FERTILITY AND STERILITY VOL. 70, NO. 1, JULY 1998 Copyright 1998 American Society for Reproductive Medicine Published by Elsevier Science Inc. Printed on acid-free paper in U.S.A. MALE FACTOR Induction of spermatogenesis and achievement of pregnancy after microsurgical in men with azoospermia and severe oligoasthenospermia Gerald J. Matthews, M.D.,* Ellen Dakin Matthews, R.N., and Marc Goldstein, M.D.* Center for Male Reproductive Medicine and Microsurgery, Department of Urology, The New York Hospital- Cornell Medical Center, New York, New York Received October 17, 1997; revised and accepted January 20, 1998. Reprint requests: Marc Goldstein, M.D., Department of Urology F- 900, The New York Hospital-Cornell Medical Center, 525 East 68th Street, New York, New York 10021 (FAX: 212-746- 8153). Supported by a grant from the American Foundation for Urologic Disease (G.J.M.). Presented at the Annual Meeting of the American Urological Association, Orlando, Florida, May 4 9, 1996. * The Population Council, Center for Biomedical Research, New York, New York. Department of Urology, New York Medical College, Valhalla, New York. 0015-0282/98/$19.00 PII S0015-0282(98)00108-3 Objective: To characterize treatment outcome after varicocele repair in men with azoospermia and severe oligoasthenospermia. Design: Prospective nonrandomized study. Setting: University-based medical center. Patient(s): Seventy-eight men with a palpable varicocele and absolute azoospermia (n 22) or severe oligoasthenospermia (n 56). Intervention(s): Microsurgical. Main Outcome Measure(s): Sperm count and pregnancy rate. Result(s): Twelve (55%) of the 22 men with azoospermia and 35 (69%) of the 51 men with zero motile sperm before surgery had motile sperm observed in their ejaculate after varicocele repair. The total number of motile sperm per ejaculate increased from 0.08 0.02 10 6 before to 7.2 2.3 10 6 afterward. Twenty-four men (31%) contributed to pregnancies leading to live births (15 unassisted [19%]), including 3 men with azoospermia preoperatively. Conclusion(s): Varicocele repair resulted in the induction or enhancement of spermatogenesis for most men with azoospermia or severe oligoasthenospermia. Unassisted pregnancies after varicocele repair in men with profound abnormalities of spermatogenesis are possible. Varicocele repair should be considered for all men with azoospermia and severe oligoasthenospermia. (Fertil Steril 1998;70:71 5. 1998 by American Society for Reproductive Medicine.) Key Words: Varicocele, azoospermia, infertility A varicocele is observed in 10% 20% of the general population (1 4), in 35% 40% of men with primary infertility (5, 6), and in up to 80% of men with secondary infertility (7, 8). Progressive deterioration of testicular function is clearly associated with varicocele (7, 9). The observation of azoospermia or severe oligoasthenospermia in association with a varicocele is common and is reported to range from 4.3% to 13.3% (10 12). Varicocele repair has been demonstrated in a prospective and controlled study to improve semen quality and fertility potential in men with oligospermia (13). The value, if any, of varicocele repair in men with azoospermia is unknown. Pregnancies established after varicocele repair by men with previous azoospermia have been reported anecdotally in series predating the availability of IVF and artery-sparing microsurgical techniques of varicocele repair (10, 14, 15). Given recent advances in IVF technology that use intracytoplasmic sperm injection (ICSI), a pregnancy now may be established with a single sperm (16, 17). For men with azoospermia or severe oligoasthenospermia, modest improvements in semen quality after varicocele repair may have a significant impact on a couples fertility options. To our knowledge, the present analysis represents the single largest series to date characterizing treatment outcomes after varicocele repair in men with azoospermia and severe oligoasthenospermia. 71
