Estradiol benzoate

Estradiol benzoate

Clinical data
Pronunciation	/ˌɛstrəˈdaɪoʊlˈbɛnzoʊeɪt/ ES-trə-DY-ohl BEN-zoh-ayt
Trade names	Agofollin Depot, Ben-Ovocylin, Benzofoline, Dimenformon, Ovocyclin M, Progynon-B, many others
Other names	EB; E2B; Oestradiol benzoate; 17β-Estradiol-3-benzoate; NSC-9566; Benzhormovarine, Difollisterol, Follicormon, Follidimyl, Follidrinbensoat, Oestro-Vitis, Oestroform
Routes of administration	Intramuscular injection, subcutaneous injection, vaginal
Drug class	Estrogen; Estrogen ester
ATC code	G03CA03 ( WHO )
Legal status
Legal status	In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	IM: High [1]
Protein binding	Estradiol: ~98% (to albumin and SHBG Tooltip sex hormone-binding globulin) [2] [3]
Metabolism	Cleavage via esterases in the liver, blood, and tissues [4] [5]
Metabolites	Estradiol, benzoic acid, and metabolites of estradiol [4] [5]
Elimination half-life	IM: 48–120 hrs (2–5 days) [6]
Duration of action	IM (0.3–1.7 mg): 2–3 days [7] [8] IM (5 mg): 4–6 days [9] [10] [11]
Excretion	Urine
Identifiers
IUPAC name [(8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-3-yl] benzoate
CAS Number	50-50-0
PubChem CID	222757
DrugBank	DB13953
ChemSpider	193412
UNII	1S4CJB5ZGN
KEGG	D01953
ChEBI	CHEBI:77006
ChEMBL	ChEMBL282575
CompTox Dashboard (EPA)	DTXSID9022998
ECHA InfoCard	100.000.040
Chemical and physical data
Formula	C25H28O3
Molar mass	376.496 g·mol−1
3D model (JSmol)	Interactive image
SMILES C[C@]12CC[C@H]3[C@H]([C@@H]1CC[C@@H]2O)CCC4=C3C=CC(=C4)OC(=O)C5=CC=CC=C5
InChI InChI=1S/C25H28O3/c1-25-14-13-20-19-10-8-18(28-24(27)16-5-3-2-4-6-16)15-17(19)7-9-21(20)22(25)11-12-23(25)26/h2-6,8,10,15,20-23,26H,7,9,11-14H2,1H3/t20-,21-,22+,23+,25+/m1/s1 Key:UYIFTLBWAOGQBI-BZDYCCQFSA-N

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. ^{[8] [12] [13]} It is also used in the treatment of prostate cancer in men. ^[8] Estradiol benzoate is used in veterinary medicine as well. ^{[14] [15]} When used clinically, the medication is given by injection into muscle usually two to three times per week. ^{[8] [12] [16]}

Side effects of estradiol benzoate include breast tenderness, breast enlargement, nausea, headache, and fluid retention. ^[17] Estradiol benzoate is an estrogen and hence is an agonist of the estrogen receptor, the biological target of estrogens like estradiol. ^{[4] [5]} It is an estrogen ester and a prodrug of estradiol in the body. ^{[4] [5]} Because of this, it is considered to be a natural and bioidentical form of estrogen. ^[4]

Estradiol benzoate was discovered in 1933 and was introduced for medical use that same year. ^{[4] [18] [19] [20] [21] [22] [23]} It was the first estradiol ester to be discovered or marketed, and was one of the first estrogens to be used in medicine. ^[24] Along with estradiol dipropionate, estradiol benzoate was among the most widely used esters of estradiol for many years following its introduction. ^[25] 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. ^[9] Nonetheless, estradiol benzoate remains widely available throughout the world. ^[15] It is not available for medical use in the United States, but is available there for use in veterinary medicine. ^{[26] [27]}

Medical uses

Main articles: Estradiol (medication) § Medical uses, and High-dose estrogen

The medical uses of estradiol benzoate are the same as those of estradiol and other estrogens. ^{[8] [12]} 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. ^{[8] [12]} It is also used in hormone therapy for transgender women. ^{[13] [28] [29]} Aside from hormone therapy, estradiol benzoate is used in the treatment of gynecological disorders such as menstrual disorders, dysfunctional uterine bleeding, and breast engorgement. ^{[8] [12]} In addition, it is used as a form of high-dose estrogen therapy in the palliative treatment of prostate cancer in men. ^[8]

Estradiol benzoate has a relatively short duration of action, and is administered by intramuscular injection usually two to three times per week. ^{[8] [12]} 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. ^{[8] [30]} The dosage used in hormone therapy for transgender women is 0.5 to 1.5 mg two to three times per week. ^[13] 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). ^[8]

