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Vasectomy Reversal Outcomes in Men Previously on Testosterone Supplementation Therapy
Infertility Vasectomy Reversal Outcomes in Men Previously on Testosterone Supplementation Therapy Robert M. Coward, Douglas A. Mata, Ryan P. Smith, Jason R. Kovac, and Larry I. Lipshultz OBJECTIVE METHODS
RESULTS
CONCLUSION
To report considerations for preoperative management and outcomes of vasectomy reversal (VR) in men with a history of testosterone supplementation therapy (TST). A retrospective review of men on TST before VR from 2010 to 2013 was performed. For inclusion, patients were required to have baseline and follow-up hormone levels as well as postoperative semen analyses. Preoperative use of medical testicular salvage therapy and testicular sperm aspiration (TESA), intraoperative findings, and pregnancies were also analyzed. Six of 265 men who underwent VR had prior TST and met inclusion criteria. Median age was 39 years with a median obstructive interval of 7.5 years. Median duration of TST was 9 months before discontinuation and transition to testicular salvage therapy with clomiphene citrate with or without human chorionic gonadotropin for a median of 2.8 months. At baseline, decreased luteinizing hormone (median, 2 mIU/mL), follicle stimulating hormone (median, 5 mIU/mL), and total testosterone (median, 249 ng/dL) were observed. Two men (33%) with uncertain recovery of spermatogenesis based on physical examination and hormone response underwent preoperative testicular sperm aspiration confirming the presence of sperm. Nine vasovasostomies and 3 epididymovasostomies were performed. Patency was 83% after a median follow-up of 6.4 months and was 100% in men undergoing at least 1 vasovasostomy. Spontaneous pregnancy was achieved by 50% during the follow-up period. Testicular salvage medical therapy may play a role in the preoperative management of VR in men with prior TST. VR after TST can have outcomes comparable to those in the general population. UROLOGY 84: 1335e1341, 2014. 2014 Elsevier Inc.
U
se of testosterone supplementation therapy (TST) has become increasingly common among younger men.1 Idiopathic biochemical hypogonadism, defined by a total testosterone level <300 ng/ dL, is observed in just over a third of all men aged 45-54 years.2 The diagnosis of hypogonadism and its treatment with TST has grown remarkably in recent years, as testosterone prescriptions have increased over 500% since 1993.3 The age group with the most rapid rate of increased utilization is men aged 40-49 years, with testosterone prescriptions increasing more than 4.2-fold Financial Disclosure: Larry Lipshultz is a paid consultant, advisor, speaker, and clinical trial investigator to Eli Lilly and Company. He is a clinical investigator, meeting participant, and speaker to Endo Pharmaceuticals. He is also a meeting participant and speaker to Pfizer. He is a clinical trial investigator and speaker to Auxilium Pharmaceuticals. The remaining authors declare that they have no relevant financial interests. From the Department of Urology, University of North Carolina School of Medicine, Chapel Hill, NC; the Scott Department of Urology, Baylor College of Medicine, Houston, TX; the Department of Biochemistry and Cell Biology, Wiess School of Natural Sciences, Rice University, Houston, TX; and the Department of Urology, School of Medicine, University of Virginia, Charlottesville, VA Address correspondence to: Robert M. Coward, M.D., 2113 Physicians Office Building, CB#7235, 170 Manning Drive, Chapel Hill, NC 27599-7235. E-mail: [email protected] Submitted: February 6, 2014, accepted (with revisions): June 16, 2014
ª 2014 Elsevier Inc. All Rights Reserved
between 2001 and 2011. In 2011, this equated to a total prevalence of 2.3% in this age group alone.1 Men undergo vasectomy at an average age of 31 years,4 whereas the average age for vasectomy reversal (VR) is 41 years.5,6 Some men within this window will be diagnosed with hypogonadism and treated with TST. Nearly all men will have some degree of suppression of spermatogenesis during treatment with TST. Exogenous testosterone typically results in atrophy of the germinal epithelium in normal men with varying degrees of suppression of spermatogenesis, including azoospermia, within several months.7,8 The level of suppression is partly dependent on the type of testosterone preparation, with topical preparations typically displaying a smaller degree of suppression of gonadotropins and thus spermatogenesis than injectable or implantable testosterone preparations.9 Sperm concentrations usually recover to pretreatment levels after the cessation of TST; however, recovery could take up to 2 years,10 and permanent detrimental effects to spermatogenesis are possible.11,12 The use of TST before VR may impact vasal fluid findings by suppressing spermatogenesis, which could complicate intraoperative decision making on the method of http://dx.doi.org/10.1016/j.urology.2014.06.081 0090-4295/14
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reconstruction, and, therefore, may impair postoperative patency and pregnancy rates. There is currently no available data for the management of exogenous testosterone-suppressed spermatogenesis in vasectomized men seeking VR. The vasectomized patient represents a particularly difficult patient in whom to assess spermatogenesis, and therefore the serum testosterone and gonadotropins, represents the most accurate initial assessment. Medical testicular salvage therapy to recover spermatogenesis in hypogonadotropic hypogonadal men may be accomplished with clomiphene citrate (CC)13 and/or human chorionic gonadotropin (hCG).14 If doubt persists whether spermatogenesis has recovered after treatment with testicular salvage therapy, a testicular sperm aspiration (TESA) in the office may be performed. Although TESA is more invasive, it can provide a definitive demonstration of spermatogenesis and represents a particularly helpful diagnostic test for the dilemma of uncertainty of active spermatogenesis in patients with obstructive azoospermia secondary to vasectomy.15 VR outcomes after TST and considerations for preoperative management have not been previously reported. Because of the increased diagnosis and treatment of androgen deficiency, we hypothesize that a growing proportion of men desiring VR will have been treated with TST. Because the effects of exogenous androgens adversely impact spermatogenesis,12 we postulated that the use of TST may play a factor in VR outcomes. We also sought to retrospectively describe a method of testicular salvage therapy to potentially reinitiate spermatogenesis as well as a method to assess for the presence of spermatogenesis before VR. In this study, we describe the results of a retrospective case series of the VR outcomes in men previously on TST with a goal to demonstrate a proof of concept of a preoperative evaluation and treatment strategy using medical management with testicular salvage therapy, and TESA in select cases, to increase the success rate of VR after TST.
METHODS After obtaining institutional review board approval, a retrospective chart review was conducted of consecutive VR cases performed in a large academic urology practice. All surgeries were performed by a single fellowship-trained microsurgeon between December 2009 and May 2013. Patients were included in the study if a history of prior TST was identified during the obstructive interval between vasectomy and VR. All patients must have had 2 separate hormone profiles along with postoperative semen analysis data available. Patients were excluded if any of these criteria were not met. Preoperative data collected included demographics, length of obstructive interval, and the formulation and length of time of TST. Because TST for all patients was prescribed by an outside facility before the patients presenting for evaluation for VR, specific prescription details including dose, usage and compliance, and improvements in symptoms and testosterone levels while on TST were not available for all patients and was 1336
therefore not included for analysis. Baseline laboratory values assessed included total testosterone level, calculated free testosterone level, luteinizing hormone (LH) level, follicle stimulating hormone (FSH) level, estradiol level, and sex hormone binding globulin level. After TST was discontinued, patients underwent medical testicular salvage therapy with CC 25 mg daily, with or without hCG 3000 units subcutaneously every other day. Both CC and hCG were recommended to all patients, with some patients taking both as recommended and others taking only CC because of patient factors such as cost considerations. It should be noted that this particular combination regimen of off-label medications has not been previously reported in the literature and only represents the authors’ practice. The regimen and the length of time on medical testicular salvage therapy were recorded. Patients returned for a secondary physical examination and laboratory assessment before VR. After approximately 3 months of testicular salvage therapy, if the recovery of spermatogenesis was clinically uncertain based on the subjective changes in testicular volume or in the hormonal profile, patients underwent TESA before VR. TESA was performed as an office-based procedure with local anesthesia on a single testicle with a single entry passage of the needle. After administration of a spermatic cord block and subcutaneous skin block with 1% lidocaine, an 18-ga 1.5-inch needle primed with sperm wash media and fixed to a fine needle aspirate piston syringe was passed into the testicular parenchyma and moved in and out with a sawing motion approximately 5 times while holding the vacuum suction on the piston syringe. The aspirate was then examined on a slide by a certified andrologist with a phase microscope at 40 times magnification for the determination of active spermatogenesis. After the secondary preoperative assessment confirmed an improvement in the physical examination and the hormonal profile or a positive TESA was performed, all patients underwent microsurgical VR by a single fellowship-trained microsurgeon with either a 2-layered vasovasostomy (VV) or intussuscepted end-to-side epididymovasostomy (EV), techniques of which were previously described in detail.16 Intraoperative data abstracted included the methods of reconstruction and the characteristics of the intravasal fluid (including its consistency and the presence or absence of sperm or sperm parts). Results of postoperative semen analyses and the achievement of pregnancy were similarly recorded. Data were analyzed by computation of appropriate descriptive summary statistics with measures of dispersion reported as interquartile range (IQR) owing to the small sample size. Comparisons between groups were performed using the Student t test. The threshold for statistical significance was defined as a 1-tailed P value <.05.
