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词条 Estradiol valerate
释义

  1. Medical uses

     Available forms 

  2. Contraindications

  3. Side effects

  4. Overdose

  5. Interactions

  6. Pharmacology

     Pharmacodynamics  Pharmacokinetics  Oral administration  Sublingual administration  Intramuscular injection  Subcutaneous injection  Intravenous injection 

  7. Chemistry

  8. History

  9. Society and culture

     Generic names  Brand names  Availability 

  10. See also

  11. References

  12. Further reading

{{Drugbox
| Verifiedfields =
| Watchedfields =
| verifiedrevid =
| IUPAC_name = [(8R,9S,13S,14S,17S)-3-hydroxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-17-yl] pentanoate
| image = Estradiol valerate.svg
| width = 250px
| image2 = Estradiol valerate molecule ball.png
| width2 = 250px
| pronounce = {{IPAc-en|ˌ|ɛ|s|t|r|ə|ˈ|d|aɪ|oʊ|l|_|ˈ|v|æ|l|ə|r|eɪ|t}}
{{respell|ES|trə|DY|ohl|_|VAL|ə|rayt}}[1]
| tradename = Delestrogen, Progynon Depot, Progynova, many others
| pregnancy_AU =
| pregnancy_US =
| pregnancy_category =
| legal_AU =
| legal_CA =
| legal_UK =
| legal_US =
| legal_status = Rx-only
| routes_of_administration = By mouth, intramuscular injection,[2] subcutaneous injection
| class = Estrogen; Estrogen ester
| bioavailability = Oral: 3–5%[3][4]
{{abbr|IM|Intramuscular injection}}: 100%[3]
| protein_bound = Estradiol: ~98% (to albumin and {{abbrlink|SHBG|sex hormone-binding globulin}})[3][4]
| 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 {{abbrlink|E2|estradiol}})[3][5]
{{abbr|IM|Intramuscular injection}}: 4–5 days[3]
| duration_of_action = {{abbr|IM|Intramuscular injection}} (5 mg): 7–8 days[13]
{{abbr|IM|Intramuscular injection}} (10–30 mg): 1–4 weeks[14]
| excretion = Urine (80%)[3]
| CAS_number_Ref =
| CAS_number = 979-32-8
| CAS_supplemental =
| ATC_prefix = G03
| ATC_suffix = CA03
| ATC_supplemental =
| PubChem = 13791
| IUPHAR_ligand =
| DrugBank_Ref =
| DrugBank = DB13956
| ChemSpiderID_Ref =
| ChemSpiderID = 13194
| UNII = OKG364O896
| KEGG = D01413
| ChEBI = 31561
| ChEMBL = 1511
| synonyms = EV; E2V; Oestradiol valerate; Estradiol pentanoate; Estradiol valerianate
| C=23 | H=32 | O=3
| molecular_weight = 356.498 g/mol
| SMILES = CCCCC(=O)O[C@H]1CC[C@@H]2[C@@]1(CC[C@H]3[C@H]2CCC4=C3C=CC(=C4)O)C
| StdInChI_Ref =
| StdInChI = 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
| StdInChIKey_Ref =
| StdInChIKey = RSEPBGGWRJCQGY-RBRWEJTLSA-N
}}Estradiol valerate (EV), 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.[6][3][14][19] It is also used in the treatment of prostate cancer in men.[14] The medication is taken by mouth or by injection into muscle once every 1 to 4 weeks.[14][19]Side effects of estradiol valerate include breast tenderness, breast enlargement, nausea, headache, and fluid retention.[23][14][19] Estradiol valerate is a synthetic estrogen and hence is an agonist of the estrogen receptor (ER), the biological target of estrogens like estradiol.[6][3][28] It is an estrogen ester and a prodrug of estradiol in the body.[28][6][3] Because of this, it is considered to be a natural and bioidentical form of estrogen.[7][8][3][9]

Estradiol valerate was first described in 1940 and was introduced for medical use in 1954.[36][37][38] Along with estradiol cypionate, it is one of the most widely used esters of estradiol.[39] Estradiol valerate is used in the United States, Canada, Europe, and throughout much of the rest of the world.[40][10] It is available as a generic medication.[11]

