Estradiol cypionate was first described as well as introduced for medical use in 1952.[18][19] Along with estradiol valerate, it is one of the most commonly used esters of estradiol.[20] Estradiol cypionate has mostly been used in the United States, but is also marketed in a few other countries.[21][22][23] The medication is not available in Europe.[24] It is not currently available as a generic medication in the United States.[25]
Estradiol cypionate is usually used at a dosage of 1 to 5mg by intramuscular injection every 3 to 4weeks in the treatment of menopausal symptoms such as hot flashes and vaginal atrophy, at a dosage of 1.5 to 2mg by intramuscular injection once a month in the treatment of female hypoestrogenism due to hypogonadism, and at a dosage of 2 to 10mg by intramuscular injection once every 1 or 2weeks for hormone therapy in transgender women.[13][16][28][27][31] The doses used to induce puberty in girls are 0.2 to 2.5mg per month, gradually increased over a period of 4years.[30][24]
Footnotes:a = No longer used or recommended, due to health concerns. b = As a single patch applied once or twice per week (worn for 3–4 days or 7 days), depending on the formulation. Note: Dosages are not necessarily equivalent. Sources: See template.
Estradiol cypionate is and has been available as an oil solution for intramuscular injection provided in vials and ampoules at concentrations of 1, 3, and 5mg/mL (and containing 5, 10, 15, 25, or 50mg estradiol cypionate total).[25][32][33] The 1 and 3mg/mL concentrations (containing 5 and 15mg estradiol cypionate total) have been discontinued in the United States, but the 5mg/mL concentration (containing 25mg estradiol cypionate total) remains available.[25][34] Aside from estradiol cypionate, the only other injectable estrogen formulations that remain available in the United States are estradiol valerate (10mg/mL, 20mg/mL, and 40mg/mL in oil) and conjugated estrogens (25mg/vial in solution).[25]
↑ This table includes primarily products available as a single-ingredient estradiol preparation—thus excluding compounds with progestogens or other ingredients included. The table furthermore does not include compounded drugs—only commercially produced products. Availability of each product varies by country.
↑ Doses are given per unit (ex: per tablet, per mL).
↑ Other brand names may be manufactured or previously manufactured.
Estradiol cypionate is an estradiol ester, or a prodrug of estradiol.[7][6] As such, it is an estrogen, or an agonist of the estrogen receptors.[7][6] The affinity of estradiol valerate for the estrogen receptor has been reported to be 50times less than that of estradiol,[3] and estradiol valerate and estradiol cypionate have been found to possess similar affinity for the estrogen receptor.[56] Both estradiol cypionate and estradiol valerate are rapidly cleaved into estradiol in the body,[7][57] and estradiol valerate has been found to be unable to reach target tissues in any concentration of significance.[3] As such, estradiol valerate is regarded as essentially inactive in terms of estrogenic effect itself, acting solely as a prodrug to estradiol,[3] and estradiol cypionate is described as a prodrug of estradiol similarly.[6] Estradiol cypionate is of about 46% higher molecular weight than estradiol due to the presence of its C17β cypionate ester, and contains about 69% of the amount of estradiol by weight.[58][21][24] Because estradiol cypionate is a prodrug of estradiol, it is considered to be a natural and bioidentical form of estrogen.[6][17][11]
A study compared the combination of 5mg estradiol cypionate and 25mg medroxyprogesterone acetate as a combined injectable contraceptive (which has been associated with peak estradiol levels of around 300pg/mL) with an ethinylestradiol-containing combined birth control pill and found that whereas the birth control pill produced significant changes in coagulation parameters, there were no significant prothrombotic effects of the combined injectable contraceptive on levels of fibrinogen, factors VII and X, plasminogen, or the activated prothrombin time.[59] As such, it appears that similarly to depot medroxyprogesterone acetate, combined injectable contraceptives with 5mg estradiol cypionate and 25mg medroxyprogesterone acetate have less or no procoagulant effect relative to combined birth control pills.[59]
