Estradiol benzoate

Last updated

Estradiol benzoate
Estradiol benzoate.svg
Estradiol benzoate molecule ball.png
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 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 class Estrogen; Estrogen ester
ATC code
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
  • [(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 InfoCard 100.000.040 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C25H28O3
Molar mass 376.496 g·mol−1
3D model (JSmol)
  • 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=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]

Contents

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

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
Oral Estradiol 0.5–1 mg/day1–2 mg/day2–4 mg/day
Estradiol valerate 0.5–1 mg/day1–2 mg/day2–4 mg/day
Estradiol acetate 0.45–0.9 mg/day0.9–1.8 mg/day1.8–3.6 mg/day
Conjugated estrogens 0.3–0.45 mg/day0.625 mg/day0.9–1.25 mg/day
Esterified estrogens 0.3–0.45 mg/day0.625 mg/day0.9–1.25 mg/day
Estropipate 0.75 mg/day1.5 mg/day3 mg/day
Estriol 1–2 mg/day2–4 mg/day4–8 mg/day
Ethinylestradiol a2.5–10 μg/day5–20 μg/day–
Nasal spray Estradiol 150 μg/day300 μg/day600 μg/day
Transdermal patch Estradiol 25 μg/dayb50 μg/dayb100 μg/dayb
Transdermal gel Estradiol 0.5 mg/day1–1.5 mg/day2–3 mg/day
Vaginal Estradiol 25 μg/day––
Estriol 30 μg/day0.5 mg 2x/week0.5 mg/day
IM Tooltip Intramuscular or SC injection Estradiol valerate ––4 mg 1x/4 weeks
Estradiol cypionate 1 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 implant Estradiol 25 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]
RouteIngredientFormDose [lower-alpha 2] Brand names [lower-alpha 3]
Oral Estradiol Tablet0.1, 0.2, 0.5, 1, 2, 4 mgEstrace, Ovocyclin
Estradiol valerate Tablet0.5, 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 acetate Ring50, 100 µg/d, 3 monthsFemring
Injection [lower-alpha 4] Estradiol Microspheres1 mg/mLJuvenum E
Estradiol benzoateOil solution0.167, 0.2, 0.333, 1, 1.67, 2, 5, 10, 20, 25 mg/mLProgynon-B
Estradiol cypionate Oil solution1, 3, 5 mg/mLDepo-Estradiol
Estradiol valerate Oil solution5, 10, 20, 40 mg/mLProgynon Depot
Implant Estradiol Pellet20, 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. Estradiol.svg
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 Tooltip Relative binding affinity (%)a REP (%)b
ER ERα ERβ
Estradiol E2100100100
Estradiol 3-sulfate E2S; E2-3S ?0.020.04
Estradiol 3-glucuronide E2-3G ?0.020.09
Estradiol 17β-glucuronide E2-17G ?0.0020.0002
Estradiol benzoateEB; Estradiol 3-benzoate101.10.52
Estradiol 17β-acetate E2-17A31–4524 ?
Estradiol diacetate EDA; Estradiol 3,17β-diacetate ?0.79 ?
Estradiol propionate EP; Estradiol 17β-propionate19–262.6 ?
Estradiol valerate EV; Estradiol 17β-valerate2–110.04–21 ?
Estradiol cypionate EC; Estradiol 17β-cypionate ?c4.0 ?
Estradiol palmitate Estradiol 17β-palmitate0 ? ?
Estradiol stearate Estradiol 17β-stearate0 ? ?
Estrone E1; 17-Ketoestradiol115.3–3814
Estrone sulfate E1S; Estrone 3-sulfate20.0040.002
Estrone glucuronide E1G; Estrone 3-glucuronide ?<0.0010.0006
Ethinylestradiol EE; 17α-Ethynylestradiol10017–150129
Mestranol EE 3-methyl ether11.3–8.20.16
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
Estradiol Aq. soln. ?–<1 d
Oil soln.40–60–1–2 ≈ 1–2 d
Aq. susp. ?3.50.5–2 ≈ 2–7 d; 3.5 ≈ >5 d
Microsph. ?–1 ≈ 30 d
Estradiol benzoateOil soln.25–35–1.66 ≈ 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.20–3055 ≈ 7–8 d; 10 ≈ 10–14 d;
40 ≈ 14–21 d; 100 ≈ 21–28 d
Estradiol benz. butyrate Oil soln. ?1010 ≈ 21 d
Estradiol cypionate Oil soln.20–30–5 ≈ 11–14 d
Aq. susp. ?55 ≈ 14–24 d
Estradiol enanthate Oil soln. ?5–1010 ≈ 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 mg/kg injectable estradiol benzoate every 12 hours (or ~0.63 mg/day for a 70-kg [154-lb] person) in transgender women. Hormone levels with twice-daily injectable estradiol benzoate in transgender women.png
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