{{TOC limit|3}}

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)[12] and as a combined injectable contraceptive.[13][14][15] 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.[16][17][18][19] It is also used as a form of high-dose estrogen therapy in the treatment of prostate cancer in men.[14]

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.[20] 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.[21] Such symptoms may include hot flashes, outbreaks of sweat, sleep disturbances, depressive moods, irritability, headaches, and dizziness.[21]

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.[20] 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.[20] 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.[17][18][16]

{{Estrogen dosages for menopausal hormone therapy}}{{Estrogen dosages for breast and prostate cancer}}

Available forms

{{See also|Estradiol valerate/norethisterone enantate|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.[22][23][24][25] In the United States, it is specifically available in formulations of 10, 20, and 40 mg/mL (as Delestrogen, as well as generics).[22] 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).[22] Some or all oral estradiol valerate tablets are micronized, similarly to oral estradiol tablets.[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 enantate as combined injectable contraceptives.[22][12][13][14][15][1] Intramuscular estradiol valerate has also been marketed in combination with testosterone enantate, but this formulation has been discontinued.[22] The availability of estradiol valerate-containing products varies throughout the world.[1]

{{Available forms of estradiol}}

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.[27][28] 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.[28]

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.[7][6] As such, it is an estrogen, or an agonist of the estrogen receptors.[6][7] 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.[40][10] 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.[7][8][9]

{{Oral potencies of estrogens}}{{Parenteral potencies and durations of estrogens}}

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.[6][7][29][6][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 medication is administered orally or parenterally.[29] 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.[29] 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).[29]

Oral administration

Esterification of the C17β position of estradiol as in estradiol valerate reduces the metabolism of estradiol valerate by 17β-hydroxysteroid dehydrogenase (17β-HSD).[6] 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.[7] However, estradiol valerate is hydrolyzed into estradiol and valeric acid in the intestines, and hence, is still subject to extensive first-pass metabolism.[6] As such, the oral bioavailability of estradiol valerate is only around 3 to 5%, and is similar to that of oral estradiol.[29][6][105] All oral tablets in the cases of both estradiol and estradiol valerate seem to be micronized.[26] Due to its nature as a rapidly converted prodrug of estradiol, the pharmacokinetics of oral estradiol valerate are similar to those of oral estradiol.[29][6] 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.[29] This is also notably true for effects on hepatic protein synthesis (e.g., of {{abbrlink|SHBG|sex hormone-binding globulin}}), again after differences in molecular weight between the two compounds are considered.[29]

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.[31] These concentrations of estradiol and estrone are comparable to those observed with 1 and 2 mg/day oral estradiol.[31] 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.[29] A study found that, in accordance with their differences in molecular weights, oral estradiol produced higher levels of estradiol than oral estradiol valerate.[32] 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).[33] 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.[105]

Sublingual administration

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.[34][35] 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.[34][35] 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.[34][35] Sublingual estradiol valerate is also used in hormone therapy for transgender women.[36]

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).[34][35] Steady-state levels of estradiol were achieved within about 2 or 3 days.[34][35] 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.[34][35] 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.[34][35][37]

Intramuscular injection

In contrast to oral administration, the bioavailability of estradiol valerate is complete (i.e., 100%) via intramuscular injection.[29][6] 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.[29] 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.[29] 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.[29][38] 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.[6] In addition, a secondary depot may also be formed in adipose tissue.[6] 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.[29] The elimination half-life of intramuscularly administered estradiol valerate in oil is reported to be 4 to 5 days.[29]

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.[39] 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.[40] 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.[41] The duration of estradiol valerate at this dose and in this study was considered to be 7 to 8 days.[41] Other studies have found that larger doses of intramuscular estradiol valerate exceeding 20 mg have a duration of more than 15 days.[41] 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.

