 | |
 | |
| Clinical data | |
|---|---|
| Pronunciation | /ˌɛstrəˈdaɪoʊlˈbɛnzoʊeɪt/ ES-trə-DY-ohlBEN-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 | |
| Legal status | |
| Legal status |
|
| Pharmacokinetic data | |
| Bioavailability | IM: High[1] |
| Protein binding | Estradiol: ~98% (toalbumin andSHBGTooltip sex hormone-binding globulin)[2][3] |
| Metabolism | Cleavage viaesterases in theliver,blood, andtissues[4][5] |
| Metabolites | Estradiol,benzoic acid, andmetabolites of estradiol[4][5] |
| Eliminationhalf-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 | |
| |
| CAS Number | |
| PubChemCID | |
| DrugBank | |
| ChemSpider | |
| UNII | |
| KEGG | |
| ChEBI | |
| ChEMBL | |
| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.000.040 |
| Chemical and physical data | |
| Formula | C25H28O3 |
| Molar mass | 376.496 g·mol−1 |
| 3D model (JSmol) | |
| |
| |
Estradiol benzoate (EB), sold under the brand nameProgynon-B among others, is anestrogen medication which is used inhormone therapy formenopausal symptoms andlow estrogen levels in women, inhormone therapy fortransgender women, and in the treatment ofgynecological disorders.[8][12][13] It is also used in the treatment ofprostate cancer in men.[8] Estradiol benzoate is used inveterinary medicine as well.[14][15] When used clinically, the medication is given byinjection into muscle usually two to three times per week.[8][12][16]
Side effects of estradiol benzoate includebreast tenderness,breast enlargement,nausea,headache, andfluid retention.[17] Estradiol benzoate is anestrogen and hence is anagonist of theestrogen receptor, thebiological target ofestrogens likeestradiol.[4][5] It is anestrogen ester and aprodrug ofestradiol in the body.[4][5] Because of this, it is considered to be anatural andbioidentical 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 firstestradiol ester to be discovered or marketed, and was one of the first estrogens to be used in medicine.[24] Along withestradiol 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 asestradiol valerate andestradiol 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 theUnited States, but is available there for use in veterinary medicine.[26][27]
Themedical uses of estradiol benzoate are the same as those of estradiol and other estrogens.[8][12] Estradiol benzoate is used inhormone therapy for the treatment ofmenopausal symptoms such ashot flashes andvaginal atrophy and in the treatment ofhypoestrogenism anddelayed puberty due tohypogonadism or other causes in women.[8][12] It is also used inhormone therapy fortransgender women.[13][28][29] Aside from hormone therapy, estradiol benzoate is used in the treatment ofgynecological disorders such asmenstrual disorders,dysfunctional uterine bleeding, andbreast engorgement.[8][12] In addition, it is used as a form ofhigh-dose estrogen therapy in thepalliative treatment ofprostate cancer in men.[8]
Estradiol benzoate has a relatively shortduration of action, and is administered byintramuscular 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]
| 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 | ||||
| Ethinylestradiola | 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 | ||||
| IMTooltip Intramuscular orSC 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. | |||||||
Estradiol benzoate is and has been available as anoil solution for intramuscular injection provided asvials andampoules 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 amicrocrystallineaqueous 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 microcrystallineprogesterone 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 microcrystallinetestosterone isobutyrate in aqueous suspension.[39][40][41][42]
Avaginaltablet formulation containing 0.125 mg estradiol benzoate and 10 mgmonalazone sodium (a vaginaldisinfectant andspermicidalcontraceptive) has been marketed under the brand name Malun 25.[43] Estradiol benzoate was also formerly available as 50 and 100 mgpellets forsubcutaneous implantation and as a 2 mg/g ointment.[44]
| 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:
| ||||
Contraindications of estrogens includecoagulation problems,cardiovascular diseases,liver disease, and certainhormone-sensitive cancers such asbreast cancer andendometrial cancer, among others.[59][60][61][62]
Theside effects of estradiol benzoate are the same as those of estradiol. Examples of such side effects includebreast tenderness andenlargement,nausea,bloating,edema,headache, andmelasma.[17]
Symptoms of estrogenoverdosage may includenausea,vomiting,bloating,increased weight,water retention,breast tenderness,vaginal discharge,heavy legs, andleg cramps.[59] These side effects can be diminished by reducing the estrogen dosage.[59]
Inhibitors andinducers ofcytochrome P450 may influence themetabolism of estradiol and by extension circulating estradiol levels.[63]
