enantate for use in menopausal hormone therapy, but the latter formulation has been discontinued. The availability of estradiol valerate-containing products varies throughout the world. Contraindications Contraindications of estrogens include coagulation problems, cardiovascular diseases, liver disease, and certain hormone-sensitive cancers such as breast cancer and endometrial cancer, among others. Side effects The side effects of estradiol valerate are the same as those of estradiol. Examples of such side effects include breast tenderness and enlargement, nausea, bloating, edema, headache, and melasma. High-dose estrogen therapy with estradiol valerate injections may also cause an increased risk of thromboembolism, changes in blood lipid profile, increased insulin resistance, and increased levels of prolactin. Overdose Estradiol valerate has been used at very high doses of 40 to 100 mg once per week in women and men, without overt signs of acute toxicity observed. Symptoms of estrogen overdosage may include nausea, vomiting, bloating, increased weight, water retention, breast tenderness, vaginal discharge, heavy legs, and leg cramps. These side effects can be diminished by reducing the estrogen dosage. Interactions Inhibitors and inducers of cytochrome P450 may influence the metabolism of estradiol and by extension circulating estradiol levels. Pharmacology Pharmacodynamics Estradiol valerate is an estradiol ester, or a prodrug of estradiol. As such, it is an estrogen, or an agonist of the estrogen receptors. The affinity of estradiol valerate for the estrogen receptor is approximately 50 times lower than that of estradiol. In addition, estradiol valerate is rapidly cleaved into estradiol and is unable to reach target tissues in concentrations of significance, if at all. As such, estradiol valerate is essentially inactive in terms of estrogenic effect itself, acting solely as a prodrug to estradiol. The molecular weight of estradiol valerate is about 131% of that of estradiol due to the presence of its C17β valerate ester, and hence estradiol valerate contains about 76% of the amount of estradiol of an equal dose of estradiol. Aside from dose adjustment to account for the difference in molecular weight, oral estradiol valerate is considered to be equivalent to oral estradiol. Because estradiol valerate is a prodrug of estradiol, it is considered to be a natural and bioidentical form of estrogen. Effects on liver protein synthesis The influence of 2 mg/day oral estradiol valerate on coagulation factors is less than that of 10 μg/day oral ethinylestradiol. Oral ethinylestradiol at 10 μg/day has been found to have about 1.5- to 2.5-fold the impact of