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.[42]

{{Pharmacokinetics of three estradiol esters by intramuscular injection}}{{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.[43][44]

Intravenous injection

The administration of estradiol valerate by intravenous injection has been studied.[29][40] It has been found to be very rapidly cleaved into estradiol.[29][40] The bioavailability and metabolism of estradiol valerate does not differ with intravenous versus intramuscular injection.[40]

Chemistry

{{See also|Estrogen ester|List of estrogen esters}}

Estradiol valerate is a synthetic estrane steroid and the C17β valerate (pentanoate) fatty acid ester of estradiol.[40][10] It is also known as estradiol 17β-valerate or as estra-1,3,5(10)-triene-3,17β-diol 17β-pentanoate.[40][10] 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.[40][10]

{{Structural properties of major estradiol esters}}

History

Estradiol valerate was patented by Ciba in 1940 and 1941, with a priority date of 1936.[23][46] It was synthesized and studied, along with a variety of other estradiol esters, by Karl Junkmann of Schering AG in 1953.[47][48] The medication first introduced for medical use by Squibb in 1954 under the brand name Delestrogen in the United States.[49][50] Subsequently, estradiol valerate was marketed widely in Europe as Progynon Depot and Progynova.[10][49] Along with estradiol benzoate (1936)[51][52] and estradiol cypionate (1952),[53] estradiol valerate has become one of the most widely used esters of estradiol.[54]

Society and culture

Generic names

Estradiol valerate is the generic name of the drug and its {{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|USAN|United States Adopted Name}}, {{abbrlink|BANM|British Approved Name}}, and {{abbrlink|JAN|Japanese Accepted Name}}, while oestradiol valerate was formerly its {{abbrlink|BANM|British Approved Name}}.[55][10][56]

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.[55][10][56]

Availability

{{See also|List of estrogens available in the United States}}

Oral estradiol valerate is used primarily in Europe, under the brand name Progynova.[57] Although oral estradiol valerate was previously available in the United States,[10] it is no longer available in this country except in combination with dienogest as a combined oral contraceptive (under the brand name Natazia).[22] 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.[22][10]

See also

  • Estradiol valerate/hydroxyprogesterone caproate
  • Estradiol valerate/norethisterone enantate

