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

Abstract

P rogress in medical knowledge can be represented by an ascending spiral in which every loop stands over previous data, adds new findings that deepen our understanding of a disease, and helps to design further research and therapeutic strategies. 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.In this regard, the spiral started in 1970 when Sj€ ovall and Sj€ ovall reported increased sulfated metabolites of progesterone in serum and urine of Swedish patients with ICP, in contrast to normal pregnancies.(2) Furthermore, this biochemical peculiarity was identified in two patients during an early stage of pregnancy, before the onset of pruritus and abnormalities in serum liver tests, suggesting that it could have predicted the development of ICP.In 1979, Giusti et al. reported that an increase in sulfated progesterone metabolites in plasma from Italian patients with ICP did not occur in patients with viral hepatitis in pregnancy, giving further support to its specificity in ICP. In the 1990s, a series of reports centered in Sj€ ovall's laboratory, in Stockholm, Sweden, using now more sophisticated and precise techniques applied to serum and urine from Chilean patients with ICP and their controls, clarified that a distinctive biochemical feature in ICP was the switch of progesterone metabolism toward a four-fold to 10-fold increase in serum and urine concentration of sulfated metabolites, with an increased ratio of 3a-hydroxysteroid sulfates to 3b-hydroxysteroid sulfates, changes that were reversed after treatment with ursodeoxycholic acid. (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.

May Circulating Steroids Reveal a Predisposition to Intrahepatic Cholestasis of Pregnancy in Non-Pregnant Women?

“…As we have previously reported, the conjugation of 5α/β-reduced-20-oxo-pregnanes in the maternal compartment increases with the approaching term (Hill et al 2010a). During enterohepatic circulation, both progesterone and estrogen metabolites may be transformed into cholestatic compounds (Reyes 2008). Although the maternal liver plays a key role in the catabolism of maternal progesterone, the formation and catabolism of female sex hormones is not limited to the maternal liver, ovaries, and adrenals.…”

“…There is a bidirectional flux to the fetal-placental unit and the fetal adrenal and placenta synthesize a substantial part of the substrates for the production of active hormones and consequently their noxious catabolites. About half of the progesterone metabolism occurs in extrahepatic sites (Hill et al 2010a, Reyes 2016. In ICP patients, the sulfated progesterone catabolites are increased 4-10 times when compared with healthy pregnant women, while glucuronidated metabolites remain unaffected by either pregnancy or ICP.…”

“…In ICP patients, the sulfated progesterone catabolites are increased 4-10 times when compared with healthy pregnant women, while glucuronidated metabolites remain unaffected by either pregnancy or ICP. The patients also show an increased ratio of 3α-to 3β-hydroxysteroid sulfates in serum (Reyes 2016). ICP symptoms withdraw shortly after birth as the placental conversion of fetal steroids disappears, and the activity of the fetal adrenal zone declines (Glantz et al 2008, Lammert et al 2000.…”

Cholestasis-Associated Pruritus and Its Pruritogens

“…It has been postulated that the long-chain monounsaturated fatty acid erucic acid and/or selenium may play a role. Furthermore, the occurrence of ICP was exceptionally high in Chile a number of decades ago, but has drastically decreased more recently, suggesting that a change in diet or unknown lifestyle factor might play a role in ICP (2,3).…”

Huangqi Decoction Alleviates Alpha-Naphthylisothiocyanate Induced Intrahepatic Cholestasis by Reversing Disordered Bile Acid and Glutathione Homeostasis in Mice

“…Intrahepatic cholestasis is a clinical syndrome characterized by systemic and intrahepatic retention of excessive toxic bile acids (BAs). It is one of the most common symptoms of several acquired and hereditary liver diseases such as hepatitis (Kang et al, 2015 ), drug-induced liver injury (Liu et al, 2013 ), pregnancy (Reyes, 2015 ), and primary biliary cirrhosis (Srivastava, 2014 ). Improper treatment of this condition may lead to the development of fibrosis, cirrhosis, and eventual liver failure.…”