EFFECTS OF URSODEOXYCHOLIC ACID ON CONJUGATED BILE-ACIDS AND PROGESTERONE METABOLITES IN SERUM AND URINE OF PATIENTS WITH INTRAHEPATIC CHOLESTASIS OF PREGNANCY

Background/Aims and Methods: The mechanism(s) behind the effects of ur sodeoxycholic acid on serum steroid sulphate profiles in patients with intrahepatic cholestasis of pregnancy is not clear. Conjugated proges terone metabolites and bile acids have therefore been analysed in seru m and urine of patients with intrahepatic cholestasis of pregnancy bef ore and during treatment with ursodeoxycholic acid using chromatograph ic and mass spectrometric methods. Results: The concentration of glyci ne-/taurine-conjugated bile acids decreased from 8.91+/-3 mu mol/l(mea n+/-SEM) before treatment to 1.8+/-0.6 mu mol/l during treatment with ursodeoxycholic acid. The total bile acid excretion in urine decreased from 56+/-14 to 32+/-5.6 mu mol/g creatinine. The proportion of choli c acid in serum and urine, and of 1 beta-, 2 beta- and 6 alpha-hydroxy lated cholic acids in urine decreased markedly during ursodeoxycholic acid while the percentages of 3 alpha,12 alpha-dihydroxy-3-oxo-4-chole noic acid and chenodeoxycholic acid were unchanged. The levels in seru m and excretion in urine of sulphated steroids decreased during ursode oxycholic acid, by 45-49% for disulphates and 33-35% for monosulphates . The ratios of 3 alpha- to 3 beta-hydroxysteroid disulphates were low ered by ursodeoxycholic acid from 1.1 (mean) to 0.68 in serum, and fro m 1.2 to 0.70 in urine. The corresponding ratios for monosulphates bef ore and during ursodeoxycholic acid mere 6.9 and 4.5, respectively, in serum, and 21 and 5.2, respectively, in urine. The major monosulphate s in urine, dominated by 5 alpha-pregnane-3 alpha, 20 alpha-diol, were also conjugated with N-acetylglucosamine. The excretion of these doub le conjugates decreased from 27+/-8.4 to 15+/-5.3 mu mol/g creatinine during ursodeoxycholic acid. In contrast to sulphated steroids, the co ncentrations of glucuronides were unchanged in serum and their excreti on in urine tended to increase during ursodeoxycholic acid. The metabo lism of ursodeoxycholic acid was similar to that described in nonpregn ant subjects. In addition to metabolites hydroxylated in the 1 beta-, 5 beta-, 6 alpha/beta and 22-positions, a 4-hydroxy-ursodeoxycholic ac id was tentatively identified. This occurred predominantly as a double conjugate with glycine/taurine and glucuronic acid, as did other 4-hy droxylated bile acids of probable foetal origin. Conclusions: The resu lts are compatible with the contention that ursodeoxycholic acid stimu lates the biliary excretion of sulphated progesterone metabolites, par ticularly those with a 3 alpha-hydroxy-5 alpha(H) configuration and di sulphates. The effect(s) appears to be independent of the stimulation of bile acid secretion. An effect of ursodeoxycholic acid on the reduc tive metabolism of progesterone cannot be excluded.