Estradiol valerate

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Estradiol valerate
Estradiol valerate.svg
Clinical data
Pronunciation /ˌɛstrəˈdaɪoʊl ˈvæləreɪt/
ES-trə-DY-ohl VAL-ə-rayt[2]
Trade names Delestrogen, Progynon Depot, Progynova, many others
Synonyms EV; E2V; Oestradiol valerate; Estradiol pentanoate; Estradiol valerianate
Routes of
administration		 By mouth, intramuscular injection,[1] subcutaneous injection
Drug class Estrogen; Estrogen ester
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability Oral: 3–5%[3][4]
IM: 100%[3]
Metabolism Cleavage via esterases in the liver, blood, and tissues[3]
Metabolites Estradiol, valeric acid, and metabolites of estradiol[3]
Elimination half-life Oral: 12–20 hours (as E2)[3][5]
IM: 4–5 days[3]
Duration of action IM (5 mg): 7–8 days[6]
IM (10–30 mg): 1–4 weeks[7]
Excretion Urine (80%)[3]
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.012.327 Edit this at Wikidata
Chemical and physical data
Formula C23H32O3
Molar mass 356.498 g/mol
3D model (JSmol)

Estradiol valerate, sold under the brand names Delestrogen, Progynon Depot, and Progynova among others, is an estrogen medication which is used in hormone therapy for menopausal symptoms and low estrogen levels in women, in hormone therapy for transgender women, and in hormonal birth control for women.[4][3][7][8] It is also used in the treatment of prostate cancer in men.[7] The medication is taken by mouth or by injection into muscle once every 1 to 4 weeks.[7][8]

Side effects of estradiol valerate include breast tenderness, breast enlargement, nausea, headache, and fluid retention.[9][7][8] Estradiol valerate is a synthetic estrogen and hence is an agonist of the estrogen receptor (ER), the biological target of estrogens like estradiol.[4][3][10] It is an estrogen ester and a prodrug of estradiol in the body.[10][4][3] Because of this, it is considered to be a natural and bioidentical form of estrogen.[10][3]

Estradiol valerate was first described in 1940 and was introduced for medical use in 1954.[11][12][13] Along with estradiol cypionate, it is one of the most widely used esters of estradiol.[14] Estradiol valerate is used in the United States, Canada, Europe, and throughout much of the rest of the world.[15][16] It is available as a generic medication.[17]

Medical uses[edit]

Main article: Estradiol (medication) § Medical uses

The medical uses of estradiol valerate are the same as those of estradiol and other estrogens. Examples of indications for the medication include hormone therapy and hormonal contraception. In regard to the latter, estradiol valerate is available in combination with a progestin as an combined estradiol-containing oral contraceptive (with dienogest)[18] and as a combined injectable contraceptive.[19][20][21] Along with estradiol cypionate, estradiol undecylate, and estradiol benzoate, estradiol valerate is used as a form of high-dose estrogen therapy in feminizing hormone therapy for transgender women.[22][23][24][25] It is also used as a form of high-dose estrogen therapy in the treatment of prostate cancer in men.[7]

In the United States, the approved indications of estradiol valerate injections include the treatment of moderate to severe hot flashes and vaginal atrophy associated with menopause in women, the treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian failure in women, and the palliative treatment of advanced prostate cancer in men.[7] Elsewhere in the world, oral estradiol valerate is similarly approved for the treatment of symptoms associated with menopause or hypoestrogenism due to castration in women.[8] Such symptoms may include hot flashes, outbreaks of sweat, sleep disturbances, depressive moods, irritability, headaches, and dizziness.[8]

Estradiol valerate by intramuscular injection is usually used at a dosage of 10 to 20 mg every 4 weeks in the treatment of menopausal symptoms and hypoestrogenism due to hypogonadism, castration, or primary ovarian failure in women.[7] It is usually used in the treatment of advanced prostate cancer in men at a dosage of 30 mg or more every 1 to 2 weeks by intramuscular injection.[7] In transgender women, estradiol valerate given by intramuscular injection is usually used at a dosage of 5 to 20 mg, but up to 30 to 40 mg, once every 2 weeks.[23][24][22]

Available forms[edit]

See also: Estradiol valerate/norethisterone enanthate and Estradiol valerate/hydroxyprogesterone caproate

Estradiol valerate is and has been available in the form of vials and ampoules for intramuscular injection in concentrations of 5, 10, 20, and 40 mg/mL and in the form of oral tablets at doses of 0.5, 1, 2, and 4 mg per tablet.[26][11][27][28] In the United States, it is specifically available in formulations of 10, 20, and 40 mg/mL (as Delestrogen, as well as generics).[26] Aside from estradiol valerate, the only other injectable estrogen formulations that remain available in the United States are estradiol cypionate (5 mg/mL in oil) and conjugated estrogens (25 mg/vial in solution).[26]

