Estradiol benzoate explained

Estradiol benzoate (EB), sold under the brand name Progynon-B among others, is an estrogen medication which is used in hormone therapy for menopausal symptoms and low estrogen levels in women, in hormone therapy for transgender women, and in the treatment of gynecological disorders. It is also used in the treatment of prostate cancer in men. Estradiol benzoate is used in veterinary medicine as well. When used clinically, the medication is given by injection into muscle usually two to three times per week.[1]

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

Estradiol benzoate was discovered in 1933 and was introduced for medical use that same year. It was the first estradiol ester to be discovered or marketed, and was one of the first estrogens to be used in medicine.[2] Along with estradiol dipropionate, estradiol benzoate was among the most widely used esters of estradiol for many years following its introduction. However, in the 1950s, longer-acting estradiol esters that necessitated less frequent injections, such as estradiol valerate and estradiol cypionate, were developed, and have since largely superseded estradiol benzoate.[3] Nonetheless, estradiol benzoate remains widely available throughout the world. It is not available for medical use in the United States, but is available there for use in veterinary medicine.

Medical uses

See main article: High-dose estrogen.

The medical uses of estradiol benzoate are the same as those of estradiol and other estrogens.[4] [5] Estradiol benzoate is used in hormone therapy for the treatment of menopausal symptoms such as hot flashes and vaginal atrophy and in the treatment of hypoestrogenism and delayed puberty due to hypogonadism or other causes in women. It is also used in hormone therapy for transgender women.[6] [7] [8] Aside from hormone therapy, estradiol benzoate is used in the treatment of gynecological disorders such as menstrual disorders, dysfunctional uterine bleeding, and breast engorgement. In addition, it is used as a form of high-dose estrogen therapy in the palliative treatment of prostate cancer in men.

Estradiol benzoate has a relatively short duration of action, and is administered by intramuscular injection usually two to three times per week. It is used in the treatment of menopausal symptoms at a dosage of 1 to 1.66 mg initially and 0.33 to 1 mg for maintenance two times per week, and in the treatment of hypoestrogenism and delayed puberty at a dosage of 1.66 mg two to three times per week.[9] The dosage used in hormone therapy for transgender women is 0.5 to 1.5 mg two to three times per week. In the treatment of prostate cancer, estradiol benzoate is used at a dosage of 1.66 mg three times per week (for a total of 5 mg per week).

Available forms

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

Estradiol benzoate is and has been available as an oil solution for intramuscular injection provided as vials and ampoules at concentrations of 0.167, 0.2, 0.33, 1, 1.67, 2, 5, 10, 20, and 25 mg/mL.[10] [11] It is also available as a microcrystalline aqueous suspension for intramuscular injection under the brand name Agofollin Depot.[12] [13] [14] Sistocyclin was the brand name of a product containing 10 mg microcrystalline estradiol benzoate and 200 mg microcrystalline progesterone in an aqueous suspension.[15] [16] [17] [18] 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.[19] [20] [21]

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.[22] Estradiol benzoate was also formerly available as 50 and 100 mg pellets for subcutaneous implantation and as a 2 mg/g ointment.[23]

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.[24] [25] [26]

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.[27]

Overdose

Symptoms of estrogen overdosage may include nausea, vomiting, bloating, increased weight, water retention, breast tenderness, vaginal discharge, heavy legs, and leg cramps.[28] These side effects can be diminished by reducing the estrogen dosage.

Interactions

Inhibitors and inducers of cytochrome P450 may influence the metabolism of estradiol and by extension circulating estradiol levels.[29]

Pharmacology

Pharmacodynamics

See also: Pharmacodynamics of estradiol.

Estradiol benzoate is an estradiol ester, or a prodrug of estradiol.[30] As such, it is an estrogen, or an agonist of the estrogen receptors. Estradiol benzoate has very low affinity for the ERs, on the order of 100-fold less than that of estradiol.[31] As such, estradiol benzoate is regarded as essentially inactive in terms of estrogenic effect itself, acting solely as a prodrug to estradiol. Estradiol benzoate is of about 38% higher molecular weight than estradiol due to the presence of its C3 benzoate ester. Because estradiol benzoate is a prodrug of estradiol, it is considered to be a natural and bioidentical form of estrogen.

