Endocrinology Vol. 139, No. 5 2223-2228
Copyright © 1998 by The Endocrine Society
Antiprogestins Suppress Basal and Activin-Stimulated Follicle-Stimulating Hormone Secretion in an Estrogen-Dependent Manner1
Marta Szabo,
Signe M. Kilen,
Sara Saberi,
Sonia J. Ringstrom and
Neena B. Schwartz
Department of Neurobiology and Physiology, Northwestern University,
Evanston, Illinois 60208
Address all correspondence and requests for reprints to: Marta Szabo, Ph.D., Department of Neurobiology and Physiology, Northwestern University, 2153 North Campus Drive, Evanston, Illinois 60208-3520. E-mail: msz729{at}nwu.edu
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Abstract
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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 FSHß 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 µM) 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.
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Introduction
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THE SECRETION of FSH is controlled,
in addition to GnRH and gonadal steroids, by the specific regulatory
proteins inhibin, activin, and follistatin, isolated originally from
the gonads (1), but shown subsequently to be widely distributed in
various tissues, including the pituitary (2, 3). Activin, in
particular, has been identified as a key physiological regulator of FSH
secretion by virtue of its ability to activate transcription of the
FSHß gene (4, 5) and, together with follistatin, mediate the effects
of pulsatile GnRH administration (6). An additional level of regulation
was suggested by previous in vivo studies from our
laboratory, which demonstrated an ability of the
antiprogestin/antiglucocorticoid RU486 to selectively lower serum FSH
(7) in an estrous cycle stage- and estrogen (E)-dependent manner (8).
These data suggested that activation of progesterone receptors (PR) is
a key component of the specific regulatory mechanism that governs the
synthesis and release of FSH. More recently, we compared the effects of
RU486 (a type II P antagonist) on FSH secretion in vivo with
those of the type I antiprogestin ZK98299; the results indicated that
the two antiprogestins, which block PR through different molecular
mechanisms (9), have differential effects on serum FSH on the morning
of estrus (10). The objective of the present work was to explore in
primary pituitary cell culture whether the antiprogestins RU486 and
ZK98299 can suppress FSH secretion directly at the level of the
gonadotrope, and whether the two antiprogestins can affect FSH
secretion differentially in this in vitro system. We
investigated the drugs’ effects on FSH secretion in the absence and
presence of E2, under both basal conditions and during
stimulation with activin and glucocorticoids, to gain insight into a
possible interaction between PR- and activin receptor-mediated
signaling in the gonadotrope. The results demonstrate equal, direct,
estradiol (E2)-dependent suppression of basal and
activin-stimulated FSH secretion by both antiprogestins and suggest
that under certain physiological conditions, E-inducible PR interact
with activin-mediated signaling to stimulate the synthesis and
release of FSH.
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Materials and Methods
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Reagents
RU486 (Roussel-UCLAF, Romainville, France), ZK98299 (Schering,
Berlin, Germany), E2, progesterone (P4), and
corticosterone (B; Sigma Chemical Co., St. Louis, MO) were dissolved in
absolute ethanol at 1000 times the desired final concentration; the
corresponding concentration of ethanol (0.1%) was used as the vehicle.
Recombinant human activin A (activin), provided by Dr. Teresa Woodruff,
Northwestern University (Evanston, IL), for the initial experiments,
and by the National Hormone and Pituitary Program for subsequent ones,
was diluted with 0.05 M Tris-HCl (pH 7.4)-0.15
M NaCl from a 0.73 µg/ml stock. Media, sera, and all
other reagents for cell culture were obtained from Life Technologies
(Grand Island, NY).
Animals
Female Sprague-Dawley rats (55–60 days old) were obtained from
Charles River (Portage, MI). Animals were housed under a 14-h light,
10-h dark schedule, with lights on at 0500 h, and were provided
with standard rat chow and tap water ad libitum. Estrous
cycles were monitored by daily vaginal cytology; only rats that
exhibited at least two consecutive 4-day estrous cycles were used.
Protocols were approved by the animal care and use committee of
Northwestern University.
Cell dissociation and culture
Anterior pituitaries were collected from 6–14 rats at
0900–1000 h on the specified day of the estrous cycle (usually
metestrus) and dissociated enzymatically as previously described (11).
