Estradiol cypionate

Estradiol cypionate
Clinical data
Pronunciation ESS-tra-DYE-ole sip-eye-oh-nate[1]
Trade names Depo-Estradiol, Depofemin, Estradep, many others
Routes of
administration		 Intramuscular injection, subcutaneous injection[2]
ATC code G03CA03 (WHO)
Legal status
Legal status
  • ℞ (Prescription only)
Pharmacokinetic data
Bioavailability Intramuscular: 100%
Metabolism Cleavage via esterases in the liver, blood, and tissues[3]
Metabolites Estradiol, cypionic acid,[3] and metabolites of estradiol
Biological half-life Intramuscular: 8–10 days[4]
Duration of action Intramuscular (5 mg): 11 days[5] or 14–24 days[4]
Identifiers
CAS Number 313-06-4
PubChem (CID) 9403
DrugBank DBSALT000067
ChemSpider 9033
UNII 7E1DV054LO
KEGG D04063
ChEBI CHEBI:34745
ChEMBL CHEMBL1200973
Chemical and physical data
Formula C26H36O3
Molar mass 396.562 g/mol
3D model (Jmol) Interactive image

Estradiol cypionate (EC, E2C) (INN, USAN) (brand name Depo-Estradiol, many others), or estradiol cipionate, also known as estradiol 17β-cyclopentylpropionate or estradiol 17β-cyclopentanepropionate, is a synthetic, steroidal estrogen and an estrogen ester – specifically, the 17β-cypionate (cyclopentylpropionate) ester of estradiol – which is marketed in the United States, Canada, Europe, and throughout much of the rest of the world.[6][7][8][9] It acts as a prodrug of estradiol, and hence, is considered to be a natural, bioidentical form of estrogen.[10] Along with estradiol valerate, estradiol cypionate is one of the most widely used esters of estradiol.[11]

Medical uses

The medical uses of estradiol cypionate are the same as those of estradiol and other estrogens. Examples of indications for the drug include hormone replacement therapy and hormonal contraception. In regards to the latter, estradiol cypionate is available as a combined injectable contraceptive in combination with medroxyprogesterone acetate.[12][13][14] Along with estradiol valerate, estradiol undecylate, and estradiol benzoate, estradiol undecylate is or has been used as an intramuscular estrogen in hormone replacement therapy for transgender women.[15]

Side effects

The side effects of estradiol cypionate are the same as those of estradiol. Examples of such side effects include breast tenderness and enlargement, nausea, bloating, edema, headache, and melasma.[16]

Pharmacology

Estradiol cypionate and estradiol valerate are both C17β esters of estradiol. The affinity of estradiol valerate for the estrogen receptor has been reported to be 50 times less than that of estradiol,[17] and estradiol valerate and estradiol cypionate have been found to possess similar affinity for the estrogen receptor.[18] Both estradiol cypionate and estradiol valerate are rapidly cleaved into estradiol in the body,[19] and estradiol valerate has been found to be unable to reach target tissues in any concentration of significance.[17] As such, estradiol valerate is regarded as essentially inactive in terms of estrogenic effect itself, acting solely as a prodrug to estradiol,[17] and estradiol cypionate is described as a prodrug of estradiol similarly.[10]

Pharmacokinetics

Intramuscular administration

Comparison of estradiol esters (5 mg intramuscular)[5]
Estrogen Peak levels Time to peak Duration
Estradiol cypionate E2: 338 pg/mL
E1: 145 pg/mL 		E2: 3.9 days
E1: 5.1 days 		11 days
Estradiol valerate E2: 667 pg/mL
E1: 324 pg/mL 		E2: 2.2 days
E1: 2.7 days 		7–8 days
Estradiol benzoate E2: 940 pg/mL
E1: 343 pg/mL 		E2: 1.8 days
E1: 2.4 days 		4–5 days

In contrast to oral administration, which is associated with very low bioavailability (<10%), the bioavailability of both estradiol and estradiol esters like estradiol valerate has been found to be complete (i.e., 100%) via intramuscular injection.[17] In addition, estradiol esters like estradiol cypionate and estradiol valerate, when given intramuscularly in oil, have a relatively long duration due to the formation of an intramuscular depot from which they are slowly released and absorbed.[17][20] 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.[19] In addition, a secondary depot may also be formed in adipose tissue.[19] The slow release of estradiol cypionate is caused by the increased lipophilicity of the drug, which in turn is due to its long fatty acid cypionic acid ester moiety.[17] The terminal half-life of intramuscularly administered estradiol cypionate in oil (as estradiol) has been reported to be approximately 8 days.[21][22]

