View source for Estradiol valerate

{{Short description|Chemical compound}}
{{Use dmy dates|date=December 2023}}{{cs1 config|name-list-style=vanc}}{{Use PMID reference names|date=December 2023}}
{{Infobox drug
| Verifiedfields     = 
| Watchedfields      = 
| verifiedrevid      = 
| IUPAC_name         = [(8''R'',9''S'',13''S'',14''S'',17''S'')-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

<!--Clinical data-->| pronounce          = {{IPAc-en|ˌ|ɛ|s|t|r|ə|ˈ|d|aɪ|oʊ|l|_|ˈ|v|æ|l|ə|r|eɪ|t|audio=LL-Q1860 (eng)-NaomiAmethyst-estradiol valerate.wav}}<br />{{respell|ES|trə|DY|ohl|_|VAL|ə|rayt}}<ref name="Drugs.com2">{{Cite web|url=https://www.drugs.com/cons/estradiol-and-dienogest.html|title=Estradiol and dienogest Advanced Patient Information|website=Drugs.com}}</ref>
| tradename          = Delestrogen, Progynon Depot, Progynova, many others
| pregnancy_AU       = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_US       = <!-- A / B / C / D / X -->
| pregnancy_category = 
| legal_AU           = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->
| legal_CA           = 
| legal_UK           = 
| legal_US           = Rx-only
| legal_status       = Rx-only
| routes_of_administration = [[Oral administration|By mouth]], [[sublingual administration|sublingual]], [[intramuscular injection]],<ref name="Zink-1988">{{Cite book | vauthors = Zink C |url=https://books.google.com/books?id=EQlvzV9V7xIC&pg=PA86 |title=Dictionary of Obstetrics and Gynecology |date=1 January 1988 |publisher=Walter de Gruyter |isbn=978-3-11-085727-6 |page=86 |access-date=20 May 2012}}</ref> [[subcutaneous injection]]
| class              = [[Estrogen (medication)|Estrogen]]; [[Estrogen ester]]

<!--Pharmacokinetic data-->| bioavailability    = Oral: 3–5%<ref name="pmid7169965" /><ref name="pmid16112947" /><br />{{abbr|IM|Intramuscular injection}} injection: 100%<ref name="pmid8013217">{{cite journal | vauthors = Seibert B, Günzel P | title = Animal toxicity studies performed for risk assessment of the once-a-month injectable contraceptive Mesigyna | journal = Contraception | volume = 49 | issue = 4 | pages = 303–333 | date = April 1994 | pmid = 8013217 | doi = 10.1016/0010-7824(94)90030-2 }}</ref><ref name="pmid7169965" />
| protein_bound      = Estradiol: ~98% (to [[human serum albumin|albumin]] and {{abbrlink|SHBG|sex hormone-binding globulin}})<ref name="pmid23375353">{{cite journal | vauthors = Stanczyk FZ, Archer DF, Bhavnani BR | title = Ethinyl estradiol and 17β-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment | journal = Contraception | volume = 87 | issue = 6 | pages = 706–727 | date = June 2013 | pmid = 23375353 | doi = 10.1016/j.contraception.2012.12.011 }}</ref><ref name="Falcone-2007">{{Cite book | vauthors = Falcone T, Hurd WW |url=https://books.google.com/books?id=fOPtaEIKvcIC&pg=PA22 |title=Clinical Reproductive Medicine and Surgery|publisher=Elsevier Health Sciences |year=2007 |isbn=978-0-323-03309-1 |pages=22,362,388}}</ref>
| metabolism         = [[Bond cleavage|Cleavage]] via [[esterase]]s in the [[liver]], [[blood]], and [[tissue (biology)|tissue]]s<ref name="pmid7169965" />
| metabolites        = [[Estradiol (medication)|Estradiol]], [[valeric acid]], and [[metabolite]]s of estradiol<ref name="pmid7169965" />
| elimination_half-life = Oral: 12–20 hours (as {{abbr|E2|estradiol}})<ref name="pmid7169965" /><ref name="pmid23375353"/><br />{{abbr|IM|Intramuscular injection}} injection: 3.5 (1.2–7.2) days<ref name="pmid22257576" />
| duration_of_action = {{abbr|IM|Intramuscular injection}} injection:<br />• 5&nbsp;mg: 7–8&nbsp;days<ref name="pmid7389356" /><br />• 10&nbsp;mg: 10–14&nbsp;days<ref name="Lauritzen-1988" /><ref name="Labhart-2012">{{Cite book | vauthors = Labhart A  |url=https://books.google.com/books?id=DAgJCAAAQBAJ&pg=PA551 |title=Clinical Endocrinology: Theory and Practice |date=6 December 2012 |publisher=Springer Science & Business Media |isbn=978-3-642-96158-8 |pages=551–}}</ref><br />• 40&nbsp;mg: 2–3&nbsp;weeks<ref name="Lauritzen-1988" /><br />• 100&nbsp;mg: 3–4&nbsp;weeks<ref name="Lauritzen-1988" />
| excretion          = [[Urine]] (80%)<ref name="pmid7169965" />

<!-- Identifiers -->| 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

<!--Chemical data-->| C                  = 23
| H                  = 32
| O                  = 3
| 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

<!-- Physical data -->| melting_point      = 144
| melting_high       = 145
}}
<!-- Definition and medical uses -->

'''Estradiol valerate''' ('''EV'''), sold for use [[oral administration|by mouth]] under the brand name '''Progynova''' and for use by [[injection (medicine)|injection]] under the brand names '''Delestrogen''' and '''Progynon Depot''' among others, is an [[estrogen (medication)|estrogen]] medication. It is used in [[menopausal hormone therapy|hormone therapy]] for [[menopausal symptoms]] and [[hypoestrogenism|low estrogen levels]], [[transgender hormone therapy (male-to-female)|hormone therapy]] for [[transgender]] people, and in [[hormonal contraception|hormonal birth control]].<ref name="pmid16112947">{{cite journal | vauthors = Kuhl H | title = Pharmacology of estrogens and progestogens: influence of different routes of administration | journal = Climacteric | volume = 8 | issue = Suppl 1 | pages = 3–63 | date = August 2005 | pmid = 16112947 | doi = 10.1080/13697130500148875 | s2cid = 24616324 }}</ref><ref name="pmid7169965" /><ref name="Delestrogen-Label" /><ref name="Progynova-Label" /> It is also used in the treatment of [[prostate cancer]].<ref name="Delestrogen-Label" /> The medication is taken [[oral administration|by mouth]] or by [[intramuscular injection|injection into muscle]] or [[subcutaneous injection|fat]] once every 1 to 4&nbsp;weeks.<ref name="Delestrogen-Label" /><ref name="Progynova-Label" />[[File:Progynova (estradiol valerate) tablets in the Chinese mainland.jpg|thumb|Progynova (estradiol valerate) 1 mg oral tablets in the Chinese mainland]]

<!-- Side effects and mechanism -->
[[Side effect]]s of estradiol valerate include [[breast tenderness]], [[breast enlargement]], [[nausea]], [[headache]], and [[water retention (medicine)|fluid retention]].<ref name="Ghosh-2010" /><ref name="Delestrogen-Label" /><ref name="Progynova-Label" /> Estradiol valerate is an [[estrogen (medication)|estrogen]] and hence is an [[agonist]] of the [[estrogen receptor]], the [[biological target]] of [[estrogen]]s like [[estradiol]].<ref name="pmid16112947" /><ref name="pmid7169965" /><ref name="Oettel-2012" /> It is an [[estrogen ester]] and a [[prodrug]] of [[estradiol (medication)|estradiol]] in the body.<ref name="Oettel-2012" /><ref name="pmid16112947" /><ref name="pmid7169965" /> Because of this, it is considered to be a [[natural product|natural]] and [[bioidentical hormone replacement therapy|bioidentical]] form of estrogen.<ref name="Oettel-2012">{{Cite book | vauthors = Oettel M, Schillinger E |url=https://books.google.com/books?id=wBvyCAAAQBAJ&pg=PA261 |title=Estrogens and Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogen |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.}}</ref><ref name="pmid17627398">{{cite journal | vauthors = Cirigliano M | title = Bioidentical hormone therapy: a review of the evidence | journal = Journal of Women's Health | volume = 16 | issue = 5 | pages = 600–631 | date = June 2007 | pmid = 17627398 | doi = 10.1089/jwh.2006.0311 }}</ref><ref name="pmid7169965" /><ref name="Seth-2012">{{Cite book | vauthors = Seth S, Nagrath A, Deoghare R | chapter = Injectable Contraceptives Till Date | veditors = Arun N, Narendra M, Shikha S |chapter-url=https://books.google.com/books?id=AS3UBAAAQBAJ&pg=PA419 |title=Progress in Obstetrics and Gynecology--3 |date=15 December 2012 |publisher=Jaypee Brothers Medical Publishers Pvt. Ltd. |isbn=978-93-5090-575-3 |pages=419–}}</ref>

<!-- History, society, and culture -->
Estradiol valerate was first described in 1940 and was introduced for medical use in 1954.<ref name="Kleemann-2014" /><ref name="Publishing2013" /><ref name="Duetsch-1969" /> Along with [[estradiol cypionate]], it is one of the most widely used esters of estradiol.<ref name="Yen-1991" /> Estradiol valerate is used in the [[United States]], [[Canada]], [[Europe]], and throughout much of the rest of the world.<ref name="Elks-2014" /><ref name="IndexNominum2000">{{Cite book |url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA405 |title=Index Nominum 2000: International Drug Directory |publisher=Taylor & Francis US |year=2000 |isbn=978-3-88763-075-1 |page=405 |access-date=20 May 2012}}</ref> It is available as a [[generic drug|generic medication]].<ref name="Drugs.com-Generic">{{Cite web|url=https://www.drugs.com/availability/generic-delestrogen.html|title=Generic Delestrogen Availability|website=Drugs.com}}</ref>

