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Estradiol valerate

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Estradiol valerate
Clinical data
Pronunciation/ˌɛstrəˈdaɪoʊl ˈvæləreɪt/
ES-trə-DY-ohl VAL-ə-rayt[1]
Trade namesDelestrogen, Progynon Depot, Progynova, many others
Other namesEV; E2V; Oestradiol valerate; Estradiol pentanoate; Estradiol valerianate
Routes of
administration		By mouth, intramuscular injection,[2] subcutaneous injection
Drug classEstrogen; Estrogen ester
ATC code
Legal status
Legal status
  • US: WARNING[3]
  • In general: ℞ (Prescription only)
Pharmacokinetic data
BioavailabilityOral: 3–5%[4][5]
IM: 100%[4]
Protein bindingEstradiol: ~98% (to albumin and SHBGTooltip sex hormone-binding globulin)[6][7]
MetabolismCleavage via esterases in the liver, blood, and tissues[4]
MetabolitesEstradiol, valeric acid, and metabolites of estradiol[4]
Elimination half-lifeOral: 12–20 hours (as E2Tooltip estradiol)[4][8]
IM: 4–5 days[4]
Duration of actionIM (5 mg): 7–8 days[9]
IM (10–30 mg): 1–4 weeks[10]
ExcretionUrine (80%)[4]
Identifiers
  • [(8R,9S,13S,14S,17S)-3-hydroxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-17-yl] pentanoate
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)
  • CCCCC(=O)O[C@H]1CC[C@@H]2[C@@]1(CC[C@H]3[C@H]2CCC4=C3C=CC(=C4)O)C
  • InChI=1S/C23H32O3/c1-3-4-5-22(25)26-21-11-10-20-19-8-6-15-14-16(24)7-9-17(15)18(19)12-13-23(20,21)2/h7,9,14,18-21,24H,3-6,8,10-13H2,1-2H3/t18-,19-,20+,21+,23+/m1/s1
  • Key:RSEPBGGWRJCQGY-RBRWEJTLSA-N

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.[5][4][10][11] It is also used in the treatment of prostate cancer in men.[10] The medication is taken by mouth or by injection into muscle once every 1 to 4 weeks.[10][11]

Side effects of estradiol valerate include breast tenderness, breast enlargement, nausea, headache, and fluid retention.[12][10][11] Estradiol valerate is a synthetic estrogen and hence is an agonist of the estrogen receptor (ER), the biological target of estrogens like estradiol.[5][4][13] It is an estrogen ester and a prodrug of estradiol in the body.[13][5][4] Because of this, it is considered to be a natural and bioidentical form of estrogen.[13][4][14]

Estradiol valerate was first described in 1940 and was introduced for medical use in 1954.[15][16][17] Along with estradiol cypionate, it is one of the most widely used esters of estradiol.[18] Estradiol valerate is used in the United States, Canada, Europe, and throughout much of the rest of the world.[19][20] It is available as a generic medication.[21]

Medical uses

See also: 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 a combined estradiol-containing oral contraceptive (with dienogest)[22] and as a combined injectable contraceptive.[23][24][25] 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.[26][27][28][29] It is also used as a form of high-dose estrogen therapy in the treatment of prostate cancer in men.[10]

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.[10] 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.[11] Such symptoms may include hot flashes, outbreaks of sweat, sleep disturbances, depressive moods, irritability, headaches, and dizziness.[11]

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.[10] 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.[10] 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.[27][28][26]

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 2.5–10 μg/day 5–20 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
IMTooltip Intramuscular 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.

Available forms

See also: Estradiol valerate/norethisterone enantate 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.[30][15][31][32] In the United States, it is specifically available in formulations of 10, 20, and 40 mg/mL (as Delestrogen, as well as generics).[30] 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).[30] Some or all oral estradiol valerate tablets are micronized, similarly to oral estradiol tablets.[33]

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 enantate as combined injectable contraceptives.[30][22][23][24][25][1] Intramuscular estradiol valerate has also been marketed in combination with testosterone enantate, but this formulation has been discontinued.[30] The availability of estradiol valerate-containing products varies throughout the world.[1]

