Production of the Neurosteroid 3alpha-Hydroxy-5alpha-pregnan-20-one in Man

Abstract The narcotically active progesterone metabolite 3alpha-hydroxy-5alpha-pregnan-20-one (HPO) modulates gamma-aminobutyric acid (GABA) neurotransmission by direct actions on the GABA(A)-receptor complex. In the present investigation, the formation of HPO was quantified in man. Twenty-four h urine samples were collected during the night (2300 to 0700 h) and day (0700 to 2300 h) from 11 healthy subjects (31 +/- 5 years) for two consecutive days. The concentration of HPO was measured after enzymatic hydrolysis of conjugated HPO and multiple chromatographic separation steps by gas chromatography-mass spectrometry. The mean excretion rates of HPO were 14.8 +/- 11.8 mug/24 h with high inter-individual variations. There were no significant differences in the production of HPO during the night and day. It seemed unlikely that HPO was primarily formed in the adrenals or gonads since the excretion rates of HPO poorly correlated with the formation of 17-ketosteroids or 17-hydroxycorticosteroids that are widely used as indices of adrenal and gonadal steroid production. The data showed for the first time that HPO is produced in male subjects in concentrations similar to that of classical steroid hormones.