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Clinical endocrinology
Feb, 2025;102 (2): 167-177.

Efficacy of Gonadotropin Treatment for Induction of Spermatogenesis in Men With Pathologic Gonadotropin Deficiency: A Meta-Analysis.

Christopher A Muir, Ting Zhang, Veena Jayadev, Ann J Conway, David J Handelsman
Author Information
  1. Christopher A Muir: Department of Andrology, Concord Repatriation General Hospital, Sydney, New South Wales, Australia. ORCID
  2. Ting Zhang: Department of Andrology, Concord Repatriation General Hospital, Sydney, New South Wales, Australia.
  3. Veena Jayadev: Department of Andrology, Concord Repatriation General Hospital, Sydney, New South Wales, Australia.
  4. Ann J Conway: Department of Andrology, Concord Repatriation General Hospital, Sydney, New South Wales, Australia.
  5. David J Handelsman: Department of Andrology, Concord Repatriation General Hospital, Sydney, New South Wales, Australia.
PMID: 39445789 DOI: 10.1111/cen.15151

Abstract

INTRODUCTION: Hypogonadotropic hypogonadism (HH) is a treatable cause of nonobstructive azoospermic male infertility. Gonadotropin treatment can successfully induce spermatogenesis in most patients, although comprehensive quantitative summary data on spermatogenic outcomes like those required to induce pregnancy is lacking in the literature.
MATERIALS AND METHODS: Systematic review and meta-analysis of outcomes related to male reproductive function following gonadotropin treatment.
RESULTS: Our search strategy identified 41 studies encompassing 1673 patients with a mean age of 25 (�����5)���years. Average sperm concentration achieved after a median of 18���months of gonadotropin treatment was 11.6���M/mL of ejaculate (95% CI 8.4-14.9). Sperm concentrations >���0, >���1, >���5, >���10 and >���20���M/mL were achieved by 78%, 55%, 36%, 24% and 15% of patients, respectively. Mean sperm output and the proportion of patients achieving all sperm thresholds were significantly greater following combined hCG/FSH treatment compared with hCG monotherapy. When compared by diagnosis, patients with congenital HH (CHH) had significantly lower mean sperm output compared with patients with hypopituitarism or mixed patient cohorts that did not differentiate between CHH and hypopituitarism. Treatment-related increases in testosterone and testicular volume (TV) were not different between hCG and combined hCG/FSH treated patients, although increases in TV were lower in men with CHH compared with those with hypopituitarism.
CONCLUSIONS: Gonadotropin treatment successfully induced spermatogenesis in most men with pathological Gonadotropin Deficiency. Sperm outputs more consistent with those typically needed to induce a natural pregnancy were less commonly achieved. Despite similar effects on serum testosterone and TV, combined hCG/FSH appeared more efficacious than hCG alone at inducing spermatogenesis.

