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Stimulation of Spermatogenesis in Hypogonadotropic Men

  • Chapter
Male Hypogonadism

Part of the book series: Contemporary Endocrinology ((COE))

Abstract

The hypothalamic—pituitary—testicular axis coordinates two principal functions that are essential for reproduction in males: the production of physiologic quantities of sex steroid hormones, primarily testosterone, and the generation of spermatogenic cells that become mature gametes capable of fertilizing oocytes. Gonadotropinreleasing hormone (GnRH) is the primary regulator of this system. It is released into the portal blood in discrete pulses and binds to specific receptors on gonadotropic cells, where it stimulates the synthesis and release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH and FSH, in turn, control development, maturation, and function of the gonad through interaction with specific membrane receptors (1). To induce and maintain quantitatively normal spermatogenesis in humans, both gonadotropins are required (2). LH binds to Leydig cells to initiate testosterone synthesis and secretion, whereas FSH binds to Sertoli cells and stimulates the production of several factors that, together with testosterone from Leydig cells, induce and maintain spermatogenesis (1).

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References

  1. Weinbauer GF, Gromoll J, Simoni M, Nieschlag E. Physiology of testicular function. In: Nieschlag E, Behre HM, eds. Andrology: Male Reproductive Health and Dysfunction, 2nd ed. Springer, Berlin, 2000, pp. 23–61.

    Google Scholar 

  2. Nieschlag E, Simoni M, Gromoll J, Weinbauer GF. Role of FSH in the regulation of spermatogenesis: clinical aspects. Clin Endocrinol 1999; 51: 139–146.

    Article  CAS  Google Scholar 

  3. Behre HM, Yeung CH, Holstein AF, Weinbauer GF, Gassner P, Nieschlag E. Diagnosis of male infertility and hypogonadism. In: Nieschlag E, Behre HM, eds. Andrology: Male Reproductive Health and Dysfunction, 2nd ed. Springer, Berlin, 2000, pp. 89–124.

    Google Scholar 

  4. Behre HM, Nieschlag E, Meschede D, Partsch CJ. Diseases of the hypothalamus and the pituitary gland. In: Nieschlag E, Behre HM, eds. Andrology: Male Reproductive Health and Dysfunction, 2nd ed. Springer, Berlin, 2000, pp. 125–143.

    Google Scholar 

  5. Ley SB, Leonard JM. Male hypogonadotropic hypogonadism: factors influencing response to human chorionic gonadotropin and human menopausal gonadotropin, including prior exogenous androgens. J Clin Endocrinol Metab 1985; 61: 746–752.

    Article  PubMed  CAS  Google Scholar 

  6. Schaison G, Young J, Pholsena M, Nahoul K, Couzinet B. Failure of combined follicle-stimulating hormone-testosterone administration to initiate and/or maintain spermatogenesis in men with hypogonadotropic hypogonadism. J Clin Endocrinol Metab 1993; 77: 1545–1549.

    Article  PubMed  CAS  Google Scholar 

  7. Buechter D, Behre HM, Kliesch S, Nieschlag E. Pulsatile GnRH or human chorionic gonadotropin/human menopausal gonadotropin as effective treatment for men with hypogonadotropic hypogonadism: a review of 42 cases. Eur J Endocrinol 1998; 139: 298–303.

    Article  Google Scholar 

  8. Johnsen SG. Maintenance of spermatogenesis induced by hMG treatment by means of continuous hCG treatment in hypogonadotropic men. Acta Endocrinol 1978; 89: 763–769.

    PubMed  CAS  Google Scholar 

  9. Depenbusch M, von Eckardstein S, Simoni M, Nieschlag E. Maintenance of spermatogenesis in hypogonadotropic hypogonadal men with hCG alone. Eur J Endocrinol 2002; 147: 617–624.

    Article  PubMed  CAS  Google Scholar 

  10. Schopohl J, Mehltretter G, von Zumbusch R, Eversmann T, von Werder K. Comparison of gonadotropin-releasing hormone and gonadotropin therapy in male patients with idiopathic hypothalamic hypogonadism. Fertil Steril 1991; 56: 1143–1150.

