Estradiol enantate (EEn or E2-EN), also spelled estradiol enanthate and sold under the brand names Perlutal and Topasel among others, is an estrogen medication which is used in hormonal birth control for women. It is formulated in combination with dihydroxyprogesterone acetophenide (DHPA; algestone acetophenide), a

progestin A progestogen, also referred to as a progestagen, gestagen, or gestogen, is a type of medication which produces effects similar to those of the natural product, natural female sex hormone progesterone in the body. A progestin is a ''synthetic co ...

, and is used specifically as a combined injectable contraceptive. Estradiol enantate is not available for medical use alone. The medication, in combination with DHPA, is given by

injection into muscle Intramuscular injection, often abbreviated IM, is the injection of a substance into a muscle. In medicine, it is one of several methods for parenteral administration of medications. Intramuscular injection may be preferred because muscles have l ...

once a month. Side effects of estradiol enantate include breast tenderness, breast enlargement, nausea,

headache Headache is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of depression in those with severe headaches. Headaches can occur as a result ...

, and fluid retention. Estradiol enantate is an estrogen and hence is an

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...

of the estrogen receptor, the biological target of estrogens like estradiol. It is an estrogen ester and a long-lasting

prodrug A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the drug ...

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.

Medical uses

Estradiol enantate is used in combination with the progestin DHPA as a once-monthly combined injectable contraceptive for women in Latin America and Hong Kong. Estradiol enantate has been studied in feminizing hormone therapy for transgender women as well. The combination of estradiol enantate and DHPA has likewise been used by transgender women for such purposes.

Available forms

The following forms of estradiol enantate are or have been available for use: * Estradiol enantate 10 mg and DHPA 150 mg (brand names Perlutal, Topasel, many others) * Estradiol enantate 5 mg and DHPA 75 mg (brand names Anafertin, Patector NF, Yectames) * Estradiol enantate 10 mg and DHPA 120 mg (brand names Unalmes, Yectuna) * Estradiol enantate 10 mg and DHPA 75 mg (brand name Ova Repos; discontinued) A 6 mg estradiol enantate and 90 mg DHPA formulation was also studied, but was never marketed. The combination of estradiol enantate and DHPA has also been studied at other doses ranging from 5 to 50 mg estradiol enantate and 75 to 200 mg DHPA. The combination of estradiol enantate and DHPA is provided in ampoules at estradiol enantate concentrations of 5 mg/mL and 10 mg/mL.

Contraindications

Contraindications of estrogens include coagulation problems,

cardiovascular disease Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, h ...

s, liver disease, and certain hormone-sensitive cancers such as breast cancer and

endometrial cancer Endometrial cancer is a cancer that arises from the endometrium (the lining of the uterus or womb). It is the result of the abnormal growth of cells that have the ability to invade or spread to other parts of the body. The first sign is most o ...

, among others.

Side effects

The side effects of estradiol enantate are the same as those of estradiol. Examples of such side effects include breast tenderness and enlargement, nausea, bloating,

edema Edema, also spelled oedema, and also known as fluid retention, dropsy, hydropsy and swelling, is the build-up of fluid in the body's Tissue (biology), tissue. Most commonly, the legs or arms are affected. Symptoms may include skin which feels t ...

, and melasma. The combination of estradiol enantate and DHPA as a combined injectable contraceptive has shown no adverse effects on liver function, lipid metabolism, or coagulation. A Brazilian case report of a prolactinoma in a transgender woman treated with 10 mg estradiol enantate every 2 weeks exists.Camara, V. L., Zanardi, U. V., Glezer, A., Paraiba, D. B., Bronstein, M. D., Mendonca, B. B., & Costa, E. M. F. (2010, June). Estrogen as a Presumed Risk Factor for Prolactinoma in a Male-to-Female Transsexual Patient. Endocrine Reviews, Supplement 1, 31(3), S347–S347. https://www.endocrine.org/-/media/endocrine/files/endo-annual-meetings/endo_abstracts_2010_02.pdf#page=347Camara, V. L. (2010). Estradiol enantate First report of prolactinoma, in a transsexual. Reactions, 1311, 24. 10.2165/00128415-201013110-00077. https://link.springer.com/article/10.2165/00128415-201013110-00077 While DHPA was not mentioned in this instance, estradiol enantate is normally formulated in combination with DHPA including in Brazil.

Overdose

Symptom Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than normal, raised or lowered blood pressure or an abnormality showin ...

s of estrogen overdosage may include nausea, vomiting, bloating, increased weight, water retention, breast tenderness, vaginal discharge, heavy legs, and

leg cramps A cramp is a sudden, involuntary, painful skeletal muscle contraction or overshortening associated with electrical activity; while generally temporary and non-damaging, they can cause significant pain and a paralysis-like immobility of the aff ...

