Recurrent Jaundice in Pregnancy. Iv. Quantitative Determination of Urinary and Biliary Estrogens, Including Studies in Pruritus Gravidarum

Adlercreutz, Herman; Tikkanen, Matti J.; Wichmann, K.; Svanborg, Alvar; Ånberg, Åke

doi:10.1097/00006254-197409000-00008

Cited by 7 publications

(7 citation statements)

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“…was the only corresponding change seen in the peripheral plasma of the other patient. It would therefore seem possible that the two subjects have a different metabolic capacity for lSa-OHE^ On the basis of previous studies (30), it has been proposed that biliary ^a-OHE! is converted to E 3 during its enterohepatic circulation.…”

Section: Portal and Peripheral Venous Levels Of Estrogens After 16ot-mentioning

confidence: 99%

Intestinal Metabolism of Estrogens1

Adlercreutz

Martin

Pulkkinen

et al. 1976

The Journal of Clinical Endocrinology & Metabolism

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147

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Estrogen metabolism in the human intestine was studied in two ways. Firstly, by measuring the excretion of 12 estrogens in pooled human late pregnancy feces before and during the administration of ampicillin (2 g/day). Secondly, by administering 5.4 and 20 mg of 16alpha-hydroxyestrone orally to two postmenopausal women and analyzing the estrogens in simultaneously drawn portal and peripheral venous blood samples at time intervals from 0 to 150 min after steroid administration. The majority of the estrogens in normal pregnancy feces were unconjugated. The amounts of estradiol, estreon and 16-epiestriol excreted, relative to the principal estrogen estriol, were greater than in pregnancy bile or urine and 16alpha-hydroxyestrone, an important biliary estrogen, was only present in trace amounts. Considerable quantities of 15alpha-hydroxyestradiol-17beta were also found. Ampicillin administration, which decreases intestinal bacterial steroid metabolism, caused a huge increase in the fecal excretion of conjugated estrogens. In particular it caused very striking increases in the excretion of both unconjugated and conjugated, estriol, 15alpha-hydroxyestrone, 15alpha-hydroxyestradiol and 2-methoxyestrone. These findings emphasize the active role played by the intestinal microflora in estrogen metabolism under normal conditions. Administration of 16alpha-hydroxyestrone resulted in increases in portal venous unconjugated and conjugated 16alpha-hydroxyestrone, 16-oxoestradiol-17beta, 15alpha-hydroxyestrone, 16-epiestriol and conjugated estriol levels. The most significant finding in both subjects was the large increase in portal venous unconjugated 15alpha-hydroxyestrone. This would suggest that the human intestine (or intestinal contents) has the ability to carry out the transformation, 16alpha-hydroxyestrone leads to 15alpha-hydroxyestrone. Increases in the same estrogens were found in peripheral plasma, with the increase in conjugated estriol occurring in peripheral blood before it was seen in portal blood. The largest elevations in peripheral plasma values were seen in unconjugated estriol and conjugated 16alpha-hydroxyestrone in the subject who received the 20 mg dose and in unconjugated 16alpha-hydroxyestrone and 16-oxoestradiol-17beta in the subject who had the 5.4 mg dose. The intestinal and enterohepatic metabolism of estrogens is discussed in relation to these findings.

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Section: Portal and Peripheral Venous Levels Of Estrogens After 16ot-mentioning

confidence: 99%

Intestinal Metabolism of Estrogens1

Adlercreutz

Martin

Pulkkinen

et al. 1976

The Journal of Clinical Endocrinology & Metabolism

Self Cite

147

View full text Add to dashboard Cite

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“…In contrast, A-ring (3-glucuronide) metabolites are choleretic (Meyers et al, 1980). Therefore, patients with obstetric cholestasis excrete more Dversus A-ring glucuronides in urine (Adlercreutz et al, 1974), suggesting that D-ring glucuronides may be involved in its pathogenesis. Moreover, in a recent work, our group demonstrated that ursodeoxycholate, a bile salt that prevents estrogen cholestasis, decreases hepatic formation of EE 17␤-glucuronide in the rat .…”

