Estradiol (medication)

Hormone therapy Menopause es per week with placebo and different doses of oral estradiol in menopausal women Estradiol is used in menopausal hormone therapy to prevent and treat moderate to severe menopausal symptoms such as hot flashes, vaginal dryness and atrophy, and osteoporosis (bone loss). This is not necessary if the woman has undergone a hysterectomy (surgical removal of the uterus). Hypogonadism Estrogen is responsible for the mediation of puberty in females, and in girls with delayed puberty due to hypogonadism (low-functioning gonads, which can result in low sex hormone levels) such as in Turner syndrome, estradiol is used to induce the development of and maintain female secondary sexual characteristics such as breasts, wide hips, and a female fat distribution. It is also used to restore estradiol levels in adult premenopausal women with hypogonadism, for instance those with premature ovarian failure or who have undergone oophorectomy. The drug is used in higher dosages prior to gender-affirming surgery or orchiectomy to help suppress testosterone levels; after this procedure, estradiol continues to be used at lower dosages to maintain estradiol levels in the normal premenopausal female range. natural estradiol itself is also used in some hormonal contraceptives, including in estradiol-containing oral contraceptives and combined injectable contraceptives. It is formulated in combination with a progestin such as dienogest, nomegestrol acetate, or medroxyprogesterone acetate, and is often used in the form of an ester prodrug like estradiol valerate or estradiol cypionate. Hormonal cancer Prostate cancer Estradiol is used as a form of high-dose estrogen therapy to treat prostate cancer and is similarly effective to other therapies such as androgen deprivation therapy with castration and antiandrogens. It is used in the form of long-lasting injected estradiol prodrugs like polyestradiol phosphate, estradiol valerate, and estradiol undecylate, and has also more recently been assessed in the form of transdermal estradiol patches. Estrogens are effective in the treatment of prostate cancer by suppressing testosterone levels into the castrate range, increasing levels of sex hormone-binding globulin (SHBG) and thereby decreasing the fraction of free testosterone, and possibly also via direct cytotoxic effects on prostate cancer cells. Parenteral estradiol is largely free of the cardiovascular side effects of the high oral dosages of synthetic estrogens like diethylstilbestrol ad ethinylestradiol that were used previously. In addition, estrogens may have advantages relative to castration in terms of hot flashes, sexual interest and function, osteoporosis, cognitive function, and quality of life. However, side effects such as gynecomastia and feminization in general may be difficult to tolerate and unacceptable for many men. Although estrogens are rarely used in the treatment of breast cancer today and synthetic estrogens like diethylstilbestrol and ethinylestradiol have most commonly been used, estradiol itself has been used in the treatment of breast cancer as well. It has been used orally at very high doses (30 mg/day) in the treatment of therapy-naive breast cancer and orally at low doses (2 to 6 mg/day) in the treatment of breast cancer in women who were previously treated with and benefited from but acquired resistance to aromatase inhibitors. Other uses Infertility Estrogens may be used in treatment of infertility in women when there is a need to develop sperm-friendly cervical mucus or an appropriate uterine lining. It is also commonly used during in vitro fertilization (IVF). Estrogen helps maintain the endometrial lining of the uterus and help prepare for pregnancy. Research shows higher pregnancy rate if the mother takes estrogen in addition to progesterone. Estradiol is the predominant form of estrogen during reproductive years and is most commonly prescribed. They do this by inducing epiphyseal closure and suppressing growth hormone-induced hepatic production and by extension circulating levels of insulin-like growth factor-1 (IGF-1), a hormone that causes the body to grow and increase in size. Breast enhancement Estrogens are involved in breast development and estradiol may be used as a form of hormonal breast enhancement to increase the size of the breasts. Both polyestradiol phosphate monotherapy and pseudopregnancy with a combination of high-dosage intramuscular estradiol valerate and hydroxyprogesterone caproate have been assessed for this purpose in clinical studies. It has been found to significantly reduce positive, negative, and cognitive symptoms, with particular benefits on positive symptoms. Other estrogens, as well as selective estrogen receptor modulators (SERMs) like raloxifene, have been found to be effective in the adjunctive treatment of schizophrenia in women similarly. Estrogens may be useful in the treatment of schizophrenia in men as well, but their use in this population is limited by feminizing side effects. SERMs, which have few or no feminizing side effects, have been found to be effective in the adjunctive treatment of schizophrenia in men similarly to in women and may be more useful than estrogens in this sex. It has specifically been used for this indication in the forms of intramuscular injections of estradiol valerate and estradiol undecylate and of subcutaneous pellet implants of estradiol. An ester may be attached to one or both of the hydroxyl groups of estradiol to improve its oral bioavailability and/or duration of action with injection. ==Contraindications==

