ANDROLOGICAL SCIENCES

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1 ISSN Journal of Vol. 17 t /P t December 2010 CONTENTS 2010;17: Vol. 17 t /P t December 2010 ORIGINAL ARTICLES Current techniques in management of obstructive azoospermia Gynecomastia: pathophysiology, clinical evaluation and management Chlamydia trachomatis infection: the urologist s point of view Peyronie s disease: endocavernous plaque excision without substitutive graft: critical 5-year experience CASE REPORT Bilateral Leydig cell tumor with adrenal hyperplasia TABLE OF CONTENTS Journal of ANDROLOGICAL SCIENCES Official Journal of the Italian Society of Andrology Efficacy of a nutraceutical preparation as add-on treatment in patients with erectile dysfunction treated with 5-PDE inhibitors: a pilot study Periodico trimestrale - POSTE ITALIANE SPA - Spedizione in Abbonamento Postale - D.L. 353/2003 conv. in L. 27/02/2004 n 46 art. 1, comma 1 DCB PISA Corporoplasty with soft axial tutors and safenous grafting. Following three years ANDROLOGICAL SCIENCES Official Journal of the Italian Society of Andrology IN THIS ISSUE OBSTRUCTIVE AZOOSPERMIA GYNECOMASTIA CHLAMIDYA TRACHOMATIS INFECTION SURGERY OF PEYRONIE S DISEASE NUTRACEUTICAL FOR ERECTILE DYSFUNCTION BILATERAL LEYDIG CELL TUMOR

2 Vol. 17 t /P t December 2010 Journal of ANDROLOGICAL SCIENCES Official Journal of the Italian Society of Andrology Cited in SCOPUS Elsevier Database Past Editors Fabrizio Menchini Fabris (Pisa) Edoardo Pescatori (Modena) Paolo Turchi (Pisa) Vincenzo Ficarra (Padova) Andrea Salonia (Milano) Editor-in-Chief Ferdinando Fusco (Napoli) Managing Editor Furio Pirozzi Farina (Sassari) Copyright 4*"4 4 S M t WJB -VJHJ #FMMPUUJ #PO 3PNB Editorial Office -VDJB $BTUFMMJ &EJUPSJBM "TTJTUBOU 5FM t 'BY MDBTUFMMJ!QBDJOJFEJUPSF JU 1BDJOJ &EJUPSF 4 Q " t 7JB " (IFSBSEFTDB 1JTB *UBMZ Publisher 1BDJOJ &EJUPSF 4 Q " 7JB " (IFSBSEFTDB 1JTB *UBMZ 5FM t 'BY *OGP!QBDJOJFEJUPSF JU XXX QBDJOJNFEJDJOB JU 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)

3 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 Gynecomastia: pathophysiology, clinical evaluation and management M. Rossato, M. Sogaro, R. Vettor Chlamydia trachomatis infection: the urologist s point of view T. Cai, S. Mazzoli, N. Mondaini, G. Malossini, R. Bartoletti 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 Corporoplasty with soft axial tutors and safenous grafting. Following three years M. Silvani, S. Pecoraro, A. Zucchi Efficacy of a nutraceutical preparation as add-on treatment in patients with erectile dysfunction treated with 5-PDE inhibitors: a pilot study G. Piubello CASE REPORT Bilateral Leydig cell tumor with adrenal hyperplasia T. Zenico, M. Saccomani, U. Salomone, E. Bercovich Table of contents

4 original article Journal of Andrological Sciences 2010;17: 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 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. Corresponding author Giovanni Liguori [email protected] 149

5 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 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- 150

6 Current techniques in management of obstructive azoospermia formed with either a modified one-layer or a twolayer technique. The modified one-layer anastomosis 7 is performed using six to eight interrupted full thickness sutures of 9-0 nylon placed equidistantly around the circumference of each end of the vas, followed by the placement of more superficial outer muscular layer sutures of 9-0 nylon between adjacent full thickness sutures. The two-layer end-to-side microsurgical anastomosis 8 is performed by placing six to eight interrupted sutures of 10-0 nylon through the mucosa of each end of the vas, followed by the placement of approximately eight interrupted sutures of 9-0 nylon through the outer muscular layer of the vas (Fig. 1). A folding vas approximating clamp is useful to perform this anastomosis 9. The one-layer technique is performed in patients in whom there is little difference in the diameters of vas deferens between the distal and the proximal sides. Nevertheless, to simplify the surgical procedure and to shorten the duration of the operation, the one-layer technique might be sufficient for vasectomy reversal. In vasovasostomy after herniorrhaphy, when there used to be a large difference in the diameters of the vas deferens between the distal and the proximal sides because of the long duration of obstruction, the two-layer technique is required to ensure the precise attachment of the mucosa of the vas deferens. When compared with the fertility rate (42% to 50%) for the patients who underwent vasectomy reversal with duration < 10 years, the results for the patients who underwent vasectomy reversal with duration > 10 years after vasectomy showed markedly poor results (37%) 10. Known inhibiting factors of pregnancy after vasovasostomy include stricture and obstruction of the seminal tract at the anastomotic site; ruptured ductus epididymis caused by Figure 1. Inner mucosal edges are approximated with interrupted 10-0 nylon sutures and outer muscular edges are approximated with interrupted 9-0 nylon sutures. occlusion or back pressure and secondary obstruction of ruptured ductus epididymidis, and antisperm antibodies have also been reported to play a role 11. Vasoepididymostomy This procedure is performed by creating vertical scrotal incisions that are adequately long to extrude the scrotal contents. Otherwise the testicles are exposed by means of an infrapubic incision according to Kelami. The presence of active spermatogenesis is an obvious prerequisite to this surgical procedure and, if a testis biopsy has not already been carried out before this surgery, it can be done in a standard fashion and the tissue examined under the microscope (400 ) for the presence of sperm, some of which may be motile. It is necessary to prove that the vasa are patent. For this reason a 27-gauge needle is inserted into the lumen of the vas, pointing away from the testicle (Fig. 2) and a vasography is carried out: a vasogram involves the injection of contrast media into the vas toward the bladder from the scrotum. Vasography can delineate the proximal vas deferens, seminal vesicle and ejaculatory duct anatomy and determine whether obstruction is present (Fig. 3). The procedure begins by first freeing up the abdominal limb of the vas deferens that will be used for the anastomosis. Mobilization of the vas with meticulous preservation of blood supply is necessary to create a tension-free anastomosis. For this purpouse the vas must be prepared to the level of the ring and drawed through an opening in the tunica vaginalis: Then the vas is brought to the epididymis in a straight-line Figure 2. A 27-gauge needle is inserted into the lumen of the vas, pointing away from the testicle and the contrast media is injected into the vas toward the bladder from the scrotum. 151

