Estradiol benzoate

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]

Estradiol benzoate
Clinical data
Pronunciation/ˌɛstrəˈdl ˈbɛnzt/
ES-trə-DY-ohl BEN-zoh-ayt
Trade namesAgofollin Depot, Ben-Ovocylin, Benzofoline, Dimenformon, Ovocyclin M, Progynon-B, many others
Other namesEB; 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 classEstrogen; Estrogen ester
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
BioavailabilityIM: High[1]
Protein bindingEstradiol: ~98% (to albumin and SHBG)[2][3]
MetabolismCleavage via esterases in the liver, blood, and tissues[4][5]
MetabolitesEstradiol, benzoic acid, and metabolites of estradiol[4][5]
Elimination half-lifeIM: 48–120 hrs (2–5 days)[6]
Duration of actionIM (0.3–1.7 mg): 2–3 days[7][8]
IM (5 mg): 4–6 days[9][10][11]
ExcretionUrine
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
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.000.040
Chemical and physical data
FormulaC25H28O3
Molar mass376.496 g·mol−1
3D model (JSmol)
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

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 in this country for use in veterinary medicine.[26][27]

Medical uses

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]

Estrogen dosages for menopausal hormone therapy
Route/formEstrogenLowStandardHigh
OralEstradiol0.5–1 mg/day1–2 mg/day2–4 mg/day
Estradiol valerate0.5–1 mg/day1–2 mg/day2–4 mg/day
Estradiol acetate0.45–0.9 mg/day0.9–1.8 mg/day1.8–3.6 mg/day
Conjugated estrogens0.3–0.45 mg/day0.625 mg/day0.9–1.25 mg/day
Esterified estrogens0.3–0.45 mg/day0.625 mg/day0.9–1.25 mg/day
Estropipate0.75 mg/day1.5 mg/day3 mg/day
Estriol1–2 mg/day2–4 mg/day4–8 mg/day
Ethinylestradiola2.5–10 μg/day5–20 μg/day
Nasal sprayEstradiol150 μg/day300 μg/day600 μg/day
Transdermal patchEstradiol25 μg/dayb50 μg/dayb100 μg/dayb
Transdermal gelEstradiol0.5 mg/day1–1.5 mg/day2–3 mg/day
VaginalEstradiol25 μg/day
Estriol30 μg/day0.5 mg 2x/week0.5 mg/day
IM or SC injectionEstradiol valerate4 mg 1x/4 weeks
Estradiol cypionate1 mg 1x/3–4 weeks3 mg 1x/3–4 weeks5 mg 1x/3–4 weeks
Estradiol benzoate0.5 mg 1x/week1 mg 1x/week1.5 mg 1x/week
SC implantEstradiol25 mg 1x/6 months50 mg 1x/6 months100 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

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]

Available forms of estradiol[lower-alpha 1]
Route Ingredient Form Dose[lower-alpha 2] Brand names[lower-alpha 3]
Oral EstradiolTablet0.1, 0.2, 0.5, 1, 2, 4 mgEstrace, Ovocyclin
Estradiol valerateTablet0.5, 1, 2, 4 mgProgynova
Transdermal Estradiol Patch14, 25, 37.5, 50, 60, 75, 100 µg/dClimara, Vivelle
Gel pump0.06% (0.52, 0.75 mg/pump)Elestrin, EstroGel
Gel packet0.1% (0.25, 0.5, 1.0 mg/pk.)DiviGel, Sandrena
Emulsion0.25% (25 µg/pouch)Estrasorb
Spray1.53 mg/sprayEvamist, Lenzetto
Vaginal Estradiol Tablet10, 25 µgVagifem
Cream0.01% (0.1 mg/gram)Estrace
Insert4, 10 µgImvexxy
Ring2 mg/ring (7.5 µg/d, 3 mon.)Estring
Estradiol acetateRing50, 100 µg/d, 3 monthsFemring
Injection[lower-alpha 4] EstradiolMicrospheres1 mg/mLJuvenum E
Estradiol benzoateOil solution0.167, 0.2, 0.333, 1, 1.67, 2, 5, 10, 20, 25 mg/mLProgynon-B
Estradiol cypionateOil solution1, 3, 5 mg/mLDepo-Estradiol
Estradiol valerateOil solution5, 10, 20, 40 mg/mLProgynon Depot
Implant EstradiolPellet20, 25, 50, 100 mg, 6 mon.Estradiol Implants
Notes and sources:
  1. 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.
  2. Doses are given per unit (ex: per tablet, per mL).
  3. Other brand names may be manufactured or previously manufactured.
  4. By intramuscular or subcutaneous injection.
Sources: [45][46][47][48][49][50][51][52][53][54][55][56][57][58]