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Estrogen dosages for menopausal hormone therapy

Route/form	Estrogen	Low	Standard	High
Oral	Estradiol	0.5–1 mg/day	1–2 mg/day	2–4 mg/day
	Estradiol valerate	0.5–1 mg/day	1–2 mg/day	2–4 mg/day
	Estradiol acetate	0.45–0.9 mg/day	0.9–1.8 mg/day	1.8–3.6 mg/day
	Conjugated estrogens	0.3–0.45 mg/day	0.625 mg/day	0.9–1.25 mg/day
	Esterified estrogens	0.3–0.45 mg/day	0.625 mg/day	0.9–1.25 mg/day
	Estropipate	0.75 mg/day	1.5 mg/day	3 mg/day
	Estriol	1–2 mg/day	2–4 mg/day	4–8 mg/day
	Ethinylestradiol a	2.5–10 μg/day	5–20 μg/day	–
Nasal spray	Estradiol	150 μg/day	300 μg/day	600 μg/day
Transdermal patch	Estradiol	25 μg/dayb	50 μg/dayb	100 μg/dayb
Transdermal gel	Estradiol	0.5 mg/day	1–1.5 mg/day	2–3 mg/day
Vaginal	Estradiol	25 μg/day	–	–
	Estriol	30 μg/day	0.5 mg 2x/week	0.5 mg/day
IM Tooltip Intramuscular or SC injection	Estradiol valerate	–	–	4 mg 1x/4 weeks
	Estradiol cypionate	1 mg 1x/3–4 weeks	3 mg 1x/3–4 weeks	5 mg 1x/3–4 weeks
	Estradiol benzoate	0.5 mg 1x/week	1 mg 1x/week	1.5 mg 1x/week
SC implant	Estradiol	25 mg 1x/6 months	50 mg 1x/6 months	100 mg 1x/6 months
Footnotes:a = No longer used or recommended, due to health concerns. b = As a single patch applied once or twice per week (worn for 3–4 days or 7 days), depending on the formulation. Note: Dosages are not necessarily equivalent. Sources: See template.

Available forms

See also: List of marketed estradiol benzoate formulations and List of combined sex-hormonal preparations

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. ^{[23] [31] [8]} It is also available as a microcrystalline aqueous suspension for intramuscular injection under the brand name Agofollin Depot. ^{[32] [33] [34] [28]} Sistocyclin was the brand name of a product containing 10 mg microcrystalline estradiol benzoate and 200 mg microcrystalline progesterone in an aqueous suspension. ^{[35] [36] [37] [38]} 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. ^{[39] [40] [41] [42]}

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. ^[43] Estradiol benzoate was also formerly available as 50 and 100 mg pellets for subcutaneous implantation and as a 2 mg/g ointment. ^[44]

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Available forms of estradiol ^[a]

Route	Ingredient	Form	Dose [b]	Brand names [c]
Oral	Estradiol	Tablet	0.1, 0.2, 0.5, 1, 2, 4 mg	Estrace, Ovocyclin
	Estradiol valerate	Tablet	0.5, 1, 2, 4 mg	Progynova
Transdermal	Estradiol	Patch	14, 25, 37.5, 50, 60, 75, 100 µg/d	Climara, Vivelle
		Gel pump	0.06% (0.52, 0.75 mg/pump)	Elestrin, EstroGel
		Gel packet	0.1% (0.25, 0.5, 1.0 mg/pk.)	DiviGel, Sandrena
		Emulsion	0.25% (25 µg/pouch)	Estrasorb
		Spray	1.53 mg/spray	Evamist, Lenzetto
Vaginal	Estradiol	Tablet	10, 25 µg	Vagifem
		Cream	0.01% (0.1 mg/gram)	Estrace
		Insert	4, 10 µg	Imvexxy
		Ring	2 mg/ring (7.5 µg/d, 3 mon.)	Estring
	Estradiol acetate	Ring	50, 100 µg/d, 3 months	Femring
Injection [d]	Estradiol	Microspheres	1 mg/mL	Juvenum E
	Estradiol benzoate	Oil solution	0.167, 0.2, 0.333, 1, 1.67, 2, 5, 10, 20, 25 mg/mL	Progynon-B
	Estradiol cypionate	Oil solution	1, 3, 5 mg/mL	Depo-Estradiol
	Estradiol valerate	Oil solution	5, 10, 20, 40 mg/mL	Progynon Depot
Implant	Estradiol	Pellet	20, 25, 50, 100 mg, 6 mon.	Estradiol Implants
Notes and sources: This table includes primarily products available as a single-ingredient estradiol preparation—thus excluding compounds with progestogens or other ingredients included. The table furthermore does not include compounded drugs—only commercially produced products. Availability of each product varies by country. Doses are given per unit (ex: per tablet, per mL). Other brand names may be manufactured or previously manufactured. By intramuscular or subcutaneous injection. Sources: [45] [46] [47] [48] [49] [50] [51] [52] [53] [54] [55] [56] [57] [58]

