Effect of Maternal Intrahepatic Cholestasis on Fetal Steroid Metabolism

Abstract

A B S T R A C T Estriol, estriol sulfate, progesterone, and 17 neutral steroid sulfates, including estriol precursors and progesterone metabolites, were determined in 27 cord plasma samples collected after pregnancies complicated by intrahepatic cholestasis of the mother. The levels of these steroids were compared with those in the cord plasma of 42 healthy controls.In the cord plasma, the steroid profile after pregnancies complicated by maternal intrahepatic cholestasis differed greatly from that seen after uncomplicated pregnancy. Two main differences were found. In the disulfate fraction, the concentrations of two pregnanediol isomers, 5a-pregnane-3a,20a-diol and 5P-pregnane3a,20a-diol, were high after cholestasis. Other investigators have shown that, as a result of cholestasis, these pregnanediol sulfates circulate in greatly elevated amounts in the maternal plasma. Our results indicate that in cholestasis these steroids cross the placenta into the fetal compartment, where they circulate in elevated amounts as disulfates. Secondly, the concentrations of several steroid sulfates known to be synthesized by the fetus were significantly lower in the cholestasis group than in the healthy controls. This was especially true of 16a-hydroxydehydroepiandrosterone sulfate and 16a-hydroxypregnenolone sulfate. These results suggest that, in pregnancies complicated by maternal intrahepatic cholestasis, impairment of fetal steroid synthesis, and especially of 16a-hydroxylation, occurs in the fetal compartment.Thus, the changes in maternal steroid metabolism caused by cholestasis are reflected in the steroid profile of the fetoplacental circulation. Furthermore, maternal intrahepatic cholestasis may result in the production of some substance which crosses the placenta and affects fetal steroid metabolism.

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

“…Similarly, PM4 is one of the most abundant PMs accumulated in the serum of ICP patients [4], and their fetuses [6,9]. These findings support the hypothesis that alterations in progesterone metabolism could be an important primary event in the etiology of ICP.…”

“…Alternatively, a primary alteration in AHP and ICP could be the overproduction of sulfated PMs. Since concentrations in cord plasma are lower than in maternal plasma, it has been suggested that PMs are generated in the mother and then transferred to the fetus [9]. However, the possibility that they could be generated, at least in part, by the placenta and then distributed asymmetrically to the fetus and mother cannot be ruled out.…”

“…However, it has also been proposed that one of the primary changes would be an increase in the reductive biotransformation of progesterone, resulting in increased formation of PMs [8]. In both cases, the accumulation of PMs was suggested to occur first in the mother, whereas alterations in steroid metabolism in the feto-placental unit are regarded as secondary to maternal disease [6,9].…”

Maternal Plasma Free Oestriol and 24 Hour Urinary Oestriol Excretion in the Assessment of Foetal Outcome

“…In maternal intrahepatic cholestasis foetal synthesis of steroids is depressed (Laatikainen et al 1974). Conceivably, therefore, subnormal oestriol levels did not give correct information about foetal distress.…”

Intrahepatic Cholestasis of Pregnancy: The Usefulness of Serum Bile Acid Profile for Diagnosis and Treatment

“…It is described in the literature the development of ICP related symptoms after the administration of progesterone in a woman with a history of ICP (Lutz et al, 1969;Mullaly et al, 2001). It was also demonstrated that the profile of progesterone metabolites in plasma from patients with ICP is markedly different from the profile observed in normal pregnants (Sjövall et al, 1970, Laatikainen et a. 1974Pascual et al 2002).…”