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Division of Reproductive Sciences, Oregon Regional Primate Research Center (C.L.C., R.L.S., D.M.D.), Beaverton, Oregon 97006; and the Department of Physiology and Pharmacology, Oregon Health Sciences University (R.L.S.), Portland, Oregon 97201
Address all correspondence and requests for reprints to: Dr. R. L. Stouffer, Division of Reproductive Sciences, Oregon Regional Primate Research Center, 505 NW 185th Avenue, Beaverton, Oregon 97006. E-mail: stouffri{at}ohsu.edu
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Abstract |
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, ERß) receptors
as well as the aryl hydrocarbon receptor (AhR) in macaque granulosa
cells during controlled ovarian stimulation cycles before (0 h)
and after (up to 36 h) administration of the ovulatory hCG bolus
with or without steroid depletion and progestin replacement. All
steroid receptor mRNAs were detected in granulosa cells before the
ovulatory stimulus, as determined by RT-PCR. PR mRNA increased
(P < 0.05) by 12 h after hCG; 24 and 36
h after hCG, levels were intermediate between 0–12 h. PR mRNA was
reduced by steroid depletion throughout the periovulatory interval
(P < 0.05); however, progestin replacement
returned PR mRNA to control levels at 12 h. AR mRNA increased
(P < 0.05) at 24 h post-hCG and remained at
this level 36 h after hCG; steroid depletion did not alter AR mRNA
levels. ER mRNA did not change, whereas ERß decreased 12–36 h
after the ovulatory stimulus (P < 0.05). Steroid
depletion reduced ER mRNA 12 h after hCG, an effect partially
reversible by progestin replacement, whereas ERß mRNA was not
affected by steroids. AhR mRNA was undetectable before the
administration of hCG, but increased by 12 h
(P < 0.05). These data demonstrate hCG-initiated,
steroid-dependent (PR, ER) and -independent (AR, ERß, AhR)
expression of receptor mRNAs in primate granulosa cells during the
periovulatory interval. Differences in patterns of expression may
relate to diverse roles for steroid hormones and AhR ligands in
periovulatory events. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In rhesus monkeys undergoing controlled ovarian stimulation, serum progesterone begins to rise within 30 min of the ovulatory stimulus, and maximum intrafollicular levels are achieved by 12 h (6). PR messenger RNA (mRNA) increases in rat and macaque granulosa cells after the LH surge. PR expression appears to be under gonadotropin regulation (7, 8, 9, 10), but homologous regulation of PR was observed in periovulatory granulosa cells of both species (11, 12).
Both 17ß-estradiol and androstenedione increase 12 h after the administration of hCG to monkeys undergoing controlled ovarian stimulation and decrease thereafter (6). Despite the presence of androgen receptors (AR) in granulosa cells of primate pre- and periovulatory follicles (13, 14, 15), very little is known concerning an ovarian role for this steroid. Likewise, estrogen action in the primate periovulatory follicle is unknown, although estradiol increases gelatinase A (MMP-2) activity in cultured human luteinizing granulosa cells and may play a role in acquisition of oocyte fertilizability (16, 17). Attempts to localize estrogen receptors (ER) to the primate ovary have yielded equivocal results (10, 18, 19), but the recent discovery of ovarian ERß has reopened the issue of ER-mediated action in the primate follicle (20, 21).
To characterize the pattern of steroid receptor gene expression during
the periovulatory interval in the primate follicle, granulosa cells
were obtained from rhesus monkeys undergoing controlled ovarian
stimulation before (0 h) and 12, 24, or 36 h after administration
of an ovulatory hCG bolus. To test the hypothesis that gonadotropin
regulation of steroid receptors is direct or by local steroid action,
mRNA levels for PR, AR, ER, and ERß were determined in
periovulatory granulosa cells of rhesus monkeys with or without steroid
depletion and progestin replacement. In addition, the expression of the
aryl hydrocarbon receptor (AhR), an orphan transcription factor
associated with the endocrine system (22), was examined.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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4 mm) were aspirated using a 22-gauge needle
during laparotomy of anesthetized animals either the morning after the
last LH/FSH treatment (0 h) or 12, 24, or 36 h after the
administration of 1000 IU rhCG (n = 3–5 monkeys/time point). An
additional group of monkeys (n = 3/time point) was stimulated in
an identical fashion, but also received the 3ß-hydroxysteroid
dehydrogenase inhibitor trilostane (TRL; Sanofi Pharmaceuticals, Inc., Research Division, Malvern, PA) orally [1 g in 8 ml
orange Kool-Aid (Kraft General Foods, Inc., White Plains, NY)
containing 1% (wt/vol) gum tragacanth (Sigma Chemical Co., St. Louis, MO)] beginning 4 h before hCG
administration and every 12 h thereafter until the time of
follicular aspiration. A third group of animals (n = 3/time point)
received TRL plus the nonmetabolizable progestin R5020 (promegestrone;
NEN Life Science Products, Boston, MA; 2.5 mg in sesame
oil, sc, once daily starting at the time of hCG administration).