. These side effects can be diminished by reducing the estrogen dosage.

Interactions

Inhibitor Inhibitor or inhibition may refer to: In biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotra ...

s and inducers of

cytochrome P450 Cytochromes P450 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...

may influence the metabolism of estradiol and by extension circulating estradiol levels.

Pharmacology

Pharmacodynamics

Estradiol enantate is an estradiol ester, or a

of estradiol. As such, it is an estrogen, or an

of the estrogen receptors. Estradiol enantate is of about 41% higher molecular weight than estradiol due to the presence of its C17β

enantate Enanthic acid, also called heptanoic acid, is an organic compound composed of a seven-carbon chain terminating in a carboxylic acid functional group. It is a colorless oily liquid with an unpleasant, rancid odor. It contributes to the odor of som ...

ester. Because estradiol enantate is a prodrug of estradiol, it is considered to be a natural and bioidentical form of estrogen. The combination of 10 mg estradiol enantate and 150 mg DHPA as a once-monthly combined injectable contraceptive (which achieves levels of estradiol of around 350 pg/mL) 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 Cortisol is a steroid hormone, in the glucocorticoid class of hormones. When used as a medication, it is known as hydrocortisone. It is produced in many animals, mainly by the ''zona fasciculata'' of the adrenal cortex in the adrenal gland ...

, corticosteroid-binding globulin, and sex hormone-binding globulin. However, it was found to significantly increase levels of triglycerides and to significantly decrease levels of total and free testosterone. In contrast to the estradiol enantate-containing combined injectable contraceptive, low-dose ethinylestradiol-containing birth control pills produce highly significant changes in all of the preceding parameters. Studies in women and female capuchin monkeys have found that injections of estradiol enantate and DHPA significantly alter levels of coagulation factors.Oliva Filho, W. M., & Santos, N. da C. (1992). Efeitos na coagulação sanguinea em usuárias da associação acetofenido de dihidroxiprogesterona 150mg e enantato de estradiol 10mg como metodo anticoncepcional injetavel. Universidade de São Paulo, São Paulo. https://bdpi.usp.br/item/000736190 The clinical estrogenic effects of estradiol enantate and ethinylestradiol have been compared in other studies as well.

Pharmacokinetics

When estradiol enantate is administered in an oil solution by

intramuscular injection Intramuscular injection, often abbreviated IM, is the injection of a substance into a muscle. In medicine, it is one of several methods for parenteral administration of medications. Intramuscular injection may be preferred because muscles have ...

, a depot effect occurs, and this results in it having a long duration of action. The duration of action of estradiol enantate is considerably longer than that of various other estradiol esters, such as estradiol benzoate, estradiol valerate, and estradiol cypionate, whereas its duration is shorter than that of estradiol undecylate. In general, the longer the fatty acid ester

chain A chain is a serial assembly of connected pieces, called links, typically made of metal, with an overall character similar to that of a rope in that it is flexible and curved in compression but linear, rigid, and load-bearing in tension. A c ...

, 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. The

pharmacokinetics Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...

of estradiol enantate have been assessed in a number of studies. It has usually been studied in combination with DHPA. Following an

of estradiol enantate, levels of estradiol have been found to peak after 3 to 8 days. Maximal levels of estradiol after a 5 mg injection of estradiol enantate have been found to be about 163 to 209 pg/mL and after a 10 mg injection of estradiol enantate have been found to be about 283 to 445 pg/mL. However, one outlying study reported peak estradiol levels of 850 pg/mL after an intramuscular injection of 10 mg estradiol enantate in three postmenopausal women. It used radioimmunoassay for the determinations, with no mention of

chromatographic separation In chemical analysis, chromatography is a laboratory technique for the separation of a mixture into its components. The mixture is dissolved in a fluid solvent (gas or liquid) called the ''mobile phase'', which carries it through a system (a ...

. Estradiol levels following an intramuscular injection of 10 mg estradiol enantate have been found to return to baseline levels of around 50 pg/mL after about 20 to 30 days. However, a

metabolic Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...

study found that traces of radiolabeled estradiol enantate remained detectable in blood for at least 30 to 40 days and for as long as 60 days. Studies have reported that the elimination half-life of estradiol enantate after a single 10 mg intramuscular injection was 5.6 to 7.5 days. The volume of distribution of estradiol enantate has been reported to be 5.087 L. Estradiol enantate is excreted preferentially in urine. There were concerns about possible accumulation of estradiol enantate 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. Subsequent clinical studies have found that there is very limited or no accumulation of estradiol enantate when it is used in once-a-month injectable contraceptives.

