to increase SHBG levels by 2.5-fold and 3.5-fold, respectively. Birth control pills containing high doses of ethinylestradiol (>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 EE 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. EE 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 EE 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 EE 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 EE and diethylstilbestrol. In addition, ethinylestradiol sulfonate (EES), an oral but parenteral-like long-lasting prodrug of EE, is used in the treatment of prostate cancer, and is said to have a considerably better profile of cardiovascular safety than EE. Because of its disproportionate effects on liver protein synthesis and associated cardiovascular risks, synthetic estrogens like EE 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, EE 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 EE, via effects on the ABCB11 (BSEP) and MRP2 (ABCC2) proteins and consequent changes