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Journal of ANDROLOGICAL SCIENCES Official Journal of the Italian Society of Andrology 2010;17:149-192

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

Vol. 17December 2010

ISSN 2035-3901

Journal of

ANDROLOGICAL

www.andrologiaitaliana.it

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


Vol. 17December 2010

Cited in

SCOPUS Elsevier Database

Copyright



Editorial Office






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Journal of

ANDROLOGICAL

SCIENCES

Official Journal of the Italian Society of Andrology

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)

www.andrologiaitaliana.it

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

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

Key words

Azoospermia • Techniques

Corresponding author

Giovanni Liguori – E-mail: gioliguori@libero.it

Journal of Andrological Sciences 2010;17:149-155

Summary

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.

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.

Current techniques in management of obstructive azoospermia

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 .

152

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


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

Current techniques in management of obstructive azoospermia

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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28 Silber SJ, Nagy Z, Devroey P, et al. The effect of female

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155


originAl Article Journal of Andrological Sciences 2010;17:156-163

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.

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 .

Corresponding author

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: marco.rossato@unipd.it

156

Key words

Gynecomastia • Pathophysiology •

Management • Estrogen • Androgen


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/m 2 ) 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

Gynecomastia: pathophysiology, clinical evaluation and management

(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 .


Gynecomastia: pathophysiology, clinical evaluation and management

Table I. Drugs inducing gynecomastia and their pathophysiological mechanism of action.

Drug class Drug MechanisM

Antiandrogens/inhibitors

Cyproterone acetate

AR blockade or inhibition of androgen synthesis

of androgen synthesis

Flutamide

Finasteride

Reduction of DHT biosynthesis

Antibiotics Ethionamide

Unknown

Isoniazid

Ketoconazole

Unknown; possible refeeding gynecomastia

Metronidazole

Decreased testosterone or DHT biosynthesis

Antiulcer drugs Cimetidine

AR blockade

Ranitidine

Unknown

Omeprazole

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

Unknown

Enalapril

Captopril

Unknown

Digitoxin

Estrogen-like activity

Digitalis

Amlodipine

Diltiazem

Estrogen-like activity

Verapamil

Nifedipine

Reserpine

Unknown

Spironolactone

Decreased testosterone or DHT biosynthesis AR blockade

Methyldopa

Unknown

Drugs of abuse Alcohol

Increased aromatization of androgens to estrogens

Amphetamines

Unknown

Heroin

Decreased testosterone biosynthesis

Marijuana

AR blockade

Methadone

Decreased testosterone biosynthesis

Hormones Androgens

Anabolic steroids

Increased aromatization of androgens to estrogens

Diethylstilbestrol

Exogenous estrogen

Human chorionic gonadotropin

Estrogens and estrogen agonists

Stimulation of testicular estrogen secretion

Growth hormone

Medroxyprogesterone acetate

Increased estrogen activity

Oral contraceptives

Unknown

Exogenous estrogens

Psychoactive drugs Diazepam

Haloperidol

Paroxetine

Phenothiazines

Risperidone

Tricyclic antidepressants

Exogenous estrogens

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

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

Unknown

Unknown

Unknown

Unknown**

Increased serum prolactin

Unknown

Unknown

Unknown

Unknown

AR: androgen receptor; * Rosenshein et al., 2004; ** Carmichael et al., 2004; *** Jover et al., 2004.

Increased estrogen activity

Unknown; possible efavirenz mediated estradiol-like effects***

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-

Gynecomastia: pathophysiology, clinical evaluation and management

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 Journal of Andrological Sciences 2010;17:164-168

Chlamydia trachomatis infection:

the urologist’s point of view

T. Cai 1 , S. Mazzoli 2 , N. Mondaini 3 , G. Malossini 1 , R. Bartoletti 3

1 Department of Urology, Santa Chiara Hospital, Trento; 2 Sexually Transmitted Disease Centre, Santa Maria Annunziata

Hospital, Florence; 3 Department of Urology, University of Florence

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.

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

year 3 . 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

Corresponding author

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

Key words

Chlamydia trachomatis • Prostatitis • Sexually

transmitted diseases • Infection • Quinolones

• 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.

