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GnRH Analogues in the Development of a Male Contraceptive: Importance of Testosterone Substitution and Reversibility of Pituitary and Testicular Suppression

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Abstract

GnRH agonists and antagonists are potent and selective inhibitors of gonadotropin synthesis and release resulting in suppression of spermatogenesis. For these reasons, GnRH analogues have received considerable attention as potential male contraceptives. The GnRH analogue-mediated suppression of LH is also associated with a reduction of androgen levels comparable to that seen after orchidectomy. Since androgens are indispensable for normal male physiology, their substitution is thus mandatory in clinical trials with GnRH analogues for male contraception. The evidence available so far, however, suggests that androgen therapy may decrease the antispermatogenic activity of GnRH analogues and careful attention needs to be given to androgen substitution. The present contribution deals with the antispermatogenic potency of GnRH analogues and the crucial role of androgen substitution. Emphasis is placed on preclinical studies in non-human primates and reference is given to relevant clinical trials.

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References

  1. Loumaye, E and Catt, KJ, (1983). Agonist-induced regulation of pituitary receptors for gonadotropin-releasing hormone. J Biol Chem, 258, 12002

    PubMed  CAS  Google Scholar 

  2. Heber, D, Dodson, L, Swerdloff, RS, Channabasavaiah, K and Stewart, JM (1982). Pituitary receptor site blockade by a gonadotropin-releasing hormone antagonist in vivo: Mechanism of action. Science, 216, 420

    Article  PubMed  CAS  Google Scholar 

  3. Mann, DR, Gould, KG and Collins, DC (1984). Influence of continuous gonadotropin-releasing hormone (GnRH) agonist treatment on luteinizing hormone and testosterone secretion, the response to GnRH and the testicular response to human chorionic gonadotropin in the male rhesus monkey. J Clin Endocrinol Metab, 58, 262

    Article  PubMed  CAS  Google Scholar 

  4. Schaison, G, Brailly, S, Vuagnat, P, Bouchard, P and Milgram, E. (1984). Absence of a direct inhibitory effect of gonadotropin- releasing hormone (GnRH) agonist D-Ser (TBU)6, des-Glu NH<Stack><Subscript>2</Subscript><Superscript>10</Superscript></Stack>-ethylamide (Buserelin) on testicular steroidogenesis in men. J Clin Endocrinol Metab, 58, 885

    Article  PubMed  CAS  Google Scholar 

  5. Sundaram, K, Thau, R, Goldstein, M, Philips, DM, Rivier, J and Bardin, CW (1983). Effects of an LHRH agonist on pituitary and testicular function in rhesus monkeys. J Reprod Fertil, 72, 365

    Google Scholar 

  6. Rajfer J, Sikka, JC and Swerdloff RS (1987). Lack of a direct effect of gonadotropin-releasing hormone agonist on human testicular steroidogenesis. J Clin Endocrinol Metab, 64, 62

    Article  PubMed  CAS  Google Scholar 

  7. Akhtar, FB, Marshall, GR., Wickings, EJ. and Nieschlag, E (1983). Reversible induction of azoospermia in rhesus monkeys by constant infusion of a gonadotropin-releasing hormone agonist using osmotic minipumps. J Clin Endocrinol Metab, 56, 453

    Article  Google Scholar 

  8. Sundaram, K, Connel, KG, Bardin, CW, Samojlik, E and Schally, AV (1982). Inhibition of pituitary-testicular function with (D-Trp6) luteinizing hormone-releasing hormone in rhesus monkeys. Endocrinology, 110, 1308

    Article  PubMed  CAS  Google Scholar 

  9. Sundaram, K, Thau, RB, Goldstein, M, Phillips, DM, Rivier, J, Vale, W and Bardin, CW (1984). Effect of an LHRH agonist on pituitary and testicular function in rhesus monkeys. J Reprod Fertil, 72, 365

    Article  PubMed  CAS  Google Scholar 

  10. Weinbauer, GF, Respondek, M, Themann, H and Nieschlag, E (1987). Reversibility of long-term effects of GnRH agonist administration on testicular histology and sperm production in the non-human primate. J Androl, 8, 319

    PubMed  CAS  Google Scholar 

  11. Sundaram, K, Keizer-Jucker, A, Thau, RB and Bardin, CW (1987). Reversal of testicular function after prolonged suppression with an LHRH agonist in rhesus monkeys. J Androl, 8, 103

    PubMed  CAS  Google Scholar 

  12. Mann, DR, Gould, KG, Smith, MM, Duffey, T and Collins, DC (1987). Influence of simultaneous gonadotropin-releasing hormone agonist and testosterone treatment on spermatogenesis and potential fertilizing capacity in male monkeys. J Clin Endocrinol Metab, 65, 1215

    Article  PubMed  CAS  Google Scholar 

  13. Vickery, BH, Mc Rae, G, Briones, WV, Roberts, BB, Worden, AC, Schanbacher, BD and Falvo, RE (1985). Dose-response studies on male reproductive parameters in dogs with nafarelin acetate, a potent LHRH agonist. J Androl, 6, 53