Control animals (hCG alone) did not receive oral or sc vehicle.
Follicles in the TRL and TRL plus R5020 groups were aspirated only at
12 and 36 h post-hCG, representing, respectively, the time point
when follicular fluid progesterone is substantially increased (6) and
the time point just before follicular rupture (24, 25). Daily blood samples were obtained from unanesthetized animals by saphenous venipuncture from the beginning of gonadotropin treatment. Serum estradiol and progesterone concentrations were determined using specific RIAs, and follicular growth was monitored using serum steroid levels and ultrasonography performed on days 6–7 of stimulation (23). The steroid milieu in follicular fluid collected from rhesus monkeys during the periovulatory interval with or without TRL with or without R5020 was reported recently by this laboratory (5, 6). Published data indicate marked depletion of progesterone and estradiol at both 12 and 36 h after TRL administration (5). In addition, we reported (4) that administration of R5020 at levels equivalent to those used in the current study was sufficient to restore ovulation and luteinization in TRL-treated monkeys. Serum concentrations of bioactive LH were determined for the 3 days before and including the day of follicle aspiration using an in vitro mouse Leydig cell bioassay; the results confirm the absence of an endogenous LH surge (26).
Follicle aspiration and granulosa cell preparation
Granulosa cells were obtained by follicle aspiration during
laparotomy of anesthetized animals (23). Cells were removed from
follicular fluids by centrifugation at 277 x g for 15
min (4 C), and the resulting follicular fluid was aliquoted into
volumes of 25–100 µl and stored at -80 C. The cell pellet was
resuspended in Tyrode’s albumin lactate pyruvate-HEPES, oocytes were
removed from the resulting pellet for use in other studies, and the
remaining aspirate was centrifuged to create an enriched
preparation of granulosa cells as described by Chaffin and Stouffer
(5). In brief, cells were centrifuged at 190 x g
(10 min, 4 C) and resuspended in Ham’s F-10 medium (Life Technologies, Inc., Grand Island, NY). The resuspension was
layered onto a gradient of 40% Percoll (Sigma Chemical Co.) and 60% HBSS with 0.1% BSA and centrifuged at 470 x
g for 30 min at 4 C. The resulting layer of granulosa cells
was resuspended in Ham’s F-10, cell numbers were determined using a
hemacytometer, and cell viability (typically 60%) was assessed by
trypan blue exclusion.
Total RNA isolation and RT-PCR
Total RNA was isolated from 104–105
granulosa cells using the Trizol reagent (BRL, Gaithersburg, MD)
according to the manufacturer’s instructions. The quality and quantity
of RNA were determined by electrophoresis of samples against known
concentrations of total ovarian RNA in a 2% agarose gel stained with
ethidium bromide. Granulosa cell RNA (500–1000 ng in 10 µl) was
treated with ribonuclease-free deoxyribonuclease I (BRL) for 15 min at
room temperature to remove contaminating genomic DNA, and
deoxyribonuclease I was subsequently inactivated by the addition of 1
µl 25 mM EDTA for 15 min at 65 C. RT was carried out for
2 h at 37 C in a 20-µl reaction volume using the 10 µl
deoxyribonuclease I reaction, 1 x RT buffer [50 mM
Tris-Cl (pH 8.3), 40 mM KCl, and 6 mM
MgCl2], 1 mM dithiothreitol, 25 pmol
oligo(deoxythymidine) primer (Promega Corp., Madison, WI),
and 200 U Moloney murine leukemia virus reverse transcriptase (BRL),
after which the reverse transcriptase was heat inactivated at 94 C for
5 min. PCR was performed using an empirically determined amount of the
RT reaction dictated by the specific PCR primer set, 1 x
Taq buffer (Promega Corp.), 1–3 mM
MgCl2, 2 µl 10 mM deoxy-NTPs, and 3 U
Taq DNA polymerase (Promega Corp.).