RESULTS Retrospective chart review identified a total of 265 patients who underwent VR between December 2009 and May 2013. Of those, 10 patients (2.7%) had a documented history of TST. After 4 patients were excluded for incomplete data, a total of 6 patients were included for analysis (Table 1). Median age at VR was 38.5 years (IQR, 36.8-40.5 years), with a median obstructive interval of 7.5 years (IQR, 5.5-8.8 years). All 6 men had previously fathered children before their vasectomy. UROLOGY 84 (6), 2014
Patent with pregnancy Patent
Patent with pregnancy Not patent
N/A Positive 5 6
CC, hCG CC, hCG 4.5 7 Topical, Injectable Injectable
Positive N/A CC, hCG CC 5 9 Injectable Injectable 3 4
CC, clomiphene citrate; EV, epididymovasostomy; hCG, human chorionic gonadotropin; N/A, not applicable; VV, vasovasostomy.
Clear; Nonmotile sperm Creamy; Vasal fluid: no sperm; Epididymal fluid: Nonmotile sperm Copious, clear; Motile sperm Clear; Nonmotile sperm
Patent Patent with pregnancy Clear; Motile sperm Creamy; Nonmotile sperm
Fluid, Right Fluid, Left
Bilateral VV Clear; Motile sperm EV/VV Creamy; Vasal fluid: no sperm; Epididymal fluid: Nonmotile sperm Bilateral VV Clear; Motile sperm Bilateral EV Creamy; Vasal fluid: no sperm; Epididymal fluid: Nonmotile sperm Bilateral VV Copious, clear; Motile sperm Bilateral VV Clear; Nonmotile sperm N/A N/A CC CC, hCG 8 20 Topical Topical, Injectable 1 2
Postoperative Patency (at Median 6.4 mo) Reversal Procedure Prior Testosterone Obstructive Salvage Preoperative Patient Supplementation Interval (y) Therapy Used TESA
Table 1. Preoperative and intraoperative factors with postoperative patency
UROLOGY 84 (6), 2014
Before initial consultation for VR, 3 patients had used injectable testosterone, 1 used topical testosterone and 2 had used either a topical or injectable preparations at different times. All 6 men were current users of TST for a median duration of 9 months (IQR, 6-22 months). Baseline hormone levels were recorded for all patients (Table 2). At baseline, hypogonadotropic hypogonadism was observed in all patients, with decreased median LH level (2 mIU/mL; IQR, 1-4 mIU/mL), FSH level (5 mIU/ mL; IQR 2-6 mIU/mL), and total testosterone level (249 ng/dL; IQR 203-375 ng/dL). All patients underwent medical testicular salvage therapy for a median of 2.8 months (IQR, 2.5-3.0 months). Two patients underwent testicular salvage therapy with CC only and 4 with CC and hCG (Table 1). Two patients (33%) with clinical uncertainty regarding the response to medical testicular salvage therapy underwent preoperative TESA, confirming the presence of active spermatogenesis before VR. Nine VVs (75%) and 3 EVs (25%) were performed in the 6 patients. Four patients underwent bilateral VV (66.7%), 1 underwent VV and EV (16.7%), and 1 underwent bilateral EV (16.7%). The fluid consistency and the presence or absence of sperms in the vasal and epididymal fluid were noted intraoperatively (Table 1). Follow-up hormone levels were available in all patients (Table 2). The follow-up LH, FSH, and total testosterone levels all increased to within normal limits and trended toward statistical significance. Median LH levels increased from 2 mIU/mL (IQR, 1-4 mIU/mL) to 4 mIU/ mL (IQR, 3-5 mIU/mL; P ¼ .08), FSH level increased from 5 mIU/mL (IQR, 2-6 mIU/mL) to 7 mIU/mL (IQR, 6-8 mIU/mL; P ¼ .07), and total testosterone level increased from 249 ng/dL (IQR, 203-375 ng/dL) to 563 ng/dL (IQR, 337-655 ng/dL; P ¼ .17). Postoperative semen analyses were available in all patients studied (Table 3). Five of 6 patients (83.3%) demonstrated patency after a median follow-up of 6.4 months (IQR, 5.5-7.0 months), and patency was 100% in men undergoing at least 1 VV. One patient who underwent a bilateral EV remained azoospermic at the end of the study follow-up period. Pregnancy was achieved by 3 men (50%) during the follow-up period. Of the 5 men who were patent, the mean seminal volume was 2.3 mL, sperm density was 27 million/mL, motility was 25%, forward progression was 2.0, total sperm count was 59 million, and total motile sperm count was 17 million (Table 3).
COMMENT A contemporary study (2006-2010) by the National Survey for Family Growth reported that 15.9% of American men aged 36-45 years have undergone a vasectomy, whereas 19.6% of vasectomized men expressed a desire for future children.17 Coupled with the latest TST prevalence statistics, indicating that younger men have the highest rate of increased utilization,1 these emerging 1337
Table 2. Baseline and follow-up hormone levels Baseline Hormone Levels Hormone LH (mIU/mL) FSH (mIU/mL) Total T (ng/dL) Free T (ng/dL) SHBG (nmol/L) Estradiol (ng/dL)
2 5 249 6 22 2
Follow-up Hormone Levels
Mean SD
Median (IQR) (1-4) (2-6) (203-375) (5-6) (14-35) (2-4)
4 5 347 8 25 3
5 4 260 8 15 2
Median (IQR) 5 7 563 10 22 5
(4-5) (6-8) (337-655) (9-12) (19-36) (2-7)
Mean SD
P
.08 .07 .17 .42 .06 .09
6 8 570 10 25 5
6 5 336 4 11 3
FSH, follicle stimulating hormone; IQR, interquartile range; LH, luteinizing hormone; SD, standard deviation; SHBG, sex hormone binding globulin; T, testosterone.
Table 3. Postoperative semen analyses of patent men (n ¼ 5; 83.3%) Semen Parameters
Median (IQR)
Volume (mL) Density (million/mL) Motility (%) Forward progression (1-4) Total count (million) Total motile count (million)
2.2 23 20 2.0 46 19
(2.0-2.5) (15-28) (15-40) (2.0-2.5) (23-70) (4-31)
Mean SD 2.3 27 25 2.0 59 17
0.7 26 17 0.6 59 15
Abbreviations as in Table 2.
data reflect the observation of a trend toward more men presenting for VR after previous TST. Prior TST may adversely affect the outcome of VR by suppressing spermatogenesis, altering the intraoperative findings used to determine the method of reconstruction, that is, VV vs EV. This effect is critical given that VR success rates depend primarily on the following 3 factors: interval time between vasectomy and VR, the intraoperative findings, and the method of reconstruction.16 During VR, microscopic identification of sperm within the intravasal fluid from the testicular end of the vas deferens predicts the increased likelihood of VR success. Patients with clear copious fluid and whole sperm have a higher chance of sperm returning to the ejaculate and therefore higher pregnancy rates after a VV.18 The intravasal fluid and sperm findings, the grading of which was first described by the Vasovasostomy Study Group in 1991,18 dictate whether to reconstruct with a VV or the more technically difficult EV. The consensus recommendations of numerous authors are that VV should only be performed if whole sperm or sperm heads and tails are identified in the vasal fluid.5,16,18-20 The consistency of the vasal fluid, when coupled with the grading of vasal spermatozoa, is another very important factor in the decision for the method of reconstruction. After microsurgical VV, patency and pregnancy rates decline as the obstructive interval increases; overall, patency after VV is 71%-97% with a 30%-76% pregnancy rate, depending on the obstructive interval.18 Patency rates for the current techniques of intussuscepted end-to-side EV are approximately 80% at the best, with a lower pregnancy rate of approximately 40%.16,19 Coviello et al21 showed that intratesticular testosterone is maintained by concurrent low-dose hCG in a randomized 1338
sample of 29 healthy volunteers with gonadotropin suppression by exogenous testosterone. The maintenance of spermatogenesis with the concurrent use of low-dose hCG with TST was recently demonstrated by Hsieh et al.22 In this 2013 retrospective study, 26 young hypogonadal men (mean age, 36 years) underwent treatment with exogenous testosterone plus hCG 500 units intramuscularly every other day. The hormone profile and semen analyses were evaluated before and during therapy for a mean follow-up of 6.2 months. Testosterone significantly increased to within normal limits, however there were no differences in semen parameters from baseline noted.22 Finally, in another small series of 13 patients with idiopathic hypogonadotropic hypogonadism and azoospermia, spermatogenesis was qualitatively maintained by hCG alone after being induced by gonadotropin-releasing hormone or combination hCG with human menopausal gonadotropins.14 Therefore, hCG has been shown to be effective at reinitiating and maintaining spermatogenesis in hypogonadotropic hypogonadal men after, and even during, TST. CC, a selective estrogen receptor modulator that increases gonadotropin secretion via estrogen receptor blockade in the hypothalamus and anterior pituitary, is used off-label to treat male secondary hypogonadism.13 Both CC and its isomer enclomiphene citrate, which is currently being tested in clinical trials, improve hypogonadotropic hypogonadism by increasing gonadotropin secretion. The increased gonadotropins result in higher endogenous testosterone through a positive LH effect, and additionally may protect and potentially improve spermatogenesis through a positive FSH effect.23,24 Although data supporting the use of CC in this specific population do not exist, CC remains a primary method of testicular salvage therapy, or as an adjunctive treatment concurrent with hCG, for spermatogenic recovery after exogenous testosterone exposure. Because CC is a lowcost generic medication with an excellent short-term safety profile, it remains a preferred method of testicular salvage therapy for all patients desiring VR after prior TST. A testicular salvage therapy combination regimen of both CC and hCG has not been previously reported in the literature. In this study, the particular regimen used represents the authors’ current practice and is not a universally accepted method of testicular salvage therapy. UROLOGY 84 (6), 2014
Figure 1. Algorithm for preoperative evaluation and treatment of men desiring vasectomy reversal after testosterone supplementation therapy (TST). hCG, human chorionic gonadotropin; TESA, testicular sperm aspiration.