In addition to single-drug formulations, oral estradiol valerate is available in combination with the progestin dienogest as a combined oral contraceptive and intramuscular estradiol valerate is marketed in combination with the progestins hydroxyprogesterone caproate and norethisterone enanthate as combined injectable contraceptives.[26][18][19][20][21][2] Intramuscular estradiol valerate has also been marketed in combination with testosterone enanthate, but this formulation has been discontinued.[26] The availability of estradiol valerate-containing products varies throughout the world.[2]

Side effects[edit]

Main article: Estradiol (medication) § Side effects

The side effects of estradiol valerate are the same as those of estradiol. Examples of such side effects include breast tenderness and enlargement, nausea, bloating, edema, headache, and melasma.[9][29] High-dose estrogen therapy with estradiol cypionate injections may also cause an increased risk of thromboembolism, changes in blood lipid profile, increased insulin resistance, and increased levels of prolactin.[29]

Pharmacology[edit]

See also: Pharmacology of estradiol

Pharmacodynamics[edit]

Estradiol valerate is an estradiol ester, or a prodrug of estradiol.[10][4] As such, it is an estrogen, or an agonist of the estrogen receptors.[4][10] The affinity of estradiol valerate for the estrogen receptor is approximately 50 times lower than that of estradiol.[3] In addition, estradiol valerate is rapidly cleaved into estradiol and is unable to reach target tissues in concentrations of significance, if at all.[3] As such, estradiol valerate is essentially inactive in terms of estrogenic effect itself, acting solely as a prodrug to estradiol.[3] Aside from dosage adjustment to account for the difference in molecular weight, oral estradiol valerate is considered to be equivalent to oral micronized estradiol.[3] Because estradiol valerate is a prodrug of estradiol, it is considered to be a natural and bioidentical form of estrogen.[10]

Pharmacokinetics[edit]

Regardless of the route of administration, estradiol valerate behaves as a prodrug of estradiol via cleavage by esterases into estradiol and the natural fatty acid valeric acid.[4][10][3][4][30] This cleavage occurs not only in the liver, but also in the blood and in tissues, and the hydrolysis of estradiol valerate into estradiol and valeric acid is complete regardless of whether the drug is administered orally or parenterally.[3] High levels of circulating estradiol are found after an intravenous injection of estradiol valerate, and this indicates very rapid cleavage of the drug upon entering circulation.[3] In contrast to estradiol, which can distribute into and exert its effects in target tissues, valeric acid is quickly metabolized via beta oxidation (see also fatty acid metabolism).[3]

Oral administration[edit]

The esterification of the C17β position of estradiol as in estradiol valerate prevents the metabolism of estradiol valerate by 17β-hydroxysteroid dehydrogenase (17β-HSD).[4] As approximately 80% of estradiol is metabolized into estrone (and estrone sulfate) by 17β-HSD during first-pass metabolism, this improves the metabolic stability and hence bioavailability of estradiol valerate.[10] However, estradiol valerate is hydrolyzed into estradiol and valeric acid in the intestines, and hence, is still subject to extensive (albeit comparatively reduced) first-pass metabolism.[4] As such, the oral bioavailability of estradiol valerate is only around 3 to 5%, and is similar to that of micronized estradiol (which has similarly improved bioavailability relative to (non-micronized) oral estradiol).[3][4][31] Due to its nature as a rapidly converted prodrug of estradiol, the pharmacokinetics of estradiol valerate are similar to those of micronized estradiol.[3][4] Moreover, the pharmacodynamics and potency (after differences in molecular weight are taken into account) of oral estradiol valerate are considered to be equivalent to those of micronized estradiol.[3] This is also notably true for effects on hepatic protein synthesis (e.g., of SHBG), again after differences in molecular weight between the two drugs are considered.[3]

A dosage of 1 mg/day oral estradiol valerate has been found to produce approximate circulating concentrations of 50 pg/mL estradiol and 160 pg/mL estrone, while a dosage of 2 mg/day results in circulating levels of 60 pg/mL estradiol and 300 pg/mL estrone.[32] These concentrations of estradiol and estrone are comparable to those observed with 1 and 2 mg/day oral micronized estradiol.[32] A review of selected studies reported a range of mean peak estradiol levels of 24 to 140 pg/mL occurring 1 to 12 hours after administration of 2 mg oral estradiol valerate.[3] A study of high-dose oral estradiol valerate found levels of about 250 pg/mL after a single 10-mg dose in women.[31] This study found nearly equal concentration–time curves for 10 mg oral estradiol valerate and 10 mg oral micronized estradiol, indicating that there are no major differences between the potencies of the two forms of oral estradiol.[31] However, one study found that, in accordance with their differences in molecular weights, oral micronized estradiol produced higher levels of estradiol than oral estradiol valerate.[33]

Intramuscular injection[edit]