Oligonucleotides used for PCR were synthesized by the Oregon Regional
Primate Research Center Molecular Biology Core Facility (Table 1
). The concentration of specific primers
was determined as part of the validation process. The reaction was
overlaid with mineral oil, and PCR was performed in a thermal cycler
(MJ Research, Inc., Watertown, MA) for an empirically
determined number of cycles of denaturing at 94 C for 30 sec, annealing
at 60 C for 1 min, and primer extension at 72 C for 1 min. Aliquots of
each PCR reaction (20 µl) were electrophoresed through a 2% agarose
gel stained with 0.1 µg/ml ethidium bromide. Gels were visualized on
a UV transilluminator and photographed using 667 Polaroid film,
and the photographs were analyzed by densitometry. All values were
normalized to the internal standard ß2-microglobulin,
glyceraldehyde-3-phosphate dehydrogenase, or cyclophilin, the choice of
which was experimentally determined. To conserve limited samples, TRL
plus R5020 RNA was not assayed unless significant differences were
observed between control and TRL groups.
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Statistical analysis
To test for heterogeneity of variance, data were subjected to a
Bartlett’s 
2 test and subsequently transformed (to
log+10) before one-way ANOVA, followed by Newman-Keuls test for
comparison between means. Because TRL and TRL plus R5020 data were
collected only at 12 and 36 h post-hCG, comparisons were made
between treatments within a time point by separate one-way ANOVAs.
Differences were considered significant at P < 0.05,
and values are presented as the mean ± SEM.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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depicts representative
RT-PCR reactions for control (hCG alone) expression of steroid receptor
mRNAs. Before the ovulatory hCG bolus (0 h), mRNAs for PR, AR, ER,
and ERß were detectable in aspirated granulosa cells by RT-PCR. PR
mRNA increased 13-fold within 12 h of the administration of hCG
(P < 0.05; Fig. 2).
However, by 24–36 h post-hCG, PR mRNA levels were intermediate between
0 and 12 h values. TRL treatment prevented the rise in PR mRNA
levels at both 12 and 36 h after hCG administration
(P < 0.05). It is noteworthy that the administration
of R5020 returned PR mRNA to time-matched control levels at 12 h,
but not 36 h, post-hCG (P < 0.05).
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). However, AR mRNA increased
2-fold (P < 0.05) between 12–24 h post-hCG and
remained at this level 36 h after the ovulatory stimulus. Steroid
depletion did not alter mRNA levels for AR at either 12 or 36 h
after hCG; thus, mRNA levels were not determined in the TRL plus R5020
treatment group.
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mRNA levels did not change during the periovulatory interval from
0–36 post-hCG administration (Fig. 4, upper panel). TRL treatment reduced levels 12 h after
hCG (P < 0.05), and coadministration of TRL and R5020
resulted in ER mRNA levels that were intermediate between values in
time-matched control and TRL treated groups; however, in two of three
samples, ER levels were equivalent to the control mean. On the
contrary, mRNA levels for ERß were reduced 4.5-fold within 12 h
post-hCG (Fig. 4, lower panel) and remained at this level
36 h after the ovulatory stimulus. Steroid depletion after TRL
treatment did not alter ERß mRNA levels 12 or 36 h post-hCG.
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), but by 12 h
after hCG, AhR mRNA was abundant (Fig. 5). Notably, AhR mRNA was reduced (but
remained detectable) 30-fold between 12–24 h (P <
0.05) and increased again 36 h post-hCG to a level equivalent to
12 h values. AhR mRNA was not altered by steroid depletion 12 or
36 h after hCG administration.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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) or steroid
independent (AR, ERß, AhR). These results are consistent with the
hypothesis that locally produced steroids play an important role in the
cascade of events leading to ovulation and luteinization of the primate
follicle. PR mRNA increases in granulosa cells of the rhesus monkey periovulatory follicle within 12 h of the ovulatory stimulus. It was reported previously that the gonadotropin surge increases the expression of PR mRNA (10) and protein (18, 31) in granulosa cells of monkeys and women, but the pattern of expression during the periovulatory interval has not been described. However, in rodents, PR mRNA is transiently increased, peaking 6 h after the onset of the gonadotropin surge, whereas PR protein may be present in vitro up to 24 h later (7, 8). It is noteworthy that the expression of PR mRNA in monkey granulosa cells declines between 12–24 h, while remaining greater than 0 h levels, but tends to increase from 24–36 h. This secondary trend for PR mRNA to increase may relate to the observed rise in PR that continues in the corpus luteum until the midluteal phase of the menstrual cycle (30, 32). It is possible that the initial periovulatory increase (i.e. 12 h) in PR may lead to the regulation of genes related to ovulation, for example, ovarian proteases (5), whereas later expression may support luteal formation and function (33).
