Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Estriol (medication): Difference between pages

{{Short description|Chemical compound}}

{{cs1 config|name-list-style=vanc|display-authors=6}}

{{About|estriol as a medication|its role as a hormone|Estriol}}

{{Drugbox

| Verifiedfields = verified

| Watchedfields = verified

| verifiedrevid = 477167082

| IUPAC_name = (8''R'',9''S'',13''S'',14''S'',16''R'',17''R'')-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[''a'']phenanthrene-3,16,17-triol

| image = Estriol.svg

| width = 250px

| image2 = Estriol molecule ball.png

| width2 = 235px

<!--Clinical data-->

| pronounce = {{IPAc-en|ˈ|ɛ|s|t|r|i|ɒ|l|,_|-|t|r|aɪ|ɒ|l}}<ref name="Dictionary.com">[http://www.dictionary.com/browse/estriol Estriol]. [[Dictionary.com]].</ref> <br />{{respell|ESS|TREE|ohl}}<ref name="Dictionary.com" />

| tradename = Ovestin, others<ref name="IndexNominum2000" /><ref name="Drugs.com" />

| 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 =

| legal_status = Rx-only

| routes_of_administration = [[Oral administration|By mouth]], [[vaginal administration|vaginal]], [[intramuscular injection]]<ref name="pmid16112947" /><ref name="OettelSchillinger2012" /><ref name="pmid11600867" />

| class = [[Estrogen (medication)|Estrogen]]

<!--Pharmacokinetic data-->

| bioavailability = [[Oral administration|Oral]]: ~1–2%<ref name="pmid16112947" /><ref name="pmid11600867" /><br />[[Vaginal administration|Vaginal]]: ~10–20%<ref name="OettelSchillinger2012" /><ref name="pmid16112947" /><ref name="pmid11600867" />

| protein_bound = 92%:<ref name="pmid16112947" /><br />• [[Human serum albumin|Albumin]]: 91%<ref name="pmid16112947" /><br />• {{abbrlink|SHBG|Sex hormone-binding globulin}}: 1%<ref name="pmid16112947" /><br />• Free: 8%<ref name="pmid16112947" />

| metabolism = [[Liver]], [[intestine]]s ([[conjugation (biochemistry)|conjugation]] ([[glucuronidation]], [[sulfation]]), [[oxidation]], [[hydroxylation]])<ref name="pmid16112947" />

| metabolites = • [[Estriol 16α-glucuronide]]<ref name="MuseyKirdani1973" /><ref name="OettelSchillinger2012" /><br />• [[Estriol 3-glucuronide]]<ref name="MuseyKirdani1973" /><ref name="OettelSchillinger2012" /><br />• [[Estriol 3-sulfate]]<ref name="MuseyKirdani1973" /><ref name="OettelSchillinger2012" /><br />• [[Estriol 3-sulfate 16α-glucuronide|Estriol 3-sulfate 16α-gluc.]]<ref name="MuseyKirdani1973" /><ref name="OettelSchillinger2012" /><br />• [[16α-Hydroxyestrone]]<ref name="pmid16112947" /><ref name="Dörwald2013" /><br />• Others (minor)<ref name="pmid16112947" />

| elimination_half-life = Oral: 5–10 hours<ref name="Wentz1988">{{cite book| vauthors = Wentz AC |title=Gynecologic Endocrinology and Infertility for the House Officer|url=https://books.google.com/books?id=3I5sAAAAMAAJ|date=January 1988|publisher=Williams & Wilkins|isbn=978-0-683-08931-8|quote=Estriol is considered a short-acting estrogen with a half-life of 5 hours.}}</ref><ref name="Dörwald2013">{{cite book| vauthors = Dörwald FZ | chapter = Steroids |title=Lead Optimization for Medicinal Chemists: Pharmacokinetic Properties of Functional Groups and Organic Compounds| chapter-url=https://books.google.com/books?id=YTeY9ZEfNccC&pg=PA486|date=4 February 2013|publisher=John Wiley & Sons|isbn=978-3-527-64565-7|pages=486–}}</ref><br />{{abbrlink|IM|Intramuscular injection}}: 1.5–5.3 hours (as {{abbr|E3|estriol (unconjugated)}})<ref name="OettelSchillinger2012" /><br />{{abbrlink|IV|Intravenous injection}}: 20&nbsp;minutes (as {{abbr|E3|estriol (unconjugated)}})<ref name="pmid18464021">{{cite journal | vauthors = Visser M, Holinka CF, Coelingh Bennink HJ | title = First human exposure to exogenous single-dose oral estetrol in early postmenopausal women | journal = Climacteric | volume = 11 | issue = Suppl 1 | pages = 31–40 | date = 2008 | pmid = 18464021 | doi = 10.1080/13697130802056511 | s2cid = 23568599 }}</ref><ref name="UniversityofCalifornia1986">{{cite book|title=Applied Biochemistry of Clinical Disorders|edition=2nd |url=https://books.google.com/books?id=as1NAQAAIAAJ|year=1986|publisher=University of California|isbn=978-0-397-50768-9|quote=Because its half-life is about 20 minutes, unconjugated estriol rapidly reflects changes in estriol production.}}</ref>

| excretion = [[Urine]]: >95% (as [[conjugation (biochemistry)|conjugate]]s)<ref name="pmid16112947" /><ref name="OettelSchillinger2012" />

<!--Identifiers-->

| CAS_number_Ref = {{cascite|correct|CAS}}

| CAS_number = 50-27-1

| CAS_supplemental = <br />1306-04-3<br />514-68-1 ([[succinate]])

| ATC_prefix = G03

| ATC_suffix = CA04

| ATC_supplemental = <br />{{ATC|G03|CC06}}

| PubChem = 5756

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank = DB04573

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| UNII_Ref = {{fdacite|correct|FDA}}

| ChEBI_Ref = {{ebicite|correct|EBI}}

| KEGG_Ref = {{keggcite|correct|kegg}}

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 193482

| IUPHAR_ligand = 2821

| synonyms = Oestriol; E3; 16α-Hydroxyestradiol; Estra-1,3,5(10)-triene-3,16α,17β-triol

<!--Chemical data-->

| C=18 | H=24 | O=3

| SMILES = Oc1cc3c(cc1)[C@H]2CC[C@@]4([C@@H](O)[C@H](O)C[C@H]4[C@@H]2CC3)C

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

<!--Physical data-->

| melting_point = 82

| melting_high = 86

| melting_notes = (experimental)

| solubility = 0.119

<!-- Definition and medical uses -->

'''Estriol''' ('''E3'''), sold under the brand name '''Ovestin''' among others, is an [[estrogen (medication)|estrogen]] medication and [[natural product|naturally occurring]] [[steroid hormone]] which is used in [[menopausal hormone therapy]].<ref name="pmid28622049">{{cite journal | vauthors = Rueda C, Osorio AM, Avellaneda AC, Pinzón CE, Restrepo OI | title = The efficacy and safety of estriol to treat vulvovaginal atrophy in postmenopausal women: a systematic literature review | journal = Climacteric | volume = 20 | issue = 4 | pages = 321–330 | date = August 2017 | pmid = 28622049 | doi = 10.1080/13697137.2017.1329291 | s2cid = 407950 }}</ref><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="pmid11600867" /><ref name="Zutshi2005" /> It is also used in [[veterinary medicine]] as '''Incurin''' to treat [[urinary incontinence]] due to [[estrogen deficiency]] in dogs.<ref name="EttingerFeldman2017" /><ref name="Boothe2011" /><ref name="BonaguraTwedt2008" /><ref name="Papich2015" /> The medication is taken [[oral administration|by mouth]] in the form of [[tablet (pharmacy)|tablet]]s, as a [[cream (pharmaceutical)|cream]] that is [[topical administration|applied to the skin]], as a cream or [[pessary]] that is [[vaginal administration|applied in the vagina]], and by [[intramuscular injection|injection into muscle]].<ref name="pmid16112947" /><ref name="OettelSchillinger2012" /><ref name="pmid11600867" />

<!-- Side effects and mechanism -->

Estriol is well-[[tolerability|tolerated]] and produces relatively few [[adverse effect]]s.<ref name="pmid28622049" /><ref name="pmid28375935" /> Side effects may include [[breast tenderness]], [[vaginal discomfort]] and [[vaginal discharge|discharge]], and [[endometrial hyperplasia]].<ref name="pmid28622049" /><ref name="pmid28375935" /> Estriol is a [[natural product|naturally occurring]] and [[bioidentical hormone therapy|bioidentical]] estrogen, or an [[agonist]] of the [[estrogen receptor]], the [[biological target]] of [[estrogen]]s like [[endogenous]] [[estradiol]].<ref name="pmid16112947" /> It is an atypical and relatively weak estrogen, with much lower [[potency (pharmacology)|potency]] than [[estradiol (medication)|estradiol]].<ref name="pmid16112947" /><ref name="pmid11600867" /><ref name="Becker2001" /> When present continuously at adequate concentrations however, estriol produces full [[estrogen (medication)|estrogenic]] effects similarly to estradiol.<ref name="pmid6356176a" /><ref name="Clark_1984" />

<!-- History, society, and culture -->

Estriol was first discovered in 1930,<ref name="Josimovich2013" /><ref name="SartorelliJohns2013" /> and was introduced for medical use shortly thereafter.<ref name="pmid13567043" /><ref name="pmid18744783" /> [[Estriol ester]]s such as [[estriol succinate]] are also used.<ref name="pmid16112947" /><ref name="pmid28375935" /><ref name="Drugs.com" /> Although it is less commonly employed than other estrogens like estradiol and [[conjugated estrogens]], estriol is widely available for medical use in [[Europe]] and elsewhere throughout the world.<ref name="pmid16112947" /><ref name="IndexNominum2000" /><ref name="Drugs.com" /><ref name="pmid11600867">{{cite journal | vauthors = Taylor M | title = Unconventional estrogens: estriol, biest, and triest | journal = Clinical Obstetrics and Gynecology | volume = 44 | issue = 4 | pages = 864–879 | date = December 2001 | pmid = 11600867 | doi = 10.1097/00003081-200112000-00024 | s2cid = 27098486 }}</ref>