The final pellet was suspended in DMEM containing 10%
charcoal-stripped FBS and 10 nM E2 as
indicated. Cells were plated in 24-well culture plates at a density of
3–5 x 105 cells/2-cm2 well and were
incubated in a humidified atmosphere of 94% air-6% CO2 at
37 C for 48 h. Media were collected, fresh media containing the
test agents were then added, and incubation was continued for an
additional 48 h. Incubation with each test agent was performed in
quadruplicate, and each experiment was repeated at least once for
confirmation.
FSH and LH release and cell content
Culture media were sampled for FSH and LH release at 48 and
96 h. At the end of the incubation (96 h), cell monolayers were
lysed in 1 ml Dulbecco’s PBS containing 0.3% BSA and 1% each of
Triton X-100 and sodium deoxycholate for determination of intracellular
hormone content. All media and lysates were stored at -20 C until
RIA.
Hormone assays
Gonadotropins released into the culture media and their content
in the cell lysates were determined by double antibody RIA (7) with
reagents supplied by the National Hormone and Pituitary Program.
Statistical analysis
All data presented are the mean ± SE of
quadruplicate incubations from a single representative experiment. Each
experiment was repeated once or twice to ensure reproducibility of the
results. The significance of differences between the vehicle- and
E2-treated cells was assessed by t test.
Significant differences among multiple treatment groups were evaluated
by multifactor ANOVA (Crisp Program, Crunch Software Corporation, San
Francisco, CA). Post-hoc comparisons of the effects of test
agents were performed using the Newman-Keuls test. P <
0.05 was considered significant.
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Results
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E2-dependent suppression of basal FSH
secretion by RU486 and ZK98299
Preliminary experiments testing the requirement for E2
in the culture medium for suppression of FSH secretion by RU486 yielded
inconsistent results; these experiments were performed with anterior
pituitary cells from rats at random stages of the estrous cycle. Based
on this finding and on previous reports demonstrating the importance of
the estrous cycle stage in determining the in vitro hormone
secretory response to secretagogues (12, 13), we used primary cell
cultures prepared from anterior pituitaries collected on metestrous
morning when the ambient estrogen background is low. In Exp 1, we
examined the effects of the antiprogestins RU486 and ZK98299 (10
nM), added to the primary pituitary cell cultures during
the second half of a 96-h incubation, on FSH release into the culture
medium (Fig. 1A
) and on the intracellular
content of FSH (Fig. 1B) upon exposure for various times to 10
nM E2. In the absence of E2
throughout the 96-h incubation, neither antiprogestin (10
nM) had a significant effect on FSH release. Addition of
E2 to the medium during either the first or the second half
of the incubation (i.e. before or during the exposure to the
antiprogestins) or throughout the entire 96-h incubation did not
significantly affect basal FSH release, but enabled the antiprogestins
to cause marked suppression of FSH release. The effects of
E2 and antiprogestins on intracellular FSH content were
qualitatively similar, but of a lesser magnitude. Because the order and
duration of exposure to E2 had no influence on
antiprogestin-induced suppression of basal FSH secretion, a protocol in
which E2 was added throughout the 96-h culture was adopted
in all subsequent experiments.
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Figure 1. Effects of treatment with 10 nM RU486
(RU) or ZK98299 (ZK) on FSH release during 48–96 h (A) and
intracellular FSH content at 96 h (B) in anterior pituitary cell
cultures exposed to vehicle or 10 nM E2 for 48
or 96 h. Pituitaries were collected on the morning of metestrus.
Each bar is the mean, and the error bar
is the SEM of four observations. In the presence of
E2, during the first or second 48-h incubation or both, the
effects of the antiprogestins on FSH release were highly significant
(P < 0.0001).
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E2-dependent suppression of basal and
activin-stimulated FSH secretion by RU486 and ZK98299: influence of
estrous cycle stage
In Exp 2, we tested the effects of RU486 and ZK98299 on FSH
release and cell content in the absence and presence of activin (10
ng/ml) in cultured cells from either metestrous or proestrous rats. As
in Exp 1, in cells from metestrous rats cultured in steroid-depleted
medium (Fig. 2A, left set of
bars), the antiprogestins had no effect on basal FSH release.
