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Estradiol valerate

Estradiol valerate
Estradiol valerate.svg
Estradiol valerate molecule ball.png
Clinical data
Pronunciation/ˌɛstrəˈdl ˈvælərt/
ES-trə-DY-ohl VAL-ə-rayt[2]
Trade namesDelestrogen, Progynon Depot, Progynova, many others
SynonymsEV; E2V; Oestradiol valerate; Estradiol pentanoate; Estradiol valerianate
Routes of
administration
By mouth, sublingual, intramuscular injection,[1] subcutaneous injection
Drug classEstrogen; Estrogen ester
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
BioavailabilityOral: 3–5%[3][4]
IM: 100%[3]
Protein bindingEstradiol: ~98% (to albumin and SHBG)[5][6]
MetabolismCleavage via esterases in the liver, blood, and tissues[3]
MetabolitesEstradiol, valeric acid, and metabolites of estradiol[3]
Elimination half-lifeOral: 12–20 hours (as E2)[3][5]
IM: 4–5 days[3]
Duration of actionIM (5 mg): 7–8 days[7]
IM (10–30 mg): 1–4 weeks[8]
ExcretionUrine (80%)[3]
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.012.327 Edit this at Wikidata
Chemical and physical data
FormulaC23H32O3
Molar mass356.498 g/mol g·mol−1
3D model (JSmol)

Estradiol valerate (EV), sold for use by mouth under the brand name Progynova and for use by injection under the brand names Delestrogen and Progynon Depot among others, is an estrogen medication. In women, it is used in hormone therapy for menopausal symptoms and low estrogen levels, hormone therapy for transgender women, and in hormonal birth control.[4][3][8][9] It is also used in the treatment of prostate cancer in men.[8] The medication is taken by mouth or by injection into muscle once every 1 to 4 weeks.[8][9]

Side effects of estradiol valerate include breast tenderness, breast enlargement, nausea, headache, and fluid retention.[10][8][9] Estradiol valerate is a synthetic estrogen and hence is an agonist of the estrogen receptor, the biological target of estrogens like estradiol.[4][3][11] It is an estrogen ester and a prodrug of estradiol in the body.[11][4][3] Because of this, it is considered to be a natural and bioidentical form of estrogen.[11][12][3][13]

Estradiol valerate was first described in 1940 and was introduced for medical use in 1954.[14][15][16] Along with estradiol cypionate, it is one of the most widely used esters of estradiol.[17] Estradiol valerate is used in the United States, Canada, Europe, and throughout much of the rest of the world.[18][19] It is available as a generic medication.[20]

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 a combined estradiol-containing oral contraceptive (with dienogest)[21] and as a combined injectable contraceptive.[22][23][24] 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.[25][26][27][28] It is also used as a form of high-dose estrogen therapy in the treatment of prostate cancer in men.[8] Low-dose oral estradiol valerate (2–6 mg/day) has been used in the treatment of breast cancer in women who were previously treated with and benefited from but acquired resistance to aromatase inhibitors as well.[29][29][30]

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.[8] 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.[9] Such symptoms may include hot flashes, outbreaks of sweat, sleep disturbances, depressive moods, irritability, headaches, and dizziness.[9]

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.[8] In the past, it was used at even higher doses of 10 to 40 every 1 to 4 weeks for estrogen replacement.[31] Estradiol valerate 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.[8] 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.[26][27][25]

