Hypothalamic-pituitary-adrenal axis reactivity in chronic fatigue syndrome and health under psychological, physiological, and pharmacological stimulation

Psychosom Med. Nov-Dec 2002;64(6):951-62. doi: 10.1097/01.psy.0000038937.67401.61.


Objectives: Subtle alterations of the hypothalamic-pituitary-adrenal (HPA) axis in chronic fatigue syndrome (CFS) have been proposed as a shared pathway linking numerous etiological and perpetuating processes with symptoms and observed physiological abnormalities. Because the HPA axis is involved in the adaptive responses to stress and CFS patients experience a worsening of symptoms after physical and psychological stress, we tested HPA axis functioning with three centrally acting stress tests.

Methods: We used two procedures mimicking real-life stressors and compared them with a standardized pharmacological neuroendocrine challenge test. CFS patients were compared with healthy control subjects regarding their cardiovascular and endocrine reactivity in a psychosocial stress test and a standardized exercise test, and their endocrine response in the insulin tolerance test (ITT).

Results: Controlling for possible confounding variables, we found significantly lower ACTH response levels in the psychosocial stress test and the exercise test, and significantly lower ACTH responses in the ITT, with no differences in plasma total cortisol responses. Also, salivary-free cortisol responses did not differ between the groups in the psychosocial stress test and the exercise test but were significantly higher for the CFS patients in the ITT. In all tests CFS patients had significantly reduced baseline ACTH levels.

Conclusions: These results suggest that CFS patients are capable of mounting a sufficient cortisol response under different types of stress but that on a central level subtle dysregulations of the HPA axis exist.

MeSH terms

  • Adult
  • Analysis of Variance
  • Area Under Curve
  • Blood Glucose / drug effects
  • Endocrine Glands / physiopathology
  • Exercise Test / psychology
  • Fatigue Syndrome, Chronic / physiopathology*
  • Fatigue Syndrome, Chronic / psychology*
  • Female
  • Heart Rate / physiology
  • Humans
  • Hypothalamo-Hypophyseal System / physiopathology*
  • Insulin / administration & dosage*
  • Male
  • Middle Aged
  • Pituitary-Adrenal System / physiopathology*
  • Psychometrics / statistics & numerical data
  • Stress, Physiological / physiopathology*
  • Stress, Physiological / psychology*
  • Stress, Psychological / physiopathology*
  • Stress, Psychological / psychology*
  • Time Factors


  • Blood Glucose
  • Insulin