Available forms of estradiol[a]
Route Ingredient Form Dose[b] Brand names[c]
Oral Estradiol Tablet 0.1, 0.2, 0.5, 1, 2, 4 mg Estrace, Ovocyclin
Estradiol valerate Tablet 0.5, 1, 2, 4 mg Progynova
Transdermal Estradiol Patch 14, 25, 37.5, 50, 60, 75, 100 µg/d Climara, Vivelle
Gel pump 0.06% (0.52, 0.75 mg/pump) Elestrin, EstroGel
Gel packet 0.1% (0.25, 0.5, 1.0 mg/pk.) DiviGel, Sandrena
Emulsion 0.25% (25 µg/pouch) Estrasorb
Spray 1.53 mg/spray Evamist, Lenzetto
Vaginal Estradiol Tablet 10, 25 µg Vagifem
Cream 0.01% (0.1 mg/gram) Estrace
Insert 4, 10 µg Imvexxy
Ring 2 mg/ring (7.5 µg/d, 3 mon.) Estring
Estradiol acetate Ring 50, 100 µg/d, 3 months Femring
Injection[d] Estradiol Microspheres 1 mg/mL Juvenum E
Estradiol benzoate Oil solution 0.167, 0.2, 0.333, 1, 1.67, 2, 5, 10, 20, 25 mg/mL Progynon-B
Estradiol cypionate Oil solution 1, 3, 5 mg/mL Depo-Estradiol
Estradiol valerate Oil solution 5, 10, 20, 40 mg/mL Progynon Depot
Implant Estradiol Pellet 20, 25, 50, 100 mg, 6 mon. Estradiol Implants
Notes and sources:
  1. ^ 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.
  2. ^ Doses are given per unit (ex: per tablet, per mL).
  3. ^ Other brand names may be manufactured or previously manufactured.
  4. ^ By intramuscular or subcutaneous injection.
Sources: [34][35][36][37][15][31][38][39][40][1][41][42][43][44]

Contraindications

See also: Estradiol (medication) § Contraindications

Side effects

See also: 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.[12][45] 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.[45]

Overdose

See also: Estradiol (medication) § Overdose

Interactions

See also: Estradiol (medication) § Interactions

Pharmacology

Pharmacodynamics

See also: Pharmacodynamics of estradiol

Estradiol valerate is an estradiol ester, or a prodrug of estradiol.[13][5] As such, it is an estrogen, or an agonist of the estrogen receptors.[5][13] The affinity of estradiol valerate for the estrogen receptor is approximately 50 times lower than that of estradiol.[4] In addition, estradiol valerate is rapidly cleaved into estradiol and is unable to reach target tissues in concentrations of significance, if at all.[4] As such, estradiol valerate is essentially inactive in terms of estrogenic effect itself, acting solely as a prodrug to estradiol.[4] 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.[19][20] Aside from dose adjustment to account for the difference in molecular weight, oral estradiol valerate is considered to be equivalent to oral estradiol.[4] Because estradiol valerate is a prodrug of estradiol, it is considered to be a natural and bioidentical form of estrogen.[13][14]

Potencies of oral estrogens[data sources 1]
Compound Dosage for specific uses (mg usually)[a]
ETD[b] EPD[b] MSD[b] MSD[c] OID[c] TSD[c]
Estradiol (non-micronized) 30 ≥120–300 120 6 - -
Estradiol (micronized) 6–12 60–80 14–42 1–2 >5 >8
Estradiol valerate 6–12 60–80 14–42 1–2 - >8
Estradiol benzoate - 60–140 - - - -
Estriol ≥20 120–150[d] 28–126 1–6 >5 -
Estriol succinate - 140–150[d] 28–126 2–6 - -
Estrone sulfate 12 60 42 2 - -
Conjugated estrogens 5–12 60–80 8.4–25 0.625–1.25 >3.75 7.5
Ethinylestradiol 200 μg 1–2 280 μg 20–40 μg 100 μg 100 μg
Mestranol 300 μg 1.5–3.0 300–600 μg 25–30 μg >80 μg -
Quinestrol 300 μg 2–4 500 μg 25–50 μg - -
Methylestradiol - 2 - - - -
Diethylstilbestrol 2.5 20–30 11 0.5–2.0 >5 3
DES dipropionate - 15–30 - - - -
Dienestrol 5 30–40 42 0.5–4.0 - -
Dienestrol diacetate 3–5 30–60 - - - -
Hexestrol - 70–110 - - - -
Chlorotrianisene - >100 - - >48 -
Methallenestril - 400 - - - -
Sources and footnotes:
  1. ^ [46][47][48][49][50][51] [52][53][54][55] [56][57][58][59][60][61][62][63][64]
  1. ^ Dosages are given in milligrams unless otherwise noted.
  2. ^ a b c Dosed every 2 to 3 weeks
  3. ^ a b c Dosed daily
  4. ^ a b In divided doses, 3x/day; irregular and atypical proliferation.
Potencies and durations of natural estrogens by intramuscular injection
Estrogen Form Dose (mg) Duration by dose (mg)
EPD CICD
Estradiol Aq. soln. ? – <1 d
Oil soln. 40–60 – 1–2 ≈ 1–2 d
Aq. susp. ? 3.5 0.5–2 ≈ 2–7 d; 3.5 ≈ >5 d
Microsph. ? – 1 ≈ 30 d
Estradiol benzoate Oil soln. 25–35 – 1.66 ≈ 2–3 d; 5 ≈ 3–6 d
Aq. susp. 20 – 10 ≈ 16–21 d
Emulsion ? – 10 ≈ 14–21 d
Estradiol dipropionate Oil soln. 25–30 – 5 ≈ 5–8 d
Estradiol valerate Oil soln. 20–30 5 5 ≈ 7–8 d; 10 ≈ 10–14 d;
40 ≈ 14–21 d; 100 ≈ 21–28 d
Estradiol benz. butyrate Oil soln. ? 10 10 ≈ 21 d
Estradiol cypionate Oil soln. 20–30 – 5 ≈ 11–14 d
Aq. susp. ? 5 5 ≈ 14–24 d
Estradiol enanthate Oil soln. ? 5–10 10 ≈ 20–30 d
Estradiol dienanthate Oil soln. ? – 7.5 ≈ >40 d
Estradiol undecylate Oil soln. ? – 10–20 ≈ 40–60 d;
25–50 ≈ 60–120 d
Polyestradiol phosphate Aq. soln. 40–60 – 40 ≈ 30 d; 80 ≈ 60 d;
160 ≈ 120 d
Estrone Oil soln. ? – 1–2 ≈ 2–3 d
Aq. susp. ? – 0.1–2 ≈ 2–7 d
Estriol Oil soln. ? – 1–2 ≈ 1–4 d
Polyestriol phosphate Aq. soln. ? – 50 ≈ 30 d; 80 ≈ 60 d
Notes and sources
Notes: All aqueous suspensions are of microcrystalline particle size. Estradiol production during the menstrual cycle is 30–640 µg/d (6.4–8.6 mg total per month or cycle). The vaginal epithelium maturation dosage of estradiol benzoate or estradiol valerate has been reported as 5 to 7 mg/week. An effective ovulation-inhibiting dose of estradiol undecylate is 20–30 mg/month. Sources: See template.