TABLE 1 Motile sperm rates and total number of motile sperm per ejaculate before and after, and postoperative pregnancy rates for women whose partners had azoospermia or severe oligoasthenospermia. No. (%) of patients with motile sperm Total no. of motile sperm ( 10 6 ) Group No. of subjects Before After Before After No. of pregnancies (%) Cohort 78 27 58 0.08 0.02 7.2 2.3* 24 (31) Azoospermia 22 NA 12 (55) NA 2.2 1.1 3 (14) Oligoasthenospermia 56 27 (48) 46 (82) 0.11 0.03 9.5 3.3* 21 (38) Note: NA not applicable. Values are expressed as means SEM unless indicated otherwise. * P 0.002 (total no. of motile sperm before treatment versus after treatment). MATERIALS AND METHODS Men with azoospermia or severe oligoasthenospermia were offered microsurgical varicocele repair. Enrollment criteria included completion of a basic infertility evaluation (18). A detailed history was obtained, and a complete physical examination was performed. A minimum duration of infertility, defined as failure to establish a pregnancy with appropriately timed and unprotected intercourse, of 12 months duration was required for study group entry. Testis volume was assessed by a single examiner (M.G.) with the use of an orchidometer. Testis atrophy was defined as any testis with a volume of 15 ml or a testis 25% or more smaller (volume/volume) than its contralateral mate. Endocrinologic evaluation included assay of serum FSH by ELISA (Boehringer-Mannheim, Indianapolis, IN). A minimum of 2 preoperative semen analyses were submitted. A minimum interval of 2 weeks separated all analyses. Semen specimens were collected and evaluated according to World Health Organization criteria (19). Only men with azoospermia or severe oligoasthenospermia were enrolled. Azoospermia was confirmed by the absence of sperm in the centrifuged semen pellet in all analyses submitted. Severe oligoasthenospermia was defined as 1 10 6 total motile sperm per ejaculate in all analyses submitted. Any man with a sperm density of 5 10 6 /ml or 1 10 6 total motile sperm per ejaculate in any analysis was excluded. All men were fructose positive. Only men with palpable varicoceles were enrolled. All men underwent a testicular artery and lymphatic-sparing technique of microsurgical (20). Men who underwent unilateral and bilateral varicocelectomies were included. Men who underwent a simultaneous procedure for relief of obstruction (vasovasostomy, vasoepididymostomy, ejaculatory duct resection, or epididymal sperm aspiration) were excluded. Postoperative evaluation included serial semen analyses at 3-month intervals for the first year after and every 6 months thereafter. Enrollment criteria for men who have yet to contribute to a pregnancy included a minimum of 3 months of follow-up and one semen analysis. Seventy-eight (10.5%) of 713 men who underwent a procedure during the review period (January 1991 to October 1996) met the enrollment criteria. The mean ( SD) duration of follow-up was 10.3 0.7 months. Sixty-four men (82%) underwent a bilateral procedure (17 of 22 with azoospermia, 47 of 56 with severe oligoasthenospermia), 12 (15%) underwent a unilateral left-sided procedure, and 2 (3%) underwent a unilateral right-sided procedure. The varicocele was considered large (visible when standing, grade 3) in 40 men (51%), moderate-sized (visible with Valsalva s maneuver when standing, grade 2) in 29 men (37%), and small (palpable with Valsalva s maneuver when standing, grade 1) in 9 men (12%). All values are reported as means SEM. Student s t-test and the 2 test were used for statistical analyses. RESULTS Twenty-two men with azoospermia and 56 men with severe oligoasthenospermia underwent microsurgical. The group with severe oligoasthenospermia included 29 men with zero total motile sperm and 27 men with sperm counts of 1 10 6. Eight (14%) of the 56 men with severe oligoasthenospermia had an initial preoperative semen analysis that demonstrated azoospermia. After surgery, the mean ( SD) postoperative sperm count for the group with severe oligoasthenospermia was 9.5 3.3 10 6 (P 0.007) (Table 1). Forty-four men (79%) demonstrated postoperative improvement in semen quality. Thirty-one men (55%) achieved mean ( SD) postoperative sperm counts of 1 10 6, and 15 men (27%) achieved mean postoperative sperm counts of 5 10 6. Thirty-five (69%) of 51 men with zero motile sperm before varicocele repair (12 of 22 with azoospermia, 23 of 29 with severe oligoasthenospermia) had motile sperm observed in postoperative semen analyses. The mean ( SD) 72 Matthews et al. Varicocelectomy in men with azoospermia Vol. 70, No. 1, July 1998
