estradiol benzoate/progesterone

EB/P4 has been used to treat menstrual disorders such as secondary amenorrhea and menstrual irregularity, as a form of emergency contraception within 48 hours of sexual intercourse,{{cite book|author1=IARC Working Group on the Evaluation of Carcinogenic Risks to Humans|author2=World Health Organization|author3=International Agency for Research on Cancer|title=Combined Estrogen-progestogen Contraceptives and Combined Estrogen-progestogen Menopausal Therapy|url=https://books.google.com/books?id=aGDU5xibtNgC&pg=PA467|year=2007|publisher=World Health Organization|isbn=978-92-832-1291-1|pages=467–}}{{cite web |url=https://www.medicamentos.com.mx/DocHTM/27809.htm |title=VERMAGEST |website=www.medicamentos.com.mx |url-status=dead |archive-url=https://web.archive.org/web/20160602181851/http://www.medicamentos.com.mx/DocHTM/27809.htm |archive-date=2016-06-02}} and as a test for pregnancy. In the form of a microcrystalline aqueous suspension, EB/P4 has particularly been used to treat functional uterine bleeding.

EB/P4 has been studied in the treatment of breast cancer in women and found to be effective.{{cite book | vauthors = Dao TL | chapter = Pharmacology and Clinical Utility of Hormones in Hormone Related Neoplasms | year = 1975 | pages = 170–192 | doi = 10.1007/978-3-642-65806-8_11 | veditors = Sartorelli AC, Johns DG | title = Antineoplastic and Immunosuppressive Agents | chapter-url = https://books.google.com/books?id=aU_oCAAAQBAJ&pg=PA170 | isbn = 978-3-642-65806-8}}{{cite journal | vauthors = Landau RL, Ehrlich EN, Huggins C | title = Estradiol benzoate and progesterone in advanced human-breast cancer | journal = JAMA | volume = 182 | issue = 6 | pages = 632–636 | date = November 1962 | pmid = 12305404 | doi = 10.1001/jama.1962.03050450032008 }}

EB/P4 is or has been available for use by intramuscular injection both in the form of short-acting oil solutions (e.g., Duogynon, Lutrogen) and long-acting microcrystalline aqueous suspensions (e.g., Clinomin Forte, Sistocyclin).{{cite book| vauthors = Knörr K, Beller FK, Lauritzen C | chapter = Zusammenstellung der gebräuchlichen Hormonpräparate |title=Lehrbuch der Gynäkologie| chapter-url = https://books.google.com/books?id=ACybBwAAQBAJ&pg=PA255|date=17 April 2013|publisher=Springer-Verlag|isbn=978-3-662-00942-0|pages=255–}}{{cite book| vauthors = Pschyrembel W | chapter = Tabellen der gebräuchlichsten Hormonpräparate |title=Praktische Gynäkologie: für Studierende und Ärzte| chapter-url= https://books.google.com/books?id=vVaTnHDFzZ0C&pg=PA598|date=1968|publisher=Walter de Gruyter|isbn=978-3-11-150424-7|pages=598, 601}}

{{cite book| vauthors = Schirren C | chapter = Die Sexualhormone | veditors = Kimmig J |title=Therapie der Haut- und Geschlechtskrankheiten| chapter-url=https://books.google.com/books?id=txrUBgAAQBAJ&pg=PA508|year=1961|publisher=Springer-Verlag|isbn=978-3-642-94850-3 | doi = 10.1007/978-3-642-94850-3_6 |pages=508–}} These are provided as ampoules, with the oil-solution ampoules containing 2–3 mg EB and 12.5–50 mg progesterone and the aqueous-suspension ampoules containing 10 mg EB and 200 mg progesterone. The crystal sizes in microcrystalline EB/P4 in aqueous suspension (Sistocyclin) are 0.01 to 0.02 mm for EB crystals and 0.02 to 0.1 mm for P4 crystals.{{cite book| vauthors = Ober KG, Meinrenken H | chapter = Die Behandlung der Uterusruptur |title=Gynäkologische Operationen| chapter-url=https://books.google.com/books?id=gGmdBwAAQBAJ&pg=PA104|year=1964|publisher=Springer-Verlag|isbn=978-3-662-11935-8|pages=104–}}{{cite journal | vauthors = Kaiser R | title = [Estrogen excretion during the cycle and after injection of estradiol esters. A contribution to therapy with depot estrogens] | language = de | journal = Geburtshilfe und Frauenheilkunde | volume = 21 | pages = 868–878 | date = September 1961 | pmid = 13750804 | trans-title = Estrogen excretion during the cycle and after injection of estradiol esters. A contribution to therapy with depot estrogens }}{{cite book | vauthors = Kaiser R | chapter = Über die Oestrogenausscheidung nach Injektion von Oestradiolestern | trans-chapter = Estrogen excretion after injection of estradiol esters | pages = 227–232 | doi = 10.1007/978-3-642-86860-3_24 | title = Gewebs-und Neurohormone: Physiologie des Melanophorenhormons | year = 1962 | trans-title = Tissue and Neurohormones: Physiology of the Melanophore Hormone | language = de | publisher = Springer, Berlin, Heidelberg | isbn = 978-3-540-02909-0}} An oil-solution ampoule containing 30 mg EB and 30 mg P4 (brand name Vermagest) is used as an injectable emergency contraceptive.{{Cite web |url=https://www.drugs.com/international/vermagest.html |title= Vermagest (Estradiol - Progesterona - Lidocaína Suspensión Inyectable) | work = drugs.com |access-date=2018-09-17 |archive-date=2018-09-17 |archive-url=https://web.archive.org/web/20180917071441/https://www.drugs.com/international/vermagest.html |url-status=dead }} Clinomin Forte is an aqueous suspension of EB/P4 that additionally contains lidocaine and remains available today.{{cite web |url=http://www.indufar.com.py/files/shares/prospectos/400000154.pdf |title=Clinomin Forte |website=www.indufar.com.py |access-date=15 January 2022 |archive-url=https://web.archive.org/web/20200818223302/http://www.indufar.com.py/files/shares/prospectos/400000154.pdf |archive-date=18 August 2020 |url-status=dead}}