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confidence: 99%

Galactosamine Prevents Ethinylestradiol-Induced Cholestasis

Crocenzi

Pellegrino²,

Catania³

et al. 2006

Drug Metab Dispos

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not alter any of the serum markers of liver injury studied (aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase) or biliary secretory function. When coadministered with EE, galactosamine partially prevented the impairment induced by this estrogen in total bile flow, the bile-salt-independent fraction of bile flow, basal bile salt secretion, and the secretory rate maximum of tauroursodeoxycholate. Uridine coadministration partially prevented galactosamine from exerting its anticholestatic effects. In conclusion, galactosamine administration partially prevented EE-induced cholestasis by a mechanism involving decreased UDP-GA availability for subsequent formation of EE 17␤-glucuronide. The evidence thus supports the hypothesis that EE 17␤-glucuronide is involved in the pathogenesis of EE cholestasis.

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“…Conversely, A-ring (3-glucuronide) metabolites and the 3-sulfate conjugate of estradiol 17␤-glucuronide cause choleresis (Meyers et al, 1980;Slikker et al, 1983). Increased proportions of D/A-ring glucuronides have been found in the urine of patients with obstetric cholestasis (Adlercreutz et al, 1974), suggesting that D-ring glucuronides may be involved in its pathogenesis. Unlike nonconjugated estrogens, which require several hours to exert their cholestatic effect (Gumucio and Valdivieso, 1971), estradiol 17␤-glucuronide-induced cholestasis is very rapid, suggesting that a metabolic step, like glucuronide conjugation, may be required for estrogens to produce their cholestatic effect.…”

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confidence: 99%

Ursodeoxycholate Reduces Ethinylestradiol Glucuronidation in the Rat: Role in Prevention of Estrogen-Induced Cholestasis

Pozzi¹,

Crocenzi²,

Pellegrino³

et al. 2003

J Pharmacol Exp Ther

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Ethinylestradiol (EE) administration (5 mg/kg, s.c., daily for 5 days) to rats leads to cholestasis, and its derivative EE 17␤-glucuronide is a likely mediator of this effect. Coadministration of ursodeoxycholate (UDC) was shown to prevent ethinylestradiol-induced cholestasis. The aim of this study was to evaluate the inhibitory effect of UDC on EE glucuronidation in vivo and in vitro as a potential mechanism to explain UDC protection. UDC treatment (25 mg/kg, i.p., daily for 5 days) decreased the biliary excretion of EE 17␤-glucuronide in bile after administration of a trace dose of [ 3 H]EE and reduced microsomal EE 17␤-glucuronidation activity by 20% and expression of UGT2B1, one of the enzymes involved in EE conjugation, by 30%. Glucuronidation kinetic studies were performed in vitro using normal microsomes and isolated hepatocytes in the presence of tauroursodeoxycholate (TUDC), the major endogenous derivative of UDC in the rat. Kinetic enzymatic studies in microsomes showed a noncompetitive inhibition of EE 17␤-glucuronidation by TUDC, which was unique for this bile salt since other endogenous bile salts such as taurocholate, taurochenodeoxycholate, or taurodeoxycholate did not affect the enzyme activity. Studies in isolated hepatocytes confirmed the inhibitory effect of TUDC on EE glucuronidation and indicated that TUDC can reach the enzyme active site in intact cells. In conclusion, both in vivo and in vitro experiments indicate that UDC decreased the metabolic pathways involved in EE glucuronidation, hence decreasing the formation of the cholestatic derivative EE 17␤-glucuronide.

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Recurrent Jaundice in Pregnancy. Iv. Quantitative Determination of Urinary and Biliary Estrogens, Including Studies in Pruritus Gravidarum

Cited by 7 publications

References 0 publications

Intestinal Metabolism of Estrogens1

Intestinal Metabolism of Estrogens1

Galactosamine Prevents Ethinylestradiol-Induced Cholestasis

Ursodeoxycholate Reduces Ethinylestradiol Glucuronidation in the Rat: Role in Prevention of Estrogen-Induced Cholestasis

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