Context.—Observational studies have found lower rates of coronary heart disease
(CHD) in postmenopausal women who take estrogen than in women who do not,
but this potential benefit has not been confirmed in clinical trials.Objective.—To determine if estrogen plus progestin therapy alters the risk for
CHD events in postmenopausal women with established coronary disease.Design.—Randomized, blinded, placebo-controlled secondary prevention trial.Setting.—Outpatient and community settings at 20 US clinical centers.Participants.—A total of 2763 women with coronary disease, younger than 80 years,
and postmenopausal with an intact uterus. Mean age was 66.7 years.Intervention.—Either 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone
acetate in 1 tablet daily (n=1380) or a placebo of identical appearance (n=1383).
Follow-up averaged 4.1 years; 82% of those assigned to hormone treatment were
taking it at the end of 1 year, and 75% at the end of 3 years.Main Outcome Measures.—The primary outcome was the occurrence of nonfatal myocardial infarction
(MI) or CHD death. Secondary cardiovascular outcomes included coronary revascularization,
unstable angina, congestive heart failure, resuscitated cardiac arrest, stroke
or transient ischemic attack, and peripheral arterial disease. All-cause mortality
was also considered.Results.—Overall, there were no significant differences between groups in the
primary outcome or in any of the secondary cardiovascular outcomes: 172 women
in the hormone group and 176 women in the placebo group had MI or CHD death
(relative hazard [RH], 0.99; 95% confidence interval [CI], 0.80-1.22). The
lack of an overall effect occurred despite a net 11% lower low-density lipoprotein
cholesterol level and 10% higher high-density lipoprotein cholesterol level
in the hormone group compared with the placebo group (each P<.001). Within the overall null effect, there was a statistically
significant time trend, with more CHD events in the hormone group than in
the placebo group in year 1 and fewer in years 4 and 5. More women in the
hormone group than in the placebo group experienced venous thromboembolic
events (34 vs 12; RH, 2.89; 95% CI, 1.50-5.58) and gallbladder disease (84
vs 62; RH, 1.38; 95% CI, 1.00-1.92). There were no significant differences
in several other end points for which power was limited, including fracture,
cancer, and total mortality (131 vs 123 deaths; RH, 1.08; 95% CI, 0.84-1.38).Conclusions.—During an average follow-up of 4.1 years, treatment with oral conjugated
equine estrogen plus medroxyprogesterone acetate did not reduce the overall
rate of CHD events in postmenopausal women with established coronary disease.
The treatment did increase the rate of thromboembolic events and gallbladder
disease. Based on the finding of no overall cardiovascular benefit and a pattern
of early increase in risk of CHD events, we do not recommend starting this
treatment for the purpose of secondary prevention of CHD. However, given the
favorable pattern of CHD events after several years of therapy, it could be
appropriate for women already receiving this treatment to continue.

https://jamanetwork.com/journals/jama/articlepdf/187879/JOC80678.pdf

Randomized Trial of Estrogen Plus Progestin for Secondary Prevention of Coronary Heart Disease in Postmenopausal Women

Background: Stool form scales are a simple method of assessing intestinal transit rate but are not widely used in clinical practice or research, possibly because of the lack of evidence that they a...

Stool Form Scale as a Useful Guide to Intestinal Transit Time

Bile acids regulate the transcription of genes that control cholesterol homeostasis through molecular mechanisms that are poorly understood. Physiological concentrations of free and conjugated chenodeoxycholic acid, lithocholic acid, and deoxycholic acid activated the farnesoid X receptor (FXR; NR1H4), an orphan nuclear receptor. As ligands, these bile acids and their conjugates modulated interaction of FXR with a peptide derived from steroid receptor coactivator 1. These results provide evidence for a nuclear bile acid signaling pathway that may regulate cholesterol homeostasis.

https://science.sciencemag.org/content/sci/284/5418/1365.full.pdf

Bile Acids: Natural Ligands for an Orphan Nuclear Receptor

Identification of membrane-type receptor for bile acids (M-BAR).

Our aim was to define mechanisms whereby conjugated estrogens (Premarin, exogenous estrogen; Ayerst Laboratories, New York) increase the risk of developing cholesterol gallstones and to determine the role, if any, of dietary cholesterol. We studied gallbladder motor function, biliary lipid composition and secretion, cholesterol absorption, cholesterol synthesis and esterification by peripheral blood mononuclear cells, the clearance of chylomicron remnants, and bile acid kinetics in 29 anovulatory women. 13 were studied on both a low (443 +/- 119 mumol/d) and high (2,021 +/- 262 mumol/d) cholesterol diet. Premarin increased the lithogenic index of bile (P less than 0.05), increased biliary cholesterol secretion (P less than 0.005), lowered chenodeoxycholate (CDCA) pool (P less than 0.001) and synthesis (P less than 0.05), altered biliary bile acid composition [( CA + DCA]/CDCA increases, P less than 0.005), stimulated cholesterol esterification (P less than 0.03), and enhanced the clearance of chylomicron remnants (P = 0.07). Increases in dietary cholesterol stimulated the biliary secretion of cholesterol (P = 0.07), bile acid (P less than 0.05), phospholipid (P = 0.07), and as a result, did not alter lithogenic index. The reduction in CDCA pool and synthesis by Premarin was reversed by increasing dietary cholesterol. Off Premarin, only 24% of the increase in cholesterol entering the body in the diet was recovered as biliary cholesterol or newly synthesized bile acid. On Premarin, 68% of this increase in cholesterol was recovered as these biliary lipids. We conclude that Premarin increases biliary cholesterol by enhancing hepatic lipoprotein uptake and inhibiting bile acid synthesis. These actions of Premarin divert dietary cholesterol into bile.

