Estradiol benzoate/progesterone

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.[1][2][3] 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.[4][5]

Estradiol benzoate/progesterone
Combination of
Estradiol benzoateEstrogen
ProgesteroneProgestogen
Clinical data
Trade namesDuogynon, Lutrogen, Sistocyclin, others
Other namesEB/P4
Routes of
administration		Intramuscular injection (oil solution, aqueous suspension)
ATC code
Identifiers
CAS Number
PubChem CID
ChemSpider

EB/P4 was one of the first combined estrogen and progestogen medications to be introduced for medical use.[6] It was first marketed in Germany 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suspension was developed and marketed under the brand name Sistocyclin several years later.[6] EB/P4 was eventually superseded by longer-acting parenteral estrogen–progestogen combinations as well as by oral estrogen–progestogen combinations.[6]

Medical uses

EB/P4 has been used to treat menstrual disorders such as secondary amenorrhea and menstrual irregularity,[4][5] as a form of emergency contraception within 48 hours of sexual intercourse,[7][8] and as a test for pregnancy.[4][5] In the form of a microcrystalline aqueous suspension, EB/P4 has particularly been used to treat functional uterine bleeding.[9][10]

EB/P4 has been studied in the treatment of breast cancer in women and found to be effective.[11][12][13]

Available forms

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., Sistocyclin).[4][5][14] 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.[4] 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.[15][16][17] An oil-solution ampoule containing 30 mg EB and 30 mg (brand name Vermagest) is used as an injectable emergency contraceptive.[18][7][8]

Side effects
See also: Estradiol (medication) § Side effects, Estradiol benzoate § Side effects, and Progesterone (medication) § Side effects

Pharmacology

Pharmacodynamics

EB is an estrogen, or an agonist of the estrogen receptors, the biological target of estrogens like endogenous estradiol.[19] 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.[19] P4 is a progestogen, or an agonist of the progesterone receptors, the biological target of progestogens like endogenous progesterone.[19]

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.[6] 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.[6] Endometrial transformation normally occurs during the luteal phase of the menstrual cycle; it is induced by endogenous progesterone following adequate priming by endogenous estradiol.[20]

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.[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 are pseudopregnancy dosages.[6]

Pharmacokinetics

EB/P4 is administered by intramuscular injection a single time or continuously at regular intervals, depending on the indication.[4][5][21] 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.[21][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 estradiol excretion on the 2nd day after injection and maintained elevated estradiol excretion for 17 days.[16][17]

