Alternate indications for varicocele repair: non-obstructive azoospermia, pain, androgen deficiency and progressive testicular dysfunction

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1 Alternate indications for varicocele repair: non-obstructive azoospermia, pain, androgen deficiency and progressive testicular dysfunction Peter N. Schlegel, M.D., and Marc Goldstein, M.D. Department of Urology, Brady Urology Foundation, Center for Male Reproductive Medicine and Microsurgery, Weill Cornell Medical College, New York Presbyterian Hospital, New York, New York Varicocele repair is indicated for infertile men with clinical varicoceles. Some men with scrotal pain, low testosterone, non-obstructive azoospermia, and who are at risk for testicular dysfunction may also benefit from varicocelectomy. (Fertil Steril Ò 2011;96: Ó2011 by American Society for Reproductive Medicine.) Varicoceles have a known effect on testicular function, and varicocele repair will reliably improve sperm production. Initial reports of randomized trials involving patients who did not have a clinical variocele or did not have evidence of abnormal semen parameters have raised questions regarding the role of varicocelectomy (1). Recent meta-analyses of randomized, controlled studies involving varicocele repair for men with clinical varicoceles and infertility have also shown an improvement in fertility from varicocelectomy (2). More recent randomized controlled trials further support the relationship between varicocele repair and improved fertility (3). Varicoceles have been associated with testicular pain, progressive testicular dysfunction, impaired testosterone production, and, for some men, non-obstructive azoospermia (4). The role of varicocele repair for management of each of these conditions will be reviewed herein. Unfortunately, most clinical reports of the effect of varicocele repair have been uncontrolled or clinically selected series. The selection of patients and uncontrolled nature of these trials may have affected accurate evaluation of the benefit of varicocele repair in each of these clinical conditions. Low Serum Testosterone The effect of palpable varicocele on Leydig cell function has recently been a focus of study. There is substantial evidence that varicocele has a negative impact on Leydig cell function and that repair may enhance Leydig cell function (5, 6) and improve testosterone levels. The evidence of a relationship between varicoceles and abnormal Leydig cell function in animals and humans is longstanding (7 9). Induction of varicocele in animal models is associated with reduced intratesticular and serum testosterone levels. We have observed that men with palpable varicoceles have lower testosterone levels at every age than a control group of vasectomy reversal patients of proven fertility, without varicoceles (6). The progressive negative effect of varicocele on Leydig cell function has been supported by animal studies showing decline in intratesticular testosterone over time in rats with surgically induced varicocele (10). Given the acute surgical onset of the varicocele in animal studies and the relatively short duration of study in animal models compared to human models, it is uncertain how translatable this data is to humans (11, 12). Received October 7, 2011; revised and accepted October 26, P.N.S. has nothing to disclose. M.G. has nothing to disclose. Reprint requests: Peter N. Schlegel, M.D., Department of Urology, Starr 9, New York Presbyterian Hospital-Weill Cornell Medical College, 525 East 68 th Street, New York, NY ( pnschleg@med.cornell.edu). Several authors have reported an association between varicocele repair and increased serum testosterone levels in humans (Table 1). Tanrikut et al. (6) reported an increase in serum testosterone levels from 358 to 454 ng/dl after microsurgical repair. This increase was apparently independent of patient age or laterality of varicocele. They concluded that men with varicoceles have significantly lower circulating testosterone levels than a comparison group of men presenting for vasectomy reversal without varicoceles. Microsurgical repair of the varicocele was associated with a significant increase in serum testosterone levels for 70% of men. These findings suggest that varicocele may be a significant risk factor for androgen deficiency and that repair may increase testosterone levels, even for older men with varicocele and low testosterone levels. Longitudinal data on the long-term maintenance of higher testosterone levels after varicocele repair have not been