「Estetrol」の版間の差分

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{{About|estetrol as a hormone|its use as a medication|Estetrol (medication)}}
#転送 [[エストロゲン]]
{{Other uses|Hydroxyestriol}}
{{Chembox
<!-- Images -->
| ImageFile = Estetrol.svg
| ImageClass = skin-invert
| ImageSize = 235px
| ImageAlt = Skeletal formula of estetrol
| ImageFile2 = Estetrol 3D ball.png
| ImageSize2 = 225px
| ImageAlt2 = Ball-and-stick model of the estetrol molecule
<!-- Names -->
| IUPACName = Estra-1,3,5(10)-triene-3,15α,16α,17β-tetrol
| SystematicName = (1''R'',2''R'',3''R'',3a''S'',3b''R'',9b''S'',11a''S'')-11a-Methyl-2,3,3a,3b,4,5,9b,10,11,11a-decahydro-1''H''-cyclopenta[''a'']phenanthrene-1,2,3,7-tetrol
| OtherNames = Oestetrol; E4; 15α-Hydroxyestriol
<!-- Sections -->
| Section1 = {{Chembox Identifiers
| CASNo = 15183-37-6
| CASNo_Ref = {{cascite|correct|CAS}}
| ChEBI = 142773
| ChEMBL = 1230314
| ChemSpiderID = 25245
| DrugBank = DB12235
| EC_number = 840-340-4
| KEGG = D11513
| PubChem = 27125
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = ENB39R14VF
| StdInChI=1S/C18H24O4/c1-18-7-6-12-11-5-3-10(19)8-9(11)2-4-13(12)14(18)15(20)16(21)17(18)22/h3,5,8,12-17,19-22H,2,4,6-7H2,1H3/t12-,13-,14-,15-,16-,17+,18+/m1/s1
| StdInChIKey = AJIPIJNNOJSSQC-NYLIRDPKSA-N
| SMILES = C[C@]12CC[C@H]3[C@H]([C@@H]1[C@H]([C@H]([C@@H]2O)O)O)CCC4=C3C=CC(=C4)O
  }}
| Section2 = {{Chembox Properties
| C=18 | H=24 | O=4
| MolarMass = 304.386 g/mol
| Appearance =
| Density =
| MeltingPt =
| BoilingPt =
| Solubility = 1.38 mg/mL
  }}
| Section3 = {{Chembox Hazards
| MainHazards =
| FlashPt =
| AutoignitionPt =
  }}
}}
 
'''Estetrol''' ('''E4'''), or '''oestetrol''', is one of the four natural estrogenic [[steroid hormone]]s found in humans, along with [[estrone]] (E1), [[estradiol]] (E2), and [[estriol]] (E3). Estetrol is a major estrogen in the body.<ref name="pmid18462934">{{cite journal | vauthors = Holinka CF, Diczfalusy E, Coelingh Bennink HJ | title = Estetrol: a unique steroid in human pregnancy | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 110 | issue = 1–2 | pages = 138–143 | date = May 2008 | pmid = 18462934 | doi = 10.1016/j.jsbmb.2008.03.027 | s2cid = 28007341 }}</ref><ref name="YenJaffe1991">{{cite book | title = Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management | edition = 3rd | veditors = Yen SS, Jaffe RB | pages = 936–981 | publisher = Copyright Elsevier/Saunders | date = 1991 }}</ref> In contrast to estrone and estradiol, estetrol is a native estrogen of [[fetus|fetal]] life. Estetrol is produced exclusively by the [[fetus|fetal]] [[liver]]<ref name="pmid18462934" /> and is found in detectable levels only during pregnancy, with relatively high levels in the fetus and lower levels in the maternal circulation.<ref name="pmid18462934" /><ref name="YenJaffe1991" />
 
In addition to its physiological role as a native hormone, estetrol can be used as a [[medication]], see [[estetrol (medication)]].  Estetrol, in combination with [[drospirenone]], has recently been approved as a new estrogenic component of a [[combined oral contraceptive]] (COC) and estetrol alone is in clinical development for the treatment of menopausal symptoms as well as breast and prostate cancer.
 