In contrast to oral administration, which is associated with very low bioavailability (<10%), the bioavailability of both estradiol and estradiol esters like estradiol valerate is complete (i.e., 100%) via intramuscular injection.[3][7] In addition, estradiol esters like estradiol cypionate and estradiol valerate when given as an injection of oil solution or microcrystallineaqueous suspension have a relatively long duration due to the formation of an intramuscular depot from which they are slowly released and absorbed.[3][60][61] Upon intramuscular injection of estradiol cypionate in an oil solution, the solvent (i.e., oil) is absorbed, and a primary microcrystalline depot is formed within the muscle at the site of injection.[7] In addition, a secondary depot may be formed in adipose tissue.[7] The slow release of estradiol cypionate from the tissue depot is caused by the high lipophilicity of the estradiol ester, which in turn is due to its long fatty acid cypionic acid ester moiety.[3] Estradiol cypionate is formulated for use alone and in combination with testosterone cypionate as an oil solution, and for use in combination with medroxyprogesterone acetate as a microcrystalline aqueous suspension.[25][32][33][34] Aqueous suspensions of steroid esters generally have longer durations by intramuscular injection than oil solutions.[61]
A single intramuscular injection of 5mg estradiol cypionate has been found to result in peak circulating concentrations of 338pg/mL estradiol and 145pg/mL estrone, which occurred at about 4 and 5days post-injection, respectively (see right table).[10] Compared to two other commonly used estradiol esters (which were also assessed in the study), estradiol cypionate had the longest duration, at approximately 11 days, whereas estradiol benzoate and estradiol valerate were found to last for 4 to 5days and 7 to 8days, respectively.[10] This is because estradiol cypionate has a more extensive fatty acid chain and in relation to this is comparatively more lipophilic.[7] For a given estradiol ester, the longer or more extensive the fatty acid chain is, the more lipophilic, longer-lasting, and more uniform/plateau-like the resultant levels of estradiol are as well as the lower the peak/maximal levels are (and hence less spike-like).[7]
Estradiol cypionate/medroxyprogesterone acetate (brand names Lunelle, Cyclofem) is a combined injectable contraceptive containing 5mg estradiol cypionate and 25mg medroxyprogesterone acetate in microcrystalline aqueous suspension for once-monthly intramuscular administration.[11][12] With this formulations, estradiol levels peak 2 to 3days post-injection with average maximal circulating levels of about 250pg/mL.[8][11][12] The elimination half-life of estradiol with these formulations is 8.4 to 10.1days, and circulating estradiol levels return to a baseline of about 50pg/mL approximately 14 to 24days post-injection.[8][11][12][9]
Hormone levels with estradiol cypionate by intramuscular injection
Estradiol levels after subcutaneous (s.c.) or intramuscular (i.m.) injection of 5 mg estradiol cypionate in aqueous suspension.[2] Assays were performed using enzyme immunoassay.[2] Source was Sierra-Ramírez et al. (2011).[2]
Estradiol levels at steady state (after the 3rd injection) with intramuscular injections of aqueous suspensions of 5mg estradiol cypionate per month in premenopausal women.[62][8] Assays were performed using enzyme immunoassay and LC-MS/MSTooltip liquid chromatography–tandem mass spectrometry.[62][8] Sources were Rahimy et al. (1999) and Thurman et al. (2013).[62][8]
Estradiol levels after a single intramuscular injection of 1.0 to 2.0 mg (average 1.67 mg) of estradiol cypionate in oil (Depo-Estradiol) in hypogonadal girls.[63][64] Assays were performed using radioimmunoassay with chromatographic separation.[63][64] Sources were Rosenfield et al. (1973, 1974).[63][64]
Estradiol levels after single intramuscular injections of 5 mg of different estradiol esters in oil in premenopausal women.[10] Assays were performed using radioimmunoassay with chromatographic separation.[10] Source was Oriowo et al. (1980).[10]
Simplified curves of estradiol levels after injection of different estradiol esters in oil solution in women.[65] Source was Garza-Flores (1994).[65]
Estradiol cypionate levels after a single injection of 5mg microcrystalline estradiol cypionate in aqueous suspension in women.[66] Assays were performed using LC-MS/MSTooltip liquid chromatography–tandem mass spectrometry. Source was Martins et al. (2019).[66]
