Cortisol and the Polycystic Ovary Syndrome

Renato Pasquali; Alessandra Gambineri


Expert Rev Endocrinol Metab. 2012;7(5):555-566. 

In This Article

Extraglandular Sources of Cortisol Production & Metabolism & Their Role in the Pathophysiology of PCOS

The regulation of peripheral cortisol metabolism, particularly in the visceral fat tissues and the liver, is of importance because of its role in the regulation of physiological processes responsible for the modulation of the metabolic pathways in peripheral tissues and the emerging potential role of a dysregulation of this system in the pathophysiology of metabolic, neurological and cardiovascular disorders. It may therefore have some relevance in the pathophysiology of PCOS.

Key enzymes controlling cortisol metabolism and reactivation from inactive compounds (cortisone) include both 5α- and 5b-reductase and 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1), respectively. This topic has been extensively reviewed in recent years.[87,88] The main determinants of glucocorticoid action are the levels of hormones in the blood, their binding by plasma CBG and the varying densities of glucocorticoid receptors in target tissues. However, it is apparent that an additional and important level of control is exerted by prereceptor metabolism of glucocorticoids by tissue-specific enzymes, in particular 11b-hydroxysteroid dehydrogenases (11b-HSDs).[87] The intracellular enzyme 11b-HSD1 catalyses the interconversion of the active 11-hydroxy glucocorticoid cortisol with its inactive 11-keto metabolite cortisone. 11b-HSD1 is predominantly a reductase in most circumstances, regenerating cortisol from cortisone and thereby increasing intracellular cortisol concentrations and amplifying local glucocorticoid action.[87] In addition, it has been recently demonstrated that cortisol regenerated by 11b-HSD1 also substantially contributes to the plasma cortisol pool.[87] The measurement of the proportion of the plasma cortisol pool derived from regeneration of cortisol by 11b-HSD1 has been recently quantified in humans using a novel stable-isotope tracer, so that the ratio between the two can be used to adequately calculate cortisol regeneration rates.[89] In this way, it has been estimated that peripheral regeneration of cortisol in healthy individuals is approximately 11 nmol/min at a time when adrenal cortisol secretion is approximately 38 nmol/min.[89]

It is well known that 11b-HSD1 is widely expressed, notably in liver, lung, adipose tissue, vasculature, ovaries and the CNS.[90,91] Adipose tissue, as much as liver, is the key target tissue in which glucocorticoid action influences susceptibility to obesity and metabolic complications. In support of this affirmation, transgenic mice overexpressing 11b-HSD1 in adipose tissue develop obesity with all the features of the metabolic syndrome,[92] while 11b-HSD1-knock-out mice are protected from obesity and its metabolic complications.[93] Intriguingly, only omental 11b-HSD1 is independently associated with the amount of visceral fat but not subcutaneous fat in women, which supports the concept that visceral fat is the major target tissue for expression of genes related to glucocorticoid action.[94] Overexpression of 11b-HSD1 in the liver does not induce obesity or hyperglycemia, although a deterioration in lipids, insulin sensitivity and blood pressure has been found.[95] By contrast, in the short term, the pharmacological inhibition of 11b-HSD1 has been found to enhance hepatic insulin sensitivity, to lower blood glucose in diabetic mice and to decrease weight in obese mice.[96] However, studies in humans on the potential role of 11b-HSD1 in determining obesity and metabolic comorbidities are controversial. This could be related to the fact that older studies measured cortisol and cortisone metabolites in urine, in order to detect a dysregulation of enzymes involved in their metabolism, although this approach had been criticized.[40] More recently, using a [2H4]-cortisol tracer technique, both the whole body[97] and splanchnic levels[98] of these steroids in fact showed no differences in cortisol regeneration rates between obese and normal-weight subjects. This unexpected result was interpreted as the consequence of upregulation of 11b-HSD1 in adipose tissue balanced by a downregulation in liver. To support this hypothesis, data has been obtained by direct in vivo measurements of liver and subcutaneous 11b-HSD1 activities. In particular, the conversion of an oral dose of cortisone into cortisol of first-pass metabolism in the liver was found to be lower in obesity[39] and, at variance, the rate of conversion of cortisone to cortisol in subcutaneous adipose tissue measured by microdialysis was found to be increased in obese with respect to lean subjects[97] and positively related with the severity of insulin resistance.[99] These recent results have caught the imagination of many investigators in a trigger role of 11b-HSD1 in the pathogenesis of obesity and the metabolic syndrome in humans. However, it should also be taken into consideration that many investigations are insufficient to support this hypothesis, as most of the human studies performed so far used methodologies that are inadequate to quantify 11b-HSD1 activity in vivo.

The attention on the activity of 11b-HSD1 in PCOS is partly related to the strong association of PCOS with obesity and the metabolic syndrome;[100] however, most of the studies performed until now to estimate 11b-HSD1 activity in vivo in PCOS have relied on the ratio of metabolites of cortisol and cortisone in urine, and these studies have therefore produced contradictory results.[101–105] In particular, one of the first studies performed on this topic reported a reduced ratio of metabolites of cortisol:cortisone, suggesting a decreased activity of 11b-HSD1 in women with PCOS.[101] These data were subsequently confirmed only in some studies,[102,103] while others described a normal activity of 11b-HSD1 in PCOS, but an increased activity of the 5α-reductase system,[104,105] which is involved in the peripheral metabolism of cortisol. Using a more sophisticated approach, a recent study investigated the whole-body 11b-HSD1 activity with [2H4]cortisol tracer in a group of obese women with PCOS with respect to a group of obese women without PCOS, and confirmed that obese and nonobese women with PCOS may have similar cortisol regeneration rates and, therefore, similar whole-body 11b-reductase activity.[106] However, another more recent study investigating the tissue-specific dysregulations of 11b-HSD1 found that obese women with PCOS had an increased activity of 11b-HSD1 in the subcutaneous adipose tissue and a reduced activity of 11b-HSD1 in the liver with respect to women with idiopathic obesity [Pasquali R, Unpublished Data]. Similar data were previously obtained in the evaluation of 11b-HSD1 mRNA expression in subcutaneous adipose tissue biopsies.[107] Overall, these preliminary data suggest that 11b-HSD1 has a specific tissue dysregulation in women with PCOS, although further research is needed in this complex area.

A wide variety of factors are known to regulate 11b-HSD1 mRNA levels and activity in rodents and in isolated cells in culture.[108] A number of these factors are involved in the pathogenesis of PCOS, including insulin, insulin-like factor 1, cytokines and peroxisome proliferator-activated receptor agonist. Although recent research has begun to address the regulation of 11b-HSD1 in healthy human subjects and suggested that its activity is influenced by nutritional status, probably mediated by hyperinsulinemia,[109] no specific data are currently available in women with PCOS. By contrast, some studies showed that genetic factors related to the activity of 11b-HSD1 may be involved in the pathophysiology of PCOS. Although several noncoding polymorphisms in the HSD11B1 gene encoding the enzyme have been identified,[110,111] none has been associated with obesity or PCOS, whereas they have been linked to the increased risk of diabetes,[111] hypertension[112] and the metabolic syndrome in general.[106] However, a polymorphism that predicts a lower expression of 11b-HSD1,[113] which seems to be protective against diabetes, has been found to be under-represented in women with obesity and PCOS,[114] in whom lower 11b-HSD1 levels may enhance cortisol clearance and even increase adrenal androgen production. These findings suggest that 11b-HSD1 may not underpin the metabolic consequences in PCOS but, rather, adrenal hyperandrogenism, at least in a subgroup of women with this disorder.