==Biological function==
So far, the physiological function of estetrol remains unknown. The potential role of estetrol as a marker for fetal well-being has been studied quite extensively, but no correlation was found<ref name=":0">{{cite journal | vauthors = Fruzzetti F, Fidecicchi T, Montt Guevara MM, Simoncini T | title = Estetrol: A New Choice for Contraception | journal = Journal of Clinical Medicine | volume = 10 | issue = 23 | pages = 5625 | date = November 2021 | pmid = 34884326 | pmc = 8658652 | doi = 10.3390/jcm10235625 | doi-access = free }}</ref> due to the large intra- and inter-individual variation in maternal estetrol plasma levels during pregnancy.<ref name="pmid5582006">{{cite journal | vauthors = Heikkilä J, Luukkainen T | title = Urinary excretion of estriol and 15 alpha-hydroxyestriol in complicated pregnancies | journal = American Journal of Obstetrics and Gynecology | volume = 110 | issue = 4 | pages = 509–21 | date = June 1971 | pmid = 5582006 | doi = 10.1016/0002-9378(71)90692-2  }}</ref><ref name="pmid805156">{{cite journal | vauthors = Tulchinsky D, Frigoletto FD, Ryan KJ, Fishman J | title = Plasma estetrol as an index of fetal well-being | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 40 | issue = 4 | pages = 560–7 | date = April 1975 | pmid = 805156 | doi = 10.1210/jcem-40-4-560  }}</ref><ref name="pmid941193">{{cite journal | vauthors = Kundu N, Grant M | title = Radioimmunoassay of 15alpha-hydroxyestriol (estetrol) in pregnancy serum | journal = Steroids | volume = 27 | issue = 6 | pages = 785–96 | date = June 1976 | pmid = 941193 | doi = 10.1016/0039-128x(76)90138-0 | s2cid = 54373667 }}</ref><ref name="pmid7266946">{{cite journal | vauthors = Kundu N, Wachs M, Iverson GB, Petersen LP | title = Comparison of serum unconjugated estriol and estetrol in normal and complicated pregnancies | journal = Obstetrics and Gynecology | volume = 58 | issue = 3 | pages = 276–81 | date = September 1981 | pmid = 7266946 | doi = | url = }}</ref>
 
==Biological activity==
Estetrol has a moderate [[affinity (pharmacology)|affinity]] for estrogen receptors alpha ([[ERα]]) and beta ([[ERβ]]), with K<sub>i</sub> values of 4.9&nbsp;nM and 19&nbsp;nM, respectively.<ref name="pmid18464023">{{cite journal |vauthors=Coelingh Bennink HJ, Holinka CF, Diczfalusy E |date=2008 |title=Estetrol review: profile and potential clinical applications |journal=Climacteric |volume=11 |issue=Suppl 1 |pages=47–58 |doi=10.1080/13697130802073425 |pmid=18464023 |s2cid=24003341}}</ref><ref name="pmid18464025">{{cite journal | vauthors = Visser M, Foidart JM, Coelingh Bennink HJ | title = In vitro effects of estetrol on receptor binding, drug targets and human liver cell metabolism | journal = Climacteric | volume = 11 | issue = Suppl 1 | pages = 64–68 | date = 2008 | pmid = 18464025 | doi = 10.1080/13697130802050340 | s2cid = 11027782 }}</ref> As such, estetrol has 4- to 5-fold preference for ERα over ERβ.<ref name="pmid18464023" /><ref name="pmid18464025" /> In different animal models, the potency of estetrol regarding its estrogenic effect observed ''in vivo'' is generally 10 to 20 times lower than the potency of ethinyl estradiol (EE) and is also lower than the potency of estradiol.<ref name="pmid18462934" /><ref name="pmid18464023" />  Estetrol displays a highly selective binding to its primary targets [[ERα]] and [[ERβ]],<ref name="pmid18464023" /><ref name="pmid18464025" /> which ensures that estetrol has a low risk of non-specific side effects.
 
