Effects of Prenatal Testosterone on the Reproductive and Metabolic Neurons of the Sheep Hypothalamus
Doctor of Philosophy
Anatomy and Cell Biology
Dr. Michael Lehman
Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders affecting reproductively aged women. Women with PCOS and ewes prenatally exposed to testosterone (T) show similar reproductive and metabolic defects, including anovulatory dysfunctions stemming from abnormal gonadotropin releasing hormone (GnRH) secretion and insulin resistance. For this dissertation, I examined the effects of prenatal T treatment on androgen receptor (AR) and insulin receptor (IR) expression with the reproductive and metabolic neurons of the hypothalamus, the ARC KNDy (co-expressing kisspeptin, neurokinin B/dynorphin), AgRP (agouti-related peptide) and proopiomelanocortin (POMC) neurons, and the preoptic area (POA) kisspeptin neurons, and the GnRH neurons. I show that prenatal T treatment increases AR-immunoreactivity in several brain areas of the sheep brain and colocalization of AR with ARC KNDy and AgRP and POA kisspeptin neurons. Conversely, prenatal T treatment decreases IR colocalization with ARC KNDy and AgRP neurons, but not POMC neurons. Prenatal, but not postnatal interventions blocking androgen action (Flutamide, F) or increasing sensitivity to insulin (Rosiglitazone, R) prevent the prenatal T induced alterations in these populations. Lastly, leptin, an important metabolic signal that can influence GnRH secretion, indirectly activates ARC KNDy neurons through a pathway that may include AgRP and POMC neurons. Overall, these results show that prenatal exposure to T masculinizes the female brain and alters insulin signalling in the reproductive and metabolic neurons of the ARC and highlights the importance of prenatal interventions in blocking these effects. These changes may contribute the reproductive and metabolic dysfunctions associated with the PCOS phenotype.
Cernea, Maria, "Effects of Prenatal Testosterone on the Reproductive and Metabolic Neurons of the Sheep Hypothalamus" (2013). Electronic Thesis and Dissertation Repository. 1425.
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