Delayed endometrial decidualisation in polycystic ovary syndrome; the role of AR-MAGEA11

Abstract

Polycystic ovary syndrome (PCOS) is a common gynaecological disorder, with a prevalence of up to 12% of women of reproductive age, and is in part characterised by elevated circulating androgens and aberrant expression of androgen receptor (AR) in the endometrium. A high percentage of PCOS patients suffer from infertility, a condition that appears to be linked to mistimed and incomplete decidualisation critically affecting events surrounding embryo implantation. The aim of this study was to examine the involvement of MAGEA11, and the genome-wide role of AR in PCOS. We determined that elevated androgen levels on PCOS cells had an impact on the delayed and incomplete decidual transformation of endometrial cells. The AR co-regulator MAGEA11, a known enhancer of AR function, was constitutively overexpressed throughout the menstrual cycle of PCOS patients, co-localised in the nucleus of PCOS stromal tissue and cells and formed a molecular complex with AR. Genome-wide AR analysis in PCOS stromal cells revealed that AR targets included genes involved in cell death and apoptosis, as well as genes commonly dysregulated in endometrial cancer. Enhanced MAGEA11 and AR-mediated transcriptional regulation may impact on a correct endometrial decidualisation response, subsequently affecting endometrial receptivity in these infertile women. Key messages MAGEA11 and AR are overexpressed in hyperandrogenic PCOS patients. MAGEA11-AR overexpression in PCOS correlates with delayed decidualisation. AR and MAGEA11 associate in a molecular complex. AR directly regulates a unique set of genes controlling gene differentiation. Electronic supplementary material The online version of this article (10.1007/s00109-019-01809-6) contains supplementary material, which is available to authorized users.

Differential regulation of osteopontin and CD44 correlates with infertility status in PCOS patients

“…In anovPCOS endometrium, which displays only proliferative features, CD44 levels were lower, whereas OPN levels were higher, compared to those of the fertiles. The high levels of OPN in anovPCOS patients could be associated with the levels of oestrogen and androgen, characterising this group of patients as OPN expression is reduced in endometrium cells exposed to the AR inhibitor flutamide and endometrial PCOS cells exhibit an increased expression of ERα nuclear receptor co-activators that may enhance the oestrogen activity in these cells [34,35]. The decreased levels of CD44 in anovPCOS during proliferative phase mirror the levels observed for ovPCOS in secretory phase promoting the concept of dysfunctional endometrium in PCOS patients, regardless of progesterone action.…”

Investigation of infertility using endometrial organoids

“…Hyperandrogenism is likely another feature of PCOS contributing to impaired endometrial function ( Simitsidellis et al 2018 ). Elevated androgens result in delayed decidualization of stromal cells which produce limited amounts of prolactin in vitro ( Younas et al 2019 ). As a consequence, the endometrium would fail to acquire a receptive state in time to support implantation.…”

Endometrial Receptivity in Patients with Polycystic Ovary Syndrome

“…It was also showed that 44% of women with unexplained infertility are probable PCOS cases, underlying that the subtle clinical phenotypes in some of the patients can be the cause of misdiagnosis and, therefore, inappropriate diagnosis and treatment [11].…”

“…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.…”