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]

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

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]

Structural properties of selected estradiol esters
EstrogenStructureEster(s)Relative
mol. weight		Relative
E2 contentb		log Pc
Position(s)Moiet(ies)TypeLengtha
Estradiol
Estradiol.svg
––––1.001.004.0
Estradiol acetate
Estradiol 3-acetate.svg
C3 Ethanoic acid Straight-chain fatty acid21.150.874.2
Estradiol benzoate
Estradiol benzoate.svg
C3 Benzoic acid Aromatic fatty acid– (~4–5)1.380.724.7
Estradiol dipropionate
Estradiol dipropionate.svg
C3, C17β Propanoic acid (×2)Straight-chain fatty acid3 (×2)1.410.714.9
Estradiol valerate
Estradiol valerate.svg
C17β Pentanoic acid Straight-chain fatty acid51.310.765.6–6.3
Estradiol benzoate butyrate
Estradiol butyrate benzoate.svg
C3, C17β Benzoic acid, butyric acid Mixed fatty acid– (~6, 2)1.640.616.3
Estradiol cypionate
Estradiol 17 beta-cypionate.svg
C17β Cyclopentylpropanoic acid Cyclic fatty acid– (~6)1.460.696.9
Estradiol enanthate
Estradiol enanthate.png
C17β Heptanoic acid Straight-chain fatty acid71.410.716.7–7.3
Estradiol dienanthate
Estradiol dienanthate.svg
C3, C17β Heptanoic acid (×2)Straight-chain fatty acid7 (×2)1.820.558.1–10.4
Estradiol undecylate
Estradiol undecylate.svg
C17β Undecanoic acid Straight-chain fatty acid111.620.629.2–9.8
Estradiol stearate
Estradiol stearate structure.svg
C17β Octadecanoic acid Straight-chain fatty acid181.980.5112.2–12.4
Estradiol distearate
Estradiol distearate.svg
C3, C17β Octadecanoic acid (×2)Straight-chain fatty acid18 (×2)2.960.3420.2
Estradiol sulfate
Estradiol sulfate.svg
C3 Sulfuric acid Water-soluble conjugate–1.290.770.3–3.8
Estradiol glucuronide
Estradiol sulfate.svg
C17β Glucuronic acid Water-soluble conjugate–1.650.612.1–2.7
Estramustine phosphate d
Estramustine phosphate.svg
C3, C17β Normustine, phosphoric acid Water-soluble conjugate–1.910.522.9–5.0
Polyestradiol phosphate e
Polyestradiol phosphate.svg
C3–C17β Phosphoric acid Water-soluble conjugate–1.23f0.81f2.9g
Footnotes:a = Length of ester in carbon atoms for straight-chain fatty acids or approximate length of ester in carbon atoms for aromatic 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

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]

Related Research Articles

<span class="mw-page-title-main">Estradiol acetate</span> Chemical compound

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

<span class="mw-page-title-main">Estradiol valerate</span> Chemical compound

Estradiol valerate (EV), sold for use by mouth under the brand name Progynova and for use by injection under the brand names Delestrogen and Progynon Depot among others, is an estrogen medication. It is used in hormone therapy for menopausal symptoms and low estrogen levels, hormone therapy for transgender people, and in hormonal birth control. It is also used in the treatment of prostate cancer. The medication is taken by mouth or by injection into muscle or fat once every 1 to 4 weeks.

<span class="mw-page-title-main">Norethisterone acetate</span> Chemical compound

Norethisterone acetate (NETA), also known as norethindrone acetate and sold under the brand name Primolut-Nor among others, is a progestin medication which is used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. The medication available in low-dose and high-dose formulations and is used alone or in combination with an estrogen. It is ingested orally.

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

<span class="mw-page-title-main">Estradiol cypionate</span> Chemical compound

Estradiol cypionate (EC), sold under the brand name Depo-Estradiol among others, is an estrogen medication which is used in hormone therapy for menopausal symptoms and low estrogen levels in women, in hormone therapy for trans women, and in hormonal birth control for women. It is given by injection into muscle once every 1 to 4 weeks.

<span class="mw-page-title-main">Estradiol enantate</span> Chemical compound

Estradiol enantate, also spelled estradiol enanthate and sold under the brand names Perlutal and Topasel among others, is an estrogen medication which is used in hormonal birth control for women. It is formulated in combination with dihydroxyprogesterone acetophenide, a progestin, and is used specifically as a combined injectable contraceptive. Estradiol enantate is not available for medical use alone. The medication, in combination with DHPA, is given by injection into muscle once a month.

