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Journal of Endocrinological Investigation

, Volume 23, Issue 3, pp 151–157 | Cite as

Comparison of the effects of antiprogestins RU38486, ZK98299 and ORG31710 on periovulatory hypophysial, ovarian and adrenal hormone secretion in the rat

  • José E. Sánchez-Criado
  • M. Tébar
  • C. Bellido
  • F. H. de Jong
Original Article

Abstract

The antiprogestin (AP) RU38486 (RU) blocks progesterone (P) and glucocorticoid (G) actions. Administration of 4 mg RU on proestrous morning to cyclic rats dissociates LH and FSH secretion on proestrous afternoon, early estrus and on estrous afternoon. In order to ascertain which action blocked by RU is predominant in the control of periovulatory LH and FSH secretion, a study was made on the effects of: a) 1 or 4 mg of ZK98299 (ZK) (type I P antagonist; Schering), b) 2 or 8 mg of Org31710 (OR) (type II P antago-nist lacking anti-G actions; Organon) or c) 1 or 4 mg of RU (type II P antagonist; Exelgyn) to 4-day cyclic rats on proestrous morning on serum concentrations of LH, FSH, inhibin-α (I), estradiol-17ß (E), progesterone (P) and corticosterone (B) at 18:30 h on proestrus and at 02:00 and 18:30 h on estrus. Controls, receiving 0.2 ml oil, had elevated serum concentrations of all six hormones on proestrous afternoon; at early estrus, only serum concentrations of FSH and P remained elevated, and, on estrous afternoon, all hormones but I and B, that peaked again, had reached their lowest serum levels. All AP treatments except 1 mg ZK had the same effects. On proestrous af-ternoon serum LH concentrations were reduced and serum FSH concentrations were suppressed whereas serum levels of I, E, P and B were unaffected. At early estrus, basal serum concentrations of LH and E increased while FSH secretion was abolished. Serum levels of I, P and B did not differ from controls. AP treatments increased basal LH concentration, hyperstimulated FSH secretion and reduced serum I concentration on the afternoon of estrus. E, P and B serum levels did not differ from controls at this stage. Treatment with 1 mg ZK was less effective in reducing serum FSH on proestrous afternoon and at early estrus, and had no effect on serum concentrations of any hormone on estrous afternoon. These results indicate that blockade of P receptor activation by P is, predominantly, the mechanism of AP action on periovulatory gonadotropin secretion in rats.

