Contraception
Volume 53, Issue 1 , Pages 55-64 , January 1996

Inhibition of ovulation by progestin analogs (agonists vs antagonists): Preliminary evidence for different sites and mechanisms of actions

  • Oskari Heikinheimo

      Affiliations

    • The Jones Institute for Reproductive Medicine, Department of Obstetrics and Gynecology, Eastern Virginia Medical School, 601 Colley Avenue, Norfolk, VA 23507, USA
    • Steroid Research Laboratory, Department of Medical Chemistry, University of Helsinki, P.O. Box 8, SF-00014, Helsinki, Finland
    • ,
  • Keith Gordon

      Affiliations

    • Corresponding Author InformationName and address for correspondence: Keith Gordon, Ph.D., The Jones Institute for Reproductive Medicine, Department of Obstetrics and Gynecology, Eastern Virginia Medical School, 601 Colley Avenue, Norfolk, VA 23507. Tel: (804) 446-8948; Fax (804) 446-8998
    • The Jones Institute for Reproductive Medicine, Department of Obstetrics and Gynecology, Eastern Virginia Medical School, 601 Colley Avenue, Norfolk, VA 23507, USA
    • ,
  • Robert F. Williams

      Affiliations

    • The Jones Institute for Reproductive Medicine, Department of Obstetrics and Gynecology, Eastern Virginia Medical School, 601 Colley Avenue, Norfolk, VA 23507, USA
    • ,
  • Gary D. Hodgen

      Affiliations

    • The Jones Institute for Reproductive Medicine, Department of Obstetrics and Gynecology, Eastern Virginia Medical School, 601 Colley Avenue, Norfolk, VA 23507, USA

Received 4 August 1995 ,Revised 24 October 1995 ,Accepted 27 October 1995.

