Combined injectable contraceptives (CICs) are a form ofhormonal birth control for women. They consist of monthlyinjections of combined formulations containing anestrogen and aprogestin to preventpregnancy.

CICs are different fromprogestogen-only injectable contraceptives (POICs), such asdepotmedroxyprogesterone acetate (DMPA; brand names Depo-Provera, Depo-SubQ Provera 104) andnorethisterone enantate (NETE; brand name Noristerat), which are not combined with an estrogen and are given once every two to three months instead of once a month.^[2]

Hormonal contraception works primarily by preventing ovulation, but it may also thicken the cervical mucus inhibiting sperm penetration.^[3][4][5] Hormonal contraceptives also have effects on the endometrium,^[6][7] that theoretically could affect implantation.^{[8][9][10][11]}

CICs are administered by intramuscular injection into thedeltoid,gluteus maximus, oranterior thigh.^[1] They are ideally administered every 28 to 30 days, though they have been demonstrated to be effective up to 33 days.^[1]

Some CICs have been said to be used bytransgender women as a means offeminizing hormone therapy as well.^[12]

A variety of different CICs, generally containing a short-acting naturalestradiol ester and a long-actingprogestin ester, are available for clinical use.^{[24][15][2][16][13]} Estrogens that are used includeestradiol valerate,estradiol cypionate,estradiol enantate,estradiol benzoate butyrate, andestradiol, while progestins that are used includenorethisterone enantate,medroxyprogesterone acetate,algestone acetophenide (dihydroxyprogesterone acetophenide),hydroxyprogesterone caproate, andmegestrol acetate.^{[15][2][16][13]}Estradiol benzoate has aduration that is too short for once-monthly CICs, and is not used in them.^[25] Conversely, estradiol enantate is said to have a duration that is too long for once-monthly CICs, but is nonetheless used in them.^[25]

Side effects of CICs, besides menstrual bleeding changes, are minimal.^[26] The most prominent side effects of CICs aremenstrual irregularities during the first 3 to 6 months of use.^[1]Dysmenorrhea has been reported in 30 to 65% of women.^[26] Other side effects includebreast tenderness/pain,headache, andlibido changes.^[26] Somefluid retention can occur, butweight gain is minimal.^[26] Localinjection site reactions have also been reported in 15 to 35% of women.^[26]

Effects of CICs oncoagulation andfibrinolysis are minimal and are not thought to be clinically relevant.^[27] Conversely,combined oral contraceptive pills containingethinylestradiol have considerable effects on coagulation and fibrinolysis.^[27] The differences can be attributed to the lack of thefirst-pass effect withparenteral administration as well asstructural andpharmacological differences between estradiol and ethinylestradiol.^[28][29]

CICs contain anestrogen and aprogestin. The estrogen is generally a short-actingestradiol ester, which acts as aprodrug ofestradiol.^[24] Esters of estradiol arenatural andbioidentical estrogens, and are believed to have more favorable effects onlipid metabolism,cardiovascular health, andhemostasis thansynthetic estrogens such asethinylestradiol.^[30][31][32] The progestin is a long-actingprogestogen ester, which may or may not act as a prodrug.^[24]Progesteronederivatives includingmedroxyprogesterone acetate,algestone acetophenide (dihydroxyprogesterone acetophenide),hydroxyprogesterone caproate, andmegestrol acetate areactive themselves and are not prodrugs, whereas thetestosterone derivativenorethisterone enantate is a prodrug ofnorethisterone. Regardless of whether they are prodrugs or not,steroid esters form adepot and have an extendedduration of action due to adepot effect when administered byintramuscular orsubcutaneous injection.

Because CICs are administeredparenterally, they bypass thefirst-pass effect in theliver andintestines that occurs withoral administration of estrogens.^[24] However, is estimated that about 20% of an administered dose does still eventually pass through the liver.^[24] Hence, these preparations are not completely liver-neutral.^[24] Nonetheless, they have dramatically reduced hepatic effects relative to oral ethinylestradiol.^[28] In addition, parenteralestradiol in general has about 4- or 5-fold reduced potency in the liver than oral estradiol.^[28]

CICs haveantigonadotropic effects via their estrogenic and progestogenic activity and inhibitfertility and suppresssex hormone levels. A single intramuscular injection ofestradiol valerate/norethisterone enanthate (5 mg/50 mg) (Mesigyna) has been found to strongly suppress testosterone levels in men.^[33] Testosterone levels decreased from a baseline of ~503 ng/dL to a trough of ~30 ng/dL (a 94% decrease) which occurred at day 7 post-injection.^[33]