{{TOC limit|3}}

==Medical uses==

Estriol is used in [[menopausal hormone therapy]] to treat [[menopausal symptoms]], such as [[hot flash]]es, [[vulvovaginal atrophy]], and [[dyspareunia]] (difficult or painful [[sexual intercourse]]).<ref name="pmid28622049" /><ref name="pmid16112947" /><ref name="Zutshi2005">{{cite book| vauthors = Zutshi V, Rathore AM, Sharma K |title=Hormones in Obstetrics and Gynaecology|url=https://books.google.com/books?id=IBxBbaDjXw0C&pg=PA101|date=1 January 2005|publisher=Jaypee Brothers Publishers|isbn=978-81-8061-427-9|pages=101–}}</ref><ref name="pmid7493689" /><ref name="pmid28375935" /> The benefits of estriol on [[bone mineral density]] and [[osteoporosis]] prevention have been inconsistent and are less clear.<ref name="pmid28375935" /><ref name="pmid28622049" /> Estriol has been found to reduce the risk of [[urinary tract infection]]s and other [[urogenital symptom]]s.<ref name="pmid16112947" /><ref name="pmid28622049" /> A combination of estriol and [[lactobacilli]] as a dual estrogen and [[probiotic]] has been marketed for the treatment of vaginal atrophy and urinary tract infections.<ref name="AdisInsight">{{Cite web|url=https://adisinsight.springer.com/drugs/800050964|title=Estriol/Lactobacillus - Acerus Pharmaceuticals/Medinova - | work = AdisInsight | publisher = Springer Nature Switzerland AG }}</ref>

{{Estrogen dosages for menopausal hormone therapy}}

===Available forms (except USA)===

Estriol is available in [[oral administration|oral]] [[tablet (pharmacy)|tablet]], [[vaginal administration|vaginal]] [[cream (pharmaceutical)|cream]], and vaginal [[suppository]] forms.<ref name="Zutshi2005" /> It is also available [[over-the-counter]] or from [[compounding pharmacy|compounding pharmacies]] in the form of [[topical medication|topical]] [[cream (pharmaceutical)|cream]]s.<ref name="pmid17627398" /> The medication is available both as estriol and in the form of [[estriol ester]] [[prodrug]]s such as [[estriol succinate]], [[estriol acetate benzoate]], and [[estriol tripropionate]], as well as the [[polymer]]ic ester prodrug [[polyestriol phosphate]].<ref name="pmid16112947" /><ref name="pmid28375935" /><ref name="Elks2014" /><ref name="IndexNominum2000" /><ref name="Drugs.com" />

Estriol was originally marketed in the 1930s in the form of oral [[capsule (pharmacy)|capsule]]s containing 0.06, 0.12, or 0.24&nbsp;mg estriol under the brand names Theelol ([[Parke-Davis]]) and Estriol ([[Eli Lilly|Lilly]], [[Abbott Laboratories|Abbott]]).<ref name="MazerIsrael1946">{{cite book| vauthors = Mazer C, Israel SL, Charny CW |title=Diagnosis and treatment of menstrual disorders and sterility|url=https://books.google.com/books?id=nNVLAAAAMAAJ|year=1946|publisher=Hoeber|page=525|quote=8. PREPARATIONS OF ESTRIOL. Estriol is the least active of all commercially available natural estrogenic substances. A milligram of estriol yields approximately 350 Allen-Doisy rat units. Estriol (Abbott). Capsules containing 0.06, 0.12, and 0.24 mg. Estriol (Lilly). Puvules containing 0.06, 0.12, and 0.24 mg. Theelol (Parke-Davis). Capsules containing 0.06, 0.12, and 0.24 mg.}}</ref><ref name="Barr1940">{{cite book| vauthors = Barr DP |title=Modern Medical Therapy in General Practice|url=https://books.google.com/books?id=V5HJymGfFP8C|year=1940|publisher=William & Wilkins Company|page=194|isbn=978-0-598-66833-2|quote=Estriol. Estriol (theelol) is trihydroxyestrin. It is a crystalline estrogenic steroid obtained from the urine of pregnant women. It is less actively estrogenic than estrone. Several pharmaceutical houses supply capsules containing 0.06 or 0.12 mg. These may be obtained as Theelol (Parke-Davis), Estriol (Abbott), and Estriol (Lilly).}}</ref><ref name="Sollmann1948">{{cite book | vauthors = Sollmann TH |title=A manual of pharmacology and its applications to therapeutics and toxicology|url=https://books.google.com/books?id=LdtsAAAAMAAJ|year=1948|publisher=W. B. Saunders|quote=Estriol (Theelol), N.N.R.; characters and solubility as for estrone; considerably less potent. Marketed as capsules of 0.06, 0.12 and 0.24 mg. Dose, 0.06 to 0.12 mg. once to four times daily.}}</ref><ref name="AMA1950">{{cite book|author=Council on Drugs (American Medical Association)|title=New and Nonofficial Drugs|url=https://books.google.com/books?id=b3YYAQAAIAAJ|year=1950|publisher=Lippincott|page=322|quote=Abbott Laboratories Capsules Estriol: 0.12 mg. and 0.24 mg. Eli Lilly and Company Pulvules Estriol: 0.06 mg., 0.12 mg. and 0.24 mg. Parke, Davis & Company Kapseals Theelol: 0.24 mg.}}</ref><ref name="NYSJM1939">{{cite book|title=New York State Journal of Medicine|url=https://books.google.com/books?id=9K5MAQAAIAAJ|year=1939|publisher=Medical Society of the State of New York|page=1760}}</ref> Subsequently, many decades later, oral tablets containing 0.35, 1, or 2&nbsp;mg estriol were introduced under brand names such as Gynäsan, Hormomed, Ovestin, and Ovo-Vinces.<ref name="Lauritzen1988">{{cite book | vauthors = Lauritzen C | chapter = Natürliche und Synthetische Sexualhormone – Biologische Grundlagen und Behandlungsprinzipien | pages = 229–306 | trans-chapter = Natural and Synthetic Sexual Hormones – Biological Basis and Medical Treatment Principles | veditors = Schneider HP, Lauritzen C, Nieschlag E | title = Grundlagen und Klinik der Menschlichen Fortpflanzung | trans-title = Foundations and Clinic of Human Reproduction | language = de | year = 1988 | publisher = Walter de Gruyter | isbn = 978-3-11-010968-9 | oclc = 35483492 | url = https://books.google.com/books?id=v4HvAQAACAAJ}}</ref>

==Contraindications==

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

General [[contraindication]]s of estrogens include [[breast cancer]], [[endometrial cancer]], and others.<ref name="Becker2001" /> In animals, estriol is contraindicated during [[pregnancy]] and in [[ferret]]s.<ref name="Papich2015" />

==Side effects==

Estriol is well-[[tolerability|tolerated]] and produces relatively few [[adverse effect]]s.<ref name="pmid28622049"/><ref name="pmid28375935" /> [[Breast tenderness]] may sometimes occur as a side effect of estriol.<ref name="pmid28622049" /> Local reactions with vaginal estriol such as [[vaginal discomfort|discomfort]] ([[vaginal irritation|irritation]], [[burning]], [[itching]]) and [[leukorrhea|discharge]] may occur.<ref name="pmid28622049" /> Estriol may produce [[endometrial hyperplasia]] similarly to estradiol and other estrogens, and hence should be combined with a [[progestogen]] in women with intact [[uterus]]es to prevent this risk.<ref name="pmid17549577">{{cite journal | vauthors = Fugh-Berman A, Bythrow J | title = Bioidentical hormones for menopausal hormone therapy: variation on a theme | journal = Journal of General Internal Medicine | volume = 22 | issue = 7 | pages = 1030–1034 | date = July 2007 | pmid = 17549577 | pmc = 2219716 | doi = 10.1007/s11606-007-0141-4 }}</ref><ref name="pmid16112947" /> However, it appears that typical clinical dosages of vaginal estriol are not associated with an important risk of endometrial proliferation or hyperplasia.<ref name="pmid28622049" /><ref name="pmid7493689">{{cite journal | vauthors = Vooijs GP, Geurts TB | title = Review of the endometrial safety during intravaginal treatment with estriol | journal = European Journal of Obstetrics, Gynecology, and Reproductive Biology | volume = 62 | issue = 1 | pages = 101–106 | date = September 1995 | pmid = 7493689 | doi = 10.1016/0301-2115(95)02170-c | hdl-access = free | hdl = 2066/21059 }}</ref> As such, combination with a progestogen may not be needed in the case of vaginal estriol.<ref name="pmid28622049" /><ref name="pmid7493689" /> Some studies suggest that this may also be true for oral estriol.<ref name="pmid28375935" /> However, dosage and frequency of administration, as well as meal consumption, may be determining factors as to whether or not estriol produces endometrial proliferation.<ref name="pmid16112947" />

==Overdose==

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

Estrogens and other [[steroid]]s are relatively safe in acute [[overdose]].{{Citation needed|date=May 2018}} Estriol has been assessed in single oral doses of up to 75&nbsp;mg.<ref name="pmid6250009">{{cite journal | vauthors = Greenblatt RB, Natrajan PK, Aksu MF, Tzingounis VA | title = The fate of a large bolus of exogenous estrogen administered to postmenopausal women | journal = Maturitas | volume = 2 | issue = 1 | pages = 29–35 | date = January 1980 | pmid = 6250009 | doi = 10.1016/0378-5122(80)90057-2 }}</ref><ref name="pmid1186230">{{cite journal | vauthors = Adlercreutz H, Martin F, Wahlroos O, Soini E | title = Mass spectrometric and mass fragmentographic determination of natural and synthetic steroids in biological fluids | journal = Journal of Steroid Biochemistry | volume = 6 | issue = 3–4 | pages = 247–259 | date = 1975 | pmid = 1186230 | doi = 10.1016/0022-4731(75)90140-5 }}</ref> General symptoms of estrogen overdose in humans may include [[nausea]], [[vomiting]], [[vaginal bleeding]], and reversible [[feminization (biology)|feminization]].<ref name="Books2005">{{cite book|author=Pocket Books|title=The PDR Pocket Guide to Prescription Drugs|url=https://books.google.com/books?id=Cm9K0j4GqTYC&pg=PA1540|year=2005|publisher=Simon and Schuster|isbn=978-1-4165-1085-7|pages=1540–}}</ref><ref name="BonaguraTwedt2008" /> While there are no known studies describing the acute [[toxicity]] of estrogen overdose in dogs, this species is known to be more sensitive to the toxic effects of estrogens than humans and other animals.<ref name="BonaguraTwedt2008" /> The most serious short-term adverse effect of estrogens in dogs is [[bone marrow suppression]] and consequent [[pancytopenia]], which can be life-threatening.<ref name="BonaguraTwedt2008" />

== Interactions ==

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

[[Drug interaction|Interaction]]s with estriol might be expected to be similar to those of [[estradiol (medication)|estradiol]].<ref name="Bratman2003">{{cite book| vauthors = Bratman S |title=Mosby's Handbook of Herbs and Supplements and Their Therapeutic Uses|url=https://archive.org/details/isbn_9780323020152|url-access=registration|year=2003|publisher=Mosby/Healthgate|isbn=978-0-323-02015-2}}</ref> No interactions with estriol have been reported in animals.<ref name="Papich2015" /> However, it should not be used in combination with other drugs that [[bone marrow suppression|suppress bone marrow production]] in dogs.<ref name="Papich2015" />