References 

  1. Goodman A, Hodgen G. Systemic versus intraovarian progesterone replacement after luteectomy in rhesus monkeys: differential patterns of gonadotropins and follicular growth. Endocrinology. 1977;45:837–840
  2. Hodgen G. Selection and ovulation of the dominant follicle: role of intraovarian progesterone. In:  van der Molen HJ,  Klopper A,  Lunenfeld B, et al. editor. Hormonal factors in fertility, infertility and contraception. Amsterdam-Oxford-Princeton: Elsevier Science Publishing; 1981;p. 28–44
  3. Goodman A, Hodgen G. Antifolliculogenic action of progesterone despite hypersecretion of FSH in monkeys. Am J Physiol. 1982;243:E387–E397
  4. Lobo R, Stanczyk F. New knowledge in the physiology of hormonal contraceptives. Am J Obstet Gynecol. 1994;170:1499–1507
  5. Liu J, Garzo G, Morris S, Stuenkel C, Ulmann A, Yen S. Disruption of follicular maturation and delay of ovulation after administration of the antiprogesterone RU486. J Clin Endocrinol Metab. 1987;65:1135–1140
  6. Luukkainen T, Heikinheimo O, Haukkamaa M, Lahteenmaki P. Inhibition of folliculogenesis and ovulation by the antiprogesterone RU486. Fertil Steril. 1988;49:961–963
  7. Danforth D, Dubois C, Ulmann A, Baulieu EE, Hodgen G. Contraceptive potential of RU486 by ovulation inhibition. III: Preliminary observations on once weekly oral administration. Contraception. 1989;40:195–200
  8. Kettel M, Liu J, Murphy A, Ulmann A, Mortola J, Yen S. Endocrine responses to long-term administration of the antiprogesterone RU486 in patients with pelvic endometriosis. Fertil Steril. 1991;56:402–407
  9. Collins R, Hodgen G. Blockade of the spontaneous midcycle gonadotropin surge in monkeys by RU486: a progesterone antagonist or agonist. J Clin Endocrinol Metab. 1986;63:1270–1276
  10. Wolf J, Hsiu J, Anderson T, Ulmann A, Baulieu EE, Hodgen G. Noncompetitive antiestrogenic effect of RU486 in blocking the estrogen-stimulated luteinizing hormone surge and the proliferative action of estradiol on endometrium in castrate monkeys. Fertil Steril. 1989;52:1055–1060
  11. Dimattina M, Albertson B, Seyler DE, Loriaux L, Falk RJ. Effect of the antiprogestin RU486 on progesterone production by cultured human granulosa cells: inhibition of the ovarian 3β-hydroxysteroid dehydrogenase. Contraception. 1986;34:199–206
  12. Parinaud J, Perret B, Ribbes H, Vieitez G, Baulieu EE. Effects of RU486 on progesterone secretion by human preovulatory granulosa cells in culture. J Clin Endocrinol Metab. 1990;70:1534–1537
  13. Wolf J, Danforth D, Ulmann A, Baulieu EE, Hodgen G. Contraceptive potential of RU486 by ovulation inhibition: II. Suppression of pituitary gonadotropin secretion in vitro. Contraception. 1989;40:185–198
  14. Heikinheimo O, Gordon K, Lahteenmaki P, Williams R, Hodgen G. Antiovulatory actions of RU486—pituitary is not a primary site of antiprogestin action in vivo. J Clin Endocrinol Metab. 1995;1859–1868
  15. Gordon K, Hodgen GD, Richardson DW. Post-partum lactational anovulation in a nonhuman primate (Macaca fascicularis): endogenous opiate mediation of suckling-induced hyperprolactinemia. J Clin Endocrinol Metab. 1992;75:59–67
  16. Merriam G, Wachter K. Algorithms for the study of episodic hormone secretion. Am J Physiol. 1982;243:E310–E318
  17. Schreiber J, Nakamura K, Erickson G. Progestins inhibit FSH-stimulated steroidogenesis cultured rat granulosa cells. Mol Cel Endocrinol. 1980;19:165–173
  18. Fortune J, Vincent S. Progesterone inhibits the induction of aromatase activity in rat granulosa cells in vitro. Biol Reprod. 1983;28:1078–1089
  19. Suzuki T, Sasano H, Kimura N, Tamura M, Fukaya T, Yajima A, et al. Immunohistochemical localization of progesterone, androgen and oestrogen receptors in the human ovary during the menstrual cycle: relationship to expression of steroidogenic enzymes. Hum Reprod. 1994;9:1589–1594
  20. Park O-K, Mayo K. Transient expression of progesterone receptor messenger RNA in ovarian granulosa cells after the preovulatory luteinizing hormone surge. Mol Endocrinology. 1991;5:967–978
  21. Chandrasekher A, Brenner R, Molskness T, Yu Q, Stouffer R. Titrating luteinizing hormone surge requirements for ovulatory changes in primate follicles. II. Progesterone receptor expression in luteinizing granulosa cells. J Clin Endocrinol Metab. 1991;73:584–589
  22. Hild-Petito S, Stouffer R, Brenner R. Immunocytochemical localization of estradiol and progesterone receptors in the monkey ovary throughout the menstrual cycle. Endocrinology. 1988;123:2896–2905
  23. Suzuki T, Sasano H, Tamura M, Aoki H, Fukaya T, Yajima A, et al. Temporal and spatial localization of the steroidogenic enzymes in premenopausal human ovaries: in situ hybridization and immunohistochemical study. Mol Cell Endocrinol. 1993;97:135–143
  24. Wiebe H, Morris C. Effect on an oral contraceptive on adrenal and ovarian androgenic steroids. Obstet Gynecol. 1984;63:12–14
  25. Inkster S, Brodie A. Expression of aromatase cytochrome P-450 in premenopausal and postmenopausal human ovaries: an immunohistochemical study. J Clin Endocrinol Metab. 1991;73:717–726
  26. Soules M, Seiner R, Clifton D, Cohen N, Aksel S, Bremner W. Progesterone modulation of pulsatile luteinizing hormone secretion in women. J Clin Endocrinol Metab. 1984;58:378–383
  27. Wildt L, Hausler A, Marshall G, Hutchison J, Plant T, Belchetz P, et al. Frequency and amplitude of gonadotropin-releasing hormone stimulation and gonadotropin secretion in the rhesus monkey. Endocrinology. 1981;109:376–385
  28. Krey L, Padmanabhan V, Beitins I. Progesterone modulation of gonadotropin secretion by dispersed rat pituitary cells in culture. IV. Follicle-stimulating hormone synthesis and release. Mol Cell Endocrinol. 1993;91:13–20
  29. Poindexter A, Didly A, Brodyand S, Snabes M. The effects of a long-acting progestin on the hypothalamic-pituitary-ovarian axis in women with normal menstrual cycles. Contraception. 1993;48:37–45
  30. Coutzinet B, Schaison G. The control of gonadotropin secretion by ovarian steroids. Hum Reprod. 1993;8:97–101
  31. Ortmann O, Catt K, Schulz KD, Emons G. Modulatory action of progesterone and progesterone antagonist on hypothalamic-pituitary function. Hum Reprod. 1994;9:53–62 (Suppl)
  32. Coutzinet B, Brailly S, Bouchard P, Schaison G. Progesterone stimulates luteinizing hormone secretion by acting directly on the pituitary. J Clin Endocrinol Metab. 1992;74:374–378
  33. Batista M, Cartledge T, Zellmer A, Nieman L, Loriaux L, Merriam G. The antiprogestin RU486 delays the midcycle gonadotropin surge and ovulation in gonadotropin-releasing hormone-induced cycles. Fertil Steril. 1994;62:28–34
  34. Dubourdieu S, Charbonnel B, d'Acremont MF, Carreau S, Spitz I, Bouchard P. Effect of administration of a gonadotropin-releasing hormone (GnRH) antagonist (NalGlu) during the periovulatory period: the luteinizing hormone surge requires secretion of GnRH. J Clin Endocrinol Metab. 1994;78:343–347
  35. Xia L, van Vugt D, Alston E, Luckhaus J, Ferin M. A surge of gonadotropin-releasing hormone accompanies the estradiol-induced gonadotropin surge in the rhesus monkey. Endocrinology. 1992;131:2812–2820
  36. Lahteenmaki P, Lahteenmaki P. Concentration dependent mechanism of ovulation inhibition by the progestin ST-1435. Fertil Steril. 1985;44:20–24
  37. Lahteenmaki P, Weiner E, Lahteenmaki P, Johansson E, Luukkainen T. Contraception with subcutaneous capsules containing ST-1435. Pituitary and ovarian function and plasma levels of ST-1435. Contraception. 1981;23:63–75
  38. Ledger W, Sweeting V, Hillier H, Baird D. Inhibition of ovulation by low dose mifepristone (RU486). Hum Reprod. 1992;7:945–950
  39. Croxatto H, Salvatierra AM, Croxatto H, Fuentealba B. Effects of continuous treatment with low dose mifepristone throughout one menstrual cycle. Hum Reprod. 1993;8:201–207

☆ Presented at the 42nd Annual Meeting of the Society for Gynecologic Investigation, Chicago, IL, March 15–18, 1995

PII: 0010-7824(95)00255-3

Contraception
Volume 53, Issue 1 , Pages 55-64 , January 1996

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