Contraindications

Main article: Estradiol (medication) § 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. ^{[59] [60] [61] [62]}

Side effects

Main article: Estradiol (medication) § 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. ^[17]

Overdose

See also: Estradiol (medication) § Overdose

Symptoms of estrogen overdosage may include nausea, vomiting, bloating, increased weight, water retention, breast tenderness, vaginal discharge, heavy legs, and leg cramps. ^[59] These side effects can be diminished by reducing the estrogen dosage. ^[59]

Interactions

See also: Estradiol (medication) § Interactions

Inhibitors and inducers of cytochrome P450 may influence the metabolism of estradiol and by extension circulating estradiol levels. ^[63]

Pharmacology

Estradiol, the active form of estradiol benzoate.

Pharmacodynamics

See also: Pharmacodynamics of estradiol

Estradiol benzoate is an estradiol ester, or a prodrug of estradiol. ^{[4] [5]} As such, it is an estrogen, or an agonist of the estrogen receptors. ^{[4] [5]} Estradiol benzoate has very low affinity for the ERs, on the order of 100-fold less than that of estradiol. ^[64] As such, estradiol benzoate is regarded as essentially inactive in terms of estrogenic effect itself, acting solely as a prodrug to estradiol. ^[5] Estradiol benzoate is of about 38% higher molecular weight than estradiol due to the presence of its C3 benzoate ester. ^{[65] [15]} Because estradiol benzoate is a prodrug of estradiol, it is considered to be a natural and bioidentical form of estrogen. ^[4]

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Affinities and estrogenic potencies of estrogen esters and ethers at the estrogen receptors

Estrogen	Other names	RBA Tooltip Relative binding affinity (%)a	REP (%)b
		ER	ERα	ERβ
Estradiol	E2	100	100	100
Estradiol 3-sulfate	E2S; E2-3S	?	0.02	0.04
Estradiol 3-glucuronide	E2-3G	?	0.02	0.09
Estradiol 17β-glucuronide	E2-17G	?	0.002	0.0002
Estradiol benzoate	EB; Estradiol 3-benzoate	10	1.1	0.52
Estradiol 17β-acetate	E2-17A	31–45	24	?
Estradiol diacetate	EDA; Estradiol 3,17β-diacetate	?	0.79	?
Estradiol propionate	EP; Estradiol 17β-propionate	19–26	2.6	?
Estradiol valerate	EV; Estradiol 17β-valerate	2–11	0.04–21	?
Estradiol cypionate	EC; Estradiol 17β-cypionate	?c	4.0	?
Estradiol palmitate	Estradiol 17β-palmitate	0	?	?
Estradiol stearate	Estradiol 17β-stearate	0	?	?
Estrone	E1; 17-Ketoestradiol	11	5.3–38	14
Estrone sulfate	E1S; Estrone 3-sulfate	2	0.004	0.002
Estrone glucuronide	E1G; Estrone 3-glucuronide	?	<0.001	0.0006
Ethinylestradiol	EE; 17α-Ethynylestradiol	100	17–150	129
Mestranol	EE 3-methyl ether	1	1.3–8.2	0.16
Quinestrol	EE 3-cyclopentyl ether	?	0.37	?
Footnotes:a = Relative binding affinities (RBAs) were determined via in-vitro displacement of labeled estradiol from estrogen receptors (ERs) generally of rodent uterine cytosol. Estrogen esters are variably hydrolyzed into estrogens in these systems (shorter ester chain length -> greater rate of hydrolysis) and the ER RBAs of the esters decrease strongly when hydrolysis is prevented. b = Relative estrogenic potencies (REPs) were calculated from half-maximal effective concentrations (EC50) that were determined via in-vitro β‐galactosidase (β-gal) and green fluorescent protein (GFP) production assays in yeast expressing human ERα and human ERβ. Both mammalian cells and yeast have the capacity to hydrolyze estrogen esters. c = The affinities of estradiol cypionate for the ERs are similar to those of estradiol valerate and estradiol benzoate (figure). Sources: See template page.

