Combined injectable birth control

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Combined injectable birth control
Background
TypeHormonal
First useBy 1969
Failure rates (first year)
Perfect use0–0.2%[1]
Typical use?
Usage
Duration effect1 month
User reminders?
Advantages and disadvantages
STI protectionNo
BenefitsEspecially 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.[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]

Medical uses[edit]

CICs are administered by intramuscular injection into the deltoid, gluteus maximus, or anterior 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 by transgender women as a means of feminizing hormone therapy as well.[12]

Available forms[edit]

A variety of different CICs, generally containing a short-acting natural estradiol ester and a long-acting progestin ester, are available for clinical use.[13][14][2][15][16] 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.[14][2][15][16] Estradiol benzoate has a duration that is too short for once-monthly CICs, and is not used in them.[17] Conversely, estradiol enantate is said to have a duration that is too long for once-monthly CICs, but is nonetheless used in them.[17]

Combined injectable contraceptives marketed for clinical use

Composition Dose Vehicle Brand Names Availability
• Estradiol valerate /
• Norethisterone enantate
5 mg EV
50 mg NETE
Oil solution 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, including Argentina, the Bahamas, Barbados, Bolivia, Brazil, Chile, Colombia, Costa Rica, the Dominican Republic, Ecuador, Egypt, El Salvador, Ghana, Grenada, Guatemala, Guyana, Haiti, Honduras, Jamaica, Kenya, Mexico, Nicaragua, Panama, Paraguay, Peru, St. Lucia, Turkey, Uruguay, Venezuela, and Zimbabwe
• Estradiol cypionate /
• Medroxyprogesterone acetate
5 mg EC
25 mg MPA
Aqueous suspension with defined particle size range Ciclofem, Ciclofemina, Cyclofem, Cyclofemina, Cyclogeston, Femelin, Femydrol, Gestin, Harmonis, Lunella, Lunelle, Novafem Approved in at least 18 countries, including Bolivia, Brazil, Chile, China, Colombia, Costa Rica, El Salvador, Guatemala, Hong Kong, Indonesia, Malaysia, Mexico, Panama, Peru, Puerto Rico, Thailand, the United States, and Zimbabwe
• Estradiol enantate /
• Algestone acetophenide
a
10 mg E2-EN
150 mg DHPA
Oil solution Acefil, Agurin, Atrimon, Ciclomes, Ciclovar, Ciclovular, Cicnor, Clinomin, Cycloven, Daiva, Damix, Deladroxate§, Deprans, Deproxone, Exuna, Ginestest, Ginoplan, 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, Progestrol, Protegin, Proter, Seguralmes, Synovular, Topasel, Unigalen, Uno-Ciclo, Vagital Approved in at least 19 countries, including Argentina, Belize, Brazil, Chile, Colombia, Costa Rica, the Dominican Republic, Ecuador, El Salvador, Guatemala, Honduras, Hong Kong, Mexico, Nicaragua, Panama, Paraguay, Peru, Portugal, and Spain
5 mg E2-EN
75 mg DHPA
Oil solution Anafertin, Patector NF, Yectames Approved at least 9 countries, including Costa Rica, the Dominican Republic, El Salvador, Guatemala, Honduras, Mexico, Nicaragua, Panama, and Spain
10 mg E2-EN
120 mg DHPA
Oil solution Unalmes, Yectuna Approved in at least 3 countries, including Brazil, Chile, and Paraguay
10 mg E2-EN
75 mg DHPA
Oil solution Ova Repos Discontinued (firm was in Spain)
• Estradiol benzoate butyrate /
• Algestone acetophenide
10 mg EBB
150 mg DHPA
Oil solution? Redimen, Soluna, Unijab, Unimens§ Approved in Peru and Singapore
• Estradiol valerate /
• Hydroxyprogesterone caproate
5 mg EV
250 mg OHPC
Oil solution Chinese Injectable No. 1 Approved in China
• Estradiol /
• Megestrol acetate
3.5 mg E2
25 mg MGA
Aqueous suspension with defined particle size range Chinese Injectable No. 2, Mego-E Approved in China
• Estradiol cypionate /
• Hydroxyprogesterone caproate
5 mg EC
250 mg OHPC
Oil solution? Sinbios Discontinued (firm was in Mexico)
• Estradiol valerate /
• Estradiol benzoate /
• Hydroxyprogesterone caproate
10 mg EV
1 mg EB
250 mg OHPC
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 E2-EN/DHPA): Evitas and Femineo. Sources: See template.

