Ethinylestradiol (EE) is an estrogen medication which is used widely in birth control pills in combination with progestins. Ethinylestradiol is widely used for various indications such as the treatment of menopausal symptoms, gynecological disorders, and certain hormone-sensitive cancers. It is usually taken by mouth but is also used as a patch and vaginal ring.
The general side effects of ethinylestradiol include breast tenderness and enlargement, headache, fluid retention, and nausea among others. In males, ethinylestradiol can additionally cause breast development, feminization in general, hypogonadism, and sexual dysfunction. Rare but serious side effects include blood clots, liver damage, and cancer of the uterus.
Ethinylestradiol is an estrogen, or an agonist of the estrogen receptors, the biological target of estrogens like estradiol. It is a synthetic derivative of estradiol, a natural estrogen, and differs from it in various ways. Compared to estradiol, ethinylestradiol is more resistant to metabolism, has greatly improved bioavailability when taken by mouth, and shows relatively increased effects in certain parts of the body like the liver and uterus. These differences make ethinylestradiol more favorable for use in birth control pills than estradiol, though also result in an increased risk of blood clots and certain other rare adverse effects.
Ethinylestradiol was developed in the 1930s and was introduced for medical use in 1943. The medication started being used in birth control pills in the 1960s. Ethinylestradiol is found in almost all combined forms of birth control pills and is nearly the exclusive estrogen used for this purpose, making it one of the most widely used estrogens. In 2023, the combination with norethisterone was the 79th most commonly prescribed medication in the United States with more than 8million prescriptions. Fixed-dose combination medications containing ethinylestradiol with other hormones are available.
Medical uses Ethinylestradiol is most commonly used as contraception in combined oral contraceptives (COC), also known as birth control, to prevent pregnancy after sex. Ethinylestradiol in its birth control formulation is not only used to prevent pregnancy, but can also be used to treat absence of menstruation, symptoms during menstruation, and acne.
Ethinylestradiol is also used as menopausal hormone therapy. The main reason for using HRT in menopausal women is to relieve common vasomotor symptoms such as hot flashes, night sweats, and flushing. Studies have found that estrogen replacement helps improve these symptoms when compared to a placebo. Other common menopause symptoms, such as vaginal dryness (which can cause pain during sexual intercourse), vaginal itching, and depressed mood, can benefit from HRT. In addition to treatment of menopausal symptoms, ethinylestradiol has been used as a component of feminizing hormone therapy for transgender women. However, it is no longer commonly used nor recommended for this purpose, with bioidentical estradiol having largely superseded it due to its increased safety and efficacy.
Ethinylestradiol can also be used to treat hypogonadism in women, prevent osteoporosis in women, and has been used as palliative care for prostate cancer in men and breast cancer in women. It has also been used to reduce sex drive in sex offenders.
Ethinylestradiol or any estrogen alone is contraindicated for women who have a uterus due to the increased risk of endometrial cancer; giving a progestogen with an estrogen mitigates the risk.
Available forms Ethinylestradiol is available in combination with a progestin in a vast number of combined oral contraceptives. It is also available in combination with progestins as a transdermal contraceptive patch and as a contraceptive vaginal ring. In addition, there is a single preparation (brand name FemHRT) containing very low doses of ethinylestradiol (2.5 and 5 μg) plus a progestin in an oral tablet that remains in use for menopausal hormone therapy. Ethinylestradiol was previously available by itself under brand names like Estinyl and Lynoral in the form of 0.002, 0.01, 0.02, 0.025, 0.05, 0.1, 0.5, and 1.0 mg (2, 10, 20, 25, 50, 100, 500, and 1000 μg) tablets.
The amount of ethinylestradiol in combined oral contraceptives has reduced over the years. Previously, combined oral contraceptives contained high doses of ethinylestradiol of as much as 100 μg/day. Doses of more than 50 μg ethinylestradiol are considered high-dose, doses of 30 and 35 μg ethinylestradiol are considered low-dose, and doses of 10 to 25 μg ethinylestradiol are considered very low dose. Combined oral contraceptives generally contain 10 to 50 μg ethinylestradiol. The higher doses of ethinylestradiol were discontinued due to a high risk of venous thromboembolism and cardiovascular problems.
Contraindications Ethinylestradiol should be avoided in individuals with a history of or known susceptibility to arterial or venous thrombosis (blood clots), due to an increased risk of cardiovascular problems such as venous thromboembolism (VTE), myocardial infarction, and ischemic stroke. This includes women with: History of deep vein thrombosis (DVT) or pulmonary embolism (PE) not receiving anticoagulants Acute DVT/PE Prolonged immobilization due to major surgery Advanced diabetes mellitus with vascular disease Migraine with aura Hypertension ≥160/100 Vascular disease Current and history of ischemic heart disease Multiple risk factors for atherosclerotic cardiovascular disease (e.g. older age, smoking, diabetes, hypertension, low HDL, high LDL, or high triglyceride levels) Age ≥35 and smoking ≥15 cigarettes/day History of cerebrovascular accident Systemic lupus erythematosus with positive (or unknown) antiphospholipid antibodies Complicated valvular heart disease
Except when being used to treat it, ethinylestradiol should be avoided in women with current breast cancer due to a possible worsening of prognosis.
