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and ß in the Rhesus Monkey Corpus Luteum during the Menstrual Cycle: Regulation by Luteinizing Hormone and Progesterone1
Division of Reproductive Sciences, Oregon Regional Primate Research Center, Beaverton, Oregon 97006
Address all correspondence to: Diane M. Duffy, Division of Reproductive Sciences, Oregon Regional Primate Research Center, 505 NW 185th Avenue, Beaverton, Oregon 97006.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and ß messenger RNA (mRNA) and protein levels in corpora
lutea (n = 3/stage) obtained from adult female rhesus monkeys at
early (days 3–5), mid (days 6–8), mid-late (days 10–12), and late
(days 14–16) luteal phase of the natural menstrual cycle. ER mRNA
levels did not vary across the stages of the luteal phase, and ER
protein was not consistently detected in luteal tissues. However, ERß
mRNA and protein levels were detectable in early and mid luteal phases
and increased (P < 0.05) to peak levels at
mid-late luteal phase before declining by late luteal phase. To
determine if ERß mRNA expression in the corpus luteum is regulated by
LH, monkeys received the GnRH antagonist antide either alone or with 3
daily injections of LH to simulate pulsatile LH release. Treatment with
antide alone or concomitant LH administration did not alter luteal
ERß mRNA levels. When monkeys also received the 3ß-hydroxysteroid
dehydrogenase inhibitor trilostane to reduce luteal progesterone
production, luteal ERß mRNA levels were 3-fold higher
(P < 0.05) than in monkeys receiving antide + LH
only. Replacement of progestin activity with R5020 reduced luteal ERß
mRNA levels to those seen in animals receiving antide + LH. Thus, there
is dynamic ERß expression in the primate corpus luteum during the
menstrual cycle, consistent with a role for estrogen in the regulation
of primate luteal function and life span via a receptor
(ERß)-mediated pathway. Increased ERß expression in the
progestin-depleted corpus luteum during LH exposure suggests that the
relative progestin deprivation experienced by the corpus luteum between
LH pulses may enhance luteal sensitivity to estrogens during the late
luteal phase of the menstrual cycle. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(3) and estrogen (4) have been proposed to act as local
luteolytic agents in the primate corpus luteum. Estradiol
administration into the corpus luteum-bearing ovary of
naturally-cycling monkeys and women caused premature cessation of
luteal function (5, 6, 7), but subsequent studies (8, 9) suggested
that this effect of estradiol was indirect via suppression of LH
secretion and declining gonadotropin support for the corpus luteum.
Inconsistent detection of ER in monkey and human luteal tissues
(10, 11, 12, 13, 14) further questioned whether the primate corpus luteum was a
target tissue for estrogen and, therefore, whether estrogen played a
local role in regulating the function or life span of the corpus luteum
during the menstrual cycle. However, the discovery of a second estrogen
receptor, ERß (15, 16), renewed the debate regarding estrogen action
in many tissues lacking ER. ERß binds estrogens (17, 18),
interacts with a variety of recognized EREs (19, 20) in homodimers or
heterodimers with ER (19, 21), and activates transcription through
EREs and other pathways used by ER (22, 23). ERß expression has
been identified in the ovaries of primate (18, 24, 25, 26) and nonprimate
(15, 27, 28) species, particularly in the granulosa cells of growing
follicles, although granulosa cell ERß messenger RNA (mRNA) levels
decline following the ovulatory gonadotropin surge in monkeys (25) and
rats (29). Limited reports suggest that ERß mRNA is expressed by the
corpus luteum of some species (30, 31), including monkey (32) and human
(14), but factors regulating luteal ERß levels in the follicle and
corpus luteum are unknown.
To reassess whether estrogen may be acting in the primate corpus luteum
via the recently discovered ERß pathway, studies were designed to
examine ER and ERß mRNA and protein levels in the monkey corpus
luteum throughout the luteal phase of the natural menstrual cycle.
