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Antifertility Effects of LH-RH and Its Agonists

  • Frederick J. Bex
  • Alan Corbin
Part of the Biochemical Endocrinology book series (BIOEND)

Abstract

The identification, characterization, and synthesis of luteinizing-hor­mone-releasing hormone (LH-RH) introduced a potential and exciting new approach for the treatment of male and female infertility. This application, which theoretically coincides with the profertility LH-re­leasing role played by endogenous LH-RH, has been and continues to be exhustively pursued, but use of the chemically and biologically identical synthetic LH-RH in a variety of clinical situations has never achieved its anticipated therapeutic promise. Primary responsibility for the inconsis­tency of the results has been attributed to the short half-life of the peptide, and it was hoped that this problem might be circumvented by increased exposure (e.g., through more frequent administration or con­stant infusion) or by employing LH-RH derivatives with prolonged activity. However, despite heroic treatment regimens and the use of a number of LH-RH agonistic analogues with much-increased potency and duration of activity, there has been little improvement in the clinical utility of this approach. In fact, comprehensive reproductive pharmaco­logical evaluation has revealed that the LH-releasing property responsible for the original profertility classification imparts definite correlatable and predictable antireproductive activity. This paradoxical relationship, first evidenced in laboratory animals by the ability of these agents to terminate pregnancy, disrupt cyclicity, retard puberty, and inhibit spermatogenesis, has been extended to humans, in whom LH-RH and its agonistic analogues have been shown to induce luteolysis and premature menstrua­tion. The identification of the antireproductive nature of LH-RH and agonists, aside from providing an explanation for their disappointing performance in treating various hypogonadal states, has, quite ironically, established the concept of these peptides as a novel class of contraceptive agents.

