Jas - Journal of ANDROLOGICAL SCIENCES

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ISSN 2035-3901
Journal of
Vol. 17t/PtDecember 2010
CONTENTS
2010;17:149-192
ORIGINAL ARTICLES
Current techniques in management of obstructive azoospermia...................................................... 149
Gynecomastia: pathophysiology, clinical evaluation and management ............................................. 156
Chlamydia trachomatis infection: the urologist’s point of view ........................................................ 164
Peyronie’s disease: endocavernous plaque excision without substitutive graft:
critical 5-year experience ............................................................................................................. 169
CASE REPORT
Bilateral Leydig cell tumor with adrenal hyperplasia ....................................................................... 183
TABLE OF CONTENTS ................................................................................................................ 186
Journal of ANDROLOGICAL SCIENCES Official Journal of the Italian Society of Andrology
Efficacy of a nutraceutical preparation as add-on treatment in patients with erectile dysfunction
treated with 5-PDE inhibitors: a pilot study.................................................................................... 178
Periodico trimestrale - POSTE ITALIANE SPA - Spedizione in Abbonamento Postale - D.L. 353/2003 conv. in L. 27/02/2004 n° 46 art. 1, comma 1 DCB PISA
Corporoplasty with soft axial tutors and safenous grafting. Following three years............................. 171
ANDROLOGICAL
SCIENCES
Official Journal of
the Italian Society of Andrology
IN THIS ISSUE
OBSTRUCTIVE AZOOSPERMIA
GYNECOMASTIA
CHLAMIDYA TRACHOMATIS INFECTION
SURGERY OF PEYRONIE’S DISEASE
NUTRACEUTICAL FOR ERECTILE DYSFUNCTION
BILATERAL LEYDIG CELL TUMOR
www.andrologiaitaliana.it
Journal of
ANDROLOGICAL
SCIENCES
Official Journal of the Italian Society of Andrology
Cited in
SCOPUS Elsevier Database
Past Editors
Fabrizio Menchini Fabris (Pisa)
1994-2004
Edoardo Pescatori (Modena)
Paolo Turchi (Pisa)
2005-2008
Vincenzo Ficarra (Padova)
Andrea Salonia (Milano)
Editor-in-Chief
Ferdinando Fusco (Napoli)
Managing Editor
Furio Pirozzi Farina (Sassari)
Copyright
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Editorial Board
Antonio Aversa (Roma)
Ciro Basile Fasolo (Pisa)
Carlo Bettocchi (Bari)
Guglielmo Bonanni (Padova)
Massimo Capone (Gorizia)
Tommaso Cai (Trento)
Luca Carmignani (Milano)
Antonio Casarico (Genova)
Carlo Ceruti (Torino)
Fulvio Colombo (Milano)
Luigi Cormio (Foggia)
Federico Dehò (Milano)
Giorgio Franco (Roma)
Andrea Galosi (Ancona)
Giulio Garaffa (London)
Andrea Garolla (Padova)
Paolo Gontero (Torino)
Vincenzo Gulino (Roma)
Massimo Iafrate (Padova)
Sandro La Vignera (Catania)
Francesco Lanzafame (Catania)
Giovanni Liguori (Trieste)
Mario Mancini (Milano)
Alessandro Mofferdin (Modena)
Nicola Mondaini (Firenze)
Giacomo Novara (Padova)
Enzo Palminteri (Arezzo)
Furio Pirozzi Farina (Sassari)
Giorgio Pomara (Pisa)
Marco Rossato (Padova)
Paolo Rossi (Pisa)
Antonino Saccà (Milano)
Gianfranco Savoca (Palermo)
Omidreza Sedigh (Torino)
Marcello Soli (Bologna)
Paolo Verze (Napoli)
Alessandro Zucchi (Perugia)
INDEX
Journal of Andrological Sciences
Original articles
Current techniques in management of obstructive azoospermia
G. Liguori, A. Zordani, R. Napoli, S. Bucci, M. Rizzo, S. Benvenuto, E. Belgrano, C. Trombetta....................................................................... 149
Gynecomastia: pathophysiology, clinical evaluation and management
M. Rossato, M. Sogaro, R. Vettor............................................................................................................................................................. 156
Chlamydia trachomatis infection: the urologist’s point of view
T. Cai, S. Mazzoli, N. Mondaini, G. Malossini, R. Bartoletti.......................................................................................................................... 164
Peyronie’s disease: endocavernous plaque excision without substitutive graft: critical 5-year experience
F. Mantovani, E. Tondelli, G. Cozzi, I. Oliva, E. Finkelberg, M. Talso, D. Varisco, C. Palumbo, F. Rocco............................................................. 169
Corporoplasty with soft axial tutors and safenous grafting. Following three years
M. Silvani, S. Pecoraro, A. Zucchi............................................................................................................................................................ 171
Efficacy of a nutraceutical preparation as add-on treatment in patients with erectile dysfunction treated with 5-PDE inhibitors: a pilot study
G. Piubello............................................................................................................................................................................................. 178
CASE REPORT
Bilateral Leydig cell tumor with adrenal hyperplasia
T. Zenico, M. Saccomani, U. Salomone, E. Bercovich.............................................................................................................................. 183
Table of contents.......................................................................................................................................................................... 186
original article
Journal of Andrological Sciences 2010;17:149-155
Current techniques in management of obstructive
azoospermia
G. Liguori, A. Zordani, R. Napoli, S. Bucci, M. Rizzo, S. Benvenuto, E. Belgrano, C. Trombetta
Department of Urology, University of Trieste, Italy
Summary
Key words
Azoospermia • Techniques
Azoospermia is the total absence of spermatozoa in the ejaculate. Azoospermia is found in 10% to 15% of male infertility cases and is caused by a
testicular insufficiency in the majority of patients. Obstructive azoospermia is
less frequent and arises in 15-20% of men with azoospermia.
Most causes of male infertility are treatable, and many treatments restore the
ability to father a children naturally.
In case of vasal or epididymal obstruction, microsurgical reconstruction of
the seminal pathways, if possible, remains the safest and most cost-effective
treatment option for these patients, allowing natural conception in many
cases.
Not all men with obstructive azoospermia are tractable by microsurgical
reconstruction. In such situations, various sperm-retrieval techniques can be
employed to take sperm for use with in vitro fertilization via intracytoplasmic
sperm injection.
Introduction
Azoospermia is defined as the total absence of spermatozoa in the
ejaculate. Azoospermia is found in 10% to 15% of male infertility
cases and is caused by a testicular insufficiency in the majority of patients. Obstructive azoospermia is less frequent and arises in 15-20%
of men with azoospermia.
Common causes of obstructive azoospermia results most commonly
from previous vasectomy, but also may be caused by epididymal,
vassal, or ejaculatory duct pathology relating to genitourinary infection, iatrogenic injury during scrotal or inguinal surgery, and congenital
anomalies 1.
Most causes of male infertility are treatable, and many treatments
restore the ability to father a children naturally.
Men with obstructive azoospermia present with normal size testes
and normal FSH. On examination, enlargement of the epididymis can
be found and sometimes the vas deferens appears absent, due to
congenital factors or previous inguinal or scrotal surgery. Although
obstructions in primary infertile men are commonly present at the
epididymal level, other sites of obstruction are the ejaculatory ducts
and the vas deferens.
Corresponding author
Giovanni Liguori – E-mail: [email protected]
149
G. Liguori, et al.
In 25% of men with a suspected obstruction, no
spermatozoa are found in the epididymis during
scrotal exploration, indicating that there is an intratesticular obstruction 2.
Moreover, clinical management of obstructive
azoospermia must also take into account any concomitant infertility factors in the female partner. As
a result, both partners should be examined before
making a specific treatment proposal.
Treatment options for obstructive azoospermia
Men with obstructive azoospermia may father children in one of two ways:
• surgical correction of the obstruction;
• retrieval of sperm directly from the epididymis or
the testis followed by in vitro fertilization (IVF) or
intracytoplasmatic sperm injection.
In case of vasal or epididymal obstruction, microsurgical reconstruction of the seminal pathways, if
possible, remains the safest and most cost-effective
treatment option for these patients, allowing natural
conception in many cases 3-5. The surgical management of OA depends on the site of obstruction: if
obstruction is present at the level of the vas deferens or epididymis microsurgery is indicated; on
the contrary, ejaculatory duct obstruction is treated
by transurethral resection of the ejaculatory ducts
(TURED) 2.
Transurethral resection of the ejaculatory
ducts
Ejaculatory duct obstruction is suspected when the
ejaculate volume is < 2.0 mL and no sperm or fructose is present. Clinical suspicion can be confirmed
by TRUS demonstration of dilated seminal vesicles
or dilated ejaculatory ducts.
Transurethral resection of the ejaculatory ducts is
performed cystoscopically. A small resectoscope
and electrocautery loop are inserted, and the verumontanum is resected in the midline. Since the area
of resection is at the prostatic apex, near the external
urethral sphincter and the rectum, careful positioning
of the resectoscope is essential. There is convincing evidence from several large studies of patients
treated for infertility that 65-70% of men show significant improvement in semen quality after TURED
and that a 20-30% pregnancy rate can be expected.
The complication rate from TURED is approximately
20%. Most complications are self-limited and include
hematospermia, hematuria, urinary tract infection,
epididymitis, and a watery ejaculate. Rarely reported
150
complications include retrograde ejaculation, rectal
perforation, and urinary incontinence.
Microsurgical reconstruction of the vas derferens and epididymis
Microsurgical reconstruction to correct male infertility, although usually performed for vasectomy
reversal, also is performed to correct other types
of iatrogenic, congenital, and post inflammatory
obstruction.
Microsurgical reconstruction of the seminal pathways may be accomplished via anastomosis of the
vasal ends (vasovasostomy) or anastomosis of the
abdominal end of the vas deferens to the epididymis
(vasoepididymostomy).
Before surgery, it is necessary for the surgeon to
alert the cryobank laboratory personnel: as a matter
of fact intraoperative retrieval of sperms from the
vas, epididymis or testis is performed in order to
cryopreserve sperm for possible later use for IVF/
ICSI in case of microsurgery failure.
Vasovasostomy or vasoepididymostomy?
Vasovasostomy almost always is performed for the
reversal of an elective vasectomy (6% of men who
undergo vasectomy ultimately request reversal), but,
vasovasostomy is not always a feasible option to restore vasal patency; as a matter of fact if epididymal
obstruction is present, whether primary or secondary
to chronic vasal obstruction, a vasoepididymostomy
is required proximal to the obstruction to restore
continuity for sperm transport 6.
Every procedure begins with the careful dissection
of the vas deferens with an intact sheath and meticulous preservation of the blood supply. Once the
site of the previous vasectomy has been identified,
the vas is transected perpendicularly on the abdominal and testicular limbs as close as possible to the
obstructed segment to preserve vasal length and
the fluid is examined under a separate bench light
microscope to determine whether vasovasostomy
or vasoepididymostomy is indicated. If copious,
clear, watery fluid is identified or if intact sperm or
sperm parts are identified, then vasovasostomy is
indicated.
Vasovasostomy
Vasovasostomy represents the simplest form of
microsurgical reconstruction of the reproductive
tract. The microsurgical anastomosis may be per-
formed with either a modified one-layer or a twolayer technique. The modified one-layer anastomosis 7 is performed using six to eight interrupted full
thickness sutures of 9-0 nylon placed equidistantly
around the circumference of each end of the vas,
followed by the placement of more superficial outer
muscular layer sutures of 9-0 nylon between adjacent full thickness sutures.
The two-layer end-to-side microsurgical anastomosis 8 is performed by placing six to eight interrupted
sutures of 10-0 nylon through the mucosa of each
end of the vas, followed by the placement of approximately eight interrupted sutures of 9-0 nylon
through the outer muscular layer of the vas (Fig. 1). A
folding vas approximating clamp is useful to perform
this anastomosis 9.
The one-layer technique is performed in patients in
whom there is little difference in the diameters of
vas deferens between the distal and the proximal
sides. Nevertheless, to simplify the surgical procedure and to shorten the duration of the operation,
the one-layer technique might be sufficient for vasectomy reversal. In vasovasostomy after herniorrhaphy, when there used to be a large difference in
the diameters of the vas deferens between the distal
and the proximal sides because of the long duration
of obstruction, the two-layer technique is required to
ensure the precise attachment of the mucosa of the
vas deferens. When compared with the fertility rate
(42% to 50%) for the patients who underwent vasectomy reversal with duration < 10 years, the results for
the patients who underwent vasectomy reversal with
duration > 10 years after vasectomy showed markedly poor results (37%) 10. Known inhibiting factors
of pregnancy after vasovasostomy include stricture
and obstruction of the seminal tract at the anastomotic site; ruptured ductus epididymis caused by
Figure 1. Inner mucosal edges are approximated with interrupted
10-0 nylon sutures and outer muscular edges are approximated
with interrupted 9-0 nylon sutures.
occlusion or back pressure and secondary obstruction of ruptured ductus epididymidis, and antisperm
antibodies have also been reported to play a role 11.
Vasoepididymostomy
This procedure is performed by creating vertical
scrotal incisions that are adequately long to extrude
the scrotal contents. Otherwise the testicles are exposed by means of an infrapubic incision according
to Kelami.
The presence of active spermatogenesis is an obvious prerequisite to this surgical procedure and, if a
testis biopsy has not already been carried out before
this surgery, it can be done in a standard fashion and
the tissue examined under the microscope (400×)
for the presence of sperm, some of which may be
motile.
It is necessary to prove that the vasa are patent. For
this reason a 27-gauge needle is inserted into the
lumen of the vas, pointing away from the testicle
(Fig. 2) and a vasography is carried out: a vasogram
involves the injection of contrast media into the vas
toward the bladder from the scrotum. Vasography
can delineate the proximal vas deferens, seminal
vesicle and ejaculatory duct anatomy and determine
whether obstruction is present (Fig. 3).
The procedure begins by first freeing up the abdominal limb of the vas deferens that will be used for the
anastomosis. Mobilization of the vas with meticulous
preservation of blood supply is necessary to create a
tension-free anastomosis. For this purpouse the vas
must be prepared to the level of the ring and drawed
through an opening in the tunica vaginalis: Then the
vas is brought to the epididymis in a straight-line
Figure 2. A 27-gauge needle is inserted into the lumen of the vas,
pointing away from the testicle and the contrast media is injected
into the vas toward the bladder from the scrotum.
151
G. Liguori, et al.
Figure 3. Vasography delineates the proximal vas deferens,
seminal vesicle and ejaculatory duct anatomy. In this case distal
obstruction is not present.
fashion and the posterior edge of the epididymal
tunic is sewed to the posterior edge of the vasal
muscularis with interrupted 9-0 nylon sutures in order to position the lumen of the vas adjacent to the
selected epididymal tubule 12.
