The Pancreas Is Altered by In Utero Androgen Exposure: Implications for Clinical Conditions Such as Polycystic Ovary Syndrome (PCOS)

Mick Rae, O Cathal Grace, Kirsten Hogg, Lisa Marie Wilson, Sophie .L McHaffie, S Ramaswamy, Janis MacCallum, Fiona Connolly, Alan McNeilly, Colin Duncan

Research output: Contribution to journalArticlepeer-review

Abstract

Using an ovine model of polycystic ovary syndrome (PCOS), (pregnant ewes injected with testosterone propionate (TP)
(100 mg twice weekly) from day (d)62 to d102 of d147 gestation (maternal injection – MI-TP)), we previously reported
female offspring with normal glucose tolerance but hyperinsulinemia. We therefore examined insulin signalling and
pancreatic morphology in these offspring using quantitative (Q) RT-PCR and western blotting. In addition the fetal
pancreatic responses to MI-TP, and androgenic and estrogenic contributions to such responses (direct fetal injection (FI) of
TP (20 mg) or diethylstilbestrol (DES) (20 mg) at d62 and d82 gestation) were assessed at d90 gestation. Fetal plasma was
assayed for insulin, testosterone and estradiol, pancreatic tissue was cultured, and expression of key b-cell developmental
genes was assessed by QRT-PCR. In female d62MI-TP offspring insulin signalling was unaltered but there was a pancreatic
phenotype with increased numbers of b-cells (P,0.05). The fetal pancreas expressed androgen receptors in islets and genes
involved in b-cell development and function (PDX1, IGF1R, INSR and INS) were up-regulated in female fetuses after d62MI-TP
treatment (P,0.05–0.01). In addition the d62MI-TP pancreas showed increased insulin secretion under euglycaemic
conditions (P,0.05) in vitro. The same effects were not seen in the male fetal pancreas or when MI-TP was started at d30,
before the male programming window. As d62MI-TP increased both fetal plasma testosterone (P,0.05) and estradiol
concentrations (P,0.05) we assessed the relative contribution of androgens and estrogens. FI-TP (commencing d62) (not FIDES
treatment) caused elevated basal insulin secretion in vitro and the genes altered by d62MI-TP treatment were similarly
altered by FI-TP but not FI-DES. In conclusion, androgen over-exposure alters fetal pancreatic development and b-cell
numbers in offspring. These data suggest that that there may be a primary pancreatic phenotype in models of PCOS, and
that there may be a distinct male and female pancreas.
Original languageEnglish
Article numbere56263
JournalPLoS ONE
Volume8
Issue number2
DOIs
Publication statusPublished - 15 Feb 2013

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