A single intramuscular injection of 5 mg estradiol cypionate has been found to result in peak circulating concentrations of 338 pg/mL estradiol and 145 pg/mL estrone, which occurred at about 4 and 5 days post-injection, respectively (see right table).[5] 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 4–5 days and 7–8 days, respectively.[5] This is because estradiol cypionate has a more extensive fatty acid chain and in relation to this is comparatively more lipophilic.[19] 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).[19]

Lunelle and Cyclofem are combined injectable contraceptives containing 5 mg estradiol cypionate and 25 mg medroxyprogesterone acetate for once-monthly intramuscular administration.[21][22] With these formulations, estradiol levels peak 2 to 3 days post-injection with average maximal circulating levels of about 250 pg/mL.[4][21][22] The terminal half-life of estradiol with these formulations is 8.4 to 10.1 days, and circulating estradiol levels return to baseline (~50 pg/mL) approximately 14 to 24 days post-injection.[4][21][22]

Subcutaneous administration

Estradiol cypionate in an aqueous suspension has been found to have equivalent effectiveness and almost identical pharmacokinetics via subcutaneous and 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 patient satisfaction and compliance.[2]

Chemistry

See also: Estrogen ester

Estradiol cypionate is an estrane (C18) steroid and the C17β cyclopentylpropionate (or cypionate) fatty acid ester of estradiol. It is also known as estra-1,3,5(10)-triene-3,17β-diol 17β-cyclopentylpropionate. Other common esters of estradiol in use include estradiol valerate, estradiol enanthate, and estradiol acetate, the former two of which are C17β esters of estradiol similarly to estradiol cypionate and the latter of which is the C3 acetate ester of estradiol.

History

Estradiol cypionate was first introduced in 1952 by Upjohn as Depo-Estradiol in the United States,[23][24] and along with estradiol valerate (1954)[24][25] and estradiol benzoate (1936)[26][27] has since become one of the most widely used esters of estradiol.[11]

Society and culture

Availability

Estradiol cypionate is available both in the U.S.[28] and in a few European countries like Spain and Italy, but has been used mostly in the U.S. similarly to testosterone cypionate (both drugs having been developed by the U.S. pharmaceutical company Upjohn).[7][29] In the U.S., it is available in a formulation of 5 mg/mL in oil (brand name Depo-Estradiol, as well as generics).[28] Lower dosage formulations of 1 mg/mL and 3 mg/mL were also previously marketed in the U.S. but have since been discontinued.[28] Aside from 5 mg/mL estradiol cypionate, the only other injectable formulations of estrogen available in the U.S. are estradiol valerate (10 mg/mL, 20 mg/mL, and 40 mg/mL in oil) and conjugated estrogens (Premarin) (25 mg/vial in solution).[28]