available in existing studies. Even in men where future fertility is not an issue, such as men with large varicoceles considering vasectomy, varicocele repair may prevent and/ or treat androgen deficiency. In men undergoing simultaneous vasectomy and varicocelectomy a microsurgical approach could allow for vasectomy with preservation of the deferential vessels for venous return (13). Some studies have suggested that the prevalence of varicocele increases with age (14). This finding is consistent with the known relationship between lower extremity varicosities (both prevalence and severity of varicose veins) and increased age. It has been suggested that venous valves become less competent due to agerelated changes within vein walls (15). It has also been well documented that the prevalence of androgen deficiency increases with age. Of note, the effect of varicocelectomy on serum testosterone levels are not affected by the age of the treated patient; older men improve as much as younger men (16). In summary, microsurgical repair of varicocele may be an important alternative to medical therapy in men with low serum testosterone and symptoms of androgen deficiency. In men with large varicoceles, prophylactic repair is likely to prevent future androgen deficiency and could even decrease the need for future testosterone replacement therapy. Varicocele Repair to Prevent Progressive Testicular Dysfunction The suggestion that varicoceles may have a progressive deleterious effect on testicular function is derived from several different observations. If varicoceles had a deleterious effect over time, then men with primary infertility would have a lower frequency of varicoceles 1288 Fertility and Sterility â Vol. 96, No. 6, December /$36.00 Copyright ª2011 American Society for Reproductive Medicine, Published by Elsevier Inc. doi: /j.fertnstert

2 TABLE 1 Serum testosterone levels pre- and post-varicocelectomy. Reference Pre-varicocelectomy testosterone, ng/dl Post-varicocelectomy testosterone, ng/dl Hudson, 1986 (48) 527 (136) 601 (149) Su, 1995 (11) 319 (12) 409 (23) Cayan, 1999 (47) 563 (140) 837 (220) Tanrikut, 2011 (6) 358 (126) 454 (168) Zohdy, 2011 (49) (205.8) (170.2) Hsiao, 2011 (16) 309 (7.4) 431 (16.2) Note: Values in parentheses represent standard deviation. than men secondary infertility. Gorelick and Goldstein (17) reported a frequency of detection of varicocele in 35% of men with primary infertility, whereas in secondary infertility it was 70%. Similarly, Witt and Lipshultz (18) reported rates of varicocele detection of 50% and 69% of men with primary and secondary infertility, respectively. These data support that varicocele causes a progressive duration-dependent decline in fertility over time. This means that men with varicoceles who were fertile when they were younger may not necessarily retain fertility when they are older. However, some studies have found a similar rate of detection of varicoceles in men with primary and secondary infertility. Jarow et al. (19) reported 44 and 45% detection of varicoceles in men with primary and secondary infertility, respectively, once patients with primary infertility who could not possibly contribute to pregnancy without treatment were excluded from consideration as having secondary infertility (e.g., vasal agenesis). Other studies suggesting a progressive negative effect of varicocele on testicular function provided longitudinal evaluation of men with unrepaired varicoceles suggesting progressive deterioration in semen analysis and testosterone levels over time compared to control men without varicocele (20, 21). The lower semen parameters seen over time with patients with varicocele could also reflect patient selection; the men with progressive decrease in semen parameters (whether due to varicocele or independent) are more likely to be followed over time than patients with maintained sperm production, who were more likely to achieve a pregnancy and be lost to pregnancy. The benefits of varicocele repair in preserving testicular function, if present, must be balanced against the risks, if any, of varicocelectomy. With the advent of effective artery and lymphatic-sparing microsurgical techniques (22, 23), the risks of surgery are minimal. The limited benefits of varicocele repair in prior studies may have been related to ineffective procedures, such as arterial ligation with retroperitoneal approaches to varicocele repair, as commonly occurs for adolescent patients. The benefits of preventing varicocele-associated progressive testicular dysfunction may be particularly