{{See also|Estradiol (medication)#Side effects|Estradiol benzoate#Side effects|Progesterone (medication)#Side effects}}

EB is an estrogen, or an agonist of the estrogen receptors, the biological target of estrogens like endogenous estradiol.{{cite journal | vauthors = Kuhl H | title = Pharmacology of estrogens and progestogens: influence of different routes of administration | journal = Climacteric | volume = 8 | pages = 3–63 | date = August 2005 | issue = Suppl 1 | pmid = 16112947 | doi = 10.1080/13697130500148875 | s2cid = 24616324 }} It is an estradiol ester and prodrug of estradiol with a longer duration of action than estradiol when administered by intramuscular injection in oil solution or aqueous suspension. P4 is a progestogen, or an agonist of the progesterone receptors, the biological target of progestogens like endogenous progesterone.

The full endometrial transformation dosage of EB/P4 in oil solution is 1 to 2 mg EB and 20 to 25 mg P4 by intramuscular injection daily for 10 to 14 days, whereas the full endometrial transformation dosage of EB/P4 in microcrystalline aqueous suspension is a single intramuscular injection of 10 mg EB and 200 mg P4. 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.{{cite book| vauthors = Patil M | chapter = Clinical Implications of Luteal Phase Defect and Impact on Early Pregnancy | veditors = Patil M, Mane SV |title=ECAB Luteal Phase Insufficiency - E-Book|chapter-url=https://books.google.com/books?id=jOO4BwAAQBAJ&pg=PA66|date=11 December 2014|publisher=Elsevier Health Sciences|isbn=978-81-312-3961-2|pages=66–}}

The decidua (pregnancy-type endometrium) induction dosage of EB/P4 in oil solution is 2 to 5 mg EB and 20 to 100 mg P4 by intramuscular injection daily for 5 to 7 weeks, whereas the decidua induction dosage of EB/P4 in microcrystalline aqueous suspension is 10 to 20 mg EB and 200 to 250 mg P4 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 EB/P4 in aqueous suspension. The decidua induction dosages of estrogen and progestogen combinations are pseudopregnancy dosages.

EB/P4 is administered by intramuscular injection a single time or continuously at regular intervals, depending on the indication. Amorphous EB/P4 in oil solution (e.g., Duogynon, Lutrogen) is reported to have a duration of action of 2 days in terms of the progestogen component, and hence is a short-acting preparation, whereas microcrystalline EB/P4 in aqueous suspension (e.g., Sistocyclin) has a duration of 10 to 12 days, and hence is a long-acting preparation.{{cite book| vauthors = Ufer J |title=Hormontherapie in der Frauenheilkunde: Grundlagen und Praxis|url=https://books.google.com/books?id=wcRsAAAAMAAJ|year=1960|publisher=Gruyter|page=153|isbn=9783111138770}} A study found that a single intramuscular injection of 10 mg microcrystalline EB in aqueous suspension with a 0.05 mm crystal size (similar to that in Sistocyclin) resulted in a maximal 7-fold increase in estradiol excretion on the 2nd day after injection and maintained elevated estradiol excretion for 17 days.