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. ^[66] The total endometrial proliferation dosage of estradiol benzoate in oil solution by intramuscular injection over 14 days is 25 to 35 mg. ^{[67] [10] [11]}

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. ^[66] 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. ^[66] Endometrial transformation normally occurs during the luteal phase of the menstrual cycle; it is induced by endogenous progesterone following adequate priming by endogenous estradiol. ^[68]

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. ^[66] 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. ^[66] The decidua induction dosages of estrogen and progestogen combinations are pseudopregnancy dosages. ^[66]

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Potencies and durations of natural estrogens by intramuscular injection

Estrogen	Form	Dose (mg)		Duration by dose (mg)
		EPD	CICD
Estradiol	Aq. soln.	?	–	<1 d
	Oil soln.	40–60	–	1–2 ≈ 1–2 d
	Aq. susp.	?	3.5	0.5–2 ≈ 2–7 d; 3.5 ≈ >5 d
	Microsph.	?	–	1 ≈ 30 d
Estradiol benzoate	Oil soln.	25–35	–	1.66 ≈ 2–3 d; 5 ≈ 3–6 d
	Aq. susp.	20	–	10 ≈ 16–21 d
	Emulsion	?	–	10 ≈ 14–21 d
Estradiol dipropionate	Oil soln.	25–30	–	5 ≈ 5–8 d
Estradiol valerate	Oil soln.	20–30	5	5 ≈ 7–8 d; 10 ≈ 10–14 d; 40 ≈ 14–21 d; 100 ≈ 21–28 d
Estradiol benz. butyrate	Oil soln.	?	10	10 ≈ 21 d
Estradiol cypionate	Oil soln.	20–30	–	5 ≈ 11–14 d
	Aq. susp.	?	5	5 ≈ 14–24 d
Estradiol enanthate	Oil soln.	?	5–10	10 ≈ 20–30 d
Estradiol dienanthate	Oil soln.	?	–	7.5 ≈ >40 d
Estradiol undecylate	Oil soln.	?	–	10–20 ≈ 40–60 d; 25–50 ≈ 60–120 d
Polyestradiol phosphate	Aq. soln.	40–60	–	40 ≈ 30 d; 80 ≈ 60 d; 160 ≈ 120 d
Estrone	Oil soln.	?	–	1–2 ≈ 2–3 d
	Aq. susp.	?	–	0.1–2 ≈ 2–7 d
Estriol	Oil soln.	?	–	1–2 ≈ 1–4 d
Polyestriol phosphate	Aq. soln.	?	–	50 ≈ 30 d; 80 ≈ 60 d
Notes and sources Notes: All aqueous suspensions are of microcrystalline particle size. Estradiol production during the menstrual cycle is 30–640 µg/d (6.4–8.6 mg total per month or cycle). The vaginal epithelium maturation dosage of estradiol benzoate or estradiol valerate has been reported as 5 to 7 mg/week. An effective ovulation-inhibiting dose of estradiol undecylate is 20–30 mg/month. Sources: See template.

Antigonadotropic effects

Levels of estradiol, testosterone, and gonadotropins with 4.5 μg/kg injectable estradiol benzoate every 12 hours (or ~0.63 mg/day for a 70-kg [154-lb] person) in transgender women.

As with other estrogens and forms of estradiol, ^{[70] [71] [72]} estradiol benzoate dose-dependently suppresses gonadotropin and testosterone levels in men and transgender women. ^[69] 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 250 pg/mL, testosterone levels decreased from around 530 ng/dL at baseline to about 55 ng/dL (–90%) within approximately 3 days of treatment. ^[69]

Pharmacokinetics

See also: Pharmacokinetics of estradiol

Following administration, estradiol benzoate acts as a prodrug of estradiol via cleavage by esterases into estradiol and the natural fatty acid benzoic acid. ^[5] This cleavage occurs not only in the liver, but also in the blood and in tissues. ^{[4] [5]} 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. ^[5] A long-lasting local tissue depot is formed by the injection that slowly releases estradiol benzoate into the circulation. ^[5]

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. ^{[7] [8]} 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). ^[73] 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). ^[6]

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. ^[9] 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. ^[9] This is because estradiol benzoate has a shorter and less bulky fatty acid chain, and in relation to this, is comparatively less lipophilic. ^[5] 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. ^[5]

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. ^{[66] [74] [75]} This is in accordance with known production rates of estradiol in women (e.g., 300 μg/day in the luteal phase). ^{[66] [76]}

