Menopause - Dossier Communications

Transcription

CPJRPC
CANADIAN
PHARMACISTS
JOURNAL
YO U R
P E E R- R EV I EW E D
REVUE DES
PHARMACIENS
DU CANADA
F O RU M
F O R
PAT I E N T- C E N T R E D
P RAC T I C E
Menopause
NOVEMBER/DECEMBER 2010
VOL 143 [SUPPL 2]
PUBLICATIONS
MAIL AGREEMENT
NO. 40064631
WWW.CPJOURNAL.CA
Contents
Research and Clinical
Overview
S4 Introduction to menopause
Clinical Review
S7Confusion about hormone therapy:
Misinterpretation of the findings
of the Women’s Health Initiative
Robert L. Reid
Guidelines
S9Pharmacist-specific summary
of menopause clinical practice
guidelines
Pharmacotherapy
S12Practical issues in hormone
therapy management
Thomas E.R. Brown
S14 Hormonal therapies for the relief
of menopausal symptoms
S16Nonhormonal therapies for the
relief of menopausal symptoms
Opinion
Clinical Briefs
S17Bioidentical hormone therapy:
A practical review for pharmacists
Editorial
S2 Menopause: Challenging natural
assumptions
Nesé Yuksel, Mary Gunther
Rosemary Killeen
S17Definition of bioidentical
hormones
Commentary
Melanie Trinacty, Anne Marie Whelan,
Tannis M. Jurgens
S21Lifestyle strategies in the
management of women’s midlife
health concerns
Megan MacInnis
S22Natural health products
S3 A call to action for women: Your
change, your life — take charge
Vyta Senikas
Guest Editorials
S6Treating menopause: Our patients
and their caregivers are confused
Serge Bélisle
Tracy Marsden
S19Helping women navigate through
menopause: Role of pharmacists
Practice Profile
Nesé Yuksel
S20Irene Hogan: Pharmacist and
NAMS Certified Menopause
Practitioner
Insert:
Menopause
Assessment Tool
Christine D. LeBlanc
Patient Handout
Nesé Yuksel
S24The menopause transition — What
you need to know
EDITORIAL
Rosemary Killeen, RPh, BScPhm
Menopause: Challenging natural
assumptions
There are few topics as potentially challenging for health
professionals as menopause. The evidence seems to change
daily,1,2 celebrities with no medical training promote themselves
as experts3 and your well-intentioned
recommendations may be met with
resistance or downright horror if they
happen to conflict with a patient’s
personal beliefs about aging, hormone
therapy or the “medicalization” of a
natural event.
What we may not realize is the current
pattern of female aging is, in fact, a pretty recent phenomenon.
In 1900 (only 110 years ago — a mere tick on the evolutionary
clock), the average age at which menopause occurred in North
America was 50. In the US at that time, the average female life
expectancy at birth was 51 and the median age at death was 58.4
Today, just over a century later, most Canadian women live 30
or more years without significant endogenous female hormone
production. Since we know that many evolutionary adaptations
take thousands of years, not decades, it may be the present-day
situation that’s not natural!
Our goal with this CPJ supplement
is to provide pharmacists with recent
evidence-based
information
and
perspective to assist them in guiding their
midlife female patients. I’d like to thank
our Guest Editors, Drs. Nesé Yuksel and
Serge Bélisle, as well as our other authors
and reviewers, for sharing their expertise and experience. n
Emerging evidence
published after this
supplement was finalized
can be accessed through
www.etherapeutics.ca
S2 Contact [email protected].
References available online at www.cpjournal.ca
C P J / R P C • N OV E M B E R / D E C E M B E R 2 0 1 0 • VO L 1 4 3 [ S U P P L 2 ]
C O M M E N TA R Y
Vyta Senikas, BSc, MDCM, FRCSC, FSOGC, CSPQ, MBA
A call to action for women:
Your change, your life — take charge
Introduction
In 2009, the largest number of women in the baby-boomer demographic turned 50, resulting in historic demand for menopausal
consulting, along with an unprecedented opportunity for health
care professionals to enhance and support women’s health at
midlife and beyond. Statistics Canada estimates the number of
women in this midlife age group will reach 6.9 million by the year
2016, and 7.9 million by the year 2026 — at which point they will
comprise 22% of the Canadian population.1
Current life expectancy for Canadian women is 82 years.2 Rising life expectancy means that not only are there increasing numbers of postmenopausal women, but also that an increasing proportion of them will live longer after menopause. The relevance to
public health of any adverse effects of menopause is of potentially
great importance to society, and possibly more so in a society with
a universal health care system such as Canada’s.
The menopause transition
For some women, the menopausal transition may be a time of
major symptoms affecting quality of life and requiring medical
assessment, which may include a prescription for medical therapy.
But the majority of women will experience menopause as a normal event without significant difficulty, and these largely asymptomatic women will not seek medical attention from a health care
professional to relieve symptoms or detect disease.
The reality is that a nutrient-rich diet, regular exercise and a
healthy lifestyle can be far more effective in preventing disease
than any medical intervention, because medical care determines
only a small portion of the health of a society. Therefore, the traditional approach of diagnosing and treating disease is no longer
sufficient; health promotion and disease prevention strategies
must be part of every health care professional’s practice.
Many women are unaware of what they can do to improve
their health and wellness, but are very motivated to hear and act
on this information. During recent public outreach events undertaken by the Society of Obstetricians and Gynaecologists of Canada (SOGC) on menopause, women were surprised to learn that
CPJRPC
CANADIAN PHARMACISTS JOURNAL
NOVEMBER/DECEMBER 2010
VOL 143 [SUPPL 2]
Tel (613) 523-7877 or 1-800-917-9489 | Fax (613) 523-0445
[email protected] • www.cpjournal.ca
cardiovascular disease (CVD) presented a far greater risk to their
long-term health than breast cancer.3 They learned that 94% of
CVD risk could be attributed to modifiable factors.4 This statistic
comes from the INTERHEART study, which examined modifiable risk factors across many populations. The factors contributing substantially to increased CVD risk include diabetes mellitus,
hypertension, abdominal obesity, current smoking and psychosocial stress. Each of these risks can be reduced through appropriate
lifestyle choices, health care professional interventions, or both.
Many women in menopause are ready to make positive changes
in their lives, and look upon this transition as a prime opportunity
to do so. Not only is there evidence that healthy lifestyles lead to
better outcomes, but there is also good evidence to demonstrate
that an intervention by a health care professional increases the
likelihood that a patient will make and maintain a healthy change.5
We all have a role in providing women with advice, encouragement and support, as well as trusted educational resources.
The SOGC is contributing by administering the Canadian
Menopause Coalition (15 national organizations concerned with
women’s health, including the Canadian Pharmacists Association), the Menopause Education and Awareness Program, and
the website menopauseandu.ca — initiatives dedicated to ensuring Canadian women have access to credible information they
can trust to help them make good choices about their health. This
supplement is a resource specifically for health care professionals
to help their clients through their transition. n
Vyta Senikas is the Associate Executive Vice-President at the Society
of Obstetricians and Gynaecologists of Canada. Contact: vsenikas@
sogc.com.
The content of this supplement has been reviewed and endorsed
by the SOGC.
EDITORIAL STAFF
Editor-in-Chief/Deputy Publisher, Rosemary Killeen, RPh, BScPhm
Managing Editor, Christine D. LeBlanc, B. Journalism
Consulting Editor, Renée Dykeman, MA
Editorial and Production Coordinator, Sara West Woods, BA
French Editors, Sylvie Marcotte, BScN; Louise Welbanks, BScPhm
Guest Editors, Nesé Yuksel, BScPharm, PharmD, ACPR, FCSHP,
NCMP; Serge Bélisle, MD, MSc
Contributing Clinical Editor, Peter Rempel
Design and Production, CPhA Graphic Communications
Executive Director, Jeff Poston
Senior Director, DPS, James de Gaspé Bonar
All published articles, including editorial
and commentary, reflect the opinions of the
authors only and do not necessarily reflect
the opinion of the Canadian Pharmacists
Association.
Publications Mail Agreement No. 40064631
ISSN 1715-1635
Printed in Canada
Publication of this supplement to the Canadian Pharmacists Journal was made possible through an unrestricted educational grant from Pfizer Canada Women’s Health Division.
C P J / R P C • N OV E M B E R / D E C E M B E R 2 0 1 0 • VO L 1 4 3 [ S U P P L 2 ] S3
OVERVIEW
Introduction to menopause
Menopause is the moment when a woman has had no menstrual
periods (amenorrhea) for 12 consecutive months. If this cessation of periods results from the spontaneous halt of ovarian
hormone production and is not the result of other physical
or pathological conditions or treatments, it’s termed natural
menopause. The average age of menopause in Canada is 51 years
and this has been constant throughout the last few centuries.1
Induced menopause is caused by medical or surgical intervention,
such as radiation or chemotherapy treatment, or ovary removal
during hysterectomy (oophorectomy). Premature menopause
refers to menopause before age 40, and early menopause refers
to menopause before age 45.2
Perimenopause is a time that begins with an alteration in
menstrual cycle length and ends 12 months after the final menstrual period. The menopause transition is a term preferred
by the Stages of Reproductive Aging Workshop (STRAW) as
more appropriate to describe this phase. The North American
Menopause Society (NAMS) uses the terms perimenopause and
menopausal transition interchangeably.
During a woman’s reproductive years, estrogen (primarily as
estradiol) and progesterone levels rise and fall with her cycles, as
the follicle-stimulating hormone (FSH) promotes follicle development and ovum release. By menopause, a woman’s ovaries
have no follicles left that respond to FSH.3 The lack of follicular stimulation and development signals the end of the regular
menstrual cycle and the monthly fluctuations of both estradiol
and progesterone concentrations. 3
Without follicular development and
TABLE 1 Menopause terminology2
the designation of a graafian (dominant) follicle, estradiol concentrations
Early menopause
Natural or induced menopause that occurs well before the
remain low and ovulation does not
average age of natural menopause (51 years), at or under age 45.
occur, so progesterone concentrations
Early postmenopause The time period within 5 years after the final menstrual period
also remain low.3 As a result, endo(FMP), resulting from natural or induced menopause.
metrial proliferation occurs rarely
EPT
Combined estrogen-progestin therapy.
and there are no secretory changes.
ET
Estrogen therapy.
The pituitary gland increases the
production and release of both FSH
FMP
Final menstrual period.
and luteinizing hormone (LH) in an
HT
Hormone therapy (encompassing both ET and EPT).
attempt to entice the ovary to initiate follicular development.3 Because
Induced menopause
Permanent cessation of menstruation after bilateral
oophorectomy (i.e., surgical menopause) or iatrogenic ablation
the ovary cannot respond, FSH and
of ovarian function (e.g., by chemotherapy or pelvic radiation
LH concentrations remain elevated,
therapy).
while estradiol and progesterone conLocal therapy
Vaginal ET administration that does not result in clinically
centrations remain low.3 Testosterone,
significant systemic absorption.
however, continues to be produced by
Natural/spontaneous
The FMP, confirmed after 12 consecutive months of amenorrhea
the ovaries after menopause.
menopause
with no obvious pathologic cause.
Cessation of menses, along with the
Perimenopause/
Span of time when menstrual cycle and endocrine changes occur
increase in FSH and LH and decrease
menopause transition a few years before and 12 months after an FMP resulting from
in estradiol and progesterone, occurs
natural menopause.
gradually over several months to
Premature menopause Menopause reached at or under age 40, whether natural or
years. 3 In perimenopause, ovary
induced.
response to FSH and LH slows, taking
Premature ovarian
Loss of ovarian function before age 40, leading to permanent
longer for follicular development and
insufficiency
or transient amenorrhea (often described as premature ovarian
endometrial proliferation to occur,
insufficiency or premature menopause).
but unlike in menopause, the follicles
Systemic therapy
HT administration that results in absorption in the blood
in the ovary are still able to respond
high enough to provide clinically significant effects; in this
supplement, the terms ET, EPT, HT and progestin are presented
and ovulation does still occur.3 These
as systemic therapy unless stated otherwise.
physiologic changes affect normal
Adapted with permission from: Estrogen and progestogen use in postmenopausal
hormone balance and can result in
women: 2010 position statement of The North American Menopause Society. Menopause
fluctuating estrogen levels that con2010;17(2):242-55.
tribute to symptoms.
