Production rates and metabolism of sulphates of 3β-hydroxy-5α-pregnane derivatives in pregnant women

Abstract

The metabolism and production rates of 3β-hydroxy-5α-pregnan-20-one sulphate and the 3- and 3,20-sulphates of 5α-pregnane-3β,20α-diol in pregnant women were studied. These steroids labelled with deuterium in the 3α,11,11- or 3α,11,11,20β-positions were injected intravenously, and the deuterium content of 13 steroids in the mono- and disulphate fractions from blood samples drawn at different times after the injection was determined by gas chromatography-mass spectrometry. Three types of metabolic reactions were observed: oxidoreduction at C-20, 16α-hydroxylation and sulphoconjugation at C-20. No evidence was obtained for a metabolic sequence involving hydrolysis, oxidoreduction and resulphation at the C-3 position. Production rates and rates of metabolic transformations were determined using different two-pool models with and without compensation for the pool expansions caused by injection of the labelled steroids. The production rate of the pregnanolone/pregnanediol monosulphate couple was about 75–100 μmol × 24h −1. In three of the four subjects, the main entry of new material was into the pregnanolone sulphate pool. The half-life times for oxidation and reduction at C-20 were roughly 0.5 h and 0.2 h, respectively, as compared to half-life times of 2.6–3.1 h for turnover of the steroid skeleton. About 10–15% of the pregnanolone/pregnanediol monosulphates became 16α-hydroxylated, the 20-ketosteroid sulphate being the preferred substrate in this reaction. The hydroxylated steroids also underwent oxidoreduction at C-20. 5α-Pregnane-3β,20α-diol disulphate was a metabolic end product accounting for 50% or more of the metabolism of the pregnanolone/pregnanediol monosulphates in four of the six subjects. Its half-life time was between 5 and 11 h. The steroid sulphates studied in this investigation may account for about 10% of progesterone metabolism in pregnancy, a possibility which is discussed in relation to published values for the excretion of pregnanolone, pregnanediol and pregnanetriol isomers in urine and faeces.