Estradiol benzoate (EB), sold under the brand name Progynon-B among others, is an

estrogen Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ...

medication which is used in

hormone therapy Hormone therapy or hormonal therapy is the use of hormones in medical treatment. Treatment with hormone antagonists may also be referred to as hormonal therapy or antihormone therapy. The most general classes of hormone therapy are hormonal therap ...

for

menopausal symptoms Menopause, also known as the climacteric, is the time when menstrual periods permanently stop, marking the end of the reproductive stage for the female human. It typically occurs between the ages of 45 and 55, although the exact timing can ...

and low estrogen levels in women, in

for

transgender women A trans woman or transgender woman is a woman who was assigned male at birth. Trans women have a female gender identity and may experience gender dysphoria (distress brought upon by the discrepancy between a person's gender identity and their ...

, and in the treatment of

gynecological disorder Gynaecology or gynecology (see American and British English spelling differences) is the area of medicine concerned with conditions affecting the female reproductive system. It is often paired with the field of obstetrics, which focuses on pre ...

s. It is also used in the treatment of

prostate cancer Prostate cancer is the neoplasm, uncontrolled growth of cells in the prostate, a gland in the male reproductive system below the bladder. Abnormal growth of the prostate tissue is usually detected through Screening (medicine), screening tests, ...

in men. Estradiol benzoate is used in

veterinary medicine Veterinary medicine is the branch of medicine that deals with the prevention, management, medical diagnosis, diagnosis, and treatment of disease, disorder, and injury in non-human animals. The scope of veterinary medicine is wide, covering all a ...

as well. When used clinically, the medication is given by injection into muscle usually two to three times per week.

Side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

s of estradiol benzoate include

breast tenderness Breast pain is the symptom of discomfort in either one or both breasts. Pain in both breasts is often described as ''breast tenderness'', is usually associated with the menstrual period and is not serious. Pain that involves only one part of a ...

, breast enlargement,

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...

headache A headache, also known as cephalalgia, 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 (mood), depression in those with severe ...

, and fluid retention. Estradiol benzoate is an

and hence is an

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

of the

estrogen receptor Estrogen receptors (ERs) are proteins found in cell (biology), cells that function as receptor (biochemistry), receptors for the hormone estrogen (17β-estradiol). There are two main classes of ERs. The first includes the intracellular estrogen ...

, the

biological target A biological target is anything within a living organism to which some other entity (like an endogenous ligand or a drug) is directed and/or binds, resulting in a change in its behavior or function. Examples of common classes of biological targets ...

s like

estradiol Estradiol (E2), also called oestrogen, oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of female reproductive cycles such as estrous and menstrual cycles. Estradiol is responsible ...

. It is an

estrogen ester An estrogen ester is an ester of an estrogen, most typically of estradiol but also of other estrogens such as estrone, estriol, and even nonsteroidal estrogens like diethylstilbestrol. Esterification renders estradiol into a prodrug of estradiol ...

and a

prodrug A prodrug is a pharmacologically inactive 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 ...

in the body. Because of this, it is considered to be a

natural Nature is an inherent character or constitution, particularly of the ecosphere or the universe as a whole. In this general sense nature refers to the laws, elements and phenomena of the physical world, including life. Although humans are part ...

and

bioidentical Bioidentical hormone replacement therapy (BHRT), also known as bioidentical hormone therapy (BHT) or natural hormone therapy, is the use of hormones that are identical on a molecular level with endogenous hormones in hormone replacement therapy. ...

form of estrogen. Estradiol benzoate was discovered in 1933 and was introduced for medical use that same year. It was the first

estradiol ester This is a list of estrogen esters, or ester prodrugs of estrogens. It includes esters, as well as ethers, of steroidal estrogens like estradiol, estrone, and estriol and of nonsteroidal estrogens like the stilbestrols diethylstilbestrol an ...

to be discovered or marketed, and was one of the first estrogens to be used in medicine. Along with

estradiol dipropionate Estradiol dipropionate (EDP), sold under the brand names Agofollin, Di-Ovocylin, and Progynon DP among others, is an estrogen medication which has been used in hormone therapy for menopausal symptoms and low estrogen levels in women and in the t ...

, estradiol benzoate was among the most widely used esters of estradiol for many years following its introduction. However, in the 1950s, longer-acting estradiol esters that necessitated less frequent injections, such as

estradiol valerate Estradiol valerate (EV), sold for use oral administration, by mouth under the brand name Progynova and for use by injection (medicine), injection under the brand names Delestrogen and Progynon Depot among others, is an estrogen (medication), es ...

and

estradiol cypionate Estradiol cypionate (EC), sold under the brand name Depo-Estradiol among others, is an estrogen medication which is used in hormone therapy for menopausal symptoms and low estrogen levels in women, in hormone therapy for trans women, and in horm ...