The results of vasoepididymostomy are increasingly
successful the lower the anastomosis is performed
in the epididymis 13. While it is important to perform
the anastomosis at the lowest possible epididymal
level, the level must be at a point in the epididymis
at which spermatozoa are present in the epididymal
tubular fluid, which assures that the anastomosis
will be performed above the obstruction in the
Figure 4. Transversal two-suture intussusceptions vasoepididymostomy. The sutures were placed transversely in the epididymal
tubule with a single, simultaneous needle placement 17.
epididymis. Although vasovasostomy may have a
successful result despite the intraoperative absence
of spermatozoa from the vas fluid, vasoepididymostomy never will be successful when performed at an
epididymal level at which spermatozoa are absent
from the epididymal tubular fluid 14.
Multiple anastomotic techniques have been described, although three variations are currently used:
direct end-to-end, direct end-to-side, and end-toside intussusceptions 15.
Of all the modifications reported in literature, intussusception vasoepididymostomy anastomotic
techniques have had the greatest impact on clinical practice and are now used widely by urologic
microsurgeons.
Berger 16 first described the use of an invagination vasoepididymostomy in clinical practice. He described
a triangulation intussusception technique using three
double-armed 10-0 nylon sutures, which would be
equivalent to six luminal sutures. In a series of 12
men who underwent bilateral vasoepididymostomy
with this technique, the patency rate was 92%.
Marmar 17 then described a two-suture intussusceptions vasoepididymostomy technique that many
regarded as another significant advance: the sutures
were placed transversely in the epididymal tubule
with a single, simultaneous needle placement. The
Cornell group also has reported on a two-suture
method. In their study, the sutures were placed longitudinally rather than transversely 18.
This maneuver then was followed by a tubulotomy
cut between the sutures. After the epididymal fluid
is tested for sperm and aspirated into micropipettes
for cryopreservation, the two needles within the
epididymal tubule are pulled through, and all four
needles are placed through the vas lumen at the
marked locations. Tying down the sutures allows
the epididymal tubule to be intussuscepted into the
vasal lumen, completing the anastomosis (Fig. 2).
The patency rate with the longitudinal intussusception vasoepididymostomy approach was over 90%
in a recent clinical series, and intussusception is the
preferred method for all vasoepididymostomies 19.
Sperm retrieval techniques
Not all men with obstructive azoospermia are tractable by microsurgical reconstruction. In such situations, various sperm-retrieval techniques can be employed to take sperm for use with in vitro fertilization
(IVF) via intracytoplasmic sperm injection (ICSI). For
obstructive azoospermia, fertilization and pregnancy
rates are comparable with those achieved with
152
ejaculated sperm. The results with frozen testicular
sperm are comparable to those obtained with fresh
testicular sperm.
Sperm retrieval with IVF/ICSI offers the possibility
of early achievement of a relatively high live delivery
rate, but any couple considering IVF/ICSI should be
apprised of the risks involved in this type of treatment. These include the possibility of ovarian hyperstimulation, the potential complications of oocyte
retrieval and the risks and consequences of multiple
gestations 20.
In men with obstructive azoospermia, sperm may
be retrieved from either the epididymis or the testis
via a variety of percutaneous, open, or microsurgical
techniques.
The microsurgical techniques may also be used concomitantly with reconstructive procedures as a means
to obtain sperm for cryopreservation in the event the
attempt at reconstruction is not successful.
The obvious advantages of percutaneous acquisition are the minimally invasive nature of this method
and the ability to sample multiple sites within the
testes with minimal potential of harm to the testis.
The obvious disadvantage is that the area of tissue
sampled is decreased markedly compared with the
open biopsy.
Sperm Retrieval Techniques
According to the Practice Committee of American Society for Reproductive Medicine Guidelines,
since only 20% to 40% of couples conceive after
attempted vasoepididymostomy despite patency
rates of 60% to 80%, it is reasonable to consider
sperm retrieval at the time of surgical reconstruction 21. If motile sperm are found at the site of
reconstruction, they may be aspirated and cryopreserved. Alternatively, sperm may be retrieved via
testicular biopsy.
The first successful attempt at ICSI using epididymal
sperm (MESA or microsurgical epididymal sperm
aspiration) was reported by Silber 22 and Tournaye 23.
Many reports have shown that the cause of obstruction is not important when considering the success
rate with MESA. The MESA procedure is performed
under general anaesthesia. After exposure a dilated
tubule of the epididymis is microsurgically opened
and its fluid examined for the presence of motile
spermatozoa. The best quality sperm are typically
found in the proximal epididymis close to the testis.
Puncture sites may be closed or cauterized. Performing aspiration under direct vision with the aid of
the operating microscope allows for procurement of
Figure 5. Longitudinal 2-suture longitudinal end-to-side vasoepididymostomy technique 18.
a large number of good quality, motile sperm from
the epididymal tubules 24.
An alternative method for epididymal aspiration of
sperm is PESA (percutaneous epididymal sperm
aspiration), being less invasive and less costly than
MESA.
Epididymal aspiration also can be performed without
surgical scrotal exploration, repeatedly, easily, and at
low cost, without an operating microscope or expertise in microsurgery. PESA can be performed under
local anesthesia. This technique is indicated in patients with obstructive azoospermia who were unable
to undergo or who decided against surgical reconstruction. A needle is introduced through the skin into
the epididymis and is then aspirated (Fig. 6). Multiple
punctures may be required to obtain sufficient fluid.
However, the numbers of sperm retrieved are often
not sufficient to allow for cryopreservation, so repeat
procedures may be warranted for multiple IVF cycles.
In addition, there is a risk for development of scrotal
hematoma or injury to the epididymal or testicular
vessels given the blind nature of this procedure.
Despite the good results with MESA and PESA, many
studies have shown that ICSI with testicular spermatozoa retrieved by TESE (testicular sperm extraction)
could also be successfully applied in almost all cases of
azoospermia. The most popular methods of sperm retrieval are conventional “open biospy” retrieval (TESE),
FNA (fine needle aspiration) or TESA (testicular sperm
aspiration). In patients with normal spermatogenesis it
seems that FNA and TESE give comparable results 25.
153
G. Liguori, et al.
Figure 6. PESA: a needle is introduced through the skin into the
epididymis and is then aspirated.
The choice of sperm retrieval method in men with
obstructive azoospermia depends primarily on the
experience and preference of both the physician
who will perform the retrieval and the IVF laboratory
embryologist. There are not enough data to conclude
that either the technique of sperm retrieval (open or
percutaneous) or the source of sperm (testicular,
epididymal, vasal or seminal vesicular) significantly
affects pregnancy rates.
Moreover, epididymal and testicular sperm could be
frozen, stored and subsequently used in future ICSI
cycles. For obstructive azoospermia, fertilization
and pregnancy rates are comparable with those using ejaculated spermatozoa, and results with frozen
sperm are comparable to those obtained with fresh
testicular sperm.
Cryopreservation of sperm is an essential technique
in the treatment of infertile couples wherein the man
has obstructive azoospermia. and, whenever available, excess retrieved spermatozoa should be cryopreserved to avoid unnecessary subsequent sperm
retrieval procedures 21.
The results achieved with retrieved sperm and
ICSI are excellent. Contemporary pregnancy rates
of 24% to 64% have been achieved using sperm
retrieved from azoospermic 26 27. Maternal factors
(maternal age, oocyte number, and oocyte quality)
alone now are considered the principal determinants
of outcomes achieved with ART and ICSI for couples
with infertility related to obstructive azoospermia 28.
Conclusion
Microsurgical reconstruction should be offered to
men having a reparable reproductive tract obstruction and is preferable to sperm retrieval with IVF/
154
ICSI in men with prior vasectomy if the obstructive
interval is less than 15 years and no female fertility
risk factors are present. If an epididymal obstruction
is present, the decision to use either microsurgical reconstruction or sperm retrieval with IVF/ICSI
should be individualized.
Vasoepididymostomy should be performed by an
expert in reproductive microsurgery.
Sperm retrieval with ART is an alternative to microsurgical repair for men with correctable reproductive
tract obstruction and represents the only treatment
that can offer men with irreparable obstruction the
opportunity to have their own genetic children. Almost all men with obstructive azoospermia have
abundant sperm in the testes that can be retrieved
successfully using a variety of different techniques.
Sperm retrieval/ICSI is preferred to surgical treatment
when (1) advanced female age is present (2) female
factors requiring IVF are present (3) the chance for success with sperm retrieval/ICSI exceeds the chance for
success with surgical treatment or (4) sperm retrieval/
ICSI is preferred by the couple for financial reasons.
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26
Craft IL, Khalifa Y, Boulos A, et al. Factors influencing
the outcome of in vitro fertilization with percutaneous
aspirated epididymal spermatozoa and intracytoplasmic sperm injection in azoospermic men. Hum Reprod
1995;10:1791-4.
27
Palermo GD, Schlegel PN, Hariprashad J, et al. Fertilization and pregnancy outcome with intracytoplasmic
sperm injection for azoospermic men. Hum Reprod
1999;14:741-8.
28
Silber SJ, Nagy Z, Devroey P, et al. The effect of female
age and ovarian reserve on pregnancy rate in male infertility: treatment of azoospermia with sperm retrieval
and intracytoplasmic sperm injection. Hum Reprod
1997;12:2693-700.
21
155
original article
Gynecomastia: pathophysiology, clinical evaluation
and management
M. Rossato, M. Sogaro, R. Vettor
University of Padova, Department of Medical and Surgical Sciences, Clinica Medica 3-Endocrine-Metabolic Unit
Summary
Introduction. Gynecomastia is a common clinical condition characterized by
an enlargement of the glandular tissue of the male breast, with a high prevalence in young and old subjects. It is due generally to an absolute or relative
increase of estrogens over androgens.
Methods. This article reviews the clinical management of gynecomastia,
with particular attention to the causes and pathophysiological mechanisms
leading to an absolute or relative excess of estrogens over androgens determining gynecomastia. We face also a brief review of all medical and surgical
therapies available to treat this condition that often troubles many patients
above all in the pubertal age.
Results. Gynecomastia may be the result of an increased absolute estrogen
production from estrogen secreting glands and/or to increased androgens
conversion in the peripheral tissues or to a relative prevalence of estrogens
over androgens. The efficacy of the management of gynecomastia depends
on its causes and the time from its appearance due to possible time-dependent fibrotic modifications of breast tissue. For its treatment, depending on
each specific cause, we can consider first the use of anti-estrogens. When
pharmacological therapy shows no efficacy, surgery might be necessary.
Conclusions. Gynecomastia is a relatively common clinical condition. Usually
a careful clinical history and physical examination are sufficient to identify the
possible different causes ranging from pubertal gynecomastia, drug-induced
causes, or an underlying pathological condition. Since gynecomastia often
resolves spontaneously (as well as pubertal gynecomastia in a large part of
pubertal boys), periodic clinical follow-up is usually sufficient to manage these
patients. Nonetheless there are conditions where further clinical evaluation is
necessary as well as medical or surgical treatment.
Key words
Gynecomastia • Pathophysiology •
Management • Estrogen • Androgen
Introduction
Gynecomastia is an enlargement of the glandular component of the
male breast due to ductular elements proliferation; it can be unilateral or bilateral. This condition has to be differentiated from excessive
breast adipose tissue accumulation, a condition known as pseudogynecomastia. Histologically, gynecomastia is characterized by the proliferation and dilatation of mammary ductules with periductal fibroconnective tissue. True terminal acini are rarely seen since acini require the
presence of both female hormones (estradiol and progesterone) 1-3.
Marco Rossato, University of Padova, Department of Medical and Surgical Sciences, Endocrine-Metabolic Unit, via Ospedale 105, 35128 Padova, Italy – Tel. +39 049
8218747 – Fax +39 049 8213332 – E-mail: [email protected]
156
Epidemiology
Gynecomastia is a common condition, being present
on physical examination in 36% of healthy young
men, 57% of healthy older men and in more than
70% of elderly hospitalized men (and as high as 85%
in older men with a body mass index greater than 25
kg/m2) 4, while in autopsy studies, its prevalence
ranges from 40 to 55% 4-7. Typically, gynecomastia
has a trimodal age distribution during life:
1. neonatal: 60-90% of infants have transient gynecomastia due to transplacentar transfer of maternal estrogens;
2. puberty: 50-60% of adolescents have gynecomastia with a peak age of onset between 13 and
14 years, followed by a progressive decline;
3. adult: up to 70%, with the highest prevalence
between age 50-80 3 8.
Pathogenesis
The pathophysiological process of gynecomastia
primarily involves an absolute or relative imbalance
between estrogen and androgen action at breast
tissue level 9-11.
Causes
The causes of gynecomastia can be distinguished
in absolute estrogen excess, absolute androgen
deficiency, relative estrogen excess/androgen deficiency, decreased androgen action.
An absolute estrogen excess directly stimulates
the growth of male breast tissue, and may be due
to endogenous estrogen overproduction as well as
exogenous estrogen administration.
Endogenous estrogen overproduction can origin
from the testis and from the adrenal gland, or from
an increased androgen aromatization.
Testis
Leydig cell tumors. Leydig cell tumors are rare,
representing the 3% of all testicular neoplasms.
The natural history is usually benign, and malignant
cases have been described in 10% of cases. They
are generally seen in young adults, although they
can occur at any age 12. Leydig cell tumors directly
produce high estrogen levels, which cause a luteinizing hormone (LH) suppression from the pituitary thus
leading to a reduction in the testicular testosterone
production. In this condition, there is an absolute
estradiol overproduction by the tumor, a reduction
of testicular testosterone production due to LH
suppression, and a sex hormone-binding globulin
(SHBG) elevation due to estrogen stimulation, thus
leading to a decrease in free testosterone concentration. All these situations contribute to the increase of
free estrogens/free androgens ratio.
Sertoli cell tumors. These tumors are very rare, and
usually benign, occurring in boys and young men.
These tumors do not directly secrete estrogens, but
overexpress aromatase, the enzyme catalyzing the
conversion of androgens to estrogens, thus leading to
increased androgen transformation to estrogens 13-15.
hCG secreting tumors. Human chorionic gonadotropin (hCG) is very close to LH in its structure and
action within the testis. Many germ cell tumors of
the testis secrete hCG together with different tumors origining from other organs. hCG preferentially
stimulates estradiol secretion from the testis, thus
contributing to a relative or absolute systemic estrogen excess.
Adrenal gland and increased androgen aromatization
Feminizing tumors. This type of tumors are generally
malignant, with a peak incidence in young and middle-aged men. This cancer may secrete estrogens
directly together with weak androgens (dehydroepiandrosterone – DHEA, androstenedione) that may be
aromatized into estrogens in peripheral tissues 16.
Increased aromatization to estrogens. Aromatase is
present in adipose tissue, in the testis, bone, brain,
muscle, hair follicles. Aromatase catalyzes the peripheral aromatization of androgens in estrogens.
All clinical conditions characterized by aromatase
overexpression lead to increased aromatization of
androgens to estrogens (i.e. Thyreotossicosis) 17 18.
Exogenous estrogen exposure. Unintentional exposure to estrogens may occur by means of food
(milk or meat from estrogen-treated cows), beer and
wine 19 20. However, these dietary estrogens are not
likely to be significant in men gynecomastia pathogenesis, unless we consider huge administration.
Absolute androgen deficiency. Primary hypogonadism of any cause can result in gynecomastia. An
absolute deficiency of testosterone contributes to a
relative estrogen excess 21 22.