==Pharmacology==

===Pharmacodynamics===

Estriol is an estrogen, or an [[agonist]] of the [[estrogen receptor]]s (ERs), [[estrogen receptor alpha|ERα]] and [[estrogen receptor beta|ERβ]].<ref name="pmid16112947" /><ref name="JaouenSalmain2015">{{cite book| vauthors = Jaouen G, Top S, McGlinchey MJ | chapter = The Biological Target Potential of Organometallic Steroids | veditors = Jaouen G, Salmain M |title=Bioorganometallic Chemistry: Applications in Drug Discovery, Biocatalysis, and Imaging|chapter-url=https://books.google.com/books?id=n7ynBQAAQBAJ&pg=PA45|date=20 April 2015|publisher=John Wiley & Sons|isbn=978-3-527-33527-5|pages=45–}}</ref><ref name="pmid16554039">{{cite journal | vauthors = Escande A, Pillon A, Servant N, Cravedi JP, Larrea F, Muhn P, Nicolas JC, Cavaillès V, Balaguer P | title = Evaluation of ligand selectivity using reporter cell lines stably expressing estrogen receptor alpha or beta | journal = Biochemical Pharmacology | volume = 71 | issue = 10 | pages = 1459–1469 | date = May 2006 | pmid = 16554039 | doi = 10.1016/j.bcp.2006.02.002 }}</ref> In terms of [[relative binding affinities]] (RBA) for the ERs compared to [[estradiol (medication)|estradiol]], it was found in one study to possess 11 to 14% of the RBA for the human ERα and 18 to 21% of the RBA for the human ERβ.<ref name="pmid16554039" /> Its [[relative transactivational capacities]] at the ERs compared to estradiol were 11% at ERα and 17% at ERβ.<ref name="pmid16554039" /> In addition to being a [[ligand (biochemistry)|ligand]] of the classical [[nuclear receptor|nuclear]] ERs, estriol is an [[receptor antagonist|antagonist]] of the [[G protein-coupled estrogen receptor]] (GPER), a [[membrane estrogen receptor]] (mER), at high concentrations (~1,000–10,000&nbsp;μM).<ref name="pmid26023144">{{cite journal | vauthors = Prossnitz ER, Arterburn JB | title = International Union of Basic and Clinical Pharmacology. XCVII. G Protein-Coupled Estrogen Receptor and Its Pharmacologic Modulators | journal = Pharmacological Reviews | volume = 67 | issue = 3 | pages = 505–540 | date = July 2015 | pmid = 26023144 | pmc = 4485017 | doi = 10.1124/pr.114.009712 }}</ref><ref name="LappanoRosano2010">{{cite journal | vauthors = Lappano R, Rosano C, De Marco P, De Francesco EM, Pezzi V, Maggiolini M | title = Estriol acts as a GPR30 antagonist in estrogen receptor-negative breast cancer cells | journal = Molecular and Cellular Endocrinology | volume = 320 | issue = 1–2 | pages = 162–170 | date = May 2010 | pmid = 20138962 | doi = 10.1016/j.mce.2010.02.006 | s2cid = 24525995 }}</ref><ref name="JaouenSalmain2015" /><ref name="GirgertEmons2014">{{cite journal | vauthors = Girgert R, Emons G, Gründker C | title = Inhibition of GPR30 by estriol prevents growth stimulation of triple-negative breast cancer cells by 17β-estradiol | journal = BMC Cancer | volume = 14 | issue = 1 | pages = 935 | date = December 2014 | pmid = 25496649 | pmc = 4364648 | doi = 10.1186/1471-2407-14-935 | doi-access = free }}</ref> This is in contrast to estradiol, which is an agonist of this receptor.<ref name="LappanoRosano2010" /><ref name="JaouenSalmain2015" /><ref name="GirgertEmons2014" /> Like other estrogens, estriol does not importantly interact with other [[steroid hormone receptor]]s.<ref name="RaynaudOjasoo1979">{{cite journal| vauthors = Raynaud JP, Ojasoo T, Bouton MM |title=Receptor Binding as a Tool in the Development of New Bioactive Steroids|year=1979|pages=169–214|doi=10.1016/B978-0-12-060308-4.50010-X| url=https://books.google.com/books?id=bhAlBQAAQBAJ&pg=PA169|journal=Drug Design|series=Medicinal Chemistry: A Series of Monographs |volume=11 |isbn=978-0-12-060308-4}}</ref><ref name="pmid359134">{{cite journal | vauthors = Ojasoo T, Raynaud JP | title = Unique steroid congeners for receptor studies | journal = Cancer Research | volume = 38 | issue = 11 Pt 2 | pages = 4186–4198 | date = November 1978 | pmid = 359134 | url = http://cancerres.aacrjournals.org/content/38/11_Part_2/4186.short }}</ref><ref name="pmid3695484">{{cite journal | vauthors = Ojasoo T, Delettré J, Mornon JP, Turpin-VanDycke C, Raynaud JP | title = Towards the mapping of the progesterone and androgen receptors | journal = Journal of Steroid Biochemistry | volume = 27 | issue = 1–3 | pages = 255–269 | date = 1987 | pmid = 3695484 | doi = 10.1016/0022-4731(87)90317-7 }}</ref><ref name="pmid7421203">{{cite journal | vauthors = Raynaud JP, Bouton MM, Moguilewsky M, Ojasoo T, Philibert D, Beck G, Labrie F, Mornon JP | title = Steroid hormone receptors and pharmacology | journal = Journal of Steroid Biochemistry | volume = 12 | pages = 143–157 | date = January 1980 | pmid = 7421203 | doi = 10.1016/0022-4731(80)90264-2 }}</ref><ref name="pmid7195404">{{cite journal | vauthors = Dunn JF, Nisula BC, Rodbard D | title = Transport of steroid hormones: binding of 21 endogenous steroids to both testosterone-binding globulin and corticosteroid-binding globulin in human plasma | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 53 | issue = 1 | pages = 58–68 | date = July 1981 | pmid = 7195404 | doi = 10.1210/jcem-53-1-58 }}</ref>

Estriol is a much less [[potency (pharmacology)|potent]] estrogen than is estradiol, and is somewhat weak and atypical in its properties.<ref name="pmid16112947" /><ref name="pmid16554039" /><ref name="LappanoRosano2010" /><ref name="Becker2001">{{cite book | vauthors = Carr BC | chapter = The maternal-fetal-placental unit. | veditors = Becker KL |title=Principles and Practice of Endocrinology and Metabolism| chapter-url = https://books.google.com/books?id=FVfzRvaucq8C&pg=PA1061|year=2001|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-1750-2|pages=932, 989, 1061}}</ref> Given by [[subcutaneous injection]] in mice, estradiol is about 10-fold more potent than [[estrone (medication)|estrone]] and about 100-fold more potent than estriol.<ref name="Labhart2012" /> With clinical use, estriol is said to be weakly estrogenic in certain [[tissue (biology)|tissues]], such as the [[liver]] and [[endometrium]], but produces pronounced and full estrogenic responses in the [[vaginal]] [[epithelium]].<ref name="pmid16112947" /> The medication has been found to reduce [[hot flash]]es, improve [[vaginal atrophy]], reverse the [[postmenopausal]] decline in [[skin thickness]] and [[collagen]] content, suppress [[gonadotropin]] secretion, and produce [[cell proliferation|proliferation]] of [[breast]] epithelium.<ref name="pmid16112947" /> Conversely, estriol does not consistently affect [[bone resorption]] or [[bone fracture|fracture]] risk, does not seem to increase [[breast density]], and, at oral doses of 2 to 4&nbsp;mg/day, does not affect [[liver protein]]s, [[lipid metabolism]], or [[hemostasis|hemostatic]] parameters.<ref name="pmid16112947" /><ref name="pmid28375935" /> Additionally, vaginal estriol does not appear to produce [[endometrial proliferation]] or increase the risk of [[endometrial hyperplasia]], and some studies have found this to be the case for oral estriol as well.<ref name="pmid16112947" /><ref name="pmid28375935" /><ref name="pmid2170822" /> On the other hand, it appears that estriol may be able to stimulate the growth of active [[breast cancer]].<ref name="pmid28375935" /><ref name="pmid28622049" /> In rodents, estriol induces mammary gland development similar to that with estrone.<ref name="Nelson1936">{{cite journal| vauthors = Nelson WO |title=Endocrine Control of the Mammary Gland|journal=Physiological Reviews|volume=16|issue=3|year=1936|pages=488–526|issn=0031-9333|doi=10.1152/physrev.1936.16.3.488}}</ref> By the oral route in women, estriol has approximately 30% of the potency of estradiol in terms of [[hot flash]]es relief and suppression of [[follicle-stimulating hormone]] [[secretion]], and about 20% of the potency of estradiol on stimulation of [[liver]] [[biosynthesis|production]] of [[high-density lipoprotein]] (HDL) [[cholesterol]].<ref name="pmid16112947" /> A study of [[ovulation]] inhibition by estrogens in women found that prevention of ovulation occurred with 5&nbsp;mg/day oral estriol in only 1 of 7&nbsp;cycles.<ref name="Greenblatt1966a">{{cite book| vauthors = Martinez-Manautou J, Rudel HW |chapter=Antiovulatory Activity of Several Synthetic and Natural Estrogens|pages=243–253| veditors = Greenblatt RB |title=Ovulation: Stimulation, Suppression, and Detection|url=https://books.google.com/books?id=le1qAAAAMAAJ|year=1966|publisher=Lippincott|isbn=978-0-397-59010-0}}</ref><ref name="HerrRevesz1970a">{{cite book | vauthors = Herr F, Revesz C, Manson AJ, Jewell JB | veditors = Bernstein S, Solomon S |title=Chemical and Biological Aspects of Steroid Conjugation|chapter=Biological Properties of Estrogen Sulfates|year=1970|pages=368–408|publisher=Springer |doi=10.1007/978-3-642-95177-0 |isbn=978-3-642-49506-9|chapter-url=https://link.springer.com/chapter/10.1007/978-3-642-95177-0_8}}</ref> Due to its differing effects from those of estradiol, estriol may be considered a safer estrogen in certain regards.<ref name="pmid28622049" />

