Elevated Endometrial Androgen Receptor Expression in Women with Polycystic Ovarian Syndrome1

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.

The Role ofHoxGenes in Female Reproductive Tract Development, Adult Function, and Fertility

“…The expression of this biomarker is decreased in endometrium from women with PCOS compared with fertile controls (Apparao et al 2002). Also, as described above, after ovulation induction treatment of infertility in PCOS, implantation rates remain low.…”

Low testosterone levels in women with diminished ovarian reserve impair embryo implantation rate: a retrospective case-control study

“…This hypothesis is supported by evidence that transient androgen supplementation significantly increased the embryo implantation rate and clinical pregnancy rate in poor responders [9]. However, embryo implantation defects coinciding with aberrant expression of avb3 integrin, glycodelin, estrogen receptor a, and HOXA10 have also been observed in polycystic ovarian syndrome patients with chronic hyperandrogenism [17,18]. These paradoxical phenomena reveal that endometrial development and embryonic implantation may require appropriate androgen levels, but the relationship will require further investigation.…”

StuI polymorphism on the androgen receptor gene is associated with recurrent spontaneous abortion

“…The effect of androgens such as testosterone and dihydrotestosterone mediated by androgen receptor (AR) that is a nuclear receptor [3]. Androgen receptor is widely expressed in female reproductive tissue such as endometrium [1] and binds to a steroid ligand and then is transferred into the nucleus, where it regulates the transcription of androgen-responsive genes [5]. The AR gene is located on the X chromosome between q11 and q12 loci and is composed of eight exons [2] that encode a 110-kd protein that contains an N-terminal transactivation domain, a central DNA-binding domain, and a C-terminal ligandbinding domain [8].…”