Because gonadotropin regulates granulosa cell ERß expression and
stimulates luteal progesterone production, the roles of both LH and
progesterone in the regulation of luteal ERß expression were
addressed.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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All corpora lutea were removed from anesthetized monkeys during aseptic surgery by Surgical Services, Division of Animal Resources, ORPRC. Preoperative medications consisted of atropine sulfate (0.04 mg/kg body weight by im injection (Fujisawa USA, Inc., Deerfield, IL) and ketamine hydrochloride (10 mg/kg body weight im; Fort Dodge Animal Health, Fort Dodge, IA). After intubation of the airway, maintenance anesthesia consisted of 1.25% isoflurane (Inhalon Pharmaceuticals, Inc., Bethlehem, PA) vaporized in 100% oxygen. Following sterile preparation and draping of the abdomen, the abdomen was entered via ventral midline laparotomy. The target ovary was identified, and the corpus luteum was removed by blunt dissection following superficial incision of the ovarian epithelium covering the luteal body. Buprenorphine (0.03 mg/kg body weight IM; Reckitt and Colman Products, Hull, UK) was administered immediately after surgery and three times more during the next 24 h for pain relief.
Corpora lutea (n = 3/stage) were obtained from monkeys experiencing spontaneous menstrual cycles at early (days 3–5), mid (days 6–8), mid-late (days 10–12), and late (days 14–16) luteal phase. In addition, whole ovaries were obtained from animals undergoing organ removal as a part of unrelated experimental protocols; nonovarian tissues were collected at autopsy.
To assess possible LH and progesterone regulation of luteal ER expression, additional animals received sc injection of the GnRH antagonist antide (3 mg/kg body weight for 3 days) beginning on day 6 of the luteal phase (2). Animals (n = 3/treatment group) received either antide alone or with concomitant administration of recombinant human LH (LH; Ares Advanced Technology, Randolph, MA) 3 times daily (at 0800, 1600, and 2400 h IM) at doses of 5 IU/injection on luteal days 6 and 7 and 10 IU/injection on luteal days 8 and 9; luteal tissues were removed on day 10. This dose and pattern of antide treatment was previously shown to ablate luteal progesterone production for the remainder of the luteal phase, while LH administered in the dose and pattern described above restored serum progesterone to control levels and resulted in a luteal phase of normal length when LH injections were continued until menstruation (2). To examine the role of progesterone in the regulation of luteal ER expression, monkeys also received antide and LH treatment as described above along with coadministration of trilostane (600 mg/day orally on luteal days 6 and 7; Sanofi Pharmaceuticals, Inc. Great Valley, Malvern, PA), an inhibitor of 3ß-hydroxysteroid dehydrogenase that was previously shown by this laboratory to ablate luteal progesterone production (37). Additional animals received antide, LH, trilostane, and the nonmetabolizable progestin R5020 (2.5 mg/day; Dupont, Boston, MA) by sc injection in a vehicle of sesame oil (Sigma, St. Louis, MO). This dose of R5020 was selected because it restored local progestin action (e.g. ovulation) in trilostane-treated monkeys during controlled ovarian stimulations (38). Three animals were also included in each of these treatment groups, and luteal tissues were also removed on day 10. Treatments were initiated on luteal day 6 because mature luteal function is achieved by this time. Day 10 was selected for luteal tissue removal because rescue of the corpus luteum by CG during early pregnancy occurs at this time (39); this protocol also allowed a reasonable (4-day) treatment interval. Time-matched control luteal tissues were also obtained on day 10 from monkeys experiencing spontaneous menstrual cycles.
ER and ERß mRNA analysis
Total RNA was obtained from corpora lutea using the cesium
chloride ultracentrifugation method of Chirgwin and colleagues (40) or,
more recently, Trizol reagent (Life Technologies, Inc.,
Rockville, MD). RNA (1 µg) was treated with DNase (Life Technologies, Inc.) before reverse transcription (RT), which was
performed using Molony Murine Leukemia Virus reverse transcriptase
(BRL) as previously described (25). Semiquantitative RT-PCR based
assays were used to assess luteal ER and ERß mRNA levels as
previously described (25). Oligonucleotides used for PCR were
synthesized by the ORPRC Molecular Biology Core Facility (Table 1
). The MgCl2
concentration, amount of complementary DNA (cDNA) included in each PCR
reaction, number of PCR cycles, and primer concentrations for which the
amount of coamplified products for experimental and the internal
standard cyclophilin were linear and parallel with increasing amount of
cDNA were determined empirically for each primer set. The products of
both primer sets were also in the exponentially increasing phase
relative to the number of PCR cycles. PCR primers were designed to
amplify the hormone binding regions of ER and ERß, and sequence
analysis was used to confirm the identity of PCR products. PCR products
were separated on 2% agarose gels and photographed using Polaroid 667
film (Polaroid Corp., Cambridge, MA). When samples were not assayed in
a single experiment, a cDNA pool was included in triplicate in each
assay and used to normalize values between assays. Intraassay variation
was less than 15%.