Secondary hypogonadism: the lack of testicular stimulation by a deficient LH secretion by the pituitary
leads to a reduction of testosterone secretion by the
testis, with relative estrogen excess; this relative estrogen prevalence is further increased by the peripheral aromatization of adrenal androgen precursors.
Peripheral deficient androgen action. In partial and
complete androgen insensitivity syndromes, defective androgen receptor function results in a
157
M. Rossato, et al.
Figure 1. Schematic summary of the different pathogenetic processes leading to gynecomastia.
decreased androgen effect, thus leading to gynecomastia. The elevation of LH and follicle-stimulating
hormone (FSH) due to the lack of inhibitory feedback
at the pituitary leads to a further increase of estradiol
synthesis, thus worsening gynecomastia.
Relative estrogen excess/androgen deficiency. There
are many different causes of relative estrogen excess, leading to an altered androgen/estrogen ratio
as detailed in Figure 1.
Male breast cancer. Male breast cancer is rare, and
usually gynecomastia does not increase the risk of
future breast carcinoma development, excluding
patients affected by Klinefelter syndrome 23 24. The
clinical features suggestive of breast cancer in male
are a hard asymmetric mass fixed to the skin and/
or underlying tissues, skin ulceration, axillary lymphadenopathy or bloody nipple discharge. In the presence of these features, breast biopsy is mandatory.
Clinical evaluation
Gynecomastia requires a careful clinical history and
an accurate physical examination.
158
A family history of gynecomastia has been reported
in 58% of patients affected by pubertal gynecomastia; history can also be helpful to reveal a causative
drug (Table I), or symptoms of hepatic, renal dysfunction, testicular insufficiency, adrenal and thyroid
hyperfunction.
Physical examination has to differentiate between true
gynecomastia from fatty enlargement of the breast
without glandular proliferation (pseudogynecomastia);
if gynecomastia is present, the examination reveals a
firm, tender and mobile mound of tissues, usually bilateral – unilateral gynecomastia may actually represent
a step in the development of bilateral disease 5 11, but
it’s important to keep in mind that male breast cancer
usually presents as unilateral –. The subareolar breast
tissue has to be at least 2 cm in diameter; this limit
was chosen to ensure the presence of gynecomastia,
in fact if the tissue is smaller than that, gynecomastia
can be considered not to be present. It is suggested to
measure it as follows: with a finger at the superior inner quadrant and thumb at the inferior outer one, pick
up a firm disc of breast tissue from the chest wall and
measure its diameter with a flexible rule 25-28.
Table I. Drugs inducing gynecomastia and their pathophysiological mechanism of action.
Drug Class
Drug
Mechanism
Antiandrogens/inhibitors
of androgen synthesis
Cyproterone acetate
Flutamide
Finasteride
AR blockade or inhibition of androgen synthesis
Antibiotics
Ethionamide
Isoniazid
Ketoconazole
Metronidazole
Unknown
Unknown; possible refeeding gynecomastia
Antiulcer drugs
Cimetidine
Ranitidine
Omeprazole
AR blockade
Unknown
Adverse reaction; possible estrogen activity; possible decreased testosterone (induction of cytocrome metabolism*)
Cancer chemotherapeutic drugs
Alkylating agents
Methotrexate
Vinca alkaloids
Combination chemother
Nitrosureas
Imatinib
Busulfan
Destruction or inhibition of Leydig cells
Cardiovascular drugs
Amiodarone
Enalapril
Captopril
Digitoxin
Digitalis
Amlodipine
Diltiazem
Verapamil
Nifedipine
Reserpine
Spironolactone
Methyldopa
Unknown
Unknown
Drugs of abuse
Alcohol
Amphetamines
Heroin
Marijuana
Methadone
Increased aromatization of androgens to estrogens
Unknown
Decreased testosterone biosynthesis
AR blockade
Decreased testosterone biosynthesis
Hormones
Androgens
Anabolic steroids
Diethylstilbestrol
Human chorionic gonadotropin
Estrogens and estrogen agonists
Growth hormone
Medroxyprogesterone acetate
Oral contraceptives
Increased aromatization of androgens to estrogens
Reduction of DHT biosynthesis
Decreased testosterone or DHT biosynthesis
Estrogen-like activity
Estrogen-like activity
Unknown
Decreased testosterone or DHT biosynthesis AR blockade
Unknown
Exogenous estrogen
Stimulation of testicular estrogen secretion
Increased estrogen activity
Unknown
Exogenous estrogens
Exogenous estrogens
Psychoactive drugs
Diazepam
Haloperidol
Paroxetine
Phenothiazines
Risperidone
Tricyclic antidepressants
Unknown
Increased serum prolactin
Unknown
(continues)
159
M. Rossato, et al.
Table I – continued.
Other drugs
Auranofin
Diethylproprion
Domperidone
Etretinate
Metoclopramide
Phenytoin
D-penicillamine
Sulindac
Theophylline
Melatonin
Furosemide
Bumetanide
Clomiphene citrate
Efavirenz
Unknown
Unknown
Unknown
Unknown**
Increased serum prolactin
Unknown
Unknown
Unknown
Unknown
Increased estrogen activity
Unknown; possible efavirenz mediated estradiol-like effects***
AR: androgen receptor; * Rosenshein et al., 2004; ** Carmichael et al., 2004; *** Jover et al., 2004.
Gynecomastia can be classified in four grades with
increasing severity, on the basis of physical examination 29:
• grade I: increase in diameter and protrusion limited to the areolar region; grade I can be monolateral or bilateral. There is no inframammary fold,
adipose tissue accumulation;
• grade II: hypertrophy of all breast components;
the areola-nipple complex is above the inframammary fold, independently from the mammary volume increase;
• grade III: hypertrophy of all breast components;
the areola-nipple complex is at the same height
as, or about 1 cm below the inframammary fold;
• grade IV: hypertrophy of all breast components;
the areola-nipple complex is more than 1 cm
below the inframammary fold. This grade is characterized by marked cutaneous ptosis.
The presence of testis cancer has to be excluded. Anthropometric measurements (body mass index – BMI)
may also be helpful, because of the association of
obesity and gynecomastia, due to an increased peripheral conversion of androgens 4. It is also important
to reveal signs and symptoms of hypogonadism, adrenal and thyroid hyperfunction, liver or renal disease.
Management
Gynecomastia is a benign, usually self-limiting condition. Most cases of pubertal gynecomastia usually
resolve in less than one year 30; if clinical work-up
does not reveal significant underlying pathologies,
periodic follow-up is suggested. Obviously, each
medical condition causing gynecomastia has to be
investigated and, if present, treated. In particular,
medications, recreational drugs or nutritional exposure causing gynecomastia should be withdrawn
160
if possible. For asymptomatic long-standing stable
gynecomastia, no specific treatment is necessary.
For symptomatic gynecomastia or if associated with
psychological distress, pharmacological and/or surgical options have to be addressed (Fig. 2).
Treatment
Medical treatment options are generally most effective during the early, proliferative, active phase of
gynecomastia. As gynecomastia is the result of a
relative or absolute estrogen excess, medical therapy
is aimed to block estrogen effects in the breast tissue
or to decrease estrogen production, or to give androgens to counteract the effects of estrogens. To this
aim selective estrogen receptor modulators (SERMs)
appear to be very effective and fairly safe drugs 8.
Tamoxifen
Tamoxifen has been used for its anti-estrogenic
activity, and is commonly used as an effective treatment of female breast cancer. In men with gynecomastia, tamoxifen is being used in doses of 10-20
mg/day for 3-9 months. Although few randomized
double-blind placebo-controlled trials have limited a
strong scientific evidence, resolution of gynecomastia has been reported in up to 90% of the treated
men 31-34. If gynecomastia recurs on the medication
withdrawing, a second attempt is suggested. Tamoxifen is usually well-tolerated.
Raloxifene
Another member of the SERM family is raloxifene, a
molecule closely related with tamoxifen and found
to be effective in reducing mammary gland in boys
presenting pubertal gynecomastia at the dose of 60
mg/once daily for 3 to 9 months 35.
Figure 2. Diagnostic flowchart of gynecomastia.
Clomiphene
Clomiphene is another molecule used for its anti-estrogenic activity that has been used in the treatment
of gynecomastia but the results obtained (at the
dose of 50 mg/once daily for 1 to 3 months) have not
been so satisfying as those obtained with tamoxifen
and raloxifene 36.
Another class of drugs that has been used in the treatment of gynecomastia is that of aromatase inhibitors.
Testolactone
Testolactone, an old aromatase inhibitor, has been
reported to be effective in the treatment of gynecomastia (450 mg/daily for 2 to 6 months), although
with lower efficacy than tamoxifen 37.
Anastrazole
Anastrazole, a relatively novel aromatase inhibitor,
has been used to treat gynecomastia (1 mg/daily for
6 to 11 months) but with low efficacy compared with
tamoxifen 38 39.
Androgens
Androgens have been used to reduce the gonado-
tropins secretion and to increase the androgenestrogen ratio. Testosterone is an obvious treatment possibly leading to the resolution of gynecomastia in male hypogonadism, but since it can
be aromatized to estradiol, testosterone treatment
may also lead to worsening of gynecomastia in
some men. To this regard, dihydrotestosterone,
a non-aromatizable androgen, has been used to
treat gynecomastia as local topical application,
and it has been shown to be effective in some
forms of gynecomastia 40.
In previous years, danazole, an androgen with weak
activity, has also been used (400 mg/daily) to reduce
gonadotropin secretion and thus testicular estradiol
production with some effect in the reduction of gynecomastia 41.
Radiotherapy
Radiotherapy directed at the mammary gland has
been previously utilized to prevent gynecomastia in
men with prostate cancer, and in pubertal boys with
gynecomastia, but in this case the long-term risk of
breast cancer due to radiation exposure is a significant concern limiting its use 42.
161
M. Rossato, et al.
Surgery
If gynecomastia has been present for more than one
year, fibrotic tissue replaces the glandular tissue
component, and thus it is unlikely its regression either spontaneously or with pharmacological therapy.
In such circumstances, surgical mastectomy or USassisted liposuction and suction-assisted lipectomy
are the best cosmetic options 43-45.
Conclusions
Gynecomastia is a relatively common clinical condition. Usually a careful clinical history and physical
examination are sufficient to identify the possible different causes ranging from pubertal gynecomastia,
drug-induced causes, or an underlying pathological
condition. The likelihood of discovering a pathological condition is low in patients with long standing asymptomatic gynecomastia. Since often these
situations resolve spontaneously (as well as pubertal
gynecomastia in a large part of pubertal boys), periodic clinical follow-up is usually sufficient to manage
these patients. Other conditions resolve promptly
after suspension of a drug causing gynecomastia.
In adults showing acute onset of gynecomastia
without an reliable cause, hormonal evaluation (hCG,
testosterone, LH and estradiol plasma levels) should
be performed to rule out pathological potentially
harmful conditions that have to be treated.
Pharmacological treatment with anti-estrogens (tamoxifen as detailed previously) may be suggested. If
the gynecomastia has not regressed by 12 months, or
in patients suffering with long-standing gynecomastia
who are psychologically embarassed by their physical
appearance, pharmacological treatment is not advisable given its possible inefficacy due to fibrotic tissue
proliferation within the breast. Thus surgical removal
of the mammary gland and subareolar fat is an option
that has quite good cosmetic and psychological result
in the large part of patients. Mammography and breast
biopsy are necessary if gynecomastia is of recent
rapid appearance, unilateral, firm, irregular and associated to mastodynia and skin retraction.
For patients who are completely asymptomatic, that
are not troubled by their gynecomastia, and do not
have a significant history or physical examination, no
further clinical evaluation nor pharmacological treatment is advisable other than weight reduction.
Acknowledgments
The Authors wish to thank Francesco Tresca for his
help in the preparation of figures.
162
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163
original article
Chlamydia trachomatis infection:
the urologist’s point of view
T. Cai1, S. Mazzoli2, N. Mondaini3, G. Malossini1, R. Bartoletti3
Department of Urology, Santa Chiara Hospital, Trento; 2 Sexually Transmitted Disease Centre, Santa Maria Annunziata Hospital, Florence; 3 Department of Urology, University of Florence
1
Summary
The role of Chlamydia trachomatis in everyday clinical practice is now on the
increase because Chlamydia trachomatis infections are the most prevalent
sexually transmitted bacterial infections worldwide. Chlamydia trachomatis
can cause urethritis, cervicitis, pharyngitis, or epididymitis, although asymptomatic infections are quite common. Chlamydia trachomatis infection
remains asymptomatic in approximately 50% of infected men and 70% of
infected women, with risk for reproductive tract sequelae both in women and
men. A proper early diagnosis and treatment is essential in order to prevent
persistent consequences. An accurate comprehension of the pathology,
diagnosis and treatment of this entity is essential for the urologist. We review
the literature about the new findings in diagnosis and treatment of Chlamydia
trachomatis infection in sexually active young men.
Key words
Chlamydia trachomatis • Prostatitis • Sexually transmitted diseases • Infection • Quinolones • Sexually active young men
Introduction
Sexually transmitted diseases (STDs) are among the first ten causes of
unpleasant diseases in young adult males in developing countries and
the second major cause of unpleasant diseases in young adult women, with an enormous health and economic consequences 1. Among
these, Chlamydia trachomatis (Ct) is the most common sexually transmitted bacterium worldwide 2 with over three million new infections per
year3. In particular, Chlamydia is the most frequently reported sexually
transmitted infection in Europe and the number of cases is steadily
increasing, with more than 255,000 cases in people below 25 years
of age 4. Ct infection could remain asymptomatic in about 70% of
cases 5-6. Ct infection long-term effects include ectopic pregnancy and
tubal inflammation with subsequent infertility 6-7. Absence of symptoms increases the risk of infecting sexual partners and may cause
long-term complications in men too, such as poor quality of semen
and infertility 5 7. Several factors contribute to make difficult detecting Ct by a conventional analysis 8. To date, the DNA recombination
techniques are universally accepted as the “gold standard” to evaluate the presence of Ct in biologic samples 9. However, immunologic
markers of Ct infection such as immunoglobulin A (IgA) antibody and
Tommaso Cai, Department of Urology, Santa Chiara Hospital, Largo Medaglie d’Oro 9, Trento, Italy – Tel. +39 0461 903306 – Fax +39 0461 903101 – E-mail: ktommy@
libero.it
164
Chlamydia trachomatis in sexually active young men
cytokines have been detected in total ejaculate and
seminal plasma samples to demonstrate their role in
monitoring men with CP 10-11. Moreover, the proper
treatment of urological Ct infection is not totally indicated. For these reasons, Ct represents a challenge
for the urologist both for diagnostic and treatment.
We summarize the most current developments in the
diagnostics and therapeutic approaches in Ct infections in sexually active young men.
Materials and methods
We conducted a search of the English-language
literature from 1960 through December 2010 with
use of the Medline computerized database of the US
National Library of Medicine (http://www.ncbi.nlm.
nih.gov/pubmed). The Medline search have been
divided into two sections: diagnosis and therapy.