Estrogenic potency

In the case of intramuscular injections of either estradiol benzoate or estradiol valerate in oil solution, the maturation dosage for the vaginal epithelium is 5 to 7 mg once per week and the endometrial proliferation dosage is 7 to 10 mg once per week. The total endometrial proliferation dosage of estradiol benzoate in oil solution by intramuscular injection over 14 days is 25 to 35 mg.[32]

The full endometrial transformation dosage of estradiol benzoate/progesterone in oil solution is 1 to 2 mg estradiol benzoate and 20 to 25 mg progesterone by intramuscular injection daily for 10 to 14 days, whereas the full endometrial transformation dosage of estradiol benzoate/progesterone in microcrystalline aqueous suspension is a single intramuscular injection of 10 mg estradiol benzoate and 200 mg progesterone. For comparison, the full endometrial transformation dosage of estradiol valerate and hydroxyprogesterone caproate in oil solution (brand name Gravibinon) is a single intramuscular injection of 10 mg estradiol valerate and 250 to 375 mg hydroxyprogesterone caproate. Endometrial transformation normally occurs during the luteal phase of the menstrual cycle; it is induced by endogenous progesterone following adequate priming by endogenous estradiol.[33]

The decidua (pregnancy-type endometrium) induction dosage of estradiol benzoate/progesterone in oil solution is 2 to 5 mg estradiol benzoate and 20 to 100 mg progesterone by intramuscular injection daily for 5 to 7 weeks, whereas the decidua induction dosage of estradiol benzoate/progesterone in microcrystalline aqueous suspension is 10 to 20 mg estradiol benzoate and 200 to 250 mg progesterone in microcrystalline aqueous suspension by intramuscular injection once per week for about 6 weeks. For comparison, the decidua induction dosage of estradiol valerate and hydroxyprogesterone caproate in oil solution is about the same as that of microcrystalline estradiol benzoate/progesterone in aqueous suspension. The decidua induction dosages of estrogen and progestogen combinations are pseudopregnancy dosages.

Antigonadotropic effects

As with other estrogens and forms of estradiol,[34] [35] [36] estradiol benzoate dose-dependently suppresses gonadotropin and testosterone levels in men and transgender women. In a study that administered estradiol benzoate twice-daily to transgender women at a dose that resulted in measured estradiol levels of about 200 to 250pg/mL, testosterone levels decreased from around 530ng/dL at baseline to about 55ng/dL (–90%) within approximately 3days of treatment.

Pharmacokinetics

See also: Pharmacokinetics of estradiol.

Following administration, estradiol benzoate acts as a prodrug of estradiol via cleavage by esterases into estradiol and the natural fatty acid benzoic acid. This cleavage occurs not only in the liver, but also in the blood and in tissues. Esters of estradiol like estradiol benzoate are readily hydrolyzed to estradiol, but have an extended duration when administered in via intramuscular or subcutaneous injection due to a depot effect afforded by their fatty acid ester moiety and consequent high lipophilicity. A long-lasting local tissue depot is formed by the injection that slowly releases estradiol benzoate into the circulation.

Intramuscular injection

Oil solution

The duration of action of estradiol benzoate in oil solution by intramuscular injection at typical clinical doses (e.g., 0.33–1.66 mg) is said to be 2 to 3 days.[37] 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).[38] The elimination half-life of estradiol benzoate in oil solution by intramuscular injection has been reported to be 48 to 120 hours (2 to 5 days).