Chlamydia trachomatis in sexually active young men

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 AM-

PLICOR 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 NIH-

CPSI, demonstrating that an improvement in QoL

(NIH-CPSI decreasing) is related to a decrease in IL-

8 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,


Table I. Randomized, controlled, clinical trials.

authOr/

year

Cai T

(2009)

Whatley JD

(1991)

Jeskanen L

(1989)

Stolz E

(1986)

Drugs Patient

nuMber

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 reported 21 . 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

clinical

efficacy

(%)

Chlamydia trachomatis in sexually active young men

MicrObiOlOgical

efficacy (%)

MicrObiOlOgical

Markers

Prulifloxacin/doxicicline 221 82.5 47.7 IL-8/IgA

Azithromycin/doxicicline 62 - - -

Ciprofloxacin/doxicicline 200 74 - -

Ciprofloxacin 250/ciprofloxacin 500 212 100 100 -

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

1 Da Ros CT, Schmitt Cda S. Global epidemiology

of sexually transmitted diseases. Asian J Androl

2008;10:110-4.

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.

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T. Cai, et al.

9 Petzold D, Gross G, editors. Diagnostik und therapie

sexuell übertragbarer Krankheiten. Leitlinien 2001 der

Deutschen STD-Gesellschaft. Berlin; Springer 2001.

10 Wagenlehner FME, Weidner W, Naber KG. Chlamydial

infections in urology. World J Urol 2006;24:4-12.

11 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.

12 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

Group of the Health Care Office (HCO) of the European

Association of Urology (EAU). Eur Urol 2001;40:576-88.

13 Bébéar C, de Barbeyrac B. Genital Chlamydia trachomatis

infections. Clin Microbiol Infect 2009;15:4-10.

14 Black CM. Current methods of laboratory diagnosis of

Chlamydia trachomatis infections. Clin Microbiol Rev

1997;10:160-84.

15 Mahilum-Tapay L, Laitila V, Wawrzyniak JJ, et al. New

point of care Chlamydia Rapid Test--bridging the gap

between diagnosis and treatment: performance evaluation

study. BMJ 2007;335:1190-4.

16 Leber AL, Hall GS, LeBar WD. Nucleic acid amplification

tests for detection of Chlamydia trachomatis and

Neisseria gonorrhoeae. In: Sharp SE, editors. Cumitech

44. Washington, DC: ASM Press 2006; pp. 1-38.

17 Ripa T, Nilsson P. A variant of Chlamydia trachomatis

with deletion in cryptic plasmid: implications for use of

PCR diagnostic tests. Euro Surveill 2006;11:E061109.

18 Persson K. The role of serology, antibiotic susceptibility

testing and serovar determination in genital chlamydial

infections. Best Pract Res Clin Obstet Gynaecol

2002;16:801-14.

19 Manavi K. A review on infection with Chlamydia

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2006;20:941-51.

20 Smelov V, Perekalina T, Gorelov A, et al. In vitro activity

of fluoroquinolones, azithromycin and doxycycline

168

against Chlamydia trachomatis cultured from men

with chronic lower urinary tract symptoms. Eur Urol

2004;46:647-50.

21 Cai T, Mazzoli S, Addonisio P, Boddi V, et al. Clinical

and microbiological efficacy of prulifloxacin for the

treatment of chronic bacterial prostatitis due to Chlamydia

trachomatis infection: results from a prospective,

randomized and open-label study. Methods Find Exp

Clin Pharmacol 2010;32:39-45.

22 Kokab A, Akhondi MM, Sadeghi MR, et al. Raised inflammatory

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23 Martínez-Prado E, Camejo Bermúdez MI. Expression of

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and anti-sperm antibodies, in semen of men

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2010;63:233-43.

24 Sziller I, Witkin SS, Ziegert M, et al. Serological responses

of patients with ectopic pregnancy to epitopes

of the Chlamydia trachomatis 60 kDa heat shock protein.

Hum Reprod 1998;13:1088-93.

25 Mascellino MT, Ciardi MR, Oliva A, et al. Chlamydia

trachomatis detection in a population of asymptomatic

and symptomatic women: correlation with the presence

of serological markers for this infection. New

Microbiol 2008;31:249-56.

26 Takahashi S, Matsukawa M, Kurimura Y, et al. Clinical

efficacy of azithromycin for male nongonococcal urethritis.

J Infect Chemother 2008;14:409-12.

27 Somani J, Bhullar VB, Workowski KA, et al. Multiple

drug-resistant Chlamydia trachomatis associated with

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28 Mourad A, Sweet RL, Sugg N, et al. Relative resistance

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29 Lefevre JC, Lepargneur JP. Comparative in vitro susceptibility

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strain isolated in Toulouse (France). Sex Transm

Dis 1998;25:350-2.


