Regulation of pulsatile and entropic ACTH secretion under fixed exogenous secretagogue clamps

Ferdinand Roelfsema, Paul Aoun, Paul Y Takahashi, Dana Erickson, Rebecca Yang, Johannes D Veldhuis

Research output: Contribution to journalArticle

Abstract

Background: Adrenocorticotropic hormone (ACTH) secretion is controlled by unobservable hypothalamic corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) pulses. Clamping exogenous CRH or AVP input could allow indirect quantification of the impact of the endogenous heterotypic hormone. Methods: We conducted a randomized, double-blind, placebo-controlled, crossover study in 28 healthy adults (16 men). Volunteers underwent a sex-steroid clamp and a cortisol clamp. ACTH was measured over 10 hours by 10-minute sampling during each of four randomized intravenous (IV) secretagogue clamps (i.e., continuous IV CRH, AVP, both peptides, or saline). Desensitization was tested by bolus injection of the noninfused peptide. Results: Mean 6 standard error of the mean 10-hour ACTH concentrations (ng/L) in the sexcombined analysis were: saline, 32 6 4.6; AVP, 29 6 4.6; CRH, 67 6 6.2; and CRH-AVP, 67 6 8.8 (any CRH vs AVP or saline, P , 0.0001). CRH and AVP increased approximate entropy (relative randomness) of ACTH release (P , 0.0001). Bolus AVP injection after CRH infusion yielded a 2.5-hour ACTH concentration of 4664.3, exceeding that seen after bolus CRH or saline injection (2663.3 and 24 6 3.6, respectively; P = 0.002 and 0.001). Sex hormone clamps did not influence ACTH levels. Conclusions: A CRH, but not AVP, clamp yields sustained pulsatile ACTH secretion with high ACTH secretory-burst mass and randomness. After 10-hour CRH infusion, bolus AVP but not CRH, evoked marked ACTH release, likely caused by heterotypic sensitization of corticotropes by CRH. Similar interactions mightunderlie chronic stress states.

Original languageEnglish (US)
Pages (from-to)2611-2619
Number of pages9
JournalJournal of Clinical Endocrinology and Metabolism
Volume102
Issue number7
DOIs
StatePublished - Jul 1 2017

Fingerprint

Corticotropin-Releasing Hormone
Clamping devices
Adrenocorticotropic Hormone
Arginine Vasopressin
Injections
Pituitary Hormone-Releasing Hormones
Peptides
Gonadal Steroid Hormones
Entropy
Constriction
Cross-Over Studies
Hydrocortisone
Volunteers
Steroids
Placebos

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

Cite this

Regulation of pulsatile and entropic ACTH secretion under fixed exogenous secretagogue clamps. / Roelfsema, Ferdinand; Aoun, Paul; Takahashi, Paul Y; Erickson, Dana; Yang, Rebecca; Veldhuis, Johannes D.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 102, No. 7, 01.07.2017, p. 2611-2619.

Research output: Contribution to journalArticle

Roelfsema, Ferdinand ; Aoun, Paul ; Takahashi, Paul Y ; Erickson, Dana ; Yang, Rebecca ; Veldhuis, Johannes D. / Regulation of pulsatile and entropic ACTH secretion under fixed exogenous secretagogue clamps. In: Journal of Clinical Endocrinology and Metabolism. 2017 ; Vol. 102, No. 7. pp. 2611-2619.
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abstract = "Background: Adrenocorticotropic hormone (ACTH) secretion is controlled by unobservable hypothalamic corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) pulses. Clamping exogenous CRH or AVP input could allow indirect quantification of the impact of the endogenous heterotypic hormone. Methods: We conducted a randomized, double-blind, placebo-controlled, crossover study in 28 healthy adults (16 men). Volunteers underwent a sex-steroid clamp and a cortisol clamp. ACTH was measured over 10 hours by 10-minute sampling during each of four randomized intravenous (IV) secretagogue clamps (i.e., continuous IV CRH, AVP, both peptides, or saline). Desensitization was tested by bolus injection of the noninfused peptide. Results: Mean 6 standard error of the mean 10-hour ACTH concentrations (ng/L) in the sexcombined analysis were: saline, 32 6 4.6; AVP, 29 6 4.6; CRH, 67 6 6.2; and CRH-AVP, 67 6 8.8 (any CRH vs AVP or saline, P , 0.0001). CRH and AVP increased approximate entropy (relative randomness) of ACTH release (P , 0.0001). Bolus AVP injection after CRH infusion yielded a 2.5-hour ACTH concentration of 4664.3, exceeding that seen after bolus CRH or saline injection (2663.3 and 24 6 3.6, respectively; P = 0.002 and 0.001). Sex hormone clamps did not influence ACTH levels. Conclusions: A CRH, but not AVP, clamp yields sustained pulsatile ACTH secretion with high ACTH secretory-burst mass and randomness. After 10-hour CRH infusion, bolus AVP but not CRH, evoked marked ACTH release, likely caused by heterotypic sensitization of corticotropes by CRH. Similar interactions mightunderlie chronic stress states.",
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T1 - Regulation of pulsatile and entropic ACTH secretion under fixed exogenous secretagogue clamps