Side effects[edit]

Side effects of CICs, besides menstrual bleeding changes, are minimal.[18] The most prominent side effects of CICs are menstrual irregularities during the first 3 to 6 months of use.[1] Dysmenorrhea has been reported in 30 to 65% of women.[18] Other side effects include breast tenderness/pain, headache, and libido changes.[18] Some fluid retention can occur, but weight gain is minimal.[18] Local injection site reactions have also been reported in 15 to 35% of women.[18]

Effects of CICs on coagulation and fibrinolysis are minimal and are not thought to be clinically relevant.[19] Conversely, combined oral contraceptive pills containing ethinylestradiol have considerable effects on coagulation and fibrinolysis.[19] 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.[20][21]

Pharmacology[edit]

Idealized curves of estradiol levels over a period of 30 days after injection of different estradiol esters in women.[15]

CICs contain an estrogen and a progestin. The estrogen is generally a short-acting estradiol ester, which acts as a prodrug of estradiol.[13] 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.[22][23][24] The progestin is a long-acting progestogen ester, which may or may not act as a prodrug.[13] 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.[13] However, is estimated that about 20% of an administered dose does still eventually pass through the liver.[13] Hence, these preparations are not completely liver-neutral.[13] Nonetheless, they have dramatically reduced hepatic effects relative to oral ethinylestradiol.[20] In addition, parenteral estradiol in general has about 4- or 5-fold reduced potency in the liver than oral estradiol.[20]

Parenteral potencies and durations of steroidal estrogens

Estrogen Form Major brand name(s) EPD (14 days) CIC-D (month) Duration
Estradiol Oil solution 40–60 mg 1–10 mg ≈ 1–2 days
Aqueous suspensiona Mego-E ? 3.5 mg 3.5 mg ≈ >5 days
Microspheres Juvenum-E, Juvenum ? 1 mg ≈ 30 days
Estradiol benzoate Oil solution Progynon-B 25–35 mg 5 mg ≈ 3–6 days
Aqueous suspension Agofollin-Depot 20 mg 10 mg ≈ 16–21 days
Estradiol dipropionate Oil solution Agofollin, Di-Ovocyclin, Progynon DP 25–30 mg 5 mg ≈ 5–8 days
Estradiol valerate Oil solution Delestrogen, Progynon Depot, Mesigyna 20–30 mg 5 mg 5 mg ≈ 7–8 days; 10 mg ≈ 10–14 days;
40 mg ≈ 14–21 days; 100 mg ≈ 21–28 days
Estradiol cypionate Oil solution Depo-Estradiol, Depofemin 20–30 mg 5 mg ≈ 11–14 days
Aqueous suspensiona Cyclofem, Lunelle ? 5 mg 5 mg ≈ 14–24 days
Estradiol benzoate butyratea Oil solution Redimen, Soluna, Unijab ? 10 mg 10 mg ≈ 21 days
Estradiol enanthatea Oil solution Perlutal, Topasel, Yectames ? 5–10 mg 10 mg ≈ 20–30 days
Estradiol undecylate Oil solution Delestrec, Progynon Depot 100 ? 10–20 mg ≈ 40–60 days; 25–50 mg ≈ 60–120 days
Polyestradiol phosphate Aqueous solution Estradurin 40–60 mg 40–50 mg ≈ 30 days; 320 mg = >84 daysb
Estrone Oil solution Kestrin, Theelin ? 1–2 mg ≈ 2–3 days
Aqueous suspension Estrone Aqueous Suspension ? ?
Estriol Oil solution ? 1–2 mg ≈ 1–4 days
Polyestriol phosphate Aqueous solution Gynäsan, Klimadurin, Triodurin ? 50 mg ≈ 30 days; 80 mg ≈ 60 days
Notes: All by intramuscular injection. The vaginal epithelium maturation dosage of estradiol benzoate or estradiol valerate is 5 to 7 mg/week. An effective ovulation-inhibiting dose of estradiol undecylate is 20–30 mg/month. Estradiol production during the menstrual cycle is 30–640 µg/day (6.4–8.6 mg total per month or cycle). Footnotes: a = Available only in combined injectable contraceptives (i.e., not available alone). b = The elimination half-life of polyestradiol phosphate after a single injection of 320 mg is 70 days. Sources: See template.

