View source for Combined injectable birth control

{{Short description|Form of hormonal birth control}}
{{Infobox Birth control
| name = Combined injectable birth control
| image = 
| width = 
| caption = 
| bc_type = Hormonal
| date_first_use = By 1969
| rate_type = Failure
| perfect_failure% = 0–0.2 
| perfect_failure_ref = <ref name="contrareportFDAAproveLunelle" />
| typical_failure% = 
| duration_effect = 1 month
| reversibility = 
| user_reminders = 
| clinic_interval = 
| STD_protection_YesNo = No
| periods_advantage = 
| benefits = Especially good if poor pill compliance
| periods_disadvantage = 
| weight_gain_loss = 
| risks = 
| medical_notes = 
}}

'''Combined injectable contraceptives''' ('''CICs''') are a form of [[hormonal contraception|hormonal birth control]] for women. They consist of monthly [[injection (medicine)|injection]]s of combined formulations containing an [[estrogen (medication)|estrogen]] and a [[progestin]] to prevent [[pregnancy]].

CICs are different from [[progestogen-only injectable contraceptive]]s (POICs), such as [[depot injection|depot]] [[medroxyprogesterone acetate]] (DMPA; brand names Depo-Provera, Depo-SubQ Provera 104) and [[norethisterone enantate]] (NETE; brand name Noristerat), which are not combined with an estrogen and are given once every two to three&nbsp;months instead of once a month.<ref name="BagadePawar2014" />

Hormonal contraception works primarily by preventing ovulation, but it may also thicken the cervical mucus inhibiting sperm penetration.<ref>Tamara Callahan MD , Aaron Caughey MD , Blueprints Obstetrics and Gynecology, 2013</ref><ref>KD Tripathi , Essentials of Medical Pharmacology, 2013</ref><ref>Dc Dutta's Textbook of Obstetrics, 2014</ref> Hormonal contraceptives also have effects on the endometrium,<ref>K. A. Petrie, A. H. Torgal, C. L. Westhoff, Matched-pairs analysis of ovarian suppressionduring oral vs. vaginal hormonal contraceptive use, „Contraception” 2011, t. 84, p. e2-3</ref><ref>R. L. Birtch, O. A. Olatunbosum, R. A. Pierson, Ovarian follicular dynamics during conventional vs continuous oral contraceptive use, „Contraception” 2006, t. 73, p. 235. p. 239.</ref> that theoretically could affect implantation.<ref>K. Bugge, K. S. Richter, J. Bromer, et al., Pregnancy rates following in vitro fertilization are reduced with a thin endometrium, but are unrelated to endometrial thickness above 10 millimeters,„Fertility and Sterility” 2004, t. 82, p. S199.</ref><ref>T. Fiumino, A. Kuwata, A. Teranischi et al., Significance of endometrium thickness to evaluate endometrial receptivity for embryos in natural cycle, „Fertility and Sterility” 2008, t. 90,p. S159.</ref><ref>K. S. Richter, K. R. Bugge, J. G. Bromer, Relationship between endometrial thickness and embryo implantation, based on 1. 294 cycles of in vitro fertilization with transfer of two blastocyst-stage embryos, „Fertility and Sterility” 2007, t. 87, p. 53.</ref><ref>{{cite journal |vauthors=Rivera R, Yacobson I, Grimes D |year=1999 |title=The mechanism of action of hormonal contraceptives and intrauterine contraceptive devices |journal=Am J Obstet Gynecol |volume=181 |issue=5 Pt 1 |pages=1263–9 |pmid=10561657 |doi=10.1016/S0002-9378(99)70120-1}}</ref>

==Medical uses==
CICs are administered by intramuscular injection into the [[deltoid muscle|deltoid]], [[gluteus maximus]], or [[anterior compartment of thigh|anterior thigh]].<ref name="contrareportFDAAproveLunelle" /> They are ideally administered every 28 to 30&nbsp;days, though they have been demonstrated to be effective up to 33&nbsp;days.<ref name="contrareportFDAAproveLunelle" />

Some CICs have been said to be used by [[transgender women]] as a means of [[feminizing hormone therapy]] as well.<ref name="Kulick2009">{{cite book|author=Don Kulick|title=Travesti: Sex, Gender, and Culture among Brazilian Transgendered Prostitutes|url=https://books.google.com/books?id=jbZyBfio-hcC&pg=PA64|date=12 January 2009|publisher=University of Chicago Press|isbn=978-0-226-46101-4|pages=64–66}}</ref>