S4 C P J / R P C • N OV E M B E R / D E C E M B E R 2 0 1 0 • VO L 1 4 3 [ S U P P L 2 ]
TABLE 2 Absolute contraindications to
estrogen and progestin therapy
Estrogen
therapy
• Undiagnosed vaginal bleeding
• Active liver disease
• Active thromboembolic disease
The risk of recurrence of breast cancer or thrombosis
following estrogen therapy is unknown. Caution is
recommended in women with cardiovascular disease. For
all women, the risk versus the benefit must be taken into
consideration when prescribing estrogen therapy.
Progestin
therapy
• Undiagnosed vaginal bleeding
• Known or suspected carcinoma of the breast
• Pregnancy
Reproduced with permission from Cullimore AJ, Menopause.
In: eTherapeutics. Available: www.etherapeutics.ca (accessed
Nov. 5, 2010).
TABLE 3 Selected estrogen product doses4
Product
Low dose
Standard dose High dose
Conjugated estrogen (oral)
Premarin, CES
0.3 mg
0.625 mg
0.9 mg or
1.25 mg
1 mg–2 mg
N/A
17b-estradiol (oral)
Estrace
0.5 mg
17b-estradiol (transdermal patches)
Climara
0.025 mg/day 0.05 mg/day
0.075 mg/
day
0.1 mg/day
Estradot
25 mcg/day
37.5 mcg/day
50 mcg/day
75 mcg/day
100 mcg/
day
Oesclim
25 mcg/day
50 mcg/day
N/A
1 actuation
2 actuations
4 actuations
17b-estradiol (topical gel)
Estrogel
N/A
The postmenopausal female continues to produce a form
of estrogen in the adipose tissue as a result of the conversion
of androstenedione (from the adrenal gland) to estrone.3 The
amount of estrone produced depends on the amount of adipose
tissue present. Estrone has a weaker effect on the endometrium
than estradiol; therefore, proliferation of endometrial tissue is
rare, except in women who are obese.
Vasomotor symptoms, commonly known as hot flashes and
night sweats, are the most common presenting complaint of
menopausal women. Bothersome hot flashes often commence
Estrogen through a woman’s life
The predominant estrogen prior to menopause is estradiol
(E2), but this shifts to estrone (E1) after menopause, as
estrone is converted from androstenedione in adipose tissue.5
Estriol (E3) is the predominant estrogen in pregnancy, as it is
produced by the placenta.6
about 2 years before the final menstrual period, with maximum
symptoms occurring within the first 2 years after the last period.
The frequency of hot flashes gradually decreases over 6 years;1,7
however, some women experience hot flashes many years after
menopause.
Other associated complaints of menopause, including vaginal symptoms such as dryness, itching, vaginitis and dyspareunia, generally persist or worsen with aging due to low estrogen
levels. Women tend to complain of vaginal symptoms a few years
after the last menstrual period. Unlike hot flashes, vaginal atrophy does not improve over time. Some women notice decreasing
libido and an alteration in sexual function with the onset of
menopause. There is a gradual decline in testosterone production from the ovaries, associated with normal aging; however,
sexual function changes are multifaceted.
Sleep disturbances and mood changes have also been
reported in the menopausal transition and may continue into
early menopause. Stress incontinence, skin changes, memory
and decreased concentration may also occur. Perimenopausal
women can also suffer from premenstrual symptoms (bloating,
water retention) and increase in headaches or migraines. Even
though there is a decline in fertility with perimenopause, pregnancy is a possibility and contraception should be continued. n
Adapted with permission from the following sources:
• Brown TER. Menopause and perimenopause. In: Repchinsky
C, editor. Patient self-care. 2nd ed. Ottawa (ON): Canadian
Pharmacists Association; 2010. p. 811-7.
• Cullimore AJ. Menopause. eTherapeutics [database]. April
2007. Available: www.etherapeutics.ca (accessed Sept. 13,
2010).
Weblinks
• Canadian Menopause Society: www. sigmamenopause.com
• North American Menopause Society: www.menopause.org
• Society of Obstetricians and Gynaecologists of Canada:
www.menopauseandu.ca
GUEST EDITORIAL
Serge Bélisle, MD, MSc
Treating menopause: Our patients and
their caregivers are confused
Canadian women spend one-third of their lives postmenopause. As
a result, the many symptoms that accompany it, as well as agerelated comorbidities, are constant challenges for women’s health
care providers.
Long considered an isolated biological event marked by the
cessation of menstrual cycles, menopause is actually part of a continuous aging process that begins in a woman’s thirties.1-3 Starting
at age 35, a woman’s ovarian follicles become depleted, leading
to granulosa cell dysfunction, resulting in decreased fertility followed by an increase in anovulatory and dysfunctional menstrual
cycles. These types of cycles, which are part of the “transition” or
perimenopausal period, occur several years before menstruation
finally ceases. The same is true of several other endocrine aspects,
particularly the decrease in adrenal androgen production and the
increase in bone resorption, both of which occur 10 to 15 years
before menopause. Therefore, any public health effort aimed at
preventing menopause-related morbidities, such as osteoporosis,
cancer, metabolic syndrome, diabetes and cardiovascular disease,
must begin early in a woman’s reproductive life, unlike in the current clinical situation, where women become aware that they have
entered menopause at a late stage, once hypoestrogenism symptoms have set in. For health care providers, this stage in a woman’s
health requires a specific approach. In addition to treating the
many symptoms, they must detect and treat the morbidities that
can accompany postmenopause.4
Several studies have assessed women’s views and fears regarding menopause.5 Findings suggest that women generally view
menopause in a fairly positive light. The vast majority do not
see menopause as a major health concern or as requiring specific
medical attention. However, more than one-third of women polled
had concerns or even a negative view. This provides an excellent
opportunity for health care providers to develop a partnership with
women at mid-life, involving them in their care and, as necessary,
developing therapeutic plans tailored to their specific needs.
Over the years, clinicians’ opinions on hormone therapy (HT)
have varied greatly, undoubtedly influencing women’s views on
this option.6 HT was initially prescribed in the early 1960s to treat
vasomotor symptoms, but its indications were soon broadened
to include treatment of hormonal deficiencies. With the discovery that estrogen alone resulted in a significant increase in uterine cancer, HT use decreased in the 1970s but rose again in the
1980s, when it was discovered that progestins protect against this
condition. The prevailing view was one of mass prevention, since
epidemiological studies showed a considerable decrease in cardiovascular disease and osteoporosis with the use of HT. Then,
in the late 1990s and early 2000s, the pendulum swung back with
S6 the publication of prospective randomized studies questioning
the cardiovascular benefits and showing an unfavourable global
health index for women using HT compared to women taking a
placebo. Current consensus recommends a therapeutic approach
based on menopause symptoms, using the lowest effective HT
dose for a short term.7 Despite a number of innovations to promote alternative medical treatments, it seems that estrogens are
still the most effective approach.8
What about the future? With human genome sequencing and
the development of proteomic medicine, we will be able to better
tailor our menopause therapy approaches to each patient. Instead
of using a population-based approach, we will be able to pinpoint
the risk factors for individual women using pharmacogenomic
principles to determine in advance those who will respond well
to HT and to predict the expression of toxicological genes responsible for major adverse effects.9 n
Serge Bélisle is an obstetrician-gynecologist and professor in the
Department of Obstetrics and Gynecology at the University of Montreal. Contact: [email protected].
References
1. Soules M, Sherman S, Parrott E, et al. Executive summary: stages of reproductive
aging workshop, Park City, Utah, July 2001. Menopause 2001;8:402-7.
2. Richardson SJ, Nelson JF. Follicular depletion during the menopausal transition.
Ann N Y Acad Sc 1990;592:13-20.
3. Burger HG, Dudley EC, Hopper JL, et al. The endocrinology of the menopausal
transition. J Clin Endocrinol Metab 1995;80:3537-45.
4. ACOG Committee Opinion No. 452. Primary and preventive care: periodic
assessments. Obstet Gynecol 2009;114(6):1444-51.
5. Barbieri RL, Lobo RA, Walsh BW, et al. Improving quality of life during menopause. APGO Educational Series on Women’s Health Issues. Crofton (MD): Association of Professors of Gynecology and Obstetrics; 2002. Available: www.apgo.
org/foundation/index.cfm?cat=educational%20series (accessed Sept. 10, 2010).
6. Shifren JL, Schiff I. Role of hormone therapy in the management of menopause.
Obstet Gynecol 2010;115(4):839-55.
7. Lukes A. Evolving issues in the clinical and managed care settings on the management of menopause following the WHI. J Manag Care Pharm 2008;14(3 suppl):713.
8. Royal College of Obstetricians and Gynaecologists. Alternatives to HRT for the
management of symptoms of the menopause. Scientific Advisory Committee
Opinion Paper 6. May 2006. Available: www.rcog.org.uk/womens-health/clinicalguidance/alternatives-hrt-management-symptoms-menopause (accessed Sept. 7,
2010).
9. Feero WG, Guttmacher AE, Collins FS. Genomic medicine — an updated
primer. N Engl J Med 2010;362(21):2001-11.
CLINICAL REVIEW
Robert L. Reid, MD, FRCSC
Confusion about hormone therapy:
Misinterpretation of the findings
of the Women’s Health Initiative
Since the publication of the first results from the Women’s
Health Initiative (WHI) randomized controlled trial of combined estrogen and progestin therapy in menopausal women in
July 2002, there has been widespread anxiety and outright fear
about the adverse effects of menopausal hormone therapy (HT).
Recent debate and reanalysis have allowed new insights into the
true benefit/risk profile for HT.
Prior to the WHI, the prevailing view was that menopausal
HT was a safe and effective treatment for vasomotor symptoms
(hot flashes and night sweats), sleep disturbance associated
with night sweats, and symptoms of urogenital atrophy (vaginal dryness and dyspareunia). Additional longer-term benefits
were thought to include reduction in bone loss, prevention of
osteoporotic fractures,1 and reduction in cardiovascular disease
(CVD).2 The effects on mood, memory and cognition were less
clear, but observational studies suggested probable benefits.3
A small increase in the risks of venous thromboembolism and
breast cancer4 was acknowledged, but for most the benefits were
thought to outweigh the risks.
The large WHI randomized controlled trial conducted by the
US National Institutes of Health (NIH) emerged from concern
among some researchers that the purported benefits for CVD
prevention might have been a spurious finding, since women who
undertook other health promotion strategies were more likely to
seek HT. This “healthy user” effect could be avoided in a clinical trial where women were randomly assigned to receive either
hormones or placebo. To address the important long-term effects
of HT on CVD and breast cancer, the study would ideally select
large groups of newly menopausal women and follow them for
many years.
Heart disease and breast cancer are uncommon in women
within the first 10 to 15 years after menopause, and recruitment
of sufficient numbers of recently menopausal women willing to
stay on placebo for a decade would be problematic. Estimates
suggested that 186,000 women would have to maintain treatment
for 10 years to detect a 10% difference in rates of CVD between
HT and placebo.5 Another difficulty was the fact that most newly
menopausal women suffer from hot flashes, and half of these
female volunteers would be assigned to placebo. The prospect for
long-term adherence to the assigned treatment was low.
The investigators made a compromise, which at the time
seemed sound, but which after careful scrutiny appears to have
distorted the WHI study results and led to misleading conclusions. They decided to recruit menopausal women up to age 79
Knowledge into practice
• For most women in their early postmenopausal years,
short‑term use (less than 5 years) of hormone therapy (HT)
will not translate into an increased risk of cardiovascular disease
or breast cancer.
• Any increased risk of breast cancer from longer-term use
of combined HT is similar to that from lifestyle factors
such as daily alcohol ingestion, lack of regular exercise and
postmenopausal obesity.
for 2 clinical trials. One trial involved 16,000 women with a uterus
(half were randomly assigned to estrogen and progestin and half
to placebo)6 and the other involved 10,000 women who had had
a hysterectomy (half assigned to estrogen alone and half to placebo).7 Two-thirds of the participants were over the age of 60.