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

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

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

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

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]

Affinities and estrogenic potencies of estrogen esters and ethers at the estrogen receptors
Estrogen Other names RBA (%)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]

Potencies and durations of natural estrogens by intramuscular injection
EstrogenFormDose (mg)Duration by dose (mg)
EPDCICD
EstradiolAq. soln. ?<1 d
Oil soln.40–601–2 ≈ 1–2 d
Aq. susp. ?3.50.5–2 ≈ 2–7 d; 3.5 ≈ >5 d
Microsph. ?1 ≈ 30 d
Estradiol benzoateOil soln.25–351.66 ≈ 2–3 d; 5 ≈ 3–6 d
Aq. susp.2010 ≈ 16–21 d
Emulsion ?10 ≈ 14–21 d
Estradiol dipropionateOil soln.25–305 ≈ 5–8 d
Estradiol valerateOil soln.20–3055 ≈ 7–8 d; 10 ≈ 10–14 d;
40 ≈ 14–21 d; 100 ≈ 21–28 d
Estradiol benz. butyrateOil soln. ?1010 ≈ 21 d
Estradiol cypionateOil soln.20–305 ≈ 11–14 d
Aq. susp. ?55 ≈ 14–24 d
Estradiol enanthateOil soln. ?5–1010 ≈ 20–30 d
Estradiol dienanthateOil soln. ?7.5 ≈ >40 d
Estradiol undecylateOil soln. ?10–20 ≈ 40–60 d;
25–50 ≈ 60–120 d
Polyestradiol phosphateAq. soln.40–6040 ≈ 30 d; 80 ≈ 60 d;
160 ≈ 120 d
EstroneOil soln. ?1–2 ≈ 2–3 d
Aq. susp. ?0.1–2 ≈ 2–7 d
EstriolOil soln. ?1–2 ≈ 1–4 d
Polyestriol phosphateAq. 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.

Pharmacokinetics

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]

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).[69] 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][70][71] This is in accordance with known production rates of estradiol in women (e.g., 300 µg/day in the luteal phase).[66][72]

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.[78][79][80][81][82][83][84][85]: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.[85][79][70][71] Its duration also surpasses that of estradiol valerate and estradiol cypionate.[85] The duration of microcrystalline aqueous suspensions administered by intramuscular injection is dependent both on concentration and on crystal size.[86][87][83][88]

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.[89][90][91]

Estradiol benzoate is active with oral and sublingual administration, similarly to estradiol valerate and estradiol acetate.[7][85]: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.[92][93][94][95] This level of oral potency has been described as remarkably high.[93] The sublingual potency of estradiol benzoate is similar to that of estradiol.[85]: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.[85]:310 Both estradiol and estradiol benzoate has a persistence of estrogenic effect with single administration of one day.[85]:310

Subcutaneous implantation of crystalline estradiol benzoate pellets has been studied, but no estradiol benzoate pellet implants have been marketed.[96]

Chemistry

Estradiol benzoate is a synthetic estrane steroid and the C3 benzoate (benzenecarboxylate) ester of estradiol.[15][65][97] It is also known as estradiol 3-benzoate or as estra-1,3,5(10)-triene-3,17β-diol 3-benzoate.[15][65][97] 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.[98]