The first review section about diagnosis has been
carried-out by using the following Medical Subject
Headings and free text terms: “Chlamydia trachomatis”, and “Chlamydia infections” (exploded) were
combined with the terms “diagnosis”, “urine”, “urethral swab”, “total ejaculate”, “serum”, “antibodies,
“prostate massage” and then limited to humans,
male and young adult: 19-24 years. The second
review section about therapy has been carried-out
by using the following Medical Subject Headings
and free text terms: “Chlamydia trachomatis”, and
“Chlamydia infections” (exploded) were combined
with the terms “treatment”, “therapy”, “antibiotic”,
“drug”, “quinolones”, “tetracycline” and then limited to humans, male and young adult: 19-24 years.
Moreover, we searched reference lists of articles to
identify potential additional references. All original
paper and review studies of Ct diagnosis and treatment in young adult have been considered for this
review. We considered also guidelines from the
National Institute for Health and Clinical Excellence
and the European Centre for Disease Prevention
and Control, the US Centers for Disease Control and
Prevention, and World Health Organization.
Results
Ct diagnosis
From an initial literature search with 188 unique
citations, a total of 27 articles were selected for
the present review. A matched research between
“Chlamydia trachomatis” and “Chlamydia infections”
(exploded) and the following terms “total ejaculated”
and “prostate massage” has not found any items.
Diagnosis of Ct infection can be made by using:
• direct detection;
• indirect detection.
Direct detection
Ct is an obligate intracellular bacterium and cell
culture remains a reference method (about 100%
specificity) 13. However, all Authors are agree that
it is not recommended for routine use, due to its
lack of sensitivity, its technical complexity and the
long turn-around time 14. Other Authors suggest that
Ct can be found by using antigen-based detection
methods 13. In particular, direct fluorescent staining with monoclonal antibodies (DFA) and enzyme
immunoassay (EIA). EIA tests are more reproducible than DFA, and the sensitivity of the best EIA is
comparable to that of culture but lower than that of
nucleic acid amplification tests (NAATs), due to the
cross-reactions with the lipopolysaccharide (LPS) of
other microorganisms 13. Recently, Mahilum-Tapay
and co-workers, evaluated the performance of the
Chlamydia Rapid Test, a new assay developed at
the Diagnostics Development Unit, University of
Cambridge 15. They compared sensitivity, specificity,
positive predictive value, and negative predictive
value of the Chlamydia Rapid Test with the gold
standard test for Ct infections (NAATs) 15. In this
study, they found a good diagnostic performance:
sensitivity 83.5%, specificity 98.9%, positive predictive value 86.7%, and negative predictive value
98.6% 15. However, NAATs are the tests of choice
for the diagnosis of Ct genital infections 13. In everyday clinical practice, several commercial NAATs are
available, and make use of different technologies:
PCR and real-time PCR (Roche Diagnostics, Abbott,
IL, USA); strand displacement amplification (Becton
Dickinson, NJ, USA); transcription-mediated amplification (Gen Probe); and nucleic acid sequencebased amplification (bioMerieux, Nancy L’Etoile,
France) 13 16. These assays are automated and can
be used for screening programmes and for the detection of Ct and Neisseria gonorrhoeae in the same
specimen 13. We currently used Roche COBAS AMPLICOR CT/NG reagents kits and instruments (Roche Molecular Systems,Branchburg, NJ) with good
level of accuracy 8. NAATs tests generally show two
important drawbacks: the cost and the presence
of inhibitors in specimens. However, they show a
high specificity 13. Finally, in 2006, a new C. trachomatis variant belonging to serovar E, with a 377-bp
deletion in the cryptic plasmid, was described in
Sweden 17. This new variant can obviously not be
detected by amplification tests targeting the deleted
165
T. Cai, et al.
area, but can be detected by amplification targeting
a chromosomal gene, e.g. ompA or a rRNA gene 17.
However, new versions of the COBAS Taqman
v2.0 test and of the Abbott test allow simultaneous
detection of the cryptic plasmid and of ompA, and
simultaneous detection of two different regions of
the cryptic plasmid, respectively 17.
Indirect detection
A recent review by Persson suggested that serology is useful only in some cases of Ct infection
and in seroepidemiological studies 18. On the other
hand, recent evidences showed that anti-Ct immunoglobulin A (IgA) in association with interleukin 8
(IL-8) evaluation appear to be the best immunologic
markers of chronic chlamydial prostatitis status 8.
Mazzoli and co-workers, highlighted, in 78 consecutive patients with a diagnosis of chronic prostatitis
due to Ct infection by IPAzyme Chlamydia IgG/IgA
by Savyon Diagnostics (Ashdod, Israel), an immuneperoxidase test, the role of immune system activation in the pathophysiology of chronic prostatitis due
to Ct infection and that seminal IL-8 and mucosal
IgA levels specific to Ct antigens appear to be the
best immunologic markers of chronic chlamydial
prostatitis status 8. They, however, did not showed
any role of serum anti-Ct immunoglobulin in Ct infection diagnosis 8.
Chlamydia trachomatis therapy
From an initial literature search with 164 unique
citations, a total of 18 articles were selected for
the present review. A matched research between
“Chlamydia trachomatis” and “Chlamydia infections”
(exploded) and the following terms “quinolones” has
not found any items.
A recent review by suggested that antimicrobial
groups effective against Ct include the macrolides,
tetracyclines, quinolones and penicillin’s 19. The
European Urological Association and the Centers
for Disease Control and Prevention guidelines suggested that doxycycline and azithromycin are considered to be equally effective in the treatment of
chlamydial infections 2 12. However, in management
and treatment of patients affected by Ct infections
the following factors should be taken into account:
a) Chlamydia are only metabolically active in the host
cell and therefore only targeted intracellularly by
antibiotics. b) Intracellularly accumulated antibiotics are tetracyclines, macrolides and quinolones 2 12.
Even if doxycycline and azithromycin are the most
widely prescribed drugs in Ct infections treatment
and recommended as the primary approach, other
166
fluoroquinolones such as ofloxacin or levofloxacin
are suggested as alternative drugs 2. Moreover,
although little is known about Ct survival in the
presence of fluoroquinolones, it is well known that
after multiple cultivation passages resistant mutant
for some fluoroquinolones were determined 20. In a
recent report, Smelov and co-workers suggested
that ofloxacin could be recommended as the primary
drug in the treatment of Chlamydia-infected patients
with CP, due to its pharmacokinetic parameters 20.
Moreover, the same Authors stated that the decision
on the prescription of pefloxacin or lomefloxacin
should be made individually, but ciprofloxacin treatment is not suggested 20. The Authors, however,
concluded that the conditions of in vitro susceptibility studies are incompatible with the infection as
it occurs in vivo even if could be useful to include
investigations for antibiotic susceptibility in every
patient prior to treatment 20. In a recent study Cai
et al., by means of a prospective, randomized and
open-label study on 221 patients affected by chronic
prostatitis due to Ct infection who had undergone
oral administered prulifloxacin 600 mg once daily for
14 days or doxycycline 100 mg orally twice daily for
21 days, found that prulifloxacin was equivalent to
the standard therapy 21. In this study, moreover, the
Authors showed that prulifloxacin was superior over
standard therapy in microbiological efficacy rates
in terms of mucosal IgA and IL-8 levels decreasing 21. This effect should be probably, due to an
anti-inflammatory effect of quinolones. The role of
pro-inflammatory cytokines such as IL-6 or IL-8 in Ct
infection is well established, discussed and used not
only in the diagnosis phase but also in management
and therapy control 8 21-23. Several reports, in fact,
suggested that IL-8 evaluation should be used, not
only as a Ct infection marker, but also as a marker
of therapy efficacy 8 21. The role of molecular markers
in the management of Ct infections is, thus, clinically useful and suggested. Mazzoli et al., recently,
demonstrated that patients who had reported the
higher mean value for IL-8 and massive presence of
mucosal IgA, making evident a strong inflammation
and a correlation with the higher level of pain and
a worse quality of life, with a significant correlation
between IL-8 and IgA values and NIH-CPSI subscale
scores 8. Moreover, in the clinical practice, Cai et al.
found a good relationship between IL-8 and NIHCPSI, demonstrating that an improvement in QoL
(NIH-CPSI decreasing) is related to a decrease in IL8 levels after theapy 21. In addition, an important role
should be given to mucosal IgA anti-Ct evaluation.
Some authors have demonstrated, in animal model,
Chlamydia trachomatis in sexually active young men
Table I. Randomized, controlled, clinical trials.
Author/
year
Drugs
Patient
number
Clinical
efficacy
(%)
Microbiological
efficacy (%)
Microbiological
markers
Cai T
(2009)
Prulifloxacin/doxicicline
221
82.5
47.7
IL-8/IgA
Whatley JD
(1991)
Azithromycin/doxicicline
62
-
-
-
Jeskanen L
(1989)
Ciprofloxacin/doxicicline
200
74
-
-
Stolz E
(1986)
Ciprofloxacin 250/ciprofloxacin 500
212
100
100
-
that a high production of IgA in genital tract secretions seems related to the presence, persistence,
and accumulation of Th2 MoPn cells in the genital
tract during chronic infections, with the consequent
inability to clear the infection 23. In particular, the
presence of an active chronic infection in patients
affected by Ct infection is also well correlated to the
presence of high levels of anti-Heat Shock Protein 60
(anti-HSP60) mucosal IgA antibodies, as proved by
the high percentage of IgA positive patients showing in western blot analysis an immunoreactions
towards high molecular weight proteins, especially
MOMP2 and HS60 8. This anti-HSP60 immunization
suggests chronic or repeated stimulation from an
endemic source of the microrganism 24, proved by
the presence of CT DNA found in young sexually
active patients affected by chronic prostatitis due to
Ct infection. Finally, any correlation between serum
IgA or IgG and the other Ct maker of infections, or
any significant change before or after therapy, have
been reported21. In fact, the role of serum IgA or IgG
anti-Ct in early diagnosis of infection and early treatment has been reported for women’s infection, but
not, up to the moment, for males 25. Clinical trials
carried out with the aim to test the microbiological or
clinical efficacy of antibiotics different to quinolones,
are very few. In a recent experience, Takahashi and
coworkers, showed a good clinical cure rate (77%)
by using a single-dose of azithromycin (1000 mg) for
13 patients with urethritis due to Ct infection 26. The
Authors concluded that a single-dose azithromycin
regimen was well tolerated and eradicated potential pathogens of NGU 26. This study, however, has
been carried out in a small cohort of patients and in
inhomogeneous group of patients. In conclusions,
the potential of Ct to develop antimicrobial resistance has not been well studied, although some case
reports suggest resistance as a cause of treatment
failure 27-29. The Table I summarized all randomized,
controlled studies in management of Ct infection in
young male patients.
Conclusions
In conclusion, additional studies of the effectiveness of the common diagnostic tests for Ct infection
would be valuable. In addition, better natural history
data on the timing of male genital Ct infection and
development of more accurate, noninvasive tools
to assess chlamydial sequelae are essential to plan
a correct treatment schedule. Finally, clinical trials
should be planned in order to evaluate the real frequency of Ct resistance to standard therapy.
References
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2
Centers for Disease Control. Sexually transmitted diseases treatment Guidelines. 2002;51(RR-6):32-6.
3
Groseclose SL, Zaidi AA, DeLisle SJ, et al. Estimated
incidence and prevalence of genital Chlamydia trachomatis infections in the United States, 1996. Sex Transm
Dis 1999;26:339-44.
4
http://www.ecdc.europa.eu/en/healthtopics/spotlight/
chlamydia/Pages/KeyMessage1.aspx.
5
Mazzoli S, Cai T, Addonisio P, et al. Chlamydia trachomatis infection is related to poor semen quality in
young prostatitis patients. Eur Urol 2009;57:708-14.
6
Park IU, Amey A, Creegan L, et al. Retesting for repeat chlamydial infection: family planning provider
knowledge, attitudes, and practices. J Womens Health
(Larchmt) 2010;19:1139-44.
7
Schachter J, Caldwell HD. Chlamydiae. Annu Rev Microbiol 1980;34:285-309.
8
Mazzoli S, Cai T, Rupealta V, et al. Interleukin 8 and
anti-Chlamydia trachomatis mucosal IgA as urogenital
immunologic markers in patients with C. trachomatis
prostatic infection. Eur Urol 2007;51:1385-93.
1
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10
11
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14
15
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18
19
20
Petzold D, Gross G, editors. Diagnostik und therapie
sexuell übertragbarer Krankheiten. Leitlinien 2001 der
Deutschen STD-Gesellschaft. Berlin; Springer 2001.
Wagenlehner FME, Weidner W, Naber KG. Chlamydial
infections in urology. World J Urol 2006;24:4-12.
Ostaszewska-Puchalska I, Zdrodowska-Stefanow B,
Badyda J, et al. Anti-chlamydial antibodies in the serum and expressed prostatic secretion in prostatitis.
Arch Immunol Ther Exp (Warsz) 2004;52:277-83.
Naber KG, Bergman B, Bishop MC, et al. EAU guidelines for the management of urinary and male genital
tract infections. Urinary Tract Infection (UTI) Working
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Bébéar C, de Barbeyrac B. Genital Chlamydia trachomatis infections. Clin Microbiol Infect 2009;15:4-10.
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Mahilum-Tapay L, Laitila V, Wawrzyniak JJ, et al. New
point of care Chlamydia Rapid Test--bridging the gap
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original article
Peyronie’s disease: endocavernous plaque excision
without substitutive graft:
critical 5-year experience
F. Mantovani, E. Tondelli, G. Cozzi, I. Oliva, E. Finkelberg, M. Talso, D. Varisco, C. Palumbo, F. Rocco
Clinica Urologica I, Università di Milano, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milano
Summary
Key words
Peyronie’s disease • Plaque excision technique
Objective. in 2004 the polish colleague Darewicz published his surgical experience of endocavernous plaque excision avoiding the use of any substitutive graft. Attracted by the extreme simplification in this new technique, we
decided to verify such a surgical approach.
Material and methods. the separation of the plaque from overlying albuginea is performed with scissors or scalpel. Once the plaque is removed, the
cavernous incision is sutured and the correct straightening is verified. In 5
years we selected 18 cases of stabilized disease and preserved erection
geometrically disturbed by the severe deformity.
Results. we obtained in all cases substantial straightening, even if in 2 cases
we added a complementary minimally invasive surgery in form of plication,
and 2 cases were converted in graft technique.
Conclusions. case study and current controls allow us to say the impression is quite good, without the necessity of autologous tissue or heterologous
matrices to be inserted, allowing a more comfortable post-operative course
and a faster and easier functional recovery.
Introduction
Despite the open and actual debate about the ideal graft to use after
plaque excision in Peyronie’s disease treatment, the polish colleague
Darewicz published his surgical experience of endocavernous plaque
excision avoiding any substitutive graft.
By an incision on the albuginea close to the plaque, the fibrotic tissue
can be exposed and after its removal the incision is sutured. Attracted
by the extreme simplification in this new technique, we decided to
verify such a surgical approach.
Material and Methods
The operation can be performed in any kind of anaesthesia. We usually
prefer local anaesthesia with Bupivacaine 5% 20 ml at the penis base.
After coronaric incision and penile degloving, the urethral-cavernous
anatomy is given complete evidence.
