McNelis, Joanne (2009)
Ph.D. thesis, University of Birmingham.
The adrenal steroid dehydroepiandrosterone (DHEA) and its sulphate ester, DHEAS are the most abundant circulating steroid hormones in humans. Uncongugated DHEA predominately exerts its effects via its downstream conversion to active sex steroids in peripheral target tissues. In contrast the conversion of DHEAS to androgens first requires cleavage of the sulfate group, catalysed by the microsomal enzyme steroid sulfatase (STS). Conversely, DHEA is converted to inactive DHEAS by the activity of the cytosolic enzyme DHEA sulphotransferase (SULT2A1). However, in addition, evidence is growing that DHEA and DHEAS can have specific, direct effects. In this thesis, I have demonstrated that abrogation of DHEA metabolism can result in the manifestation of pathophysiological conditions. SULT2A1 requires 3'-phosphoadenosine-5'-phosphosulfate (PAPS) for catalytic activity. I have identified compound heterozygous mutations in the gene encoding human PAPS synthase 2 (PAPSS2) in a girl with androgen excess and confirmed the inactivating nature of the mutations via in vitro activity analysis. These observations indicate that PAPSS2 deficiency is a novel monogenic adrenocortical cause of androgen excess. In addition, I have demonstrated that DHEA can have specific direct effects, attenuates human adipogenesis, while enhancing glucose uptake in mature adipocytes. These findings highlight DHEA metabolism, particularly by SULT2A1, as important mechanisms regulating DHEA activity.
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