A single intramuscular injection of 5 mg estradiol benzoate in oil solution has been found to result in peak circulating concentrations of 940 pg/mL estradiol and 343 pg/mL estrone, which occurred at about 2 days post-injection. Compared to two other commonly used estradiol esters, estradiol benzoate had the shortest duration, at approximately 4 to 5 days, whereas estradiol valerate and estradiol cypionate were found to last for 7 to 8 days and 11 days, respectively. This is because estradiol benzoate has a shorter and less bulky fatty acid chain, and in relation to this, is comparatively less lipophilic. For a given estradiol ester, the shorter or less bulky the fatty acid chain is, the less lipophilic, shorter-lasting, and less uniform/plateau-like the resultant levels of estradiol are as well as the higher (and hence more spike-like) the peak/maximal levels are.

Daily intramuscular injections of 1 mg estradiol benzoate in oil solution have been found to produce estradiol excretion rates almost double those of the normal luteal phase.[39] [40] [41] This is in accordance with known production rates of estradiol in women (e.g., 300 μg/day in the luteal phase).[42]

Aqueous suspension

Microcrystalline estradiol benzoate in aqueous suspension (brand names Agofollin Depot and Ovocyclin M alone and Follivirin in combination with testosterone isobutyrate) has been found to have a longer duration of action than amorphous estradiol benzoate in oil solution when administered via intramuscular injection.[43] [44] [45] [46] [47] [48] [49] [50] Whereas the duration of a single intramuscular injection of estradiol benzoate in oil solution is 6 days, the duration of a single intramuscular injection of microcrystalline estradiol benzoate in aqueous suspension is 16 to 21 days. Its duration also surpasses that of estradiol valerate and estradiol cypionate. The duration of microcrystalline aqueous suspensions administered by intramuscular injection is dependent both on concentration and on crystal size.[51] [52] [53]

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.[54] [55] [56]

Estradiol benzoate is active with oral and sublingual administration, similarly to estradiol valerate and estradiol acetate. However, it is not marketed in any formulation for use by these routes. Oral estradiol benzoate has been reported to possess about one-third to half the potency of intramuscular injection of estradiol benzoate.[57] [58] [59] [60] This level of oral potency has been described as remarkably high. The sublingual potency of estradiol benzoate is similar to that of estradiol. 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. Both estradiol and estradiol benzoate has a persistence of estrogenic effect with single administration of one day.

Subcutaneous implantation of crystalline estradiol benzoate pellets has been studied, but no estradiol benzoate pellet implants have been marketed.[61]

Chemistry

See also: Estrogen ester.

Estradiol benzoate is a synthetic estrane steroid and the C3 benzoate (benzenecarboxylate) ester of estradiol. It is also known as estradiol 3-benzoate or as estra-1,3,5(10)-triene-3,17β-diol 3-benzoate. 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.[62]

History

Estradiol benzoate was one of the first estrogens to be developed and marketed. In 1932, Adolf Butenandt described estrone benzoate and reported that it had a prolonged duration of action.[63] [64] 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.[65] [66] 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.[67] [68] [69] [70] 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.[71] [72] [73] [74] [75] [76] [77] By the early 1940s, Ben-Ovocylin had been introduced by Ciba as well. In the late 1940s, the brand name Ben-Ovocylin was changed by Ciba to Ovocylin Benzoate.[78] Following their introduction, estradiol benzoate and estradiol dipropionate were the most widely used esters of estradiol for many years. 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.

Society and culture

Generic names

Estradiol benzoate is the generic name of the drug and its,, and, while oestradiol benzoate was formerly its .[79] [80] [81] [82]

Brand names

The major brand name of estradiol benzoate is Progynon-B. 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.[83]

Availability

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

Estradiol benzoate is available in Europe and in other parts of the world. It was previously available for medical use in the United States, but is no longer marketed in this country.[84] [85] 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).[86] [87] Outside of the United States, estradiol benzoate is also marketed in combination with progesterone for use as an intramuscular injection.[88]

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.[89]

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.[90]