F. Mantovani, Clinica Urologica I, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, via Commenda 15, 20122 Milano, Italy – Tel. +39 02 5503 4509 – Email: [email protected]
169
F. Mantovani, et al.
Figure 3. Anatomical identification of the 3 layers: Plaque, Albuginea, Bundle (PAB).
Figure 1. Endocavernous plaque excision by scissors.
Figure 2. Endocavernous clearance even of
the smallest plaques.
The albuginea is incised till the erectile tissue, which
is moved by blunt, few millimetres at the side of the
plaque and for its length, or at the opposite site in
case of lateral bending.
The separation of the hardened lesion from the overlying albuginea is performed with scissors or scalpel
(Fig. 1); this cleavage plane is clearly identified only
during surgery, otherwise the procedure is converted into traditional plaque excision with substitutive
graft. Once the plaque is removed, the cavernous
incision is sutured and the correct straightening is
verified. The operation concludes with penile reassembly and adherent medication.
In case of staghorn plaque developed along the
synusoids, by a single cavernous incision, the clearance of all the parts of the plaque can be performed
including the smallest, just like in pyelolithotomy
(Fig. 2).
Separation of Plaque, Albuginea and neurovascolar
Bundle (PAB) is the demonstration of the anatomical
feasibility of this operation (Fig. 3).
In 5 years we selected 18 cases, with stabilized
170
disease and preserved erection but geometrically
disturbed for the severe deformity.
Results
We obtained in all cases substantial straightening, even if in 2 cases we added a complementary
minimally invasive surgery in form of plication, and 2
cases were converted in graft technique.
Conclusions
PAB just takes away any doubt about the surgical
anatomy of this operation, which can be preferred to
other ones, less simple and more charged of risk and
complications, in order to prevent juridical troubles
too.
Peyronie’s disease surgical treatment is critical for
everyone: our efforts are in favour of easier approaches and better outcomes.
References
Darewicz JS, Darewicz BA, Galek LM, Kudelski J, Badri
BM. Surgical treatment of Peyronie’s disease by the intracavernosal plaque excision method: a new surgical technique. Eur Urol 2004;45:77-81.
original article
Corporoplasty with soft axial tutors and safenous
grafting. Following three years
La corporoplastica con tutore assiale soffice di piccolo
calibro e grafting di safena. Osservazioni di tecnica
chirurgica e follow-up a tre anni
M. Silvani, S. Pecoraro*, A. Zucchi**
Department of Urology, ASL BI Hospitals Infermi, Biella; * Department of Urology and Andrology, Clinica “Malzoni”,
Avellino; ** Clinical Urological and Andrological University, Perugia
Summary
Key words
Peyronie’s disease • Plaque surgery •
Safenous grafting
Peyronie’s disease (PPI) is today an andrological disease in which we know,
better than in past time, aethiological and pathogenetic mechanisms, but far
are ideal therapeutical solutions, till now. Lots of therapeutical options are at
the moment shown, but no one of these has demonstrated to be the best
in efficacy. 0,3-2% of men are affected to PPI and the physical and psychological problem are of relevant importance. Medical therapy has the only role
to try to slow down or stop the developing of cheloids plaques, from the
first clinical acute phlogystic phase to the cronic evolution on subalbugineal
fascia. PPI has an irregular but slow clinic evolution, “a pousseè” alternating
acute development to apparent relief.
Medical therapy is recommended in patients characterized by:
• early phase illness;
• unstable progressive plaque;
• painful erections.
Patients refusing surgery, or clinical intercurrent controindications.
Nowadays is stated conservative therapy for PPI show itself as absolutely
lacking of universally accepted protocols or acknowledgement. No standardized therapy is defined for PPI.
Clinically we can recognize two separate phases of illness:
Active: clinical duration perhaps 12-18 months, accompanied with painful
erections, sometimes associated to recurvatum.
Chronic: frequent erectile dysfunction, presence of recurvatum, progressive
shortening of penis length, rarely arriving to micropoenis.
Main pathological factor in stabile disease is plaque, representing the main
characteristic of illness.
Surgery is preferred in chronical stabilized phase, in which we try to reach
the following objectives:
1) penile straigthening;
2) penile lengthening;
3) return to penetrative coital activity.
Mauro Silvani, Direttore f.f. s.c. Urologia ASL BI, Ospedale degli Infermi, Biella, Italy – Tel. 339210402– E-mail: [email protected]
171
M. Silvani, et al.
Introduzione
L’induratio penis plastica (IPP) è una malattia della
quale oggi si conoscono meglio, rispetto al passato,
i possibili meccanismi etiopatogenetici ma per la
quale sono ancora lontane le soluzioni ideali. Innumerevoli tuttavia sono le bandiere terapeutiche che
sventolano orgogliose del proprio messaggio curativo, del quale ognuno ostenta la propria efficacia. La
IPP colpisce lo 0,3-2% degli uomini costituendo un
problema fisico e psicologico rilevante. La terapia
medica e farmaco fisica sono concepite esclusivamente con la finalità di rallentare o meglio arrestare
l’evoluzione della malattia, dalla fase flogistico acuta
verso, quella cronica impedendo la formazione del
cheloide sub fasciale albugineo. In realtà la malattia
di La Peyronie ha un andamento capriccioso ma
lentamente evolutivo a poussèe, con riacutizzazione
e remissione.
La terapia medica è indicata in pazienti con:
• malattia in fase precoce;
• placca, deformità instabile o in progressione;
• erezioni dolorose;
• rifiuto o controindicazioni assolute alla chirurgia.
Ad oggi si può affermare che la terapia conservativa
dell’induratio penis plastica è articolata e dispersiva,
in assenza di protocolli universalmente accettati e
riconosciuti. Non esiste uno standard terapeutico
per la malattia di La Peyronie. Sul piano clinico la
malattia decorre in due fasi:
• attiva: durata 12-18 mesi (dolore in erezione, possibile recurvatum);
• cronica: (possibile disfunzione erettile, tecurvatum, accorciamento progressivo del pene, fino al
micropene).
Il fattore patologico centrale della malattia stabilizzata è la placca che risulta coinvolta in tutti i sintomi
della IPP. La terapia chirurgica è riservata preferibilmente alla fase cronica stabilizzata della malattia ed
solo sintomatica con i seguenti obiettivi:
1. raddrizzamento del pene;
2. allungamento;
3. ripristino della capacità penetrativa e coitale.
Opzioni chirurgiche
Le scelte tecniche sono costituite dalla:
1. Chirurgia di placca. È indicata in caso di:
- malattia stabilizzata;
- placca singola non infiltrante il tessuto erettile
sottostante;
- buona rigidità erettile.
Si esegue un’incisione di rilassamento della placca e si innesta un graft di tessuto autologo o un
172
patch eterologo. Le tecniche di escissione sono
ormai abbandonate per le note sequele funzionali. Tra le diverse tecniche spicca la corporoplastica con principi geometrici secondo Paulo Egydio
che, prevede l’utilizzo di un patch di collagene di
matrice di pericardio bovino. Si tratta di procedura
complessa che richiede una serie di misurazioni,
eseguite in erezione, e finalizzate al calcolo delle
esatte dimensioni del patch. L’erezione viene realizzata con iniezione intracavernosa di Pge1 che
è da preferire rispetto alla idraulica. Quest’ultima
modalità di erezione indotta può deformare le
linee di forza del pene determinando misurazioni
incongrue del patch. Per la realizzazione della
chirurgia di placca è mandatoria una perfetta integrità erettile pre-intervento.
2. Tecniche di correzione del recurvatum con accorciamento selettivo dell’albuginea
Intervento di Nesbit o Yachia. Si tratta di un minimalismo chirurgico. I risultati estetici sono insoddisfacenti. La riduzione di lunghezza dell’asta è
proporzionale al grado di recurvatum e può essere
calcolata misurando la differenza tra la curva maggiore e quella minore con il pene in completa erezione. È una tecnica diffusamente praticata nelle S.C.
urologiche per la facilità di esecuzione. È riservata
ai pazienti con asta non corta e recurvatum laterale
o ventrale non superiore ai 35-40°, età avanzata,
presenza di fattori di comorbilità che aumentano
il rischio operatorio. Il vantaggio possibile di tale
tecnica è costituito dal fatto che accorciando l’asta
diminuisce il volume dei cc e pertanto possono
essere corrette alcune forme di disfunzione erettile,
specie se su base veno-occlusiva.
3. Chirurgia di placca unitamente ad impianto protesico
Occorre differenziare in questa categoria i pazienti
con recurvatum e deficit erettile severo e pazienti
con recurvatum e deficit erettile lieve moderata.
Per i primi è prevista l’implantologia protesica
idraulica e l’incisione di placca con innesto di patch
eterologo o semplice manovra di Wilson o anche la
sola incisione della placca senza rivestimento del
corpo cavernoso con patch eterologo. Ai pazienti
con recurvatum e deficit erettile lieve-moderato
è possibile invece, riservare l’impianto di tutore
a spinta assiale soffice di piccolo calibro con
incisione di rilassamento di placca ed innesto di
monograft safenico prelevato alla cross. La tecnica
messo a punto dal prof. E. Austoni e collaboratori
è stata divulgata largamente attraverso la Scuola
Itinerante di Andrologia e trova oggi applicazione
in diverse realtà urologiche italiane (Fig. 1).
Obiettivi
Lo scopo di questo articolo è quello di comunicare la
propria personale esperienza e gli accorgimenti tecnici apportati alla tecnica originale del prof. E. Austoni. Tali riflessioni nascono dalle difficoltà tecniche in
cui gli Autori si sono imbattuti al tavolo operatorio di
fronte a situazioni apparentemente di relativa semplice soluzione ma in realtà di elevata complessità
ove, non è stato possibile rispettare rigorosamente
la tecnica originale.
Ricordiamo innanzitutto i principi chirurgici della tecnica del prof. E. Austoni:
• impianto mininvasivo di tutore assiale soffice
di calibro 9-10 mm e di 2 cm più lungo dei con
l’obiettivo di evidenziare in modo ottimale la sede
del recurvatum;
• unica calibrazione dei cc con Hegar 10 onde risparmiare al massimo il tessuto cavernoso;
• incisione di rilassamento della tonaca albuginea
autoregolata, guidata sulla spinta del tutore soffice con, risparmio del tessuto erettile sottostante.
L’incisione determina una losanga ad angoli acuti
parauretrali ed ha massima estensione nella parte
concava dell’albuginea (Fig. 2);
• la losanga viene ricoperta con un graft di safena
prelevata alla cross. Anche un graft esiguo per
dimensioni, grazie alle caratteristiche di elasticità
della safena stessa può rivestire difetti ampi di
albuginea. L’anastomosi safeno-albuginea è confezionata con monofilamento tre zeri in continua
incavigliata (Fig. 3);
• l’intervento è completato con l’esecuzione di una
circoncisione regolata e un drenaggio sub dartoico in aspirazione. La medicazione è eseguita
in modo contenitivo non compressivo in scarico
così da favorire le erezioni notturne e permettere
il drenaggio delle secrezioni siero ematiche.
Figura 2. Graft safenico prelevato alla cross.
bro 7 fr a rigidità differenziata con l’obiettivo di:
• risparmiare quanto più possibile il tessuto
erettile dislocato a lato del tutore;
• favorire la penetrazione;
• rendere la presenza del tutore nascondibile;
2. la lunghezza del tutore supera di solo 1 cm quella
dei corpi cavernosi. Questa scelta deriva dalle
seguenti constatazioni:
• la liberazione del fascio vascolo nervoso dorsale, è spesso non agevole e completa nella
IPP poiché, interessato dalla fibrosi albuginea.
Se eccessivamente scheletrizzato e in tensione sono possibili disturbi trofici del glande fino
alla necrosi dello stesso;
• un tutore eccessivamente lungo sul piano
estetico configura un pene eretto e non esteFigura 3. Graft safenico disteso sul difetto albugineo a rivestire il
tessuto cavernoso.
Rispetto alla tecnica descritta gli Autori hanno adottato i seguenti accorgimenti:
1. impianto di tutore assiale soffice di piccolo cali-
Figura 1.
173
M. Silvani, et al.
so come invece prevede la tecnica originale
(Figg. 4-6);
• incisione della placca con bisturi lama undici
utilizzando in tale fase anche un sistema di
magnificazione ottica (Loops x 2,5-3) al fine
di ottimizzare il risparmio del tessuto erettile
sottostante;
3. nei casi di recurvatum superiori a 50°-60° gli
autori utilizzano al posto della safena un patch di
matrice di collagene di pericardio bovino. Questo
soluzione deriva dalla constatazione che, per
curvature severe, la losanga che si determina incidendo la tonaca albuginea, presenta dimensioni
cospicue e non risulta agevolmente rivestibile
con un solo monograft safenico. Il tipo di patch
utilizato (Hydrix) presenta caratteristiche di particolare sofficità e maneggevolezza. Dopo solo 72
ore dall’innesto il patch è inoculato nel tessuto
ospite e dopo 3 mesi non è più distinguibile dal
tessuto albugineo;
4. nei casi di placca parzialmente calcifica è consigliabile per agevolare l’innesto della safena o del
patch sub lussare sul versante endocavernoso la
placca.
La tecnica descritta è applicabile a tutti i tipi di recurvatum: dorsale puro, dorso-laterale dx o sx e laterale
nonché ventrale. Nel recurvatum laterale e ventrale
esistono tuttavia alcuni accorgimenti rispettare.
Figura 4. Perfetta congruità del graft safenico sulla losanga di albuginea disegnata dall’incisione della placca nel punto di maggior
recurvatum.
Figura 5 (gentile concessione prof. E. Austoni). Lunghezza del
tutore: 1 cm più lungo dei corpi cavernosi (tecnica originale del
prof. E. Austoni 2 cm).
Recurvatum laterale puro
Si tratta di una situazione non agevole. In tal caso
la lunghezza dei due tutori dovrà comunque, essere
la stessa per entrambi i corpi cavernosi. La liberazione del fascio vascolonervoso dorsale (FVND)
deve essere sempre molto accurata, deve iniziare
con incisione parauretrale della fascia di Buck dal
lato sede di curvatura ed estesa fino alla superficie
laterale del corpo cavernoso opposto alla sede di
recurvatum. Gli autori isolano anche l’uretra fino al
piatto uretrale dal lato sede della curvatura. L’incisione dell’albuginea avviene pertanto coinvolgendo il
corpo cavernoso sede di recurvatum dorsalmente e
ventralmente. In questo caso l’albuginea del cc sede
del recurvatum viene incisa da ore 12 ad ore 6, cioè
dal lato dorsale fino a quello ventrale a semicerchio
e si innesta poi il graft o il patch. Il risultato è una
correzione completa del recurvatum laterale.
Figura 6. Allungamento del pene da 1,2 a 2,3 cm (casistica Silvani
& Pecoraro).