Addition of activin caused a robust increase in FSH release, which was
also unaffected by the concurrent addition of the antiprogestins. In
contrast, when cells from metestrous rats were cultured in medium
supplemented with E2 (Fig. 2A, right), both
antiprogestins elicited marked suppression of basal and
activin-stimulated FSH release; E2 enhanced the effects of
both activin alone and the antiprogestins on activin-induced FSH
release. During the first 48 h of incubation without test agents,
addition of E2 to the cell cultures caused a small, but
highly significant (P < 0.0001), increase in FSH
released from 21.4 ± 0.53 to 25.1 ± 0.32 ng/ml (data not
shown). In cells prepared from pituitaries collected on proestrous
morning, i.e. cells derived from a high ambient estrogen
environment, the antiprogestins suppressed basal FSH release even in
the absence of added E2 (Fig. 2C, left). It
should be noted, however, that the antiprogestins suppressed only
basal, but not activin-stimulated, FSH release in these cultures.
Addition of E2 to the medium in which cells from proestrous
rats were cultured enhanced the FSH response to both activin
(stimulation) and the antiprogestins (suppression; Fig. 2C, right). In contrast to cultured cells from metestrous rats,
basal release of FSH was unaffected by addition of E2 to
the culture medium during the first 48-h incubation (46.4 ± 1.2
vs.. 47.6 ± 1.2 ng/ml FSH released in the absence and
presence of 10 nM E2, respectively; data not
shown). In cell cultures from both metestrous and proestrous rats, the
effects of activin and the antiprogestins on intracellular FSH content
were qualitatively similar to those on medium FSH, although of a lesser
magnitude (Fig. 2, B and D). The in vitro effects of activin
and the antiprogestins were concentration dependent (data not shown);
the 10 ng/ml activin and 10 nM antiprogestins used in the
above studies represent submaximal stimulatory and inhibitory
concentrations of the drugs. The in vitro potency of ZK98299
was slightly, but significantly (P < 0.01), greater
than that of RU486 in this and several other experiments, including one
in which cells had been prepared from pituitaries collected on estrous
morning.
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Figure 2. Effects of treatment with 10 nM RU486
(RU) or ZK98299 (ZK) on basal and recombinant human activin (Act; 10
ng/ml)-stimulated FSH release during 48–96 h (A and C) and on
intracellular FSH content at 96 h (B and D) in anterior pituitary
cell cultures from metestrous (A and B) and proestrous (C and D) rats
exposed to vehicle or 10 nM E2 throughout the
96-h incubation. Each bar is the mean, and the
error bar the SEM of four observations. In
cultured cells from metestrous rats, addition of E2
increased the effect of activin (P = 0.01) and the
antiprogestins on activin-induced FSH release (P =
0.02). In the presence of E2, the effect of the
antiprogestins on FSH release was highly significant overall
(P < 0.0001). In cells prepared from pituitaries
collected on proestrous morning, the antiprogestins suppressed basal,
but not activin-stimulated, FSH release even in the absence of added
E2 (P = 0.0005). In the presence of
E2 added to the cultures, antiprogestins potently
suppressed both basal and activin-stimulated FSH release
(P < 0.0001).
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Agonist/antagonist relationship between P4
and antiprogestins
To investigate the possibility that RU486 and ZK98299 affected FSH
secretion in cultured anterior pituitary cells through an agonist-like
action, as has been reported in other in vitro systems (14, 15), in Exp 3, we compared the effects of the antiprogestins on FSH
release with those of the natural agonist, P4, in cultured
cells from metestrous rats (Fig. 3A). In
the absence of E2, 10 nM P4
significantly increased FSH release; this increase was completely
reversed by both antiprogestins. The small additional FSH response to
P4 above that induced by activin alone was similarly
blocked by the antiprogestins. Addition of E2 to the cell
cultures increased the effects of P4 on both basal and
activin-stimulated FSH release and strongly enhanced the suppressive
effects of the antiprogestins. P4 did not have a
significant effect on intracellular FSH content in the absence of
E2, but increased this parameter significantly in
E2-treated cells both under basal conditions and in
combination with activin (Fig. 3B).
