Cortisol and ACTH Response to Oral Dexamethasone in Obesity and Effects of Sex, Body Fat Distribution, and Dexamethasone Concentrations: A Dose-Response Study

Abstract

There is increasing evidence that the abdominal obesity phenotype may be associated with multiple alterations of the hypothalamic-pituitary-adrenocortical (HPA) axis activity in both sexes. Our hypothesis is that the lack of adequate cortisol suppression after the dexamethasone test may constitute an indirect marker of HPA axis hyperactivity in the presence of the abdominal obesity phenotype. A total of 34 normal-weight (13 men and 21 women) and 87 obese (36 men and 51 women), healthy, nondepressed subjects therefore underwent four different dexamethasone suppression tests randomly performed at varying intervals of at least 1 wk between each test. After a standard overnight 1-mg dexamethasone test, which served as a reference, three other tests were randomly performed at 1-wk intervals by administering 0.0035, 0.0070, and 0.015 mg oral dexamethasone per kilogram of body weight overnight. Blood samples were obtained for cortisol, ACTH, and dexamethasone. Results were analyzed separately in men and women as well as in normal-weight [body mass index (BMI) <25 kg/m 2 ] and overweight or obese (BMI >25 kg/m 2 ) subjects. The waist circumference and the waist to hip ratio (WHR) were used as markers of body fat distribution. After the standard 1-mg test, cortisol suppression was greater than 90% in all subjects. However, after each test, obese women had significantly higher values of percent cortisol and percent ACTH suppression than normal-weight women without any difference between obese and normal-weight men. Considering the response to the three variable-dose tests, a clear doseresponse pattern (P < 0.001 for trend analysis) in percent cortisol and percent ACTH suppression was found in all subjects. After each test men had significantly higher dexamethasone levels than women, regardless of BMI. However, obese women, but not men, had significantly higher dexamethasone levels after each test than their normal-weight counterpart. Plasma dexamethasone concentrations were dose related (P < 0.001 for trend analysis) in all subjects, but the doserelated increase was significantly higher in normal-weight men than normal-weight women, whereas it was similar in obese subjects of both sexes. Stepwise multiple regression analysis revealed that both percent cortisol and percent ACTH variations were significantly and negatively influenced by dexamethasone levels, as well as by waist circumference values in men, and independently by BMI and waist circumference in women. However, in contrast to what has been found in men, a divergent contribution of BMI and waist circumference was found in women indicating that, with increasing waist values, a smaller suppression of the HPA axis was found with respect to that expected on the basis of BMI values. In conclusion, this study provides data of both physiological and physiopathological relevance. Overall, our data indicated that adjustment of the dexamethasone dose to body weight does not seem to substantially improve the sensitivity of the test, even in obese individuals, particularly w...

Cortisol clearance and associations with insulin sensitivity, body fat and fatty liver in middle-aged men

“…Moreover, the value of the dexamethasone suppression test is limited in these circumstances [32]. Subjects with decreased dexamethasone suppression have more rapid dexamethasone clearance [33], the rate of dexamethasone metabolism is increased in people in whom the suppression of cortisol during the dexamethasone suppression test is decreased [32,33], and the rate of metabolic clearance of dexamethasone is higher in obese people than in people of normal weight [34]. Furthermore, the capacity of the liver to metabolise dexamethasone is related to liver function parameters that are known to be abnormal in NAFLD [35].…”

Adipose tissue expression of 11beta-Hydroxysteroid dehydrogenase type 1 in cushing's syndrome and in obesity

“…The proposed alterations include resistance to the negative feedback (impaired suppression) exerted by low oral dexamethasone or intravenous doses of glucocorticoids (17)(18)(19); elevated diurnal ACTH levels and altered pulsatile secretory ACTH dynamics (20), hyperesponsiveness to different peptides (CRH, AVP) (21), and increased cortisol production rate, as measured by stable isotope ratio (22).…”

Stress-induced cytokine responses and central adiposity in young women

“…[6][7][8] Similarly, heightened cortisol responses to acute laboratory stress, as well as impaired dexamethasone suppression of cortisol have been associated with increased waist-hip ratio in healthy men and women. [9][10][11] Disturbances in sympathetic responsiveness to psychological stress have also been linked to abdominal obesity. Waist-hip ratio was associated with heightened stress-related increases in diastolic BP and total peripheral resistance in a study of pre-menopausal women, 12 and waist circumference correlated with greater systolic and diastolic BP and heart rate reactivity to mental stress in older African men and women.…”