7 G. Liguori, et al. Figure 3. Vasography delineates the proximal vas deferens, seminal vesicle and ejaculatory duct anatomy. In this case distal obstruction is not present. fashion and the posterior edge of the epididymal tunic is sewed to the posterior edge of the vasal muscularis with interrupted 9-0 nylon sutures in order to position the lumen of the vas adjacent to the selected epididymal tubule 12. The results of vasoepididymostomy are increasingly successful the lower the anastomosis is performed in the epididymis 13. While it is important to perform the anastomosis at the lowest possible epididymal level, the level must be at a point in the epididymis at which spermatozoa are present in the epididymal tubular fluid, which assures that the anastomosis will be performed above the obstruction in the Figure 4. Transversal two-suture intussusceptions vasoepididymostomy. The sutures were placed transversely in the epididymal tubule with a single, simultaneous needle placement 17. epididymis. Although vasovasostomy may have a successful result despite the intraoperative absence of spermatozoa from the vas fluid, vasoepididymostomy never will be successful when performed at an epididymal level at which spermatozoa are absent from the epididymal tubular fluid 14. Multiple anastomotic techniques have been described, although three variations are currently used: direct end-to-end, direct end-to-side, and end-toside intussusceptions 15. Of all the modifications reported in literature, intussusception vasoepididymostomy anastomotic techniques have had the greatest impact on clinical practice and are now used widely by urologic microsurgeons. Berger 16 first described the use of an invagination vasoepididymostomy in clinical practice. He described a triangulation intussusception technique using three double-armed 10-0 nylon sutures, which would be equivalent to six luminal sutures. In a series of 12 men who underwent bilateral vasoepididymostomy with this technique, the patency rate was 92%. Marmar 17 then described a two-suture intussusceptions vasoepididymostomy technique that many regarded as another significant advance: the sutures were placed transversely in the epididymal tubule with a single, simultaneous needle placement. The Cornell group also has reported on a two-suture method. In their study, the sutures were placed longitudinally rather than transversely 18. This maneuver then was followed by a tubulotomy cut between the sutures. After the epididymal fluid is tested for sperm and aspirated into micropipettes for cryopreservation, the two needles within the epididymal tubule are pulled through, and all four needles are placed through the vas lumen at the marked locations. Tying down the sutures allows the epididymal tubule to be intussuscepted into the vasal lumen, completing the anastomosis (Fig. 2). The patency rate with the longitudinal intussusception vasoepididymostomy approach was over 90% in a recent clinical series, and intussusception is the preferred method for all vasoepididymostomies 19. Sperm retrieval techniques Not all men with obstructive azoospermia are tractable by microsurgical reconstruction. In such situations, various sperm-retrieval techniques can be employed to take sperm for use with in vitro fertilization (IVF) via intracytoplasmic sperm injection (ICSI). For obstructive azoospermia, fertilization and pregnancy rates are comparable with those achieved with 152

8 Current techniques in management of obstructive azoospermia ejaculated sperm. The results with frozen testicular sperm are comparable to those obtained with fresh testicular sperm. Sperm retrieval with IVF/ICSI offers the possibility of early achievement of a relatively high live delivery rate, but any couple considering IVF/ICSI should be apprised of the risks involved in this type of treatment. These include the possibility of ovarian hyperstimulation, the potential complications of oocyte retrieval and the risks and consequences of multiple gestations 20. In men with obstructive azoospermia, sperm may be retrieved from either the epididymis or the testis via a variety of percutaneous, open, or microsurgical techniques. The microsurgical techniques may also be used concomitantly with reconstructive procedures as a means to obtain sperm for cryopreservation in the event the attempt at reconstruction is not successful. The obvious advantages of percutaneous acquisition are the minimally invasive nature of this method and the ability to sample multiple sites within the testes with minimal potential of harm to the testis. The obvious disadvantage is that the area of tissue sampled is decreased markedly compared with the open biopsy. Sperm Retrieval Techniques According to the Practice Committee of American Society for Reproductive Medicine Guidelines, since only 20% to 40% of couples conceive after attempted vasoepididymostomy despite patency rates of 60% to 80%, it is reasonable to consider sperm retrieval at the time of surgical reconstruction 21. If motile sperm are found at the site of reconstruction, they may be aspirated and cryopreserved. Alternatively, sperm may be retrieved via testicular biopsy. The first successful attempt at ICSI using epididymal sperm (MESA or microsurgical epididymal sperm aspiration) was reported by Silber 22 and Tournaye 23. Many reports have shown that the cause of obstruction is not important when considering the success rate with MESA. The MESA procedure is performed under general anaesthesia. After exposure a dilated tubule of the epididymis is microsurgically opened and its fluid examined for the presence of motile spermatozoa. The best quality sperm are typically found in the proximal epididymis close to the testis. Puncture sites may be closed or cauterized. Performing aspiration under direct vision with the aid of the operating microscope allows for procurement of Figure 5. Longitudinal 2-suture longitudinal end-to-side vasoepididymostomy technique 18. a large number of good quality, motile sperm from the epididymal tubules 24. An alternative method for epididymal aspiration of sperm is PESA (percutaneous epididymal sperm aspiration), being less invasive and less costly than MESA. Epididymal aspiration also can be performed without surgical scrotal exploration, repeatedly, easily, and at low cost, without an operating microscope or expertise in microsurgery. PESA can be performed under local anesthesia. This technique is indicated in patients with obstructive azoospermia who were unable to undergo or who decided against surgical reconstruction. A needle is introduced through the skin into the epididymis and is then aspirated (Fig. 6). Multiple punctures may be required to obtain sufficient fluid. However, the numbers of sperm retrieved are often not sufficient to allow for cryopreservation, so repeat procedures may be warranted for multiple IVF cycles. In addition, there is a risk for development of scrotal hematoma or injury to the epididymal or testicular vessels given the blind nature of this procedure. Despite the good results with MESA and PESA, many studies have shown that ICSI with testicular spermatozoa retrieved by TESE (testicular sperm extraction) could also be successfully applied in almost all cases of azoospermia. The most popular methods of sperm retrieval are conventional open biospy retrieval (TESE), FNA (fine needle aspiration) or TESA (testicular sperm aspiration). In patients with normal spermatogenesis it seems that FNA and TESE give comparable results

9 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 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/ 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. References 1 Sheynkin YR, Hendin BN, Schlegel PN, et al. Microsurgical repair of iatrogenic injury to the vas deferens. J Urol 1998;159: Practice Committee of the American Society for Reproductive Medicine. The management of infertility due to obstructive azoospermia. Fertil Steril 2008;90 (Suppl 3): Donovan JF Jr, Di Baise M, Sparks AE, et al. Comparison of microscopic epididymal sperm aspiration and intracytoplasmic sperm injection/in-vitro fertilization with repeat microscopic reconstruction following vasectomy: is second attempt vas reversal worth the effort? Hum Reprod 1998;13: Pavlovich CP, Schlegel PN. Fertility options after vasectomy: a cost-effectiveness analysis. Fertil Steril 1997;67: Kolettis PN, Thomas AJ. Vasoepididymostomy for vasectomy reversal: a critical assessment in the era of intracytoplasmic sperm injection. J Urol 1997;158: Goldstein M, Li PS, Matthews GJ. Microsurgical vasovasostomy: the microdot technique of precision suture placement. J Urol 1998;159: Schmidt SS. Vasovasostomy. Urol Clin North Am 1978;5: Belker AM. Microsurgical two-layer vasovasostomy. Simplified technique using hinged, folding-approximating clamp. Urology 1980;16: Belker AM, Thomas AJ Jr, Fuchs EF, et al. Results of 1,469 microsurgical vasectomy reversals by the vasovasostomy Study Group. J Urol 1991;145: Nagler HM, Jung H. Factors predicting successful microsurgical vasectomy reversal. Urol Clin North Am 2009;36:

10 Current techniques in management of obstructive azoospermia 11 Royle MG, Parslow ]M, Kingscott MMB, et al. Reversal of vasectomy: the effect of sperm antibodies on subsequent fertility. Br J Urol 1981;53: Kolettis PN. Restructuring reconstructive techniques-- advances in reconstructive techniques. Urol Clin North Am 2008;35: Jarow JP, Oates RD, Buch JP. Epididymovasostomy outcomes based upon level of anastomosis and intraepididymal sperm quality. Assisted Reprod Reviews 1997;7: Niederberger C, Ross LS. Microsurgical epididymovasostomy: predictors of success. J Urol 1993;149: Lipshultz L, Homas A Jr, Khera M. Surgical management of male infertility. In: Wein A, Kavoussi L, Novick A, et al., editors. Campbell-Walsh Urology, vol th edn. Philadelphia: Saunders Elsevier Berger R. Triangulation end-to-side vasoepididymostomy. J Urol 1998;159: Marmar JL. Modified vasoepididymostomy with simultaneous double needle placement, tubulotomy, and tubular invagination. J Urol 2000;163: Chan P, Li P, Goldstein M. Microsurgical vasoepididymostomy: a prospective, randomized study of three intussusceptions techniques in rats. J Urol 2003;169: Chan PT, Brandell RA, Goldstein M. Prospective analysis of outcomes after microsurgical intussusception vasoepididymostomy. BJU Int 2005;964: Schlegel PN, Girardi SK. Clinical review 87: in vitro fertilization for male factor infertility. J Clin Endocrinol Metab 1997;82: Practice Committee of American Society for Reproductive Medicine. Sperm retrieval for obstructive azoospermia. Fertil Steril 2008;90 (5 Suppl):S Silber SJ, Nagy ZP, Liu J, et al. Conventional in-vitro fertilization versus intracytoplasmic sperm injection for patients requiring microsurgical sperm aspiration. Hum Reprod 1994;9: Tournaye H, Devroey P, Liu J, et al. Microsurgical epididymal sperm aspiration and intracytoplasmic sperm injection: a new effective approach to infertility as a result of congenital bilateral absence of the vas deferens. Fertil Steril 1994;61: Nudell DM, Conaghan J, Pedersen RA, et al. The mini-micro-epididymal sperm aspiration for sperm retrieval: a study of urological outcomes. Hum Reprod 1998;13: Tournaye H. Use of testicular spermfor the treatment of male infertility. Baillieres Clin Obstet Gynaecol 1997;11: Craft IL, Khalifa Y, Boulos A, et al. Factors influencing the outcome of in vitro fertilization with percutaneous aspirated epididymal spermatozoa and intracytoplasmic sperm injection in azoospermic men. Hum Reprod 1995;10: Palermo GD, Schlegel PN, Hariprashad J, et al. Fertilization and pregnancy outcome with intracytoplasmic sperm injection for azoospermic men. Hum Reprod 1999;14: Silber SJ, Nagy Z, Devroey P, et al. The effect of female age and ovarian reserve on pregnancy rate in male infertility: treatment of azoospermia with sperm retrieval and intracytoplasmic sperm injection. Hum Reprod 1997;12:

11 original article Journal of Andrological Sciences 2010;17: Gynecomastia: pathophysiology, clinical evaluation and management M. Rossato, M. Sogaro, R. Vettor University of Padova, Department of Medical and Surgical Sciences, Clinica Medica 3-Endocrine-Metabolic Unit Summary Introduction. Gynecomastia is a common clinical condition characterized by an enlargement of the glandular tissue of the male breast, with a high prevalence in young and old subjects. It is due generally to an absolute or relative increase of estrogens over androgens. Methods. This article reviews the clinical management of gynecomastia, with particular attention to the causes and pathophysiological mechanisms leading to an absolute or relative excess of estrogens over androgens determining gynecomastia. We face also a brief review of all medical and surgical therapies available to treat this condition that often troubles many patients above all in the pubertal age. Results. Gynecomastia may be the result of an increased absolute estrogen production from estrogen secreting glands and/or to increased androgens conversion in the peripheral tissues or to a relative prevalence of estrogens over androgens. The efficacy of the management of gynecomastia depends on its causes and the time from its appearance due to possible time-dependent fibrotic modifications of breast tissue. For its treatment, depending on each specific cause, we can consider first the use of anti-estrogens. When pharmacological therapy shows no efficacy, surgery might be necessary. Conclusions. Gynecomastia is a relatively common clinical condition. Usually a careful clinical history and physical examination are sufficient to identify the possible different causes ranging from pubertal gynecomastia, drug-induced causes, or an underlying pathological condition. Since gynecomastia often resolves spontaneously (as well as pubertal gynecomastia in a large part of pubertal boys), periodic clinical follow-up is usually sufficient to manage these patients. Nonetheless there are conditions where further clinical evaluation is necessary as well as medical or surgical treatment. Key words Gynecomastia Pathophysiology Management Estrogen Androgen Introduction Gynecomastia is an enlargement of the glandular component of the male breast due to ductular elements proliferation; it can be unilateral or bilateral. This condition has to be differentiated from excessive breast adipose tissue accumulation, a condition known as pseudogynecomastia. Histologically, gynecomastia is characterized by the proliferation and dilatation of mammary ductules with periductal fibroconnective tissue. True terminal acini are rarely seen since acini require the presence of both female hormones (estradiol and progesterone) 1-3. Corresponding author Marco Rossato, University of Padova, Department of Medical and Surgical Sciences, Endocrine-Metabolic Unit, via Ospedale 105, Padova, Italy Tel Fax [email protected] 156

12 Gynecomastia: pathophysiology, clinical evaluation and management 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 Pathogenesis The pathophysiological process of gynecomastia primarily involves an absolute or relative imbalance between estrogen and androgen action at breast tissue level Causes The causes of gynecomastia can be distinguished in absolute estrogen excess, absolute androgen deficiency, relative estrogen excess/androgen deficiency, decreased androgen action. An absolute estrogen excess directly stimulates the growth of male breast tissue, and may be due to endogenous estrogen overproduction as well as exogenous estrogen administration. Endogenous estrogen overproduction can origin from the testis and from the adrenal gland, or from an increased androgen aromatization. Testis Leydig cell tumors. Leydig cell tumors are rare, representing the 3% of all testicular neoplasms. The natural history is usually benign, and malignant cases have been described in 10% of cases. They are generally seen in young adults, although they can occur at any age 12. Leydig cell tumors directly produce high estrogen levels, which cause a luteinizing hormone (LH) suppression from the pituitary thus leading to a reduction in the testicular testosterone production. In this condition, there is an absolute estradiol overproduction by the tumor, a reduction of testicular testosterone production due to LH suppression, and a sex hormone-binding globulin (SHBG) elevation due to estrogen stimulation, thus leading to a decrease in free testosterone concentration. All these situations contribute to the increase of free estrogens/free androgens ratio. Sertoli cell tumors. These tumors are very rare, and usually benign, occurring in boys and young men. These tumors do not directly secrete estrogens, but overexpress aromatase, the enzyme catalyzing the conversion of androgens to estrogens, thus leading to increased androgen transformation to estrogens 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) Exogenous estrogen exposure. Unintentional exposure to estrogens may occur by means of food (milk or meat from estrogen-treated cows), beer and wine 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 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

13 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 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. 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

14 Gynecomastia: pathophysiology, clinical evaluation and management Table I. Drugs inducing gynecomastia and their pathophysiological mechanism of action. Drug Class Drug Mechanism Antiandrogens/inhibitors of androgen synthesis Cyproterone acetate Flutamide Finasteride AR blockade or inhibition of androgen synthesis Reduction of DHT biosynthesis Antibiotics Antiulcer drugs Cancer chemotherapeutic drugs Cardiovascular drugs Drugs of abuse Hormones Ethionamide Isoniazid Ketoconazole Metronidazole Cimetidine Ranitidine Omeprazole Alkylating agents Methotrexate Vinca alkaloids Combination chemother Nitrosureas Imatinib Busulfan Amiodarone Enalapril Captopril Digitoxin Digitalis Amlodipine Diltiazem Verapamil Nifedipine Reserpine Spironolactone Methyldopa Alcohol Amphetamines Heroin Marijuana Methadone Androgens Anabolic steroids Diethylstilbestrol Human chorionic gonadotropin Estrogens and estrogen agonists Growth hormone Medroxyprogesterone acetate Oral contraceptives Unknown Unknown; possible refeeding gynecomastia Decreased testosterone or DHT biosynthesis AR blockade Unknown Adverse reaction; possible estrogen activity; possible decreased testosterone (induction of cytocrome metabolism*) Destruction or inhibition of Leydig cells Unknown Unknown Estrogen-like activity Estrogen-like activity Unknown Decreased testosterone or DHT biosynthesis AR blockade Unknown Increased aromatization of androgens to estrogens Unknown Decreased testosterone biosynthesis AR blockade Decreased testosterone biosynthesis Increased aromatization of androgens to estrogens Exogenous estrogen Stimulation of testicular estrogen secretion Increased estrogen activity Unknown Exogenous estrogens Psychoactive drugs Diazepam Haloperidol Paroxetine Phenothiazines Risperidone Tricyclic antidepressants Exogenous estrogens Unknown Increased serum prolactin Unknown (continues) 159

