Instruct: Given a question, retrieve relevant passages that can help answer the question.
Query: Is estradiol available as a drug?
Estradiol is used as part of feminizing hormone therapy for transgender women.[32][15] The drug is used in higher dosages prior to sex reassignment 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.[32][15]
Estradiol enantate, sold under the brand names Perlutal and Topasel among others, is an estrogen medication which is used in hormonal birth control. It is formulated in combination with dihydroxyprogesterone acetophenide (DHPA; algestone acetophenide), a progestin, and is used as a combined injectable contraceptive. Estradiol enantate is not available alone. The medication is given by injection into muscle once a month.
Side effects of estradiol enantate include breast tenderness, breast enlargement, nausea, headache, and fluid retention. The drug is a synthetic estrogen and hence is an agonist of the estrogen receptor (ER), the biological target of estrogens like estradiol. Estradiol enantate is an estrogen ester and a long-lasting prodrug of estradiol in the body. Because of this, it is considered to be a natural and bioidentical form of estrogen.
Estradiol enantate was first described by 1954, and was first studied in combination with DHPA as a combined injectable contraceptive in 1964. The combination was introduced for clinical use by the mid-1970s. Estradiol enantate is not available as a standalone medication (i.e., by itself without DHPA). The combination is available in Latin America and Hong Kong, and was also previously marketed in Spain and Portugal.
Estradiol, estrone, and estriol have all been approved as pharmaceutical drugs and are used medically. Estetrol is currently under development for medical indications, but has not yet been approved in any country. A variety of synthetic estrogen esters, such as estradiol valerate, estradiol cypionate, estradiol acetate, estradiol benzoate, estradiol undecylate, and polyestradiol phosphate, are used clinically. The aforementioned compounds behave as prodrugs to estradiol, and are much longer-lasting in comparison when administered by intramuscular or subcutaneous injection. Esters of estrone and estriol also exist and are or have been used in clinical medicine, for example estrone sulfate (e.g., as estropipate), estriol succinate, and estriol glucuronide (as Emmenin and Progynon).
As the sodium salt, sodium estradiol sulfate, E2S is present as a minor constituent (0.9%) of conjugated equine estrogens (CEEs), or Premarin. It effectively functions as a prodrug to estradiol in this preparation, similarly to E1S. E2S is also formed as a metabolite of estradiol, as well as of estrone and E1S. Aside from its presence in CEEs, E2S is not available as a commercial pharmaceutical drug.
Estradiol can be administered in the form of a very long-lasting subcutaneous pellet implant. These implants are replaced once every 6 to 12 months, and can achieve high and very constant circulating levels of estradiol. They are surgically inserted by a trained physician in a medical office or clinic and can be placed into locations including the lower abdomen, lower back, buttocks, or hips. Subcutaneous implants containing 25, 50, and 100 mg estradiol for replacement usually once every 6 months are available as approved pharmaceutical medications. Up to 800 mg estradiol per implantation has been used. Pharmaceutical estradiol implants have been said to be used almost exclusively in the United Kingdom. An estradiol implant has not been approved by the FDA as a pharmaceutical medication in the United States, but hormone implants, including estradiol implants, are available as custom compounded products in this country.
The medical uses of estradiol cypionate are the same as those of estradiol and other estrogens. Examples of indications for the drug include hormone therapy and hormonal contraception. In regard to the latter, estradiol cypionate has been used in combination with medroxyprogesterone acetate as a combined injectable contraceptive. Along with estradiol valerate, estradiol undecylate, and estradiol benzoate, estradiol cypionate is used as a form of high-dose estrogen therapy in feminizing hormone therapy for transgender women.
Cyclodiol (developmental code name ZK-115194; also known as 14α,17α-ethano-17β-estradiol) is a synthetic estrogen which was studied in the 1990s and was never marketed. It is a derivative of estradiol with a bridge between the C14α and C17α positions. Cyclodiol has 100% of the relative binding affinity of estradiol for the human ERα and similar transactivational capacity as estradiol at the receptor. It has comparable potency to estradiol when administered by subcutaneous injection. The drug shows genotoxicity similarly to estradiol. Cyclodiol showed an absolute bioavailability of 33 ± 19% and a terminal half-life of 28.7 hours in pharmacokinetic studies in women.
