Prognostic and mechanistic potential of progesterone sulfates in intrahepatic cholestasis of pregnancy and pruritus gravidarum

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)

Immunology of hepatic diseases during pregnancy

“…Liver enzymes (e.g., ALT) have a limited use as markers due to huge intrapatient variations [59,71]. Instead, an increased serum autotaxin (lysophospholipase D) activity or progesterone sulfates are novel diagnostic markers, distinguishing ICP from other pruritic disorders of pregnancy and pregnancy-related liver diseases [72,73].…”

Sulfated progesterone metabolites in the pathogenesis of intrahepatic cholestasis of pregnancy: Another loop in the ascending spiral of medical knowledge

“…(4) Among other important steps in this research line, Glantz et al, in Sweden, reported similar changes in the pattern of progesterone metabolites in urine of ICP patients, with a reversal after ursodeoxycholic acid administration, correlating with an improvement in maternal pruritus (5) ; and Abu-Hayyeh et al also reported increased levels of progesterone sulfates in ICP patients studied in the United Kingdom. (6) Therefore, this metabolic pattern has been detected in ICP patients from different geographic locations and ethnic origins.The present study (1) identified three sulfated progesterone metabolites, 5a-pregnan-3a,-20a-diol-3,20-disulfate, 5b-pregnan-3a-20a-diol-3-sulfate, and 5b-pregnan-3a-20a-diol-3,20-disulfate, that were present in ICP patients in serum samples obtained even at 9-15 Abbreviations: ICP, intrahepatic cholestasis of pregnancy; PG, pruritus gravidarum. …”

“…The present study (1) identified three sulfated progesterone metabolites, 5a-pregnan-3a,-20a-diol-3,20-disulfate, 5b-pregnan-3a-20a-diol-3-sulfate, and 5b-pregnan-3a-20a-diol-3,20-disulfate, that were present in ICP patients in serum samples obtained even at [9][10][11][12][13][14][15] Abbreviations: ICP, intrahepatic cholestasis of pregnancy; PG, pruritus gravidarum.…”

“…New loops are frequently inspired by novel approaches to accepted hypotheses and usually supported by the use of more advanced technologies, as seems to be the case in the article by Abu-Hayyeh et al (1) Intrahepatic cholestasis of pregnancy (ICP), a frequent liver disorder of pregnancy, implies an unpredictable risk of fetal distress, with premature deliveries and stillbirths. Its pathogenesis has been linked to effects of sex hormones during pregnancy, and in recent decades successive reports have revealed a role for progesterone derivatives.…”

Advances in obstetric dermatology: A better understanding of skin disease in pregnancy

“…The group of Williamson has contributed greatly to this field by performing some of the most important work on the management and development of predictive biomarkers enabling targeted obstetric care to women at risk of developing obstetric cholestasis from early pregnancy on. Putative predictive biomarkers, such as autotaxin and the sulphated progesterone metabolites, 6 have been suggested and seem promising for future larger-scale studies. The authors discuss future directions in the field, including prevention of disease onset and determining which cholestasis pregnancies are associated with adverse fetal outcomes.…”