Parenteral potencies and durations of steroidal estrogens
EstrogenFormMajor brand name(s)EPD (14 days)CIC-D (month)Duration
EstradiolOil solution–40–60 mg–1–10 mg ≈ 1–2 days
Aqueous suspensionaMego-E?3.5 mg3.5 mg ≈ >5 days
MicrospheresJuvenum-E, Juvenum?–1 mg ≈ 30 days
Estradiol benzoateOil solutionProgynon-B25–35 mg–5 mg ≈ 3–6 days
Aqueous suspensionAgofollin-Depot20 mg–10 mg ≈ 16–21 days
Estradiol dipropionateOil solutionAgofollin, Di-Ovocyclin, Progynon DP25–30 mg–5 mg ≈ 5–8 days
Estradiol valerateOil solutionDelestrogen, Progynon Depot, Mesigyna20–30 mg5 mg5 mg ≈ 7–8 days; 10 mg ≈ 10–14 days;
40 mg ≈ 14–21 days; 100 mg ≈ 21–28 days
Estradiol cypionateOil solutionDepo-Estradiol, Depofemin20–30 mg–5 mg ≈ 11–14 days
Aqueous suspensionaCyclofem, Lunelle?5 mg5 mg ≈ 14–24 days
Estradiol benzoate butyrateaOil solutionRedimen, Soluna, Unijab?10 mg10 mg ≈ 21 days
Estradiol enanthateaOil solutionPerlutal, Topasel, Yectames?5–10 mg10 mg ≈ 20–30 days
Estradiol undecylateOil solutionDelestrec, Progynon Depot 100?–10–20 mg ≈ 40–60 days; 25–50 mg ≈ 60–120 days
Polyestradiol phosphateAqueous solutionEstradurin40–60 mg–40 mg ≈ 30 days; 80 mg ≈ 60 days;
160 mg ≈ 120 days
EstroneOil solutionKestrin, Theelin?–1–2 mg ≈ 2–3 days
Aqueous suspensionEstrone Aqueous Suspension?–?
EstriolOil solution–?–1–2 mg ≈ 1–4 days
Polyestriol phosphateAqueous solutionGynäsan, Klimadurin, Triodurin?–50 mg ≈ 30 days; 80 mg ≈ 60 days
Notes: All by intramuscular injection. All aqueous suspensions are of microcrystalline particle size. Estradiol production during the menstrual cycle is 30–640 µg/day (6.4–8.6 mg total per month or cycle). The vaginal epithelium maturation dosage of estradiol benzoate or estradiol valerate is 5 to 7 mg/week. An effective ovulation-inhibiting dose of estradiol undecylate is 20–30 mg/month. Footnotes: a = Available only in combined injectable contraceptives (i.e., not available alone). Sources: See template.
Parenteral potencies and durations of progestogens
ProgestogenFormMajor brand namesClassTFD
(14 days)		POIC-D
(2–3 months)		CIC-D
(month)		Duration
Algestone acetophenideOil solutionPerlutal, Topasel, YectamesPregnane?–75–150 mg100 mg ≈ 14–32 days
Cyproterone acetateOil solutionAndrocur DepotPregnane?––300 mg ≈ 20 days
DydrogesteroneaAqueous suspension–Retropregnane?––100 mg ≈ 16–38 days
Gestonorone caproateOil solutionDepostat, PrimostatNorpregnane50 mg––25–50 mg ≈ 8–13 days
Hydroxyprogesterone acetateaAqueous suspension–Pregnane350 mg––150–350 mg ≈ 9–16 days
Hydroxyprogesterone caproateOil solutionDelalutin, Proluton, MakenaPregnane250–500 mgb–250–500 mg65–500 mg ≈ 5–21 days
Levonorgestrel butanoateaAqueous suspension–Gonane?––5–50 mg ≈ 3–6 months
Lynestrenol phenylpropionateaOil solution–Estrane?––50–100 mg ≈ 14–30 days
Medroxyprogesterone acetateAqueous suspensionDepo-ProveraPregnane50–100 mg150 mg25 mg50–150 mg ≈ 14–50+ days
Megestrol acetateAqueous suspensionMego-EPregnane?–25 mg25 mg ≈ >14 daysc
Norethisterone enanthateOil solutionNoristerat, MesigynaEstrane100–200 mg200 mg50 mg50–200 mg ≈ 11–52 days
Oxogestone phenylpropionateaOil solution–Norpregnane?––100 mg ≈ 19–20 days
ProgesteroneOil solutionProgestaject, Gestone, StronePregnane200 mgb––25–350 mg ≈ 2–6 days
Aqueous suspensionAgolutin DepotPregnane50–200 mg––50–300 mg ≈ 7–14 days
Note: All by intramuscular or subcutaneous injection. All are synthetic except for P4, which is bioidentical. P4 production during the luteal phase is ~25 (15–50) mg/day. The OID of OHPC is 250 to 500 mg/month. Footnotes: a = Never marketed by this route. b = In divided doses (2 × 125 or 250 mg for OHPC, 10 × 20 mg for P4). c = Half-life is ~14 days. Sources: Main: See template.

History

EB/P4 in oil solution for use by intramuscular injection was first marketed in Germany in 1950.[6] It was one of the first combined estrogen and progestogen medications to be introduced for medical use.[6] To achieve a longer duration of action, microcrystalline EB/P4 with defined crystal sizes in aqueous suspension was developed, studied in 1954,[22] and marketed under the brand name Sistocyclin shortly thereafter in the 1950s.[11][9][10][5][14] 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.[6] 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.[6]

Society and culture

Brand names

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][23]

Availability

EB/P4 was originally developed and marketed in Europe.[4][5] 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.[1][2][3] EB/P4 is available specifically as an injectable emergency contraceptive in El Salvador, Honduras, and Nicaragua.[18][7][8]

EB/P4 in oil solution remains widely available throughout the world.[1][2][24][25] Conversely, Sistocyclin, or microcrystalline EB/P4 in aqueous suspension, is no longer marketed.[1][2][24][25] However, individual formulations of microcrystalline EB in aqueous suspension (brand name Agofollin Depot)[26] and microcrystalline P4 in aqueous suspension (brand name Agolutin Depot)[27] remain available in some countries, including the Czech Republic and Slovakia.[1][2][24][25]