, were developed, and have since largely superseded estradiol benzoate. Nonetheless, estradiol benzoate remains widely available throughout the world. It is not available for medical use in the

United States The United States of America (USA), also known as the United States (U.S.) or America, is a country primarily located in North America. It is a federal republic of 50 U.S. state, states and a federal capital district, Washington, D.C. The 48 ...

, but is available there for use in veterinary medicine.

Medical uses

The

medical use Medicine is the science and Praxis (process), practice of caring for patients, managing the Medical diagnosis, diagnosis, prognosis, Preventive medicine, prevention, therapy, treatment, Palliative care, palliation of their injury or disease, ...

s of estradiol benzoate are the same as those of estradiol and other estrogens. Estradiol benzoate is used in

for the treatment of

such as

hot flash Hot flushes are a form of flushing, often caused by the changing hormone levels that are characteristic of menopause. They are typically experienced as a feeling of intense heat with sweating and rapid heartbeat, and may typically last from t ...

es and

vaginal atrophy Atrophic vaginitis is inflammation of the vagina as a result of tissue thinning due to low estrogen levels. Symptoms may include pain during penetrative sex, vaginal itchiness or dryness, and an urge to urinate or burning with urination. It ...

and in the treatment of

hypoestrogenism Hypoestrogenism, or estrogen deficiency, refers to a lower than normal level of estrogen. It is an umbrella term used to describe estrogen deficiency in various conditions. Estrogen deficiency is also associated with an increased risk of cardiov ...

and

delayed puberty Delayed puberty is when a person lacks or has incomplete development of specific sexual characteristics past the usual age of onset of puberty. The person may have no physical or hormone, hormonal signs that puberty has begun. In the United States ...

due to

hypogonadism Hypogonadism means diminished functional activity of the human gonad, gonads—the testicles or the ovary, ovaries—that may result in diminished biosynthesis, production of sex hormones. Low androgen (e.g., testosterone) levels are referred t ...

or other causes in women. It is also used in

for

. Aside from hormone therapy, estradiol benzoate is used in the treatment of

s such as

menstrual disorder A menstrual disorder is characterized as any abnormal condition with regards to a woman's menstrual cycle. There are many different types of menstrual disorders that vary with signs and symptoms, including pain during menstruation, heavy bleeding, ...

dysfunctional uterine bleeding Abnormal uterine bleeding is vaginal bleeding from the uterus that is abnormally frequent, lasts excessively long, is heavier than normal, or is irregular. The term "dysfunctional uterine bleeding" was used when no underlying cause was presen ...

, and

breast engorgement Breast engorgement occurs in the mammary glands due to expansion and pressure exerted by the synthesis and storage of breast milk. It is also a main factor in altering the ability of the infant to latch-on. Engorgement changes the shape and cu ...

. In addition, it is used as a form of

high-dose estrogen High-dose estrogen therapy (HDE) is a type of hormone therapy in which high doses of estrogens are given. When given in combination with a high dose of progestogen, it has been referred to as pseudopregnancy. It is called this because the estrog ...

therapy in the

palliative Palliative care (from Latin root "to cloak") is an interdisciplinary medical care-giving approach aimed at optimizing quality of life and mitigating or reducing suffering among people with serious, complex, and often terminal illnesses. Man ...

treatment of

in men. Estradiol benzoate has a relatively short

duration of action Pharmacodynamics (PD) is the study of the biochemical and physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or combinations of organisms (fo ...

, and is administered by

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

usually two to three times per week. It is used in the treatment of menopausal symptoms at a dosage of 1 to 1.66 mg initially and 0.33 to 1 mg for maintenance two times per week, and in the treatment of hypoestrogenism and delayed puberty at a dosage of 1.66 mg two to three times per week. The dosage used in hormone therapy for transgender women is 0.5 to 1.5 mg two to three times per week. In the treatment of prostate cancer, estradiol benzoate is used at a dosage of 1.66 mg three times per week (for a total of 5 mg per week).

Available forms

Estradiol benzoate is and has been available as an

oil solution An oil is any nonpolar chemical substance that is composed primarily of hydrocarbons and is hydrophobic (does not mix with water) and lipophilic (mixes with other oils). Oils are usually flammable and surface active. Most oils are unsaturat ...

for intramuscular injection provided as

vial A vial (also known as a phial or flacon) is a small glass or plastic vessel or bottle, often used to store medication in the form of liquids, powders, or capsules. They can also be used as scientific sample vessels; for instance, in autosam ...

s and

ampoule An ampoule (also ampul and ampule) is a small sealed vial which is used to contain and preserve a sample, usually a solid or liquid. Ampoules are usually made of glass. Modern ampoules are most commonly used to contain pharmaceuticals and chem ...

