Pharmacological Profile of RU 486 in Animals

  • D. Philibert
  • M. Moguilewsky
  • I. Mary
  • D. Lecaque
  • C. Tournemine
  • J. Secchi
  • R. Deraedt
Part of the Reproductive Biology book series (RBIO)

Summary

RU 486 is an original multifaceted antihormone. It appears to be a potent progestin and glucocorticoid antagonist while exhibiting no agonistic effect, even at very high doses. Thus, according to the bioassay used, RU 486 administered orally at doses between 3 and 20 mg/kg completely inhibits the effect of exogenous progesterone on the endometrial proliferation in rabbits, on the volume density of uterine gland cell mitochondria, on the deciduomata formation and on the maintenance of pregnancy in ovariectomized rats. Furthermore, it proves to be antinidatory and abortive in rats and mice. In cycling monkeys it induces menstruation when administered during the mid-luteal phase.

Acting as an antiglucocorticoid component, RU 486 effectively antagonizes, at 10M−6, dexamethasone’s effect on uridine incorporation into rat thymocytes RNA and on ACTH secretion from rat pituitary cells. In vivo (at a dose of 10 mg/kg to adrenalectomized rats) it fully prevents the thymolytic effect of corticosterone and dexamethasone; it also completely blocks urinary volume increase and potassium excretion induced by dexamethasone. In this latter test, its antiglucocorticoid activity is rapidly and fully reversed by increasing doses of dexamethasone. Using a perifusion technique, we observe that RU 486 does not inhibit corticosterone biosynthesis in rat adrenal cells stimulated by ACTH. The compound also possesses a moderate antiandrogenic activity on seminal vesicles and prostate weights, about 20 times weaker than its two other antagonist properties (evaluated in rats). In various species (rats, rabbits and mice) it exhibits a slight uterotrophic activity, approximately 10,000 times weaker than that of estradiol; but, unlike estrogens, it fails to induce estrus in ovariectomized rats given up to 300 mg/kg. When RU 486 is administered chronically for 15 days in adult female rats, it displays no antiovulatory activity; on the contrary, it provokes dose-dependent increases in serum LH and progesterone levels and ovarian weight.