{{TOC limit|3}}

==Medical uses==
{{See also|Estradiol (medication)#Medical uses}}

The [[medical use]]s of estradiol valerate are the same as those of estradiol and other estrogens. Examples of indications for the medication include [[hormone replacement therapy|hormone therapy]] and [[hormonal contraception]]. In regard to the latter, estradiol valerate is available in combination with a [[progestin]] as a [[combined oral contraceptive|combined]] [[estradiol-containing oral contraceptive]] (with [[dienogest]])<ref name="pmid21151673">{{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 | pages = 279–290 | date = August 2010 | pmid = 21151673 | pmc = 2990895 | doi = 10.2147/IJWH.S6954 | doi-access = free }}</ref> and as a [[combined injectable contraceptive]].<ref name="pmid12290848">{{cite journal | vauthors = Newton JR, D'arcangues C, Hall PE | title = A review of "once-a-month" combined injectable contraceptives | journal = Journal of Obstetrics and Gynaecology | volume = 4 | issue = Suppl 1 | pages = S1-34 | year = 1994 | pmid = 12290848 | doi = 10.3109/01443619409027641 }}</ref><ref name="pmid19076955">{{cite journal | vauthors = Rowlands S | title = New technologies in contraception | journal = BJOG | volume = 116 | issue = 2 | pages = 230–239 | date = January 2009 | pmid = 19076955 | doi = 10.1111/j.1471-0528.2008.01985.x | s2cid = 3415547 | url = http://wrap.warwick.ac.uk/28852/1/WRAP_Rowlands_NewtechnologiesincontraceptionBJOG2008_Uni_repos_version.pdf }}</ref> 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]].<ref name="pmid28159148">{{cite journal | vauthors = Wesp LM, Deutsch MB | title = Hormonal and Surgical Treatment Options for Transgender Women and Transfeminine Spectrum Persons | journal = The Psychiatric Clinics of North America | volume = 40 | issue = 1 | pages = 99–111 | date = March 2017 | pmid = 28159148 | doi = 10.1016/j.psc.2016.10.006 }}</ref><ref name="pmid25220381">{{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 = 1282–1297 | date = December 2014 | pmid = 25220381 | doi = 10.1002/phar.1487 | s2cid = 26979177 }}</ref><ref name="Ettner-2016">{{Cite book | vauthors = Ettner R, Monstrey S, Coleman E  |url=https://books.google.com/books?id=LwszDAAAQBAJ&pg=PA216 |title=Principles of Transgender Medicine and Surgery  |date=20 May 2016 |publisher=Routledge |isbn=978-1-317-51460-2 |pages=216–}}</ref><ref name="Israel-2001">{{Cite book | vauthors = Israel GE, Tarver DE, Shaffer JD |url=https://books.google.com/books?id=IlPX6E5glDEC&pg=PA64 |title=Transgender Care: Recommended Guidelines, Practical Information, and Personal Accounts |date=1 March 2001 |publisher=Temple University Press |isbn=978-1-56639-852-7 |pages=64–}}</ref> It is also used as a form of high-dose estrogen therapy in the treatment of prostate cancer in men.<ref name="Delestrogen-Label" /> Low-dose oral estradiol valerate (2–6&nbsp;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 inhibitor]]s as well.<ref name="pmid27889048">{{cite journal | vauthors = Coelingh Bennink HJ, Verhoeven C, Dutman AE, Thijssen J | title = The use of high-dose estrogens for the treatment of breast cancer | journal = Maturitas | volume = 95 | pages = 11–23 | date = January 2017 | pmid = 27889048 | doi = 10.1016/j.maturitas.2016.10.010 | doi-access = free }}</ref><ref name="pmid23933149">{{cite journal | vauthors = Palmieri C, Patten DK, Januszewski A, Zucchini G, Howell SJ | title = Breast cancer: current and future endocrine therapies | journal = Molecular and Cellular Endocrinology | volume = 382 | issue = 1 | pages = 695–723 | date = January 2014 | pmid = 23933149 | doi = 10.1016/j.mce.2013.08.001 | s2cid = 3363705 }}</ref> Injectable estradiol valerate has been used to suppress [[sex drive]] in [[sex offender]]s.<ref name="Chatz-1972">{{cite journal | vauthors = Chatz TL | title = Recognizing and Treating Dangerous Sex Offenders | journal = International Journal of Offender Therapy and Comparative Criminology | date = June 1972 | volume = 16 | issue = 2 | pages = 109–115 | issn = 0306-624X | eissn = 1552-6933 | doi = 10.1177/0306624X7201600202 | pmid = | s2cid = 74365268 | url = }}</ref>

In the [[United States]], the approved indications of estradiol valerate injections include the treatment of moderate to severe [[hot flash]]es 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 care|palliative]] treatment of [[advanced prostate cancer]] in men.<ref name="Delestrogen-Label">{{cite web | title = DELESTROGEN (estradiol valerate injection, USP) | date = November 2017 | url = https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/009402s052lbl.pdf | archive-url = https://web.archive.org/web/20190329131413/https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/009402s052lbl.pdf | url-status = dead | archive-date = 29 March 2019 | work = Par Pharmaceutical, Inc. | publisher = U.S. Food and Drug Administration }}</ref> 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.<ref name="Progynova-Label">{{cite web | title = PROGYNOVA Product Information | date = 20 October 2016 | url = http://www.bayerresources.com.au/resources/uploads/pi/file9418.pdf | archive-url = https://web.archive.org/web/20180916055936/http://www.bayerresources.com.au/resources/uploads/pi/file9418.pdf | archive-date = 16 September 2018 | work = Bayer group, Germany }}</ref> Such symptoms may include hot flashes, [[sweating|outbreaks of sweat]], [[sleep disturbance]]s, [[depression (mood)|depressive mood]]s, [[irritability]], [[headache]]s, and [[dizziness]].<ref name="Progynova-Label" />

Estradiol valerate by intramuscular injection is usually used at a dosage of 10 to 20&nbsp;mg every 4&nbsp;weeks in the treatment of menopausal symptoms and hypoestrogenism due to hypogonadism, castration, or primary ovarian failure in women.<ref name="Delestrogen-Label" /> In the past, it was used at even higher doses of 10 to 40&nbsp;every 1 to 4&nbsp;weeks for estrogen replacement.<ref name="AMA1977">{{Cite book | author1 = American Medical Association. Dept. of Drugs |url=https://books.google.com/books?id=0h7s_rfEZgkC |title=AMA drug evaluations | author2 = Council on Drugs (American Medical Association) | author3 = American Society for Clinical Pharmacology and Therapeutics |date=1 February 1977 |publisher=Publishing Sciences Group |isbn=978-0-88416-175-2 |pages=540–572 |chapter=Estrogens, Progestagens, Oral Contraceptives, and Ovulatory Agents |quote=Intramuscular: For replacement therapy, (Estradiol, Estradiol Benzoate) 0.5 to 1.5 mg two or three times weekly; (Estradiol Cypionate) 1 to 5 mg weekly for two or three weeks; (Estradiol Dipropionate) 1 to 5 mg every one to two weeks; (Estradiol Valerate) 10 to 40 mg every one to four weeks.}}</ref> Estradiol valerate is usually used in the treatment of advanced prostate cancer in men at a dosage of 30&nbsp;mg or more every 1 to 2&nbsp;weeks by intramuscular injection.<ref name="Delestrogen-Label" /> In transgender women, estradiol valerate given by intramuscular injection is usually used at a dosage of 5 to 20&nbsp;mg, but up to 30 to 40&nbsp;mg, once every 2&nbsp;weeks.<ref name="pmid25220381" /><ref name="Ettner-2016" /><ref name="pmid28159148" /> Estradiol valerate has also been used at a dose of 10 to 40&nbsp;mg by intramuscular injection to [[hemostasis|limit bleeding]] in women with [[hemorrhage]] due to [[dysfunctional uterine bleeding]].<ref name="Horský-1981">{{Cite book | vauthors = Horský J, Presl J |title=Ovarian Function and its Disorders |date=1981 |publisher=Springer Science & Business Media |isbn=978-94-009-8195-9 | veditors = Horsky J, Presl J |pages=309–332 |chapter=Hormonal Treatment of Disorders of the Menstrual Cycle |doi=10.1007/978-94-009-8195-9_11 |chapter-url=https://books.google.com/books?id=7IrpCAAAQBAJ&pg=PA310}}</ref>{{Rp|318}}<ref name="Piersol-1975">{{Cite book | vauthors = Piersol G |url=https://books.google.com/books?id=RiE9K5bgKcsC |title=The Cyclopedia of Medicine, Surgery, Specialties |publisher=F. A. Davis Company |year=1975}}</ref>{{RP|60}}

{{Estrogen dosages for menopausal hormone therapy}}

===Available forms===
{{See also|Estradiol valerate/norethisterone enantate|Estradiol valerate/hydroxyprogesterone caproate|Estradiol valerate/prasterone enanthate}}

Estradiol valerate is and has been available in the form of [[vial]]s and [[ampoule]]s of [[oil solution]] for intramuscular injection in concentrations of 4, 5, 10, 20, and 40&nbsp;mg/mL and in the form of oral [[tablet (pharmacy)|tablet]]s at doses of 0.5, 1, 2, and 4&nbsp;mg per tablet.<ref name="Drugs@FDA2">{{Cite web |title=Drugs@FDA: FDA Approved Drug Products |url=https://www.accessdata.fda.gov/scripts/cder/daf/ |access-date=16 November 2016 |publisher=United States Food and Drug Administration}}</ref><ref name="Kleemann-2014">{{Cite book | vauthors = Kleemann A, Engel J, Kutscher B, Reichert D |url=https://books.google.com/books?id=fO2IAwAAQBAJ&pg=PA1167 |title=Pharmaceutical Substances, 5th Edition, 2009: Syntheses, Patents and Applications of the most relevant APIs  |date=14 May 2014 |publisher=Thieme |isbn=978-3-13-179525-0 |pages=1167–1174}}</ref><ref name="Muller1998b">{{Cite book | vauthors = Muller |url=https://books.google.com/books?id=2HBPHmclMWIC&pg=PA276 |title=European Drug Index: European Drug Registrations | edition = Fourth |date=19 June 1998 |publisher=CRC Press |isbn=978-3-7692-2114-5 |pages=276, 313, 379, 561, 566}}</ref><ref name="Becker-2001">{{Cite book | vauthors = Becker KL |url=https://books.google.com/books?id=FVfzRvaucq8C&pg=PA2153 |title=Principles and Practice of Endocrinology and Metabolism |publisher=Lippincott Williams & Wilkins |year=2001 |isbn=978-0-7817-1750-2 |pages=2153–}}</ref> In the [[United States]], it is specifically available in formulations of 10, 20, and 40&nbsp;mg/mL in oil solution (as Delestrogen, as well as [[generic drug|generics]]).<ref name="Drugs@FDA2" /> Aside from estradiol valerate, the only other injectable estrogen formulations that remain available in the United States are [[estradiol cypionate]] (5&nbsp;mg/mL in oil solution) and [[conjugated estrogens]] (25&nbsp;mg/vial in solution).<ref name="Drugs@FDA2" /> Some or all oral estradiol valerate tablets are [[micronization|micronized]], similarly to oral estradiol tablets.<ref name="pmid10098476">{{cite journal | vauthors = Devroey P, Pados G | title = Preparation of endometrium for egg donation | journal = Human Reproduction Update | volume = 4 | issue = 6 | pages = 856–861 | date = 1998 | pmid = 10098476 | doi = 10.1093/humupd/4.6.856 | 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 [...] | doi-access =  }}</ref>