Notes and References

  1. Book: IARC Working Group on the Evaluation of Carcinogenic Risks to Humans . Combined Estrogen-progestogen Contraceptives and Combined Estrogen-progestogen Menopausal Therapy . World Health Organization . International Agency for Research on Cancer . World Health Organization . 2007 . 978-92-832-1291-1 . 388–.
  2. Book: Raviña E, Kubinyi H . The Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs . 16 May 2011 . John Wiley & Sons . 978-3-527-32669-3 . 175 . 20 May 2012.
  3. 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 . 10.1016/S0010-7824(80)80018-7 . 7389356.
  4. 1949 . 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 . 10.1016/S0095-9561(16)31995-8 . 0095-9561.
  5. Swyer GI . April 1959 . The oestrogens . Br Med J . 1 . 5128 . 1029–31 . 10.1136/bmj.1.5128.1029 . 1993181 . 13638626.
  6. Book: Israel GE . Transgender Care: Recommended Guidelines, Practical Information, and Personal Accounts . March 2001 . Temple University Press . 978-1-56639-852-7 . 64–.
  7. Book: Fifková H, Weiss P, Procházka I, Cohen-Kettenis PT, Pfäfflin F, Jarolím L, Veselý J, Weiss V . 6 . Transsexualita a jiné poruchy pohlavní identity . Transsexuality and other gender identity disorders . Czech . 4 August 2008 . Grada Publishing a.s. . 978-80-247-6962-2 . 95– . 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..
  8. Book: Weiss P . Sexuologie . 1 January 2010 . Grada Publishing a.s. . 978-80-247-2492-8 . 452–.
  9. Book: American Medical Association. Dept. of Drugs . AMA drug evaluations . Council on Drugs (American Medical Association) . American Society for Clinical Pharmacology and Therapeutics . 1 February 1977 . Publishing Sciences Group . 978-0-88416-175-2 . 540–572 . Estrogens, Progestagens, Oral Contraceptives, and Ovulatory Agents . 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..
  10. Book: Kleemann A, Engel J, Kutscher B, Reichert D . Pharmaceutical Substances, 5th Edition, 2009: Syntheses, Patents and Applications of the most relevant APIs . 14 May 2014 . Thieme . 978-3-13-179525-0 . 1167–1174.
  11. Book: Muller NF, Dessign RP . European Drug Index: European Drug Registrations, Fourth Edition . 19 June 1998 . CRC Press . 978-3-7692-2114-5 . 150, 349, 370.
  12. Book: Review of Czechoslovak Medicine . Avicenum - Czechoslovak Medical Press . 1973 . 5 . Oestradiol benzoate, aqueous microcrystalline suspension (Agofollin Depot SPOFA)..
  13. Web site: AGOFOLLIN Depot . https://web.archive.org/web/20190519104654/http://www.sukl.cz/download/pil/PI16221.pdf . 19 May 2019 . 15 January 2022 . www.sukl.cz.
  14. Book: Marek J . Farmakoterapie vnitřních nemocí - 4. zcela přepracované a doplněné vydání . 1 January 2010 . Grada Publishing a.s. . 978-80-247-2639-7 . 377– . 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..
  15. Book: Ufer J . Die Gestagene . Springer-Verlag . 1968 . 978-3-642-99941-3 . 1026–1124 . Progestogens . Die therapeutische Anwendung der Gestagene beim Menschen . Handbuch der experimentellen Pharmakologie / Handbook of Experimental Pharmacology . Therapeutic Use of Progestagens in Humans . 10.1007/978-3-642-99941-3_7 . 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..
  16. Book: 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..
  17. Book: Ciba Zeitschrift . 1957 . 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 [...].
  18. Book: Pschyrembel W . Praktische Gynäkologie: für Studierende und Ärzte . 15 June 2011 . Walter de Gruyter . 978-3-11-150424-7 . 601–.