References

  1. M. L. Eisenberg, S. C. Esteves, D. J. Lamb, et al., ���Male Infertility,��� Nature Reviews Disease Primers 9, no. 1 (2023): 49.
  2. S. Barak and H. W. G. Baker, ���Clinical Management of Male Infertility,��� in Endotext, eds. K. R. Feingold, B. Anawalt, M. R. Blackman, et al. (South Dartmouth, MA: MDText.com Inc., 2016).
  3. J. Young, C. Xu, G. E. Papadakis, et al., ���Clinical Management of Congenital Hypogonadotropic Hypogonadism,��� Endocrine Reviews 40, no. 2 (2019): 669���710.
  4. E. C. Alexander, D. Faruqi, R. Farquhar, et al., ���Gonadotropins for Pubertal Induction in Males With Hypogonadotropic Hypogonadism: Systematic Review and Meta���Analysis,��� European Journal of Endocrinology 190, no. 1 (2024): S1���S11.
  5. A. A. Dwyer, T. Raivio, and N. Pitteloud, ���Gonadotrophin Replacement for Induction of Fertility in Hypogonadal Men,��� Best Practice & Research Clinical Endocrinology & Metabolism 29, no. 1 (2015): 91���103.
  6. P. Y. Liu, H. W. G. Baker, V. Jayadev, M. Zacharin, A. J. Conway, and D. J. Handelsman, ���Induction of Spermatogenesis and Fertility during Gonadotropin Treatment of Gonadotropin���Deficient Infertile Men: Predictors of Fertility Outcome,��� Journal of Clinical Endocrinology & Metabolism 94, no. 3 (2009): 801���808.
  7. G. Rastrelli, G. Corona, E. Mannucci, and M. Maggi, ���Factors Affecting Spermatogenesis Upon Gonadotropin���Replacement Therapy: A Meta���Analytic Study,��� Andrology 2, no. 6 (2014): 794���808.
  8. Z. Liu, J. Mao, X. Wu, et al., ���Efficacy and Outcome Predictors of Gonadotropin Treatment for Male Congenital Hypogonadotropic Hypogonadism: A Retrospective Study of 223 Patients,��� Medicine 95, no. 9 (2016): e2867.
  9. T. H. Barker, C. B. Migliavaca, C. Stein, et al., ���Conducting Proportional Meta���Analysis in Different Types of Systematic Reviews: A Guide for Synthesisers of Evidence,��� BMC Medical Research Methodology 21 (2021): 189.
  10. X. Wan, W. Wang, J. Liu, and T. Tong, ���Estimating the Sample Mean and Standard Deviation From the Sample Size, Median, Range and/or Interquartile Range,��� BMC Medical Research Methodology 14 (2014): 135.
  11. G. Schwarzer, ���Meta: An R Package for Meta���Analysis,��� R News 7, no. 3 (2007): 40���45.
  12. H. Abbasi, A. Dadkhah, D. Moshtaghi, and M. A. Hamiditabar, ���Gonadotropins in Infertile Men With Idiopathic Hypogonadotropic Hypogonadism,��� International Journal of Fertility and Sterility 2, no. 3 (2008): 113���114.
  13. R. Barrio, D. de Luis, M. Alonso, A. Lamas, and J. C. Moreno, ���Induction of Puberty With Human Chorionic Gonadotropin and Follicle���Stimulating Hormone in Adolescent Males With Hypogonadotropic Hypogonadism,��� Fertility and Sterility 71, no. 2 (1999): 244���248.
  14. P. M. G. Bouloux, E. Nieschlag, H. G. Burger, et al., ���Induction of Spermatogenesis by Recombinant Follicle���Stimulating Hormone (Puregon) in Hypogonadotropic Azoospermic Men Who Failed to Respond to Human Chorionic Gonadotropin Alone,��� Journal of Andrology 24, no. 4 (2003): 604���611.
  15. D. Buchter, H. Behre, S. Kliesch, and E. Nieschlag, ���Pulsatile GnRH or Human Chorionic Gonadotropin/Human Menopausal Gonadotropin as Effective Treatment for Men With Hypogonadotropic Hypogonadism: A Review of 42 Cases,��� European Journal of Endocrinology 139, no. 3 (1998): 298���303.
  16. S. Burgues and M. D. Calderon, ���Subcutaneous Self���Administration of Highly Purified Follicle Stimulating Hormone and Human Chorionic Gonadotrophin for the Treatment of Male Hypogonadotrophic Hypogonadism. Spanish Collaborative Group on Male Hypogonadotropic Hypogonadism,��� Human Reproduction 12, no. 5 (1997): 980���986.
  17. A. S. Burris, H. W. Rodbard, S. J. Winters, and R. J. Sherins, ���Gonadotropin Therapy in Men With Isolated Hypogonadotropic Hypogonadism: The Response to Human Chorionic Gonadotropin Is Predicted by Initial Testicular Size,��� Journal of Clinical Endocrinology & Metabolism 66, no. 6 (1988): 1144���1151.
  18. A. S. Burris, R. V. Clark, D. J. Vantman, and R. J. Sherins, ���A Low Sperm Concentration Does Not Preclude Fertility in Men With Isolated Hypogonadotropic Hypogonadism After Gonadotropin Therapy,��� Fertility and Sterility 50, no. 2 (1988): 343���347.
  19. B. Cangiano, G. Goggi, S. Federici, et al., ���Predictors of Reproductive and Non���Reproductive Outcomes of Gonadotropin Mediated Pubertal Induction in Male Patients With Congenital Hypogonadotropic Hypogonadism (Chh),��� Journal of Endocrinological Investigation 44 (2021): 2445���2454.
  20. Y.���W. Chen, Y.���H. Niu, H. Xu, et al., ���Testosterone Undecanoate Supplementation Together With Human Chorionic Gonadotropin Does Not Impair Spermatogenesis in Males With Isolated Hypogonadotropic Hypogonadism: A Retrospective Study,��� Asian Journal of Andrology 21, no. 4 (2019): 413.
