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Department of Pathology and Laboratory Medicine (C.W.G., R.A.L., B.A.L.); Department of Pediatrics (E.M.W.), Laboratory for Reproductive Biology and Department of Biochemistry and Biophysics; and Department of Obstetrics and Gynecology (K.B.C.A., W.R.M., A.K., B.A.L., M.A.F.), Division of Reproductive Endocrinology and Infertility, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599
Address all correspondence and requests for reprints to: Bruce A. Lessey, Department of Obstetrics and Gynecology, The University of North Carolina, CB 7570, Chapel Hill, North Carolina 27599. E-mail: . lessey{at}med.unc.edu
Abstract
The endometrium of reproductive aged women undergoes cyclic developmental changes in preparation for implantation in response to estrogen and progesterone. These steroids and their receptors are tightly regulated throughout the menstrual cycle, and their actions are facilitated by the presence of steroid receptor coactivators of the p160 family. In this study using immunohistochemistry and Western blot analysis, we characterize the expression patterns of three coactivators, steroid receptor coactivator-1, amplified in breast cancer-1 (AIB1), and transcriptional intermediary factor-2 in human endometrium obtained prospectively from normal fertile women throughout the menstrual cycle. With the exception of glandular AIB1, which increased in the late secretory phase, none of the coactivators changed significantly during the menstrual cycle. We compared coactivator expression patterns in fertile endometrium to the endometrium of anovulatory (proliferative; n = 3) and clomiphene-induced ovulatory (secretory; n = 13) women with polycystic ovarian syndrome (PCOS), a group that have a higher likelihood of developing estrogen-induced endometrial hyperplasia and cancer. To control for the effect of clomiphene citrate, an additional group was included consisting of ovulatory women treated with clomiphene citrate for "male factor" infertility. Compared with both fertile and infertile controls, PCOS women exhibited elevated levels of AIB1 and transcriptional intermediary factor-2 expression in both epithelial and stromal cells. We postulate that increased coactivator expression may render the endometrium more sensitive to estrogen. In support of this, we describe an increased expression of ER
(an estrogen-induced gene product) during the menstrual cycle in PCOS endometrium compared with fertile controls. In summary, we demonstrate that the expression of p160 coactivators are regulated in endometrium during the menstrual cycle in normal fertile women but are overexpressed in the endometrium of women with PCOS. Based on these findings, we suggest a possible mechanism to explain the poor reproductive performance observed in PCOS and the increased incidence of endometrial hyperplasia and cancer noted in this group of women.
ER BELONGS TO A large class of ligand-dependent transcription factors that positively and negatively control gene expression in target tissues exerting critical influence on cell growth and differentiation (1). The endometrium is one of several target tissues for steroid hormones (2). In the adult human female, the endometrium undergoes cyclic growth and development in response to estrogen and progesterone, acting through specific steroid receptors, ER and the PR (3). Like breast and prostate, the endometrium is highly responsive to steroid hormones. Endometrial development occurs in a cyclic fashion for the purpose of establishing pregnancy. In the follicular phase, ovarian follicles secrete E2 that induces proliferative changes and increases endometrial sensitivity to estrogen and progesterone by increasing the levels of ER and PR. Conversely, with ovulation, progesterone from the corpus luteum induces secretory changes and dampens the response to estrogen and progesterone (4, 5, 6). As a target tissue for estrogen, the endometrium is a common site of hyperplasia and cancer, occurring more frequently in women receiving unopposed estrogen and in women with ovulatory dysfunction (7).
