Estradiol enanthate

Available forms

The following forms of estradiol enanthate are or have been available for use:^{[11][28][29][23][2]}

• Estradiol enanthate 10 mg and DHPA 150 mg (brand names Perlutal, Topasel, many others)
• Estradiol enanthate 5 mg and DHPA 75 mg (brand names Anafertin, Patector NF, Yectames)
• Estradiol enanthate 10 mg and DHPA 120 mg (brand names Unalmes, Yectuna)
• Estradiol enanthate 10 mg and DHPA 75 mg (brand name Ova Repos; discontinued)

A 6 mg estradiol enanthate and 90 mg DHPA formulation was also studied, but was never marketed.^[30][31][32] The combination of estradiol enanthate and DHPA has also been studied at other doses ranging from 5 to 50 mg estradiol enanthate and 75 to 200 mg DHPA.^[33]

The combination of estradiol enanthate and DHPA is provided in ampoules at estradiol enanthate concentrations of 5 mg/mL and 10 mg/mL.

Pharmacodynamics

Estradiol enanthate is an estradiol ester, or a prodrug of estradiol.^[5][6] As such, it is an estrogen, or an agonist of the estrogen receptors.^[5][6] Estradiol enanthate is of about 41% higher molecular weight than estradiol due to the presence of its C17β enanthate ester.^[42][15] Because estradiol enanthate is a prodrug of estradiol, it is considered to be a natural and bioidentical form of estrogen.^[5][17]

The combination of 10 mg estradiol enanthate and 150 mg DHPA as a once-monthly combined injectable contraceptive (which achieves levels of estradiol of around 350 pg/mL)^[10][43][44] has been found to have little to no effect on many markers of estrogen-modulated liver protein synthesis, including circulating levels of HDL and LDL cholesterol, copper, ceruloplasmin, total and free cortisol, corticosteroid-binding globulin, and sex hormone-binding globulin.^[45][46] However, it was found to significantly increase levels of triglycerides and to significantly decrease levels of total and free testosterone.^[46] In contrast to the estradiol enanthate-containing combined injectable contraceptive, low-dose ethinylestradiol-containing birth control pills produce highly significant changes in all of the preceding parameters.^[45][46]

Studies in women and female capuchin monkeys have found that injections of estradiol enanthate and DHPA significantly alter levels of coagulation factors.^[47][48]

The clinical estrogenic effects of estradiol enanthate and ethinylestradiol have been compared in other studies as well.^[49]

Pharmacokinetics

When estradiol enanthate is administered in an oil solution by intramuscular injection, a depot effect occurs, and this results in it having a long duration of action.^[10][6][50] The duration of action of estradiol enanthate is considerably longer than that of various other estradiol esters, such as estradiol benzoate and estradiol valerate, whereas its duration is shorter than that of estradiol undecylate.^[10][51][52] In general, the longer the fatty acid ester chain, the more lipophilic the estradiol ester, the more slowly it is released from the depot and absorbed into the circulation, and the longer its duration of action.^[6][50]

The pharmacokinetics of estradiol enanthate have been assessed in a number of studies.^{[10][53][43][7][44][54]} It has usually been studied in combination with DHPA.^{[10][53][43][44]} Following an intramuscular injection of estradiol enanthate, levels of estradiol have been found to peak after 3 to 8 days.^[10][44][7] Maximal levels of estradiol after a 5 mg injection of estradiol enanthate have been found to be about 163 to 209 pg/mL and after a 10 mg injection of estradiol enanthate have been found to be about 283 to 445 pg/mL.^[10][43][44] However, one outlying study reported peak estradiol levels of 850 pg/mL after an intramuscular injection of 10 mg estradiol enanthate in three postmenopausal women.^[7] It used radioimmunoassay for the determinations, with no mention of chromatographic separation.^[7] Estradiol levels following an intramuscular injection of 10 mg estradiol enanthate have been found to return to baseline levels of around 50 pg/mL after about 20 to 30 days.^{[43][7][5][54][10]} However, a metabolic study found that traces of radiolabeled estradiol enanthate remained detectable in blood for at least 30 to 40 days and for as long as 60 days.^[53] Studies have reported that the elimination half-life of estradiol enanthate after a single 10 mg intramuscular injection was 5.6 to 7.5 days.^[7][1][8] The volume of distribution of estradiol enanthate has been reported to be 5.087 L.^[9] Estradiol enanthate is excreted preferentially in urine.^[22]

