Androgen signalling in the ovaries and endometrium

Abstract

Currently, our understanding of hormonal regulation within the female reproductive system is largely based on our knowledge of estrogen and progesterone signalling. However, while the important functions of androgens in male physiology are well known, it is also recognized that androgens play critical roles in the female reproductive system. Further, androgen signalling is altered in a variety of gynaecological conditions, including endometriosis and polycystic ovary syndrome, indicative of regulatory roles in endometrial and ovarian function. Co-regulatory mechanisms exist between different androgens, estrogens, and progesterone, resulting in a complex network of steroid hormone interactions. Evidence from animal knockout studies, in vitro experiments, and human data indicate that androgen receptor expression is cell-specific and menstrual cycle stage-dependent, with important regulatory roles in the menstrual cycle, endometrial biology, and follicular development in the ovaries. This review will discuss the expression and co-regulatory interactions of androgen receptors, highlighting the complexity of the androgen signalling pathway in the endometrium and ovaries, and the synthesis of androgens from additional alternative pathways previously disregarded as male-specific. Moreover, it will illustrate the challenges faced when studying androgens in female biology, and the need for a more in-depth, integrative view of androgen metabolism and signalling in the female reproductive system.

Keywords: androgens; endometrium; estrogen; female; ovaries; progesterone; receptor; steroid hormones; testosterone.

Figure 1.

Androgen synthesis pathways in the female reproductive system. Conversion of cholesterol-derived progesterone to androgens, and androgens to estrogens, by steroidogenic hormones expressed by adrenal and ovarian tissues, via the (A) classical, (B) backdoor, (C) c11-oxy, and (D) c11-oxy backdoor pathways. 11KA4, 11-ketoandrostenedione; 11KDHT, 11-ketodihydrotestosterone; 11KT, 11-ketotestosterone; 11OHA4, 11 beta-hydroxyandrostenedione; 11OHP4, 11 beta-hydroxyprogesterone; 11OHT, 11 beta-hydroxytestosterone; 21dF, 21-deoxycortisol; AKR, aldoketo reductases; CYP, cytochrome p450 enzymes; DHEA, dehydroepiandrosterone; DHT, dihydrotestosterone; HSD, hydroxysteroid dehydrogenases; POR, cytochrome P450 oxidoreductase; SRD5A, 5-alpha reductase; StAR, steroidogenic acute regulatory protein. Reprinted with permissions from Naamneh Elzenaty et al. (2022).

Figure 2.

Summary of key androgen signalling pathways and effectors, and interactions with other steroid hormone receptors in the female reproductive system. The complex network of reproductive steroid hormones—estrogens, progesterone, and androgens—their interaction with receptors, and the co-regulatory interactions between them that co-ordinate their effects in the ovaries and endometrium is shown. Arrows between steroids denote conversion. Arrows between steroids and receptors denote binding; a thick arrow indicates high-affinity binding of DHT to AR compared to other androgens; similarly, a dotted arrow denotes a comparatively weak binding affinity of DHEA to AR. DHEA, dehydroepiandrosterone; DHT, dihydrotestosterone; AR, androgen receptor; ONR, orphan nuclear receptors; PPAR, peroxisome proliferator-activated receptor; PXR, pregnane X receptor; CAR, constitutive androstane receptor; NR4A1, nuclear receptor subfamily 4 group A member 1; ERα, estrogen receptor alpha; ERβ, estrogen receptor beta; GPER, G-protein-coupled estrogen receptor; PR, progesterone receptor; TF, transcription factor; ERE, estrogen response element; ARE, androgen response element; PRE, progesterone response element; ORE, orphan nuclear receptor response element. Figure created using BioRender.com.

Figure 3.

Steroid hormones and receptor expression in the female reproductive system. Summary of relative estrogen, progesterone, and total estimated androgen levels and their receptors in relation to the ovarian and menstrual cycles. ERα, estrogen receptor alpha; ERβ, estrogen receptor beta; PRA, progesterone receptor isoform A; PRB, progesterone receptor isoform B; AR, androgen receptor. Collated data used to estimate relative circulating hormone levels (Guerrero et al., 1975; Dawood and Saxena, 1976; Vermeulen and Verdonck, 1976; Massafra et al., 1999; Salonia et al., 2008; Rothman et al., 2011; Skiba et al., 2019; Atukorala et al., 2022; Krüger et al., 2023) and relative receptor expression patterns in the endometrium (Mote et al., 2000; Mertens et al., 2001; Hapangama et al., 2015; Gibson et al., 2018a, 2014). No information could be found regarding specific receptor expressions in the ovary. Figure created using BioRender.com.