[[File:Nuclear retention of the uterine receptor estrogen complex with an injection of estradiol, estriol, or a combination of estradiol and estriol in rats.png|thumb|right|400px|[[Nuclear retention]] of the [[protein–ligand complex|receptor estrogen complex]] in the [[uterus]] with a single short-acting [[subcutaneous injection]] of 0.1&nbsp;μg [[estradiol (medication)|estradiol]] (E2), 1.0&nbsp;μg estriol (E3), or a combination of 0.1&nbsp;μg estradiol and 1.0&nbsp;μg estriol in [[aqueous solution]] in rats.<ref name="ClarkPeck1979">{{cite book| vauthors = Clark JH, Peck EJ |chapter=Control of Steroid Receptor Levels and Steroid Antagonism|title=Female Sex Steroids: Receptors and Function|series=Monographs on Endocrinology|volume=14|year=1979|pages=99–134|publisher=Springer |issn=0077-1015|doi=10.1007/978-3-642-81339-9_6|pmid=390365|isbn=978-3-642-81341-2}}</ref><ref name="pmid830547a">{{cite journal | vauthors = Clark JH, Paszko Z, Peck EJ | title = Nuclear binding and retention of the receptor estrogen complex: relation to the agonistic and antagonistic properties of estriol | journal = Endocrinology | volume = 100 | issue = 1 | pages = 91–96 | date = January 1977 | pmid = 830547 | doi = 10.1210/endo-100-1-91 }}</ref> Estriol displaces estradiol from the estrogen receptors and, due to the shorter nuclear retention of estriol, it thereby antagonizes overall nuclear retention.<ref name="ClarkPeck1979" /><ref name="pmid830547a" /> No antagonism occurs when long-acting [[subcutaneous pellet]]s of estriol are used instead.<ref name="ClarkPeck1979" /><ref name="pmid830547a" />]]

The weak and atypical estrogenicity of estriol is thought to be related to its short [[duration of action|duration]] in the body and hence the fact that it stays bound to the ER for a relatively short amount of time.<ref name="pmid16112947" /><ref name="Clark_1984">{{cite journal | vauthors = Clark JH, Markaverich BM | title = The agonistic and antagonistic actions of estriol | journal = Journal of Steroid Biochemistry | volume = 20 | issue = 4B | pages = 1005–1013 | date = April 1984 | pmid = 6202959 | doi = 10.1016/0022-4731(84)90011-6 }}</ref> Whereas estradiol remains bound to the ER for 6 to 24&nbsp;hours with a single short-acting [[injection (medicine)|injection]], estriol dissociates from the receptor much more rapidly and stays bound for only 1 to 6&nbsp;hours.<ref name="pmid16112947" /><ref name="Clark_1984" /><ref name="RunnebaumRabe2013">{{cite book| vauthors = Rabe T, Runnebaum B, Kellermeier-Wittlinger S | chapter = Hormontherapie | veditors = Runnebaum B, Rabe T |title=Gynäkologische Endokrinologie und Fortpflanzungsmedizin: Band 1: Gynäkologische Endokrinologie| chapter-url=https://books.google.com/books?id=mBF9BwAAQBAJ&pg=PA88|date=17 April 2013|publisher=Springer-Verlag|isbn=978-3-662-07635-4|pages=88–}}</ref><ref name="Kopera1991a">{{cite book | vauthors = Kopera H |title=Hormonelle Therapie für die Frau|chapter=Hormone der Gonaden|series=Kliniktaschenbücher|year=1991|pages=59–124|publisher=Springer |issn=0172-777X|doi=10.1007/978-3-642-95670-6_6|isbn=978-3-540-54554-5}}</ref> As a result, estriol can only induce estrogenic effects which require short-term interaction with the ERs.<ref name="pmid16112947" /><ref name="Clark_1984" /> Induction of [[endometrium|endometrial]] [[mitosis|mitoses]] requires the ligand to remain bound for at least 9 to 12&nbsp;hours, and this is thought to be responsible for the lack of endometrial proliferation with estriol in many studies.<ref name="pmid16112947" /><ref name="Clark_1984" /> If estriol is delivered more continuously than a single administration per day however, for instance if it is given as a [[subcutaneous pellet]], as a [[depot injection]], or in multiple doses two or three times per day, this results in more sustained exposure to estriol and full estrogenic responses equivalent to those of estradiol occur.<ref name="pmid16112947" /><ref name="Clark_1984" /><ref name="pmid28622049" /> For these reasons, estriol has been described as a "short-acting" estrogen and it has been said that descriptors like "weak" and "impeded" are inaccurate.<ref name="Clark_1984" /> Consumption of food after oral administration of estriol also results in more prolonged exposure to estriol, due to [[enterohepatic recycling]] and resurgences in estriol levels.<ref name="pmid16112947" /> As such, if avoidance of endometrial hyperplasia or other full estrogenic effects is intended, it may be preferable to take estriol in a single dose, as low as possible, once per day at night before bedtime.<ref name="pmid16112947" /><ref name="pmid2170822" />

Although estriol is an estrogen, it has also been reported to have mixed [[agonist–antagonist]] or [[partial agonist]] activity at the ERs.<ref name="pmid16112947" /><ref name="Clark_1984" /><ref name="Becker2001" /> On its own, it is said to be weakly estrogenic, but in the presence of estradiol, it has been found to be [[antiestrogen]]ic.<ref name="pmid16112947" /><ref name="LappanoRosano2010" /> However, this is again due to the fact that estriol is a "short-acting" estrogen.<ref name="Clark_1984" /> If estriol is present continuously with estradiol, it shows no antagonism of estradiol.<ref name="Clark_1984" /> The co-administration of estriol with estradiol has been found not to influence the effects of the latter in women, including neither enhancing nor antagonizing the effects of estradiol.<ref name="pmid2170822">{{cite journal | vauthors = Kuhl H | title = Pharmacokinetics of oestrogens and progestogens | journal = Maturitas | volume = 12 | issue = 3 | pages = 171–197 | date = September 1990 | pmid = 2170822 | doi = 10.1016/0378-5122(90)90003-O }}</ref><ref name="pmid6429481">{{cite journal | vauthors = Hellberg D, Nilsson S | title = Comparison of a triphasic oestradiol/norethisterone acetate preparation with and without an oestriol component in the treatment of climacteric complaints | journal = Maturitas | volume = 5 | issue = 4 | pages = 233–243 | date = April 1984 | pmid = 6429481 | doi = 10.1016/0378-5122(84)90016-1 }}</ref>

{{Affinities of estrogen receptor ligands for the ERα and ERβ}}

{{Relative affinities of estrogens for steroid hormone receptors and blood proteins}}

{{Selected biological properties of endogenous estrogens in rats}}

{{Relative oral potencies of estrogens}}

{{Oral potencies of estrogens}}

{{Parenteral potencies and durations of steroidal estrogens}}

{{Classification of estrogens and antiestrogens after a single injection}}

===Pharmacokinetics===

[[File:Levels of estriol with administration of 8 mg oral estriol or 0.5 mg vaginal estriol in women.png|thumb|right|400px|Estriol (E3) levels after a single dose during continuous daily administration of 8&nbsp;mg oral estriol (with or without a meal at 4&nbsp;hours) or 0.5&nbsp;mg vaginal estriol.<ref name="pmid16112947" /> Note the second peak with oral estriol caused by consumption of a meal at 4&nbsp;hours, which is due to enterohepatic recycling of the compound and a consequent resurgence in levels.<ref name="pmid16112947" />]]

====Absorption====

Estriol has significant [[bioavailability]], but its [[potency (pharmacology)|potency]] is limited by rapid [[metabolism]] and [[excretion]] and its relatively weak estrogenic activity.<ref name="pmid11600867" /><ref name="pmid28375935" /> With [[oral administration]], during [[first-pass metabolism]], a considerable portion of estriol is [[conjugation (biochemistry)|conjugated]] via [[sulfation]] into [[estriol sulfate]] and rapidly excreted.<ref name="pmid11600867" /><ref name="pmid16112947" /><ref name="pmid2170822" /> Only about 10 to 20% of a dose of estriol remains in the circulation, and of this, only about 1 to 2% is present in its active, unconjugated form.<ref name="pmid16112947" /><ref name="pmid11600867" /><ref name="pmid2170822" /> [[Cmax (pharmacology)|Peak]] levels of estriol occur about 1 to 3&nbsp;hours after an oral dose.<ref name="pmid16112947" /><ref name="OettelSchillinger2012" /> Similarly to the case of [[progesterone (medication)|progesterone]], taking oral estriol with food greatly enhances its [[absorption (pharmacokinetics)|absorption]].<ref name="pmid11600867" /> In addition, due to [[enterohepatic recycling]], consuming a meal 4&nbsp;hours after taking oral estriol can produce a second peak in estriol levels.<ref name="pmid16112947" /><ref name="OettelSchillinger2012" /> Dosages of oral estriol of 4 to 10&nbsp;mg have been found to result in a fairly large range of maximal estriol levels of 80 to 340&nbsp;pg/mL.<ref name="OettelSchillinger2012" /> After a single oral dose of 8&nbsp;mg estriol in [[postmenopausal]] women, maximal levels of 65&nbsp;pg/mL estriol and 60&nbsp;ng/mL estriol conjugates were produced within an hour.<ref name="pmid16112947" /> With continued daily administration, this increased to peak levels of 130&nbsp;pg/mL estriol, whereas maximal levels of estriol conjugates remained at 60&nbsp;ng/mL.<ref name="pmid16112947" /> Levels of estriol rapidly decreased to low levels following occurrence of peak levels.<ref name="pmid16112947" /> Consumption of a meal 4&nbsp;hours after taking an oral dose of 8&nbsp;mg estriol during continuous daily administration resulted in a second estriol peak 2&nbsp;hours later of 120&nbsp;pg/mL, with estriol levels declining slowly thereafter to about 25&nbsp;pg/mL after 24&nbsp;hours.<ref name="pmid16112947" />