{{Selected biological properties of endogenous estrogens in rats}}
 
== Mode of action ==
 
=== Tissue-selective effect ===
Estetrol shows selective estrogenic, neutral or anti-estrogenic activities in certain cell types and tissues.<ref name="pmid18464025" /><ref name="pmid26212489" /><ref name=":1">{{cite journal | vauthors = Gérard C, Blacher S, Communal L, Courtin A, Tskitishvili E, Mestdagt M, Munaut C, Noel A, Gompel A, Péqueux C, Foidart JM | display-authors = 6 | title = Estetrol is a weak estrogen antagonizing estradiol-dependent mammary gland proliferation | journal = The Journal of Endocrinology | volume = 224 | issue = 1 | pages = 85–95 | date = January 2015 | pmid = 25359896 | doi = 10.1530/JOE-14-0549 | doi-access = free }}</ref> In rodent models, estetrol has shown to elicit potent estrogenic activity on ovulation,<ref>{{cite journal | vauthors = Coelingh Bennink HJ, Skouby S, Bouchard P, Holinka CF | title = Ovulation inhibition by estetrol in an in vivo model | language = English | journal = Contraception | volume = 77 | issue = 3 | pages = 186–190 | date = March 2008 | pmid = 18279689 | doi = 10.1016/j.contraception.2007.11.014 }}</ref> brain,<ref>{{cite journal | vauthors = Pluchino N, Santoro AN, Casarosa E, Giannini A, Genazzani A, Russo M, Russo N, Petignat P, Genazzani AR | display-authors = 6 | title = Effect of estetrol administration on brain and serum allopregnanolone in intact and ovariectomized rats | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 143 | pages = 285–290 | date = September 2014 | pmid = 24787659 | doi = 10.1016/j.jsbmb.2014.04.011 | s2cid = 21359519 }}</ref> bone tissue,<ref>{{cite journal | vauthors = Coelingh Bennink HJ, Heegaard AM, Visser M, Holinka CF, Christiansen C | title = Oral bioavailability and bone-sparing effects of estetrol in an osteoporosis model | journal = Climacteric | volume = 11 | issue = sup1 | pages = 2–14 | date = 2008-01-01 | pmid = 18464016 | doi = 10.1080/13697130701798692 | s2cid = 42275885 }}</ref> cardiovascular system,<ref name=":2">{{cite journal | vauthors = Abot A, Fontaine C, Buscato M, Solinhac R, Flouriot G, Fabre A, Drougard A, Rajan S, Laine M, Milon A, Muller I, Henrion D, Adlanmerini M, Valéra MC, Gompel A, Gerard C, Péqueux C, Mestdagt M, Raymond-Letron I, Knauf C, Ferriere F, Valet P, Gourdy P, Katzenellenbogen BS, Katzenellenbogen JA, Lenfant F, Greene GL, Foidart JM, Arnal JF | display-authors = 6 | title = The uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor α modulation, uncoupling nuclear and membrane activation | journal = EMBO Molecular Medicine | volume = 6 | issue = 10 | pages = 1328–1346 | date = October 2014 | pmid = 25214462 | pmc = 4287935 | doi = 10.15252/emmm.201404112 }}</ref> and uterus, associated with ovulation inhibition, prevention of bone demineralization, cardioprotective effects and maintenance of uterovaginal tissues, respectively.<ref name=":2" /><ref>{{cite journal | vauthors = Benoit T, Valera MC, Fontaine C, Buscato M, Lenfant F, Raymond-Letron I, Tremollieres F, Soulie M, Foidart JM, Game X, Arnal JF | display-authors = 6 | title = Estetrol, a Fetal Selective Estrogen Receptor Modulator, Acts on the Vagina of Mice through Nuclear Estrogen Receptor α Activation | language = English | journal = The American Journal of Pathology | volume = 187 | issue = 11 | pages = 2499–2507 | date = November 2017 | pmid = 28827141 | doi = 10.1016/j.ajpath.2017.07.013 | doi-access = free }}</ref>
 