  19. Kubíková D . 2014 . Menopauzální symptomy a hormonální substituční terapie . Menopausal symptoms and hormone replacement therapy . Praktické Lékárenství . cs . 10 . 2 . 68–73 . 1801-2434 . http://www.solen.sk/pdf/95e898d92100a736e32110dd1b846a9e.pdf --> .
  20. Book: Marek J . Farmakoterapie vnitřních nemocí: 4., zcela přepracované a doplněné vydání . 14 May 2010 . Grada Publishing a.s. . 978-80-247-9524-9 . 380– . 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..
  21. Book: Ciba Symposium: 1953/57:Index . Ciba . 1953 . 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..
  22. Book: Leidenberger FA . Klinische Endokrinologie für Frauenärzte . 17 April 2013 . Springer-Verlag . 978-3-662-08110-5 . 527–.
  23. Book: Martindale W . The Extra Pharmacopoeia . Pharmaceutical Press . 1958 . 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..
  24. Book: Lauritzen C, Studd JW . Current Management of the Menopause . 22 June 2005 . CRC Press . 978-0-203-48612-2 . 95–98,488.
  25. Book: Laurtizen C . Menopause – Andropause: Hormone Replacement Therapy Through the Ages . Krause & Pachernegg: Gablitz . 2001 . 978-3-901299-34-6 . Fisch FH . 67–88 . Hormone Substitution Before, During and After Menopause . https://www.kup.at/kup/pdf/4978.pdf.
  26. Book: Midwinter A . 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 . 1976 . 978-94-011-6167-1 . Campbell S . 377–382 . Contraindications to estrogen therapy and management of the menopausal syndrome in these cases . 10.1007/978-94-011-6165-7_33.
  27. Book: Ghosh AK . Mayo Clinic Internal Medicine Board Review . 23 September 2010 . OUP USA . 978-0-19-975569-1 . 222–.
  28. Lauritzen C . September 1990 . Clinical use of oestrogens and progestogens . Maturitas . 12 . 3 . 199–214 . 10.1016/0378-5122(90)90004-P . 2215269.
  29. 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 . 11741520.
  30. Kuhl H . 2005 . Pharmacology of estrogens and progestogens: influence of different routes of administration . Climacteric . 8 . Suppl 1 . 3–63 . 10.1080/13697130500148875 . 16112947 . 24616324.
  31. 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 . 10.1016/j.jsbmb.2004.03.118 . 15276617 . 54320898.
  32. Book: Lauritzen C . Grundlagen und Klinik der Menschlichen Fortpflanzung . Walter de Gruyter . 1988 . 978-3110109689 . Schneider HP, Lauritzen C, Nieschlag E . 229–306 . de . Foundations and Clinic of Human Reproduction . Natürliche und Synthetische Sexualhormone – Biologische Grundlagen und Behandlungsprinzipien . Natural and Synthetic Sexual Hormones – Biological Basis and Medical Treatment Principles . 35483492 .
  33. Book: Patil M, Mane SV . ECAB Luteal Phase Insufficiency - E-Book . 11 December 2014 . Elsevier Health Sciences . 978-81-312-3961-2 . 66–.
  34. Cox RL, Crawford ED . Estrogens in the treatment of prostate cancer . J Urol . 154 . 6 . 1991–8 . December 1995 . 7500443 . 10.1016/S0022-5347(01)66670-9.
  35. Ockrim J, Lalani EN, Abel P . Therapy Insight: parenteral estrogen treatment for prostate cancer--a new dawn for an old therapy . Nat Clin Pract Oncol . 3 . 10 . 552–63 . October 2006 . 17019433 . 10.1038/ncponc0602 . 6847203 .
  36. Henriksson P, Carlström K, Pousette A, Gunnarsson PO, Johansson CJ, Eriksson B, Altersgård-Brorsson AK, Nordle O, Stege R . 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 . July 1999 . 10386467 . 10.1002/(sici)1097-0045(19990701)40:2<76::aid-pros2>3.0.co;2-q . 12240276 .