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&nbsp;mg/mL in combination with the progestin [[hydroxyprogesterone caproate]] and with the progestin [[norethisterone enantate]] as [[combined injectable contraceptive]]s.<ref name="Drugs@FDA2" /><ref name="pmid21151673" /><ref name="pmid12290848" /><ref name="pmid19076955" /><ref name="Drugs.com2" /> Intramuscular estradiol valerate is also marketed at a concentration of 4&nbsp;mg/mL in combination with the weak [[androgen]] and [[neurosteroid]] [[prasterone enanthate]] ({{abbr|DHEA|dehydroepiandrosterone}} enanthate) and with the androgen [[testosterone enantate]] for use in menopausal hormone therapy, but the latter formulation has been discontinued.<ref name="Notelovitz-2012">{{Cite book | vauthors = Notelovitz M, van Keep PA |url=https://books.google.com/books?id=VM0hBQAAQBAJ&pg=PA397 |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 |date=6 December 2012 |publisher=Springer Science & Business Media |isbn=978-94-009-4145-8 |pages=397, 399}}</ref><ref name="Drugs@FDA2" /> The availability of estradiol valerate-containing products varies throughout the world.<ref name="Drugs.com2" />

{{Available forms of estradiol}}

==Contraindications==
{{See also|Estradiol (medication)#Contraindications}}

[[Contraindication]]s of estrogens include [[coagulation]] problems, [[cardiovascular disease]]s, [[liver disease]], and certain [[hormone-sensitive cancer]]s such as [[breast cancer]] and [[endometrial cancer]], among others.<ref name="pmid2215269" /><ref name="Lauritzen-2005">{{Cite book | vauthors = Lauritzen C, Studd JW |url=https://books.google.com/books?id=WD7S7677xUUC&pg=PA95 |title=Current Management of the Menopause  |date=22 June 2005 |publisher=CRC Press |isbn=978-0-203-48612-2 |pages=95–98,488}}</ref><ref name="Laurtizen-2001">{{Cite book | vauthors = Laurtizen C |title=Menopause – Andropause: Hormone Replacement Therapy Through the Ages |publisher=Krause & Pachernegg: Gablitz |year=2001 |isbn=978-3-901299-34-6 | veditors = Fisch FH |pages=67–88 |chapter=Hormone Substitution Before, During and After Menopause |chapter-url=https://www.kup.at/kup/pdf/4978.pdf}}</ref><ref name="Midwinter-1976">{{Cite book | vauthors = Midwinter A |title=The Management of the Menopause & Post-Menopausal Years: The Proceedings of the International Symposium held in London 24–26 November 1975 Arranged by the Institute of Obstetrics and Gynaecology, The University of London |publisher=MTP Press Limited |year=1976 |isbn=978-94-011-6167-1 | veditors = Campbell S |pages=377–382 |chapter=Contraindications to estrogen therapy and management of the menopausal syndrome in these cases |doi=10.1007/978-94-011-6165-7_33}}</ref>

==Side effects==
{{See also|Estradiol (medication)#Side effects}}

The [[side effect]]s of estradiol valerate are the same as those of estradiol. Examples of such side effects include [[breast tenderness]] and [[breast enlargement|enlargement]], [[nausea]], [[bloating]], [[edema]], [[headache]], and [[melasma]].<ref name="Ghosh-2010">{{Cite book | vauthors = Ghosh AK |url=https://books.google.com/books?id=LS65jBzoD40C&pg=PA222 |title=Mayo Clinic Internal Medicine Board Review |date=23 September 2010 |publisher=OUP USA |isbn=978-0-19-975569-1 |pages=222–}}</ref><ref name="pmid26684553">{{cite journal | vauthors = Bishop BM | title = Pharmacotherapy Considerations in the Management of Transgender Patients: A Brief Review | journal = Pharmacotherapy | volume = 35 | issue = 12 | pages = 1130–1139 | date = December 2015 | pmid = 26684553 | doi = 10.1002/phar.1668 | s2cid = 37001563 }}</ref> [[High-dose estrogen]] therapy with estradiol valerate injections may also cause an increased risk of [[thromboembolism]], changes in [[blood lipids|blood lipid]] [[lipid profile|profile]], increased [[insulin resistance]], and increased levels of [[prolactin]].<ref name="pmid26684553" />

==Overdose==
{{See also|Estradiol (medication)#Overdose}}

Estradiol valerate has been used at very high doses of 40 to 100&nbsp;mg once per week in women and men, without overt signs of acute [[toxicity]] observed.<ref name="Göretzlehner-2008">{{Cite book | vauthors = Göretzlehner G, Lauritzen C, Göretzlehner U |title=Praktische Hormontherapie in der Gynäkologie|date=10 December 2008 |publisher=Walter de Gruyter |isbn=978-3-11-020864-1 |pages=245–314 |chapter=Hormontherapie bei gynäkologischen Erkrankungen |quote=Dosierungsbeispiele bei Mammahypoplasie und Infantilismus [...] Parenteral 1. 40 mg Estradiolvalerat (Estradiol-Depot 10 mg JENAPHARM) und 250 mg Hydroxyprogesteroncaproat (Progesteron-Depot JENAPHARM, Proluton Depot) i. m. einmal wöchentlich über 15–20 Wochen lang. 2. 20–40 mg Estradiolvalerat (Estradiol-Depot 10 mg JENAPHARM) i. m. in der ersten und zweiten Woche. 40 mg Estradiolvalerat (Estradiol-Depot 10 mg JENAPHARM) und 250 mg Hydroxyprogesteroncaproat (Progesteron-Depot JENAPHARM, Proluton Depot) i. m. in der dritten und vierten Woche. Therapiedauer 4–5 Monate. Evtl. Abstand zwischen 2 Injektionen auf 2 Wochen erweitern (Abb. 6.2). |chapter-url=https://books.google.com/books?id=E3SuivmVMnQC&pg=PA245}}</ref><ref name="pmid7835827" /><ref name="pmid6014870">{{cite journal | vauthors = Notter G, Kaigas M | title = [The treatment of inoperable and metastasizing breast carcinoma with gestational and estrogenci hormones] | language = de | journal = Munchener Medizinische Wochenschrift | volume = 108 | issue = 39 | pages = 1920–1923 | date = September 1966 | pmid = 6014870 | trans-title = The treatment of inoperable and metastasizing breast carcinoma with gestational and estrogenic hormones }}</ref><ref name="pmid5529652">{{cite journal | vauthors = Berndt G, Stender HS | title = [The combined estrogen-gestagen treatment of metastasizing mammary carcinoma using with SH 834] | language = de | journal = Deutsche Medizinische Wochenschrift | volume = 95 | issue = 48 | pages = 2399+ | date = November 1970 | pmid = 5529652 | doi = 10.1055/s-0028-1108843 | s2cid = 70908169 | trans-title = The combined estrogen-gestagen treatment of metastasizing mammary carcinoma using with SH 834 }}</ref><ref name="Berndt">{{Cite journal |vauthors=Berndt G, Eckel H, Notter G, Stender HS |title=Die Wirkung einer Ostrogen-Gestagen-Kombinationstherapie beim fortgeschrittenen Mammakarzinom mit besonderer Berucksichtigung der Lungenmetastasen |trans-title=Effect of combined estrogen-gestagen therapy on advanced breast carcinoma with special consideration of lung metastases |url=https://www.popline.org/node/485956 |journal=Strahlentherapie |language=de |volume=141 |issue=5 |pages=540–548 |issn=0039-2073}}</ref><ref name="pmid1202923">{{cite journal | vauthors = Notter G, Berndt G | title = Hormonal treatment of mammary carcinoma with Progynon-Depot and Depostat | journal = Acta Radiologica | volume = 14 | issue = 5 | pages = 433–442 | date = October 1975 | pmid = 1202923 | doi = 10.3109/02841867509132684 }}</ref><ref name="pmid968923">{{cite journal | vauthors = Firusian N, Schietzel M | title = [Additive treatment of metastasizing breast cancer with special reference to postmenopausal age (results of a randomized study)] | language = de | journal = Strahlentherapie | volume = 152 | issue = 3 | pages = 235–247 | date = September 1976 | pmid = 968923 | trans-title = Additive treatment of metastasizing breast cancer with special reference to postmenopausal age (results of a randomized study) }}</ref><ref name="pmid4142204">{{cite journal | vauthors = Schubert GE, Ziegler H, Völter D | title = [Comparison of histological and cytological studies of the prostate with special reference to oestrogene induced changes (author's transl)] | language = de | journal = Verhandlungen der Deutschen Gesellschaft für Pathologie | volume = 57 | pages = 315–318 | year = 1973 | pmid = 4142204 | url = https://www.popline.org/node/508573 | trans-title = Comparison of histological and cytological studies of the prostate with special reference to oestrogene induced changes | access-date = 11 June 2019 | archive-date = 23 November 2018 | archive-url = https://web.archive.org/web/20181123201118/https://www.popline.org/node/508573 | url-status = dead }}</ref><ref name="pmid4142482">{{cite journal | vauthors = Ziegler H, Völter D, Schubert GE | title = Morphological criteria for the control of carcinoma of the prostate with estrogen therapy | journal = International Urology and Nephrology | volume = 6 | issue = 3–4 | pages = 195–200 | year = 1974 | pmid = 4142482 | doi = 10.1007/BF02089265 | s2cid = 39028149 }}</ref><ref name="Benjamin-1966">{{Cite book | vauthors = Benjamin H, Lal GB, Green R, Masters RE |url=https://books.google.com/books?id=hArbAAAAMAAJ |title=The Transsexual Phenomenon  |publisher=Ace Publishing Company |year=1966 |page=107 |quote=In my own practice, Squibb's Delestrogen for intramuscular injections was employed with much satisfaction and positive results. This is a slowly absorbing, well-tolerated, potent preparation (chemically, Estradiol Valerate), and was applied in doses of 20 to 60 mg. (½ to 1 ½ cc.). Usually 30 to 60 mg. of Delalutin (Squibb) was added, an equally potent progesterone. This combination was given once a week or once in two to three weeks, according to the response as measured by the patient's emotional balance and physical feminization symptoms. Generally I found that dosage seems less important than length and regularity of administration.}}</ref><ref name="Benjamin-1967">{{Cite journal | vauthors = Benjamin H |year=1967 |title=Transvestism and Transsexualism in the male and female1 |journal=Journal of Sex Research |volume=3 |issue=2 |pages=107–127 |doi=10.1080/00224496709550519 |issn=0022-4499 |quote=Estrogen treatment—as already indicated—helps greatly but does not cure. I have employed either Squibb's Delestrogen, a slowly absorbing, highly potent preparation which is, chemically, estradiol valerate (40 mg. to 1 cc); or the still more potent Delestrec, which is estradiol undecylate (100 mg. to 1 cc). This preparation, however, is not yet on the market in this country, though it is widely used in Europe. In the majority of cases, I used from 30 to 100 mg. weekly, or every two to three weeks, by intramuscular injection.}}</ref> [[Symptom]]s of estrogen [[overdose|overdosage]] may include [[nausea]], [[vomiting]], [[bloating]], [[weight gain|increased weight]], [[water retention (medicine)|water retention]], [[breast tenderness]], [[vaginal discharge]], [[heavy legs]], and [[leg cramps]].<ref name="pmid2215269">{{cite journal | vauthors = Lauritzen C | title = Clinical use of oestrogens and progestogens | journal = Maturitas | volume = 12 | issue = 3 | pages = 199–214 | date = September 1990 | pmid = 2215269 | doi = 10.1016/0378-5122(90)90004-P }}</ref> These side effects can be diminished by reducing the estrogen dosage.<ref name="pmid2215269" />

== Interactions ==

{{See also|Estradiol (medication)#Interactions}}

[[Enzyme inhibitor|Inhibitor]]s and [[enzyme inducer|inducer]]s of [[cytochrome P450]] may influence the [[metabolism]] of estradiol and by extension circulating estradiol levels.<ref name="pmid11741520">{{cite journal | vauthors = Cheng ZN, Shu Y, Liu ZQ, Wang LS, Ou-Yang DS, Zhou HH | title = Role of cytochrome P450 in estradiol metabolism in vitro | journal = Acta Pharmacologica Sinica | volume = 22 | issue = 2 | pages = 148–154 | date = February 2001 | pmid = 11741520 }}</ref>

==Pharmacology==
[[File:Estradiol.svg|thumb|right|225px|[[Estradiol (medication)|Estradiol]], the [[active metabolite|active form]] of estradiol valerate.]]