There were concerns about possible accumulation of estradiol enanthate and consequent estrogenic overexposure with once-monthly combined injectable contraceptives containing the medication due its long duration, and this may have limited the use of such combined injectable contraceptives.^[8][10] Subsequent clinical studies have found that there is very limited or no accumulation of estradiol enanthate when it is used in once-a-month injectable contraceptives.^[8][38][2]

Generic names

Estradiol enantate is the British English generic name of the medication and its INNMTooltip International Nonproprietary Name and BANMTooltip British Approved Name, while estradiol enanthate is its USANTooltip United States Adopted Name and American English generic name.^{[42][15][12][64]} Its generic names in other languages are as follows:^[13][12]

• French: enantate d'estradiol and estradiol enantate
• German: estradiol enantat
• Italian: estradiolo enantato
• Portuguese and Spanish: enantato de estradiol and estradiol enantato

Estradiol enanthate is also known by its former developmental code name SQ-16150.^[65] It has been referred to as estradiol heptanoate.^{[15][42][14][12][13]}

Brand names

Estradiol enanthate has been marketed under a wide variety of brand names.^{[13][12][66][67][11][68][29][69][23][2][10]} It has been marketed in a few different preparations, with varying doses of estradiol enanthate and DHPA.^{[29][11][68][28][23][2][10]} These formulations all have different brand names, which include the following (^† = discontinued):^{[13][12][66][67][28][29][11][68][2][70]}

• EEn 10 mg / DHPA 150 mg: Acefil, Agurin^†, Atrimon^†, Ciclomes, Ciclovar, Ciclovular, Cicnor^†, Clinomin, Cycloven, Daiva, Damix, Deprans, Deproxone, Exuna, Ginestest, Ginoplan^†, Gynomes, Horprotal, Listen, Luvonal, Neogestar, Neolutin, Nomagest, Nonestrol, Normagest, Normensil, Novular, Oterol, Ovoginal, Patector, Patectro, Perludil, Perlumes, Perlutal, Perlutale, Perlutan, Perlutin, Perlutin-Unifarma, Permisil, Preg-Less, Pregnolan, Progestrol^†, Protegin, Proter, Seguralmes, Synovular, Topasel, Unigalen, Uno-Ciclo, and Vagital.
• EEn 10 mg / DHPA 120 mg: Anafertin^†, Patector NF, and Yectames.
• EEn 5 mg / DHPA 75 mg: Unalmes and Yectuna.
• EEn 10 mg / DHPA 75 mg: Ova Repos^†.
• Unsorted: Evitas^†, Femineo^†, and Primyfar^†.

The combination of EEn 10 mg and DHPA 150 mg was developed under the developmental brand name Deladroxate, but this brand name was never used commercially.^[23][2]

Availability

Estradiol enanthate has been marketed in combination with DHPA as a combined injectable contraceptive in at least 19 countries, mostly in Latin America.^{[11][68][29][69][13][12][66][67]} A few different preparations, with varying doses of EEn and DHPA and varying availability, have been introduced.^{[29][11][68][28][23][2][10]} These formulations have the following approval and availability (^† = discontinued in this country):^{[13][12][66][67][28][29][11][68][2]}

• EEn 10 mg / DHPA 150 mg: at least 19 countries, including Argentina, Belize, Brazil, Chile, Colombia, Costa Rica, the Dominican Republic, Ecuador, El Salvador, Guatemala, Honduras, Hong Kong, Mexico, Nicaragua, Panama, Paraguay, Peru, Portugal^†, and Spain^†.
• EEn 10 mg / DHPA 120 mg: at least 3 countries, including Brazil^†, Chile, and Paraguay.
• EEn 5 mg / DHPA 75 mg: at least 9 countries, including Costa Rica, the Dominican Republic, El Salvador, Guatemala, Honduras, Mexico, Nicaragua, Panama, and Spain^†.

EEn is also available in Canada in combination with estradiol benzoate and testosterone enanthate for veterinary use as Uni-Bol.^[71]

Usage

EEn/DHPA is the most widely used combined injectable contraceptive in Latin America.^[72] It was estimated in 1995 that EEn/DHPA was used as a combined injectable contraceptive in Latin America by at least 1 million women.^[29] However, combined injectable contraceptives like EEn/DHPA are unlikely to constitute a large proportion of total contraceptive use in the countries in which they are available.^[29]