Hormone levels with estradiol benzoate by intramuscular injection

• 
  Estradiol levels after single intramuscular injections of 0.5, 1.5, or 2.5 mg estradiol benzoate in oil in 5 premenopausal women each. ^[77] Assays were performed using radioimmunoassay. ^[77] Source was Shaw et al. (1975). ^[77]
• 
  Estradiol levels after single intramuscular injections of 5 mg of different estradiol esters in oil in about 10 premenopausal women each. ^[9] Assays were performed using radioimmunoassay with chromatographic separation. ^[9] Source was Oriowo et al. (1980). ^[9]
• 
  Estradiol levels after a short intravenous infusion of 20 mg estradiol in aqueous solution or an intramuscular injection of equimolar doses of estradiol esters in oil solution in postmenopausal women. ^{[78] [79]} Assays were performed using RIA with CS. ^{[78] [79]} Source was Geppert (1975). ^{[78] [79]}
• 
  Simplified curves of estradiol levels after injection of different estradiol esters in women. ^[80] Source was Garza-Flores (1994). ^[80]
• 
  Vaginal cornification with a single intramuscular injection of different estradiol esters in oil solution in women. ^[25] Source was Schwartz & Soule (1955). ^[25]

Aqueous suspension

Microcrystalline estradiol benzoate in aqueous suspension (brand names Agofollin Depot and Ovocyclin M alone and Follivirin in combination with testosterone isobutyrate) ^{[33] [39]} has been found to have a longer duration of action than amorphous estradiol benzoate in oil solution when administered via intramuscular injection. ^{[81] [82] [83] [84] [85] [86] [87] [88] : 310} 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. ^{[88] [82] [74] [75]} Its duration also surpasses that of estradiol valerate and estradiol cypionate. ^[88] The duration of microcrystalline aqueous suspensions administered by intramuscular injection is dependent both on concentration and on crystal size. ^{[89] [90] [86] [91]}

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. ^{[92] [93] [94]}

Estradiol benzoate is active with oral and sublingual administration, similarly to estradiol valerate and estradiol acetate. ^{[7] [88] : 310} However, it is not marketed in any formulation for use by these routes. ^[23] Oral estradiol benzoate has been reported to possess about one-third to half the potency of intramuscular injection of estradiol benzoate. ^{[95] [96] [97] [98]} This level of oral potency has been described as remarkably high. ^[96] The sublingual potency of estradiol benzoate is similar to that of estradiol. ^{[88] : 310} 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. ^{[88] : 310} Both estradiol and estradiol benzoate has a persistence of estrogenic effect with single administration of one day. ^{[88] : 310}

Subcutaneous implantation of crystalline estradiol benzoate pellets has been studied, but no estradiol benzoate pellet implants have been marketed. ^[99]

Chemistry

See also: Estrogen ester and List of estrogen esters § Estradiol esters

Estradiol benzoate is a synthetic estrane steroid and the C3 benzoate (benzenecarboxylate) ester of estradiol. ^{[15] [65] [100]} It is also known as estradiol 3-benzoate or as estra-1,3,5(10)-triene-3,17β-diol 3-benzoate. ^{[15] [65] [100]} Two estradiol esters that are related to estradiol benzoate are estradiol dipropionate, the C3,17β dipropionate ester of estradiol, and estradiol acetate, the C3 acetate ester of estradiol.

The experimental octanol/water partition coefficient (logP) of estradiol benzoate is 4.7. ^[101]

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Structural properties of selected estradiol esters

Estrogen	Structure	Ester(s)				Relative mol. weight	Relative E2 contentb	log Pc
		Position(s)	Moiet(ies)	Type	Lengtha
Estradiol		–	–	–	–	1.00	1.00	4.0
Estradiol acetate		C3	Ethanoic acid	Straight-chain fatty acid	2	1.15	0.87	4.2
Estradiol benzoate		C3	Benzoic acid	Aromatic fatty acid	– (~4–5)	1.38	0.72	4.7
Estradiol dipropionate		C3, C17β	Propanoic acid (×2)	Straight-chain fatty acid	3 (×2)	1.41	0.71	4.9
Estradiol valerate		C17β	Pentanoic acid	Straight-chain fatty acid	5	1.31	0.76	5.6–6.3
Estradiol benzoate butyrate		C3, C17β	Benzoic acid, butyric acid	Mixed fatty acid	– (~6, 2)	1.64	0.61	6.3
Estradiol cypionate		C17β	Cyclopentylpropanoic acid	Cyclic fatty acid	– (~6)	1.46	0.69	6.9
Estradiol enanthate		C17β	Heptanoic acid	Straight-chain fatty acid	7	1.41	0.71	6.7–7.3
Estradiol dienanthate		C3, C17β	Heptanoic acid (×2)	Straight-chain fatty acid	7 (×2)	1.82	0.55	8.1–10.4
Estradiol undecylate		C17β	Undecanoic acid	Straight-chain fatty acid	11	1.62	0.62	9.2–9.8
Estradiol stearate		C17β	Octadecanoic acid	Straight-chain fatty acid	18	1.98	0.51	12.2–12.4
Estradiol distearate		C3, C17β	Octadecanoic acid (×2)	Straight-chain fatty acid	18 (×2)	2.96	0.34	20.2
Estradiol sulfate		C3	Sulfuric acid	Water-soluble conjugate	–	1.29	0.77	0.3–3.8
Estradiol glucuronide		C17β	Glucuronic acid	Water-soluble conjugate	–	1.65	0.61	2.1–2.7
Estramustine phosphate d		C3, C17β	Normustine, phosphoric acid	Water-soluble conjugate	–	1.91	0.52	2.9–5.0
Polyestradiol phosphate e		C3–C17β	Phosphoric acid	Water-soluble conjugate	–	1.23f	0.81f	2.9g
Footnotes:a = Length of ester in carbon atoms for straight-chain fatty acids or approximate length of ester in carbon atoms for aromatic or cyclic fatty acids. b = Relative estradiol content by weight (i.e., relative estrogenic exposure). c = Experimental or predicted octanol/water partition coefficient (i.e., lipophilicity/hydrophobicity). Retrieved from PubChem, ChemSpider, and DrugBank. d = Also known as estradiol normustine phosphate. e = Polymer of estradiol phosphate (~13 repeat units). f = Relative molecular weight or estradiol content per repeat unit. g = log P of repeat unit (i.e., estradiol phosphate). Sources: See individual articles.