References

  1. ↑ https://www.drugs.com/cdi/estradiol-cypionate.html
  2. 1 2 3 Sierra-Ramírez JA, Lara-Ricalde R, Lujan M, Velázquez-Ramírez N, Godínez-Victoria M, Hernádez-Munguía IA, et al. (2011). "Comparative pharmacokinetics and pharmacodynamics after subcutaneous and intramuscular administration of medroxyprogesterone acetate (25 mg) and estradiol cypionate (5 mg)". Contraception. 84 (6): 565–70. doi:10.1016/j.contraception.2011.03.014. PMID 22078184.
  3. 1 2 Kuhnz, W.; Blode, H.; Zimmermann, H. (1993). "Pharmacokinetics of Exogenous Natural and Synthetic Estrogens and Antiestrogens". 135 / 2: 261–322. doi:10.1007/978-3-642-60107-1_15. ISSN 0171-2004.
  4. 1 2 3 4 Thurman A, Kimble T, Hall P, Schwartz JL, Archer DF (2013). "Medroxyprogesterone acetate and estradiol cypionate injectable suspension (Cyclofem) monthly contraceptive injection: steady-state pharmacokinetics". Contraception. 87 (6): 738–43. doi:10.1016/j.contraception.2012.11.010. PMID 23265980.
  5. 1 2 3 4 Oriowo MA, Landgren BM, Stenström B, Diczfalusy E (April 1980). "A comparison of the pharmacokinetic properties of three estradiol esters". Contraception. 21 (4): 415–24. doi:10.1016/s0010-7824(80)80018-7. PMID 7389356.
  6. ↑ A. D. Roberts (1991). Dictionary of Steroids: Chemical Data, Structures, and Bibliographies. CRC Press. p. 415. ISBN 978-0-412-27060-4. Retrieved 20 May 2012.
  7. 1 2 Index Nominum 2000: International Drug Directory. Taylor & Francis US. 2000. p. 405. ISBN 978-3-88763-075-1. Retrieved 20 May 2012.
  8. ↑ ROBINSON WW (1953). "Estradiol cyclopentylpropionate: a new, long-acting, injectable estrogen". J. Clin. Endocrinol. Metab. 13 (10): 1279–80. doi:10.1210/jcem-13-10-1279. PMID 13096552.
  9. ↑ SCHWARTZ MM, SOULE SD (1955). "Estradiol 17-beta-cyclopentylpropionate, a long-acting estrogen". Am. J. Obstet. Gynecol. 70 (1): 44–50. PMID 14388061.
  10. 1 2 Michael Oettel; Ekkehard Schillinger (6 December 2012). Estrogens and Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogen. Springer Science & Business Media. pp. 261–. ISBN 978-3-642-60107-1.
  11. 1 2 Samuel S. C. Yen (1991). Reproductive endocrinology: physiology, pathophysiology, and clinical management. Saunders. ISBN 978-0-7216-3206-3. Retrieved 20 May 2012.
  12. ↑ 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.
  13. ↑ http://www.wjpps.com/download/article/1412071798.pdf
  14. ↑ Rowlands, S (2009). "New technologies in contraception". BJOG: An International Journal of Obstetrics & Gynaecology. 116 (2): 230–239. doi:10.1111/j.1471-0528.2008.01985.x. ISSN 1470-0328.
  15. ↑ Gianna E. Israel; Donald E. Tarver; Joy Diane Shaffer (1 March 2001). Transgender Care: Recommended Guidelines, Practical Information, and Personal Accounts. Temple University Press. pp. 64–. ISBN 978-1-56639-852-7.
  16. ↑ Amit K. Ghosh (23 September 2010). Mayo Clinic Internal Medicine Board Review. OUP USA. pp. 222–. ISBN 978-0-19-975569-1.
  17. 1 2 3 4 5 6 Düsterberg B, Nishino Y (December 1982). "Pharmacokinetic and pharmacological features of oestradiol valerate". Maturitas. 4 (4): 315–24. doi:10.1016/0378-5122(82)90064-0. PMID 7169965.
  18. ↑ Dubey RK, Jackson EK, Gillespie DG, Zacharia LC, Imthurn B, Keller PJ (2000). "Clinically used estrogens differentially inhibit human aortic smooth muscle cell growth and mitogen-activated protein kinase activity". Arterioscler. Thromb. Vasc. Biol. 20 (4): 964–72. PMID 10764660.
  19. 1 2 3 4 5 Kuhl H (2005). "Pharmacology of estrogens and progestogens: influence of different routes of administration". Climacteric. 8 Suppl 1: 3–63. doi:10.1080/13697130500148875. PMID 16112947.
  20. ↑ Sriram. Medicinal Chemistry. Pearson Education India. p. 427. ISBN 978-81-317-0031-0. Retrieved 20 May 2012.
  21. 1 2 3 4 Nagrath Arun; Malhotra Narendra; Seth Shikha (15 December 2012). Progress in Obstetrics and Gynecology--3. Jaypee Brothers Medical Publishers Pvt. Ltd. pp. 416–418. ISBN 978-93-5090-575-3.
  22. 1 2 3 4 Rahimy, Mohamad H; Ryan, Kristi K; Hopkins, Nancy K (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): 209–214. doi:10.1016/S0010-7824(99)00086-4. ISSN 0010-7824.
  23. ↑ Marshall Sittig (1 January 1988). Pharmaceutical Manufacturing Encyclopedia. William Andrew. pp. 575–576. ISBN 978-0-8155-1144-1. Retrieved 20 May 2012.
  24. 1 2 William Andrew Publishing (22 October 2013). Pharmaceutical Manufacturing Encyclopedia, 3rd Edition. Elsevier. pp. 1476–1477. ISBN 978-0-8155-1856-3.
  25. ↑ Larry L. Duetsch (1969). Research and development, market power, and patent policy in ethical drugs. University of Wisconsin--Madison. p. 95.
  26. ↑ Enrique Raviña; Hugo Kubinyi (16 May 2011). The Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs. John Wiley & Sons. p. 175. ISBN 978-3-527-32669-3. Retrieved 20 May 2012.
  27. ↑ Folley SJ (December 1936). "The effect of oestrogenic hormones on lactation and on the phosphatase of the blood and milk of the lactating cow" (PDF). The Biochemical Journal. 30 (12): 2262–72. PMC 1263335Freely accessible. PMID 16746289.
  28. 1 2 3 4 "Drugs@FDA: FDA Approved Drug Products". United States Food and Drug Administration. Retrieved 12 October 2016.
  29. ↑ William Llewellyn (2011). Anabolics. Molecular Nutrition Llc. pp. 426–. ISBN 978-0-9828280-1-4.


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