===Available forms===
{| class="wikitable floatright" style="width:35%; font-size:small; margin-left: auto; margin-right: auto; border: none;"
|+ {{nowrap|[[Combined injectable contraceptive]]s marketed for clinical use}}
|-
! style="width:110px;" | Composition !! style="width: 85px;" | Dose !!  Vehicle || Brand Names !! Availability
|-
| [[Estradiol valerate/norethisterone enantate|Estradiol valerate / Norethisterone enantate]] || 5&nbsp;mg /<br />50&nbsp;mg || Oil solution || Multiple{{efn|group=brands|Chinese Injectable No. 3, Efectimes, Ginediol, Mesigyna, Mesilar, Meslart, Mesocept, Mesygest, Nofertyl, Nofertyl Lafrancol, Noregyna, Norestrin, Norifam, Norigynon, Nostidyn, Sexseg, Solouna}} || Approved in at least 36 countries
|-
| [[Estradiol cypionate/medroxyprogesterone acetate|Estradiol cypionate / Medroxyprogesterone acetate]] || 5&nbsp;mg /<br />25&nbsp;mg || Microcrystalline aqueous suspension || Multiple{{efn|group=brands|Ciclofem, Ciclofemina, Cyclofem, Cyclofemina, Cyclogeston, Femelin, Femydrol, Gestin, Harmonis, Lunella, Lunelle<sup>†</sup>, Novafem}} || Approved in at least 18 countries
|-
| rowspan="4" | [[Estradiol enantate/algestone acetophenide|Estradiol enantate / Algestone acetophenide]]<sup>a</sup> || 10&nbsp;mg /<br />150&nbsp;mg || Oil solution || Multiple{{efn|group=brands|Acefil, Agurin<sup>†</sup>, Atrimon<sup>†</sup>, Ciclomes, Ciclovar, Ciclovular, Cicnor<sup>†</sup>, Clinomin, Cycloven, Daiva, Damix, Deladroxate<sup>§</sup>, Deprans, Deproxone, Exuna, Ginestest, Ginoplan<sup>†</sup>, Gynomes, Horprotal, Listen, Luvonal, Neogestar, Neolutin, Nomagest, Nonestrol, Normagest, Normensil, Novular, Oterol, Ovoginal, Patector, Patectro, Perludil, Perlumes, Perlutal, Perlutale, Perlutan, Perlutin, Perlutin-Unifarma, Permisil, Preg-Less, Pregnolan, Primyfar<sup>†</sup>, Progestrol<sup>†</sup>, Protegin, Proter, Seguralmes, Synovular, Topasel, Unigalen, Uno-Ciclo, Vagital}} || Approved in at least 19 countries
|-
| 5&nbsp;mg /<br />75&nbsp;mg || Oil solution || Anafertin<sup>†</sup>, Patector NF, Yectames || Approved at least 9 countries
|-
| 10&nbsp;mg /<br />120&nbsp;mg || Oil solution || Unalmes, Yectuna || Approved in at least 3&nbsp;countries
|-
| 10&nbsp;mg /<br />75&nbsp;mg || Oil solution || Ova Repos<sup>†</sup> || Discontinued (firm was in Spain)
|-
| [[Estradiol benzoate butyrate/algestone acetophenide|Estradiol benzoate butyrate / Algestone acetophenide]] || 10&nbsp;mg /<br />150&nbsp;mg || Oil solution? || Redimen, Soluna, Unijab, Unimens<sup>§</sup> || Approved in Peru and Singapore
|-
| [[Estradiol valerate/hydroxyprogesterone caproate|Estradiol valerate / Hydroxyprogesterone caproate]] || 5&nbsp;mg /<br />250&nbsp;mg || Oil solution || Chinese Injectable No. 1 || Approved in China
|-
| [[Estradiol/megestrol acetate|Estradiol / Megestrol acetate]] || 3.5&nbsp;mg /<br />25&nbsp;mg || Microcrystalline aqueous suspension || Chinese Injectable No. 2, Mego-E || Approved in China
|-
| [[Estradiol cypionate/hydroxyprogesterone caproate|Estradiol cypionate / Hydroxyprogesterone caproate]] || 5&nbsp;mg /<br />250&nbsp;mg || Oil solution? || Sinbios<sup>†</sup> || Discontinued (firm was in Mexico)
|-
| [[Estradiol valerate/estradiol benzoate/hydroxyprogesterone caproate|Estradiol valerate / Estradiol benzoate / Hydroxyprogesterone caproate]] || 10&nbsp;mg /<br />1&nbsp;mg /<br />250&nbsp;mg || Oil solution? || Sin-Ol<sup>†</sup> || Discontinued (firm was in Mexico)
|- class="sortbottom"
| colspan="5" style="width:1px; background:#eaecf0; text-align:center;"| '''Notes:''' All are given by [[intramuscular injection]] once a month. '''Footnotes:''' <sup>†</sup> = Discontinued. <sup>§</sup> = Never marketed. <sup>a</sup> = Unsorted brand names (doses unknown; for {{abbrlink|E2-EN/DHPA|estradiol enantate/algestone acetophenide}}): Evitas<sup>†</sup> and Femineo<sup>†</sup>. '''Sources:''' <ref name="HumansCancer1999">{{cite book|author1=IARC Working Group on the Evaluation of Carcinogenic Risks to Humans|author2=International Agency for Research on Cancer|title=Hormonal Contraception and Post-menopausal Hormonal Therapy|date=1 January 1999|publisher=IARC|isbn=978-92-832-1272-0|page=65|url=https://monographs.iarc.fr/wp-content/uploads/2018/06/mono72.pdf#page=76|access-date=18 September 2018|archive-date=28 August 2021|archive-url=https://web.archive.org/web/20210828080855/https://monographs.iarc.who.int/wp-content/uploads/2018/06/mono72.pdf#page=76|url-status=dead}}</ref><ref name="BagadePawar2014"/><ref name="SenanayakePotts2008">{{cite book|author1=Pramilla Senanayake|author2=Malcolm Potts|title=Atlas of Contraception, Second Edition|url=https://books.google.com/books?id=7dDKBQAAQBAJ&pg=PA50|date=14 April 2008|publisher=CRC Press|isbn=978-0-203-34732-4|pages=50–}}</ref><ref name="pmid12290848">{{cite journal | vauthors = Newton JR, D'arcangues C, Hall PE | title = A review of "once-a-month" combined injectable contraceptives | journal = J Obstet Gynaecol (Lahore) | volume = 4 Suppl 1 | pages = S1–34 | year = 1994 | pmid = 12290848 | doi = 10.3109/01443619409027641}}</ref><ref name="pmid8013219">{{cite journal | vauthors = Garza-Flores J | title = Pharmacokinetics of once-a-month injectable contraceptives | journal = Contraception | volume = 49 | issue = 4 | pages = 347–59 | date = April 1994 | pmid = 8013219 | doi = 10.1016/0010-7824(94)90032-9 }}</ref><ref name="HumansOrganization2007">{{cite book|author1=IARC Working Group on the Evaluation of Carcinogenic Risks to Humans|author2=World Health Organization|author3=International Agency for Research on Cancer|title=Combined Estrogen-progestogen Contraceptives and Combined Estrogen-progestogen Menopausal Therapy|url=https://books.google.com/books?id=aGDU5xibtNgC&pg=PA431|year=2007|publisher=World Health Organization|isbn=978-92-832-1291-1|pages=431–}}</ref><ref name="pmid8666089">{{cite journal | vauthors = Klitsch M | title = Still waiting for the contraceptive revolution | journal = Fam Plann Perspect | volume = 27 | issue = 6 | pages = 246–53 | date = 1995 | pmid = 8666089 | doi = 10.2307/2136177 | jstor = 2136177 }}</ref><ref name="pmid23641480">{{cite journal | vauthors = Gallo MF, Grimes DA, Lopez LM, Schulz KF, d'Arcangues C | title = Combination injectable contraceptives for contraception | journal = Cochrane Database Syst Rev | volume = 2013 | pages = CD004568 | date = 2013 | issue = 3 | pmid = 23641480 | doi = 10.1002/14651858.CD004568.pub3 | pmc = 6513542 }}</ref><ref name="Tausk1972">{{cite book | author1 = Harry W. Rudel | author2 = Fred A. Kinel | chapter = Oral Contraceptives. Human Fertility Studies and Side Effects | pages = 385–469 <!-- Table on page 402 --> | editor1 = M. Tausk | title = Pharmacology of the Endocrine System and Related Drugs: Progesterone, Progestational Drugs and Antifertility Agents | volume = II | url = https://books.google.com/books?id=Nv5sAAAAMAAJ | date = September 1972 | publisher = Pergamon Press | isbn = 978-0080168128 | oclc = 278011135}}</ref><ref name="Drugs.com-International">{{cite web|url=https://www.drugs.com/international/ |title=International Drug Names from |publisher=Drugs.com |date= |accessdate=2022-04-30}}</ref><ref name="Martindale">{{cite book |editor=Sweetman, Sean C. |chapter=Sex hormones and their modulators |title=Martindale: The Complete Drug Reference |edition=36th |year=2009 |page=2082 |publisher=Pharmaceutical Press |location=London|isbn=978-0-85369-840-1}}</ref><ref name="Micromedex">{{cite web|url=http://www.micromedexsolutions.com/micromedex2/librarian/|title=Micromedex Products: Please Login}}</ref>
{{noteslist|group=brands}}
|}
A variety of different CICs, generally containing a short-acting natural [[estradiol ester]] and a long-acting [[progestin ester]], are available for clinical use.<ref name="UnzeitigLunsen2000">{{cite book|author1=V. Unzeitig|author2=Rick H.W. van Lunsen|title=Contraceptive Choices and Realities: Proceedings of the 5th Congress of the European Society of Contraception|url=https://books.google.com/books?id=-FliV0TxtEEC&pg=PA136|date=15 February 2000|publisher=CRC Press|isbn=978-1-85070-067-8|pages=133, 136}}</ref><ref name="pmid12290848"/><ref name="BagadePawar2014">{{cite journal | vauthors = Bagade O, Pawar V, Patel R, Patel B, Awasarkar V, Diwate S | title = Increasing use of long-acting reversible contraception: safe, reliable, and cost-effective birth control | journal = World J Pharm Pharm Sci | volume = 3 | issue = 10 | pages = 364–392 | year = 2014 | issn = 2278-4357 | url = http://www.wjpps.com/download/article/1412071798.pdf | access-date = 2016-08-24 | archive-url = https://web.archive.org/web/20170810000242/http://www.wjpps.com/download/article/1412071798.pdf | archive-date = 2017-08-10 | url-status = dead }}</ref><ref name="pmid8013219"/><ref name="HumansCancer1999"/> Estrogens that are used include [[estradiol valerate]], [[estradiol cypionate]], [[estradiol enantate]], [[estradiol benzoate butyrate]], and [[estradiol (medication)|estradiol]], while progestins that are used include [[norethisterone enantate]], [[medroxyprogesterone acetate]], [[algestone acetophenide]] (dihydroxyprogesterone acetophenide), [[hydroxyprogesterone caproate]], and [[megestrol acetate]].<ref name="pmid12290848" /><ref name="BagadePawar2014" /><ref name="pmid8013219" /><ref name="HumansCancer1999" /> [[Estradiol benzoate]] has a [[duration of action|duration]] that is too short for once-monthly CICs, and is not used in them.<ref name="pmid8013216a">{{cite journal |vauthors=Toppozada MK |title=Existing once-a-month combined injectable contraceptives |journal=Contraception |volume=49 |issue=4 |pages=293–301 |date=April 1994 |pmid=8013216 |doi=10.1016/0010-7824(94)90029-9}}</ref> Conversely, estradiol enantate is said to have a duration that is too long for once-monthly CICs, but is nonetheless used in them.<ref name="pmid8013216a" />