Parenteral potencies and durations of progestogens

Progestogen Form Major brand names Class TFD
(14 days)
POIC-D
(2–3 months)
CIC-D
(month)
Duration
Algestone acetophenide Oil solution Perlutal, Topasel, Yectames Pregnane ? 75–150 mg 100 mg ≈ 14–32 days
Cyproterone acetate Oil solution Androcur Depot Pregnane ? 300 mg ≈ 20 days
Dydrogesteronea Aqueous suspension Retropregnane ? 100 mg ≈ 16–38 days
Gestonorone caproate Oil solution Depostat, Primostat Norpregnane 50 mg 25–50 mg ≈ 8–13 days
Hydroxyprogesterone acetatea Aqueous suspension Pregnane 350 mg 150–350 mg ≈ 9–16 days
Hydroxyprogesterone caproate Oil solution Delalutin, Proluton, Makena Pregnane 250–500 mgb 250–500 mg 65–500 mg ≈ 5–21 days
Levonorgestrel butanoatea Aqueous suspension Gonane ? 5–50 mg ≈ 3–6 months
Lynestrenol phenylpropionatea Oil solution Estrane ? 50–100 mg ≈ 14–30 days
Medroxyprogesterone acetate Aqueous suspension Depo-Provera Pregnane 50–100 mg 150 mg 25 mg 50–150 mg ≈ 14–50+ days
Megestrol acetate Aqueous suspension Mego-E Pregnane ? 25 mg 25 mg ≈ >14 daysc
Norethisterone enanthate Oil solution Noristerat, Mesigyna Estrane 100–200 mg 200 mg 50 mg 50–200 mg ≈ 11–52 days
Oxogestone phenylpropionatea Oil solution Norpregnane ? 100 mg ≈ 19–20 days
Progesterone Oil solution Progestaject, Gestone, Strone Pregnane 200 mgb 25–350 mg ≈ 2–6 days
Aqueous suspension Agolutin Depot Pregnane 50–200 mg 50–300 mg ≈ 7–14 days
Note: All by intramuscular or subcutaneous injection. All are synthetic except for P4, which is bioidentical. P4 production during the luteal phase is ~25 (15–50) mg/day. The OID of OHPC is 250 to 500 mg/month. Footnotes: a = Never marketed by this route. b = In divided doses (2 × 125 or 250 mg for OHPC, 10 × 20 mg for P4). c = Half-life is ~14 days. Sources: Main: See template.

History[edit]

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.[18][17] In 1967, E2-EN/DHPA was in the late stages of clinical development.[25][18] By 1969, the medication was available for medical use under the brand name Perlutal.[26] Within a few years, it was marketed under other brand names such as Topasel and Ova-Repos as well.[27][28][29][30] In addition, several other CICs had been introduced for medical use by 1972.[30] 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.[31] These CICs have been described as first-generation CICs.[31] 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.[32][33][14] On 5 October 2000, Pharmacia received FDA approval for Lunelle Monthly Contraceptive Injection.[1] In April 2003, Pharmacia was acquired by Pfizer (makers of depot medroxyprogesterone acetate).[citation needed] In October 2003, Lunelle was discontinued in the United States.[citation needed]

Society and culture[edit]

Availability[edit]