AU - Roelfsema, Ferdinand

AU - Aoun, Paul

AU - Takahashi, Paul Y

AU - Erickson, Dana

AU - Yang, Rebecca

AU - Veldhuis, Johannes D

PY - 2017/7/1

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N2 - Background: Adrenocorticotropic hormone (ACTH) secretion is controlled by unobservable hypothalamic corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) pulses. Clamping exogenous CRH or AVP input could allow indirect quantification of the impact of the endogenous heterotypic hormone. Methods: We conducted a randomized, double-blind, placebo-controlled, crossover study in 28 healthy adults (16 men). Volunteers underwent a sex-steroid clamp and a cortisol clamp. ACTH was measured over 10 hours by 10-minute sampling during each of four randomized intravenous (IV) secretagogue clamps (i.e., continuous IV CRH, AVP, both peptides, or saline). Desensitization was tested by bolus injection of the noninfused peptide. Results: Mean 6 standard error of the mean 10-hour ACTH concentrations (ng/L) in the sexcombined analysis were: saline, 32 6 4.6; AVP, 29 6 4.6; CRH, 67 6 6.2; and CRH-AVP, 67 6 8.8 (any CRH vs AVP or saline, P , 0.0001). CRH and AVP increased approximate entropy (relative randomness) of ACTH release (P , 0.0001). Bolus AVP injection after CRH infusion yielded a 2.5-hour ACTH concentration of 4664.3, exceeding that seen after bolus CRH or saline injection (2663.3 and 24 6 3.6, respectively; P = 0.002 and 0.001). Sex hormone clamps did not influence ACTH levels. Conclusions: A CRH, but not AVP, clamp yields sustained pulsatile ACTH secretion with high ACTH secretory-burst mass and randomness. After 10-hour CRH infusion, bolus AVP but not CRH, evoked marked ACTH release, likely caused by heterotypic sensitization of corticotropes by CRH. Similar interactions mightunderlie chronic stress states.

AB - Background: Adrenocorticotropic hormone (ACTH) secretion is controlled by unobservable hypothalamic corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) pulses. Clamping exogenous CRH or AVP input could allow indirect quantification of the impact of the endogenous heterotypic hormone. Methods: We conducted a randomized, double-blind, placebo-controlled, crossover study in 28 healthy adults (16 men). Volunteers underwent a sex-steroid clamp and a cortisol clamp. ACTH was measured over 10 hours by 10-minute sampling during each of four randomized intravenous (IV) secretagogue clamps (i.e., continuous IV CRH, AVP, both peptides, or saline). Desensitization was tested by bolus injection of the noninfused peptide. Results: Mean 6 standard error of the mean 10-hour ACTH concentrations (ng/L) in the sexcombined analysis were: saline, 32 6 4.6; AVP, 29 6 4.6; CRH, 67 6 6.2; and CRH-AVP, 67 6 8.8 (any CRH vs AVP or saline, P , 0.0001). CRH and AVP increased approximate entropy (relative randomness) of ACTH release (P , 0.0001). Bolus AVP injection after CRH infusion yielded a 2.5-hour ACTH concentration of 4664.3, exceeding that seen after bolus CRH or saline injection (2663.3 and 24 6 3.6, respectively; P = 0.002 and 0.001). Sex hormone clamps did not influence ACTH levels. Conclusions: A CRH, but not AVP, clamp yields sustained pulsatile ACTH secretion with high ACTH secretory-burst mass and randomness. After 10-hour CRH infusion, bolus AVP but not CRH, evoked marked ACTH release, likely caused by heterotypic sensitization of corticotropes by CRH. Similar interactions mightunderlie chronic stress states.

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