  37. Book: Buchsbaum HJ . The Menopause . 6 December 2012 . Springer Science & Business Media . 978-1-4612-5525-3 . 62–.
  38. Vizziello G, D'Amato G, Trentadue R, Fanizza G . 1993 . [Estradiol benzoate test in the study of pituitary block induced by triptorelin] . Minerva Ginecol . it . 45 . 4 . 185–9 . 8506068.
  39. Kaiser R . [Gestagen-estrogen combinations in gynecology. On the history, dosage and use of a hormone principle] . Geburtshilfe und Frauenheilkunde . 53 . 7 . 503–513 . July 1993 . 8370495 . 10.1055/s-2007-1022924 . 71261744 .
  40. Kaiser R . [Estrogen excretion during the cycle and after injection of estradiol esters. A contribution to therapy with depot estrogens] . de . Geburtshilfe und Frauenheilkunde . 21 . 868–878 . September 1961 . 13750804 . Estrogen excretion during the cycle and after injection of estradiol esters. A contribution to therapy with depot estrogens .
  41. Book: Kaiser R . Gewebs-und Neurohormone: Physiologie des Melanophorenhormons . Springer, Berlin, Heidelberg . 1962 . 978-3-540-02909-0 . 227–232 . de . Tissue and Neurohormones: Physiology of the Melanophore Hormone . Über die Oestrogenausscheidung nach Injektion von Oestradiolestern . Symposion der Deutschen Gesellschaft für Endokrinologie . Estrogen excretion after injection of estradiol esters . 10.1007/978-3-642-86860-3_24.
  42. Nichols KC, Schenkel L, Benson H . 17 beta-estradiol for postmenopausal estrogen replacement therapy . Obstetrical & Gynecological Survey . 39 . 4 . 230–245 . April 1984 . 6717863 . 10.1097/00006254-198404000-00022 .
  43. von Wattenwyl H . Über eine neue Anwendungsart oestrogener Substanzen . 1944 . Schweiz. Med. Wochenschr. . 74 . 159–161 . A new type of application of estrogenic substances . de.
  44. Toppozada HK . 1950 . Oestrogenic Therapy with Prolonged Action . Obstetrical & Gynecological Survey . 5 . 4 . 531 . 10.1097/00006254-195008000-00021 . 0029-7828.
  45. Ferin J . 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 . January 1952 . 14907837 . 10.1210/jcem-12-1-28 .
  46. Ober KG, Klein I, Weber M . [The problem of progesterone therapy; experimental studies on the Hooker-Forbes test and clinical observations on crystalline suspensions] . Archiv für Gynäkologie . 184 . 5 . 543–616 . 1954 . 13198154 . 10.1007/BF00976991 . On the question of progesterone treatment: experimental studies with the Hooker-Forbes test and clinical observations with crystal suspensions . 42832785 .
  47. Field-Richards S . 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 . April 1955 . 14368390 . 10.1111/j.1471-0528.1955.tb14121.x . 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. . 41256797 .
  48. Lens J, Overbeek GA, Polderman J . The effect of sex hormones in some organic solvents; emulsified in water . Acta Endocrinologica . 2 . 4 . 396–404 . 1949 . 18140399 . 10.1530/acta.0.0020396 .
  49. Book: Dorfman RI . Steroidal Activity in Experimental Animals and Man . 5 December 2016 . Elsevier Science . 978-1-4832-7299-3 . 40– . 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..
  50. Book: Horský J, Presl J . Ovarian Function and its Disorders: Diagnosis and Therapy . 1981 . Springer Science & Business Media . 978-94-009-8195-9 . 309–332 . Hormonal Treatment of Disorders of the Menstrual Cycle . Developments in Obstetrics and Gynecology . 10.1007/978-94-009-8195-9_11 . https://books.google.com/books?id=7IrpCAAAQBAJ&pg=PA310.