Keywords

Luteinizing Hormone Luteinizing Hormone Release Hormone Luteinizing Hormone Level Luteinizing Hormone Receptor Luteinizing Hormone Release Hormone 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Arimura, A., Serafini, Y.C., and Sonntag, W., 1979, Does LHRH agonist decrease ovarian and testicular LH/hCG receptors by direct action?, Program of the 61st Annual Meeting of the Endocrine Society, Anaheim, California, Abstract 433.Google Scholar
  2. Auclair, C., Kelly, P.A., Labrie, F., Coy, D.H., and Schally, A.V., 1977a, Inhibition of testicular luteinizing hormone receptor level by treatment with a potent luteinizing hormone releasing hormone agonist or human chorionic gonadotropin, Biochem. Biophys. Res. Commun. 76: 855.CrossRefGoogle Scholar
  3. Auclair, C., Kelly, P.A., Coy, D.H., Schally, A.V., and Labrie, F., 19776, Potent inhibitory activity of [D-Lete,des-Gly-NH210] LHRH ethylamide on LH/hCG and PRL testicular receptor levels in the rat, Endocrinology 101: 1890.Google Scholar
  4. Badger, T.M., Beitins, I.Z., Ostrea, T., Crisafulli, J., Little, R., and Saidel, M., 1979, Effects of luteinizing hormone releasing hormone and one of its highly potent analogs (D-Trp“-Pro”-NHEt-LRF) on in Nitro testosterone synthesis, Program of the 61st Annual Meeting of the Endocrine Society, Anaheim, California, Abstract 430.Google Scholar
  5. Banik, U.K., and Givner, M.L., 1975, Ovulation induction and antifertility effects of an LH-RH analogue (Ay-25,205) in cyclic rats, J. Reprod. Fertil. 44: 87.CrossRefGoogle Scholar
  6. Banik, U.K., and Givner, M.L., 1976, Effects of a luteinizing hormone-releasing hormone analog on mating and fertility in rats, Fertil. Steril. 27: 1078.Google Scholar
  7. Beattie, C.W., and Corbin, A., 1977, Pre-and postcoital contraceptive activity of LH-RH in the rat, Biol. Reprod. 16: 333.CrossRefGoogle Scholar
  8. Beattie, C.W., Corbin, A., Cole, G., Corry, S., Jones, R.C., Koch, K., and Tracy, J., 1977, Mechanism of the post-coital contraceptive effect of LH-RH in the rat. I. Serum hormone levels during chronic LH-RH administration, Biol. Reprod. 16: 322.CrossRefGoogle Scholar
  9. Belanger, A., Auclair, C., and Caron, S., 1979, Role of prolactin in the LHRH agonistinduced blockage of testicular steroidogenesis, Program of the 61st Annual Meeting of the Endocrine Society, Anaheim, California, Abstract 717.Google Scholar
  10. Bergquist, C., Nillius, S.J., and Wide, L., 1979a, Inhibition of ovulation in women by intranasal treatment with a luteinizing hormone-releasing hormone agonist, Contraception 19: 497.CrossRefGoogle Scholar
  11. Bergquist, C., Nillius, S.J., and Wide, L., 19796, Intranasal gonadotropin-releasing hormone agonist as a contraceptive agent. Lancet 1979: 215.Google Scholar
  12. Bex, F.J., and Corbin, A., 1978, Inhibition of reproductive processes in the immature andGoogle Scholar
  13. mature male rat with an LHRH agonist, Program of the 3rd Annual Meeting of the American Society of Andrology, Nashville, Tennessee, Abstract 6.Google Scholar
  14. Bex, F.J., and Corbin, A., 1979a, Mechanism of the postcoital contraceptive effect of luteinizing hormone-releasing hormone: Ovarian luteinizing hormone receptor interactions, Endocrinology 105: 139.CrossRefGoogle Scholar
  15. Bex, F.J., and Corbin, A., 1979b, LHRH or LHRH agonist-induced termination of pregnancy in hypophysectomized (HYPX) rats: Extrapituitary site of action, Program of the 61st Annual Meeting of the Endocrine Society, Anaheim, California, Abstract 436.Google Scholar
  16. Casper, R.F., and Yen, S.S.C., 1979, Induction of luteolysis in the human with a long-acting analog of luteinizing hormone-releasing factor, Science 205: 408.CrossRefGoogle Scholar
