Conclusions and clinical implications

Due to the adverse side effects of the anti-androgens and the risk of feminization of a male fetus (65), the use of anti-androgens are contraindicated during pregnancy. However, insulin sensitizers, such as Rosiglitazone have been widely used in pregnant women with PCOS to reduce gestational complications such as miscarriage, gestational diabetes and pre-eclampsia in the mother (66-67). However, studies examining the effects of prenatal treatment with insulin sensitizers on offspring, during infancy and adult life, are limited. Carlsen and Vanky (2009) showed that newborns of mothers with PCOS treated with the insulin sensitizer Metformin during gestation had higher levels of SHBG, which is suppressed by hyperinsulinemia (49), but no change in androgen or estrogen levels (68-69), suggesting a role for insulin sensitizer in improving gestation

hyperinsulinemia. However, due to the shortage of studies examining the effects of prenatal exposure to insulin sensitizers during adulthood, we cannot conclude whether this intervention influences testosterone levels or improves metabolic and reproductive functions later in life.

The findings from this study provide evidence in the support of prenatal programming of receptors that are involved in insulin and androgen signaling within reproductive and metabolic neurons of the hypothalamus, the KNDy and AgRP neuronal populations,

respectively. The programming of these receptors provides a framework though which hyperandrogenemia and hyperinsulinemia are able to exert their effects on these neuronal populations. The ability of prenatal, but not postnatal intervention with insulin sensitizer to block the effects of prenatal T treatment on the IR and AR colocalization within KNDy and AgRP neurons suggests that the prenatal period may provide a critical time point to intervene and prevent long-term changes in hypothalamic peptide/receptor expression, which otherwise may remain permanently modified by prenatal T. This study is among the first to show that prenatal interventions blocking fetal exposure to excess androgen or insulin levels may prevent some fundamental disturbances in receptor balance which, in turn, may subsequently alter the threshold required for normal metabolic and reproductive functions. In this way, the changes we identified may represent a potential neuroendocrine basis for the effectiveness of therapies that are already being used in the treatment of women with PCOS.

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