s at concentrations of 0.167, 0.2, 0.33, 1, 1.67, 2, 5, 10, 20, and 25 mg/mL. It is also available as a

microcrystalline A microcrystalline material is a crystallized substance or rock that contains small crystals visible only through microscopic examination. There is little agreement on the range of crystal sizes that should be regarded as microcrystalline, but ...

aqueous suspension In chemistry, a suspension is a heterogeneous mixture of a fluid that contains solid particles sufficiently large for sedimentation. The particles may be visible to the naked eye, usually must be larger than one micrometer, and will eventually s ...

for intramuscular injection under the brand name Agofollin Depot. Sistocyclin was the brand name of a product containing 10 mg microcrystalline estradiol benzoate and 200 mg microcrystalline

progesterone Progesterone (; P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the ma ...

in an aqueous suspension. Follivirin (and previously Femandren M) is the brand name of a product containing 2.5 mg microcrystalline estradiol benzoate and 25 to 50 mg microcrystalline

testosterone isobutyrate Testosterone isobutyrate, sold under the brand names Agovirin-Depot and Perandren M among others, is an androgen and anabolic steroid medication and a testosterone ester which is used for indications such as low testosterone levels in men and de ...

in aqueous suspension. A

vaginal In mammals and other animals, the vagina (: vaginas or vaginae) is the elastic, muscular reproductive organ of the female genital tract. In humans, it extends from the vulval vestibule to the cervix (neck of the uterus). The vaginal introit ...

tablet formulation containing 0.125 mg estradiol benzoate and 10 mg monalazone sodium (a vaginal

disinfectant A disinfectant is a chemical substance or compound used to inactivate or destroy microorganisms on inert surfaces. Disinfection does not necessarily kill all microorganisms, especially resistant bacterial spores; it is less effective than ...

and

spermicidal Spermicide is a contraceptive substance that destroys sperm, inserted vaginally prior to intercourse to prevent pregnancy. As a contraceptive, spermicide may be used alone. However, the pregnancy rate experienced by couples using only spermici ...

contraceptive Birth control, also known as contraception, anticonception, and fertility control, is the use of methods or devices to prevent pregnancy. Birth control has been used since ancient times, but effective and safe methods of birth control only be ...

) has been marketed under the brand name Malun 25. Estradiol benzoate was also formerly available as 50 and 100 mg pellets for subcutaneous implantation and as a 2 mg/g ointment.

Contraindications

Contraindication In medicine, a contraindication is a condition (a situation or factor) that serves as a reason not to take a certain medical treatment due to the harm that it would cause the patient. Contraindication is the opposite of indication, which is a rea ...

s of estrogens include

coagulation Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a thrombus, blood clot. It results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The process of co ...

problems,

cardiovascular disease Cardiovascular disease (CVD) is any disease involving the heart or blood vessels. CVDs constitute a class of diseases that includes: coronary artery diseases (e.g. angina, heart attack), heart failure, hypertensive heart disease, rheumati ...

liver disease Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common. Liver diseases File:Ground gla ...

, and certain

hormone-sensitive cancer A hormone-sensitive cancer, or hormone-dependent cancer, is a type of cancer that is dependent on a hormone for growth and/or survival. Examples include breast cancer, which is dependent on estrogens like estradiol, and prostate cancer, which is ...

s such as

breast cancer Breast cancer is a cancer that develops from breast tissue. Signs of breast cancer may include a Breast lump, lump in the breast, a change in breast shape, dimpling of the skin, Milk-rejection sign, milk rejection, fluid coming from the nipp ...

and

endometrial cancer Endometrial cancer is a cancer that arises from the endometrium (the epithelium, lining of the uterus or womb). It is the result of the abnormal growth of cells (biology), cells that can invade or spread to other parts of the body. The first s ...

, among others.

Side effects

The

side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

s of estradiol benzoate are the same as those of estradiol. Examples of such side effects include

and enlargement,

bloating Abdominal bloating (or simply bloating) is a short-term disease that affects the gastrointestinal tract. Bloating is generally characterized by an excess buildup of gas, air or fluids in the stomach. A person may have feelings of tightness, pressu ...

edema Edema (American English), also spelled oedema (British English), and also known as fluid retention, swelling, dropsy and hydropsy, is the build-up of fluid in the body's tissue (biology), tissue. Most commonly, the legs or arms are affected. S ...

, and

melasma Melasma (also known as chloasma faciei,James, William; Berger, Timothy; Elston, Dirk (2005). ''Andrews' Diseases of the Skin: Clinical Dermatology''. (10th ed.). Saunders. . or the mask of pregnancy when present in pregnant women) is a tan or dar ...

