Endometrial expression of anti-Müllerian hormone and its type II receptor in women with polycystic ovary syndrome

Abstract

Research question

Is endometrial expression of anti-Müllerian hormone (AMH) and its receptor II (AMH-R) altered in women with polycystic ovary syndrome (PCOS) and affected by lifestyle intervention?

Design

Endometrial immunostaining of AMH and AMH-R was evaluated in obese women with PCOS (OB-PCOS, n = 18) before and after 3 months of lifestyle intervention, as well as in BMI-matched controls (OB-C, n = 10), normal-weight women with PCOS (n = 11) and healthy normal-weight controls (n = 11).

Results

Before lifestyle modification, serum concentrations of AMH were higher in women with PCOS compared with BMI-matched controls, but there were no differences in endometrial immunostaining of AMH or AMH-R between the groups. Following lifestyle modification, a subgroup of OB-PCOS women started to ovulate. Still, there were no differences in endometrial immunostaining of AMH between ovulatory and anovulatory women with PCOS and controls, and no variation within the menstrual cycle. However, immunostaining of stromal AMH-R increased from cycle days 6–8 to 21–23 in all three groups. Furthermore, endometrial immunostaining of AMH-R correlated positively with oestrogen receptor alpha on cycle days 21–23 in the groups of women with PCOS, as well as in the controls (r = 0.66, P = 0.007 and r = 0.85, P < 0.001, respectively).

Conclusions

Although PCOS is associated with increased serum concentrations of AMH, protein expression of AMH and its receptor in the endometrium was no different to controls, and moreover not affected by lifestyle modification. These results imply that circulating AMH is not affecting expression of AMH and its receptor in the endometrium.

Introduction

Polycystic ovary syndrome (PCOS) is a common reproductive disorder affecting around 10% of women of fertile age (Goodarzi et al., 2011; Rosenfield and Ehrmann, 2016). The main features of PCOS are menstrual dysfunction, hyperandrogenism and polycystic ovaries (Goodarzi et al., 2011; Rosenfield and Ehrmann, 2016). Apart from reproductive impairment, the syndrome can present metabolic disorders such as obesity, insulin resistance and hyperinsulinemia (Goodarzi et al., 2011; Rosenfield and Ehrmann, 2016). It is evident that the endocrine and metabolic abnormalities present in PCOS might impair the endometrium, as indicated by altered expression of proteins related to endometrial function (Bellver et al., 2011; Hulchiy et al., 2016; Paulson et al., 2017), and increased risk of endometrial hyperplasia and cancer (Giudice, 2006; Piltonen, 2016). Proliferative abnormalities and dysfunction of the endometrium in PCOS are commonly attributed to chronic anovulation and an imbalance between oestrogen and progesterone. However, other mechanisms for altered endometrial function cannot be excluded (Giudice, 2006; Piltonen, 2016).

Anti-Müllerian hormone (AMH) is a member of the transforming growth factor beta family and is mainly produced by the granulosa cells of early developing follicles (Ledger, 2010; Visser and Themmen, 2005). This hormone is therefore considered to be a marker of the ovarian reserve (Ledger, 2010; Visser and Themmen, 2005). AMH regulates follicular growth and development by inhibiting follicular maturation and recruitment. Serum concentrations of AMH remain stable during the menstrual cycle but gradually decrease throughout reproductive life (Ledger, 2010).

Women with PCOS exhibit increased serum concentrations of AMH due to an increased number of small follicles (Dumont et al., 2015; Piltonen et al., 2005). Intra-ovarian hyperandrogenism is likely to be responsible for the follicle excess in PCOS because androgens stimulate the early phases of follicular growth (Jonard and Dewailly, 2004). The androgen-induced increase in number of follicles and thereby AMH production, as well as an increased AMH production per granulosa cell, could explain elevated serum concentrations of AMH in women with PCOS (Jonard and Dewailly, 2004). Serum concentrations of AMH, together with other measures, are used to evaluate a patient’s fertility potential and to predict the ovarian response to FSH treatment to avoid ovarian hyperstimulation syndrome. However, little is known about the significance of serum AMH in endometrial function of women with PCOS.

Although AMH production is predominantly restricted to small developing follicles, local production of AMH in the endometrium has also been proposed (Wang et al., 2009). AMH exerts its effects via binding to a transmembrane receptor complex consisting of a type I (ALK2, ALK3 and ALK6) and a type II receptor (AMH-R) (Visser, 2003). Endometrial AMH and AMH-R expression displayed a cyclic variation during the menstrual cycle in non-PCOS women with higher concentrations in the secretory phase compared with the proliferative phase of the menstrual cycle (Wang et al., 2009). The role of AMH and its receptor in the endometrium is not fully known. However, an in-vitro experiment proposed that activation of the AMH receptor complex leads to decreased viability of endometrial cells (Wang et al., 2009). An inhibitory effect of AMH on cell proliferation and growth was also found in endometrial cells from patients with cancer (Renaud et al., 2005) and endometriosis (Signorile et al., 2014).

Despite the clear involvement of AMH/AMH-R pathways in endometrial remodelling, no study has examined its expression in women with PCOS. Taking into consideration that serum concentrations of AMH are increased and endometrial abnormalities are common in women with PCOS, the aim of the present study was therefore to investigate the expression of AMH and AMH-R in the endometrium of women with PCOS in comparison to BMI-matched controls and following lifestyle intervention.