Estradiol benzoate/progesterone (EB/P4), sold under the brand names Duogynon and Sistocyclin among others, is a combination medication of

estradiol benzoate Estradiol benzoate (EB), sold under the brand name Progynon-B among others, is an estrogen medication which is used in hormone therapy for menopausal symptoms and low estrogen levels in women, in hormone therapy for transgender women, and in the ...

(EB), an estrogen, and

progesterone Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the m ...

(P4), a

progestogen Progestogens, also sometimes written progestagens or gestagens, are a class of natural or synthetic steroid hormones that bind to and activate the progesterone receptors (PR). Progesterone is the major and most important progestogen in the body. ...

. It has been formulated both as short-acting

oil solution An oil is any nonpolar chemical substance that is composed primarily of hydrocarbons and is hydrophobic (does not mix with water) & lipophilic (mixes with other oils). Oils are usually flammable and surface active. Most oils are unsaturated ...

s and long-acting microcrystalline

aqueous suspension In chemistry, a suspension is a Mixture#Homogeneous and heterogeneous mixtures, heterogeneous mixture of a fluid that contains solid particles sufficiently large for sedimentation. The particles may be macroscopic, visible to the naked eye, usual ...

s and is given by

injection into muscle Intramuscular injection, often abbreviated IM, is the injection of a substance into a muscle. In medicine, it is one of several methods for parenteral administration of medications. Intramuscular injection may be preferred because muscles have l ...

either once or continuously at regular intervals. EB/P4 was one of the first combined estrogen and progestogen medications to be introduced for medical use. It was first marketed in Germany as an oil solution in 1950. Microcrystalline EB/P4 in aqueous suspension was developed and marketed under the brand name Sistocyclin several years later. EB/P4 was eventually superseded by longer-acting

parenteral A route of administration in pharmacology and toxicology is the way by which a drug, fluid, poison, or other substance is taken into the body. Routes of administration are generally classified by the location at which the substance is applied. ...

estrogen–progestogen combinations as well as by oral estrogen–progestogen combinations.

Medical uses

EB/P4 has been used to treat

menstrual disorder A menstrual disorder is characterized as any abnormal condition with regards to a person's menstrual cycle. There are many different types of menstrual disorders that vary with signs and symptoms, including pain during menstruation, heavy bleeding ...

s such as

secondary amenorrhea Amenorrhea is the absence of a menstrual period in a woman of reproductive age. Physiological states of amenorrhoea are seen, most commonly, during pregnancy and lactation (breastfeeding). Outside the reproductive years, there is absence of menses ...

and

menstrual irregularity Irregular menstruation is a menstrual disorder whose manifestations include irregular cycle lengths as well as metrorrhagia (vaginal bleeding between expected periods). The possible causes of irregular menstruation may vary. The common factors of ...

, as a form of emergency contraception within 48 hours of

sexual intercourse Sexual intercourse (or coitus or copulation) is a sexual activity typically involving the insertion and thrusting of the penis into the vagina for sexual pleasure or reproduction.Sexual intercourse most commonly means penile–vaginal penetrat ...

, and as a test for pregnancy. In the form of a microcrystalline

, EB/P4 has particularly been used to treat

functional uterine bleeding Abnormal uterine bleeding (AUB), also known as (AVB) or as atypical vaginal bleeding, is vaginal bleeding from the uterus that is abnormally frequent, lasts excessively long, is heavier than normal, or is irregular. The term dysfunctional uterin ...

. EB/P4 has been studied in the treatment of breast cancer in women and found to be effective.

Available forms

EB/P4 is or has been available for use by

intramuscular injection Intramuscular injection, often abbreviated IM, is the injection of a substance into a muscle. In medicine, it is one of several methods for parenteral administration of medications. Intramuscular injection may be preferred because muscles have ...

both in the form of short-acting

s (e.g., Duogynon, Lutrogen) and long-acting microcrystalline

s (e.g., Clinomin Forte, Sistocyclin). 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. An oil-solution ampoule containing 30 mg EB and 30 mg P4 (brand name Vermagest) is used as an injectable emergency contraceptive. Clinomin Forte is an

of EB/P4 that additionally contains

lidocaine Lidocaine, also known as lignocaine and sold under the brand name Xylocaine among others, is a local anesthetic of the amino amide type. It is also used to treat ventricular tachycardia. When used for local anaesthesia or in nerve blocks, lidoca ...

and remains available today.