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Figure 3. Effects of treatment with 10 nM
progesterone (P4) without or with 10 nM RU486
(RU) or ZK98299 (ZK) on basal and recombinant human activin (Act; 10
ng/ml)-stimulated FSH release during 48–96 h (A) and intracellular FSH
content at 96 h (B) in anterior pituitary cell cultures from
metestrous rats exposed to vehicle or 10 nM E2
throughout the 96-h incubation. Each bar is the mean,
and the error bar the SEM of four
observations. Addition of E2 to the cell cultures increased
the effects of P4 on both basal and Act-stimulated FSH
release and enhanced the suppressive effects of the antiprogestins
(P = 0.004 for the effect of E2
overall). The effect of P4 on intracellular FSH content was
not significant in the absence of E2, but was highly
significant (P < 0.0001) in cells incubated with
E2 under both basal conditions and in combination with
Act.
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Suppression of B-stimulated FSH secretion by the
antiprogestins
Because previous work from our laboratory identified
glucocorticoids as potent direct secretagogues for FSH (11, 16), and
because RU486 (17), but not ZK98299 (18), is an antiglucocorticoid as
well as an antiprogestin, in Exp 4 we investigated whether the
antiprogestins could suppress B-stimulated FSH secretion differentially
or similarly. The effective concentration of B used in the previous
studies ranged from 0.17–1.7 µM; the concentration of
the antiprogestins added to the culture medium was, therefore,
increased to 1 µM to match that of B used in the present
study. As depicted in Fig. 4, in
E2-treated cells from metestrous rats, RU486 and ZK98299
induced similar suppression of both basal and B-stimulated secretion of
FSH (P < 0.0001 overall); the magnitude of this
suppression of FSH release by ZK98299 was slightly, but significantly
(P = 0.01), greater than that by RU486.
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Figure 4. Effects of treatment with 1 µM RU486
(RU) or ZK98299 (ZK) on basal and B (1 µM)-stimulated FSH
release during 48–96 h (A) and intracellular FSH content at 96 h
(B) in anterior pituitary cell cultures from metestrous rats exposed to
10 nM E2 throughout the 96-h incubation. Each
bar is the mean, and the error bar the
SEM of eight observations. RU486 and ZK98299 induced
similar suppression of both basal and B-stimulated secretion of FSH
(P < 0.0001 overall); the magnitude of this
suppression of FSH release by ZK98299 was slightly, but significantly
(P = 0.01), greater than that by RU486.
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Differential responsiveness of FSH and LH to antiprogestins in
vitro
The observed effects of the antiprogestins were highly specific
for FSH. In no experiment could we demonstrate suppression of LH
secretion by the antiprogestins; on the contrary, in several
experiments in which LH was measured, ZK98299, but not RU486,
significantly increased LH release in an E2-dependent
manner. LH release measured in the same experiment for which FSH
measurements are depicted in Fig. 1
, is shown in Table 1. LH release, but not intracellular LH
content, was selectively stimulated by ZK98299.
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Discussion
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This is the first report demonstrating that the effects of activin
on FSH secretion can be antagonized by antiprogestins. Our data clearly
indicate that both type I (ZK98299) and type II (RU486) antiprogestins
are capable of causing profound suppression of FSH secretion only in
gonadotropes that had been primed with E2. The present
findings are consistent with our earlier demonstration of an E
requirement for RU486 to lower serum FSH in vivo and
implicate E-inducible PR as mediators of this suppression. In
E2-primed anterior pituitary cells, the antiprogestins
induced profound, specific suppression of both basal and activin- or
glucocorticoid-stimulated FSH secretion.
Previous work from our laboratory and others demonstrated that RU486 is
capable of suppressing FSH secretion in in vitro systems
after prior in vivo administration of the drug to the
pituitary donor animals (19) or upon direct addition to primary
anterior pituitary cell culture (20). It is likely, however, that
because of accumulation of locally produced activin (21) in the static
cultures used in the latter study as well as in the present work, basal
FSH secretion may, in fact, represent secretion stimulated by the
autocrine or paracrine actions of endogenous activin (6). Moreover, the
effect of glucocorticoids may also be mediated by endogenous activin
production; thus, all of the observed effects of the antiprogestins may
have been on activin-stimulated FSH secretion.