Overdose

Symptom Signs and symptoms are diagnostic indications of an illness, injury, or condition. Signs are objective and externally observable; symptoms are a person's reported subjective experiences. A sign for example may be a higher or lower temperature ...

s of estrogen overdosage may include

vomiting Vomiting (also known as emesis, puking and throwing up) is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteritis, pre ...

, increased weight, water retention,

vaginal discharge Vaginal discharge is a mixture of liquid, cells, and bacteria that lubricate and protect the vagina. This mixture is constantly produced by the cells of the vagina and cervix, and it exits the body through the vaginal opening. The composition, ...

heavy legs Heavy legs is a condition described as an unpleasant sensation of pain and heaviness in the lower limbs. Symptoms include legs feeling weighted, stiff, and tired. Heavy legs can be caused by a wide-ranging collection of disorders including but n ...

, 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 affe ...

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

Interactions

Inhibitor Inhibitor or inhibition may refer to: 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 neurotransmi ...

s and

inducer In molecular biology, an inducer is a molecule that regulates gene expression. An inducer functions in two ways; namely: *By disabling repressors. The gene is expressed because an inducer binds to the repressor. The binding of the inducer to the r ...

s of

cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...

may influence the

metabolism Metabolism (, from ''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 cellular processes; the co ...

of estradiol and by extension circulating estradiol levels.

Pharmacology

Pharmacodynamics

Estradiol benzoate is an

, or a

. As such, it is an

, or an

of the

s. Estradiol benzoate has very low

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...

for the ERs, on the order of 100-fold less than that of estradiol. As such, estradiol benzoate is regarded as essentially inactive in terms of estrogenic effect itself, acting solely as a

to estradiol. Estradiol benzoate is of about 38% higher

molecular weight A molecule is a group of two or more atoms that are held together by Force, attractive forces known as chemical bonds; depending on context, the term may or may not include ions that satisfy this criterion. In quantum physics, organic chemi ...

than estradiol due to the presence of its C3

benzoate Benzoic acid () is a white (or colorless) solid organic compound with the formula , whose structure consists of a benzene ring () with a carboxyl () substituent. The benzoyl group is often abbreviated "Bz" (not to be confused with "Bn," which ...

ester. Because estradiol benzoate is a prodrug of estradiol, it is considered to be a

and

form of estrogen.

Estrogenic potency

In the case of intramuscular injections of either estradiol benzoate or

in oil solution, the maturation dosage for the

vagina In mammals and other animals, the vagina (: vaginas or vaginae) is the elastic, muscular sex organ, reproductive organ of the female genital tract. In humans, it extends from the vulval vestibule to the cervix (neck of the uterus). The #Vag ...

epithelium Epithelium or epithelial tissue is a thin, continuous, protective layer of cells with little extracellular matrix. An example is the epidermis, the outermost layer of the skin. Epithelial ( mesothelial) tissues line the outer surfaces of man ...

is 5 to 7 mg once per week and the

endometrial The endometrium is the inner epithelium, epithelial layer, along with its mucous membrane, of the mammalian uterus. It has a basal layer and a functional layer: the basal layer contains stem cells which regenerate the functional layer. The funct ...

proliferation dosage is 7 to 10 mg once per week. The total endometrial proliferation dosage of estradiol benzoate in oil solution by intramuscular injection over 14 days is 25 to 35 mg. The full

endometrial transformation Decidualization is a process that results in significant changes to cells of the endometrium in preparation for, and during, pregnancy. This includes morphological and functional changes (the decidual reaction) to endometrial stromal cells (ESCs) ...

dosage of

estradiol benzoate/progesterone Estradiol benzoate/progesterone (EB/P4), sold under the brand names Duogynon and Sistocyclin among others, is a combination medication of estradiol benzoate (EB), an estrogen, and progesterone (P4), a progestogen. It has been formulated both as ...

in oil solution is 1 to 2 mg estradiol benzoate and 20 to 25 mg progesterone by intramuscular injection daily for 10 to 14 days, whereas the full endometrial transformation dosage of estradiol benzoate/progesterone in microcrystalline aqueous suspension is a single intramuscular injection of 10 mg estradiol benzoate and 200 mg progesterone. For comparison, the full endometrial transformation dosage of estradiol valerate and

hydroxyprogesterone caproate Hydroxyprogesterone caproate, sold under the brand name Delalutin among others, is a medication used to reduce the risk of preterm birth in women pregnant with one baby who have a history of spontaneous preterm birth. In March 2023, the manuf ...

in oil solution (brand name

Gravibinon Estradiol valerate/hydroxyprogesterone caproate (EV/OHPC), sold under the brand names Gravibinon and Injectable No. 1 (or Chinese Injectable No. 1) among others, is a combined estrogen and progestogen medication which is used in the treatment of ...