Data from preclinical studies also suggest that estetrol has ''anti-estrogenic like effects'' on the breast and a limited impact on normal or malignant breast tissue when used at therapeutic concentration.<ref name=":1" /><ref>{{cite journal | vauthors = Gallez A, Blacher S, Maquoi E, Konradowski E, Joiret M, Primac I, Gérard C, Taziaux M, Houtman R, Geris L, Lenfant F, Marangoni E, Sounni NE, Foidart JM, Noël A, Péqueux C | display-authors = 6 | title = Estetrol Combined to Progestogen for Menopause or Contraception Indication Is Neutral on Breast Cancer | journal = Cancers | volume = 13 | issue = 10 | pages = 2486 | date = May 2021 | pmid = 34065180 | pmc = 8160902 | doi = 10.3390/cancers13102486 | doi-access = free }}</ref> This property of estetrol is associated with antagonistic effects on breast cell proliferation, migration and invasion in the presence of estradiol.<ref name=":1" /><ref>{{cite journal | vauthors = Giretti MS, Montt Guevara MM, Cecchi E, Mannella P, Palla G, Spina S, Bernacchi G, Di Bello S, Genazzani AR, Genazzani AD, Simoncini T | display-authors = 6 | title = Effects of Estetrol on Migration and Invasion in T47-D Breast Cancer Cells through the Actin Cytoskeleton | journal = Frontiers in Endocrinology | volume = 5 | pages = 80 | date = 2014-05-26 | pmid = 24904530 | pmc = 4033260 | doi = 10.3389/fendo.2014.00080 | doi-access = free }}</ref>
 
The molecular mechanisms of action driving its tissue-selective actions rely on a specific profile of ERα activation, uncoupling nuclear and membrane activation.
 
In the liver, Estetrol has a neutral activity, which is reflected by a minimal impact on synthesis of hepatic coagulation factors, minimal impact on [[sex hormone-binding globulin]] (SHBG) synthesis and limited impact on lipid parameters, including triglycerides.<ref>{{cite journal | vauthors = Klipping C, Duijkers I, Mawet M, Maillard C, Bastidas A, Jost M, Foidart JM | title = Endocrine and metabolic effects of an oral contraceptive containing estetrol and drospirenone | journal = Contraception | volume = 103 | issue = 4 | pages = 213–221 | date = April 2021 | pmid = 33428907 | doi = 10.1016/j.contraception.2021.01.001 | s2cid = 231585130 | doi-access = free }}</ref>
 
Estetrol can therefore be described as the first Native Estrogen with Selective Tissue activity (NEST).<ref>{{Cite journal | vauthors = Gérard C, Jost M, Oligschläger Y, Foidart JM |date=2021 |title=Estetrol, a natural estrogen with selective tissue activity (NEST). Poster Abstract |journal=International Journal of Gynecology & Obstetrics |volume=155 |pages=127–532}}</ref><ref name=":3">{{cite journal | vauthors = Gérard C, Arnal JF, Jost M, Douxfils J, Lenfant F, Fontaine C, Houtman R, Archer DF, Reid RL, Lobo RA, Gaspard U, Coelingh Bennink HJ, Creinin MD, Foidart JM | display-authors = 6 | title = Profile of estetrol, a promising native estrogen for oral contraception and the relief of climacteric symptoms of menopause | journal = Expert Review of Clinical Pharmacology | volume = 15 | issue = 2 | pages = 121–137 | date = February 2022 | pmid = 35306927 | doi = 10.1080/17512433.2022.2054413 | s2cid = 247583084 | doi-access = free }}</ref>
 