Estradiol levels following single intramuscular injections of 5 mg of different estradiol esters in oil in women.[6] The dashed line at 0.5 days marks when the injections were given.[6]
Idealized curves of estradiol levels over a period of 30 days after injection of different estradiol esters in women.[34] Four data points were used to generate the curves (day 0, peak day, a third day, and day 30).[34] The measurements from which the points were drawn were taken at 24-hour intervals.[34] The estradiol esters were given mostly as combined injectable contraceptives together with a progestin.[34]

In contrast to oral administration, the bioavailability of estradiol valerate has been found to be complete (i.e., 100%) via intramuscular injection.[3][4] Due to the far greater bioavailability of intramuscular estradiol valerate relative to oral, the former is substantially stronger (in terms of potency) than the latter.[3] As an example, a single 4 mg intramuscular injection is said to be approximately equivalent to 2 mg/day of the drug administered orally over the course of 3 weeks.[3] Estradiol valerate, when given intramuscularly in oil, has a relatively long duration due to the formation of an intramuscular depot from which the drug is slowly released and absorbed.[3][35] Upon intramuscular injection of estradiol valerate 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.[4] In addition, a secondary depot may also be formed in adipose tissue.[4] The slow release of estradiol valerate is caused by the increased lipophilicity of the drug, which in turn is due to its long fatty acid valeric acid ester moiety.[3] The terminal half-life of intramuscularly administered estradiol valerate in oil is reported to be 4 to 5 days.[3]

A single intramuscular injection of 4 mg estradiol valerate has been found to result in maximal circulating levels of estradiol of about 390 pg/mL within 3 days of administration, with levels declining to 100 pg/mL (baseline, in the study) by 12 to 13 days.[36] Another study found that a single intramuscular injection of 5 mg estradiol valerate resulted in peak circulating levels of 667 pg/mL estradiol and 324 pg/mL estrone within approximately 2 and 3 days, respectively (see right/above table).[6] The duration of estradiol valerate at this dose and in this study was considered to be 7 to 8 days.[6] Other studies have found that larger doses of intramuscular estradiol valerate exceeding 20 mg have a duration of more than 15 days.[6] A third study, in contrast to the preceding study, found that a single 10 mg intramuscular injection of estradiol valerate resulted in maximal estradiol levels of 506 to 544 pg/mL and maximal estrone levels of 205 to 219 pg/mL in postmenopausal women.[37]

A study of high-dose combined intramuscular administration of 40 mg estradiol valerate and 250 mg hydroxyprogesterone caproate per week for 6 months (described as a "pseudopregnancy" regimen) in hypogonadal women found that circulating levels of estradiol increased from 27.8–34.8 pg/mL to 3028–3226 pg/mL after three months and to 2491–2552 pg/mL after 6 months of treatment.[38]

Comparison of estradiol esters (5 mg intramuscular)[6]
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

Chemistry[edit]

See also: Estrogen ester and List of estrogen esters
Estradiol plus the fatty acid valeric acid (valerate) equals estradiol valerate, a C17β ester of estradiol.[31]

Estradiol valerate is a synthetic estrane steroid and the C17β valerate (pentanoate) fatty acid ester of estradiol.[15][16] It is also known as estradiol 17β-valerate or as estra-1,3,5(10)-triene-3,17β-diol 17β-pentanoate.[15][16] Other common esters of estradiol in use include estradiol cypionate, estradiol enanthate, and estradiol acetate, the former two of which are C17β esters of estradiol similarly to estradiol valerate and the latter of which is the C3 acetate ester of estradiol.[15][16]

History[edit]

Estradiol valerate was patented by Ciba in 1940 and 1941, with a priority date of 1936.[11][39] It was first introduced for medical use by Squibb in 1954 under the brand name Delestrogen in the United States.[12][13] Subsequently, estradiol valerate was marketed widely in Europe as Progynon Depot and Progynova.[16][12] Along with estradiol benzoate (1936)[40][41] and estradiol cypionate (1952),[42] estradiol valerate has become one of the most widely used esters of estradiol.[14]

Society and culture[edit]

Generic names[edit]

Estradiol valerate is the generic name of the drug and its INN, USAN, BANM, and JAN, while oestradiol valerate was formerly its BANM.[15][16][43]

Brand names[edit]

Estradiol valerate is or has been marketed under the brand names Altadiol, Deladiol, Delestrogen, Estraval, Progynon Depot, Progynova, and Valergen, among many others.[15][16][43]

Availability[edit]

See also: List of estrogens available in the United States

Oral estradiol valerate is used primarily in Europe, under the brand name Progynova.[44] Although oral estradiol valerate was previously available in the United States,[16] it is no longer available in this country except in combination with dienogest as a combined oral contraceptive (under the brand name Natazia).[26] Estradiol valerate by intramuscular injection is available under the brand name Delestrogen in the United States and Canada and under the brand name Progynon Depot in Europe and elsewhere in the world.[26][16]

See also[edit]

References[edit]

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Further reading[edit]

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