The in vitro effects of the two antiprogestins on FSH
secretion were qualitatively and quantitatively similar under virtually
all experimental conditions; ZK98299 exhibited slightly, but
significantly, greater biopotency than RU486 despite reports that the
latter binds PR with 5- or 10-fold higher affinity (22, 23). It is of
interest to note that the only differential action of the two drugs
observed in the present study was on LH release in
E2-primed cells: only ZK98299, not RU486, increased LH
release. Thus, the present results do not provide insight into the
mechanism underlying the differential in vivo effects of the
two antiprogestins on serum FSH on estrous morning. More recently, we
performed an experiment (Szabo, M., S. M. Kilen, and N. B. Schwartz,
unpublished) to investigate the possibility that the failure of
ZK98299, administered on proestrus, to suppress serum FSH on the
morning of estrus was due to its more rapid metabolic clearance than
that of RU486. Administration of a second dose of ZK98299 6 h
before blood collection resulted in suppression of serum FSH on estrous
morning comparable to that induced by a single injection of RU486 on
proestrus, lending support to the assumption that ZK98299 is, indeed,
cleared more rapidly from the circulation.
Suppression of FSH secretion by the antiprogestins was demonstrated in
the absence of the natural ligand for PR, P4, in the
pituitary cell culture. It is reasonable to conclude, therefore, that
ligand-independent activation of PR may interact with activin
receptor-mediated signal transduction in activating the transcription
of genes that are required for synthesis of the FSHß subunit and FSH
biosynthesis and release. Such hypothetical, ligand-independent
activation of PR-mediated processes by peptide hormone-mediated
signaling is analogous to the GnRH self-priming phenomenon described by
Turgeon and Waring (24). These researchers demonstrated that a pulse of
GnRH administered to pituitary cells cultured in the presence of
E2, but in the absence of P4, potentiated the
LH secretory response to subsequent pulses of GnRH or cAMP analog.
Potentiation could be blocked by RU486, prompting the researchers to
propose cross-communication between a GnRH receptor-activated protein
kinase A pathway and PR. That ligand-independent activation of PR
contributes to the primary and secondary surges of FSH was also
suggested, but not proven conclusively, by our previous demonstration
that RU486 is capable of attenuating the preovulatory and secondary FSH
surges under conditions where circulating P4 is virtually
eradicated by aminoglutethimide administration (25).
It is well established that RU486 can act as an agonist when
cAMP-mediated signaling is activated (14, 26, 27), and P4
itself has been reported to have both stimulatory and inhibitory
effects on FSH secretion (28). Based on this evidence, we considered
the possibility that the in vitro suppression of FSH
secretion by the antiprogestins may have been due to agonist-like
effects of the drugs. That this was not the case was clearly indicated
by the finding that P4 induced potent,
concentration-dependent stimulation of FSH secretion, enhanced by
priming with E2, in agreement with earlier reports by
Drouin and Labrie (29) and Krey and co-workers (20). Both
antiprogestins added at a low concentration antagonized this action of
P4 independent of E2. Thus, the antiprogestins
clearly affected FSH secretion through blockade of PR rather than
through their activation.
In conclusion, we demonstrated E2-dependent suppression of
activin-induced FSH secretion by RU486 and ZK98299 in primary anterior
pituitary cell culture in vitro. The data suggest that
E-inducible PR play a role as a regulator of FSH secretion through
interaction with activin-mediated signal transduction pathways.
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Acknowledgments
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We are grateful to Roussel-UCLAF (Romainville, France) and to
Dr. K. Stoeckemann of Schering (Berlin, Germany) for the supply of
RU486 and ZK98299 used in this study. We thank Brigitte Mann and
Stephanie Kluge for performance of the RIAs.
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Footnotes
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1 This work was supported in part by NIH Grants R01-HD-07504,
P01-HD-21921, and P30-HD-28048. Presented in part at the 79th Annual
Meeting of The Endocrine Society, Minneapolis, MN (Abstract
P3-341). 
Received November 18, 1997.
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Abstract
Introduction