As steroid depletion prevented, and R5020 restored, the gonadotropin-induced rise in PR mRNA in granulosa cells of monkey periovulatory follicles within the first 12 h of the ovulatory stimulus, progesterone may promote its actions in periovulatory events through enhancement of PR. The up-regulation of PR by its ligand runs counter to classical models of progesterone action, for example, in uterus, where progesterone decreases the expression of PR (34). However, the finding that progesterone increases PR mRNA at this time point does not obviate a role for gonadotropins in the periovulatory rise in PR. Preovulatory granulosa cells from rats do not increase expression for PR in vitro in response to progesterone or estradiol (9, 35). On the contrary, treatment of rats with antiprogestin at the time of hCG results in decreased PR protein 6 h after hCG (12), indicating that an ovulatory stimulus is necessary for homologous regulation of PR by progesterone.
Steroid depletion also reduced PR mRNA in macaque granulosa cells at 36 h after hCG, but coadministration of R5020 did not return PR to control levels. The finding that ER and AR mRNA are expressed by granulosa cells at this time point (see below) is consistent with the idea that other steroids, such as androgens and/or estrogens, may regulate PR expression in the periovulatory follicle. In monkey luteinizing granulosa cells (27 h post-hCG) cultured for 24 h in the presence of TRL, the number of PR-positive cells is reduced in a hCG-dependent manner (11), suggesting an interaction between hCG and steroids in PR regulation. The ovulatory hCG bolus may be essential for the initial increase in PR mRNA, but later (i.e. 36 h) expression may be mostly steroid dependent. Whether androgens and/or estrogens mediate or modulate gonadotropin action to promote PR mRNA expression between 12–36 h in the late periovulatory interval awaits further study.
The dynamic regulation by gonadotropins, progesterone, and possibly other steroids suggests that PR expression is controlled in a manner dependent upon the degree of granulosa cell differentiation. Duffy and Stouffer (30) reported that luteinizing granulosa cells express predominantly a 0.7-kb PR transcript, whereas monkey luteal tissues synthesize 12- and 2.7-kb PR mRNA. Thus, changes in PR mRNA levels between 12–36 h may be associated with changes in mRNA splicing, raising the intriguing possibility that the ratio of PR isoforms may change over the course of the periovulatory interval (36).
In rhesus monkeys, AR mRNA is detectable in granulosa cells from preovulatory follicles and increases, albeit temporally later and of less magnitude than PR mRNA, in response to the ovulatory gonadotropin stimulus. Although AR mRNA decreases during follicular growth in primates and rats (15, 37, 38), it remains easily detectable by RT-PCR in granulosa cells in the current study. The increase in AR mRNA 24 h post-hCG, and the rapid, transient rise in follicular fluid androstenedione (6) are consistent with a role for androgens via AR-mediated actions in the periovulatory follicle (13). Using our gonadotropin-stimulated, steroid-depleted macaque model, Hibbert et al. (4) demonstrated that dihydrotestosterone could not induce follicular rupture or luteinization, but it partially reversed the loss of oocyte fertilizability in vitro that accompanies steroid depletion. Vendola et al. (39) and Weil et al. (15) reported that testosterone was not associated with apoptosis in preovulatory follicles, although increased androgen/estrogen ratios have been associated with atresia of periovulatory follicles (40). Increased granulosa cell apoptosis is a feature of the ovine follicle just before rupture (41), and androgens may participate in these events through an AR-mediated mechanism. Alternatively, other steroids, for example, progesterone, may act through AR when present at high concentrations near the time of ovulation (6, 42).