Pharmacokinetics

See also: Pharmacokinetics of estradiol

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.[5][13][4][5][65] 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.[4] 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.[4] 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).[4]

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.[66]

Esterification of the C17β position of estradiol as in estradiol valerate reduces the metabolism of estradiol valerate by 17β-hydroxysteroid dehydrogenase (17β-HSD).[5] 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.[13] However, estradiol valerate is hydrolyzed into estradiol and valeric acid in the intestines, and hence, is still subject to extensive first-pass metabolism.[5] As such, the oral bioavailability of estradiol valerate is only around 3 to 5%, and is similar to that of oral estradiol.[4][5][67] All oral tablets in the cases of both estradiol and estradiol valerate seem to be micronized.[33] Due to its nature as a rapidly converted prodrug of estradiol, the pharmacokinetics of oral estradiol valerate are similar to those of oral estradiol.[4][5] 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.[4] This is also notably true for effects on hepatic protein synthesis (e.g., of SHBGTooltip sex hormone-binding globulin), again after differences in molecular weight between the two compounds are considered.[4]

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.[68] These concentrations of estradiol and estrone are comparable to those observed with 1 and 2 mg/day oral estradiol.[68] 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.[4] A study found that, in accordance with their differences in molecular weights, oral estradiol produced higher levels of estradiol than oral estradiol valerate.[66] 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).[69] 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.[67]

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.[70][71]

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.[70][71] 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.[70][71] 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.[70][71] The administration of 2 mg oral micronized estradiol valerate tablets (Progynova, Schering) sublingually 3 or 4 times per day resulted in circulating estradiol levels of about 290 pg/mL to 460 pg/mL in premenopausal women (time of measurements not given).[70][71] Steady-state levels of estradiol were achieved within about 2 or 3 days.[70][71] 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.[70][71] 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 both estradiol valerate and estradiol.[70][71][72]

Intramuscular injection

In contrast to oral administration, the bioavailability of estradiol valerate is complete (i.e., 100%) via intramuscular injection.[4][5] 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.[4] 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.[4] 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.[4][73] 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.[5] In addition, a secondary depot may also be formed in adipose tissue.[5] 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.[4] The elimination half-life of intramuscularly administered estradiol valerate in oil is reported to be 4 to 5 days.[4]

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.[74] 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.[75] 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.[9] The duration of estradiol valerate at this dose and in this study was considered to be 7 to 8 days.[9] Other studies have found that larger doses of intramuscular estradiol valerate exceeding 20 mg have a duration of more than 15 days.[9] 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.[76]

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.[77]

Pharmacokinetics of three estradiol esters by intramuscular injection
Estrogen Dose Cmax Tmax 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.

