Combined injectable birth control explained

Combined injectable birth control
Bc Type:Hormonal
Date First Use:By 1969
Rate Type:Failure
Perfect Failure%:0–0.2
Duration Effect:1 month
Std Protection Yesno:No
Benefits:Especially good if poor pill compliance

Combined injectable contraceptives (CICs) are a form of hormonal birth control for women. They consist of monthly injections of combined formulations containing an estrogen and a progestin to prevent pregnancy.

CICs are different from progestogen-only injectable contraceptives (POICs), such as 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 months instead of once a month.

Hormonal contraception works primarily by preventing ovulation, but it may also thicken the cervical mucus inhibiting sperm penetration.[1] [2] [3] Hormonal contraceptives also have effects on the endometrium,[4] [5] that theoretically could affect implantation.[6] [7] [8] [9]

Medical uses

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.[10]

Available forms

Composition Dose Vehicle Brand Names !Availability
5 mg /
50 mg 		Oil solution Multiple Approved in at least 36 countries
5 mg /
25 mg 		Microcrystalline aqueous suspension Multiple Approved in at least 18 countries
Estradiol enantate / Algestone acetophenidea 10 mg /
150 mg 		Oil solution Multiple Approved in at least 19 countries
5 mg /
75 mg 		Oil solution Anafertin†, Patector NF, Yectames Approved at least 9 countries
10 mg /
120 mg 		Oil solution Unalmes, Yectuna Approved in at least 3 countries
10 mg /
75 mg 		Oil solution Ova Repos† Discontinued (firm was in Spain)
10 mg /
150 mg 		Oil solution? Redimen, Soluna, Unijab, Unimens§ Approved in Peru and Singapore
5 mg /
250 mg 		Oil solution Chinese Injectable No. 1 Approved in China
3.5 mg /
25 mg 		Microcrystalline aqueous suspension Chinese Injectable No. 2, Mego-E Approved in China
5 mg /
250 mg 		Oil solution? Sinbios† Discontinued (firm was in Mexico)
10 mg /
1 mg /
250 mg 		Oil solution? Sin-Ol† Discontinued (firm was in Mexico)
Notes: All are given by intramuscular injection once a month. Footnotes: † = Discontinued. § = Never marketed. a = Unsorted brand names (doses unknown; for): Evitas† and Femineo†. Sources: [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21]
A variety of different CICs, generally containing a short-acting natural estradiol ester and a long-acting progestin ester, are available for clinical use.[22] [23] [24] [25] [26] 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.[27] 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

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.[28] 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.[29] [30]

Pharmacology

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.[31] [32] [33] 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.[34] In addition, parenteral estradiol in general has about 4- or 5-fold reduced potency in the liver than oral estradiol.

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.[35] 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.

Estradiol levels with combined injectable contraceptives! Preparation! Form! Dose! Estradiol Cmax! Estradiol Tmax
EV/NETEOil solution5 mg/50 mg232–428 pg/mL2 days
EC/MPAAqueous suspension5 mg/25 mg184–736 pg/mL2–4 days
EEn/DHPAOil solution10 mg/150 mg314–317 pg/mL4.2–8.1 days
5 mg/75 mg148 pg/mL6.5 days

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.[36] In 1967, E2-EN/DHPA was in the late stages of clinical development.[37] By 1969, the medication was available for medical use under the brand name Perlutal.[38] Within a few years, it was marketed under other brand names such as Topasel and Ova-Repos as well.[39] [40] [41] [42] 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.[43] These CICs have been described as first-generation CICs.[43] 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.[44] On 5 October 2000, Pharmacia received FDA approval for Lunelle Monthly Contraceptive Injection.[45] In April 2003, Pharmacia was acquired by Pfizer (makers of depot medroxyprogesterone acetate). In October 2003, Lunelle was discontinued in the United States.

Society and culture

Availability

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.[46] [47] [48] [49] [50] They were also previously available in the United States, Portugal, and Spain, but have been discontinued in these countries.

Research

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:

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.[52]

The following are CICs that have never been marketed:

See also

Further reading

Notes and References

  1. Tamara Callahan MD, Aaron Caughey MD, Blueprints Obstetrics and Gynecology, 2013
  2. KD Tripathi, Essentials of Medical Pharmacology, 2013
  3. Dc Dutta's Textbook of Obstetrics, 2014
  4. 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
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. Rivera R, Yacobson I, Grimes D . 1999 . The mechanism of action of hormonal contraceptives and intrauterine contraceptive devices . Am J Obstet Gynecol . 181 . 5 Pt 1 . 1263–9 . 10561657 . 10.1016/S0002-9378(99)70120-1.
  10. Book: Don Kulick. Travesti: Sex, Gender, and Culture among Brazilian Transgendered Prostitutes. 12 January 2009. University of Chicago Press. 978-0-226-46101-4. 64–66.
  11. Book: IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. International Agency for Research on Cancer. Hormonal Contraception and Post-menopausal Hormonal Therapy. 1 January 1999. IARC. 978-92-832-1272-0. 65.
  12. Book: Pramilla Senanayake. Malcolm Potts. Atlas of Contraception, Second Edition. 14 April 2008. CRC Press. 978-0-203-34732-4. 50–.
  13. Newton JR, D'arcangues C, Hall PE . A review of "once-a-month" combined injectable contraceptives . J Obstet Gynaecol (Lahore) . 4 Suppl 1 . S1–34 . 1994 . 12290848 . 10.3109/01443619409027641.
  14. Garza-Flores J . Pharmacokinetics of once-a-month injectable contraceptives . Contraception . 49 . 4 . 347–59 . April 1994 . 8013219 . 10.1016/0010-7824(94)90032-9 .
  15. Book: IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. World Health Organization. International Agency for Research on Cancer. Combined Estrogen-progestogen Contraceptives and Combined Estrogen-progestogen Menopausal Therapy. 2007. World Health Organization. 978-92-832-1291-1. 431–.
  16. Klitsch M . Still waiting for the contraceptive revolution . Fam Plann Perspect . 27 . 6 . 246–53 . 1995 . 8666089 . 10.2307/2136177 . 2136177 .
  17. Gallo MF, Grimes DA, Lopez LM, Schulz KF, d'Arcangues C . Combination injectable contraceptives for contraception . Cochrane Database Syst Rev . 3 . CD004568 . 2013 . 23641480 . 10.1002/14651858.CD004568.pub3 . 6513542 .
  18. Book: Harry W. Rudel . Fred A. Kinel . Oral Contraceptives. Human Fertility Studies and Side Effects . 385–469 . M. Tausk . Pharmacology of the Endocrine System and Related Drugs: Progesterone, Progestational Drugs and Antifertility Agents . II . September 1972 . Pergamon Press . 978-0080168128 . 278011135.
  19. Web site: International Drug Names from . Drugs.com . 2022-04-30.
  20. Book: Sweetman, Sean C. . Sex hormones and their modulators . Martindale: The Complete Drug Reference . 36th . 2009 . 2082 . Pharmaceutical Press . London. 978-0-85369-840-1.
  21. Web site: Micromedex Products: Please Login.
  22. Book: V. Unzeitig. Rick H.W. van Lunsen. Contraceptive Choices and Realities: Proceedings of the 5th Congress of the European Society of Contraception. 15 February 2000. CRC Press. 978-1-85070-067-8. 133, 136.
  23. Newton JR, D'arcangues C, Hall PE . A review of "once-a-month" combined injectable contraceptives . J Obstet Gynaecol (Lahore) . 4 Suppl 1 . S1–34 . 1994 . 12290848 . 10.3109/01443619409027641.
  24. Bagade O, Pawar V, Patel R, Patel B, Awasarkar V, Diwate S . Increasing use of long-acting reversible contraception: safe, reliable, and cost-effective birth control . World J Pharm Pharm Sci . 3 . 10 . 364–392 . 2014 . 2278-4357 . 2016-08-24 . https://web.archive.org/web/20170810000242/http://www.wjpps.com/download/article/1412071798.pdf . 2017-08-10 . dead .
  25. Garza-Flores J . Pharmacokinetics of once-a-month injectable contraceptives . Contraception . 49 . 4 . 347–59 . April 1994 . 8013219 . 10.1016/0010-7824(94)90032-9 .
  26. Book: IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. International Agency for Research on Cancer. Hormonal Contraception and Post-menopausal Hormonal Therapy. 1 January 1999. IARC. 978-92-832-1272-0. 65.
  27. Toppozada MK . Existing once-a-month combined injectable contraceptives . Contraception . 49 . 4 . 293–301 . April 1994 . 8013216 . 10.1016/0010-7824(94)90029-9.
  28. Facts about once-a-month injectable contraceptives: memorandum from a WHO meeting . Bull. World Health Organ. . 71 . 6 . 677–89 . 1993 . 8313486 . 2393537 .
  29. Kuhl H . Pharmacology of estrogens and progestogens: influence of different routes of administration . Climacteric . 8 Suppl 1 . 3–63 . 2005 . 16112947 . 10.1080/13697130500148875 . 24616324 .
  30. von Schoultz. Bo. Carlström. Kjell. Collste. Lars. Eriksson. Ambjörn. Henriksson. Peter. Pousette. Åke. Stege. Reinhard. Åke Pousette. Estrogen therapy and liver function—metabolic effects of oral and parenteral administration. The Prostate. 14. 4. 1989. 389–395. 0270-4137. 10.1002/pros.2990140410. 2664738. 21510744.
  31. Book: Michael Oettel. Ekkehard Schillinger. Estrogens and Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogen. 6 December 2012. Springer Science & Business Media. 978-3-642-60107-1. 235–237, 261, 271. 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..