The bioavailability of estriol is markedly increased with [[vaginal administration]] compared to oral administration.<ref name="pmid11600867" /> The relative bioavailability of oral estriol was found to be about 10% of that of vaginal estriol.<ref name="OettelSchillinger2012" /> In accordance, a single dose of 8&nbsp;mg oral estriol and of 0.5&nbsp;mg vaginal estriol have been found to produce similar circulating concentrations of estriol.<ref name="pmid16112947" /> It has been said that 0.5 to 1&nbsp;mg vaginal estriol may be equivalent in clinical effect to 8 to 12&nbsp;mg oral estriol.<ref name="pmid28375935">{{cite journal | vauthors = Ali ES, Mangold C, Peiris AN | title = Estriol: emerging clinical benefits | journal = Menopause | volume = 24 | issue = 9 | pages = 1081–1085 | date = September 2017 | pmid = 28375935 | doi = 10.1097/GME.0000000000000855 | s2cid = 41137736 }}</ref> The high bioavailability of vaginal estriol is due to rapid absorption and low metabolism in atrophic vaginal mucosa.<ref name="pmid16112947" /> Vaginal estriol at typical clinical dosages results both in high local concentrations of estriol in the [[vagina]] and in systemic action.<ref name="pmid16112947" /> Vaginal administration of low doses of 30&nbsp;μg estriol and of higher doses of 0.5 and 1&nbsp;mg estriol have been found to produce equivalent local effects in the vagina and improvement of vaginal symptoms, suggesting that a saturation of estrogenic effect of vaginal estriol has been reached in the vagina by a dose of only 30&nbsp;μg estriol.<ref name="pmid16112947" /> In contrast to higher doses of vaginal estriol however, 30&nbsp;μg/day estriol is not associated with systemic effects.<ref name="pmid16112947" /> Similarly, the use of 0.5&nbsp;mg vaginal estriol twice a week instead of daily has been said to largely attenuate the systemic effects of estriol.<ref name="pmid16112947" /> Whereas oral estriol results in high levels of estriol conjugates which greatly exceed those of unconjugated estriol, vaginal estriol has been found to produce levels of unconjugated estriol and estriol conjugates that are similar.<ref name="pmid16112947" />

The absorption of estrogens by the skin is described as low for estriol, moderate for estradiol, and high for estrone.<ref name="pmid16112947" /> This is related to the number of [[hydroxyl group]]s in the molecules; the more hydroxyl groups, the lower the skin permeability.<ref name="pmid16112947" /> This may account for the relative lack of use of [[transdermal]] or [[topical administration|topical]] estriol.<ref name="pmid11600867" />

[[Rectal administration]] of estriol has been assessed in one study.<ref name="pmid8288717">{{cite journal | vauthors = Moran DJ, McGarrigle HH, Lachelin GC | title = Maternal plasma progesterone levels fall after rectal administration of estriol | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 78 | issue = 1 | pages = 70–72 | date = January 1994 | pmid = 8288717 | doi = 10.1210/jcem.78.1.8288717 }}</ref> Administration of a rectal [[suppository]] containing 100&nbsp;mg estriol resulted in estriol levels in [[pregnancy|pregnant]] women [[childbirth|at term]] increasing by about 53%.<ref name="pmid8288717" /> Estriol levels at term are normally between 5,000 and 20,000&nbsp;pg/mL, which suggests that estriol levels may have increased following the suppository by about 5,000 to 10,000&nbsp;pg/mL (precise levels were not provided).<ref name="NormanLitwack1997">{{cite book| vauthors = Norman AW, Litwack G |title=Hormones|url=https://archive.org/details/hormones00norm|url-access=registration|date=23 October 1997|publisher=Academic Press|isbn=978-0-08-053413-8|pages=[https://archive.org/details/hormones00norm/page/398 398]–}}</ref><ref name="KurjakChervenak2006">{{cite book| vauthors = Kurjak A, Chervenak FA |title=Textbook of Perinatal Medicine, Second Edition|url=https://books.google.com/books?id=qQpz7Oj5zZMC&pg=PA699|date=25 September 2006|publisher=CRC Press|isbn=978-1-4398-1469-7|pages=699–}}</ref><ref name="GreeneCreasy2008">{{cite book| vauthors = Greene MF, Creasy RK, Resnik R, Iams JD, Lockwood CJ, Moore T |title=Creasy and Resnik's Maternal-Fetal Medicine: Principles and Practice E-Book|url=https://books.google.com/books?id=AvwqSi_MbNMC&pg=PA115|date=25 November 2008|publisher=Elsevier Health Sciences|isbn=978-1-4377-2135-5|pages=115–}}</ref>

[[Estriol succinate]] is an [[ester]] [[prodrug]] of estriol which is used medically via oral and vaginal routes similarly.<ref name="pmid16112947" /> In estriol succinate, two of the [[hydroxyl group]]s of estriol, those at the C16α and C17β positions, are esterified with [[succinic acid]].<ref name="pmid16112947" /> As such, when adjusted for differences in [[molecular weight]], a dose of 2&nbsp;mg estriol succinate is equivalent to 1.18&nbsp;mg unconjugated estriol.<ref name="pmid16112947" /> Unlike other estrogen esters, such as [[estradiol valerate]], estriol succinate is [[hydrolysis|hydrolyzed]] almost not at all in the [[intestinal]] [[mucosa]] when taken orally, and in relation to this, is absorbed more slowly than is estriol.<ref name="pmid16112947" /> Consequently, oral estriol succinate is a longer-acting form of estriol than oral estriol.<ref name="pmid6356176a">{{cite journal | vauthors = Clark JH, Markaverich BM | title = The agonistic and antagonistic effects of short acting estrogens: a review | journal = Pharmacology & Therapeutics | volume = 21 | issue = 3 | pages = 429–453 | date = 1983 | pmid = 6356176 | doi = 10.1016/0163-7258(83)90063-3 }}</ref> Instead of in the [[gastrointestinal tract]], oral estriol succinate is [[bond cleavage|cleaved]] into estriol mainly in the [[liver]].<ref name="pmid16112947" /> After a single 8&nbsp;mg oral dose of estriol succinate, maximum levels of circulating estriol of 40&nbsp;pg/mL are attained within 12&nbsp;hours, and this increases up to 80&nbsp;pg/mL with continued daily administration.<ref name="pmid16112947" />

====Distribution====

Similarly to estradiol, but unlike [[estrone (medication)|estrone]], estriol is accumulated in target tissues.<ref name="pmid16112947" /><ref name="pmid6847874">{{cite journal | vauthors = Wiegerinck MA, Poortman J, Donker TH, Thijssen JH | title = In vivo uptake and subcellular distribution of tritium-labeled estrogens in human endometrium, myometrium, and vagina | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 56 | issue = 1 | pages = 76–86 | date = January 1983 | pmid = 6847874 | doi = 10.1210/jcem-56-1-76 | doi-access = free }}</ref> The [[plasma protein binding]] of estriol is approximately 92%, with about 91% bound to [[human serum albumin|albumin]], 1% bound to [[sex hormone-binding globulin]] (SHBG), and 8% free or unbound.<ref name="pmid16112947" /> Estriol has very low [[affinity (pharmacology)|affinity]] for SHBG, with only about 0.3% of the affinity of [[testosterone (medication)|testosterone]] for this protein (or about 0.6% of that of estradiol).<ref name="pmid16112947" /><ref name="Buchsbaum2012">{{cite book | vauthors = Buchsbaum HJ |title= The Menopause |url= https://books.google.com/books?id=z0LuBwAAQBAJ&pg=PA62 |date=6 December 2012 |publisher= Springer Science & Business Media |isbn= 978-1-4612-5525-3 |pages= 62–}}</ref><ref name="LorenzoHorowitz2015">{{cite book | vauthors = Lorenzo J, Horowitz M, Choi Y, Takayanagi H, Schett G |title= Osteoimmunology: Interactions of the Immune and Skeletal Systems |url= https://books.google.com/books?id=eOGcBAAAQBAJ&pg=PA216 |date= 23 September 2015 |publisher= Elsevier Science |isbn= 978-0-12-800627-6|pages=216–}}</ref> Relative to estradiol, which is about 98% plasma protein-bound, a significantly greater fraction of estriol is unbound in the circulation and hence available for biological activity (2% relative to 8%, respectively).<ref name="LorenzoHorowitz2015" /><ref name="pmid16112947" /><ref name="pmid28375935" /> This appears to account for the greater than expected biological activity of estriol relative to estradiol when considering its affinities for the [[estrogen receptor]]s.<ref name="pmid4366454">{{cite journal | vauthors = Anderson JN, Peck EJ, Clark JH | title = Nuclear receptor-estrogen complex: in vivo and in vitro binding of estradiol and estriol as influenced by serum albumin | journal = Journal of Steroid Biochemistry | volume = 5 | issue = 2 | pages = 103–107 | date = April 1974 | pmid = 4366454 | doi = 10.1016/0022-4731(74)90114-9 }}</ref>

====Metabolism====

Estriol is [[metabolism|metabolized]] extensively via [[conjugation (biochemistry)|conjugation]], including [[glucuronidation]] and [[sulfation]].<ref name="pmid16112947" /><ref name="pmid11600867" /><ref name="OettelSchillinger2012" /><ref name="MuseyKirdani1973" /> Glucuronidation of estriol takes place mainly in the [[intestinal]] [[mucosa]], while sulfation occurs in the [[liver]].<ref name="pmid16112947" /> More minor amounts of estriol can be [[oxidized]] and [[hydroxylated]] at various positions.<ref name="pmid16112947" /> One such reaction is transformation into [[16α-hydroxyestrone]].<ref name="pmid16112947" /> Estriol is an end-product of [[Drug metabolism#Phase I – modification|phase I]] estrogen metabolism and cannot be converted into estradiol or estrone.<ref name="pmid16112947" /><ref name="pmid2170822" /> The main [[metabolite]]s of estriol are [[estrogen conjugate]]s, including [[estriol sulfate]]s, [[estriol glucuronide]]s, and mixed [[estriol sulfate glucuronide|estriol sulfate/glucuronide]] conjugates.<ref name="pmid16112947" /> [[16α-Hydroxyestrone]] is known to occur as a metabolite of estriol as well.<ref name="pmid3227988">{{cite journal | vauthors = van Haaften M, Donker GH, Tas AA, Gramberg LG, Blankenstein MA, Thijssen JH | title = Identification of 16 alpha-hydroxy-estrone as a metabolite of estriol | journal = Gynecological Endocrinology | volume = 2 | issue = 3 | pages = 215–221 | date = September 1988 | pmid = 3227988 | doi = 10.3109/09513599809029346 }}</ref><ref name="pmid2357005">{{cite journal | vauthors = Thijssen JH, Blankenstein MA | title = Uptake and metabolism of estradiol by normal and abnormal breast tissues | journal = Annals of the New York Academy of Sciences | volume = 586 | issue = 1 | pages = 252–258 | date = 1990 | pmid = 2357005 | doi = 10.1111/j.1749-6632.1990.tb17813.x | s2cid = 35881837 | bibcode = 1990NYASA.586..252T }}</ref><ref name="pmid6847874"/>

The [[biological half-life]] of oral estriol has been reported to be in the range of 5 to 10&nbsp;hours.<ref name="Wentz1988" /><ref name="Dörwald2013" /><ref name="pmid2170822" /> The [[elimination half-life]] of estriol following an [[intramuscular injection]] of 1&nbsp;mg estriol has been found to be 1.5 to 5.3&nbsp;hours.<ref name="OettelSchillinger2012" /> The [[blood half-life]] of unconjugated estriol has been reported to be 20&nbsp;minutes.<ref name="pmid18464021" /><ref name="UniversityofCalifornia1986" /> The [[metabolic clearance rate]] of estriol is approximately 1,110&nbsp;L/day/m², which is about twice that of estradiol.<ref name="pmid16112947" /> Hence, estriol is [[elimination (pharmacology)|eliminated]] from the body more rapidly than is estradiol.<ref name="pmid16112947" /> [[Enterohepatic recycling]] may extend the duration of oral estriol.<ref name="pmid28375935" />