By recruiting older women, the investigators were able to
improve protocol adherence, since few had severe hot flashes
(only 500 women reported hot flashes at enrollment). Because
subclinical CVD increases with time since menopause,8 they presumed it would take less time to see if differences in cardiovascular outcomes would occur. Similarly they would be better able to
study other age-related diseases like osteoporosis, breast cancer
and dementia.
Hormone therapy and cardiovascular disease
Following the first WHI report in 2002, there was extensive
media coverage of the fact that risk for CVD actually increased
for women assigned to receive combined estrogen and progestin.
The risk was not large (6 more cases per 10,000 women per year),
but the publicity triggered a prompt and sustained decline in HT
prescriptions. Doctors became fearful of liability and started recommending complementary and alternative therapies of questionable benefit for vasomotor symptoms instead.9
The basic flaw with the study design was that HT effects differ
according to the status of the woman at the time of initiation. There
is growing evidence that HT in younger, healthy women will prevent atherosclerosis, whereas the initiation of HT in older women
with pre-existing atherosclerosis can trigger a coronary event.10
When the WHI reported the effects of HT on CVD, no distinction
was made about age at initiation, so the findings of the older WHI
population were extrapolated to newly menopausal women.
CLINICAL REVIEW
By analogy, if the WHI investigators were studying the effects
of exercise as a CVD prevention strategy and used the same population of women, it would not be surprising if a few of the women
in their 70s had a heart attack when assigned to run on a treadmill.
Yet this is far from convincing evidence that exercise in younger
women is not an effective strategy to delay CVD development.
An editorial in JAMA subsequently pointed out that, “Women in
their 50s have half the (baseline) risk of women in their 60s and
one-quarter the risk of women in their 70s.”11 There emerged a
growing chorus of criticism of the WHI for extrapolating results
from older women to newly menopausal women seeking relief
from hot flashes.12-15
Finally, in 2007, the WHI published a subgroup analysis that
examined the results of HT on CVD according to age at initiation and years since menopause onset.16 This offered a reassuring
message that only women
in their 70s showed an
increased risk of CVD
after starting HT. Women
started on HT within a
decade of onset of menopause had a reduction in
CVD deaths (1 less CVD
death/1000 women per year). This finding is supported by a
recent meta-analysis of observational trials and randomized controlled trials in which HT was found to reduce cardiovascular
mortality when started in newly menopausal women.17
At the same time, the WHI investigators published 2 other
papers examining the effects of HT on the development of coronary artery calcification as a marker for coronary atherosclerosis.
Both studies demonstrated reduced plaque buildup in women
receiving estrogen therapy.18-19 In one report that examined
plaque buildup after oophorectomy with and without subsequent
estrogen replacement, the authors concluded, “The findings are
consistent with the thesis that the estrogen deficiency associated
with bilateral oophorectomy is related to an increased burden of
calcified plaque in the coronary arteries that can be countered
by HT.”19
Together these observations support the thesis that exposure
of healthy coronary arteries to estrogen will delay plaque development and reduce deaths from CVD,20 quite the opposite of the
2002 message. Unfortunately, this news never received the widespread publicity that characterized the initial worrisome findings.
Women need to
understand that
CVD, not breast
cancer, constitutes
their greatest threat
never-users of HT between the ages of 50 and 70 years. Use of HT
for 5, 10 and 15 years of this 20-year period increased the risk of
breast cancer by 2, 6 and 12 cancers/1000 women, respectively.
The earliest WHI report claimed a 26% increase in the risk
of breast cancer among women who used combined estrogen
and progestin therapy. This number, widely cited by the media,
alarmed many women and their health care providers. However,
it is important to know the baseline risk when examining a percentage increase. Calculation of the attributable risk due to HT
showed that women who used combined estrogen and progestin
therapy had 8 more breast cancers per 10,000 women per year, or
an absolute increase of 0.08%. Careful examination of the actual
WHI publication showed that first-time users of combined HT
actually had no increased risk of breast cancer during the 5.2 years
of follow-up. When the estrogen-only WHI trial results were published in 2004, the WHI investigators reported no increased risk
of breast cancer in women receiving estrogen alone for 6.8 years.
While most published data suggest that combined estrogen
and progestin exposure causes a slight increase in breast cancer
and that estrogen alone has a lesser effect, it is important to place
these risks into perspective. First, women need to understand that
CVD, not breast cancer, constitutes their greatest threat. This differential risk has been well described.21 Between the ages of 50 and
60, 5 women of every 1000 will die from breast cancer, while 55
will die from other causes. Between ages 60 and 70, the numbers
are 7 women of every 1000 for breast cancer deaths and 126 per
1000 for other causes. Between 70 and 80 years, the gap widens
further, with 9 breast cancer deaths per 1000 women compared
to 309 deaths per 1000 women from other causes (mostly CVD).
Any treatment that has a potential protective effect on CVD while
resulting in a very small increase in breast cancer is likely to be
beneficial overall to women’s health.
Second, it is important to put the actual risk of breast cancer
due to HT into perspective with other risk factors. The actual risk
of breast cancer in women who use combined HT for at least 5
years (relative risk [RR] = 1.3) approximates or is less than the
risks women have if they have early menarche (RR = 1.3), late
menopause (RR = 1.2 to 1.5), a first pregnancy after age 30 (RR
= 1.7 to 1.9), excessive alcohol ingestion (RR = 1.2) or postmenopausal obesity (RR = 1.2).22
When presented this way, many women better understand the
level of risk associated with HT and are willing to use the most
effective therapy for relief of distressing vasomotor symptoms at
menopause, if it is appropriate for them. n
Hormone therapy and breast cancer
Breast cancer remains the other big worry for women considering HT. In 1997, the ��
Collaborative Group on Hormonal Factors in Breast Cancer compiled and examined data from more
than 50,000 women with breast cancer and 100,000 controls.4
The investigators found that breast cancer occurred in 45/1000
S8 Robert Reid is a professor of obstetrics and gynaecology and chair,
Division of Reproductive Endocrinology and Infertility at Queen’s
University, Kingston, Ontario. Contact: [email protected].
GUIDELINES
Pharmacist-specific summary of menopause
clinical practice guidelines
The following summary has been adapted with permission from:
• Society of Obstetricians and Gynaecologists of Canada. Menopause and Osteoporosis
Update. JOGC 2009;31(suppl 1). Available: www.sogc.org/guidelines/documents/
Menopause_JOGC-Jan_09.pdf. SOGC
• Estrogen and progestogen use in postmenopausal women: 2010 position statement of
The North American Menopause Society. Menopause 2010;17(2):242-55.
Available: www.menopause.org/PSht10.pdf. NAMS
Introduction
While lifestyle modifications are the mainstay of therapy for
women experiencing menopausal symptoms, most questions
pharmacists receive from clients concern hormone therapy (HT)
and other therapeutic issues. To help pharmacists address these
inquiries, key points from current, evidence-based clinical practice
guidelines are summarized below. For more information, including levels of evidence, please refer to the original documents.
Treatment issues/pretreatment evaluation
NAMS Recognize that a woman’s values, education, needs, preferences and emotions affect the way she considers risk, so data
alone may not influence her.
NAMS HT should be considered only when an indication for
therapy has been clearly identified, contraindications ruled out
and the potential individual benefits and risks adequately discussed with each woman so that an informed decision can be
made. Before initiating HT, a comprehensive history and physical examination are essential. The North American Menopause
Society (NAMS) recommends assessment of risk factors for
stroke, cardiovascular disease (CVD), venous thromboembolism
(VTE), osteoporosis and breast cancer, and discussion of these
results with each woman before initiating therapy. Mammography
should be performed according to national guidelines and age,
but preferably within the 12 months before initiation of therapy.
Other specific examinations, such as bone densitometry, may be
considered on a case-by-case basis.
Timing of initiation
NAMS Emerging data reveal that the timing of HT initiation in
relation to proximity to menopause may be important.
NAMS Women older than age 60 who experienced natural
menopause at the median age and have never used HT will have
elevated baseline risks of CVD, stroke, VTE and breast cancer, and
HT should therefore not be initiated.
NAMS Premature menopause and premature ovarian insufficiency are conditions associated with a lower risk of breast
cancer and earlier onset of osteoporosis and CVD, but there are
Terminology:
Discussion of ET, EPT and HT
refers to commercially prepared,
Health Canada–approved
formulations.
no clear data as to whether estrogen therapy (ET) or estrogenprogestin therapy (EPT) will affect morbidity or mortality from
these conditions.
NAMS Younger women with premature menopause might also
require higher doses of HT for menopause symptom relief than
the doses currently recommended for women ages 50 to 59.
Progestin indication
NAMS All women with an intact uterus who use systemic ET
should also be prescribed adequate progestin. Postmenopausal
women without a uterus should not be prescribed a progestin
with systemic ET. A progestin is generally not indicated when ET
at the recommended low doses is administered locally for vaginal
atrophy. Concomitant progestin may improve the efficacy of lowdose ET in treating vasomotor symptoms.
Individualization of therapy is key
NAMS An individual risk profile is essential for every woman
contemplating any regimen of HT. Moreover, because incidence
of disease outcomes increases with age and time since menopause,
the benefit-risk ratio for HT is more likely to be acceptable for
short-term use for symptom reduction in a younger population.
NAMS When HT is desired by patients, individualization of
therapy is key to providing health benefits with minimal risks,
thereby enhancing quality of life.
Vasomotor symptoms
SOGC Lifestyle modifications, including reducing core body
temperature, regular exercise, weight management, smoking
cessation, and avoidance of known triggers such as hot drinks
and alcohol, may be recommended to reduce mild vasomotor
symptoms.
NAMS ET, with or without a progestin, is the most effective
treatment for menopause-related vasomotor symptoms (e.g., hot
flashes and night sweats) and their potential consequences (e.g.,
diminished sleep quality, irritability and reduced quality of life).
Treatment of moderate to severe vasomotor symptoms remains
the primary indication for HT. Every systemic ET and EPT prod-
GUIDELINES
uct has regulatory agency approval for this indication.
SOGC Progestins alone or low-dose oral contraceptives can be
offered as alternatives for the relief of menopausal symptoms during the menopausal transition.
SOGC Nonhormonal prescription therapies, including treatment
with gabapentin, clonidine, Bellergal or certain antidepressant
agents, may afford some relief from hot flashes, but have their
own side effects. These alternatives can be considered when HT
is contraindicated or not desired.
SOGC There is limited evidence of the benefit of most complementary and alternative approaches to the management of hot
flashes. Without good evidence for effectiveness, and in the face
of minimal data on safety, these approaches should be recommended with caution. Women should be advised that most have
not been rigorously tested for the treatment of moderate to severe
hot flashes, and many lack evidence of efficacy and safety. (See
article on page S22.)
SOGC Any unexpected vaginal bleeding that occurs after 12
months of amenorrhea is considered postmenopausal bleeding
and should be investigated.
SOGC Following treatment of adenocarcinoma of the endometrium (stage 1), ET may be offered to women distressed by moderate to severe menopausal symptoms.
Urogenital concerns
SOGC Routine progestin cotherapy is not required for endometrial
protection in women receiving vaginal ET in appropriate dose.
SOGC Lifestyle modification, bladder drill and antimuscarinic
therapy are recommended for the treatment of urge urinary
incontinence.
SOGC As part of the management of stress incontinence, women
should be encouraged to try nonsurgical options, such as weight
loss (in obese women), pelvic floor physiotherapy, with or without
biofeedback, weighted vaginal cones, functional electrical stimulation and/or intravaginal pessaries.
SOGC ET should not be recommended for the treatment of
postmenopausal urge or stress urinary incontinence but may be
recommended before corrective surgery.
SOGC Vaginal ET can be recommended for the prevention of
recurrent urinary tract infections in postmenopausal women.
NAMS When HT is used for systemic vasomotor symptoms,
enquiry about the adequacy of therapy for urogenital atrophy is
important. When HT is considered solely for urogenital atrophy,
local vaginal ET is generally recommended.
NAMS ET is the most effective treatment for moderate to severe
symptoms of vulvar and vaginal atrophy (e.g., vaginal dryness,
dyspareunia and atrophic vaginitis).