References

1. ^1 2 https://www.drugs.com/cons/estradiol-and-dienogest.html
2. ^{{cite book | author = Christoph Zink | title = Dictionary of Obstetrics and Gynecology | url = https://books.google.com/books?id=EQlvzV9V7xIC&pg=PA86 | accessdate = 20 May 2012 | date = 1 January 1988 | publisher = Walter de Gruyter | isbn = 978-3-11-085727-6 | page = 86}}
3. ^{{cite journal|last1=Stanczyk|first1=Frank Z.|last2=Archer|first2=David F.|last3=Bhavnani|first3=Bhagu R.|title=Ethinyl estradiol and 17β-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment|journal=Contraception|volume=87|issue=6|year=2013|pages=706–727|issn=0010-7824|doi=10.1016/j.contraception.2012.12.011|pmid=23375353}}
4. ^{{cite book|author1=Tommaso Falcone|author2=William W. Hurd|title=Clinical Reproductive Medicine and Surgery|url=https://books.google.com/books?id=fOPtaEIKvcIC&pg=PA22|year=2007|publisher=Elsevier Health Sciences|isbn=0-323-03309-1|pages=22,362,388}}
5. ^{{cite journal|last1=Stanczyk|first1=Frank Z.|last2=Archer|first2=David F.|last3=Bhavnani|first3=Bhagu R.|title=Ethinyl estradiol and 17β-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment|journal=Contraception|volume=87|issue=6|year=2013|pages=706–727|issn=0010-7824|doi=10.1016/j.contraception.2012.12.011|pmid=23375353}}
6. ^1 2 3 4 5 6 7 8 9 10 11 12 13 14 {{cite journal | vauthors = Kuhl H | title = Pharmacology of estrogens and progestogens: influence of different routes of administration | journal = Climacteric | volume = 8 Suppl 1 | issue = | pages = 3–63 | year = 2005 | pmid = 16112947 | doi = 10.1080/13697130500148875 | url = http://hormonebalance.org/images/documents/Kuhl%2005%20%20Pharm%20Estro%20Progest%20Climacteric_1313155660.pdf}}
7. ^1 2 3 4 5 6 7 {{cite book|author1=Michael Oettel|author2=Ekkehard Schillinger|title=Estrogens and Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogen|url=https://books.google.com/books?id=wBvyCAAAQBAJ&pg=PA261|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-60107-1|page=261|quote=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.}}
8. ^1 {{cite journal | vauthors = Cirigliano M | title = Bioidentical hormone therapy: a review of the evidence | journal = J Womens Health (Larchmt) | volume = 16 | issue = 5 | pages = 600–31 | date = June 2007 | pmid = 17627398 | doi = 10.1089/jwh.2006.0311 | url = }}
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10. ^1 2 3 4 5 6 7 8 9 {{cite book | title = Index Nominum 2000: International Drug Directory | url = https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA405 | accessdate = 20 May 2012 | year = 2000 | publisher = Taylor & Francis US | isbn = 978-3-88763-075-1 | page = 405}}
11. ^https://www.drugs.com/availability/generic-delestrogen.html
12. ^1 {{cite journal | vauthors = Guida M, Bifulco G, Di Spiezio Sardo A, Scala M, Fernandez LM, Nappi C | title = Review of the safety, efficacy and patient acceptability of the combined dienogest/estradiol valerate contraceptive pill | journal = International Journal of Women's Health | volume = 2 | issue = | pages = 279–90 | year = 2010 | pmid = 21151673 | pmc = 2990895 | doi = 10.2147/IJWH.S6954 | url = }}
13. ^1 {{cite journal | vauthors = Newton JR, D'arcangues C, Hall PE | title = A review of "once-a-month" combined injectable contraceptives | journal = J Obstet Gynaecol (Lahore) | volume = 4 Suppl 1 | issue = | pages = S1–34 | year = 1994 | pmid = 12290848 | doi = 10.3109/01443619409027641| url = }}
14. ^1 http://www.wjpps.com/download/article/1412071798.pdf
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17. ^1 {{cite journal | vauthors = Smith KP, Madison CM, Milne NM | title = Gonadal suppressive and cross-sex hormone therapy for gender dysphoria in adolescents and adults | journal = Pharmacotherapy | volume = 34 | issue = 12 | pages = 1282–97 | date = December 2014 | pmid = 25220381 | doi = 10.1002/phar.1487 | url = }}
18. ^1 {{cite book|author1=Randi Ettner|author2=Stan Monstrey|author3=Eli Coleman|title=Principles of Transgender Medicine and Surgery|url=https://books.google.com/books?id=LwszDAAAQBAJ&pg=PA216|date=20 May 2016|publisher=Routledge|isbn=978-1-317-51460-2|pages=216–}}
19. ^{{cite book|author1=Gianna E. Israel|author2=Donald E. Tarver|author3=Joy Diane Shaffer|title=Transgender Care: Recommended Guidelines, Practical Information, and Personal Accounts|url=https://books.google.com/books?id=IlPX6E5glDEC&pg=PA64|date=1 March 2001|publisher=Temple University Press|isbn=978-1-56639-852-7|pages=64–}}
20. ^1 2 3 4 5 6 7 8 https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/009402s052lbl.pdf
21. ^1 2 3 4  
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24. ^{{cite book|author=Muller|title=European Drug Index: European Drug Registrations, Fourth Edition|url=https://books.google.com/books?id=2HBPHmclMWIC&pg=PA276|date=19 June 1998|publisher=CRC Press|isbn=978-3-7692-2114-5|pages=276, 313, 379, 561, 566}}