History

Estradiol benzoate was one of the first estrogens to be developed and marketed. ^[21] In 1932, Adolf Butenandt described estrone benzoate and reported that it had a prolonged duration of action. ^{[11] [102]} Schwenk and Hildebrant at Schering discovered estradiol via reduction of estrone in 1933, and they proceeded to synthesize estradiol benzoate from estradiol the same year. ^{[4] [18]} Estradiol benzoate was patented by Schering in 1933 and was introduced in an oil solution for use by intramuscular injection under the brand name Progynon B that year as well. ^{[19] [20] [21] [22] [23]} 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-Organon, and Oestroform B by British Drug Houses. ^{[103] [104] [105] [106] [107] [108] [109]} By the early 1940s, Ben-Ovocylin had been introduced by Ciba as well. ^{[104] [105] [106]} In the late 1940s, the brand name Ben-Ovocylin was changed by Ciba to Ovocylin Benzoate. ^[110] Following their introduction, estradiol benzoate and estradiol dipropionate were the most widely used esters of estradiol for many years. ^[25] However, estradiol valerate and estradiol cypionate, 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. ^[9]

Society and culture

Generic names

Estradiol benzoate is the generic name of the drug and its INN Tooltip International Nonproprietary Name, BANM Tooltip British Approved Name, and JAN Tooltip Japanese Accepted Name, while oestradiol benzoate was formerly its BANM Tooltip British Approved Name. ^{[14] [15] [65] [100]}

Brand names

The major brand name of estradiol benzoate is Progynon-B. ^{[15] [65] [100]} 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. ^{[15] [65] [100] [111]}

Availability

See also: List of marketed estradiol benzoate formulations and List of combined sex-hormonal preparations

Estradiol benzoate is available in Europe and in other parts of the world. ^{[15] [23]} It was previously available for medical use in the United States, but is no longer marketed in this country. ^{[15] [27] [23] [26]} However, it is approved and marketed in the United States for veterinary use as a subdermal implant both alone and in combination with the androgen/anabolic steroid trenbolone acetate (brand names Celerin and Synovex, respectively). ^{[27] [112] [113]} Outside of the United States, estradiol benzoate is also marketed in combination with progesterone for use as an intramuscular injection. ^{[14] [114]}

Microcrystalline estradiol benzoate in aqueous suspension is available in the Czech Republic and Slovakia alone under the brand name Agofollin Depot and in combination with microcrystalline testosterone isobutyrate under the brand name Folivirin. ^{[33] [39] [14]}

Research

Estradiol benzoate has been studied in combination with norethisterone enanthate as a once-a-month combined injectable contraceptive, but ultimately did not complete development for this indication. ^[115]