Estrogen dosages for menopausal hormone therapy

Route/form Estrogen Low Standard High
Oral Estradiol 0.5–1 mg/day 1–2 mg/day 2–4 mg/day
Estradiol valerate 0.5–1 mg/day 1–2 mg/day 2–4 mg/day
Estradiol acetate 0.45–0.9 mg/day 0.9–1.8 mg/day 1.8–3.6 mg/day
Conjugated estrogens 0.3–0.45 mg/day 0.625 mg/day 0.9–1.25 mg/day
Esterified estrogens 0.3–0.45 mg/day 0.625 mg/day 0.9–1.25 mg/day
Estropipate 0.75 mg/day 1.5 mg/day 3 mg/day
Estriol 1–2 mg/day 2–4 mg/day 4–8 mg/day
Ethinylestradiola 5–10 μg/day
Nasal spray Estradiol 150 μg/day 300 μg/day 600 μg/day
Transdermal patch Estradiol 25 μg/dayb 50 μg/dayb 100 μg/dayb
Transdermal gel Estradiol 0.5 mg/day 1–1.5 mg/day 2–3 mg/day
Vaginal Estradiol 25 μg/day
Estriol 30 μg/day 0.5 mg 2x/week 0.5 mg/day
IM or SC injection Estradiol valerate 4 mg 1x/4 weeks
Estradiol cypionate 1 mg 1x/3–4 weeks 3 mg 1x/3–4 weeks 5 mg 1x/3–4 weeks
Estradiol benzoate 0.5 mg 1x/week 1 mg 1x/week 1.5 mg 1x/week
SC implant Estradiol 25 mg 1x/6 months 50 mg 1x/6 months 100 mg 1x/6 months
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.

Estrogen dosages for prostate cancer

Route/form Estrogen Dosage
Oral Estradiol 1–2 mg 3x/day
Conjugated estrogens 1.25–2.5 mg 3x/day
Ethinylestradiol 0.15–2 mg/day
Ethinylestradiol sulfonate 1–2 mg 1x/week
Diethylstilbestrol 1–3 mg/day
Dienestrol 5 mg/day
Hexestrol 5 mg/day
Fosfestrol 120–480 mg 1–3x/day
Chlorotrianisene 12–24 mg/day
Quadrosilan 900 mg/day
Estramustine phosphate 140–1400 mg/day
Transdermal patch Estradiol 2–6x 100 μg/day
Scrotal: 1x 100 μg/day
IM or SC injection Estradiol benzoate 1.66 mg 3x/week
Estradiol dipropionate 5 mg 1x/week
Estradiol valerate 10–40 mg 1x/1–2 weeks
Estradiol undecylate 100 mg 1x/4 weeks
Polyestradiol phosphate Alone: 160–320 mg 1x/4 weeks
With oral EE: 40–80 mg 1x/4 weeks
Estrone 2–4 mg 2–3x/week
IV injection Fosfestrol 300–1200 mg 1–7x/week
Estramustine phosphate 240–450 mg/day
Note: Dosages are not necessarily equivalent. Sources: See template.

Estrogen dosages for breast cancer

Route/form Estrogen Dosage
Oral Estradiol 10 mg 3x/day
AI-resistant: 2 mg 1–3x/day
Estradiol valerate AI-resistant: 2 mg 1–3x/day
Conjugated estrogens 10 mg 3x/day
Ethinylestradiol 0.5–1 mg 3x/day
Diethylstilbestrol 5 mg 3x/day
Dienestrol 5 mg 3x/day
IM or SC injection Estradiol benzoate 5 mg 2–3x/week
Estradiol dipropionate 5 mg 2–3x/week
Estradiol valerate 30 mg 1x/2 weeks
Polyestradiol phosphate 40–80 mg 1x/4 weeks
Estrone 5 mg ≥3x/week
Notes: (1) Only in women who are at least 5 years postmenopausal. (2) Dosages are not necessarily equivalent. Sources: See template.

