Study Title:

LiverTox: Clinical and Research Information on Drug-Induced Liver Injury

Study Abstract

Estrogens and oral contraceptives are both associated with several liver related complications including intrahepatic cholestasis, sinusoidal dilatation, peliosis hepatis, hepatic adenomas, hepatocellular carcinoma, hepatic venous thrombosis and an increased risk of gallstones. These side effects are more common with higher doses of estrogens, as were used in the early high dose estrogen formulation of oral contraceptives, but they have also been described with use of more modern birth control pills and with low dose, estrogen hormonal replacement therapy.

Synthetic estrogens for regulation of menstrual cycles and hormonal replacement therapy were developed in the early 1950s and came into increasing use in thereafter. Oral contraceptives (OCCs) were approved for use in the United States in 1960 and became widely used. Initial OCCs (first generation) used somewhat high doses of estrogens (50 μg of mestranol or 20 to 50 μg of ethinyl estradiol) in combination with a progestin and had appreciable rates of estrogenic side effects. Second and third generation OCCs introduced in the 1980s and 1990s have lower doses of ethinyl estradiol (15 to 35 μg) and more modern forms of progestins (norgestrel, desogestrel and others), which have been associated with lower rates of estrogenic and other adverse side effects. Hormonal replacement therapy became increasing popular in the 1980s and 1990s. Both estrogen only and combination forms of hormonal replacement therapy were used. In women with a uterus, combination hormonal replacement therapy was recommended usually combining a conjugated equine estrogen with medroxyprogesterone. The estrogen doses used in hormonal replacement therapy were 5 to 6 times lower than the equivalent ethinylestradiol doses used in OCCs. The popularity of hormonal replacement therapy decreased in the late 1990s when prospective studies demonstrated excess morbidity and mortality associated with replacement therapy in postmenopausal women. Commercially available OCCs include monophasic, biphasic, triphasic, extended cycle and progestin only formulations. Hormonal replacement therapy usually employs conjugated equine estrogen in doses of 1.25 mg per day, with medroxyprogesterone late in the menstrual cycle.

Study Information

[Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Estrogens and Oral Contraceptives. [Updated 2020 May 28]. Available from:

Full Study