===Pharmacodynamics===
{{See also|Pharmacodynamics of estradiol}}

Estradiol valerate is an [[estradiol ester]], or a [[prodrug]] of [[estradiol (medication)|estradiol]].<ref name="Oettel-2012" /><ref name="pmid16112947" /> As such, it is an [[estrogen (medication)|estrogen]], or an [[agonist]] of the [[estrogen receptor]]s.<ref name="pmid16112947" /><ref name="Oettel-2012" /> The [[affinity (pharmacology)|affinity]] of estradiol valerate for the [[estrogen receptor]] is approximately 50&nbsp;times lower than that of estradiol.<ref name="pmid7169965" /> In addition, estradiol valerate is rapidly cleaved into estradiol and is unable to reach target tissues in concentrations of significance, if at all.<ref name="pmid7169965" /> As such, estradiol valerate is essentially inactive in terms of estrogenic effect itself, acting solely as a [[prodrug]] to estradiol.<ref name="pmid7169965" /> The [[molecular weight]] of estradiol valerate is about 131% of that of estradiol due to the presence of its C17β [[valeric acid|valerate]] ester, and hence estradiol valerate contains about 76% of the amount of estradiol of an equal dose of estradiol.<ref name="Elks-2014" /><ref name="IndexNominum2000" /> Aside from dose adjustment to account for the difference in molecular weight, oral estradiol valerate is considered to be equivalent to oral estradiol.<ref name="pmid7169965" /> Because estradiol valerate is a prodrug of estradiol, it is considered to be a [[natural product|natural]] and [[bioidentical hormone replacement therapy|bioidentical]] form of estrogen.<ref name="Oettel-2012" /><ref name="pmid17627398" /><ref name="Seth-2012" />

{{Affinities and estrogenic potencies of estrogen esters and ethers at the estrogen receptors}}

{{Oral potencies of estrogens}}

{{Relative oral potencies of estrogens}}

{{Parenteral potencies and durations of steroidal estrogens}}

====Effects on liver protein synthesis====
The influence of 2&nbsp;mg/day oral estradiol valerate on [[coagulation factor]]s is less than that of 10&nbsp;μg/day oral [[ethinylestradiol]].<ref name="pmid23239397">{{cite journal | vauthors = Micks EA, Jensen JT | title = Treatment of heavy menstrual bleeding with the estradiol valerate and dienogest oral contraceptive pill | journal = Advances in Therapy | volume = 30 | issue = 1 | pages = 1–13 | date = January 2013 | pmid = 23239397 | doi = 10.1007/s12325-012-0071-3 | s2cid = 31125733 }}</ref><ref name="pmid21151673" /><ref name="pmid19524378">{{cite journal | vauthors = Hardman SM, Gebbie AE | title = Hormonal contraceptive regimens in the perimenopause | journal = Maturitas | volume = 63 | issue = 3 | pages = 204–212 | date = July 2009 | pmid = 19524378 | doi = 10.1016/j.maturitas.2009.05.001 }}</ref><ref name="pmid2526387">{{cite journal | vauthors = Lindberg UB, Crona N, Stigendal L, Teger-Nilsson AC, Silfverstolpe G | title = A comparison between effects of estradiol valerate and low dose ethinyl estradiol on haemostasis parameters | journal = Thrombosis and Haemostasis | volume = 61 | issue = 1 | pages = 65–69 | date = February 1989 | pmid = 2526387 | doi = 10.1055/s-0038-1646528 | s2cid = 20631200 }}</ref><ref name="pmid15288212">{{cite journal | vauthors = Wiegratz I, Lee JH, Kutschera E, Winkler UH, Kuhl H | title = Effect of four oral contraceptives on hemostatic parameters | journal = Contraception | volume = 70 | issue = 2 | pages = 97–106 | date = August 2004 | pmid = 15288212 | doi = 10.1016/j.contraception.2004.03.004 }}</ref> Oral ethinylestradiol at 10&nbsp;μg/day has been found to have about 1.5- to 2.5-fold the impact of 2&nbsp;mg/day oral estradiol valerate on [[HDL cholesterol]] and [[triglyceride]]s.<ref name="pmid22244780">{{cite journal | vauthors = Trémollieres F | title = [Oral combined contraception: is there any difference between ethinyl-estradiol and estradiol?] | language = fr | journal = Gynécologie, Obstétrique & Fertilité | volume = 40 | issue = 2 | pages = 109–115 | date = February 2012 | pmid = 22244780 | doi = 10.1016/j.gyobfe.2011.10.009 | trans-title = Oral combined contraception: is there any difference between ethinyl-estradiol and estradiol? }}</ref><ref name="pmid2170823">{{cite journal | vauthors = L'Hermite M | title = Risks of estrogens and progestogens | journal = Maturitas | volume = 12 | issue = 3 | pages = 215–246 | date = September 1990 | pmid = 2170823 | doi = 10.1016/0378-5122(90)90005-q | url = https://dipot.ulb.ac.be/dspace/bitstream/2013/352796/3/MATURITAS1990MLHEPRISKS.pdf }}</ref><ref name="pmid3817605">{{cite journal | vauthors = Ottosson UB, Carlström K, Johansson BG, von Schoultz B | title = Estrogen induction of liver proteins and high-density lipoprotein cholesterol: comparison between estradiol valerate and ethinyl estradiol | journal = Gynecologic and Obstetric Investigation | volume = 22 | issue = 4 | pages = 198–205 | date = 1986 | pmid = 3817605 | doi = 10.1159/000298914 }}</ref> The influence of 20 or 50&nbsp;μg/day oral ethinylestradiol on coagulation factors and HDL cholesterol is markedly greater than that of 2&nbsp;mg/day oral estradiol valerate.<ref name="pmid22244780" /><ref name="pmid3173937">{{cite journal | vauthors = Fåhraeus L | title = The effects of estradiol on blood lipids and lipoproteins in postmenopausal women | journal = Obstetrics and Gynecology | volume = 72 | issue = 5 | pages = 18S–22S | date = November 1988 | pmid = 3173937 }}</ref>

[[Estradiol-containing birth control pill]]s, which contain 1 to 3&nbsp;mg/day estradiol or estradiol valerate, have been found to increase [[sex hormone-binding globulin]] (SHBG) levels by 1.5-fold.<ref name="pmid21538049">{{cite journal | vauthors = Sitruk-Ware R, Nath A | title = Metabolic effects of contraceptive steroids | journal = Reviews in Endocrine & Metabolic Disorders | volume = 12 | issue = 2 | pages = 63–75 | date = June 2011 | pmid = 21538049 | doi = 10.1007/s11154-011-9182-4 | s2cid = 23760705 }}</ref><ref name="pmid22468839">{{cite journal | vauthors = Fruzzetti F, Trémollieres F, Bitzer J | title = An overview of the development of combined oral contraceptives containing estradiol: focus on estradiol valerate/dienogest | journal = Gynecological Endocrinology | volume = 28 | issue = 5 | pages = 400–408 | date = May 2012 | pmid = 22468839 | pmc = 3399636 | doi = 10.3109/09513590.2012.662547 }}</ref> Oral estradiol valerate at 6&nbsp;mg/day has been found to increase SHBG levels by 2.5- to 3-fold in [[transgender women]].<ref name="pmid15994752">{{cite journal | vauthors = Mueller A, Dittrich R, Binder H, Kuehnel W, Maltaris T, Hoffmann I, Beckmann MW | title = High dose estrogen treatment increases bone mineral density in male-to-female transsexuals receiving gonadotropin-releasing hormone agonist in the absence of testosterone | journal = European Journal of Endocrinology | volume = 153 | issue = 1 | pages = 107–113 | date = July 2005 | pmid = 15994752 | doi = 10.1530/eje.1.01943 | doi-access = free }}</ref><ref name="pmid16673210">{{cite journal | vauthors = Mueller A, Binder H, Cupisti S, Hoffmann I, Beckmann MW, Dittrich R | title = Effects on the male endocrine system of long-term treatment with gonadotropin-releasing hormone agonists and estrogens in male-to-female transsexuals | journal = Hormone and Metabolic Research = Hormon- und Stoffwechselforschung = Hormones et Métabolisme | volume = 38 | issue = 3 | pages = 183–187 | date = March 2006 | pmid = 16673210 | doi = 10.1055/s-2006-925198 | s2cid = 21521025 }}</ref> For comparison, [[combined birth control pill]]s containing ethinylestradiol and a progestin with minimal androgenic or antiandrogenic activity have been found to increase SHBG levels by about 3- to 4-fold.<ref name="pmid12047300">{{cite journal | vauthors = Odlind V, Milsom I, Persson I, Victor A | title = Can changes in sex hormone binding globulin predict the risk of venous thromboembolism with combined oral contraceptive pills? | journal = Acta Obstetricia et Gynecologica Scandinavica | volume = 81 | issue = 6 | pages = 482–490 | date = June 2002 | pmid = 12047300 | doi = 10.1034/j.1600-0412.2002.810603.x | s2cid = 26054257 | doi-access = free }}</ref>

===Pharmacokinetics===
{{See also|Pharmacokinetics of estradiol}}

Regardless of the [[route of administration]], estradiol valerate behaves as a [[prodrug]] of estradiol via [[bond cleavage|cleavage]] by [[esterase]]s into estradiol and the natural [[fatty acid]] [[valeric acid]].<ref name="pmid16112947" /><ref name="Oettel-2012" /><ref name="pmid7169965" /><ref name="Progynova">{{Cite web |title=Progynova 1mg (SPC) &#124; Drugs.com |url=https://www.drugs.com/uk/progynova-1mg-spc-3430.html |access-date=6 September 2012}}</ref> This cleavage occurs not only in the [[liver]], but also in the [[blood]] and in [[tissue (biology)|tissue]]s, and the [[hydrolysis]] of estradiol valerate into estradiol and valeric acid is complete regardless of whether the medication is administered [[oral administration|orally]] or [[parenteral]]ly.<ref name="pmid7169965" /> 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.<ref name="pmid7169965" />

