UNLABELLED: 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.
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机译：胎记：产科面临的挑战是将病理症状与与正常妊娠变化相关的病理症状区分开，以区分皮肤妊娠性瘙痒是妊娠肝内胆汁淤积症（ICP）的早期症状还是由于妊娠性良性瘙痒症为特征。 ICP的特点是血清胆汁酸升高，并伴有自然早产和死产。 ICP的生物标志物对于早期诊断和治疗以及使其与其他产妇疾病区分开来将是无价的。在三组ICP患者的血清中新合成和分析了三种浓度尚未研究的硫酸孕酮化合物，发现它们在妊娠9-15周和症状发作之前的ICP中明显更高（第1组）病例/样本：ICP n = 35/80，无并发症妊娠= 29/100），表明所有三种硫酸孕酮均对ICP有预后。硫酸孕酮的浓度与瘙痒的严重程度有关，并与自分泌运动素联合使用，可区分具有瘙痒症状的孕妇，这些孕妇随后会从妊娠瘙痒症发展出ICP（第2组：ICP n = 41，妊娠瘙痒n = 14）。在第三组孕中期样本中，低风险无症状妇女的血清中所有孕酮硫酸盐的含量均显着升高，这些妇女随后发展为ICP（ICP /无并发症妊娠，n = 54/51）。最后，我们从机理上证明了硫酸孕酮通过引起小鼠Tgr5依赖性的刮擦反应来介导瘙痒。结论：我们的发现硫酸化孕酮代谢物是ICP的预后指标，将有助于预测ICP的发作并将其与良性瘙痒性瘙痒症区别开来，从而使针对高危人群的产科护理成为可能。硫酸孕酮-TGR5瘙痒轴的轮廓确定了ICP瘙痒治疗的治疗目标。
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