  21. O. Efesoy, S. ��ayan, and E. Akbay, ���The Efficacy of Recombinant Human Follicle���Stimulating Hormone in the Treatment of Various Types of Male���Factor Infertility at a Single University Hospital,��� Journal of Andrology 30, no. 6 (2009): 679���684.
  22. Group EMHS, ���Efficacy and Safety of Highly Purified Urinary Follicle���Stimulating Hormone With Human Chorionic Gonadotropin for Treating Men With Isolated Hypogonadotropic Hypogonadism,��� Fertility and Sterility 70, no. 2 (1998): 256���262.
  23. D. M. Finkel, J. L. Phillips, and P. J. Snyder, ���Stimulation of Spermatogenesis by Gonadotropins in Men With Hypogonadotropic Hypogonadism,��� New England Journal of Medicine 313, no. 11 (1985): 651���655.
  24. H. Fuse, T. Akashi, T. Kazama, and T. Katayama, ���Gonadotropin Therapy in Males With Hypogonadotropic Hypogonadism: Factors Affecting Induction of Spermatogenesis After Gonadotropin Replacement,��� International Urology and Nephrology 28 (1996): 367���374.
  25. F. Gattuccio, O. D'alia, G. L. Bartolo, et al., ���Gonadotropic Therapy in Men With Hypogonadotropic Hypogonadism,��� Journal of Andrology 5, no. S2 (1984): 106���110.
  26. J. M. W. Kirk, M. O. Savage, D. B. Grant, P. M. G. Bouloux, and G. M. Besser, ���Gonadal Function and Response to Human Chorionic and Menopausal Gonadotrophin Therapy in Male Patients With Idiopathic Hypogonadotrophic Hypogonadism,��� Clinical Endocrinology 41, no. 1 (1994): 57���63.
  27. S. Kliesch, H. M. Behre, and E. Nieschlag, ���High Efficacy of Gonadotropin or Pulsatile Gonadotropin���Releasing Hormone Treatment in Hypogonadotropic Hypogonadal Men,��� European Journal of Endocrinology 131, no. 4 (1994): 347���354.
  28. A. W. C. Kung, Y. Y. Zhong, K. S. L. Lam, and C. Wang, ���Induction of Spermatogenesis With Gonadotrophins in Chinese Men With Hypogonadotrophic Hypogonadism,��� International Journal of Andrology 17, no. 5 (1994): 241���247.
  29. S. B. Ley and J. M. Leonard, ���Male Hypogonadotropic Hypogonadism: Factors Influencing Response to Human Chorionic Gonadotropin and Human Menopausal Gonadotropin, Including Prior Exogenous Androgens,��� Journal of Clinical Endocrinology & Metabolism 61, no. 4 (1985): 746���752.
  30. L. Liu, N. Chaudhari, D. Corle, and R. J. Sherins, ���Comparison of Pulsatile Subcutaneous Gonadotropin���Releasing Hormone and Exogenous Gonadotropins in the Treatment of Men With Isolated Hypogonadotropic Hypogonadism,��� Fertility and Sterility 49, no. 2 (1988): 302���308.
  31. W. Ma, J. Mao, M. Nie, et al., ���Gonadotropin Therapy Once a Week for Spermatogenesis in Hypogonadotropic Hypogonadism,��� Endocrine Practice 27, no. 11 (2021): 1119���1127.
  32. A. M. Matsumoto, P. J. Snyder, S. Bhasin, et al., ���Stimulation of Spermatogenesis With Recombinant Human Follicle���Stimulating Hormone (Follitropin Alfa; Gonal���F��): Long���Term Treatment in Azoospermic Men With Hypogonadotropic Hypogonadism,��� Fertility and Sterility 92, no. 3 (2009): 979���990.
  33. Y. Miyagawa, A. Tsujimura, K. Matsumiya, et al., ���Outcome of Gonadotropin Therapy for Male Hypogonadotropic Hypogonadism at University Affiliated Male Infertility Centers: A 30���Year Retrospective Study,��� Journal of Urology 173, no. 6 (2005): 2072���2075.
  34. E. Nieschlag, P.���M. G. Bouloux, B. J. Stegmann, et al., ���An Open���Label Clinical Trial to Investigate the Efficacy and Safety of Corifollitropin Alfa Combined With hCG in Adult Men With Hypogonadotropic Hypogonadism,��� Reproductive Biology and Endocrinology 15, no. 1 (2017): 17.
  35. N. B. Oldereid, T. ��byholm, and T. G. Tanbo, ���Spermatogenesis and Fertility Outcome in Male Hypogonadotrophic Hypogonadism,��� Human Fertility 13, no. 2 (2010): 83���89.
  36. M. Ortac, M. Hidir, E. Salabas, et al., ���Evaluation of Gonadotropin���Replacement Therapy in Male Patients With Hypogonadotropic Hypogonadism,��� Asian Journal of Andrology 21, no. 6 (2019): 623.
  37. J. Rohayem, N. Sinthofen, E. Nieschlag, S. Kliesch, and M. Zitzmann, ���Causes of Hypogonadotropic Hypogonadism Predict Response to Gonadotropin Substitution in Adults,��� Andrology 4, no. 1 (2016): 87���94.
  38. J. Rohayem, B. P. Hauffa, M. Zacharin, S. Kliesch, M. Zitzmann, Group��� GAHHS, et al., ���Testicular Growth and Spermatogenesis: New Goals for Pubertal Hormone Replacement in Boys With Hypogonadotropic Hypogonadism? A Multicentre Prospective Study of hCG/rFSH Treatment Outcomes during Adolescence,��� Clinical Endocrinology 86, no. 1 (2017): 75���87.
  39. W. Saal, J. Happ, U. Cordes, R. P. Baum, and M. Schmidt, ���Subcutaneous Gonadotropin Therapy in Male Patients With Hypogonadotropic Hypogonadism,��� Fertility and Sterility 56, no. 2 (1991): 319���324.
  40. J. Schopohl, G. Mehltretter, R. von Zumbusch, T. Eversmann, and K. von Werder, ���Comparison of Gonadotropin���Releasing Hormone and Gonadotropin Therapy in Male Patients With Idiopathic Hypothalamic Hypogonadism,��� Fertility and Sterility 56, no. 6 (1991): 1143���1150.
