Abstract
A challenge in obstetrics is to distinguish pathological symptoms from those associated with normal changes of pregnancy, typified by the need to differentiate whether gestational pruritus of the skin is an early symptom of intrahepatic cholestasis of pregnancy (ICP) or due to benign pruritus gravidarum. ICP is characterized by raised serum bile acids and complicated by spontaneous preterm labor and stillbirth. A biomarker for ICP would be invaluable for early diagnosis and treatment and to enable its differentiation from other maternal diseases. Three progesterone sulfate compounds, whose concentrations have not previously been studied, were newly synthesized and assayed in the serum of three groups of ICP patients and found to be significantly higher in ICP at 9‐15 weeks of gestation and prior to symptom onset (group 1 cases/samples: ICP n = 35/80, uncomplicated pregnancy = 29/100), demonstrating that all three progesterone sulfates are prognostic for ICP. Concentrations of progesterone sulfates were associated with itch severity and, in combination with autotaxin, distinguished pregnant women with itch that would subsequently develop ICP from pruritus gravidarum (group 2: ICP n = 41, pruritus gravidarum n = 14). In a third group of first‐trimester samples all progesterone sulfates were significantly elevated in serum from low‐risk asymptomatic women who subsequently developed ICP (ICP/uncomplicated pregnancy n = 54/51). Finally, we show mechanistically that progesterone sulfates mediate itch by evoking a Tgr5‐dependent scratch response in mice. Conclusion: Our discovery that sulfated progesterone metabolites are a prognostic indicator for ICP will help predict onset of ICP and distinguish it from benign pruritus gravidarum, enabling targeted obstetric care to a high‐risk population. Delineation of a progesterone sulfate‐TGR5 pruritus axis identifies a therapeutic target for itch management in ICP. (Hepatology 2016;63:1287–1298)
Highlights
A challenge in obstetrics is to distinguish pathological symptoms from those associated with normal changes of pregnancy, typified by the need to differentiate whether gestational pruritus of the skin is an early symptom of intrahepatic cholestasis of pregnancy (ICP) or due to benign pruritus gravidarum
We obtained the following progesterone sulfate standards, which were previously implicated in ICP based on analysis of gas chromatograhic/mass spectrometric spectra[22,23] and all of which were synthesized de novo: 5a-pregnan-3a,20a-diol-3,20-disulfate (PM2DiS), 5b-pregnan-3a,20a-diol-3-sulfate (PM3S), and 5b-pregnan-3a,20a-diol-3,20-disulfate (PM3DiS) (Supporting Fig. S1)
Our results show that the sulfated progesterone metabolites PM2DiS, PM3S, and PM3DiS are prognostic for ICP as their concentrations are elevated during early gestation when patients are asymptomatic
Summary
A challenge in obstetrics is to distinguish pathological symptoms from those associated with normal changes of pregnancy, typified by the need to differentiate whether gestational pruritus of the skin is an early symptom of intrahepatic cholestasis of pregnancy (ICP) or due to benign pruritus gravidarum. Several endogenous compounds have been proposed as biochemical mediators of pruritus in ICP, including lysophosphatidic acid, a neuronal activator that can act as a pruritogen, the formation of which is catalyzed by the enzyme autotaxin.[7,8] These molecules are raised in the serum of women with ICP after disease onset.[8] The secondary bile acids deoxycholic acid and lithocholic acid can activate the G protein-coupled receptor TGR5 on sensory nerves to stimulate release of itch-selective neuropeptides in the spinal cord and evoke a Tgr5-dependent itch response in mice.[9] These results indicate that bile acids may induce pruritus but require further evaluation in ICP as secondary bile acids are not typically raised in the condition and concentrations of total maternal serum bile acids do not correlate with pruritus severity.[10] studies of urine samples from ICP cases implicate progesterone sulfates as pruritogens,[11] the precise structures of the compounds and their capacity to cause pruritus remain to be determined
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