Available forms

Estradiol valerate is and has been available in the form of vials and ampoules of oil solution for intramuscular injection in concentrations of 4, 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.[32][14][33][34] In the United States, it is specifically available in formulations of 10, 20, and 40 mg/mL in oil solution (as Delestrogen, as well as generics).[32] 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 solution) and conjugated estrogens (25 mg/vial in solution).[32] Some or all oral estradiol valerate tablets are micronized, similarly to oral estradiol tablets.[35]

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 at a concentration of 5 mg/mL in combination with the progestin hydroxyprogesterone caproate and with the progestin norethisterone enantate as combined injectable contraceptives.[32][21][22][23][24][2] Intramuscular estradiol valerate is also marketed at a concentration of 4 mg/mL in combination with the weak androgen and neurosteroid prasterone enanthate (DHEA enanthate) and with the androgen testosterone enantate for use in menopausal hormone therapy, but the latter formulation has been discontinued.[36][32] The availability of estradiol valerate-containing products varies throughout the world.[2]

Available forms of estradiol

Route Ingredient Form Dose Major brand names
Oral Estradiol Tablets 0.1, 0.2, 0.5, 1, 2, or 4 mg per tablet Estrace, Ovocyclin
Estradiol acetateb Tablets 0.45, 0.9, or 1.8 mg per tablet Femtrace
Estradiol valerate Tablets 0.5, 1, 2, or 4 mg per tablet Progynova
Intranasal Estradiolb Nasal sprays 150 µg per spray (60 sprays per bottle) Aerodiol
Transdermal Estradiol Patches 14, 25, 37.5, 50, 60, 75, or 100 µg E2 per 24 hours for 3–4 or 7 days Climara, Estraderm, Vivelle
Gel dispensers 0.06% (0.87 or 1.25 g gel or 0.52 or 0.75 mg E2 per activation) Elestrin, EstroGel
Gel packets 0.1% (0.25, 0.5, or 1.0 g gel or 2.5, 5, or 10 mg E2 per packet) DiviGel, Sandrena
Emulsions 0.14% (1.74 g emulsion or 4.35 mg E2 per pouch; delivers 50 µg E2 per day) Estrasorb
Sprays 1.53 mg per spray Evamist
Vaginal Estradiol Tablets 10 or 25 µg per tablet Vagifem
Creams 0.01% (0.1 mg E2 per 1.0 g cream) Estrace
Suppositoriesb 4 or 40 μg per suppository Ovocyclin
Inserts 4 or 10 µg per insert (replaced daily for 2 weeks and then twice weekly) Imvexxy
Rings 2 mg per ring (provides 7.5 µg E2 per 24 hours for 3 months) Estring
Estradiol acetate Rings 12.4 or 24.8 mg per ring (provide 50 or 100 µg E2 per 24 hours for 3 months) Femring
Intramuscular
injection
Estradiola Ampoules 1.0 mg/mL Juvenum E
Estradiol benzoate Vials/ampoules 0.167, 0.2, 0.333, 1, 1.67, 2, 5, 10, 20, or 25 mg/mL Progynon-B
Estradiol cypionate Vials/ampoules 1, 3, or 5 mg/mL Depo-Estradiol
Estradiol dipropionateb Vials/ampoules 0.1, 0.2, 0.5, 1, 2.5, or 5 mg/mL Di-Ovocylin, Progynon-DP
Estradiol enantate Vials/ampoules 5 or 10 mg/mL (available only in combination with a progestin) Perlutal, Topasel
Estradiol undecylateb Vials/ampoules 100 mg/mL Delestrec, Progynon Depot 100
Estradiol valerate Vials/ampoules 5, 10, 20, or 40 mg/mL Delestrogen, Progynon Depot
Polyestradiol phosphate Vials/ampoules 40 or 80 mg per vial/ampoule Estradurin
Subcutaneous Estradiolc Implants 20, 25, 50, or 100 mg per implant (usually replaced every 6 months) Estradiol Implants, Meno-Implant
Abbreviations: E2 = Estradiol. Footnotes: a = Encapsulated in microspheres. b = Discontinued. c = Mostly discontinued. Notes: (1): This table does not include combination products, for instance estradiol formulated in combination with a progestogen or androgen. (2): This table does not include compounded estradiol products; only approved pharmaceutical preparations are included. (3): The availability of pharmaceutical estradiol products differs by country (see Estradiol (medication) § Availability). (4): Some of these formulations have been marketed previously but may no longer be available. Sources: See template.