Recurvatum ventrale
Si tratta della situazione più complessa in cui l’intervento prevede l’isolamento del FVND e dell’uretra
pendula nella sede di recurvatum. In questa situazione conviene comunque isolare estesamente il FVND
174
nella sede opposta a quella della curvatura onde
permettere una leggera ipercorrezione del recurvatum stesso. La particolare attenzione in tal caso va
riposta nella liberazione anatomica dell’uretra dal
piatto ventrale dei cc evitando la scheletrizzazione e
le manipolazioni eccessive che pure possono avere
riflessi negativi sulla vascolarizzazione dell’uretra
stessa e del glande.
Materiali e metodi
Con tale tecnica chirurgica dal settembre 2005 al
dicembre 2008 gli Autori hanno sottoposto a intervento 48 pazienti, età 44-76 anni. Follow-up da
uno a 3 anni. L’attività sessuale era completamente
conservata in 12 pazienti che tuttavia presentavano
alcuni fattori di rischio predittivi di disfunzione erettile quali ipertensione in terapia e dislipidemia severa,
di questi 6 erano forti fumatori. I rimanenti 36 erano
affetti da deficit erettile di grado lieve-moderato, 6 di
tali pazienti erano diabetici in terapia con ipoglicemizzanti orali e in buon compenso glico-metabolico.
Le indagini preoperatorie eseguite sono state quelle
classiche ivi compreso uno screening urologico:
• ecocolor doppler penieno dinamico;
• foto documentazione;
• RMN dimanica peniena in 10 pazienti;
• PSA f/t;
• uroflussometria;
• ecografia reno vescicale;
• questionario IIEF 5;
• SEP2 e SEP3;
• la valutazione nel follow-up è stata volta anche
a indagare le eventuali variazioni nella vita sentimentale della coppia.
Le dimensioni della placca, sempre peraltro unica,
erano comprese in lunghezza tra 1,2 e 2,6 cm, larghezza 0,8-1,9 cm. Il recurvatum era:
• dorsale puro > 45° in 28 pazienti;
• dorsolaterale sn > 40° in 8;
• ventrale > 40° in 6;
• laterale sx > 45° in 4;
• dorsolaterale dx > 45° in 2.
In tutti i pazienti l’intervento è stato condotto con
degloving sub coronale, in sei pazienti contro incisione scrotale. In 30 pazienti i tutori assiali impiantati
sono stati di 7/fr del tipo Virilis II in sette di tipo Virilis
I sempre 7/fr in otto pazienti di 10 fr del tipo Virilis I,
in 3 pazienti 9,5 fr del tipo SSDA.
• La lunghezza dei tutori impiantati era compresa tra
16,6 e 20 cm calcolata dalle crura all’apice dei cc.
• In 36 pazienti è stata utilizzata safena prelevata
alla cross.
• In 12 (recurvatum maggiore di 60°) è stato impiegato patch di matrice di collagene di pericardio
bovino (Veritas-Hydrix).
• Tutti i pazienti sono stati sottoposti dal 15° giorno
post operatorio a rieducazione del tessuto erettile
con iPDE5 bisettimanalmente per 45 giorni con
finalità eutrofiche sul tessuto erettile residuo dislocato alla periferia del tutore.
• La valutazione post operatoria è stata eseguita a 15-30-60-90 gg, 4-8-12-16-24-36 mesi
post intervento. Valutazione con IIEF 5, SEP2,
SEP3.
Risultati
Il follow-up di cui disponiamo ad oggi va, da uno a
3 anni:
• allungamento dell’asta da 1,2 a 2,3 cm;
• correzione completo del recurvatum in tutti i pazienti;
• ripresa dell’attività sessuale penetrativa a 60 gg
in 31 pazienti;
in 11 pazienti;
6 pazienti;
• l’attività sessuale penetrativa a 4 mesi era buona
nel 65% dei casi, deludente nel 35%;
• a 8 mesi attività sessuale penetrativa buona nel
75%, discreta nel 25%;
• a 12-16-24-36 mesi attività sessuale penetrativa
ottima nello 75%, buona nel 20%, deludente nel
5% (sensazione di glande freddo, eiaculazione
ritardata, aspetto innaturale del pene per la costante iperestensione);
• il 20% dei pazienti (8) riferisce di ricorrere, da
3 a 5 volte al mese all’utilizzo di iPDE5 per una
migliore performance erettile;
• il 25% dei pazienti operati riferisce di aver rapporti con più di una partner abitualmente;
• il 15% a distanza di 2 anni dall’intervento ha iniziato una relazione stabile con una nuova partner
(separazione coniugale);
• nessuno dei pazienti ha sviluppato LUTS (lower
urinary tract symptoms).
Discussione
I risultati riportati inducono a una serie di riflessioni:
1. rispetto alla tecnica originale l’impianto di tutori
di piccolo calibro a rigidità differenziata risulta
maggiormente rispettosa del tessuto cavernoso
residuo;
2. la pseudo capsula che circonda il tutore di piccolo calibro,presente già a 2 mesi, coinvolge in
misura ridotta il tessuto erettile circostante;
175
M. Silvani, et al.
3. è mandatorio l’utilizzo di iPDE5 per i primi 2 mesi
post operatori, con finalità eutrofiche e stabilizzanti sull’endotelio cavernoso nel periodo di
formazione della pseudo capsula;
4. è prudente una misurazione della lunghezza del
tutore non eccessivamente più lunga di quella del
cc stesso. L’eccesso di 1 cm in lunghezza è infatti
sufficiente a evidenziare il recurvatum. Misurazioni
più lunghe non producono un allungamento maggiore in quanto nella IPP spesso tutta l’albuginea
è coinvolta dalla patologia, con il risultato di un
accorciamento dell’asta. Il FVND è inoltre spesso,
coinvolto dalla fibrosi albuginea e la sua liberazione non è sempre così agevole ed estesa. Una
scheletrizzazione spinta e uno stiramento esagerato della stesso, sulla spinta assiale del tutore, possono provocare disturbi trofici del glande fino alla
necrosi. Recentemente Austoni e coll. propongono
di posizionare un tutore la cui lunghezza supera
quella del cc di un cm per ogni 30° di recurvatum;
5. una lunghezza eccessiva del tutore determina il
posizionamento del pene in costante erezione o
semierezione, contrariamente agli obiettivi finali
della tecnica originale che sono quelli di un pene in estensione il quale, all’atto dell’erezione,
si posiziona ad angolo acuto sul pube così da
permettere una penetrazione agevole. Una quota
seppure ridotta dei nostri pazienti ha dichiarato
un “discomfort genitale” legato ad un pene eccessivamente disteso e poco occultabile;
6. riteniamo inoltre che nei recurvatum di grado
severo cioè > 50° sia preferibile non ricorrere
al prelievo del monograft di safena che risulta spesso insufficiente a ricoprire una losanga
troppo ampia. Il patch di pericardio inoltre offre
garanzie di elasticità e biocompatibilità elevate.
L’inosculazione tissutale albuginea è completa
e rapida. Non sono descritti casi di fibromatosi
cicatriziale successivi al suo utilizzo. Il non utilizzo
della safena riduce i tempi operatori e le eventuali
complicanze associate al prelievo stesso.
Conclusioni
L’intervento descritto costituisce un’invidiabile soluzione per tutte le forme di Induratio Penis Plastica
associate a recurvatum tale, da ostacolare l’attività
sessuale penetrativa, associata o meno a disfunzione
erettile lieve moderata. La metodica è di facile apprendimento e agevolmente riproducibile. Il tutore,
costituisce una garanzia di conservazione nel tempo
dell’estensione dell’asta rispetto, ad altre metodiche
di correzione del recurvatum. Il tutore soffice non
176
costituisce in realtà una protesi propriamente detta in
quanto l’erezione avviene spontaneamente sfruttando
l’azione residua del tessuto endoteliale risparmiato.
Non è infatti necessario ricorrere a manipolazione del
tutore per ottenere l’erezione al contrario delle protesi
semirigide o delle idrauliche bi o tricomponenti. Le
alternative chirurgiche a tale opzione sono rappresentate dalla corporoplastica geometrica secondo Paulo
Egydio e l’implantologia protesica idraulica associata
o meno a chirurgia di placca. La prima soluzione è
comunque di complesso apprendimento, alla portata
di équipe di consolidata esperienza e riservata solo a
pazienti con funzione erettile ottimamente conservata.
L’implantologia protesica idraulica con possibile chirurgia di placca è riservata solo ai pazienti con malattia
di la Peyronie e disfunzione erettile grave. Non sempre
il paziente comunque è psicologicamente incline ad
una soluzione che rende l’erezione un atto assolutamente artificiale. Questo costituisce un aspetto del
counselling psicosessuologico che va riservato a ogni
paziente con IPP candidato ad intervento chirurgico. Il
pensiero del paziente con IPP è infatti focalizzato alla
risoluzione del recurvatum che costituisce l’elemento cardinale della malattia sul piano clinico. Spesso
il paziente all’atto della consultazione, sottovaluta
il problema della funzione erettile che comunque è
sempre presente in vario grado e riconducibile alla
disfunzione veno occlusiva relativa alla fibrosi sub
albuginea. Questa serie di considerazioni unitamente
al relativo facile apprendimento della metodica da noi
adottata, ci portano a ritenere la tecnica descritta un
gold standard per tutti i casi di IPP con recurvatum >
35-40° laterale, ventrale o dorsale con attività erettile
conservata o disfunzione lieve moderata.
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original article
Efficacy of a nutraceutical preparation as addon treatment in patients with erectile dysfunction
treated with 5-PDE inhibitors: a pilot study
G. Piubello
U.O. Medicina Interna D, Università di Verona, Policlinico “G.B. Rossi”, Verona
Summary
The aim of the present study was a pilot assessment of the effect of Ezerex™, a combination of propionyl-L-carnitine fumarate, L-arginine, and nicotinic acid, in erectile dysfunction (ED) patients.
In arm A of the trial 82 patients treated for the first time with phosphodiesterase-5 (5-PDE) inhibitors were randomized to add-on Ezerex™ therapy,
or to a control group which did not receive the add-on therapy.
The IIEF-5 score significantly improved at follow-up both in the control group
and in the treatment group (p < 0.0001 for both), but the increase was significantly higher in the treatment group (p < 0.0001).
In arm B 72 patients who were poor responders to 5-PDE inhibitors were
enrolled. Baseline IIEF-5 median score was 12; it increased significantly to
18.5 at follow-up (p < 0.0001).
Despite the absence of a placebo control group, the results of this pilot study
suggest the usefulness of Ezerex™ as add-on treatment both in patients
starting ED therapy and in patients already known to be poor responders
to 5-PDE inhibitors. These results need to be tested in a larger randomised,
double-blind, placebo-controlled study.
Key words
Erectile dysfunction • Propionyl-L-carnitine
• L-arginine • Nicotinic acid
Introduction
Erectile dysfunction (ED) is a very common condition, with an estimated prevalence of 152 million males in the world 1. With the approval of phosphodiesterase-5 (5-PDE) inhibitors in 1998, a highly
efficacious therapy became available. Nevertheless, some patients
respond poorly or not at all; for example, as many as 74-83% of men
prescribed sildenafil 2 3 discontinue treatment.
Due to the limitations of this first-line treatment, there is interest in
identifying add-on therapies to increase its effect. In the last few years,
preparations based on dietary supplements, vitamin complexes and
nutritional principles, classified as nutraceuticals, have come to be
used in ED.
Recently in Italy a product called Ezerex™ (Sigma Tau) has been proposed, which is made up of propionyl-L-carnitine fumarate, 250 mg,
L-arginine, 2.5 g and nicotinic acid, 20 mg.
Piubello Giorgio, U.O. Medicina Interna D, Università di Verona, Policlinico “G.B. Rossi”, Piazzale A. Scuro 1, 37134 Verona, Italy – E-mail: [email protected]
178
The purpose of the present pilot study was to make
a preliminary assessment of the efficacy of this
combination of components as add-on therapy,
both in patients treated for the first time with 5-PDE
inhibitors and in patients who were poor responders
to 5-PDE inhibitors.
Materials and methods
EVA (Ezerex Veneto study as Add-on therapy) is a
multicentre pilot study, conducted in 7 outpatient
andrology clinics.
Inclusion criteria
Patients included were male, aged up to 65 years,
with at least one major cardiovascular risk factor
(smoking, arterial hypertension on therapy, dyslipidemia, abdominal obesity, diabetes on therapy). ED
was assessed by a history of problems in sexual intercourse lasting at least one year and confirmed by
a score ≤ 20 on the sexual activity questionnaire (the
abridged 5-item version of the International Index of
Erectile Function-IIEF-5) 4. Moreover, patients to be
enrolled in arm A had to be treated for the first time
with a 5-PDE inhibitor.
The choice of 5-PDE inhibitor to be used was left to
the andrologist. Patients to be enrolled in arm B had
to have been on treatment with any 5-PDE inhibitor for at least 2 months and, nevertheless, to have
symptoms of ED and a low IIEF-5 score (≤ 20).
Treatment
Patients enrolled in arm A began treatment with a
5-PDE inhibitor, selected according to the andrologist’s clinical judgment; they were randomized to
add-on therapy with Ezerex™ or to the control
group, which did not receive any add-on treatment.
Patients enrolled in arm B received add-on therapy
with Ezerex™ while maintaining 5‑PDE inhibitor
therapy without any change.
Patients assigned to Ezerex treatment gave their
informed consent.
Patients were re-assessed after a median period of
75 days (interquartile range 61-86) and were asked
to fill in a new IIEF-5 questionnaire. The questionnaire
was assessed anonymously, but it was paired to the
baseline questionnaire by a numerical code. The researchers evaluating the questionnaires were blinded
to the patients’ identity; the only information they had
from the baseline questionnaire was the patient’s age
and the 5-PDE inhibitor with which he was treated.
Efficacy assessment
The primary outcome measure was the change in
the IIEF-5 score from baseline to follow-up. The
degree of ED was classified as: mild (17-21), mild
to moderate (12-16), moderate (8-11) and severe
(5-7) 5. The percentage of patients whose IIEF-5
scores had increased to a normal value(> 21) was
also assessed.
Statistical methods
Results are reported as average value ± 1 standard
deviation for variables with Gaussian distribution,
otherwise as median (interquartile range).
Between-group comparisons were performed using the Wilcoxon ranksum test, while within-group
comparisons were performed using the Wilcoxon
matched-pairs signed-ranks test.
All statistical tests were two-tailed and were considered significant when p was below 0.05.
Results
Eighty-two patients were enrolled in arm A over an
eight-month period; 41 were randomized to add-on
treatment, 41 to the control group. Their average age
was 52 ± 4.9 years. The prescribed 5‑PDE inhibitor
was vardenafil in 46 patients (56.1%), sildenafil in 26
(31.7%), and tadalafil in 10 (12.2%).
Baseline IIEF-5 median score was 13 (interquartile
range 10-15); despite the randomized assignment to
treatment, the median IIEF-5 score was significantly
higher in the control group (median 14, interquartile
range 11.5-17) than in the treatment group (median
12, interquartile range 9-14; z = 3.36, p = 0.0008). In
fact, in the treatment group, no patient had mild ED,
23 had mild to moderate, 12 moderate and 6 severe
ED. In the control group 11 patients had mild ED, 20
mild to moderate, 7 moderate and 3 severe ED. Details of the individual items of the questionnaire are
reported in Table I.