Keywords

Luteinizing Hormone Corticosterone Estrous Cycle Inhibin Gonadotropin Surge 
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. 1.
    Freeman M.E. The ovarian cycle of the rat. In: Knobil E., Neill J. (Eds.), The Physiology of Reproduction. Raven Press Ltd., New York, 1988, vol. 2, p. 1893.Google Scholar
  2. 2.
    Grady R.R., Schwartz N.B. Role of gonadal feedback in the differential regula tion of LH and FSH. In: Franchimont P., Channing C.P. (Eds.), Intrago-nadal Regulation of Reproduction. Academic Press, London, 1981, p. 377.Google Scholar
  3. 3.
    Chappel S. Factors that regulate follicle stimulating hormone biosynthesis and secretion. In: Burger H.G., de Kretser D.M., Findlay J.K., Igarashi M. (Eds.), Inhibin-Non-Steroidal Regulation of Follicle Stimulating Hormone Secretion. Raven Press, New York, 1987, p. 1.Google Scholar
  4. 4.
    Baulieu E.E. Contragestion and other clinical applications of RU486, an antiprogestagen at the receptor. Science 1989, 245: 1351–1357.PubMedCrossRefGoogle Scholar
  5. 5.
    Rao I.M., Mahesh V.B. Role of progesterone in the modulation of the pre-ovulatory surge of gonadotropins and ovulation in the pregnant mare’s serum gonadotropin primed immature rat and the adult rat. Biol. Reprod. 1986, 35: 1154–1161.PubMedCrossRefGoogle Scholar
  6. 6.
    Knox K.L., Ringstrom S.J., Schwartz N.B. RU486 Block the effects of inhibin or luteinizing hormone on the second follicle-stimulating hormone surge. Endocrinology 1993, 133: 277–283.PubMedGoogle Scholar
  7. 7.
    Tébar M., Bellido C., Sánchez-Criado J.E. Luteinizing hormone (LH) and corticosterone in proe-strous afternoon restore the follicle-stimulating hormone secretion at early estrus in adrenalectomized LH-releasing hormone antagonist-treated rats. Biol. Reprod. 1995, 52: 63–67PubMedCrossRefGoogle Scholar
  8. 8.
    Tébar M., Bellido C., Sánchez-Criado J.E. Evidence for a permissive effect of extraovarian steroids on the release of FSH at early estrus in rats lacking inhibin secretion or action. Neuroendocrinol. Let. 1995, 17: 21–27.Google Scholar
  9. 9.
    Sánchez-Criado J.E., Hernandez G., Bellido C., Gonzalez D., Tébar M., Diaz-Cruz A., Alonso R. Periovulatory LHRH, LH and FSH secretion in cyclic rats treated with RU486: effects of exogenous LHRH and LHRH antagonist on LH and FSH secretion at early oestrus. J. Endocrinol. 1994, 141: 7–14.PubMedCrossRefGoogle Scholar
  10. 10.
    Szabo M., Knox K.L., Ringstrom S.J., Perlyn C.A., Sutandi S., Schwartz N.B. Mechanism of the inhibitory action of RU486 on the secondary follicle-stimulating hormone surge. Endocrinology 1996, 137: 85–89.PubMedGoogle Scholar
  11. 11.
    Sánchez-Criado J.E., Tébar M., Ruiz A., Padrón L. The steroid antagonist RU486 given at pro-oestrus induces hypersecretion of follicle-stimulating hormone from oestrus afternoon to early metoestrus in the rat. Eur. J. Endocrinol. 1997, 137: 281–286.PubMedCrossRefGoogle Scholar
  12. 12.
    Tébar M., Ruiz A., Gaytán F., Sánchez-Criado J.E. Follicular and luteal progesterone play different roles synchronizing pituitary and ovarian events in the 4-day cyclic rat. Biol. Reprod. 1995, 53: 1183–1189.PubMedCrossRefGoogle Scholar
  13. 13.
    Horwitz K. The molecular biology of RU486. Is there a role for antiprogestins in the treatment of breast cancer? Endocr. Rev. 1992, 13: 146–163.PubMedGoogle Scholar
  14. 14.
    Philibert D., Moguilewsky M., Mary I., Lecaque D., Tournemine C., Secchi J., Deraedt R. Pharmacological profile of RU486 in animals. In: Baulieu E.E., Segal S.J. (Eds.), The Antiprogestin Steroid RU486 and Human Fertility Control. Plenum Press, New York, 1985, p. 49.CrossRefGoogle Scholar