==Side effects==
Side effects of CICs, besides menstrual bleeding changes, are minimal.<ref name="BenagianoPrimiero1983" /> The most prominent side effects of CICs are [[menstrual irregularity|menstrual irregularities]] during the first 3 to 6&nbsp;months of use.<ref name="contrareportFDAAproveLunelle" /> [[Dysmenorrhea]] has been reported in 30 to 65% of women.<ref name="BenagianoPrimiero1983" /> Other side effects include [[breast tenderness/pain]], [[headache]], and [[libido]] changes.<ref name="BenagianoPrimiero1983" /> Some [[water retention (medicine)|fluid retention]] can occur, but [[weight gain]] is minimal.<ref name="BenagianoPrimiero1983" /> Local [[injection site reaction]]s have also been reported in 15 to 35% of women.<ref name="BenagianoPrimiero1983" />

Effects of CICs on [[coagulation]] and [[fibrinolysis]] are minimal and are not thought to be clinically relevant.<ref name="pmid8313486">{{cite journal | title = Facts about once-a-month injectable contraceptives: memorandum from a WHO meeting | journal = Bull. World Health Organ. | volume = 71 | issue = 6 | pages = 677–89 | date = 1993 | pmid = 8313486 | pmc = 2393537 }}</ref> Conversely, [[combined oral contraceptive pill]]s containing [[ethinylestradiol]] have considerable effects on coagulation and fibrinolysis.<ref name="pmid8313486" /> The differences can be attributed to the lack of the [[first-pass effect]] with [[parenteral administration]] as well as [[chemical structure|structural]] and [[pharmacology|pharmacological]] differences between estradiol and ethinylestradiol.<ref name="pmid16112947">{{cite journal | vauthors = Kuhl H | title = Pharmacology of estrogens and progestogens: influence of different routes of administration | journal = Climacteric | volume = 8 Suppl 1 | pages = 3–63 | year = 2005 | pmid = 16112947 | doi = 10.1080/13697130500148875 | s2cid = 24616324 | url = http://hormonebalance.org/images/documents/Kuhl%2005%20%20Pharm%20Estro%20Progest%20Climacteric_1313155660.pdf}}</ref><ref name="von SchoultzCarlström1989">{{cite journal|last1=von Schoultz|first1=Bo|last2=Carlström|first2=Kjell|last3=Collste|first3=Lars|last4=Eriksson|first4=Ambjörn|last5=Henriksson|first5=Peter|last6=Pousette|first6=Åke|last7=Stege|first7=Reinhard|author-link6=Åke Pousette|title=Estrogen therapy and liver function—metabolic effects of oral and parenteral administration|journal=The Prostate|volume=14|issue=4|year=1989|pages=389–395|issn=0270-4137|doi=10.1002/pros.2990140410|pmid=2664738|s2cid=21510744}}</ref>

==Pharmacology==
[[File:Idealized curves of estradiol levels after injection of different estradiol esters in women.png|thumb|right|400px|Idealized curves of estradiol levels over a period of 30 days after injection of different estradiol esters in women.<ref name="pmid8013219"/>]]

CICs contain an [[estrogen (medication)|estrogen]] and a [[progestin]]. The estrogen is generally a short-acting [[estradiol ester]], which acts as a [[prodrug]] of [[estradiol (medication)|estradiol]].<ref name="UnzeitigLunsen2000" /> Esters of estradiol are [[natural product|natural]] and [[bioidentical]] estrogens, and are believed to have more favorable effects on [[lipid metabolism]], [[cardiovascular]] health, and [[hemostasis]] than [[synthetic compound|synthetic]] estrogens such as [[ethinylestradiol]].<ref name="OettelSchillinger2012">{{cite book|author1=Michael Oettel|author2=Ekkehard Schillinger|title=Estrogens and Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogen|url=https://books.google.com/books?id=wBvyCAAAQBAJ&pg=PA261|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-60107-1|pages=235–237, 261, 271|quote=Natural estrogens considered here include: [...] Esters of 17β-estradiol, such as estradiol valerate, estradiol benzoate and estradiol cypionate. Esterification aims at either better absorption after oral administration or a sustained release from the depot after intramuscular administration. During absorption, the esters are cleaved by endogenous esterases and the pharmacologically active 17β-estradiol is released; therefore, the esters are considered as natural estrogens.}}</ref><ref name="ArunNarendra2012">{{cite book|author1=Nagrath Arun|author2=Malhotra Narendra|author3=Seth Shikha|title=Progress in Obstetrics and Gynecology--3|url=https://books.google.com/books?id=AS3UBAAAQBAJ&pg=PA419|date=15 December 2012|publisher=Jaypee Brothers Medical Publishers Pvt. Ltd.|isbn=978-93-5090-575-3|pages=419–}}</ref><ref name="pmid8013220a">{{cite journal | vauthors = Sang GW | title = Pharmacodynamic effects of once-a-month combined injectable contraceptives | journal = Contraception | volume = 49 | issue = 4 | pages = 361–85 | date = April 1994 | pmid = 8013220 | doi = 10.1016/0010-7824(94)90033-7 }}</ref> The progestin is a long-acting [[progestogen ester]], which may or may not act as a prodrug.<ref name="UnzeitigLunsen2000" /> [[Progesterone (medication)|Progesterone]] [[chemical derivative|derivative]]s including [[medroxyprogesterone acetate]], [[algestone acetophenide]] (dihydroxyprogesterone acetophenide), [[hydroxyprogesterone caproate]], and [[megestrol acetate]] are [[biological activity|active]] themselves and are not prodrugs, whereas the [[testosterone (medication)|testosterone]] derivative [[norethisterone enantate]] is a prodrug of [[norethisterone]]. Regardless of whether they are prodrugs or not, [[steroid ester]]s form a [[depot injection|depot]] and have an extended [[duration of action]] due to a [[depot effect]] when administered by [[intramuscular injection|intramuscular]] or [[subcutaneous injection]].

