Pathophysiology of hypercortisolism in depression: pituitary and adrenal responses to low glucocorticoid feedback.

Journal Article (Journal Article)

OBJECTIVE: To test three theories of hypercortisolemia in depression-hypothalamic overdrive, impaired glucocorticoid feedback, or autonomous cortisol production. METHOD: We applied an overnight low-cortisol feedback strategy by administering metyrapone to hypercortisolemic depressed in-patients and control subjects. RESULTS: Under metyrapone, the increases of plasma adrenocorticotropic hormone (ACTH) concentrations and of basal and pulsatile ACTH secretion were not exaggerated in hypercortisolemic depressed patients compared with control subjects. ACTH approximate entropy (ApEn) did not differ at baseline or under metyrapone. Thus, neither hypothalamic overdrive nor irregular ACTH secretion was seen. We did not detect impaired cortisol feedback: the ACTH response was not reduced, and ApEn measures that are sensitive to feedback changes were comparable in both groups. Metyrapone disrupted cortisol secretory regularity in depressed and control subjects. On the baseline day, basal cortisol secretion was significantly increased and was highly irregular (high ApEn), and ACTH-cortisol cross-ApEn was markedly elevated in high-cortisol patients. CONCLUSION: Classical feed-forward overdrive and impaired feedback theories of hypercortisolemia in depression were not supported. Depressive hypercortisolemia may result from alternative pathophysiological mechanisms involving irregular basal hypersecretion of cortisol, associated with adrenal enlargement, possibly through splanchnic sympathetic activation of the adrenal cortex.

Full Text

Duke Authors

Cited Authors

  • Carroll, BJ; Iranmanesh, A; Keenan, DM; Cassidy, F; Wilson, WH; Veldhuis, JD

Published Date

  • June 2012

Published In

Volume / Issue

  • 125 / 6

Start / End Page

  • 478 - 491

PubMed ID

  • 22211368

Pubmed Central ID

  • PMC3893569

Electronic International Standard Serial Number (EISSN)

  • 1600-0447

Digital Object Identifier (DOI)

  • 10.1111/j.1600-0447.2011.01821.x


  • eng

Conference Location

  • United States