important in couples desiring to have more than one child. In these couples, although an initial pregnancy may be possible with assisted reproductive techniques such as IUI or IVF, progressive, duration dependent decline in fertility could make future pregnancies more difficult or require higher levels of assisted reproduction. Varicocele repair is likely to halt further decline in testicular function. In addition, since the majority of men experience an increase in sperm quality after repair of palpable varicoceles, future pregnancies could be conceived with lower levels of assisted reproduction. Patients could be upgraded from requiring ICSI to only needing IUI or from IUI to naturally conceived pregnancies. With this background, it is worthwhile to ask couples at initial interview how many children they would like to have and over what period of time. Female age is also an important factor. If the female is over 35 years of age and couples desire a large family, protection against decline of male fertility becomes even more important. In summary, for couples desiring future fertility, and in men who already have low or below normal serum testosterone levels, varicocelectomy may prevent further decline in testicular function. Furthermore, modern microsurgical methods of repair are associated with very low morbidity and recurrence rates. It is possible that the conservative treatment of varicoceles, especially in men with large, palpable varicoceles and ipsilateral pre-existing atrophy and/or abnormalities in semen analysis and/or low testosterone levels, is to repair them. Unfortunately, existent published studies of the effect of varicocele repair on testosterone levels have not had control arms (nor consecutive study of patients), so some of the observed increase in testosterone levels could reflect selection of patients with low, but variable serum testosterone levels. The postoperative results could reflect regression to the mean of testosterone levels unless control (non-operated) patients are studied, which may reflect why guidelines of practice do not currently recommend varicocele repair for low testosterone levels. Testicular Pain Standard urologic practice has suggested that varicocele repair may be indicated for varicoceles associated with pain (4). A Medline search was carried out in September, 2011 using search terms of varicocelectomy and pain as well as varicocele repair and pain. The resulting literature search is the source of information presented here. Varicocele-associated pain is typically thought to be a dull ache or scrotal heaviness (24). The pain typically is greater when the patient is standing, and can be alleviated with the patient lying down. Some studies have suggested that relief of pain after varicocele repair is independent of the type of pain (25), however, nearly all patients who had varicocele repair in this study had dull or throbbing pain prior to varicocelectomy. Other studies have related the relief of pain to the duration of pain; men with more chronic scrotal pain associated with varicocele are more likely to respond to surgical correction (25, 26). Nearly every study recommends conservative measures (scrotal support, rest, etc) prior to consideration of varcicocelectomy. In the management of patients with scrotal pain, the consideration of retroperitoneal, ureteral, and spinal sources of discomfort should be entertained before surgical intervention, as recommended in most published papers on this subject. 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3 Other authors have suggested certain technical aspects of repair that are important for success. Maghraby (27) has reported that laparoscopic varicocele repair is successful for relief of pain. In distinction, Karademir et al. (28) found that external spermatic vein ligation was critical to the success of varicocele repair for pain that, of course, would not be accomplished by a laparoscopic approach. Parekattil and Brahmbhatt (29) reported on a robotic approach to varicocelectomy for testicular pain (orchialgia). Nearly all other contemporary studies have used a microsurgical subinguinal approach (30, 31) that is widely accepted to be safe and effective for repair of a varicocele. Results of varicocele repair for relief of pain are presented in Table 2. Overall, most studies suggest a high rate of success for varicocele repair. Obviously, studies have not evaluated the potential placebo effect of varicocele repair, and some studies have suggested that spermatic cord dissection alone can result in decreased scrotal