The higher risk of VTE with oral estradiol can be attributed to the first pass and a disproportionate effect on liver synthesis of coagulation factors. Even high doses of parenteral estradiol, such as high-dose polyestradiol phosphate, have minimal influence on coagulation factors, in contrast to oral estrogen therapy. However, sufficient doses of parenteral estradiol, for instance very high doses of estradiol valerate by intramuscular injection, can nonetheless activate coagulation, presumably increasing VTE risk.In addition to the route of administration, the type of estrogen influences VTE risk. Oral conjugated estrogens are associated with a higher risk of VTE than oral estradiol. Estradiol- and estradiol valerate-containing birth control pills are associated with a lower risk of VTE than birth control pills containing ethinylestradiol. The relative risk of VTE is thought to be highest with oral ethinylestradiol, intermediate with oral conjugated estrogens, low with oral estradiol and parenteral estradiol valerate, and very low with transdermal estradiol. Conjugated estrogens and ethinylestradiol are thought to have a higher risk of VTE than estradiol because they are resistant to hepatic metabolism and have a disproportionate influence on liver production of coagulation factors.The combination of oral or transdermal estradiol and a progestin is associated with a higher risk of VTE than estradiol alone. Dydrogesterone is associated with a lower risk than other progestins such as medroxyprogesterone acetate and norethisterone, while oral progesterone is associated with no increase in risk of VTE.
Estradiol should be avoided when there is undiagnosed abnormal vaginal bleeding, known, suspected or a history of breast cancer, current treatment for metastatic disease, known or suspected estrogen-dependent neoplasia, deep vein thrombosis, pulmonary embolism or history of these conditions, active or recent arterial thromboembolic disease such as stroke, myocardial infarction, liver dysfunction or disease. Estradiol should not be taken by people with a hypersensitivity/allergy or those who are pregnant or are suspected pregnant. Side effects
Common side effects of estradiol in women include headache, breast pain or tenderness, breast enlargement, irregular vaginal bleeding or spotting, abdominal cramps, bloating, fluid retention, and nausea. Other possible side effects of estrogens may include high blood pressure, high blood sugar, enlargement of uterine fibroids, melasma, vaginal yeast infections, and liver problems. In men, estrogens can cause breast pain or tenderness, gynecomastia (male breast development), feminization, demasculinization, sexual dysfunction (decreased libido and erectile dysfunction), hypogonadism, testicular atrophy, and infertility. Blood clots
Oral estradiol and estradiol valerate, for instance in menopausal hormone therapy or birth control pills, are associated with a significantly higher risk of venous thromboembolism (VTE) than non-use. Higher doses of oral estrogens are associated with higher risks of VTE. In contrast to oral estradiol, transdermal and vaginal estradiol at menopausal replacement dosages are not associated with a higher incidence of VTE. Low doses (e.g., 50 μg/day) and high doses (e.g., 100 μg/day) of transdermal estradiol for menopausal replacement do not differ in terms of VTE risk.