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Antifertility Effects of LH-RH and Its Agonists

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Reproductive Processes and Contraception

Part of the book series: Biochemical Endocrinology ((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.

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References

  • 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 

  • 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.

    Article  CAS  Google Scholar 

  • 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 

  • 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 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    CAS  Google Scholar 

  • Beattie, C.W., and Corbin, A., 1977, Pre-and postcoital contraceptive activity of LH-RH in the rat, Biol. Reprod. 16: 333.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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 

  • 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.

    Article  CAS  Google Scholar 

  • Bergquist, C., Nillius, S.J., and Wide, L., 19796, Intranasal gonadotropin-releasing hormone agonist as a contraceptive agent. Lancet 1979: 215.

    Google Scholar 

  • Bex, F.J., and Corbin, A., 1978, Inhibition of reproductive processes in the immature and

    Google Scholar 

  • 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 

  • 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.

    Article  CAS  Google Scholar 

  • 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 

  • 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.

    Article  CAS  Google Scholar 

  • 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 

  • 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.

    Article  CAS  Google Scholar 

  • Corbin, A., and Beattie, C.W., 1975b, Post-coital contraceptive and uterotrophic effects of luteinizing hormone releasing hormone, Endocr. Res. Commun. 2: 445.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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 

  • 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 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    CAS  Google Scholar 

  • 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.

    CAS  Google Scholar 

  • 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 

  • Hsueh, A.J.W., and Erickson, G.F., 1979, Extrapituitary action of gonadotropin-releasing hormone: Direct inhibition of ovarian steroidogenesis, Science 204: 854.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    CAS  Google Scholar 

  • 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 

  • Khodr, G.S., and Siler-Khodr, T., 1978a, Localization of luteinizing hormone-releasing factor in the human placenta, Fertil. Steril. 29: 523.

    CAS  Google Scholar 

  • Khodr, G.S., and Siler-Khodr, T., 1978b, The effect of luteinizing hormone-releasing factor on human chorionic gonadotropin secretion, Fertil. Steril. 30: 301.

    CAS  Google Scholar 

  • 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.

    CAS  Google Scholar 

  • 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.

    CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    CAS  Google Scholar 

  • 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.

    CAS  Google Scholar 

  • 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 

  • Macdonald, G.J., and Beattie, C.W., 1979, Pregnancy failure in hypophysectomized rats following LHRH administration, Life Sci. 24: 1103.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    CAS  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    CAS  Google Scholar 

  • 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 

  • 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 

  • 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.

    CAS  Google Scholar 

  • Sharpe, R.M., 1976, hCG-induced decrease in availability of rat testes receptors, Nature (London) 264: 644.

    Google Scholar 

  • 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.

    CAS  Google Scholar 

  • Taymor, M.L., 1974, The use of luteinizing hormone-releasing hormone in gynecologic endocrinology, Fertil. Steril. 25: 992.

    CAS  Google Scholar 

  • 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.

    Article  Google Scholar 

  • Vilchez-Martinez, J.A., Pedroza, E., Arimura, A., and Schally, A.V., 1979, Paradoxical

    Google Scholar 

  • effects of o-Trp“-leuteinizing hormone-releasing hormone on the hypothalamic pituitary—gonadal axis in immature female rats, Fertil. Steril. 31:677.

    Google Scholar 

  • 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.

    CAS  Google Scholar 

  • 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 

  • 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 

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Authors and Affiliations

  1. Endocrinology Section, Wyeth Laboratories, Inc., Philadelphia, Pennsylvania, 19101, USA

    Frederick J. Bex & Alan Corbin

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  1. Frederick J. Bex
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  2. Alan Corbin
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  1. The International Society for Biochemical Endocrinology, Blue Hill Falls, Maine, USA

    Kenneth W. McKerns

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© 1981 Plenum Press, New York

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Bex, F.J., Corbin, A. (1981). Antifertility Effects of LH-RH and Its Agonists. In: McKerns, K.W. (eds) Reproductive Processes and Contraception. Biochemical Endocrinology. Springer, Boston, MA. https://doi.org/10.1007/978-1-4684-3824-6_5

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  • DOI: https://doi.org/10.1007/978-1-4684-3824-6_5

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