Based on the limited data available, patients in the present study had TST discontinued and were started on CC 25 mg daily with or without hCG 3000 units subcutaneously every other day for testicular salvage therapy. Two of 6 patients (33.3%) underwent TESA to assess for spermatogenesis before VR. Based on our early experience, we propose the following preoperative management algorithm (Fig. 1). If interested in VR, it is recommended to directly inquire regarding a patient’s use of TST to assess the risk of gonadotropin suppression. If the history is suggestive of gonadotropin suppression, then the physical examination during the initial encounter should include an assessment of testicular volume coupled with a hormone profile including total and free testosterone, LH, and FSH levels. If testicular volumes are low and gonadal suppression is confirmed, discontinuation of TST is recommended with transition to CC with or without hCG for a duration of 3 months (ie, testicular salvage). After 3 months, the patient should have another clinic visit for a repeat physical examination and hormone profile. In men with an uncertain response to therapy (eg, persistently soft, small testes, or no improvement in the laboratory assessment of hypogonadotropic hypogonadism), an in-office TESA may be considered to definitively determine the presence of spermatogenesis. After the examination and hormone profile improve, or if a TESA is positive for active spermatogenesis, one can proceed to microsurgical VR in the standard fashion. As with every VR, the option remains for concurrent cryopreservation of sperm, particularly when a successful outcome is less certain. Although the sample size was small, the results observed in this case series are promising and suggest that outcomes using this preoperative strategy for patients with previous TST may approach those seen in the general population. After 9 VVs and 3 EVs were performed, with UROLOGY 84 (6), 2014
2 of 6 patients (33.3%) undergoing at least 1 EV, the men demonstrated an overall patency of 83.3% after a median follow-up of 6.4 months, with 100% patency among men undergoing at least 1 VV. Remarkably, pregnancy was achieved by 50% during the short follow-up period. The results in the present case series compare quite closely with a recently published, large, contemporary series of 1229 VRs where the rate of at least 1 EV was 33%, and the overall patency rate was 84% after a median obstructive interval of 10 years.6 Limitations of the study include its retrospective nature, small sample size, and that all cases were performed at a single institution in an urban setting. Additionally, without a control arm, it is possible that some patients may have naturally achieved return of spermatogenesis over time,10 which would make the actual benefit of a 3-month course of medical testicular salvage therapy not entirely certain. Because previous TST dose, usage, and compliance were not available for all patients, specific conclusions regarding the exact exogenous testosterone exposure in the study population cannot be made. For all these reasons, the results must be cautiously interpreted in this context, and the recommendations for preoperative management herein should be used in centers of excellence by physicians already experienced with using testicular salvage therapy. The exact best regimen of testicular salvage therapy cannot be fully elucidated from this small cohort in the present study. These limitations in a study such as this reinforce the dire need for multicentered prospective data for the treatment of male fertility. We have demonstrated a proof of concept that men with suppression of their hypothalamic pituitary gonadal axis, potentially resulting in decreased spermatogenesis from exogenous testosterone use, can have spermatogenic recovery before VR and achieve favorable outcomes compared with other larger contemporary series. 1339
CONCLUSION Preoperative medical testicular salvage therapy with CC with or without hCG may improve the accuracy of the decision for the best method of reconstruction, VV or EV, therefore increasing the success of VR in patients with a history of TST. If managed appropriately, VR in men after TST can have outcomes comparable with the general population. References 1. Baillargeon J, Urban RJ, Ottenbacher KJ, et al. Trends in androgen prescribing in the United States, 2001 to 2011. JAMA Intern Med. 2013;173:1465-1466. 2. Mulligan T, Frick MF, Zuraw QC, et al. Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract. 2006;60:762-769. 3. Bassil N, Alkaade S, Morley JE. The benefits and risks of testosterone replacement therapy: a review. Ther Clin Risk Manag. 2009;5:427-448. 4. Eisenberg ML, Lipshultz LI. Estimating the number of vasectomies performed annually in the United States: data from the National Survey of Family Growth. J Urol. 2010;184:2068-2072. 5. Schwarzer JU. Vasectomy reversal using a microsurgical three-layer technique: one surgeon’s experience over 18 years with 1300 patients. Int J Androl. 2012;35:706-713. 6. Mui P, Perkins A, Burrows PJ, et al. The need for epididymovasostomy at vasectomy reversal plateaus in older vasectomies: a study of 1229 cases. Andrology. 2014;2:25-29. 7. Liu PY, Swerdloff RS, Anawalt BD, et al. Determinants of the rate and extent of spermatogenic suppression during hormonal male contraception: an integrated analysis. J Clin Endocrinol Metab. 2008; 93:1774-1783. 8. Roth MY, Ilani N, Wang C, et al. Characteristics associated with suppression of spermatogenesis in a male hormonal contraceptive trial using testosterone and Nestorone() gels. Andrology. 2013;1:899-905. 9. Manetti GJ, Honig SC. Update on male hormonal contraception: is the vasectomy in jeopardy? Int J Impot Res. 2010;22:159-170. 10. Liu PY, Swerdloff RS, Christenson PD, et al; Hormonal Male Contraception Summit Group. Rate, extent, and modifiers of spermatogenic recovery after hormonal male contraception: an integrated analysis. Lancet. 2006;367:1412-1420. 11. Jarow JP, Lipshultz LI. Anabolic steroid-induced hypogonadotropic hypogonadism. Am J Sports Med. 1990;18:429-431. 12. Moss JL, Crosnoe LE, Kim ED. Effect of rejuvenation hormones on spermatogenesis. Fertil Steril. 2013;99:1814-1820. 13. Katz DJ, Nabulsi O, Tal R, Mulhall JP. Outcomes of clomiphene citrate treatment in young hypogonadal men. BJU Int. 2012;110: 573-578. 14. Depenbusch M, von Eckardstein S, Simoni M, Nieschlag E. Maintenance of spermatogenesis in hypogonadotropic hypogonadal men with human chorionic gonadotropin alone. Eur J Endocrinol. 2002;147:617-624. 15. Kessaris DN, Wasserman P, Mellinger BC. Histopathological and cytopathological correlations of percutaneous testis biopsy and open testis biopsy in infertile men. J Urol. 1995;153:1151-1155. 16. Lipshultz LI, Rumohr JA, Bennett RC. Techniques for vasectomy reversal. Urol Clin North Am. 2009;36:375-382. 17. Sharma V, Le BV, Sheth KR, et al. Vasectomy demographics and postvasectomy desire for future children: results from a contemporary national survey. Fertil Steril. 2013;99:1880-1885. 18. Belker AM, Thomas AJ Jr, Fuchs EF, et al. Results of 1,469 microsurgical vasectomy reversals by the Vasovasostomy Study Group. J Urol. 1991;145:505-511. 19. Schiff J, Chan P, Li PS, et al. Outcome and late failures compared in 4 techniques of microsurgical vasoepididymostomy in 153 consecutive men. J Urol. 2005;174:651-655; quiz 801. 20. Smith RP, Khanna A, Kovac JR, et al. The significance of sperm heads and tails within the vasal fluid during vasectomy reversal. Indian J Urol. 2014;30:23-27.