) is a single intramuscular injection of 10 mg estradiol valerate and 250 to 375 mg hydroxyprogesterone caproate. Endometrial transformation normally occurs during the

luteal phase The menstrual cycle is on average 28 days in length. It begins with Menstruation, menses (day 1–7) during the follicular phase (day 1–14), followed by ovulation (day 14) and ending with the luteal phase (day 14–28). While historically, medi ...

of the

menstrual cycle The menstrual cycle is a series of natural changes in hormone production and the structures of the uterus and ovaries of the female reproductive system that makes pregnancy possible. The ovarian cycle controls the production and release of eg ...

; it is induced by

endogenous Endogeny, in biology, refers to the property of originating or developing from within an organism, tissue, or cell. For example, ''endogenous substances'', and ''endogenous processes'' are those that originate within a living system (e.g. an ...

progesterone following adequate priming by endogenous estradiol. The

decidua The decidua is the modified mucosal lining of the uterus (that is, modified endometrium) that forms every month, in preparation for pregnancy. It is shed off each month when there is no fertilized egg to support. The decidua is under the influe ...

(

pregnancy Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...

-type

endometrium The endometrium is the inner epithelium, epithelial layer, along with its mucous membrane, of the mammalian uterus. It has a basal layer and a functional layer: the basal layer contains stem cells which regenerate the functional layer. The funct ...

) induction dosage of estradiol benzoate/progesterone in oil solution is 2 to 5 mg estradiol benzoate and 20 to 100 mg progesterone by intramuscular injection daily for 5 to 7 weeks, whereas the decidua induction dosage of estradiol benzoate/progesterone in microcrystalline aqueous suspension is 10 to 20 mg estradiol benzoate and 200 to 250 mg progesterone in microcrystalline aqueous suspension by intramuscular injection once per week for about 6 weeks. For comparison, the decidua induction dosage of estradiol valerate and hydroxyprogesterone caproate in oil solution is about the same as that of microcrystalline estradiol benzoate/progesterone in aqueous suspension. The decidua induction dosages of estrogen and progestogen combinations are

pseudopregnancy In mammalian species, pseudopregnancy is a physical state whereby all the signs and symptoms of pregnancy are exhibited, with the exception of the presence of a fetus, creating a false pregnancy. The corpus luteum (the remains of an ovulated ovar ...

dosages.

Antigonadotropic effects

Hormone levels with twice-daily injectable estradiol benzoate in transgender women

As with other estrogens and forms of estradiol, estradiol benzoate dose-dependently suppresses

gonadotropin Gonadotropins are glycoprotein hormones secreted by gonadotropic cells of the anterior pituitary of vertebrates. They are central to the complex endocrine system that regulates normal growth, sexual development, and reproductive function. T ...

and

testosterone Testosterone is the primary male sex hormone and androgen in Male, males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testicles and prostate, as well as promoting se ...

levels in men and

. In a study that administered estradiol benzoate twice-daily to transgender women at a dose that resulted in measured estradiol levels of about 200 to 250pg/mL, testosterone levels decreased from around 530ng/dL at baseline to about 55ng/dL (–90%) within approximately 3days of treatment.

Pharmacokinetics

Following administration, estradiol benzoate acts as a

of estradiol via

cleavage Cleavage may refer to: Science * Cleavage (crystal), the way in which a crystal or mineral tends to split * Cleavage (embryo), the division of cells in an early embryo * Cleavage (geology), foliation of rock perpendicular to stress, a result of ...

esterase In biochemistry, an esterase is a class of enzyme that splits esters into an acid and an alcohol in a chemical reaction with water called hydrolysis (and as such, it is a type of hydrolase). A wide range of different esterases exist that differ ...

s into estradiol and the natural

fatty acid In chemistry, in particular in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated and unsaturated compounds#Organic chemistry, saturated or unsaturated. Most naturally occurring fatty acids have an ...

benzoic acid Benzoic acid () is a white (or colorless) solid organic compound with the formula , whose structure consists of a benzene ring () with a carboxyl () substituent. The benzoyl group is often abbreviated "Bz" (not to be confused with "Bn," which ...

. This cleavage occurs not only in the

liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

, but also in the

blood Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood is com ...

and in tissues. Esters of estradiol like estradiol benzoate are readily

hydrolyzed Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile. Biological hydrolysi ...

to estradiol, but have an extended duration when administered in via

intramuscular 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 hav ...

subcutaneous injection Subcutaneous administration is the insertion of medications beneath the skin either by injection or infusion. A subcutaneous injection is administered as a bolus (medicine), bolus into the subcutis, the layer of skin directly below the dermis and ...

due to a

depot Depot may refer to: Places * Depot, Poland, a village * Depot Glacier (disambiguation) * Depot Island (disambiguation) * Depot Nunatak * Depot Peak Brands and enterprises * Maxwell Street Depot, a restaurant in Chicago, United States * Of ...

effect afforded by their

ester

moiety Moiety may refer to: __NOTOC__ Anthropology * Moiety (kinship), either of two groups into which a society is divided ** A division of society in the Iroquois societal structure in North America ** An Australian Aboriginal kinship group ** Native Ha ...

and consequent high

lipophilicity Lipophilicity (from Greek λίπος "fat" and φίλος "friendly") is the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such compounds are called lipophilic (translated ...