A single 1 to 2&nbsp;mg dose of estriol in oil solution by intramuscular injection has a duration of about 3 or 4&nbsp;days.<ref name="Brown1957">{{cite journal | vauthors = Brown JB | title = The relationship between urinary oestrogens and oestrogens produced in the body | journal = The Journal of Endocrinology | volume = 16 | issue = 2 | pages = 202–212 | date = December 1957 | pmid = 13491750 | doi = 10.1677/joe.0.0160202 }}</ref> [[Estriol ester]]s such as [[estriol dipropionate]] and [[estriol dihexanoate]], when administered via intramuscular injection in an [[oil solution]], have been found to maintain elevated levels of estriol for much longer amounts of time than oral or vaginal estriol, in the range of days to months.<ref name="OettelSchillinger2012" /> These two estriol esters have not been marketed, but [[estriol acetate benzoate]] and [[estriol tripropionate]] are medically used estriol esters which are given via [[depot injection|depot]] intramuscular injection and are long-acting similarly.<ref name="Elks2014" /> [[Polyestriol phosphate]] is an ester of estriol in the form of a [[polymer]], and has a very long duration of action.<ref name="pmid13759555">{{cite journal | vauthors = Lauritzen C, Velibese S | title = Clinical investigations of a long-acting oestriol (polyoestriol phosphate) | journal = Acta Endocrinologica | volume = 38 | issue = 1 | pages = 73–87 | date = September 1961 | pmid = 13759555 | doi = 10.1530/acta.0.0380073 }}</ref><ref name="Labhart2012" />

====Excretion====

Estriol is [[excretion|excreted]] more than 95% in [[urine]].<ref name="pmid16112947" /> This is due to the fact that estriol conjugates in the [[large intestine|colon]] are completely [[hydrolysis|hydrolyzed]] via [[bacteria]]l [[enzyme]]s and in turn estriol in this part of the body is reabsorbed into the body.<ref name="pmid16112947" /> The main urinary [[metabolite]]s of [[exogenous]] estriol administered via [[intravenous injection]] in [[baboon]]s have been found to be [[estriol 16α-glucuronide]] (65.8%), [[estriol 3-glucuronide]] (14.2%), [[estriol 3-sulfate]] (13.4%), and [[estriol 3-sulfate 16α-glucuronide]] (5.1%).<ref name="OettelSchillinger2012">{{cite book | vauthors = Oettel M, Schillinger E |title= Estrogens and Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogen |url= https://books.google.com/books?id=wBvyCAAAQBAJ&pg=PA265 |date= 6 December 2012 |publisher= Springer Science & Business Media |isbn= 978-3-642-60107-1 |pages=265, 273}}</ref><ref name="MuseyKirdani1973">{{cite journal | vauthors = Musey PI, Kirdani RY, Bhanalaph T, Sandberg AA | title = Estriol metabolism in the baboon: analysis of urinary and biliary metabolites | journal = Steroids | volume = 22 | issue = 6 | pages = 795–817 | date = December 1973 | pmid = 4203562 | doi = 10.1016/0039-128X(73)90054-8 }}</ref> The [[metabolism]] and [[excretion]] of estriol in these animals closely resembled that which has been observed in humans.<ref name="MuseyKirdani1973" />

==Chemistry==

{{Chemical structures of major endogenous estrogens medication version|align=right|caption=Note the [[hydroxyl group|hydroxyl]] (–OH) [[functional group|group]]s: estrone (E1) has one, estradiol (E2) has two, estriol (E3) has three, and estetrol (E4) has four.}}

Estriol, also known as 16α-hydroxyestradiol or as estra-1,3,5(10)-triene-3,16α,17β-triol, is a [[natural compound|naturally occurring]] [[estrane]] [[steroid]] with [[double bond]]s between the C1 and C2, C3 and C4, and C5 and C10 positions and [[hydroxyl group]]s at the C3, C16α, and C17β positions.<ref name="Elks2014" /><ref name="IndexNominum2000" /> The name ''estriol'' and the abbreviation ''E3'' were derived from the chemical terms ''[[estrin (compound)|'''estr'''in]]'' (estra-1,3,5(10)-triene) and '''''[[triol]]''''' (three hydroxyl groups).<ref name="ColeKramer2015">{{cite book| vauthors = Cole LA, Kramer PR |title=Human Physiology, Biochemistry and Basic Medicine|url=https://books.google.com/books?id=BzYdCAAAQBAJ&pg=PA122|date=13 October 2015|publisher=Elsevier Science|isbn=978-0-12-803717-1|pages=122–}}</ref>

===Analogues===

{{See also|List of estrogens#Estriol derivatives|List of estrogen esters#Estriol esters}}

A variety of [[structural analog|analogue]]s of estriol are known, including both naturally occurring [[isomer]]s and [[synthetic compound|synthetic]] [[substituent|substituted]] [[chemical derivative|derivative]]s and [[ester]]s.<ref name="Elks2014" /><ref name="IndexNominum2000" /> [[16β-Epiestriol]] (epiestriol), [[17α-epiestriol]], and [[16β,17α-epiestriol]] are isomers of estriol that are endogenous weak estrogens.<ref name="Elks2014" /> [[Mytatrienediol]] (16α-methyl-16β-epiestriol 3-methyl ether) is a synthetic derivative of 16β-epiestriol that was never marketed.<ref name="Elks2014" /> [[Estriol acetate benzoate]], [[estriol succinate]], and [[estriol tripropionate]] are synthetic [[estriol ester]]s that have been marketed for medical use, whereas [[estriol dihexanoate]], [[estriol dipropionate]], and [[estriol triacetate]] have not been introduced.<ref name="Elks2014" /><ref name="IndexNominum2000" /> [[Quinestradol]] is the 3-cyclopentyl [[ether]] of estriol and has also been marketed.<ref name="Elks2014" /><ref name="IndexNominum2000" /> [[Polyestriol phosphate]], an ester of estriol in the form of a [[polymer]], has been marketed previously as well.<ref name="pmid13759555" /><ref name="pmid5107471">{{cite journal | vauthors = Bachmann FF | title = [Treatment of menopausal complants with polyoestriol-phosphate. Experiences with Gynäsan injections] | language = de | journal = Munchener Medizinische Wochenschrift | volume = 113 | issue = 5 | pages = 166–169 | date = January 1971 | pmid = 5107471 | trans-title = Treatment of menopausal complants with polyoestriol-phosphate. Experiences with Gynäsan injections }}</ref><ref name="Labhart2012">{{cite book| vauthors = Labhart A |title=Clinical Endocrinology: Theory and Practice|url=https://books.google.com/books?id=DAgJCAAAQBAJ&pg=PA551|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-96158-8|pages=548,551|quote=The polymer of estradiol or estriol and phosphoric acid has an excellent depot action when given intramuscularly (polyestriol phosphate or polyestradiol phosphate) (Table 16). Phosphoric acid combines with the estrogen molecule at C3 and C17 to form a macromolecule. The compound is stored in the liver and spleen where the estrogen is steadily released by splitting off of the phosphate portion due to the action of alkaline phosphatase. [...] Conjugated estrogens and polyestriol and estradiol phosphate can also be given intravenously in an aqueous solution. Intravenous administration of ovarian hormones offers no advantages, however, and therefore has no practical significance. [...] The following duarations of action have been obtained with a single administration (WlED, 1954; LAURITZEN, 1968): [...] 50 mg polyestradiol phosphate ~ 1 month; 50 mg polyestriol phosphate ~ 1 month; 80 mg polyestriol phosphate ~ 2 months.}}</ref><ref name="Campbell2012">{{cite book| vauthors = Campbell S |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|url=https://books.google.com/books?id=WT3sCAAAQBAJ&pg=PA395|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-94-011-6165-7|pages=395–|quote=In the Federal Republic of Germany between 10 and 20% of all climacteric women are on estrogen treatment. We have the following oral estrogens for a treatment. (t) Conjugated estrogens, (2) estradiol valerate, (3) ethinyl-estradiol and its cyclopentyl-enol ether, (4) stilbestrol, (5) ethinyl-estradiol-methyltestosterone, (6) estriol and estriol succinate, most of them as coated tablets. Several long acting injectable preparations are available: several esters of combined estradiol-testosterone, one of estradiol-dehydroepiandrosterone enanthate and a prolonged polyestriol phosphate are also available. Lastly, depot injections of estradiol- and stilbestrol-esters are on the market.}}</ref> These esters, ethers, and polymers are [[prodrug]]s of estriol.<ref name="pmid16112947" /> [[Ethinylestriol]] and [[nilestriol]] are synthetic C17α [[ethynyl group|ethynyl]]ated derivatives of estriol.<ref name="Elks2014" /><ref name="IndexNominum2000" /> Ethinylestriol has not been marketed, but nilestriol, which is the 3-cyclopentyl ether of ethinylestriol and a prodrug of it, has been.<ref name="Elks2014" /><ref name="IndexNominum2000" />

[[Estetrol (medication)|Estetrol]] (E4), also known as 15α-hydroxyestriol, is a [[natural product|naturally occurring]] analogue of estriol with an additional [[hydroxyl group]], at the C15α position.<ref name="pmid18464023">{{cite journal | vauthors = Coelingh Bennink HJ, Holinka CF, Diczfalusy E | title = Estetrol review: profile and potential clinical applications | journal = Climacteric | volume = 11| issue = Suppl 1 | pages = 47–58 | date = 2008 | pmid = 18464023 | doi = 10.1080/13697130802073425 | s2cid = 24003341 }}</ref><ref name="pmid19167495">{{cite journal | vauthors = Visser M, Coelingh Bennink HJ | title = Clinical applications for estetrol | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 114 | issue = 1–2 | pages = 85–89 | date = March 2009 | pmid = 19167495 | doi = 10.1016/j.jsbmb.2008.12.013 | s2cid = 32081001 }}</ref> It is closely related to estriol and has similar but non-identical [[pharmacological]] properties.<ref name="pmid18464023" /><ref name="pmid19167495" /> Like estriol, estetrol is a relatively weak and atypical estrogen.<ref name="pmid18464023" /><ref name="pmid19167495" /> Estetrol is under development for potential clinical use for a variety of indications, such as menopausal hormone therapy and [[hormonal birth control]].<ref name="AdisInsight-E4">{{Cite web|url=http://adisinsight.springer.com/drugs/800044874|title = Estetrol - Mithra Pharmaceuticals/Pantarhei Bioscience | work = AdisInsight | publisher = Springer Nature Switzerland AG }}</ref><ref name="AdisInsight-E4/DRSP">{{Cite web|url=https://adisinsight.springer.com/drugs/800034634|title=Drospirenone/Estetrol - Mithra Pharmaceuticals | work = AdisInsight | publisher = Springer Nature Switzerland AG }}</ref>