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21. Coviello AD, Matsumoto AM, Bremner WJ, et al. Low-dose human chorionic gonadotropin maintains intratesticular testosterone in normal men with testosterone-induced gonadotropin suppression. J Clin Endocrinol Metab. 2005;90:2595-2602. 22. Hsieh TC, Pastuszak AW, Hwang K, Lipshultz LI. Concomitant intramuscular human chorionic gonadotropin preserves spermatogenesis in men undergoing testosterone replacement therapy. J Urol. 2013;189:647-650. 23. Kaminetsky J, Hemani ML. Clomiphene citrate and enclomiphene for the treatment of hypogonadal androgen deficiency. Expert Opin Investig Drugs. 2009;18:1947-1955. 24. Kaminetsky J, Werner M, Fontenot G, Wiehle RD. Oral enclomiphene citrate stimulates the endogenous production of testosterone and sperm counts in men with low testosterone: comparison with testosterone gel. J Sex Med. 2013;10:1628-1635.
EDITORIAL COMMENT Increased awareness about potential links between hypogonadism and metabolic syndrome, sexual dysfunction, mood disorders, and physical fitness in men leads to dramatic increase in utilization of testosterone replacement therapy (TRT).1 Some of the men treated with TRT either never had children or remarry and decide to have children with their new spouses.2 TRT by lowering serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) can lead to suppression of spermatogenesis. When human chorionic gonadotropin (hCG) was given with TRT, no suppression of spermatogenesis was observed providing convincing evidence that it is not TRT per se causing spermatogenic suppression but decrease in serum LH and FSH levels as a result of TRT. As no reliable method exists at this point to predict which men will suppress their sperm production while on TRT, it is wise to stop TRT to allow for LH and FSH recovery before vasectomy reversal for at least 3-6 months. However, if such an approach is necessary in men who have normal LH and FSH levels despite TRT is an area of debate. From a purely physiological perspective, if LH and FSH are within normal range then it would be unlikely that suppression of spermatogenesis would occur with normal LH and FSH levels despite of TRT.3 The choice of anastomosis during vasectomy reversal depends on the presence of sperms in the testicular end of vas, thus it is paramount that spermatogenesis is optimized before an attempt at reconstruction. The authors present their experience with 6 men who wished vasectomy reversal after TRT. Based on few published observational studies using clomiphene citrate and/or hCG to restore normal pituitary function in men with suppression of LH and FSH after TRT, authors used 25 mg with or without hCG 3 times a week to restore spermatogenesis. It is reassuring to notice that within minimum of 3 months of therapy with clomiphene citrate and/or hCG, sperms were identified in all 6 subjects. In addition, results of vasectomy reversal seem to reflect the type of anastomosis, with bilateral vasoepididymostomy resulting in azoospermia on follow-up semen analysis despite the presence of nonmotile sperms in epididymal fluid rather than the medical treatment used. This article brings an important issue of inherited risks of spermatogenic suppression in some if not all men on TRT. Lack of a control arm makes it unclear if any form of therapy other than stopping TRT and following FSH and LH is indeed necessary; hence, additional studies with larger numbers of subjects are needed. Clomiphene citrate and hCG treatments add additional cost and the need for injections in addition to not being Food and Drug Administrationeapproved treatments for male infertility. UROLOGY 84 (6), 2014
One cannot forget that clomiphene citrate has been linked to thromboembolic catastrophic events in males and females including stroke and pulmonary embolism (0.1-1%) as per FDA labeling.5 Thus, “wait and see” approach for 3 months with assessment of LH, FSH, testosterone, and testicular volume may be the prudent initial approach.4 Regardless of its limitations, authors should be applauded for their work as they bring an important issue that full history and physical examination and correction of underlying endocrinologic issues is mandatory in all men undergoing vasectomy reversal. Darius A. Paduch, M.D., Ph.D., James Buchanan Brady Urological Health Center, Weill Cornell Medical College, New York, NY
References 1. Corona G, Rastrelli G, Forti G, et al. Update in testosterone therapy for men. J Sex Med. 2011;8:639-654; quiz 655. 2. Giagulli VA, Triggiani V, Corona G, et al. Evidence-based medicine update on testosterone replacement therapy (TRT) in male hypogonadism: focus on new formulations. Curr Pharm Des. 2011;17:1500-1511. 3. Hsieh TC, Pastuszak AW, Hwang K, et al. Concomitant intramuscular human chorionic gonadotropin preserves spermatogenesis in men undergoing testosterone replacement therapy. J Urol. 2013;189:647-650. 4. Politou M, Gialeraki A, Merkouri E, et al. Central retinal vein occlusion secondary to clomiphene treatment in a male carrier of factor V Leiden. Genet Test Mol Biomarkers. 2009;13:155-157. 5. FDA labeling for clomiphene citrate. U.S. Food and Drug Administration. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/ 016131s026lbl.pdf. Accessed September 30, 2014.
unknown and likely exceedingly small. Indeed, recent literature attests to the safety of clomiphene citrate in hypogonadal men.2 Despite varying degrees of suppression of gonadotropins with TST that depend on many factors, most patients develop suppression of spermatogenesis ranging from oligospermia to azoospermia.3 Although two-thirds of men re-establish “normal” sperm concentrations of >20 million/mL within 6 months after discontinuation of TST, 10% require between 1 and 2 years to reach this result.3 Although the preoperative hormone assessment provides initial guidance, gonadotropin levels unfortunately do not always correlate with spermatogenesis while on TST.4 Although our study does not definitively prove that salvage therapy provides benefit for vasectomy reversal outcomes because of its study design, it does provide a proof of concept. The proposed alternative to salvage therapy of abrupt withdrawal of TST and “wait and see” has a myriad of drawbacks. First, it is impossible to know how long it will take for spermatogenesis to return, especially given the inability to assess progress via semen analysis. More importantly, abrupt withdrawal of TST is a cruel punishment leading to very severe hypogonadal symptoms. Because most patients on TST will become profoundly hypogonadal with serum levels <100 ng/dL after cessation of TST, the side effects could mirror those observed with androgen deprivation therapy for metastatic prostate cancer including severe sexual symptoms, extreme fatigability, and mood disorders. Finally, and more practically speaking, patients and their partners desiring vasectomy reversal for conception may not tolerate a prolonged waiting period of unknown length before surgery. The authors’ proposed algorithm provides a safe option to facilitate the preoperative recovery of spermatogenesis.
http://dx.doi.org/10.1016/j.urology.2014.06.082 UROLOGY 84: 1340e1341, 2014. 2014 Elsevier Inc.
REPLY Lost in the aftermath of the exponential growth of testosterone supplementation therapy (TST) are numerous downstream effects dealt with by the male fertility specialist. One previously unappreciated effect of TST is how the suppression of spermatogenesis creates a dilemma for the vasectomy reversal surgeon, potentially affecting the method of reconstruction, and thus, the outcomes. In the present article, preoperative testicular salvage therapy was used to optimize spermatogenesis before reversal. The proposed protocol for salvage therapy after discontinuation of TST routinely recommended included a combination of clomiphene citrate (25 mg daily) with human chorionic gonadotropin (3000 units subcutaneously every other day) for a period of 3 months before reassessment. In this study, because some patients elected to only use clomiphene, the population ultimately studied included men who received clomiphene with or without human chorionic gonadotropin. One of the primary criticisms cited in the editorial comment dealt with supposed “catastrophic events” resulting from the use of clomiphene citrate. However, in spite of decades of use, the only example stated was a case report detailing a single patient with factor V Leidenecarrier status presenting with 1 week of unilateral blurry vision after clomiphene therapy. The patient’s visual acuity was 20/60 on presentation, and after he was diagnosed with central retinal vein occlusion and treated with clopidogrel, his vision returned to normal.1 Notwithstanding case reports of thrombotic complications, the true incidence of such events is UROLOGY 84 (6), 2014
Robert M. Coward, M.D., Department of Urology, University of North Carolina School of Medicine, Chapel Hill, NC Douglas A. Mata, M.D., Scott Department of Urology, Baylor College of Medicine, Houston, TX; Department of Biochemistry and Cell Biology, Wiess School of Natural Sciences, Rice University, Houston, TX Ryan P. Smith, M.D., Department of Urology, School of Medicine, University of Virginia, Charlottesville, VA Jason R. Kovac, M.D., Ph.D., and Larry I. Lipshultz, M.D., Scott Department of Urology, Baylor College of Medicine, Houston, TX
References 1. Politou M, Gialeraki A, Merkouri E, et al. Central retinal vein occlusion secondary to clomiphene treatment in a male carrier of factor V Leiden. Genet Test Mol Biomarkers. 2009;13:155-157. 2. Moskovic DJ, Katz DJ, Akhavan A, et al. Clomiphene citrate is safe and effective for long-term management of hypogonadism. BJU Int. 2012;110:1524-1528. 3. Liu PY, Swerdloff RS, Christenson PD, et al; Hormonal Male Contraception Summit Group. Rate, extent, and modifiers of spermatogenic recovery after hormonal male contraception: an integrated analysis. Lancet. 2006;367:1412-1420. 4. Amory JK, Anawalt BD, Bremner WJ, Matsumoto AM. Daily testosterone and gonadotropin levels are similar in azoospermic and nonazoospermic normal men administered weekly testosterone: implications for male contraceptive development. J Androl. 2001;22:1053-1060.
http://dx.doi.org/10.1016/j.urology.2014.06.083 UROLOGY 84: 1341, 2014. 2014 Elsevier Inc.
