Fatigue is one of the most common non-specific symptoms associated with several disease states including
liver diseases. Recently, it was reported that levels of
progesterone metabolites such as
allopregnanolone (3alpha,5alpha-tetrahydroprogesterone; 3alpha,5alpha-THP) and isopregnanolone (3beta,5alpha-THP) were increased in plasma of patients with
chronic fatigue syndrome. We hypothesize that THP metabolites might be associated with
fatigue commonly observed in chronic
liver diseases. We evaluated
fatigue scores and plasma levels of five
progesterone metabolites in 16 patients with
primary biliary cirrhosis (PBC), 12 patients with
chronic hepatitis C (CHC) and 11 age-matched controls. The
fatigue impact scale (FIS) ratio was significantly increased (P < 0.01) in patients with PBC and CHC compared to controls. Plasma levels of 3alpha,5alpha-THP and
pregnanolone (3alpha,5beta-THP) were significantly increased in PBC and CHC patients. The other
progesterone metabolites, i.e. 3beta,5alpha-THP, 3beta,5beta-THP and 3alpha,5alpha-tetrahydrodeoxycorticosterone were either undetectable or detected only in some patients. Plasma levels of 3alpha,5alpha-THP and 3alpha,5beta-THP were found to be significantly higher in patients with
fatigue (P < 0.05), while those of patients without
fatigue were not significantly different from controls. Both 3alpha,5alpha-THP and 3alpha,5beta-THP are positive allosteric modulators of the
gamma-aminobutyric acid type A (
GABA-A) receptor and readily cross the blood-brain barrier. The present preliminary findings suggest that increased inhibition through
GABA-A receptors due to the accumulation of neuroinhibitory
steroids may represent an important pathophysiological mechanism of
fatigue in chronic
liver diseases.