Relationship between asymptomatic hypercholanaemia of pregnancy and progesterone metabolism

Abstract

The aim of this study was to identify a subgroup of pregnant women with asymptomatic hypercholanaemia of pregnancy (AHP), in which the relationship between alterations in the level and pattern of serum bile acids (BAs) and of progesterone plus progesterone metabolites could be investigated in the absence of overt impairment of hepatobiliary function. Cholanaemia and serum concentrations of progesterone were assayed by an enzymic technique and by ELISA respectively, while BA molecular species and progesterone metabolites were measured by GC-MS, in the serum of 411 healthy pregnant women. Samples were collected after an overnight fast in the final week of each trimester of gestation. Two pregnant women were excluded because of the suspicion of intrahepatic cholestasis of pregnancy (ICP). Cholanaemia was found to increase progressively throughout pregnancy, but with normal mean values lower than 3.0 microM. Thus in our series AHP was defined arbitrarily as the presence of serum total BA concentrations 2-fold higher than this value, i.e. 6 microM, in the absence of hepatobiliary disease or symptoms of ICP. The prevalence of this condition was observed to increase with gestational age. Changes in the pattern of serum BAs in AHP were also found. These were reflected in a marked increase in the proportion of cholic acid together with a decrease in that of deoxycholic acid, while the proportions of chenodeoxycholic acid and lithocholic acid changed only moderately. When groups at the same gestational age were compared, serum progesterone levels were always significantly lower, while those of progesterone metabolites were higher, in women with AHP. Our results suggest that AHP is a relatively common condition in our geographical location, where ICP is rarely diagnosed. Changes in the serum BA pattern in hypercholanaemia resemble these described in ICP. The simultaneous finding of lower serum total progesterone levels along with an increase in its metabolites supports the hypothesis that a primary defect in progesterone metabolism may be involved in the aetiology of ICP.

Inhibition of Na+-Taurocholate Co-transporting Polypeptide-mediated Bile Acid Transport by Cholestatic Sulfated Progesterone Metabolites

“…Furthermore, the mechanism of P4-S-mediated inhibition of bile acid uptake appeared to be mainly competitive in nature in PHH, and this was confirmed in the NTCP-expressing oocytes. These findings are of likely physiological relevance as P4-S rises in normal pregnancy (19), and our data are consistent with these metabolites contributing to the asymptomatic hypercholanemia that is observed in some pregnant women with otherwise normal biochemical liver tests (1,2). Serum levels of P4-S rise further in pregnancies complicated by ICP (21,22) and therefore they may play a role in the hypercholanemia that is reported in this condition.…”

“…Normal pregnancy is characterized by altered bile acid homeostasis, and two recent studies have reported asymptomatic hypercholanemia of pregnancy in 10 -40% of pregnant women (1,2). Approximately 25% of women with asymptomatic hypercholanemia of pregnancy subsequently develop intrahepatic cholestasis of pregnancy (ICP), 4 a liver disorder that presents with pruritus, raised serum bile acids, and liver transaminases (3).…”

Potential role of trans-inhibition of the bile salt export pump by progesterone metabolites in the etiopathogenesis of intrahepatic cholestasis of pregnancy

“…The present study provides information regarding the mechanisms of cholestasis induced by these compounds, in particular some of the PMs that are elevated in the serum of women with AHP [12] or ICP [4,6]. The present study suggests that inhibition of BA secretion into bile, mainly mediated by BSEP [25], may play an important role in the cholestatic effect induced by metabolites of both estrogens and progesterone.…”

“…It is noteworthy that serum concentrations of these PMs are in the micromolar range in healthy pregnant women, are elevated in women with ICP [4] or AHP [12], and are probably further concentrated in bile. Indeed, one of these compounds (PM4-S), when administered to isolated perfused rat livers, was several-fold concentrated in bile (Figs.…”

“…In the absence of clinical manifestations, some apparently normal pregnancies presented the so-called asymptomatic hypercholanemia of pregnancy (AHP) [12], which probably reflects a continuum between normal pregnancy and overt disease (ICP), and which is accompanied by decreased serum concentrations of progesterone, but increased levels of several PMs, such as 5a-pregnan-3a-ol-20-one (PM4) [12]. Similarly, PM4 is one of the most abundant PMs accumulated in the serum of ICP patients [4], and their fetuses [6,9].…”