The Role of Obesity in Modulating the Activity of the HPA Axis in PCOS
Obesity represents a potential factor responsible for altered HPA axis functioning in PCOS, and this may be supported by the strong association between these two disorders and by the fact that the pulsatile and spiky activity of ACTH secretion are under the influence of body fat and body composition, as well as age; this may be due to the fact that these confounders were not adequately taken into account. In fact, several studies performed in women with different phenotypes of obesity have shown that a dysregulation of the HPA axis may exist in this population, particularly those with the abdominal phenotype. In these women, basal blood levels of ACTH and cortisol are usually normal, as are ACTH and cortisol daily rhythms. However, one study performed to investigate the pulsatile secretion of cortisol and ACTH during the daytime in women with different obesity phenotypes showed that those with visceral obesity had higher ACTH pulse frequency and lower ACTH pulse amplitude, particularly in the morning, but similar mean ACTH basal concentrations, in comparison with their gluteofemoral type obese counterpart and normal-weight controls, suggesting an increased sensitivity of cortisol secretion to non-ACTH-dependent pathways, such as the peripheral noradrenergic regulatory system, particularly during the zenith phase of the daily rhythm. Several other studies used the urinary free-cortisol (UFC) excretion as an integrated measurement of daily cortisol excretion rate, and reported higher than normal 24-h UFC excretion rates in women with abdominal obesity, and a significant positive correlation with the extent of abdominal adiposity.[27–29] Interestingly, there are data supporting the concept that UFC excretion rates during the night-time but not the day may be of particular interest to detect subtle alterations of cortisol secretion rates in obese individuals. Dynamic studies in which the HPA axis was either stimulated or inhibited provided the most convincing evidence for a dysregulation of the system in abdominal obesity. They demonstrated higher than normal cortisol responses after laboratory stress tests, or after challenges of the HPA axis by administering CRH or arginine-vasopressin alone, or in combination in women with abdominal obesity with respect to those with the peripheral phenotype, even regardless of psychiatric disorders. The strong reproducibility of the CRH test among individuals is undoubtedly a strength factor supporting the reliability of these data. Similar differences between abdominal and peripheral obese women have been reported by using the ACTH (1–24) stimulatory test, using either maximal or low doses. The suppressive challenge of the HPA axis using low-dose (i.e., ≤0.5 mg overnight) dexamethasone provided relatively confirmatory results. A blunted inhibition of cortisol secretion, suggesting a reduced sensitivity to inhibition by low-dose dexamethasone via downregulation of central glucocorticoid receptors, has been reported. Another study, in both obese and normal-weight individuals who randomly underwent different low-dose dexamethasone doses showed that, unlike men, with increasing amounts of abdominal fat, women tended to show a significant lower suppression of blood cortisol levels with respect to that expected on the basis of increasing dexamethasone doses, further confirming the potential impairment of sensitive feedback signals in abdominally obese women.
In an attempt to clarify whether the discrepancies observed in studies performed in women with PCOS may depend on the heterogeneity of the cohorts included in each study and/or to the impact of obesity, Roelfsema et/al. performed a 24-h blood sampling at 20-min intervals for a cortisol assay (Figure 1), in two BMI-matched groups of obese PCOS women and healthy obese controls with a regular menstrual cycle. The data showed that basal, pulsatile and total cortisol production (expressed per liter of distribution volume, per square meter of body surface and as absolute amount per 24-h) was similar in PCOS patients and matched healthy controls. Accordingly, the regularity of cortisol secretion and the diurnal properties or circadian rhythm were identical. However, compared with ten lean control women, mean cortisol production per liter of distribution volume was similar in the three groups, but the total 24-h cortisol production was increased in obese control women and PCOS women. These data confirm previous studies investigating cortisol secretion in obesity assessed with different methods, including isotopic dilution, measurement of UFC and C21 metabolites, that have invariably shown increased cortisol production in obesity.[37–42] Therefore, it is probable that obesity, rather than PCOS status per se, may be responsible for subtle alterations of cortisol dynamics.
Mean 24-h serum cortisol concentration time series in 15 polycystic ovary syndrome patients and 15 age- and BMI-matched controls.
PCOS: Polycystic ovary syndrome.
Reproduced with permission from .
Expert Rev Endocrinol Metab. 2012;7(5):555-566. © 2012 Expert Reviews Ltd.