Massive Weight Loss Decreases Corticosteroid-Binding Globulin Levels and Increases Free Cortisol in Healthy Obese Patients

Abstract

OBJECTIVE -Obesity, insulin resistance, and weight loss have been associated with changes in hypothalamic-pituitary-adrenal (HPA) axis. So far, no conclusive data relating to this association are available. In this study, we aim to investigate the effects of massive weight loss on cortisol suppressibility, cortisol-binding globulin (CBG), and free cortisol index (FCI) in formerly obese women.RESEARCH DESIGN AND METHODS -Ten glucose-normotolerant, fertile, obese women (BMI Ͼ40 kg/m 2 , aged 38.66 Ϯ 13.35 years) were studied before and 2 years after biliopancreatic diversion (BPD) when stable weight was achieved and were compared with age-matched healthy volunteers. Cortisol suppression was evaluated by a 4-mg intravenous dexamethasone suppression test (DEX-ST). FCI was calculated as the cortisol-to-CBG ratio. Insulin sensitivity was measured by an euglycemic-hyperinsulinemic clamp, and insulin secretion was measured by a C-peptide deconvolution method. RESULTS-No difference was found in cortisol suppression after DEX-ST before or after weight loss. A decrease in ACTH was significantly greater in control subjects than in obese (P ϭ 0.05) and postobese women (P Յ 0.01) as was the decrease in dehydroepiandrosterone (P Յ 0.05 and P Յ 0.01, respectively). CBG decreased from 51.50 Ϯ 12.76 to 34.33 Ϯ 7.24 mg/l (P Յ 0.01) following BPD. FCI increased from 11.15 Ϯ 2.85 to 18.16 Ϯ 6.82 (P Յ 0.05). Insulin secretion decreased (52.04 Ϯ 16.71 vs. 30.62 Ϯ 16.32 nmol/m Ϫ2 ; P Յ 0.05), and insulin sensitivity increased by 163% (P Յ 0.0001). Serum CBG was related to BMI (r 0 ϭ 0.708; P ϭ 0.0001), body weight (r 0 ϭ 0.643; P ϭ 0.0001), body fat percent (r 0 ϭ 0.462; P ϭ 0.001), C-reactive protein (r 0 ϭ 0.619; P ϭ 0.004), and leptin (r 0 ϭ 0.579; P ϭ 0.007) and negatively to M value (r 0 ϭ Ϫ0.603; P ϭ 0.005).CONCLUSIONS -After massive weight loss in morbidly obese subjects, an increase of free cortisol was associated with a simultaneous decrease in CBG levels, which might be an adaptive phenomenon relating to environmental changes. This topic, not addressed before, adds new insight into the complex mechanisms linking HPA activity to obesity. Diabetes Care 30:1494-1500, 2007N utritional status and activity of the hypothalamic-pituitary-adrenal (HPA) axis are strictly associated (1,2). However, little is known about the effect of starvation and intentional calorie deprivation on the HPA axis (3,4). The HPA axis controls the secretion of cortisol with excessive secretion being inhibited by negative feedback. Several studies suggest that abnormalities in cortisol action and HPA axis control may be a factor that links disturbances of carbohydrate metabolism (which characterize insulin resistance) and obesity (5-6). In obesity, estimation of plasma cortisol does not reflect the function of the HPA axis (7), and levels of cortisol in obese patients have been reported to be normal (8), low (9), or increased (10). On the contrary, response to different stimuli (high secretion of cortisol after laboratory stress tests or after different exo...

Sex defines the age dependence of endogenous ACTH-cortisol dose responsiveness

“…Previous reports suggest variously that BMI does not predict (53), predicts decreased (33,67,70), and predicts increased (1,20,23,68,76) cortisol concentrations, production and/or metabolism. The current analyses show that higher BMI in men is associated with lower calculated ACTH potency (higher ED 50 ), but no difference in 24-h cortisol secretion. The decline in ACTH potency with increased BMI cannot be readily explained by changes in CBG concentrations, which change principally with massive increases in BMI in unmedicated and nonhormonally treated adults (43,45,50).…”

“…The current analyses show that higher BMI in men is associated with lower calculated ACTH potency (higher ED 50 ), but no difference in 24-h cortisol secretion. The decline in ACTH potency with increased BMI cannot be readily explained by changes in CBG concentrations, which change principally with massive increases in BMI in unmedicated and nonhormonally treated adults (43,45,50). On technical grounds, variations in CBG could influence efficacy calculations but would not affect analytical estimates of potency as determined here (35,37).…”

“…Thus, sex affects the age dependence of ACTH efficacy in this cohort. This outcome was specific, since regressions of ACTH ED 50 , and secondarily adrenal sensitivity and basal cortisol secretion on age, yielded no age or sex dependencies ( Table 2). The opposite effects of age on ACTH efficacy in men and women were reflected in analogous differences in both total (pulsatile plus basal) daily cortisol secretion (sex effect P ϭ 0.01) and the mass of cortisol secreted per burst (sex effect: P ϭ 0.03).…”

Metabolic endotoxemia and saturated fat contribute to circulating NGAL concentrations in subjects with insulin resistance

“…Similar changes in the daily profile of other hormones involved in the immune response, such as cortisol and leptin, have been observed. 38,39 NGAL maintained a circadian rhythm, even though it was significantly different compared with the baseline. Biliopancreatic diversion is able to affect both the degree of insulin resistance and circulating TNF-a.…”

Intentional weight loss and risk of lymphohematopoietic cancers

“…Furthermore, reduction of weight among overweight adults has been shown to improve blood pressure, lipid profiles, insulin sensitivity, and inflammation [5][6][7][8][9][10], and to reduce diabetes incidence and mortality in high-risk persons [6,[11][12][13]. Nevertheless, other endpoints may be adversely affected by weight loss.…”