Estrogens like estradiol have a number of contraindications. 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. 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. 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. 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. Estradiol- and estradiol valerate-containing birth control pills are associated with a lower risk of VTE than birth control pills containing ethinylestradiol. 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. Risk of VTE with estrogen therapy is highest at the start of treatment, particularly during the first year, and decreases over time. Women who are not on a birth control pill or hormone therapy have a risk of VTE of about 1 to 5 out of 10,000 women per year. Hormone therapy for transgender women likewise is associated with a lower risk of VTE than birth control pills containing ethinylestradiol and a progestin. Advantages may include reduced or no risk of venous thromboembolism, cardiovascular disease, and breast cancer, among others. ==Overdose==

Estrogens are relatively safe in overdose. In late pregnancy, the body produces and secretes approximately 100 mg of estrogens, including estradiol, estrone, and estriol, per day. Serious adverse effects have not been described following acute overdose of large doses of estrogen- and progestogen-containing birth control pills by small children. == Interactions ==

Inducers of cytochrome P450 enzymes like CYP3A4 such as St. John's wort, phenobarbital, carbamazepine and rifampicin decrease the circulating levels of estradiol by accelerating its metabolism, whereas inhibitors of cytochrome P450 enzymes like CYP3A4 such as erythromycin, cimetidine, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may slow its metabolism resulting in increased levels of estradiol in the circulation. This appears to be due to a decrease in hepatic 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD2) activity and hence estradiol inactivation into estrone due to an alcohol-mediated increase in the ratio of NADH to NAD in the liver. ==Pharmacology==

Pharmacodynamics Estradiol is an estrogen, or an agonist of the estrogen receptors (ERs), the and . Estradiol is highly selective for these ERs and mERs, and does not interact importantly with other steroid hormone receptors. It is far more potent as an estrogen than are other bioidentical estrogens like estrone and estriol. The ERs are expressed widely throughout the body, including in the breasts, uterus, vagina, fat, skin, bone, liver, pituitary gland, hypothalamus, and other parts of the brain. Among other effects, estradiol produces breast development, feminization, changes in the female reproductive system, changes in liver protein synthesis, and changes in brain function. ==Chemistry==

Estradiol is a naturally occurring estrane steroid. It is also known as 17β-estradiol (to distinguish it from 17α-estradiol) or as estra-1,3,5(10)-triene-3,17β-diol. Hemihydrate A hemihydrate form of estradiol, estradiol hemihydrate, is widely used medically under a large number of brand names similarly to estradiol. In terms of activity and bioequivalence, estradiol and its hemihydrate are identical, with the only disparities being an approximate 3% difference in potency by weight (due to the presence of water molecules in the hemihydrate form of the substance) and a slower rate of release with certain formulations of the hemihydrate. This is because estradiol hemihydrate is more hydrated than anhydrous estradiol, and for this reason, is more insoluble in water in comparison, which results in slower absorption rates with specific formulations of the drug such as vaginal tablets. Estradiol hemihydrate is used in place of estradiol in some estradiol products. Derivatives A variety of C17β and/or C3 ester prodrugs of estradiol, such as estradiol acetate, estradiol benzoate, estradiol cypionate, estradiol dipropionate, estradiol enanthate, estradiol undecylate, estradiol valerate, and polyestradiol phosphate (an estradiol ester in polymeric form), among many others, have been developed and introduced for medical use as estrogens. Estramustine phosphate is also an estradiol ester, but with a nitrogen mustard moiety attached, and is used as a cytostatic antineoplastic agent in the treatment of prostate cancer. Cloxestradiol acetate and promestriene are ether prodrugs of estradiol that have been introduced for medical use as estrogens as well, although they are little known and rarely used. ==History==

