Massive Weight Loss Decreases Corticosteroid-Binding Globulin Levels and Increases Free Cortisol in Healthy Obese Patients An adaptive phenomenon? MELANIA MANCO, MD, PHD 1 JOS ´ E M. FERN ´ ANDEZ-REAL 2 MARIA E. VALERA-MORA 3 HENRI D´ ECHAUD 4 GIUSEPPE NANNI 5 VINCENZO TONDOLO 5 MENOTTI CALVANI 3 MARCO CASTAGNETO 5 MICHEL PUGEAT 4 GELTRUDE MINGRONE 3 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 for- merly obese women. RESEARCH DESIGN AND METHODS — Ten glucose-normotolerant, fertile, obese women (BMI 40 kg/m 2 , aged 38.66  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 secre- tion 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 = 0.05) and postobese women (P  0.01) as was the decrease in dehydroepiandrosterone (P  0.05 and P  0.01, respectively). CBG decreased from 51.50  12.76 to 34.33  7.24 mg/l (P  0.01) following BPD. FCI increased from 11.15  2.85 to 18.16  6.82 (P  0.05). Insulin secretion decreased (52.04  16.71 vs. 30.62  16.32 nmol/m -2 ; P  0.05), and insulin sensitivity increased by 163% (P  0.0001). Serum CBG was related to BMI (r 0 = 0.708; P = 0.0001), body weight (r 0 = 0.643; P = 0.0001), body fat percent (r 0 = 0.462; P = 0.001), C-reactive protein (r 0 = 0.619; P = 0.004), and leptin (r 0 = 0.579; P = 0.007) and negatively to M value (r 0 =-0.603; P = 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 mecha- nisms linking HPA activity to obesity. Diabetes Care 30:1494–1500, 2007 N 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 sug- gest that abnormalities in cortisol action and HPA axis control may be a factor that links disturbances of carbohydrate me- tabolism (which characterize insulin re- sistance) and obesity (5– 6). In obesity, estimation of plasma cortisol does not re- flect 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, re- sponse to different stimuli (high secretion of cortisol after laboratory stress tests or after different exogenous neuropeptides) has been found to be altered (11). Com- pared with these tests, the dexamethasone suppression test (DEX-ST), mainly used in the diagnosis of Cushing’s disease, ap- pears to be inadequate. Nevertheless, it has been widely used to evaluate the HPA axis in obesity, and the outcomes are con- tradictory (12–14). The free cortisol in- dex (FCI)— the total cortisol-to-cortisol– binding globulin ratio (CBG) — has also been proposed to be able to evaluate HPA axis activity (7,15) since it reflects the bi- ologically active fraction of total cortisol (7). Moreover, FCI is significantly associ- ated with several features of insulin resis- tance syndrome (15). CBG levels are generally decreased in obese and diabetic subjects, although genetic factors are also known to play a role in the interindividual variation in CBG levels (16,17). Reduced ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● From the 1 Liver Unit, “Bambino Gesu ` ” Hospital and Research Institute, Rome, Italy; the 2 Department of Diabetes, Endocrinology, and Nutrition, University Hospital of Girona, Girona, Spain; the 3 Department of Internal Medicine, Catholic University, Rome, Italy; the 4 Fe ´de `ration d’Endocrinologie, Hospital Neuro- Cardiologique, Hospices Civils, Lyon, France; and the 5 Department of Surgery, Catholic University; Rome, Italy. Address correspondence and reprint requests to Melania Manco, MD, PhD, via Pineta Sacchetti, 484, 00168, Rome, Italy. E-mail: melaniamanco@tiscali.it. Received for publication 30 June 2006 and accepted in revised form 21 December 2006. M.C. is employed by Sigma-Tau (Italy). Abbreviations: BPD, biliopancreatic diversion; CBG, cortisol-binding globulin; CRP, C-reactive protein; DEX, dexamethasone; DEX-ST, DEX suppression test; FCI, free cortisol index; FFM, fat-free mass; HPA, hypothalamic-pituitary-adrenal; OGTT, oral glucose tolerance test; RIA, radioimmunoassay. A table elsewhere in this issue shows conventional and Syste `me International (SI) units and conversion factors for many substances. DOI: 10.2337/dc06-1353 © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Pathophysiology/Complications O R I G I N A L A R T I C L E 1494 DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007