Elevated endometrial androgen receptor expression in women with polycystic ovarian syndrome.
ABSTRACT Androgen receptors (AR) have been identified in human endometrium; however, their role in endometrial cyclic development and function remains poorly understood. The objective of the present study was to investigate the profile of endometrial AR in normal menstrual cycles and in the endometrium of women with polycystic ovarian syndrome (PCOS). This syndrome is characterized by chronic hyperandrogenism and oligo-ovulation, and it is often associated with poor reproductive performance. Using immunohistochemistry and reverse transcription-polymerase chain reaction, we found that women with PCOS exhibited elevated endometrial AR expression compared to normal, fertile controls. This increase was most apparent in glandular and luminal epithelium. Furthermore, when compared to endometrium from fertile women, PCOS endometrium showed other abnormalities in endometrial development, including delay or absence of the alpha(v)beta3 integrin, a well-characterized biomarker of uterine receptivity described previously (Lessey et al., JCI 1992; 90:188-195). To better understand and to gain insights regarding these findings, we used in vitro cell-culture models to study the regulation of AR in primary endometrial stromal and the well-differentiated epithelial cell line (Ishikawa). Based on Western blot analysis, epithelial AR is up-regulated by estrogens and androgens and is inhibited by progestins and epidermal growth factor (EGF). On the other hand, EGF significantly induced the expression of alpha(v)beta3, whereas estrogen and androgen treatment inhibited its expression. Collectively, these results suggest that the poor reproductive performance observed in women with PCOS may be due, in part, to the concomitant increase in both serum androgens and elevations in endometrial AR. This combination may reduce endometrial receptivity as judged by the down-regulation of alpha(v)beta3 integrin.
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ABSTRACT: The endometrium is a multicellular, steroid-responsive tissue that undergoes dynamic remodeling every menstrual cycle in preparation for implantation and, in absence of pregnancy, menstruation. Androgen receptors are present in the endometrium. The objective of the study was to investigate the impact of androgens on human endometrial stromal cells (hESC). Bioinformatics was used to identify an androgen-regulated gene set and processes associated with their function. Regulation of target genes and impact of androgens on cell function were validated using primary hESC. The study was conducted at the University Research Institute. Endometrium was collected from women with regular menses; tissues were used for recovery of cells, total mRNA, or protein and for immunohistochemistry. A new endometrial androgen target gene set (n = 15) was identified. Bioinformatics revealed 12 of these genes interacted in one pathway and identified an association with control of cell survival. Dynamic androgen-dependent changes in expression of the gene set were detected in hESC with nine significantly down-regulated at 2 and/or 8 h. Treatment of hESC with dihydrotestosterone reduced staurosporine-induced apoptosis and cell migration/proliferation. Rigorous in silico analysis resulted in identification of a group of androgen-regulated genes expressed in human endometrium. Pathway analysis and functional assays suggest androgen-dependent changes in gene expression may have a significant impact on stromal cell proliferation, migration, and survival. These data provide the platform for further studies on the role of circulatory or local androgens in the regulation of endometrial function and identify androgens as candidates in the pathogenesis of common endometrial disorders including polycystic ovarian syndrome, cancer, and endometriosis.The Journal of clinical endocrinology and metabolism 08/2011; 96(11):E1746-55. · 6.50 Impact Factor
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ABSTRACT: Transcription factor-based cellular reprogramming has opened the way to converting somatic cells to a pluripotent state, but has faced limitations resulting from the requirement for transcription factors and the relative inefficiency of the process. We show here that expression of the miR302/367 cluster rapidly and efficiently reprograms mouse and human somatic cells to an iPSC state without a requirement for exogenous transcription factors. This miRNA-based reprogramming approach is two orders of magnitude more efficient than standard Oct4/Sox2/Klf4/Myc-mediated methods. Mouse and human miR302/367 iPSCs display similar characteristics to Oct4/Sox2/Klf4/Myc-iPSCs, including pluripotency marker expression, teratoma formation, and, for mouse cells, chimera contribution and germline contribution. We found that miR367 expression is required for miR302/367-mediated reprogramming and activates Oct4 gene expression, and that suppression of Hdac2 is also required. Thus, our data show that miRNA and Hdac-mediated pathways can cooperate in a powerful way to reprogram somatic cells to pluripotency.Cell stem cell 04/2011; 8(4):376-88. · 23.56 Impact Factor
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ABSTRACT: To compare the ovulation rate between raloxifene and clomiphene citrate (CC) in patients with polycystic ovary syndrome (PCOS). Double-blind, randomized, superiority clinical trial. Tertiary university hospital. Women with ovulatory dysfunction and PCOS based on the Rotterdam criteria. One of two oral treatments: 5 days of 100 mg/day of CC or R. Ovulation, based on follicle collapse on serial ultrasound and midsecretory serum progesterone concentration (≥3 ng/dL). The women with PCOS (n = 82) were randomized to receive CC (n = 40) or raloxifene (n = 42). From these, 68 patients finished the trial according to the protocol (CC: n = 37; raloxifene: n = 31). There were no statistically significant differences between the groups in ovulation rates per an intention-to-treat analysis based on ultrasound alone (CC: 21 of 40 vs. raloxifene: 17 of 42) or on progesterone levels (CC: 16 of 40 vs. raloxifene: 11 of 42). No serious adverse events were observed in either group. No statistically significant difference in ovulation was observed between raloxifene and clomiphene citrate in patients with PCOS with ovulatory dysfunction.Fertility and sterility 07/2011; 96(3):769-73. · 3.97 Impact Factor