15 M. Rossato, et al. Table I continued. Other drugs Auranofin Diethylproprion Domperidone Etretinate Metoclopramide Phenytoin D-penicillamine Sulindac Theophylline Melatonin Furosemide Bumetanide Clomiphene citrate Efavirenz Unknown Unknown Unknown Unknown** Increased serum prolactin Unknown Unknown Unknown Unknown AR: androgen receptor; * Rosenshein et al., 2004; ** Carmichael et al., 2004; *** Jover et al., Increased estrogen activity Unknown; possible efavirenz mediated estradiol-like effects*** 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 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 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 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

16 Gynecomastia: pathophysiology, clinical evaluation and management 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 Androgens Androgens have been used to reduce the gonadotropins 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

17 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 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. References 1 Braunstein GD. Gynecomastia. N Engl J Med 2007;357: Narula HS, Carlson HE. Gynecomastia. Endocrinol Metab Clin N Am 2007;36: Gikas P, Mokbel K. Management of gynaecomastia: an update. Int J Clin Pract 2007;61: Niewoehner CB, Nuttall FQ. Gynecomastia in an hospitalized male population. Am J Med 1984; 77: Andersen JA, Gram JB. Male breast at autopsy. Acta Pathol Microbiol Immunol Scand (Sect A) 1982;90: Williams MJ. Gynecomastia: its incidence, recognition and host characterization in 447 autopsy cases. Am J Med 1963;34: Nuttall FQ. Gynecomastia as a physical finding in normal men. J Clin Endocrinol Metab 1979;48: Johnson RE, Murad MH. Gynecomastia: pathophysiology, evaluation, and management. Mayo Clin Proc 2009;84: Marthur R, Braunstein GD. Gynecomastia: pathomechanisms and treatment strategies. Horm Res 1997;48: Rochefort H, Garcia M. The estrogenic and antiestrogenic activities of androgens in female target tissues. Pharmacol Ther 1983;23: Wilson JD, Aiman J, MacDonald PC. The pathogenesis of gynaecomastia. Adv Intern Med 1980;25: Rossato M, Tavolini IM, Calcagno A, et al. The novel hormone INSL3 is expressed in human testicular Leydig cell tumors: a clinical and immunohistochemical study. Urol Oncol 2008;29: Gabrilove JL, Nicolis GL, Mitty HA, Sohval AR. Feminizing interstitial cell tumor of the testis; personal observations and a review of the literature. Cancer 1975;35: Bercovici JP, Nahoul K, Tater D, et al. Hormonal prolife of Leydig cell tumors with gynecomastia. J Clin Endocrinol Metab 1984;59: Young S, Gooneratne S, Straus FH, et al. Feminizing Sertoli cell tumors in boys with Peutz-Jeghers syndrome. Am J Surg Pathol 1995;19: Gabrilove JL, Sharma DC, Wotiz HH, et al. Feminizing adrenal cortical tumors in the male: a review of 52 cases including a case report. Medicine 1965;44: Bulun SE, Fang JZ, Gurates B, et al. Aromatase in health and disease. Endocrinologist 2003;13: Braunstein GD. Aromatase and gynecomastia. Endocr- Relat Cancer 1999;6: Daxenberger A, Ibarreta D, Meyer HH. Possible health impact of animal oestrogens in food. Hum Reprod Update 2001; 7: Gavaler JS, Rosenblum ER, Deal SR, et al. The phytoestrogen congeners of alcoholic beverages: current status. Proc Soc Exp Biol Med 1995;208: Smyth CM, Bremner WJ. Klinefelter syndrome. Arch Intern Med 1998;158: Lanfranco F, Kamischke A, Zitzmann M, et al. Klinefelter s syndrome. Lancet 2004;364:

18 Gynecomastia: pathophysiology, clinical evaluation and management 23 Fentiman IS, Fourquet A, Hortobagyi GN. Male breast cancer. Lancet 2006;367: Swerdlow AJ, Schoemaker MJ, Higgins CD, et al.; UK Clinical Cytogenetics Group. Cancer incidence and mortality in men with Klinefelter syndrome: a cohort study. J Natl Cancer Inst 2005;97: Georgiadis E, Papandreou L, Evangelopoulou C, et al. Incidence of gynecomastia in 954 young males and its relationship to somatometric parameters. Ann Hum Biol 1994; 21: Cavanaugh J, Niewoehner CB, Nuttall FQ. Gynecomastia and cirrhosis of the liver. Arch Intern Med 1990;150: Hudson B, Burger HG, De Krester DM. Virility and fertility. In: Shearman RP, editor. Clinical Reproductive Endocrinology. Edinburgh, United kingdom: Churchill Livingston 1985; pp Ersoz H, Onde ME, Terekeci H, et al. Causes of gynecomastia in young adult males and factors associated with idiopathic gynecomastia. Int J Androl 2002;25: Cordova A, Moschella F. Algorithm for clinical evaluation and surgical treatment of gynecomastia. J Plast Reconstruct Aesthet Surg 2008;61: Biro FM, Lucky AW, Huster GA, et al. Hormonal studies and physical maturation in adolescent gynecomastia. J Pediatr 1990;116: Treves N. Gynecomastia: the origins of mammary swelling in the male: an analysis of 406 patients with breast ipertrophy, 525 with testicular tumors, and 13 with adrenal neoplasms. Cancer 1958;11: Gruntmanis U, Braunstein GD. Treatment of gynecomastia. Curr Opin Investig Drugs 2001;2: Ting ACW, Chow LWC, Leung YF. Comparison of tamoxifen with danazol in the management of idiopathic gynecomastia. Am Surg 2000;66: Khan HN, Rampaul R, Blamey RW. Management of physiological gynecomastia with tamoxifen. Breast 2004;13: Lawrence SE, Faught KA, Vethamuthu J, et al. Beneficial effects of raloxifene and tamoxifen in the treatment of pubertal gynecomastia. J Pediatr 2004;145: Plourde PV, Kulin HE, Santner SJ. Clomiphene in the treatment of adolescent gynecomastia. Clinical and endocrine studies. Am J Dis Child 1983;137: Braunstein GD. Aromatase and gynecomastia. Endocr Relat Cancer 1999; 6: Boccardo F, Rubagotti A, Battaglia M, et al. Evaluation of tamoxifen and anastrazole in the prevention of ginecomastia and breast pain induced by bicalutamide monotherapy of prostate cancer. J Clin Oncol 2005;23: Plourde PV, Reiter EO, Jou HC, et al. Safety and efficacy of anastrazole for the treatment of pubertal gynecomastia: a randomized, double-blind, placebo-controlled trial. J Clin Endocrinol Metab 2004;89: Benveniste O, Simon A, Herson S. Successful percutaneous dyhidrotestosterone treatment of ginecomastia occurring during highly active antiretroviral therapy: four cases and a review of the literature. Clin Infect Dis 2001;33: Ting AC, Chow LW, Leung YF. Comparison of tamoxifen with danazol in the management of idiopathic gynecomastia. Am Surg 2000;66: Dicker AP. The safety and tolerability of low-dose irradiation for the management of gynecomastia caused by antiandrogen monotherapy. Lancet Oncol 2003;4: Rohrich RJ, Ha RY, Kenkel JM, et al. Classification and management of gynecomastia: defining the role of ultrasound-assisted liposuction. Plast Reconstr Surg 2003;111: Tashkandi M, Al-Qattan MM, Hassanain JM, et al. The surgical management of high-grade gynecomastia. Ann Plast Surg 2004;53: Hines SL, Tan WW, Yasrebi M, et al. The role of mammography in male patients with breast symptoms. Mayo Clin Proc 2007;82:

