Antiprogestins suppress basal and activin-stimulated follicle-stimulating hormone secretion in an estrogen-dependent manner.
Previous studies from our laboratory, demonstrating that suppression of serum FSH by RU486 requires a high estrogen (E) background, suggested that E-inducible progesterone receptors play a role in the regulation of FSH secretion. We demonstrated further that the type II antiprogestin RU486 and the type I antiprogestin ZK98299 both suppressed the elevated serum FSH and FSHbeta messenger RNA levels similarly on the evening of proestrus, but had divergent effects on the morning of estrus, when only RU486, but not ZK98299, lowered the elevated serum FSH level (secondary FSH surge). In the present work we used primary anterior pituitary cell culture to examine whether RU486 caused direct, E-dependent suppression of basal and recombinant human activin A (activin)-induced FSH secretion in the gonadotrope and to compare this direct effect, if any, with that of ZK98299. Primary cell cultures were prepared from anterior pituitaries collected from cycling female rats either on metestrous or proestrous morning and cultured in DMEM, supplemented with charcoal-stripped serum without or with 10 nM estradiol (E2) for 96 h; exposure to test agents occurred during the last 48 h of culture. FSH released into the medium and intracellular FSH content were determined by RIA. In cells from the anterior pituitary of metestrous rats cultured in E2-free medium, neither antiprogestin (10 nM) affected FSH release; in contrast, when cells were cultured in medium to which E2 had been added, both antiprogestins caused profound suppression of both basal and activin (10 ng/ml)-stimulated FSH release. In cell cultures from proestrous rats, both antiprogestins caused a slight, but significant, suppression of basal FSH release even in the absence of added E2; activin-stimulated FSH release, however, was not affected. Upon exposure of the cells from proestrous rats to E2, the antiprogestins potently suppressed both basal and activin-stimulated FSH secretion. Because the foregoing incubations were performed in culture medium devoid of progesterone (P4), the actions of the antiprogestins on FSH secretion were independent of the natural ligand. Addition of P4 (10 nM) to the cell cultures stimulated basal and activin-induced FSH release more in the presence than in the absence of E2. The FSH response to P4 was completely blocked by both antiprogestins in both the absence and presence of E2. Finally, both RU486 and ZK98299 blocked the stimulatory effect of corticosterone (1 microM) on FSH secretion. The observed effects of P4 and antiprogestins were specific for FSH secretion; LH secretion was not similarly suppressed by either antiprogestin, but was, in fact, stimulated by ZK98299 in E2-treated cells. We conclude that 1) E2-inducible progesterone receptors interact with activin-mediated signal transduction to regulate FSH secretion, and 2) unlike on the morning of estrus in vivo, RU486 and ZK98299 affect FSH secretion similarly in the gonadotrope in vitro.
Szabo
M
M
Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois 60208-3520, USA. msz729@nwu.edu
Kilen
S M
SM
Saberi
S
S
Ringstrom
S J
SJ
Schwartz
N B
NB
D028341:Activins; D000818:Animals; D002478:Cells, Cultured; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D005640:Follicle Stimulating Hormone / Q000378:metabolism*; D006067:Gonanes / Q000494:pharmacology; D006727:Hormone Antagonists / Q000494:pharmacology*; D007265:Inhibins / Q000494:pharmacology*; D007986:Luteinizing Hormone / Q000378:metabolism; D008686:Metestrus; D015735:Mifepristone / Q000494:pharmacology; D010903:Pituitary Gland, Anterior / Q000187:drug effects / Q000378:metabolism*; D011359:Proestrus; D011372:Progestins / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley
D006067:Gonanes; D006727:Hormone Antagonists; D011372:Progestins; D028341:Activins; D015735:Mifepristone; D004958:Estradiol; D007265:Inhibins; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; C053238:onapristone