the way together.

BIOMEDICAL SIDE EFFECTS OF DOPING Biomedical Side Effects

Transcription

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