Vaginalcornification with a single intramuscular injection of different estradiol esters in oil solution in women.[67] Source was Schwartz & Soule (1955).[67]
Subcutaneous injection
Estradiol cypionate in a microcrystallineaqueous suspension has been found to have equivalent effectiveness and virtually identical pharmacokinetics when administered by subcutaneous injection versus intramuscular injection.[2] However, subcutaneous injection is considered to be easier and less painful relative to intramuscular injection, and for these reasons, may result in comparatively greater satisfaction and compliance.[2]
Estradiol cypionate was patented by Upjohn in 1952, with a priority date of 1951.[32] It was first introduced for medical use by Upjohn in 1952 under the brand name Depo-Estradiol in the United States.[18][19][69] Subsequently, it was also marketed in other countries such as European countries and Japan.[32][19][21] The first clinical reports of estradiol cypionate were published in 1952 and thereafter.[70][71][72][73][67] It was initially known as estradiol cyclopentylpropionate (ECP), and did not become known as estradiol cypionate until over a decade later in the mid-to-late 1960s.[71][72][74] Along with estradiol valerate (1954)[19][75] and estradiol benzoate (1933),[76][77][78] estradiol cypionate has become one of the most commonly used esters of estradiol.[20]
When estradiol cypionate was to be combined with medroxyprogesterone acetate as a once-a-month injectable contraceptive, there was a problem in that estradiol cypionate was prepared as an oil solution while medroxyprogesterone acetate was used as a microcrystallineaqueous suspension.[79] This issue was resolved by switching to a microcrystalline aqueous suspension in the case of estradiol cypionate, allowing it to be combined with medroxyprogesterone acetate in a single suspension.[79] As a result, single-drug preparations of estradiol cypionate are oil solutions, while the combination of estradiol cypionate and medroxyprogesterone acetate are microcrystalline aqueous suspensions.[79]
Society and culture
Generic names
Estradiol cypionate is the generic name of the drug and its INNTooltip International Nonproprietary Name and USANTooltip United States Adopted Name.[58][21][22] It is also known as estradiol cyclopentylpropionate (ECP).[71][72]
Brand names
Estradiol cypionate has been marketed under the brand names Cicloestradiolo, D-Est, depGynogen, Depo-Estradiol, Depoestra, Depofemin, Depogen, Dura-Estrin, E-Cypionate, E-Ionate, Estradep, Estro-Cyp, Estrofem, Estroject, Estromed-PA, Estronol, Femovirin, Neoginon Depositum, Oestradiol-Retard, Pertradiol, Spendepiol, and T-E Cypionate, among others.[58][21][19][22]
Estradiol cypionate is available in the United States.[25][22][24] It was previously marketed in Spain and Italy, but was discontinued in these countries and is no longer available in Europe.[21][24] Estradiol cypionate has mostly been used in the United States, similarly to testosterone cypionate, with both of these medications having been developed by Upjohn, an American pharmaceutical company.[21][23] Besides the United States, estradiol cypionate has been marketed in France, Germany, Italy, Spain, and Japan, among other countries.[32][19][21] Estradiol cypionate for human use is not available in Canada, although it is marketed in several veterinary formulations in this country.[80]
1 2 3 4 5 6 7 8 9 Oettel M, Schillinger E (6 December 2012). Estrogens and Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogen. Springer Science & Business Media. p.261. ISBN978-3-642-60107-1. 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.
1 2 3 Smith KP, Madison CM, Milne NM (December 2014). "Gonadal suppressive and cross-sex hormone therapy for gender dysphoria in adolescents and adults". Pharmacotherapy. 34 (12): 1282–1297. doi:10.1002/phar.1487. PMID25220381. S2CID26979177.
1 2 Cirigliano M (June 2007). "Bioidentical hormone therapy: a review of the evidence". J Womens Health (Larchmt). 16 (5): 600–31. doi:10.1089/jwh.2006.0311. PMID17627398.
1 2 Wesp LM, Deutsch MB (March 2017). "Hormonal and Surgical Treatment Options for Transgender Women and Transfeminine Spectrum Persons". The Psychiatric Clinics of North America. 40 (1): 99–111. doi:10.1016/j.psc.2016.10.006. PMID28159148.
1 2 Rosenfield RL, Kiess W, de Muinck Keizer-Schrama S (2006). "Physiologic induction of puberty in Turner syndrome with very low-dose estradiol". International Congress Series. 1298: 71–79. doi:10.1016/j.ics.2006.07.003. ISSN0531-5131.