References

1. Düsterberg B, Nishino Y (December 1982). "Pharmacokinetic and pharmacological features of oestradiol valerate". Maturitas. 4 (4): 315–324. doi:10.1016/0378-5122(82)90064-0. PMID   7169965.
2. Stanczyk FZ, Archer DF, Bhavnani BR (June 2013). "Ethinyl estradiol and 17β-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment". Contraception. 87 (6): 706–727. doi:10.1016/j.contraception.2012.12.011. PMID   23375353.
3. Falcone T, Hurd WH (2007). Clinical Reproductive Medicine and Surgery. Elsevier Health Sciences. pp. 22, 362, 388. ISBN   978-0-323-03309-1.
4. Oettel M, Schillinger E (6 December 2012). Estrogens and Antiestrogens I: Physiology and Mechanisms of Action of Estrogens and Antiestrogens. Springer Science & Business Media. pp. 8–. ISBN   978-3-642-58616-3.
5. Kuhl H (2005). "Pharmacology of estrogens and progestogens: influence of different routes of administration" (PDF). Climacteric. 8 (Suppl 1): 3–63. doi:10.1080/13697130500148875. PMID   16112947. S2CID   24616324.
6. Runnebaum B, Rabe T (17 April 2013). Gynäkologische Endokrinologie und Fortpflanzungsmedizin: Band 1: Gynäkologische Endokrinologie. Springer-Verlag. pp. 86–. ISBN   978-3-662-07635-4.
7. Buchsbaum HJ (6 December 2012). The Menopause. Springer Science & Business Media. pp. 62–. ISBN   978-1-4612-5525-3.
8. "NNR: Products Recently Accepted by the A. M. A. Council on Pharmacy and Chemistry". Journal of the American Pharmaceutical Association (Practical Pharmacy Ed.). 10 (11): 692–694. 1949. doi:10.1016/S0095-9561(16)31995-8. ISSN   0095-9561.
9. Oriowo MA, Landgren BM, Stenström B, Diczfalusy E (April 1980). "A comparison of the pharmacokinetic properties of three estradiol esters". Contraception. 21 (4): 415–24. doi:10.1016/S0010-7824(80)80018-7. PMID   7389356.
10. Knörr K, Knörr-Gärtner H, Beller FK, Lauritzen C (8 March 2013). Lehrbuch der Geburtshilfe und Gynäkologie: Physiologie und Pathologie der Reproduktion. Springer-Verlag. pp. 508–. ISBN   978-3-662-00526-2.
11. Labhart A (6 December 2012). Clinical Endocrinology: Theory and Practice. Springer Science & Business Media. pp. 512–. ISBN   978-3-642-96158-8.
12. Swyer GI (April 1959). "The oestrogens". Br Med J. 1 (5128): 1029–31. doi:10.1136/bmj.1.5128.1029. PMC   1993181 . PMID   13638626.
13. Israel GE (March 2001). Transgender Care: Recommended Guidelines, Practical Information, and Personal Accounts. Temple University Press. pp. 64–. ISBN   978-1-56639-852-7.
14. "Estradiol". Drugs.com.
15. Index Nominum 2000: International Drug Directory. Taylor & Francis US. 2000. p. 406. ISBN   978-3-88763-075-1.
16. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, World Health Organization, International Agency for Research on Cancer (2007). Combined Estrogen-progestogen Contraceptives and Combined Estrogen-progestogen Menopausal Therapy. World Health Organization. pp. 388–. ISBN   978-92-832-1291-1.
17. Ghosh AK (23 September 2010). Mayo Clinic Internal Medicine Board Review. OUP USA. pp. 222–. ISBN   978-0-19-975569-1.
18. Miescher K, Scholz C, Tschopp E (August 1938). "The activation of female sex hormones: Mono-esters of alpha-oestradiol". The Biochemical Journal. 32 (8): 1273–1280. doi:10.1042/bj0321273b. PMC   1264184 . PMID   16746750.
19. Kaufman C (1933). "Die Behandlung der Amenorrhöe mit Hohen Dosen der Ovarialhormone". Klinische Wochenschrift. 12 (40): 1557–1562. doi:10.1007/BF01765673. ISSN   0023-2173. S2CID   25856898.
20. Buschbeck H (1934). "Neue Wege der Hormontherapie in der Gynäkologie" [New ways of hormonal therapy in gynecology]. Deutsche Medizinische Wochenschrift. 60 (11): 389–393. doi:10.1055/s-0028-1129842. ISSN   0012-0472. S2CID   72668930.
21. Biskind MS (1935). "Commercial Glandular Products". Journal of the American Medical Association. 105 (9): 667. doi:10.1001/jama.1935.92760350007009a. ISSN   0002-9955. Progynon-B, Schering Corporation: This is crystalline hydroxyestrin benzoate obtained by hydrogenation of theelin and subsequent conversion to the benzoate. [...] Progynon-B is marketed in ampules containing 1 cc. of a sesame oil solution of hydroxyestrin benzoate of either 2,500, 5,000, 10,000 or 50,000 international units.
