This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart 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 Roelfsema, F. Articles by Veldhuis, J. D. Search for Related Content PubMed PubMed Citation Articles by Roelfsema, F. Articles by Veldhuis, J. D.

Patients with Cushing’s Disease Secrete Adrenocorticotropin and Cortisol Jointly More Asynchronously than Healthy Subjects

Department of Endocrinology (F.R), Leiden University Medical Center, Leiden 2333AA, The Netherlands; Guilford, Connecticut (S.M.P.); Department of Medicine, National Science Foundation Center for Biological Timing, University of Virginia Health Sciences Center (J.D.V.), Charlottesville, Virginia 22908

Address correspondence and requests for reprints to: Dr. F. Roelfsema, Department of Endocrinology, Leiden University Medical Center, Albinusdreef 2, 2333AA, Leiden, The Netherlands. E-mail: roelfsema{at}rullf2.MedFac.LeidenUniv.nl

We examined serum concentration time-series for ACTH and cortisol in 20 patients with pituitary-dependent ACTH excess (Cushing’s disease) and in 29 age- and gender-matched controls. For each subject, blood samples were obtained at 10-min intervals for 24 h. Joint ACTH-cortisol synchrony was quantified using the recently introduced cross-approximate entropy (cross-ApEn) statistic. In patients, cross-ApEn was greater than in controls (1.686 ± 0.051 vs. 1.077 ± 0.039, P = 3.45 x 10^-16), giving a sensitivity of 85%. In control subjects, but not in patients, cross-ApEn was correlated positively with age (r = 0.465, P = 0.011) There was no gender difference in cross-ApEn, nor a relationship between cross-ApEn and the 24-h ACTH and cortisol secretion, in patients or controls. In contrast, the maximal cross- correlation coefficient for the ACTH and cortisol series after detrending the series was 0.394 ± 0.033 in controls and 0.297 ± 0.034 in patients with considerable overlap of the subgroups, giving a sensitivity for this index of only 5%. In addition to previous findings of increased individual irregularity of ACTH and cortisol release in Cushing’s disease, we can now also demonstrate greater joint asynchrony of the circulating concentrations of these hormones. Thus, Cushing’s disease disrupts ensemble network secretory dynamics over individual hormone output. We conclude that, like GH-secreting pituitary and aldosterone-secreting adrenal tumors, ACTH-secreting pituitary tumors exhibit significant loss of orderly hormone release patterns. Moreover, Cushing’s disease is marked further by deterioriation of bihormonal synchrony between ACTH and cortisol release, thus suggesting further erosion of within-axis feedback control.

This article has been cited by other articles:

				D. L. Waters, C. R. Qualls, R. I. Dorin, J. D. Veldhuis, and R. N. Baumgartner Altered Growth Hormone, Cortisol, and Leptin Secretion in Healthy Elderly Persons With Sarcopenia and Mixed Body Composition Phenotypes J. Gerontol. A Biol. Sci. Med. Sci., May 1, 2008; 63(5): 536 - 541. [Abstract] [Full Text] [PDF]

				J M Hanson, H S Kooistra, J A Mol, E Teske, and B P Meij Plasma profiles of adrenocorticotropic hormone, cortisol, {alpha}-melanocyte-stimulating hormone, and growth hormone in dogs with pituitary-dependent hyperadrenocorticism before and after hypophysectomy. J. Endocrinol., September 1, 2006; 190(3): 601 - 609. [Abstract] [Full Text] [PDF]

				P. Y. Liu, S. M. Pincus, P. Y. Takahashi, P. D. Roebuck, A. Iranmanesh, D. M. Keenan, and J. D. Veldhuis Aging attenuates both the regularity and joint synchrony of LH and testosterone secretion in normal men: analyses via a model of graded GnRH receptor blockade Am J Physiol Endocrinol Metab, January 1, 2006; 290(1): E34 - E41. [Abstract] [Full Text] [PDF]