25. ^{{cite book|author=Kenneth L. Becker|title=Principles and Practice of Endocrinology and Metabolism|url=https://books.google.com/books?id=FVfzRvaucq8C&pg=PA2153|year=2001|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-1750-2|pages=2153–}}
26. ^1 {{cite journal | vauthors = Devroey P, Pados G | title = Preparation of endometrium for egg donation | journal = Hum. Reprod. Update | volume = 4 | issue = 6 | pages = 856–61 | date = 1998 | pmid = 10098476 | doi = 10.1093/humupd/4.6.856 | url = | quote = 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 [...]}}
27. ^1 {{cite book|author=Amit K. Ghosh|title=Mayo Clinic Internal Medicine Board Review|url=https://books.google.com/books?id=LS65jBzoD40C&pg=PA222|date=23 September 2010|publisher=OUP USA|isbn=978-0-19-975569-1|pages=222–}}
28. ^1 {{cite journal | vauthors = Bishop BM | title = Pharmacotherapy Considerations in the Management of Transgender Patients: A Brief Review | journal = Pharmacotherapy | volume = 35 | issue = 12 | pages = 1130–9 | date = December 2015 | pmid = 26684553 | doi = 10.1002/phar.1668 | url = }}
29. ^1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 {{cite journal |vauthors=Düsterberg B, Nishino Y | title = Pharmacokinetic and pharmacological features of oestradiol valerate | journal = Maturitas | volume = 4 | issue = 4 | pages = 315–24 |date=December 1982 | pmid = 7169965 | doi = 10.1016/0378-5122(82)90064-0| url = http://linkinghub.elsevier.com/retrieve/pii/0378-5122(82)90064-0}}
30. ^{{cite web | url = https://www.drugs.com/uk/progynova-1mg-spc-3430.html | title = Progynova 1mg (SPC) | Drugs.com | work = | accessdate = 2012-09-06}}
31. ^1 {{cite journal | vauthors = O'Connell MB | title = Pharmacokinetic and pharmacologic variation between different estrogen products | journal = J Clin Pharmacol | volume = 35 | issue = 9 Suppl | pages = 18S–24S | year = 1995 | pmid = 8530713 | doi = 10.1002/j.1552-4604.1995.tb04143.x }}
32. ^1 {{cite journal | vauthors = Wiegratz I, Fink T, Rohr UD, Lang E, Leukel P, Kuhl H | title = Überkreuz-Vergleich der Pharmakokinetik von Estradiol unter der Hormonsubstitution mit Estradiolvalerat oder mikronisiertem Estradiol | trans-title = Cross-over comparison of the pharmacokinetics of estradiol during hormone replacement therapy with estradiol valerate or micronized estradiol | language = German | journal = Zentralbl Gynakol | volume = 123 | issue = 9 | pages = 505–12 | date = September 2001 | pmid = 11709743 | doi = 10.1055/s-2001-18223 | url = }}
33. ^{{cite journal | vauthors = Vree TB, Timmer CJ | title = Enterohepatic cycling and pharmacokinetics of oestradiol in postmenopausal women | journal = J. Pharm. Pharmacol. | volume = 50 | issue = 8 | pages = 857–64 | date = August 1998 | pmid = 9751449 | doi = 10.1111/j.2042-7158.1998.tb04000.x | url = }}
34. ^1 2 3 4 5 6 7 {{cite journal | vauthors = Serhal PF, Craft IL | title = Oocyte donation in 61 patients | journal = Lancet | volume = 1 | issue = 8648 | pages = 1185–7 | date = May 1989 | pmid = 2566746 | doi = 10.1016/S0140-6736(89)92762-1 | url = }}
35. ^1 2 3 4 5 6 7 {{cite journal | vauthors = Serhal P | title = Oocyte donation and surrogacy | journal = Br. Med. Bull. | volume = 46 | issue = 3 | pages = 796–812 | date = July 1990 | pmid = 2207608 | doi = 10.1093/oxfordjournals.bmb.a072432 | url = }}
36. ^{{cite journal | vauthors = Lim HH, Jang YH, Choi GY, Lee JJ, Lee ES | title = Gender affirmative care of transgender people: a single center's experience in Korea | journal = Obstet Gynecol Sci | volume = 62 | issue = 1 | pages = 46–55 | date = January 2019 | pmid = 30671393 | pmc = 6333764 | doi = 10.5468/ogs.2019.62.1.46 | url = | quote = When we prescribed estradiol, we preferred sublingual estradiol valerate instead of the oral form for feminizing HT since prior researchers have reported the effectiveness of sublingual administration in maintaining high blood estradiol concentration and low E1/E2 ratio [13].}}
37. ^{{cite journal | vauthors = Pines A, Averbuch M, Fisman EZ, Rosano GM | title = The acute effects of sublingual 17beta-estradiol on the cardiovascular system | journal = Maturitas | volume = 33 | issue = 1 | pages = 81–5 | date = September 1999 | pmid = 10585176 | doi = 10.1016/S0378-5122(99)00036-5 | url = }}
38. ^{{cite book | author = Sriram | title = Medicinal Chemistry | url = https://books.google.com/books?id=9HSoZrcBRl0C&pg=PA427 | accessdate = 20 May 2012 | publisher = Pearson Education India | isbn = 978-81-317-0031-0 | page = 427}}
39. ^{{cite book|author1=M. Notelovitz|author2=P.A. van Keep|title=The Climacteric in Perspective: Proceedings of the Fourth International Congress on the Menopause, held at Lake Buena Vista, Florida, October 28–November 2, 1984|url=https://books.google.com/books?id=VM0hBQAAQBAJ&pg=PA399|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-94-009-4145-8|pages=399–}}