  17. Comaru, A.M.de M., Rodrigues, J., Povoa, L.C., Franco, S., Dimetz, T., Novellino, P., Coy, D.H., and Schally, A.V., 1976, Clinical use of luteinizing hormone-releasing hormone and its long-acting analogues, in: Recent Advances in Human Reproduction ( A. Campos, D.A. Paz, V.A. Drill, M. Hayashi, W. Rodrigues, and A.V. Schally, eds.), p. 140, Excerpta Medica, Amsterdam.Google Scholar
  18. Corbin, A., and Beattie, C.W., 1975a, Inhibition of the pre-ovulatory proestrous gonadotropin surge, ovulation and pregnancy with a peptide analogue of luteinizing hormone releasing hormone, Endocr. Res. Commun. 2: 1.CrossRefGoogle Scholar
  19. Corbin, A., and Beattie, C.W., 1975b, Post-coital contraceptive and uterotrophic effects of luteinizing hormone releasing hormone, Endocr. Res. Commun. 2: 445.CrossRefGoogle Scholar
  20. Corbin, A., and Beattie, C.W., 1976, Effect of luteinizing hormone releasing hormone (LHRH) and an LHRH antagonist on hypothalamic and plasma LHRH of hypophysectomized rats, Endocrinology 98: 247.CrossRefGoogle Scholar
  21. Corbin, A., and Bex, F., 1979. Inhibition of male reproductive processes with an LHRH agonist, Program of the 1st Pan American Congress of Andrology, Caracas, Venezuela, Abstract 251.Google Scholar
  22. Corbin, A., Beattie, C.W., Yardley, J., and Foell, T.J., 1976, Post-coital contraceptive effects of an agonistic analogue of luteinizing hormone releasing hormone, Endocr. Res. Commun. 3: 359.CrossRefGoogle Scholar
  23. Corbin, A., Beattie, C.W., Tracy, J., Jones, R., Foell, T.J., Yardley, J., and Rees, R.W.A., 1978, The anti-reproductive pharmacology of LH-RH and agonistic analogues, /nt. J. Fertil. 23: 81.Google Scholar
  24. Corbin, A., Bex, F.J., Yardley, J.P., Rees, R.W.A., Foell, T.J., and Sarantakis, D., 1979a, Agonist (ovulation induction) and post-coital contraceptive properties of [o-Alai] and [o-Trp“]-LHRH series, Endocr. Res. Commun. 6: 1.CrossRefGoogle Scholar
  25. Corbin, A., Beattie, C.W., Jones, R., and Bex, F., 1979b, Peptide contraception: Antifertility properties of LH-RH analogues, Int. J. Gynaecol. Obstet. 16: 379.Google Scholar
  26. Corbin, A., Rosanoff, E., and Bex, F.J., 1980, LHRH and agonists: Paradoxical antifertility effects, mechanisms of action and therapeutic relevance to steroid dependent tumors, in: Progress in Cancer Research and Therapy, Vol. 14 ( S. Iacobelli, H.R. Lindner, R.J.B. King, and M.E. Lippman, eds.), p. 533, Raven Press, New York.Google Scholar
  27. Coy, D.H., Labrie, F., Savary, M., Coy, E.J., and Schally, A.V., 1975, LH-releasing activity of potent LH-RH analogs in vitro, Biochem. Biophys. Res. Commun. 67: 576.CrossRefGoogle Scholar
  28. Cusan, L., Auclair, C., Bélanger, A., Ferland, L., Kelly, P.A., Séguin, C., and Labrie, F., 1979, Inhibitory effects of long-term treatment with a luteinizing hormone-releasing hormone agonist on the pituitary—gonadal axis in male and female rats, Endocrinology 104: 1369.CrossRefGoogle Scholar
  29. Danguy, A., Legros, N., Heuson-Stiennon, J.A., Pasteels, J.L., Atassi, G., and Heuson, J.C., 1977, Effects of a gonadotropin-releasing hormone (GnRH) analogue (A-43818) on 7,12-dimethylbenz(a)anthracene-induced rat mammary tumors: Histological and endocrine studies, Eur. J. Cancer 13: 1089.CrossRefGoogle Scholar
  30. Desombre, E.R., Johnson, E.S., and White, W.F., 1976, Regression of rat mammary tumors effected by a gonadoliberin analog, Cancer Res. 36: 3830.Google Scholar
  31. Dutta, A.S., Furr, B.J.A., Giles, M.B., Valaccia, B., and Walpole, A.L., 1978, Potent agonist and antagonist analogues of luliberin containing an azaglycine residue in position 10, Biochem. Biophys. Res. Commun. 81: 382.CrossRefGoogle Scholar
  32. Edgren, R.A., Windsor, B.L., Bousley, F.G., and Humphrey, R.R., 1977, Absence of a prenidatory effect of luteinizing hormone releasing hormone (LHRH) in hamsters, int. J. Fertil. 22: 40.Google Scholar
  33. Hilliard, J., Pang, C.N., and Sawyer, C.H., 1976, Effects of luteinizing hormone releasing hormone on fetal survival in pregnant rabbits, Ferri!. Steril. 27: 421.Google Scholar