=== Differences vs SERMs ===
The selective tissue activity of estetrol is different from the effects of selective estrogen receptor modulators (SERMs), like tamoxifen and raloxifene.<ref name=":4">{{cite journal | vauthors = Garefalakis M, Hickey M | title = Role of androgens, progestins and tibolone in the treatment of menopausal symptoms: a review of the clinical evidence | language = English | journal = Clinical Interventions in Aging | volume = 3 | issue = 1 | pages = 1–8 | date = 2008-03-07 | pmid = 18488873 | pmc = 2544356 | doi = 10.2147/CIA.S1043 | doi-access = free }}</ref> Estetrol, like SERMs, has selective tissue activity. However, SERMs interact with the ligand binding domain of ERα in a manner that is distinct from that of estrogens, including estetrol.<ref name=":4" /> Estetrol recruits the same co-regulators as other estrogens, while SERMs recruit other co-regulators.<ref name=":3" />
 
=== ERα activation ===
Estrogens can elicit their effects via nuclear ERα and/or membrane ERα signaling pathways. Estetrol presents a distinctive mode of action in terms of ERα activation. Like other estrogens, estetrol binds to, and activates the nuclear ERα to induce gene transcription. However, estetrol induces very limited activity via membrane ERα in several tissues (e.g. in the breast) and antagonizes this pathway in the presence of estradiol, thereby uniquely uncoupling nuclear and membrane activation.<ref name=":2" />
 
==Biochemistry==
 
===Biosynthesis===
In the [[fetus|fetal]] [[liver]], estetrol is synthesized from [[estradiol]] (E2) and [[estriol]] (E3) by two fetal liver [[enzyme]]s, 15α- and 16α-hydroxylase, through hydroxylation.<ref name="Schwers_1965">{{cite journal | vauthors = Schwers J, Eriksson G, Diczfalusy E | title = 15a-hydroxylation: A new pathway of estrogen metabolism in the human fetus and newborn | journal = Biochimica et Biophysica Acta | volume = 100 | issue = | pages = 313–6 | date = April 1965 | pmid = 14323645 | doi = 10.1016/0304-4165(65)90464-2 }}</ref><ref name="Schwers_1965b">{{cite journal | vauthors = Schwers J, Govaerts-Videtsky M, Wiqvist N, Diczfalusy E | title = Metabolism of oestrone sulphate by the previable human foetus | journal = Acta Endocrinologica | volume = 50 | issue = 4 | pages = 597–610 | date = December 1965 | pmid = 5897909 | doi = 10.1530/acta.0.0500597 }}</ref><ref name="pmid4229819">{{cite journal | vauthors = Mancuso S, Benagiano G, Dell'Acqua S, Shapiro M, Wiqvist N, Diczfalusy E | title = Studies on the metabolism of C-19 steroids in the human foeto-placental unit. 4. Aromatisation and hydroxylation products formed by previable foetuses perfused withandrostenedione and testosterone | journal = Acta Endocrinologica | volume = 57 | issue = 2 | pages = 208–27 | date = February 1968 | pmid = 4229819 | doi = 10.1530/acta.0.0570208 }}</ref><ref name="StraussBarbieri2009">{{cite book| vauthors = Strauss JF, Barbieri RL |title=Yen and Jaffe's Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management |url=https://books.google.com/books?id=NudwnhxY8kYC&pg=PA262|year=2009|publisher=Elsevier Health Sciences|isbn=978-1-4160-4907-4|pages=262}}</ref> Estetrol can be detected in maternal urine from the 9th week of gestation.<ref name="YenJaffe1991" /><ref>{{cite journal | vauthors = Heikkilä J, Adlercreutz H | title = A method for the determination of urinary 15α-hydroxyestriol and estriol: Preliminary results of 15α-hydroxyestriol determinations in pregnancy urine. | journal = Journal of Steroid Biochemistry | date = September 1970 | volume = 1 | issue = 3 | pages = 243–253 | doi = 10.1016/0022-4731(70)90020-8 }}</ref><ref>{{cite journal | vauthors = Heikkilä J | title = Excretion of 15α-hydroxyestriol and estriol in maternal urine during normal pregnancy. | journal = Journal of Steroid Biochemistry | date = February 1971 | volume = 2 | issue = 83–93 | pages = 83–93 | doi = 10.1016/0022-4731(71)90012-4 }}</ref> After birth, the neonatal liver rapidly loses its capacity to synthesize estetrol. During the second trimester of pregnancy, high levels of estetrol can be found in maternal plasma, with steadily rising concentrations of unconjugated estetrol to about 1&nbsp;ng/mL (>3&nbsp;nM) towards the end of pregnancy. Fetal plasma levels have been reported to be over 10 times higher than maternal plasma levels at parturition.<ref name="pmid18462934" />
 
