Cortisol and the Polycystic Ovary Syndrome

Renato Pasquali; Alessandra Gambineri

Disclosures

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

In This Article

Dynamic Tests Assessing the Activity of the HPA Axis in PCOS

There are only a few studies that have investigated the functioning of the adrenals following neuropeptide administration or specific challenges able to evoke primary neurooendocrine overactivation stimuli. Some evaluated the HPA axis response to ovine (oCRH) or human (hCRH) stimulation at different doses in PCOS. Lanzone et/al. found that both ACTH and cortisol response to hCRH were markedly greater and more prolonged in women with PCOS as compared with controls.[14] Later, the same group found that after 6 weeks of treatment with a somatostatin analog, octreotide treatment (100 mg subcutaneously, twice daily), ACTH and cortisol response significantly decreased in women with PCOS, and no difference was present with respect to controls, suggesting that a hyperfunction of the HPA axis secondary to central and/or peripheral somatostatinergic activity in these women might exist.[15] Another study[16] investigated whether women with PCOS characterized by DHEAS excess differed, with respect to those with normal DHEAS blood values or controls (matched for age and BMI), in the response to oCRH stimulation (1 mcg/kg) or an 8-h incremental intravenous stimulation with ACTH (1–24) at doses ranging from 20 to 2880 ng/1.5 m2 × h with a final bolus of 0.25 mg. No significant differences in the net maximal response for ACTH, dehydroxyepiandrosterone (DHEA), androstenedione or cortisol were observed; nonetheless, the net response of the DHEA/cortisol ratio and of the areas under the curve for DHEA and the DHEA/cortisol ratio indicated a greater response for PCOS women with high DHEAS levels compared with both their counterparts. Moreover, no difference in the sensitivity (i.e., threshold or minimal stimulatory dose) to ACTH was noted between the groups for any of the steroids measured; however, the average dose of ACTH (1–24) required for a threshold response was higher for DHEA than for cortisol and androstenedione in all groups. In addition, no difference in mean responsivity (slope of response to incremental ACTH stimulation) was observed for DHEA and cortisol between the study groups, whereas the responsivity of androstenedione was higher in PCOS women with high DHEAS than in those with normal DHEAS. Collectively, the data of this complex study seem to support the concept that adrenal androgen excess in PCOS patients is related to an exaggerated secretory response of the adrenal cortex (for DHEA and androstenedione), but not to an altered pituitary responsivity to CRH or to increased sensitivity of these androgens to ACTH stimulation. However, the data could not define whether the increased responsivity to ACTH for these steroids might be secondary to increased zona reticularis mass or to differences in P450c17a activity, particularly of the delta-4 pathway. In this regard, an interesting study[17] has suggested that, in women with PCOS, ovarian hyperandrogenicity may potentially directly contribute to the enhanced adrenal P450c17a activity and subsequent delta-4 androgen reserve revealed by an ACTH (1–24) stimulation, independently of mechanisms regulating adrenal cortisol secretion. Intriguingly, this might imply a functional crosstalk between the ovaries and the adrenals. A third study evaluating the dynamics of the pituitary–adrenal hormone response to hCRH in women with PCOS, Kondoh et/al. found that plasma ACTH and cortisol response were significantly higher with respect to controls only in a subgroup of women with PCOS, and that these women were also characterized by higher blood levels of DHEAS, but greater suppression of androstenedione following dexamethasone administration.[18] Mechanisms responsible for an increased responsiveness of the HPA axis – which can be detected only in specific subsets of women with PCOS – are still unclear, although altered somatostatinergic[15] and opioid system[19,20] functions, possibly contributing to a hyperactive HPA axis have been suggested. Whether this regulatory network plays a role in the control of adrenal steroidogenesis in women with PCOS needs, however, further and more sophisticated investigation.

Finally, one study investigated the HPA response to insulin-induced hypoglycemia in a small group of women with PCOS and weight-matched controls.[21] It was found that, compared with controls, women with PCOS had a significantly lower ACTH response, and a quantitatively comparable and more prompt cortisol response than the controls, resulting in a higher molar ratio between the maximum increments of cortisol and ACTH. Furthermore, a more rapid decline in cortisol levels occurs in PCOS than the controls, whereas the responses of the androgens and intermediate adrenal steroids were similar in both PCOS and control women. The findings may suggest an adaptation to increased adrenal reactivity to endogenous ACTH in women with PCOS, although this model, used to investigate neuroendocrine reactivity, did not show hypersecretion of adrenal androgens and revealed no signs of steroid enzyme disturbances. Questions of the extent with differences in enzyme activities in the cortisol metabolism contribute to the rise in production remain unresolved because a quantitative kinetic model of cortisol metabolism is not available. Therefore, understanding the mechanisms responsible for altered cortisol and eventually adrenal androgens after stimulatory challenges is still a difficult task. In line with these findings, a potential indirect role of nutrients and insulin in the regulation of adrenal steroidogenesis has also been suggested by a recent study showing that, in women with PCOS, the presence of obesity and insulin resistance is associated with lower morning cortisol and DHEAS but increased cortisol and DHEA responses during an oral glucose tolerance test. Specifically, those women who had higher BMI and lower insulin sensitivity indices also had a higher early (at 60 min) response to glucose load and a later lower late nadir (at 180–240 min) glucose values. These nadir values were significantly associated with late cortisol increase and with higher scores in shakiness, sweatiness, weakness and hunger, suggesting the presence of reactive hypoglycemia in these women and, therefore, explaining the reactive cortisol increase.[22] Intriguingly, this hormonal imbalance in obese insulin resistant and hyperinsulinemic patients with PCOS might have important long-term consequences because of repeated stimulation of the HPA axis by nutrients. In fact, it is conceivable that ingestion of simple sugars can cause even mild postprandial hypoglycemia, thereby stimulating secretion of adrenal steroids that, in turn, may favor further weight gain and insulin resistance, thus creating a vicious cycle.

To summarize, all available studies support the possibility that the HPA axis response to neuroendocrine stimuli may be altered only in a subset of women with PCOS, in whom metabolic factors, such as obesity and insulin excess, may play a role in determining abnormalities in the regulation of the adrenal axis. Although potential factors responsible for steroid abnormalities in normal-weight women with PCOS have been poorly investigated, available data suggest that they rarely occur in these women.

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