Structural properties of selected estradiol esters
EstrogenStructureEster(s)Relative
mol. weight
Relative
E2 contentb
log Pc
Position(s)Moiet(ies)TypeLengtha
Estradiol
1.001.004.0
Estradiol acetate
C3Ethanoic acidStraight-chain fatty acid21.150.874.2
Estradiol benzoate
C3Benzenecarboxylic acidAromatic fatty acid– (~4–5)1.380.724.7
Estradiol dipropionate
C3, C17βPropanoic acid (×2)Straight-chain fatty acid3 (×2)1.410.714.9
Estradiol valerate
C17βPentanoic acidStraight-chain fatty acid51.310.765.6–6.3
Estradiol benzoate butyrate
C3, C17βBenzoic acid, butyric acidMixed fatty acid– (~6, 2)1.640.616.3
Estradiol cypionate
C17βCyclopentylpropanoic acidAromatic fatty acid– (~6)1.460.696.9
Estradiol enanthate
C17βHeptanoic acidStraight-chain fatty acid71.410.716.7–7.3
Estradiol dienanthate
C3, C17βHeptanoic acid (×2)Straight-chain fatty acid7 (×2)1.820.558.1–10.4
Estradiol undecylate
C17βUndecanoic acidStraight-chain fatty acid111.620.629.2–9.8
Estradiol stearate
C17βOctadecanoic acidStraight-chain fatty acid181.980.5112.2–12.4
Estradiol distearate
C3, C17βOctadecanoic acid (×2)Straight-chain fatty acid18 (×2)2.960.3420.2
Estradiol sulfate
C3Sulfuric acidWater-soluble conjugate1.290.770.3–3.8
Estradiol glucuronide
C17βGlucuronic acidWater-soluble conjugate1.650.612.1–2.7
Estramustine phosphated
C3, C17βNormustine, phosphoric acidWater-soluble conjugate1.910.522.9–5.0
Polyestradiol phosphatee
C3–C17βPhosphoric acidWater-soluble conjugate1.23f0.81f2.9g
Footnotes: a = Length of ester in carbon atoms for straight-chain fatty acids or approximate length of ester in carbon atoms for aromatic 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][99] 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.[100][101][102][103][104][105][106] By the early 1940s, Ben-Ovocylin had been introduced by Ciba as well.[101][102][103] In the late 1940s, the brand name Ben-Ovocylin was changed by Ciba to Ovocylin Benzoate.[107] 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, BANM, and JAN, while oestradiol benzoate was formerly its BANM.[14][15][65][97]

Brand names

The major brand name of estradiol benzoate is Progynon-B.[15][65][97] 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][97][108]

Availability

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][109][110] Outside of the United States, estradiol benzoate is also marketed in combination with progesterone for use as an intramuscular injection.[14][111]

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.[112]

References

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  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.
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  36. Ciba Symposium. Ciba. 1957. CIBA's range of hormone preparations has been increased with the advent of "Sistocyclin", one ampoule of which contains 200 mg progesterone and 10 mg oestradiol monobenzoate in crystalline suspension; it thus meets the requirements—in line with the most recent findings of the KAUFMANN Clinic—of cases marked by deficiency of corpus luteum hormone, e. g. in functional bleeding such as metropathia haemorrhagica.
  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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  77. 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.
  78. von Wattenwyl H (1944). "Über eine neue Anwendungsart oestrogener Substanzen" [A new type of application of estrogenic substances]. Schweiz. Med. Wochenschr. (in German). 74: 159–161.
  79. Toppozada HK (1950). "Oestrogenic Therapy with Prolonged Action". Obstetrical & Gynecological Survey. 5 (4): 531. doi:10.1097/00006254-195008000-00021. ISSN 0029-7828.
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  81. Ober KG, Klein I, Weber M (1954). "[The problem of progesterone therapy; experimental studies on the Hooker-Forbes test and clinical observations on crystalline suspensions]" [On the question of progesterone treatment: experimental studies with the Hooker-Forbes test and clinical observations with crystal suspensions]. Archiv für Gynäkologie. 184 (5): 543–616. doi:10.1007/BF00976991. PMID 13198154. S2CID 42832785.
  82. Field-Richards S (April 1955). "A preliminary series of cases of uterine hypoplasia treated by local injection of an oestrogenic emulsion". The Journal of Obstetrics and Gynaecology of the British Empire. 62 (2): 205–213. doi:10.1111/j.1471-0528.1955.tb14121.x. PMID 14368390. S2CID 41256797. Oestradiol monobenzoate or oestradiol diproprionate are slowly absorbed from oily solution after intramuscular injection and for this purpose are to be preferred to the unesterified form. As an even slower absorption of oestradiol monobenzoate can be obtained from an aqueous emulsion of this hormone (Lens, Overbeek and Polderman, 1949). Such a preparation for parenteral use was made available for this experiment by Messrs. Organon Laboratories Limited.
  83. Lens J, Overbeek GA, Polderman J (1949). "The effect of sex hormones in some organic solvents; emulsified in water". Acta Endocrinologica. 2 (4): 396–404. doi:10.1530/acta.0.0020396. PMID 18140399.
  84. Dorfman RI (5 December 2016). Steroidal Activity in Experimental Animals and Man. Elsevier Science. pp. 40–. ISBN 978-1-4832-7299-3. Ferin (1952) also studied duration of action in women with estrogen deficiency by recording the days of freedom from hot flushes. He rates estradiol-3-benzoate, estradiol-3-furoate, estradiol dipropionate, estradiol-17-caprylate, estradiol-3-benzoate-17-caprylate in oil, and finally estradiol-3-benzoate in emulsion or as microcrystals in that order of duration of action. After 10 mg. of each of the above preparations, a woman would typically remain free of symptoms for 10 days. This could, however, be as much as 50 days.
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