===Distribution===
In terms of [[plasma protein binding]], estetrol displays moderate binding to [[human serum albumin|albumin]], and shows no binding to SHBG.<ref name="Visser_2008">{{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 | pages = 31–40 | date = 2008 | issue = Suppl 1 | pmid = 18464021 | doi = 10.1080/13697130802056511 | s2cid = 23568599 }}</ref><ref name="pmid18464022">{{cite journal | vauthors = Hammond GL, Hogeveen KN, Visser M, Coelingh Bennink HJ | title = Estetrol does not bind sex hormone binding globulin or increase its production by human HepG2 cells | journal = Climacteric | volume = 11 | pages = 41–46 | date = 2008 | issue = Suppl 1 | pmid = 18464022 | doi = 10.1080/13697130701851814 | s2cid = 22715507 }}</ref> The overall low plasma protein binding results in a ~50% free active fraction.<ref name="Visser_2008" /> This compares to a 1% active form for EE and ~2% for estradiol.<ref>{{cite journal | vauthors = Stanczyk FZ, Archer DF, Bhavnani BR | title = Ethinyl estradiol and 17β-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment | language = English | journal = Contraception | volume = 87 | issue = 6 | pages = 706–727 | date = June 2013 | pmid = 23375353 | doi = 10.1016/j.contraception.2012.12.011 }}</ref>  Estetrol is equally distributed between red blood cells and plasma.<ref name=":0" />
 
===Metabolism===
Cytochrome P450 (CYP) enzymes do not play a major role in the metabolism of estetrol.<ref name="pmid18464023" />  Instead, estetrol undergoes extensive phase 2 metabolism in the liver to form glucuronide and sulphate conjugates.<ref name="pmid18464023" /><ref name="pmid26212489">{{cite journal | vauthors = Mawet M, Maillard C, Klipping C, Zimmerman Y, Foidart JM, Coelingh Bennink HJ | title = Unique effects on hepatic function, lipid metabolism, bone and growth endocrine parameters of estetrol in combined oral contraceptives | journal = The European Journal of Contraception & Reproductive Health Care | volume = 20 | issue = 6 | pages = 463–475 | date = 2015 | pmid = 26212489 | pmc = 4699469 | doi = 10.3109/13625187.2015.1068934 | doi-broken-date = 1 November 2024 }}</ref><ref name=":7">{{Cite web |title=Nexstellis Label |url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/214154s000lbl.pdf |access-date=2022-04-12 |website=FDA}}</ref><ref name=":8">{{Cite web |title=Drovelis Label |url=https://www.ema.europa.eu/en/documents/product-information/drovelis-epar-product-information_en.pdf |access-date=2022-04-12 |website=EMA}}</ref> The two main metabolites, estetrol-3-glucuronide and estetrol-16-glucuronide, have negligible estrogenic activity.<ref name=":7" /><ref name=":8" /> ''(see [[Drospirenone/estetrol]])''
 
===Excretion===
Estetrol is mainly [[excretion|excreted]] in [[urine]].<ref name="pmid18464023" /><ref name="pmid26212489" /> Estetrol is an end-stage product of metabolism, which is not converted back into active metabolites like estriol, estradiol or estrone.<ref name="pmid18464025" /><ref name="Visser_2008" />
 
