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Disordered and Increased Adrenocorticotropin Secretion with Diminished Adrenocorticotropin Potency in Obese in Premenopausal Women

Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, 2333ZA Leiden, The Netherlands

Address all correspondence and requests for reprints to: Dr. Ferdinand Roelfsema, Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Albinusdreef 2, 2333ZA Leiden, The Netherlands. E-mail: f.roelfsema{at}lumc.nl.

Context: The pituitary-adrenal ensemble of obese humans is marked by increased urinary excretion of cortisol and its metabolites in the face of normal circulating cortisol levels. For better understanding of the (patho) physiological meaning of these changes, the mechanistic underpinnings need to be clarified.

Intervention and Methods: We investigated 17 obese women [body mass index (BMI) 30–39.4 kg/m²] and 14 normal women (BMI, 18.3–24.8 kg/m²) who underwent 24-h blood sampling at 10-min intervals, and plasma ACTH and cortisol concentrations were measured with sensitive assays. Data were analyzed with a new deconvolution program, approximate entropy (ApEn) analyses, and cosinor regression.

Outcome: ACTH and cortisol production rates were higher in obese women than in controls and correlated with BMI. Secretion of ACTH correlated with leptin (R = 0.63; P = 0.0001) and insulin (R = 0.67; P = 0.0001). ACTH ApEn and forward ACTH-cortisol cross-ApEn were diminished in obese women. The half-maximal effective concentration (ED₅₀) of ACTH pulses vs. cortisol pulses was higher in obese women (38.3 ± 4.9 vs. 25.1 ± 3.7 ng/liter; P = 0.03), indicating decreased potency of ACTH. The diurnal properties of ACTH and cortisol secretion were unchanged in obese females.

Conclusion: Obese women exhibit enhanced ACTH and cortisol 24-h production compared with lean controls. The amplified ACTH drive is accompanied by decreased secretory regularity and diminished forward coupling between ACTH and cortisol. In addition, the potency of ACTH is decreased in obesity.