<span class="mw-page-title-main">Estradiol undecylate</span> Chemical compound

Estradiol undecylate, also known as estradiol undecanoate and formerly sold under the brand names Delestrec and Progynon Depot 100 among others, is an estrogen medication which has been used in the treatment of prostate cancer in men. It has also been used as a part of hormone therapy for transgender women. Although estradiol undecylate has been used in the past, it was discontinued .The medication has been given by injection into muscle usually once a month.

<span class="mw-page-title-main">Estradiol dipropionate</span> Chemical compound

Estradiol dipropionate (EDP), sold under the brand names Agofollin, Di-Ovocylin, and Progynon DP among others, is an estrogen medication which has been used in hormone therapy for menopausal symptoms and low estrogen levels in women and in the treatment of gynecological disorders. It has also been used in feminizing hormone therapy for transgender women and in the treatment of prostate cancer in men. Although widely used in the past, estradiol dipropionate has largely been discontinued and is mostly no longer available today. It appears to remain in use only in Japan, Macedonia, and Australia. Estradiol dipropionate is given by injection into muscle at intervals ranging from once or twice a week to once every week and a half to two weeks.

An estrogen ester is an ester of an estrogen, most typically of estradiol but also of other estrogens such as estrone, estriol, and even nonsteroidal estrogens like diethylstilbestrol. Esterification renders estradiol into a prodrug of estradiol with increased resistance to first-pass metabolism, slightly improving its oral bioavailability. In addition, estrogen esters have increased lipophilicity, which results in a longer duration when given by intramuscular or subcutaneous injection due to the formation of a long-lasting local depot in muscle and fat. Conversely, this is not the case with intravenous injection or oral administration. Estrogen esters are rapidly hydrolyzed into their parent estrogen by esterases once they have been released from the depot. Because estradiol esters are prodrugs of estradiol, they are considered to be natural and bioidentical forms of estrogen.

<span class="mw-page-title-main">Estradiol hexahydrobenzoate</span> Chemical compound

Estradiol hexahydrobenzoate (EHHB), sold under a number of brand names including Benzo-Ginoestril A.P., BenzoGynoestryl Retard, Ginestryl-15-Depot, Menodin, and Tardoginestryl, is an estrogen medication which was previously used for indications such as menopausal hormone therapy and gynecological disorders. EHHB is given by injection into muscle at regular intervals, for instance once every few weeks.

<span class="mw-page-title-main">Estradiol phenylpropionate</span> Chemical compound

Estradiol phenylpropionate (EPP), also known as estradiol 17β-phenylpropionate and sold under the brand name Menformon Prolongatum, is an estrogen which is no longer marketed. It is an estrogen ester, specifically the C17β phenylpropionate ester of estradiol.

<span class="mw-page-title-main">Estradiol dienantate</span> Chemical compound

Estradiol dienanthate (EDE), sold under the brand names Climacteron among others, is a long-acting estrogen medication which was previously used in menopausal hormone therapy for women and to suppress lactation in women. It was formulated in combination with estradiol benzoate (EB), a short-acting estrogen, and testosterone enanthate benzilic acid hydrazone (TEBH), a long-acting androgen/anabolic steroid. EDE has not been made available for medical use alone. The medication, in combination with EB and TEBH, was given by injection into muscle once or at regular intervals, for instance once every 6 weeks.

<span class="mw-page-title-main">Estradiol benzoate butyrate</span> Chemical compound

Estradiol benzoate butyrate (EBB), sold under the brand names Neolutin N, Redimen, Soluna, and Unijab and formerly known under the developmental code name Unimens, is an estrogen medication which is used in hormonal birth control for women. It is formulated in combination with dihydroxyprogesterone acetophenide, a progestin, and is used specifically as a combined injectable contraceptive. EBB is not available for medical use alone. The medication, in combination with DHPA, is given by injection into muscle once a month.

<span class="mw-page-title-main">Estradiol (medication)</span> Steroidal hormone medication

Estradiol (E2) is a medication and naturally occurring steroid hormone. It is an estrogen and is used mainly in menopausal hormone therapy and to treat low sex hormone levels in women. It is also used in hormonal birth control for women, in feminizing hormone therapy for transgender women, and in the treatment of hormone-sensitive cancers like prostate cancer in men and breast cancer in women, among other uses. Estradiol can be taken by mouth, held and dissolved under the tongue, as a gel or patch that is applied to the skin, in through the vagina, by injection into muscle or fat, or through the use of an implant that is placed into fat, among other routes.

