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Combined Receptor Antagonist Stimulation of the Hypothalamic-Pituitary-Adrenal Axis Test Identifies Impaired Negative Feedback Sensitivity to Cortisol in Obese Men

Department of Public Health and Clinical Medicine (C.M., K.S., T.O.), Umeå University Hospital, S-901 85 Umeå, Sweden; and Endocrinology Unit (R.M.R., B.R.W.), University of Edinburgh, Centre for Cardiovascular Science, Queen’s Medical Research Institute, Edinburgh EH16 4TJ, Scotland, United Kingdom

Address all correspondence and requests for reprints to: Dr. Rebecca Reynolds, Endocrinology Unit, University of Edinburgh, Centre for Cardiovascular Science, Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, Scotland, United Kingdom. E-mail: r.reynolds{at}ed.ac.uk.

Context: Hypothalamic-pituitary-adrenal (HPA) axis dysregulation may underlie disorders including obesity, depression, cognitive decline, and the metabolic syndrome. Conventional tests of HPA axis negative feedback rely on glucocorticoid receptor (GR) agonists such as dexamethasone but do not test feedback by endogenous cortisol, potentially mediated by both GR and mineralocorticoid receptors (MR).

Objective: The objective of the study was to use a combination of GR (RU38486, mifepristone) and MR (spironolactone) antagonists to explore the poorly understood activation of the HPA axis that occurs in obesity.

Design: This was a double-blind, placebo-controlled, randomized, crossover study.

Setting: The study was conducted at a clinical research facility.

Participants: Participants included 15 lean (body mass index 22.0 ± 1.6 kg/m²) and 16 overweight/obese (body mass index 30.1 ± 3.5 kg/m²) men.

Intervention: Subjects attended on four occasions for blood and saliva sampling every 30 min between 1800 and 2200 h. At 1100 and 1600 h before visits, subjects took 200 mg spironolactone, 400 mg RU38486, 200 mg spironolactone + 400 mg RU38486, or placebo orally.

Main Outcome Measures: Serum cortisol levels after drug or placebo were measured.

Results: Cortisol levels did not differ between lean and obese after placebo. Spironolactone and RU38486 alone had modest effects, increasing cortisol by less than 50% in both groups. However, combined spironolactone plus RU38486 elevated cortisol concentrations substantially, more so in lean than obese men [2.9- (0.3) vs. 2.2 (0.3)-fold elevation, P = 0.002].

Conclusions: Combined receptor antagonist stimulation of the HPA axis reveals redundancy of MR and GR in negative feedback in humans. Obese men have impaired responses to combined receptor antagonist stimulation, suggesting impaired negative feedback by endogenous cortisol. Such an approach may be useful to dissect abnormal HPA axis control in neuropsychiatric and other disorders.

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