====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).<ref name="pmid16112947" /> 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.<ref name="Oettel-2012" /> However, estradiol valerate is hydrolyzed into estradiol and valeric acid in the [[intestine]]s, and hence, is still subject to extensive first-pass metabolism.<ref name="pmid16112947" /> As such, the oral bioavailability of estradiol valerate is only around 3 to 5%, and is similar to that of oral estradiol.<ref name="pmid7169965" /><ref name="pmid16112947" /><ref name="Shellenberger-1986" /> All oral tablets in the cases of both estradiol and estradiol valerate seem to be micronized.<ref name="pmid10098476" /> Due to its nature as a rapidly converted prodrug of estradiol, the [[pharmacokinetics]] of oral estradiol valerate are similar to those of oral estradiol.<ref name="pmid7169965" /><ref name="pmid16112947" /> Moreover, the [[pharmacodynamics]] and [[potency (pharmacology)|potency]] (after differences in [[molecular weight]] are taken into account) of oral estradiol valerate are considered to be equivalent to those of oral estradiol.<ref name="pmid7169965" /> 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.<ref name="pmid7169965" />

A dosage of 1&nbsp;mg/day oral estradiol valerate has been found to produce approximate circulating concentrations of 50&nbsp;pg/mL estradiol and 160&nbsp;pg/mL estrone, while a dosage of 2&nbsp;mg/day results in circulating levels of 60&nbsp;pg/mL estradiol and 300&nbsp;pg/mL estrone.<ref name="pmid8530713">{{cite journal | vauthors = O'Connell MB | title = Pharmacokinetic and pharmacologic variation between different estrogen products | journal = Journal of Clinical Pharmacology | volume = 35 | issue = 9S | pages = 18S–24S | date = September 1995 | pmid = 8530713 | doi = 10.1002/j.1552-4604.1995.tb04143.x | s2cid = 10159196 }}</ref> These concentrations of estradiol and estrone are comparable to those observed with 1 and 2&nbsp;mg/day oral estradiol.<ref name="pmid8530713" /> A review of selected studies reported a range of mean peak estradiol levels of 24 to 140&nbsp;pg/mL occurring 1 to 12&nbsp;hours after administration of 2&nbsp;mg oral estradiol valerate.<ref name="pmid7169965" /> A study found that, in accordance with their differences in molecular weights, oral estradiol produced higher levels of estradiol than oral estradiol valerate.<ref name="pmid11709743">{{cite journal | vauthors = Wiegratz I, Fink T, Rohr UD, Lang E, Leukel P, Kuhl H | title = [Cross-over comparison of the pharmacokinetics of estradiol during hormone replacement therapy with estradiol valerate or micronized estradiol] | language = de | journal = Zentralblatt für Gynäkologie | volume = 123 | issue = 9 | pages = 505–512 | date = September 2001 | pmid = 11709743 | doi = 10.1055/s-2001-18223 | s2cid = 260353858 | trans-title = Cross-over comparison of the pharmacokinetics of estradiol during hormone replacement therapy with estradiol valerate or micronized estradiol }}</ref> Likewise, other studies found that levels of estradiol and estrone are very similar after oral administration of roughly equimolar doses of estradiol (1.5&nbsp;mg) and estradiol valerate (2&nbsp;mg).<ref name="pmid20004267">{{cite journal | vauthors = Fruzzetti F, Bitzer J | title = Review of clinical experience with estradiol in combined oral contraceptives | journal = Contraception | volume = 81 | issue = 1 | pages = 8–15 | date = January 2010 | pmid = 20004267 | doi = 10.1016/j.contraception.2009.08.010 }}</ref><ref name="pmid9751449">{{cite journal | vauthors = Vree TB, Timmer CJ | title = Enterohepatic cycling and pharmacokinetics of oestradiol in postmenopausal women | journal = The Journal of Pharmacy and Pharmacology | volume = 50 | issue = 8 | pages = 857–864 | date = August 1998 | pmid = 9751449 | doi = 10.1111/j.2042-7158.1998.tb04000.x | s2cid = 23550553 | doi-access = free }}</ref><ref name="pmid10412891">{{cite journal | vauthors = Timmer CJ, Geurts TB | title = Bioequivalence assessment of three different estradiol formulations in postmenopausal women in an open, randomized, single-dose, 3-way cross-over study | journal = European Journal of Drug Metabolism and Pharmacokinetics | volume = 24 | issue = 1 | pages = 47–53 | date = 1999 | pmid = 10412891 | doi = 10.1007/BF03190010 | s2cid = 20513936 }}</ref> A study of high-dose oral estradiol valerate found levels of estradiol of about 250&nbsp;pg/mL after a single 10-mg dose in three women.<ref name="Shellenberger-1986" />

{{Gallery
| title=Hormone levels with oral estradiol valerate
| width=400 | height=300
| align=center
| style="font-size:small;"

| File:Estradiol levels with oral micronized estradiol and oral estradiol valerate in postmenopausal women.png | Baseline-adjusted estradiol levels after a single oral dose of 1.5&nbsp;mg micronized estradiol or 2.0&nbsp;mg estradiol valerate in postmenopausal women.<ref name="Jensen-2013">{{Cite journal | vauthors = Jensen J, Bitzer J, Serrani M |year=2013 |title=Comparison of the pharmacologic and clinical profiles of new combined oral contraceptives containing estradiol |journal=Open Access Journal of Contraception |pages=39 |doi=10.2147/OAJC.S50693 |issn=1179-1527 |doi-access=free}}</ref><ref name="pmid10412891"/> Source was Timmer & Geurts (1999).<ref name="pmid10412891" />

| File:Estradiol levels after a single dose and with continuous administration of oral estradiol or oral estradiol valerate in women.png | Estradiol levels after a single oral dose of 2&nbsp;mg micronized estradiol or 2&nbsp;mg estradiol valerate and with continuous oral administration of 2&nbsp;mg/day micronized estradiol or 2&nbsp;mg/day estradiol valerate (at steady state) in postmenopausal women.<ref name="pmid11709743"/> Source was Wiegratz et al. (2001).<ref name="pmid11709743" />
}}

====Sublingual administration====
[[File:Hormone levels with oral estradiol valerate tablets (Progynova) taken sublingually in premenopausal women.png|thumb|right|425px|Hormone levels with 2-mg oral micronized estradiol valerate tablets (Progynova, Schering) taken continuously 3 or 4&nbsp;times per day by the [[sublingual administration|sublingual]] route in premenopausal women.<ref name="pmid2566746" /><ref name="pmid2207608" />]]

Estradiol valerate has been studied by [[sublingual administration]] in premenopausal women for the purpose of [[menstrual cycle|cycle]] control and [[ovulation]] suppression in [[egg donation]] and [[surrogacy]].<ref name="pmid2566746">{{cite journal | vauthors = Serhal PF, Craft IL | title = Oocyte donation in 61 patients | journal = Lancet | volume = 1 | issue = 8648 | pages = 1185–1187 | date = May 1989 | pmid = 2566746 | doi = 10.1016/S0140-6736(89)92762-1 | s2cid = 21953983 }}</ref><ref name="pmid2207608">{{cite journal | vauthors = Serhal P | title = Oocyte donation and surrogacy | journal = British Medical Bulletin | volume = 46 | issue = 3 | pages = 796–812 | date = July 1990 | pmid = 2207608 | doi = 10.1093/oxfordjournals.bmb.a072432 }}</ref> It has been investigated for this indication, along with [[vaginal estradiol|vaginal]] and [[transdermal estradiol]], because oral estradiol valerate is sometimes unable to achieve adequate estradiol levels and hence proper cycle control in this situation.<ref name="pmid2566746" /><ref name="pmid2207608" /> Sublingual administration of estradiol valerate bypasses the [[first-pass metabolism|first pass]] that occurs with the oral route and results in higher levels of estradiol and improved cycle control.<ref name="pmid2566746" /><ref name="pmid2207608" /> Sublingual estradiol valerate is also used in hormone therapy for transgender women.<ref name="pmid30671393">{{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 = Obstetrics & Gynecology Science | volume = 62 | issue = 1 | pages = 46–55 | date = January 2019 | pmid = 30671393 | pmc = 6333764 | doi = 10.5468/ogs.2019.62.1.46 | 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]. }}</ref>

The administration of 2&nbsp;mg oral micronized estradiol valerate tablets (Progynova, Schering) sublingually 3 or 4&nbsp;times per day has been found to result in circulating estradiol levels of about 290&nbsp;pg/mL to 460&nbsp;pg/mL in premenopausal women (time of measurements not given).<ref name="pmid2566746" /><ref name="pmid2207608" /> [[Steady-state levels]] of estradiol were achieved within about 2 or 3&nbsp;days.<ref name="pmid2566746" /><ref name="pmid2207608" /> 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.<ref name="pmid2566746" /><ref name="pmid2207608" /> 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.<ref name="pmid2566746" /><ref name="pmid2207608" /><ref name="pmid10585176">{{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 = 81–85 | date = September 1999 | pmid = 10585176 | doi = 10.1016/S0378-5122(99)00036-5 }}</ref>

====Intramuscular injection====
In contrast to oral administration, the bioavailability of estradiol valerate is complete (i.e., 100%) via intramuscular injection.<ref name="pmid8013217" /><ref name="pmid7169965" /><ref name="pmid16112947" /> 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.<ref name="pmid7169965" /> As an example, a single 4&nbsp;mg intramuscular injection is said to be approximately equivalent to 2&nbsp;mg/day of the medication administered orally over the course of 3 weeks.<ref name="pmid7169965" /> Estradiol valerate, when given intramuscularly in [[oil]], has a relatively long duration due to the formation of an intramuscular [[depot injection|depot]] from which the medication is slowly released and absorbed.<ref name="pmid7169965" /><ref name="Sriram-2007">{{Cite book | vauthors = Sriram D, Yogeeswari P | chapter = Steroids | chapter-url = https://books.google.com/books?id=9HSoZrcBRl0C&pg=PA427 |title=Medicinal Chemistry |publisher=Pearson Education India |year=2007 |isbn=978-81-317-0031-0 |page=427 |access-date=20 May 2012}}</ref> 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.<ref name="pmid16112947" /> In addition, a secondary depot may also be formed in [[adipose tissue]].<ref name="pmid16112947" /> 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 (chemistry)|moiety]].<ref name="pmid7169965" /> The [[elimination half-life]] of estradiol valerate in oil by intramuscular injection (brand names Estradiol-Depot 10&nbsp;mg, Progynon Depot-10) is about 3.5&nbsp;days, with a range of 1.2&nbsp;days to 7.2&nbsp;days in different individuals.<ref name="pmid22257576" /> Α couple of older studies from the 1980s with [[sample size]]s of only 2 or 3 individuals reported an elimination half-life of 4 to 5&nbsp;days.<ref name="pmid7169965" /><ref name="pmid6220949" /><ref name="pmid2987096" />