  15. 15.
    Baulieu E.E. The antisteroid RU486. Its cellular and molecular mode of action. TEM 1991, 2: 233–239.PubMedGoogle Scholar
  16. 16.
    Waring D.W., Turgeon J.L. A pathway for luteinizing hormone releasing-hor-mone self potentiation: cross-talk with the progesterone receptor. Endocrinology 1992, 130: 3275–3282.PubMedGoogle Scholar
  17. 17.
    Turgeon J.L., Waring D.W. Activation of the progesterone receptor by the go-nadotropin-releasing hormone self-priming signaling pathway. Mol. Endocrinol. 1994, 8: 860–869.PubMedGoogle Scholar
  18. 18.
    Brann D.W., Putnam C.D., Mahesh V.B. Validation of the mechanism proposed for the stim ulatory and inhibitory effects of progesterone on go- nadotropin secretion in the estrogen-primed rat: a possible role for adrenal steroids. Steroids 1991, 56: 103–111.PubMedCrossRefGoogle Scholar
  19. 19.
    Brann D.W., Putnam C.D., Mahesh V.B. Corticosteroid regulation of gonadotropin and prolactin secretion in the rat. Endocrinology 1990, 126: 159–166.PubMedCrossRefGoogle Scholar
  20. 20.
    Levine J.E. New concepts of the neuroendocrine regulation of gonadotropin surges in rats. Biol. Reprod. 1997, 56: 293–302.PubMedCrossRefGoogle Scholar
  21. 21.
    Beck C.A., Zhang Y., Weigel N.L., Edwards D.P. Two types of antiprogestins have distinc effects on site-specific phosphorylation of human progesterone receptor. J. Biol. Chem. 1996, 271: 1209–1217.PubMedCrossRefGoogle Scholar
  22. 22.
    Beck C.A., Estes P.A., Bona B.J., Muro-Cacho C.A., Nordeen S.K., Edwards D.P. The steroid antagonist RU486 exerts different ef-fects on the glucocorticoid and progesterone re-ceptors. Endocrinology 1993, 133: 728–740.PubMedGoogle Scholar
  23. 23.
    Mizutani T., Bhakta A., Kloosteroboer H.J., Moudgil V.K. Novel anti-progestins Org31806 and Org31710 in-teraction with mammalian progesterone receptor and DNA binding of anti-steroid receptor com-plexes. J. Steroid Biochem. Mol. Biol. 1992, 42: 695–704.PubMedCrossRefGoogle Scholar
  24. 24.
    Greenwood F.C., Hunter W.M., Glover J.S. The preparation of 131-I-labeled human growth hormone of high specific radioactivity. Biochem. J. 1963, 89: 114–123.PubMedCentralPubMedGoogle Scholar
  25. 25.
    Robertson D.M, Hayward S., Irby D., Jacobse J., Clarke L., McLachlan R.L., de Kretser D.M. Radioimmunoassay of rat serum inhibin: changes af ter PMSG stimulation and gonadectomy. Mol. Cell. Endocrinol. 1988, 58: 1–8.PubMedCrossRefGoogle Scholar
  26. 26.
    Grootenhuis A.J., Steenbergen J., Timmerman M.A., Dorsman A.N., Schaaper W.M., Meloen R.H., de Jong F.H. Inhibin and activin-like activity in fluids from male and female gonads: different molecular weight form and bioactivity/immunoactivity ratios. J. Endocrinol. 1989, 122: 293–301.PubMedCrossRefGoogle Scholar
  27. 27.
    McDonnell D.P. Unraveling the human progesterone receptor sig-nal transduction pathway. Insights into antiproge-stin action. TEM 1995, 6: 133–138.PubMedGoogle Scholar
  28. 28.
    Shaikh A.A., Shaikh S.A. Adrenal and ovarian steroid secretion in the rat es-trous cycle temporally related to gonadotropins and steroid levels found in peripheral plasma. Endocrinology 1975, 96: 37–44.PubMedCrossRefGoogle Scholar
  29. 29.
    Buckingham J.C., Döhler K.D., Wilson C.A. Activity of the pituitary-adrenocortical system and thyroid gland during the oestrous cycle of the rat. J. Endocrinol. 1978, 78: 359–366.PubMedCrossRefGoogle Scholar
  30. 30.
    DePaolo L.V. Attenuation of preovulatory gonadotropin surges by epostane: a new inhibitor of 39-hydroxysteroid de-hydrogenase. J. Endocrinol. 1988, 118: 59–68.PubMedCrossRefGoogle Scholar