↑ American Medical Association. Dept. of Drugs; Council on Drugs (American Medical Association); American Society for Clinical Pharmacology and Therapeutics (1 February 1977). "Estrogens, Progestagens, Oral Contraceptives, and Ovulatory Agents". AMA drug evaluations. Publishing Sciences Group. pp.540–572. ISBN978-0-88416-175-2. Intramuscular: For replacement therapy, (Estradiol, Estradiol Benzoate) 0.5 to 1.5 mg two or three times weekly; (Estradiol Cypionate) 1 to 5 mg weekly for two or three weeks; (Estradiol Dipropionate) 1 to 5 mg every one to two weeks; (Estradiol Valerate) 10 to 40 mg every one to four weeks.
↑ "NNR: Products Recently Accepted by the A. M. A. Council on Pharmacy and Chemistry". Journal of the American Pharmaceutical Association (Practical Pharmacy ed.). 10 (11): 692–694. 1949. doi:10.1016/S0095-9561(16)31995-8. ISSN0095-9561.
↑ Sahin FK, Koken G, Cosar E, Arioz DT, Degirmenci B, Albayrak R, Acar M (2008). "Effect of Aerodiol administration on ocular arteries in postmenopausal women". Gynecol. Endocrinol. 24 (4): 173–7. doi:10.1080/09513590701807431. PMID18382901. 300 μg 17β-estradiol (Aerodiol®; Servier, Chambrayles-Tours, France) was administered via the nasal route by a gynecologist. This product is unavailable after March 31, 2007 because its manufacturing and marketing are being discontinued.
↑ Midwinter A (1976). "Contraindications to estrogen therapy and management of the menopausal syndrome in these cases". In Campbell S (ed.). The Management of the Menopause & Post-Menopausal Years: The Proceedings of the International Symposium held in London 24–26 November 1975 Arranged by the Institute of Obstetrics and Gynaecology, The University of London. MTP Press Limited. pp.377–382. doi:10.1007/978-94-011-6165-7_33. ISBN978-94-011-6167-1.
↑ McLiver B, Tebben PJ, Shah P (23 September 2010). "Endocrinology". In Ghosh AK (ed.). Mayo Clinic Internal Medicine Board Review. OUP USA. pp.222–. ISBN978-0-19-975569-1.
1 2 Bishop BM (December 2015). "Pharmacotherapy Considerations in the Management of Transgender Patients: A Brief Review". Pharmacotherapy. 35 (12): 1130–9. doi:10.1002/phar.1668. PMID26684553. S2CID37001563.
↑ Cheng ZN, Shu Y, Liu ZQ, Wang LS, Ou-Yang DS, Zhou HH (February 2001). "Role of cytochrome P450 in estradiol metabolism in vitro". Acta Pharmacol. Sin. 22 (2): 148–54. PMID11741520.
↑ MacLusky NJ, Larner JM, Hochberg RB (January 1989). "Actions of an estradiol-17-fatty acid ester in estrogen target tissues of the rat: comparison with other C-17 metabolites and a pharmacological C-17 ester". Endocrinology. 124 (1): 318–24. doi:10.1210/endo-124-1-318. PMID2909371.
↑ Sriram D, Yogiswari P (2007). "Steroids". Medicinal Chemistry. Pearson Education India. p.427. ISBN978-81-317-0031-0. Retrieved 20 May 2012.
1 2 Crabbé P, Archer S, Benagiano G, Diczfalusy E, Djerassi C, Fried J, Higuchi T (March 1983). "Long-acting contraceptive agents: design of the WHO Chemical Synthesis Programme". Steroids. 41 (3): 243–253. doi:10.1016/0039-128X(83)90095-8. PMID6658872. S2CID12896179.
1 2 3 Rahimy MH, Ryan KK, Hopkins NK (October 1999). "Lunelle monthly contraceptive injection (medroxyprogesterone acetate and estradiol cypionate injectable suspension): steady-state pharmacokinetics of MPA and E2 in surgically sterile women". Contraception. 60 (4): 209–14. doi:10.1016/S0010-7824(99)00086-4. PMID10640167.