pain (32). Reporting bias and patient s known tendency to report results to surgeons that reflect success are factors that may overestimate the benefits of a surgical series, especially for patients who have an intervention for pain. Varicocelectomy for Non-Obstructive Azoospermia Since the anecdotal report of Tulloch in 1955 (33) reporting return of sperm to the ejaculate and natural pregnancy in patients with non-obstructive azoopermia, the role of varicocelectomy in azoospermia has been a source of potential controversy. For azoospermic men, fertility treatment would require testicular sperm extraction and in vitro fertilization/icsi. If sperm were present in the ejaculate, IVF/ICSI alone could be used for treatment, potentially avoiding sperm retrieval surgery. Unfortunately, series of men with NOA have not typically included serial follow-up of their course of infertility care, (or availability of adequate sperm in the ejaculate to avoid sperm retrieval surgery), only the report of sperm in the ejaculate. Varicocelectomy could also enhance spermatogenesis within the testis, potentially increasing the chance of successful testicular sperm extraction surgery. A Medline search of azoospermia and varicocelectomy was carried out in September 2011 and the results reviewed for relevant articles reporting results of treatment of men with non-obstructive azoospermia (NOA). Czaplicki et al. (34) reported on 33 patients with NOA. Of patients who had surgical repair of a varicocele, 34% (12 patients) had return of sperm to the ejaculate. It is not clear how many patients could have had sperm in the ejaculate with no treatment (or may have had cryptozoospermia prior to therapy), as there was no control group followed over time. Tung et al. (35) also reported on 8 patients with azoospermia who underwent varicocelectomy. None of these patients had return of sperm to the ejaculate (0%). Matthews et al. (36) reported return of sperm to the ejaculate in 12 of 22 (55%) men operated for non-obstructive azoospermia. Three of the 12 men also reported unassisted pregnancy after varicocelectomy. Pasqualotto et al. (37) reported results of varicocelectomy for NOA in 2003 and again in Nine of 27 patients with NOA had sperm return to the ejaculate after varicocele repair (33%). They reported one patient (3%) who had an unassisted pregnancy. He had maturation arrest on testis biopsy at the time of varicocelectomy. Schlegel and Kaufmann (38) reported detection of sperm in the ejaculate as well as the need for testicular sperm extraction after varicocelectomy in a carefully evaluated series of men with NOA and clinical varicoceles. They found that 22% of 31 men who underwent TABLE 2 Varicocele repair for pain. Reference Pain resolved Pain improved Yaman, 2000 (24) 72/82 (88%) 77/82 (94%) Maghraby, 2002 (27) 49/58 (84%) 55/58 (94%) Tung, 2004 (35) 28/31 (94%) 31/31 (100%) Chawla, 2005 (30) 6/11 (54%) 10/11 (91%) Karadenia, 2005 (56) 74/104 (73%) 101/121 (84%) Resorlu, 2010 (31) 17/18 (95%) Altunoluk, 2010 (26) 265/284 (93%) Parekattil, 2011 (29) 42/45 (94%) Park, 2011 (25) 28/53 (53%) 22/53 (42%) Totals 299/395 (76%) 578/797 (72%) varicocelectomy had sperm seen in the ejaculate on at least one semen analysis postoperatively. However, less than 10% of men had adequate sperm in the ejaculate to avoid testicular sperm extraction after varicocelectomy. Some would consider this a 90% failure rate of varicocelectomy in NOA. Unfortunately, no other studies have had longitudinal evaluation of patients to determine the success in avoiding TESE surgery. The question of whether varicocelectomy improved sperm production in men with azoospermia, increasing the chance of subsequent testicular sperm extraction (TESE) was also addressed in their series. Using a retrospective analysis of patients who underwent TESE by Schlegel (38), men with clinical varicoceles who had varicocele repair prior to TESE had a sperm retrieval rate of 60%, identical to the 60% for men with clinical varicoceles who had sperm retrieval attempted with TESE without prior varicocele repair. Other investigators have retrospectively evaluated the effect of prior varicocele repair in patients with non-obstructive azoospermia. Inci et al., in 2009, reported that patients with NOA and clinical varicoceles who underwent prior varicocele repair had a sperm retrieval rate of 53%, vs. a sperm retrieval rate of 30% for men with clinical varicoceles who did not have prior varicocelectomy (39). Interestingly, the overall retrieval rate in this series was 45%, suggesting that failure to