Endocrine Abstracts

Exposure of pregnant sheep to increased concentrations of testosterone during midgestation results in a PCOS-like condition in the female offspring that includes increased hepatic IGF1. The aim of this study was to investigate the molecular pathophysiology of this increase. We studied 11-month-old female offspring whose mother had been treated with testosterone propionate (TP: 100 mg) in oil (n=8), or oil control (n=4) twice weekly from day 62 to 102 gestation. The first experiment was to determine if altered IGF1 was a consequence of prenatally programmed differential gene methylation. We assessed IGF1 CpG methylation using pyrosequencing. There was no IGF1 gene hypomethylation (P>0.05) associated with prenatal TP exposure. The next experiment was to assess if the prenatally programmed primary hyperinsulinaemia, resulted in augmented IGF1 through altered GH secretion or action. There was no difference in pituitary GH1 expression (P>0.05), number of somatotrophs assessed by immunohistochemistry (P>0.05) or serum GH concentrations (P>0.05). In addition there were no differences in hepatic GHR (P>0.05) or expression of other GH-regulated genes including HNF6/ONECUT1, G6PC and SLC2A2 (P>0.05). The next experiment was to determine if contemporaneous androgen exposure was involved. The sheep express higher hepatic AR as well as having increased capacity for ovarian and adrenal androgen synthesis. We investigated the effects of two weeks of TP (100 mg twice weekly) (n=5) or control (n=5) on normal female sheep. This regimen did not alter hepatic IGF1 expression (P>0.05). To date the pathophysiology of increased hepatic IGF1 in the ovine model of PCOS is unclear. As circulating insulin and hepatic NR3C1 (P<0.05) and HSD11B1 (P<0.05) are increased and both insulin and glucocorticoids can augment STAT5 we now plan to assess intra-hepatocyte signalling pathways. This clinically realistic, prenatally programmed, ovine model can be used increase our understanding of the molecular pathophysiology of metabolic dysfunction in PCOS.