Dose of<unk>  in birth control pills and risk of venous thromboembolism (VTE)<unk>  dose No. of VTE cases Woman-years VTE rate Adjusted a Low (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<unk> . General side effects of<unk>  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<unk> , can cause breast tenderness and fullness. In males,<unk>  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<unk>  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 COCs) 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 VTE 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 VTE due to their effects on liver synthesis of coagulation factors.<unk>  carries a greater risk of blood clot formation and VTE 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 VTE is 2 per 10,000 women for non-use, 8 per 10,000 women for<unk>  and levonorgestrel-containing birth control pills, and 10 to 15 per 10,000 women for birth control pills containing<unk>  and a third- or fourth-generation progestin such as desogestrel or drospirenone. For comparison, the absolute risk of VTE 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. Modern COCs are associated with about a 2- to 4-fold higher risk of VTE than non-use. The route of administration of<unk>  does not appear to influence VTE risk, as<unk> /progestin-containing contraceptive vaginal rings and contraceptive patches have the same or even higher risk of VTE than COCs. Pregnancy is associated with about a 4.3-fold increase in risk of VTE. It has been estimated that at least 300 to 400 healthy young women die each year in the United States due to VTE caused by<unk> -containing birth control pills. Modern COCs contain 10 to 35 μg<unk> , but typically 20, 30, or 35 μg. The initial formulations of COCs that were introduced in the 1960s contained 100 to 150 μg<unk> . However, it was soon found that<unk>  is associated with increased risk of VTE and that the risk is dose-dependent. Following these events, the dose of<unk>  was greatly reduced, and is now always less than 50 μg. These lower doses have a significantly reduced risk of VTE with no loss of contraceptive effectiveness. Gerstman et al. (1991) found that COCs containing more than 50 μg<unk>  had 1.7-fold and COCs containing 50 μg<unk>  1.5-fold the risk of VTE of COCs containing less than 50 μg. A 2014 Cochrane review found that COCs containing 50 μg<unk>  with levonorgestrel had 2.1- to 2.3-fold the risk of COCs containing 30 μg or 20 μg<unk>  with levonorgestrel, respectively. COCs containing 20 μg<unk>  are likewise associated with a significantly lower risk of cardiovascular events than COCs containing 30 or 40 μg<unk> . However, discontinuation of COCs is more common with doses of<unk>  from 10 to 20 μg due to problematic changes in bleeding patterns. Women with thrombophilia have a dramatically higher risk of VTE with<unk> -containing contraception than women without thrombophilia. Depending on the condition, risk of VTE can be increased 5- to 50-fold relative to non-use in such women. Sex hormone-binding globulin (SHBG) levels indicate hepatic estrogenic exposure and may be a surrogate marker for coagulation and VTE risk with estrogen therapy, although this topic has been debated. SHBG levels with birth control pills containing different progestins are increased by 1.5 to 2-fold with levonorgestrel, 2.5- to 4-fold with desogestrel and gestodene, 3.5- to 4-fold with drospirenone and dienogest, and 4- to 5-fold with cyproterone acetate. Contraceptive vaginal rings and contraceptive patches likewise have been found to increase SHBG levels by 2.5-fold and 3.5-fold, respectively. Birth control pills containing high doses of<unk>  (>50 μg) can increase SHBG levels by 5- to 10-fold, which is similar to the increase that occurs during pregnancy. Conversely, increases in SHBG levels are much lower with estradiol, especially when used parenterally. High-dose parenteral polyestradiol phosphate therapy has been found to increase SHBG levels by about 1.5-fold. Cardiovascular issues When used orally at high dosages, for instance as a form of high-dose estrogen therapy in men with prostate cancer and in women with breast cancer, synthetic and non-bioidentical estrogens like<unk>  and diethylstilbestrol are associated with fairly high rates of severe cardiovascular complications such as VTE, myocardial infarction, and stroke. Diethylstilbestrol has been associated with an up to 35% risk of cardiovascular toxicity and death and a 15% incidence of VTE in men treated with it for prostate cancer.<unk>  has a to some degree lower risk of cardiovascular complications than does diethylstilbestrol when used in the treatment of prostate cancer in men. However, both<unk>  and diethylstilbestrol nonetheless have highly disproportionate effects on liver protein synthesis, which is thought to be responsible for their cardiovascular toxicity. In contrast to oral synthetic estrogens like<unk>  and diethylstilbestrol, high-dosage polyestradiol phosphate and transdermal estradiol have not been found to increase the risk of cardiovascular mortality or thromboembolism in men with prostate cancer. However, significantly increased cardiovascular morbidity has been observed with high-dosage polyestradiol phosphate. In any case, these estrogens are considered to be much safer than oral synthetic estrogens like<unk>  and diethylstilbestrol. In addition,<unk>  sulfonate <unk> S), an oral but parenteral-like long-lasting prodrug of<unk> , is used in the treatment of prostate cancer, and is said to have a considerably better profile of cardiovascular safety than<unk> . Because of its disproportionate effects on liver protein synthesis and associated cardiovascular risks, synthetic estrogens like<unk>  and diethylstilbestrol are no longer used in menopausal hormone therapy. They are also being replaced by parenteral forms of estradiol like polyestradiol phosphate and transdermal estradiol in the treatment of prostate cancer. Liver damage At the lower dosages that are now used in birth control pills,<unk>  has been associated rarely with cholestatic hepatotoxicity similarly to 17α-alkylated androgens/anabolic steroids and 17α-ethynylated 19-nortestosterone progestins. Cholestasis can manifest as pruritus and jaundice. Glucuronide metabolites of<unk> , via effects on the ABCB11 (BSEP) and MRP2 (ABCC2) proteins and consequent changes in bile flow and bile salt excretion, appear to be responsible for the cholestasis. Very high concentrations of estradiol, via its metabolite estradiol glucuronide, are also implicated in cholestasis, for instance in cholestasis of pregnancy. However, the incidence and severity of cholestatic hepatotoxicity appear to be much greater with<unk>  than with estradiol, which is thought to be due to the reactive C17α ethynyl substitution in<unk>  as well as its greatly reduced susceptibility to hepatic metabolism. Whereas abnormal liver function tests (LFTs) are normally found in about 1% of women not on birth control pills or taking lower-dose<unk> -containing birth control pills, this increases to more than 10% of women taking birth control pills containing 50 μg/day<unk>  or more. With birth control pills containing 50 μg/day<unk> , alanine aminotransferase (ALT) levels increase by 50%, hematocrit by 19%, and leukocytes by 50%, while gamma-glutamyltransferase (GGT) decreases by 30%. However, the values usually remain in the normal range. In addition to abnormal LFTs, pathological changes in partial liver functions and liver morphology can be observed in half of women
Ethinylestradiol
Vinyltestosterone
Haloprogesterone
Ethyltestosterone
Progestogen
Progestogen 
Methylestradiol
Cloxestradiol acetate