40. ^1 2 3 {{cite journal | vauthors = Düsterberg B, Schmidt-Gollwitzer M, Hümpel M | title = Pharmacokinetics and biotransformation of estradiol valerate in ovariectomized women | journal = Horm. Res. | volume = 21 | issue = 3 | pages = 145–54 | date = 1985 | pmid = 2987096 | doi = 10.1159/000180039 | url = }}
41. ^1 2 3 {{cite journal | vauthors = Oriowo MA, Landgren BM, Stenström B, Diczfalusy E | title = A comparison of the pharmacokinetic properties of three estradiol esters | journal = Contraception | volume = 21 | issue = 4 | pages = 415–24 | date = April 1980 | pmid = 7389356 | doi = 10.1016/S0010-7824(80)80018-7 | url = }}
42. ^{{vcite2 journal | vauthors = Ulrich U, Pfeifer T, Lauritzen C | title = Rapid increase in lumbar spine bone density in osteopenic women by high-dose intramuscular estrogen-progestogen injections. A preliminary report | journal = Horm. Metab. Res. | volume = 26 | issue = 9 | pages = 428–31 | year = 1994 | pmid = 7835827 | doi = 10.1055/s-2007-1001723 | url = }}
43. ^{{cite journal | vauthors = Unger CA | title = Hormone therapy for transgender patients | journal = Transl Androl Urol | volume = 5 | issue = 6 | pages = 877–884 | date = December 2016 | pmid = 28078219 | pmc = 5182227 | doi = 10.21037/tau.2016.09.04 | url = }}
44. ^{{vcite2 journal | vauthors = Sierra-Ramírez JA, Lara-Ricalde R, Lujan M, Velázquez-Ramírez N, Godínez-Victoria M, Hernádez-Munguía IA, Padilla A, Garza-Flores J | title = Comparative pharmacokinetics and pharmacodynamics after subcutaneous and intramuscular administration of medroxyprogesterone acetate (25 mg) and estradiol cypionate (5 mg) | journal = Contraception | volume = 84 | issue = 6 | pages = 565–70 | year = 2011 | pmid = 22078184 | doi = 10.1016/j.contraception.2011.03.014 | url = }}
45. ^1 2 {{cite journal|last1=Shellenberger|first1=T. E.|title=Pharmacology of estrogens|year=1986|pages=393–410|doi=10.1007/978-94-009-4145-8_36|url=https://books.google.com/books?id=VM0hBQAAQBAJ&pg=PA401}}
46. ^https://patents.google.com/patent/US2205627A/en
47. ^{{cite journal | vauthors = Shoham Z, Kopernik G | title = Tools for making correct decisions regarding hormone therapy. part I: background and drugs | journal = Fertil. Steril. | volume = 81 | issue = 6 | pages = 1447–57 | date = June 2004 | pmid = 15193460 | doi = 10.1016/j.fertnstert.2003.10.052 | url = }}
48. ^{{cite journal|last1=Junkmann|first1=Karl|title=Über protrahiert wirksame Östrogene|trans-title=Over protracted effective estrogens|journal=Naunyn-Schmiedebergs Archiv für Experimentelle Pathologie und Pharmakologie|volume=220|issue=5|year=1953|issn=0028-1298|doi=10.1007/BF00246561}}
49. ^1 2 {{cite book|author=William Andrew Publishing|title=Pharmaceutical Manufacturing Encyclopedia, 3rd Edition|url=https://books.google.com/books?id=_J2ti4EkYpkC&pg=PA1477|date=22 October 2013|publisher=Elsevier|isbn=978-0-8155-1856-3|pages=1477–}}
50. ^1 {{cite book|author=Larry L. Duetsch|title=Research and development, market power, and patent policy in ethical drugs|url=https://books.google.com/books?id=4vdsAAAAMAAJ|year=1969|publisher=University of Wisconsin--Madison|page=95}}
51. ^{{cite book | author1 = Enrique Raviña | author2 = Hugo Kubinyi | title = The Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs | url = https://books.google.com/books?id=iDNy0XxGqT8C&pg=PA175 | accessdate = 20 May 2012 | date = 16 May 2011 | publisher = John Wiley & Sons | isbn = 978-3-527-32669-3 | page = 175}}
52. ^{{cite journal | author = Folley SJ | title = The effect of oestrogenic hormones on lactation and on the phosphatase of the blood and milk of the lactating cow | journal = The Biochemical Journal | volume = 30 | issue = 12 | pages = 2262–72 |date=December 1936 | pmid = 16746289 | pmc = 1263335 | doi = | url = http://www.biochemj.org/bj/30/2262/bj302262.pdf}}
53. ^{{cite book | author = Marshall Sittig | title = Pharmaceutical Manufacturing Encyclopedia | url = https://books.google.com/books?id=X2EyLsG4bcUC&pg=PA576 | accessdate = 20 May 2012 | date = 1 January 1988 | publisher = William Andrew | isbn = 978-0-8155-1144-1 | pages = 575–576}}
54. ^1 {{cite book | author = Samuel S. C. Yen | title = Reproductive endocrinology: physiology, pathophysiology, and clinical management | url = https://books.google.com/books?id=RN1qAAAAMAAJ | accessdate = 20 May 2012 | year = 1991 | publisher = Saunders | isbn = 978-0-7216-3206-3}}
55. ^1 2 3 4 5 6 {{cite book|author=J. Elks|title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies|url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA898|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=898–}}
56. ^1 https://www.drugs.com/international/estradiol.html
57. ^{{cite book|author=Joseph S. Sanfilippo|title=Primary Care in Obstetrics and Gynecology: A Handbook for Clinicians|url=https://books.google.com/books?id=jfmB3aNSGfoC&pg=PA227|date=January 1998|publisher=Springer Science & Business Media|isbn=978-0-387-94739-6|pages=227–}}