  41. R. Shah, V. Patil, V. Sarathi, et al., ���Prior Testosterone Replacement Therapy May Impact Spermatogenic Response to Combined Gonadotropin Therapy in Severe Congenital Hypogonadotropic Hypogonadism,��� Pituitary 24 (2021): 326���333.
  42. A. A. Sinisi, D. Esposito, L. Maione, et al., ���Seminal Anti���Mullerian Hormone Level Is a Marker of Spermatogenic Response During Long���Term Gonadotropin Therapy in Male Hypogonadotropic Hypogonadism,��� Human Reproduction 23, no. 5 (2008): 1029���1034.
  43. A. A. Sinisi, D. Esposito, G. Bellastella, et al., ���Efficacy of Recombinant Human Follicle Stimulating Hormone at Low Doses in Inducing Spermatogenesis and Fertility in Hypogonadotropic Hypogonadism,��� Journal of Endocrinological Investigation 33 (2010): 618���623.
  44. E. Vicari, A. Mongio��, A. E. Calogero, et al., ���Therapy With Human Chorionic Gonadotrophin Alone Induces Spermatogenesis in Men With Isolated Hypogonadotrophic Hypogonadism���Long���Term Follow���Up,��� International Journal of Andrology 15, no. 4 (1992): 320���329.
  45. M. Zacharin, M. A. Sabin, V. V. Nair, and P. Dagabdhao, ���Addition of Recombinant Follicle���Stimulating Hormone to Human Chorionic Gonadotropin Treatment in Adolescents and Young Adults With Hypogonadotropic Hypogonadism Promotes Normal Testicular Growth and May Promote Early Spermatogenesis,��� Fertility and Sterility 98, no. 4 (2012): 836���842.
  46. M. Zhang, G. Tong, Y. Liu, et al., ���Sequential Versus Continual Purified Urinary Fsh/Hcg in Men With Idiopathic Hypogonadotropic Hypogonadism,��� Journal of Clinical Endocrinology & Metabolism 100, no. 6 (2015): 2449���2455.
  47. L. Zhang, K. Cai, Y. Wang, et al., ���The Pulsatile Gonadorelin Pump Induces Earlier Spermatogenesis Than Cyclical Gonadotropin Therapy in Congenital Hypogonadotropic Hypogonadism Men,��� American Journal of Men's Health 13, no. 1 (2019): 1557988318818280.
  48. J. Zhang, Y. Zhu, R. Zhang, et al., ���Pulsatile Gonadotropin���Releasing Hormone Therapy Is Associated With Better Spermatogenic Outcomes Than Gonadotropin Therapy in Patients With Pituitary Stalk Interruption Syndrome,��� Endocrine Practice 30, no. 2 (2024): 146���154.
  49. T. Raivio, A. M. Wikstr��m, and L. Dunkel, ���Treatment of Gonadotropin���Deficient Boys With Recombinant Human FSH: Long���Term Observation and Outcome,��� European Journal of Endocrinology 156 (2007): 105���111.
  50. A. Okuyama, M. Nakamura, M. Namiki, et al., ���Testicular Responsiveness to Long���Term Administration of hCG and hMG in Patients With Hypogonadotrophic Hypogonadism,��� Hormone Research 23 (1986): 21���30.
  51. T. G. Cooper, E. Noonan, S. Von Eckardstein, et al., ���World Health Organization Reference Values for Human Semen Characteristics,��� Human Reproduction Update 16, no. 3 (2010): 231���245.
  52. J. Rohayem, E. C. Alexander, S. Heger, A. Nordenstr��m, and S. R. Howard, ���Mini���Puberty, Physiological and Disordered: Consequences and Potential for Therapeutic Replacement,��� Endocrine Reviews 45 (2024): 460���492.
  53. P. Y. Liu, R. S. Swerdloff, P. D. Christenson, D. J. Handelsman, and C. Wang, ���Rate, Extent, and Modifiers of Spermatogenic Recovery After Hormonal Male Contraception: An Integrated Analysis,��� Lancet 367, no. 9520 (2006): 1412���1420.
  54. A. M. Matsumoto, C. A. Paulsen, and W. J. Bremner, ���Stimulation of Sperm Production by Human Luteinizing Hormone in Gonadotropin���Suppressed Normal Men,��� Journal of Clinical Endocrinology & Metabolism 59, no. 5 (1984): 882���887.
  55. A. M. Matsumoto, A. E. Karpas, C. A. Paulsen, and W. J. Bremner, ���Reinitiation of Sperm Production in Gonadotropin���Suppressed Normal Men by Administration of Follicle���Stimulating Hormone,��� Journal of Clinical Investigation 72, no. 3 (1983): 1005���1015.
  56. A. M. Matsumoto, A. E. Karpas, and W. J. Bremner, ���Chronic Human Chorionic Gonadotropin Administration in Normal Men: Evidence That Follicle���Stimulating Hormone Is Necessary for the Maintenance of Quatitatively Normal Spermatogenesis in Man,��� Journal of Clinical Endocrinology & Metabolism 62, no. 6 (1986): 1184���1192.
  57. A. M. Matsumoto and W. J. Bremner, ���Stimulation of Sperm Production By Human Chorionic Gonadotropin After Prolonged Gonadotropin Suppression in Normal Men,��� Journal of Andrology 6, no. 3 (1985): 137���143.
  58. G. Schaison, J. Young, M. Pholsena, K. Nahoul, and B. Couzinet, ���Failure of Combined Follicle���Stimulating Hormone���Testosterone Administration to Initiate and/or Maintain Spermatogenesis in Men With Hypogonadotropic Hypogonadism,��� Journal of Clinical Endocrinology & Metabolism 77, no. 6 (1993): 1545���1549.
  59. M. Becker and V. Hesse, ���Minipuberty: Why Does It Happen,��� Hormone Research in Paediatrics 93, no. 2 (2020): 76���84.

