Regulation of androgen action during establishment of pregnancy

Abstract

During the establishment of pregnancy, the ovarian-derived hormones progesterone and oestradiol regulate remodelling of the endometrium to promote an environment that is able to support and maintain a successful pregnancy. Decidualisation is characterised by differentiation of endometrial stromal cells that secrete growth factors and cytokines that regulate vascular remodelling and immune cell influx. This differentiation process is critical for reproduction, and inadequate decidualisation is implicated in the aetiology of pregnancy disorders such as foetal growth restriction and preeclampsia. In contrast to progesterone and oestradiol, the role of androgens in regulating endometrial function is poorly understood. Androgen receptors are expressed in the endometrium, and androgens are reported to regulate both the transcriptome and the secretome of endometrial stromal cells. In androgen-target tissues, circulating precursors are activated to mediate local effects, and recent studies report that steroid concentrations detected in endometrial tissue are distinct to those detected in the peripheral circulation. New evidence suggests that decidualisation results in dynamic changes in the expression of androgen biosynthetic enzymes, highlighting a role for pre-receptor regulation of androgen action during the establishment of pregnancy. These results suggest that such enzymes could be future therapeutic targets for the treatment of infertility associated with endometrial dysfunction. In conclusion, these data support the hypothesis that androgens play a beneficial role in regulating the establishment and maintenance of pregnancy. Future studies should be focussed on investigating the safety and efficacy of androgen supplementation with the potential for utilisation of novel therapeutics, such as selective androgen receptor modulators, to improve reproductive outcomes in women.

Pregnancy-Induced Perturbation of Urinary Androgenic Steroid Disposition

“…There are also reasons to believe that androgens are related to preeclampsia, although their role in regulating endometrial function and vascular function in pregnancy is poorly understood [ 31 ]. Androgen receptors are expressed in the endometrium, and androgens could negatively regulate placental oxygenation and may oppose the progesterone/estrogen-mediated decrease of the resistance in the uterine arteries [ 32 ].…”

Endometrial Intracrinology: Oestrogens, Androgens and Endometrial Disorders

“…Specifically, human primary stromal cells are AR-positive and treatment of cells from proliferative phase endometrium with DHT has identified a number of androgen-regulated genes [ 28 ]. Complementary studies by Gibson et al [ 43 ], in which primary cells were stimulated to decidualise, showed local intracrine biosynthesis of androgens may play a critical role in maintenance of a decidual phenotype, with addition of flutamide reducing biosynthesis of the decidualisation marker IGFBP1 [ 43 , 59 ]. These studies complement and extend those of Cloke et al [ 60 , 61 ], who showed that AR and PR regulated distinct genomic pathways during decidualisation, consistent with a role for androgens (either local or peripheral) in regulation of fertility.…”

“…We further demonstrated that supplementation with the androgen precursor DHEA increases biosynthesis of T and DHT and is associated with dose-dependent increases in expression of the decidualisation markers IGFBP1 and prolactin, as well as the endometrial receptivity marker SPP1 [ 40 ]. Taken together, these studies suggest both local activation and metabolism of androgens occur during decidualisation and that temporal regulation of intracrine androgen bioavailability is a critical mediator of endometrial competence during remodelling required for establishment of pregnancy [ 39 , 59 ]. These studies are of particular relevance to the impact of aging on fertility, as circulating concentrations of androgens precursors, such as DHEA and A4 as well as T and DHT decline with age [ 38 , 63 ].…”

Dehydroepiandrosterone enhances decidualization in women of advanced reproductive age

“…In women, the androgen receptor agonists T and dihydrotestosterone (DHT) are synthesized within peripheral tissues from DHEA by the actions of the enzymes 3β- and 17β-hydroxysteroid dehydrogenases (3BHSD, 17BHSD) and 5α-reductases. All these enzymes are expressed in the normal endometrium (9) . Whether changes in the bioavailability of DHEA determine the capacity for androgen biosynthesis in the premenopausal endometrium is not known.…”