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RESULTS
CONCLUSION
To report considerations for preoperative management and outcomes of vasectomy reversal (VR) in men with a history of testosterone supplementation therapy (TST). A retrospective review of men on TST before VR from 2010 to 2013 was performed. For inclusion, patients were required to have baseline and follow-up hormone levels as well as postoperative semen analyses. Preoperative use of medical testicular salvage therapy and testicular sperm aspiration (TESA), intraoperative findings, and pregnancies were also analyzed. Six of 265 men who underwent VR had prior TST and met inclusion criteria. Median age was 39 years with a median obstructive interval of 7.5 years. Median duration of TST was 9 months before discontinuation and transition to testicular salvage therapy with clomiphene citrate with or without human chorionic gonadotropin for a median of 2.8 months. At baseline, decreased luteinizing hormone (median, 2 mIU/mL), follicle stimulating hormone (median, 5 mIU/mL), and total testosterone (median, 249 ng/dL) were observed. Two men (33%) with uncertain recovery of spermatogenesis based on physical examination and hormone response underwent preoperative testicular sperm aspiration confirming the presence of sperm. Nine vasovasostomies and 3 epididymovasostomies were performed. Patency was 83% after a median follow-up of 6.4 months and was 100% in men undergoing at least 1 vasovasostomy. Spontaneous pregnancy was achieved by 50% during the follow-up period. Testicular salvage medical therapy may play a role in the preoperative management of VR in men with prior TST. VR after TST can have outcomes comparable to those in the general population. UROLOGY 84: 1335e1341, 2014. 2014 Elsevier Inc.
U
se of testosterone supplementation therapy (TST) has become increasingly common among younger men.1 Idiopathic biochemical hypogonadism, defined by a total testosterone level <300 ng/ dL, is observed in just over a third of all men aged 45-54 years.2 The diagnosis of hypogonadism and its treatment with TST has grown remarkably in recent years, as testosterone prescriptions have increased over 500% since 1993.3 The age group with the most rapid rate of increased utilization is men aged 40-49 years, with testosterone prescriptions increasing more than 4.2-fold Financial Disclosure: Larry Lipshultz is a paid consultant, advisor, speaker, and clinical trial investigator to Eli Lilly and Company. He is a clinical investigator, meeting participant, and speaker to Endo Pharmaceuticals. He is also a meeting participant and speaker to Pfizer. He is a clinical trial investigator and speaker to Auxilium Pharmaceuticals. The remaining authors declare that they have no relevant financial interests. From the Department of Urology, University of North Carolina School of Medicine, Chapel Hill, NC; the Scott Department of Urology, Baylor College of Medicine, Houston, TX; the Department of Biochemistry and Cell Biology, Wiess School of Natural Sciences, Rice University, Houston, TX; and the Department of Urology, School of Medicine, University of Virginia, Charlottesville, VA Address correspondence to: Robert M. Coward, M.D., 2113 Physicians Office Building, CB#7235, 170 Manning Drive, Chapel Hill, NC 27599-7235. E-mail: [email protected] Submitted: February 6, 2014, accepted (with revisions): June 16, 2014
ª 2014 Elsevier Inc. All Rights Reserved
between 2001 and 2011. In 2011, this equated to a total prevalence of 2.3% in this age group alone.1 Men undergo vasectomy at an average age of 31 years,4 whereas the average age for vasectomy reversal (VR) is 41 years.5,6 Some men within this window will be diagnosed with hypogonadism and treated with TST. Nearly all men will have some degree of suppression of spermatogenesis during treatment with TST. Exogenous testosterone typically results in atrophy of the germinal epithelium in normal men with varying degrees of suppression of spermatogenesis, including azoospermia, within several months.7,8 The level of suppression is partly dependent on the type of testosterone preparation, with topical preparations typically displaying a smaller degree of suppression of gonadotropins and thus spermatogenesis than injectable or implantable testosterone preparations.9 Sperm concentrations usually recover to pretreatment levels after the cessation of TST; however, recovery could take up to 2 years,10 and permanent detrimental effects to spermatogenesis are possible.11,12 The use of TST before VR may impact vasal fluid findings by suppressing spermatogenesis, which could complicate intraoperative decision making on the method of http://dx.doi.org/10.1016/j.urology.2014.06.081 0090-4295/14
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reconstruction, and, therefore, may impair postoperative patency and pregnancy rates. There is currently no available data for the management of exogenous testosterone-suppressed spermatogenesis in vasectomized men seeking VR. The vasectomized patient represents a particularly difficult patient in whom to assess spermatogenesis, and therefore the serum testosterone and gonadotropins, represents the most accurate initial assessment. Medical testicular salvage therapy to recover spermatogenesis in hypogonadotropic hypogonadal men may be accomplished with clomiphene citrate (CC)13 and/or human chorionic gonadotropin (hCG).14 If doubt persists whether spermatogenesis has recovered after treatment with testicular salvage therapy, a testicular sperm aspiration (TESA) in the office may be performed. Although TESA is more invasive, it can provide a definitive demonstration of spermatogenesis and represents a particularly helpful diagnostic test for the dilemma of uncertainty of active spermatogenesis in patients with obstructive azoospermia secondary to vasectomy.15 VR outcomes after TST and considerations for preoperative management have not been previously reported. Because of the increased diagnosis and treatment of androgen deficiency, we hypothesize that a growing proportion of men desiring VR will have been treated with TST. Because the effects of exogenous androgens adversely impact spermatogenesis,12 we postulated that the use of TST may play a factor in VR outcomes. We also sought to retrospectively describe a method of testicular salvage therapy to potentially reinitiate spermatogenesis as well as a method to assess for the presence of spermatogenesis before VR. In this study, we describe the results of a retrospective case series of the VR outcomes in men previously on TST with a goal to demonstrate a proof of concept of a preoperative evaluation and treatment strategy using medical management with testicular salvage therapy, and TESA in select cases, to increase the success rate of VR after TST.
METHODS After obtaining institutional review board approval, a retrospective chart review was conducted of consecutive VR cases performed in a large academic urology practice. All surgeries were performed by a single fellowship-trained microsurgeon between December 2009 and May 2013. Patients were included in the study if a history of prior TST was identified during the obstructive interval between vasectomy and VR. All patients must have had 2 separate hormone profiles along with postoperative semen analysis data available. Patients were excluded if any of these criteria were not met. Preoperative data collected included demographics, length of obstructive interval, and the formulation and length of time of TST. Because TST for all patients was prescribed by an outside facility before the patients presenting for evaluation for VR, specific prescription details including dose, usage and compliance, and improvements in symptoms and testosterone levels while on TST were not available for all patients and was 1336
therefore not included for analysis. Baseline laboratory values assessed included total testosterone level, calculated free testosterone level, luteinizing hormone (LH) level, follicle stimulating hormone (FSH) level, estradiol level, and sex hormone binding globulin level. After TST was discontinued, patients underwent medical testicular salvage therapy with CC 25 mg daily, with or without hCG 3000 units subcutaneously every other day. Both CC and hCG were recommended to all patients, with some patients taking both as recommended and others taking only CC because of patient factors such as cost considerations. It should be noted that this particular combination regimen of off-label medications has not been previously reported in the literature and only represents the authors’ practice. The regimen and the length of time on medical testicular salvage therapy were recorded. Patients returned for a secondary physical examination and laboratory assessment before VR. After approximately 3 months of testicular salvage therapy, if the recovery of spermatogenesis was clinically uncertain based on the subjective changes in testicular volume or in the hormonal profile, patients underwent TESA before VR. TESA was performed as an office-based procedure with local anesthesia on a single testicle with a single entry passage of the needle. After administration of a spermatic cord block and subcutaneous skin block with 1% lidocaine, an 18-ga 1.5-inch needle primed with sperm wash media and fixed to a fine needle aspirate piston syringe was passed into the testicular parenchyma and moved in and out with a sawing motion approximately 5 times while holding the vacuum suction on the piston syringe. The aspirate was then examined on a slide by a certified andrologist with a phase microscope at 40 times magnification for the determination of active spermatogenesis. After the secondary preoperative assessment confirmed an improvement in the physical examination and the hormonal profile or a positive TESA was performed, all patients underwent microsurgical VR by a single fellowship-trained microsurgeon with either a 2-layered vasovasostomy (VV) or intussuscepted end-to-side epididymovasostomy (EV), techniques of which were previously described in detail.16 Intraoperative data abstracted included the methods of reconstruction and the characteristics of the intravasal fluid (including its consistency and the presence or absence of sperm or sperm parts). Results of postoperative semen analyses and the achievement of pregnancy were similarly recorded. Data were analyzed by computation of appropriate descriptive summary statistics with measures of dispersion reported as interquartile range (IQR) owing to the small sample size. Comparisons between groups were performed using the Student t test. The threshold for statistical significance was defined as a 1-tailed P value <.05.