    PubMed  CAS  Google Scholar 

  11. Conn PM, Crowley JR. Gonadotropin-releasing hormone and its analogs. N Engl J Med 1991; 324: 93–103.

    Article  PubMed  CAS  Google Scholar 

  12. Whitcomb RW, Crowley WF. Clinical review 4: diagnosis and treatment of isolated gonadotropinreleasing hormone deficiency in men. J Clin Endocrinol Metab 1990; 70: 3–7.

    Article  PubMed  CAS  Google Scholar 

  13. Caron P, Chauvin S, Christin-Maitre S, et al. Resistance of hypogonadic patients with mutated GnRH receptor genes to pulsatile GnRH administration. J Clin Endocrinol Metab 1999; 84: 990–996.

    Article  PubMed  CAS  Google Scholar 

  14. De Roux N, Young J, Misrahi M, et al. A family with hypogonadotropic hypogonadism and mutations in the gonadotropin-releasing hormone receptor. N Engl J Med 1997; 337: 1597–1602.

    Article  PubMed  Google Scholar 

  15. Layman LC, Cohen DP, Jin M, et al. Mutations in the gonadotropin-releasing hormone receptor gene cause hypogonadotropic hypogonadism. Nat Genet 1998; 18: 14–15.

    Article  PubMed  CAS  Google Scholar 

  16. Quinton R, Barnett P, Coskeran P, Bouloux PM. Gordon Holmes spinocerebellar ataxia: a gonadotropin deficiency syndrome resistant to treatment with pulsatile gonadotropin-releasing hormone. Clin Endocrinol 1999; 51: 525–529.

    Article  CAS  Google Scholar 

  17. Morris DV, Adeniyi-Jones R, Wheeler M, Sonksen P, Jacobs HS. The treatment of hypogonadotropic hypogonadism in men by the pulsatile infusion of luteinizing hormone-releasing hormone. Clin Endocrinol 1984; 21: 189–200.

    Article  CAS  Google Scholar 

  18. Blumenfeld Z, Frisch L, Conn PM. Gonadotropin-releasing hormone (GnRH) antibodies formation in hypogonadotropic azoospermic men treated with pulsatile GnRH-diagnosis and possible alternative treatment. Fertil Steril 1988; 50: 622–629.

    PubMed  CAS  Google Scholar 

  19. Finkel DM, Phillips BA, Snyder PJ. Stimulation of spermatogenesis by gonadotropins in men with hypogonadotropic hypogonadism. N Engl J Med 1985; 313: 651–655.

    Article  PubMed  CAS  Google Scholar 

  20. Burris AS, Rodbard HW, Winters SJ, Sherins RJ. Gonadotropin therapy in men with isolated hypogonadotropic hypogonadism: the response to human chorionic gonadotropin is predicted by initial testicular size. J Clin Endocrinol Metab 1988; 66: 1144–1151.

    Article  PubMed  CAS  Google Scholar 

  21. Kirk JMW, Savage MO, Grant DB, Bouloux P-MG, Besser GM. Gonadal function and response to human chorionic and menopausal gonadotropin therapy in male patients with idiopathic hypogonadotropic hypogonadism. Clin Endocrinol 1994; 41: 57–63.

    Article  CAS  Google Scholar 

  22. Simoni M, Nieschlag E. FSH in therapy: physiological basis, new preparations and clinical use. Reprod Med Rev 1995; 4: 163–177.

    Article  Google Scholar 

  23. Sokol RZ, McClure RD, Peterson M, Swerdloff RS. Gonadotropin therapy failure secondary to human chorionic gonadotropin-induced antibodies. J Clin Endocrinol Metab 1981; 52: 929–933.

    Article  PubMed  CAS  Google Scholar 

  24. Vicari E, Mongioi A, Calogero AE, et al. Therapy with human chorionic gonadotropin alone induces spermatogenesis in men with isolated hypogonadotropic hypogonadism—long-term follow-up. Int J Androl 1992; 15: 320–329.

