Endocrine Abstracts

Background: The potential for a healthy life is programmed by in utero development. Fetal development is impacted by perturbed hormonal signalling, with lifelong consequences. Polycystic Ovary Syndrome (PCOS), affecting over 10% of women, is an important condition linked to an altered prenatal endocrine environment. Women with PCOS have increased androgen concentrations, including during pregnancy. Increased prenatal androgen exposure is associated with a PCOS-phenotype in adult life, including insulin resistance, fatty liver and obesity. Male offspring of women with PCOS develop dyslipidaemia and hyperinsulinemia. We used an ovine model of prenatal androgen exposure, faithfully recreating PCOS offspring phenotypes, to provide crucial mechanistic understanding of metabolic disturbances programmed in utero manifesting in adolesence.

Methods: Ovine fetuses were directly injected with 200 µl of testosterone propionate (PA; 20 mg) or vehicle control (C) at day 62 and 82 of gestation. Male offspring (C, n = 14; PA, n = 14) and female offspring (C, n = 10; PA, n = 15) were studied during adolescence. Hepatic transcriptome and proteome were determined (Illumina RNA sequencing and LC-MS/MS respectively). Plasma proteins and analytes were measured using LC-MS/MS, ELISA and clinical biochemistry autoanalysers. Statistical analysis between C and PA groups was carried out using pairwise comparisons, with false discovery rate correction, accepting adjusted P < 0.05 as significant.

Results: Prenatally androgenised males and females displayed multiple metabolic perturbations, including hyperinsulinemia, dyslipidaemia, fatty liver, increased fibrosis, cholestasis-like phenotype. These were not all present in both sexes, with striking sex specificity in terms of lipid handling and liver function. PA females had increased plasma free fatty acids (FA), normal plasma triglycerides (TGs) concentrations, but increased hepatic TGs accumulation. This was coupled with reduced hepatic beta and omega oxidation potential. PA males had increased plasma FA, TGs and cholesterol concentrations in the absence of increased hepatic TGs accumulation. PA males displayed increased hepatic mitochondrial uptake of FA, however, they had decreased expression of genes and proteins involved in mitochondrial oxidative phosphorylation. This mismatch between mitochondrial FA oxidation without concomitant up-regulation of mitochondrial respiratory chain activity resulted in increased hepatic content of reactive oxygen species.

Conclusion: In both sexes, but with different mechanisms in terms of altered hepatic function, lipid handling in the liver was perturbed in postnatal life, as a legacy of prenatal androgen excess. Not all of these health-relevant outcomes were found in each sex however, demonstrating that sex-specificity must be accounted for in understanding of how the prenatal environment colours lifelong health.