  31. 31.
    Mahesh V.B., Brann D.W. Interactions between ovarian and adrenal steroids in the regulation of gonadotropin secretion. J. Steroid Biochem. Mol. Biol. 1992, 41: 495–513.PubMedCrossRefGoogle Scholar
  32. 32.
    Szabo M., Kilen S.M., Saberi S., Ringstrom S.J., Schwartz N.B. Antiprogestins suppress basal and activin-stimulat-ed follicle-stimulating hormone secretion in an estrogen dependent manner. Endocrinology 1998, 139: 2223–2228.PubMedGoogle Scholar
  33. 33.
    Freeman M.E., Dupke K.C., Croteau C.M. Extintion of the estrogen-induced daily signal for LH release in the rat: a role for the proestrous surge of progesterone. Endocrinology 1976, 99: 223–229.PubMedCrossRefGoogle Scholar
  34. 34.
    Lustig R.H., Pfaff D.W., Fishman J. Induction of LH hypersecretion in cyclic rats during the afternoon of oestrus by oestrogen in conjunction with progesterone antagonism or opioidergic blockade. J. Endocrinol. 1988, 117: 229–235.PubMedCrossRefGoogle Scholar
  35. 35.
    Hasegawa Y., Miyamoto K., Igarashi M. Changes in serum concentrations of immunoreactive inhibin during the oestrous cycle of the rat. J. Endocrinol. 1989, 121: 91–100.PubMedCrossRefGoogle Scholar
  36. 36.
    Tébar M., Ruiz A., Gonzalez D., Hernandez G., Alonso R., Sánchez-Criado J.E. Effect of RU486 on proestrous morning on LHRH, LH and 17ß-estradiol secretion during the estrous cycle in the rat. J. Physiol. Biochem. 1998, 54: 91–98.PubMedGoogle Scholar
  37. 37.
    Sarkar D.K., Fink G. Effects of gonadal steroids on output of luteinizing hormone releasing factor into pituitary stalk blood in the female rat. J. Endocrinol. 1979, 80: 303–313.PubMedCrossRefGoogle Scholar
  38. 38.
    McPherson J.C., Mahesh V.B. Dose related effects of a single injection of progesterone on gonadotropin secretion and pituitary sensitivity to LHRH in estrogen-primed castrate female rats. Biol. Reprod. 1979, 20: 763–772.PubMedCrossRefGoogle Scholar
  39. 39.
    Power R.F., Mani S.K., Codina J., Conneely O.M., O’Malley B.W. Dopaminergic and ligand-independent activation of steroid hormone receptors. Science 1991, 254: 1636–1639.PubMedCrossRefGoogle Scholar
  40. 40.
    Ignar-Trowbridge D.M., Teng C.T., Ross K.A., Parker M.G., Korach K.S., McLachlan J.A. Peptide growth factors elicit estrogen receptor-de-pendent transcriptional activation of an estrogen-responsive element. Mol. Endocrinol. 1993, 7: 992–998.PubMedGoogle Scholar
  41. 41.
    Katzenellenbogen B.S. Estrogen receptors: bioactivities and interactions with cell signalling pathways. Biol. Reprod. 1996, 54: 287–293.PubMedCrossRefGoogle Scholar
  42. 42.
    Mani S.K, Allen J.M.C., Clark J.H., Blaustein J.D., O’Malley B.W. Convergent pathways for steroid hormone-and neu-rotransmitter-induced rat sexual behavior. Science 1994, 265: 1246–1249.PubMedCrossRefGoogle Scholar
  43. 43.
    Ringstrom S.J., Szabo M., Kilen S.M., Saberi S., Knox K.L., Schwartz N.B. The antiprogestins RU486 and ZK98299 affect follicle stimulating hormone secretion differentially on estrus, but not on proestrus. Endocrinology 1997, 38: 2286–2290.Google Scholar

Copyright information

© Italian Society of Endocrinology (SIE) 2000

Authors and Affiliations

  • José E. Sánchez-Criado
    • 1
  • M. Tébar
    • 2
  • C. Bellido
    • 1
  • F. H. de Jong
    • 2
  1. 1.Department of Physiology, Faculty of MedicineUniversity of CórdobaCórdobaSpain
  2. 2.Department of Endocrinology and Reproduction, Faculty of Medicine and Health SciencesErasmus UniversityRotterdamThe Netherlands

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