Hypocortisolemic Clamp Unmasks Jointly Feedforward- and Feedback-dependent Control of Overnight ACTH Secretion

Overview

Journal Eur J Endocrinol

Publisher Oxford University Press

Specialty Endocrinology

Date 2008 Aug 21

PMID 18713842

Citations 8

Authors

Ali Iranmanesh

Johannes D Veldhuis

Affiliations

Soon will be listed here.

Abstract

Background: ACTH secretion is under hypothalamic stimulatory (feedforward) and adrenal inhibitory (feedback) control.

Hypothesis: Assessment of overnight ACTH secretion during a hypocortisolemic clamp will permit the estimation of changing feedforward and feedback.

Subjects: Seven healthy men.

Interventions: An oral dose of placebo (PLAC), metyrapone (METY, 3 g), or ketoconazole (KTCZ, 1.2 g) was given at midnight (MN) to block glucocorticoid synthesis. Plasma ACTH was sampled every 10 min (MN to 0800 h).

Analysis: Variable-waveform deconvolution analysis of ACTH secretion and approximate entropy (ApEn) analysis of pattern regularity.

Results: Compared with PLAC, administration of METY and KTCZ reduced morning cortisol concentrations by >or=77 and 54% respectively (P<0.001). Hypocortisolemia elevated pulsatile ACTH secretion by 8.2- (METY) and 5.3-fold (KTCZ; both P<0.001). Basal ACTH secretion rose by 3.4-fold under METY-induced cortisol depletion (P=0.020). ACTH secretory-burst shape and half-life were stable. ApEn of ACTH release declined overnight (P=0.021) and with the drug (P=0.001), denoting enhanced feedforward coordination.

Conclusion: The combined data predict overnight amplification and coordination of hypothalamic feedforward drive onto ACTH release. Therefore, disruption of either mechanism might contribute to clinical pathophysiology, such as late-day elevations of cortisol output in fasting, alcoholism, depression, or aging.

Citing Articles

Clamping Cortisol and Testosterone Mitigates the Development of Insulin Resistance during Sleep Restriction in Men.

Liu P, Lawrence-Sidebottom D, Piotrowska K, Zhang W, Iranmanesh A, Auchus R J Clin Endocrinol Metab. 2021; 106(9):e3436-e3448.

PMID: 34043794 PMC: 8660069. DOI: 10.1210/clinem/dgab375.

Interleukin-2 drives cortisol secretion in an age-, dose-, and body composition-dependent way.

Roelfsema F, Liu P, Yang R, Takahashi P, Veldhuis J Endocr Connect. 2020; 9(7):637-648.

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Enhanced Coupling Within Gonadotropic and Adrenocorticotropic Axes by Moderate Exercise in Healthy Men.

Roelfsema F, Yang R, Olson T, Joyner M, Takahashi P, Veldhuis J J Clin Endocrinol Metab. 2017; 102(7):2482-2490.

PMID: 28453740 PMC: 5505190. DOI: 10.1210/jc.2017-00036.

Pulsatile Cortisol Feedback on ACTH Secretion Is Mediated by the Glucocorticoid Receptor and Modulated by Gender.

Roelfsema F, Aoun P, Veldhuis J J Clin Endocrinol Metab. 2016; 101(11):4094-4102.

PMID: 27548106 PMC: 5095237. DOI: 10.1210/jc.2016-2405.

Impact of Adiposity and Fat Distribution on the Dynamics of Adrenocorticotropin and Cortisol Rhythms.

Roelfsema F, Pereira A, Veldhuis J Curr Obes Rep. 2015; 3(4):387-95.

PMID: 26626915 DOI: 10.1007/s13679-014-0118-7.

References

Carroll B, Cassidy F, Naftolowitz D, Tatham N, Wilson W, Iranmanesh A . Pathophysiology of hypercortisolism in depression. Acta Psychiatr Scand Suppl. 2007; (433):90-103. DOI: 10.1111/j.1600-0447.2007.00967.x. View

Luque R, Gahete M, Hochgeschwender U, Kineman R . Evidence that endogenous SST inhibits ACTH and ghrelin expression by independent pathways. Am J Physiol Endocrinol Metab. 2006; 291(2):E395-403. DOI: 10.1152/ajpendo.00038.2006. View

Iranmanesh A, Lizarralde G, Short D, Veldhuis J . Intensive venous sampling paradigms disclose high frequency adrenocorticotropin release episodes in normal men. J Clin Endocrinol Metab. 1990; 71(5):1276-83. DOI: 10.1210/jcem-71-5-1276. View

Pincus S, Gevers E, Robinson I, van den Berg G, Roelfsema F, Hartman M . Females secrete growth hormone with more process irregularity than males in both humans and rats. Am J Physiol. 1996; 270(1 Pt 1):E107-15. DOI: 10.1152/ajpendo.1996.270.1.E107. View

