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The steroid metabolome in the isolated ovarian follicle and its response to androgen exposure and antagonism.
Endocrinology. 2017 Feb 23;:
Authors: Lebbe M, Taylor AE, Visser JA, Kirkman-Brown J, Woodruff TK, Arlt W
Abstract
The ovarian follicle is a major site of steroidogenesis, crucially required for normal ovarian function and female reproduction. Our understanding of androgen synthesis and metabolism in the developing follicle has been limited by sensitivity and specificity issues of previously used assays. Here we used liquid chromatography-tandem mass spectrometry to map the stage-dependent endogenous steroid metabolome in an encapsulated in vitro follicle growth system, from murine secondary through antral follicles. Furthermore, follicles were cultured in the presence of androgen precursors, non-aromatizable active androgen and androgen receptor (AR) antagonist to assess effects on steroidogenesis and follicle development.Cultured follicles showed a stage-dependent increase in endogenous androgen, estrogen and progesterone production, and incubations with the sex steroid precursor dehydroepiandrosterone revealed the follicle as capable of active androgen synthesis at early developmental stages. Androgen exposure and antagonism demonstrated androgen receptor-mediated effects on follicle growth and antrum formation that followed a biphasic pattern, with low levels of androgens inducing more rapid follicle maturation while high doses inhibited oocyte maturation and follicle growth. Crucially, our study provides evidence for an intra-follicular feedback circuit regulating steroidogenesis, with decreased follicle androgen synthesis after exogenous androgen exposure and increased androgen output after additional androgen receptor antagonist treatment. We propose that this feedback circuit serves maintaining an equilibrium of androgen exposure in the developing follicle. The observed biphasic response of follicle growth and function to increasing androgen supplementations has implications for our understanding of polycystic ovary syndrome pathophysiology and the dose-dependent utility of androgens in in vitro fertilisation settings.
PMID: 28323936 [PubMed - as supplied by publisher]