Estradiol benzoate is anestradiol ester, or aprodrug ofestradiol.[4][5] As such, it is anestrogen, or anagonist of theestrogen receptors.[4][5] Estradiol benzoate has very lowaffinity 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 aprodrug to estradiol.[5] Estradiol benzoate is of about 38% highermolecular weight than estradiol due to the presence of its C3benzoate ester.[65][15] Because estradiol benzoate is a prodrug of estradiol, it is considered to be anatural andbioidentical form of estrogen.[4]
| Estrogen | Other names | RBATooltip 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 viain-vitro displacement oflabeledestradiol fromestrogen receptors (ERs) generally ofrodentuterinecytosol.Estrogen esters are variablyhydrolyzed 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 fromhalf-maximal effective concentrations (EC50) that were determined viain-vitroβ‐galactosidase (β-gal) andgreen fluorescent protein (GFP)productionassays inyeast expressing humanERα and humanERβ. Bothmammaliancells and yeast have the capacity to hydrolyze estrogen esters.c = The affinities ofestradiol cypionate for the ERs are similar to those ofestradiol valerate and estradiol benzoate (figure).Sources: See template page. | ||||||
In the case of intramuscular injections of either estradiol benzoate orestradiol valerate in oil solution, the maturation dosage for thevaginalepithelium is 5 to 7 mg once per week and theendometrialproliferation 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 fullendometrial transformation dosage ofestradiol 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 andhydroxyprogesterone caproate in oil solution (brand nameGravibinon) is a single intramuscular injection of 10 mg estradiol valerate and 250 to 375 mg hydroxyprogesterone caproate.[66] Endometrial transformation normally occurs during theluteal phase of themenstrual cycle; it is induced byendogenous progesterone following adequate priming by endogenous estradiol.[68]
Thedecidua (pregnancy-typeendometrium) 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 arepseudopregnancy dosages.[66]
| 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: Allaqueous suspensions are ofmicrocrystallineparticle size.Estradiol production during themenstrual cycle is 30–640 µg/d (6.4–8.6 mg total per month or cycle). Thevaginalepithelium maturation dosage ofestradiol benzoate orestradiol valerate has been reported as 5 to 7 mg/week. An effectiveovulation-inhibiting dose ofestradiol undecylate is 20–30 mg/month.Sources: See template. | |||||
As with other estrogens and forms of estradiol,[70][71][72] estradiol benzoatedose-dependently suppressesgonadotropin andtestosterone levels in men andtransgender 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]
Following administration, estradiol benzoate acts as aprodrug of estradiol viacleavage byesterases into estradiol and the naturalfatty acidbenzoic acid.[5] This cleavage occurs not only in theliver, but also in theblood and intissues.[4][5] Esters of estradiol like estradiol benzoate are readilyhydrolyzed to estradiol, but have an extended duration when administered in viaintramuscular orsubcutaneous injection due to adepot effect afforded by theirfatty acid estermoiety and consequent highlipophilicity.[5] A long-lasting local tissue depot is formed by the injection that slowly releases estradiol benzoate into the circulation.[5]
Theduration 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 toGnRH analogue therapy withtriptorelin).[73] Theelimination 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, whereasestradiol valerate andestradiol 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 bulkyfatty acidchain, and in relation to this, is comparatively lesslipophilic.[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 estradiolexcretion rates almost double those of the normalluteal 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]
Microcrystalline estradiol benzoate inaqueous suspension (brand names Agofollin Depot and Ovocyclin M alone andFollivirin in combination withtestosterone isobutyrate)[33][39] has been found to have a longerduration of action thanamorphous 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 ofestradiol valerate andestradiol cypionate.[88] The duration of microcrystalline aqueous suspensions administered by intramuscular injection is dependent both onconcentration and oncrystal size.[89][90][86][91]
Theduration of estradiol benzoate is not prolonged if it is administered directly into thecirculation viaintravenous injection, in contrast to intramuscular injection.[92][93][94]
Estradiol benzoate is active withoral andsublingual administration, similarly toestradiol valerate andestradiol 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 thepotency 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 forendometrial 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 ofcrystalline estradiol benzoate pellets has been studied, but no estradiol benzoate pellet implants have been marketed.[99]
Estradiol benzoate is asyntheticestranesteroid and the C3benzoate (benzenecarboxylate)ester ofestradiol.[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 areestradiol dipropionate, the C3,17β dipropionate ester of estradiol, andestradiol acetate, the C3 acetate ester of estradiol.
