Molecular Mechanisms of Androstenediol in the Regulation of the Proliferative Process of Human Endometrial Cells

Abstract

Proliferation in endometria of women with polycystic ovarian syndrome (PCOS) is increased, similar to the biosynthesis of androstenediol (estrogenic metabolite). As previously shown, in human endometrial cells, androstenediol increases CYCLIN D1 levels and KI67 and decreases P27 content. The objective of the present investigation was to determine the mechanisms by which androstenediol promotes endometrial cell-cycle progression. Estrogen receptor α (ERα) activation and changes in CYCLIN D1 and P27 levels were evaluated by Western blot in T-HESC and St-T1b endometrial cell lines, using receptor antagonists; activation of PI3K-protein kinase B (AKT) and mitogen-activated protein kinases-extracellular signal-regulated kinases (MAPK-ERK)1/2 pathways was evaluated using PI3K, MAPK/ERK kinase (MEK)1/2, and RNA-polymerase II inhibitors. The data showed that androstenediol treatment significantly increases CYCLIN D1 and decreases P27 levels through ERα activation ( P < .05). In addition, an increase in AKT/ERK1/2 phosphorylations was determined ( P < .05). In the presence of RNA-polymerase II inhibitor, phosphorylation of AKT/ERK1/2 decreased ( P < .05), meaning that endometrial cells need transcriptional activity to activate the kinases involved. It was also observed that PI3K action is required for P27 and CYCLIN D1 changes. Therefore, the action of androstenediol in endometria depends on PI3K-AKT and MAPK-ERK1/2 pathways activation, together with cell transcriptional machinery. This could be of clinical significance, as in pathologies such as PCOS, increased endometrial levels of androstenediol together with a high prevalence of endometrial hyperplasia and adenocarcinoma have been reported.

Effect of TNF-α on Molecules Related to the Insulin Action in Endometrial Cells Exposed to Hyperandrogenic and Hyperinsulinic Conditions Characteristics of Polycystic Ovary Syndrome

“…Interestingly, TNFR2 is more related to proliferative and proinflammatory process than to apoptosis, 28 which is concordant to the fact that women with PCOS have a higher risk of developing endometrial hyperplasia and endometrial adenoma or carcinoma. 29,30 Consequently, the failures in insulin signaling observed in endometrium from obese women with PCOS may be the result of an increase in TNF-a activity, which may negatively affect insulin action through different mechanisms. One of these mechanisms is the increase in interleukin (IL)-6 expression via NFkB activation, 19,20,31 since this proinflammatory cytokine is closely related to insulin resistance and increased serum levels have been detected in obese women with PCOS.…”

“…Interestingly, TNFR2 is more related to proliferative and proinflammatory process than to apoptosis, 28 which is concordant to the fact that women with PCOS have a higher risk of developing endometrial hyperplasia and endometrial adenoma or carcinoma. 29,30…”

Endometrial Receptivity in Patients with Polycystic Ovary Syndrome

“…Enhanced ER-α activation was associated with rare or absent apoptosis and increased in cell proliferation in the endometrium in the mid luteal phase [30,[36][37][38]. On the other hand, it is possible that high circulating estrogens as in patients performing ovarian stimulation to determine the apoptosis of the endometrial glandular cells, as showed by an experimental study by Chen et al [39].…”

“…In the endometrium of PCOS women the androgen receptor (AR) mRNA and protein expression is increased [23] and coactivators of AR were found to be overexpressed as well [37]. Among these coactivators, Melanoma-associated antigen 11 (MAGEA11) was showed to bind to AR resulting in alteration of window of implantation [11].…”

“…Endometrial microenvironment can also contribute to over-exposure to androgen. Thus, low level of SHBG can increase the bioavailable testosteron at endometrial level [53] and increased activity of endometrial 5a-reductase generates potent androgens such as di-hydro-testosterone [37]. The uptake of intracrine precursors of testosterone [38,54] and increased activity of hydroxi-steroiddehydrogenase might contribute to high androgen exposure of endometrium in PCOS [55].…”