Some aspects of the interaction between natural and synthetic female sex hormones and the liver

Adlercreutz, Herman; Tenhunen, Raimo

doi:10.1016/s0002-9343(70)80130-9

Cited by 188 publications

(28 citation statements)

References 136 publications

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“…Changes in membrane structure are closely correlated with sodium pump activity and bile flow, suggesting that the physical state of membrane lipids plays an important role in regulating transport across membranes. These observations may explain the reductions in organic anion transport previously reported for ethinyl estradiol treatment in human beings and rats (43).…”

supporting

confidence: 62%

Alterations of hepatic Na ⁺ ,K ⁺ -ATPase and bile flow by estrogen: Effects on liver surface membrane lipid structure and function

Davis

Kern

Showalter

et al. 1978

Proc. Natl. Acad. Sci. U.S.A.

169

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Administration of the synthetic estrogen ethinyl estradiol (17a-ethinyl-1,3,5-estratriene-3,173diol) decreases hepatic Na+,K+-ATPase (ATP phosphohydrolase; EC 3.6.1.3) activity and bile flow to 50% and alters the composition and structure of surface membrane lipid in rats. Although the content of phospholipids was not changed by treatment, free cholesterol (130%) and cholesterol esters (400%) were increased in liver surface membrane fractions. These observations correlate with changes in membrane viscosity, as shown by electron spin resonance probes. Both rotational correlation time, using the isotropic probe methyl (12-nitroxyl)stearate, and the order parameter, determined by the anisotropic probe 5-nitroxylstearic acid, were significantly increased in liver surface membrane fractions from rats treated with ethinyl estradiol. Administration of Triton WR-1339, a nonionic detergent that corrects hepatic and serum lipid changes caused by ethinyl estradiol treatment, restored toward normal elevated membrane lipids and viscosity as well as Na+,K+-ATPase activity and bile flow. Although restoration of normal liver surface membrane structure and function may be due to reversal of abnormal lipid composition, detergents also may directly alter membrane enzyme activity. Addition of Triton WR-1339 in vitro increased Na+,K+-ATPase activity and reduced membrane viscosity of surface membranes from rats treated with ethinyl estradiol. Triton had no effect on either parameter in normal membrane preparations. Studies of membrane structure and function both in vivo and in vitro suggest that alterations in lipid composition may alter Na+,K+-ATPase function and bile flow. Na+,K+-ATPase (ATP phosphohydrolase, EC 3.6.1.3) is a mammalian surface membrane that is sensitive to the lipid structure of the membrane bilayer (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)). An important function of Na+,K+-ATPase in the hepatocyte may be the active secretion of sodium into the bile canaliculus, thus driving water across the canalicular membrane (8,9). This fraction has been called bile salt-independent bile flow, and recent studies have demonstrated a strong correlation between hepatic Na+, K+-ATPase activity and bile flow (10), supporting the hypothesis that this component of bile flow is regulated by the sodium pump. One drug consistently shown to reduce bile salt-independent bile flow is the synthetic estrogen derivative ethinyl estradiol (17a-ethinyl-1,3,5-estratriene-3,17f3-diol) (10)(11)(12)(13).The aim of the present study was to examine whether Na+, K+-ATPase activity is reduced after ethinyl estradiol treatment and, if so, what possible mechanisms might be involved. We recently found that ethinyl estradiol significantly increases hepatic cholesterol ester concentrations by activating hepatic microsomal cholesterol acyl-CoA transferase (14).The possibility that altered membrane lipid composition was involved in the mechanism through which ethinyl estradiolThe publication costs of this article were defrayed in part by page charge payment. Thi...

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supporting

confidence: 62%

Alterations of hepatic Na ⁺ ,K ⁺ -ATPase and bile flow by estrogen: Effects on liver surface membrane lipid structure and function

Davis

Kern

Showalter

et al. 1978

Proc. Natl. Acad. Sci. U.S.A.

169

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“…As a result, the diagnosis in all these cases was intrahepatic cholestasis of pregnancy. There is widespread agreement that patients chosen on the above mentioned criteria have a disease with a common etiology which is not known, but which may have a hormonal basis (9,10). In plasma of pregnant women with pruritus concentrations of C21-steroid sulfates with a 3a-hydroxy-5a and 3a-hydroxy-5P structure were recently shown to be increased (4).…”

Section: Resultsmentioning

confidence: 99%

Effect of Maternal Intrahepatic Cholestasis on Fetal Steroid Metabolism

Laatikainen¹,

Peltonen²,

Nylander³

1974

J. Clin. Invest.

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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.

