MECHANISM OF THE INHIBITORY-ACTION OF RU486 ON THE SECONDARY FOLLICLE-STIMULATING-HORMONE SURGE

Recent evidence utilizing RU486 has implicated progesterone (P) and gl ucocorticoids, in addition to a drop in serum inhibin, in the developm ent of the secondary FSH surge on the morning of estrus. To assess the role of these steroids, we treated proestrous female rats with the an tiprogestin/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 biosynt hesis inhibitor aminoglutethimide (AG; 150 mg/kg ip) at 1030 h, alone or in combination with RU486. The effects of these treatments on uteri ne ballooning and intraluminal fluid content (an index of P action), o vulation, and serum levels of P, corticosterone (B), FSH, LH, and inhi bin-alpha at 1830 h proestrus and 0900 h estrus were examined. Tn acco rd with previous work from our laboratory, RU486 caused uterine intral uminal fluid retention on the morning of estrus and significantly supp ressed the preovulatory surges of both FSH and LH, and the secondary s urge of FSH without affecting the fall in inhibin-alpha. Treatment wit h dex alone raised serum FSH at both 1830 h proestrus and 0900 h estru s, coincident with suppression of serum inhibin-alpha. When administer ed in combination with RU486, dex partially reversed the increased ute rine 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 sig nificantly suppressed serum P , B, and gonadotropins (LH to a greater extent than FSH) at 1830 h pro estrus 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 befo re RU486, AG did not prevent the RU486-induced inhibition of the prima ry gonadotropin surges or the secondary FSH surge. We conclude from th ese results that development of the secondary FSH surge does not requi re P or glucocorticoid action and that RU486 suppression of the second ary FSH surge does not involve blockade of binding of these steroids t o their receptors. Our data are compatible with ligand-independent act ivation of the P receptor, susceptible to blockade by RU486, as the me chanism underlying the enhanced secretion of FSH from the gonadotrope on the morning of estrus.