Because CICs are administered [[parenteral]]ly, they bypass the [[first-pass metabolism|first-pass effect]] in the [[liver]] and [[intestine]]s that occurs with [[oral administration]] of estrogens.<ref name="UnzeitigLunsen2000" /> However, is estimated that about 20% of an administered dose does still eventually pass through the liver.<ref name="UnzeitigLunsen2000" /> Hence, these preparations are not completely liver-neutral.<ref name="UnzeitigLunsen2000" /> Nonetheless, they have dramatically reduced hepatic effects relative to oral ethinylestradiol.<ref name="pmid16112947"/> In addition, parenteral [[estradiol (medication)|estradiol]] in general has about 4- or 5-fold reduced potency in the liver than oral estradiol.<ref name="pmid16112947" />

[[File:Hormone levels in men with a single intramuscular injection of 5 mg estradiol valerate and 50 mg norethisterone enanthate in oil.png|thumb|right|400px|Hormone levels following a single intramuscular injection of [[estradiol valerate/norethisterone enanthate]] (5&nbsp;mg/50&nbsp;mg) (Mesigyna) in healthy young men.<ref name="ValleAlvarez2011" /> Testosterone levels were maximally suppressed by about 94%, to ~30&nbsp;ng/dL, when measured at day 7 post-injection.<ref name="ValleAlvarez2011" />]]

CICs have [[antigonadotropic]] effects via their estrogenic and progestogenic activity and inhibit [[fertility]] and suppress [[sex hormone]] levels. A single intramuscular injection of [[estradiol valerate/norethisterone enanthate]] (5&nbsp;mg/50&nbsp;mg) (Mesigyna) has been found to strongly suppress testosterone levels in men.<ref name="ValleAlvarez2011">{{cite thesis | type = MSc | author-last = Valle Alvarez | author-first = Doris del Cisne | title = Efecto de una Dosis de 50 mg de Enantato de Noretisterona y 5 mg de Valerato de Estradiol en los Niveles de Testosterona Total en Hombres Mexicanos Sanos | trans-title = Effect of a Dose of 50 mg of Norethisterone Enanthate and 5 mg of Estradiol Valerate on Total Testosterone Levels in Healthy Mexican Men | date = 11 May 2011 | publisher = National Polytechnic Institute of Mexico | url = http://repositoriodigital.ipn.mx/handle/123456789/12490}}</ref> Testosterone levels decreased from a baseline of ~503&nbsp;ng/dL to a trough of ~30&nbsp;ng/dL (a 94% decrease) which occurred at day&nbsp;7 post-injection.<ref name="ValleAlvarez2011" />

{| class="wikitable"
|+ Estradiol levels with combined injectable contraceptives<ref name="pmid8013219" />
! Preparation
! Form
! Dose
! Estradiol C<sub>max</sub>
! Estradiol T<sub>max</sub>
|-
| [[Estradiol valerate/norethisterone enanthate|EV/NETE]]
| Oil solution
| 5 mg/50 mg
| 232–428 pg/mL
| 2 days
|-
| [[Estradiol cypionate/medroxyprogesterone acetate|EC/MPA]]
| Aqueous suspension
| 5 mg/25 mg
| 184–736 pg/mL
| 2–4 days
|-
| rowspan="2" | [[Estradiol enanthate/dihydroxyprogesterone acetophenide|EEn/DHPA]]
| rowspan="2" | Oil solution
| 10 mg/150 mg
| 314–317 pg/mL
| 4.2–8.1 days
|-
| 5 mg/75 mg
| 148 pg/mL
| 6.5 days
|}