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 and South America, in Mexico and the Caribbean, in China, in several Southeast Asian and African countries, and in Turkey.[34][35][36][16][2][33][14][15][37] They were also previously available in the United States, Portugal, and Spain, but have been discontinued in these countries.[35][36]

Research[edit]

Many other CICs have been studied but have not been approved or marketed for clinical use.[14][15][38][17][39][2]

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.[40]

The following are CICs that have never been marketed:

See also[edit]

References[edit]

  1. ^ a b c d e "FDA Approves Combined Monthly Injectable Contraceptive". Contraception Report. 12 (3). 2001. Archived from the original on September 26, 2006.
  2. ^ a b c d e f Bagade O, Pawar V, Patel R, Patel B, Awasarkar V, Diwate S (2014). "Increasing use of long-acting reversible contraception: safe, reliable, and cost-effective birth control" (PDF). World J Pharm Pharm Sci. 3 (10): 364–392. ISSN 2278-4357.
  3. ^ Tamara Callahan MD , Aaron Caughey MD , Blueprints Obstetrics and Gynecology, 2013
  4. ^ KD Tripathi , Essentials of Medical Pharmacology, 2013
  5. ^ Dc Dutta's Textbook of Obstetrics, 2014
  6. ^ 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
  7. ^ 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.
  8. ^ 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.
  9. ^ 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.
  10. ^ 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.
  11. ^ 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. doi:10.1016/S0002-9378(99)70120-1. PMID 10561657.
  12. ^ Don Kulick (12 January 2009). Travesti: Sex, Gender, and Culture among Brazilian Transgendered Prostitutes. University of Chicago Press. pp. 64–66. ISBN 978-0-226-46101-4.
  13. ^ a b c d e f V. Unzeitig; Rick H.W. van Lunsen (15 February 2000). Contraceptive Choices and Realities: Proceedings of the 5th Congress of the European Society of Contraception. CRC Press. pp. 133, 136. ISBN 978-1-85070-067-8.
  14. ^ a b c d e f g h i j k l m n o p q Newton JR, D'arcangues C, Hall PE (1994). "A review of "once-a-month" combined injectable contraceptives". J Obstet Gynaecol (Lahore). 4 Suppl 1: S1–34. doi:10.3109/01443619409027641. PMID 12290848.
  15. ^ a b c d e f g h i j k l m 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.
  16. ^ a b c IARC Working Group on the Evaluation of Carcinogenic Risks to Humans; International Agency for Research on Cancer (1 January 1999). Hormonal Contraception and Post-menopausal Hormonal Therapy (PDF). IARC. p. 65. ISBN 978-92-832-1272-0.
  17. ^ a b c d e f g h i j k l Toppozada MK (April 1994). "Existing once-a-month combined injectable contraceptives". Contraception. 49 (4): 293–301. doi:10.1016/0010-7824(94)90029-9. PMID 8013216.
  18. ^ a b c d e f g Benagiano, G.; Primiero, F.M. (1983). "Long Acting Contraceptives Present Status". Drugs. 25 (6): 570–609. doi:10.2165/00003495-198325060-00003. ISSN 0012-6667.
  19. ^ a b "Facts about once-a-month injectable contraceptives: memorandum from a WHO meeting". Bull. World Health Organ. 71 (6): 677–89. 1993. PMC 2393537. PMID 8313486.
  20. ^ a b c Kuhl H (2005). "Pharmacology of estrogens and progestogens: influence of different routes of administration" (PDF). Climacteric. 8 Suppl 1: 3–63. doi:10.1080/13697130500148875. PMID 16112947.
  21. ^ von Schoultz, Bo; Carlström, Kjell; Collste, Lars; Eriksson, Ambjörn; Henriksson, Peter; Pousette, Åke; Stege, Reinhard (1989). "Estrogen therapy and liver function—metabolic effects of oral and parenteral administration". The Prostate. 14 (4): 389–395. doi:10.1002/pros.2990140410. ISSN 0270-4137.