The experimentaloctanol/water partition coefficient (logP) of estradiol benzoate is 4.7.[101]
| 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 phosphated |  | C3, C17β | Normustine,phosphoric acid | Water-soluble conjugate | – | 1.91 | 0.52 | 2.9–5.0 | |
| Polyestradiol phosphatee |  | C3–C17β | Phosphoric acid | Water-soluble conjugate | – | 1.23f | 0.81f | 2.9g | |
| Footnotes:a = Length ofester incarbonatoms forstraight-chain fatty acids or approximate length of ester in carbon atoms foraromatic orcyclic fatty acids.b = Relative estradiol content by weight (i.e., relativeestrogenic exposure).c = Experimental or predictedoctanol/water partition coefficient (i.e.,lipophilicity/hydrophobicity). Retrieved fromPubChem,ChemSpider, andDrugBank.d = Also known asestradiol normustine phosphate.e =Polymer ofestradiol phosphate (~13repeat 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. | |||||||||
Estradiol benzoate was one of the first estrogens to be developed and marketed.[21] In 1932,Adolf Butenandt describedestrone benzoate and reported that it had a prolongedduration of action.[11][102] Schwenk and Hildebrant atSchering discovered estradiol viareduction ofestrone in 1933, and they proceeded to synthesize estradiol benzoate from estradiol the same year.[4][18] Estradiol benzoate waspatented by Schering in 1933 and was introduced in anoil solution for use byintramuscular injection under the brand nameProgynon 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 namesProgynon B by Schering,Dimenformon Benzoate byRoche-Organon, andOestroform B byBritish Drug Houses.[103][104][105][106][107][108][109] By the early 1940s,Ben-Ovocylin had been introduced byCiba as well.[104][105][106] In the late 1940s, the brand nameBen-Ovocylin was changed by Ciba toOvocylin Benzoate.[110] Following their introduction, estradiol benzoate andestradiol dipropionate were the most widely used esters of estradiol for many years.[25] However,estradiol valerate andestradiol 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]
Estradiol benzoate is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name,BANMTooltip British Approved Name, andJANTooltip Japanese Accepted Name, whileoestradiol benzoate was formerly itsBANMTooltip British Approved Name.[14][15][65][100]
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]
Estradiol benzoate is available inEurope and in other parts of the world.[15][23] It was previously available for medical use in theUnited States, but is no longer marketed in this country.[15][27][23][26] However, it is approved and marketed in the United States forveterinary use as asubdermal implant both alone and in combination with theandrogen/anabolic steroidtrenbolone acetate (brand names Celerin and Synovex, respectively).[27][112][113] Outside of the United States, estradiol benzoate is also marketedin combination with progesterone for use as an intramuscular injection.[14][114]
Microcrystalline estradiol benzoate inaqueous suspension is available in theCzech Republic andSlovakia alone under the brand name Agofollin Depot and in combination with microcrystallinetestosterone isobutyrate under the brand name Folivirin.[33][39][14]
Estradiol benzoate has been studied in combination withnorethisterone enanthate as a once-a-monthcombined injectable contraceptive, but ultimately did not complete development for this indication.[115]
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.
Progynon B (Schering), in 1 cc. ampules, of 10,000 or 50,000 international units of hydroxyestrin benzoate in sesame oil.
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.
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.
Oestradiol benzoate, aqueous microcrystalline suspension (Agofollin Depot SPOFA).
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.
C. Dysfunktionelle Uterusblutungen. [...] 1. Depotinjektionen. 1. Originalmethode nach KAUFMANN und OBER. Es wird 1 Amp. mit 200 mg Progesteron und 10 mg Oestradiol-Monobenzoat als Kristallsuspension (Sistocyclin) injiziert [676, 678, 679, 295, 482, 365, 434, 563, 400]. [...] Beispiele. KAUFMANN et al. [485]: 400 mg Progesteron + 20 mg Oestradiolmonobenzoat Kristallsuspension. ELERT [224] U. HERRMANN [363]: 200 mg Progesteron + 10 mg Oestradiolmono benzoat Kristallsuspension.
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.
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 [...]
In addition, testosterone isobutyrate in FOLIVIRIN, Biotika, an injection containing 25 mg testosterone isobutyrate and 2.5 mg estradiol benzoate is available. It is applied every 4-6 weeks depending on the effect.
Femandren M. C'est le nom des nouvelles ampoules cristallines destinées au traitement associé œs- trogène-androgène. Elles renferment, sous forme de microcristaux, 2,5 mg de mono- benzoate d'œstradiol et 50 mg d'isobutyra- te de testostérone ; elles sont indiquées pour traiter les cas où il convient d'administrer simultanément de l'hormone femelle et de l'hormone mâle et où il importe aussi d'obtenir un effet prolongé, par exemple lors de symptômes d'insuffisance à la ménopause ou après castration. L'effet d'une injection se prolonge pendant 3-6 semaines.
PROPRIETARY PREPARATIONS CONTAINING OESTRADIOL MONOBENZOATE. Benztrone (Paines & Byrne). Oestradiol monobenzoate, available as an injection in 1-ml. Ampoules of 1, 2, and 5 mg., and in 2-ml. ampoules of 10 mg.; and as Implants of 50 and 100 mg. Dimenformon (Organon). [...] Also available as an Ointment containing 2 mg. per g. in a fatty basis.
300 μg 17β-estradiol (Aerodiol®; Servier, Chambrayles-Tours, France) was administered via the nasal route by a gynecologist. This product is unavailable after March 31, 2007 because its manufacturing and marketing are being discontinued.
{{cite book}}:ISBN / Date incompatibility (help)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.
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.
{{cite book}}:ISBN / Date incompatibility (help){{cite book}}:ISBN / Date incompatibility (help)