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“…The total concentra-disease and of its clinical consequences is still obscure, altion of conjugated bile acids in the 11 patients was 25 { 6 though a role of female sex hormones and/or their metabommol/L (mean { SEM) and decreased to 6.3 { 3.5 mmol/L lites is suggested by several studies. [5][6][7][8] While estrogens have in the 7 patients responding to treatment with UDCA. The received most attention as potential inducers of ICP, it is of level of 7a-hydroxy-4-cholesten-3-one was significantly lower interest that 10 of the 13 patients studied by Bacq et al 4 had (7.2 { 2.2 ng/mL) in patients with ICP than in healthy preg-been given daily doses of 0.2 to 1 g of progesterone shortly nancy (18 { 4.6 ng/mL) (P õ .05).…”

mentioning

confidence: 99%

Progesterone metabolites and bile acids in serum of patients with intrahepatic cholestasis of pregnancy: Effect of ursodeoxycholic acid therapy

et al. 1997

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The concentrations in serum of sulfated metabolites of proIntrahepatic cholestasis of pregnancy (ICP) is charactergesterone are known to be elevated in patients with intrahe-ized by skin pruritus appearing in late pregnancy, coinciding patic cholestasis of pregnancy (ICP). The profiles of these with a moderate or mild increase in serum bile acids (mainly metabolites and conjugated bile acids were analyzed in serum cholic acid), a mild rise in serum aminotransferases and bilifrom 11 patients with ICP before and during administration rubin, and a subclinical steatorrhea, all of them subsiding of ursodeoxycholic acid (UDCA) (8 patients) or placebo (3 soon after delivery. [1][2][3][4] Its main clinical consequences are the patients). The clinical condition of 7 of the patients given disturbed maternal status caused by pruritus and the risk of UDCA improved markedly, and 1 patient given placebo had stillbirths and premature deliveries. The pathogenesis of the a spontaneous remission of the disease. The total concentra-disease and of its clinical consequences is still obscure, altion of conjugated bile acids in the 11 patients was 25 { 6 though a role of female sex hormones and/or their metabommol/L (mean { SEM) and decreased to 6.3 { 3.5 mmol/L lites is suggested by several studies. [5][6][7][8] While estrogens have in the 7 patients responding to treatment with UDCA. The received most attention as potential inducers of ICP, it is of level of 7a-hydroxy-4-cholesten-3-one was significantly lower interest that 10 of the 13 patients studied by Bacq et al. 4 had (7.2 { 2.2 ng/mL) in patients with ICP than in healthy preg-been given daily doses of 0.2 to 1 g of progesterone shortly nancy (18 { 4.6 ng/mL) (P õ .05). The concentrations of 5a-before the development of ICP. pregnane-3a,20a-diol mono-and disulfates decreased by 52%The daily synthesis of progesterone in late pregnancy is { 7.9% and 68% { 5.5%, respectively, in the patients re-approximately 250 to 350 mg/d. 9 The hepatic metabolism of sponding to treatment. Similar decreases were observed for progesterone involves 5a and 5b reduction of the 4,5-double the mono-and disulfates of 5a-pregnane-3a,20a,21-triol and bond and reduction of the 3-and 20-oxo groups to yield a 5b-pregnane-3a,20a-diol. The disulfate of 5a-pregnane-number of isomeric pregnanolones and pregnanediols. The 3b,20a-diol showed a smaller decrease, while glucuronidated 5b-isomers are mostly glucuronidated, while 5a-isomers are steroids were not affected. The 3a-/3b-hydroxysteroid ratio sulfated. [10][11][12] The monosulfates may be hydroxylated in the and di-/monosulfate ratio decreased significantly during 16 or 21 positions. 10,11 The sulfated pregnanolones, preg-UDCA. The magnitudes of the changes of bile acid and steroid nanediols and 5a-pregnane-3a,20a,21-triol are present in concentrations during UDCA were not correlated to each mmolar concentrations in plasma, and the concentrations inother. The results suggest that UDCA stimulates the biliary crease with time of gestation. 12 Women with ICP...

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Some aspects of the interaction between natural and synthetic female sex hormones and the liver

Cited by 188 publications

References 136 publications

Alterations of hepatic Na ⁺ ,K ⁺ -ATPase and bile flow by estrogen: Effects on liver surface membrane lipid structure and function

Alterations of hepatic Na ⁺ ,K ⁺ -ATPase and bile flow by estrogen: Effects on liver surface membrane lipid structure and function

Effect of Maternal Intrahepatic Cholestasis on Fetal Steroid Metabolism

Progesterone metabolites and bile acids in serum of patients with intrahepatic cholestasis of pregnancy: Effect of ursodeoxycholic acid therapy

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Some aspects of the interaction between natural and synthetic female sex hormones and the liver

Cited by 188 publications

References 136 publications

Alterations of hepatic Na + ,K + -ATPase and bile flow by estrogen: Effects on liver surface membrane lipid structure and function

Alterations of hepatic Na + ,K + -ATPase and bile flow by estrogen: Effects on liver surface membrane lipid structure and function

Effect of Maternal Intrahepatic Cholestasis on Fetal Steroid Metabolism

Progesterone metabolites and bile acids in serum of patients with intrahepatic cholestasis of pregnancy: Effect of ursodeoxycholic acid therapy

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Product

Resources

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Alterations of hepatic Na ⁺ ,K ⁺ -ATPase and bile flow by estrogen: Effects on liver surface membrane lipid structure and function

Alterations of hepatic Na ⁺ ,K ⁺ -ATPase and bile flow by estrogen: Effects on liver surface membrane lipid structure and function