    PubMed  CAS  Google Scholar 

  14. Weinbauer, GF, Surmann, FJ, Akhtar, FB, Shah, GV, Vickery, BH and Nieschlag, E. (1984). Reversible inhibition of testicular function by a gonadotropin-releasing hormone antagonist in monkeys (M. fascicularis). Fertil Steril, 42, 906

    PubMed  CAS  Google Scholar 

  15. Akhtar, BF, Weinbauer, GF and Nieschlag, E (1985). Acute and chronic effects of a gonadotropin-releasing hormone antagonist on pituitary and testicular function in monkeys. J Endocrinol, 104, 345

    Article  CAS  Google Scholar 

  16. Akhtar, FB, Wickings, EJ, Jaidi, P and Nieschlag, E (1982). Pituitary and testicular functions in sexually mature rhesus monkeys under high-dose LHRH-agonist treatment. Acta Endocrinol, 101, 1013

    Google Scholar 

  17. Pineda, JL, Lee, BC, Spiliotis, BE, Vale, W, Rivier, J, Brown TJ and Bereu. BB (1980). Effect of GnRH antagonist [Ac- 3Pro1, pFDPhe2, DTrp3,6]-GnRH on pulsatile gonadotropin secretion in the castrate male primate. Endocrinology, 56, 420

    Google Scholar 

  18. Adams, LA, Bremner, WJ, Nestor, JJ Jr., Vickery, BH and Steiner, R (1986). Suppression of plasma gonadotropins and testosterone in adult male monkeys (Macaca fascicularis) by a potent inhibitory analogue of gonadotropin-releasing hormone. J Clin Endocrinol Metab, 62, 58

    Article  PubMed  CAS  Google Scholar 

  19. Linde, R, Doelle, GC, Alexander, N, Kirchner, F, Vale W, Rivier, J and Rabin, D (1981). Reversible inhibition of testicular steroidogenesis and spermatogenesis by a potent gonadotropin- releasing hormone agonist in normal men. N Engl J Med, 305, 663

    Article  PubMed  CAS  Google Scholar 

  20. Frick, J and Autlitzky, W (1986). Effects of a potent LHRH-agonist on the pituitary-gonadal axis with and without testosterone substitution. Urol Res, 14, 261

    Article  PubMed  CAS  Google Scholar 

  21. Bergquist, C, Ni11ius, SJ, Bergh, T, Skarin, G and Wide, C (1979). Inhibitory effects on gonadotropin secretion and gonadal function in men during chronic treatment with a potent stimulatory luteinizing hormone-releasing hormone analogue. Acta Endocrinol, 91, 601

    PubMed  CAS  Google Scholar 

  22. Bhasin, S, Heber, D, Steiner, BS, Handelsman, DJ and Swerdloff, RS (1985). Hormonal effects of gonadotropin-releasing hormone (GnRH) agonist in the human male. III. Effects of long-term combined treatment with GnRH agonist and androgen. J Clin Endocrinol Metab, 60, 998

    Article  PubMed  CAS  Google Scholar 

  23. Bhasin, S, Yuan, QX, Steiner, BS and Swerdloff, RS (1987). Hormonal effects of gonadotropin-releasing hormone (GnRH) agonist in normal men: Effects of long-term treatment with GnRH agonist infusion and androgen. J Clin Endocrinol Metab, 65, 568

    Article  PubMed  CAS  Google Scholar 

  24. Bouchard, P, Blondet, C, Spitz, I, Brailly, S, Jouannet, P and Schaison, G (1986). Sperm suppression by long-acting GnRH agonist therapy in men: Critical effect of testosterone substitution and duration of therapy. 68th Meeting Endocr. Soc, Anaheim, USA, Abstr, No 498

    Google Scholar 

  25. Doelle, GC, Alexander, AN, Evans, RM, Linde, R, Rivier, J, Vale, W and Rabin, D (1983). Combined treatment with an LHRH-agonist and testosterone in man. J Androl, 4, 298

    PubMed  CAS  Google Scholar 

  26. Michel, E, Bents, H, Akhtar, FB, Hönigl, W, Knuth, UA, Sandow, J and Nieschlag, E (1985). Failure of high-dose sustained release luteinizing hormone releasing hormone agonist (Buserelin) plus oral testosterone to suppress male fertility. Clin Endocrinol, 23, 663

    Article  CAS  Google Scholar 

  27. Rabin, D, Evans, RM, Alexander, AN, Doelle, GC, Rivier, J, Vale, W and Liddle, G (1984). Heterogenicity of sperm density profiles following 20-week therapy with high dose LHRH analogue plus testosterone. J Androl, 5, 176

    PubMed  CAS  Google Scholar 

  28. Schürmeyer, Th, Knuth, UA, Freischem, CW, Sandow, J, Akhtar, FB and Nieschlag, E (1984). Suppression of pituitary and testicular function in normal men by constant gonadotropin-releasing hormone agonist infusion. J Clin Endocrinol Metab, 59, 1