SOGC Conjugated estrogen cream, an intravaginal sustainedrelease estradiol ring or estradiol vaginal tablets are recommended
as effective treatment for vaginal atrophy.
SOGC Vaginal lubricants may be recommended for subjective
symptom improvement of dyspareunia.
S10 SOGC Health care providers can offer polycarbophil gel (a vaginal moisturizer) as an effective treatment for symptoms of vaginal
atrophy, including dryness and dyspareunia.
Sexual concerns
SOGC A biopsychosexual assessment of preferably both partners
(when appropriate), identifying intrapersonal, contextual, interpersonal and biological factors, is recommended prior to treatment of women’s sexual problems.
SOGC Routine evaluation of sex hormone levels in postmenopausal women with sexual problems is not recommended. Available androgen assays neither reflect total androgen activity, nor
correlate with sexual function.
SOGC Testosterone therapy, when included in the management
of selected women with acquired sexual desire disorder, should
only be initiated by clinicians experienced in women’s sexual dysfunction and with informed consent from the woman. The lack of
long-term safety data and the need for concomitant ET mandate
careful follow-up.
Mood, memory and cognition
SOGC Estrogen alone may be offered as an effective treatment for
depressive disorders in perimenopausal women and may augment
the clinical response to antidepressant treatment, specifically with
selective serotonin reuptake inhibitors. The use of antidepressant
medication, however, is supported by most research evidence.
SOGC Estrogen can be prescribed to enhance mood in women
with depressive symptoms. The effect appears to be greater for
perimenopausal symptomatic women than for postmenopausal
women.
NAMS Although HT might have a positive effect on mood and
behaviour, it is not an antidepressant and should not be considered as such.
SOGC ET is not currently recommended for reducing the risk of
dementia developing in postmenopausal women or for retarding
the progression of diagnosed Alzheimer’s disease, although limited data suggest that early use of HT in the menopause may be
associated with diminished risk of later dementia.
Dosages
NAMS The lowest effective dose of estrogen consistent with treatment goals, benefits and risks for the individual woman should be
the therapeutic goal, with a corresponding low dose of progestin
added to counter the adverse effects of systemic ET on the uterus.
Lower HT doses are better tolerated and may have a more favourable benefit-risk ratio than standard doses.
NAMS Some women may require additional local ET for persistent vaginal symptoms while on systemic therapy.
Duration of use
NAMS Provided that the lowest effective dose is used, that the
woman is well aware of the potential benefits and risks, and that
GUIDELINES
there is clinical supervision, extending HT use for an individual
woman’s treatment goals is acceptable under some circumstances,
including:
• The woman for whom, in her own opinion, the benefits of
menopause symptom relief outweigh risks, notably after failing
an attempt to stop HT
• The woman with established reduction in bone mass for whom
alternate therapies are not appropriate or cause unacceptable side
effects, or the benefit-risk ratio of extended use is unknown.
Symptom recurrence
NAMS Vasomotor symptoms have an approximately 50% chance
of recurring when HT is discontinued, independent of age and
duration of use. The decision to continue HT should be individualized on the basis of severity of symptoms and current benefitrisk ratio considerations, provided the woman in consultation
with her health care provider believes that continuation of therapy
is warranted.
Discontinuance
NAMS Current data suggest that the rates of vasomotor symptom recurrence are similar when HT is either tapered or abruptly
discontinued. No recommendation can be made as to how to discontinue therapy.
SOGC If prescribing HT to older postmenopausal women, health
care providers should address cardiovascular risk factors; low- or
ultralow-dose estrogen therapy is preferred.
SOGC Health care providers may prescribe HT to diabetic
women for the relief of menopausal symptoms.
Osteoporosis
(Watch for our next supplement on osteoporosis, Spring 2011.)
NAMS No HT product has regulatory agency approval for treatment of osteoporosis. Many systemic HT products, however, have
regulatory agency approval for prevention of postmenopausal
osteoporosis through long-term treatment.
NAMS The benefits of HT on bone mass dissipate quickly after
discontinuation of treatment.
Endometrial cancer
NAMS Unopposed systemic ET in postmenopausal women with
an intact uterus is associated with increased endometrial cancer
risk related to the ET dose and duration of use.
NAMS To negate this increased risk, adequate concomitant progestin is recommended for women with an intact uterus when
using systemic ET (see progestin indication). HT is not recommended in women with a history of endometrial cancer.
Change in body weight/mass
Hormone therapy and breast cancer
(See article on page S7.)
SOGC Health care providers may prescribe HT for menopausal
symptoms in women at increased risk of breast cancer with appropriate counselling and surveillance.
SOGC Health care providers should periodically review the risks
and benefits of prescribing HT to a menopausal woman in light
of the association between duration of use and breast cancer risk.
SOGC Health care providers should clearly discuss the uncertainty of risks associated with HT after a diagnosis of breast cancer
in women seeking treatment for distressing symptoms.
Cardiovascular disease
NAMS HT is currently not recommended as a sole or primary
indication for coronary protection in women of any age. Initiation of HT by women ages 50 to 59 years or by those within 10
years of menopause to treat typical menopause symptoms (e.g.,
vasomotor, vaginal) does not seem to increase the risk of CVD
events. There is emerging evidence that initiation of ET in early
postmenopause may reduce CVD risk.
SOGC Health care providers should initiate other evidence-based
therapies and interventions to effectively reduce the risk of CVD
events in women with or without vascular disease.
SOGC Health care providers should abstain from prescribing HT
in women at high risk for venous thromboembolic disease.
SOGC Risk factors for stroke (obesity, hypertension and cigarette
smoking) should be addressed in all postmenopausal women.
NAMS No statistically significant difference in mean weight gain
or body mass index has been demonstrated between women who
use HT and those who do not.
Premature menopause and premature ovarian
insufficiency
NAMS Women experiencing premature menopause (#40 years)
or premature ovarian insufficiency are medically a distinctly different group than women who reach menopause at the median
age of 51.3 years. Premature menopause and premature ovarian
insufficiency are associated with a lower risk of breast cancer and
earlier onset of osteoporosis, CVD, Parkinson’s disease; premature bilateral oophorectomy is possibly associated with cognitive
decline as well. There are inadequate data regarding HT in these
populations. Most observational reports suggest an increased risk
of CVD with early natural or surgical menopause in the absence
of HT and a protective effect of HT when HT is administered. The
existing data regarding HT in women experiencing menopause at
the median age should not be extrapolated to women experiencing premature menopause and initiating HT at that time. The
risks attributable to HT use by these young women receiving HT
may be smaller and the benefits potentially greater than those in
older women who commence HT at or beyond the median age of
menopause, although no comparative data exist.
SOGC HT should be offered to women with premature ovarian
failure or early menopause, and it can be recommended until the
C P J / R P C • N OV E M B E R / D E C E M B E R 2 0 1 0 • VO L 1 4 3 [ S U P P L 2 ] Continued on page S23
S11
PHARMACOTHERAPY
Thomas E.R. Brown, PharmD
Practical issues in hormone therapy
management
There are many different types of hormone therapy (HT) products available in Canada that contain various
estrogens and progestins. They are available in a wide variety of formulations, doses and routes of administration. There
are significant differences in the pharmacological action of the hormones and on surrogate endpoints, depending on
routes of administration. Overall clinical outcomes may be similar between the agents; however, large inter- and intrapatient variability between products requires individualization of pharmacotherapy to optimize patient outcomes and
quality of life. (See page S14.)
Types of estrogen
Commercially available HT products primarily contain
17b-estradiol or estrone, which makes it possible to select
hormones chemically identical to those produced by women.
Conjugated equine estrogens (CEE) come from animal sources,
whereas the other estrogens, including conjugated estrone sulfate and estradiol, are derived from plants. Estriol is used in some
compounded products; however, due to lack of evidence of benefit and safety, the US Food and Drug Administration requires
pharmacies that compound estriol to have an investigational
new drug authorization. While no such requirement exists in
Canada, products containing estriol cannot currently be recommended because of the lack of evidence.
Estrogens are large molecules easily broken down by the
digestive tract, so to maximize bioavailability they need to be
altered for administration (e.g., estrone can be conjugated, estradiol can be micronized). While there are no clinically significant
differences between estrogens used in HT, individuals may experience different side effects with different estrogens; therefore, if
a patient is having difficulty with one type it would be reasonable
to try a different type of estrogen before abandoning HT.
Types of progestin
A woman’s body produces only one type of progestin and that
is progesterone. While most of the commercially available HT
products contain synthetically derived progestins, oral micronized progesterone (OMP) is chemically identical to that produced by a woman. There are some significant differences
between the progestins that are available. OMP can cause sedation, improve sleep hygiene and does not appear to blunt the
positive effects of oral estrogens on high-density lipoprotein
(HDL) cholesterol.1-3 Other progestins have not been shown to
have these pharmacological properties. Drospirenone’s antimineralocorticoid activity, in addition to its progestational action,
results in diuretic effects.
Regimens
Estrogens in HT provide symptomatic relief of menopausal
S12 symptoms. Progestins are included to protect the endometrial
lining from being over-stimulated by estrogen; their only role
in HT is to prevent endometrial hyperplasia and uterine cancer. Estrogens can be used by themselves if a woman has had a
hysterectomy.
There are primarily 2 different regimens for HT, with several
variations. Regardless of regimen, estrogen should always be
dosed in a continuous (daily) manner. There is no physiological
need to cycle estrogen therapy for 21 days with 7 days off, which
could result in the return of menopausal symptoms in the pillfree period. Continuous-cyclic HT regimens provide estrogen
daily and a progestin for at least 12 to 14 days each month, which
often results in a regular monthly menstrual-like withdrawal
period. The bleeding is predictable, usually after the 10th day
of progestin therapy. If bleeding occurs prior to the 10th day of
progestin therapy, a woman should be advised to consult her
physician to undergo endometrial surveillance.4 Some women
may not bleed, depending on the dose of estrogen or the type of
progestin administered. Long-cycle regimens in which progestin
is given less often than monthly (e.g., once every 3 months) are
not routinely recommended, as endometrial safety has not been
established. If long-cycle regimens are used, patients should have
regular endometrial surveillance and any intra-cycle spotting or
bleeding should be reported to a physician.
Continuous-combined HT regimens provide both an estrogen and a progestin daily. Patients on this type of regimen may
initially experience unpredictable spotting or bleeding, amenorrhea or full periods. While the bleeding may be a nuisance,
it is not a medical concern until after 12 months of therapy, at
which time the woman should be referred to a physician for
endometrial surveillance.5
Doses
The lowest possible dose of estrogen (e.g., 0.3 mg CEE or 0.5
mg 17b-estradiol) to alleviate menopausal symptoms should
be used, but there is no conclusive data that lower doses have
better safety profiles than standard doses. Oral estrogens may
be administered every other day and estrogen-only transder-
mal matrix patches may be cut as long as they remain effective.
Progestins are dosed differently, depending on the regimen with
cyclic regimes requiring larger doses than continuous doses. The
amount of progestin also depends on the amount of estrogen.
Larger estrogen doses (standard dose is 0.625 mg CEE or equivalent) may stimulate the endometrial lining to a greater extent
and therefore require higher doses of progestin for protection.
Progestin doses are usually doubled if larger than standard doses
of estrogen are used.
Routes of administration
Oral estrogens have a significant first-pass effect on the liver
resulting in metabolic changes not seen with transdermal or
vaginal therapy (Table 1).6-9
TABLE 1
forms
Comparison of estrogen dosage
Oral estrogens
Transdermal estrogens
• \ clotting factors,
triglycerides and HDL
cholesterol
• Can exacerbate
gallbladder disease
• Metabolized more
rapidly by smokers
due to enzyme
induction
• Do not ↑ triglycerides
• Minimal effects on HDL cholesterol
• Do not appear to exacerbate
gallbladder disease
• Less effect on clotting factors
• Less risk of VTE (observational
data)
• RCT data not available
• Adverse effects include skin
irritation
• May benefit women with
malabsorption conditions
The vaginal estrogen ring and tablet have minimal systemic
absorption at usual doses, so they have little potential to stimulate the endometrium and do not require progestin. The risk
for patients with breast cancer is still unclear, but lower-dose
formulations of vaginal estrogen tablets are being brought to
market. The vaginal estrogen cream used daily at standard doses
can have significant systemic absorption and may require progestin therapy or endometrial surveillance.10 Lower doses may
not require progestin therapy.