Keenan D, Roelfsema F, Biermasz N, Veldhuis J . Physiological control of pituitary hormone secretory-burst mass, frequency, and waveform: a statistical formulation and analysis. Am J Physiol Regul Integr Comp Physiol. 2003; 285(3):R664-73. DOI: 10.1152/ajpregu.00195.2003. View

Nickel W, Wieland F . Biosynthetic protein transport through the early secretory pathway. Histochem Cell Biol. 1998; 109(5-6):477-86. DOI: 10.1007/s004180050249. View

Veldhuis J, Straume M, Iranmanesh A, Mulligan T, Jaffe C, Barkan A . Secretory process regularity monitors neuroendocrine feedback and feedforward signaling strength in humans. Am J Physiol Regul Integr Comp Physiol. 2001; 280(3):R721-9. DOI: 10.1152/ajpregu.2001.280.3.R721. View

Horrocks P, Jones A, Ratcliffe W, Holder G, White A, Holder R . Patterns of ACTH and cortisol pulsatility over twenty-four hours in normal males and females. Clin Endocrinol (Oxf). 1990; 32(1):127-34. DOI: 10.1111/j.1365-2265.1990.tb03758.x. View

Pincus S, Hartman M, Roelfsema F, Thorner M, Veldhuis J . Hormone pulsatility discrimination via coarse and short time sampling. Am J Physiol. 1999; 277(5):E948-57. DOI: 10.1152/ajpendo.1999.277.5.E948. View

10.

von Zastrow M, Castle J . Protein sorting among two distinct export pathways occurs from the content of maturing exocrine storage granules. J Cell Biol. 1987; 105(6 Pt 1):2675-84. PMC: 2114720. DOI: 10.1083/jcb.105.6.2675. View

11.

Hartman M, Pincus S, Johnson M, Matthews D, Faunt L, Vance M . Enhanced basal and disorderly growth hormone secretion distinguish acromegalic from normal pulsatile growth hormone release. J Clin Invest. 1994; 94(3):1277-88. PMC: 295213. DOI: 10.1172/JCI117446. View

12.

Iranmanesh A, Veldhuis J, Johnson M, Lizarralde G . 24-hour pulsatile and circadian patterns of cortisol secretion in alcoholic men. J Androl. 1989; 10(1):54-63. DOI: 10.1002/j.1939-4640.1989.tb00062.x. View

13.

Van Cauter E, Leproult R, Kupfer D . Effects of gender and age on the levels and circadian rhythmicity of plasma cortisol. J Clin Endocrinol Metab. 1996; 81(7):2468-73. DOI: 10.1210/jcem.81.7.8675562. View

14.

Silva A, Schoeffter P, Weckbecker G, Bruns C, Schmid H . Regulation of CRH-induced secretion of ACTH and corticosterone by SOM230 in rats. Eur J Endocrinol. 2005; 153(3):R7-R10. DOI: 10.1530/eje.1.01998. View

15.

Labeur M, Arzt E, Stalla G, Paez-Pereda M . New perspectives in the treatment of Cushing's syndrome. Curr Drug Targets Immune Endocr Metabol Disord. 2004; 4(4):335-42. DOI: 10.2174/1568008043339703. View

16.

Veldhuis J, Iranmanesh A, Johnson M, Lizarralde G . Twenty-four-hour rhythms in plasma concentrations of adenohypophyseal hormones are generated by distinct amplitude and/or frequency modulation of underlying pituitary secretory bursts. J Clin Endocrinol Metab. 1990; 71(6):1616-23. DOI: 10.1210/jcem-71-6-1616. View

17.

Rivier C, Vale W . Modulation of stress-induced ACTH release by corticotropin-releasing factor, catecholamines and vasopressin. Nature. 1983; 305(5932):325-7. DOI: 10.1038/305325a0. View

18.

Veldhuis J, Metzger D, Martha Jr P, Mauras N, Kerrigan J, Keenan B . Estrogen and testosterone, but not a nonaromatizable androgen, direct network integration of the hypothalamo-somatotrope (growth hormone)-insulin-like growth factor I axis in the human: evidence from pubertal pathophysiology and sex-steroid hormone.... J Clin Endocrinol Metab. 1997; 82(10):3414-20. DOI: 10.1210/jcem.82.10.4317. View

19.

Peterfreund R, Vale W . Ovine corticotropin-releasing factor stimulates somatostatin secretion from cultured brain cells. Endocrinology. 1983; 112(4):1275-8. DOI: 10.1210/endo-112-4-1275. View

20.

Erkut Z, Pool C, Swaab D . Glucocorticoids suppress corticotropin-releasing hormone and vasopressin expression in human hypothalamic neurons. J Clin Endocrinol Metab. 1998; 83(6):2066-73. DOI: 10.1210/jcem.83.6.4881. View