{{Parenteral potencies and durations of steroidal estrogens}}

{{Parenteral potencies and durations of progestogens}}

EB/P4 in oil solution for use by intramuscular injection was first marketed in Germany in 1950. It was one of the first combined estrogen and progestogen medications to be introduced for medical use. To achieve a longer duration of action, microcrystalline EB/P4 with defined crystal sizes in aqueous suspension was developed, studied in 1954,{{cite journal | vauthors = Ober KG, Klein I, Weber M | title = [The problem of progesterone therapy; experimental studies on the Hooker-Forbes test and clinical observations on crystalline suspensions] | journal = Archiv für Gynäkologie | volume = 184 | issue = 5 | pages = 543–616 | year = 1954 | pmid = 13198154 | doi = 10.1007/BF00976991 | trans-title = On the question of progesterone treatment: experimental studies with the Hooker-Forbes test and clinical observations with crystal suspensions | s2cid = 42832785 }} and marketed under the brand name Sistocyclin shortly thereafter in the 1950s.{{cite book | vauthors = Ufer J |chapter=Die therapeutische Anwendung der Gestagene beim Menschen |trans-chapter=Therapeutic Use of Progestagens in Humans |pages=1026–1124 |doi=10.1007/978-3-642-99941-3_7 |title=Die Gestagene |trans-title=Progestogens |year=1968 |publisher=Springer-Verlag |isbn=978-3-642-99941-3 |url=https://books.google.com/books?id=t8GpBgAAQBAJ&pg=PA1058 |quote=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.}}{{cite book |title=Ciba Symposium |url=https://books.google.com/books?id=KwkbAQAAMAAJ |year=1957 |publisher=Ciba |quote=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.}}{{cite book |title=Ciba Zeitschrift |url=https://books.google.com/books?id=WgpOAQAAIAAJ |year=1957 |page=3001 |quote=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 [...]}} Formulations containing a combination of EB or estradiol valerate (an estradiol ester with a longer duration than EB) and the longer-acting synthetic progestogen hydroxyprogesterone caproate in oil solution (brand names Primosiston, Gravibinon) were introduced in 1955 and eventually superseded EB/P4. Oral estrogen–progestogen combinations, such as mestranol/noretynodrel (brand name Enovid), were also introduced in the 1950s, and soon replaced EB/P4 for menstrual and other indications as well.

EB/P4 has been marketed under a large number of brand names including Component E-C, Component E-S, Di Pro Oleosum, Duogynon, Duogynon ampule, Duogynon forte, Duogynon simplex, Duoton Fort T P, Emmenovis, Estroprogyn, Gestrygen, Implus-C, Implus S, Jephagynon, Klimovan, Limovanil, Lutofolone, Menovis, Menstrogen Forte, Mestrolar, Metrigen Fuerte, Nomestrol, Phenokinon-F, Pro-Estramon-S, Prodiol, Proger F, Progestediol, Sistocyclin, Synovex C, Synovex S, and Tonevex S.{{cite web|url=https://pubchem.ncbi.nlm.nih.gov/compound/56840923|title = Synovex C | work = PubChem | publisher = U.S. National Library of Medicine }}

EB/P4 was originally developed and marketed in Europe. Today, it is available in a number of places in the world including various Latin American countries, Egypt, Italy, Lebanon, Taiwan, Thailand, Turkey, Malaysia, and Ethiopia. EB/P4 is available specifically as an injectable emergency contraceptive in El Salvador, Honduras, and Nicaragua.

EB/P4 in oil solution remains widely available throughout the world. Conversely, Sistocyclin, or microcrystalline EB/P4 in aqueous suspension, is no longer marketed.{{cite book | editor = Sweetman, Sean C. | chapter = Sex hormones and their modulators | title = Martindale: The Complete Drug Reference | edition = 36th | year = 2009 | pages = 2133–2134 | publisher = Pharmaceutical Press | location = London | isbn = 978-0-85369-840-1}}{{cite web |url=https://www.micromedexsolutions.com/ |title=Home |website=micromedexsolutions.com}} However, individual formulations of microcrystalline EB in aqueous suspension (brand name Agofollin Depot){{cite web |url=http://www.sukl.cz/download/pil/PI16221.pdf |title=AGOFOLLIN DEPOT |website=www.sukl.cz |access-date=15 January 2022 |archive-url=https://web.archive.org/web/20190519104654/http://www.sukl.cz/download/pil/PI16221.pdf |archive-date=19 May 2019 |url-status=dead}} and microcrystalline P4 in aqueous suspension (brand name Agolutin Depot){{cite web |url=http://www.sukl.cz/download/spc/SPC14550.pdf |title=AGOLUTIN DEPOT

|access-date=2019-05-19 |archive-url=https://web.archive.org/web/20190519061250/http://www.sukl.cz/download/spc/SPC14550.pdf |archive-date=2019-05-19 |url-status=live }} remain available in some countries, including the Czech Republic and Slovakia.

EB/P4 is used in veterinary medicine under the brand names Component E-C, Component E-S, Synovex C, and Synovex S, among others.

• List of combined sex-hormonal preparations § Estrogens and progestogens
• List of sex-hormonal aqueous suspensions

{{Reflist}}

{{Estrogens and antiestrogens}}

{{Progestogens and antiprogestogens}}

{{Estrogen receptor modulators}}

{{Progesterone receptor modulators}}

{{Portal bar|Medicine}}

{{DEFAULTSORT:Estradiol benzoate progesterone}}

Category:Combined estrogen–progestogen formulations

Category:Combined injectable contraceptives