Contraindications

Contraindications of estrogens include coagulation problems, cardiovascular diseases, liver disease, and certain hormone-sensitive cancers such as breast cancer and endometrial cancer, among others.[37][38][39][40]

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.[10][41] High-dose estrogen therapy with estradiol valerate injections may also cause an increased risk of thromboembolism, changes in blood lipid profile, increased insulin resistance, and increased levels of prolactin.[41]

Overdose

Estradiol valerate has been used at very high doses of 40 to 100 mg once per week in women and men, without overt signs of acute toxicity observed.[42][43][44][45][46][47][48][49][50][51][52] Symptoms of estrogen overdosage may include nausea, vomiting, bloating, increased weight, water retention, breast tenderness, vaginal discharge, heavy legs, and leg cramps.[37] These side effects can be diminished by reducing the estrogen dosage.[37]

Interactions

Inhibitors and inducers of cytochrome P450 may influence the metabolism of estradiol and by extension circulating estradiol levels.[53]

Pharmacology

Estradiol, the active form of estradiol valerate.

Pharmacodynamics

Estradiol valerate is an estradiol ester, or a prodrug of estradiol.[11][4] As such, it is an estrogen, or an agonist of the estrogen receptors.[4][11] 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] The molecular weight of estradiol valerate is about 131% of that of estradiol due to the presence of its C17β valerate ester, and hence estradiol valerate contains about 76% of the amount of estradiol of an equal dose of estradiol.[18][19] Aside from dose adjustment to account for the difference in molecular weight, oral estradiol valerate is considered to be equivalent to oral estradiol.[3] Because estradiol valerate is a prodrug of estradiol, it is considered to be a natural and bioidentical form of estrogen.[11][12][13]

Oral potencies of estrogens

Estrogen Type Class ETD
(mg/14 days)
EPD
(mg/14 days)
EPD
(mg/day)
MSD
(mg/14 days)
MSD
(mg/day)
TSD
(mg/day)
Estradiol (micronized) Bioidentical Steroidal ? 60–80 4.3 14–28 1.0–2.0 >8
Estradiol valerate Bioidentical Steroidal 6–10 60–80 4.3 14–28 1.0–2.0 >8
Estriol Bioidentical Steroidal 20a 120–150b 10.0–10.7b 28–84 1.0–6.0 ?
Estriol succinate Bioidentical Steroidal ? 140–150b 10.0–10.7b 28–84 2.0–6.0 ?
Conjugated estrogens Natural Steroidal 5–12 60–80 4.3 8.4–17.5 0.625–1.25 7.5
Ethinylestradiol Synthetic Steroidal 0.2 1.0–2.0 0.071–0.11 0.28 0.02 0.1
Mestranol Synthetic Steroidal 0.3 1.5–3.0 0.11–0.13 0.3–0.5 0.025 ?
Quinestrol Synthetic Steroidal 0.3 2.0–4.0 0.14–0.29 ? 0.025–0.05 ?
Methylestradiol Synthetic Steroidal ? 2.0 ? ? ? ?
Diethylstilbestrol Synthetic Nonsteroidal 2.5 20–30 1.4–2.1 ? 0.5–2.0 3
Diethylstilbestrol dipropionate Synthetic Nonsteroidal ? 15–30 1.1–1.4 ? ? ?
Dienestrol Synthetic Nonsteroidal ? 30 ? ? 0.5–4.0 ?
Dienestrol diacetate Synthetic Nonsteroidal 3–5 30–60 2.9–4.3 ? ? ?
Hexestrol Synthetic Nonsteroidal ? 70–110 ? ? ? ?
Hexestrol diacetate Synthetic Nonsteroidal ? 45 ? ? ? ?
Chlorotrianisene Synthetic Nonsteroidal ? >100 ? ? ? ?
Methallenestril Synthetic Nonsteroidal ? 400 ? ? ? ?
Note: The OID of EE is 0.1 mg/day. Footnotes: a = Very variable, often higher. b = In divided doses, 3x/day; irregular and atypical proliferation. Sources: See template.