sperm count for the group with azoospermia after varicocele repair was 2.2 1.1 10 6 (P 0.06) (Table 1). Seven (33%) of 22 men with azoospermia achieved mean postoperative sperm counts of 1 10 6. No statistically significant difference was observed between the percentage of men with azoospermia (33%) and severe oligoasthenospermia (55%) who achieved post sperm counts of 1 10 6 (P NS). Twenty-four (31%) of the cohort of 78 men have contributed to pregnancies leading to live births after (Table 1). Fifteen of the pregnancies (19%) were unassisted and 9 (12%) were achieved with IUI (n 3), IVF (n 1), or IVF with ICSI (n 5). Unassisted pregnancy rates (PRs) for the partners of men with oligoasthenospermia, oligospermia with nonmotile sperm only, and azoospermia were 30% (8/27), 17% (5/29), and 9% (2/22), respectively. The mean ( SD) and median intervals to pregnancy after microsurgical for the 15 unassisted pregnancies were 11.4 1.9 months and 8 months, respectively. Seventeen (45%) of 38 men with post sperm counts of 1 10 6 have contributed to a pregnancy (11 unassisted [29%], 6 assisted [16%]). Seven (23%) of 31 men with sperm counts of 1 10 6 have contributed to a pregnancy (4 unassisted, 3 assisted). The spontaneous PRs for the partners of men with sperm counts of 1 10 6 (29%) and 1 10 6 (13%) after were not statistically different (P NS). Three men with initial azoospermia have contributed to pregnancies (2 unassisted, 1 assisted by IVF with ICSI). The mean preoperative FSH level for the cohort was 17.8 1.8 miu/ml (normal, 1.5 9.0 miu/ml). The FSH levels in the groups with azoospermia (19.6 4.5 miu/ml) and severe oligoasthenospermia (17.1 1.9 miu/ml) were similar (P NS). Fifty-two men (67%) had elevated preoperative serum FSH levels. Serum FSH levels were more than twice the upper limit of normal in 29 men and more than 3 times the upper limit of normal in 19 men. Preoperative FSH levels in the men who did (16 2 miu/ml) and did not (22.3 3.9 miu/ml) show improvement in semen parameters after were not significantly different (P NS). The unassisted PRs for the partners of men with normal preoperative FSH levels, FSH levels less than twice the upper limit of normal, and FSH levels more than twice the upper limit of normal were 19%, 17%, and 21%, respectively; the difference was not statistically significant. Atrophic testes (16 unilateral, 19 bilateral) were observed in 35 men (44%). Improvement in semen parameters was observed in 35 (81%) of the 43 men without atrophic testes and 26 (74%) of the 35 men with atrophic testes (P NS). The unassisted PR for the partners of men without atrophic testes (21%) was similar to that of the partners of men with atrophic testes (17%). The unassisted PRs for the partners of men with bilateral (16%) and unilateral (19%) testicular atrophy were similar. DISCUSSION Azoospermia and severe oligoasthenospermia present a significant barrier to the male factor contribution to an unassisted pregnancy. Treatment options for men with nonobstructive azoospermia who desire to contribute to a pregnancy with their own biologic materials include testicular sperm extraction with ICSI. Similarly, for men with severe oligoasthenospermia, options include the use of ICSI with ejaculated sperm or ICSI with testicular sperm extraction. With either option, the couple relies on assisted reproductive techniques in initiating a pregnancy. This study suggests that men who have nonobstructive azoospermia or severe oligoasthenospermia in association with a palpable varicocele may expand their reproductive options after varicocele repair. Semen parameters were improved for most men, and nearly 20% of couples achieved an unassisted pregnancy. Data supporting the efficacy of varicocele repair in improving semen parameters and PRs are compelling (20 22). The only randomized controlled study of varicocele repair, however, excluded men with sperm concentrations of 5 10 6 /ml (13). The data concerning varicocele repair in men with azoospermia or severe oligoasthenospermia have been conflicting (10, 11, 14). The occurrence of azoospermia or severe oligoasthenospermia in association with a clinically palpable varicocele is common. We observed azoospermia or severe oligoasthenospermia ( 1 10 6 total motile sperm) in association with a clinically palpable varicocele in 6% of a population of 500 consecutively seen men presenting for infertility evaluation and 12% of men with a clinically palpable varicocele. A higher rate of bilateral varicoceles (82%) and large (grade 3) varicoceles (51%) was observed than is expected in an unselected cohort of men presenting with varicocele-related infertility. Because the current series presents only men with profound abnormalities in sperm production and is drawn from the lowest 10% (based on sperm count) of a larger cohort of men with varicocele, selection bias may be inevitable. No difference was noted in the rate of bilaterality between men with azoospermia (77%) and men with severe oligoasthenospermia (84%). For the present analysis, improvement in semen quality was observed in 72% of the men and spontaneous, unassisted pregnancies were observed in 19.3% of the couples. Pregnancy rates were maximized by IVF with ICSI. Of the 51 men with azoospermia or zero motile sperm, 69% demonstrated motile sperm in their ejaculate and 24% contributed to pregnancies (7 unassisted, 5 assisted) after varicocele repair. Among the men with azoospermia, 55% were ob- FERTILITY & STERILITY 73
