Androgen Stimulates Growth of Mouse Preantral Follicles In Vitro: Interaction With Follicle-Stimulating Hormone and With Growth Factors of the TGFβ Superfamily

Abstract

Androgens are essential for the normal function of mature antral follicles but also have a role in the early stages of follicle development. Polycystic ovary syndrome (PCOS), the most common cause of anovulatory infertility, is characterized by androgen excess and aberrant follicle development that includes accelerated early follicle growth. We have examined the effects of testosterone and dihydrotestosterone (DHT) on development of isolated mouse preantral follicles in culture with the specific aim of investigating interaction with follicle-stimulating hormone (FSH), the steroidogenic pathway, and growth factors of the TGFβ superfamily that are known to have a role in early follicle development. Both testosterone and DHT stimulated follicle growth and augmented FSH-induced growth and increased the incidence of antrum formation among the granulosa cell layers of these preantral follicles after 72 hours in culture. Effects of both androgens were reversed by the androgen receptor antagonist flutamide. FSH receptor expression was increased in response to both testosterone and DHT, as was that of Star, whereas Cyp11a1 was down-regulated. The key androgen-induced changes in the TGFβ signaling pathway were down-regulation of Amh, Bmp15, and their receptors. Inhibition of Alk6 (Bmpr1b), a putative partner for Amhr2 and Bmpr2, by dorsomorphin resulted in augmentation of androgen-stimulated growth and modification of androgen-induced gene expression. Our findings point to varied effects of androgen on preantral follicle growth and function, including interaction with FSH-activated growth and steroidogenesis, and, importantly, implicate the intrafollicular TGFβ system as a key mediator of androgen action. These findings provide insight into abnormal early follicle development in PCOS.

Neonatal Exposure to Agonists and Antagonists of Sex Steroid Receptors Affects AMH and FSH Plasma Level and Their Receptors Expression in the Adult Pig Ovary

“…Moreover, FSHR expression at mRNA and protein level was increased in preantral follicles from TP-exposed pigs at the neonatal life. Androgens have also been shown to exert a stimulatory effect on growth of preantral follicles by increasing FSH responsiveness via up-regulation of FSHR expression [24]. Considering our results, lower plasma AMH and FSH level as well as higher AMHR2 and FSHR expression in preantral follicles, which result from neonatal androgen excess or deficiency, may promote the initial recruitment of follicles in pigs.…”

Accelerated Episodic Luteinizing Hormone Release Accompanies Blunted Progesterone Regulation in PCOS-like Female Rhesus Monkeys (Macaca Mulatta) Exposed to Testosterone during Early-to-Mid Gestation

“…High frequency episodic release of GnRH from the hypothalamus typifies many women with PCOS [9,10] and enables both LH hypersecretion contributing to ovarian hyperandrogenism [11] and relative follicle stimulating hormone (FSH) deficiency encouraging ovarian follicular arrest [12,13]. Such gonadotropin imbalance is consistent with recent identification of PCOS risk genes implicated in the regulation of pituitary gonadotropin release [5,14] as well as functional clinical studies demonstrating diminished negative feedback regulation on LH, and probably GnRH release, mediated by estradiol and progesterone [3,15].…”

Expression of genes controlling steroid metabolism and action in granulosa-lutein cells of women with polycystic ovaries

“…Nevertheless, in animal 330 experiments, excess androgens have also been shown to have an inhibitory action on 331 CYP11A1 expression. In mouse follicles treated in-vitro with testosterone or DHT there is a 332 reduction in Cyp11a1 protein (Laird et al 2017). Furthermore, CYP11A1 gene expression is 333 reduced in ovaries of day 90 fetal sheep whose mothers treated in-utero with testosterone 334 We describe a 7-fold increase in SULT1E1 expression in GL cells from women with both 339 ovulatory or anovulatory PCOS.…”