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and ERß protein analysis
and ERß were performed essentially as described for the monkey
progesterone receptor (41), with the exception that the urea
denaturation step was omitted and primary antibody incubations were
performed for 3 h at room temperature. Detection of ER was
performed using H-222, a polyclonal rat antibody generated against
human ER [generously provided by Dr. G. Greene, Ben May Institute,
University of Chicago, Chicago, IL (42)] and previously shown to
recognize monkey ER (10). Western blotting for ERß was performed
using PAI-311, a polyclonal rabbit antibody generated against a
synthetic peptide based on the human ERß sequence (Affinity BioReagents, Inc., Golden, CO). Primary antibody concentrations
were 2 µg/ml. Secondary antibodies conjugated with horseradish
peroxidase generated against rat IgG (Santa Cruz Biotechnology, Inc., Santa Cruz, CA) and rabbit IgG (Amersham Pharmacia Biotech, Piscataway, NJ) were used at dilutions of 1:20,000 and
1:10,000, respectively. ER proteins were visualized using an ECL kit
(Amersham Pharmacia Biotech) and Kodak X-OMAT
film (Eastman Kodak Co., Rochester, NY). Specificity of
these antibodies for the appropriate ER and generation of a standard
curve for quantitative analysis of monkey luteal ERß were performed
using recombinant human (rh-) ER and ERß proteins (PanVera
Corporation, Madison, WI). Size standards (Bio-Rad Laboratories, Inc. Hercules, CA) as well as rh-ER and rh-ERß proteins
were included on each gel to aid in identification of bands
representing monkey ER and ERß proteins.
Data analysis
All gels and films were scanned, and specific bands were
analyzed densitometrically using NIH Image 1.40 (Research Services
Branch, NIMH, Bethesda, MD), which compared band size and intensity to
a standard curve and calculated the optical density of each band. Data
were assessed for heterogeneity of variance using Bartlett’s test and
log transformed when necessary. Changes within each experiment were
determined using one-way ANOVA, followed by Newman-Keuls test or
t tests when indicated. The sigmoidal curve for the rh-ERß
standard was determined using Origin (Microcal Software, Inc.,
Northampton, MA). Data are presented as mean ±
SEM, and significance was set at
P < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and ERß expression in the monkey corpus luteum and ERß mRNA levels were determined for corpora lutea
throughout the luteal phase of the menstrual cycle (Fig. 1). ER mRNA was detected in all luteal
tissues, but ER mRNA content did not change significantly during the
luteal phase of the menstrual cycle. ERß mRNA was also detected in
all samples assayed, but luteal ERß levels varied across the luteal
phase. ERß mRNA content was low during the early and mid luteal
phase, rose 9-fold (P < 0.05) to peak at mid-late
luteal phase, and then declined (P < 0.05) to
intermediate levels by late luteal phase.
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and ERß proteins were expressed by the monkey
corpus luteum, Western blotting was performed. The antihuman ERa
antibody H-222 recognized recombinant human (rh-)ER but not rh-ERß
protein (Fig. 2, upper panel).
In addition, H-222 recognized a band in cytosol prepared from monkey
oviduct that was similar in size to rh-ER; comparable bands were not
detected in cytosols prepared from monkey spleen and prostate.
Detection of ER in luteal cytosol was inconsistent, with a faint
band (like that in Fig. 2) occasionally seen. The antihuman ERß
antibody PAI-311 recognized rh-ERß but not rh-ER protein (Fig. 2, lower panel). Using PAI-311, a band similar in size to
rh-ERß was seen in all monkey tissues examined; ERß levels were
highest in oviduct > corpus luteum > spleen >
prostate. An additional band denoted by arrows on the right
of each panel in Fig. 2 was also seen when the primary antibody was
omitted and, therefore, not considered to represent monkey ER or
ERß.