The IIEF-5 score significantly improved at followup both in the control group (median 18, interquartile range 16.5-20; z = 5.51, p < 0.0001) and
in the treatment group (median 22, interquartile
range 20-23; z = 5.59, p < 0.0001). However, the
increase in the IIEF-5 score was significantly higher
in the treatment group (median 10, interquartile
range 8-12) than in the control group (median 4,
interquartile range 2.5-5; z = 6.56, p < 0.0001). The
changes in the assesed ED category are reported
in Table II.
179
G. Piubello
Table I. Details on the individual items of the IIEF-5 questionnaire in arm A patients.
Ezerex
Baseline
Control
Follow-up
Variation
Baseline
Follow-up
Variation
Question 1
2 (2-3)
4 (3-4)
2 (1-2)
3 (2-3)
3 (3-4)
1 (0-1)
Question 2
2 (2-3)
5 (4-5)
2 (2-3)
3 (2-4)
4 (3-4)
1 (0-1)
Question 3
2 (2-3)
4 (4-5)
2 (1-3)
3 (2-3)
4 (3-4)
1 (0-1)
Question 4
2 (1-3)
4 (4-4.5)
2 (1-3)
3 (2-3)
4 (3-4)
1 (0-1)
Question 5
2 (1-3)
4 (4-5)
2 (1.5-3)
3 (2-3)
4 (3-4)
1 (0-1)
All the comparisons (baseline vs. follow-up), both in the Ezerex group and in the control group, are statistically significant with p < 0.0001.
Table II. Change in the categorical assessment of ED.
Ezerex
Control
Baseline
Follow-up
No ED
0
21 (51.2%)
0
2 (4.5%)
Mild
0
19 (46.3%)
11 (26.8%)
29 (70.7%)
Mild to moderate
23 (56.1%)
1 (2.4%)
20 (48.8%)
10 (24.4%)
Moderate
12 (29.3%)
0
7 (17.1%)
0
Severe
6 (14.6%)
0
3 (7.3%)
0
Seventy-two patients were enrolled in arm B. Their
average age was 55.5 ± 6.1 years. The prescribed
5-PDE inhibitor was tadalafil in 35 patients (48.6%),
vardenafil in 21 (29.2%), and sildenafil in 16 (22.2%).
Baseline IIEF-5 median score was 12 (interquartile
range 10-15); despite therapy with 5-PDE inhibitors ED was mild in 5 (7%), mild to moderate in 40
(55.6%), moderate in 21 (29.2%) and severe in 6
(8.3%). IIEF-5 score increased to 18.5 at follow-up
(interquartile range 15-20); the median increase with
treatment was 5 (interquartile range 3-7.8) and it was
statistically significant (z = 7.35, p < 0.0001). Details
of the individual items of the questionnaire are reported in Table III. ED became mild in 38 (52.8%),
mild to moderate in 22 (30.6%), and moderate in 3
(4.2%). In 9 patients (12.5%) the IIEF-5 score was
above the threshold for ED.
Table III. Details on the individual items of the IIEF-5 questionnaire in arm B patients.
Baseline
Follow-up
Variation
Question 1
2 (2-3)
3 (3-4)
1 (0-2)
Question 2
2 (2-3)
4 (3-4)
1 (1-2)
Question 3
2 (2-3)
4 (3-4)
1 (1-2)
Question 4
3 (2-3)
4 (3-4)
1 (1-2)
Question 5
3 (2-3)
4 (3-4)
1 (0-2)
All the comparisons (baseline vs. follow-up) are statistically significant with p < 0.0001.
180
Baseline
Follow-up
Discussion
Phosphodiesterase type 5 inhibitors are the standard treatment for ED. Their pharmacological activity, through PDE-5 inhibition, is linked to endothelial NO synthesis: any alteration in this mechanism,
determining reduced endothelial NO production,
leads to failure in increasing intracellular levels of
cGMP, thus reducing the clinical efficacy of the drug
in proportion to the endothelial damage. The latter can therefore be considered a primary factor in
poor response to 5-PDE inhibition, both at the start
of treatment and during chronic treatment. On the
basis of these assumptions, any intervention able to
improve endothelial function and thus positively affect NO production could improve the response rate
to 5-PDE inhibitors. The need for such an improvement is confirmed by our results: fewer than 5% of
patients treated for the first time with a 5-PDE inhibitor had a normal IIEF-5 score after treatment.
Nutraceuticals is a new term which derives from the
combination of the words “nutrition” and “pharmaceutical”. Ezerex™ is a nutraceutical combination of
propionyl-L-carnitine, L-arginine and nicotinic acid.
Propionyl-L-carnitine is an endothelium-dependent
vasodilator, the mechanism of which is partially mediated by prostaglandin synthesis, but which also
appears to have a modest effect on smooth muscle
cells at higher concentrations. Therefore the beneficial cardiovascular effects of this compound may be
related, in part, to vasodilation and enhanced blood
flow 6. In fact, carnitine has proved to increase walking distance in claudicatio intermittens patients 7
and to improve the cardiac tolerance for stress associated with an increase in heart rate and pressurerate product 8. The use of propionyl-L-carnitine as
add-on treatment in diabetic patients was tested in
a randomised double-blind study 9; the improvement
in the Q3 and Q4 domains of the IIEF questionnaire,
testing the ability to achieve an erection sufficient for
sexual intercourse and the ability to maintain erection after penetration, were significantly higher with
the combination therapy than with sildenafil alone.
L-arginine is an NO donor which may increase NOS
activity and affect penile erection 10, although the
effect of L-arginine supplementation proved to be
effective in men with ED only if they showed decreased NO excretion or production 11.
Nicotinic acid improves endothelial dysfunction in patients with CAD and dyslipidemia 12 and has proved to
have positive effects, alone or in combination, on all
cardiovascular events and on atherosclerosis 13.
There is, therefore, a rationale for using the association of these three nutraceuticals as an add-on treatment with 5-PDE inhibitors.
A brief report on diabetic patients recently described
an increase of 2 points in the IIEF-5 score with Ezerex™ treatment, while no increment was observed in
the placebo group 14.
The present study was designed to assess the feasibility of a large randomised clinical study in ED
patients with at least one cardiovascular risk factor.
In patients starting ED therapy, the association of
Ezerex™ with a 5-PDE inhibitor produced an increase
in the IIEF score which was higher than that of patients randomised to a 5-PDE inhibitor alone. In fact,
with Ezerex™ plus a 5-PDE inhibitor 97,5% of the
patients arrived at a normal IIEF-5 score, while with a
5-PDE inhibitor alone the percentage was 75,6%.
The first part of this pilot study was designed to test
the efficacy of the combination therapy. The major
clinical interest was, of course, in the treatment of
patients who were poor responders to classical
5-PDE inhibitors. In patients for whom a poor response can be forecast, such as diabetic patients, a
combination therapy that takes endothelial dysfunction into account could be considered.
In most of the patients already on treatment who
were evaluated as poor responders to 5-PDE inhibitors, the starting IIEF-5 score identified ED as at
least mild to moderate. The association of Ezerex™
determined an improvement to normal values of
IIEF-5 or mild ED in almost two-thirds of the patients.
Therefore Ezerex™ would seem to be a useful add-
on in poor responder patients, to be tried before
considering intracavernous injection therapy.
Limitations
Due to the small sample size, the two groups were
unbalanced despite randomization. The experience
of this pilot study suggests that in a larger study, randomization should be stratified on the severity of ED.
This was a pilot study and no placebo was used;
this is an obvious limitation. However, for patients
in arm A a placebo effect which would influence the
results is difficult to invoke, because patients were
not aware that some of them were receiving a single
drug while others were also receiving an add-on
treatment.
The absence of a placebo control may have had a
greater effect on the results in arm B, where adding
“something” to a partly ineffective treatment could
have influenced the results.
Patients over 65 were not enrolled in this study in
order to rule out the effects of frequent comorbidities and concomitant pharmacotherapies. Moreover,
the frequency of sexual activity tends to be lower in
that age group.
Conclusions
In this pilot study Ezerex™ proved its usefulness as
an add-on treatment in patients starting ED therapy.
Even more interesting are the results obtained in
patients who were poor responders to 5-PDE inhibitors. These latter results will be tested in a larger randomised, double-blind, placebo-controlled study.
Acknowledgments
The authors wish to thank doctor Luisa Zanolla for
statistical and methodological support.
References
McKinlay B. The worldwide prevalence and epidemiology of erectile dysfunction. Int J Impot Res
2000;12(Suppl 4):6-11.
2
Fagelman E, Fagelman A, Shabsigh R. Efficacy, safety,
and use of sildenafil in urologic practice. Urology
2001:57:1141-4.
3
Souverein PC, Egberts AC, Meuleman EJ, et al. Incidence and determinants of sildenafil (dis)continuation:
the Dutch cohort of sildenafil users. Int J Impot Res
2002;14:259-65.
4
Rosen RC, Riley A, Wagner G, et al. Development and
evaluation of an abridged, 5-item version of the International Index of Erectile Function (IIEF-5) as a diagnostic tool
for erectile dysfunction. Int J Impot Res 1999;11:319-26.
1
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Tannini EA, Lenzi A, Maggi M. Sessuologia Medica.
Milano: Elsevier Masson 2007.
6
Cipolla MJ, Nicoloff A, Rebello T, et al. Propionyl-Lcarnitine dilates human subcutaneous arteries through
an endothelium-dependent mechanism. J Vasc Surg
1999;29:1097-103.
7
Brevetti G, Perna S, Sabba C, et al. Propionyl-Lcarnitine in intermittent claudication: a double-blind,
placebo-controlled, dose-titration, multi-center study.
J Am Coll Cardiol 1995;26:1411-6.
8
Thomsen JH, Shug AL, Yap VU, et al. Improved pacing
tolerance of the ischemic human myocardium after administration of carnitine. Am J Cardiol 1979;43:300-6.
9
Gentile V, Vicini P, Prigiotti G, et al. Preliminary observations on the use of propionyl-L-carnitine in combination with sildenafil in patients with erectile dysfunction
and diabetes. Curr Med Res Opin 2004;20:1377-84.
10
Zorgniotti AW, Lizza EF. Effect of large doses of the
nitric oxide precursor, L-arginine, on erectile dysfunction. Int J Impot Res 1994;6:33-5.
5
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Chen J, Wollman Y, Chernichovsky T, et al. Effect of
oral administration of high-dose nitric oxide donor L-arginine in men with organic erectile dysfunction: results
of a double-blind, randomized, placebo-controlled
study. BJU Int 1999;83:269-73.
12
Warnholtz A, Wild P, Ostad MA, et al. Effects of oral
niacin on endothelial dysfunction in patients with coronary artery disease: results of the randomized, doubleblind, placebo-controlled INEF study. Atherosclerosis
2009;204:216-21.
13
Bruckert E, Labreuche J, Amarenco P. Meta-analysis of
the effect of nicotinic acid alone or in combination on
cardiovascular events and atherosclerosis. Atherosclerosis 2010;210:353-61.
14
Gentile V, Antonini G, Antonella Bertozzi M, et al. Effect of propionyl-L-carnitine, L‑arginine and nicotinic
acid on the efficacy of vardenafil in the treatment of
erectile dysfunction in diabetes. Curr Med Res Opin
2009;25:2223-8.
11
Case report
T. Zenico, M. Saccomani, U. Salomone, E. Bercovich
Department of Urology, Morgagni-Pierantoni Hospital, Forlì, Italy
Summary
Key words
Leydig cell tumors • Adrenal hyperplasia
Leydig cell tumors (LCT) are extremely rare, representing 1-3% of all testicular cancer, which in itself constitutes only 1% of male tumors (about 2
cases/100,000 men). Only 3% of LCT are bilateral. We present a case of
bilateral Leydig cell tumor with adrenal hyperplasia in a young man.
Introduction
Leydig cell tumors (LCT) are very rare (1-3% of all testicular cancer)
and only 3% are bilateral. Although the etiology of testicular interstitial
cell tumors is still unknown, hormonal imbalance seems to play an important role in the induction of Leydig cell hyperplasia and successive
development of the tumor. Studies conducted on animal models have
shown that prolonged exposure to estrogens or antiandrogens blocks
normal testosterone feedback at the hypothalamus-pituitary axis, with
consequent hyperproliferation of Leydig cells 1 2. LCT occurs mainly
in children before puberty and in adults between 20 and 50 years of
age 1. Typical pathological features of LCT in the latter are altered
hormone status, reduced libido and gynecomasty due to high levels of
estrogens in Leydig cells or to a significant androgenic block. Gynecomasty is bilateral in 90% of cases. The biochemical profile of patients
with LCT varies and can make diagnosis difficult. Although hormone
levels generally return to normal after the tumor has been removed,
they remain high in some patients 3. Lesions are generally small, localized, and very rarely hemorrhagic or necrotic. Tumor cells present lipidic vacuolization and characteristic cytoplasmic inclusions known as
Reinke crystals in about 40% of adult LCT and very rarely in childhood
tumors. The presence of such crystals may be associated with the
reduced capacity of Leydig cells to produce steroids. Only about 10%
of LCTs are malignant 4, generally presenting in older patients with an
average age of 60. Inguinal orchiectomy is the treatment of choice in
these cases. The presence of metastases, generally in regional lymph
nodes, liver, lung and bone, is regarded as the only reliable criterion to
determine malignancy. However, histological evidence of large areas
of atypical necroses, vascular or lymphatic invasion, high mitotic activity and nuclei anomalies are also strongly suggestive of neoplastic
disease 5. Malignant LCTs are usually radio- and chemoresistant and
Teo Zenico, Department of Urology, Morgagni-Pierantoni Hospital, via Forlanini 34, 47100 Forlì, Italy – Tel. 39 0543 735045 – Fax 39 0543 735019 – E-mail: [email protected]
183
T. Zenico, et al.
have a poor prognosis, with mean patient survival after surgery of about 3 years 6. A timely and accurate
diagnosis is therefore vital.
Figure 1. Anechogenic area of the left testicle associated with
hypervascularization.
Case report
In November 2006 a 39-year-old man was seen
in our Urology Department for infertility problems.
Laboratory tests revealed that he was azoospermic,
without Y chromosome microdeletions and with
a normal karyotype. Clinical examination revealed
enlarged testicles with multiple surface irregularities. Blood levels of total testosterone were slightly
increased (12.0 ng/ml), while free testosterone (24.3
pg/ml), SHBG (34 nmol/l), somatotropin (0.1 ng/ml),
alfafetoprotein (4.30 ng/ml) and betaHCG (0.00 U/
ml) were normal. Very high serum levels of ACTH
(1104.0 pg/ml), prolactin (46.1 ng/ml) and estradiol
(69.0 pg/ml) were present, while FSH and LH values
were much lower than normal (0.1 MIU/ml for both).
An MRI scan of the sella turcica was performed
to rule out the presence of a pituitary adenoma.
A brain, chest and abdomen CT scan highlighted
enlarged adrenal glands with calcification, and a
CT-guided adrenal biopsy was therefore performed.