A single intramuscular injection of 4&nbsp;mg estradiol valerate has been found to result in maximal circulating levels of estradiol of about 390&nbsp;pg/mL within 3&nbsp;days of administration, with levels declining to 100&nbsp;pg/mL (baseline, in the study) by 12 to 13&nbsp;days.<ref name="Notelovitz-2012" /> Studies in general have found that a single intramuscular injection of 4&nbsp;mg estradiol valerate results in peak levels of estradiol of 240 to 540&nbsp;pg/mL after 1 to 5&nbsp;days following administration.<ref name="pmid2987096">{{cite journal | vauthors = Düsterberg B, Schmidt-Gollwitzer M, Hümpel M | title = Pharmacokinetics and biotransformation of estradiol valerate in ovariectomized women | journal = Hormone Research | volume = 21 | issue = 3 | pages = 145–154 | date = 1985 | pmid = 2987096 | doi = 10.1159/000180039 | doi-broken-date = 1 November 2024 }}</ref> A study found that a single intramuscular injection of 5&nbsp;mg estradiol valerate resulted in peak circulating levels of 667&nbsp;pg/mL estradiol and 324&nbsp;pg/mL estrone within approximately 2 and 3&nbsp;days, respectively.<ref name="pmid7389356">{{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 = 415–424 | date = April 1980 | pmid = 7389356 | doi = 10.1016/S0010-7824(80)80018-7 }}</ref> The duration of estradiol valerate at this dose and in this study was considered to be 7 to 8&nbsp;days.<ref name="pmid7389356" /> Other studies have found that larger doses of intramuscular estradiol valerate exceeding 20&nbsp;mg have a duration of more than 15&nbsp;days.<ref name="pmid7389356" /> A third study, in contrast to the preceding study, found that a single 10&nbsp;mg intramuscular injection of estradiol valerate resulted in maximal estradiol levels of 506 to 544&nbsp;pg/mL and maximal estrone levels of 205 to 219&nbsp;pg/mL in postmenopausal women.<ref name="pmid22257576" />

With intramuscular injections of estradiol valerate, it has been reported that a dose of 5&nbsp;mg has a duration of 7 to 8&nbsp;days, 10&nbsp;mg a duration of 10 to 14&nbsp;days, 40&nbsp;mg a duration of 2 to 3&nbsp;weeks (14 to 21&nbsp;days), and 100&nbsp;mg a duration of 3 to 4&nbsp;weeks (21 to 28&nbsp;days).<ref name="Lauritzen-1988">{{Cite book | vauthors = Lauritzen C |url=https://books.google.com/books?id=v4HvAQAACAAJ |title=Grundlagen und Klinik der Menschlichen Fortpflanzung |publisher=Walter de Gruyter |year=1988 |isbn=978-3110109689 | veditors = Schneider HP, Lauritzen C, Nieschlag E |pages=229–306 |language=de |trans-title=Foundations and Clinic of Human Reproduction |chapter=Natürliche und Synthetische Sexualhormone – Biologische Grundlagen und Behandlungsprinzipien |trans-chapter=Natural and Synthetic Sexual Hormones – Biological Basis and Medical Treatment Principles |oclc=35483492 }}</ref><ref name="Labhart-2012"/><ref name="pmid7389356" />

A study of [[pseudopregnancy]] with [[intramuscular injection]]s of 40&nbsp;mg/week estradiol valerate and 250&nbsp;mg/week [[hydroxyprogesterone caproate]] in women with [[estrogen deficiency]] observed estradiol levels of about 3,100&nbsp;pg/mL at 3&nbsp;months of therapy and 2,500&nbsp;pg/mL at 6&nbsp;months of therapy.<ref name="pmid7835827">{{cite 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 = Hormone and Metabolic Research = Hormon- und Stoffwechselforschung = Hormones et Métabolisme | volume = 26 | issue = 9 | pages = 428–431 | date = September 1994 | pmid = 7835827 | doi = 10.1055/s-2007-1001723 | s2cid = 260169203 }}</ref>

{{Pharmacokinetics of three estradiol esters by intramuscular injection}}

{{Gallery
| title=Hormone levels with estradiol valerate by intramuscular injection
| width=300 | height=210
| align=center
| style="font-size:small;"

| File:Estrogen levels after a single intramuscular injection of 10 mg estradiol valerate in postmenopausal women.png | Estrogen levels after a single intramuscular injection of 10 mg estradiol valerate in oil in 24 postmenopausal women.<ref name="pmid22257576">{{cite journal | vauthors = Schug BS, Donath F, Blume HH | title = Bioavailability and pharmacodynamics of two 10-mg estradiol valerate depot formulations following IM single dose administration in healthy postmenopausal volunteers | journal = International Journal of Clinical Pharmacology and Therapeutics | volume = 50 | issue = 2 | pages = 100–117 | date = February 2012 | pmid = 22257576 | doi = 10.5414/CP201589 }}</ref> Determinations were made for both Progynon Depot 10 and Estradiol Depot 10, for a total of 48 measurements per point.<ref name="pmid22257576" /> Assays were performed using [[Gas chromatography–mass spectrometry|GC/MS]]-[[Negative chemical ionization|NCI]]/[[Selected ion monitoring|SIM]].<ref name="pmid22257576" /> Source was Schug et al. (2012).<ref name="pmid22257576" />

| File:Hormone levels after a single intramuscular injection of 5 mg estradiol valerate in postmenopausal women.png | Hormone levels after a single intramuscular injection of 5 mg estradiol valerate in oil in 17 postmenopausal women.<ref name="Göretzlehner-2002">{{Cite journal |vauthors=Göretzlehner G, Ackermann W, Angelow K, Bergmann G, Bieck E, Golbs S, Kliem O |year=2002 |title=Pharmakokinetik von Estron, Estradiol, FSH, LH und Prolaktin nach intramuskulärer Applikation von 5 mg Estradiolvalerat |trans-title=Pharmacokinetics of estradiol valerate in postmenopausal women after intramuscular administration |url=https://www.kup.at/journals/summary/1071.html |journal=Journal für Menopause |volume=9 |issue=2 |pages=51–55}}</ref> Assays were performed using [[ELISA|EIA]].<ref name="Göretzlehner-2002" /> Estrone levels were likely overestimated, possibly due to cross reactivity of the assay with [[estrogen conjugate]]s.<ref name="pmid22257576" /> Source was Göretzlehner et al. (2002).<ref name="Göretzlehner-2002" />

| File:Hormone levels in men with a single intramuscular injection of 5 mg estradiol valerate and 50 mg norethisterone enanthate in oil.png | Hormone levels after a single intramuscular injection of [[estradiol valerate/norethisterone enanthate]] (5&nbsp;mg/50&nbsp;mg) (Mesigyna) in healthy young men.<ref name="del Cisne Valle Alvarez-2011">{{cite thesis | type = MSc | vauthors = del Cisne Valle Alvarez D | title = Efecto de una Dosis de 50 mg de Enantato de Noretisterona y 5 mg de Valerato de Estradiol en los Niveles de Testosterona Total en Hombres Mexicanos Sanos | trans-title = Effect of a Dose of 50 mg of Norethisterone Enanthate and 5 mg of Estradiol Valerate on Total Testosterone Levels in Healthy Mexican Men | date = 11 May 2011 | publisher = National Polytechnic Institute of Mexico | url = http://repositoriodigital.ipn.mx/handle/123456789/12490}}</ref> Testosterone decreased from ~503&nbsp;ng/dL to ~30&nbsp;ng/dL (–94%).<ref name="del Cisne Valle Alvarez-2011" /> Source was Valle Alvarez (2011).<ref name="del Cisne Valle Alvarez-2011" />

| File:Estradiol levels after a single 5 mg intramuscular injection of estradiol esters.png | Estradiol levels after single intramuscular injections of 5 mg of different estradiol esters in oil in about 10 premenopausal women each.<ref name="pmid7389356"/> Assays were performed using [[radioimmunoassay|RIA]] with [[chromatographic separation|CS]].<ref name="pmid7389356" /> Source was Oriowo et al. (1980).<ref name="pmid7389356" />

| File:Estradiol levels after a single intramuscular injection of 10 mg estradiol valerate and 100 mg estradiol undecylate.png | Estradiol levels after a single intramuscular injection of 10 mg estradiol valerate or 100 mg [[estradiol undecylate]] in oil both in 4 individuals each.<ref name="pmid1231448">{{cite journal | vauthors = Vermeulen A | title = Longacting steroid preparations | journal = Acta Clinica Belgica | volume = 30 | issue = 1 | pages = 48–55 | date = 1975 | pmid = 1231448 | doi = 10.1080/17843286.1975.11716973 }}</ref> Subject characteristics and assay method were not described.<ref name="pmid1231448" /> Source was Vermeulen (1975).<ref name="pmid1231448" />

| File:Estradiol and dehydroepiandrosterone levels after a single intramuscular injection of Gynodian Depot in women.png | Estradiol and {{abbr|DHEA|dehydroepiandrosterone}} levels after a single intramuscular injection of [[estradiol valerate/prasterone enanthate|Gynodian Depot]] (4&nbsp;mg estradiol valerate, 200&nbsp;mg [[prasterone enanthate]] in oil) or Primogyn Depot (10&nbsp;mg estradiol valerate in oil) in women.<ref name="Kuhl-1987">{{Cite book | vauthors = Kuhl H, Taubert HD |title=Das Klimakterium – Pathophysiologie, Klinik, Therapie|publisher=[[Thieme Medical Publishers|Thieme Verlag]] |year=1987 |isbn=978-3137008019 |location=Stuttgart, Germany |page=122 |language=de |trans-title=The Climacteric – Pathophysiology, Clinic, Therapy}}</ref><ref name="pmid6220949">{{cite journal | vauthors = Düsterberg B, Wendt H | title = Plasma levels of dehydroepiandrosterone and 17 beta-estradiol after intramuscular administration of Gynodian-Depot in 3 women | journal = Hormone Research | volume = 17 | issue = 2 | pages = 84–89 | date = 1983 | pmid = 6220949 | doi = 10.1159/000179680 | doi-broken-date = 1 November 2024 }}</ref><ref name="pmid7402086">{{cite journal | vauthors = Rauramo L, Punnonen R, Kaihola LH, Grönroos M | title = Serum oestrone, oestradiol and oestriol concentrations in castrated women during intramuscular oestradiol valerate and oestradiolbenzoate-oestradiolphenylpropionate therapy | journal = Maturitas | volume = 2 | issue = 1 | pages = 53–58 | date = January 1980 | pmid = 7402086 | doi = 10.1016/0378-5122(80)90060-2 }}</ref> Assays were performed using [[radioimmunoassay|RIA]].<ref name="pmid6220949" /><ref name="pmid7402086" /> Sources were Düsterberg & Wendt (1983) and Rauramo et al. (1980).<ref name="Kuhl-1987" /><ref name="pmid6220949" /><ref name="pmid7402086" />