Estradiol was first discovered and synthesized in 1933 via reduction of estrone. It was also originally known as dihydroxyestrin, dihydrofolliculin, or alpha-estradiol. Estradiol itself was also marketed in the 1930s and 1940s in the form of oral tablets and solutions, vaginal suppositories, and topical ointments under a variety of brand names including Dimenformon, Gynoestryl, Ovocyclin, Progynon, and Progynon DH. Marketed vaginal estradiol suppositories were also used rectally. Estradiol dipropionate, another short-acting ester of estradiol in oil solution for use by intramuscular injection, was marketed under the brand name Di-Ovocylin by 1939. Delivery of estrogens by nasal spray was studied in 1929, and an estradiol nasal spray for local use was marketed by Schering under the brand name Progynon DH Nasal Spray by 1941. Sublingual administration of estradiol was first described in the early 1940s. Buccal estradiol tablets were marketed by Schering under the brand name Progynon Buccal Tablets by 1949. Estradiol tablets for use by the sublingual route were marketed under the brand name Estradiol Membrettes in 1950, as well as under the brand name Diogynets by 1952. Longer-acting esters of estradiol in oil solution like estradiol valerate (Delestrogen, Progynon Depot), estradiol cypionate (Depo-Estradiol), and estradiol undecylate (Delestrec, Progynon Depot 100), as well as the polymeric estradiol ester polyestradiol phosphate in aqueous solution (Estradurin), were developed and introduced for use by intramuscular injection in the 1950s. Due to poor absorption and low potency relative to other estrogens, oral estradiol was not widely used as late as the early 1970s. Instead, synthetic and animal-derived estrogens like conjugated estrogens, ethinylestradiol, and diethylstilbestrol were typically used by the oral route. Esterification of estradiol, as in estradiol valerate, was believed to improve its metabolic stability with oral administration. In 1972, micronization of estradiol was studied in women and was likewise found to improve the absorption and potency of estradiol by the oral route. However, oral micronized estradiol valerate had been introduced by Schering in 1968. Oral micronized estradiol and oral estradiol valerate have similar bioavailability and are both now widely used throughout the world. Transdermal estradiol gel did not become available in the United States until 2004, when EstroGel was introduced in this country as well. Estraderm, a reservoir patch and the first transdermal estradiol patch to be marketed, was introduced in Europe in 1985 and in the United States in 1986. The first transdermal matrix estradiol patches to be introduced were Climara and Vivelle between 1994 and 1996, and were followed by many others. Ethinylestradiol, a synthetic derivative of estradiol, was synthesized from estradiol by Inhoffen and Hohlweg in 1938 and was introduced for oral use by Schering in the United States under the brand name Estinyl in 1943. Starting in the 1950s, ethinylestradiol became widely used in birth control pills. Development of birth control pills containing estradiol was motivated by the thrombotic risks of ethinylestradiol that were uncovered in the 1960s and 1970s. Subsequently, estradiol valerate/dienogest (Natazia, Qlaira) was marketed as a birth control pill in 2008 and estradiol/nomegestrol acetate (Naemis, Zoely) was introduced in 2012. ==Society and culture==

Generic names Estradiol is the generic name of estradiol in American English and its , , , , , and . Estradiolo is the name of estradiol in Italian and the and estradiol benzoate is marketed with progesterone as Mestrolar and Nomestrol. Availability Estradiol and/or its esters are widely available in countries throughout the world in a variety of formulations. United States , estradiol is available in the United States in the following forms: • Oral tablets (Femtrace (as estradiol acetate), Gynodiol, Innofem, generics) • Transdermal patches (Alora, Climara, Esclim, Estraderm, FemPatch, Menostar, Minivelle, Vivelle, Vivelle-Dot, generics) • Topical gels (Divigel, Elestrin, EstroGel, Sandrena), emulsions (Estrasorb), and sprays (Evamist) • Vaginal tablets (Vagifem, generics), creams (Estrace), inserts (Imvexxy), and rings (Estring, Femring (as estradiol acetate)) • Oil solution for intramuscular injection (Delestrogen (as estradiol valerate), Depo-Estradiol (as estradiol cypionate)) Oral estradiol valerate (Progynova) and other esters of estradiol that are used by injection like estradiol benzoate, estradiol enantate, and estradiol undecylate all are not marketed in the US. Estradiol is also available in the US in combination with progestogens for the treatment of menopausal symptoms and as a combined hormonal contraceptive: • Oral tablets with drospirenone (Angeliq) and norethisterone acetate (Activella, Amabelz) and as estradiol valerate with dienogest (Natazia) • Transdermal patches with levonorgestrel (Climara Pro) and norethisterone acetate (Combipatch) Estradiol and estradiol esters are also available in custom preparations from compounding pharmacies in the US. This includes subcutaneous pellet implants, which are not available in the United States as FDA-approved pharmaceutical drugs. In addition, topical creams that contain estradiol are generally regulated as cosmetics rather than as drugs in the US and hence are also sold over-the-counter and may be purchased without a prescription on the Internet. Other countries Pharmaceutical estradiol subcutaneous pellet implants were formerly available in the United Kingdom and Australia under the brand name Estradiol Implants or Oestradiol Implants (Organon; 25, 50, or 100 mg), but have been discontinued. However, an estradiol subcutaneous implant with the brand name Meno-Implant (Organon; 20 mg) continues to be available in the Netherlands. Previously, for instance in the 1970s and 1980s, other subcutaneous estradiol implant products such as Progynon Pellets (Schering; 25 mg) and Estropel Pellets (25 mg; Bartor Pharmacol) were marketed. It has been said that pharmaceutical estradiol implants have been almost exclusively used in the United Kingdom. Subcutaneous estradiol implants are also available as custom compounded products in some countries. Economics Generic oral estradiol tablets are much less expensive than other forms of estradiol such as transdermal gel and patches and vaginal rings. ==Research==

A variety of estradiol-containing combined birth control pills were studied but never marketed. Estradiol has been studied in the treatment of postpartum depression and postpartum psychosis. Estrogens such as estradiol appear to improve sexual desire and function in women. However, the available evidence overall does not support the use of estradiol and other estrogens for improving sexual desire and function in women as of 2016. == References ==