Endocrinology, Vol 137, 85-89, Copyright © 1996 by Endocrine Society

ARTICLES

Mechanism of the inhibitory action of RU486 on the secondary follicle- stimulating hormone surge

M Szabo, KL Knox, SJ Ringstrom, CA Perlyn, S Sutandi and NB Schwartz
Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois 60208, USA.

Recent evidence utilizing RU486 has implicated progesterone (P) and glucocorticoids, in addition to a drop in serum inhibin, in the development of the secondary FSH surge on the morning of estrus. To assess the role of these steroids, we treated proestrous female rats with the antiprogestin/antiglucocorticoid RU486 (6 mg/kg sc) at 1230 h, and with dexamethasone (dex; 8.4 or 16.2 mg/kg sc), or with the steroid biosynthesis inhibitor aminoglutethimide (AG; 150 mg/kg ip) at 1030 h, alone or in combination with RU486. The effects of these treatments on uterine ballooning and intraluminal fluid content (an index of P action), ovulation, and serum levels of P, corticosterone (B), FSH, LH, and inhibin-alpha at 1830 h proestrus and 0900 h estrus were examined. In accord with previous work from our laboratory, RU 486 caused uterine intraluminal fluid retention on the morning of estrus and significantly suppressed the preovulatory surges of both FSH and LH, and the secondary surge of FSH without affecting the fall in inhibin-alpha. Treatment with dex alone raised serum FSH at both 1830 h proestrus and 0900 h estrus, coincident with suppression of serum inhibin-alpha. When administered in combination with RU486, dex partially reversed the increased uterine intraluminal fluid retention at 0900 h estrus, but did not modify the inhibitory effect of RU486 on the primary gonadotropin surges or the secondary surge of FSH. AG alone significantly suppressed serum P, B, and gonadotropins (LH to a greater extent than FSH) at 1830 h proestrus and blocked ovulation and uterine intraluminal fluid release at 0900 h estrus; it did not, however, suppress the secondary FSH surge or prevent the fall in serum inhibin- alpha. When administered 2 h before RU486, AG did not prevent the RU486- induced inhibition of the primary gonadotropin surges or the secondary FSH surge. We conclude from these results that development of the secondary FSH surge does not require P or glucocorticoid action and that RU486 suppression of the secondary FSH surge does not involve blockade of binding of these steroids to their receptors. Our data are compatible with ligand-independent activation of the P receptor, susceptible to blockade by RU486, as the mechanism underlying the enhanced secretion of FSH from the gonadotrope on the morning of estrus.

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