Template:Hormone levels with intramuscular estradiol valerate

Subcutaneous injection

Estradiol esters like estradiol valerate and estradiol cypionate can be given by subcutaneous injection instead of intramuscular injection.[78][79]

Intravenous injection

The administration of estradiol valerate by intravenous injection has been studied.[4][75] It has been found to be very rapidly cleaved into estradiol.[4][75] The bioavailability and metabolism of estradiol valerate does not differ with intravenous versus intramuscular injection.[75]

Chemistry

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.[67]

Estradiol valerate is a synthetic estrane steroid and the C17β valerate (pentanoate) fatty acid ester of estradiol.[19][20] It is also known as estradiol 17β-valerate or as estra-1,3,5(10)-triene-3,17β-diol 17β-pentanoate.[19][20] 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.[19][20]

Structural properties of selected estradiol esters
Estrogen Structure Ester(s) Relative
mol. weight		 Relative
E2 contentb		 log Pc
Position(s) Moiet(ies) Type Lengtha
Estradiol
– – – – 1.00 1.00 4.0
Estradiol acetate
C3 Ethanoic acid Straight-chain fatty acid 2 1.15 0.87 4.2
Estradiol benzoate
C3 Benzoic acid Aromatic fatty acid – (~4–5) 1.38 0.72 4.7
Estradiol dipropionate
C3, C17β Propanoic acid (×2) Straight-chain fatty acid 3 (×2) 1.41 0.71 4.9
Estradiol valerate
C17β Pentanoic acid Straight-chain fatty acid 5 1.31 0.76 5.6–6.3
Estradiol benzoate butyrate
C3, C17β Benzoic acid, butyric acid Mixed fatty acid – (~6, 2) 1.64 0.61 6.3
Estradiol cypionate
C17β Cyclopentylpropanoic acid Cyclic fatty acid – (~6) 1.46 0.69 6.9
Estradiol enanthate
C17β Heptanoic acid Straight-chain fatty acid 7 1.41 0.71 6.7–7.3
Estradiol dienanthate
C3, C17β Heptanoic acid (×2) Straight-chain fatty acid 7 (×2) 1.82 0.55 8.1–10.4
Estradiol undecylate
C17β Undecanoic acid Straight-chain fatty acid 11 1.62 0.62 9.2–9.8
Estradiol stearate
C17β Octadecanoic acid Straight-chain fatty acid 18 1.98 0.51 12.2–12.4
Estradiol distearate
C3, C17β Octadecanoic acid (×2) Straight-chain fatty acid 18 (×2) 2.96 0.34 20.2
Estradiol sulfate
C3 Sulfuric acid Water-soluble conjugate – 1.29 0.77 0.3–3.8
Estradiol glucuronide
C17β Glucuronic acid Water-soluble conjugate – 1.65 0.61 2.1–2.7
Estramustine phosphated
C3, C17β Normustine, phosphoric acid Water-soluble conjugate – 1.91 0.52 2.9–5.0
Polyestradiol phosphatee
C3–C17β Phosphoric acid Water-soluble conjugate – 1.23f 0.81f 2.9g
Footnotes: a = Length of ester in carbon atoms for straight-chain fatty acids or approximate length of ester in carbon atoms for aromatic or cyclic fatty acids. b = Relative estradiol content by weight (i.e., relative estrogenic exposure). c = Experimental or predicted octanol/water partition coefficient (i.e., lipophilicity/hydrophobicity). Retrieved from PubChem, ChemSpider, and DrugBank. d = Also known as estradiol normustine phosphate. e = Polymer of estradiol phosphate (~13 repeat units). f = Relative molecular weight or estradiol content per repeat unit. g = log P of repeat unit (i.e., estradiol phosphate). Sources: See individual articles.

History

Estradiol valerate was patented by Ciba in 1940 and 1941, with a priority date of 1936.[15][80] It was synthesized and studied, along with a variety of other estradiol esters, by Karl Junkmann of Schering AG in 1953.[81][82] The medication first introduced for medical use by Squibb in 1954 under the brand name Delestrogen in the United States.[16][17] Subsequently, estradiol valerate was marketed widely in Europe as Progynon Depot and Progynova.[20][16] Along with estradiol benzoate (1936)[83][84] and estradiol cypionate (1952),[85] estradiol valerate has become one of the most widely used esters of estradiol.[18]

Society and culture

Generic names

Estradiol valerate is the generic name of the drug and its INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, BANMTooltip British Approved Name, and JANTooltip Japanese Accepted Name, while oestradiol valerate was formerly its BANMTooltip British Approved Name.[19][20][86]

Brand names

Estradiol valerate is or has been marketed under the brand names Altadiol, Deladiol, Delestrogen, Estraval, Estraval Depot, Neofollin, Progynon Depot, Progynova, and Valergen, among many others.[19][20][86]

Availability

See also: List of estrogens available in the United States

Oral estradiol valerate is used primarily in Europe, under the brand name Progynova.[87] Although oral estradiol valerate was previously available in the United States,[20] it is no longer available in this country except in combination with dienogest as a combined oral contraceptive (under the brand name Natazia).[30] 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.[30][20]

