Dehydroepiandrosterone replacement therapy.

Dehydroepiandrosterone (DHEA) and its sulphated derivative DHEAS are the most abundant circulating steroids, and are derived from the zona reticularis of the adrenal cortex. The foetal adrenals synthesise signi®cant quantities of DHEA, but production of this steroid falls postnatally. The onset of adrenarche (between the ages of 6 and 8 years) is characterised by increasing biosynthesis of DHEA, and circulating DHEA(S) levels reach a peak in the third decade of life (1). Thereafter, there is an inexorable decline in DHEA production, such that, by the age of 80 years, subjects show DHEA levels that are only 10±20% of those in young adults (2); circulating cortisol levels, however, remain relatively unchanged. The physiological role of DHEA is not completely understood. DHEA is a substrate for androstenedione and testosterone synthesis, and adrenarche is accompanied by pubic and axillary hair development, suggesting that one of the actions of DHEA is as an adrenal androgen. However, there is evidence to suggest that it may also exert effects in the central nervous system. It is an antagonist at the gamma amino butyric acid receptor and an agonist at the NMDA receptor (3). It also opposes the action of glucocorticoids, antagonising glucocorticoid-induced thymic involution or corticosterone neurotoxicity in the hippocampus (4, 5). However, to date, a speci®c receptor which mediates the action of DHEA has not been identi®ed ± and it remains to be determined as to whether it acts at the cell surface or intracellularly. Unfortunately, studies of DHEA administration in non-primate species are of limited value for two reasons: ®rst, there is no rise in DHEAS levels with adrenarche; secondly, there is no age-related decline in circulating levels of this steroid. Here, we review clinical studies of DHEA treatment in humans in two contexts: (i) as a supplement for normal elderly subjects, to reverse the age-related decline in circulating DHEA levels; and (ii) replacement in patients with adrenal insuf®ciency and who have a near-absolute de®ciency of this steroid.