  34. Hsueh, A.J.W., 1979, Extrapituitary action of gonadotropin releasing hormone (GnRH): Direct inhibition of ovarian and testicular responses, Program of the 61st Annual Meeting of the Endocrine Society, Anaheim, California, Abstract 198.Google Scholar
  35. Hsueh, A.J.W., and Erickson, G.F., 1979, Extrapituitary action of gonadotropin-releasing hormone: Direct inhibition of ovarian steroidogenesis, Science 204: 854.CrossRefGoogle Scholar
  36. Hsueh, A.J., Dufau, M.L., and Catt, K.J., 1976, Regulation of luteinizing hormone receptors in testicular interstitial cells by gonadotropin, Biochem. Biophys. Res. Commun. 72: 1145.CrossRefGoogle Scholar
  37. Hsueh, A.J.W., Dufau, M.L., and Catt, K.J., 1977, Gonadotropin-induced regulation of luteinizing hormone receptors and desensitization of testicular 3’,5’-cyclic AMP and testosterone responses, Proc. Natl. Acad. Sci. U.S.A. 74: 592.CrossRefGoogle Scholar
  38. Humphrey, R.R., Windsor, B.L., Reel, J.R., and Edgren, R.A., 1977, The effects of luteinizing hormone (LHRH) in pregnant rats. 1. Postnidatory effects, Biol. Reprod. 16: 614.CrossRefGoogle Scholar
  39. Johnson, E.S., Gendrich, R.L., and White, W.F., 1976a, Delay of puberty and inhibition of reproductive processes in the rat by a gonadotropin-releasing hormone agonist analog, Fertil. Steril. 27: 853.Google Scholar
  40. Johnson, E.S., Seely, J.H., White, W.F., and DeSombre, E.R., 19766, Endocrine-dependent rat mammary tumor regression: Use of a gonadotropin releasing hormone analog, Science 194: 329.Google Scholar
  41. Khodr, G.S., and Siler-Khodr, T., 1978a, Localization of luteinizing hormone-releasing factor in the human placenta, Fertil. Steril. 29: 523.Google Scholar
  42. Khodr, G.S., and Siler-Khodr, T., 1978b, The effect of luteinizing hormone-releasing factor on human chorionic gonadotropin secretion, Fertil. Steril. 30: 301.Google Scholar
  43. Kledzik, G.S., Cusan, L., Auclair, C., Kelly, P.A., and Labrie, F., 1978a, Inhibitory effect of a luteinizing hormone (LH)-releasing hormone agonist on rat ovarian LH and follicle-stimulating hormone receptor levels during pregnancy, Fertil. Steril. 29: 560.Google Scholar
  44. Kledzik, G.S., Cusan, L., Auclair, C., Kelly, Y.A., and Labrie, F., 1978b, Inhibition of ovarian luteinizing hormone (LH) and follicle-stimulating hormone receptor levels with an LH-releasing hormone agonist during the estrous cycle in the rat, Fertil. Steril. 30: 348.Google Scholar
  45. Koch, Y., Baram, T., Hazum, E., and Fridkin, M., 1977, Resistance to enzymatic degradation of LH-RH analogues possessing increased biological activity, Biochem. Biophys. Res. Common. 74: 488.CrossRefGoogle Scholar
  46. Koyama, T., Ohkura, T., Kumasaka, T., and Saito, M., 1978, Effect of postovulatory treatment with a luteinizing hormone-releasing hormone analog on the plasma level of progesterone in women, Fertil. Steril. 30: 549.Google Scholar
  47. Lemay, A., Labrie, F., Ferland, L., and Raynaud, J., 1979, Possible luteolytic effects of luteinizing hormone-releasing hormone in normal women, Fertil. Steril. 31: 29.Google Scholar
  48. Lemay, A., Labrie, F., and Raynaud, J.P., 1980, Luteolytic activity of LHRH and IDSer(TBU)’’,des-Gly-NH2“’JLHRH ethylamide: A new and physiological approach to contraception in women, /nt. J. Fertil. 5: 203.Google Scholar
  49. Macdonald, G.J., and Beattie, C.W., 1979, Pregnancy failure in hypophysectomized rats following LHRH administration, Life Sci. 24: 1103.CrossRefGoogle Scholar
  50. Matsuo, H., Baba, Y., Nair, R.M.G., Arimura, A., and Schally, A.V., 1971a, Structure of the porcine LH- and FSH-releasing hormone. I. The proposed animo acid sequence, Biochem. Biophys. Res. Commun. 43: 1334.CrossRefGoogle Scholar
  51. Matsuo, H., Arimura, A., Nair, R.M.G., and Schally, A.V., 1971b, Synthesis of the porcine LH- and FSH releasing hormone by the solid-phase method, Biochem. Biophys. Res. Commun. 45: 822.CrossRefGoogle Scholar
