Abstract and Introduction
Adrenal steroidogenesis is under the control of the hypothalamic–pituitary–adrenal (HPA) axis. Furthermore, metabolic factors including insulin and obesity-related signals may play a role in the regulation of both enzymes involved in the steroidogenetic pathways, as well as in the regulation of the HPA axis. In women with the polycystic ovary syndrome (PCOS), cortisol production rate is probably normal, although adrenal androgens can be overproduced in a subset of affected women. Cortisol metabolism and regeneration from inactive glucocorticoids can also be disrupted in PCOS, thereby contributing to determining an adrenal hyperandrogenic state. Finally, overactivity of the HPA axis may be related to the high prevalence of psychopathological and eating disorders in women with PCOS, implying a maladaptive allostatic load in the adaptive mechanisms to chronic stress exposure.
The polycystic ovary syndrome (PCOS), one of the most common causes of female infertility, affects approximately 6–8% of women of a reproductive age. The diagnostic criteria of PCOS are currently based on the presence of clinical or biochemical hyperandrogenism in association with chronic oligo-anovulation and/or polycystic ovarian morphology at ultrasound, after the exclusion of other causes. According to the Androgen Excess & PCOS Society, the hyperandrogenic state should, however, be considered as the prerequisite to define the classic form of PCOS; nonetheless, nonclassic forms are frequently present, and they define the extremely heterogeneous phenotypes of this common disorder. Apart from the criteria used for the diagnosis of PCOS, many other aspects should be considered to fully characterize how the disorder can be expressed in each individual, with relevant differences according to age (e.g., from adolescence to postmenopause) and ethnicity. Major issues are in fact represented by the presence of metabolic abnormalities that may be very common in women with PCOS, particularly insulin resistance and obesity. In fact, as insulin is a true gonadotropic hormone that synergizes with the luteinizing hormone (LH) in the regulation of ovarian steroidogenesis; it may amplify ovarian androgen production rates, thereby representing a triggering factor in the pathogenesis of hyperandrogenism. In addition, insulin negatively regulates the synthesis of the major carrier protein of androgens, the sex-hormone-binding globulin, and therefore reduces circulating sex-hormone-binding globulin levels that, in turn, increase the availability of free testosterone in peripheral tissues and cells. Hyperandrogenism, in turn, contributes to the generation of insulin resistance through the stimulation of lipolysis, and therefore the increased blood availability of free fatty acids and the modification of muscle–skeletal structure and metabolic activity. Obesity may also play an important role in the pathophysiology of PCOS; therefore, obesity per se represents a condition of sex-hormone imbalance in women. In fact, testosterone production rate can be significantly increased whereas its metabolic clearance rate remains unchanged, and the availability of free testosterone may increase along with the production rate of estrogens. In addition, the presence of obesity implies an important additional contribution in determining the insulin-resistant states and in increasing blood insulin concentrations. Finally, lipid soluble steroids, including androgens, can be stored in the adipose tissue, where concentrations may be higher than in the blood, thereby determi-ning that the steroid pool in obese subjects is greater than that in normal-weight individuals. In addition, steroids are actively metabolized or interconverted in the adipose tissue, because of the presence of steroidogenenic enzymes, such as 3b-dehydrogenase, 17b-hydroxydehydrogenase and the aromatase system. Alterations in these metabolic pathways may contribute to increased androgen peripheral production rates in obese women with PCOS. In turn, androgens may also promote the differentiation of preadipocytes into mature adipocytes, particularly in the visceral fat.
This short review will focus on the role of alteration in adrenal or extraglandular cortisol secretion and metabolism in women with PCOS, and on the potential role of these factors in the pathophysiology of androgen excess and associated metabolic alterations.
Expert Rev Endocrinol Metab. 2012;7(5):555-566. © 2012 Expert Reviews Ltd.