Chemistry

Estradiol enantate, also known as estradiol 17β-enantate or estra-1,3,5(10)-triene-3,17β-diol 17β-heptanoate, is a

synthetic Synthetic things are composed of multiple parts, often with the implication that they are artificial. In particular, 'synthetic' may refer to: Science * Synthetic chemical or compound, produced by the process of chemical synthesis * Synthetic o ...

estrane

steroid A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and a ...

and the C17β

(heptanoate) fatty acid ester of estradiol. Other common esters of estradiol used clinically include estradiol benzoate, estradiol cypionate, estradiol undecylate, and estradiol valerate. Estradiol dienantate (component of Climacteron), or estradiol 3,17β-dienantate, has also been used. The experimental octanol/water partition coefficient (logP) of estradiol enanthate is 6.7.

History

Estradiol enantate was first described, along with a variety of other estradiol esters, by Karl Junkmann of Schering AG in 1953. The first clinical study of estradiol enantate and DHPA as a combined injectable contraceptive was conducted in 1964. The combination was marketed by the mid-1970s.

Society and culture

Generic names

''Estradiol enantate'' is the British English generic name of the medication and its and , while ''estradiol enanthate'' is its and

American English American English, sometimes called United States English or U.S. English, is the set of variety (linguistics), varieties of the English language native to the United States. English is the Languages of the United States, most widely spoken lan ...

generic name. Its generic names in other languages are as follows: *

French French (french: français(e), link=no) may refer to: * Something of, from, or related to France ** French language, which originated in France, and its various dialects and accents ** French people, a nation and ethnic group identified with Franc ...

: ''enantate d'estradiol'' and ''estradiol enantate'' * German: ''estradiol enantat'' * Italian: ''estradiolo enantato'' * Portuguese and Spanish: ''enantato de estradiol'' and ''estradiol enantato'' Estradiol enantate is also known by its former developmental code name ''SQ-16150''. It has been referred to as ''estradiol heptanoate''.

Brand names

Estradiol enantate has been marketed under a wide variety of brand names. It has been marketed in a few different preparations, with varying doses of estradiol enantate and DHPA. These formulations all have different brand names, which include the following (^† = discontinued): * 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.

Availability

Estradiol enantate has been marketed in combination with DHPA as a combined injectable contraceptive in at least 19 countries, mostly in Latin America.
/ref> A few different preparations, with varying doses of EEn and DHPA and varying availability, have been introduced. These formulations have the following approval and availability (^† = discontinued in this country): * EEn 10 mg / DHPA 150 mg: at least 19 countries, including Argentina, Belize, Brazil, Chile,

Colombia Colombia (, ; ), officially the Republic of Colombia, is a country in South America with insular regions in North America—near Nicaragua's Caribbean coast—as well as in the Pacific Ocean. The Colombian mainland is bordered by the Car ...

Costa Rica Costa Rica (, ; ; literally "Rich Coast"), officially the Republic of Costa Rica ( es, República de Costa Rica), is a country in the Central American region of North America, bordered by Nicaragua to the north, the Caribbean Sea to the no ...

, the Dominican Republic, Ecuador,

El Salvador El Salvador (; , meaning " The Saviour"), officially the Republic of El Salvador ( es, República de El Salvador), is a country in Central America. It is bordered on the northeast by Honduras, on the northwest by Guatemala, and on the south b ...

Guatemala Guatemala ( ; ), officially the Republic of Guatemala ( es, República de Guatemala, links=no), is a country in Central America. It is bordered to the north and west by Mexico; to the northeast by Belize and the Caribbean; to the east by H ...

Honduras Honduras, officially the Republic of Honduras, is a country in Central America. The republic of Honduras is bordered to the west by Guatemala, to the southwest by El Salvador, to the southeast by Nicaragua, to the south by the Pacific Oce ...

, 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

, the Dominican Republic,

, Mexico, Nicaragua, Panama, and Spain^†. EEn is also available in Canada in combination with estradiol benzoate and testosterone enantate for veterinary use as Uni-Bol.

Usage

EEn/DHPA is the most widely used combined injectable contraceptive in Latin America. It was estimated in 1995 that EEn/DHPA was used as a combined injectable contraceptive in Latin America by at least 1 million women. 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.

References

{{Estrogen receptor modulators Antigonadotropins Enanthate esters Estradiol esters Hormonal contraception Phenols Prodrugs Synthetic estrogens Veterinary drugs