Role of androgens in normal and pathological ovarian function

Abstract

Androgens mediate their actions via the androgen receptor (AR), a member of the nuclear receptor superfamily. AR-mediated androgen action is essential in male reproductive development and function; however, only in the last decade has the suspected but unproven role for AR-mediated actions in female reproduction been firmly established. Deciphering the specific roles and precise pathways by which AR-mediated actions regulate ovarian function has been hindered by confusion on how to interpret results from pharmacological studies using androgens that can be converted into oestrogens, which exert actions via the oestrogen receptors. The generation and analysis of global and cell-specific female Ar knockout mouse models have deduced a role for AR-mediated actions in regulating ovarian function, maintaining female fertility, and have begun to unravel the mechanisms by which AR-mediated androgen actions regulate follicle health, development and ovulation. Furthermore, observational findings from human studies and animal models provide substantial evidence to support a role for AR-mediated effects not only in normal ovarian function but also in the development of the frequent ovarian pathological disorder, polycystic ovarian syndrome (PCOS). This review focuses on combining the findings from observational studies in humans, pharmacological studies and animal models to reveal the roles of AR-mediated actions in normal and pathological ovarian function. Together these findings will enable us to begin understanding the important roles of AR actions in the regulation of female fertility and ovarian ageing, as well as providing insights into the role of AR actions in the androgen-associated reproductive disorder PCOS.Reproduction (2015) 149 R193-R218

Androgen receptor and miRNA-126* axis controls follicle-stimulating hormone receptor expression in porcine ovarian granulosa cells

“…*P < 0.05; **P < 0.01. Walters 2015), including pGCs (Durlej et al 2011); however, no study to date has examined regulation of FSHR expression via AR in GCs.…”

“…FSH can synergize with androgens to regulate FSHR expression in follicles (Sen et al 2014, Walters 2015. Previous studies have shown that low-to-moderate doses of testosterone, a principal androgen, significantly increase FSHR mRNA levels in human luteinized GCs, whereas higher doses of testosterone do not further increase the FSHR mRNA levels and have no effect on FSHR protein expression (Garcia-Velasco et al 2012).…”

Expression of aldo-keto reductase family 1, member C14 during ovulation in the rat

“…If Akr1c14 is not expressed, excessive androgens would accumulate in preovulatory follicles and thus affect the ovulatory process. Indeed, in vivo administration of DHT to immature female rats at the time of hCG injection reduces the ovulation rate [7]. The importance of 3α-HSD/ Akr1c14 in the removal of excessive androgens is well documented in the prostate [12] and liver [11].…”

“…Dihydrotestosterone (DHT) at a dose of 0.25 mg/kg, but not 25 mg/kg, improved the ovulatory response to superovulation in mice [6]. Conversely, DHT at a dose of 1 mg/kg decreased ovulation rates in immature rats, implying that optimal levels of androgens are required to maintain normal ovulatory function [7]. Excessive androgen signaling may lead to abnormal follicle growth.…”

Aromatase inhibitors in “poor” ovarian responders undergoing in vitro fertilization

“…Андрогены уже на начальных этапах участвуют в процессе фолликулогенеза, рецепторы к ним обнаруживаются в первичных фолликулах при вовлечении их в растущий пул и далее на всех этапах созревания. Так, в преантральных фол-ликулах рецепторы к андрогенам экспресси-руются клетками гранулезы, тека-клетками и ооцитами [40,41]. Также описана экспрессия андрогеновых рецепторов и в клетках стромы яичника, особенно выраженная вокруг неболь-ших растущих фолликулов [42].…”