It is becoming clear that the actions of steroid receptors are influenced by specific coactivators and corepressors that function to mediate steroid hormone action. At least three coactivators have been identified within the p160 family, and include steroid receptor coactivator-1 (SRC1) (8), amplified in breast cancer-1 (AIB1) (9) and transcriptional intermediary factor-2 (TIF2) (10). Each is thought to function by facilitating steroid receptor activation of gene transcription (8, 9, 10). There is great interest in the function and regulation of this class of coactivators in the endometrium given that the endometrium is a target tissue for estrogen and progesterone. Nevertheless, currently there is no information available detailing the expression pattern of these coactivators in human endometrium during the menstrual cycle. In the present study, we compare the relative expression of the p160 coactivators in normal endometrium to that in women with anovulation and polycystic ovarian syndrome (PCOS). As a group, women with PCOS have a low cycle fecundity and higher than expected incidence of endometrial hyperplasia and cancer. Recent reports from our laboratory have shown that women with PCOS overexpress the AR (11), an estrogen-responsive gene in endometrial epithelium (12). Based on the current investigation, we suggest that overexpression of one or more p160 coactivators renders the endometrium more sensitive to estrogen, and thus may account for the higher incidence of endometrial abnormalities seen in women with PCOS.
Materials and Methods
Human samples
Endometrium was obtained from 49 women (fertile and infertile) seen at the North Carolina Memorial Hospital at the University of North Carolina in Chapel Hill. Thirty-three fertile women volunteers were recruited for timed endometrial biopsy in the proliferative (n = 9) and secretory (n = 24) phase of the menstrual cycle. Luteal phase samples were obtained in the early secretory (LH d 1–5; cycle d 15–19; n = 13), midsecretory (LH d 6–10, cycle d 20–24; n = 5) and late secretory (LH d 11–14, cycle d 25- 28; n = 6) phases. Sixteen women with hyperandrogenism and ovulatory dysfunction (oligoovulation or amenorrhea) who underwent endometrial biopsy as part of their clinical evaluation for PCOS were also included. Insulin resistance was not a requirement for their diagnosis of PCOS. Biopsies came from both the proliferative (n = 3) and midsecretory (n = 13) phase, in this group. Of these, 6 showed histologic delay, 6 were histologically in phase, and 1 was histologically advanced. Six otherwise healthy women whose husbands were diagnosed with "male factor" infertility underwent timed midsecretory phase endometrial biopsy as part of a clomiphene citrate treatment cycle (clomid controls). All luteal phase endometrial biopsies were timed to the urinary LH surge (Ovuquick, Quidel, San Diego, CA). Evaluation of proliferative phase endometrium was categorized based on histology. Histologic dating of secretory phase biopsies was assigned using the criteria of Noyes et al. (13). Because the patients with PCOS do not typically ovulate in a spontaneous and predictable manner, all secretory phase biopsies were timed to the urinary LH surge in therapeutic cycles, in which clomiphene citrate (50–150 mg/d for 5 d in the early proliferative phase) was administered. Fertile volunteers had endometrial biopsies randomly assigned to 1 of 14 luteal days. Proliferative phase samples were obtained in fertile controls at the time of tubal ligation. Recurrent prostate cancer specimens (poorly differentiated, Gleason sum 9), used as a positive control for these studies, were generously provided by Dr. James L. Mohler (Department of Surgery, University of North Carolina at Chapel Hill). All protocols involved in this study were approved by the Committee for the Protection of Human Subjects at the University of North Carolina at Chapel Hill.