==History==

{{See also|Estriol#History}}

Estriol was discovered in 1930.<ref name="Josimovich2013">{{cite book| vauthors = Josimovich JB |title=Gynecologic Endocrinology|url=https://books.google.com/books?id=9vv2BwAAQBAJ&pg=PA31|date=11 November 2013|publisher=Springer Science & Business Media|isbn=978-1-4613-2157-6|pages=31–}}</ref><ref name="SartorelliJohns2013">{{cite book| vauthors = Sartorelli AC, Johns DG |title=Antineoplastic and Immunosuppressive Agents|url=https://books.google.com/books?id=aU_oCAAAQBAJ&pg=PA104|date=27 November 2013|publisher=Springer Science & Business Media|isbn=978-3-642-65806-8|pages=104–}}</ref> Subsequently, it was introduced for medical use in [[oral administration|oral]] and [[transdermal administration|transdermal]] formulations under brand names such as ''Estriol'', ''Oestrosalve'', ''Theelol'', and ''Tridestrin''.<ref name="Greene1941">{{cite journal| vauthors = Greene RR |title=Endocrine Therapy for Gynecologic Disorders|journal=Medical Clinics of North America|volume=25|issue=1|year=1941|pages=155–168|issn=0025-7125|doi=10.1016/S0025-7125(16)36624-X}}</ref><ref name="pmid29648134">{{cite journal | vauthors = Johnstone RW | title = Sex Hormone Therapy in Gynæcology | journal = Edinburgh Medical Journal | volume = 43 | issue = 11 | pages = 680–695 | date = November 1936 | pmid = 29648134 | pmc = 5303355 }}</ref><ref name="pmid18746057">{{cite journal | vauthors = Reilly WA | title = Estrogens: Their Use in Pediatrics | journal = California and Western Medicine | volume = 55 | issue = 5 | pages = 237–239 | date = November 1941 | pmid = 18746057 | pmc = 1634235 }}</ref><ref name="pmid18744783">{{cite journal | vauthors = Fluhmann CF | title = Estrogenic Hormones: Their Clinical Usage | journal = California and Western Medicine | volume = 49 | issue = 5 | pages = 362–366 | date = November 1938 | pmid = 18744783 | pmc = 1659459 }}</ref><ref name="Fluhmann1944">{{cite journal| vauthors = Fluhmann CF |title=Clinical Use of Extracts from the Ovaries|journal=Journal of the American Medical Association|volume=125|issue=1|year=1944|pages=1|issn=0002-9955|doi=10.1001/jama.1944.02850190003001}}</ref><ref name="pmid29646930">{{cite journal | vauthors = Macpherson AI | title = The Use of Œstrogens in Obstetrics and Gynæcology | journal = Edinburgh Medical Journal | volume = 47 | issue = 6 | pages = 406–424 | date = June 1940 | pmid = 29646930 | pmc = 5306594 }}</ref><ref name="pmid13567043">{{cite journal | vauthors = Merrill RC | title = Estriol: a review | journal = Physiological Reviews | volume = 38 | issue = 3 | pages = 463–480 | date = July 1958 | pmid = 13567043 | doi = 10.1152/physrev.1958.38.3.463 }}</ref> In addition, [[conjugated estriol]], containing mainly [[estriol glucuronide]], was marketed in the 1930s, under the brand names ''Emmenin'' and ''Progynon''.<ref name="Greene1941" /><ref name="pmid18746057" /><ref name="pmid18744783" /><ref name="Fluhmann1944" /><ref name="Rooke2012" /><ref name="Pincus2013" /> They were the first orally active estrogen preparations to be introduced in medicine.<ref name="Rooke2012" /><ref name="Pincus2013" /> In contrast to estrone, free estriol was never introduced for use by [[intramuscular injection]].<ref name="pmid13359169">{{cite journal | vauthors = Cantor EB | title = A survey of estrogens | journal = Postgraduate Medicine | volume = 20 | issue = 3 | pages = 224–231 | date = September 1956 | pmid = 13359169 | doi = 10.1080/00325481.1956.11691266 }}</ref> Estriol continues to be used medically today, widely throughout the world and in a variety of different formulations and brand names.<ref name="IndexNominum2000" /><ref name="Drugs.com" /><ref name="pmid11600867" />

==Society and culture==

===Generic names===

''Estriol'' is the [[generic term|generic name]] of estriol in [[American English]] and its {{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|USP|United States Pharmacopeia}}, {{abbrlink|BAN|British Approved Name}}, {{abbrlink|DCF|Dénomination Commune Française}}, and {{abbrlink|JAN|Japanese Accepted Name}}.<ref name="Elks2014">{{cite book| vauthors = Elks J |title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies|url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA899|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=899–}}</ref><ref name="IndexNominum2000">{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA407|date=January 2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=407–}}</ref><ref name="MortonHall2012">{{cite book| vauthors = Morton IK, Hall JM |title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms|url=https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA206|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-94-011-4439-1|pages=206, 905}}</ref><ref name="Drugs.com">{{Cite web|url=https://www.drugs.com/international/estriol.html|title=Estriol|access-date=2018-05-20|archive-date=2018-07-05|archive-url=https://web.archive.org/web/20180705180111/https://www.drugs.com/international/estriol.html|url-status=dead}}</ref> It is pronounced {{IPAc-en|ˌ|ɛ|s|t|r|aɪ|oʊ|l}} {{respell|ESS|TREE|ohl}}.<ref name="Dictionary.com" /> ''Estriolo'' is the name of estriol in [[Italian language|Italian]]<ref name="Drugs.com" /> and ''estriolum'' is its name in [[Latin]], whereas its name remains unchanged as ''estriol'' in [[Spanish language|Spanish]], [[Portuguese language|Portuguese]], [[French language|French]], and [[German language|German]].<ref name="Drugs.com" /><ref name="IndexNominum2000" /> ''Oestriol'', in which the "O" is silent, was the former {{abbrlink|BAN|British Approved Name}} of estriol and its name in [[British English]],<ref name="Elks2014" /><ref name="MortonHall2012" /><ref name="IndexNominum2000" /> but the spelling was eventually changed to ''estriol''.<ref name="Drugs.com" />

===Brand names===

Estriol is or has been marketed under a variety of brand names throughout the world, including Aacifemine, Colpogyn, Elinol, Estriel, Estriol, Estriosalbe, Estrokad, Evalon, Gydrelle, Gynäsan, Gynest, Gynoflor (in combination with [[lactobacilli]]), Incurin ([[veterinary medicine|veterinary]]), Klimax-E, OeKolp, Oestro-Gynaedron, Orgestriol, Ortho-Gynest, Ovesterin, Ovestin, Ovestinon, Ovestrion, Ovo-Vinces, Pausanol, Physiogine, Sinapause, Synapause, Synapause-E, Trophicrème, Vago-Med, Vacidox, and Xapro.<ref name="IndexNominum2000" /><ref name="Drugs.com" />

[[Estriol succinate]] has been marketed under the brand names Blissel, Evalon, Gelistrol, Hemostyptanon, Orgastyptin, Ovestin, Pausan, Sinapause, Styptanon, Synapsa, Synapasa, Synapausa, and Synapause.<ref name="Elks2014" /><ref name="IndexNominum2000" /><ref name="Drugs.com" /> [[Estriol diacetate benzoate]] has been marketed under the brand name Holin-Depot and [[estriol tripropionate]] has been marketed under the brand name Estriel.<ref name="Elks2014" /> [[Polyestriol phosphate]] has been marketed under the brand names Gynäsan, Klimadurin, and Triodurin.<ref name="pmid5107471" /><ref name="NegwerScharnow2001">{{cite book| vauthors = Negwer M, Scharnow HG |title=Organic-chemical drugs and their synonyms: (an international survey)|url=https://books.google.com/books?id=zWpqAAAAMAAJ|date=4 October 2001|publisher=Wiley-VCH|isbn=978-3-527-30247-5|quote=8075-01 (6628-01) 37452-43-0 R Polymeric ester with phosphoric acid S Klimadurin, Polyestriol phosphate, Polyostriolphosphat, Triodurin U Depot-estrogen}}</ref><ref name="MartindaleSciences1993">{{cite book| vauthors = Martindale W | collaboration =Royal Pharmaceutical Society of Great Britain. Dept. of Pharmaceutical Sciences|title=The Extra Pharmacopoeia|url=https://books.google.com/books?id=EGZWAAAAYAAJ|year=1993|publisher=Pharmaceutical Press|isbn=978-0-85369-300-0|page=2258|quote=Polyoestriol Phosphate. [...] ingredient of Klimadurin. [...] Triodurin [...].}}</ref> [[Emmenin]] and [[Progynon]] were estriol products marketed in the 1930s which were manufactured from the [[urine]] of [[pregnancy|pregnant]] women and contained [[estriol conjugate]]s, primarily [[estriol glucuronide]].<ref name="Rooke2012">{{cite book| vauthors = Rooke T |title=The Quest for Cortisone|url=https://books.google.com/books?id=70vvFrtpePoC&pg=PT54|date=1 January 2012|publisher=MSU Press|isbn=978-1-60917-326-5|pages=54–}}</ref><ref name="Pincus2013">{{cite book| vauthors = Grant GA, Beall D | chapter = Studies on estrogen conjugates | veditors = Pincus G |title=Recent Progress in Hormone Research: The Proceedings of the Laurentian Hormone Conference|chapter-url=https://books.google.com/books?id=jgTgBAAAQBAJ&pg=PA307|date=22 October 2013|publisher=Elsevier Science|isbn=978-1-4832-1945-5|pages=307–}}</ref>

Estriol for [[multiple sclerosis]] had the tentative brand name Trimesta but did not complete development and was never marketed.<ref name="ES-MS-AdisInsight" />