RESULTS Retrospective chart review identified a total of 265 patients who underwent VR between December 2009 and May 2013. Of those, 10 patients (2.7%) had a documented history of TST. After 4 patients were excluded for incomplete data, a total of 6 patients were included for analysis (Table 1). Median age at VR was 38.5 years (IQR, 36.8-40.5 years), with a median obstructive interval of 7.5 years (IQR, 5.5-8.8 years). All 6 men had previously fathered children before their vasectomy. UROLOGY 84 (6), 2014
Patent with pregnancy Patent
Patent with pregnancy Not patent
N/A Positive 5 6
CC, hCG CC, hCG 4.5 7 Topical, Injectable Injectable
Positive N/A CC, hCG CC 5 9 Injectable Injectable 3 4
CC, clomiphene citrate; EV, epididymovasostomy; hCG, human chorionic gonadotropin; N/A, not applicable; VV, vasovasostomy.
Clear; Nonmotile sperm Creamy; Vasal fluid: no sperm; Epididymal fluid: Nonmotile sperm Copious, clear; Motile sperm Clear; Nonmotile sperm
Patent Patent with pregnancy Clear; Motile sperm Creamy; Nonmotile sperm
Fluid, Right Fluid, Left
Bilateral VV Clear; Motile sperm EV/VV Creamy; Vasal fluid: no sperm; Epididymal fluid: Nonmotile sperm Bilateral VV Clear; Motile sperm Bilateral EV Creamy; Vasal fluid: no sperm; Epididymal fluid: Nonmotile sperm Bilateral VV Copious, clear; Motile sperm Bilateral VV Clear; Nonmotile sperm N/A N/A CC CC, hCG 8 20 Topical Topical, Injectable 1 2
Postoperative Patency (at Median 6.4 mo) Reversal Procedure Prior Testosterone Obstructive Salvage Preoperative Patient Supplementation Interval (y) Therapy Used TESA
Table 1. Preoperative and intraoperative factors with postoperative patency
UROLOGY 84 (6), 2014
Before initial consultation for VR, 3 patients had used injectable testosterone, 1 used topical testosterone and 2 had used either a topical or injectable preparations at different times. All 6 men were current users of TST for a median duration of 9 months (IQR, 6-22 months). Baseline hormone levels were recorded for all patients (Table 2). At baseline, hypogonadotropic hypogonadism was observed in all patients, with decreased median LH level (2 mIU/mL; IQR, 1-4 mIU/mL), FSH level (5 mIU/ mL; IQR 2-6 mIU/mL), and total testosterone level (249 ng/dL; IQR 203-375 ng/dL). All patients underwent medical testicular salvage therapy for a median of 2.8 months (IQR, 2.5-3.0 months). Two patients underwent testicular salvage therapy with CC only and 4 with CC and hCG (Table 1). Two patients (33%) with clinical uncertainty regarding the response to medical testicular salvage therapy underwent preoperative TESA, confirming the presence of active spermatogenesis before VR. Nine VVs (75%) and 3 EVs (25%) were performed in the 6 patients. Four patients underwent bilateral VV (66.7%), 1 underwent VV and EV (16.7%), and 1 underwent bilateral EV (16.7%). The fluid consistency and the presence or absence of sperms in the vasal and epididymal fluid were noted intraoperatively (Table 1). Follow-up hormone levels were available in all patients (Table 2). The follow-up LH, FSH, and total testosterone levels all increased to within normal limits and trended toward statistical significance. Median LH levels increased from 2 mIU/mL (IQR, 1-4 mIU/mL) to 4 mIU/ mL (IQR, 3-5 mIU/mL; P ¼ .08), FSH level increased from 5 mIU/mL (IQR, 2-6 mIU/mL) to 7 mIU/mL (IQR, 6-8 mIU/mL; P ¼ .07), and total testosterone level increased from 249 ng/dL (IQR, 203-375 ng/dL) to 563 ng/dL (IQR, 337-655 ng/dL; P ¼ .17). Postoperative semen analyses were available in all patients studied (Table 3). Five of 6 patients (83.3%) demonstrated patency after a median follow-up of 6.4 months (IQR, 5.5-7.0 months), and patency was 100% in men undergoing at least 1 VV. One patient who underwent a bilateral EV remained azoospermic at the end of the study follow-up period. Pregnancy was achieved by 3 men (50%) during the follow-up period. Of the 5 men who were patent, the mean seminal volume was 2.3 mL, sperm density was 27 million/mL, motility was 25%, forward progression was 2.0, total sperm count was 59 million, and total motile sperm count was 17 million (Table 3).
COMMENT A contemporary study (2006-2010) by the National Survey for Family Growth reported that 15.9% of American men aged 36-45 years have undergone a vasectomy, whereas 19.6% of vasectomized men expressed a desire for future children.17 Coupled with the latest TST prevalence statistics, indicating that younger men have the highest rate of increased utilization,1 these emerging 1337
Table 2. Baseline and follow-up hormone levels Baseline Hormone Levels Hormone LH (mIU/mL) FSH (mIU/mL) Total T (ng/dL) Free T (ng/dL) SHBG (nmol/L) Estradiol (ng/dL)
2 5 249 6 22 2
Follow-up Hormone Levels
Mean SD
Median (IQR) (1-4) (2-6) (203-375) (5-6) (14-35) (2-4)
4 5 347 8 25 3
5 4 260 8 15 2
Median (IQR) 5 7 563 10 22 5
(4-5) (6-8) (337-655) (9-12) (19-36) (2-7)
Mean SD
P
.08 .07 .17 .42 .06 .09
6 8 570 10 25 5
6 5 336 4 11 3
FSH, follicle stimulating hormone; IQR, interquartile range; LH, luteinizing hormone; SD, standard deviation; SHBG, sex hormone binding globulin; T, testosterone.
Table 3. Postoperative semen analyses of patent men (n ¼ 5; 83.3%) Semen Parameters
Median (IQR)
Volume (mL) Density (million/mL) Motility (%) Forward progression (1-4) Total count (million) Total motile count (million)
2.2 23 20 2.0 46 19
(2.0-2.5) (15-28) (15-40) (2.0-2.5) (23-70) (4-31)
Mean SD 2.3 27 25 2.0 59 17
0.7 26 17 0.6 59 15
Abbreviations as in Table 2.
data reflect the observation of a trend toward more men presenting for VR after previous TST. Prior TST may adversely affect the outcome of VR by suppressing spermatogenesis, altering the intraoperative findings used to determine the method of reconstruction, that is, VV vs EV. This effect is critical given that VR success rates depend primarily on the following 3 factors: interval time between vasectomy and VR, the intraoperative findings, and the method of reconstruction.16 During VR, microscopic identification of sperm within the intravasal fluid from the testicular end of the vas deferens predicts the increased likelihood of VR success. Patients with clear copious fluid and whole sperm have a higher chance of sperm returning to the ejaculate and therefore higher pregnancy rates after a VV.18 The intravasal fluid and sperm findings, the grading of which was first described by the Vasovasostomy Study Group in 1991,18 dictate whether to reconstruct with a VV or the more technically difficult EV. The consensus recommendations of numerous authors are that VV should only be performed if whole sperm or sperm heads and tails are identified in the vasal fluid.5,16,18-20 The consistency of the vasal fluid, when coupled with the grading of vasal spermatozoa, is another very important factor in the decision for the method of reconstruction. After microsurgical VV, patency and pregnancy rates decline as the obstructive interval increases; overall, patency after VV is 71%-97% with a 30%-76% pregnancy rate, depending on the obstructive interval.18 Patency rates for the current techniques of intussuscepted end-to-side EV are approximately 80% at the best, with a lower pregnancy rate of approximately 40%.16,19 Coviello et al21 showed that intratesticular testosterone is maintained by concurrent low-dose hCG in a randomized 1338
sample of 29 healthy volunteers with gonadotropin suppression by exogenous testosterone. The maintenance of spermatogenesis with the concurrent use of low-dose hCG with TST was recently demonstrated by Hsieh et al.22 In this 2013 retrospective study, 26 young hypogonadal men (mean age, 36 years) underwent treatment with exogenous testosterone plus hCG 500 units intramuscularly every other day. The hormone profile and semen analyses were evaluated before and during therapy for a mean follow-up of 6.2 months. Testosterone significantly increased to within normal limits, however there were no differences in semen parameters from baseline noted.22 Finally, in another small series of 13 patients with idiopathic hypogonadotropic hypogonadism and azoospermia, spermatogenesis was qualitatively maintained by hCG alone after being induced by gonadotropin-releasing hormone or combination hCG with human menopausal gonadotropins.14 Therefore, hCG has been shown to be effective at reinitiating and maintaining spermatogenesis in hypogonadotropic hypogonadal men after, and even during, TST. CC, a selective estrogen receptor modulator that increases gonadotropin secretion via estrogen receptor blockade in the hypothalamus and anterior pituitary, is used off-label to treat male secondary hypogonadism.13 Both CC and its isomer enclomiphene citrate, which is currently being tested in clinical trials, improve hypogonadotropic hypogonadism by increasing gonadotropin secretion. The increased gonadotropins result in higher endogenous testosterone through a positive LH effect, and additionally may protect and potentially improve spermatogenesis through a positive FSH effect.23,24 Although data supporting the use of CC in this specific population do not exist, CC remains a primary method of testicular salvage therapy, or as an adjunctive treatment concurrent with hCG, for spermatogenic recovery after exogenous testosterone exposure. Because CC is a lowcost generic medication with an excellent short-term safety profile, it remains a preferred method of testicular salvage therapy for all patients desiring VR after prior TST. A testicular salvage therapy combination regimen of both CC and hCG has not been previously reported in the literature. In this study, the particular regimen used represents the authors’ current practice and is not a universally accepted method of testicular salvage therapy. UROLOGY 84 (6), 2014
Figure 1. Algorithm for preoperative evaluation and treatment of men desiring vasectomy reversal after testosterone supplementation therapy (TST). hCG, human chorionic gonadotropin; TESA, testicular sperm aspiration.