Veterinary uses

EB/P4 is used in veterinary medicine under the brand names Component E-C, Component E-S, Synovex C, and Synovex S, among others.[1][2]

See also

References
  1. "Estradiol". Drugs.com. Retrieved 2018-07-31.
  2. "Progesterone". Drugs.com. Retrieved 2018-07-31.
  3. Muller (19 June 1998). European Drug Index: European Drug Registrations, Fourth Edition. CRC Press. pp. 349–. ISBN 978-3-7692-2114-5.
  4. Karl Knörr; Fritz K. Beller; Christian Lauritzen (17 April 2013). Lehrbuch der Gynäkologie. Springer-Verlag. pp. 255–. ISBN 978-3-662-00942-0.
  5. Willibald Pschyrembel (1968). Praktische Gynäkologie: für Studierende und Ärzte. Walter de Gruyter. pp. 601–. ISBN 978-3-11-150424-7.
  6. Kaiser, R. (2008). "Gestagen-Östrogen-Kombinationen in der Gynäkologie. Zur Geschichte, Dosierung und Anwendung eines Hormonprinzips" [Progestogen-Estrogen Combinations in Gynecology. History, Dosage, and Use of a Hormone Principle]. Geburtshilfe und Frauenheilkunde. 53 (07): 503–513. doi:10.1055/s-2007-1022924. ISSN 0016-5751. 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).
  7. 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. 467–. ISBN 978-92-832-1291-1.
  8. https://www.medicamentos.com.mx/DocHTM/27809.htm
  9. 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.
  10. 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 [...]
  11. Ufer, Joachim (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. 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.
  12. Dao, Thomas L. (1975). "Pharmacology and Clinical Utility of Hormones in Hormone Related Neoplasms". In Alan C. Sartorelli; David G. Johns (eds.). Antineoplastic and Immunosuppressive Agents. pp. 170–192. doi:10.1007/978-3-642-65806-8_11. ISBN 978-3-642-65806-8.
  13. Landau, Richard L. (1962). "Estradiol Benzoate and Progesterone in Advanced Human-Breast Cancer". JAMA. 182 (6): 632. doi:10.1001/jama.1962.03050450032008. ISSN 0098-7484.
  14. Josef Kimmig (1961). Therapie der Haut- und Geschlechtskrankheiten. Springer-Verlag. pp. 508–. ISBN 978-3-642-94850-3.
  15. K. G. Ober; H. Meinrenken (1964). Gynäkologische Operationen. Springer-Verlag. pp. 104–. ISBN 978-3-662-11935-8.
  16. Kaiser R (September 1961). "Die Östrogenausscheidung im Zyklus und nach Injektion von Östradiolestern. Ein Beitrag zur Therapie mit Depotöstrogenen" [Estrogen excretion during the cycle and after injection of estradiol esters. A contribution to therapy with depot estrogens]. Geburtshilfe Frauenheilkd (in German). 21: 868–78. ISSN 0016-5751. PMID 13750804.
  17. Kaiser, R. "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. ISBN 978-3-540-02909-0.
  18. https://www.drugs.com/international/vermagest.html
  19. 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.
  20. Madhuri Patil; Sheela V Mane (11 December 2014). ECAB Luteal Phase Insufficiency - E-Book. Elsevier Health Sciences. pp. 66–. ISBN 978-81-312-3961-2.
  21. Joachim Ufer (1960). Hormontherapie in der Frauenheilkunde: Grundlagen und Praxis. Gruyter. p. 153.
  22. Ober, K. G.; Klein, Irmhild; Weber, Marianne (1954). "Zur Frage einer Progesteronbehandlung: Experimentelle Untersuchungen mit dem Hooker-Forbes-Test und klinische Beobachtungen mit Kristallsuspensionen" [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. ISSN 0003-9128.
  23. https://pubchem.ncbi.nlm.nih.gov/compound/56840923
  24. Sweetman, Sean C., ed. (2009). "Sex hormones and their modulators". Martindale: The Complete Drug Reference (36th ed.). London: Pharmaceutical Press. pp. 2133–2134. ISBN 978-0-85369-840-1.
  25. https://www.micromedexsolutions.com/
  26. https://web.archive.org/web/20190519104654/http://www.sukl.cz/download/pil/PI16221.pdf
  27. "Archived copy" (PDF). Archived (PDF) from the original on 2019-05-19. Retrieved 2019-05-19.CS1 maint: archived copy as title (link)


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