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Daily Cortisol Production Rate in Man Determined by Stable Isotope Dilution/Mass Spectrometry

Laboratory of Theoretical and Physical Biology (N.V.E., A.L.Y.) and the Developmental Endocrinology Branch (T.L., J.K.Z., D.L.L.), National Institute of Child Health and Human Development, National Institutes of Health Bethesda, Maryland 20892
the Department of Medicine, McMaster University (J.D.B.) Hamilton, Ontario, L8N 3Z5 Canada
East Tennesse Children’s Hospital (J.C.W.) Knoxville, Tennessee 37901

Address all correspondence and requests for reprints to: Nora V. Esteban, M.D., Laboratory of Theoretical and Physical Biology, National Institutes of Health, Building 10, Room 10C-212, Bethesda, Maryland 20892.

Growth retardation as well as the development of Cushingoid features in adrenally insufficient patients treated with the currently accepted replacement dose of cortisol (33–41µmol/day · m²; 12–15 mg/m²·day) prompted us to reevaluate the cortisol production rate (FPR) in normal subjects and patients with Cushing’s syndrome, using a recently developed thermospray liquid chromatography-mass spectrometry method. The stable isotope [9,12,12-²H₃]cortisol was infused continuously for 31 h at about 5% of the anticipated FPR. Blood samples were obtained at 20-min intervals for 24 h, spun, and pooled in 4-h groups. Tracer dilution in plasma was determined by liquid chromatography/mass spectrometry. The method was validated with controlled infusions in 6 patients with adrenal insufficiency. Results from 12 normal volunteers revealed a FPR of 27.3 ± 7.5 µmol/day (9.9 ± 2.7 mg/day) or 15.7 µmol/day · m²; 5.7 mg/m²·day). A previously unreported circadian variation in FPR was observed. Patients with Cushing’s syndrome demonstrated unequivocal elevation of FPR (84.7 ± 25.7 µmol/day) and loss of circadian rhythm. FPR and cortisol concentration correlated during each sample period in normal volunteers, indicating that cortisol secretion, rather than metabolism, is mainly responsible for changes in plasma cortisol. Our data suggest that the FPR in normal subjects may be lower than previously believed.

Received May 16, 1990.

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