Adrenal Andropause and Aging

Abstract

Adrenocortical function undergoes diverse changes throughout development and aging. Aging in humans is accompanied by an increase in adrenal glucocorticoid secretion and a decline in adrenal androgen synthesis and secretion. In recent years, the intense interest in adrenal function and aging is, in large measure, generated by the potential impact of cortisol excess in the development of cognitive impairment and hippocampal neuronal loss, and by the potential beneficial effects in providing hormone replacement (dehydroepiandrosterone; DHEA) and healthy aging. While the preliminary data is tantalizing, solid scientific evidence is not at hand. It is apparent that both issues are extremely complex. DHEA and its 3β-sulfate (DHEA-S) are fascinating molecules, including their synthesis and actions in the brain. Recent studies have shown that DHEA/DHEA-S may have regulatory functions in hepatic lipid metabolism and in the immune system in humans: DHEA-S, but not DHEA, activates hepatic (PPARα) peroxisome proliferator-activated receptor α, a nuclear receptor that mediates the induction of enzymes involved in β-oxidation of lipids. Thus, DHEA-S may serve as a physiological modulator of liver fatty-acid metabolism and peroxisomal enzyme expression and, thereby, may contribute to the regulation of lipid homeostasis. Furthermore, the age-associated elevation of serum interleukin-6 (IL-6) in men and women can be normalized by physiological concentrations of DHEA, an observation that is consistent with endocrine—immune-system interaction. The life-sustaining role of adrenal cortisol secretion and its regulation of metabolism via catabolic actions may be modulated by its partner DHEA and by DHEA-S. During the anabolic growth period (childhood and early adulthood), the body is exposed to relatively high levels of DHEA/DHEA-S, but during infancy and aging relatively high levels of cortisol are dominant. The cortisol/DHEA-S molar ratio during the life span follows a U-shape curve, which may an indicator that we should explore these two critical adrenal steroids in tandem.