Insulin and Adrenal Androgens

Over the past decade, it has been well established that insulin resistance, accompanied by compensatory hyperinsulinemia (i.e., hyperinsulinemic insulin resistance), plays a pivotal role in the ovarian hyperandrogenism of women with the polycystic ovary syndrome (PCOS). Insulin both enhances ovarian androgen production and decreases circulating sex hormone-binding globulin levels in this disorder. Less well-understood is the possible role of either hyperinsulinemia or insulin resistance in the modulation of human adrenal androgen metabolism, and whether these factors play a role in the elevation of serum adrenal androgens observed in some women with PCOS. Several lines of evidence suggest that insulin influences adrenal androgen production. Insulin receptors and insulin-like growth factor I receptors have both been identified on human adrenal glands,' suggesting a possible role for these peptides in the modulation of adrenal function. We have shown that when insulin is infused acutely into women or men and serum glucose kept constant, serum levels of the adrenal androgens dehydroepiandrosterone (DA) and dehydroepiandrosterone sulfate (DS) decline progressively. This insulin-induced decline in serum DA and DS has been confirmed by four other groups, and has been demonstrated in response to both exogenous and endogenous elevation of serum insulin into the high physiologic range. It should be noted, however, that not all studies have demonstrated a fall in these adrenal androgens in response to acute hyperinsulinemia. Insulin could reduce circulating DA or DS levels by either decreasing the production rate (PR) and/or increasing the metabolic clearance rate (MCR) for these androgens. The observation that acute hyperinsulinemia inhibits human adrenal 17,20-lyase activity in vivo suggests that insulin decreases the PR of adrenal androgens. Moreover, insulin-induced inhibition of the PR of adrenal androgens may underlie the agerelated dissociation of serum adrenal androgens from other adrenal steroids—i.e., serum DA and DS levels fall by >90% with aging while serum glucocorticoid and mineralocorticoid levels remain relatively stable. The aging process is characterized by worsening hyperinsulinemic insulin resistance, which theoretically could lead to a progressive reduction in the PR of adrenal androgens. In support of this idea, Liu and colleagues have shown that postmenopausal women manifest a selective reduction in adrenal 17,20-lyase activity compared to women 20 years younger. It seems likely that insulin also increases the MCR of adrenal androgens. In this regard, it is instructive to review the dynamics of adrenal androgen metabolism in obesity—another common condition characterized by hyperinsulinemia and insulin resistance. The MCR of adrenal androgens is markedly (2to 5-fold) increased in obesity, and declines with fasting. ' Although this has been attributed to increased deposition of androgens into fat tissue, studies have failed to show a clear relationship between indices of overall adiposity (body mass index or percentage of ideal body weight) and serum adrenal androgen levels. In contrast, a significant positive correlation exists between fasting serum insulin and MCR. Hence, it seems probable that, although fat tissue may act as a storage site for androgens, it is the hyperinsulinemia of obesity that is directly responsible for the increased MCR.