<span class="mw-page-title-main">Estrone (medication)</span> Estrogen medication

Estrone (E1), sold under the brand names Estragyn, Kestrin, and Theelin among many others, is an estrogen medication and naturally occurring steroid hormone which has been used in menopausal hormone therapy and for other indications. It has been provided as an aqueous suspension or oil solution given by injection into muscle and as a vaginal cream applied inside of the vagina. It can also be taken by mouth as estradiol/estrone/estriol and in the form of prodrugs like estropipate and conjugated estrogens.

<span class="mw-page-title-main">Pharmacokinetics of estradiol</span>

The pharmacology of estradiol, an estrogen medication and naturally occurring steroid hormone, concerns its pharmacodynamics, pharmacokinetics, and various routes of administration.

<span class="mw-page-title-main">Estradiol benzoate/progesterone</span> Drug combination

Estradiol benzoate/progesterone (EB/P4), sold under the brand names Duogynon and Sistocyclin among others, is a combination medication of estradiol benzoate (EB), an estrogen, and progesterone (P4), a progestogen. It has been formulated both as short-acting oil solutions and long-acting microcrystalline aqueous suspensions and is given by injection into muscle either once or continuously at regular intervals.

<span class="mw-page-title-main">Estradiol benzoate/estradiol dienanthate/testosterone enanthate benzilic acid hydrazone</span> Combination drug

Estradiol benzoate/estradiol dienanthate/testosterone enanthate benzilic acid hydrazone (EB/EDE/TEBH), sold under the brand names Climacteron, Lactimex, Lactostat, and Amenose, is an injectable combination medication of estradiol benzoate (EB), an estrogen, estradiol dienanthate (EDE), an estrogen, and testosterone enanthate benzilic acid hydrazone (TEBH), an androgen/anabolic steroid, which is used in menopausal hormone therapy for peri- and postmenopausal women and to suppress lactation in postpartum women. Clinical studies have assessed this formulation.

<span class="mw-page-title-main">Estradiol benzoate/estradiol phenylpropionate</span> Combination drug

Estradiol benzoate/estradiol phenylpropionate (EB/EPP), sold under the brand name Dimenformon Prolongatum, is an injectable combination formulation of estradiol benzoate (EB), a shorter-acting estrogen, and estradiol phenylpropionate (EPP), a longer-acting estrogen, which has been used in menopausal hormone therapy for women in Europe but appears to no longer be available. It has also been used to suppress lactation in women and has been used in feminizing hormone therapy for transgender women. It has been provided in the form of 1 mL ampoules containing 2.5 mg EB and 10 mg EPP in oil solution and is administered by intramuscular injection at regular intervals.