    Article  PubMed  CAS  Google Scholar 

  25. Liu PY, Wishart SM, Handelsman DJ. A double-blind placebo-controlled, randomized clinical trial of recombinant human chorionic gonadotropin on muscle strength and physical function and activity in older men with partial age-related androgen deficiency. J Clin Endocrinol Metab 2002; 87: 3125–3135.

    Article  PubMed  CAS  Google Scholar 

  26. The European Recombinant LH Study Group. Human recombinant luteinizing hormone is as effective as, but safer than, urinary human chorionic gonadotropin in inducing final follicular maturation and ovulation in in vitro fertilization procedures: results of a multicenter double-blind study. J Clin Endocrinol Metab 2001; 86: 2607–2618.

    Google Scholar 

  27. Choung P, Kenley S, Burns T, et al. Recombinant human chorionic gonadotropin (rhCG) in assisted reproductive technology: results of a clinical trial comparing two doses of rhCG (Ovidrel) to urinary hCG (Profasi) for induction of final follicular maturation in in vitro fertilization-embryo transfer. Fertil Steril 2001; 76: 67–74.

    Article  Google Scholar 

  28. Burris AS, Clark RV, Vantman DJ, Sherins RJ. A low sperm concentration does not preclude fertility in men with isolated hypogonadotropic hypogonadism after gonadotropin therapy. Fertil Steril 1988; 50: 343–347.

    PubMed  CAS  Google Scholar 

  29. Barrio R, de Luis D, Alonso M, Lamas A, Moreno JC. Induction of puberty with human chorionic gonadotropin and follicle-stimulating hormone in adolescent males with hypogonadotropic hypogonadism. Fertil Steril 1999; 71: 244–248.

    Article  PubMed  CAS  Google Scholar 

  30. European Metrodin HP Study Group. Efficacy and safety of highly purified urinary follicle-stimulating hormone with human chorionic gonadotropin for treating men with isolated hypogonadotropic hypogonadism. Fertil Steril 1998; 70: 256–262.

    Google Scholar 

  31. Mastrogiacomo I, Motta RG, Botteon S, Bonanni G, Schiesaro M. Achievement of spermatogenesis and genital tract maturation in hypogonadotropic subjects during long-term treatment with gonadotropins or LHRH. Andrologia 1991; 23: 285–289.

    Article  PubMed  CAS  Google Scholar 

  32. Burgués S, Calderón MD, the Spanish Collaborative Group on Male Hypogonadotropic Hypogonadism. Subcutaneous self-administration of highly purified follicle-stimulating hormone and human chorionic gonadotropin for the treatment of male hypogonadotropic hypogonadism. Hum Reprod 1997; 12: 980–986.

    Article  PubMed  Google Scholar 

  33. Harlin J, Csemiczky G, Wramsby H, Fried G. Recombinant follicle-stimulating hormone in in-vitro fertilization treatment—clinical experience with follitropin alpha and follitropin beta. Hum Reprod 2000; 15: 239–244.

    Article  PubMed  CAS  Google Scholar 

  34. Bouloux P, Nieschlag E, Burger HG, et al. Induction of spermatogenesis by recombinant follicle-stimulating hormone (Puregon) in hypogonadotropic azoospermic men who failed to respond to human chorionic gonadotropin alone. J Androl 2003; 24: 604–611.

    PubMed  CAS  Google Scholar 

  35. Liu PY, Turner L, Rushford D, et al. Efficacy and safety of recombinant human follicle-stimulating hormone (Gonal-F) with urinary human chorionic gonadotropin for induction of spermatogenesis and fertility in gonadotropin-deficient men. Hum Reprod 1999; 14: 1540–1545.

    Article  PubMed  CAS  Google Scholar 

  36. Bouloux PMG, Warne DW, Loumaye E. Efficacy and safety of recombinant human follicle-stimulating hormone in men with isolated hypogonadotropic hypogonadism. Fertil Steril 2002; 77: 270–273.