MPA is available alone in the form of 2.5, 5, and 10 mg oral tablets, as a 150 mg/mL (1 mL) or 400 mg/mL (2.5 mL) aqueous suspension for intramuscular injection, and as a 104 mg (0.65 mL of 160 mg/mL) aqueous suspension for subcutaneous injection. It has also been marketed in the form of 100, 200, 250, 400, and 500 mg oral tablets; 500 and 1,000 mg oral suspensions; and as a 50 mg/mL aqueous suspension for intramuscular injection. A 100 mg/mL aqueous suspension for intramuscular injection was previously available. In addition to single-drug formulations, MPA is available in the form of oral tablets in combination with conjugated estrogens (CEEs), estradiol, and estradiol valerate for use in menopausal hormone therapy, and is available in combination with estradiol cypionate as a combined injectable contraceptive.
A hemihydrate form of estradiol, estradiol hemihydrate, is widely used medically under a large number of brand names similarly to estradiol.[109] In terms of activity and bioequivalence, estradiol and its hemihydrate are identical, with the only disparities being an approximate 1% 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.[112][113] 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.[113] Estradiol hemihydrate has also been shown to result in less systemic absorption as a vaginal tablet formulation relative to other topical estradiol formulations such as vaginal creams.[114] Estradiol hemihydrate is used in place of estradiol in some estradiol products.[115][116][117]
Estradiol valerate is and has been available in the form of vials and ampoules for intramuscular injection in concentrations of 5, 10, 20, and 40 mg/mL and in the form of oral tablets at doses of 0.5, 1, 2, and 4 mg per tablet. In the United States, it is specifically available in formulations of 10, 20, and 40 mg/mL (as Delestrogen, as well as generics). Aside from estradiol valerate, the only other injectable estrogen formulations that remain available in the United States are estradiol cypionate (5 mg/mL in oil) and conjugated estrogens (25 mg/vial in solution).
In addition to single-drug formulations, oral estradiol valerate is available in combination with the progestin dienogest as a combined oral contraceptive and intramuscular estradiol valerate is marketed in combination with the progestins hydroxyprogesterone caproate and norethisterone enantate as combined injectable contraceptives. Intramuscular estradiol valerate has also been marketed in combination with testosterone enantate, but this formulation has been discontinued. The availability of estradiol valerate-containing products varies throughout the world.
The medical uses of estradiol valerate are the same as those of estradiol and other estrogens. Examples of indications for the medication include hormone therapy and hormonal contraception. In regard to the latter, estradiol valerate is available in combination with a progestin as a combined estradiol-containing oral contraceptive (with dienogest) and as a combined injectable contraceptive. Along with estradiol cypionate, estradiol undecylate, and estradiol benzoate, estradiol valerate is used as a form of high-dose estrogen therapy in feminizing hormone therapy for transgender women. It is also used as a form of high-dose estrogen therapy in the treatment of prostate cancer in men.
Estradiol 3-saccharinylmethyl ether, or 3-"O"-(saccharinylmethyl)-17β-estradiol, is a synthetic estrogen and estrogen ether – specifically, the C3 saccharinylmethyl ether of estradiol – which was described in the mid-1990s and was never marketed. It is a prodrug of estradiol, and has been found to be 9-fold as potent as estradiol via the oral route in rats. Similarly, its bioavailability (16%) was 5-fold greater than that of estradiol via the oral route in rats, and the elimination half-life of estradiol released from the drug was 5- to 7-fold longer than that of regular estradiol. Conversely, when estradiol 3-saccharinylmethyl ether and estradiol were given intravenously in rats, there was no difference between them in terms of potency. "In vitro" studies revealed that saccarinylmethylestradiol is not hydrolyzed to estradiol enzymatically but rather is hydrolyzed chemically in biological media such as plasma, apparently dependent on the concentration of protein. Taken together, saccarinylmethylestradiol appears to be partially protected from first-pass metabolism in the liver and intestines with oral administration and shows greatly improved oral potency compared to estradiol.