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

Key words

Peyronie’s disease • Plaque excision technique

Journal of Andrological Sciences 2010;17:169-170

Summary

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.

Corresponding author

F. Mantovani, Clinica Urologica I, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, via Commenda 15, 20122 Milano, Italy – Tel. +39 02 5503 4509 – Email:

mantovanifranco@yahoo.it

169


F. Mantovani, et al.

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

Figure 1. Endocavernous plaque excision

by scissors.

Figure 2. Endocavernous clearance even of

the smallest plaques.

Figure 3. Anatomical identification of the 3 layers: Plaque, Albuginea,

Bundle (PAB).

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

Key words

Peyronie’s disease • Plaque surgery •

Safenous grafting

Summary

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.

Corresponding author

Mauro Silvani, Direttore f.f. s.c. Urologia ASL BI, Ospedale degli Infermi, Biella, Italy – Tel. 339210402– E-mail: dr.silvani@libero.it

Journal of Andrological Sciences 2010;17:171-177

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.

Rispetto alla tecnica descritta gli Autori hanno adottato

i seguenti accorgimenti:

1. impianto di tutore assiale soffice di piccolo cali-

Figura 1.

Corporoplasty with soft axial tutors and safenous grafting. Following three years

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 este-

Figura 3. Graft safenico disteso sul difetto albugineo a rivestire il

tessuto cavernoso.

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.

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.

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

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).

Figura 6. Allungamento del pene da 1,2 a 2,3 cm (casistica Silvani

& Pecoraro).

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).

Corporoplasty with soft axial tutors and safenous grafting. Following three years

• 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;

• ripresa dell’attività sessuale penetrativa a 90 gg

in 11 pazienti;

• ripresa dell’attività sessuale penetrativa a 120 gg

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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disease. Part I Tecnique. J Urol 1988;160:2047-9.

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patients. J Urol 2002;167:2066-9.

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originAl Article

178

Journal of Andrological Sciences 2010;17:178-182

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.

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.

Key words

Erectile dysfunction • Propionyl-L-carnitine

• L-arginine • Nicotinic acid

Corresponding author

Piubello Giorgio, U.O. Medicina Interna D, Università di Verona, Policlinico “G.B. Rossi”, Piazzale A. Scuro 1, 37134 Verona, Italy – E-mail: giorgiopiubello@alice.it


Efficacy of a nutraceutical preparation as add-on treatment in patients with erectile dysfunction treated with 5-PDE inhibitors: a pilot study

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.

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.

180

ezerex cOntrOl

baseline 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 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

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.

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


Efficacy of a nutraceutical preparation as add-on treatment in patients with erectile dysfunction treated with 5-PDE inhibitors: a pilot study

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

1 McKinlay B. The worldwide prevalence and epidemiology

of erectile dysfunction. Int J Impot Res

2000;12(Suppl 4):6-11.

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evaluation of an abridged, 5-item version of the International

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cASe rePort

Bilateral leydig cell tumor with adrenal hyperplasia

T. Zenico, M. Saccomani, U. Salomone, E. Bercovich

Department of Urology, Morgagni-Pierantoni Hospital, Forlì, Italy

Key words

Leydig cell tumors • Adrenal hyperplasia

Summary

Journal of Andrological Sciences 2010;17:183-185

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

Corresponding author

Teo Zenico, Department of Urology, Morgagni-Pierantoni Hospital, via Forlanini 34, 47100 Forlì, Italy – Tel. 39 0543 735045 – Fax 39 0543 735019 – E-mail: androzen@alice.it

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.

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 1. Anechogenic area of the left testicle associated with

hypervascularization.

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

Bilateral Leydig cell tumor with adrenal hyperplasia

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

1 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

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2002;88:75-6.

7 Battaglia M, Ditonno P, Palazzo S, et al. Bilateral tumors

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adrenal hyperplasia. Urol Oncol 2005;23:178-80.

185


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da far


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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

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190

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Vol. 17December 2010

CONTENTS

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

Corporoplasty with soft axial tutors and safenous grafting. Following three years............................. 171

Efficacy of a nutraceutical preparation as add-on treatment in patients with erectile dysfunction

treated with 5-PDE inhibitors: a pilot study.................................................................................... 178

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 2010;17:149-192

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