See also

References

  1. ^ a b c d https://www.drugs.com/cons/estradiol-and-dienogest.html Cite error: The named reference "Drugs.com" was defined multiple times with different content (see the help page).
  2. ^ Christoph Zink (1 January 1988). Dictionary of Obstetrics and Gynecology. Walter de Gruyter. p. 86. ISBN 978-3-11-085727-6. Retrieved 20 May 2012.
  3. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.
  4. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af 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.
  5. ^ a b c d e f g h i j k l m n o Kuhl H (2005). "Pharmacology of estrogens and progestogens: influence of different routes of administration" (PDF). Climacteric. 8 Suppl 1: 3–63. doi:10.1080/13697130500148875. PMID 16112947.
  6. ^ Stanczyk, Frank Z.; Archer, David F.; Bhavnani, Bhagu R. (2013). "Ethinyl estradiol and 17β-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment". Contraception. 87 (6): 706–727. doi:10.1016/j.contraception.2012.12.011. ISSN 0010-7824. PMID 23375353.
  7. ^ Tommaso Falcone; William W. Hurd (2007). Clinical Reproductive Medicine and Surgery. Elsevier Health Sciences. pp. 22, 362, 388. ISBN 0-323-03309-1.
  8. ^ Stanczyk, Frank Z.; Archer, David F.; Bhavnani, Bhagu R. (2013). "Ethinyl estradiol and 17β-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment". Contraception. 87 (6): 706–727. doi:10.1016/j.contraception.2012.12.011. ISSN 0010-7824. PMID 23375353.
  9. ^ a b c d 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.
  10. ^ a b c d e f g h i https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/009402s052lbl.pdf
  11. ^ a b c d e [1]
  12. ^ a b Amit K. Ghosh (23 September 2010). Mayo Clinic Internal Medicine Board Review. OUP USA. pp. 222–. ISBN 978-0-19-975569-1.
  13. ^ a b c d e f g h Michael Oettel; Ekkehard Schillinger (6 December 2012). Estrogens and Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogen. Springer Science & Business Media. p. 261. ISBN 978-3-642-60107-1. 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.
  14. ^ a b Nagrath Arun; Malhotra Narendra; Seth Shikha (15 December 2012). Progress in Obstetrics and Gynecology--3. Jaypee Brothers Medical Publishers Pvt. Ltd. pp. 419–. ISBN 978-93-5090-575-3.
  15. ^ a b c d A. Kleemann; J. Engel; B. Kutscher; D. Reichert (14 May 2014). Pharmaceutical Substances, 5th Edition, 2009: Syntheses, Patents and Applications of the most relevant APIs. Thieme. pp. 1167–1174. ISBN 978-3-13-179525-0. Cite error: The named reference "KleemannEngel2014" was defined multiple times with different content (see the help page).
  16. ^ a b c William Andrew Publishing (22 October 2013). Pharmaceutical Manufacturing Encyclopedia, 3rd Edition. Elsevier. pp. 1477–. ISBN 978-0-8155-1856-3.
  17. ^ a b Larry L. Duetsch (1969). Research and development, market power, and patent policy in ethical drugs. University of Wisconsin--Madison. p. 95.
  18. ^ a b Samuel S. C. Yen (1991). Reproductive endocrinology: physiology, pathophysiology, and clinical management. Saunders. ISBN 978-0-7216-3206-3. Retrieved 20 May 2012.
  19. ^ a b c d e f g J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 898–. ISBN 978-1-4757-2085-3.
  20. ^ a b c d e f g h i j Index Nominum 2000: International Drug Directory. Taylor & Francis US. 2000. p. 405. ISBN 978-3-88763-075-1. Retrieved 20 May 2012.
  21. ^ https://www.drugs.com/availability/generic-delestrogen.html
  22. ^ a b Guida M, Bifulco G, Di Spiezio Sardo A, Scala M, Fernandez LM, Nappi C (2010). "Review of the safety, efficacy and patient acceptability of the combined dienogest/estradiol valerate contraceptive pill". International Journal of Women's Health. 2: 279–90. doi:10.2147/IJWH.S6954. PMC 2990895. PMID 21151673.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  23. ^ a b 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.
  24. ^ a b http://www.wjpps.com/download/article/1412071798.pdf
  25. ^ a b 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.