/pdf/mechanisms-of-gallstone-formation-in-women-effects-of-4ffg9xvjkj.pdf

Mechanisms of gallstone formation in women : effects of exogenous estrogen (premarin) and dietary cholesterol on hepatic lipid metabolism

https://www.gastrojournal.org/article/0016-5085(82)90316-X/pdf

Gallbladder function in the human female: Effect of the ovulatory cycle, pregnancy, and contraceptive steroids

To study the events that might lead to an increased risk of cholesterol gallstones, we examined biliary lipid composition and secretion and bile acid composition and kinetics at different stages of pregnancy or ovulation in young, nonobese, healthy women. Lipid composition and bile acid distribution were determined in duodenal fluid obtained in the fasting state and after stimulation of the gallbladder. Biliary lipid secretion was measured by the marker-perfusion technique. Bile acid kinetics were determined with cholic and chenodeoxycholic acids labeled with carbon13, by measuring the relative abundance of 13C in duodenal bile acids for 4--5 d. In a subset of patients we measured gallbladder storage and emptying during the kinetic study. The phase of the ovulatory cycle had no effects, but there were significant changes during pregnancy. The lithogenic or cholesterol saturation index of fasting hepatic and gallbladder bile increased during the second and third trimesters. The mean secretion rate of biliary lipids was not altered, but in the last two-thirds of pregnancy, cholesterol secretion increased in relation to bile acid and phospholipid secretion. There was a progressive decrease in the percentage of chenodeoxycholic acid and a similar increase in the percentage of cholic acid. The pool size of each major bile acid increased in the first trimester. Chenodeoxycholic acid and deoxycholic acid pools, but not cholic acid pools, subsequently decreased. The fractional turnover rate of both primary bile acids was slower during pregnancy. The synthesis rate of chenodeoxycholic but not cholic acid decreased in a linear manner during the first 20 wk of pregnancy. The rate of enterohepatic cycling of the bile acid pool was reduced throughout pregnancy. The volume of the fasting gallbladder and the residual volume after a physiologically stimulated contraction were directly correlated with bile acid pool size. The residual volume was also directly related to total bile acid synthesis.

/pdf/biliary-lipids-bile-acids-and-gallbladder-function-in-the-4prg5nimw7.pdf

Biliary lipids, bile acids, and gallbladder function in the human female. Effects of pregnancy and the ovulatory cycle.

Administration of the synthetic estrogen ethinyl estradiol (17α-ethinyl-1,3,5-estratriene-3,17β-diol) 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.

https://www.pnas.org/content/pnas/75/9/4130.full.pdf

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

Fecal bile salt excretion was studied in healthy volunteers, patients with regional ileitis, and patients with ileal resection. 10 muc of carboxyl-(14)C-cholic acid was given orally. Stools and urine were collected daily for 5-10 days, the bile salts extracted, and the radioactivity assayed. Urinary excretion was negligible. All patients with ileal resection excreted bile salts in the feces significantly faster than controls, and five of the six excreted 50% of the radioactivity within 24 hr. Their mean intestinal transit time was 5.6 hr compared to 26 hr for the controls. Two of the three patients with regional ileitis excreted bile salts almost as rapidly as patients with ileal resection. Vitamin B(12) absorption was also defective in those patients, but the intestinal transit time was not decreased. To study the effect of rapid intestinal transit on bile salt excretion, four of the control subjects were given orally 1200 ml of 10% mannitol for 7 days, and the labeled cholic acid excretion rate was again studied. The mean intestinal transit time was markedly shortened, mild steatorrhea developed, and the fecal bile salt excretion rate increased slightly. It is concluded that ileal resection and ileal disease are major factors and rapid intestinal transit is a minor factor in causing excessive fecal bile salt loss. The relevance of bile salt wastage to lipid malabsorption is unknown because of insufficient information about compensatory jejunal absorption, maximum rate of hepatic bile salt synthesis, and the minimum necessary intraluminal concentration of conjugated bile salt.

/pdf/bile-salt-malabsorption-in-regional-ileitis-ileal-resection-18xverwqz5.pdf

Fred Kern

Papers

Mechanisms of gallstone formation in women : effects of exogenous estrogen (premarin) and dietary cholesterol on hepatic lipid metabolism

Gallbladder function in the human female: Effect of the ovulatory cycle, pregnancy, and contraceptive steroids

Biliary lipids, bile acids, and gallbladder function in the human female. Effects of pregnancy and the ovulatory cycle.

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

Bile salt malabsorption in regional ileitis, ileal resection, and mannitol-induced diarrhea