Circadian endocrine rhythms: the hypothalamic-pituitary-adrenal axis and its actions

Ann N Y Acad Sci. 2014 May:1318:71-80. doi: 10.1111/nyas.12464.


The stress system effectively restores the internal balance--or homeostasis--of living organisms in the face of random external or internal changes, the stressors. This highly complex system helps organisms to provide a series of neuroendocrine responses to stressors--the stress response--through coordinated activation of the hypothalamic-pituitary-adrenal (HPA) axis and the locus coeruleus/norepinephrine autonomic nervous systems. In addition to stressors, life is influenced by daily light/dark changes due to the 24-h rotation of Earth. To adjust to these recurrent day/night cycles, the biological clock system employs the heterodimer of transcription factors circadian locomotor output cycle kaput/brain-muscle-arnt-like protein 1 (CLOCK/BMAL1), along with a set of other transcription factors, to regulate the circadian pattern of gene expression. Interestingly, the stress system, through the HPA axis, communicates with the clock system; therefore, any uncoupling or dysregulation could potentially cause several disorders, such as metabolic, autoimmune, and mood disorders. In this review, we discuss the biological function of the two systems, their interactions, and the clinical implications of their dysregulation or uncoupling.

Keywords: HPA axis; acetylation; circadian clock system; glucocorticoid receptor; glucocorticoids.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • ARNTL Transcription Factors / metabolism
  • Animals
  • CLOCK Proteins / metabolism
  • Circadian Rhythm*
  • Gene Expression Regulation
  • Glucocorticoids / physiology
  • Humans
  • Hypothalamo-Hypophyseal System / physiology*
  • Pituitary-Adrenal System / physiology*
  • Receptors, Glucocorticoid / genetics
  • Receptors, Glucocorticoid / metabolism


  • ARNTL Transcription Factors
  • ARNTL protein, human
  • Glucocorticoids
  • Receptors, Glucocorticoid
  • CLOCK Proteins
  • CLOCK protein, human