M. Szabo et al., ANTIPROGESTINS SUPPRESS BASAL AND ACTIVIN-STIMULATED FOLLICLE-STIMULATING-HORMONE SECRETION IN AN ESTROGEN-DEPENDENT MANNER, Endocrinology, 139(5), 1998, pp. 2223-2228
Previous studies from our laboratory, demonstrating that suppression o
f serum FSH by RU486 requires a high estrogen (E) background, suggeste
d that E-inducible progesterone receptors play a role in the regulatio
n of FSH secretion. We demonstrated further that the type II antiproge
stin RU486 and the type I antiprogestin ZK98299 both suppressed the el
evated serum FSH and FSH beta messenger RNA levels similarly on the ev
ening of proestrus, but had divergent effects on the morning of estrus
, when only RU486, but not ZK98299, lowered the elevated serum FSH lev
el (secondary FSH surge). In the present work we used primary anterior
pituitary cell culture to examine whether RU486 caused direct, E-depe
ndent suppression of basal and recombinant human activin A (activin)-i
nduced FSH secretion in the gonadotrope and to compare this direct eff
ect, if any, with that of ZK98299. Primary cell cultures were prepared
from anterior pituitaries collected from cycling female rats either o
n metestrous or proestrous morning and cultured in DMEM, supplemented
with charcoal-stripped serum without or with 10 nM estradiol (E-2) for
96 h; exposure to test agents occurred during the last 48 h of cultur
e. FSH released into the medium and intracellular FSH content were det
ermined by RIA. In cells from the anterior pituitary of metestrous rat
s cultured in E-2-free medium, neither antiprogestin (10 nM) affected
FSH release; in contrast, when cells were cultured in medium to which
E-2 had been added, both antiprogestins caused profound suppression of
both basal and activin (10 ng/ml)-stimulated FSH release. In cell cul
tures from proestrous rats, both antiprogestins caused a slight, but s
ignificant, suppression of basal FSH release even in the absence of ad
ded E-2; activin-stimulated FSH release, however, was not affected. Up
on exposure of the cells from proestrous rats to E-2, the antiprogesti
ns potently suppressed both basal and activin-stimulated FSH secretion
. Because the foregoing incubations were performed in culture medium d
evoid of progesterone (P-4), the actions of the antiprogestins on FSH
secretion were independent of the natural ligand. Addition of P-4 (10
nM) to the cell cultures stimulated basal and activin-induced FSH rele
ase more in the presence than in the absence off,. The FSH response to
P, was completely blocked by both antiprogestins in both the absence
and presence of E-2. Finally, both RU486 and ZK98299 blocked the stimu
latory effect of corticosterone (1 mu M) on FSH secretion. The observe
d effects of P-4 and antiprogestins were specific for FSH secretion; L
H secretion was not similarly suppressed by either antiprogestin, but
was, in fact, stimulated by ZK98299 in E-2-treated cells. We conclude
that 1) E-2-inducible progesterone receptors interact with activin-med
iated 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.