  32. Book: Nagrath Arun. Malhotra Narendra. Seth Shikha. Progress in Obstetrics and Gynecology--3. 15 December 2012. Jaypee Brothers Medical Publishers Pvt. Ltd.. 978-93-5090-575-3. 419–.
  33. Sang GW . Pharmacodynamic effects of once-a-month combined injectable contraceptives . Contraception . 49 . 4 . 361–85 . April 1994 . 8013220 . 10.1016/0010-7824(94)90033-7 .
  34. Kuhl H . Pharmacology of estrogens and progestogens: influence of different routes of administration . Climacteric . 8 Suppl 1 . 3–63 . 2005 . 16112947 . 10.1080/13697130500148875 . 24616324 .
  35. MSc . Valle Alvarez . Doris del Cisne . 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 . Effect of a Dose of 50 mg of Norethisterone Enanthate and 5 mg of Estradiol Valerate on Total Testosterone Levels in Healthy Mexican Men . 11 May 2011 . National Polytechnic Institute of Mexico .
  36. Benagiano. G.. Primiero. F.M.. Long Acting Contraceptives Present Status. Drugs. 25. 6. 1983. 570–609. 0012-6667. 10.2165/00003495-198325060-00003. 6223801. 45898359.
  37. 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
  38. Book: Hispano americano. May 1969. Tiempo. 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.. 46.
  39. 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
  40. Book: Universidad Complutense de Madrid. Revista de la Universidad de Madrid. 1971. Prensa de la Universidad de Madrid.. 11.
  41. 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
  42. Book: Harry W. Rudel . Fred A. Kinel . Oral Contraceptives. Human Fertility Studies and Side Effects . 385–469 . M. Tausk . Pharmacology of the Endocrine System and Related Drugs: Progesterone, Progestational Drugs and Antifertility Agents . II . September 1972 . Pergamon Press . 978-0080168128 . 278011135.
  43. Book: J. Bringer. B. Hedon. Fertility and Sterility: A Current Overview. 15 September 1995. CRC Press. 978-1-85070-694-6. 47–.
  44. d'Arcangues C . Once-a-month injectable contraceptives . World Health Forum . 14 . 4 . 439–40 . 1993 . 8185807 .
  45. FDA Approves Combined Monthly Injectable Contraceptive . Contraception Report . 2001 . 12 . 3 . dead . https://web.archive.org/web/20060926040811/http://www.contraceptiononline.org/contrareport/article01.cfm?art=176 . September 26, 2006 .
  46. Web site: International Drug Names from . Drugs.com . 2022-04-30.
  47. Book: Sweetman, Sean C. . Sex hormones and their modulators . Martindale: The Complete Drug Reference . 36th . 2009 . 2082 . Pharmaceutical Press . London. 978-0-85369-840-1.
  48. Web site: Micromedex Products: Please Login.
  49. Book: Pramilla Senanayake. Malcolm Potts. Atlas of Contraception, Second Edition. 14 April 2008. CRC Press. 978-0-203-34732-4. 50–.
  50. Book: IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. World Health Organization. International Agency for Research on Cancer. Combined Estrogen-progestogen Contraceptives and Combined Estrogen-progestogen Menopausal Therapy. 2007. World Health Organization. 978-92-832-1291-1. 431–.
  51. Koetsawang S . Once-a-month injectable contraceptives: efficacy and reasons for discontinuation . Contraception . 49 . 4 . 387–98 . April 1994 . 8013221 . 10.1016/0010-7824(94)90034-5 .
  52. Book: Unlisted Drugs Pharm AID. 1993. Unlisted Drugs. 978-0-913210-14-7. 247.
  53. Book: Mokhtar K. Toppozada . Monthly Injectable Contraceptives . 93–103 . Alfredo Goldsmith . Mokhtar Toppozada . Long-Acting Contraception . 1983 . 35018604 .
  54. Toppozada M . The clinical use of monthly injectable contraceptive preparations . Obstet Gynecol Surv . 32 . 6 . 335–47 . June 1977 . 865726 . 10.1097/00006254-197706000-00001 .
  55. de Souza . J. C. . Coutinho . Elsimar M. . Control of fertility by monthly injections of a mixture of norgestrel and a long-acting estrogen . Contraception . 5 . 5 . 1972 . 395–399 . 0010-7824 . 4650657 . 10.1016/0010-7824(72)90031-5 .
  56. Garza-Flores J, Fatinikun T, Hernandez L, Ramos I, Cardenas M, Menjivar M . A pilot study on the assessment of a progesterone/estradiol sustained release as once-a-month-injectable contraceptive . Contraception . 44 . 1 . 45–59 . July 1991 . 1893701 . 10.1016/0010-7824(91)90105-O.
  57. Garza-Flores J, Hall PE, Perez-Palacios G . Long-acting hormonal contraceptives for women . J. Steroid Biochem. Mol. Biol. . 40 . 4–6 . 697–704 . 1991 . 1958567 . 10.1016/0960-0760(91)90293-E. 26021562 .
  58. Book: Joseph William Goldzieher. Kenneth Fotherby. Pharmacology of the contraceptive steroids. 1994. Raven Press. 978-0-7817-0097-9. 154.
  59. Zañartu J, Rice-Wray E, Goldzieher JW . Fertility control with long-acting injectable steroids. A preliminary report . Obstet Gynecol . 28 . 4 . 513–5 . October 1966 . 5925038 .
  60. Book: Harry Beckman. The Year Book of Drug Therapy. 1967. Year Book Publishers.

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