Endocrine Abstracts

Introduction: Adult male offspring of women with PCOS have increased dyslipidaemia, characterised by elevated triglycerides (TG), increased total and LDL-cholesterol (LDL-C), and hyperinsulinaemia. As altered intrauterine endocrine environments can ‘programme’ adverse health outcomes in adulthood we hypothesised that this dyslipidaemia was a consequence of a hyperandrogenic intrauterine environment. We used an outbred large animal model to identify if prenatal androgen excess could be causally linked to male hepatic dysfunction and investigate the underpinning mechanisms of dyslipidaemia.

Methods: Ovine fetuses were directly injected with a 200 μl bolus of testosterone propionate (PA; 20 mg) or vehicle control (C) at day 62 and 82 of gestation. Male adolescent offspring were studied at 6 months postnatal age (C, n=14; PA, n=14). Hepatic transcriptome and proteome were determined using Illumina RNA sequencing and liquid chromatography-mass spectrometer (LC-MS/MS), respectively. Plasma proteins and analytes were measured using LC-MS/MS, ELISA or benchtop 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: Adolescent PA ovine males had increased levels of total cholesterol, LDL-C, TG and insulin (all P<0.05), reproducing metabolic disturbances observed in sons of PCOS patients. Plasma protein analysis showed increased levels of circulating apolipoproteins, including APOA4, APOC3, APOD and APOM (all P<0.05) indicating altered cholesterol homeostasis. However, genes and proteins involved in cholesterol biosynthesis pathway were downregulated (all P<0.05) (HMGCS1, HMGCR, MVD, FDPS, Q15LE, CYP51A1, HSD17B7, NSDHL and DHCR7). There was upregulated expression of hepatic cholesterol transporters, ABCG5 and ABCG8 (all P<0.05) and decreased expression of CYP7A1 (P<0.05), the rate limiting enzyme in bile acid synthesis.

Conclusions: Androgen overexposure in utero leaves a legacy in adolescent life of male offspring that is characterised by hypercholesterolemia. This is directly programmed in utero and suggests that dyslipidaemia in the sons of women with PCOS may have a significant environmental rather than genetic component. This effect is underpinned by altered expression of gene/protein pathways responsible for bile acid synthesis and de novo cholesterol synthesis in the liver. As the cholesterol biosynthesis pathway is decreased standard therapeutic strategies to reduce cholesterol may be less effective. In addition to providing understanding of molecular mechanisms underpinning such adolescent development of hepatic dysfunction and targets with utility for potential intervention, our data also provide potential biomarker identification.