Side effects

Pharmacology

Pharmacodynamics

EB is an estrogen, or an

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...

of the estrogen receptors, the biological target of estrogens like

endogenous Endogenous substances and processes are those that originate from within a living system such as an organism, tissue, or cell. In contrast, exogenous substances and processes are those that originate from outside of an organism. For example, es ...

estradiol. It is an estradiol ester and

prodrug A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the drug ...

of estradiol with a longer

duration of action Pharmacodynamics (PD) is the study of the biochemical and physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or combinations of organisms (for ...

than estradiol when administered by

. P4 is a

, or an agonist of the

progesterone receptor The progesterone receptor (PR), also known as NR3C3 or nuclear receptor subfamily 3, group C, member 3, is a protein found inside cells. It is activated by the steroid hormone progesterone. In humans, PR is encoded by a single ''PGR'' gene resid ...

s, the biological target of progestogens like endogenous

. The full

endometrial transformation Decidualization is a process that results in significant changes to cells of the endometrium in preparation for, and during, pregnancy. This includes morphological and functional changes (the decidual reaction) to endometrial stromal cells (ESCs), ...

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 Estradiol valerate/hydroxyprogesterone caproate (EV/OHPC), sold under the brand names Gravibinon and Injectable No. 1 (or Chinese Injectable No. 1) among others, is a combined estrogen and progestogen medication which is used in the treatment of ...

) 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 The menstrual cycle is a series of natural changes in hormone production and the structures of the uterus and ovaries of the female reproductive system that make pregnancy possible. The ovarian cycle controls the production and release of eggs a ...

; it is induced by

progesterone following adequate priming by endogenous estradiol. The decidua ( pregnancy-type

endometrium The endometrium is the inner epithelial layer, along with its mucous membrane, of the mammalian uterus. It has a basal layer and a functional layer: the basal layer contains stem cells which regenerate the functional layer. The functional laye ...

) 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 In mammalian species, pseudopregnancy is a physical state whereby all the signs and symptoms of pregnancy are exhibited, with the exception of the presence of a fetus, creating a false pregnancy. The corpus luteum (the remains of an ovulated ovari ...

dosages.

Pharmacokinetics

EB/P4 is administered by

a single time or continuously at regular intervals, depending on the indication.

Amorphous In condensed matter physics and materials science, an amorphous solid (or non-crystalline solid, glassy solid) is a solid that lacks the long-range order that is characteristic of a crystal. Etymology The term comes from the Greek ''a'' ("wi ...

EB/P4 in

(e.g., Duogynon, Lutrogen) is reported to have a

of 2 days in terms of the progestogen component, and hence is a short-acting preparation, whereas microcrystalline EB/P4 in

(e.g., Sistocyclin) has a duration of 10 to 12 days, and hence is a long-acting preparation. 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.

History

EB/P4 in

for use by

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

, microcrystalline EB/P4 with defined crystal sizes in

was developed, studied in 1954, and marketed under the brand name Sistocyclin shortly thereafter in the 1950s. Formulations containing a combination of EB or estradiol valerate (an estradiol ester with a longer duration than EB) and the longer-acting

synthetic Synthetic things are composed of multiple parts, often with the implication that they are artificial. In particular, 'synthetic' may refer to: Science * Synthetic chemical or compound, produced by the process of chemical synthesis * Synthetic o ...

progestogen hydroxyprogesterone caproate in oil solution (brand names

Primosiston Estradiol benzoate/hydroxyprogesterone caproate (EB/OHPC), sold under the brand name Primosiston among others, is a combined estrogen and progestogen medication which is used to treat gynecological disorders and habitual abortion. It contains es ...

) 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.

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.

Availability

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 Emergency contraception (EC) is a birth control measure, used after sexual intercourse to prevent pregnancy. There are different forms of EC. Emergency contraceptive pills (ECPs), sometimes simply referred to as emergency contraceptives (ECs), ...

El Salvador El Salvador (; , meaning " The Saviour"), officially the Republic of El Salvador ( es, República de El Salvador), is a country in Central America. It is bordered on the northeast by Honduras, on the northwest by Guatemala, and on the south b ...

Honduras Honduras, officially the Republic of Honduras, is a country in Central America. The republic of Honduras is bordered to the west by Guatemala, to the southwest by El Salvador, to the southeast by Nicaragua, to the south by the Pacific Oce ...

, 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. However, individual formulations of microcrystalline EB in aqueous suspension (brand name Agofollin Depot) and microcrystalline P4 in aqueous suspension (brand name Agolutin Depot) remain available in some countries, including the Czech Republic and Slovakia.

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.

References

{{DEFAULTSORT:Estradiol benzoate progesterone Combined estrogen–progestogen formulations Combined injectable contraceptives