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The metabolic consequences of an altered in utero steroid environment are emerging as features of fetal programming that are associated with endocrine and reproductive anomalies present in women with polycystic ovary syndrome (PCOS). Animal models of maternal prenatal androgenization reveal increased adiposity, hyperinsulinemia and insulin resistance in parallel with the development of polycystic ovaries, disrupted estrous cycles and perturbed gonadotropin profiles. Here, we assess the effects prenatal androgenization on the metabolic phenotype of young adult sheep with particular focus on the liver. Pregnant Scottish Greyface ewes were administered testosterone propionate (TP in vegetable oil, 100mg i.m twice weekly; n=5) or vehicle control (C; n=9) from day (d)60-100 of gestation (term ~147 days). Since androgens can be metabolized by the placenta into products such as estrogen, we also assessed the direct effect of androgens on the fetus. Thus in an additional cohort C or TP (20mg) was administered directly by injection into the fetal flank under ultrasonic guidance. Two separate injections were performed over early (d62 and 72; C=4, TP=8) or late (d62 and 82; C=4, TP=7) time-points. This direct treatment significantly raises circulating fetal testosterone (P<0.001) without changing fetal estradiol concentrations. Offspring were sacrificed at 11 months of age following an intravenous glucose tolerance test and a portion of liver collected and stored for mRNA and protein studies. Examination of frozen liver sections using a lipid-specific histological stain revealed the presence of early fatty liver changes in offspring that were indirectly exposed to prenatal androgens by maternal TP treatment (P<0.05), independent of obesity. In these animals hepatic steatosis was associated with an increased insulin response to glucose load (P<0.05) indicating early signs of insulin resistance. Gene expression analysis also revealed increased hepatic androgen receptor (AR; P<0.05) and insulin-like growth factor 1 (IGF1; P<0.01), independent of serum androgen concentrations. There was no effect on the hepatic gene expression of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK). In contrast there was no difference between TP and C treatment in fatty liver changes after early or late direct fetal prenatal androgenization. In addition there were no significant differences in the insulin response to glucose load and there was no effect on hepatic AR or IGF1 mRNA expression. Direct fetal TP exposure did however result in reduced PEPCK mRNA expression (P<0.05) in adult livers when compared to C injection. Additionally, there was an adult hepatic phenotype associated with direct fetal injection including early fatty liver changes (P<0.05) and increased PEPCK gene expression (P<0.05)As direct prenatal exposure to TP did not mimic the effects of maternal TP exposure on the adult liver it is likely that alternate pathways are involved in these aspects of fetal metabolic programming. This is also supported by hepatic changes seen after direct injection of the fetus in the absence of TP. These results suggest that androgens per se may not be the primary mediators of the metabolic changes seen in the prenatal andogenization models of PCOS using maternal administration. The authors have nothing to disclose. This work was funded by a Medical Research Council Project Grant (G0500717).

(poster)

Copyright 2011 by The Society for the Study of Reproduction.
Issue Section:
8/1/2011
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