  52. Mayar, M.Q., Tarnaysky, G.K., and Reeves, J.J., 1979, Ovarian growth and uptake of iodinated D-Leu,des-Gly-NH,’“-LHRH ethylamide in HCG treated rats, Proc. Soc. Exp. Biol. Med. 161: 216.Google Scholar
  53. Nillius, S.J., Bergquist, C., and Wide, L., 1978, Inhibition of ovulation in women by chronic treatment with a stimulatory LRH analogue—a new approach to birth control?, Contraception 17: 537.CrossRefGoogle Scholar
  54. Pelletier, G., Cusan, L., Auclair, C., Kelly, P.A., Desy, L., and Labrie, F., 1978, Inhibition of spermatogenesis in the rat by treatment with [D-Ala“,des-Gly-NH210JLHRH ethylamide, Endocrinology 103: 641.CrossRefGoogle Scholar
  55. Rao, M.C., Richards, J.S., Midgley, A.R., Jr., and Reichert, L.E., Jr., 1977, Regulation of gonadotropin receptors by luteinizing hormone in granulosa cells, Endocrinology 101: 512.CrossRefGoogle Scholar
  56. Richards, J.S., Ireland, J.J., Rao, M.C., Bernath, G.A., Midgley, A.R., Jr., and Reichert, L.E., Jr., 1976, Ovarian follicular development in the rat: Hormone receptor regulation by estradiol, follicle stimulating hormone and luteinizing hormone, Endocrinology 99: 1562.CrossRefGoogle Scholar
  57. Rippel, R.H., and Johnson, E.S., 1976a, Regression of corpora lutea in the rabbit after injection of a gonadotropin-releasing peptide, Proc. Soc. Exp. Biol. Med. 152: 29.Google Scholar
  58. Rippel, R.H., and Johnson, E.S., 19766, Inhibition of HCG-induced ovarian and uterine weight augmentation in the immature rat by analogs of GnRH, Proc. Soc. Exp. Biol. Med. 152: 432.Google Scholar
  59. Rivier, J.E., and Vale, W.W., 1978, [o-pGlu’,D-Phe2,D-Trp.“]-LRF: A potent luteinizing hormone releasing factor antagonist in vitro and inhibitor of ovulation in the rat, Life Sci. 23: 869.Google Scholar
  60. Schally, A.V., Kastin, A.J., and Arimura, A., 1971, Hypothalamic follicle-stimulating hormone (FSH) and luteinizing hormone (LH)-regulating hormone: Structure, physiology, and clinical studies, Fertil. Steril. 22: 703.Google Scholar
  61. Sharpe, R.M., 1976, hCG-induced decrease in availability of rat testes receptors, Nature (London) 264: 644.Google Scholar
  62. Siler-Khodr, T.M., and Khodr, G.S., 1978, Content of luteinizing hormone-releasing factor in the human placenta, Am. J. Obstet. Gynecol. 130: 216.Google Scholar
  63. Taymor, M.L., 1974, The use of luteinizing hormone-releasing hormone in gynecologic endocrinology, Fertil. Steril. 25: 992.Google Scholar
  64. Vale, W., Rivier, C., Brown, M., Leppaluoto, J., Ling, N., Monahan, M., and Rivier, J., 1976, Pharmacology of hypothalamic regulatory peptides, Clin. Endocrinol. 5 (Suppl.): 2615.CrossRefGoogle Scholar
  65. Vilchez-Martinez, J.A., Pedroza, E., Arimura, A., and Schally, A.V., 1979, ParadoxicalGoogle Scholar
  66. effects of o-Trp“-leuteinizing hormone-releasing hormone on the hypothalamic pituitary—gonadal axis in immature female rats, Fertil. Steril. 31:677.Google Scholar
  67. Windsor, B.L., Humphrey, R.R., Reel, J.R., and Edgren, R.A., 1977, Postnidatory effects of luteinizing hormone releasing hormone (LHRH) in hamsters, Int. J. Fertil. 22: 184.Google Scholar
  68. Ying, S., and Guillemin, R., 1979, (o-Trp6-Pro9-NEt)-Luteinizing hormone-releasing factor inhibits follicular development in hypophysectomized rats, Nature (London) 280: 593.Google Scholar
  69. Yoshinaga, K., 1978, Effect of an LHRH analog on the pituitary function of pregnant rats, Program of the 60th Annual Meeting of the Endocrine Society, Miami, Florida, Abstract 495.Google Scholar

Copyright information

© Plenum Press, New York 1981

Authors and Affiliations

  • Frederick J. Bex
    • 1
  • Alan Corbin
    • 1
  1. 1.Endocrinology SectionWyeth Laboratories, Inc.PhiladelphiaUSA

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