. A long-lasting local tissue depot is formed by the injection that slowly releases estradiol benzoate into the circulation.

Intramuscular injection

=Oil solution

= The

of estradiol benzoate in oil solution by intramuscular injection at typical clinical doses (e.g., 0.33–1.66 mg) is said to be 2 to 3 days. A single dose of 2.5 mg estradiol benzoate in oil solution by intramuscular injection was found to produce plasma estradiol levels of greater than 400 pg/mL, measured 24 hours post-injection, in a group of patients with minimal baseline levels of estradiol (due to

GnRH analogue A GnRH modulator, or GnRH receptor modulator, also known as an LHRH modulator or LHRH receptor modulator, is a type of medication which modulates the GnRH receptor, the biological target of the hypothalamic hormone gonadotropin-releasing horm ...

therapy with

triptorelin Triptorelin, sold under the brand name Decapeptyl among others, is a medication that acts as an agonist analog of gonadotropin-releasing hormone, repressing expression of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). It is a ...

). The

elimination half-life Biological half-life (elimination half-life, pharmacological half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the blood plasma. ...

of estradiol benzoate in oil solution by intramuscular injection has been reported to be 48 to 120 hours (2 to 5 days). A single intramuscular injection of 5 mg estradiol benzoate in oil solution has been found to result in peak circulating concentrations of 940 pg/mL estradiol and 343 pg/mL estrone, which occurred at about 2 days post-injection. Compared to two other commonly used estradiol esters, estradiol benzoate had the shortest duration, at approximately 4 to 5 days, whereas

and

were found to last for 7 to 8 days and 11 days, respectively. This is because estradiol benzoate has a shorter and less bulky

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 ...

, and in relation to this, is comparatively less

lipophilic Lipophilicity (from Greek language, Greek λίπος "fat" and :wikt:φίλος, φίλος "friendly") is the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such compounds are c ...

. For a given estradiol ester, the shorter or less bulky the fatty acid chain is, the less lipophilic, shorter-lasting, and less uniform/plateau-like the resultant levels of estradiol are as well as the higher (and hence more spike-like) the peak/maximal levels are. Daily intramuscular injections of 1 mg estradiol benzoate in oil solution have been found to produce estradiol

excretion Excretion is elimination of metabolic waste, which is an essential process in all organisms. In vertebrates, this is primarily carried out by the lungs, Kidney (vertebrates), kidneys, and skin. This is in contrast with secretion, where the substa ...

rates almost double those of the normal

. This is in accordance with known production rates of estradiol in women (e.g., 300 μg/day in the luteal phase).

=Aqueous suspension

Microcrystalline A microcrystalline material is a crystallized substance or rock that contains small crystals visible only through microscopic examination. There is little agreement on the range of crystal sizes that should be regarded as microcrystalline, but ...

estradiol benzoate in

(brand names Agofollin Depot and Ovocyclin M alone and Follivirin in combination with

) has been found to have a longer

than

amorphous In condensed matter physics and materials science, an amorphous solid (or non-crystalline solid) is a solid that lacks the long-range order that is a characteristic of a crystal. The terms "glass" and "glassy solid" are sometimes used synonymousl ...

estradiol benzoate in oil solution when administered via intramuscular injection. Whereas the duration of a single intramuscular injection of estradiol benzoate in oil solution is 6 days, the duration of a single intramuscular injection of microcrystalline estradiol benzoate in aqueous suspension is 16 to 21 days. Its duration also surpasses that of

and

. The duration of microcrystalline aqueous suspensions administered by intramuscular injection is dependent both on

concentration In chemistry, concentration is the abundance of a constituent divided by the total volume of a mixture. Several types of mathematical description can be distinguished: '' mass concentration'', '' molar concentration'', '' number concentration'', ...

and on crystal size.

Other routes

The duration of estradiol benzoate is not prolonged if it is administered directly into the circulation via

intravenous injection Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...

, in contrast to intramuscular injection. Estradiol benzoate is active with

oral The word oral may refer to: Relating to the mouth * Relating to the mouth, the first portion of the alimentary canal that primarily receives food and liquid **Oral administration of medicines ** Oral examination (also known as an oral exam or ora ...

and

sublingual administration Sublingual (abbreviated SL), from the Latin for "under the tongue", refers to the pharmacological route of administration by which substances diffuse into the blood through tissues under the tongue. Many drugs are absorbed through sublingual a ...