    Article  Google Scholar 

  29. Karten, MJ and Rivier, J, (1986). Gonadotropin-releasing hormone analogue design. Structure-function studies towards the development of agonists and antagonists: rationale and perspective. Endocr Rev, 7, 44

    Article  PubMed  CAS  Google Scholar 

  30. Pavlou, SN, Debold, CR, Island, DP, Wakefield, G, Rivier, J, Vale, W and Rabin, D (1986). Single subcutaneous doses of a luteinizing hormone-releasing hormone antagonist suppress serum gonadotropin and testosterone levels in normal men. J Clin Endocrinol Metab, 63, 303

    Article  PubMed  CAS  Google Scholar 

  31. Pavlou, SN, Wakefield, GB, Kamilaris, TC, Lindner, J, Island, DP and Kovacs, WJ (1987). Clinical studies using “Nal-Glu”, a new LHRH antagonist. 69th Annual Meeting Endocr Soc, Indianapolis, USA, Abstr, No 914

    Google Scholar 

  32. Matsumoto, AM and Bremner, WJ (1985). Stimulation of sperm production by human chorionic gonadotropin after prolonged gonadotropin suppression in normal men. J Androl 6, 137

    PubMed  CAS  Google Scholar 

  33. Marshall, GR, Wickings, EJ, Lüdecke, DK and Nieschlag, E (1983). Stimulation of spermatogenesis in stalk-sectioned rhesus monkeys by testosterone alone. J Clin Endocrinol Metab, 57, 152

    Article  PubMed  CAS  Google Scholar 

  34. Marshall, GR, Jockenhövel, F, Lüdecke, DK and Nieschlag, E (1986). Maintenance of complete but quantitatively reduced spermatogenesis in hypophysectomized monkeys by testosterone alone. Acta Endocrinol, 113, 424

    PubMed  CAS  Google Scholar 

  35. Akhtar, FB, Marshall, GR and Nieschlag, E (1983). Testosterone supplementation attenuates the antifertility effects of an LHRH agonist in male monkeys. Int J Androl, 6, 461

    Article  PubMed  CAS  Google Scholar 

  36. Weinbauer, GF, Surmann, FJ and Nieschlag, E (1987). Suppression of spermatogenesis in a non-human primate (Macaca fascicularis) by concomitant gonadotropin-releasing hormone antagonist and testosterone treatment. Acta Endocrinol, 114, 138

    PubMed  CAS  Google Scholar 

  37. Weinbauer, GF, Marshall, GR and Nieschlag, E (1986). New injectable testosterone ester maintains serum testosterone in the normal range for four months. Acta Endocrinol, 113, 128

    PubMed  CAS  Google Scholar 

  38. Lefebvre, FA, Belanger, A, Pelletier, G and Labrie, F (1984): Recovery of gonadal functions in the adult male rat following cessation of five-months daily treatment with an LHRH agonist. J Androl, 5, 181

    PubMed  CAS  Google Scholar 

  39. Waxman, MD, Lowe, D, Whitfield, HN, Hendry, BF and Besser, GM (1987): The effect of a gonadotropin-releasing hormone agonist on testicular histology. Fertil Steril, 48, 1067

    PubMed  CAS  Google Scholar 

  40. Smith, JA Jr and Urry, RL (1985): Testicular histology after prolonged treatment with a gonadotropin-releasing hormone analogue. J Urol, 133, 612

    PubMed  Google Scholar 

  41. Rajfer, J, Swerdloff, RS and Heber, DM (2984): Testicular histology following chronic gonadotropin-releasing hormone agonist treatment. Fertil Steril, 42, 765

    Google Scholar 

  42. Belkien, L, Schürmeyer, Th, Hano, R, Gunnarson, PO and Nieschlag, E (1985): Pharmacokinetics of 19-nortestosterone esters in normal men. J Steroid Biochem, 22, 623

    Article  PubMed  CAS  Google Scholar 

  43. Bals-Pratsch, M, Knuth, UA, Yoon, YD and Nieschlag, E (1986). Transdermal testosterone substitution therapy for male hypogonadism. Lancet, II, 943

    Article  Google Scholar 

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© 1990 Kluwer Academic Publishers

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Weinbauer, G.F., Nieschlag, E. (1990). GnRH Analogues in the Development of a Male Contraceptive: Importance of Testosterone Substitution and Reversibility of Pituitary and Testicular Suppression. In: Vickery, B.H., Lunenfeld, B. (eds) GnRH Analogues in Cancer and Human Reproduction. Springer, Dordrecht. https://doi.org/10.1007/978-94-009-0725-6_12

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  • DOI: https://doi.org/10.1007/978-94-009-0725-6_12

  • Publisher Name: Springer, Dordrecht

  • Print ISBN: 978-94-010-6811-6

  • Online ISBN: 978-94-009-0725-6

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