Estradiol benzoate (EB), sold under the brand name Progynon-B 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 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 an estrogen and hence is an agonist of the estrogen receptor, 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 that same year. It was the first estradiol ester to be discovered or marketed, and was one of the first estrogens to be used in medicine. Along with estradiol dipropionate, 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less frequent injections, such as estradiol valerate and estradiol cypionate, were developed, and have since largely superseded estradiol benzoate.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, but is available there for use in veterinary medicine.
Medical uses
The medical uses of estradiol benzoate are the same as those of estradiol and other estrogens. Estradiol benzoate is used in hormone therapy for the treatment of menopausal symptoms such as hot flashes and vaginal atrophy and in the treatment of hypoestrogenism and delayed puberty due to hypogonadism or other causes in women. It is also used in hormone therapy for transgender women. Aside from hormone therapy, estradiol benzoate is used in the treatment of gynecological disorders such as menstrual disorders, dysfunctional uterine bleeding, and breast engorgement. In addition, it is used as a form of high-dose estrogen therapy in the palliative treatment of prostate cancer in men.
Estradiol benzoate has a relatively short duration of action, and is administered by intramuscular injection 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 for intramuscular injection provided as vials and ampoules 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 aqueous suspension 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 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 in aqueous suspension.
A vaginal tablet formulation containing 0.125 mg estradiol benzoate and 10 mg monalazone sodium (a vaginal disinfectant and spermicidal contraceptive) 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
Contraindications of estrogens include coagulation problems, cardiovascular diseases, liver disease, and certain hormone-sensitive cancers such as breast cancer and endometrial cancer, among others.
Side effects
The side effects of estradiol benzoate are the same as those of estradiol. Examples of such side effects include breast tenderness and enlargement, nausea, bloating, edema, headache, and melasma.
Overdose
Symptoms of estrogen overdosage may include nausea, vomiting, bloating, increased weight, water retention, breast tenderness, vaginal discharge, heavy legs, and leg cramps. These side effects can be diminished by reducing the estrogen dosage.
Interactions
Inhibitors and inducers of cytochrome P450 may influence the metabolism of estradiol and by extension circulating estradiol levels.
Pharmacology
Pharmacodynamics
Estradiol benzoate is an estradiol ester, or a prodrug of estradiol. As such, it is an estrogen, or an agonist of the estrogen receptors. Estradiol benzoate has very low affinity 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 prodrug to estradiol. Estradiol benzoate is of about 38% higher molecular weight than estradiol due to the presence of its C3 benzoate ester. Because estradiol benzoate is a prodrug of estradiol, it is considered to be a natural and bioidentical form of estrogen.
Estrogenic potency In the case of intramuscular injections of either estradiol benzoate or estradiol valerate in oil solution, the maturation dosage for the vaginal epithelium is 5 to 7 mg once per week and the endometrial 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 dosage of estradiol benzoate/progesterone 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 in oil solution (brand name Gravibinon) 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 of the menstrual cycle; it is induced by endogenous progesterone following adequate priming by endogenous estradiol.
The decidua (pregnancy-type endometrium) 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 dosages.
Antigonadotropic effects
As with other estrogens and forms of estradiol, estradiol benzoate dose-dependently suppresses gonadotropin and testosterone levels in men and transgender women. 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 prodrug of estradiol via cleavage by esterases into estradiol and the natural fatty acid benzoic acid. This cleavage occurs not only in the liver, but also in the blood and in tissues. Esters of estradiol like estradiol benzoate are readily hydrolyzed to estradiol, but have an extended duration when administered in via intramuscular or subcutaneous injection due to a depot effect afforded by their fatty acid ester moiety and consequent high lipophilicity. A long-lasting local tissue depot is formed by the injection that slowly releases estradiol benzoate into the circulation.
Intramuscular injection Oil solution The duration of action 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 therapy with triptorelin). The elimination half-life 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 estradiol valerate and estradiol cypionate were found to last for 7 to 8 days and 11 days, respectively. This is because estradiol benzoate has a shorter and less bulky fatty acid chain, and in relation to this, is comparatively less lipophilic. 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 rates almost double those of the normal luteal phase. This is in accordance with known production rates of estradiol in women (e.g., 300 μg/day in the luteal phase).
Aqueous suspension Microcrystalline estradiol benzoate in aqueous suspension (brand names Agofollin Depot and Ovocyclin M alone and Follivirin in combination with testosterone isobutyrate) has been found to have a longer duration of action than amorphous 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 estradiol valerate and estradiol cypionate. The duration of microcrystalline aqueous suspensions administered by intramuscular injection is dependent both on 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, in contrast to intramuscular injection.