The first CIC to be studied wasestradiol valerate/hydroxyprogesterone caproate (EV/OHPC) in 1963, and the second CIC to be studied wasestradiol enantate/algestone acetophenide (E2-EN/DHPA) in 1964.^[26][25] In 1967, E2-EN/DHPA was in the late stages of clinical development.^[53][26] By 1969, the medication was available for medical use under the brand name Perlutal.^[54] Within a few years, it was marketed under other brand names such as Topasel and Ova-Repos as well.^{[55][56][57][58]} In addition, several other CICs had been introduced for medical use by 1972.^[58] By 1976, two major CICs were in use: E2-EN/DHPA (brand names Perlutan, Topasel) inSpain andLatin America, and EV/OHPC (brand name Injectable No. 1) inChina.^[59] These CICs have been described as first-generation CICs.^[59] Two second-generation CICs,estradiol cypionate/medroxyprogesterone acetate (EC/MPA; brand names Cyclofem and later Lunelle) andestradiol valerate/norethisterone enantate (EV/NETE; brand name Mesigyna), were introduced for clinical use in 1993.^[60][14][15] On 5 October 2000,Pharmacia received FDA approval for Lunelle Monthly Contraceptive Injection.^[1] In April 2003, Pharmacia was acquired byPfizer (makers ofdepot medroxyprogesterone acetate).^{[citation needed]} In October 2003, Lunelle was discontinued in theUnited States.^{[citation needed]}

CICs are available in many countries throughout the world, including widely throughoutCentral andSouth America, inMexico and theCaribbean, inChina, in severalSoutheast Asian andAfrican countries, and inTurkey.^{[21][22][23][13][2][14][15][16][17]} They were also previously available in theUnited States,Portugal, andSpain, but have been discontinued in these countries.^[22][23]

Many other CICs have been studied but have not been approved or marketed for clinical use.^{[15][16][61][25][62][2]}

The following are marketed CICs at different doses than those that are approved:

• Estradiol valerate 2.5 to 5 mg +norethisterone enantate 50 to 80 mg in anoil solution^[15][16]
• Estradiol valerate 10 mg +hydroxyprogesterone caproate 500 mg in an oil solution^[15]
• Estradiol cypionate 2.5 to 10 mg +medroxyprogesterone acetate 12.5 to 50 mg in amicrocrystallineaqueous suspension^[15][16]
• Estradiol enantate 5 to 50 mg +algestone acetophenide 75 to 200 mg in an oil solution^[61][15]

The half-progestin-dose formulation of estradiol valerate/norethisterone enantate (5 mg / 25 mg) is also known as HRP-103 and the half-progestin-dose formulation of estradiol cypionate/medroxyprogesterone acetate (5 mg / 12.5 mg) is also known as HRP-113.^[63]

The following are CICs that have never been marketed:

• Estradiol valerate 20 mg +medroxyprogesterone acetate 100 mg in a microcrystalline aqueous suspension^[15][16]
• Estradiol undecylate 5 to 10 mg +norethisterone enantate 50 to 70 mg in an oil solution^{[25][15][62][64]}
• Estradiol cypionate +norethisterone enantate^[62][15]
• Estradiol valerate 10 mg +methenmadinone caproate 60 mg (Lutofollin)^[25][62][64]
• Estradiol hexahydrobenzoate 5 mg (oil solution) +norgestrel 25 mg (aqueous suspension)^{[25][15][62][64][65]}
• Estradiol cypionate 3.5 to 5 mg +megestrol acetate 25 mg in a microcrystalline aqueous suspension (marketed in China?)^[25][15][62]
• Estradiol valerate 3 to 5 mg +chlormadinone caproate 80 mg in an oil solution^[25][15][62]
• Estradiol valerate 5 mg +megestrol acetate 15 mg in anaqueous suspension ofgelatinmicrospheres (50–80 μm)^{[25][16][62][32]}
• Estradiol 5 mg +levonorgestrel 7 mg in anaqueous suspension ofmonolithicmicrospheres (80 μm) or in amacrocrystalline suspension (15 μm)^[16][32]
• Estradiol cypionate 5 mg +levonorgestrel butanoate 7 mg in anaqueous suspension^[16]
• Estradiol benzoate 5 to 10 mg +norethisterone enanthate 50 to 100 mg^[62]
• Mestranol 1.0–1.2 mg +norethisterone 10–12 mg in amicrocrystallineaqueous suspension of definedparticle sizes (125–177 μm)^{[25][16][62][32]}
• Ethinylestradiol +norethisterone^[15]
• Estradiol 5 mg andprogesterone 100 to 300 mg in anaqueous suspension ofmonolithicmicrospheres or in amacrocrystalline suspension^{[25][16][2][15][66][67][32]}
• Polyestradiol phosphate 40 mg +medroxyprogesterone acetate 150 mg^[68][69][70]

• Special Programme on Human Reproduction
• Concept Foundation
• Extended cycle combined hormonal contraceptive
• Reproductive Health Supplies Coalition
• Estradiol-containing oral contraceptive

• Garza-Flores J (April 1994). "Pharmacokinetics of once-a-month injectable contraceptives".Contraception.49 (4):347–59.doi:10.1016/0010-7824(94)90032-9.PMID 8013219.
• Sang GW (April 1994). "Pharmacodynamic effects of once-a-month combined injectable contraceptives".Contraception.49 (4):361–85.doi:10.1016/0010-7824(94)90033-7.PMID 8013220.

• Combined injectable contraceptives
• Estradiol

• CS1: long volume value
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