19 original article Journal of Andrological Sciences 2010;17: 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. Key words Chlamydia trachomatis Prostatitis Sexually transmitted diseases Infection Quinolones Sexually active young men Introduction Sexually transmitted diseases (STDs) are among the first ten causes of unpleasant diseases in young adult males in developing countries and the second major cause of unpleasant diseases in young adult women, with an enormous health and economic consequences 1. Among these, Chlamydia trachomatis (Ct) is the most common sexually transmitted bacterium worldwide 2 with over three million new infections per 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 Fax ktommy@ libero.it 164

20 Chlamydia trachomatis in sexually active young men cytokines have been detected in total ejaculate and seminal plasma samples to demonstrate their role in monitoring men with CP 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 ( 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: 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: years. Moreover, we searched reference lists of articles to identify potential additional references. All original paper and review studies of Ct diagnosis and treatment in young adult have been considered for this review. We considered also guidelines from the National Institute for Health and Clinical Excellence and the European Centre for Disease Prevention and Control, the US Centers for Disease Control and Prevention, and World Health Organization. Results Ct diagnosis From an initial literature search with 188 unique citations, a total of 27 articles were selected for the present review. A matched research between Chlamydia trachomatis and Chlamydia infections (exploded) and the following terms total ejaculated and prostate massage has not found any items. Diagnosis of Ct infection can be made by using: direct detection; indirect detection. Direct detection Ct is an obligate intracellular bacterium and cell culture remains a reference method (about 100% specificity) 13. However, all Authors are agree that it is not recommended for routine use, due to its lack of sensitivity, its technical complexity and the long turn-around time 14. Other Authors suggest that Ct can be found by using antigen-based detection methods 13. In particular, direct fluorescent staining with monoclonal antibodies (DFA) and enzyme immunoassay (EIA). EIA tests are more reproducible than DFA, and the sensitivity of the best EIA is comparable to that of culture but lower than that of nucleic acid amplification tests (NAATs), due to the cross-reactions with the lipopolysaccharide (LPS) of other microorganisms 13. Recently, Mahilum-Tapay and co-workers, evaluated the performance of the Chlamydia Rapid Test, a new assay developed at the Diagnostics Development Unit, University of Cambridge 15. They compared sensitivity, specificity, positive predictive value, and negative predictive value of the Chlamydia Rapid Test with the gold standard test for Ct infections (NAATs) 15. In this study, they found a good diagnostic performance: sensitivity 83.5%, specificity 98.9%, positive predictive value 86.7%, and negative predictive value 98.6% 15. However, NAATs are the tests of choice for the diagnosis of Ct genital infections 13. In everyday clinical practice, several commercial NAATs are available, and make use of different technologies: PCR and real-time PCR (Roche Diagnostics, Abbott, IL, USA); strand displacement amplification (Becton Dickinson, NJ, USA); transcription-mediated amplification (Gen Probe); and nucleic acid sequencebased amplification (biomerieux, Nancy L Etoile, France) 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

21 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 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 Even if doxycycline and azithromycin are the most widely prescribed drugs in Ct infections treatment and recommended as the primary approach, other 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 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 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, 166

22 Chlamydia trachomatis in sexually active young men Table I. Randomized, controlled, clinical trials. Author/ Drugs year Cai T (2009) Whatley JD (1991) Jeskanen L (1989) Stolz E (1986) Patient number Clinical efficacy (%) Microbiological efficacy (%) Microbiological markers Prulifloxacin/doxicicline IL-8/IgA Azithromycin/doxicicline Ciprofloxacin/doxicicline Ciprofloxacin 250/ciprofloxacin 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 failure 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: Centers for Disease Control. Sexually transmitted diseases treatment Guidelines. 2002;51(RR-6): Groseclose SL, Zaidi AA, DeLisle SJ, et al. Estimated incidence and prevalence of genital Chlamydia trachomatis infections in the United States, Sex Transm Dis 1999;26: 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: 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: Schachter J, Caldwell HD. Chlamydiae. Annu Rev Microbiol 1980;34: 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:

23 T. Cai, et al. 9 Petzold D, Gross G, editors. Diagnostik und therapie sexuell übertragbarer Krankheiten. Leitlinien 2001 der Deutschen STD-Gesellschaft. Berlin; Springer Wagenlehner FME, Weidner W, Naber KG. Chlamydial infections in urology. World J Urol 2006;24: 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: 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: Bébéar C, de Barbeyrac B. Genital Chlamydia trachomatis infections. Clin Microbiol Infect 2009;15: Black CM. Current methods of laboratory diagnosis of Chlamydia trachomatis infections. Clin Microbiol Rev 1997;10: 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: 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 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:E Persson K. The role of serology, antibiotic susceptibility testing and serovar determination in genital chlamydial infections. Best Pract Res Clin Obstet Gynaecol 2002;16: Manavi K. A review on infection with Chlamydia trachomatis. Best Pract Res Clin Obstet Gynaecol 2006;20: Smelov V, Perekalina T, Gorelov A, et al. In vitro activity of fluoroquinolones, azithromycin and doxycycline against Chlamydia trachomatis cultured from men with chronic lower urinary tract symptoms. Eur Urol 2004;46: 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: Kokab A, Akhondi MM, Sadeghi MR, et al. Raised inflammatory markers in semen from men with asymptomatic chlamydial infection. J Androl 2010;31: Martínez-Prado E, Camejo Bermúdez MI. Expression of IL-6, IL-8, TNF-alpha, IL-10, HSP-60, anti-hsp-60 antibodies, and anti-sperm antibodies, in semen of men with leukocytes and/or bacteria. Am J Reprod Immunol 2010;63: 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: 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: Takahashi S, Matsukawa M, Kurimura Y, et al. Clinical efficacy of azithromycin for male nongonococcal urethritis. J Infect Chemother 2008;14: Somani J, Bhullar VB, Workowski KA, et al. Multiple drug-resistant Chlamydia trachomatis associated with clinical treatment failure. J Infect Dis 2000;181: Mourad A, Sweet RL, Sugg N, et al. Relative resistance to erythromycin in Chlamydia trachomatis. Antimicrob Agents Chemother 1980;18: Lefevre JC, Lepargneur JP. Comparative in vitro susceptibility of a tetracycline-resistant Chlamydia trachomatis strain isolated in Toulouse (France). Sex Transm Dis 1998;25:

24 original article Journal of Andrological Sciences 2010;17: 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 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, Milano, Italy Tel E- mail: [email protected] 169

25 F. Mantovani, et al. Figure 3. Anatomical identification of the 3 layers: Plaque, Albuginea, Bundle (PAB). Figure 1. Endocavernous plaque excision by scissors. Figure 2. Endocavernous clearance even of the smallest plaques. disease and preserved erection but geometrically disturbed for the severe deformity. 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 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:

26 original article Journal of Andrological Sciences 2010;17: 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 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 [email protected] 171

27 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 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 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). 172

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

29 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 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 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 174