Keywords

Estrogen Cortisol Testosterone Tryptophan Androgen 

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References

  1. Allen, E., and Doisy, E., 1923, An ovarian hormone. Preliminary report on its localization. Extraction and partial purification and action in test animals, J. Am. Med. Ass., 81: 819CrossRefGoogle Scholar
  2. Azadian-Boulanger, G., Secchi, J., and Sakiz, E., 1971, Biological study of the antiprogesterone effect of R 2323, Excerpta Med. Inst. Congr. Ser., 278:129Google Scholar
  3. Baxter, J. D., and Rousseau, G. G., eds., 1979, in: “Glucocorticoid Hormones Action,” Springer-Verlag, New York.Google Scholar
  4. Bennett, J. P., Valiance, D. K., and Vickery, B. H., 1967, A method for the direct observation of ovulation in the mature rat, J. Reprod. Fert., 13: 567.CrossRefGoogle Scholar
  5. Bourgeois, S., Pfahl, M., and Baulieu, E. E., 1984, DNA binding properties of glucocorticosteroid receptors bound to the steroid antagonist RU 486, The EMBO Journal, 3: 751.PubMedGoogle Scholar
  6. Chambon, Y., 1952, Sur le conditionnement endocrinien du déciduome traumatique chez la rate castrée, C. R. Soc. Biol., 146: 1095.Google Scholar
  7. Chasserot-Golaz, S., and Beck, G., An approach to the mechanism of the potent antiglucocorticoid: 176-hydroxy-l1ß 4-dimethylaminophenyl-17alpha-propynyl-estra-4, 9-dien-3-one, submitted to J. Ster. Biochem.Google Scholar
  8. Chobert, M. N., Barouki, R., Finidor, J., Aggerbeck, M., Hanoune, J., Philibert, D., and Deraedt, R., 1983, Antiglucocorticoid properties of RU 38 486 in a differentiated hepatoma cell line, Biochem. Pharmacol., 32: 3481.PubMedCrossRefGoogle Scholar
  9. Chrousos, G. P., Barnes, K. M Sauer, M. A., Loriaux, D. L., and Cutler, G.B., Jr., 1980, deltal,9 1)_11-deoxycortisol, An improved glucocorticoid antagonist, Endocrinology, 107: 472.Google Scholar
  10. Chrousos, G. P., Cutler, G. B., Jr., Simons, S. S., Jr., Pons, M., Loriaux, D. L., John, L. S., and Moriarty, R. M., 1982a, Development of antiglucocorticoids with potential clinical usefulness in: “Progress in Research and Clinical Applications of Corticosteroids,” H. J. Lee and T. J. Fitzgerald, eds., Heyden and Son Co., Philadelphia.Google Scholar
  11. Chrousos, G. P., Sauer, M. A., Cutler, G. B., Jr., and Loriaux, D. L., 1982b, deltal-11-oxa-11-Deoxycortisol: A new antiglucocorticoid with activity in vivo, Steroids, 40: 425.PubMedCrossRefGoogle Scholar
  12. Chrousos, G. P., Cutler, G. B., Jr., Sauer, M., Simons, S. S., Jr., Loriaux, D. L., 1983, Development of glucocorticoid antagonists, Pharmac. Ther., 20: 263.Google Scholar
  13. Chrousos, G. P., Nieman, L., Healy, D., Spitz, I., Hodgen, G., Bardin,C. W., Cutler, G. B. Jr., Schulte, H. M., Merriam, G. R., Brandon,D. D., and Loriaux, D. L., Antiglucocorticoids: General aspects and clinical implications.Google Scholar
  14. Cutler, G. B., Jr., Barnes, K. M., Sauer, M. A., and Loriaux, D. L., 1979, 11-Deoxycortisol: A glucocorticoid antagonist in vivo, Endocrinology, 104: 1839.Google Scholar
  15. Dausse, J. P., Duval, D., Meyer, P., Gaignault, J. C., Marchandeau, C., and Raynaud, J. P., 1977, The relationship between glucocorticoid structure and effects upon thymocytes, Mol. Pharmacol., 13: 948.Google Scholar
  16. Dunnett, C. W., 1955, A multiple comparison procedure for comparing several treatments with a control, Am. Stat. Assoc. J., 50: 1096.Google Scholar
  17. Duval, D., Durant, S., and Homo-Delarche, F., 1984, Effect of antiglucocorticoids on dexamethasone-induced inhibition of uridine incorporation and cell lysis in isolated mouse thymocytes, J. Steroid Biochem., 20: 283.PubMedCrossRefGoogle Scholar
  18. Gagne, D., Pons, M., and Philibert, D., RU 486, a potent antiglucocorticoid in vitro and in vivo, submitted to J. Steroid Biochem.Google Scholar
  19. Healy, D. L., Baulieu, E. E., and Hodgen, G. D., 1983, Induction of menstruation by an antiprogesterone steroid (RU 486) in primates: site of action, dose-response relationship, and hormonal effects, Fertility and Sterility, 4: 253.Google Scholar
  20. Johnson Bía, M., Tyler, K., and De Fronzo, R. A., 1982, The effect of dexamethasone on renal electrolyte excretion in the adrenalectomized rat, Endocrinology, 111: 882.PubMedCrossRefGoogle Scholar
  21. Jung-Testas, I., and Baulieu, E. E., 1984, Anti-steroid action in cultured L-929 mouse fibroblasts, J. Steroid Biochem., 20: 301.PubMedCrossRefGoogle Scholar
  22. Kagawa, C., 1960, Blocking the renal electrolyte effects of mineralocorticoids with an orally active steroidal spironolactone, Endocrinology, 67: 125.PubMedCrossRefGoogle Scholar
  23. Kaiser, N., Milholland, R. J., Turnell, R. W., and Rosen, F., 1972, Cortexolone: binding to glucocorticoid receptors in rat thymocytes and mechanism of its antiglucocorticoid action, Biochem. Biophys. Res. Comm., 49: 516.Google Scholar