Further reading

  • {{cite journal | vauthors = Vermeulen A | title = Longacting steroid preparations | journal = Acta Clin Belg | volume = 30 | issue = 1 | pages = 48–55 | year = 1975 | pmid = 1231448 | doi = 10.1080/17843286.1975.11716973 | url = }}
  • {{cite journal | vauthors = Düsterberg B, Nishino Y | title = Pharmacokinetic and pharmacological features of oestradiol valerate | journal = Maturitas | volume = 4 | issue = 4 | pages = 315–24 | year = 1982 | pmid = 7169965 | doi = 10.1016/0378-5122(82)90064-0| url = }}
  • {{cite journal | vauthors = Sang GW | title = Pharmacodynamic effects of once-a-month combined injectable contraceptives | journal = Contraception | volume = 49 | issue = 4 | pages = 361–85 | year = 1994 | pmid = 8013220 | doi = 10.1016/0010-7824(94)90033-7| url = }}
  • {{cite journal | vauthors = O'Connell MB | title = Pharmacokinetic and pharmacologic variation between different estrogen products | journal = J Clin Pharmacol | volume = 35 | issue = 9 Suppl | pages = 18S–24S | year = 1995 | pmid = 8530713 | doi = 10.1002/j.1552-4604.1995.tb04143.x }}
  • {{cite journal | vauthors = Kuhl H | title = Pharmacology of estrogens and progestogens: influence of different routes of administration | journal = Climacteric | volume = 8 Suppl 1 | issue = | pages = 3–63 | year = 2005 | pmid = 16112947 | doi = 10.1080/13697130500148875 | url = http://hormonebalance.org/images/documents/Kuhl%2005%20%20Pharm%20Estro%20Progest%20Climacteric_1313155660.pdf}}
  • {{cite journal|last1=Stanczyk|first1=Frank Z.|last2=Archer|first2=David F.|last3=Bhavnani|first3=Bhagu R.|title=Ethinyl estradiol and 17β-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment|journal=Contraception|volume=87|issue=6|year=2013|pages=706–727|issn=0010-7824|doi=10.1016/j.contraception.2012.12.011|pmid=23375353}}
{{Estradiol}}{{Estrogens and antiestrogens}}{{Estrogen receptor modulators}}

10 : Alcohols|Antigonadotropins|Estradiol esters|Estranes|Hormonal antineoplastic drugs|Prodrugs|Prostate cancer|Synthetic estrogens|Valerates|Transgender_and_medicine
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