1 2 3 Rosenfield RL, Fang VS, Dupon C, Kim MH, Refetoff S (October 1973). "The effects of low doses of depot estradiol and testosterone in teenagers with ovarian failure and Turner's syndrome". J. Clin. Endocrinol. Metab. 37 (4): 574–80. doi:10.1210/jcem-37-4-574. PMID4742538.
1 2 3 Rosenfield RL, Fang VS (December 1974). "The effects of prolonged physiologic estradiol therapy on the maturation of hypogonadal teen-agers". J Pediatr. 85 (6): 830–7. doi:10.1016/s0022-3476(74)80355-0. PMID4370903.
1 2 Martins RS, Antunes NJ, Comerlatti G, Caraccio G, Moreno RA, Frecentese F, Caliendo G, De Nucci G (June 2019). "Quantification of estradiol cypionate in plasma by liquid chromatography coupled with tandem mass spectrometry: Application in a pharmacokinetic study in healthy female volunteers". J Pharm Biomed Anal. 170: 273–278. doi:10.1016/j.jpba.2019.03.053. PMID30947128. S2CID96433789.
↑ Shearman AM, Vogel M, Mcgavack TH (October 1952). "Responses of the vaginal epithelium of postmenopausal women to single doses of estrogens". Journal of Gerontology. 7 (4): 549–554. doi:10.1093/geronj/7.4.549. PMID13000121.
1 2 3 Shearman AM, Mcgavack TH (July 1953). "A comparison of the influence of alpha-estradiol dipropionate and of estradiol cyclopentylpropionate on the vaginal mucosa of nonmenstruating and irregularly menstruating women". American Journal of Obstetrics and Gynecology. 66 (1): 178–181. doi:10.1016/0002-9378(53)90300-7. PMID13057994.
1 2 3 Robinson WW (October 1953). "Estradiol cyclopentylpropionate: a new, long-acting, injectable estrogen". The Journal of Clinical Endocrinology and Metabolism. 13 (10): 1279–1280. doi:10.1210/jcem-13-10-1279. PMID13096552.
↑ Buschbeck H (2009). "Neue Wege der Hormontherapie in der Gynäkologie" [New ways of hormonal therapy in gynecology]. Deutsche Medizinische Wochenschrift. 60 (11): 389–393. doi:10.1055/s-0028-1129842. ISSN0012-0472. S2CID72668930.
↑ Biskind MS (1935). "Commercial Glandular Products". Journal of the American Medical Association. 105 (9): 667. doi:10.1001/jama.1935.92760350007009a. ISSN0002-9955. Progynon-B, Schering Corporation: This is crystalline hydroxyestrin benzoate obtained by hydrogenation of theelin and subsequent conversion to the benzoate. [...] Progynon-B is marketed in ampules containing 1 cc. of a sesame oil solution of hydroxyestrin benzoate of either 2,500, 5,000, 10,000 or 50,000 international units.
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Estradiol levels after subcutaneous (s.c.) or intramuscular (i.m.) injection of 5 mg estradiol cypionate in aqueous suspension. [2] Assays were performed using enzyme immunoassay. [2] Source was Sierra-Ramírez et al. (2011). [2]
Estradiol levels at steady state (after the 3rd injection) with intramuscular injections of aqueous suspensions of 5 mg estradiol cypionate per month in premenopausal women. [62] [8] Assays were performed using enzyme immunoassay and LC-MS/MS . [62] [8] Sources were Rahimy et al. (1999) and Thurman et al. (2013). [62] [8]
Estradiol levels after a single intramuscular injection of 1.0 to 2.0 mg (average 1.67 mg) of estradiol cypionate in oil (Depo-Estradiol) in hypogonadal girls. [63] [64] Assays were performed using radioimmunoassay with chromatographic separation. [63] [64] Sources were Rosenfield et al. (1973, 1974). [63] [64]
Estradiol levels after single intramuscular injections of 5 mg of different estradiol esters in oil in premenopausal women. [10] Assays were performed using radioimmunoassay with chromatographic separation. [10] Source was Oriowo et al. (1980). [10]
Vaginal cornification with a single intramuscular injection of different estradiol esters in oil solution in women. [67] Source was Schwartz & Soule (1955). [67]