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). Optical densities resulting from
western blotting of cytosols obtained from corpora lutea were compared
with this standard curve to determine the ERß content. The pattern of
ERß protein levels varied (P < 0.05) across the
luteal phase (Fig. 4). ERß rose from
early luteal phase (4.2 ± 0.4 ng rh-ERß equivalents/µg luteal
cytosol) to peak levels (5.4 ± 0.5 ng rh-ERß equivalents/µg
luteal cytosol) at mid-late luteal phase, then fell to lowest levels by
late luteal phase (3.9 ± 0.3 ng rh-ERß equivalents/µg luteal
cytosol).
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, upper panel) at the time of
removal of the corpus luteum were lower (P < 0.05)
than untreated time-matched (control) animals. Co-administration of
antide and LH [3 times daily in a pattern of changing doses previously
shown to restore normal luteal function and lifespan (2)] yielded
progesterone levels higher than those seen animals treated with antide
only (P < 0.05) and similar to controls. In addition
to antide + LH, administration of the 3ß-hydroxy-steroid
dehydrogenase inhibitor trilostane to reduce luteal progesterone
production, without and with the nonmetabolizable progestin R5020,
reduced serum progesterone to levels lower than those measured in
control animals or those receiving antide + LH treatment
(P < 0.05). However, estradiol levels (Fig. 5, lower panel) were not different between the control and
treatment groups, as determined by one-way ANOVA.
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). ERß mRNA levels measured in monkeys
receiving antide with LH replacement were similar to those observed in
controls and monkeys receiving antide only. However, treatment with
antide, LH, and trilostane raised (P < 0.05) luteal
ERß levels 3-fold above levels seen in tissues following treatment
with antide alone or antide + LH. Administration of antide, LH,
trilostane, and R5020 reduced luteal ERß expression to levels seen
with antide or antide + LH treatment.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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mRNA was detected in the monkey corpus luteum at all stages of
the luteal phase, inconsistent detection of ER protein by Western
blotting suggests that levels of ER in the primate corpus luteum are
very low. Previous studies have failed to detect ER in the monkey
(10) and human (11) corpus luteum by immunocytochemistry, but detection
of ER in the monkey corpus luteum has been reported using Western
blotting and gel shift analysis (13). If minimal ER is present in
the primate corpus luteum, this tissue may represent a physiologic
situation were ERß transduces estrogenic effects in the virtual
absence of ER protein. Both pituitary gonadotropins and locally produced ovarian steroids are likely regulators of ERß in the primate corpus luteum, but the mechanism appears to be complex. In the present study, simultaneous gonadotropin and progesterone deprivation resulting from antide exposure did not alter luteal ERß expression at mid-late luteal phase, whereas administration of antide with LH replacement resulted in ERß mRNA levels that were not different from control. Serum progesterone levels were not different between controls and monkeys receiving antide + LH, so these data suggest that basal ERß expression in the corpus luteum may be independent of gonadotropin and progesterone. However, progesterone deprivation due to trilostane treatment during antide and concomitant LH administration resulted in elevated ERß mRNA levels. Replacement of progestin activity with R5020 resulted in ERß mRNA levels similar to those seen after treatment with antide or antide + LH, demonstrating that the effect of trilostane on ERß expression was specifically due to reduced progestin activity. Thus, while LH exposure may permit progesterone regulation of luteal ERß, progesterone acts more directly to reduce ERß expression in the primate corpus luteum. Though serum estradiol levels were not different between these treatment groups, it is possible that intraluteal levels of estradiol or other steroids may be altered. Changing levels of other estrogens and androgens may modulate luteal ERß expression directly, or these steroids may regulate other intracellular mediators (e.g. progesterone receptors), which could be involved in modulation of ERß levels in primate luteal tissues. However, these data do suggest that the loss of progesterone action may be important for the observed increase in ERß levels in the corpus luteum by mid-late luteal phase.
