Estrogen-induced gallstone formation in males. Relation to changes in serum and biliary lipids during hormonal treatment of prostatic carcinoma.

Henriksson, Peter; Einarsson, Kurt; Eriksson, Anders; Kelter, U; Angelin, Bo

doi:10.1172/jci114240

Cited by 98 publications

(44 citation statements)

References 44 publications

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“…The lower HMG-CoAR activity in the female rat should mean a lower cholesterol synthesis and cholesterol content in the blood; on the contrary, the plasma cholesterol levels are not different between sexes. It is well known that the presence of estrogens markedly augment intestinal cholesterol absorption in animals and humans (Henriksson et al 1989, Wang et al 2004, consequently balancing the minor synthesis, and this could explain the comparable amount of cholesterol in males and females. So, the observed protection from cholesterol-dependent diseases could be explained only by the already known different plasma ratio of LDL and HDL cholesterol (Heiss et al 1980).…”

Section: Discussionmentioning

confidence: 99%

Sex differences in hepatic regulation of cholesterol homeostasis

Marinis¹,

Martini²,

Trentalance³

et al. 2008

Journal of Endocrinology

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Physiological sex differences may influence metabolic status and then alter the onset of some diseases. According to recent studies, it is now well established that females are more protected from hypercholesterolemia-related diseases, such as cardiovascular diseases until menopause. Female protection from hypercholesterolemia is mediated by the hypolipidemic properties of estrogens, even if mechanisms underlying this protection remain still debated. Even though the regulatory mechanisms of cholesterol homeostasis maintenance are well known, few data are available on the supposed differences between male and female in these processes. So, the aim of this work was to define, through an in vivo study, the putative sex-dependent regulation of the processes underlying cholesterol homeostasis maintenance. We examined 3-hydroxy 3-methylglutaryl coenzyme A reductase and its regulatory protein network as well as the amount of low-density lipoprotein receptor and cholesterol. The study was conducted in the liver and plasma of male and female rats, on adults and during postnatal development, and on 17-b-estradiol-treated male rats. Our data support that physiological differences in proteins involved in cholesterol balance are present between the sexes and, in particular, 3-hydroxy 3-methylglutaryl coenzyme A reductase shows lower activity and expression in female and 17-b-estradioltreated male rats than in adult untreated male. Our data suggest that sex differences in enzyme expression depend on variation in regulatory proteins and seem to be related to estrogen presence. This work adds new evidence in the complicated picture of sex-dependent cellular physiology and establishes a new role for reductase regulatory proteins as a link between estrogen protective effects and cholesterol homeostasis.

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Section: Discussionmentioning

confidence: 99%

Sex differences in hepatic regulation of cholesterol homeostasis

Marinis¹,

Martini²,

Trentalance³

et al. 2008

Journal of Endocrinology

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“…A large number of human and animal studies have proposed that estrogen increases the risk of developing cholesterol gallstones by augmenting the hepatic secretion of biliary cholesterol that leads to an increase in cholesterol saturation of bile (4,(8)(9)(10)(26)(27)(28)(29)(30)(31)(32). The major findings of this study are that i) high physiological doses of E 2 delivered via subcutaneous hormone-release pellets significantly enhance the hepatic output of newly synthesized cholesterol, thereby increasing biliary total cholesterol output in a gallstone-resistant strain of OVX AKR mice; ii) during E 2 treatment, even under high dietary cholesterol loads, mice continue to synthesize cholesterol in the liver because the negative feedback regulation of cholesterol biosynthesis determined by the SREBP-2 pathway is inhibited by E 2 through the hepatic ERa; and iii) these biological effects of E 2 can be completely blocked by the antiestrogenic agent ICI 182,780 through a mechanism involved in the inhibition of hepatic ERa activity.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of estrogen receptor α increases hepatic cholesterogenesis, leading to biliary hypersecretion in mice

