PROFILES OF BILE-ACIDS AND PROGESTERONE METABOLITES IN THE URINE AND SERUM OF WOMEN WITH INTRAHEPATIC CHOLESTASIS OF PREGNANCY

Background/Aims and Methods: The etiology of intrahepatic cholestasis of pregnancy (ICP) is unknown. We have performed comprehensive chromat ographic and mass spectrometric analyses of progesterone metabolites a nd bile acids in serum and urine of six patients in order to character ize changes that might be of importance for the development of the dis ease. Results: Conjugated bile acids were increased in serum and urine of patients with ICP while the levels of unconjugated bile acids were similar in healthy pregnancies and ICP. Unconjugated and conjugated 7 alpha,12 alpha-dihydroxy-3-oxo-4-cholenoic acid was excreted in urine both in healthy pregnancies and in ICP, possibly indicating a rate li mitation of 3-oxo-Delta(4)-steroid 5 beta-reductase in pregnancy. The serum levels and urinary excretion of total sulfated progesterone meta bolites were increased in ICP while the glucuronides were unchanged or low confirming previous results, the fraction of metabolites with 3 a lpha-hydroxy-5 alpha(H) configuration was increased. The urinary excre tion of 5 alpha-pregnane-3 alpha,20 alpha-diol 3-sulfate,20-N-acetylgl ucosaminide was greatly increased in ICP, as was that of 3 alpha-hydro xy-5 alpha-androstane-17 beta-carboxylic acid, assumed to be a progest erone metabolite. Conclusions: The combined results of this and previo us studies are compatible with a primary change in the reductive metab olism of progesterone in ICP, resulting in increased formation of meta bolites with a 3 alpha-hydroxy-5 alpha(H) configuration and a larger f raction of sulfates. There also seems to be a selective defect in the biliary secretion of sulfated metabolites, particularly disulfates.