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. 1 2 3 4 5 6 7 8 9 10 11 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. 1 2 3 4 5 6 7 8 9 10 11 12 13 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. 1 2 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. 1 2 3 Buchsbaum HJ (6 December 2012). The Menopause. Springer Science & Business Media. pp. 62–. ISBN   978-1-4612-5525-3.
  8. 1 2 3 4 5 6 7 8 9 10 11 12 13 "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. 1 2 3 4 5 6 7 8 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. 1 2 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. 1 2 3 Labhart A (6 December 2012). Clinical Endocrinology: Theory and Practice. Springer Science & Business Media. pp. 512–. ISBN   978-3-642-96158-8.
  12. 1 2 3 4 5 6 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. 1 2 3 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. 1 2 3 4 "Estradiol". Drugs.com.
  15. 1 2 3 4 5 6 7 8 9 10 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. 1 2 Ghosh AK (23 September 2010). Mayo Clinic Internal Medicine Board Review. OUP USA. pp. 222–. ISBN   978-0-19-975569-1.
  18. 1 2 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. 1 2 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. 1 2 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. 1 2 3 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. 1 2 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. 1 2 3 4 5 6 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. 1 2 3 4 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. 1 2 "Drugs@FDA: FDA Approved Drug Products". United States Food and Drug Administration. Retrieved 26 July 2018.
  27. 1 2 3 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. 1 2 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. 1 2 3 "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.
  35. ↑ Ufer J (1968). "Die therapeutische Anwendung der Gestagene beim Menschen" [Therapeutic Use of Progestagens in Humans]. Die Gestagene [Progestogens]. Handbuch der experimentellen Pharmakologie / Handbook of Experimental Pharmacology. Springer-Verlag. pp. 1026–1124. doi:10.1007/978-3-642-99941-3_7. ISBN   978-3-642-99941-3. 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.
  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 [...]
  38. ↑ Pschyrembel W (15 June 2011). Praktische Gynäkologie: für Studierende und Ärzte. Walter de Gruyter. pp. 601–. ISBN   978-3-11-150424-7.
  39. 1 2 3 "FOLIVIRIN Injekční suspenze (Estradioli benzoas, testosteroni isobutyras)" (PDF). www.sukl.cz. Archived from the original (PDF) on 20 May 2019. Retrieved 15 January 2022.
  40. ↑ Kubíková D (2014). "Menopauzální symptomy a hormonální substituční terapie" [Menopausal symptoms and hormone replacement therapy]. Praktické Lékárenství (in Czech). 10 (2): 68–73. ISSN   1801-2434.
  41. ↑ Marek J (14 May 2010). Farmakoterapie vnitřních nemocí: 4., zcela přepracované a doplněné vydání. Grada Publishing a.s. pp. 380–. ISBN   978-80-247-9524-9. 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.
  42. ↑ Ciba Symposium: 1953/57:Index. Ciba. 1953. p. 197. 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.
  43. ↑ Leidenberger FA (17 April 2013). Klinische Endokrinologie für Frauenärzte. Springer-Verlag. pp. 527–. ISBN   978-3-662-08110-5.
  44. ↑ Martindale W (1958). The Extra Pharmacopoeia. Pharmaceutical Press. p. 960. 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.
  45. ↑ "Drugs@FDA: FDA Approved Drug Products". United States Food and Drug Administration. Retrieved 26 July 2018.
  46. ↑ Lobo RA (5 June 2007). Treatment of the Postmenopausal Woman: Basic and Clinical Aspects. Academic Press. pp. 177, 217–226, 770–771. ISBN   978-0-08-055309-2.
  47. ↑ Falcone T, Hurd WW (14 June 2017). Clinical Reproductive Medicine and Surgery: A Practical Guide. Springer. pp. 179–. ISBN   978-3-319-52210-4.
  48. ↑ Becker KL (2001). Principles and Practice of Endocrinology and Metabolism. Lippincott Williams & Wilkins. pp. 889, 1059–1060, 2153. ISBN   978-0-7817-1750-2.
  49. ↑ 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.
  50. ↑ Muller (19 June 1998). European Drug Index: European Drug Registrations, Fourth Edition. CRC Press. pp. 276, 454–455, 566–567. ISBN   978-3-7692-2114-5.
  51. ↑ Krishna UR, Sheriar NK (1996). Menopause. Orient Blackswan. pp. 70–. ISBN   978-81-250-0910-8.
  52. ↑ "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.