  51. Shearman RP . The development of depot contraceptives . Journal of Steroid Biochemistry . 6 . 6 . 899–902 . June 1975 . 1177432 . 10.1016/0022-4731(75)90323-4 .
  52. Edkins RP . 1959 . The Modification of the Duration of Drug Action . Journal of Pharmacy and Pharmacology . 11 . S1 . 54T–66T . 10.1111/j.2042-7158.1959.tb10412.x . 0022-3573 . 78850713.
  53. Herrmann U . 1958 . Abhängigkeit der durch Oestrogen- und Progesteron-Kristalle induzierten Abbruchblutung von der Korngröße . Gynecologic and Obstetric Investigation . 146 . 4 . 318–323 . 10.1159/000306607 . 1423-002X.
  54. Parkes AS . February 1938 . Effective Absorption of Hormones . Br Med J . 1 . 4024 . 371–3 . 10.1136/bmj.1.4024.371 . 2085798 . 20781252.
  55. Book: Dorfman RI . Steroidal Activity in Experimental Animals and Man . 1964 . Elsevier Science . 978-1-4832-7299-3 . 4–.
  56. Book: Emmens CW . Hormone Assay . 22 October 2013 . Elsevier Science . 978-1-4832-7286-3 . 395–.
  57. Book: Stanczyk FZ . Estrogens and Progestogens in Clinical Practice . Churchill Livingstone . 1998 . 978-0-443-04706-0 . Fraser IS, Jansen RP, Lobo RA, Whitehead MI . 27–39 . Structure-function relationships and metabolism of estrogens and progestogens .
  58. Book: Henzl MR . Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management . Saunders . 1978 . 978-0-7216-9625-6 . Yen SS, Jaffe RB . 421–468 . Natural and Synthetic Female Sex Hormones .
  59. Book: Dorfman RI . Steroidal Activity in Experimental Animals and Man . 1964 . Elsevier Science . 978-1-4832-7299-3 . 40–.
  60. 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.
  61. Bishop PM, Folley SJ . August 1951 . Absorption of hormone implants in man . Lancet . 2 . 6676 . 229–32 . 10.1016/S0140-6736(51)93237-0 . 14862159.
  62. Web site: 17β-estradiol 3-benzoate | C25H28O3 | ChemSpider. www.chemspider.com.
  63. Book: Labhart A . Clinical Endocrinology: Theory and Practice . 6 December 2012 . Springer Science & Business Media . 978-3-642-96158-8 . 512–.
  64. 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 . 10.1515/bchm2.1932.208.4.129 . 0018-4888.
  65. Book: Oettel M, Schillinger E . Estrogens and Antiestrogens I: Physiology and Mechanisms of Action of Estrogens and Antiestrogens . 6 December 2012 . Springer Science & Business Media . 978-3-642-58616-3 . 8–.
  66. Miescher K, Scholz C, Tschopp E . The activation of female sex hormones: Mono-esters of alpha-oestradiol . The Biochemical Journal . 32 . 8 . 1273–1280 . August 1938 . 16746750 . 1264184 . 10.1042/bj0321273b .
  67. Kaufman C . 1933 . Die Behandlung der Amenorrhöe mit Hohen Dosen der Ovarialhormone . Klinische Wochenschrift . 12 . 40 . 1557–1562 . 10.1007/BF01765673 . 0023-2173 . 25856898.
  68. Buschbeck H . 1934 . Neue Wege der Hormontherapie in der Gynäkologie . New ways of hormonal therapy in gynecology . Deutsche Medizinische Wochenschrift . 60 . 11 . 389–393 . 10.1055/s-0028-1129842 . 72668930 . 0012-0472 .
  69. Biskind MS . 1935 . Commercial Glandular Products . Journal of the American Medical Association . 105 . 9 . 667 . 10.1001/jama.1935.92760350007009a . 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..
  70. Novak E . 1935 . The Therapeutic Use of Estrogenic Substances . JAMA: The Journal of the American Medical Association . 104 . 20 . 1815 . 10.1001/jama.1935.92760200002012 . 0098-7484 . Progynon B (Schering), in 1 cc. ampules, of 10,000 or 50,000 international units of hydroxyestrin benzoate in sesame oil..