30 Corporoplasty with soft axial tutors and safenous grafting. Following three years 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 anni. Follow-up da uno a 3 anni. L attività sessuale era completamente conservata in 12 pazienti che tuttavia presentavano alcuni fattori di rischio predittivi di disfunzione erettile quali ipertensione in terapia e dislipidemia severa, di questi 6 erano forti fumatori. I rimanenti 36 erano affetti da deficit erettile di grado lieve-moderato, 6 di tali pazienti erano diabetici in terapia con ipoglicemizzanti orali e in buon compenso glico-metabolico. Le indagini preoperatorie eseguite sono state quelle classiche ivi compreso uno screening urologico: ecocolor doppler penieno dinamico; foto documentazione; RMN dimanica peniena in 10 pazienti; PSA f/t; uroflussometria; ecografia reno vescicale; questionario IIEF 5; SEP2 e SEP3; la valutazione nel follow-up è stata volta anche a indagare le eventuali variazioni nella vita sentimentale della coppia. Le dimensioni della placca, sempre peraltro unica, erano comprese in lunghezza tra 1,2 e 2,6 cm, larghezza 0,8-1,9 cm. Il recurvatum era: dorsale puro > 45 in 28 pazienti; dorsolaterale sn > 40 in 8; ventrale > 40 in 6; laterale sx > 45 in 4; dorsolaterale dx > 45 in 2. In tutti i pazienti l intervento è stato condotto con degloving sub coronale, in sei pazienti contro incisione scrotale. In 30 pazienti i tutori assiali impiantati sono stati di 7/fr del tipo Virilis II in sette di tipo Virilis I sempre 7/fr in otto pazienti di 10 fr del tipo Virilis I, in 3 pazienti 9,5 fr del tipo SSDA. La lunghezza dei tutori impiantati era compresa tra 16,6 e 20 cm calcolata dalle crura all apice dei cc. In 36 pazienti è stata utilizzata safena prelevata alla cross. In 12 (recurvatum maggiore di 60 ) è stato impiegato patch di matrice di collagene di pericardio bovino (Veritas-Hydrix). Tutti i pazienti sono stati sottoposti dal 15 giorno post operatorio a rieducazione del tessuto erettile con ipde5 bisettimanalmente per 45 giorni con finalità eutrofiche sul tessuto erettile residuo dislocato alla periferia del tutore. La valutazione post operatoria è stata eseguita a gg, 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 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

31 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 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 > laterale, ventrale o dorsale con attività erettile conservata o disfunzione lieve moderata. References 1 Swharzer U, Sommer F, et al. The prevalence of Peyronie s disease: results of a large survey BJU Int 2001;88: Devine CJ Jr, Horton CE. Surgical treatment of Peyronie s disease whith a dermal graft. J Urol 1974;111: Lue TF, El-Sakka Al. Venous pacth graft for Peyronie s disease. Part I Tecnique. 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32 Corporoplasty with soft axial tutors and safenous grafting. Following three years experience and long term follow-up on 145 operated patients. European Urology 2005;47: Egydio PH, Lucon AM and Arap S. A single relaxing incision to correct different types of penile curvature: surgical technique based on geometrical principles. BJU Int 2004;94: Austoni E, Colombo F, Mantovani F, et al. Chirurgia radicale e conservazione dell erezione nella malattia di La Peyronie. Arch It Urol 1995;67: Wilson SK, Cleves Ma, Del JR. Long-term followup of treatment for Peyronie s disease: modelling the penis an inflate penile prosthesis. J Urol 2001;165: Carson CC. Penile prosthesis implantation in the treatment for Peyronie s disease. Int J Impot Res 1998;10: Montorsi F, Guazzoni G, Bergamaschi F, et al. Vascular abnormalities in Peyronie s disease.the role of colour Doppler sonography. J Urology 1994;151: Chilton CP, Castle WM, Pryor JP, et al. Factors associated in the aetiology of Peyronie s disease. Br J Urol 1982;54: Knoll LD. Use of small intestinal submucosa graft for the surgical management of Peyronie s disease. J Urol 2007;178: Vardi Y, Levine LA, Chen J, Schum JS. There a place fo conservative treatment in Peyronie s disease? J Sex Med 2009;6: Taylor FL, Levine LA, Non surgical therapy of Peyronie s disease. Asian J Androl 2008;10: Porena M, Mearini L, Costantini E, et al. Peyronie s disease using saphenous vein pacth-graft. Urol In t 2002;68: Kadiouglu L, Sauli O, Akkan J, et al. Surgical treatment of Peyronie s disease a single centre experience with 145 patients. Eur Urol 2008;53: Nesbit RM. Congenital curvature of the fallus: report of three cases with description of corrective operation. J Urol 1965;93: Shenfel OZ. Re: Midline dorsal placation technique for penile curvature repair. J Urol 2005:173: Austoni E, et al. a cura di. Reconstructive surgery for Peyronie s disease. In: Atlas of reconstructive penile surgery. Pisa: Pacini Editore

33 original article Journal of Andrological Sciences 2010;17: 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 < for both), but the increase was significantly higher in the treatment group (p < ). 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 < ). Despite the absence of a placebo control group, the results of this pilot study suggest the usefulness of Ezerex as add-on treatment both in patients starting ED therapy and in patients already known to be poor responders to 5-PDE inhibitors. These results need to be tested in a larger randomised, double-blind, placebo-controlled study. Key words Erectile dysfunction Propionyl-L-carnitine L-arginine Nicotinic acid Introduction Erectile dysfunction (ED) is a very common condition, with an estimated prevalence of 152 million males in the world 1. With the approval of phosphodiesterase-5 (5-PDE) inhibitors in 1998, a highly efficacious therapy became available. Nevertheless, some patients respond poorly or not at all; for example, as many as 74-83% of men prescribed sildenafil 2 3 discontinue treatment. Due to the limitations of this first-line treatment, there is interest in identifying add-on therapies to increase its effect. In the last few years, preparations based on dietary supplements, vitamin complexes and nutritional principles, classified as nutraceuticals, have come to be used in ED. Recently in Italy a product called Ezerex (Sigma Tau) has been proposed, which is made up of propionyl-l-carnitine fumarate, 250 mg, L-arginine, 2.5 g and nicotinic acid, 20 mg. Corresponding author Piubello Giorgio, U.O. Medicina Interna D, Università di Verona, Policlinico G.B. Rossi, Piazzale A. Scuro 1, Verona, Italy [email protected] 178

34 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 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 ) than in the treatment group (median 12, interquartile range 9-14; z = 3.36, p = ). 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 ; z = 5.51, p < ) and in the treatment group (median 22, interquartile range 20-23; z = 5.59, p < ). 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 < ). The changes in the assesed ED category are reported in Table II. 179

35 G. Piubello Table I. Details on the individual items of the IIEF-5 questionnaire in arm A patients. 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 < 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 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 < ). Details of the individual items of the questionnaire are reported in Table III. ED became mild in 38 (52.8%), mild to moderate in 22 (30.6%), and moderate in 3 (4.2%). In 9 patients (12.5%) the IIEF-5 score was above the threshold for ED. Table III. Details on the individual items of the IIEF-5 questionnaire in arm B patients. Baseline Follow-up Variation Question 1 2 (2-3) 3 (3-4) 1 (0-2) Question 2 2 (2-3) 4 (3-4) 1 (1-2) Question 3 2 (2-3) 4 (3-4) 1 (1-2) Question 4 3 (2-3) 4 (3-4) 1 (1-2) Question 5 3 (2-3) 4 (3-4) 1 (0-2) All the comparisons (baseline vs. follow-up) are statistically significant with p < 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 180

36 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 addon 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): Fagelman E, Fagelman A, Shabsigh R. Efficacy, safety, and use of sildenafil in urologic practice. Urology 2001:57: Souverein PC, Egberts AC, Meuleman EJ, et al. Incidence and determinants of sildenafil (dis)continuation: the Dutch cohort of sildenafil users. Int J Impot Res 2002;14: Rosen RC, Riley A, Wagner G, et al. Development and evaluation of an abridged, 5-item version of the International Index of Erectile Function (IIEF-5) as a diagnostic tool for erectile dysfunction. Int J Impot Res 1999;11:

37 G. Piubello 5 Tannini EA, Lenzi A, Maggi M. Sessuologia Medica. Milano: Elsevier Masson Cipolla MJ, Nicoloff A, Rebello T, et al. Propionyl-Lcarnitine dilates human subcutaneous arteries through an endothelium-dependent mechanism. J Vasc Surg 1999;29: Brevetti G, Perna S, Sabba C, et al. Propionyl-Lcarnitine in intermittent claudication: a double-blind, placebo-controlled, dose-titration, multi-center study. J Am Coll Cardiol 1995;26: Thomsen JH, Shug AL, Yap VU, et al. Improved pacing tolerance of the ischemic human myocardium after administration of carnitine. Am J Cardiol 1979;43: Gentile V, Vicini P, Prigiotti G, et al. Preliminary observations on the use of propionyl-l-carnitine in combination with sildenafil in patients with erectile dysfunction and diabetes. Curr Med Res Opin 2004;20: Zorgniotti AW, Lizza EF. Effect of large doses of the nitric oxide precursor, L-arginine, on erectile dysfunction. Int J Impot Res 1994;6: Chen J, Wollman Y, Chernichovsky T, et al. Effect of oral administration of high-dose nitric oxide donor L-arginine in men with organic erectile dysfunction: results of a double-blind, randomized, placebo-controlled study. BJU Int 1999;83: Warnholtz A, Wild P, Ostad MA, et al. Effects of oral niacin on endothelial dysfunction in patients with coronary artery disease: results of the randomized, doubleblind, placebo-controlled INEF study. Atherosclerosis 2009;204: Bruckert E, Labreuche J, Amarenco P. Meta-analysis of the effect of nicotinic acid alone or in combination on cardiovascular events and atherosclerosis. Atherosclerosis 2010;210: Gentile V, Antonini G, Antonella Bertozzi M, et al. Effect of propionyl-l-carnitine, L arginine and nicotinic acid on the efficacy of vardenafil in the treatment of erectile dysfunction in diabetes. Curr Med Res Opin 2009;25:

38 Case report Journal of Andrological Sciences 2010;17: 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 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, Forlì, Italy Tel Fax [email protected] 183

39 T. Zenico, et al. have a poor prognosis, with mean patient survival after surgery of about 3 years 6. A timely and accurate diagnosis is therefore vital. Figure 1. Anechogenic area of the left testicle associated with hypervascularization. Case report In November 2006 a 39-year-old man was seen in our Urology Department for infertility problems. Laboratory tests revealed that he was azoospermic, without Y chromosome microdeletions and with a normal karyotype. Clinical examination revealed enlarged testicles with multiple surface irregularities. Blood levels of total testosterone were slightly increased (12.0 ng/ml), while free testosterone (24.3 pg/ml), SHBG (34 nmol/l), somatotropin (0.1 ng/ml), alfafetoprotein (4.30 ng/ml) and betahcg (0.00 U/ ml) were normal. Very high serum levels of ACTH ( 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 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, 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 184

40 Bilateral Leydig cell tumor with adrenal hyperplasia our clinical case were the oversecretion of estradiol, low FSH and LH values and, in particular, a high level of ACTH, which highlighted the presence of adrenal hyperplasia. This condition, often diagnosed by chance, is found in 18% [7] of patients who seek medical advice for a scrotal mass 1. It is important to distinguish between LCT and nodular testicular hyperplasia (21-α hydroxylase congenital deficiency) associated with adrenogenital syndrome, an extremely rare disease affecting the fetal stage or young adults, which is occasionally associated with gynecomasty (found, conversely, in about one third of LCT patients). Urinary 17-ketosteroids, normally used as biochemical markers, may be present in both diseases. Steroid therapy with dexamethasone generally suppresses the increase in ACTH levels and reduces hyperplasia, which, in turn, results in a concomitant regression of testicular tumor volume in 75% of cases 7. This, however, did not occur in our patient. Final diagnosis can only be made by histological examination of the bioptic sample. Polygonal cells with abundant granular or eosinophil cytoplasm separated by dense fibrotic tissue are present in nodular testicular hyperplasia. Conversely, Reinke crystals are a specific characteristic of LCT, present in 20-40% of these tumors. Conclusions Leydig cell tumors are extremely rare, especially when bilateral. Adrenal gland evaluation (imaging and laboratory exams) and testicular biopsy are required for a differential diagnosis. Bilateral orchiectomy and hormone replacement therapy are indicated when histology reveals the presence of Reinke crystals but absence of nodular testicular hyperplasia due to 21-α hydroxylase deficiency. Adrenal hyperplasia associated with bilateral Leydig cell tumor, albeit even rarer, has well defined clinical, diagnostic and therapeutic parameters. References 1 Rich MA, Keating MA. Leydig cell tumors and tumors associated with congenital adrenal hyperplasia. Urol Clin North Am 2000;27: 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: 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: Drut R, Wludarski S, Segatelli V, et al. Leydig cell tumor of the testis with histological and immunohistochemical features of malignancy in a 1-year-old boy with isosexual pseudoprecocity. Int J Surg Pathol 2006;14: Sugimoto K, Matsumoto S, Nose K, et al. A malignant Leydig cell tumor of the testis. Int Urol Nephrol 2006;38: Rao SR, Mistry RC, Parikh DM. Leydig cell tumor: a case report and review of the literature. Tumori 2002;88: Battaglia M, Ditonno P, Palazzo S, et al. Bilateral tumors of the testis in 21-alpha hydroxylase deficiency without adrenal hyperplasia. Urol Oncol 2005;23:

41 Journal of Andrological Sciences 2011;18: Indice degli autori Abatangelo G., 54 Abbadessa D., 72 Abdollah F., 50 Albanesi L., 51, 72, 73 Alei G., 14, 18, 25, 29, 46, 56, 65, 66 Alei L., 14, 18, 25, 29, 46, 65, 66 Anceschi R., 72 Angelozzi G., 15 Antoniazzi F., 42, 73 Antonini F., 63 Antonini G., 41, 46 Arcoria D., 8 Arduini M., 54 Arduino C., 31 Arena G., 39 Argese N., 72 Attanasio A., 73 Attisani F., 51, 72, 73 Atzori P., 13, 21, 22 Augusto Negro C.L., 16 Austoni E., 18, 19, 20, 27, 69, 71 Badano G.M., 29 Barbagli G., 10, 71, 72 Barbanti G., 13 Barbera M., 71, 73 Bartalucci A., 62 Bartelloni M., 35 Bartoletti R., 46 Bauco S., 54 Belgrano E., 14, 20, 25, 64, 67 Bellocchi A., 43 Benedetto G., 54 Benedusi F., 10, 66 Beneventano G., 2 Benvenuto S., 14, 20, 50, 64, 67 Berardi A., 62 Berdondini E., 11, 13 Beretta G., 37 Bergamasco L., 72, 73 Berta G., 66 Bertolotto M., 64 Biagiotti G., 37 Bianchessi I., 7 Bigotto C., 72 Bischoff C., 10, 66 Bitelli M., 62 Bizzarri C.N., 17, 25, 48, 58 Bocca B., 45 Bonaparte E., 32 Bonari A., 57 Bonazzi A., 46 Borgoni G., 63 Borsa R., 62 Borsellino A., 13, 21, 22 Bragaglia A., 62 Brancato T., 45 Bratti E., 54 Briganti A., 50 Brunocilla E., 25 Brunori S., 51, 72, 73 Bucci S., 14, 20, 25, 50, 64 Busetto G.M., 46 Cai T., 6, 8, 21 Calisti A., 42, 43 Callea F., 21 Calogero A.E., 2 Cambi M., 35 Camilli M., 22, 65 Campo G., 41, 51 Campo S., 51 Canclini L.P., 49 Cannizzaro F., 71 Capitanio U., 50, 53 Caponecchia L., 36 Capparelli G., 6 Caraceni E., 15 Carbonaro F., 62 Cardo G., 49 Carluccio G., 41 Carmignani G., 18, 45, 56 Carnaccini D., 58 Caroassai Grisanti S., 71, 72 Caroli Casavola V., 33 Carollo G., 71, 73 Carparelli G., 41 Caruana G., 72 Caruso A., 72 Casciani E., 63 Casilio M., 71, 72, 73 Casolari E., 43 Cassoli S., 58 Castelli L., 24 Castiglione F., 31, 34, 35, 53, 60 Castiglione R., 2, 8 Castiglioni M., 32, 32, 39 Catalano F., 8 Cattaneo E., 66 Cava M., 50 Cavallini G., 37, 40 Ceccarelli S., 11 Ceruti C., 1, 16, 24, 26, 26, 31, 63, 68 Chierigo P., 59 Chironi C., 42 Christopher A.N., 12, 15, 16, 24, 27, 47, 64 Cicuto S., 6, 8, 21 Cipriani S., 38 Claudini R., 23 Coccarelli F., 6, 8, 21 Colapietro P., 32 Coletta R., 42 Colombo F., 17, 25, 48, 58 Colpi E.M., 39 Colpi G.M., 32, 39 Condorelli R., 2, 8 Contalbi G., 32 Conti E., 22, 65 Coppola A., 18, 56 Coppola G.A., 33 Coppola L., 18, 33, 56 Cordari M., 23 Cosmi V., 56, 57 Costa F., 19 Cotrufo S., 49 Cozza P.P., 38, 39, 72 Cozzi G., 72 Crimi S., 36 Crisafulli C., 2 da far 186

