In vitro and in vivo analysis of the effects of dehydroepiandrosterone on metabolic and vascular risk

Abstract

DHEA is an adrenal derived hormone with a unique secretory pattern with highest serum concentrations observed in middle age. Individuals with adrenal insufficiency exhibit gross DHEA deficiency though its replacement in this context is not commonplace. DHEA is known to behave as a pro-hormone with the ability to be converted into either androgenic or oestrogenic terminal hormones whether this is its sole physiological role still remains unclear. Various animal and in vitro studies have suggested that treatment with DHEA can precipitate improvements in body fat, adipocytokine profiles, insulin resistance and estimates of vascular disease. Human studies have demonstrated inconsistent results and have tended to focus on the physiological deficiency of DHEA associated with normal aging and not the pathological DHEA deficiency seen in adrenal insufficiency. The aims of this thesis were: (1) To determine the effect of DHEA on preadipocyte (cell line and primary) proliferation and differentiation and to examine the mechanisms behind any observed effects. (2) To evaluate the effect of replacing DHEA on vascular function and body composition in subjects with primary and secondary adrenal insufficiency. (1) DHEA inhibited proliferation in all preadipocytes examined secondary, at least in part, to cell cycle blockade. DHEA inhibited adipogenesis in omental but not subcutaneous derived preadiocytes. (2) Arterial stiffness and endothelial function was not affected the total population but stratification by study group showed that DHEA replacement reduced central blood pressure in patients with secondary adrenal insufficiency. Body composition was not affected in either subject group