| File:Estradiol levels after injections of estradiol, estradiol benzoate, estradiol valerate, and estradiol undecylate in women.png | Estradiol levels after a short intravenous infusion of 20 mg estradiol in aqueous solution or an intramuscular injection of equimolar doses of estradiol esters in oil solution in postmenopausal women.<ref name="Geppert-1975">{{Cite book | vauthors = Geppert G  |url=https://books.google.com/books?id=cJ82vwEACAAJ |title=Untersuchungen zur Pharmakokinetik von Östradiol-17β, Östradiol-Benzoat, Östradiol-Valerianat und Östradiol-Undezylat bei der Frau: der Verlauf der Konzentrationen von Östradiol-17β, Östron, LH und FSH im Serum |year=1975 |pages=1–34 |trans-title=Studies on the pharmacokinetics of estradiol-17β, estradiol benzoate, estradiol valerate, and estradiol undecylate in women: the progression of serum estradiol-17β, estrone, LH, and FSH concentrations |oclc=632312599}}</ref><ref name="pmid1150068">{{cite journal | vauthors = Leyendecker G, Geppert G, Nocke W, Ufer J | title = [Estradiol-17beta, estrone, LH and FSH in serum after administration of estradiol-17beta, estradiolbenzoate, estradiol-valeriate and estradiol-undecylate in the female (author's transl)] | language = de | journal = Geburtshilfe und Frauenheilkunde | volume = 35 | issue = 5 | pages = 370–374 | date = May 1975 | pmid = 1150068 | trans-title = Estradiol 17β, estrone, LH and FSH in serum after administration of estradiol 17β, estradiol benzoate, estradiol valeriate and estradiol undecylate in the female }}</ref> Assays were performed using [[radioimmunoassay|RIA]] with [[chromatographic separation|CS]].<ref name="Geppert-1975" /><ref name="pmid1150068" /> Source was Geppert (1975).<ref name="Geppert-1975" /><ref name="pmid1150068" />

| File:Estradiol levels after an intramuscular injection of Climacteron or estradiol valerate in ovariectomized women.png | Estradiol levels after an intramuscular injection of 10&nbsp;mg estradiol valerate in oil, [[Climacteron]] (150&nbsp;mg [[testosterone enanthate]], 1&nbsp;mg [[estradiol benzoate]], 7.5&nbsp;mg [[estradiol dienanthate]] in oil), and control group in 20, 11, and 11 ovariectomized women, respectively.<ref name="pmid3826177">{{cite journal | vauthors = Sherwin BB, Gelfand MM, Schucher R, Gabor J | title = Postmenopausal estrogen and androgen replacement and lipoprotein lipid concentrations | journal = American Journal of Obstetrics and Gynecology | volume = 156 | issue = 2 | pages = 414–419 | date = February 1987 | pmid = 3826177 | doi = 10.1016/0002-9378(87)90295-x }}</ref> Assays were performed using [[radioimmunoassay|RIA]].<ref name="pmid3826177" /> Source was Sherwin et al. (1987).<ref name="pmid3826177" />

| File:Idealized curves of estradiol levels after injection of different estradiol esters in women.png | Simplified curves of estradiol levels after injection of different estradiol esters in women.<ref name="pmid8013219">{{cite journal | vauthors = Garza-Flores J | title = Pharmacokinetics of once-a-month injectable contraceptives | journal = Contraception | volume = 49 | issue = 4 | pages = 347–359 | date = April 1994 | pmid = 8013219 | doi = 10.1016/0010-7824(94)90032-9 }}</ref> Source was Garza-Flores (1994).<ref name="pmid8013219" />
}}

====Subcutaneous injection====
Estradiol esters like estradiol valerate and [[estradiol cypionate]] can be given by [[subcutaneous injection]] instead of intramuscular injection.<ref name="pmid28078219">{{cite journal | vauthors = Unger CA | title = Hormone therapy for transgender patients | journal = Translational Andrology and Urology | volume = 5 | issue = 6 | pages = 877–884 | date = December 2016 | pmid = 28078219 | pmc = 5182227 | doi = 10.21037/tau.2016.09.04 | doi-access = free }}</ref><ref name="pmid22078184">{{cite journal | vauthors = Sierra-Ramírez JA, Lara-Ricalde R, Lujan M, Velázquez-Ramírez N, Godínez-Victoria M, Hernádez-Munguía IA, Padilla A, Garza-Flores J | display-authors = 6 | 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 = 565–570 | date = December 2011 | pmid = 22078184 | doi = 10.1016/j.contraception.2011.03.014 }}</ref>

====Intravenous injection====
The administration of estradiol valerate by intravenous injection has been studied.<ref name="pmid7169965" /><ref name="pmid2987096" /> It has been found to be very rapidly cleaved into estradiol.<ref name="pmid7169965" /><ref name="pmid2987096" /> The bioavailability and metabolism of estradiol valerate does not differ with intravenous versus intramuscular injection.<ref name="pmid2987096" /> Conversely, intravenous injection of estradiol valerate has a very short duration, whereas intramuscular injection has a long duration and [[elimination half-life]].<ref name="pmid2987096" />

==Chemistry==
{{See also|Estrogen ester|List of estrogen esters#Estradiol esters}}
[[File:Estradiol esterification into estradiol valerate.png|thumb|right|325px|[[Estradiol (medication)|Estradiol]] plus the [[fatty acid]] [[valeric acid]] (valerate) equals estradiol valerate, a C17β ester of estradiol.<ref name="Shellenberger-1986">{{Cite book | vauthors = Shellenberger TE |title=The Climacteric in Perspective |year=1986 |isbn=978-94-010-8339-3 |pages=393–410 |chapter=Pharmacology of estrogens |doi=10.1007/978-94-009-4145-8_36 |chapter-url=https://books.google.com/books?id=VM0hBQAAQBAJ&pg=PA401}}</ref>]]

Estradiol valerate is a [[synthetic compound|synthetic]] [[estrane]] [[steroid]] and the C17β [[valeric acid|valerate]] (pentanoate) [[fatty acid]] [[ester]] of [[estradiol (medication)|estradiol]].<ref name="Elks-2014" /><ref name="IndexNominum2000" /> It is also known as estradiol 17β-valerate or as estra-1,3,5(10)-triene-3,17β-diol 17β-pentanoate.<ref name="Elks-2014" /><ref name="IndexNominum2000" /> 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.<ref name="Elks-2014" /><ref name="IndexNominum2000" />

The experimental log [[octanol/water partition coefficient]] (log P) of estradiol valerate is 5.6.<ref name="ChemSpider">{{Cite web|url=http://www.chemspider.com/Chemical-Structure.13194.html|title=Estradiol valerate &#124; C23H32O3 &#124; ChemSpider|website=www.chemspider.com}}</ref>

{{Structural properties of selected estradiol esters}}

==History==
Estradiol valerate was [[patent]]ed by [[Ciba Specialty Chemicals|Ciba]] in 1940 and 1941, with a [[Priority right|priority date]] of 1936.<ref name="Kleemann-2014" /><ref name="US2205627A">{{Cite web|url=https://patents.google.com/patent/US2205627A/en|title=Esters of unsaturated polyhydroxy estrane}}</ref> It was [[chemical synthesis|synthesized]] and studied, along with a variety of other [[estradiol ester]]s, by Karl Junkmann of [[Schering AG]] in 1953.<ref name="pmid15193460">{{cite journal | vauthors = Shoham Z, Kopernik G | title = Tools for making correct decisions regarding hormone therapy. part I: background and drugs | journal = Fertility and Sterility | volume = 81 | issue = 6 | pages = 1447–1457 | date = June 2004 | pmid = 15193460 | doi = 10.1016/j.fertnstert.2003.10.052 | doi-access = free }}</ref><ref name="Junkmann-1953">{{Cite journal | vauthors = Junkmann K |year=1953 |title=Über protrahiert wirksame Östrogene |trans-title=Over protracted effective estrogens |journal=Naunyn-Schmiedebergs Archiv für Experimentelle Pathologie und Pharmakologie |volume=220 |issue=5 |doi=10.1007/BF00246561 |issn=0028-1298 |s2cid=20753905}}</ref> 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 [[Bristol-Myers Squibb|Squibb]] in the [[United States]] under the brand name Delestrogen.<ref name="Publishing2013">{{Cite book | author = William Andrew Publishing |url=https://books.google.com/books?id=_J2ti4EkYpkC&pg=PA1477 |title=Pharmaceutical Manufacturing Encyclopedia, 3rd Edition |date=22 October 2013 |publisher=Elsevier |isbn=978-0-8155-1856-3 |pages=1477–1478}}</ref><ref name="Duetsch-1969">{{Cite book | vauthors = Duetsch LL |url=https://books.google.com/books?id=4vdsAAAAMAAJ&q=Delestrogen |title=Research and development, market power, and patent policy in ethical drugs |publisher=University of Wisconsin--Madison |year=1969 |page=95 |quote=1954. Delestrogen. Estradiol valerate.}}</ref><ref name="Ehrengut-1954">{{Cite journal | vauthors = Ehrengut W |year=1954 |title=Über ovarielle Agenesie |journal=Zeitschrift für Kinderheilkunde |volume=75 |issue=3 |pages=224–234 |doi=10.1007/BF00439822 |issn=0340-6199 |quote=Um die "Menarche" sollte eine verstärkte Substitutionstherapie (20 Tage lang tgl. 0,1 mg Follikelhormon per os oder einmalig Progynon-Depot (10 mg i.m.), [...] |s2cid=29364660}}</ref> In 1966, oral estradiol valerate was introduced by Schering for medical use in Europe under the brand name Progynova.<ref name="Kuhl-2008">{{Cite book | vauthors = Kuhl H, Wiegratz I |title=Klimakterium, Postmenopause und Hormonsubstitution |date=1 January 2008 |publisher=UNI-MED-Verlag |isbn=978-3-83742-043-2 |edition=4 |page=18 |language=de |trans-title=Climacteric, Postmenopause and Hormone Replacement |quote=With Progynon Depot-10, an oily solution of 10 mg estradiol valerate, an injection preparation had been available since 1953 and since 1966 coated tablets with estradiol valerate for oral therapy. The first Schering preparation containing micronized estradiol was marketed in 1968 as Progynova 21 (2 mg) and Progynova 21 mite (1 mg).}}</ref><ref name="Klinische Wochenschrift-1966">{{Cite journal |year=1966 |title=Neue Spezialitäten |journal=Klinische Wochenschrift |volume=44 |issue=23 |pages=1381 |doi=10.1007/BF01747900 |issn=0023-2173 |quote=NEUE SPEZIALITATEN [...] Progynova. 1 Dragee enthält 2 mg Oestradiolvalerinat (Klimakterium). Hersteller: Schering AG, Berlin 65. |s2cid=20357182}}</ref><ref name="pmid5593020">{{cite journal | vauthors = Dapunt O | title = [The management of climacteric disorders using estradiol valerate (Progynova)] | language = de | journal = Medizinische Klinik | volume = 62 | issue = 35 | pages = 1356–61 passim | date = September 1967 | pmid = 5593020 | trans-title = The management of climacteric disorders using estradiol valerate (Progynova) }}</ref><ref name="pmid5728263">{{cite journal | vauthors = Velikay L | title = [The peroral treatment of the climacteric syndrome with estradiol valerate] | language = de | journal = Wiener Klinische Wochenschrift | volume = 80 | issue = 12 | pages = 229–233 | date = March 1968 | pmid = 5728263 | trans-title = The peroral treatment of the climacteric syndrome with estradiol valerate }}</ref><ref name="pmid5045321">{{cite journal | vauthors = Koed J | title = [Therapy of climacteric deficiency symptoms using progynova] | language = de | journal = Die Medizinische Welt | volume = 23 | issue = 22 | pages = 834–836 | date = May 1972 | pmid = 5045321 | trans-title = Therapy of climacteric deficiency symptoms using Progynova }}</ref> A report of its metabolism was published in 1967.<ref name="Kolb-1967">{{Cite journal |vauthors=Kolb KH |year=1967 |title=The metabolism of oestradiol valerate |url=https://scholar.google.com/scholar?cluster=14998892125998427533 |journal=Medizinische Mitteilungen (Schering) |volume=28 |pages=16– |issn=0301-2492}}</ref> [[Esterification]] of estradiol, as in estradiol valerate, has been claimed to improve its [[metabolic stability]] with oral administration.<ref name="pmid16112947" /><ref name="pmid7169965">{{cite journal | vauthors = Düsterberg B, Nishino Y | title = Pharmacokinetic and pharmacological features of oestradiol valerate | journal = Maturitas | volume = 4 | issue = 4 | pages = 315–324 | date = December 1982 | pmid = 7169965 | doi = 10.1016/0378-5122(82)90064-0 }}</ref><ref name="Estrace-FDA">{{Cite web|url=https://www.accessdata.fda.gov/scripts/cder/daf/|archive-url=https://web.archive.org/web/20161104020628/http://www.accessdata.fda.gov/scripts/cder/daf/|url-status=dead|archive-date=4 November 2016|title=Drugs@FDA: FDA-Approved Drugs|website=www.accessdata.fda.gov}}</ref> In 1968, [[micronized]] preparations of oral estradiol valerate were first introduced under the brand names Progynova 21 and Progynova 21 mite.<ref name="Kuhl-2008" /> Along with [[estradiol benzoate]] (1933)<ref name="Kaufman-1933">{{Cite journal | vauthors = Kaufman C |year=1933 |title=Die Behandlung der Amenorrhöe mit Hohen Dosen der Ovarialhormone |journal=Klinische Wochenschrift |volume=12 |issue=40 |pages=1557–1562 |doi=10.1007/BF01765673 |issn=0023-2173 |s2cid=25856898}}</ref><ref name="Buschbeck-2009">{{Cite journal | vauthors = Buschbeck H |year=2009 |title=Neue Wege der Hormontherapie in der Gynäkologie |trans-title=New ways of hormonal therapy in gynecology |journal=Deutsche Medizinische Wochenschrift |volume=60 |issue=11 |pages=389–393 |doi=10.1055/s-0028-1129842 |s2cid=72668930 |issn=0012-0472}}</ref><ref name="Biskind-1935">{{Cite journal | vauthors = Biskind MS |year=1935 |title=Commercial Glandular Products |journal=Journal of the American Medical Association |volume=105 |issue=9 |pages=667 |doi=10.1001/jama.1935.92760350007009a |issn=0002-9955 |quote=Progynon-B, Schering Corporation: This is crystalline hydroxyestrin benzoate obtained by hydrogenation of theelin and subsequent conversion to the benzoate. [...] Progynon-B is marketed in ampules containing 1 cc. of a sesame oil solution of hydroxyestrin benzoate of either 2,500, 5,000, 10,000 or 50,000 international units.}}</ref> and [[estradiol cypionate]] (1952),<ref name="Sittig-1988">{{Cite book | vauthors = Sittig M |url=https://books.google.com/books?id=X2EyLsG4bcUC&pg=PA576 |title=Pharmaceutical Manufacturing Encyclopedia |date=1 January 1988 |publisher=William Andrew |isbn=978-0-8155-1144-1 |pages=575–576 |access-date=20 May 2012}}</ref> estradiol valerate is one of the most widely used esters of estradiol.<ref name="Yen-1991">{{Cite book | vauthors = Yen SS |url=https://books.google.com/books?id=RN1qAAAAMAAJ |title=Reproductive endocrinology: physiology, pathophysiology, and clinical management |publisher=Saunders |year=1991 |isbn=978-0-7216-3206-3 |access-date=20 May 2012}}</ref>