There are generally no significantly different metabolic effects
between the routes of progestin therapy, except with OMP
administration. OMP does not cause sedation when administered vaginally, whereas oral administration may produce significant sedation.
Initiating therapy
Initial HT therapy should be selected using an individual woman’s risk benefit profile and her personal preferences. Oral or
transdermal therapy may be used to treat systemic symptoms,
whereas vaginal therapy may be considered if urogenital symptoms are the primary concern. Choosing the estrogen dose may
appear challenging. Most individuals want to start with the lowest dose possible and then increase the medication slowly. The
opposite approach may be more successful. Start with standard
doses to get control of symptoms and then taper to the lowest
effective dose. Estrogen and progestin can be started at the same
time when using continuous regimens. In cyclic therapy, estrogen may be given alone (up to 3 to 4 weeks) before progestin.
Vasomotor symptoms should start to resolve within 2 weeks of
initiation, whereas vaginal symptoms may take up to 3 months.
Patients may find it takes longer to see benefits from lower doses.
Up to 40% of patients may continue to experience urogenital
symptoms while taking oral HT and may require concomitant
vaginal estrogen therapy. Note that randomized controlled trial
results should not be extrapolated to premature menopause.
Women experiencing induced menopause can initiate therapy
as above. Perimenopausal women experiencing symptoms can
be offered low-dose oral contraceptives.
Adjusting therapy
It is important to find a balance between symptom control and
adverse effects. Dose-related side effects of estrogen include nausea, headache and breast tenderness (see table on page S14). These
adverse effects may resolve over time as the body gets used to HT
or the dose of estrogen may need to be decreased if the patient’s
quality of life is negatively affected. It is difficult to decrease progestin, as doses need to be maintained to ensure endometrial
protection. If a woman is experiencing mood swings, bloating
or irritability, trying a different type of progestin or route of
administration would be a reasonable approach.
Duration of therapy
There is no absolute length of time for which the risk of taking HT outweighs the benefit. Given the risks of breast cancer,
stroke, cardiovascular disease and venous thromboembolism, a
woman should take HT for the shortest possible length of time.
The decision to continue HT should be individualized and based
on the severity of symptoms and the patient’s current riskbenefit ratio.11
Discontinuation of therapy
HT may be either tapered or abruptly discontinued, according to
patient preference. If it is tapered, only the estrogen component
should be gradually reduced in dose or frequency, as the progestin is required for endometrial protection. Once the estrogen
dose is discontinued, the progestin agent may also be stopped. n
Thomas Brown is Director of Pharmacy Services, Women’s College Hospital, Toronto, Ontario. Contact: [email protected].
PHARMACOTHERAPY
TABLE 1
Hormonal therapies for the relief of menopausal symptoms
The following table was created by Melanie Trinacty, Anne Marie Whelan and Tannis M. Jurgens, with supplemental information
used by permission from Cullimore AJ. Menopause. Available: www.etherapeutics.ca (accessed Oct. 21, 2010).
Drug
Active
ingredient source
Dose
Available strengths
conjugated estrogen†
Premarin
0.3–1.25 mg po daily
0.3, 0.625 and
1.25 mg tablets
conjugated estrogen sulfate§
CES, generics
0.3–1.25 mg po daily
0.3, 0.625, 0.9 and
1.25 mg tablets
17b-estradiol micronized
Estrace
0.5–2 mg po daily
0.5, 1 and 2 mg
17b-estradiol, patch
Climara, Estraderm,
Estradot, Oesclim, generics
Climara: 1 patch applied weekly
Estraderm, etc.: 1 patch 2x/wk
17b-estradiol, topical gel
Estrogel
Climara: 0.025, 0.05, Plant2
0.075, 0.1 mg/d
Estraderm: 25, 50,
100 µg/d
Estradot: 25, 37.5, 50,
75, 100 µg/d
Oesclim: 25, 50 µg/d
0.06%–2.5 g of gel
Plant2
(1.5 mg estradiol)
0.75 mg estradiol per 1.25 g
metered dose actuation:
0.75–1.5 mg (1–2 actuations)
applied to arms, abdomen or
thighs daily (always in same spot)
Patch should be applied 2x/wk,
4, 6, 8 mg patches
Synthetic‡
i.e., changed once every 3-4 d3
corresponding to 50,
75, 100 µg/d
Bio-identical?* Adverse effects/Notes
Estrogens, oral
From natural
No
sources, blended
to represent the
average composition
of material derived
from pregnant
mares’ urine3
Equine2, ‡
Plant sterols1
No
Bloating, headache,
nausea, breast tenderness,
dose‑related bleeding
Soybeans1
Yes
See above
Yes
Bloating, headache,
dose‑related bleeding,
redness, skin irritation.
Estraderm is a reservoir
patch; the others are matrix
patches
Bloating, headache,
dose‑related bleeding,
redness, skin irritation
See above
Estrogens, transdermal
17b-estradiol (estradiol
hemihydrate)1
Sandoz-Estradiol Derm
(patch)1
Yes
Yes
Estrogens, vaginal
conjugated estrogen,† vaginal 0.5 mg daily for 2 wks then q2-3d 0.625 mg/g
cream
Premarin
17b-estradiol, vaginal ring
Estring
17b-estradiol, vaginal tablet
Vagifem
estrone 0.1%3
Estragyn, Neo-Estrone
(vaginal cream)3
Progestins, oral
medroxyprogesterone acetate
Provera, Provera Pak
Insert 1 ring vaginally every
3 months; delivers 7.5 µg estradiol
over 24-h period at a sustained
rate for up to 12 wks
1 tablet daily x 2 wks, then 1 tablet
2x/wk
2-4 g intravaginally/d adjusted to
the lowest amount that controls
symptoms; daily for 2 wks then
q2-3d; there is 1 mg of estrone per
1 g of cream‡
2 mg vaginal
Plant2
ring (7.5 µg of
17b-estradiol per
day)
10, 25 µg vaginal
Plant1
tablets1
0.1% w/w Estrone
Plant (soy)‡
Vaginal Cream
(1 mg of estrone per
1 g of cream)
In combination with estrogen in 2.5, 5, 10, 100 mg
patients with a uterus: 5-10 mg po tablets
daily cyclically or 2.5 mg daily
for low to standard estrogen
doses, 5 mg for higher doses
(>0.625 mg CE or equivalent).
For prevention of hot flashes:
20 mg po daily
medroxyprogesterone acetate 5-10 mg daily for 12-14 d3
Apo-medroxy: 2.5, 5,
Apo-medroxy,3
10 mg tablets
Teva-medroxyprogesterone,‡
Teva: 2.5, 5, 10,
pms-medroxyprogesterone3
100 mg tablets
S14 Equine2
No
Yes
Yes
Vaginal secretion, discomfort
Yes
Provera: Synthetic1
Provera Pak:
Soybeans1
Soybeans3
Local burning, irritation,
vaginal leakage. Can be
used daily or as directed
intravaginally or topically.
Progestins needed if used
daily
Spotting, discharge, genital
pruritus
Bloating, irritability, weight
gain, mood swings
No
PHARMACOTHERAPY
Drug
Dose
megestrol acetate
Megace, generics
norethindrone
Micronor
progesterone, micronized
Prometrium
For prevention of hot flashes:
20 mg po daily
0.35–0.7 mg po daily continuously
In combination with estrogen
in patients with a uterus:
200–300 mg po at bedtime
cyclically or 100–200 mg po
at bedtime continuously
Available strengths
Active
ingredient source
Bio-identical?* Adverse effects/Notes
gain, mood swings
See above
100 mg capsules
Plant2
Yes
See above. Contains peanut
oil. Better side effect profile
and beneficial effect on sleep
Progestins, intrauterine system (IUS)
levonorgestrel
Mirena
52 mg/IUS
Combined estrogens and progestins, oral
estradiol hemihydrates/
In patients with uterus:
norethindrone acetate
1 mg/0.5 mg tablet daily,
Activelle
continuously
gain and mood swings
(to a lesser extent compared
to medroxyprogesterone
acetate)
Estradiol: Plant‡
NA: Synthetic1
Estradiol: Yes
NA: No
17b-estradiol 0.5 mg; Estradiol: Plant‡
NA: Synthetic1
NA 0.1 mg
Estradiol: Yes
NA: No
17b-estradiol 1 mg;
NA 0.5 mg
estradiol hemihydrates/
norethindrone acetate
Activelle LD
17b-estradiol/drospirenone
Angeliq
0.5 mg/0.5 mg tablet daily,
continuously
1 mg/1 mg tablet daily,
continuously
conjugated estrogen† /
medroxyprogesterone acetate
Premplus
In patients with uterus: 0.625 mg CE 0.625 mg,
CE daily for first 14 d of cycle,
MPA 2.5 mg or CE
then 0.625 mg CE plus MPA
0.625 mg, MPA 5 mg
(2.5 mg or 5 mg) daily for the last
14 d of cycle
ethinyl estradiol3/
0.5 mg/2.5 mg once daily3
norethindrone acetate3
femHRT3
Combined estrogens and progestins, transdermal
17b-estradiol/norethindrone In patients with uterus: 1
patch applied twice weekly
acetate
(delivers 50 µg 17b-estradiol
Estalis
plus 140 µg norethindrone or
50 µg 17b-estradiol plus 250 µg
norethindrone acetate/d)
17b-estradiol/levonorgestrel
Climara Pro
In patients with uterus: 1 patch
applied once weekly (delivers
45 µg 17b-estradiol and 15 µg
levonorgestrel/d)
17b-estradiol 1 mg;
DRSP 1 mg
Estradiol: Synthetic‡ Estradiol: Yes
DRSP: Synthetic1
DRSP: No
CE: natural sources, CE: No
blended to represent MP: No
the average
composition of
material derived
from pregnant
mares’ urine3
CE: Equine2,‡
MPA: Synthetic2
EE 2.5 µg, NA 0.5 mg EE: Synthetic3
No
or EE 5 µg, NA 1 mg NA: Synthetic2
Estradiol 50 µg/d, NA Estradiol: Plant2
140 µg/d or estradiol NA: Synthetic2
50 µg/d, NA 250 µg/d
Estradiol: Yes
NA: No
Estradiol 45 µg/d,
levonorgestrel
15 µg/d
Estradiol: Yes
Levonorgestrel:
No
Breakthrough bleeding/
spotting, nausea/vomiting,
bloating, chloasma, breast
tenderness, mood changes
such as depression, headaches
See above
See above. Risk of
hyperkalemia in patients
prone to ↑ K+ (e.g., renal
disease, concomitant ACEI,
ARB, potassium-sparing
diuretics, NSAID). Check K+
after 1st cycle
See above
Breakthrough bleeding/
spotting, nausea/vomiting,
bloating, chloasma,
breast tenderness, mood
changes such as depression,
headaches, redness, skin
irritation. Matrix patch
See above
Note: For information on combined oral hormonal contraception, please see: Graves G. Contraception. Available: www.etherapeutics.ca (accessed Oct. 21, 2010).
* Bioidentical hormones are chemical substances identical in molecular structure to human hormones.
† Conjugated estrogen contains a mixture of estrone, equilin, 17a-dihydroequilin, 17a-estradiol, 17b-dihydroequilin, d8,9-dehydroestrone, 17-estradiol,
equilenin, 17a-dihydroequilenin, 17b-dihydroequilenin as salts of their sulfate esters.
‡ Personal communication with manufacturer to verify or obtain information not found in other sources (telephone calls made July 14-20, 2010).
§ Conjugated estrogen sulfate contains estrone, equilin, 17a-dihydroequilin, 17a-estradiol, equilenin and 17a-dihydroequilenin as salts of their sulfate esters.
Abbreviations: CE = conjugated estrogen; DRSP = drospirenone; EE = ethinyl estradiol; MPA = medroxyprogesterone acetate; NA = norethindrone acetate.