  24. Kendle, K. E., 1979, Current investigations of antiprogestational steroids, in: “Antihormones,” M. K. Agarwal, ed., Elsevier/North Holland Biomedical Press, New York.Google Scholar
  25. Kendle, K. E., 1982, Advances in the study of antiprogestational agents, in: “Hormone Antagonists,” M. K. Agarwal, ed., Walter de Gruyter, Berlin and New York.Google Scholar
  26. Leboulanger, F., Delarue, C., Tonon, M. C., Jegou, S., and Vaudry, H., 1978, In vitro study of frog ( Rana redebunda Pallas) interrenal function by use of a simplified perifusion system, Gen. Comp. Endocrinol., 36: 327.CrossRefGoogle Scholar
  27. Ljunkvist, I., 1971, Attachment reaction of rat uterine luminal epithelium. II. The effect of progesterone on the morphology of the uterine glands and the luminal epithelium on the spayed virgin rat, Acta Soc. Med. Uppsalien, 76: 110.Google Scholar
  28. Lowry, P. J., McMartin, C., and Peteras, J., 1973, Properties of a simplified bioassay for adrenocorticotrophic activity using the steroidogenic response of isolated cells, J. Endocr., 59: 43.PubMedCrossRefGoogle Scholar
  29. McGinty, D. A., Anderson, L. P., and McCullough, N. B., 1939, Effect of local application of progesterone on the rabbit uterus, Endocrinology, 24: 829.CrossRefGoogle Scholar
  30. McPhail, M. K., 1934, The assay of progestin, J. Physiol., Lond., 83: 145.Google Scholar
  31. Nilsson, O., 1975, Influence of progesterone on the mitochondrial size in the uterine glands of the rat, mouse, hamster and guinea-pig, Acta Endocr., 78: 349.PubMedGoogle Scholar
  32. Philibert, D., Deraedt, R., and Teutsch, G., 1981, RU 38486: a potent antiglucocorticoid in vivo, VIII Int. Congr. of Pharmacology, Tokyo, abstract no. 1463.Google Scholar
  33. Philibert, D., Deraedt, R., Teutsch, G., Tournemine, C., and Sakiz, E., 1982, A new lead for steroidal antihormones, Endocrine Society, 64th annual meeting, San Francisco, abstract no. 668.Google Scholar
  34. Philibert, D., 1984, RU 38 486: an original multifaceted antihormone in vivo, in: “Adrenal Steroid Antagonism,” M. K. Agarwal, ed., Walter de Gruyter and Co., Berlin and New York.Google Scholar
  35. Potts, G. O., Greange, J. E., Harding, H. R., and Schane, H. P., 1978, Trílostane: an orally active inhibitor of steroid biosynthesis, Steroids, 32: 257.PubMedCrossRefGoogle Scholar
  36. Raynaud, J. P., 1977, R5020, a tag for the progestin receptor, in: “Progesterone Receptors in Normal and Neoplastic Tissues,” W. L. McGuire, J. P. Raynaud and E. E. Baulieu, eds., Raven Press, New York.Google Scholar
  37. Rotsztejn, W. H., Dusaillant, M., Nobou, S., and Rosselin, G., 1981, Rapid glucocorticoid inhibition of vasoactive peptide (VIP)-induced cyclic AMP accumulation and prolactin release on rat anterior pituitary cells in culture, Proc. Natl. Acad. Sci. USA, 78: 7584.Google Scholar
  38. Rousseau, G. G., Kirchhoff, J., Formstecher, P., and Lustenberger, P., 1979, 17–43 carboxamides steroids are a new class of glucocortícoid antagonists, Nature, 279: 158.Google Scholar
  39. Rubin, B. L., Dorfman, A. S., Black, L., and Dorfman, R. I., 1951, Bioassay of estrogens using the mouse uterine response, Endocrinology, 49:429. Sakiz, E., and Azadian-Boulanger, G., 1971, R 2323, An original contraceptive compound, Excerpta Med. Int. Congr. Ser., 219: 865.Google Scholar
  40. Sakly, M., Philibert, D., Lutz-Bucher, B., and Koch, B., 1984, Paradoxical involvement of glucocorticoid receptors in the aldosterone-induced impairment of ACTH secretion from perifused pituitary glands, J. Steroid Biochem, 20: 1101PubMedCrossRefGoogle Scholar
  41. Secchi, J., and Lecaque, D., 1984, Effects of progestins and antiprogestins on mitochondria in uterine glandular cells in the rat: a quantitative investigation, Cell and Tissue Res., 238: 247.CrossRefGoogle Scholar
  42. Simons, S. S., Jr., Thompson, E. B., and Johnson, D. F., 1980, Unique long active antiglucocorticoid in whole and broken cell systems, Proc. Natl. Acad. Sci. USA, 77: 5167PubMedCrossRefGoogle Scholar
  43. Simons, S. S., Jr., and Thompson, E. B., 1981, Dexamethasone-2l-mesylate: An affinity label of glucocorticoid receptors from rat hepatoma tissue culture cells, Proc. Natl. Acad. Sci. USA, 78: 3541.PubMedCrossRefGoogle Scholar
  44. Tachi, C., and Tachi, S., 1974, Cellular aspects of ovum implantation and decidualization in the rat, in: “Physiology and the Genetics of Reproduction,” Part B, E. M. Coutinho and F. Fuchs, eds., Plenum Press, New York and London.Google Scholar

Copyright information

© Plenum Press, New York 1985

Authors and Affiliations

  • D. Philibert
    • 1
  • M. Moguilewsky
    • 1
  • I. Mary
    • 1
  • D. Lecaque
    • 1
  • C. Tournemine
    • 1
  • J. Secchi
    • 1
  • R. Deraedt
    • 1
  1. 1.Centre de Recherches Roussel UclafRomainvilleFrance

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