Immunohistochemistry
Immunostaining for SRC1, AIB1, TIF2, and ER was performed on 5- to 6-µm sections of formalin fixed, paraffin-embedded endometrial biopsies using the Vectastain Elite ABC kits (Vector Laboratories, Inc., Burlingame, CA). Diaminobenzidine (Sigma, St. Louis, MO) was used as the chromagen. Tissue sections were deparaffinized in xylene and hydrated in a series of graded ethanols. Following a rinse in PBS, pH 7.4, endogenous peroxidase activity was quenched upon incubation for 30 min with 0.3% H2O2 in absolute ethanol, followed by a 10-min rehydration in PBS. Tissue sections were heated in a microwave for 12 min in antigen retrieval solution (10 mM citrate buffer) before incubation with primary antibody. After initial incubation with blocking serum for 30 min at room temperature (4% normal goat serum), sections were incubated with mouse monoclonal antibodies against human SRC1 (Affinity BioReagents, Inc., Golden, CO), AIB1 and TIF2 (Transduction Laboratories, Lexington, KY) and ER (Novocastra, New Castle upon Tyne, UK). Negative controls were analyzed on adjacent sections incubated without primary antibody. Each primary antibody was serially diluted to achieve maximum sensitivity and specificity. A PBS rinse was followed by treatment of secondary antibody consisting of biotinylated goat antimouse antibody for 30 min. After this incubation, sections were washed and incubated with avidin:biotinylated horseradish peroxidase macromolecular complex for 60 min. Visualization of peroxidase was carried out by adding diaminobenzidine and incubated for 10 min to complete the reaction. As a final step, sections were counterstained with hematoxylin, dehydrated in a graded series of ethanols, cleared with xylene, and a coverslip placed over Permount for evaluation by light microscopy. Recurrent prostate cancer was used as a positive control. The resulting staining was evaluated using a Nikon microscope (Tokyo, Japan), by a single observer (B.A.L.) without knowledge of the specimen’s identity.
Assessment of staining intensity and distribution was made using the semiquantitative histologic score (HSCORE) system. HSCORE was calculated using the following equation: HSCORE = 
Pi (i+1), where i = intensity of staining with a value of 1, 2, or 3, (weak, moderate or strong, respectively) and Pi = the percentage of stained endometrial stromal and epithelial cells for each intensity, varying from 0–100%. Low intraobserver (r = 0.983; P < 0.0001) and interobserver (r = 0.994; P < 0.0001) differences for HSCORE in uterine tissues have been previously reported using this technique (14), and similar results have been obtained in the author’s laboratory (B.A.L., Ref. 15).
Western blot analysis
Endometrial biopsies from normal and PCOS women were homogenized on ice using RIPA extraction buffer (10 mM Tris HCl, pH 8.0; 10 mM EDTA, pH 8.0; 0.15 M NaCl; 1% NP-40; 0.5% SDS) containing protease inhibitor cocktail (Roche Molecular Biochemicals, Indianapolis, IN). After centrifugation at 14,000 rpm/10 min, protein concentrations were determined using the Bio-Rad Laboratories, Inc. (Hercules, CA) protein assay kit. Total proteins (100 µg from each sample) were denatured in Laemmli buffer, fractionated using 8% one-dimensional-SDS-PAGE and transferred to nitrocellulose membrane. Blots were blocked for 1 h in TBST (20 mM Tris, pH 7.5; 137 mM NaCl; 0.2% Tween 20) containing 10% nonfat dry milk. Blots were washed twice for 5 min each in TBST and then incubated with monoclonal antibodies against human SRC1, AIB1, and TIF2 overnight with rocking at 4 C. The blots were washed for 30 min twice with TBST, followed by incubating for 1 h at room temperature with peroxidase-conjugated antimouse IgG while rocking. After washing twice for 30 min each with TBST, the immunoreactive protein complexes were detected using enhanced chemiluminescence (Amersham Pharmacia Biotech Inc., Piscataway, NJ).
Statistical analysis
Relative levels of coactivators or ER were estimated using the semiquantitative HSCORE, a numerical score ranging from 0 to 4. Comparison of this continuous variable between groups was made using ANOVA with Scheffé’s correction.
Results
Immunostaining for the p160 coactivators, SRC1, AIB1, and TIF2, in proliferative and secretory endometrium is shown in Fig. 1
. In each case, recurrent prostate cancer was used as a control tissue, as previously described (16). SRC1 exhibited the greatest staining intensity and was uniformly present in all three cell types (glandular epithelium, luminal epithelium, and stroma). Immunostaining for AIB1 was the least of the three coactivators studied, but intensity increased significantly in the late luteal phase in glandular epithelium (P = 0.03) compared with the early secretory phase. TIF2 immunostaining was intermediate between the other two coactivators and its expression, like SRC1, did not change significantly during the cycle in each cell type. These results are summarized in Fig. 2.