  26. ^ a b Wesp LM, Deutsch MB (March 2017). "Hormonal and Surgical Treatment Options for Transgender Women and Transfeminine Spectrum Persons". Psychiatr. Clin. North Am. 40 (1): 99–111. doi:10.1016/j.psc.2016.10.006. PMID 28159148.
  27. ^ a b 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): 1282–97. doi:10.1002/phar.1487. PMID 25220381.
  28. ^ a b Randi Ettner; Stan Monstrey; Eli Coleman (20 May 2016). Principles of Transgender Medicine and Surgery. Routledge. pp. 216–. ISBN 978-1-317-51460-2.
  29. ^ 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.
  30. ^ a b c d e f g "Drugs@FDA: FDA Approved Drug Products". United States Food and Drug Administration. Retrieved 16 November 2016.
  31. ^ a b Muller (19 June 1998). European Drug Index: European Drug Registrations, Fourth Edition. CRC Press. pp. 276, 313, 379, 561, 566. ISBN 978-3-7692-2114-5. Cite error: The named reference "Muller1998" was defined multiple times with different content (see the help page).
  32. ^ Kenneth L. Becker (2001). Principles and Practice of Endocrinology and Metabolism. Lippincott Williams & Wilkins. pp. 2153–. ISBN 978-0-7817-1750-2.
  33. ^ a b Devroey P, Pados G (1998). "Preparation of endometrium for egg donation". Hum. Reprod. Update. 4 (6): 856–61. doi:10.1093/humupd/4.6.856. PMID 10098476. Oestradiol valerate and oestradiol in a micronized form are the most widely used oestrogen per os for steroid substitution therapy. Our regimen, as of most other groups [...] is oestradiol valerate (Progynova; Schering, Berlin, Germany) given in various concentrations throughout the cycle [...]. According to Norfolk's protocol, 2 mg of micronized oestradiol valerate are given on cycle days 1–5. [...] In tablet form, micronized oestradiol valerate is also efficiently absorbed [...]
  34. ^ "Drugs@FDA: FDA Approved Drug Products". United States Food and Drug Administration. Retrieved 26 July 2018.
  35. ^ Lobo RA (5 June 2007). Treatment of the Postmenopausal Woman: Basic and Clinical Aspects. Academic Press. pp. 177, 217–226, 770–771. ISBN 978-0-08-055309-2.
  36. ^ Falcone T, Hurd WW (14 June 2017). Clinical Reproductive Medicine and Surgery: A Practical Guide. Springer. pp. 179–. ISBN 978-3-319-52210-4.
  37. ^ Becker KL (2001). Principles and Practice of Endocrinology and Metabolism. Lippincott Williams & Wilkins. pp. 889, 1059–1060, 2153. ISBN 978-0-7817-1750-2.
  38. ^ Krishna UR, Sheriar NK (1996). Menopause. Orient Blackswan. pp. 70–. ISBN 978-81-250-0910-8.
  39. ^ "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. ISSN 0095-9561.
  40. ^ "AERODIOL (Oestradiol hemihydrate 150 micrograms/actuation)" (PDF). Servier Laboratories (Aust) Pty Ltd.
  41. ^ 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. PMID 18382901. 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.
  42. ^ Plouffe Jr L, Ravnikar VA, Speroff L, Watts NB (6 December 2012). Comprehensive Management of Menopause. Springer Science & Business Media. pp. 271–. ISBN 978-1-4612-4330-4.
  43. ^ Hospital Formulary and Compendium of Useful Information. University of California Press. 1952. pp. 49–. GGKEY:2UAAZRZ5LN0.
  44. ^ Leidenberger FA (17 April 2013). Klinische Endokrinologie für Frauenärzte. Springer-Verlag. pp. 527–. ISBN 978-3-662-08110-5.
  45. ^ a b 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. PMID 26684553.
  46. ^ Lauritzen C (September 1990). "Clinical use of oestrogens and progestogens". Maturitas. 12 (3): 199–214. doi:10.1016/0378-5122(90)90004-P. PMID 2215269.
  47. ^ Lauritzen C (June 1977). "[Estrogen thearpy in practice. 3. Estrogen preparations and combination preparations]" [Estrogen therapy in practice. 3. Estrogen preparations and combination preparations]. Fortschritte Der Medizin (in German). 95 (21): 1388–92. PMID 559617.
  48. ^ Wolf AS, Schneider HP (12 March 2013). Östrogene in Diagnostik und Therapie. Springer-Verlag. pp. 78–. ISBN 978-3-642-75101-1.
  49. ^ Göretzlehner G, Lauritzen C, Römer T, Rossmanith W (1 January 2012). Praktische Hormontherapie in der Gynäkologie. Walter de Gruyter. pp. 44–. ISBN 978-3-11-024568-4.
