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Developmental programming of polycystic ovary syndrome (PCOS): prenatal androgens establish pancreatic islet α/β cell ratio and subsequent insulin secretion

Ramaswamy, S.; McNeilly, A. S.; Rae, M. T.; Ramaswamy, Seshadri; Grace, C.; Mattei, A. A.; Siemienowicz, K.; Brownlee, W.; MacCallum, J.; McNeilly, Alan S; Duncan, W. C.; Rae, Mick T

Authors

S. Ramaswamy

A. S. McNeilly

M. T. Rae

Seshadri Ramaswamy

C. Grace

A. A. Mattei

W. Brownlee

Alan S McNeilly

W. C. Duncan



Abstract

Exogenous androgenic steroids applied to pregnant sheep programmes a PCOS-like phenotype in female offspring. Via ultrasound guidance we applied steroids directly to ovine fetuses at d62 and d82 of gestation, and examined fetal (day 90 gestation) and postnatal (11 months old) pancreatic structure and function. Of three classes of steroid agonists applied (androgen - Testosterone propionate (TP), estrogen - Diethystilbesterol (DES) and glucocorticoid - Dexamethasone (DEX)), only androgens (TP) caused altered pancreatic development. Beta cell numbers were significantly elevated in prenatally androgenised female fetuses (P=0.03) (to approximately the higher numbers found in male fetuses), whereas alpha cell counts were unaffected, precipitating decreased alpha:beta cell ratios in the developing fetal pancreas (P=0.001), sustained into adolescence (P=0.0004).
In adolescence basal insulin secretion was significantly higher in female offspring from androgen-excess pregnancies (P=0.045), and an exaggerated, hyperinsulinaemic response to glucose challenge (P=0.0007) observed, whereas prenatal DES or DEX treatment had no effects upon insulin secretion. Postnatal insulin secretion correlated with beta cell numbers (P=0.03). We conclude that the pancreas is a primary locus of androgenic stimulation during development, giving rise to postnatal offspring whose pancreas secreted excess insulin due to excess beta cells in the presence of a normal number of alpha cells.

Journal Article Type Article
Acceptance Date May 25, 2016
Online Publication Date Jun 6, 2016
Publication Date 2016-07
Deposit Date May 27, 2016
Publicly Available Date Jun 8, 2017
Journal Scientific Reports
Electronic ISSN 2045-2322
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 6
Issue 1
Article Number 27408
DOI https://doi.org/10.1038/srep27408
Keywords Androgenic steroids; PCOS-like phenotype; pancreatic structure; Postnatal insulin secretion; polycystic ovary syndrome (PCOS);
Public URL http://researchrepository.napier.ac.uk/id/eprint/10296
Contract Date Jun 8, 2017

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This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/




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