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). Expression of SRC1, AIB1, and TIF2 were compared between PCOS and both fertile and infertile (clomid treated) controls during the secretory phase (Fig. 3). Overall, PCOS endometrium from the secretory phase expressed more AIB1 and TIF2 than comparably timed biopsies from fertile controls (P < 0.001). As a more concise comparison, we included only those samples from the midsecretory phase in which histologic advancement was consistent with the urinary LH day (LH d 20- 24), consistent with the window of implantation. In the glandular epithelium (Fig. 3A), PCOS endometrium exhibited significant increases in AIB1 compared with both normal fertile controls and clomid controls (both P < 0.001). TIF2 was also significantly higher in PCOS endometrium in midsecretory glandular epithelium (both P = 0.004). Results for stromal cells (Fig. 3B) and luminal epithelium (Fig. 3C) also detected significant elevations in AIB1, specifically in PCOS endometrium during the midsecretory phase, when compared with either fertile controls or clomid controls (all, P < 0.01). TIF2 expression was elevated in the luminal compartment for PCOS compared with fertile and clomid controls (P = 0.001 and P = 0.01, respectively) but only greater than clomid controls in the stroma compartment (P < 0.01).
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3-fold increase; P < 0.02). Luminal cells from PCOS endometrium expressed a 3- to 5-fold increase of TIF2 in the proliferative phase (P = 0.01) samples compared with normal endometrium (data not shown).
The changes in coactivator expression observed using immunohistochemistry was further confirmed by Western blot analysis. Total cellular protein obtained from a midsecretory phase endometrium of normal women (Fig. 4, lanes 1 and 2) were compared with similarly timed samples from PCOS women (Fig. 4, lanes 3 and 4). There was a dramatic increase in AIB1 and a moderate increase in TIF2 observed in PCOS endometrium compared with fertile controls. No discernable difference was noted for SRC1 between the normal and PCOS samples (Fig. 4).
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expression by immunohistochemistry in normal and PCOS endometrium during the midsecretory phase (cycle d 20–24 based on the urinary LH surge). We previously demonstrated that ER levels are minimal during this time in the menstrual cycle (4). As shown in Fig. 5, ER immunostaining was strong during the proliferative phase in epithelial (arrowheads) and stromal cells (asterisk) but was undetectable in the endothelium (arrows) (Fig. 5A). ER immunostaining declined in all cell types during the early secretory phase (Fig. 5B) and was largely absent by the midsecretory phase (Fig. 5C). In contrast, endometrium from the midsecretory phase in a woman with PCOS exhibited much greater immunostaining for ER (Fig. 5D), with positive staining in the glandular (arrowhead) and stromal cells (asterisk), as well as the luminal epithelium (not shown). The differences in ER expression between normal vs. PCOS endometrium during the midsecretory phase is shown in Fig. 6. There was a significant increase in ER immunostaining noted in each cell type between midsecretory endometrium from normal and PCOS women (glands, P = 0.01, stroma, P = 0.002, and lumen, P = 0.01).
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In the present study we demonstrate that the expression of the p160 coactivators AIB1 and TIF2 are strikingly elevated in both the proliferative and secretory phases of the menstrual cycle of the endometrium from PCOS patients compared with controls, whereas levels of SRC1, another p160 coactivator, were similar between normal and PCOS endometrium. Although clomiphene citrate was used to induce ovulation in the PCOS patients, and may therefore contribute to these effects, the "male factor" controls who also received clomiphene citrate did not exhibit this increase in p160 coactivators expression. In addition to AIB1 and TIF2, ER levels were also elevated in PCOS endometrium compared with normal midsecretory endometrium. We had previously demonstrated elevated AR expression in women with PCOS (11). The genes for both ER and AR are estrogen-responsive genes and show increased expression after estrogen treatment in human and primate endometrium (4, 12, 17, 18). A combination of increased p160 coactivator expression and ER and AR during the secretory phase suggests a heightened sensitivity of the PCOS endometrium to estrogen and may account for the noted increased incidence in hyperplasia and endometrial cancer (19) as well as the diminished capacity for sustained pregnancy (7) in this population of women.