MeSH Term

Humans
Male
Spermatogenesis
Gonadotropins
Hypogonadism
Adult
Chorionic Gonadotropin
Azoospermia
Sperm Count
Treatment Outcome
Infertility, Male

Chemicals

Gonadotropins
Chorionic Gonadotropin
Journal Article Meta-Analysis Systematic Review Review

Word Cloud

Created with Highcharts 10.0.0patientstreatmentGonadotropinspermcomparedinducespermatogenesisgonadotropinachievedcombinedhCG/FSHhCGCHHhypopituitarismTVHHmalesuccessfullyalthoughoutcomespregnancyfollowingmeanSpermoutputsignificantlylowerincreasestestosteronemenINTRODUCTION:HypogonadotropichypogonadismtreatablecausenonobstructiveazoospermicinfertilitycancomprehensivequantitativesummarydataspermatogeniclikerequiredlackingliteratureMATERIALSANDMETHODS:Systematicreviewmeta-analysisrelatedreproductivefunctionRESULTS:searchstrategyidentified41studiesencompassing1673age25�����5���yearsAverageconcentrationmedian18���months116���M/mLejaculate95%CI84-149concentrations>���0>���1>���5>���10>���20���M/mL78%55%36%24%15%respectivelyMeanproportionachievingthresholdsgreatermonotherapydiagnosiscongenitalmixedpatientcohortsdifferentiateTreatment-relatedtesticularvolumedifferenttreatedCONCLUSIONS:inducedpathologicaldeficiencyoutputsconsistenttypicallyneedednaturallesscommonlyDespitesimilareffectsserumappearedefficaciousaloneinducingEfficacyTreatmentInductionSpermatogenesisMenPathologicDeficiency:Meta-Analysis

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