Estradiol benzoate/progesterone
Drug combination
From Wikipedia, the free encyclopedia
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]
| |
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| Combination of | |
|---|---|
| Estradiol benzoate | Estrogen |
| Progesterone | Progestogen |
| Clinical data | |
| Trade names | Clinomin Forte, Duogynon, Lutrogen, Sistocyclin, Vermagest, others |
| Other names | EB/P4 |
| Routes of administration | Intramuscular injection (oil solution, aqueous suspension) |
| ATC code | |
| Identifiers | |
| CAS Number | |
| PubChem CID | |
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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suspension was developed and marketed under the brand name Sistocyclin several years later.[6] EB/P4 was eventually superseded by longer-acting parenteral estrogen–progestogen combinations as well as by oral estrogen–progestogen combinations.[6]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., Clinomin Forte, 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 P4 (brand name Vermagest) is used as an injectable emergency contraceptive.[18][7][8] Clinomin Forte is an aqueous suspension of EB/P4 that additionally contains lidocaine and remains available today.[19]
Side effects
Pharmacology
Pharmacodynamics
EB is an estrogen, or an agonist of the estrogen receptors, the biological target of estrogens like endogenous estradiol.[20] 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.[20] P4 is a progestogen, or an agonist of the progesterone receptors, the biological target of progestogens like endogenous progesterone.[20]
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.[21]
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][22] 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.[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 estradiol excretion on the 2nd day after injection and maintained elevated estradiol excretion for 17 days.[16][17]
| Estrogen | Form | Dose (mg) | Duration by dose (mg) | ||
|---|---|---|---|---|---|
| EPD | CICD | ||||
| Estradiol | Aq. soln. | ? | – | <1 d | |
| Oil soln. | 40–60 | – | 1–2 ≈ 1–2 d | ||
| Aq. susp. | ? | 3.5 | 0.5–2 ≈ 2–7 d; 3.5 ≈ >5 d | ||
| Microsph. | ? | – | 1 ≈ 30 d | ||
| Estradiol benzoate | Oil 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. | 20–30 | 5 | 5 ≈ 7–8 d; 10 ≈ 10–14 d; 40 ≈ 14–21 d; 100 ≈ 21–28 d | |
| Estradiol benz. butyrate | Oil soln. | ? | 10 | 10 ≈ 21 d | |
| Estradiol cypionate | Oil soln. | 20–30 | – | 5 ≈ 11–14 d | |
| Aq. susp. | ? | 5 | 5 ≈ 14–24 d | ||
| Estradiol enanthate | Oil soln. | ? | 5–10 | 10 ≈ 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. | |||||
| Compound | Form | Dose for specific uses (mg)[c] | DOA[d] | |||
|---|---|---|---|---|---|---|
| TFD[e] | POICD[f] | CICD[g] | ||||
| Algestone acetophenide | Oil soln. | – | – | 75–150 | 14–32 d | |
| Gestonorone caproate | Oil soln. | 25–50 | – | – | 8–13 d | |
| Hydroxyprogest. acetate[h] | Aq. susp. | 350 | – | – | 9–16 d | |
| Hydroxyprogest. caproate | Oil soln. | 250–500[i] | – | 250–500 | 5–21 d | |
| Medroxyprog. acetate | Aq. susp. | 50–100 | 150 | 25 | 14–50+ d | |
| Megestrol acetate | Aq. susp. | – | – | 25 | >14 d | |
| Norethisterone enanthate | Oil soln. | 100–200 | 200 | 50 | 11–52 d | |
| Progesterone | Oil soln. | 200[i] | – | – | 2–6 d | |
| Aq. soln. | ? | – | – | 1–2 d | ||
| Aq. susp. | 50–200 | – | – | 7–14 d | ||
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Notes and sources:
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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,[42] 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][43]
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][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 the Czech Republic and Slovakia.[1][2][44][45]
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]