Steroid receptor coactivator expression has not been systematically studied in human endometrium, although sporadic reports have suggested their importance in this tissue (20, 21, 22, 23). This is the first study documenting the relative levels of expression of SRC1, AIB1, and TIF2 in human endometrium and the first to examine their expression in endometrium from women with PCOS. As demonstrated by both immunohistochemistry and Western blot, AIB1 and TIF2 are significantly increased in PCOS endometrium compared with endometrium from normal fertile volunteers. Aside from the suggestion that the apparent increase in coactivators confers an increased risk for hyperplasia and cancer due to elevated estrogen sensitivity, other reproductive sequelae may occur. This group of patients exhibits a low cycle fecundability and when they do conceive, exhibit a high miscarriage rate approaching 60–70% (24, 25). We previously reported that one biomarker of uterine receptivity, the vß3 integrin, which is normally expressed at the time of implantation in women (26), is reduced or absent in women with PCOS (11, 15). As estrogen appears to inhibit the expression of this integrin in endometrial epithelium (27, 28, 29), we postulate that enhanced ER and estrogen responsiveness could account for this finding of diminished integrin expression. The normal loss of ER in epithelium that occurs during the midsecretory phase results in a functional estrogen withdrawal at the time of implantation in human and mouse endometrium (4, 5, 30).
Recent studies have implicated steroid receptor coactivators as important modulators of ER function in breast and ovarian cancer (9, 23, 31, 32, 33). We recently demonstrated the overexpression of TIF2 and SRC1 in recurrent prostate cancer compared with androgen-dependent cancer and showed that binding of adrenal androgens and possibly other lower affinity ligands to the AR ligand binding domain favors recruitment of TIF2, thus providing a mechanism for AR mediated transactivation in the absence of circulating testosterone in recurrent prostate cancer (16). Androgens also appear to inhibit the expression of endometrial proteins including the vß3 integrin (11). It is likely that p160 coactivator overexpression coupled with elevated AR could also contribute to endometrial dysfunction in this group of women. Such a mechanism is consistent with our hypothesis that inappropriate expression of estrogen, progesterone, or androgen during the midsecretory phase will result in the inhibition of key midluteal endometrial proteins. Based on these observations in PCOS endometrium, we suspect that there may be other genes that are aberrantly expressed.
In summary, patients with PCOS have elevated expression of ER and two of the three known p160 steroid receptor coactivators. This increase in endometrial ER and coactivators likely renders PCOS endometrium more sensitive to estrogen and/or androgen and may allow androgens to cross-react with ER (or vice versa) to stimulate the endometrium to proliferate. In addition, inappropriate estrogen action during the time of maximal uterine receptivity may alter the normal receptive pattern of gene expression and reduce the fertility of women with PCOS or make them more prone to pregnancy loss. As a major target for steroid hormones, the endometrium is vulnerable to the combined increase in estrogenic and androgenic action. Future studies will be necessary to fully understand and appreciate the implications of these observations.
Footnotes
This research was supported by NICHD/NIH through cooperative agreement U54 HD-35041 (to B.A.L. and E.M.W.) as part of the Specialized Cooperative Centers Program in Reproduction Research, the National Cooperative Program on Markers of Uterine Receptivity for Blastocyst Implantation (HD-34824, to B.A.L.), by NICHD Grant HD-6910 (to E.M.W.), by the United States Army Medical Research and Material Command Grant DAMD17-00-1-0094 (to E.M.W.), by NIH Grant P01-CA-77739 (to C.W.G. and E.M.W.), and by the International Training and Research in Population and Health Program supported by the Fogerty International Center and NICHD, NIH (to K.B.C.A.).
Abbreviations: AIB1, Amplified in breast cancer-1; HSCORE, histologic score; PCOS, polycystic ovarian syndrome; SRC1, steroid receptor coactivator-1; TIF2, transcriptional intermediary factor-2.
Received November 15, 2001.
Accepted March 6, 2002.
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