repair the varicocele had a lower chance of success than other patients with NOA. Hayardedeoglu reported a retrieval rate of 60% for 31 men who had prior varicocele repair and non-obstructive azoospermia, whereas 38% of 65 men who did not have varicocelectomy had sperm retrieved (40). The criteria for varicocele repair were not provided. Remarkably, the pregnancy rate for men who had prior varicocele repair was 74%, with a 52% rate for men who did not have prior varicocelectomy. Since most centers have a pregnancy rate less than 40%, these pregnancy results are nearly unbelievable. It would be hard to justifiably quote a 74% pregnancy rate to any patient undergoing IVF, especially in a subset of patients commonly considered difficult to treat. Other studies have reported a return of sperm to the ejaculate in approximately one-third of patients (Table 1) with a 5% rate of natural pregnancy after varicocelectomy alone (41 45). The results of varicocelectomy in non-obstructive azoospermia suggest that nearly a third of patients will have sperm return to the ejaculate in at least one semen analysis and it is possible that up to 10% of men will have enough sperm in the ejaculate to avoid TESE. In addition, improved sperm production in the testis might 1290 Schlegel and Goldstein Alternate indications for varicocele repair Vol. 96, No. 6, December 2011

4 enhance the chance of sperm retrieval in the remainder of patients (Table 3). However, no studies had a control group. Further, the patients who benefitted from varicocelectomy were those who were likely to have sperm found on a repeat semen analysis, if done on the day of planned testicular sperm extraction. Patients with non-obstructive azoospermia will have sperm, adequate for use with ICSI, found in the semen for up to 10% of patients scheduled at our Center for testicular sperm extraction in a programmed IVF cycle. The men with maturation arrest or hypospermatogenesis on biopsy, who are most likely to benefit from varicocelectomy (45), are also the patients most likely to have sperm in the ejaculate. A financial analysis modeled on published data by Lee et al. (46) has suggested that varicocele repair for all patients is not cost-effective. In this study, the authors modeled the approaches of initial varicocele repair versus testicular sperm extraction-icsi for men with non-obstructive azoospermia. The expected results with each treatment was derived from published studies, and costs were estimated based on charges at the five largest IVF centers in the United States as well as Medicare-based charges for surgical procedures and expected complication rates (Fig. 1). For younger couples, varicocelectomy may be of some value in the management of non-obstructive azoospermia. The magnitude of that benefit, if any, should be determined from randomized controlled trials of men with varicoceles and non-obstructive azoospermia. TABLE 3 Varicocele repair in non-obstructive azoospermia. Reference Return of sperm to the ejaculate Pregnancy rate Czaplicki, 1979 (34) 12/33 (34%) 3/33 (9%) Matthews, 1998 (36) 12/22 (55%) 3/22 (15%) Kim, 1999 (50) 12/28 (43%) 2/28 (7%) Kadioglu, 2001 (51) 5/24 (21%) 0/24 (0%) Schlegel, 2004 (38) 7/31 (22%) a 0/31 (0%) Cakan, 2004 (52) 3/13 (23%) 0/13 (0%) Esteves, 2005 (53) 8/17 (47%) 1/17 (6%) Gat, 2005 (54) 18/32 (56%) b 4/18 (12%) Poulakis, 2006 (55) 7/14 (50%) 2/14 (14%) Pasqualotto, 2006 (37) 9/27 (33%) b 1/33 (3%) Ishikawa, 2007 (42) 2/6 (33%) 0/6 (0%) Lee, 2007 (43) 7/19 (36%) b 1/19 (5%) Cocuzza, 2009 (41) 3/10 (30%) Youssef, 2009 (44) 14/51 (28%) 2/51 (4%) Totals 119/327 (36%) 18/317 (6%) a Only study to report the outcome of adequate sperm in the ejaculate to avoid TESE (9.6%) in this study. b In these studies, 7/18, 5/9, and 2/7 men who had sperm in the ejaculate at some point became azoospermic with continued follow-up. FIGURE 1 Decision analytic model for varicocele repair versus primary treatment with testicular sperm extraction-icsi in men with non-obstructive azoospermia (reprinted with permission from Lee et al., Fertil Steril 2009;92:188). Fertility and Sterility â 1291