References
1. eCPS Drug Monographs. Available: www.etherapeutics.ca (accessed Aug. 12, 2010).
2. Postmenopausal Pharmacotherapy Comparison Chart — RxFiles. Available: www.rxfiles.ca/rxfiles/uploads/documents/members/CHT-PostmenopausalRxandHerbal.pdf (accessed Aug. 12, 2010).
3. Health Canada Product Monographs. Available: http://webprod.hc-sc.gc.ca/dpd-bdpp (accessed Aug. 12, 2010).
PHARMACOTHERAPY
TABLE 2
Nonhormonal therapies for the relief of menopausal symptoms
Adapted with permission from Cullimore AJ. Menopause. Available: www.etherapeutics.ca (accessed Oct. 21, 2010).
Drug
Dose
Adverse effects
Comments
0.05 mg po bid
Dizziness, dry
mouth, drowsiness,
constipation
Indicated for the treatment of vasomotor symptoms in patients who do not want
to take or cannot take estrogens. Discontinue if no benefit after 2-4 wks or side
effects. Monitor blood pressure with concomitant use of other antihypertensives.
1 tablet po in the
morning and 1
tablet po in the
evening
Max: 16 tabs/wk
Dizziness, dry
mouth, drowsiness,
constipation
Indicated for the treatment of vasomotor symptoms in patients who do not
want to take or cannot take estrogens. Avoid in combination with CYP3A4
inhibitors, e.g., erythromycin, clarithromycin, ritonavir, nelfinavir, ketoconazole,
itraconazole.
Alpha2-adrenergic agonists
clonidine
Dixarit, generics
Ergot combination products
ergotamine/belladonna
alkaloids/phenobarbital
Bellergal Spacetabs
Gamma aminobutyric acid derivatives
gabapentin
Neurontin, generics
300 mg po tid
Somnolence, dizziness For vasomotor symptoms in patients who do not want to take or cannot take
estrogens. Start at 300 mg daily and ↑ to 300 mg tid over 3-7 d. Discontinue over
a 1-wk period.
Lubricants, vaginal
vaginal gels or jelly
K-Y Jelly, Gynemoistrin,
Astroglide
Apply when needed
Provides rapid, short-term relief. Can be applied to the opening of vagina to
decrease discomfort in dyspareunia.
Apply 2-3 x/wk
Provides longer duration of action than vaginal lubricants. Used on a continuous
basis. Replens was equivalent to local hormone therapy for improvement of
dyspareunia. Provides long-term relief (2-3 d) of vaginal dryness by changing
fluid content of epithelium and lowering vaginal pH.
Moisturizers, vaginal
polycarbophil gel
Replens
Serotonin-norepinephrine reuptake inhibitors
venlafaxine
Effexor XR, generics
37.5-75 mg daily
Gastrointestinal upset, Not an approved indication for the treatment of vasomotor symptoms.
nervousness, insomnia For vasomotor symptoms in patients who do not want to take or cannot take
estrogens. Start with 37.5 mg daily and ↑ to 75 mg daily after 1 wk, if necessary.
Higher doses are not useful for the treatment of vasomotor symptoms and are
associated with side effects. Results may take 2-3 wks. Taper gradually when
stopping.
Selective serotonin reuptake inhibitors
fluoxetine
Prozac, generics
12.5-25 mg po daily Gastrointestinal upset, Not an approved indication for the treatment of vasomotor symptoms.
nervousness, insomnia For vasomotor symptoms in patients who do not want to take or cannot take
estrogens. Results may take 2–3 wks. Taper gradually when stopping.
Avoid combination with sibutramine. May ↓ efficacy of tamoxifen.
20 mg po daily
See above
Not an approved indication for the treatment of vasomotor symptoms.
For vasomotor symptoms in patients who do not want to take or cannot take
estrogens. Results may take 2–3 wks. Avoid combination with sibutramine.
May ↓ efficacy of tamoxifen.
\
paroxetine
Paxil CR
Note: A systematic review showed reduced frequency and severity of menopausal hot flashes with paroxetine, venlafaxine, clonidine and gabapentin in
highly symptomatic women. Their use may be limited by side effects. Clonidine, a centrally acting antihypertensive, and a combination product containing
phenobarbital, ergotamine and belladonna (Bellergal Spacetabs), are indicated for the relief of hot flashes, but are associated with side effects. For more
information, see: Cullimore AJ. Menopause. Available: www.etherapeutics.ca (accessed Oct. 21, 2010).
CLINICAL BRIEF
Bioidentical hormone therapy:
A practical review for pharmacists
Nesé Yuksel, BScPharm, PharmD, ACPR, FCSHP, NCMP; Mary Gunther, BScPharm, ACPR
Definition of bioidentical hormones
Much confusion surrounds the term “bioidentical hormone”
(BH). The Food and Drug Administration (FDA) in the United States does not recognize the term and there are claims it is
not even a medical term.1,2 Several medical dictionaries do not
provide definitions.3,4 Despite this, there are many definitions
in the popular press and the scientific literature, including position and policy papers from various health organizations.5-7
Most agree that BHs are identical to human hormones; however, the description and origin of the BH varies considerably.
Some definitions state BHs are “natural,” which can vary in
interpretation from having a natural source such as a plant, to
implying that using BHs is a more natural and therefore safer
approach. This lack of consensus creates significant confusion
for both the medical community and the general public.
The following definition reflects the commonalities among
definitions and illustrates what make BHs unique: “BioidentiMany women stopped using hormone therapy (HT) after the
2002 publication of the Women’s Health Initiative (WHI)
results.1,2 Lately, there has been a resurgence of HT use, but in
“bioidentical” form.
Estrogen
There are 3 endogenous estrogens: estradiol, estrone and estriol.
Estradiol, the most potent, is produced by the ovaries and is
reversibly metabolized to estrone in the liver. Both estradiol and
estrone are metabolized to estriol, the weakest and shortest-acting
estrogen.3 Like all hormones, estrogens act as either agonists or
antagonists at specific receptors. Estrogen receptors occur in 2
main subtypes, a and b, with differing distributions in the body.
Estrogen receptor a is largely found in the endometrium, breast
cancer cells and ovarian stroma cells, whereas estrogen receptor b
is found in the kidney, intestinal mucosa, lungs, bone and brain.4
Progesterone
Endogenous human progestogens occur in only one form as
progesterone. Its various actions occur through interactions
with progesterone receptors. Progesterone receptor activation
can suppress gene transcription, reducing the activity of estrogen, androgen, glucocorticoid and mineralocorticoid receptors.
Progesterone exerts strong antiestrogenic activities in the endometrium and cervix, yet enhances estrogen-induced proliferation of breast tissue.5
cal hormones are chemical substances identical in
molecular structure to human hormones.”
Examples of BHs used for the management of menopauserelated symptoms include estriol, estradiol, estrone and progesterone, all of which are identical in molecular structure to
human hormones. BHs are available in a variety of forms. They
can be custom-compounded into preparations for specific patients by pharmacists in compounding pharmacies. They are
also available to consumers in commercial products approved
by Health Canada (see table, page S14).
— Melanie Trinacty, BSc, BScPharm; Anne Marie Whelan, PharmD,
FCSHP; Tannis M. Jurgens, PhD. From the College of Pharmacy at
Dalhousie University, Halifax, NS. Funding for Ms. Trinacty was
provided by the Dalhousie Pharmacy Endowment Fund.
Why the controversy?
Bioidentical hormones are believed to be more “natural”
Describing bioidentical hormones as more “natural” can be misleading. While derived from plant sources such as soy or wild yam,
they are still converted through a synthetic process to a chemical
structure similar to the body’s hormones. No bioidentical hormone therapy (BHT) used to treat menopausal symptoms is truly
100% natural.6
Confusion with the term
Even though many commercial hormone therapy products can be
considered bioidentical, the term BHT is often used to describe
compounded hormone preparations containing estriol, estradiol,
estrone, progesterone or testosterone. Additionally, BHT often
refers to the process of tailoring a patient’s therapy by determining salivary hormone levels, then replacing “deficient” hormones
in precise amounts individualized to the patient. The evidence to
support the practice of basing HT on saliva levels is unclear.
Compounded BHT
Any of the hormones can be compounded to provide a variety of
doses and administration routes (e.g., capsules, troches). The most
commonly compounded preparations contain formulations with
estriol or the use of natural progesterone creams. Estriol is commercially available in some European countries, but in Canada it
is available only in compounded preparations. Estriol products
CLINICAL BRIEF
• All hormone therapy, bioidentical or otherwise, has benefits and
risks; base the decision to initiate on a careful weighing of individual needs.
• Patient symptoms should guide treatment initiation and dosing
changes.
• Until larger-scale studies prove otherwise, the generalized efficacy
and safety profiles should apply equally to both commercial HT
and compounded BHT.
• In women receiving estrogen supplementation, there is inadequate evidence to support the use of transdermal progesterone
cream in providing endometrial protection.
• If patients or prescribers want to use BHT, there are many Health
Canada–approved, commercially prepared bioidentical formulations available.
• If patients choose to use a compounded preparation, they should
ensure they are receiving the product from a pharmacy with a
quality assurance process in place.
are usually compounded as a combination of either 3 estrogens
(Tri-Est, containing estriol, estradiol and estrone in an 8:1:1 ratio),
or 2 estrogens (Bi-Est, containing estriol and estradiol in a ratio of
8:2 or 5:5).7 These combinations were initially developed to mimic
estrogen levels in the body. Bases and formulations vary, depending on the practice of the individual compounding pharmacy.
Compounded BHT is an option for some women and can
provide alternative delivery methods not commercially available.
However, these are sometimes promoted as being better tolerated
or less risky than conventional HT. Unfortunately, it is difficult to
support or disprove these claims at this time as further studies
are needed.8,9
Cardiovascular disease (CVD)
BHT proponents attribute the increase in cardiovascular risk seen
with the WHI to the use of synthetic, non-bioidentical hormones.
However, without similar random controlled trials comparing
BHT with placebo, it is difficult to draw conclusions.
Smaller studies have assessed surrogate outcomes. CEE contributes to greater increases in triglyceride levels compared to
estradiol and estriol.21,22 How this translates to differences in CVD
risk is unclear. Administration route may also affect risk. Transdermal estrogen may have a better safety profile than oral, including no changes in triglycerides or C-reactive protein, less effect on
blood pressure and decreased thrombotic risk.23
Natural progesterone may have a positive effect on the cardiovascular system compared to synthetic progestins. For example,
medroxyprogesterone (MPA) attenuates the beneficial effects of
estrogen on high-density lipoprotein cholesterol, which is not
seen with oral micronized progesterone.12,14 Progesterone may
have other beneficial effects on arteriosclerosis and vascular tone.24
Endometrial cancer
Efficacy in menopausal symptoms
The efficacy of estrogens, including many of the commercially
available bioidentical estrogens such as 17b-estradiol, has been
well established for improving vasomotor symptoms and vaginal atrophy. Estriol formulations also relieve these symptoms.7,10
However, there is little data to support greater efficacy of estriol
over other estrogens.
Oral micronized progesterone alone has been shown to reduce
vasomotor symptoms.11 Natural progesterone has mild sedative
effects due to the direct effects of its metabolites on brain tissue.12
Transdermal progesterone creams may help relieve vasomotor
symptoms, but study results have been mixed. Some trials have
shown transdermal progesterone creams to improve vasomotor
symptoms,13 whereas others have found this no more effective
than placebo.14,15
Efficacy in bone loss prevention
Much of the evidence in preventing bone loss and reducing fractures has been with conjugated equine estrogen (CEE), a nonS18 bioidentical hormone.1,16 Several studies demonstrated the benefit
of 17b-estradiol in maintaining bone mineral density (BMD).17
Most regulated HT products are indicated for osteoporosis prevention. Two small studies with compounded estriol products
hinted they may preserve BMD,18,19 but there is insufficient evidence for fracture prevention.15 Further data is needed to establish
estriol’s role in maintaining BMD or reducing fractures.
Studies with transdermal progesterone cream in postmenopausal women have failed to show improvement in BMD.13,14,20 No
studies have examined the effect of progesterone cream on fractures. There is no evidence to support the use of transdermal progesterone cream alone for osteoporosis prevention or treatment.