Parenteral potencies and durations of steroidal estrogens

Estrogen EPD (14 days) CIC-D (month) Duration
Estradiol 40–60 mg 10 mg ≈ 2 days
Estradiol benzoate 25–35 mg 5–10 mga 5 mg ≈ 3–6 days
Estradiol dipropionate 25–30 mg 5 mg ≈ 5–8 days
Estradiol valerate 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 20–30 mg 5 mg ≈ 11–14 days
Estradiol benzoate (aq. susp.) 20 mg 10 mg ≈ 16–21 days
Estradiol cypionate (aq. susp.) ? 5 mg 5 mg ≈ 14–24 days
Estradiol enantate ? 5–10 mg 10 mg ≈ 20–30 days
Estradiol undecylateb ? 5–10 mga 10–20 mg ≈ 40–60 days; 25–50 mg ≈ 60–120 days
Polyestradiol phosphate 40–60 mg 40–50 mg ≈ 30 days; 320 mg = >84 daysc
Estriol ? 1 mg ≈ <1 day
Polyestriol phosphate ? 50 mg ≈ 30 days; 80 mg ≈ 60 days
Estrone (aq. susp.) ? ?
Note: All are via i.m. injection of oil solution, unless noted otherwise (except for PEP and PE3P, which are used as aqueous solutions). Footnotes: a = Studied but never marketed. b = An effective OID of EU is 20–30 mg/month. c = The t1/2 of PEP after a 320-mg dose is 70 days. Sources: See template.

Pharmacokinetics

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][11][3][4][54] 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 medication 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 medication 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

Estradiol levels after a single dose of 2 mg oral estradiol or 2 mg oral estradiol valerate and with continuous administration of 2 mg/day oral estradiol or 2 mg/day oral estradiol valerate (at steady state) in postmenopausal women.[55]

Esterification of the C17β position of estradiol as in estradiol valerate reduces 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.[11] However, estradiol valerate is hydrolyzed into estradiol and valeric acid in the intestines, and hence, is still subject to extensive first-pass metabolism.[4] As such, the oral bioavailability of estradiol valerate is only around 3 to 5%, and is similar to that of oral estradiol.[3][4][56] All oral tablets in the cases of both estradiol and estradiol valerate seem to be micronized.[35] Due to its nature as a rapidly converted prodrug of estradiol, the pharmacokinetics of oral estradiol valerate are similar to those of oral 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 oral 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 compounds 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.[57] These concentrations of estradiol and estrone are comparable to those observed with 1 and 2 mg/day oral estradiol.[57] 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 found that, in accordance with their differences in molecular weights, oral estradiol produced higher levels of estradiol than oral estradiol valerate.[55] Likewise, another study found that levels of estradiol and estrone were very similar after oral administration of roughly equimolar doses of estradiol (1.5 mg) and estradiol valerate (2 mg).[58] A study of high-dose oral estradiol valerate found levels of estradiol of about 250 pg/mL after a single 10-mg dose in three women.[56]

Sublingual administration

Hormone levels with 2-mg oral micronized estradiol valerate tablets (Progynova, Schering) taken continuously 3 or 4 times per day by the sublingual route in premenopausal women.[59][60]

Estradiol valerate has been studied by sublingual administration in premenopausal women for the purpose of cycle control and ovulation suppression in egg donation and surrogacy.[59][60] It has been investigated for this indication, along with vaginal and transdermal estradiol, because oral estradiol valerate is sometimes unable to achieve adequate estradiol levels and hence proper cycle control in this situation.[59][60] Sublingual administration of estradiol valerate bypasses the first pass that occurs with the oral route and results in higher levels of estradiol and improved cycle control.[59][60] Sublingual estradiol valerate is also used in hormone therapy for transgender women.[61]