5 Summary Varicocele repair is indicated for repair of clinical varicoceles in infertile men with definable abnormalities of sperm production or function and is associated with increased pregnancy rates. Even men with severe abnormalities of sperm production (non-obstructive azoospermia) may benefit from varicocele repair. Indeed, varicocele repair may be of benefit to prevent testicular dysfunction over time, including men with impaired testosterone production. Despite strong evidence of the potential benefits of varicocele repair, properly designed, randomized controlled studies have not been done to adequately define the exact benefits of varicocelectomy for men with potential alternative indications for varicocele repair. REFERENCES 1. Evers JH, Collins J, Clarke J. Surgery or embolisation for varicoceles in subfertile men. Cochrane Database Syst Rev 2009;Jan 21;(1):CD Ficarra V, Cerruto MA, Liguori G, Mazzoni G, Minucci S, Tracia A, Gentile V. Treatment of varicocele in subfertile men: The Cochrane Review a contrary opinion. Eur Urol 2006;49: Abdel-Meguid T, Al-Sayyad A, Tayib A, Farsi H. Does varicocele repair improve infertility? An evidence-based perspective from a randomized, controlled trial. Eur Urol 2011;59: Goldstein M. Surgical management of male infertility. In: Wein A, Kavoussi LR, Novick AC, Partin AW, Peters C, eds. Campbell s urology, Vol 1., 10th ed. Philadelphia: WB Saunders, Co; 2011: Weiss D, Rodriguez-Rigua L, Smith K, Steinberger E. Leydig cell function in oligospermic men with varicocele. J Urol 1978;120: Tanrikut C, Goldstein M, Rosoff J, Lee R, Nelson C, Mulhall J. Varicocele as a risk factor for androgen deficiency and effect of repair. BJU Int 2011; 108: Comhaire F, Vermeulen A. Plasma testosterone in patients with varicocele and sexual inadequacy. J Clin Endocrinol Metabl 1975;40: Pirke K, Vogt H, Sintermann R, Spyra B. Testosterone in peripheral plasma, spermatic vein and in testicular tissue under basal conditions and after HCGstimulation in patients with varicocele. Andrologia 1983;15: Ando S, Giacchetto C, Colpi G, Beraldi E, Panno ML, Lombardi A, et al. Physiopathologic aspects of Leydig cell function in varicocele patients. J Androl 1984;5: Luo D, Yang G, Liu J, Yang Y, Dong Q. Effects of varicocele on testosterone, apoptosis and expression of StAR mrna in rat Leydig cells. Asian J Androl 2011;13: Su L, Goldstein M, Schlegel P. The effect of varicocelectomy on serum testosterone levels in infertile men with varicocele. J Urol 1995;154: Younes A. Improvement of sexual activity, pregnancy rate, and low plasma testosterone after bilateral varicocelectomy in impotence and male infertility patients. Arch Androl 2003;49: Lee R, Li P, Goldstein M. Simultaneous vasectomy and varicocelectomy: Indications and technique. Urology 2007;70: Canales B, Zapzalka D, Ercole C, Carey P, Haus E, Aeppli D, Pryor JL. Prevalence and effect of varicoceles in an elderly population. J Urol 2005;66: Clarke G, Vasdekis S, Hobbs J, Nicolaides A. Venous wall function in the pathogenesis of varicose veins. Surgery 1992;111: Hsiao W, Rosoff J, Pale J, Greenwood E, Goldstein M. Older age is associatd with similar improvements in semen parameters and testosterone levels after subinguinal microsurgical varicocelectomy. J Urol 2011;185: Gorelick J, Goldstein M. Loss of fertility in men with varicocele. Fertil Steril 1993;59: Witt M, Lipschultz L. Varicocele: a progressive or static lesion? Urology 1993;42: Jarow JP, Coburn M, Sigman M. Incidence of varicoceles in men with primary and secondary infertility. Urology 1996;47: Lipschultz L, Corriere J. Progressive testicular atrophy in the varicocele patient. J Urol 1977;117: Cheval M, Purcell M. Deterioration of semen parameters over time in men with untreated varicocele: evidence of progressive testicular damage. Fertil Steril 1992;57: Goldstein M, Gilbert B, Dicker A, Dwosh J, Gnecco C. Microsurgical inguinal varicocelectomy with delivery of the testis: an artery and lymphatic sparing technique. J Urol 1992;148: Marmar J, Kim Y. Subinguinal microsurgical varicocelectomy: a technical critique and statistical analysis of semen and pregnancy data. J Urol 1994;152: Yaman O, Ozdiler E, Anafarta K, Gogus O. Effect of Microsurgical Subinguinal Varicocele Ligation to Treat Pain. Urology 2000;55: Park HJ, Lee SS, Park NC. Predictors of pain resolution after varicocelectomy for painful varicocele. Asian J Androl 2011;13: Altunoluk B, Soylemez H, Efe E, Malkoc O. Duration of preoperative scrotal pain may predict the success of microsurgical varicocelectomy. Int Braz J Urol 2010;36: Maghraby HA. Laparoscopic Varicocelectomy for Painful Varicoceles: Merits and Outcomes. J Endourol 2002;16: Karademir K, Senkul T, Baykal K, Ates F, Iseri C, Erden D. Evaluation of the role of varicocelectomy including external spermatic vein ligation in patients with scrotal pain. International J Urol 2005;12: Parekattil SJ, Brahmbhatt JV. Robotic approaches for male infertility and chronic orchialgia microsurgery. Curr Opin Urol 2011;21: Chawla