  53. ↑ "AERODIOL (Oestradiol hemihydrate 150 micrograms/actuation)" (PDF). Servier Laboratories (Aust) Pty Ltd.
  54. ↑ "Estradiol". Drugs.com.
  55. ↑ Sahin FK, Koken G, Cosar E, Arioz DT, Degirmenci B, Albayrak R, Acar M (2008). "Effect of Aerodiol administration on ocular arteries in postmenopausal women". Gynecol. Endocrinol. 24 (4): 173–7. doi:10.1080/09513590701807431. PMID   18382901. 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.
  56. ↑ Plouffe Jr L, Ravnikar VA, Speroff L, Watts NB (6 December 2012). Comprehensive Management of Menopause. Springer Science & Business Media. pp. 271–. ISBN   978-1-4612-4330-4.
  57. ↑ University of California (1868-1952) (1952). Hospital Formulary and Compendium of Useful Information. University of California Press. pp. 49–. GGKEY:2UAAZRZ5LN0.{{cite book}}: CS1 maint: numeric names: authors list (link)
  58. ↑ Leidenberger FA (17 April 2013). Klinische Endokrinologie für Frauenärzte. Springer-Verlag. pp. 527–. ISBN   978-3-662-08110-5.
  59. 1 2 3 Lauritzen C (September 1990). "Clinical use of oestrogens and progestogens". Maturitas. 12 (3): 199–214. doi:10.1016/0378-5122(90)90004-P. PMID   2215269.
  60. ↑ Lauritzen C, Studd JW (22 June 2005). Current Management of the Menopause. CRC Press. pp. 95–98, 488. ISBN   978-0-203-48612-2.
  61. ↑ Laurtizen C (2001). "Hormone Substitution Before, During and After Menopause" (PDF). In Fisch FH (ed.). Menopause – Andropause: Hormone Replacement Therapy Through the Ages. Krause & Pachernegg: Gablitz. pp. 67–88. ISBN   978-3-901299-34-6.
  62. ↑ Midwinter A (1976). "Contraindications to estrogen therapy and management of the menopausal syndrome in these cases". In Campbell S (ed.). The Management of the Menopause & Post-Menopausal Years: The Proceedings of the International Symposium held in London 24–26 November 1975 Arranged by the Institute of Obstetrics and Gynaecology, The University of London. MTP Press Limited. pp. 377–382. doi:10.1007/978-94-011-6165-7_33. ISBN   978-94-011-6167-1.
  63. ↑ Cheng ZN, Shu Y, Liu ZQ, Wang LS, Ou-Yang DS, Zhou HH (February 2001). "Role of cytochrome P450 in estradiol metabolism in vitro". Acta Pharmacol. Sin. 22 (2): 148–54. PMID   11741520.
  64. ↑ Bovee TF, Helsdingen RJ, Rietjens IM, Keijer J, Hoogenboom RL (2004). "Rapid yeast estrogen bioassays stably expressing human estrogen receptors alpha and beta, and green fluorescent protein: a comparison of different compounds with both receptor types". J. Steroid Biochem. Mol. Biol. 91 (3): 99–109. doi:10.1016/j.jsbmb.2004.03.118. PMID   15276617. S2CID   54320898.
  65. 1 2 3 4 5 6 Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 897–. ISBN   978-1-4757-2085-3.
  66. 1 2 3 4 5 6 7 8 Kaiser R (July 1993). "[Gestagen-estrogen combinations in gynecology. On the history, dosage and use of a hormone principle]". Geburtshilfe und Frauenheilkunde. 53 (7): 503–513. doi:10.1055/s-2007-1022924. PMID   8370495. S2CID   71261744.
  67. ↑ Lauritzen C (1988). "Natürliche und Synthetische Sexualhormone – Biologische Grundlagen und Behandlungsprinzipien" [Natural and Synthetic Sexual Hormones – Biological Basis and Medical Treatment Principles]. In Schneider HP, Lauritzen C, Nieschlag E (eds.). Grundlagen und Klinik der Menschlichen Fortpflanzung [Foundations and Clinic of Human Reproduction] (in German). Walter de Gruyter. pp. 229–306. ISBN   978-3110109689. OCLC   35483492.
  68. ↑ Patil M, Mane SV (11 December 2014). ECAB Luteal Phase Insufficiency - E-Book. Elsevier Health Sciences. pp. 66–. ISBN   978-81-312-3961-2.
  69. 1 2 3 Gooren LJ, Rao BR, van Kessel H, Harmsen-Louman W (1984). "Estrogen positive feedback on LH secretion in transsexuality". Psychoneuroendocrinology. 9 (3): 249–59. doi:10.1016/0306-4530(84)90004-0. PMID   6436856. S2CID   45688010.
  70. ↑ Cox RL, Crawford ED (December 1995). "Estrogens in the treatment of prostate cancer". J Urol. 154 (6): 1991–8. doi:10.1016/S0022-5347(01)66670-9. PMID   7500443.
  71. ↑ Ockrim J, Lalani EN, Abel P (October 2006). "Therapy Insight: parenteral estrogen treatment for prostate cancer--a new dawn for an old therapy". Nat Clin Pract Oncol. 3 (10): 552–63. doi:10.1038/ncponc0602. PMID   17019433. S2CID   6847203.
  72. ↑ Henriksson P, Carlström K, Pousette A, Gunnarsson PO, Johansson CJ, Eriksson B, Altersgård-Brorsson AK, Nordle O, Stege R (July 1999). "Time for revival of estrogens in the treatment of advanced prostatic carcinoma? Pharmacokinetics, and endocrine and clinical effects, of a parenteral estrogen regimen". Prostate. 40 (2): 76–82. doi:10.1002/(sici)1097-0045(19990701)40:2<76::aid-pros2>3.0.co;2-q. PMID   10386467. S2CID   12240276.