In the current study, steroid depletion did not alter AR mRNA levels in granulosa cells. This finding is consistent with that of Weil et al. (15), who showed that 10 days after implantation of a testosterone-containing capsule in rhesus monkeys, AR mRNA in granulosa cells was unchanged vs. that in controls. Therefore, the rise in AR mRNA at 24 h is mediated either directly by gonadotropins or through the action of local nonsteroidal factors. Further studies are needed to establish the follicular regulation and localization of this receptor in relation to the periovulatory interval.
Although both ER and ERß mRNA are expressed in granulosa cells
before the ovulatory gonadotropin stimulus, their pattern of expression
during the periovulatory interval differed. The preovulatory expression
of ER mRNA supports previous reports showing the presence of ER protein
in granulosa cells from the dominant preovulatory follicle in primates
(31, 43, 44). Whereas ER mRNA levels are unchanged, ERß mRNA
rapidly decreases after administration of the ovulatory hCG stimulus.
The profiles for both ER subtypes are consistent with reports in rats
(21, 45). However, the expression of ER protein in luteinizing
granulosa cells and corpora lutea in primates has not yet been
convincingly demonstrated (18, 19, 31, 44, 46, 47). This controversy
has no doubt been exacerbated by the wide variety of techniques
employed and the presence of at least one additional form of ER. It is
interesting, however, that Chandrasekher et al. (10) were
unable to detect ER mRNA using RT-PCR in luteinizing granulosa
cells, although the differences from the present study may be technical
in nature, reflecting the increased sensitivity of the RT-PCR assay and
the relatively purer granulosa cells preparations used in the current
experiments. Further studies of ER and ERß mRNA and receptor
proteins in both luteinizing granulosa cells and the corpus luteum will
help clarify the sites of estrogen action.
The role of steroids in granulosa cell ER expression has not
been well studied. There is no evidence either in rodents or
primates (Ref. 21 and current study) that the expression of ERß is
regulated by steroids. The novel finding that ER mRNA may be
progesterone regulated 12 h after the ovulatory stimulus suggests
a previously unsuspected interaction between the progesterone and
estrogen signaling pathways.
The ovulatory gonadotropin stimulus also induces the expression of AhR mRNA, a transcription factor for which the endogenous ligand is not known. AhR can bind and be activated by a wide variety of xenobiotic compounds, resulting in changes to several endocrine systems (reviewed in Ref. 48). In addition, there is clear evidence for cross-talk between steroid and Ah receptor signaling pathways, although data pertaining to steroid-AhR complexes remain equivocal (49, 50, 51, 52). The gonadotropin-regulated pattern of AhR expression in macaque granulosa cells suggests that this receptor has a potentially important role in ovulation and luteinization. Dey and Nebert (53) recently reported that fertilized mouse ova transiently express mRNA for cytochrome P450IA1, which is up-regulated by ligands to AhR. Also, administration of AhR agonists to human luteinized granulosa cells in culture decreases cAMP, estradiol, and progesterone production (54, 55). In rats, AhR ligands increase the expression of urokinase plasminogen activator and interleukin-1ß, two factors considered to be involved in follicular rupture (56). Analysis of essential cofactors for AhR, such as the AhR nuclear translocator protein, and members of the Ah gene battery will help clarify a potential role for AhR in periovulatory events (57).
In conclusion, an ovulatory stimulus given to rhesus monkeys undergoing
hormonally controlled ovarian stimulation results in significant
changes in expression of mRNAs for PR, AR, ERß, and AhR in granulosa
cells. All of the steroid receptors were detectable before hCG
administration, but showed different patterns of expression and steroid
regulation during the periovulatory interval. Depletion of follicular
fluid steroids using the 3ß-hydroxysteroid dehydrogenase inhibitor
TRL and replacement with the nonmetabolizable progestin R5020
demonstrate that PR and ER are gonadotropin and progesterone
dependent during the early (12 h), but not the late (36 h),
periovulatory interval, whereas AR, ERß, and AhR are not steroid
dependent. Additional studies detailing mRNA localization and protein
levels of these genes will address the hypothesis that the diverse
patterns of expression and regulation of these receptors relate to
specific local roles for steroids in processes leading to ovulation and
luteinization of the primate follicle.
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Acknowledgments |
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Footnotes |
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Received March 11, 1999.
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References |
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ovary. Folia Histochem Cytobiol 35:101–102[Medline]
in human uterine endometrial adenocarcinoma RL95–2 cells.
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