				P. Y. Liu, S. M. Pincus, D. M. Keenan, F. Roelfsema, and J. D. Veldhuis Joint synchrony of reciprocal hormonal signaling in human paradigms of both ACTH excess and cortisol depletion Am J Physiol Endocrinol Metab, July 1, 2005; 289(1): E160 - E165. [Abstract] [Full Text] [PDF]

				S. W. Kok, F. Roelfsema, S. Overeem, G. J. Lammers, M. Frolich, A. E. Meinders, and H. Pijl Altered setting of the pituitary-thyroid ensemble in hypocretin-deficient narcoleptic men Am J Physiol Endocrinol Metab, May 1, 2005; 288(5): E892 - E899. [Abstract] [Full Text] [PDF]

				M. O. van Aken, A. M Pereira, S. W. van Thiel, G. van den Berg, M. Frolich, J. D. Veldhuis, J. A. Romijn, and F. Roelfsema Irregular and Frequent Cortisol Secretory Episodes with Preserved Diurnal Rhythmicity in Primary Adrenal Cushing's Syndrome J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1570 - 1577. [Abstract] [Full Text] [PDF]

				P. Y. Liu, S. M. Pincus, D. M. Keenan, F. Roelfsema, and J. D. Veldhuis Analysis of bidirectional pattern synchrony of concentration-secretion pairs: implementation in the human testicular and adrenal axes Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2005; 288(2): R440 - R446. [Abstract] [Full Text] [PDF]

				M. O. van Aken, A. M. Pereira, M. Frolich, J. A. Romijn, H. Pijl, J. D. Veldhuis, and F. Roelfsema Growth hormone secretion in primary adrenal Cushing's syndrome is disorderly and inversely correlated with body mass index Am J Physiol Endocrinol Metab, January 1, 2005; 288(1): E63 - E70. [Abstract] [Full Text] [PDF]

				S. W. Kok, F. Roelfsema, S. Overeem, G. J. Lammers, M. Frolich, A. E. Meinders, and H. Pijl Pulsatile LH release is diminished, whereas FSH secretion is normal, in hypocretin-deficient narcoleptic men Am J Physiol Endocrinol Metab, October 1, 2004; 287(4): E630 - E636. [Abstract] [Full Text] [PDF]

				D. M. Keenan, F. Roelfsema, and J. D. Veldhuis Endogenous ACTH concentration-dependent drive of pulsatile cortisol secretion in the human Am J Physiol Endocrinol Metab, October 1, 2004; 287(4): E652 - E661. [Abstract] [Full Text] [PDF]

				E. Charmandari, S. M. Pincus, D. R. Matthews, A. Johnston, C. G. D. Brook, and P. C. Hindmarsh Oral Hydrocortisone Administration in Children with Classic 21-Hydroxylase Deficiency Leads to More Synchronous Joint GH and Cortisol Secretion J. Clin. Endocrinol. Metab., May 1, 2002; 87(5): 2238 - 2244. [Abstract] [Full Text] [PDF]

				J. Lado-Abeal, J. D. Veldhuis, and R. L. Norman Glucose Relays Information Regarding Nutritional Status to the Neural Circuits That Control the Somatotropic, Corticotropic, and Gonadotropic Axes in Adult Male Rhesus Macaques Endocrinology, February 1, 2002; 143(2): 403 - 410. [Abstract] [Full Text] [PDF]

				N. Porksen, M. Hollingdal, C. Juhl, P. Butler, J. D. Veldhuis, and O. Schmitz Pulsatile Insulin Secretion: Detection, Regulation, and Role in Diabetes Diabetes, February 1, 2002; 51(90001): S245 - 254. [Abstract] [Full Text] [PDF]

				I. Clarke, L. Moore, and J. Veldhuis Intensive Direct Cavernous Sinus Sampling Identifies High-Frequency, Nearly Random Patterns of FSH Secretion in Ovariectomized Ewes: Combined Appraisal by RIA and Bioassay Endocrinology, January 1, 2002; 143(1): 117 - 129. [Abstract] [Full Text] [PDF]