  73. ↑ Vizziello G, D'Amato G, Trentadue R, Fanizza G (1993). "[Estradiol benzoate test in the study of pituitary block induced by triptorelin]". Minerva Ginecol (in Italian). 45 (4): 185–9. PMID   8506068.
  74. 1 2 Kaiser R (September 1961). "[Estrogen excretion during the cycle and after injection of estradiol esters. A contribution to therapy with depot estrogens]" [Estrogen excretion during the cycle and after injection of estradiol esters. A contribution to therapy with depot estrogens]. Geburtshilfe und Frauenheilkunde (in German). 21: 868–878. PMID   13750804.
  75. 1 2 Kaiser R (1962). "Über die Oestrogenausscheidung nach Injektion von Oestradiolestern" [Estrogen excretion after injection of estradiol esters]. Gewebs-und Neurohormone: Physiologie des Melanophorenhormons[Tissue and Neurohormones: Physiology of the Melanophore Hormone]. Symposion der Deutschen Gesellschaft für Endokrinologie (in German). Springer, Berlin, Heidelberg. pp. 227–232. doi:10.1007/978-3-642-86860-3_24. ISBN   978-3-540-02909-0.
  76. ↑ Nichols KC, Schenkel L, Benson H (April 1984). "17 beta-estradiol for postmenopausal estrogen replacement therapy". Obstetrical & Gynecological Survey. 39 (4): 230–245. doi:10.1097/00006254-198404000-00022. PMID   6717863.
  77. 1 2 3 Shaw RW, Butt WR, London DR (May 1975). "The effect of oestrogen pretreatment on subsequent response to luteinizing hormone releasing hormone in normal women". Clin. Endocrinol. (Oxf). 4 (3): 297–304. doi:10.1111/j.1365-2265.1975.tb01537.x. PMID   1097136. S2CID   12139717.
  78. 1 2 3 Geppert G (1975). Untersuchungen zur Pharmakokinetik von Östradiol-17β, Östradiol-Benzoat, Östradiol-Valerianat und Östradiol-Undezylat bei der Frau: der Verlauf der Konzentrationen von Östradiol-17β, Östron, LH und FSH im Serum [Studies on the pharmacokinetics of estradiol-17β, estradiol benzoate, estradiol valerate, and estradiol undecylate in women: the progression of serum estradiol-17β, estrone, LH, and FSH concentrations]. pp. 1–34. OCLC   632312599.
  79. 1 2 3 Leyendecker G, Geppert G, Nocke W, Ufer J (May 1975). "Untersuchungen zur Pharmakokinetik von Östradiol-17β, Östradiol-benzoat, Östradiol-Valerianat un Östradiol-Undezylat bei der Frau: Der Verlauf der Konzentration von Östradiol-17β, Östron, LH und FSH im Serum" [Estradiol 17β, estrone, LH and FSH in serum after administration of estradiol 17β, estradiol benzoate, estradiol valeriate and estradiol undecylate in the female]. Geburtshilfe Frauenheilkd (in German). 35 (5): 370–374. ISSN   0016-5751. PMID   1150068.
  80. 1 2 Garza-Flores J (April 1994). "Pharmacokinetics of once-a-month injectable contraceptives". Contraception. 49 (4): 347–59. doi:10.1016/0010-7824(94)90032-9. PMID   8013219.
  81. ↑ 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.
  82. 1 2 Toppozada HK (1950). "Oestrogenic Therapy with Prolonged Action". Obstetrical & Gynecological Survey. 5 (4): 531. doi:10.1097/00006254-195008000-00021. ISSN   0029-7828.
  83. ↑ Ferin J (January 1952). "Relative duration of action of natural and synthetic estrogens administered parenterally in women with estrogen deficiency". The Journal of Clinical Endocrinology and Metabolism. 12 (1): 28–35. doi:10.1210/jcem-12-1-28. PMID   14907837.
  84. ↑ 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.
  85. ↑ 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.
  86. 1 2 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.
  87. ↑ 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.
  88. 1 2 3 4 5 6 7 Horský J, Presl J (1981). "Hormonal Treatment of Disorders of the Menstrual Cycle". Ovarian Function and its Disorders: Diagnosis and Therapy. Developments in Obstetrics and Gynecology. Springer Science & Business Media. pp. 309–332. doi:10.1007/978-94-009-8195-9_11. ISBN   978-94-009-8195-9.
  89. ↑ Shearman RP (June 1975). "The development of depot contraceptives". Journal of Steroid Biochemistry. 6 (6): 899–902. doi:10.1016/0022-4731(75)90323-4. PMID   1177432.
  90. ↑ Edkins RP (1959). "The Modification of the Duration of Drug Action". Journal of Pharmacy and Pharmacology. 11 (S1): 54T–66T. doi:10.1111/j.2042-7158.1959.tb10412.x. ISSN   0022-3573. S2CID   78850713.
  91. ↑ Herrmann U (1958). "Abhängigkeit der durch Oestrogen- und Progesteron-Kristalle induzierten Abbruchblutung von der Korngröße". Gynecologic and Obstetric Investigation. 146 (4): 318–323. doi:10.1159/000306607. ISSN   1423-002X.