  22. ^ Michael Oettel; Ekkehard Schillinger (6 December 2012). Estrogens and Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogen. Springer Science & Business Media. pp. 235–237, 261, 271. ISBN 978-3-642-60107-1. 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.
  23. ^ Nagrath Arun; Malhotra Narendra; Seth Shikha (15 December 2012). Progress in Obstetrics and Gynecology--3. Jaypee Brothers Medical Publishers Pvt. Ltd. pp. 419–. ISBN 978-93-5090-575-3.
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  25. ^ 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}}
  26. ^ Hispano americano. Tiempo. May 1969. p. 46. 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.
  27. ^ 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
  28. ^ Universidad Complutense de Madrid (1971). Revista de la Universidad de Madrid. Prensa de la Universidad de Madrid. p. 11.
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  30. ^ a b Harry W. Rudel; Fred A. Kinel (September 1972). "Oral Contraceptives. Human Fertility Studies and Side Effects". In M. Tausk (ed.). Pharmacology of the Endocrine System and Related Drugs: Progesterone, Progestational Drugs and Antifertility Agents. II. Pergamon Press. pp. 385–469. ISBN 978-0080168128. OCLC 278011135.
  31. ^ a b J. Bringer; B. Hedon (15 September 1995). Fertility and Sterility: A Current Overview. CRC Press. pp. 47–. ISBN 978-1-85070-694-6.
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  33. ^ a b Pramilla Senanayake; Malcolm Potts (14 April 2008). Atlas of Contraception, Second Edition. CRC Press. pp. 50–. ISBN 978-0-203-34732-4.
  34. ^ https://www.drugs.com/international/
  35. ^ a b Sweetman, Sean C., ed. (2009). "Sex hormones and their modulators". Martindale: The Complete Drug Reference (36th ed.). London: Pharmaceutical Press. p. 2082. ISBN 978-0-85369-840-1.
  36. ^ a b http://www.micromedexsolutions.com/micromedex2/librarian/
  37. ^ IARC Working Group on the Evaluation of Carcinogenic Risks to Humans; World Health Organization; International Agency for Research on Cancer (2007). Combined Estrogen-progestogen Contraceptives and Combined Estrogen-progestogen Menopausal Therapy. World Health Organization. pp. 431–. ISBN 978-92-832-1291-1.
  38. ^ a b Koetsawang S (April 1994). "Once-a-month injectable contraceptives: efficacy and reasons for discontinuation". Contraception. 49 (4): 387–98. doi:10.1016/0010-7824(94)90034-5. PMID 8013221.
  39. ^ a b c d e f g h i j Goldsmith, A., & Toppozada, M. (1983). Long-acting contraception. pp. 94-95 https://www.popline.org/node/423289
  40. ^ Unlisted Drugs Pharm AID. Unlisted Drugs. 1993. p. 247. ISBN 978-0-913210-14-7.
  41. ^ a b c Toppozada M (June 1977). "The clinical use of monthly injectable contraceptive preparations". Obstet Gynecol Surv. 32 (6): 335–47. doi:10.1097/00006254-197706000-00001. PMID 865726.
  42. ^ de Souza, J. C.; Coutinho, Elsimar M. (1972). "Control of fertility by monthly injections of a mixture of norgestrel and a long-acting estrogen". Contraception. 5 (5): 395–399. doi:10.1016/0010-7824(72)90031-5. ISSN 0010-7824. PMID 4650657.
  43. ^ Garza-Flores J, Fatinikun T, Hernandez L, Ramos I, Cardenas M, Menjivar M (July 1991). "A pilot study on the assessment of a progesterone/estradiol sustained release as once-a-month-injectable contraceptive". Contraception. 44 (1): 45–59. doi:10.1016/0010-7824(91)90105-O. PMID 1893701.
  44. ^ Garza-Flores J, Hall PE, Perez-Palacios G (1991). "Long-acting hormonal contraceptives for women". J. Steroid Biochem. Mol. Biol. 40 (4–6): 697–704. doi:10.1016/0960-0760(91)90293-E. PMID 1958567.

Further reading[edit]