The steroid metabolome in the isolated ovarian follicle and its response to androgen exposure and antagonism
File(s)
Published version
Author(s)
Type
Journal Article
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 the 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, nonaromatizable active androgen, and androgen receptor (AR) antagonists 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 AR–mediated effects on follicle growth and antrum formation that followed a biphasic pattern, with low levels of androgens inducing more rapid follicle maturation and high doses inhibiting oocyte maturation and follicle growth. Crucially, our study provides evidence for an intrafollicular feedback circuit regulating steroidogenesis, with decreased follicle androgen synthesis after exogenous androgen exposure and increased androgen output after additional AR antagonist treatment. We propose that this feedback circuit helps maintain an equilibrium of androgen exposure in the developing follicle. The observed biphasic response of follicle growth and function in increasing androgen supplementations has implications for our understanding of polycystic ovary syndrome pathophysiology and the dose-dependent utility of androgens in in vitro fertilization settings.
Date Issued
2017-05-01
Date Acceptance
2017-02-17
Citation
Endocrinology, 2017, 158 (5), pp.1474-1485
ISSN
0013-7227
Publisher
Oxford University Press
Start Page
1474
End Page
1485
Journal / Book Title
Endocrinology
Volume
158
Issue
5
Copyright Statement
This article has been published under the terms of the Creative Commons Attribution License (CCBY;https://creativecommons.org/licenses/by/4.0/), whichpermits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Copyright for this article is retained by the author(s).
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/28323936
PII: 3048741
Subjects
DEHYDROEPIANDROSTERONE
Endocrinology & Metabolism
GRANULOSA-CELLS
GROWTH-FACTOR-I
INSULIN
Life Sciences & Biomedicine
NORMAL WOMEN
POLYCYSTIC OVARIES
Science & Technology
SECONDARY FOLLICLES
STIMULATING-HORMONE
TESTOSTERONE
VITRO DEVELOPMENT
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2017-02-23