Adrenal androgen excess in the polycystic ovary syndrome

Androgen excess is the most common reproductive endocrinologic abnormality of women. Most of these patients suffer from the polycystic ovary syndrome (PCOS), which affects approximately 4% of reproductive aged women. Although the majority of patients with PCOS demonstrate an ovarian source for their high androgen secretion, 30-50% also display adrenal androgen (AA) excess, generally defined by high serum levers of dehydroepiandrosterone sulfate (DHEAS). Family studies suggest that PCOS with AA excess is inherited at a rate similar to that of PCOS without AA excess. AA excess may be considered a separate risk factor for the development of PCOS, such that individuals who are genetically predisposed to excess AA secretion will be at greater risk for developing PCOS. The AA excess of PCOS results from a generalized adrenocortical hyperresponsivity to ACTH stimulation, rather than from deficiencies in specific enzymatic steps, altered pituitary responsivity to corticotropin-releasing hormone, or increased sensitivity of these AAs to ACTH. Whether the increased responsivity to ACTH for these steroids is secondary to increased zona reticularis mass or overactivity of specific enzymatic steps remains unclear. AA excess in PCOS appears to occur independently of ovarian androgen excess, suggesting that it may represent an intrinsic, and possibly primary, abnormality of adrenocortical steroidogenesis. Nonetheless, it is possible that other extra adrenal factors, such as hyperinsulinemia, could play an etiologic role in AA excess. Contrary to the stimulatory action of insulin on ovarian androgens, some studies have suggested that insulin actually decreases circulating DHEAS levels, although there is no consensus. More recently it has become apparent that the insulin-induced inhibition of AAs may be gender specific, and that hyperinsulinism may not result in a decrease in DHEAS, particularly in insulin-resistant PCOS women. In fact, some studies actually suggest a positive link between insulin resistance, hyperinsulinism and AA excess in PCOS women. For example, girls with premature pubarche and exaggerated AA secretion have been reported to demonstrate hyperinsulinism and insulin resistance as well, and are at increased risk for developing PCOS in adulthood. In accordance with the presumption that AAs play a role in the ovulatory dysfunction of women with PCOS, a number of investigators have noted a beneficial effect of glucocorticoid administration on ovulation. However, in a prospective study continuous dexamethasone suppression did not result in consistent ovulation in PCOS, regardless of basal DHEAS levels. This suggests that, although AA excess may play a role in the establishment or initiation of PCOS, it has a limited role in maintaining the ovulatory dysfunction of the disorder. In conclusion, AA excess affects between 30% and 50% of PCOS, which appears to arise from a generalized adrenocortical hyperresponsiveness to ACTH. It is possible that the over-secretion of AA represents an inherited trait that increases the risk of developing PCOS in a multifactorial fashion, Overall, furthering our understanding of the etiology and role of AA excess in PCOS may lead us to identify the underlying mechanism(s) for PCOS, because the adrenal and ovary have in common significant portions of their steroidogenic pathways.