EB/P4 was one of the first combined estrogen and progestogen medications to be introduced for medical use.[6] It was first marketed inGermany as an oil solution in 1950.[6] Microcrystalline EB/P4 in aqueous suspension was developed and marketed under the brand name Sistocyclin several years later.[6] EB/P4 was eventually superseded by longer-actingparenteral estrogen–progestogen combinations as well as byoral estrogen–progestogen combinations.[6]
EB/P4 is or has been available for use byintramuscular injection both in the form of short-actingoil solutions (e.g., Duogynon, Lutrogen) and long-actingmicrocrystallineaqueous suspensions (e.g., Clinomin Forte, Sistocyclin).[4][5][14] These are provided asampoules, 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.[4] Thecrystal 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.[15][16][17] An oil-solution ampoule containing 30 mg EB and 30 mg P4 (brand name Vermagest) is used as an injectable emergency contraceptive.[18][7][8] Clinomin Forte is anaqueous suspension of EB/P4 that additionally containslidocaine and remains available today.[19]
The fullendometrial 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.[6] For comparison, the full endometrial transformation dosage ofestradiol valerate andhydroxyprogesterone caproate in oil solution (brand nameGravibinon) is a single intramuscular injection of 10 mg estradiol valerate and 250 to 375 mg hydroxyprogesterone caproate.[6] Endometrial transformation normally occurs during theluteal phase of themenstrual cycle; it is induced byendogenous progesterone following adequate priming by endogenous estradiol.[21]
Thedecidua (pregnancy-typeendometrium) 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.[6] 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.[6] The decidua induction dosages of estrogen and progestogen combinations arepseudopregnancy dosages.[6]
EB/P4 is administered byintramuscular injection a single time or continuously at regular intervals, depending on the indication.[4][5][22]Amorphous EB/P4 inoil solution (e.g., Duogynon, Lutrogen) is reported to have aduration of action of 2 days in terms of the progestogen component, and hence is a short-acting preparation, whereasmicrocrystalline EB/P4 inaqueous suspension (e.g., Sistocyclin) has a duration of 10 to 12 days, and hence is a long-acting preparation.[22][5] 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 estradiolexcretion on the 2nd day after injection and maintained elevated estradiol excretion for 17 days.[16][17]
EB/P4 inoil solution for use byintramuscular injection was first marketed inGermany in 1950.[6] It was one of the first combined estrogen and progestogen medications to be introduced for medical use.[6] To achieve a longerduration of action, microcrystalline EB/P4 with definedcrystal sizes inaqueous suspension was developed, studied in 1954,[42] and marketed under the brand name Sistocyclin shortly thereafter in the 1950s.[11][9][10][5][14] Formulations containing a combination of EB orestradiol valerate (an estradiol ester with a longer duration than EB) and the longer-actingsynthetic progestogenhydroxyprogesterone caproate in oil solution (brand namesPrimosiston,Gravibinon) were introduced in 1955 and eventually superseded EB/P4.[6]Oral estrogen–progestogen combinations, such asmestranol/noretynodrel (brand name Enovid), were also introduced in the 1950s, and soon replaced EB/P4 for menstrual and other indications as well.[6]
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.[1][2][3][43]
EB/P4 in oil solution remains widely available throughout the world.[1][2][44][45] Conversely, Sistocyclin, or microcrystalline EB/P4 in aqueous suspension, is no longer marketed.[1][2][44][45] However, individual formulations of microcrystalline EB in aqueous suspension (brand name Agofollin Depot)[46] and microcrystalline P4 in aqueous suspension (brand name Agolutin Depot)[47] remain available in some countries, including theCzech Republic andSlovakia.[1][2][44][45]
^abcdefghijklmKaiser R (July 1993). "[Gestagen-estrogen combinations in gynecology. On the history, dosage and use of a hormone principle]" [Progestogen-Estrogen Combinations in Gynecology. History, Dosage, and Use of a Hormone Principle].Geburtshilfe und Frauenheilkunde.53 (7):503–513.doi:10.1055/s-2007-1022924.PMID8370495.S2CID71261744.Zur kombinierten Anwendung von Gestagen en und Östrogenen stand en zunächst ölgelöstes Östradiolbenzoat und Progesteron zur Verfügung. Das erste derartige Mischpräparat kam in Deutschland 1950 auf den Mark t. Dem Wunsch nach verlän gerter Wirkungsdauer entsprach en dann Kristallmischsuspension en verschiedener Korngröße aus Östradiolmonobenzoat + Progesteron, deren Anwendung sich auf klinische Untersuchungen besch ränkte (83). Ölgelöste Depotpräparate mit Östradiolbenzoat oder -valerat + 17-hydroxyprogesteroncaproat wurden ab 1955 in die Therapie eingeführt (45.46).
^abCiba 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.
^abCiba 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 [...]
^abUfer J (1968). "Die therapeutische Anwendung der Gestagene beim Menschen" [Therapeutic Use of Progestagens in Humans].Die Gestagene [Progestogens]. Springer-Verlag. pp. 1026–1124.doi:10.1007/978-3-642-99941-3_7.ISBN978-3-642-99941-3.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.
^abKaiser 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.PMID13750804.
^abKaiser 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] (in German). Springer, Berlin, Heidelberg. pp. 227–232.doi:10.1007/978-3-642-86860-3_24.ISBN978-3-540-02909-0.{{cite book}}:ISBN / Date incompatibility (help)
^Henzl MR, Edwards JA (10 November 1999). "Pharmacology of Progestins: 17α-Hydroxyprogesterone Derivatives and Progestins of the First and Second Generation". In Sitruk-Ware R, Mishell DR (eds.).Progestins and Antiprogestins in Clinical Practice. Taylor & Francis. pp. 101–132.ISBN978-0-8247-8291-7.
^Becker H, Düsterberg B, Klosterhalfen H (1980). "[Bioavailability of cyproterone acetate after oral and intramuscular application in men (author's transl)]" [Bioavailability of Cyproterone Acetate after Oral and Intramuscular Application in Men].Urologia Internationalis.35 (6):381–385.doi:10.1159/000280353.PMID6452729.
^Moltz L, Haase F, Schwartz U, Hammerstein J (May 1983). "[Treatment of virilized women with intramuscular administration of cyproterone acetate]" [Efficacy of Intra muscularly Applied Cyproterone Acetate in Hyperandrogenism].Geburtshilfe und Frauenheilkunde.43 (5):281–287.doi:10.1055/s-2008-1036893.PMID6223851.
^Chu YH, Li Q, Zhao ZF (April 1986)."Pharmacokinetics of megestrol acetate in women receiving IM injection of estradiol-megestrol long-acting injectable contraceptive".The Chinese Journal of Clinical Pharmacology.The results showed that after injection the concentration of plasma MA increased rapidly. The meantime of peak plasma MA level was 3rd day, there was a linear relationship between log of plasma MA concentration and time (day) after administration in all subjects, elimination phase half-life t1/2β = 14.35 ± 9.1 days.
^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.PMID13198154.S2CID42832785.
^"Synovex C".PubChem. U.S. National Library of Medicine.
^abcSweetman, Sean C., ed. (2009). "Sex hormones and their modulators".Martindale: The Complete Drug Reference (36th ed.). London: Pharmaceutical Press. pp. 2133–2134.ISBN978-0-85369-840-1.