    Article  PubMed  Google Scholar 

  37. O’Dea L, Hemsey G, Brentzel J, Bock D, Matsumoto AM. Long-term treatment with follitropin Alfa (Gonal-F®) in male hypogonadotropic hypogonadism (HH). Endocrine Society, San Francisco, 2002, (Abstract) pp. 2–661.

    Google Scholar 

  38. Bouloux P, Handelsman DJ, Jockenhövel F, et al. FSH-CTP study group. First human exposure to FSH-CTP in hypogonadotropic hypogonadal males. Hum Reprod 2001; 16: 1592–1597.

    Article  PubMed  CAS  Google Scholar 

  39. Zitzmann M, Nieschlag E. Hormone substitution in male hypogonadism. Mol Cell Endocrinol 2000; 161: 73–88.

    Article  PubMed  CAS  Google Scholar 

  40. Spratt DI, Carr DB, Merriam GR, Scully RE, Rao PN, Crowley WF. The spectrum of abnormal patterns of gonadotropin-releasing hormone secretion in men with idiopathic hypogonadotropic hypogonadism: clinical and laboratory correlations. J Clin Endocrinol Metab 1987; 64: 283–291.

    Article  PubMed  CAS  Google Scholar 

  41. Mengel W, Hienz HA, Sippe WG, Hecker WC. Studies on cryptorchidism: a comparison of histological findings in the germinative epithelium before and after the second year of life. J Pediatr Surg 1974; 9: 445–450.

    Article  PubMed  CAS  Google Scholar 

  42. Pitteloud N, Hayes FJ, Boepple PA, et al. The role of prior pubertal development, biochemical markers of testicular maturation, and genetics in elucidating the phenotypic heterogeneity of idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab 2002; 87: 152–160.

    Article  PubMed  CAS  Google Scholar 

  43. Nieschlag E. Scope and goals of andrology. In: Nieschlag E, Behre HM, eds. Andrology: Male Reproductive Health and Dysfunction, 2nd ed. Springer, Berlin, 2000, pp. 1–8.

    Google Scholar 

  44. Knuth UA, Schneider HPG, Behre HM. Gynecology relevant to andrology. In: Nieschlag E, Behre HM, eds. Andrology: Male Reproductive Health and Dysfunction, 2nd ed. Springer, Berlin, 2000, pp. 271–309.

    Google Scholar 

  45. Liu L, Chaudhari N, Corle D, Sherins RJ. Comparison of pulsatile subcutaneous gonadotropin-releasing hormone and exogenous gonadotropins in the treatment of men with isolated hypogonadotropic hypogonadism. Fertil Steril 1988; 49: 302–308.

    PubMed  CAS  Google Scholar 

  46. Zwart-van Rijkom JEF, Broekmans FJ, Leufkens HGM. From hMG through purified urinary FSH preparations to recombinant FSH: a substitution study. Hum Reprod 2002; 17: 857–865.

    Article  CAS  Google Scholar 

  47. Debate group: “Bye-bye urinary gonadotropins?” Matorra R, Rodriguez-Escudero F. “The use of urinary gonadotropins should be discouraged.” Crosignani PG. “Risk of infection is not the main problem.” Balen A. “Is there a risk of prion disease after the administration of urinary-derived gonadotropins?” Dyer J. “The conflict between effective and affordable health care—a perspective from the developing world.” Hum Reprod 2002; 17: 1675–1683.

    Google Scholar 

  48. Mannaerts B, Fauser B, Lahlou N, et al. Serum hormone concentrations during treatment with multiple rising doses of recombinant follicle stimulating hormone (Puregon) in men with hypogonadotropic hypogonadism. Fertil Steril 1996; 65: 406–410.

    PubMed  CAS  Google Scholar 

  49. Le Cotonnec JY, Porchet HC, Beltrami V, Khan A, toon S, Rowland M. Clinical pharmacology of recombinant human follicle-stimulating hormone (FSH). I. comparative pharmacokinetics with urinary human FSH. Fertil Steril 1994; 61: 669–678.