, similarly to

and

estradiol acetate Estradiol acetate (EA), sold under the brand names Femtrace, Femring, and Menoring, is an estrogen medication which is used in hormone therapy for the treatment of menopausal symptoms in women. It is taken by mouth once daily or given as a vagin ...

. However, it is not marketed in any formulation for use by these routes. Oral estradiol benzoate has been reported to possess about one-third to half the

potency Potency may refer to: * Potency (pharmacology), a measure of the activity of a drug in a biological system * Virility * Cell potency, a measure of the differentiation potential of stem cells * In homeopathic dilutions, potency is a measure of ho ...

of intramuscular injection of estradiol benzoate. This level of oral potency has been described as remarkably high. The sublingual potency of estradiol benzoate is similar to that of estradiol. A study found that the total dose of estradiol benzoate needed for endometrial proliferation in women was 60 to 140 mg, relative to 60 to 180 mg for estradiol. Both estradiol and estradiol benzoate has a persistence of estrogenic effect with single administration of one day.

Subcutaneous implant In medicine, a subcutaneous implant is an implant (medicine), implant that is delivered under the skin into the subcutaneous tissue, subcutaneous tissue (biology), tissue by surgery or injection (medicine), injection and is used to deliver a drug ...

ation of

crystalline A crystal or crystalline solid is a solid material whose constituents (such as atoms, molecules, or ions) are arranged in a highly ordered microscopic structure, forming a crystal lattice that extends in all directions. In addition, macrosc ...

estradiol benzoate pellets has been studied, but no estradiol benzoate pellet implants have been marketed.

Chemistry

Estradiol benzoate is a

synthetic Synthetic may refer to: Science * Synthetic biology * Synthetic chemical or compound, produced by the process of chemical synthesis * Synthetic elements, chemical elements that are not naturally found on Earth and therefore have to be created in ...

estrane Estrane is a C18 steroid derivative, with a gonane core. ''Estrenes'' are estrane derivatives that contain a double bond, with an example being nandrolone. ''Estratrienes'' (estrins) are estrane derivatives that contain three double bonds, for i ...

steroid A steroid is an organic compound with four fused compound, fused rings (designated A, B, C, and D) arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes t ...

and the C3

(benzenecarboxylate)

ester In chemistry, an ester is a compound derived from an acid (either organic or inorganic) in which the hydrogen atom (H) of at least one acidic hydroxyl group () of that acid is replaced by an organyl group (R). These compounds contain a distin ...

. It is also known as estradiol 3-benzoate or as estra-1,3,5(10)-triene-3,17β-diol 3-benzoate. Two estradiol esters that are related to estradiol benzoate are

, the C3,17β dipropionate ester of estradiol, and

, the C3 acetate ester of estradiol. The experimental octanol/water partition coefficient (logP) of estradiol benzoate is 4.7.

History

Estradiol benzoate was one of the first estrogens to be developed and marketed. In 1932,

Adolf Butenandt Adolf Friedrich Johann Butenandt (; 24 March 1903 – 18 January 1995) was a German biochemist. He was awarded the Nobel Prize in Chemistry in 1939 for his "work on sex hormones." He initially rejected the award in accordance with government pol ...

described estrone benzoate and reported that it had a prolonged

. Schwenk and Hildebrant at Schering discovered estradiol via reduction of

estrone Estrone (E1), also spelled oestrone, is a steroid, a weak estrogen, and a minor female sex hormone. It is one of three major endogenous estrogens, the others being estradiol and estriol. Estrone, as well as the other estrogens, are synthesized ...

in 1933, and they proceeded to synthesize estradiol benzoate from estradiol the same year. Estradiol benzoate was

patent A patent is a type of intellectual property that gives its owner the legal right to exclude others from making, using, or selling an invention for a limited period of time in exchange for publishing an sufficiency of disclosure, enabling discl ...

ed by Schering in 1933 and was introduced in an

for use by

under the brand name ''Progynon B'' that year as well. By 1936, multiple formulations of estradiol benzoate in oil solution had been marketed, including under the brand names ''Progynon B'' by Schering, ''Dimenformon Benzoate'' by

Roche F. Hoffmann-La Roche AG, commonly known as Roche (), is a Switzerland, Swiss multinational corporation, multinational holding healthcare company that operates worldwide under two divisions: Pharmaceuticals and Diagnostics. Its holding company, ...

Organon The ''Organon'' (, meaning "instrument, tool, organ") is the standard collection of Aristotle's six works on logical analysis and dialectic. The name ''Organon'' was given by Aristotle's followers, the Peripatetics, who maintained against the ...