				M. S. Gill, V. Tillmann, J. D. Veldhuis, and P. E. Clayton Patterns of GH Output and Their Synchrony with Short-Term Height Increments Influence Stature and Growth Performance in Normal Children J. Clin. Endocrinol. Metab., December 1, 2001; 86(12): 5860 - 5863. [Abstract] [Full Text] [PDF]

				J. D. Veldhuis, M. L. Johnson, O. L. Veldhuis, M. Straume, and S. M. Pincus Impact of pulsatility on the ensemble orderliness (approximate entropy) of neurohormone secretion Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2001; 281(6): R1975 - R1985. [Abstract] [Full Text] [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]

				D. M. Keenan and J. D. Veldhuis Hypothesis testing of the aging male gonadal axis via a biomathematical construct Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2001; 280(6): R1755 - R1771. [Abstract] [Full Text] [PDF]

				J. A. Gusenoff, S. M. Harman, J. D. Veldhuis, J. J. Jayme, C. St. Clair, T. Munzer, C. Christmas, K. G. O'Connor, T. E. Stevens, M. F. Bellantoni, et al. Cortisol and GH secretory dynamics, and their interrelationships, in healthy aged women and men Am J Physiol Endocrinol Metab, April 1, 2001; 280(4): E616 - E625. [Abstract] [Full Text] [PDF]

				J. D. Veldhuis, M. Straume, A. Iranmanesh, T. Mulligan, C. Jaffe, A. Barkan, M. L. Johnson, and S. Pincus Secretory process regularity monitors neuroendocrine feedback and feedforward signaling strength in humans Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2001; 280(3): R721 - R729. [Abstract] [Full Text] [PDF]

				J. D. Veldhuis, S. M. Pincus, R. Mitamura, K. Yano, N. Suzuki, Y. Ito, Y. Makita, and A. Okuno Developmentally Delimited Emergence of More Orderly Luteinizing Hormone and Testosterone Secretion during Late Prepuberty in Boys J. Clin. Endocrinol. Metab., January 1, 2001; 86(1): 80 - 89. [Abstract] [Full Text]

				M. Bergendahl, A. Iranmanesh, C. Pastor, W. S. Evans, and J. D. Veldhuis Homeostatic Joint Amplification of Pulsatile and 24-Hour Rhythmic Cortisol Secretion by Fasting Stress in Midluteal Phase Women: Concurrent Disruption of Cortisol-Growth Hormone, Cortisol-Luteinizing Hormone, and Cortisol-Leptin Synchrony J. Clin. Endocrinol. Metab., November 1, 2000; 85(11): 4028 - 4035. [Abstract] [Full Text]

				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]

				J. D. Veldhuis, A. Iranmanesh, M. Godschalk, and T. Mulligan Older Men Manifest Multifold Synchrony Disruption of Reproductive Neurohormone Outflow J. Clin. Endocrinol. Metab., April 1, 2000; 85(4): 1477 - 1486. [Abstract] [Full Text]

				M. Bergendahl, A. Iranmanesh, W. S. Evans, and J. D. Veldhuis Short-Term Fasting Selectively Suppresses Leptin Pulse Mass and 24-Hour Rhythmic Leptin Release in Healthy Midluteal Phase Women without Disturbing Leptin Pulse Frequency or Its Entropy Control (Pattern Orderliness) J. Clin. Endocrinol. Metab., January 1, 2000; 85(1): 207 - 213. [Abstract] [Full Text]

				M. Bergendahl, W. S. Evans, C. Pastor, A. Patel, A. Iranmanesh, and J. D. Veldhuis Short-Term Fasting Suppresses Leptin and (Conversely) Activates Disorderly Growth Hormone Secretion in Midluteal Phase Women--A Clinical Research Center Study J. Clin. Endocrinol. Metab., March 1, 1999; 84(3): 883 - 894. [Abstract] [Full Text]

				A. Giustina and J. D. Veldhuis Pathophysiology of the Neuroregulation of Growth Hormone Secretion in Experimental Animals and the Human Endocr. Rev., December 1, 1998; 19(6): 717 - 797. [Abstract] [Full Text]