Wang

Afdhal

Wang

2006

Journal of Lipid Research

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We explored whether there is an ''estrogen-ERa-SREBP-2'' (for estrogen-estrogen receptor subtype a-sterolregulatory element binding protein-2) pathway for regulating hepatic cholesterol biosynthesis in ovariectomized AKR mice treated with 17b-estradial (E 2 ) at 6 mg/day or E 2 plus the antiestrogenic agent ICI 182,780 at 125 mg/day and on chow or fed a high-cholesterol (1%) diet for 14 days. To monitor changes in cholesterol biosynthesis and newly synthesized cholesterol secreted into bile, incorporation into digitonin-precipitable sterols in mice treated with 25 mCi of [ 3 H]water was measured in extracts of liver and extrahepatic organs 1 h later and in hepatic biles 6 h later. ERa upregulated SREBP-2, with resulting activation of SREBP-2-responsive genes in the cholesterol biosynthetic pathway. The E 2 -treated mice continued to synthesize cholesterol in spite of its excess availability from high dietary cholesterol, which reflects a loss in controlling the negative feedback regulation of cholesterol synthesis. These alterations augmented biliary cholesterol secretion and enhanced the lithogenicity of bile. However, these lithogenic effects of E 2 were fully blocked by ICI 182,780. We conclude that during estrogen treatment, more newly synthesized cholesterol determined by the estrogen-ERa-SREBP-2 pathway is secreted into bile, leading to biliary cholesterol hypersecretion. These studies provide insights into therapeutic approaches to cholesterol gallstones in high-risk subjects, especially those exposed to high levels of estrogen.-Wang, H. H., N. H. Afdhal, and D. Q-H. Wang. Overexpression of estrogen receptor a increases hepatic cholesterogenesis, leading to biliary hypersecretion in mice. J. Lipid Res. 2006. 47: 778-786.

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“…In a previous paper (6) we demonstrated that the biliary secretion of cholesterol was increased during estrogen therapy, and that the resulting change in biliary cholesterol was related to the degree of reduction in serum LDL cholesterol levels. In the present study we have investigated the effect on LDL kinetics of both short-term (acute) and long-term estrogen administration to males with prostatic carcinoma (6).…”

Section: Introductionmentioning

confidence: 88%

“…Fertile women have lower levels of LDL than men of similar age, whereas this sex difference is diminished after menopause (3). When estrogens are administered to males, reduced plasma levels of LDL are seen (4)(5)(6), but very little information on the mechanism behind this change is presently available.…”

Section: Introductionmentioning

confidence: 99%

Effects of estrogen on low density lipoprotein metabolism in males. Short-term and long-term studies during hormonal treatment of prostatic carcinoma.

Eriksson¹,

Berglund²,

Rudling³

et al. 1989

J. Clin. Invest.

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To characterize the effects of estrogen treatment on the metabolism of LDL we studied six males with metastatic prostatic carcinoma before and during the initiation of therapy; a repeated study was performed in five participants after 3-6 mo of treatment. The fractional catabolic rate (FCR) of autologous -25ILDL was calculated both from elimination curves of plasma radioactivity and from urine/plasma (U/P) radioactivity ratios.Within 1-2 d of onset of estrogen therapy a more rapid decay of plasma radioactivity occurred, and FCR measured from U/P ratios increased by 20%. Concomitantly, LDL cholesterol levels decreased by 16%. After 3-6 mo of treatment FCR determined by both techniques was almost doubled, and LDL cholesterol was reduced by 34%. This occurred despite a 29% increase in the calculated synthesis rate of LDL. Tissue culture studies demonstrated that the receptor affinity of LDL isolated from patients on long-term estrogen therapy was reduced.We conclude that a profound increase in LDL catabolism is induced through administration of pharmacological doses of estrogen in males, and hypothesize that this is the consequence of an increased expression of hepatic LDL receptors. This enhanced catabolism of LDL leaves LDL particles in plasma with lower affinity for the LDL receptor.

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Estrogen-induced gallstone formation in males. Relation to changes in serum and biliary lipids during hormonal treatment of prostatic carcinoma.

Cited by 98 publications

References 44 publications

Sex differences in hepatic regulation of cholesterol homeostasis

Sex differences in hepatic regulation of cholesterol homeostasis

Overexpression of estrogen receptor α increases hepatic cholesterogenesis, leading to biliary hypersecretion in mice

Effects of estrogen on low density lipoprotein metabolism in males. Short-term and long-term studies during hormonal treatment of prostatic carcinoma.

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