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Journal of Clinical Endocrinology & Metabolism Vol. 71, No. 2 452-463
doi:10.1210/jcem-71-2-452
Copyright © 1990 by the Endocrine Society.
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Amplitude, but not Frequency, Modulation of Adrenocorticotropin Secretory Bursts Gives Rise to the Nyctohemeral Rhythm of the Corticotropic Axis in Man*

JOHANNES D. VELDHUIS, ALI IRANMANESH, MICHAEL L. JOHNSON and GERMAN LIZARRALDE

Interdisciplinary Graduate Biophysics Program and Division of Endocrinology and Metabolism, Departments of Internal Medicine and Pharmacology, University of Virginia Health Sciences Center (J.D.V., M.L.J.) Charlottesuille, Virginia 22908
The Section of Endocrinology, Department of Internal Medicine, Veteran’s Administration Hospital (A.I., G.L.) Salem, Virginia 24153

Address all correspondence and requests for reprints to: Dr. Johannes D. Veldhuis, Box 202, Department of Internal Medicine, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908.

The ACTH-adrenal axis is a critical stress-responsive system with prominent circadian rhythmicity. To test the basis for the circadian ACTH physiology, we have used 1) a sensitive and specific two-site immunoradiometric assay to estimateplasma ACTH-(l–39) concentrations during intensive (every 10 min) and extended (24-h) blood sampling to capture complete diurnal ACTH profiles in eight normal men, and 2) a novel deconvolution model designed to resolve the number, amplitude, and duration of ACTH secretory bursts and simultaneously estimate subject-specific ACTH half-lives under physiological conditions in vivo. Deconvolution revealed 40 ± 1.5 significant ACTH secretory bursts/24 h, with a mean interburst interval of 39 ± 2.3 min. ACTH secretory bursts were discrete punctuated events arising without tonic interpulse secretion and had a half-duration (duration at half-maximal amplitude) of 19 ± 2 min. The estimated half-life of endogenous ACTH was 15 ± 1.2 min, and its daily production rate was 0.96 ± 0.16 ng/mL (0.21 ± 0.035 nmol/L) distribution volume. Cosinor analysis revealed a significant (3.8-fold) 24-h rhythm in the mass (or rate) of ACTH secreted per burst (maximal at 0818 h), but no nyctohemeral variation in ACTH secretory pulse frequency. The validity of ACTH pulse analysis was supported by the significantly nonrandom associations among ACTH, β-endorphin, and cortisol peaks in the same subjects. Specifically, we found that ACTH and β-endorphin bursts occurred simultaneously (P < 10–4) and were both followed in 10 min by a cortisol pulse (P < 10–4).

We conclude that 1) selective amplitude control of a punctuated burst-like mode of ACTH secretion can give rise to the nyctohemeral corticotropic rhythm without the need to postulate any tonic (or interpulse basal) component of ACTH release; and 2) there is exquisite 3-fold temporal synchrony among bursts of ACTH, β-endorphin, and cortisol release in normal men.

* This work was supported in part by NIH Grant RR-00847 (to the Clinical Research Center of the University of Virginia), Research Career Development Award 1-KO4-HD-00634 (to J.D.V.), V.A. Medical Research Funds (to A.I.), NIH Grants AM-30302 and GM-28928 (to M.L.J.), Diabetes and Research Training Center Grant 5-P60-AM-22125–05, and NIH-supported Clinfo Data Reduction Systems.

Received December 1, 1989.




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