Elevated levels of some neuroactive progesterone metabolites, particularly isopregnanolone, in women with chronic fatigue syndrome

• Published in: Psychoneuroendocrinology Vol. 29; no. 2; pp. 245 - 268
• Main Authors: Murphy, B.E.Pearson, Abbott, F.V., Allison, C.M., Watts, C., Ghadirian, A.-M.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.02.2004; Elsevier
• Subjects: Adult; Analysis of Variance; Antidepressive Agents - pharmacology; Antidepressive Agents - therapeutic use; Behavioral psychophysiology; Biological and medical sciences; Chronic fatigue syndrome; Depression; Epipregnanolone; Fatigue Syndrome, Chronic - blood; Fatigue Syndrome, Chronic - drug therapy; Female; Fundamental and applied biological sciences. Psychology; Hormones and behavior; Humans; Isopregnanolone; Matched-Pair Analysis; Middle Aged; Ovarian Follicle - metabolism; Pregnanedione; Pregnanolone; Pregnanolone - blood; Pregnenolone; Progesterone; Progesterone - blood; Psychology. Psychoanalysis. Psychiatry; Psychology. Psychophysiology; Psychotropic Drugs - pharmacology; Psychotropic Drugs - therapeutic use; Reference Values; Isopregnanolone; Pregnanedione; Depression; Progesterone; Pregnanolone; Epipregnanolone; Chronic fatigue syndrome; Pregnenolone; Mood disorder; Human; Healthy subject; Evaluation scale; Metabolite; Ovarian hormone; Investigation method; Female; Sex steroid hormone; Comparative study
• DOI: 10.1016/S0306-4530(03)00026-X
• ISSN: 0306-4530

Chronic fatigue syndrome (CFS) is a controversial entity whose cause is unknown. In this study we have explored the possibility that progesterone metabolites may be involved. Plasma levels of the progesterone precursor pregnenolone, progesterone itself, and five ring A-reduced metabolites of progesterone were measured in 20 women with CFS and in 13 age-matched controls. To minimize the contribution of the ovary, women were either post-menopausal or in the follicular phase of the menstrual cycle (day 4–8), and progesterone levels were all well within the expected range (≤3.5 nmol/l). Mean values for progesterone and all of its metabolites were higher in CFS patients, the most marked being a 2.3-fold elevation in isopregnanolone (3β,5α-tetrahydroprogesterone; p≤0.001). Progesterone levels were correlated with those of its metabolites, but even after controlling for progesterone by ANCOVA, isopregnanolone levels were still elevated ( p≤0.001). These elevated levels of isopregnanolone could not be attributed to medications (antidepressants and anxiolytics). When the CFS patients were divided into two groups according to their Hamilton depression scale ratings, mean (±SD) isopregnanolone levels were higher (274±160 vs 197±119 pmol/l) in the less depressed group (ratings 2–14) than in the more depressed group (ratings 17–28), although this difference did not reach significance. Progesterone levels were negatively correlated with Hamilton depression rating scores ( r=−0.56; p<0.01). These results suggest that increases in ring A-reduced progesterone metabolites, particularly isopregnanolone, are associated with CFS, and that the pathophysiology of CFS is unlikely to be due to depression.