A, Kulkarni G, Kamal K, Zini A. Microsurgical Varicocelectomy for recurrent or persistent varicoceles associated with orchalgia. Urology 2005;66: Resorlu B, Kara C, Sahin E, Unsal A. The significance of age on success of surgery for patients with varicocele. Int Urol Nephrol 2010;42: Levine LA, Matkov TG, Lubenow TR. Microsurgical denervation of the spermatic cord: a surgical alternative in the treatment of chronic orchialgia. J Urol 1996;155: Tulloch WS. Varicocele in subfertility: results of treatment. Br Med J 1955;2: Czaplicki M, Bablok L, Janczewski Z. Varicocelectomy in patients with azoospermia. Arch Androl 1979;3: Tung MC, Huang WJ, Chen KK. Modified subinguinal varicocelectomy for painful varicocele and varicocele-associated infertility. J Chin Med Assoc 2004;67: Matthews GJ, Matthews ED, Goldstein M. Induction of spermatogenesis and achievement of pregnancy after microsurgical varicocelectomy in men with azoospermia and severe oligoasthenospermia. Fertil Steril 1998;70: Pasqualotto FF, Sobreiro BP, Hallak J, Pasqualotto EB, Lucon AM. Induction of spermatogenesis in azoospermic men after varicocelectomy repair: an update. Fertil Steril 2006;85: Schlegel PN, Kaufmann J. Role of varicocelelectomy in men with non-obstructive azoospermia. Fertil Steril 2004;81: Inci K, Hascicek M, Kara O, Dikmen AV, Gurgan T, Ergen A. Sperm retrieval and intracytoplasmic sperm injection in men with nonobstructive azoospermia, and treated and untreated varicocele. J Urol 2009;182: Haydardedeoglu B, Turunc T, Kilicdag EB, Gul U, Bagis T. The effect of prior varicocelectomy in patient with nonobstructive azoospermia on intracytoplasmic sperm injection outcomes: a retrospective pilot study. J Urol 2010;75: Cocuzza M, Pagani R, Lopes RI, Athayde KS, Lucon AM, Srougi M, et al. Use of subinguinal incision for microsurgical testicular biopsy during varicocelectomy in men with nonobstructive azoospermia. Fertil Steril 2009;91: Ishikawa T, Kondo Y, Yamaguchi K, Sakamoto Y, Fujisawa M. Effect of Varicocelectomy on patients with unobstructive azoospermia and severe oligospermia. BJU Intl 2007;101: Lee JS, Park HJ, Seo JT. What is the indication of varicocelectomy in men with nonobstructive azoospermia? J Urol 2007;69: Youssef T, Abd-Elaal E, Gaballah G, Elhanbly S, Eldosoky E. Varicocelectomy in men with nonobstructive azoospermia: Is it beneficial? Intl J Surg 2009;7: Weedin JW, Khera M, Lipshultz LI. Varicocele repair in patients with nonobstructive azoospermia: a metaanalysis. J Urol 2010;183: Lee R, Li PS, Goldstein M, Schattman G, Schlegel PN. A decision analysis of treatments for nonobstructive azoospermia associated with varicocele. Fertil Steril 2009;92: Cayan S, Kadioglu A, Orhan I, Kandirali E, Tefekli A, Tellaloglu S. The effect of microsurgical varicocelectomy on serum follicle stimulating hormone, testosterone and free testosterone levels in infertile men with varicocele. BJU Int 1999;84: Hudson RW, Perez-Marrero RA, Crawford VA, McKay DE. Hormonal parameters in incidental varicoceles and those causing infertility. Fertil Steril 1986;45: Zohdy W, Ghazi S, Arafa M. Impact of varicocelectomy on gonadal and erectile functions in men with hypogonadism and infertility. J Sex Med 2011;8: Kim ED, Leibman BB, Grinblat DM, Lipshultz LI. Varicocele repair improves semen parameters in azoospermic men with spermatogenic failure. J Urol 1999;162: Kadioglu A, Tefekli A, Cayan S, Kandirali E, Erdemir F, Tellaloglu S. Microsurgical inguinal varicocele repair in azoospermic men. Urology 2001;57: Cakan M, Altug U. Induction of spermatogenesis by inguinal varicocele repair in azoospermic men. Arch Androl 2004;50: Schlegel and Goldstein Alternate indications for varicocele repair Vol. 96, No. 6, December 2011

6 53. Esteves SC, Glina S. Recovery of spermatogenesis after microsurgical subinguinal varico- cele repair in azoospermic men based on testicular histology. Int Braz J Urol 2005;31: Gat Y, Bachar GN, Everaert K, Levinger U, Gornish M. Induction of spermatogenesis in azoospermic men after internal spermatic vein embolization for the treatment of varicocele. Hum Reprod 2005;20: Poulakis V, Ferakis N, devries R, Witzsch, Becht E. Induction of spermatogenesis in men with azoospermia or severe oligoteratoasthenospermia after antegrade internal spermatic vein sclerotherapy for the treatment of varicocele. Asian J Androl 2006;8: Karademir K, Enkul T, Baykal K, Ate F, Eri CI, Erden DA. Evaluation of the role of varicocelectomy including external spermatic vein ligation in patients with scrotal pain. Int J Urol 2005;12: Fertility and Sterility â 1293