served to have motile sperm in their ejaculate after surgery and 3 contributed to pregnancies (2 unassisted). Observations drawn from the present analysis are tempered by the absence of a control (nontreatment) arm. The spontaneous PR among the partners of men with an untreated unilateral left-sided varicocele and sperm counts between 5 10 6 /ml and 20 10 6 /ml is reported to be 10% at 12 months (13). For the present analysis, a minimum duration of infertility of 12 months was required for study entry. The mean ( SD) interval between initial evaluation and varicocele repair was 11.6 0.8 months. Although contribution to an unassisted pregnancy by a man with azoospermia or zero motile sperm cannot be excluded, this is an exceedingly remote possibility. Similarly, the data do not address a longitudinal analysis of azoospermia or severe oligoasthenospermia. For the present cohort, a mean ( SD) interval of 6.8 2.2 months elapsed between the first and last semen analyses before varicocele repair. During this interval, 8 (27%) of 30 men with initial semen analyses demonstrating azoospermia were observed to have sperm in a subsequent specimen; however, only 2 demonstrated motile sperm. In contrast, among the 22 men with azoospermia who underwent varicocele repair, the motile sperm recovery rate was 55%. Advances in assisted reproductive technology have enabled the establishment of pregnancy with only a single sperm. Modest improvements in spermatogenesis may have a profound effect on a couples reproductive options. Because varicocele is associated with impaired spermatogenesis, repair of a varicocele should optimize the testicular environment for spermatogenesis. Recent reports of testicular sperm extraction in men with nonobstructive azoospermia indicate that sperm are recovered from testicular tissue in 50% 60% of such men (23 25). Our observation of a 55% recovery rate of motile sperm in the ejaculate of men with previous azoospermia after varicocele repair suggests that enhances spermatogenesis even for men with profound abnormalities in sperm production. Ten of 22 men with azoospermia in our study underwent testis biopsy before varicocele repair. In 7, a maturation arrest or hypospermatogenesis pattern was identified. All these men were found to have motile sperm after varicocele repair. Three men with Sertoli cell only patterns still had azoospermia after varicocele repair. This current cohort is too small to obtain statistically significant results. In addition, the value of varicocele repair in men with azoospermia who have a Sertoli cell only histologic pattern and who still have azoospermia after varicocele repair cannot be assessed fully without a postoperative testis biopsy. Although testis biopsy in the setting of severe oligoasthenospermia is useful in distinguishing production abnormalities from obstructive lesions, histologic evaluation of the biopsy specimen offered no prognostic benefit for the current cohort of men with severe oligoasthenospermia. Varicocele repair in men with severe oligoasthenospermia or in select men with nonobstructive azoospermia offers a viable alternative to testicular sperm extraction and ICSI or donor insemination and an opportunity to contribute to an unassisted pregnancy. An elevated serum FSH level has been reported as a contraindication to varicocele repair (26). The present analysis, however, does not support this recommendation. To the contrary, we observed that postoperative semen quality and contribution to a pregnancy were unrelated to serum FSH levels. Similarly, the presence of unilateral or bilateral testis atrophy did not appear to be related to treatment outcome. Steckel et al. (27) reported that improvement in semen quality after varicocele repair in men with unilateral leftsided varicoceles was related inversely to varicocele grade. For the current study, improvements in semen quality and contribution to a pregnancy were unrelated to varicocele grade. Collectively, our observations suggest that in men with azoospermia or severe oligoasthenospermia who have a palpable varicocele, treatment response is unrelated to preoperative serum FSH levels, the presence of testis atrophy, or varicocele grade. Induction of spermatogenesis with the appearance of motile sperm in the ejaculate occurred in 55% of men with absolute azoospermia and 82% of men with severe oligoasthenospermia after repair of a palpable varicocele. Preoperative serum FSH levels, the presence of testis atrophy, and varicocele grade did not predict treatment outcome. Pregnancies were achieved for 31% of the cohort, without assistance in 19% and with the use of assisted reproductive techniques in 12%. We recommend that varicocele repair be considered for all men with azoospermia or severe oligoasthenospermia who have a clinically palpable varicocele. The value of varicocele repair in men with azoospermia who have a Sertoli cell only histologic pattern is uncertain. References 1. Johnson DE, Pohl DR, Rivera-Correa H. Varicocele: an innocuous condition. South Med J 1970;63:34 6. 