Based on the limited data available, patients in the present study had TST discontinued and were started on CC 25 mg daily with or without hCG 3000 units subcutaneously every other day for testicular salvage therapy. Two of 6 patients (33.3%) underwent TESA to assess for spermatogenesis before VR. Based on our early experience, we propose the following preoperative management algorithm (Fig. 1). If interested in VR, it is recommended to directly inquire regarding a patient’s use of TST to assess the risk of gonadotropin suppression. If the history is suggestive of gonadotropin suppression, then the physical examination during the initial encounter should include an assessment of testicular volume coupled with a hormone profile including total and free testosterone, LH, and FSH levels. If testicular volumes are low and gonadal suppression is confirmed, discontinuation of TST is recommended with transition to CC with or without hCG for a duration of 3 months (ie, testicular salvage). After 3 months, the patient should have another clinic visit for a repeat physical examination and hormone profile. In men with an uncertain response to therapy (eg, persistently soft, small testes, or no improvement in the laboratory assessment of hypogonadotropic hypogonadism), an in-office TESA may be considered to definitively determine the presence of spermatogenesis. After the examination and hormone profile improve, or if a TESA is positive for active spermatogenesis, one can proceed to microsurgical VR in the standard fashion. As with every VR, the option remains for concurrent cryopreservation of sperm, particularly when a successful outcome is less certain. Although the sample size was small, the results observed in this case series are promising and suggest that outcomes using this preoperative strategy for patients with previous TST may approach those seen in the general population. After 9 VVs and 3 EVs were performed, with UROLOGY 84 (6), 2014
2 of 6 patients (33.3%) undergoing at least 1 EV, the men demonstrated an overall patency of 83.3% after a median follow-up of 6.4 months, with 100% patency among men undergoing at least 1 VV. Remarkably, pregnancy was achieved by 50% during the short follow-up period. The results in the present case series compare quite closely with a recently published, large, contemporary series of 1229 VRs where the rate of at least 1 EV was 33%, and the overall patency rate was 84% after a median obstructive interval of 10 years.6 Limitations of the study include its retrospective nature, small sample size, and that all cases were performed at a single institution in an urban setting. Additionally, without a control arm, it is possible that some patients may have naturally achieved return of spermatogenesis over time,10 which would make the actual benefit of a 3-month course of medical testicular salvage therapy not entirely certain. Because previous TST dose, usage, and compliance were not available for all patients, specific conclusions regarding the exact exogenous testosterone exposure in the study population cannot be made. For all these reasons, the results must be cautiously interpreted in this context, and the recommendations for preoperative management herein should be used in centers of excellence by physicians already experienced with using testicular salvage therapy. The exact best regimen of testicular salvage therapy cannot be fully elucidated from this small cohort in the present study. These limitations in a study such as this reinforce the dire need for multicentered prospective data for the treatment of male fertility. We have demonstrated a proof of concept that men with suppression of their hypothalamic pituitary gonadal axis, potentially resulting in decreased spermatogenesis from exogenous testosterone use, can have spermatogenic recovery before VR and achieve favorable outcomes compared with other larger contemporary series. 1339
CONCLUSION Preoperative medical testicular salvage therapy with CC with or without hCG may improve the accuracy of the decision for the best method of reconstruction, VV or EV, therefore increasing the success of VR in patients with a history of TST. If managed appropriately, VR in men after TST can have outcomes comparable with the general population. References 1. Baillargeon J, Urban RJ, Ottenbacher KJ, et al. Trends in androgen prescribing in the United States, 2001 to 2011. JAMA Intern Med. 2013;173:1465-1466. 2. Mulligan T, Frick MF, Zuraw QC, et al. Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract. 2006;60:762-769. 3. Bassil N, Alkaade S, Morley JE. The benefits and risks of testosterone replacement therapy: a review. Ther Clin Risk Manag. 2009;5:427-448. 4. Eisenberg ML, Lipshultz LI. Estimating the number of vasectomies performed annually in the United States: data from the National Survey of Family Growth. J Urol. 2010;184:2068-2072. 5. Schwarzer JU. Vasectomy reversal using a microsurgical three-layer technique: one surgeon’s experience over 18 years with 1300 patients. Int J Androl. 2012;35:706-713. 6. Mui P, Perkins A, Burrows PJ, et al. The need for epididymovasostomy at vasectomy reversal plateaus in older vasectomies: a study of 1229 cases. Andrology. 2014;2:25-29. 7. Liu PY, Swerdloff RS, Anawalt BD, et al. Determinants of the rate and extent of spermatogenic suppression during hormonal male contraception: an integrated analysis. J Clin Endocrinol Metab. 2008; 93:1774-1783. 8. Roth MY, Ilani N, Wang C, et al. Characteristics associated with suppression of spermatogenesis in a male hormonal contraceptive trial using testosterone and Nestorone() gels. Andrology. 2013;1:899-905. 9. Manetti GJ, Honig SC. Update on male hormonal contraception: is the vasectomy in jeopardy? Int J Impot Res. 2010;22:159-170. 10. Liu PY, Swerdloff RS, Christenson PD, et al; Hormonal Male Contraception Summit Group. Rate, extent, and modifiers of spermatogenic recovery after hormonal male contraception: an integrated analysis. Lancet. 2006;367:1412-1420. 11. Jarow JP, Lipshultz LI. Anabolic steroid-induced hypogonadotropic hypogonadism. Am J Sports Med. 1990;18:429-431. 12. Moss JL, Crosnoe LE, Kim ED. Effect of rejuvenation hormones on spermatogenesis. Fertil Steril. 2013;99:1814-1820. 13. Katz DJ, Nabulsi O, Tal R, Mulhall JP. Outcomes of clomiphene citrate treatment in young hypogonadal men. BJU Int. 2012;110: 573-578. 14. Depenbusch M, von Eckardstein S, Simoni M, Nieschlag E. Maintenance of spermatogenesis in hypogonadotropic hypogonadal men with human chorionic gonadotropin alone. Eur J Endocrinol. 2002;147:617-624. 15. Kessaris DN, Wasserman P, Mellinger BC. Histopathological and cytopathological correlations of percutaneous testis biopsy and open testis biopsy in infertile men. J Urol. 1995;153:1151-1155. 16. Lipshultz LI, Rumohr JA, Bennett RC. Techniques for vasectomy reversal. Urol Clin North Am. 2009;36:375-382. 17. Sharma V, Le BV, Sheth KR, et al. Vasectomy demographics and postvasectomy desire for future children: results from a contemporary national survey. Fertil Steril. 2013;99:1880-1885. 18. Belker AM, Thomas AJ Jr, Fuchs EF, et al. Results of 1,469 microsurgical vasectomy reversals by the Vasovasostomy Study Group. J Urol. 1991;145:505-511. 19. Schiff J, Chan P, Li PS, et al. Outcome and late failures compared in 4 techniques of microsurgical vasoepididymostomy in 153 consecutive men. J Urol. 2005;174:651-655; quiz 801. 20. Smith RP, Khanna A, Kovac JR, et al. The significance of sperm heads and tails within the vasal fluid during vasectomy reversal. Indian J Urol. 2014;30:23-27.
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21. Coviello AD, Matsumoto AM, Bremner WJ, et al. Low-dose human chorionic gonadotropin maintains intratesticular testosterone in normal men with testosterone-induced gonadotropin suppression. J Clin Endocrinol Metab. 2005;90:2595-2602. 22. Hsieh TC, Pastuszak AW, Hwang K, Lipshultz LI. Concomitant intramuscular human chorionic gonadotropin preserves spermatogenesis in men undergoing testosterone replacement therapy. J Urol. 2013;189:647-650. 23. Kaminetsky J, Hemani ML. Clomiphene citrate and enclomiphene for the treatment of hypogonadal androgen deficiency. Expert Opin Investig Drugs. 2009;18:1947-1955. 24. Kaminetsky J, Werner M, Fontenot G, Wiehle RD. Oral enclomiphene citrate stimulates the endogenous production of testosterone and sperm counts in men with low testosterone: comparison with testosterone gel. J Sex Med. 2013;10:1628-1635.