, and ''Oestroform B'' by

British Drug Houses The Merck Group, branded and commonly known as Merck, is a German Multinational corporation, multinational science and technology company headquartered in Darmstadt, with about 60,000 employees and a presence in 66 countries. The group include ...

. By the early 1940s, ''Ben-Ovocylin'' had been introduced by Ciba as well. In the late 1940s, the brand name ''Ben-Ovocylin'' was changed by Ciba to ''Ovocylin Benzoate''. Following their introduction, estradiol benzoate and

were the most widely used esters of estradiol for many years. However,

and

, which are longer-acting esters that require less frequent administration, were developed and introduced in the 1950s, and have since largely superseded estradiol benzoate and estradiol dipropionate.

Society and culture

Generic names

''Estradiol benzoate'' is the generic name of the drug and its , , and , while ''oestradiol benzoate'' was formerly its .

Brand names

The major brand name of estradiol benzoate is Progynon-B. It has also been sold under a variety of other brand names including Agofollin Depot, Ben-Ovocylin, Benzhormovarine, Benzoestrofol, Benzofoline, Benzo-Ginestryl, Benzo-Ginoestril, Benzo-Gynoestryl, Benzoate d'oestradiol P.A. Intervet, Benztrone, Benztrone Pabyrn, Diffollisterol, Di-Folliculine, Dimenformon, Dimenformon Benzoate, Dimenformone, Diogyn B, EBZ, Eston-B, Estradiolo Amsa, Femestrone, Follicormon, Follidrin, Graafina, Gynecormone, Gynecormone Gouttes, Gynformone, Metroval, Hidroestron, Hormogynon, Oestradiol Benzoat, Oestradiol-Benzoat Intervet, Oestradiol-K Streuli, Oestradiolium Benzoicum, Oestraform, Ostrin, Ovahormon Benzoate, Ovasterol-B, Ovex, Ovocyclin Benzoate, Ovocyclin M, Primogyn B, Primogyn B Oleosum, Primogyn I, Progynon Benzoate, Recthormone, Oestradiol, Reglovar, Solestro, and Unistradiol, among others.

Availability

Estradiol benzoate is available in

Europe Europe is a continent located entirely in the Northern Hemisphere and mostly in the Eastern Hemisphere. It is bordered by the Arctic Ocean to the north, the Atlantic Ocean to the west, the Mediterranean Sea to the south, and Asia to the east ...

and in other parts of the world. It was previously available for medical use in the

, but is no longer marketed in this country. However, it is approved and marketed in the United States for veterinary use as a

subdermal implant A subdermal implant is a body modification placed under the skin, allowing the body to heal over the implant and creating a raised design. Such implants fall under the broad category of body modification. Many subdermal implants are made out of si ...

both alone and in combination with the

androgen An androgen (from Greek ''andr-'', the stem of the word meaning ) is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This includes ...

anabolic steroid Anabolic steroids, also known as anabolic-androgenic steroids (AAS), are a class of drugs that are structurally related to testosterone, the main male sex hormone, and produce effects by binding to the androgen receptor (AR). Anabolism, Anaboli ...

trenbolone acetate Trenbolone acetate, sold under brand names such as Finajet and Finaplix among others, is an androgen and anabolic steroid (AAS) medication used in veterinary medicine, specifically to increase the profitability of livestock by promoting muscle g ...

(brand names Celerin and Synovex, respectively). Outside of the United States, estradiol benzoate is also marketed in combination with progesterone for use as an intramuscular injection.

estradiol benzoate in

is available in the

Czech Republic The Czech Republic, also known as Czechia, and historically known as Bohemia, is a landlocked country in Central Europe. The country is bordered by Austria to the south, Germany to the west, Poland to the northeast, and Slovakia to the south ...

and

Slovakia Slovakia, officially the Slovak Republic, is a landlocked country in Central Europe. It is bordered by Poland to the north, Ukraine to the east, Hungary to the south, Austria to the west, and the Czech Republic to the northwest. Slovakia's m ...

alone under the brand name Agofollin Depot and in combination with microcrystalline

under the brand name Folivirin.

Research

Estradiol benzoate has been studied in combination with

norethisterone enanthate Norethisterone enanthate (NETE), also known as norethindrone enanthate, is a form of hormonal birth control which is used to prevent pregnancy in women. It is used both as a form of progestogen-only injectable birth control and in combined inje ...

as a once-a-month

combined injectable contraceptive Combined injectable contraceptives (CICs) are a form of hormonal birth control for women. They consist of monthly injections of combined formulations containing an estrogen and a progestin to prevent pregnancy. CICs are different from progestog ...

, but ultimately did not complete development for this indication.

References

{{Estrogen receptor modulators Antigonadotropins Benzoate esters Estradiol esters Hormonal antineoplastic drugs Hormonal contraception Secondary alcohols Synthetic estrogens Veterinary drugs