Estradiol is also widely available in combination with progestogens.[130] It is available in combination with norethisterone acetate under the major brand names Activelle, Cliane, Estalis, Eviana, Evorel Conti, Evorel Sequi, Kliogest, Novofem, Sequidot, and Trisequens; with drospirenone as Angeliq; with dydrogesterone as Femoston, Femoston Conti; and with nomegestrol acetate as Zoely.[130] Estradiol valerate is available with cyproterone acetate as Climen; with dienogest as Climodien and Qlaira; with norgestrel as Cyclo-Progynova and Progyluton; with levonorgestrel as Klimonorm; with medroxyprogesterone acetate as Divina and Indivina; and with norethisterone enantate as Mesigyna and Mesygest.[130] Estradiol cypionate is available with medroxyprogesterone acetate as Cyclo-Provera, Cyclofem, Feminena, Lunelle, and Novafem;[14] estradiol enantate with algestone acetophenide as Deladroxate and Topasel;[130][133][134] and estradiol benzoate is marketed with progesterone as Mestrolar and Nomestrol.[130]
Oral estradiol valerate is used primarily in Europe, under the brand name Progynova. Although oral estradiol valerate was previously available in the United States, it is no longer available in this country except in combination with dienogest as a combined oral contraceptive (under the brand name Natazia). Estradiol valerate by intramuscular injection is available under the brand name Delestrogen in the United States and Canada and under the brand name Progynon Depot in Europe and elsewhere in the world.
Estradiol benzoate, sold under the brand name Progynon-B among others, is a medication which is used in hormone therapy for menopausal symptoms and low estrogen levels in women, in hormone therapy for transgender women, and in the treatment of gynecological disorders. It is also used in the treatment of prostate cancer in men. Estradiol benzoate is used in veterinary medicine as well. When used clinically, the medication is given by injection into muscle usually two to three times per week.
Side effects of estradiol benzoate include breast tenderness, breast enlargement, nausea, headache, and fluid retention. Estradiol benzoate is a synthetic estrogen and hence is an agonist of the estrogen receptor (ER), the biological target of estrogens like estradiol. It is an estrogen ester and a prodrug of estradiol in the body. Because of this, it is considered to be a natural and bioidentical form of estrogen.
Estradiol benzoate was discovered in 1933 and was introduced for medical use in 1936. It was the first estradiol ester to be discovered or marketed, and was one of the first estrogens to be introduced for medical use. Along with estradiol dipropionate, it was among the most widely used esters of estradiol for many years following its introduction. However, in the 1950s, longer-acting estradiol esters that necessitate less frequent injections, such as estradiol valerate and estradiol cypionate, were developed, and have since mostly superseded estradiol benzoate. Nonetheless, estradiol benzoate remains widely available throughout the world. It is no longer available for medical use in the United States.
"Estradiol undecylate" is the generic name of the drug and its and . It is also spelled in some publications as "estradiol unducelate" and is also known as "estradiol undecanoate". In German, it is known under a variety of spellings including as "estradiolundecylat", "östradiolundecylat", "östradiolundezylat", "oestradiolundecylat", "oestradiolundezylat", and others. Estradiol undecylate is known by its former developmental code names "RS-1047" and "SQ-9993" as well.
Estradiol is available in a variety of different formulations, including oral, intranasal, transdermal/topical, vaginal, injectable, and implantable preparations.[9][67] 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.[9] Such modifications give rise to forms such as estradiol acetate (oral and vaginal), estradiol valerate (oral and injectable), estradiol cypionate (injectable), estradiol benzoate (injectable), estradiol undecylate (injectable), and polyestradiol phosphate (injectable; a polymerized ester of estradiol), which are all prodrugs of estradiol.[9][67][68]
Estradiol stearate (brand name Depofollan), or estradiol octadecanoate, is a naturally occurring steroidal estrogen and an estrogen ester – specifically, the C17β stearate ester of estradiol. It occurs in the body as a very long-lasting metabolite and prohormone of estradiol. In addition, estradiol stearate is or has been available as a pharmaceutical drug for use via depot intramuscular injection. The drug was introduced in 1941 as Depofollan and was the first long-acting estrogen, although it has never been widely used. It has been reported in at least one source to have a duration of at least one month.