    PubMed  Google Scholar 

  50. Out HJ, Driessen SGAJ, Mannaerts BMJL, Coelingh Bennink HJT. Recombinant follicle-stimulating hormone (follitropin beta, Puregon) yields higher pregnancy rates in in vitro fertilization than urinary gonadotropins. Fertil Steril 1997; 68: 138–142.

    Article  PubMed  CAS  Google Scholar 

  51. Daya S, Gunby J. Recombinant versus urinary follicle-stimulating hormone for ovarian stimulation in assisted reproduction. Hum Reprod 1999; 14: 2207–2215.

    Article  PubMed  CAS  Google Scholar 

  52. Agrawal R, Holmes J, Howard SJ. Follicle-stimulating hormone or human menopausal gonadotropin for ovarian stimulation in in vitro fertilization cycles: a meta-analysis. Fertil Steril 2000; 73: 338–343.

    Article  PubMed  CAS  Google Scholar 

  53. Arsenijevic Y, Wehrenberg WB, Conz A, Eshkol A, Sizonenko PC, Aubert NL. Growth hormone (GH) deprivation induced by passive immunization against rat GH-releasing factor delays sexual maturation in the male rat. Endocrinology 1989; 124: 3050–3059.

    Article  PubMed  CAS  Google Scholar 

  54. Chatelain PG, Sanchez P, Saez JM. Growth hormone and insulin-like growth factor I treatment increases testicular luteinizing hormone receptor and steroidogenic responsiveness of growth hormone deficient dwarf mice. Endocrinology 1991; 128: 1857–1862.

    Article  PubMed  CAS  Google Scholar 

  55. Syed V, Khan SA, Nieschlag E. Epidermal growth factor stimulates testosterone production on human Leydig cells in vitro. J Endocrinol Invest 199 1; 14: 93–97.

    Google Scholar 

  56. Bebaker M, Honour JW, Foster D, Liu YL, Jacobes HS. Regulation of testicular function by insulin and transforming growth factor-P. Steroids 1990; 55: 266–270.

    Article  Google Scholar 

  57. Kulin HE, Samojlik E, Santen R, Santner S. The effect of growth hormone on the Leydig cell response to chorionic gonadotropin in boys with hypopituitarism. Clin Endocrinol 1981; 15: 463–472.

    Article  CAS  Google Scholar 

  58. Shoham Z, Conway GS, Ostergaard H, Lahlou N, Bouchard P, Jacobs HS. Cotreatment with growth hormone for induction of spermatogenesis in patients with hypogonadotropic hypogonadism. Fertil Steril 1992; 57: 1044–1051.

    PubMed  CAS  Google Scholar 

  59. Giagulli VA. Absence of effect of recombinant growth hormone to classic gonadotropin treatment on spermatogenesis of patients with severe hypogonadotropic hypogonadism. Arch Androl 1999; 43: 47–53.

    Article  PubMed  CAS  Google Scholar 

  60. Carani C, Granata AR, De Rosa M, et al. The effect of chronic treatment with GH on gonadal function in men with isolated GH deficiency. Eur J Endocrinol 1999; 140: 224–230.

    Article  PubMed  CAS  Google Scholar 

  61. White BJ, Rogol AD, Brown KS, Lieblich JM, Rosen SW. The syndrome of anosmia with hypogonadotropic hypogonadism: a genetic study of 18 new families and a review. Am J Med Genet 1983; 15: 417–435.

    Article  PubMed  CAS  Google Scholar 

  62. Dean JCS, Johnston AW, Klopper AI. Isolated hypogonadotropic hypogonadism: a family with autosomal dominant inheritance. Clin Endocrinol 1990; 32: 341–347.

    Article  CAS  Google Scholar 

  63. Chaussian JL, Toublanc JE, Feingold J, Naud C, Vassal J, Job JC. Mode of inheritance in familial cases of primary gonadotropic deficiency. Horm Res 1988; 29: 202–206.

    Article  Google Scholar 

  64. Franco B, Guioli S, Pragliola A, et al. A gene deleted in Kallmann’s syndrome shares homology with neural cell adhesion and axonal path-finding molecules. Nature 1991; 353: 529–536.