  92. ↑ Parkes AS (February 1938). "Effective Absorption of Hormones". Br Med J. 1 (4024): 371–3. doi:10.1136/bmj.1.4024.371. PMC   2085798 . PMID   20781252.
  93. ↑ Dorfman RI (1964). Steroidal Activity in Experimental Animals and Man. Elsevier Science. pp. 4–. ISBN   978-1-4832-7299-3.
  94. ↑ Emmens CW (22 October 2013). Hormone Assay. Elsevier Science. pp. 395–. ISBN   978-1-4832-7286-3.
  95. ↑ Stanczyk FZ (1998). "Structure-function relationships and metabolism of estrogens and progestogens". In Fraser IS, Jansen RP, Lobo RA, Whitehead MI (eds.). Estrogens and Progestogens in Clinical Practice. Churchill Livingstone. pp. 27–39. ISBN   978-0-443-04706-0.
  96. 1 2 Henzl MR (1978). "Natural and Synthetic Female Sex Hormones". In Yen SS, Jaffe RB (eds.). Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management. Saunders. pp. 421–468. ISBN   978-0-7216-9625-6.
  97. ↑ Dorfman RI (1964). Steroidal Activity in Experimental Animals and Man. Elsevier Science. pp. 40–. ISBN   978-1-4832-7299-3.
  98. ↑ Ferin J (1941). "L'activité comparée de diverses substances oestrogènes naturelles et du stilboestrol administrés par voie orale, trans-hépatique, chez la femme ovariectomisée" [The comparative activity of various natural estrogen substances and stilboestrol administered by the oral, transhepatic route, in ovariectomized women]. Revue Belge des Sciences Médicales. 13: 177–198.
  99. ↑ Bishop PM, Folley SJ (August 1951). "Absorption of hormone implants in man". Lancet. 2 (6676): 229–32. doi:10.1016/S0140-6736(51)93237-0. PMID   14862159.
  100. 1 2 3 4 5 Roberts AD (1991). Dictionary of Steroids: Chemical Data, Structures, and Bibliographies. CRC Press. p. 415. ISBN   978-0-412-27060-4 . Retrieved 20 May 2012.
  101. ↑ "17β-estradiol 3-benzoate | C25H28O3 | ChemSpider". www.chemspider.com.
  102. ↑ Butenandt A, Störmer I (1932). "Über isomere Follikelhormone. Untersuchungen über das weibliche Sexualhormon, 7. Mitteilung" [About isomeric follicle hormones. Studies on the female sex hormone, 7th communication.]. Hoppe-Seyler's Zeitschrift für physiologische Chemie. 208 (4): 129–148. doi:10.1515/bchm2.1932.208.4.129. ISSN   0018-4888.
  103. ↑ Johnstone RW (November 1936). "Sex Hormone Therapy in Gynæcology". Edinburgh Medical Journal. 43 (11): 680–695. PMC   5303355 . PMID   29648134.
  104. 1 2 Reilly WA (November 1941). "Estrogens: Their Use in Pediatrics". California and Western Medicine. 55 (5): 237–239. PMC   1634235 . PMID   18746057.
  105. 1 2 Greene RR (1941). "Endocrine Therapy for Gynecologic Disorders". Medical Clinics of North America. 25 (1): 155–168. doi:10.1016/S0025-7125(16)36624-X. ISSN   0025-7125.
  106. 1 2 Fluhmann CF (1944). "Clinical Use of Extracts from the Ovaries". Journal of the American Medical Association. 125 (1): 1. doi:10.1001/jama.1944.02850190003001. ISSN   0002-9955.
  107. ↑ Taylor HC (October 1938). "The Present Status of Gynecologic Endocrine Therapy". Bulletin of the New York Academy of Medicine. 14 (10): 608–634. PMC   1911308 . PMID   19312076.
  108. ↑ Watson MC (March 1936). "The Sex Hormones and Their Value as Therapeutic Agents". Canadian Medical Association Journal. 34 (3): 293–298. PMC   1561541 . PMID   20320193.
  109. ↑ Bishop PM (April 1937). "Hormones in the Treatment of Menstrual Disturbances". British Medical Journal. 1 (3979): 763–765. doi:10.1136/bmj.1.3979.763. PMC   2088583 . PMID   20780598.
  110. ↑ "New Prescription Products". Journal of the American Pharmaceutical Association (Practical Pharmacy Ed.). 10 (4): 198–206. 1949. doi:10.1016/S0095-9561(16)31795-9. ISSN   0095-9561.
  111. ↑ Lewis RJ (13 June 2008). Hazardous Chemicals Desk Reference. John Wiley & Sons. pp. 593–. ISBN   978-0-470-18024-2.
  112. ↑ "Microencapsulated Estradiol Benzoate Suspension Implant" (PDF). SUPPLEMENTAL NEW ANIMAL DRUG APPLICATION. Food and Drug Administration. Archived from the original (PDF) on 5 May 2017. Retrieved 16 December 2019.
  113. ↑ "SYNOVEXÒ Plus (Estradiol Benzoate and Trenbolone Acetate)" (PDF). FREEDOM OF INFORMATION SUMMARY. Food and Drug Administration. Archived from the original (PDF) on 5 May 2017. Retrieved 16 December 2019.
  114. ↑ "Progesterone". Drugs.com. Retrieved 31 July 2018.
  115. ↑ Toppozada M, Goldsmith A, eds. (1983). Long-acting Contraception (Report). Program for Applied Research on Fertility Regulation, Northwestern University. pp. 94–95. Archived from the original on 24 March 2019.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.