combined injectable birth control

CICs are administered by intramuscular injection into the deltoid, gluteus maximus, or anterior thigh. They are ideally administered every 28 to 30 days, though they have been demonstrated to be effective up to 33 days.

Some CICs have been said to be used by transgender women as a means of feminizing hormone therapy as well.{{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}}

A variety of different CICs, generally containing a short-acting natural estradiol ester and a long-acting progestin ester, are available for clinical use.{{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}}{{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 }} Estrogens that are used include estradiol valerate, estradiol cypionate, estradiol enantate, estradiol benzoate butyrate, and estradiol, while progestins that are used include norethisterone enantate, medroxyprogesterone acetate, algestone acetophenide (dihydroxyprogesterone acetophenide), hydroxyprogesterone caproate, and megestrol acetate. Estradiol benzoate has a duration that is too short for once-monthly CICs, and is not used in them.{{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}} Conversely, estradiol enantate is said to have a duration that is too long for once-monthly CICs, but is nonetheless used in them.

Side effects of CICs, besides menstrual bleeding changes, are minimal. The most prominent side effects of CICs are menstrual irregularities during the first 3 to 6 months of use. Dysmenorrhea has been reported in 30 to 65% of women. Other side effects include breast tenderness/pain, headache, and libido changes. Some fluid retention can occur, but weight gain is minimal. Local injection site reactions have also been reported in 15 to 35% of women.

Effects of CICs on coagulation and fibrinolysis are minimal and are not thought to be clinically relevant.{{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 }} Conversely, combined oral contraceptive pills containing ethinylestradiol have considerable effects on coagulation and fibrinolysis. The differences can be attributed to the lack of the first-pass effect with parenteral administration as well as structural and pharmacological differences between estradiol and ethinylestradiol.{{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}}{{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}}

File:Idealized curves of estradiol levels after injection of different estradiol esters in women.png

CICs contain an estrogen and a progestin. The estrogen is generally a short-acting estradiol ester, which acts as a prodrug of estradiol. Esters of estradiol are natural and bioidentical estrogens, and are believed to have more favorable effects on lipid metabolism, cardiovascular health, and hemostasis than synthetic estrogens such as ethinylestradiol.{{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.}}{{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–}}{{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 }} The progestin is a long-acting progestogen ester, which may or may not act as a prodrug. Progesterone derivatives including medroxyprogesterone acetate, algestone acetophenide (dihydroxyprogesterone acetophenide), hydroxyprogesterone caproate, and megestrol acetate are active themselves and are not prodrugs, whereas the testosterone derivative norethisterone enantate is a prodrug of norethisterone. Regardless of whether they are prodrugs or not, steroid esters form a depot and have an extended duration of action due to a depot effect when administered by intramuscular or subcutaneous injection.

Because CICs are administered parenterally, they bypass the first-pass effect in the liver and intestines that occurs with oral administration of estrogens. However, is estimated that about 20% of an administered dose does still eventually pass through the liver. Hence, these preparations are not completely liver-neutral. Nonetheless, they have dramatically reduced hepatic effects relative to oral ethinylestradiol. In addition, parenteral estradiol in general has about 4- or 5-fold reduced potency in the liver than oral estradiol.

File:Hormone levels in men with a single intramuscular injection of 5 mg estradiol valerate and 50 mg norethisterone enanthate in oil.png (5 mg/50 mg) (Mesigyna) in healthy young men. Testosterone levels were maximally suppressed by about 94%, to ~30 ng/dL, when measured at day 7 post-injection.]]

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 mg/50 mg) (Mesigyna) has been found to strongly suppress testosterone levels in men.{{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}} 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.

{{Parenteral potencies and durations of estrogens}}

{{Parenteral potencies and durations of progestogens}}

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.{{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}} In 1967, E2-EN/DHPA was in the late stages of clinical development.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 By 1969, the medication was available for medical use under the brand name Perlutal.{{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}} Within a few years, it was marketed under other brand names such as Topasel and Ova-Repos as well.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{{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}}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{{cite book | author1 = Harry W. Rudel | author2 = Fred A. Kinel | chapter = Oral Contraceptives. Human Fertility Studies and Side Effects | pages = 385–469 | 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}} In addition, several other CICs had been introduced for medical use by 1972. 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.{{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–}} These CICs have been described as first-generation CICs. 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.{{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 }} On 5 October 2000, Pharmacia received FDA approval for Lunelle Monthly Contraceptive Injection.{{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 }} 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}}

File:Combined injectable contraceptive availability.png

CICs are available in many countries throughout the world, including widely throughout Central and South America, in Mexico and the Caribbean, in China, in several Southeast Asian and African countries, and in Turkey. They were also previously available in the United States, Portugal, and Spain, but have been discontinued in these countries.

Many other CICs have been studied but have not been approved or marketed for clinical use.

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 an oil solution
• Estradiol valerate 10 mg + hydroxyprogesterone caproate 500 mg in an oil solution
• Estradiol cypionate 2.5 to 10 mg + medroxyprogesterone acetate 12.5 to 50 mg in a microcrystalline aqueous suspension
• Estradiol enantate 5 to 50 mg + algestone acetophenide 75 to 200 mg in an oil solution{{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 }}

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.{{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}}

The following are CICs that have never been marketed:

• Estradiol valerate 20 mg + medroxyprogesterone acetate 100 mg in a microcrystalline aqueous suspension
• Estradiol undecylate 5 to 10 mg + norethisterone enantate 50 to 70 mg in an oil solution{{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}}{{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 }}
• Estradiol cypionate + norethisterone enantate
• Estradiol valerate 10 mg + methenmadinone caproate 60 mg (Lutofollin)
• Estradiol hexahydrobenzoate 5 mg (oil solution) + norgestrel 25 mg (aqueous suspension){{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 }}
• Estradiol cypionate 3.5 to 5 mg + megestrol acetate 25 mg in a microcrystalline aqueous suspension (marketed in China?)
• Estradiol valerate 3 to 5 mg + chlormadinone caproate 80 mg in an oil solution
• Estradiol valerate 5 mg + megestrol acetate 15 mg in an aqueous suspension of gelatin microspheres (50–80 μm)
• Estradiol 5 mg + levonorgestrel 7 mg in an aqueous suspension of monolithic microspheres (80 μm) or in a macrocrystalline suspension (15 μm)
• Estradiol cypionate 5 mg + levonorgestrel butanoate 7 mg in an aqueous suspension
• Estradiol benzoate 5 to 10 mg + norethisterone enanthate 50 to 100 mg
• Mestranol 1.0–1.2 mg + norethisterone 10–12 mg in a microcrystalline aqueous suspension of defined particle sizes (125–177 μm)
• Ethinylestradiol + norethisterone
• Estradiol 5 mg and progesterone 100 to 300 mg in an aqueous suspension of monolithic microspheres or in a macrocrystalline suspension{{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}}{{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 }}
• Polyestradiol phosphate 40 mg + medroxyprogesterone acetate 150 mg{{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}}{{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}}{{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}}

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

{{reflist}}

• {{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