Little is known about the regulation of ERß expression in mammalian tissues. ERß mRNA levels in ovarian granulosa cells decreased following administration of an ovulatory gonadotropin bolus in monkeys (25) and rats (29); further studies determined that this effect of gonadotropin was mediated by cAMP (29). In addition, progesterone and estrogen deprivation during the ovulatory gonadotropin stimulus in vivo did not alter ERß mRNA levels in monkey granulosa cells (25). Treatment of rat granulosa cells with estrogen in vitro increased ERß levels after 24 h of exposure but decreased ERß content at 48 h of culture (43). Thus, gonadotropin and steroid control of ERß appears distinctly different within the cells of the ovulatory follicle compared with the corpus luteum; the degree of differentiation of granulosa-luteal cells may influence steroid regulation of ERß. While estrogen regulation of granulosa cell ERß expression is equivocal (25, 43), estrogen exposure enhanced ERß mRNA levels in GH3 cells, a rat pituitary cell line (44) but did not alter ERß expression by the rat uterus (45). ERß has been localized to steroidogenic cells of the corpus luteum (29, 32), but, based on other reports (46), we cannot rule out ERß expression by microvascular or other luteal cell types. Clearly, further studies will be required to understand the hormonal regulation of ERß expression in the ovary and other tissues.
A causal role for estrogen in primate luteolysis remains controversial.
While it is debatable whether the primate corpus luteum contains
appreciable levels of ER capable of transducing estrogen action (10, 11), ERß expression by monkey (current study) and human (14) luteal
tissues has revived the possibility that locally produced estrogen
plays an important role in regulating the structure and function of the
primate corpus luteum. While luteal estradiol levels do not change
across the luteal phase in monkeys (47, 48), luteal estrone (47) and
ERß (present study) concentrations peak during the second half of the
luteal phase; these data are consistent with the hypothesis that
receptor-mediated estrogen action increases in the corpus luteum around
the time of luteolysis. Studies published in the 1970s demonstrated
that intraovarian administration of estrogen could induce premature
functional luteolysis in monkeys (5, 6). However, subsequent reports
suggested that elevated plasma estrogen resulting from this local
administration could reduce pituitary LH release and, therefore,
deprive the corpus luteum of adequate gonadotropin support (8, 9).
GnRH-clamped monkeys were used to address this issue, but circulating
LH levels were not measured following luteal and systemic estradiol
administration (9), so the site(s) of estrogen action in these studies
is still unclear.
Taken together, these findings suggest a mechanism by which locally produced estrogens could mediate functional and structural luteolysis in the primate. In the nonfertile menstrual cycle, decreasing LH pulse frequency (49) creates lengthening periods of relative progesterone deprivation, which may result in increased luteal ERß levels and enhanced luteal sensitivity to locally produced estrogens. Estrogen has been shown to decrease luteal 3ß-hydroxysteroid dehydrogenase activity in vitro (50, 51), providing a mechanism by which estrogens may further reduce luteal progesterone production in vivo. Lowered intraluteal progesterone has been shown to result in decreased luteal weight and other structural changes in the corpus luteum consistent with luteolysis (37). In early pregnancy, enhanced gonadotropin support in the form of CG from an implanting blastocyst can maintain luteal structure and progesterone production during early pregnancy (52), thereby delaying luteolysis. It is unknown if CG exposure alters luteal ERß content or estrogen sensitivity. This proposed mechanism, though speculative, suggests the need for further studies examining estrogen regulation of luteal function and life span in a gonadotropin-controlled environment which may resolve the question of a role for estrogen in primate luteolysis.
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Acknowledgments |
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Footnotes |
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1 This research was supported by NICHD/NIH through cooperative
agreement (HD-8185) as part of the Specialized Cooperative Centers
Program in Reproductive Research. Also supported by NIH Grants HD-20869
(to R.L.S.) and RR00163. Presented in part at the 31st Annual Meeting
of the Society for the Study of Reproduction, 1998 (Abstract
118). 
Received October 26, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ß mRNA in corpus luteum of human subjects. Mol Human Reprod 5:17–21
and estrogen receptor ß to partial estrogen agonists/antagonists. Mol
Pharmacol 54:105–112 and ß. Endocrinology 138:863–870. J Biol Chem 272:25832–25838 and ß with the same naturally
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and ERß at AP1 sites. Science 277:1508–1510 mRNA expression in male and female rhesus
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and ß in the rat corpus luteum of
pregnancy: regulation by prolactin and placental lactogens.
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T.M. Hazzard, L.K. Christenson, and R.L. Stouffer Changes in expression of vascular endothelial growth factor and angiopoietin-1 and -2 in the macaque corpus luteum during the menstrual cycle Mol. Hum. Reprod., November 1, 2000; 6(11): 993 - 998. [Abstract] [Full Text] [PDF]
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