  50. ^ Knörr K, Beller FK, Lauritzen C (17 April 2013). Lehrbuch der Gynäkologie. Springer-Verlag. pp. 212–213. ISBN 978-3-662-00942-0.
  51. ^ Horský J, Presl J (1981). "Hormonal Treatment of Disorders of the Menstrual Cycle". In Horsky J, Presl J (eds.). Ovarian Function and its Disorders: Diagnosis and Therapy. Springer Science & Business Media. pp. 309–332. doi:10.1007/978-94-009-8195-9_11. ISBN 978-94-009-8195-9.
  52. ^ Pschyrembel W (1968). Praktische Gynäkologie: für Studierende und Ärzte. Walter de Gruyter. pp. 598–599. ISBN 978-3-11-150424-7.
  53. ^ Lauritzen CH (January 1976). "The female climacteric syndrome: significance, problems, treatment". Acta Obstetricia Et Gynecologica Scandinavica. Supplement. 51: 47–61. doi:10.3109/00016347509156433. PMID 779393.
  54. ^ Lauritzen C (1975). "The Female Climacteric Syndrome: Significance, Problems, Treatment". Acta Obstetricia et Gynecologica Scandinavica. 54 (s51): 48–61. doi:10.3109/00016347509156433. ISSN 0001-6349.
  55. ^ Kopera H (1991). "Hormone der Gonaden". Hormonelle Therapie für die Frau. Kliniktaschenbücher. pp. 59–124. doi:10.1007/978-3-642-95670-6_6. ISBN 978-3-540-54554-5. ISSN 0172-777X.
  56. ^ Scott WW, Menon M, Walsh PC (April 1980). "Hormonal Therapy of Prostatic Cancer". Cancer. 45 (Suppl 7): 1929–1936. doi:10.1002/cncr.1980.45.s7.1929. PMID 29603164.
  57. ^ Leinung MC, Feustel PJ, Joseph J (2018). "Hormonal Treatment of Transgender Women with Oral Estradiol". Transgender Health. 3 (1): 74–81. doi:10.1089/trgh.2017.0035. PMC 5944393. PMID 29756046.
  58. ^ Ryden AB (1950). "Natural and synthetic oestrogenic substances; their relative effectiveness when administered orally". Acta Endocrinologica. 4 (2): 121–39. doi:10.1530/acta.0.0040121. PMID 15432047.
  59. ^ Ryden AB (1951). "The effectiveness of natural and synthetic oestrogenic substances in women". Acta Endocrinologica. 8 (2): 175–91. doi:10.1530/acta.0.0080175. PMID 14902290.
  60. ^ Kottmeier HL (1947). "Ueber blutungen in der menopause: Speziell der klinischen bedeutung eines endometriums mit zeichen hormonaler beeinflussung: Part I". Acta Obstetricia et Gynecologica Scandinavica. 27 (s6): 1–121. doi:10.3109/00016344709154486. ISSN 0001-6349. There is no doubt that the conversion of the endometrium with injections of both synthetic and native estrogenic hormone preparations succeeds, but the opinion whether native, orally administered preparations can produce a proliferation mucosa changes with different authors. PEDERSEN-BJERGAARD (1939) was able to show that 90% of the folliculin taken up in the blood of the vena portae is inactivated in the liver. Neither KAUFMANN (1933, 1935), RAUSCHER (1939, 1942) nor HERRNBERGER (1941) succeeded in bringing a castration endometrium into proliferation using large doses of orally administered preparations of estrone or estradiol. Other results are reported by NEUSTAEDTER (1939), LAUTERWEIN (1940) and FERIN (1941); they succeeded in converting an atrophic castration endometrium into an unambiguous proliferation mucosa with 120–300 oestradiol or with 380 oestrone.
  61. ^ Rietbrock N, Staib AH, Loew D (11 March 2013). Klinische Pharmakologie: Arzneitherapie. Springer-Verlag. pp. 426–. ISBN 978-3-642-57636-2.
  62. ^ Martinez-Manautou J, Rudel HW (1966). "Antiovulatory Activity of Several Synthetic and Natural Estrogens". In Robert Benjamin Greenblatt (ed.). Ovulation: Stimulation, Suppression, and Detection. Lippincott. pp. 243–253.
  63. ^ Herr F, Revesz C, Manson AJ, Jewell JB (1970). "Biological Properties of Estrogen Sulfates". Chemical and Biological Aspects of Steroid Conjugation. pp. 368–408. doi:10.1007/978-3-642-49793-3_8. ISBN 978-3-642-49506-9.
  64. ^ Duncan CJ, Kistner RW, Mansell H (October 1956). "Suppression of ovulation by trip-anisyl chloroethylene (TACE)". Obstetrics and Gynecology. 8 (4): 399–407. PMID 13370006.
  65. ^ "Progynova 1mg (SPC) | Drugs.com". Retrieved 2012-09-06.