All estrogens have a hyperproliferative effect on the endometrial
lining counteracted by progesterone. Oral estriol has also been
shown to increase endometrial thickness.25 In a retrospective case
control study, women on oral estriol alone had a higher incidence
of endometrial cancer.26 Estriol should never be used alone without progesterone in women with a uterus.
Concerns have been raised that the amount of progesterone
absorbed from transdermal progesterone creams may not be
adequate for endometrial protection. Transdermal progesterone
may cause a slight increase in serum progesterone levels, with wide
variability between women.27,28 However, there is still uncertainty
about the serum progesterone levels required for endometrial
protection. In a small study, progesterone cream reduced endometrial proliferation when used with CEE over 4 weeks.29 In
contrast, studies of longer duration of up to 48 weeks demonstrated inadequate protection of the endometrial lining.30,31 Cases
of endometrial cancer have also been reported in women taking
compounded BHT therapy.32 At this time, progesterone cream
Continued on page S23
GUEST EDITORIAL
Nesé Yuksel, BScPharm, PharmD, ACPR, FCSHP, NCMP
Helping women navigate through
menopause: Role of pharmacists
Menopause management has evolved dramatically over the last
decade. After the release of the Women’s Health Initiative (WHI)
results in 2002, there was a remarkable drop in the use of hormone therapy (HT). Many parts of the world reported prescriptions of HT plummeting by 30% to 60% within the first year of
publication.1 More recently, data
have indicated that there is a window of opportunity in the first 10
years postmenopause where HT
use may actually reduce cardiovascular risk.2 Guidelines from
the Society of Obstetricians and
Gynaecologists (SOGC) and the
North American Menopause
Society (NAMS) continue to
recommend HT for moderate to
severe menopausal symptoms.3,4
We have seen a shift back to HT,
including using lower doses for
shorter durations and with different formulations being available.
More information is also available
on other treatment options for
menopausal symptoms, including non-hormonal medications
and lifestyle management.
Every woman’s experience of
menopause is different and is shaped by her perceptions and
beliefs. For many, the transition can be a confusing time. Even
though information about menopause and treatment approaches
is widely available, it is often contradictory. A Google search using
the terms “menopause” or “hormone therapy” resulted in more
than 16 million hits! Where does a woman start? Unfortunately,
many women do not seek out health care providers, with more
than 70% of women relying on information from friends, colleagues or the media.5
Surveys show that women’s attitudes and behaviours with HT
can be strongly influenced by the media.6 Recently there has been
a lot of attention in the media and in popular books promoting
a “more natural way of treating menopause” through the use of
hormones similar to those produced by the human body: bio
identical hormones. There are many misconceptions about this
term, as women often do not realize that many commercially
available products could be considered bioidentical. One can
imagine how frustrating and frightening it must be for a woman
to decipher often contradictory information. There is a real need
for health professionals such as pharmacists to provide balanced
and evidence-based information.
Even with all the available options, undertreatment of menopausal symptoms is common.7 Many women never initiate therapy
or may discontinue it prematurely.7 Adherence to HT is low, with
rates ranging up to 30%.8 Fear of cancer and side effects such as
bleeding are commonly reported
reasons for nonadherence. Studies show that women discontinuing therapy prematurely are at risk
for continued symptoms or other
adverse outcomes.7,9
Pharmacists are well positioned to provide guidance, support and information to women
through the menopausal transition. Various programs describe
the benefits of pharmacists
in contributing to the care of
menopausal women, from education programs to consultation
services.8,10 Patient perceptions
of pharmacists’ abilities and their
willingness to pay for consultations have been reported to be
positive.8 Pharmacists can actively
collaborate with other health care
providers in empowering women
to make informed decisions about their options. Education could
be as simple as providing information at the time of dispensing,
or more involved when conducting menopause consultations or
presenting at public forums. Menopause can be a springboard for
discussion of preventive care strategies for cardiovascular disease,
osteoporosis and weight management. Interventions found to
be most helpful in improving patients’ adherence include time
spent with a health care professional, such as when picking up
prescription refills, and early, frequent follow-ups.11
As this area continues to evolve, it is our job as health providers to keep abreast of new developments. This is especially
important as we help women navigate through available information. This supplement provides a practical summary of the
recent evidence and current guidelines from SOGC and NAMS,
as well as tools to help you in your practice. n
There is a real need for
health professionals such as
pharmacists to provide balanced
and evidence-based information
Nesé Yuksel is an associate professor in the Faculty of Pharmacy and
Pharmaceutical Sciences at the University of Alberta in Edmonton.
Contact: [email protected].
S19
PRACTICE PROFILE
Christine D. LeBlanc, B Journalism
Irene Hogan: Pharmacist and NAMS
Certified Menopause Practitioner
Certified menopause practitioner Irene Stronczak Hogan enjoys
seeing the difference pharmacists can make in patients’ lives. As
the women’s health consultant at a Rexall compounding pharmacy in Hamilton, ON, she works with clients on drug therapy,
lifestyle issues, nutrition and even food allergy testing. “It grew
out of the women’s health practice, as I realized all the other
things you need to incorporate.”
Irene works with a full-time assistant who books appointments and follows up with physicians. She consults with 5 to 6
patients daily for 45 to 60 minutes each and has a patient roster
of at least 4000. She also gives presentations to the public and
other health care practitioners.
A big challenge for Irene was the doubt cast on the safety
of hormone therapy (HT) after the Women’s Health Initiative
(WHI) study results were publicized in 2002. “It was like a curveball. Nobody knew what to do — they thought hormones were
dangerous. Women were miserable.”
Although many of the original WHI conclusions have been
refuted (see page S7), even now the study’s shadow is felt, as
many health care professionals and patients are not familiar
with the current guidelines from the Society of Obstetricians
and Gynaecologists of Canada (SOGC) and the North American
Menopause Society (NAMS) (see page S9).
Irene says NAMS certification gave her more credibility in
the eyes of physicians, and the confidence to say, “These are my
recommendations, they’re based in research or the highest level
of evidence.”
She has built many good relationships with physicians who
now refer patients to her and share test results. Patients in turn
often refer their mothers, daughters or friends — even men who
might originally have accompanied their wives have ended up
consulting her.
“They do pay me for my time, otherwise they would never
get to spend enough time with a health care practitioner actually
talking about all the things going on with them,” she says.
Irene Hogan, left, consults with patient Maxine McGoldrick.
To develop a menopause focus in your pharmacy practice,
Irene suggests starting by talking to 1 patient a day. “Know your
patients, listen to your patients... make sure you have clinical
information about them.”
She stresses that certified menopause practitioners are not
limited to working in the area of menopause symptoms. Many
focus on women’s health during multiple phases of life, which
can involve prevention strategies for other conditions such as
cardiovascular disease and osteoporosis. “As a menopause practitioner you have the opportunity to educate your patients, and
be part of their overall health plan.”
She sees pharmacists as key in improving patient outcomes,
especially as changes in regulations facilitate expanded scopes
of practice and increased time for consultation. “As long as you
have the right information, are knowledgeable and always act in
the best interests of the patient, you’ll never go wrong.
“It’s so satisfying for you as a professional, and for the patient
as well. You improve patient care, not a doubt about it.” n
The NAMS Certified Menopause Practitioner Program was developed in 2002, and is open to any licensed health
care practitioner, including pharmacists, physicians, nurses and psychologists. After submitting an application and
fee, participants take an exam of 100 multiple choice questions in English at 1 of 120 international exam locations.
The NCMP credential is valid for 3 years, and can be maintained either by repeating the exam or submitting proof of
approved continuing education. For more information, see www.menopause.org/compexam.aspx.
CLINICAL BRIEF
Megan MacInnis, RD
Lifestyle strategies in the management
of women’s midlife health concerns
All health care professionals should discuss and promote healthy
lifestyle choices with their clients, in order to lower their risk of
disease and certain conditions throughout midlife.
Menopause symptoms
Having a higher body mass index predisposes women to more
frequent and severe hot flashes, possibly due to increased insulation from body fat causing increased core body temperature.1-3
Maintaining a healthy body weight also helps with urinary
incontinence.1
Physically active women report fewer and less severe hot
flashes than those with sedentary lifestyles. However, strenuous
exercise causing perspiration may trigger hot flashes in symptomatic women.1-3
Alcohol consumption, depending on the amount, has been
associated with both health risks and benefits and may worsen
some menopause symptoms, such as hot flashes, sleep disruption and depression.1-4 Women should have no more than 2 standard drinks per day and no more than 9 per week (1 drink =
355 mL/12 oz beer, 150 mL/5 oz wine or 45 mL/1.5 oz liquor).5
Cigarette smoking increases the rate at which estrogen is
metabolized,6 which increases the risk of hot flashes. Smokers
experience menopause on average 2 years earlier than nonsmokers.2-4 Smokers may have a higher degree of success if they quit
while going through a life transition.4
Components of a healthy lifestyle
Weight maintenance
Overweight and obesity are a growing concern in Canada
and are associated with numerous other chronic diseases
such as heart disease, type 2 diabetes and certain cancers.1,2,7
As women age, their metabolism changes, which can
cause an increase in total body weight. Women should be
encouraged to eat a healthy diet based on Eating Well with
Canada’s Food Guide.12 A woman’s body mass index (BMI)
should be between 18.5 and 24.9, and her waist circumference no more than 88 cm (35 inches).13 When setting goals
for weight loss, the rate should be no more than 0.5 kg to 1
kg (1 to 2 pounds) per week. Higher rates of weight loss do
not achieve better long-term results.14
Physical activity
Engaging in 30 to 60 minutes of moderate physical activity
most days12 assists with weight management, menopause
symptoms, heart health and cancer. It is also important for
Osteoporosis
As women age, they may be at increased risk for inadequate
intake of micronutrients such as calcium if they eat less when
their metabolism changes.7 Many women may rely on nutrient supplements, but may require guidance on appropriate
supplementation.7
Osteoporosis Canada recommends that women over age 50
take 1200 mg of elemental calcium per day through food and
supplements, and 800 IU to 2000 IU of vitamin D per day from
supplements, in addition to dietary intake or sun exposure, as it
is difficult to obtain adequate amounts.8
It is also important to monitor the intake of foods such as
sodium and caffeine, which, when consumed in excessive quantities, may lead to calcium loss through urine.3,8
Heart health
Following a heart-healthy diet after menopause is particularly
important, as the risk of heart disease increases at this time.2
Elevated serum cholesterol levels are a major risk factor for heart
disease.1,2
Heart-healthy eating recommendations include limiting total
fat intake to 20% to 35% of total calories, with saturated fat
contributing <7% total calories and limiting trans fat to <1%
of total calories.9 Saturated and trans fat have been associated
Continued on page S23
healthy bones, especially weight-bearing activity and
strength training,1,2,8 which maintain bone mass and reduce
the risk of falls that may lead to fractures.1,2
Nutrition
Women age 51 to 70 should aim to consume no more than
1300 mg per day of sodium,15 which is less than 1 teaspoon.
The majority of dietary salt comes from processed food, not
table salt, so such foods should be limited. For all adults, the
upper limit for daily sodium intake should be less than 2300
mg per day.15
Excessive caffeine intake can worsen some menopause
symptoms (e.g., hot flashes, sleep disruption) and cause calcium loss that contributes to osteoporosis. Limiting caffeine
intake to no more than 400 mg per day, the equivalent of 3
cups of brewed coffee, can minimize these symptoms.3,4,16 If
consuming >4 cups of coffee or cola per day, an additional
cup of milk for every cup of caffeine-containing beverage is
recommended.8
Tracy Marsden, BScPharm
CLINICAL BRIEF
Natural health products
More than 70% of menopausal women experience vasomotor
symptoms in the form of hot flashes and/or night sweats. Vasomotor symptoms are affected by factors such as diet, body mass,
smoking, and race or ethnicity, and are often relieved by hormone
therapy (HT).1 However, concerns about the long-term safety
of HT have led to natural health products like phytoestrogens
and black cohosh being promoted as safer alternatives for mild
symptoms.
