Restoration of aging growth hormone cells by dehydroepiandrosterone via estrogen receptors

Dehydroepiandrosterone (DHEA) is the most abundant circulating steroid in humans. With progressive aging there is a decline in the levels of DHEA, growth hormone (GH) and sex steroids. DHEA levels seem to correlate inversely with morbidity and mortality associated with aging. Hence, it is widely used as an anti-aging supplement to counter these effects. DHEA is considered traditionally as a precursor hormone for estrogens and androgens and to have no function of its own, as it does not have a specific receptor. The decline in GH levels with aging is associated with a loss of GH cells (somatotropes) in the pituitary. The objective of this study was to learn if the functions of somatotropes can be restored in aging female rats (12--14-months and 18-months) to levels seen in young, diestrous rats (3--4 months). Using in vitro and in vivo methods, the results indicate that DHEA acts directly at the level of the pituitary to restore GH gene expression to levels seen in young rats. The study employed cytochemical and molecular techniques (immunocytochemistry, in-situ hybridization, QRT-PCR) to assess the function and gene expression of somatotropes. This is the first study to our knowledge, to show a loss of GH-releasing hormone-receptor (GHRH-R) binding cells in aging female rat pituitaries, which could also be a contributory factor in the decline of GH levels. Short-term DHEA treatment of 18-month-old rats, in vivo, increases the number of GHRH-binding cells in the pituitary resulting in a two-fold increase in serum GH. The study also addresses mechanisms behind DHEA's restoration of aging somatotropes in vitro using inhibitors (trilostane and aminoglutethemide) that block specific metabolic pathways of DHEA. The study shows that DHEA needs to be aromatized to estrogen to restore GH expression in aging somatotropes. ICI 182,780, an estrogen receptor (ER) antagonist, also blocked the restorative effects of DHEA, suggesting that ERs play a key role in DHEA's action on aging somatotropes. In summary, this study shows that DHEA has direct actions on the pituitary, possibly after aromatization to estrogen. The findings in aging rats suggest that DHEA replacement might benefit individuals with low GH levels.