Bile acids and progesterone metabolites in intrahepatic cholestasis of pregnancy

The pathogenesis of intrahepatic cholestasis of pregnancy (ICP) can be rela ted to abnormalities in the metabolism and disposition of sex hormones and/ or bile acids, determined by a genetic predisposition interacting with envi ronmental factors. The total amount of oestrogens and progesterone circulat ing in the blood or excreted in the urine of ICP patients is similar to nor mal pregnancies. Thus, the search for the cause has been focused on abnorma l hormone metabolites, The cholestatic potential of some D-ring oestrogen m etabolites is supported by experimental and clinical data. Similar observat ions with regard to bile acids and progesterone metabolites are still scarc e. This article reviews current knowledge in this field, including our own data. Bile acid synthesis appears to be reduced in patients with ICP, in wh om primary conjugated bile acids are retained in blood. The major bile acid in blood and urine of these patients is cholic acid instead of chenodeoxyc holic acid present in normal pregnancies. Hydroxylation and sulfation of bi le acids are enhanced, while glucuronidation appears to be of lesser import ance. The synthesis of progesterone appears unimpaired, while the profiles of progesterone metabolites in plasma and urine are different from normal p regnancies, with a larger proportion of mono- and disulfated metabolites, m ainly 3 alpha,5 alpha isomers. Glucuronidated metabolites, however, are unc hanged. With the administration of ursodeoxycholic acid (UDCA) to patients with ICI, pruritus and serum liver values are improved, the concentration o f bile acids in blood is diminished and the proportion of their conjugated metabolites returned to normal. Simultaneously, the concentration of sulfat ed progesterone metabolites in blood and their urinary excretion are reduce d. The serum levels of bile acids and progesterone metabolites before UDCA administration and their decrease during treatment do riot correlate with e ach other. We propose that patients with ICP have a selective defect in the secretion of sulfated progesterone metabolites into bile and speculate tha t this may be caused by genetic polymorphism of canalicular transporter(s) for steroid sulfates or their regulation. Interaction with oestrogen metabo lites and/or some exogenous compounds may further enhance the process trigg ering ICP in genetically predisposed individuals.