The administration of 2 mg oral micronized estradiol valerate tablets (Progynova, Schering) sublingually 3 or 4 times per day has been found to result in circulating estradiol levels of about 290 pg/mL to 460 pg/mL in premenopausal women (time of measurements not given).[59][60] Steady-state levels of estradiol were achieved within about 2 or 3 days.[59][60] Levels of progesterone, luteinizing hormone, and follicle-stimulating hormone were all considerably suppressed, and ovulation, as well as the associated mid-cycle hormonal surges, were prevented.[59][60] Similarly to oral administration of estradiol, but in contrast to the vaginal and transdermal routes, the ratio of estradiol to estrone is decreased with sublingual administration of either estradiol valerate or estradiol.[59][60][62]

Intramuscular injection

In contrast to oral administration, the bioavailability of estradiol valerate is 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 medication 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 medication is slowly released and absorbed.[3][63] 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 medication, which in turn is due to its long fatty acid valeric acid ester moiety.[3] The elimination 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] Studies in general have found that a single intramuscular injection of 4 mg estradiol valerate results in peak levels of estradiol of 240 to 540 pg/mL after 1 to 5 days following administration.[64] A 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.[7] The duration of estradiol valerate at this dose and in this study was considered to be 7 to 8 days.[7] Other studies have found that larger doses of intramuscular estradiol valerate exceeding 20 mg have a duration of more than 15 days.[7] 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.[65]

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.[43]

Pharmacokinetics of three estradiol esters by intramuscular injection

Estrogen Dose Peak levels Time to peak Duration
Estradiol benzoate 5 mg E2: 940 pg/mL
E1: 343 pg/mL
E2: 1.8 days
E1: 2.4 days
4–5 days
Estradiol valerate 5 mg E2: 667 pg/mL
E1: 324 pg/mL
E2: 2.2 days
E1: 2.7 days
7–8 days
Estradiol cypionate 5 mg E2: 338 pg/mL
E1: 145 pg/mL
E2: 3.9 days
E1: 5.1 days
11 days
Notes: All via i.m. injection of oil solution. Determinations via radioimmunoassay with chromatographic separation. Sources: See template.

Subcutaneous injection

Estradiol esters like estradiol valerate and estradiol cypionate can be given by subcutaneous injection instead of intramuscular injection.[73][74]

Intravenous injection

The administration of estradiol valerate by intravenous injection has been studied.[3][64] It has been found to be very rapidly cleaved into estradiol.[3][64] The bioavailability and metabolism of estradiol valerate does not differ with intravenous versus intramuscular injection.[64] Conversely, intravenous injection of estradiol valerate has a very short duration, whereas intramuscular injection has a long duration and elimination half-life.[64]

Chemistry

Estradiol plus the fatty acid valeric acid (valerate) equals estradiol valerate, a C17β ester of estradiol.[56]

Estradiol valerate is a synthetic estrane steroid and the C17β valerate (pentanoate) fatty acid ester of estradiol.[18][19] It is also known as estradiol 17β-valerate or as estra-1,3,5(10)-triene-3,17β-diol 17β-pentanoate.[18][19] Other common esters of estradiol in use include estradiol cypionate, estradiol enantate, 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.[18][19]