===Availability===

Estriol is marketed widely throughout the world, including in [[Europe]], [[South Africa]], [[Australia]], [[New Zealand]], [[Asia]], [[Latin America]], and elsewhere.<ref name="IndexNominum2000" /><ref name="Drugs.com" /> The medication is also available in some countries in the form of [[estriol succinate]], an [[ester]] [[prodrug]] of estriol.<ref name="IndexNominum2000" /><ref name="Elks2014" /><ref name="Platt2012">{{cite book| vauthors = Platt D |title=Geriatrics 3: Gynecology · Orthopaedics · Anesthesiology · Surgery · Otorhinolaryngology · Ophthalmology · Dermatology|url=https://books.google.com/books?id=vwzpCAAAQBAJ&pg=PA6|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-68976-5|pages=6–}}</ref> Estriol and its esters are not approved for use in the [[United States]] or [[Canada]], although estriol has been produced and sold by [[compounding|compounding pharmacies]] in [[North America]] for use as a component of [[bioidentical hormone replacement therapy|bioidentical hormone therapy]].<ref name="pmid17549577" /><ref name="pmid21531972">{{cite journal | vauthors = Files JA, Ko MG, Pruthi S | title = Bioidentical hormone therapy | journal = Mayo Clinic Proceedings | volume = 86 | issue = 7 | pages = 673–80, quiz 680 | date = July 2011 | pmid = 21531972 | pmc = 3127562 | doi = 10.4065/mcp.2010.0714 }}</ref> In addition, topical creams containing estriol are not regulated in the United States and are available [[over-the-counter]] in this country.<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>

==Research==

Estriol may have [[immunomodulatory]] effects and has been of investigational interest in the treatment of [[multiple sclerosis]] and a number of other conditions.<ref name="pmid28375935" /> [[Estriol succinate]] was under development for the treatment of multiple sclerosis in the [[United States]] and worldwide, and reached [[Phases of clinical research#Phase II|phase II]] [[clinical trial]]s for this indication, but development was discontinued due to insufficient effectiveness.<ref name="ES-MS-AdisInsight">{{Cite web|url=https://adisinsight.springer.com/drugs/800026520|title=Estriol succinate - Synthetic Biologics | work = AdisInsight | publisher = Springer Nature Switzerland AG }}</ref> It had the tentative brand name Trimesta.<ref name="ES-MS-AdisInsight" />

==Veterinary use==

Estriol is used in [[veterinary medicine]], under the brand name Incurin, in the treatment of [[urinary incontinence]] due to [[estrogen deficiency]] in dogs.<ref name="EttingerFeldman2017">{{cite book| vauthors = Ettinger SJ, Feldman EC, Cote E |title=Textbook of Veterinary Internal Medicine - eBook|url=https://books.google.com/books?id=57XBDQAAQBAJ&pg=PT6017|date=11 January 2017|publisher=Elsevier Health Sciences|isbn=978-0-323-31239-4|pages=6017, 6380}}</ref><ref name="Boothe2011">{{cite book | vauthors = Boothe DM |title=Small Animal Clinical Pharmacology and Therapeutics - E-Book|url=https://books.google.com/books?id=yDjDr_MLGSsC&pg=PT2350|date=25 July 2011|publisher=Elsevier Health Sciences|isbn=978-1-4377-2357-1|pages=2350–2351}}</ref><ref name="BonaguraTwedt2008">{{cite book| vauthors = Bonagura JD, Twedt DC |title=Kirk's Current Veterinary Therapy XIV - E-Book|url=https://books.google.com/books?id=NaamlrzbTwoC&pg=PT4442|date=10 July 2008|publisher=Elsevier Health Sciences|isbn=978-1-4377-1152-3|pages=772, 4442}}</ref><ref name="Papich2015">{{cite book| vauthors = Papich MG |title=Saunders Handbook of Veterinary Drugs: Small and Large Animal|url=https://books.google.com/books?id=ip8_CwAAQBAJ&pg=PA304|date=1 October 2015|publisher=Elsevier Health Sciences|isbn=978-0-323-24485-5|pages=304–}}</ref> Certain estrogens, like [[estradiol (medication)|estradiol]], can cause [[bone marrow suppression]] in dogs, which can be fatal, but estriol appears to pose less or possibly no risk.<ref name="Papich2015" /><ref name="FeldmanNelson2004">{{cite book| vauthors = Feldman EC, Nelson RW |title=Canine and Feline Endocrinology and Reproduction|url=https://books.google.com/books?id=elPuvsucuY8C&pg=PA839|date=1 January 2004|publisher=Elsevier Health Sciences|isbn=0-7216-9315-6|pages=839–}}</ref>

==References==

{{Reflist}}

== Further reading ==

{{refbegin|30em}}

* {{cite journal | vauthors = Merrill RC | title = Estriol: a review | journal = Physiological Reviews | volume = 38 | issue = 3 | pages = 463–480 | date = July 1958 | pmid = 13567043 | doi = 10.1152/physrev.1958.38.3.463 }}

* {{cite journal | vauthors = Clark JH, Hardin JW, McCormack SA | title = Mechanism of action of estrogen agonists and antagonists | journal = Journal of Animal Science | volume = 49 | issue = Suppl 2 | pages = 46–65 | date = 1979 | pmid = 400777 | doi = 10.1093/ansci/49.supplement_ii.46 }}

* {{cite journal | vauthors = Clark JH, Markaverich BM | title = The agonistic and antagonistic effects of short acting estrogens: a review | journal = Pharmacology & Therapeutics | volume = 21 | issue = 3 | pages = 429–453 | date = 1983 | pmid = 6356176 | doi = 10.1016/0163-7258(83)90063-3 }}

* {{cite journal | vauthors = Clark JH, Markaverich BM | title = The agonistic and antagonistic actions of estriol | journal = Journal of Steroid Biochemistry | volume = 20 | issue = 4B | pages = 1005–1013 | date = April 1984 | pmid = 6202959 | doi = 10.1016/0022-4731(84)90011-6 }}

* {{cite journal | vauthors = Heimer GM | title = Estriol in the postmenopause | journal = Acta Obstetricia et Gynecologica Scandinavica. Supplement | volume = 139 | pages = 2–23 | date = 1987 | pmid = 3475930 | doi = 10.3109/00016348709156470 | s2cid = 38712328 }}

* {{cite journal | vauthors = Esposito G | title = Estriol: a weak estrogen or a different hormone? | journal = Gynecological Endocrinology | volume = 5 | issue = 2 | pages = 131–153 | date = June 1991 | pmid = 1927578 | doi = 10.3109/09513599109028436 }}

* {{cite journal | vauthors = Vooijs GP, Geurts TB | title = Review of the endometrial safety during intravaginal treatment with estriol | journal = European Journal of Obstetrics, Gynecology, and Reproductive Biology | volume = 62 | issue = 1 | pages = 101–106 | date = September 1995 | pmid = 7493689 | doi = 10.1016/0301-2115(95)02170-c | hdl-access = free | hdl = 2066/21059 }}

* {{cite journal | vauthors = Head KA | title = Estriol: safety and efficacy | journal = Alternative Medicine Review | volume = 3 | issue = 2 | pages = 101–113 | date = April 1998 | pmid = 9577246 | url = http://archive.foundationalmedicinereview.com/publications/3/2/101.pdf }}

* {{cite journal | vauthors = Taylor M | title = Unconventional estrogens: estriol, biest, and triest | journal = Clinical Obstetrics and Gynecology | volume = 44 | issue = 4 | pages = 864–879 | date = December 2001 | pmid = 11600867 | doi = 10.1097/00003081-200112000-00024 | s2cid = 27098486 }}

* {{cite journal | vauthors = Ciszko B, Zdrojewicz Z | title = [Compliance endogenous and exogenous estriol in clinical practice] | language = pl | journal = Ginekologia Polska | volume = 77 | issue = 7 | pages = 559–565 | date = July 2006 | pmid = 17076208 | trans-title = Compliance endogenous and exogenous estriol in clinical practice }}

* {{cite journal | vauthors = Perepanova TS, Khazan PL | title = [The role of estriol in therapy of urogenital disorders in postmenopausal women] | language = ru | journal = Urologiia | issue = 3 | pages = 102–4, 107 | date = 2007 | pmid = 17722629 }}

* {{cite journal | vauthors = Holtorf K | title = The bioidentical hormone debate: are bioidentical hormones (estradiol, estriol, and progesterone) safer or more efficacious than commonly used synthetic versions in hormone replacement therapy? | journal = Postgraduate Medicine | volume = 121 | issue = 1 | pages = 73–85 | date = January 2009 | pmid = 19179815 | doi = 10.3810/pgm.2009.01.1949 | s2cid = 2060730 }}

* {{cite journal | vauthors = Unlü C, Donders G | title = Use of lactobacilli and estriol combination in the treatment of disturbed vaginal ecosystem: a review | journal = Journal of the Turkish German Gynecological Association | volume = 12 | issue = 4 | pages = 239–246 | date = 2011 | pmid = 24592002 | pmc = 3939257 | doi = 10.5152/jtgga.2011.57 }}

* {{cite journal | vauthors = Ali ES, Mangold C, Peiris AN | title = Estriol: emerging clinical benefits | journal = Menopause | volume = 24 | issue = 9 | pages = 1081–1085 | date = September 2017 | pmid = 28375935 | doi = 10.1097/GME.0000000000000855 | s2cid = 41137736 }}

* {{cite journal | vauthors = Rueda C, Osorio AM, Avellaneda AC, Pinzón CE, Restrepo OI | title = The efficacy and safety of estriol to treat vulvovaginal atrophy in postmenopausal women: a systematic literature review | journal = Climacteric | volume = 20 | issue = 4 | pages = 321–330 | date = August 2017 | pmid = 28622049 | doi = 10.1080/13697137.2017.1329291 | s2cid = 407950 }}

* {{cite journal | vauthors = Mueck AO, Ruan X, Prasauskas V, Grob P, Ortmann O | title = Treatment of vaginal atrophy with estriol and lactobacilli combination: a clinical review | journal = Climacteric | volume = 21 | issue = 2 | pages = 140–147 | date = April 2018 | pmid = 29381086 | doi = 10.1080/13697137.2017.1421923 | doi-access = free }}

* {{cite journal | vauthors = La Rosa VL, Ciebiera M, Lin LT, Fan S, Butticè S, Sathyapalan T, Jędra R, Lordelo P, Favilli A | title = Treatment of genitourinary syndrome of menopause: the potential effects of intravaginal ultralow-concentration oestriol and intravaginal dehydroepiandrosterone on quality of life and sexual function | journal = Przeglad Menopauzalny = Menopause Review | volume = 18 | issue = 2 | pages = 116–122 | date = June 2019 | pmid = 31488961 | pmc = 6719636 | doi = 10.5114/pm.2019.86836 }}

{{refend}}

{{Estrogens and antiestrogens}}

{{Estrogen receptor modulators}}

[[Category:Antigonadotropins]]

[[Category:Estranes]]

[[Category:Estrogens]]

[[Category:Immunomodulating drugs]]

[[Category:Phenols]]

[[Category:Triols]]

[[Category:Veterinary drugs]]