{{Parenteral potencies and durations of estrogens}}

{{Parenteral potencies and durations of progestogens}}

==History==
The first CIC to be studied was [[estradiol valerate/hydroxyprogesterone caproate]] (EV/OHPC) in 1963, and the second CIC to be studied was [[estradiol enantate/algestone acetophenide]] (E2-EN/DHPA) in 1964.<ref name="BenagianoPrimiero1983">{{cite journal|last1=Benagiano|first1=G.|last2=Primiero|first2=F.M.|title=Long Acting Contraceptives Present Status|journal=Drugs|volume=25|issue=6|year=1983|pages=570–609|issn=0012-6667|doi=10.2165/00003495-198325060-00003|pmid=6223801|s2cid=45898359}}</ref><ref name="pmid8013216a" /> In 1967, E2-EN/DHPA was in the late stages of clinical development.<ref name="Hecht-Lucari1967">Hecht-Lucari, G. (1967). Recientes Progresos de la Terapia Hormonal en Ginecología. Revista Colombiana de Obstetricia y Ginecología, 18(5), 307-319. 10.18597/rcog.2584 https://revista.fecolsog.org/index.php/rcog/article/view/2584</ref><ref name="BenagianoPrimiero1983" /> By 1969, the medication was available for medical use under the brand name Perlutal.<ref name="Tiempo1969">{{cite book|title=Hispano americano|url=https://books.google.com/books?id=xpQYAQAAIAAJ|date=May 1969|publisher=Tiempo|quote=Entre los anovulatorios más usados están los siguientes: Prolestrín, Sequens, Anovlar, Sequentex, Orlex, Ginovlar, Enginón, Perlutal, Depo-proveda, Aconcén, Ovral, Retex, Lorophyn y otros menos solicitados.|page=46}}</ref> Within a few years, it was marketed under other brand names such as Topasel and Ova-Repos as well.<ref name="Botella-Llusia1970">Botella-Llusia, J. (1970). Les ovaires au cours de l'administration des sterpides anticonceptionnels. [The ovaries during administration of contraceptive steroids.] In: Netter, A. L'Inhibition de l'ovulation; Colloque de la Societe Nationale pour l'Etude de la Sterilite et de la Fecondite. (Inhibition of ovulation: Proceedings of the National Society for the Study of Sterility and Fertility.) Paris, Masson, 1970. p. 141-156</ref><ref name="Madrid1971">{{cite book|author=Universidad Complutense de Madrid|title=Revista de la Universidad de Madrid|url=https://books.google.com/books?id=IlJdLcRUfLIC|year=1971|publisher=Prensa de la Universidad de Madrid.|page=11}}</ref><ref name="Liria1972">Liria, R. H. (1972). Anticoncepcionismo (Un problema de hoy, de ayer y de siempre). In Anales de medicina y cirugía (Vol. 52, No. 230, pp. 329-348). https://www.raco.cat/index.php/AnalesMedicina/article/download/99455/152590</ref><ref name="RudelKinel1972">{{cite book | author1 = Harry W. Rudel | author2 = Fred A. Kinel | chapter = Oral Contraceptives. Human Fertility Studies and Side Effects | pages = 385–469 <!-- Table on page 401 --> | editor1 = M. Tausk | title = Pharmacology of the Endocrine System and Related Drugs: Progesterone, Progestational Drugs and Antifertility Agents | volume = II | url = https://books.google.com/books?id=Nv5sAAAAMAAJ | date = September 1972 | publisher = Pergamon Press | isbn = 978-0080168128 | oclc = 278011135}}</ref> In addition, several other CICs had been introduced for medical use by 1972.<ref name="RudelKinel1972" /> By 1976, two major CICs were in use: E2-EN/DHPA (brand names Perlutan, Topasel) in [[Spain]] and [[Latin America]], and EV/OHPC (brand name Injectable No. 1) in [[China]].<ref name="BringerHedon1995">{{cite book|author1=J. Bringer|author2=B. Hedon|title=Fertility and Sterility: A Current Overview|url=https://books.google.com/books?id=vZirsEgpXiMC&pg=PA47|date=15 September 1995|publisher=CRC Press|isbn=978-1-85070-694-6|pages=47–}}</ref> These CICs have been described as first-generation CICs.<ref name="BringerHedon1995"/> Two second-generation CICs, [[estradiol cypionate/medroxyprogesterone acetate]] (EC/MPA; brand names Cyclofem and later Lunelle) and [[estradiol valerate/norethisterone enantate]] (EV/NETE; brand name Mesigyna), were introduced for clinical use in 1993.<ref name="pmid8185807">{{cite journal | vauthors = d'Arcangues C | title = Once-a-month injectable contraceptives | journal = World Health Forum | volume = 14 | issue = 4 | pages = 439–40 | date = 1993 | pmid = 8185807 }}</ref><ref name="SenanayakePotts2008" /><ref name="pmid12290848" /> On 5 October 2000, [[Pharmacia]] received FDA approval for Lunelle Monthly Contraceptive Injection.<ref name="contrareportFDAAproveLunelle">{{cite journal|title=FDA Approves Combined Monthly Injectable Contraceptive |journal=Contraception Report |year=2001 |volume=12 |issue=3 |url=http://www.contraceptiononline.org/contrareport/article01.cfm?art=176 |url-status=dead |archive-url=https://web.archive.org/web/20060926040811/http://www.contraceptiononline.org/contrareport/article01.cfm?art=176 |archive-date=September 26, 2006 }}</ref> In April 2003, Pharmacia was acquired by [[Pfizer]] (makers of [[depot medroxyprogesterone acetate]]).{{Citation needed|date=July 2019}} In October 2003, Lunelle was discontinued in the [[United States]].{{Citation needed|date=July 2019}}

==Society and culture==

===Availability===
[[File:Combined injectable contraceptive availability.png|thumb|right|400px|Known availability of CICs in countries throughout the world (as of September 2018).]]