  66. ^ a b Wiegratz I, Fink T, Rohr UD, Lang E, Leukel P, Kuhl H (September 2001). "Überkreuz-Vergleich der Pharmakokinetik von Estradiol unter der Hormonsubstitution mit Estradiolvalerat oder mikronisiertem Estradiol" [Cross-over comparison of the pharmacokinetics of estradiol during hormone replacement therapy with estradiol valerate or micronized estradiol]. Zentralbl Gynakol (in German). 123 (9): 505–12. doi:10.1055/s-2001-18223. PMID 11709743.
  67. ^ a b c Shellenberger, T. E. (1986). "Pharmacology of estrogens": 393–410. doi:10.1007/978-94-009-4145-8_36. {{cite journal}}: Cite journal requires |journal= (help)
  68. ^ a b O'Connell MB (1995). "Pharmacokinetic and pharmacologic variation between different estrogen products". J Clin Pharmacol. 35 (9 Suppl): 18S–24S. doi:10.1002/j.1552-4604.1995.tb04143.x. PMID 8530713.
  69. ^ Vree TB, Timmer CJ (August 1998). "Enterohepatic cycling and pharmacokinetics of oestradiol in postmenopausal women". J. Pharm. Pharmacol. 50 (8): 857–64. doi:10.1111/j.2042-7158.1998.tb04000.x. PMID 9751449.
  70. ^ a b c d e f g h Serhal PF, Craft IL (May 1989). "Oocyte donation in 61 patients". Lancet. 1 (8648): 1185–7. doi:10.1016/S0140-6736(89)92762-1. PMID 2566746.
  71. ^ a b c d e f g h Serhal P (July 1990). "Oocyte donation and surrogacy". Br. Med. Bull. 46 (3): 796–812. doi:10.1093/oxfordjournals.bmb.a072432. PMID 2207608.
  72. ^ Pines A, Averbuch M, Fisman EZ, Rosano GM (September 1999). "The acute effects of sublingual 17beta-estradiol on the cardiovascular system". Maturitas. 33 (1): 81–5. doi:10.1016/S0378-5122(99)00036-5. PMID 10585176.
  73. ^ Sriram. Medicinal Chemistry. Pearson Education India. p. 427. ISBN 978-81-317-0031-0. Retrieved 20 May 2012.
  74. ^ M. Notelovitz; P.A. van Keep (6 December 2012). The Climacteric in Perspective: Proceedings of the Fourth International Congress on the Menopause, held at Lake Buena Vista, Florida, October 28–November 2, 1984. Springer Science & Business Media. pp. 399–. ISBN 978-94-009-4145-8.
  75. ^ a b c d Düsterberg B, Schmidt-Gollwitzer M, Hümpel M (1985). "Pharmacokinetics and biotransformation of estradiol valerate in ovariectomized women". Horm. Res. 21 (3): 145–54. doi:10.1159/000180039. PMID 2987096.
  76. ^ Cite error: The named reference pmid22257576 was invoked but never defined (see the help page).
  77. ^ Ulrich U, Pfeifer T, Lauritzen C (1994). "Rapid increase in lumbar spine bone density in osteopenic women by high-dose intramuscular estrogen-progestogen injections. A preliminary report". Horm. Metab. Res. 26 (9): 428–31. doi:10.1055/s-2007-1001723. PMID 7835827.
  78. ^ Unger CA (December 2016). "Hormone therapy for transgender patients". Transl Androl Urol. 5 (6): 877–884. doi:10.21037/tau.2016.09.04. PMC 5182227. PMID 28078219.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  79. ^ Sierra-Ramírez JA, Lara-Ricalde R, Lujan M, Velázquez-Ramírez N, Godínez-Victoria M, Hernádez-Munguía IA, Padilla A, Garza-Flores J (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.
  80. ^ https://patents.google.com/patent/US2205627A/en
  81. ^ Shoham Z, Kopernik G (June 2004). "Tools for making correct decisions regarding hormone therapy. part I: background and drugs". Fertil. Steril. 81 (6): 1447–57. doi:10.1016/j.fertnstert.2003.10.052. PMID 15193460.
  82. ^ Junkmann, Karl (1953). "Über protrahiert wirksame Östrogene" [Over protracted effective estrogens]. Naunyn-Schmiedebergs Archiv für Experimentelle Pathologie und Pharmakologie. 220 (5). doi:10.1007/BF00246561. ISSN 0028-1298.
  83. ^ 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.
  84. ^ 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 1263335. PMID 16746289.
  85. ^ Marshall Sittig (1 January 1988). Pharmaceutical Manufacturing Encyclopedia. William Andrew. pp. 575–576. ISBN 978-0-8155-1144-1. Retrieved 20 May 2012.
  86. ^ a b https://www.drugs.com/international/estradiol.html
  87. ^ Joseph S. Sanfilippo (January 1998). Primary Care in Obstetrics and Gynecology: A Handbook for Clinicians. Springer Science & Business Media. pp. 227–. ISBN 978-0-387-94739-6.

Further reading

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