Structural properties of major estradiol esters

Estrogen Structure Ester(s) Relative
mol. weight
Relative
E2 contentb
Durationc
Position(s) Moiety Type Lengtha Rank Group
Estradiol
Estradiol.svg
1.00 1.00 9 Short
Estradiol acetate
Estradiol 3-acetate.svg
C3 Ethanoic acid Straight-chain fatty acid 2 1.15 0.87 8 Short
Estradiol benzoate
Estradiol benzoate.svg
C3 Benzenecarboxylic acid Aromatic fatty acid – (~4–5) 1.38 0.72 7 Short
Estradiol dipropionate
Estradiol dipropionate.svg
C3, C17β Propanoic acid (×2) Straight-chain fatty acid 3 (×2) 1.41 0.71 6 Short
Estradiol valerate
Estradiol valerate.svg
C17β Pentanoic acid Straight-chain fatty acid 5 1.31 0.76 5 Moderate
Estradiol cypionate
Estradiol 17 beta-cypionate.svg
C17β Cyclopentylpropanoic acid Aromatic fatty acid – (~6) 1.46 0.69 4 Moderate
Estradiol enantate
Estradiol enanthate.png
C17β Heptanoic acid Straight-chain fatty acid 7 1.41 0.71 3 Moderate
Estradiol undecylate
Estradiol undecylate.svg
C17β Undecanoic acid Straight-chain fatty acid 11 1.62 0.62 2 Long
Polyestradiol phosphated
Polyestradiol phosphate.svg
C3–C17β Phosphoric acid Organophosphate linker 1.23e 0.81e 1 Long
Footnotes: a = Length of ester in carbon atoms for straight-chain fatty acids or approximate length of ester in carbon atoms for aromatic fatty acids. b = Relative estradiol content by weight (i.e., relative estrogenic potency). c = Duration by intramuscular or subcutaneous injection in oil solution (except PEP, which is in aqueous solution). d = Polymer of estradiol phosphate (~13 repeat units). e = Relative molecular weight or estradiol content per repeat unit. Sources: See individual articles.

History

Estradiol valerate was patented by Ciba in 1940 and 1941, with a priority date of 1936.[14][75] It was synthesized and studied, along with a variety of other estradiol esters, by Karl Junkmann of Schering AG in 1953.[76][77] The medication was first introduced for medical use via intramuscular injection in 1954 by Schering in Europe under the brand name Progynon Depot and by Squibb in the United States under the brand name Delestrogen.[15][16][78] In 1966, oral estradiol valerate was introduced by Schering for medical use in Europe under the brand name Progynova.[79][80][81][82] Esterification of estradiol, as in estradiol valerate, improved its metabolic stability with oral administration, providing it with similar bioavailability and potency as oral micronized estradiol (1975).[4][3][83] Along with estradiol benzoate (1933)[84][85][86] and estradiol cypionate (1952),[87] estradiol valerate is one of the most widely used esters of estradiol.[17]

Society and culture

Generic names

Estradiol valerate is the generic name of the drug and its INN, USAN, BANM, and JAN, while oestradiol valerate was formerly its BANM.[18][19][88]

Brand names

Estradiol valerate has been marketed under the brand names Altadiol, Androtardyl-Oestradiol, Ardefem, Climaval, Cyclabil, Cyclocur, Deladiol, Delahormone Unimatic, Delestrogen, Delestrogen 4X, Depogen, Diol-20, Dioval, Ditate, Dura-Estate, Dura-Estradiol, Duratrad, Duragen, Estate, Estra-L, Estradiol Depot, Estraval, Estraval Depot, Estraval PA, Estravel, Femogen, Femogex, Gynogen L.A., Gynokadin, Lastrogen, Menaval, Merimono, Neofollin, Nuvelle, Oestrogynal, Ostrin Depo, Pelanin, Pharlon, Postoval, Primogyna, Primogyn, Primogyn Depot, Progynon, Progynon Depot, Progynova, Repestrogen, Repo-Estra, Reposo-E, Retestrin, Ronfase, Span-Est, Testaval, and Valergen, among others.[18][19][15][89][88] Neofollin is an oil solution of estradiol valerate.[90][91]

Availability

Oral estradiol valerate is used primarily in Europe, under the brand name Progynova.[92] Although oral estradiol valerate was previously available in the United States,[19] it is no longer available in this country except in combination with dienogest as a combined oral contraceptive (under the brand name Natazia).[32] 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.[32][19]

Research

SH-834 was a combination of 90 mg estradiol valerate and 300 mg gestonorone caproate for weekly intramuscular injection that was developed by Schering in the 1970s.[93][94][95] It was investigated clinically as a treatment for breast cancer and was found to be effective, but does not seem to have been marketed.[93][96][95]

See also

References

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