The Link Between Estrogen and Gallbladder Disease

1. The Link Between Estrogen and Gallbladder Disease Kelly Butler Advisor: Dr. Grimes April 18, 2008

2. The Gallbladder • Storage and concentrating unit for bile • Contracts to release bile in response to food, especially fatty foods • Dysfunction occurring to slow or obstruct the flow of bile from the gallbladder results in gallbladder disease

3. Epidemiology • Common around the world • Higher rates of gallstone formation in western Caucasian, Hispanic, and Native American populations • Lower rates in eastern European countries, African Americans, and Japanese • Eastern Kentucky, there is an abnormally high incidence of gallbladder disease with gallstone formation. • Female > male

4. Pathophysiology • Includes inflammation, infection, stones, sludge, or obstruction of the gallbladder or its duct • Cholesterol gallstone formation is thought to rely on three factors, which include: (1) supersaturation of biliary cholesterol from liver oversecretion, (2) nucleation of cholesterol monohydrate crystals, and (3) gallbladder hypomotility

5. Estrogen • Primary female sex hormones • Regulating the development of secondary sex characteristics • Regulate the menstrual cycle • Stimulate the uterine lining to thicken

6. Estrogen Receptors • The liver, which produces bile, has estrogen receptors present. Endogenous estrogens act on these receptors to cause cholesterol saturation in the bile. Exogenous estrogens have been shown to affect physiologic markers in a pattern that favors gallstone formation. Progestin’s, which are often given in combination with estrogen for therapy, inhibit gallbladder contraction which increases bile stasis and can decrease the gallbladders response to cholecystokinin

7. Pregnancy Induced • Alterations in cholesterol metabolism and decreased gallbladder motility • Increasing # pregnancies = increased risk of developing gallstones • Ireland study • Usually asymptomatic after delivery • Levels of estrogen return to normal cycling after delivery

8. Oral Contraceptives • Accelerate the development of cholesterol gallstones in women who are already susceptible because cholesterol saturation is higher in persons using oral contraceptives as compared to nonusers • Medical University in Bangladesh

9. Post-menopausal Women and HRT • Women’s Health Initiative • Estrogen alone (with hysterectomy) or E+P group (without hystectomy) • Risk for gallstones or cholecystectomy is increased by a factor of 2-3 in postmenopausal women receiving estrogen • Causal relationship between estrogen therapy and gallstones and risk of surgical procedure among women using estrogen alone or a combination of estrogen and progestin

10. Prostate Carcinoma • Study in Sweden looked at the development of gallstones in men with prostate cancer who received estrogen therapy vs. orchidectomy • Before treatment, gallbladder disease affected a quarter of the patients equally distributed between the groups • Five patients previously without gallstones before treatment in the estrogen group developed new gallstones • Four patients in the estrogen group with previous gallstones had an increase in the number or size of gallstones and increasing symptomatic pain • Biliary lipids analysis showed an increase in the concentration of cholesterol and cholesterol saturation of bile during estrogen treatment

11. Male-to-Female Transsexuals • One known health risk seen is that estrogen can cause male-to-female transsexual patients to be at a higher risk for gallbladder disease • Hospital in Germany, over 800 patients, elevated liver enzymes and symptomatic gallstones

12. Conclusions • OC’s should be used with caution in those women who have a pre-existing or predisposition to gallbladder disease • Further Research: Women’s International Study of Long Duration Estrogen after Menopause in 14 countries, results expected in 2012 • The risks for males is shown to be the same as in females • Estrogen is probably a contributing factor in the development of gallstones

13. References • Scragg, R.K.R., A.J. McMichael, and R.F. Searmark. 1984. Oral Contraceptives, Pregnancy, and Endogenous Oestrogen in Gall Stone Disease - A Case Control Study. British Medical Joural. Vol. 288, p. 1795-1800 • Richardson, J. David, F.Douglas Scutchfield, Warren H. Proudfoot, and Abram S. Benenson. 1973. Epidemiology of Gallbladder Disease in an Appalachian Community: Comparisons with the Framingham and Pima Indian Studies. Health Services Reports. Vol. 88, No. 3. • Oriel, Kathleen A. 2000. Medical Care of Transsexual Patients: Clinical Update. Journal of the Gay and Lesbian Medical Association. Vol. 4, No. 4. • Medline Plus Medical Encyclopedia. Gallbladder Disease. http://www.nlm.nih.gov/medlineplus/print/ency/article/001138.htm Accessed: November, 2007. • McCollum, Basso L., M.R. Darling, A. Tocchi, and W.A. Tanner. 1992. A Study of Cholelithiasis During Pregnancy and Its Relationship with Age, Parity, Menarche, Breast-feeding, Dysmenorrhea, Oral Contraception, and a Maternal History of Cholelithiasis. Surgical Gynecology and Obstetrics. Vol. 175, No. 1: 41-46. • Henriksson, Peter, Kurt Einarsson, Ambjörn Eriksson, Ulrike Kelter, and Bo Angelin. 1989. Estrogen-Induced Gallstone Formation in Males: Relation to Changes in Serum and Biliary Lipids during Hormonal Treatment of Prostatic Carcinoma. Journal of Clinical Investigation. Vol. 84, p. 811-816. • Everson, Gregory T., Carol McKinley, and Fred Kern, Jr. 1991. Mechanisms of Gallstone Formation in Women: Effects of Exogenous Estrogen (Premarin) and Dietary Cholesterol on Hepatic Lipid Metabolism. Journal of Clinical Investigation. Vol. 87, p. 237-246. • Bateson, Malcolm C. 1999. Gallbladder Disease: Fortnightly Review. British Medical Journal. Vol. 318: 1745-1748.