Estradiol benzoate/progesterone

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

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]

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suspension was developed and marketed under the brand name Sistocyclin several years later.[6] EB/P4 was eventually superseded by longer-acting parenteral estrogen–progestogen combinations as well as by oral estrogen–progestogen combinations.[6]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

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.[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]

Potencies and durations of natural estrogens by intramuscular injection
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.
Parenteral potencies and durations of progestogens[a][b]
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
Notes and sources:
  1. ^ Sources: [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41]
  2. ^ All given by intramuscular or subcutaneous injection.
  3. ^ Progesterone production during the luteal phase is ~25 (15–50) mg/day. The OIDTooltip ovulation-inhibiting dose of OHPC is 250 to 500 mg/month.
  4. ^ Duration of action in days.
  5. ^ Usually given for 14 days.
  6. ^ Usually dosed every two to three months.
  7. ^ Usually dosed once monthly.
  8. ^ Never marketed or approved by this route.
  9. ^ a b In divided doses (2 × 125 or 250 mg for OHPC, 10 × 20 mg for P4).

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]

See also

References

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