42 Indice degli autori are!!! Curreli A., 9, 29 D Amato F., 72 D Ambrosio G., 51 d Anzeo G., 4, 49, 59 D Ascenzo R., 45 D Orazio V., 18, 56 Dachille G., 49 Daniele G., 6, 41 De Luca G., 72 De Rose A.F., 3, 18 De Berardinis E., 41, 46 De Concilio B., 14, 25, 50 De Dominicis C., 12, 15, 16, 24, 27, 37, 40, 47, 57, 64 De Fortuna E., 52 De Luca F., 63 De Nunzio C., 11 De Rose A.F., 29, 33, 45, 56 De Santis C., 62 Debole M., 69 Dedola S., 59 Del Popolo G., 3, 4, 61 Del Prete M., 67 Del Rosso A., 73 Delfino M., 72 Dell Atti L., 6, 41 Delle Rose A., 71, 72 Delle Cave A., 52 Dellerose A., 49 Dente D., 12, 15, 16, 24, 27, 37, 40, 47, 64 Di Marco M., 46 Di Gregorio C., 2 Di Guardo A., 2 Di Lauro G., 5 Di Palma P., 55 Di Pierro E.D., 72, 73 Di Silverio A., 19 Di Trapani Danilo, 71, 73 Di Trapani Dario, 71, 73 Di Trapani E., 71, 73 Djinovic R., 71, 72, 73 Donatelli G., 23 Drei B., 17 Eleuteri S., 53 Elia J., 72 Emili E., 19 Ennas M., 18, 29, 45, 56 Et-Tamimi A., 23 Fabbri F., 10 Fabrizi A., 55 Fasolis G., 22, 65 Fasolo P.P., 22, 65 Federico E., 50 Ferlosio A., 73 Ferraretti A.P., 40 Ferrari M., 31, 34, 34, 35, 50, 53, 60 Ferro F., 13 Ferro G., 72 Festa R., 33 Fienga A., 67, 68 Filippone R., 73 Finita Celso M., 3, 4, 61 Fiocca G., 42, 43 Fiori C., 36, 54 Fiorito C., 46, 66 Florio M., 71, 72 Fontana D., 16, 24, 26, 26, 31, 63, 68 Fontana G., 62 Forte F., 7, 54 Franceschelli A., 17, 25, 48, 58 Franco G., 11, 12, 15, 16, 24, 27, 37, 40, 47, 57, 63, 64 Franzolin N., 59 Galizia G., 18, 19, 27, 69, 71 Galletto E., 16, 24, 26, 26, 31, 63, 68 Galletto L., 68 Gallina A., 31, 32, 34, 35, 60 Gallo A., 30 Gallo L., 30 Gallo N., 39 Gambino G., 56, 57 Gandaglia G., 31, 34, 34, 35, 53, 60 Garaffa G., 12, 15, 15, 16, 24, 27, 47, 64 Gasparri L., 59 Gazzano G., 32, 39 Gentile B.C., 51, 72, 73 Gentile G., 41 Gentile T., 37 Gentile V., 11, 12, 41, 46, 56, 57 Ghedini G., 27 Ghedini N., 69 Ghidini N., 19, 71 Ghini M., 19 Gholam Alipour M., 72 Giacchetta D., 39 Giammusso B., 73 Gianaroli L., 40 Giannella R., 67, 68 Gillo A., 66 Giubilei G., 46 Giulianelli R., 51, 72, 73 Giuliani M., 53 Gontero P., 46, 66 Gualdi G., 63 Guarino N., 42 Guazzoni G., 10 Guerra A., 40 Guglielmino S., 62 Guida J., 37 Hind A., 43 Iacono F., 5 Iannotta L., 11, 13 Iapicca G., 5 Imbrogno N., 72 Ippolito C., 6, 41 Jelo P., 21, 69 Kalsy J., 37, 40 La Pera G., 55 La Vignera S., 2, 8, 44 La Sala G.B., 43 Lacquaniti S., 22, 65 Lauretti S., 55 Lazzeri M., 10, 71, 72 Leonardi R., 21, 69 Leonardo C., 56 Leoni S., 43 Letizia P., 14, 18, 25, 29, 46, 56, 65, 66 Liberti M., 63 Ligato P., 72 Liguori G., 14, 20, 25, 50, 64, 67 Lissiani A., 67 Littarru G.P., 33 Lombardi G., 3, 4, 61 Longo R., 29,

43 Indice de Indice degli autori 188

44 Indice degli autori degli autori 189

45 Indice degli Indice degli autori 190

46 Indice degli autori li autori 191

47 Indice degli autori 192

48 Instructions for Authors General Information The Journal of Andrological Sciences is the official journal of the Italian Society of Andrology in the field of Medical Education. It publishes contributions in the form of editorials, updates, original articles, case reports, educational articles. Each contribution undergoes a double-blind peer-reviewing process and is evaluated on the basis of the most recent Guidelines and International Consensus Conferences. The eventual acceptance of articles for publication is conditional upon the implementation of any changes requested by reviewers, and the final decision of the Editor. Authors will be informed about acceptance of the manuscript within 60 days; they will be given 72 hours for proof-correction (only a set of proofs will be sent to Authors): corrections should be reduced to the minimum and must be made directly on the received proofs. A form for reprints order and payment will be sent together with the proofs. 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50 ISSN Journal of Vol. 17 t /P t December 2010 CONTENTS 2010;17: Vol. 17 t /P t December 2010 ORIGINAL ARTICLES Current techniques in management of obstructive azoospermia Gynecomastia: pathophysiology, clinical evaluation and management Chlamydia trachomatis infection: the urologist s point of view Peyronie s disease: endocavernous plaque excision without substitutive graft: critical 5-year experience CASE REPORT Bilateral Leydig cell tumor with adrenal hyperplasia TABLE OF CONTENTS Journal of ANDROLOGICAL SCIENCES Official Journal of the Italian Society of Andrology Efficacy of a nutraceutical preparation as add-on treatment in patients with erectile dysfunction treated with 5-PDE inhibitors: a pilot study Periodico trimestrale - POSTE ITALIANE SPA - Spedizione in Abbonamento Postale - D.L. 353/2003 conv. in L. 27/02/2004 n 46 art. 1, comma 1 DCB PISA Corporoplasty with soft axial tutors and safenous grafting. Following three years ANDROLOGICAL SCIENCES Official Journal of the Italian Society of Andrology IN THIS ISSUE OBSTRUCTIVE AZOOSPERMIA GYNECOMASTIA CHLAMIDYA TRACHOMATIS INFECTION SURGERY OF PEYRONIE S DISEASE NUTRACEUTICAL FOR ERECTILE DYSFUNCTION BILATERAL LEYDIG CELL TUMOR