Androgen stimulates growth of mouse preantral follicles in vitro: interaction with follicle stimulating hormone and with growth factors of the TGFβ superfamily.
File(s)en.2016-1538.pdf (2.82 MB)
Published version
Author(s)
Type
Journal Article
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 commonest 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 aims of investigating interaction with FSH, the steroidogenic pathway and with 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 72h in culture. Effects of both androgens were reversed by the androgen receptor antagonist flutamide. FSH receptor (Fshr) expression was increased in response to both testosterone and DHT, as was that of Star, whereas Cyp11a1 was downregulated. The key androgen-induced changes in the TGFβ signaling pathway were downregulation 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 intra-follicular TGFβ system as a key mediator of androgen action. These findings provide insight into abnormal early follicle development in PCOS.
Date Issued
2017-01-24
Date Acceptance
2017-01-13
Citation
Endocrinology, 2017, 158 (4), pp.920-935
ISSN
0013-7227
Publisher
Oxford University Press (OUP)
Start Page
920
End Page
935
Journal / Book Title
Endocrinology
Volume
158
Issue
4
Copyright Statement
© 2017 The Authors. License (CC BY; https://creativecommons.org/licenses/by/4.0/), which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and
source are credited.
use, distribution, and reproduction in any medium, provided the original author and
source are credited.
Sponsor
Medical Research Council (MRC)
MRC
Medical Research Council (MRC)
Genesis Research Trust
Genesis Research Trust
Identifier
http://www.ncbi.nlm.nih.gov/pubmed/28324051
PII: 2952607
Grant Number
MR/M012638/1
G0802782
G0802782
WSCR_P36429
01028
Subjects
Science & Technology
Life Sciences & Biomedicine
Endocrinology & Metabolism
POLYCYSTIC-OVARY-SYNDROME
GRANULOSA-CELL PROLIFERATION
MORPHOGENETIC PROTEIN 15
GENE-EXPRESSION
MEDICAL PROGRESS
ANTRAL FOLLICLES
PRIMATE OVARY
RECEPTOR
MODELS
MICE
Androgen Receptor Antagonists
Androgens
Animals
Cells, Cultured
Dihydrotestosterone
Down-Regulation
Female
Flutamide
Follicle Stimulating Hormone
Granulosa Cells
Mice
Ovarian Follicle
Receptors, FSH
Signal Transduction
Testosterone
Transforming Growth Factor beta
Ovarian Follicle
Granulosa Cells
Cells, Cultured
Animals
Mice
Flutamide
Dihydrotestosterone
Testosterone
Follicle Stimulating Hormone
Transforming Growth Factor beta
Receptors, FSH
Androgens
Signal Transduction
Down-Regulation
Female
Androgen Receptor Antagonists
Endocrinology & Metabolism
07 Agricultural and Veterinary Sciences
11 Medical and Health Sciences
06 Biological Sciences
Publication Status
Published
Coverage Spatial
United States