EDITORIAL COMMENT Increased awareness about potential links between hypogonadism and metabolic syndrome, sexual dysfunction, mood disorders, and physical fitness in men leads to dramatic increase in utilization of testosterone replacement therapy (TRT).1 Some of the men treated with TRT either never had children or remarry and decide to have children with their new spouses.2 TRT by lowering serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) can lead to suppression of spermatogenesis. When human chorionic gonadotropin (hCG) was given with TRT, no suppression of spermatogenesis was observed providing convincing evidence that it is not TRT per se causing spermatogenic suppression but decrease in serum LH and FSH levels as a result of TRT. As no reliable method exists at this point to predict which men will suppress their sperm production while on TRT, it is wise to stop TRT to allow for LH and FSH recovery before vasectomy reversal for at least 3-6 months. However, if such an approach is necessary in men who have normal LH and FSH levels despite TRT is an area of debate. From a purely physiological perspective, if LH and FSH are within normal range then it would be unlikely that suppression of spermatogenesis would occur with normal LH and FSH levels despite of TRT.3 The choice of anastomosis during vasectomy reversal depends on the presence of sperms in the testicular end of vas, thus it is paramount that spermatogenesis is optimized before an attempt at reconstruction. The authors present their experience with 6 men who wished vasectomy reversal after TRT. Based on few published observational studies using clomiphene citrate and/or hCG to restore normal pituitary function in men with suppression of LH and FSH after TRT, authors used 25 mg with or without hCG 3 times a week to restore spermatogenesis. It is reassuring to notice that within minimum of 3 months of therapy with clomiphene citrate and/or hCG, sperms were identified in all 6 subjects. In addition, results of vasectomy reversal seem to reflect the type of anastomosis, with bilateral vasoepididymostomy resulting in azoospermia on follow-up semen analysis despite the presence of nonmotile sperms in epididymal fluid rather than the medical treatment used. This article brings an important issue of inherited risks of spermatogenic suppression in some if not all men on TRT. Lack of a control arm makes it unclear if any form of therapy other than stopping TRT and following FSH and LH is indeed necessary; hence, additional studies with larger numbers of subjects are needed. Clomiphene citrate and hCG treatments add additional cost and the need for injections in addition to not being Food and Drug Administrationeapproved treatments for male infertility. UROLOGY 84 (6), 2014
One cannot forget that clomiphene citrate has been linked to thromboembolic catastrophic events in males and females including stroke and pulmonary embolism (0.1-1%) as per FDA labeling.5 Thus, “wait and see” approach for 3 months with assessment of LH, FSH, testosterone, and testicular volume may be the prudent initial approach.4 Regardless of its limitations, authors should be applauded for their work as they bring an important issue that full history and physical examination and correction of underlying endocrinologic issues is mandatory in all men undergoing vasectomy reversal. Darius A. Paduch, M.D., Ph.D., James Buchanan Brady Urological Health Center, Weill Cornell Medical College, New York, NY
References 1. Corona G, Rastrelli G, Forti G, et al. Update in testosterone therapy for men. J Sex Med. 2011;8:639-654; quiz 655. 2. Giagulli VA, Triggiani V, Corona G, et al. Evidence-based medicine update on testosterone replacement therapy (TRT) in male hypogonadism: focus on new formulations. Curr Pharm Des. 2011;17:1500-1511. 3. Hsieh TC, Pastuszak AW, Hwang K, et al. Concomitant intramuscular human chorionic gonadotropin preserves spermatogenesis in men undergoing testosterone replacement therapy. J Urol. 2013;189:647-650. 4. Politou M, Gialeraki A, Merkouri E, et al. Central retinal vein occlusion secondary to clomiphene treatment in a male carrier of factor V Leiden. Genet Test Mol Biomarkers. 2009;13:155-157. 5. FDA labeling for clomiphene citrate. U.S. Food and Drug Administration. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/ 016131s026lbl.pdf. Accessed September 30, 2014.
unknown and likely exceedingly small. Indeed, recent literature attests to the safety of clomiphene citrate in hypogonadal men.2 Despite varying degrees of suppression of gonadotropins with TST that depend on many factors, most patients develop suppression of spermatogenesis ranging from oligospermia to azoospermia.3 Although two-thirds of men re-establish “normal” sperm concentrations of >20 million/mL within 6 months after discontinuation of TST, 10% require between 1 and 2 years to reach this result.3 Although the preoperative hormone assessment provides initial guidance, gonadotropin levels unfortunately do not always correlate with spermatogenesis while on TST.4 Although our study does not definitively prove that salvage therapy provides benefit for vasectomy reversal outcomes because of its study design, it does provide a proof of concept. The proposed alternative to salvage therapy of abrupt withdrawal of TST and “wait and see” has a myriad of drawbacks. First, it is impossible to know how long it will take for spermatogenesis to return, especially given the inability to assess progress via semen analysis. More importantly, abrupt withdrawal of TST is a cruel punishment leading to very severe hypogonadal symptoms. Because most patients on TST will become profoundly hypogonadal with serum levels <100 ng/dL after cessation of TST, the side effects could mirror those observed with androgen deprivation therapy for metastatic prostate cancer including severe sexual symptoms, extreme fatigability, and mood disorders. Finally, and more practically speaking, patients and their partners desiring vasectomy reversal for conception may not tolerate a prolonged waiting period of unknown length before surgery. The authors’ proposed algorithm provides a safe option to facilitate the preoperative recovery of spermatogenesis.
http://dx.doi.org/10.1016/j.urology.2014.06.082 UROLOGY 84: 1340e1341, 2014. 2014 Elsevier Inc.
REPLY Lost in the aftermath of the exponential growth of testosterone supplementation therapy (TST) are numerous downstream effects dealt with by the male fertility specialist. One previously unappreciated effect of TST is how the suppression of spermatogenesis creates a dilemma for the vasectomy reversal surgeon, potentially affecting the method of reconstruction, and thus, the outcomes. In the present article, preoperative testicular salvage therapy was used to optimize spermatogenesis before reversal. The proposed protocol for salvage therapy after discontinuation of TST routinely recommended included a combination of clomiphene citrate (25 mg daily) with human chorionic gonadotropin (3000 units subcutaneously every other day) for a period of 3 months before reassessment. In this study, because some patients elected to only use clomiphene, the population ultimately studied included men who received clomiphene with or without human chorionic gonadotropin. One of the primary criticisms cited in the editorial comment dealt with supposed “catastrophic events” resulting from the use of clomiphene citrate. However, in spite of decades of use, the only example stated was a case report detailing a single patient with factor V Leidenecarrier status presenting with 1 week of unilateral blurry vision after clomiphene therapy. The patient’s visual acuity was 20/60 on presentation, and after he was diagnosed with central retinal vein occlusion and treated with clopidogrel, his vision returned to normal.1 Notwithstanding case reports of thrombotic complications, the true incidence of such events is UROLOGY 84 (6), 2014
Robert M. Coward, M.D., Department of Urology, University of North Carolina School of Medicine, Chapel Hill, NC Douglas A. Mata, M.D., Scott Department of Urology, Baylor College of Medicine, Houston, TX; Department of Biochemistry and Cell Biology, Wiess School of Natural Sciences, Rice University, Houston, TX Ryan P. Smith, M.D., Department of Urology, School of Medicine, University of Virginia, Charlottesville, VA Jason R. Kovac, M.D., Ph.D., and Larry I. Lipshultz, M.D., Scott Department of Urology, Baylor College of Medicine, Houston, TX
References 1. Politou M, Gialeraki A, Merkouri E, et al. Central retinal vein occlusion secondary to clomiphene treatment in a male carrier of factor V Leiden. Genet Test Mol Biomarkers. 2009;13:155-157. 2. Moskovic DJ, Katz DJ, Akhavan A, et al. Clomiphene citrate is safe and effective for long-term management of hypogonadism. BJU Int. 2012;110:1524-1528. 3. Liu PY, Swerdloff RS, Christenson PD, et al; Hormonal Male Contraception Summit Group. Rate, extent, and modifiers of spermatogenic recovery after hormonal male contraception: an integrated analysis. Lancet. 2006;367:1412-1420. 4. Amory JK, Anawalt BD, Bremner WJ, Matsumoto AM. Daily testosterone and gonadotropin levels are similar in azoospermic and nonazoospermic normal men administered weekly testosterone: implications for male contraceptive development. J Androl. 2001;22:1053-1060.
http://dx.doi.org/10.1016/j.urology.2014.06.083 UROLOGY 84: 1341, 2014. 2014 Elsevier Inc.
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