    Article  PubMed  CAS  Google Scholar 

  65. Pralong FP, Gomez F, Castillo E, et al. Complete hypogonadotropic hypogonadism associated with a novel inactivating mutation of the gonadotropin-releasing hormone receptor. J Clin Endocrinol Metab 1999; 84: 3811–3816.

    Article  PubMed  CAS  Google Scholar 

  66. De Roux N, Young J, Brailly-Tabard S, Misrahi M, Milgrom E, Schaison G. The same molecular defects of the gonadotropin-releasing hormone receptor determine a variable degree of hypogonadism in affected kindred. J Clin Endocrionl Metab 1999; 84: 567–572.

    Article  Google Scholar 

  67. Zanaria E, Muscatelli F, Bardoni B, et al. An unusual member of the nuclear hormone receptor super-family responsible for X-linked adrenal hypoplasia congenita. Nature 1994; 372: 635–641.

    Article  PubMed  CAS  Google Scholar 

  68. Habiby RL, Boepple P, Nachtigall L, Sluss PM, Crowley WF, Jameson JL. Adrenal hypoplasia congenita with hypogonadotropic hypogonadism: evidence that the DAX-1 mutations lead to combined hypothalamic and pituitary defects in gonadotropin production. J Clin Invest 1996; 98: 1055–1062.

    Article  PubMed  CAS  Google Scholar 

  69. Wu W, Cogan JD, Pfaeffle RW, et al. Mutations in PROP 1 cause familial combined pituitary hormone deficiency. Nat Genet 1998; 18: 147–149.

    Article  PubMed  CAS  Google Scholar 

  70. Vermeulen S, Messiaen L, Scheir P, De Bie S, Speleman F, De Paepe A. Kallmann syndrome in a patient with congenital spherocytosis and an interstitial 8p11.2 deletion. Am J Med Genet 2002; 108: 315–318.

    Article  PubMed  Google Scholar 

  71. Netchine I, Sobrier ML, Krude H, et al. Mutations in LHX 3 result in a new syndrome revealed by combined pituitary hormone deficiency. Nat Genet 2000; 25: 182–186.

    Article  PubMed  CAS  Google Scholar 

  72. Dattani MT, Martinez-Barbera JP, Thomas PQ, et al. Mutations in the homebox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse. Nat Genet 1998; 19: 125–133.

    Article  PubMed  CAS  Google Scholar 

  73. Strobel A, Issad T, Camoin L, Ozata M, Strosberg AD. A leptin missense mutation associated with hypogonadism and morbid obesity. Nat Genet 1998; 18: 213–215.

    Article  PubMed  CAS  Google Scholar 

  74. Clément K, Vaisse C, Lahlou N, et al. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 1998; 392: 398–401.

    Article  PubMed  Google Scholar 

  75. Jackson RS, Creemers JW, Ohagi S, et al. Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat Genet 1997; 16: 303–306.

    Article  PubMed  CAS  Google Scholar 

  76. Quinton R, Duke VM, Robertson A, et al. Idiopathic gonadotropin deficiency: genetic questions addressed through phenotypic characterization. Clin Endocrinol 2001; 55: 163–174.

    Article  CAS  Google Scholar 

  77. Georgopoulos NA, Pralong FP, Seidman CE, Seidman JG, Crowley WF, Vallejo M. Genetic heterogeneity evidenced by low incidence of KAL-1 gene mutations in sporadic cases of gonadotropinreleasing hormone deficiency. J Clin Endocrinol Metab 1997; 82: 213–217.

    Article  PubMed  CAS  Google Scholar 

  78. Merriam GR, Beitins IZ, Bode HH. Father-to-son transmission of hypogonadism with anosmia: Kallmann’s syndrome. Am J Dis Child 1977; 131: 1216–1219.

    PubMed  CAS  Google Scholar 

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Depenbusch, M., Nieschlag, E. (2004). Stimulation of Spermatogenesis in Hypogonadotropic Men. In: Winters, S.J. (eds) Male Hypogonadism. Contemporary Endocrinology. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-727-7_19

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