This Article Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by VELDHUIS, J. D. Articles by LIZARRALDE, G. Search for Related Content PubMed PubMed Citation Articles by VELDHUIS, J. D. Articles by LIZARRALDE, G.

Amplitude, but not Frequency, Modulation of Adrenocorticotropin Secretory Bursts Gives Rise to the Nyctohemeral Rhythm of the Corticotropic Axis in Man^*

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.

This article has been cited by other articles:

				T. Dickmeis Glucocorticoids and the circadian clock J. Endocrinol., January 1, 2009; 200(1): 3 - 22. [Abstract] [Full Text] [PDF]

				J. D. Veldhuis, D. M. Keenan, and S. M. Pincus Motivations and Methods for Analyzing Pulsatile Hormone Secretion Endocr. Rev., December 1, 2008; 29(7): 823 - 864. [Abstract] [Full Text] [PDF]

				J. D. Veldhuis, A. Iranmanesh, K. Mielke, J. M. Miles, P. C. Carpenter, and C. Y. Bowers Ghrelin Potentiates Growth Hormone Secretion Driven by Putative Somatostatin Withdrawal and Resists Inhibition by Human Corticotropin-Releasing Hormone J. Clin. Endocrinol. Metab., June 1, 2006; 91(6): 2441 - 2446. [Abstract] [Full Text] [PDF]

				E. A. Young and J. D. Veldhuis Disordered Adrenocorticotropin Secretion in Women with Major Depression J. Clin. Endocrinol. Metab., May 1, 2006; 91(5): 1924 - 1928. [Abstract] [Full Text] [PDF]

				P. Kok, S. W. Kok, M. M. Buijs, J. J. M. Westenberg, F. Roelfsema, M. Frolich, M. P. M. Stokkel, A. E. Meinders, and H. Pijl Enhanced circadian ACTH release in obese premenopausal women: reversal by short-term acipimox treatment Am J Physiol Endocrinol Metab, November 1, 2004; 287(5): E848 - E856. [Abstract] [Full Text] [PDF]

				D. M. Keenan and J. D. Veldhuis Cortisol feedback state governs adrenocorticotropin secretory-burst shape, frequency, and mass in a dual-waveform construct: time of day-dependent regulation Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2003; 285(5): R950 - R961. [Abstract] [Full Text] [PDF]

				E. B. Klerman, H. B. Gershengorn, J. F. Duffy, and R. E. Kronauer Comparisons of the Variability of Three Markers of the Human Circadian Pacemaker J Biol Rhythms, April 1, 2002; 17(2): 181 - 193. [Abstract] [PDF]

				J. D. Veldhuis, A. Iranmanesh, D. Naftolowitz, N. Tatham, F. Cassidy, and B. J. Carroll Corticotropin Secretory Dynamics in Humans under Low Glucocorticoid Feedback J. Clin. Endocrinol. Metab., November 1, 2001; 86(11): 5554 - 5563. [Abstract] [Full Text] [PDF]

				E. N. Brown, P. M. Meehan, and A. P. Dempster A stochastic differential equation model of diurnal cortisol patterns Am J Physiol Endocrinol Metab, March 1, 2001; 280(3): E450 - E461. [Abstract] [Full Text] [PDF]

				R. G. Veldman, M. Frölich, S. M. Pincus, J. D. Veldhuis, and F. Roelfsema Apparently Complete Restoration of Normal Daily Adrenocorticotropin, Cortisol, Growth Hormone, and Prolactin Secretory Dynamics in Adults with Cushing's Disease after Clinically Successful Transsphenoidal Adenomectomy J. Clin. Endocrinol. Metab., November 1, 2000; 85(11): 4039 - 4046. [Abstract] [Full Text]

				M. Bergendahl, A. Iranmanesh, T. Mulligan, and J. D. Veldhuis Impact of Age on Cortisol Secretory Dynamics Basally and as Driven by Nutrient-Withdrawal Stress J. Clin. Endocrinol. Metab., June 1, 2000; 85(6): 2203 - 2214. [Abstract] [Full Text]

				F. Chapotot, C. Gronfier, C. Jouny, A. Muzet, and G. Brandenberger Cortisol Secretion Is Related to Electroencephalographic Alertness in Human Subjects during Daytime Wakefulness J. Clin. Endocrinol. Metab., December 1, 1998; 83(12): 4263 - 4268. [Abstract] [Full Text]

				R. J. Windle, S. A. Wood, S. L. Lightman, and C. D. Ingram The Pulsatile Characteristics of Hypothalamo-Pituitary-Adrenal Activity in Female Lewis and Fischer 344 Rats and Its Relationship to Differential Stress Responses Endocrinology, October 1, 1998; 139(10): 4044 - 4052. [Abstract] [Full Text] [PDF]

				C. Gronfier, F. Chapotot, L. Weibel, C. Jouny, F. Piquard, and G. Brandenberger Pulsatile cortisol secretion and EEG delta waves are controlled by two independent but synchronized generators Am J Physiol Endocrinol Metab, July 1, 1998; 275(1): E94 - E100. [Abstract] [Full Text] [PDF]

				G. P. Chrousos Editorial: Ultradian, Circadian, and Stress-Related Hypothalamic-Pituitary-Adrenal Axis Activity--A Dynamic Digital-to-Analog Modulation Endocrinology, February 1, 1998; 139(2): 437 - 440. [Full Text] [PDF]

				R. J. Windle, S. A. Wood, N. Shanks, S. L. Lightman, and C. D. Ingram Ultradian Rhythm of Basal Corticosterone Release in the Female Rat: Dynamic Interaction with the Response to Acute Stress Endocrinology, February 1, 1998; 139(2): 443 - 450. [Abstract] [Full Text] [PDF]

				M. Stowasser, M. G. Gartside, W. L. Taylor, T. J. Tunny, and R. D. Gordon In Familial Hyperaldosteronism Type I, Hybrid Gene-Induced Aldosterone Production Dominates That Induced by Wild-Type Genes J. Clin. Endocrinol. Metab., November 1, 1997; 82(11): 3670 - 3676. [Abstract] [Full Text] [PDF]

				D. N. Orth Cushing's Syndrome N. Engl. J. Med., March 23, 1995; 332(12): 791 - 803. [Full Text] [PDF]

				J. A. Enyeart, L. Xu, and J. J. Enyeart A Bovine Adrenocortical Kv1.4 K+ Channel Whose Expression Is Potently Inhibited by ACTH J. Biol. Chem., October 27, 2000; 275(44): 34640 - 34649. [Abstract] [Full Text] [PDF]