Color doppler ultrasound revealed multiple anechogenic masses, 4 in the left testis and 3 in the right,
ranging from 0.8 to 1.5 cm in diameter. The lesions
had hypervascular areas and increased pigmentation in peripheral and central areas (Figs. 1, 2).
Bilateral inguinal orchiectomy was carried out after
extemporaneous histological examination and a
testicular prosthesis was inserted. Iliac, inguinal and
para-aortic lymph nodes were biopsied during surgery performed for a large post-laparotomy hernia.
Although cytological examination of the adrenal fine
needle aspirate did not reveal any atypical elements,
it did highlight epithelial cells with regular central
nucleus, voluminous, sometimes frothy cytoplasm
and numerous lipofuscinic pigment inclusions. The
findings were compatible with a diagnosis of pigmented nodular adrenocortical disease. Histopathological examination of the testicular tissue showed
some elements with morphological characteristics
of bilateral LCT such as lesion dimension > 0.5 cm
and epididymal parenchyma substitution by Leydig
cell proliferation and by the fatty component of the
tumor. Extemporaneous intraoperative histopathological evaluation of lymph nodes was negative,
which thus ruled out the presence of metastases and
consequently the malignant nature of the tumor.
Three months after bilateral orchiectomy the patient
showed slightly increased levels of LH and FSH (0.1
184
Figure 2. Anechogenic area of the right testicle.
and 0.5 MIU/ml, respectively), while estradiol values
had decreased to 29.0 pg/ml and testosterone to 1.6
ng/ml. ACTH and prolactin levels were also lower,
826.0 pg/ml and 8.2 ng/ml, respectively, indicating a
normalization of hormone levels. The patient is being
followed up.
Discussion
Leydig cell tumors are extremely rare and a specific diagnostic process is required to identify their
presence in high-risk subjects such as those with
problems of infertility or gynecomasty. In addition to
a detailed anamnesis, clinical examination and testicular palpation, patients must undergo hormonal
and biochemical profile evaluation, echo color doppler to determine the presence of hypoechogenic
lesions, and testicular biopsy. The peculiarities of
our clinical case were the oversecretion of estradiol,
low FSH and LH values and, in particular, a high
level of ACTH, which highlighted the presence of
adrenal hyperplasia. This condition, often diagnosed
by chance, is found in 18% [7] of patients who seek
medical advice for a scrotal mass 1.
It is important to distinguish between LCT and nodular
testicular hyperplasia (21-α hydroxylase congenital
deficiency) associated with adrenogenital syndrome,
an extremely rare disease affecting the fetal stage or
young adults, which is occasionally associated with
gynecomasty (found, conversely, in about one third
of LCT patients). Urinary 17-ketosteroids, normally
used as biochemical markers, may be present in
both diseases. Steroid therapy with dexamethasone
generally suppresses the increase in ACTH levels
and reduces hyperplasia, which, in turn, results in a
concomitant regression of testicular tumor volume in
75% of cases 7. This, however, did not occur in our
patient. Final diagnosis can only be made by histological examination of the bioptic sample. Polygonal
cells with abundant granular or eosinophil cytoplasm
separated by dense fibrotic tissue are present in
nodular testicular hyperplasia. Conversely, Reinke
crystals are a specific characteristic of LCT, present
in 20-40% of these tumors.
Conclusions
Leydig cell tumors are extremely rare, especially
when bilateral. Adrenal gland evaluation (imaging and
laboratory exams) and testicular biopsy are required
for a differential diagnosis. Bilateral orchiectomy and
hormone replacement therapy are indicated when
histology reveals the presence of Reinke crystals
but absence of nodular testicular hyperplasia due
to 21-α hydroxylase deficiency. Adrenal hyperplasia
associated with bilateral Leydig cell tumor, albeit
even rarer, has well defined clinical, diagnostic and
therapeutic parameters.
References
Rich MA, Keating MA. Leydig cell tumors and tumors
associated with congenital adrenal hyperplasia. Urol
Clin North Am 2000;27:519-28.
2
Viguier-Martinez MC, Hochereau de Reviers MT, Barenton B, et al. Effect of a non-steroidal antiandrogen,
flutamide, on the hypothalamo-pituitary axis, genital
tract and testis in growing male rats: endocrinological and histological data. Acta Endocrinol (Copenh)
1983;102:299-306.
3
Mineur P, De Cooman S, Hustin J, et al. Feminizing testicular Leydig cell tumor: hormonal profile before and
after unilateral orchidectomy. J Clin Endocrinol Metab
1987;64:686-91.
4
Drut R, Wludarski S, Segatelli V, et al. Leydig cell tumor
of the testis with histological and immunohistochemical
features of malignancy in a 1-year-old boy with isosexual pseudoprecocity. Int J Surg Pathol 2006;14:344-8.
5
Sugimoto K, Matsumoto S, Nose K, et al. A malignant Leydig cell tumor of the testis. Int Urol Nephrol
2006;38:291-2.
6
Rao SR, Mistry RC, Parikh DM. Leydig cell tumor:
a case report and review of the literature. Tumori
2002;88:75-6.
7
Battaglia M, Ditonno P, Palazzo S, et al. Bilateral tumors
of the testis in 21-alpha hydroxylase deficiency without
adrenal hyperplasia. Urol Oncol 2005;23:178-80.
1
185
Indice degli autori
Abatangelo G., 54
Abbadessa D., 72
Abdollah F., 50
Albanesi L., 51, 72, 73
Alei G., 14, 18, 25, 29, 46, 56, 65, 66
Alei L., 14, 18, 25, 29, 46, 65, 66
Anceschi R., 72
Angelozzi G., 15
Antoniazzi F., 42, 73
Antonini F., 63
Antonini G., 41, 46
Arcoria D., 8
Arduini M., 54
Arduino C., 31
Arena G., 39
Argese N., 72
Attanasio A., 73
Attisani F., 51, 72, 73
Atzori P., 13, 21, 22
Augusto Negro C.L., 16
Austoni E., 18, 19, 20, 27, 69, 71
Badano G.M., 29
Barbagli G., 10, 71, 72
Barbanti G., 13
Barbera M., 71, 73
Bartalucci A., 62
Bartelloni M., 35
Bartoletti R., 46
Bauco S., 54
Belgrano E., 14, 20, 25, 64, 67
Bellocchi A., 43
Benedetto G., 54
Benedusi F., 10, 66
Beneventano G., 2
Benvenuto S., 14, 20, 50, 64, 67
Berardi A., 62
Berdondini E., 11, 13
Beretta G., 37
Bergamasco L., 72, 73
Berta G., 66
Bertolotto M., 64
Biagiotti G., 37
Bianchessi I., 7
Bigotto C., 72
Bischoff C., 10, 66
Bitelli M., 62
Bizzarri C.N., 17, 25, 48, 58
Bocca B., 45
Bonaparte E., 32
Bonari A., 57
Bonazzi A., 46
Borgoni G., 63
Borsa R., 62
Borsellino A., 13, 21, 22
Bragaglia A., 62
Brancato T., 45
Bratti E., 54
Briganti A., 50
Brunocilla E., 25
Brunori S., 51, 72, 73
Bucci S., 14, 20, 25, 50, 64
Busetto G.M., 46
Cai T., 6, 8, 21
186
Calisti A., 42, 43
Callea F., 21
Calogero A.E., 2
Cambi M., 35
Camilli M., 22, 65
Campo G., 41, 51
Campo S., 51
Canclini L.P., 49
Cannizzaro F., 71
Capitanio U., 50, 53
Caponecchia L., 36
Capparelli G., 6
Caraceni E., 15
Carbonaro F., 62
Cardo G., 49
Carluccio G., 41
Carmignani G., 18, 45, 56
Carnaccini D., 58
Caroassai Grisanti S., 71, 72
Caroli Casavola V., 33
Carollo G., 71, 73
Carparelli G., 41
Caruana G., 72
Caruso A., 72
Casciani E., 63
Casilio M., 71, 72, 73
Casolari E., 43
Cassoli S., 58
Castelli L., 24
Castiglione F., 31, 34, 35, 53, 60
Castiglione R., 2, 8
Castiglioni M., 32, 32, 39
Catalano F., 8
Cattaneo E., 66
Cava M., 50
Cavallini G., 37, 40
Ceccarelli S., 11
Ceruti C., 1, 16, 24, 26, 26, 31, 63, 68
Chierigo P., 59
Chironi C., 42
Christopher A.N., 12, 15, 16, 24, 27, 47, 64
Cicuto S., 6, 8, 21
Cipriani S., 38
Claudini R., 23
Coccarelli F., 6, 8, 21
Colapietro P., 32
Coletta R., 42
Colombo F., 17, 25, 48, 58
Colpi E.M., 39
Colpi G.M., 32, 39
Condorelli R., 2, 8
Contalbi G., 32
Conti E., 22, 65
Coppola A., 18, 56
Coppola G.A., 33
Coppola L., 18, 33, 56
Cordari M., 23
Cosmi V., 56, 57
Costa F., 19
Cotrufo S., 49
Cozza P.P., 38, 39, 72
Cozzi G., 72
Crimi S., 36
Crisafulli C., 2
da far
fare!!!
Indice degli autori
Curreli A., 9, 29
D’Amato F., 72
D’Ambrosio G., 51
d’Anzeo G., 4, 49, 59
D’Ascenzo R., 45
D’Orazio V., 18, 56
Dachille G., 49
Daniele G., 6, 41
De Luca G., 72
De Rose A.F., 3, 18
De Berardinis E., 41, 46
De Concilio B., 14, 25, 50
De Dominicis C., 12, 15, 16, 24, 27, 37, 40, 47, 57, 64
De Fortuna E., 52
De Luca F., 63
De Nunzio C., 11
De Rose A.F., 29, 33, 45, 56
De Santis C., 62
Debole M., 69
Dedola S., 59
Del Popolo G., 3, 4, 61
Del Prete M., 67
Del Rosso A., 73
Delfino M., 72
Dell’Atti L., 6, 41
Delle Rose A., 71, 72
Delle Cave A., 52
Dellerose A., 49
Dente D., 12, 15, 16, 24, 27, 37, 40, 47, 64
Di Marco M., 46
Di Gregorio C., 2
Di Guardo A., 2
Di Lauro G., 5
Di Palma P., 55
Di Pierro E.D., 72, 73
Di Silverio A., 19
Di Trapani Danilo, 71, 73
Di Trapani Dario, 71, 73
Di Trapani E., 71, 73
Djinovic R., 71, 72, 73
Donatelli G., 23
Drei B., 17
Eleuteri S., 53
Elia J., 72
Emili E., 19
Ennas M., 18, 29, 45, 56
Et-Tamimi A., 23
Fabbri F., 10
Fabrizi A., 55
Fasolis G., 22, 65
Fasolo P.P., 22, 65
Federico E., 50
Ferlosio A., 73
Ferraretti A.P., 40
Ferrari M., 31, 34, 34, 35, 50, 53, 60
Ferro F., 13
Ferro G., 72
Festa R., 33
Fienga A., 67, 68
Filippone R., 73
Finita Celso M., 3, 4, 61
Fiocca G., 42, 43
Fiori C., 36, 54
Fiorito C., 46, 66
Florio M., 71, 72
Fontana D., 16, 24, 26, 26, 31, 63, 68
Fontana G., 62
Forte F., 7, 54
Franceschelli A., 17, 25, 48, 58
Franco G., 11, 12, 15, 16, 24, 27, 37, 40, 47, 57, 63, 64
Franzolin N., 59
Galizia G., 18, 19, 27, 69, 71
Galletto E., 16, 24, 26, 26, 31, 63, 68
Galletto L., 68
Gallina A., 31, 32, 34, 35, 60
Gallo A., 30
Gallo L., 30
Gallo N., 39
Gambino G., 56, 57
Gandaglia G., 31, 34, 34, 35, 53, 60
Garaffa G., 12, 15, 15, 16, 24, 27, 47, 64
Gasparri L., 59
Gazzano G., 32, 39
Gentile B.C., 51, 72, 73
Gentile G., 41
Gentile T., 37
Gentile V., 11, 12, 41, 46, 56, 57
Ghedini G., 27
Ghedini N., 69
Ghidini N., 19, 71
Ghini M., 19
Gholam Alipour M., 72
Giacchetta D., 39
Giammusso B., 73
Gianaroli L., 40
Giannella R., 67, 68
Gillo A., 66
Giubilei G., 46
Giulianelli R., 51, 72, 73
Giuliani M., 53
Gontero P., 46, 66
Gualdi G., 63
Guarino N., 42
Guazzoni G., 10
Guerra A., 40
Guglielmino S., 62
Guida J., 37
Hind A., 43
Iacono F., 5
Iannotta L., 11, 13
Iapicca G., 5
Imbrogno N., 72
Ippolito C., 6, 41
Jelo P., 21, 69
Kalsy J., 37, 40
La Pera G., 55
La Vignera S., 2, 8, 44
La Sala G.B., 43
Lacquaniti S., 22, 65
Lauretti S., 55
Lazzeri M., 10, 71, 72
Leonardi R., 21, 69
Leonardo C., 56
Leoni S., 43
Letizia P., 14, 18, 25, 29, 46, 56, 65, 66
Liberti M., 63
Ligato P., 72
Liguori G., 14, 20, 25, 50, 64, 67
Lissiani A., 67
Littarru G.P., 33
Lombardi G., 3, 4, 61
Longo R., 29, 55
187
Indice degli autori
Indice de
188
Indice degli autori
degli autori
189
Indice degli autori
Indice degli
190
Indice degli autori
gli autori
191
Indice degli autori
192
Instructions for Authors
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ISSN 2035-3901
Journal of
CONTENTS
2010;17:149-192
ORIGINAL ARTICLES
Current techniques in management of obstructive azoospermia...................................................... 149
Gynecomastia: pathophysiology, clinical evaluation and management ............................................. 156
Chlamydia trachomatis infection: the urologist’s point of view ........................................................ 164
Peyronie’s disease: endocavernous plaque excision without substitutive graft:
critical 5-year experience ............................................................................................................. 169
CASE REPORT
Bilateral Leydig cell tumor with adrenal hyperplasia ....................................................................... 183
TABLE OF CONTENTS ................................................................................................................ 186
Journal of ANDROLOGICAL SCIENCES Official Journal of the Italian Society of Andrology
Efficacy of a nutraceutical preparation as add-on treatment in patients with erectile dysfunction
treated with 5-PDE inhibitors: a pilot study.................................................................................... 178
Periodico trimestrale - POSTE ITALIANE SPA - Spedizione in Abbonamento Postale - D.L. 353/2003 conv. in L. 27/02/2004 n° 46 art. 1, comma 1 DCB PISA
Corporoplasty with soft axial tutors and safenous grafting. Following three years............................. 171
ANDROLOGICAL
SCIENCES
Official Journal of
the Italian Society of Andrology
IN THIS ISSUE
OBSTRUCTIVE AZOOSPERMIA
GYNECOMASTIA
CHLAMIDYA TRACHOMATIS INFECTION
SURGERY OF PEYRONIE’S DISEASE
NUTRACEUTICAL FOR ERECTILE DYSFUNCTION
BILATERAL LEYDIG CELL TUMOR

Jas - Journal of ANDROLOGICAL SCIENCES

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