Ethinylestradiol should also be avoided in breastfeeding women who are less than 21 days postpartum due to an increased risk of venous thromboembolism. Ethinylestradiol use in breastfeeding women who are at least 21 days postpartum should be discussed with a provider and include information on the advantages, disadvantages, and alternatives for using ethinylestradiol.
Due to risk of cholestatic hepatotoxicity, it is widely considered that combined oral contraceptives containing ethinylestradiol should be avoided in women with a history of cholestasis of pregnancy, hepatic tumors, active hepatitis, and familial defects in biliary excretion.
Side effects Dose of ethinylestradiol in birth control pills and risk of venous thromboembolism (VTE) Ethinylestradiol dose No. of VTE cases Woman-years VTE rate Adjusted a Low (<50 μg) 53 127,000 4.2 in 10,000 woman-years 1.0 Intermediate (50 μg) 69 98,000 7.0 in 10,000 woman-years 1.5 High (>50 μg) 20 20,000 10.0 in 10,000 woman-years 1.7 All 142 245,000 5.8 in 10,000 woman-years – Footnotes: a = Relative to low-dose (not to non-use). Notes: In birth control pills containing a first-generation progestin, such as norethisterone or levonorgestrel. Sources: Main: Additional: The severity of side effects can vary based on the dose and administration route of ethinylestradiol. General side effects of ethinylestradiol are the same as for other estrogens and include breast tenderness, headache, fluid retention (bloating), nausea, dizziness, and weight gain. The estrogen component of oral contraceptives, which is almost always ethinylestradiol, can cause breast tenderness and fullness. In males, ethinylestradiol has additional side effects, including gynecomastia (breast development), feminization in general, hypogonadism, infertility, and sexual dysfunction (e.g., reduced libido and erectile dysfunction). In men who received high-dose estrogen therapy with 200 μg/day oral ethinylestradiol for more than three months, gynecomastia occurred in 98% and decreased libido occurred in 42 to 73%.
Long-term effects Beneficial and adverse effects of -containing birth control pills Beneficial effects Adverse effects Disease Disease Iron-deficiency anemia 0.58 Cardiovascular diseases (total) 1.5 Menorrhagia 0.52 Myocardial infarction (heart attack) (total) 3.3 Irregular menstruation 0.65 Myocardial infarction (non-smokers) 1.0 Intermenstrual bleeding 0.72 Myocardial infarction (light smokers) 3.5 Dysmenorrhea 0.37 Myocardial infarction (heavy smokers) 20 Pelvic inflammatory disease (incidence) 0.50 Cerebrovascular diseases (total) 1.4 Pelvic inflammatory disease (hospitalization) 0.22 Cerebral thromboses (strokes) 2.5 Trichomonas vaginitis 0.56 Subarachnoidal bleeding (heavy smokers) 10 Benign breast disease 0.69 Pulmonary embolism 3.0 Fibrocystic breast disease 0.66 Deep vein thromboses 2.5 Benign breast fibroadenomas 0.35 Gall-bladder diseases 3.0 Rheumatoid arthritis 0.49 Benign liver tumors 50 Endometrial cancer 0.40–0.50 Hepatocellular carcinoma 3.0 Ovarian cancer (incidence) 0.37–0.64 Erythema nodosum et multiforme 3.0 Ovarian cancer (death) 0.20 Pruritus (itching) 2.0 Benign follicular cysts (high-dose combined oral contraceptives) 0.24 Photosensitive eczema 4.0 Acne vulgaris 0.44 Irritant agent eczema 2.0 Low bone mineral density (later in life) 0.35a Dermatitis (eczema) 2.0 Ectopic pregnancy 0.19 Chloasma (melasma) 1.5 Cervicitis (6 years of use) 3.0 Chlamydia infections 2.5 Footnotes: a = Odds ratio. Sources:
Blood clots
Venous thromboembolism is a blood clot in a vein, and includes deep vein thrombosis (DVT) and pulmonary embolism (PE). Estrogens are known to increase the risk of venous thromboembolism due to their effects on liver synthesis of coagulation factors. Ethinylestradiol carries a greater risk of blood clot formation and venous thromboembolism than does natural estradiol, which is thought to be due to structural differences between the two compounds and different susceptibilities to liver inactivation.
A 2012 meta-analysis estimated that the absolute risk of venous thromboembolism is 2 per 10,000 women for non-use, 8 per 10,000 women for ethinylestradiol and levonorgestrel-containing birth control pills, and 10 to 15 per 10,000 women for birth control pills containing ethinylestradiol and a third- or fourth-generation progestin such as desogestrel or drospirenone. For comparison, the absolute risk of venous thromboembolism is generally estimated as 1 to 5 per 10,000 woman–years for non-use, 5 to 20 per 10,000 woman–years for pregnancy, and 40 to 65 per 10,000 woman–years for the postpartum period. Combined oral contraceptives are associated with about a 2- to 4-fold higher risk of venous thromboembolism than non-use. The route of administration of ethinylestradiol does not appear to influence venous thromboembolism risk, as ethinylestradiol/progestin-containing contraceptive vaginal rings and contraceptive patches have the same or even higher risk of venous thromboembolism than combined oral contraceptives. Pregnancy is associated with about a 4.3-fold increase in risk of venous thromboembolism. It has been estimated that at least 300 to 400 healthy young women die each year in the United States due to venous thromboembolism caused by ethinylestradiol-containing birth control pills.