22. Novak E (1935). "The Therapeutic Use of Estrogenic Substances". JAMA: The Journal of the American Medical Association. 104 (20): 1815. doi:10.1001/jama.1935.92760200002012. ISSN   0098-7484. Progynon B (Schering), in 1 cc. ampules, of 10,000 or 50,000 international units of hydroxyestrin benzoate in sesame oil.
23. Kleemann A, Engel J, Kutscher B, Reichert D (14 May 2014). Pharmaceutical Substances, 5th Edition, 2009: Syntheses, Patents and Applications of the most relevant APIs. Thieme. pp. 1167–1174. ISBN   978-3-13-179525-0.
24. Raviña E, Kubinyi H (16 May 2011). The Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs. John Wiley & Sons. p. 175. ISBN   978-3-527-32669-3 . Retrieved 20 May 2012.
25. Schwartz MM, Soule SD (July 1955). "Estradiol 17-beta-cyclopentylpropionate, a long-acting estrogen". Am. J. Obstet. Gynecol. 70 (1): 44–50. doi:10.1016/0002-9378(55)90286-6. PMID   14388061.
26. "Drugs@FDA: FDA Approved Drug Products". United States Food and Drug Administration. Retrieved 26 July 2018.
27. Witherspoon R (1 June 1994). Presidents List of Articles Which May Be Designated Or Modified As Eligible Articles for Purposes of the U.S. Generalized System of Preferences. DIANE Publishing. pp. 64–. ISBN   978-0-7881-1433-5.
28. Fifková H, Weiss P, Procházka I, Cohen-Kettenis PT, Pfäfflin F, Jarolím L, et al. (4 August 2008). Transsexualita a jiné poruchy pohlavní identity [Transsexuality and other gender identity disorders] (in Czech). Grada Publishing a.s. pp. 95–. ISBN   978-80-247-6962-2. Injection of estradiol benzoate is supplied as Agofollin Depot inj. 10 mg, Biotika and as estradiol valerate Neofollin inj., 5 mg, Hoechst-Biotika. Depot estrogen injections are not recommended due to side effects. Possibility "overdose" of the patient is higher (in some individuals receiving doses "the higher the better," and parenteral drug administration may in some instances these cause serious side effects). While misuse of the drug with peroral administration also occurs, the problems are not so extreme.
29. Weiss P (1 January 2010). Sexuologie. Grada Publishing a.s. pp. 452–. ISBN   978-80-247-2492-8.
30. American Medical Association. Dept. of Drugs, Council on Drugs (American Medical Association), American Society for Clinical Pharmacology and Therapeutics (1 February 1977). "Estrogens, Progestagens, Oral Contraceptives, and Ovulatory Agents". AMA drug evaluations. Publishing Sciences Group. pp. 540–572. ISBN   978-0-88416-175-2. Intramuscular: For replacement therapy, (Estradiol, Estradiol Benzoate) 0.5 to 1.5 mg two or three times weekly; (Estradiol Cypionate) 1 to 5 mg weekly for two or three weeks; (Estradiol Dipropionate) 1 to 5 mg every one to two weeks; (Estradiol Valerate) 10 to 40 mg every one to four weeks.
31. Muller NF, Dessign RP, eds. (19 June 1998). European Drug Index: European Drug Registrations, Fourth Edition. CRC Press. pp. 150, 349, 370. ISBN   978-3-7692-2114-5.
32. Review of Czechoslovak Medicine. Avicenum - Czechoslovak Medical Press. 1973. p. 5. Oestradiol benzoate, aqueous microcrystalline suspension (Agofollin Depot SPOFA).
33. "AGOFOLLIN Depot" (PDF). www.sukl.cz. Archived from the original (PDF) on 19 May 2019. Retrieved 15 January 2022.
34. Marek J (1 January 2010). Farmakoterapie vnitřních nemocí - 4. zcela přepracované a doplněné vydání. Grada Publishing a.s. pp. 377–. ISBN   978-80-247-2639-7. Injection of estrogenic preparations - Injectable preparations are AGOFOLLIN, inj. 5 mg (estradiol dipropionate), AGOFOLLIN DEPOT, inj. 10 mg (estradiol benzoate), and NEOFOLLIN, inj. 5 mg (estradiol valerate). The producer of all these preparations is Biotika. Non-protracted AGOFOLLIN is used only for initiation of treatment, then it is continued with depot injections, which are administered three times: cycle day 4, 11 and 18. At the same time, [progesterone] (AGOLUTIN DEPOT, Biotika, amp. 2 ml / 50 mg, cycle day 18 and 25) is administered. Estrogen injection is not completely physiological - after application, the estrogen plasma concentration increases unnecessarily high and then decreases rapidly.
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37. Ciba Zeitschrift. 1957. p. 3001. Sistocyclin - a microcrystal suspension containing 200 mg progesterone and 10 mg oestradiol monobenzoate per ampoule - has become particularly useful in the treatment of so-called, functional [...]
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