2. MacLeod J. Further observations in the role of varicocele in human male infertility. Fertil Steril 1969;20:545 63. 3. Vestroppen GR, Steeno OP. Varicocele and pathogenesis of the associated subfertility: a review of various theories. II. Results of surgery. Andrologia 1977;9:293 300. 4. Greenberg SH. Varicocele and male fertility. Fertil Steril 1977;28:699 706. 5. Dubin L, Amelar RD. Etiologic factors in 1294 consecutive cases of male infertility. Fertil Steril 1971;22:469 74. 6. Greenberg SH, Lipshultz LI, Wein AJ. Experience with 425 subfertile male patients. J Urol 1978;119:507 10. 7. Gorelick JI, Goldstein M. Loss of fertility in men with varicocele. Fertil Steril 1993;59:613 6. 8. Witt MA, Lipshultz LI. Varicocele: a progressive or static lesion? Urology 1993;42:541 3. 9. Chehval MJ, Purcell MH. Deterioration of semen parameters over time in men with untreated varicocele: evidence of progressive testicular damage. Fertil Steril 1992;57:174 7. 10. Czaplicki M, Bablok L, Janczewski Z. Varicocelectomy in patients with azoospermia. Arch Androl 1979;3:51 5. 11. D Ottavio G, Lagana A, Pozza D, Mezzetti M, Toscana C. Risultati del 74 Matthews et al. Varicocelectomy in men with azoospermia Vol. 70, No. 1, July 1998
trattamanto chirugico di varicocelectomia in pazienti con azoospermia. Minerva Chir 1987;42:489 91. 12. Pontonnier F, Mansat A, Mieusset R, Malonga G, Gautier JR, Ioualalen A. Varicocélectomie pour infertilité est plus efficace dans les cas de numération inférieure à cinq millions/ml. Ann Urol 1986;20:249 51. 13. Magdar I, Weissenberg R, Lunenfeld B, Karasik A, Goldwasser B. Controlled trial of high spermatic vein ligation for varicocele in infertile men. Fertil Steril 1995;63:120 4. 14. Mehan DJ. Results of ligation of internal spermatic in the treatment of infertility in azoospermic patients. Fertil Steril 1976;27:110 4. 15. Tulloch WS. Consideration of sterility; subfertility in the male. Edinburgh Med J 1952;59:29. 16. Palermo G, Joris H, Devroey P, Van Steirteghen AC. Pregnancies after intracytoplasmic injection of single spermatozoon into an oocyte. Lancet 1992;340:17. 17. Schlegel PN, Berkeley AS, Goldstein M, Cohen J, Alikani M, Adler A, et al. Epididymal micropuncture with in vitro fertilization and oocyte micromanipulation for the treatment of unreconstructable azoospermia. Fertil Steril 1994;61:895 901. 18. Goldstein M. New tests in the evaluation of male infertility. In: Ball TP, editor. AUA update series. Houston (TX): AUA Office of Education, 1984:3. 19. World Health Organization. Laboratory manual for the examination of human semen and semen-cervical mucus interaction. 3rd ed. New York: Cambridge University Press, 1993: 20. Goldstein M, Gilbert BR, Dicker AP, Dwosh J, Gnecco C. Microsurgical inguinal with delivery of the testis: an artery and lymphatic sparing technique. J Urol 1992;148:1808 11. 21. Dubin L, Amelar RD. Varicocelectomy: 986 cases in a twelve-year study. Urology 1977;10:446 8. 22. Brown JS. Varicocelectomy in the subfertile male: a ten-year experience with 295 cases. Fertil Steril 1976;27:1046 53. 23. Schlegel PN, Palermo GD, Goldstein M, Menendez S, Zaninovic N, Veeck LL, et al. Testicular sperm extraction with intracytoplasmic sperm injection for nonobstructive azoospermia. Urology 1997;49: 434 40. 24. Silber SJ, Van Steirteghem AC, Liu J, Nagy Z, Tournaye H, Devroey P. High fertilization and pregnancy rate after intracytoplasmic sperm injection with spermatozoa obtained from testicular biopsy. Hum Reprod 1995;10:148 52. 25. Devroey P, Liu J, Nagy Z, Gossens A, Tournaye H, Camus H, et al. Pregnancies after testicular sperm extraction and intracytoplasmic sperm injection in non-obstructive azoospermia. Hum Reprod 1995;10: 1457 60. 26. Miċiċ S, Illiċ V,Iśvaneski M. Correlation of hormone and histologic parameters in infertile men with varicocele. Urol Int 1983;38:187 90. 27. Steckel J, Dicker AP, Goldstein M. Relationship between varicocele size and response to. J Urol 1993;149:769 71. FERTILITY & STERILITY 75