Phytoestrogens are estrogen-like plant compounds that bind
to estrogen receptors, producing either estrogenic or anti-estrogenic effects.2 The 3 main phytoestrogens are isoflavones, lignans and coumestans. Isoflavones found in red clover and soy
are most estrogenic, followed by the lignans found in flaxseed,
and coumestans in clover and alfalfa.
Despite the publication of numerous positive trials, a 2007
Cochrane Review found no conclusive evidence that soy or red
clover reliably reduced hot flash frequency or severity.3 A possible
explanation given for the inconsistent results was that only 30%
to 40% of people possess the gut flora needed to convert isoflavones to their most potent form.2 A strong placebo effect (up to
59%) also makes efficacy difficult to establish.3 A 2010 review
found inconclusive evidence for soy isoflavones, but noted some
indications of a benefit.4 Both reviews concluded that isoflavones
appear safe, at least during the first year of use.2
The use of flaxseed to relieve vasomotor symptoms has not
been well researched. A small open trial by the Mayo Clinic found
hot flash frequency and hot flash scores decreased significantly
with 40 g of ground flaxseed daily. Abdominal distress was a frequent side effect. Researchers concluded that flaxseed showed
promise for reducing hot flash frequency and breast cancer risk,
but that longer-term studies were needed.5
Black cohosh is commonly used for vasomotor symptom
relief. According to a 2010 meta-analysis, black cohosh improves
vasomotor symptoms by an estimated 26%.6 The exact mechanism of action is unknown, but black cohosh appears to have
effects similar to selective serotonin reuptake inhibitors. It is not
considered estrogenic.7
A combination of St. John’s wort (SJW) and black cohosh
is often used to treat menopausal mood symptoms. SJW has
also been shown to help relieve hot flashes.8 The most common
adverse reactions to SJW are mild, moderate or transient and
• Natural health products are frequently promoted for the
treatment of vasomotor and other symptoms, often without
quality evidence to support their use.
• There is evidence that black cohosh can improve mild
vasomotor symptoms.
• Patients need to be aware of the potential for significant
adverse reactions and drug interactions with natural health
products.
include gastrointestinal upset, allergic reactions, fatigue and
dry mouth.9 Other potential reactions include skin rash, photodermatitis and a link to increased incidence of cataracts.10
Drug interactions are a major concern with SJW, as it is a strong
inducer of the P-glycoprotein drug transport molecule and the
cytochrome p450 enzymes.9,11 The CYP 3A4 enzyme is used by
at least 50% of all marketed medications, and is significantly
induced by SJW.12 Because SJW has numerous active chemical
constituents, the magnitude of the interaction may vary significantly between preparations. Clinically significant reactions
occur with many prescription medications, including (but not
limited to) oral contraceptives, antiretrovirals, anti-arrhythmics,
warfarin and cyclosporine.9,11 Concomitant use of SJW and selective serotonin reuptake inhibitors is not recommended because
of concerns regarding serotonin syndrome.
Valerian root is often used in menopause formulas to ameliorate sleep disturbances. A meta-analysis of valerian for insomnia
found that there is subjective evidence of benefit, but that objective data are lacking.13 Gradual withdrawal is recommended if
valerian is taken for an extended period of time.
Phytoestrogen use for vasomotor symptom relief is not supported by good-quality evidence; however, there is no evidence
of harmful side effects.3 There is evidence that some commercial
black cohosh products provide modest relief of vasomotor symptoms.14 Combining black cohosh with SJW may provide additional benefit, particularly for mood symptoms associated with
menopause. Valerian provides subjective improvement in sleep,
although studies specific to menopausal women are lacking. n
Tracy Marsden is a pharmacist and natural medicine consultant in Calgary, Alberta. Contact: [email protected].
Guidelines: Continued from page S11
age of natural menopause.
SOGC ET can be offered to women who have undergone surgical
menopause for the treatment of endometriosis.
Bioidentical hormones
NAMS In the absence of efficacy and safety data for any specific
prescription, the generalized benefit-risk ratio data of commercially available HT products should apply equally to bioidentical
hormone therapy. For the vast majority of women, regulatory
agency–approved HT will provide appropriate therapy without
the risks and cost of custom (compounded) preparations. (See
article on page S17.) n
Bioidentical: Continued from page S18
should not be used in combination with estrogen for endometrial
protection.
Breast cancer
The risk of breast cancer with BHT has not been assessed in wellcontrolled studies. Estriol has been shown to stimulate breast cancer cells similar to other estrogens.33 The belief that estriol may
competitively inhibit estradiol binding on breast tissue has not
been proven in controlled studies.34 It is too early to conclude that
estriol has a comparatively lower effect on a woman’s breast cancer
risk than other types of estrogen.
It is unclear if there are differences between the effects of different progestogens on breast cancer risk.23 One large observational
study suggested progesterone, in combination with estrogen,
posed a lower risk of breast cancer compared to synthetic progestin. Although promising, this area requires more study.35
Salivary testing
centrations better reflect free hormone concentrations.36 Although
some studies have shown salivary and serum hormone levels to
correlate,37 this is not consistent in all situations and levels can
vary depending on the hormone tested, storage conditions, time
of day and inter-assay variability.4 Fluctuating hormone levels
in perimenopausal women make it difficult to interpret a single
value, correlate to symptoms or predict response.37 HT use should
be guided primarily by patient symptoms, with the role of salivary
testing still to be determined.
As pharmacists, we are best able to support our patients
through the menopausal transition by being aware of the current evidence and helping them make informed decisions through
education. n
Nesé Yuksel is an associate professor in the Faculty of Pharmacy and
Pharmaceutical Sciences at the University of Alberta, and Mary
Gunther is a clinical pharmacist at the University of Alberta Hospital in Edmonton, Alberta. Contact: [email protected].
Salivary hormone levels are used to guide therapy, along with
patients self-reported symptoms, in the belief that salivary con-
Lifestyle: Continued from page S21
with an increase in low-density lipoprotein (LDL) cholesterol,
which is strongly associated with heart disease,10 while a higher
intake of omega-3 fatty acids has been linked to a reduced risk of
cardiovascular disease (CVD).1 For CVD prevention, it is recommended that the whole population consume two 3 oz servings
of fatty fish per week, providing 450 mg to 500 mg of the dietary
omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) per day.1,9
Soy consumption has demonstrated a benefit on cardiovascular risk factors, although randomized controlled trials are
required to demonstrate a reduction in CVD.3
Cancer
It is estimated that 30% to 40% of all cancers could be prevented
through modifying lifestyle factors such as diet, physical activity and weight.1 There is no one nutrient or food group that
has been shown to reduce the risk of breast cancer or ovarian
cancer; rather, there are general recommendations towards living a healthier lifestyle and minimizing weight gain.11 Women
should focus on staying physically active, limiting alcohol, avoiding being overweight and eating a diet high in plant-based foods,
such as vegetables, fruits and whole grains.1,7,11
Iron deficiency
Perimenopausal women may be at risk for iron deficiency, especially if experiencing frequent or heavy menses, and may require
additional iron if unable to meet requirements through food
sources.11 Due to cessation of menstrual periods, postmenopausal women are at low risk of iron deficiency because iron
stores increase after menopause.11
Role of the pharmacist
Pharmacists have a unique opportunity to encourage healthy
lifestyle choices for their female clients at midlife, as people are
more motivated to make changes to optimize their health while
experiencing a life transition.1 n
Megan MacInnis is a Women’s Wellness Dietitian at the Lois Hole
Hospital for Women in the Royal Alexandra Hospital in Edmonton,
Alberta. Contact: [email protected].
C P J / R P C • N OV E M B E R / D E C E M B E R 2 0 1 0 • VO L 1 4 3 [ S U P P L 2 ] References available online at www.cpjournal.ca
S23
PAT I E N T H A N D O U T
The menopause transition — What you need to know
Adapted with permission from: Brown T. Menopause and perimenopause. In: Repchinsky C, editor. Patient self-care. 2nd
ed. Ottawa (ON): Canadian Pharmacists Association; 2010.
What is menopause?
Menopause is a woman’s final menstrual period, indicating the
end of her childbearing years. Occurring on average around age
51, it is a natural phase of life related to a change in the ovaries’
production of estrogen and other hormones.
The period of time before menstruation finally stops is perimenopause, which typically begins 2 to 8 years before the final
period and includes the full 12 months following. Postmenopause
is the time after menopause. Each stage may require different
strategies to optimize health.
Most women will notice changes during this transition as their
hormone levels fluctuate, but each woman’s experience will be
different. Many women will start having symptoms in perimenopause that may get worse as they reach menopause.1
What are the common symptoms?
•Changes in menstrual cycles — One of the first signs of
approaching menopause. Periods may be closer together, farther apart or skipped altogether.
•Hot flashes (hot flushes or night sweats) — The most common
symptom of menopause and one of the major causes of sleep
disturbances.
•Vaginal dryness — The vagina may lose its ability to produce lubrication, particularly during sex, which can make sex
uncomfortable, even painful, for some women.
•Loss of bladder control — Can lead to increased urinary frequency and/or leakage of urine, particularly when coughing,
sneezing or with physical activity.
•Skin changes — The skin begins to get thinner and drier, leading to more wrinkles.
•Decreased libido (sex drive) — There may be less interest in
sex. Note that although a woman’s fertility may be lower during
perimenopause, there is still a risk of pregnancy.
•Cognitive changes — Difficulty with remembering and
decreased concentration may happen more often, especially
when tired or stressed.
What can be done to relieve symptoms?
To reduce hot flashes:
• Avoid hot or spicy foods, drink less alcohol and caffeine.
• Stop smoking.
• Keep room temperatures comfortably cool, especially at night.
• Dress in layers and remove as needed to prevent excess warmth.
•Exercise regularly — try to exercise for at least 30 minutes, ideally on most days but a minimum of 3 times a week.
• Reduce stress.2
S24 To prevent pain during sex:
•Use a lubricant (such as K-Y Jelly or Gyne-Moistrin) before sex.
•Use a moisturizer (such as Replens) every few days in and
around the vagina to help relieve dryness. Prescription products
are also available.
•Any sexual activity will help keep the vagina moist, not just
intercourse.
To improve bladder control:
•Try Kegel exercises. Squeeze your pelvic muscles as if you are
trying to delay a bowel movement. Hold for a count of 5, then
relax for a count of 10. Repeat the squeezing and relaxing 10
times for 1 set. Do 3 sets a day, or more if feeling the urge to
cough or sneeze.2
Hormone therapy (HT) can help relieve many menopausal
symptoms. HT includes the use of estrogen and progestin
together, or estrogen alone. Women should discuss the benefits
and risks with their health care providers to decide if it is right for
them. There are also other prescription medications to help with
menopausal symptoms if HT is not an option (e.g., venlafaxine
or gabapentin).
Why is midlife an important time for women’s health?
A woman’s risk for certain conditions and diseases begins to
increase at midlife. Perimenopause is a good time for preventive
health care based on individualized risk assessments, adoption of
a healthy lifestyle and involvement in decisions regarding treatment options.1
It is more important than ever for women to work with their
pharmacist and other health care professionals to prevent osteoporosis, heart disease and cancer, by planning for a healthy future
today. n
We acknowledge the contribution of Carole Beveridge, RPh, NCMP,
ROHP, DiHom, DHPh, DWH Hom, HD(RHom), certified menopause practitioner and certified compounding pharmacist.
References
1. Society of Obstetricians and Gynaecologists of Canada. The Canadian Consensus Conference on Menopause and Osteoporosis 2002 Update. J Obstet Gynaecol
Can 2002;24(10)[suppl]:1-90.
2. North American Menopause Society. Menopause practice: a clinician’s guide. 3rd
ed. Mayfield Heights (OH): North American Menopause Society; 2007.

Menopause - Dossier Communications

Transcription

Similar documents

redactioneel - menopauze.indd

Menopause - Time to Pause - Center for Hormonal Health and Well

Dr. Cynthia Williams

Menopause Update 2014

The Debate - HysterSisters

Women`s Health Brochure

Managing the post menopausal woman

Hormonal Imbalance and Menopause

Susan E.D. Doughty, APRN, CWHNP