  71. Johnstone RW . Sex Hormone Therapy in Gynæcology . Edinburgh Medical Journal . 43 . 11 . 680–695 . November 1936 . 29648134 . 5303355 .
  72. Reilly WA . Estrogens: Their Use in Pediatrics . California and Western Medicine . 55 . 5 . 237–239 . November 1941 . 18746057 . 1634235 .
  73. Greene RR . 1941 . Endocrine Therapy for Gynecologic Disorders . Medical Clinics of North America . 25 . 1 . 155–168 . 10.1016/S0025-7125(16)36624-X . 0025-7125.
  74. Fluhmann CF . 1944 . Clinical Use of Extracts from the Ovaries . Journal of the American Medical Association . 125 . 1 . 1 . 10.1001/jama.1944.02850190003001 . 0002-9955.
  75. Taylor HC . The Present Status of Gynecologic Endocrine Therapy . Bulletin of the New York Academy of Medicine . 14 . 10 . 608–634 . October 1938 . 19312076 . 1911308 .
  76. Watson MC . The Sex Hormones and Their Value as Therapeutic Agents . Canadian Medical Association Journal . 34 . 3 . 293–298 . March 1936 . 20320193 . 1561541 .
  77. Bishop PM . Hormones in the Treatment of Menstrual Disturbances . British Medical Journal . 1 . 3979 . 763–765 . April 1937 . 20780598 . 2088583 . 10.1136/bmj.1.3979.763 .
  78. 1949 . New Prescription Products . Journal of the American Pharmaceutical Association (Practical Pharmacy Ed.) . 10 . 4 . 198–206 . 10.1016/S0095-9561(16)31795-9 . 0095-9561.
  79. Web site: Estradiol. Drugs.com.
  80. Book: Index Nominum 2000: International Drug Directory . Taylor & Francis US . 2000 . 978-3-88763-075-1 . 406.
  81. Book: Elks J . The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies . 14 November 2014 . Springer . 978-1-4757-2085-3 . 897–.
  82. Book: Roberts AD . Dictionary of Steroids: Chemical Data, Structures, and Bibliographies . CRC Press . 1991 . 978-0-412-27060-4 . 415 . 20 May 2012.
  83. Book: Lewis RJ . Hazardous Chemicals Desk Reference . 13 June 2008 . John Wiley & Sons . 978-0-470-18024-2 . 593–.
  84. Book: Witherspoon R . Presidents List of Articles Which May Be Designated Or Modified As Eligible Articles for Purposes of the U.S. Generalized System of Preferences . 1 June 1994 . DIANE Publishing . 978-0-7881-1433-5 . 64–.
  85. Web site: Drugs@FDA: FDA Approved Drug Products . 26 July 2018 . United States Food and Drug Administration.
  86. Web site: Microencapsulated Estradiol Benzoate Suspension Implant . SUPPLEMENTAL NEW ANIMAL DRUG APPLICATION . https://web.archive.org/web/20170505225943/https://www.fda.gov/downloads/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/FOIADrugSummaries/ucm116143.pdf . 5 May 2017 . 16 December 2019 . Food and Drug Administration.
  87. Web site: SYNOVEXÒ Plus (Estradiol Benzoate and Trenbolone Acetate) . FREEDOM OF INFORMATION SUMMARY . https://web.archive.org/web/20170505230004/https://www.fda.gov/downloads/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/FOIADrugSummaries/UCM338208.pdf . 5 May 2017 . 16 December 2019 . Food and Drug Administration.
  88. Web site: Progesterone . 31 July 2018 . Drugs.com.
  89. Web site: FOLIVIRIN Injekční suspenze (Estradioli benzoas, testosteroni isobutyras). https://web.archive.org/web/20190520031642/http://www.sukl.cz/download/pil/PI15789.pdf . 20 May 2019 . 15 January 2022 . www.sukl.cz.
  90. Toppozada M, Goldsmith A . Long-acting Contraception. . Program for Applied Research on Fertility Regulation, Northwestern University . 1983 . 94–95 . https://web.archive.org/web/20190324131844/https://www.popline.org/node/423289 . 24 March 2019.

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