Estradiol cypionate

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Estradiol cypionate
Estradiol 17 beta-cypionate.svg
Systematic (IUPAC) name
[(8R,9S,13S,14S,17S)-3-hydroxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-17-yl] 3-cyclopentylpropanoate
Clinical data
Trade names Depo-Estradiol, Depofemin, Estradep, many others
Routes of
Intramuscular, subcutaneous[1]
Legal status
Legal status
  • ℞ (Prescription only)
Pharmacokinetic data
Bioavailability Intramuscular: 100%[citation needed]
Metabolism Cleavage via esterases in the liver, blood, and tissues[2]
Metabolites Estradiol, cypionic acid,[2] and metabolites of estradiol
Biological half-life Intramuscular: 8–10 days[3]
CAS Number 313-06-4
ATC code G03CA03 (WHO)
PubChem CID 9403
DrugBank DBSALT000067
ChemSpider 9033
KEGG D04063
Chemical data
Formula C26H36O3
Molar mass 396.562 g/mol

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 semisynthetic, steroidal estrogen and an estrogen ester – specifically, the 17β-cyclopentylpropionate (or cypionic acid) ester of estradiol – which is marketed in the United States, Canada, Europe, and throughout much of the rest of the world.[4][5][6][7] It acts as a prodrug of estradiol, and hence, is considered to be natural, bioidentical estrogen.[8] Along with estradiol valerate, estradiol cypionate is one of the most widely used esters of estradiol.[9]

Medical uses[edit]

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.[10][11][12] 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.[13]

Side effects[edit]

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.[14]


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,[15] and estradiol valerate and estradiol cypionate have been found to possess similar affinity for the estrogen receptor.[16] Both estradiol cypionate and estradiol valerate are rapidly cleaved into estradiol in the body,[17] and estradiol valerate has been found to be unable to reach target tissues in any concentration of significance.[15] As such, estradiol valerate is regarded as essentially inactive in terms of estrogenic effect itself, acting solely as a prodrug to estradiol,[15] and estradiol cypionate is described as a prodrug of estradiol similarly.[8]


Intramuscular administration[edit]

Comparison of estradiol esters (5 mg intramuscular)[18]
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.[15] 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.[15][19] 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.[17] In addition, a secondary depot may also be formed in adipose tissue.[17] 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.[15] The terminal half-life of intramuscularly administered estradiol cypionate in oil (as estradiol) has been reported to be approximately 8 days.[20][21]

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).[18] 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.[18] This is because estradiol cypionate has a more extensive fatty acid chain and in relation to this is comparatively more lipophilic.[17] 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).[17]

Lunelle and Cyclofem are combined injectable contraceptives containing 5 mg estradiol cypionate and 25 mg medroxyprogesterone acetate for once-monthly intramuscular administration.[20][21] With these formulations, estradiol levels peak 2 to 3 days post-injection with average maximal circulating levels of about 250 pg/mL.[20][21][3] 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.[3].[20][21]

Subcutaneous administration[edit]

Estradiol cypionate in oil has been found to have equivalent effectiveness and almost identical pharmacokinetics via subcutaneous and intramuscular injection.[1] 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.[1]


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.


Estradiol cypionate was first introduced in 1952 by Upjohn as Depo-Estradiol in the United States,[22][23] and along with estradiol valerate (1954),[23][24] and estradiol benzoate (1936)[25][26] has since become one of the most widely used esters of estradiol.[9]

Society and culture[edit]


Intramuscular estradiol cypionate is available both in the U.S.[27] and in Europe.[5] In the U.S., it is available in a formulation of 5 mg/mL in oil (brand name Delestrogen, as well as generics).[27] Lower dosage formulations of 1 mg/mL and 3 mg/mL were also previously marketed in the U.S. but have since been discontinued.[27] 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).[27]


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