Reproduction Abstracts

Introduction: Maternal androgen excess in pregnant sheep programmes a PCOS-like phenotype in female offspring. We previously demonstrated a hyperinsulinaemic offspring phenotype in response to maternal androgen excess, but such regimens also increase estradiol concentrations, and may effect adrenal steroidogenesis, hence the role of androgens remains unclear.

Materials and Methods: To examine contributions of different steroid classes, and to determine if adult hyperinsulinaemia is a direct consequence of altered pancreatic development during fetal life, we applied steroids directly to ovine fetuses at d62 and d82 of gestation, and examined fetal (d90) and postnatal (11 months old) pancreatic structure and function. Alpha and beta cell content was determined by immunohistochemistry, insulin secretion by ELISA, and insulin signalling by QPCR and Western blotting.

Results: Of three classes (androgen – Testosterone propionate (TP), estrogen – Diethystilbesterol (DES) and glucocorticoid – Dexamethasone (DEX)) of steroid agonists applied, only androgens (TP) 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 ratios in the 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 a hyperinsulinaemic response to glucose challenge (P=0.0007) observed. Postnatal insulin secretion correlated with beta cell numbers (P=0.03). No alterations in insulin signalling components were evident.

Discussion and Conclusions: Male and female pancreatic structure differs during fetal life, likely due to androgen concentrations. Androgenic stimulation during development gives rise to female postnatal offspring whose pancreas secreted excess insulin due to excess beta cells in the presence of a normal number of alpha cells. We identify that these animal models of PCOS have primary hyperinsulinaemia prior to any insulin resistance-driven compensatory hyperinsulinaemia.