Estradiol cypionate is and has been available as an oil solution for intramuscular injection provided in vials and ampoules at concentrations of 1, 3, and 5 mg/mL (and containing 5, 10, 15, 25, or 50 mg estradiol cypionate total). The 1 and 3 mg/mL concentrations (containing 5 and 15 mg estradiol cypionate total) have been discontinued in the United States, but the 5 mg/mL concentration (containing 25 mg estradiol cypionate total) remains available. Aside from estradiol cypionate, the only other injectable estrogen formulations that remain available in the United States are estradiol valerate (10 mg/mL, 20 mg/mL, and 40 mg/mL in oil) and conjugated estrogens (25 mg/vial in solution).
In contrast to oral administration, which is associated with very low bioavailability (<10%), the bioavailability of both estradiol and estradiol esters like estradiol valerate has been found to be complete (i.e., 100%) via intramuscular injection. In addition, estradiol esters like estradiol cypionate and estradiol valerate, when given intramuscularly in oil, have a relatively long duration due to the formation of an intramuscular depot from which they are slowly released and absorbed. Upon intramuscular injection of estradiol cypionate in an oil solution, the solvent (i.e., oil) is absorbed, and a primary microcrystalline depot is formed within the muscle at the site of injection. In addition, a secondary depot may also be formed in adipose tissue. The slow release of estradiol cypionate is caused by the increased lipophilicity of the drug, which in turn is due to its long fatty acid cypionic acid ester moiety. The elimination half-life of intramuscularly administered estradiol cypionate in oil (as estradiol) has been reported to be approximately 8 days.
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 U.S.[115] Polyestradiol phosphate (Estradurin) was marketed in the U.S. previously but is no longer available.[115]
Transdermal estradiol is available in the forms of patches, gels, emulsions, and sprays. In the case of gels, emulsions, and sprays, the route is sometimes referred to as "topical" rather than as transdermal. Estradiol patches have an extended duration and are available for twice-weekly (3–4-day) and once-weekly (7-day) application, while gels, emulsions, and sprays are administered daily. There are two types of estradiol patches: reservoir patches, which have been described as first-generation patches, and matrix patches, which are considered to be improved second-generation patches. Reservoir patches were designed for twice-weekly application, while matrix patches have been produced for both twice-weekly and once-weekly application. Reservoir patches of estradiol (e.g., Estraderm) are mostly no longer used, with most estradiol patches available today being matrix patches (e.g., Alora, Climara, Esclim, Estradot, FemPatch, Menostar, Oesclim, Vivelle, and Vivelle-Dot). When estradiol is administered as a hydroalcoholic gel such as EstroGel, it dries within 2 to 5 minutes following application to the skin.
EC508, also known as estradiol 17β-(1-(4-(aminosulfonyl)benzoyl)--proline), is an estrogen which is under development by Evestra for use in menopausal hormone therapy and as a hormonal contraceptive for the prevention of pregnancy in women. It is an orally active estrogen ester – specifically, a C17β sulfonamide–proline ester of the natural and bioidentical estrogen estradiol – and acts as a prodrug of estradiol in the body. However, unlike oral estradiol and conventional oral estradiol esters such as estradiol valerate, EC508 undergoes little or no first-pass metabolism, has high oral bioavailability, and does not have disproportionate estrogenic effects in the liver. As such, it has a variety of desirable advantages over oral estradiol, similarly to parenteral estradiol, but with the convenience of oral administration. EC508 is a candidate with the potential to replace not only estradiol in clinical practice, but also ethinylestradiol in oral contraceptives. Evestra intends to seek Investigational New Drug status for EC508 in the second quarter of 2018.
Estradiol phenylpropionate (EPP), also known as estradiol 17β-phenylpropionate, is a steroidal estrogen. It is the C17β phenylpropionate ester of estradiol. EPP is marketed in combination with estradiol benzoate under the brand name Dimenformon Prolongatum in the Netherlands and in combination with estradiol benzoate, testosterone propionate, testosterone phenylpropionate, and testosterone isocaproate under the brand name Mixogen (a balanced mixture of estradiol and testosterone esters). Both of these drug combinations are long-acting injectables indicated in hormone replacement therapy for women in menopause. Dimenformon Prolongatum has also been investigated as a single injection, "morning after" post-coital contraceptive, and is additionally used as a component of hormone replacement therapy for transgender women.