==Chemistry==
{{See also|List of estrogens}}
{{Chemical structures of major endogenous estrogens|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.}}
 
Estetrol, also known as 15α-hydroxyestriol or as estra-1,3,5(10)-triene-3,15α,16α,17β-tetrol, is an [[estrane]] [[steroid]] and [[chemical derivative|derivative]] of [[estrin (compound)|estrin]] (estratriene).<ref name="pmid18464023" /><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 | url = http://www.kup.at/kup/pdf/9090.pdf }}</ref> It is structurally different from the other estrogens because of the presence of four [[hydroxyl group]]s, which explains the abbreviation E4.<ref name="pmid18464023" /><ref name="pmid19167495" />
 
===Synthesis===
Estetrol itself is a naturally-produced estrogen by the human fetal liver. However, for human use, estetrol is synthesized from estrone, which is obtained from phytosterols extracted from soybeans. The synthesis of estetrol results in very pure estetrol (>99.9%)<ref name="pmid18464024">{{cite journal | vauthors = Warmerdam EG, Visser M, Coelingh Bennink HJ, Groen M | title = A new route of synthesis of estetrol | journal = Climacteric | volume = 11 | pages = 59–63 | date = 2008 | issue = Suppl 1 | pmid = 18464024 | doi = 10.1080/13697130802054078 | s2cid = 42017011 }}</ref> without contaminants.
 
==History==
Estetrol was first described in 1965 by Egon Diczfalusy and coworkers at the [[Karolinska Institute]] in Stockholm, Sweden,<ref name="pmid14303250">{{cite journal | vauthors = Hagen AA, Barr M, Diczfalusy E | title = METABOLISM OF 17β-OESTRADIOL-4-14C IN EARLY INFANCY | journal = Acta Endocrinologica | volume = 49 | issue = 2 | pages = 207–220 | date = June 1965 | pmid = 14303250 | doi = 10.1530/acta.0.0490207 }}</ref><ref name="Schwers_1965" /><ref name="Schwers_1965b" /><ref>{{cite journal | vauthors = Zucconi G, Lisboa BP, Simonitsch E, Roth L, Hagen AA, Diczfalusy E | title = Isolation of 15-alpha-hydroxy-oestriol from pregnancy urine and from the urine of newborn infants | journal = Acta Endocrinologica | volume = 56 | issue = 3 | pages = 413–423 | date = November 1967 | pmid = 6072461 | doi = 10.1530/acta.0.0560413 }}</ref> who identified and isolated this novel, native estrogen from late pregnancy urine and from the urine of newborn infants. Basic research on estetrol was conducted from 1965 to 1984.<ref name="pmid18462934"/><ref name="YenJaffe1991"/> It was established that estetrol is exclusively synthesized in the human fetal liver. Since 1984, further research was virtually abandoned because estetrol was regarded as a weak and unimportant pregnancy estrogen.<ref name="pmid18462934"/><ref name="YenJaffe1991"/>  In 2001 Herjan Coelingh Bennink at Pantarhei Bioscience in the Netherlands re-started the investigation of estetrol as a potentially useful natural estrogen for human use,<ref name="pmid18462934"/> resulting in the introduction of E4 as the estrogenic component of a combined oral contraceptive in 2021.
 
== References ==
{{Reflist}}
 
{{Endogenous steroids}}
{{Estrogen receptor modulators}}
 
[[Category:Animal reproductive system]]
[[Category:Estranes]]
[[Category:Estrogens]]
[[Category:Hormones of the hypothalamus-pituitary-gonad axis]]
[[Category:Hormones of the pregnant female]]
[[Category:Human female endocrine system]]
[[Category:Hydroxyarenes]]
[[Category:Polyols]]
[[Category:Sex hormones]]
[[Category:Orphan drugs]]
[[Category:Tetrols]]

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