==Society and culture==

===Generic names===
''Estradiol valerate'' is the [[generic term|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}}.<ref name="Elks-2014">{{Cite book | vauthors = Elks J |url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA898 |title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies |date=14 November 2014 |publisher=Springer |isbn=978-1-4757-2085-3 |pages=898–}}</ref><ref name="IndexNominum2000" /><ref name="Drugs.com-2">{{Cite web|url=https://www.drugs.com/international/estradiol.html|title=Estradiol|website=Drugs.com}}</ref>

===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.<ref name="Elks-2014" /><ref name="IndexNominum2000" /><ref name="Publishing2013" /><ref name="Lewis-2008">{{Cite book | vauthors = Lewis RJ |url=https://books.google.com/books?id=WZeBDwAAQBAJ&pg=PA594 |title=Hazardous Chemicals Desk Reference |date=13 June 2008 |publisher=John Wiley & Sons |isbn=978-0-470-18024-2 |pages=594–}}</ref><ref name="Drugs.com-2" /> Neofollin is an [[oil solution]] of estradiol valerate.<ref name="Kubíková-2014">{{Cite journal | vauthors = Kubíková D |date=2014 |title=Menopauzální symptomy a hormonální substituční terapie |trans-title=Menopausal symptoms and hormone replacement therapy |url=http://www.medvik.cz/link/bmc14059249 | journal=Praktické Lékárenství |language=cs |volume=10 |issue=2 |pages=68–73 |issn=1801-2434 <!-- |url2=http://www.solen.sk/pdf/95e898d92100a736e32110dd1b846a9e.pdf --> }}</ref><ref name="Neofollin-Label">{{cite web | title = NEOFOLLIN Injekční roztok (Estradioli valeras) | url = http://www.sukl.cz/download/pil/PI16359.pdf}}</ref>

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

Oral estradiol valerate is used primarily in [[Europe]], under the brand name Progynova.<ref name="Sanfilippo-1998">{{Cite book | vauthors = Sanfilippo JS |url=https://books.google.com/books?id=jfmB3aNSGfoC&pg=PA227 |title=Primary Care in Obstetrics and Gynecology: A Handbook for Clinicians |date=January 1998 |publisher=Springer Science & Business Media |isbn=978-0-387-94739-6 |pages=227–}}</ref> Although oral estradiol valerate was previously available in the [[United States]],<ref name="IndexNominum2000" /> it is no longer available in the country except in combination with [[dienogest]] as a [[combined oral contraceptive]] (under the brand name Natazia).<ref name="Drugs@FDA2" /> 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.<ref name="Drugs@FDA2" /><ref name="IndexNominum2000" />

==Research==
[[SH-834]] was a combination of 90&nbsp;mg estradiol valerate and 300&nbsp;mg [[gestonorone caproate]] for weekly intramuscular injection that was developed by Schering in the 1970s.<ref name="pmid1202923"/><ref name="pmid4555897">{{cite journal | vauthors = Ward HW | title = Progestogen therapy for ovarian carcinoma | journal = The Journal of Obstetrics and Gynaecology of the British Commonwealth | volume = 79 | issue = 6 | pages = 555–559 | date = June 1972 | pmid = 4555897 | doi = 10.1111/j.1471-0528.1972.tb14200.x | s2cid = 2586346 }}</ref><ref name="pmid5088730">{{cite journal | vauthors = Berndt G, Eckel H, Notter G, St Stender H | title = [Effect of estrogen-gestagen combination therapy in advanced breast carcinoma with special reference to pulmonary metastases] | language = de | journal = Strahlentherapie | volume = 141 | issue = 5 | pages = 540–548 | date = May 1971 | pmid = 5088730 | url = https://www.popline.org/node/485956 | trans-title = Effect of Estrogen-Gestagen Combination Therapy in Advanced Breast Carcinoma with Special Reference to Pulmonary Metastases }}</ref> It was investigated clinically as a treatment for [[breast cancer]] and was found to be effective, but was never marketed.<ref name="pmid1202923" /><ref name="pmid5529652"/>

== See also ==
* [[Estradiol valerate/hydroxyprogesterone caproate]]
* [[Estradiol valerate/norethisterone enantate]]
* [[Estradiol valerate/prasterone enanthate]]
* [[Estradiol valerate/testosterone enanthate]]

== References ==
{{Reflist}}

== Further reading ==
{{refbegin}}
* {{cite journal | vauthors = Vermeulen A | title = Longacting steroid preparations | journal = Acta Clinica Belgica | volume = 30 | issue = 1 | pages = 48–55 | year = 1975 | pmid = 1231448 | doi = 10.1080/17843286.1975.11716973 }}
* {{cite journal | vauthors = Düsterberg B, Nishino Y | title = Pharmacokinetic and pharmacological features of oestradiol valerate | journal = Maturitas | volume = 4 | issue = 4 | pages = 315–324 | date = December 1982 | pmid = 7169965 | doi = 10.1016/0378-5122(82)90064-0 }}
* {{cite journal | vauthors = Sang GW | title = Pharmacodynamic effects of once-a-month combined injectable contraceptives | journal = Contraception | volume = 49 | issue = 4 | pages = 361–385 | date = April 1994 | pmid = 8013220 | doi = 10.1016/0010-7824(94)90033-7 }}
* {{cite journal | vauthors = O'Connell MB | title = Pharmacokinetic and pharmacologic variation between different estrogen products | journal = Journal of Clinical Pharmacology | volume = 35 | issue = 9S | pages = 18S–24S | date = September 1995 | pmid = 8530713 | doi = 10.1002/j.1552-4604.1995.tb04143.x | s2cid = 10159196 }}
* {{cite journal | vauthors = Kuhl H | title = Pharmacology of estrogens and progestogens: influence of different routes of administration | journal = Climacteric | volume = 8 | issue = Suppl 1 | pages = 3–63 | date = August 2005 | pmid = 16112947 | doi = 10.1080/13697130500148875 | s2cid = 24616324 }}
* {{cite journal | vauthors = Stanczyk FZ, Archer DF, Bhavnani BR | title = Ethinyl estradiol and 17β-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment | journal = Contraception | volume = 87 | issue = 6 | pages = 706–727 | date = June 2013 | pmid = 23375353 | doi = 10.1016/j.contraception.2012.12.011 }}
{{refend}}

{{Estradiol}}
{{Estrogens and antiestrogens}}
{{Estrogen receptor modulators}}

[[Category:Antigonadotropins]]
[[Category:Estradiol esters]]
[[Category:Hormonal antineoplastic drugs]]
[[Category:Hormonal contraception]]
[[Category:Hydroxyarenes]]
[[Category:Synthetic estrogens]]
[[Category:Valerate esters]]