CICs are available in many countries throughout the world, including widely throughout [[Central America|Central]] and [[South America]], in [[Mexico]] and the [[Caribbean]], in [[China]], in several [[Southeast Asia]]n and [[Africa]]n countries, and in [[Turkey]].<ref name="Drugs.com-International"/><ref name="Martindale"/><ref name="Micromedex"/><ref name="HumansCancer1999" /><ref name="BagadePawar2014" /><ref name="SenanayakePotts2008"/><ref name="pmid12290848" /><ref name="pmid8013219" /><ref name="HumansOrganization2007"/> They were also previously available in the [[United States]], [[Portugal]], and [[Spain]], but have been discontinued in these countries.<ref name="Martindale" /><ref name="Micromedex" />

==Research==
Many other CICs have been studied but have not been approved or marketed for clinical use.<ref name="pmid12290848" /><ref name="pmid8013219" /><ref name="pmid8013221" /><ref name="pmid8013216a" /><ref name="Toppozada1983" /><ref name="BagadePawar2014" />

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

* [[Estradiol valerate]] 2.5 to 5&nbsp;mg + [[norethisterone enantate]] 50 to 80&nbsp;mg in an [[oil solution]]<ref name="pmid12290848" /><ref name="pmid8013219" />
* [[Estradiol valerate]] 10&nbsp;mg + [[hydroxyprogesterone caproate]] 500&nbsp;mg in an oil solution<ref name="pmid12290848" />
* [[Estradiol cypionate]] 2.5 to 10&nbsp;mg + [[medroxyprogesterone acetate]] 12.5 to 50&nbsp;mg in a [[microcrystalline]] [[aqueous suspension]]<ref name="pmid12290848" /><ref name="pmid8013219" />
* [[Estradiol enantate]] 5 to 50&nbsp;mg + [[algestone acetophenide]] 75 to 200&nbsp;mg in an oil solution<ref name="pmid8013221">{{cite journal | vauthors = Koetsawang S | title = Once-a-month injectable contraceptives: efficacy and reasons for discontinuation | journal = Contraception | volume = 49 | issue = 4 | pages = 387–98 | date = April 1994 | pmid = 8013221 | doi = 10.1016/0010-7824(94)90034-5 }}</ref><ref name="pmid12290848" />

The half-progestin-dose formulation of estradiol valerate/norethisterone enantate (5&nbsp;mg / 25&nbsp;mg) is also known as HRP-103 and the half-progestin-dose formulation of estradiol cypionate/medroxyprogesterone acetate (5&nbsp;mg / 12.5&nbsp;mg) is also known as HRP-113.<ref name="UnlistedDrugs1993">{{cite book|title=Unlisted Drugs Pharm AID|url=https://books.google.com/books?id=SRRtAAAAMAAJ|year=1993|publisher=Unlisted Drugs|isbn=978-0-913210-14-7|page=247}}</ref>

The following are CICs that have never been marketed:

* [[Estradiol valerate]] 20&nbsp;mg + [[medroxyprogesterone acetate]] 100&nbsp;mg in a microcrystalline aqueous suspension<ref name="pmid12290848" /><ref name="pmid8013219" />
* [[Estradiol undecylate]] 5 to 10&nbsp;mg + [[norethisterone enantate]] 50 to 70&nbsp;mg in an oil solution<ref name="pmid8013216a" /><ref name="pmid12290848" /><ref name="Toppozada1983">{{cite book | author = Mokhtar K. Toppozada | chapter = Monthly Injectable Contraceptives | pages = 93–103 | editor1 = Alfredo Goldsmith | editor2 = Mokhtar Toppozada | title = Long-Acting Contraception | year = 1983 | oclc = 35018604 | url = https://scholar.google.com/scholar?cluster=14664537528797672080}}</ref><ref name="pmid865726">{{cite journal | vauthors = Toppozada M | title = The clinical use of monthly injectable contraceptive preparations | journal = Obstet Gynecol Surv | volume = 32 | issue = 6 | pages = 335–47 | date = June 1977 | pmid = 865726 | doi = 10.1097/00006254-197706000-00001 }}</ref>
* [[Estradiol cypionate]] + [[norethisterone enantate]]<ref name="Toppozada1983" /><ref name="pmid12290848" />
* [[Estradiol valerate]] 10&nbsp;mg + [[methenmadinone caproate]] 60&nbsp;mg (Lutofollin)<ref name="pmid8013216a" /><ref name="Toppozada1983" /><ref name="pmid865726" />
* [[Estradiol hexahydrobenzoate]] 5&nbsp;mg (oil solution) + [[norgestrel]] 25&nbsp;mg (aqueous suspension)<ref name="pmid8013216a" /><ref name="pmid12290848" /><ref name="Toppozada1983" /><ref name="pmid865726" /><ref name="pmid4650657">{{cite journal | last1 = de Souza | first1 = J. C. | last2 = Coutinho | first2 = Elsimar M. | title = Control of fertility by monthly injections of a mixture of norgestrel and a long-acting estrogen | journal = Contraception | volume = 5 | issue = 5 | year = 1972 | pages = 395–399 | issn = 0010-7824 | pmid = 4650657 | doi = 10.1016/0010-7824(72)90031-5 }}</ref>
* [[Estradiol cypionate]] 3.5 to 5&nbsp;mg + [[megestrol acetate]] 25&nbsp;mg in a microcrystalline aqueous suspension (marketed in China?)<ref name="pmid8013216a" /><ref name="pmid12290848" /><ref name="Toppozada1983" />
* [[Estradiol valerate]] 3 to 5&nbsp;mg + [[chlormadinone caproate]] 80&nbsp;mg in an oil solution<ref name="pmid8013216a" /><ref name="pmid12290848" /><ref name="Toppozada1983" />
* [[Estradiol valerate]] 5&nbsp;mg + [[megestrol acetate]] 15&nbsp;mg in an [[aqueous suspension]] of [[gelatin]] [[microsphere]]s (50–80&nbsp;μm)<ref name="pmid8013216a" /><ref name="pmid8013219" /><ref name="Toppozada1983" /><ref name="pmid8013220a" />
* [[Estradiol (medication)|Estradiol]] 5&nbsp;mg + [[levonorgestrel]] 7&nbsp;mg in an [[aqueous suspension]] of [[:wikt:monolithic|monolithic]] [[microspheres]] (80&nbsp;μm) or in a [[macrocrystalline]] suspension (15&nbsp;μm)<ref name="pmid8013219" /><ref name="pmid8013220a" />
* [[Estradiol cypionate]] 5&nbsp;mg + [[levonorgestrel butanoate]] 7&nbsp;mg in an [[aqueous suspension]]<ref name="pmid8013219" />
* [[Estradiol benzoate]] 5 to 10&nbsp;mg + [[norethisterone enanthate]] 50 to 100&nbsp;mg<ref name="Toppozada1983" />
* [[Mestranol]] 1.0–1.2&nbsp;mg + [[norethisterone]] 10–12&nbsp;mg in a [[microcrystalline]] [[aqueous suspension]] of defined [[particle size]]s (125–177&nbsp;μm)<ref name="pmid8013216a" /><ref name="pmid8013219" /><ref name="Toppozada1983" /><ref name="pmid8013220a" />
* [[Ethinylestradiol]] + [[norethisterone]]<ref name="pmid12290848" />
* [[Estradiol (medication)|Estradiol]] 5&nbsp;mg and [[progesterone (medication)|progesterone]] 100 to 300&nbsp;mg in an [[aqueous suspension]] of [[:wikt:monolithic|monolithic]] [[microsphere]]s or in a [[macrocrystalline]] suspension<ref name="pmid8013216a" /><ref name="pmid8013219" /><ref name="BagadePawar2014" /><ref name="pmid12290848" /><ref name="pmid1893701">{{cite journal | vauthors = Garza-Flores J, Fatinikun T, Hernandez L, Ramos I, Cardenas M, Menjivar M | title = A pilot study on the assessment of a progesterone/estradiol sustained release as once-a-month-injectable contraceptive | journal = Contraception | volume = 44 | issue = 1 | pages = 45–59 | date = July 1991 | pmid = 1893701 | doi = 10.1016/0010-7824(91)90105-O}}</ref><ref name="pmid1958567">{{cite journal |vauthors=Garza-Flores J, Hall PE, Perez-Palacios G |title=Long-acting hormonal contraceptives for women |journal=J. Steroid Biochem. Mol. Biol. |volume=40 |issue=4–6 |pages=697–704 |date=1991 |pmid=1958567 |doi=10.1016/0960-0760(91)90293-E|s2cid=26021562 }}</ref><ref name="pmid8013220a" />
* [[Polyestradiol phosphate]] 40&nbsp;mg + [[medroxyprogesterone acetate]] 150&nbsp;mg<ref name="GoldzieherFotherby1994">{{cite book|author1=Joseph William Goldzieher|author2=Kenneth Fotherby|title=Pharmacology of the contraceptive steroids|url=https://books.google.com/books?id=bJRsAAAAMAAJ|year=1994|publisher=Raven Press|isbn=978-0-7817-0097-9|page=154}}</ref><ref name="pmid5925038">{{cite journal | vauthors = Zañartu J, Rice-Wray E, Goldzieher JW | title = Fertility control with long-acting injectable steroids. A preliminary report | journal = Obstet Gynecol | volume = 28 | issue = 4 | pages = 513–5 | date = October 1966 | pmid = 5925038 | url = https://journals.lww.com/greenjournal/citation/1966/10000/fertility_control_with_long_acting_injectable.11.aspx}}</ref><ref name="Beckman1967">{{cite book|author=Harry Beckman|title=The Year Book of Drug Therapy|url=https://books.google.com/books?id=sRc-AQAAIAAJ|year=1967|publisher=Year Book Publishers}}</ref>

==See also==
* [[Special Programme on Human Reproduction]]
* [[Concept Foundation]]
* [[Extended cycle combined hormonal contraceptive]]
* [[Reproductive Health Supplies Coalition]]
* [[Estradiol-containing oral contraceptive]]

==References==
{{reflist}}

==Further reading==
* {{cite journal | vauthors = Garza-Flores J | title = Pharmacokinetics of once-a-month injectable contraceptives | journal = Contraception | volume = 49 | issue = 4 | pages = 347–59 | date = April 1994 | pmid = 8013219 | doi = 10.1016/0010-7824(94)90032-9 }}
* {{cite journal | vauthors = Sang GW | title = Pharmacodynamic effects of once-a-month combined injectable contraceptives | journal = Contraception | volume = 49 | issue = 4 | pages = 361–85 | date = April 1994 | pmid = 8013220 | doi = 10.1016/0010-7824(94)90033-7 }}

{{Estradiol}}
{{Birth control methods}}
{{Hormonal contraceptives}}
{{PATH (global health organization)}}

[[Category:Combined injectable contraceptives]]
[[Category:Estradiol]]