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{{About|estetrol as a hormone|its use as a medication|Estetrol (medication)}}
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{{Other uses|Hydroxyestriol}}
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'''Estetrol''' ('''E4'''), or '''oestetrol''', is a weak [[estrogen]] [[steroid hormone]], which is found in detectable levels only during [[pregnancy]] in humans.<ref name="pmid18462934">{{cite journal | vauthors = Holinka CF, Diczfalusy E, Coelingh Bennink HJ | title = Estetrol: a unique steroid in human pregnancy | journal = J. Steroid Biochem. Mol. Biol. | volume = 110 | issue = 1–2 | pages = 138–43 | date = May 2008 | pmid = 18462934 | doi = 10.1016/j.jsbmb.2008.03.027 | s2cid = 28007341 }}</ref><ref name="YenJaffe1991">Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management, 3rd ed., SSC Yen and RB Jaffe (eds.), pp. 936–981, Copyright Elsevier/Saunders 1991</ref> It is produced exclusively by the [[fetus|fetal]] [[liver]].<ref name="pmid18462934" /> Estetrol is closely related to [[estriol]] (E3), which is also a weak estrogen that is found in high quantities only during pregnancy.<ref name="pmid18462934" /><ref name="YenJaffe1991" /> Along with [[estradiol]] (E2), [[estrone]] (E1), and E3, estetrol (E4) is a major estrogen in the body, although only during pregnancy.<ref name="pmid18462934" />
'''Estetrol''' ('''E4'''), or '''oestetrol''', is one of the four natural estrogenic [[steroid hormone|steroid hormones]] found in humans. Along with [[estrone]] (E1), [[estradiol]] (E2), and estriol (E3), estetrol is a major estrogen in the body, which is primarily found in humans.<ref name="pmid18462934">{{cite journal | vauthors = Holinka CF, Diczfalusy E, Coelingh Bennink HJ | title = Estetrol: a unique steroid in human pregnancy | journal = J. Steroid Biochem. Mol. Biol. | volume = 110 | issue = 1–2 | pages = 138–43 | date = May 2008 | pmid = 18462934 | doi = 10.1016/j.jsbmb.2008.03.027 | s2cid = 28007341 }}</ref><ref name="YenJaffe1991">Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management, 3rd ed., SSC Yen and RB Jaffe (eds.), pp. 936–981, Copyright Elsevier/Saunders 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 dectable 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 role as a natural hormone, estetrol is under clinical development for use as a [[medication]], for instance in hormonal contraception (in combination with [[drospirenone]]) and as [[menopausal hormone therapy]]; for information on estetrol as a medication, see the [[estetrol (medication)]] article.
In addition to its physiological role as a native hormone, estetrol can be used as a [[medication]], see [[estetrol (medication)]]. E4, in combination with [[drospirenone]], has recently been approved as a new estrogenic component of a combined oral contraceptive (COC) and E4 alone is in clinical development for the treatment of menopausal symptoms as well as breast and prostate cancer.


==Biological function==
==Biological function==
Estetrol is an [[estrogen]] and has [[estrogen]]ic effects in various [[tissue (biology)|tissue]]s.<ref name="pmid18462934" /> Estetrol interacts with the nuclear [[estrogen receptor alpha]] (ERα) in a manner identical to that of the other estrogens and distinct from that observed with [[selective estrogen receptor modulators]] (SERMs).<ref>{{Cite journal|last1=Abot|first1=Anne|last2=Fontaine|first2=Coralie|last3=Buscato|first3=Mélissa|last4=Solinhac|first4=Romain|last5=Flouriot|first5=Gilles|last6=Fabre|first6=Aurélie|last7=Drougard|first7=Anne|last8=Rajan|first8=Shyamala|last9=Laine|first9=Muriel|last10=Milon|first10=Alain|last11=Muller|first11=Isabelle|date=2014|title=The uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor α modulation, uncoupling nuclear and membrane activation|url= |journal=EMBO Molecular Medicine|language=en|volume=6|issue=10|pages=1328–1346|doi=10.15252/emmm.201404112|issn=1757-4676|pmc=4287935|pmid=25214462}}</ref><ref>{{Cite journal|last1=Foidart|first1=JM|last2=Arnal|first2=JF|last3=Lenfant|first3=F|display-authors=1|date=2019|title=30th Annual Meeting of The North America Menopause Society September 25 – 28, 2019, Chicago, IL|url=https://dx.doi.org/10.1097/GME.0000000000001456|journal=Menopause|language=en|volume=26|issue=12|pages=1445–1481|doi=10.1097/GME.0000000000001456|s2cid=243519374|issn=1530-0374}}</ref> So far the physiological function of estetrol is unknown. The possible use of estetrol as a marker for fetal well-being has been studied quite extensively. However, due to the large intra- and inter-individual variation of maternal estetrol plasma levels during pregnancy, this appeared not to be feasible.<ref>J. Heikkilä, T. Luukkainen, Urinary excretion of estriol and 15a-hydroxyestriol in complicated pregnancies, Am. J. Obstet. Gynecol. 110 (1971) 509-521.</ref><ref>D. Tulchinsky, F.D. Frigoletto, K.J. Ryan, J. Fishman, Plasma estetrol as an index of fetal well-being, J. Clin. Endocrinol. Metab. 40 (1975) 560-567</ref><ref>A.D. Notation, G.E. Tagatz, Unconjugated estriol and 15a-hydroxyestriol in complicated pregnancies, Am. J. Obstet. Gynecol. 128 (1977) 747-756.</ref><ref>N. Kundu, M. Grant, Radioimmunoassay of 15a-hydroxyestriol (estetrol) in pregnancy serum, Steroids 27 (1976) 785-796.</ref><ref>N. Kundu, M. Wachs, G.B. Iverson, L.P. Petersen, Comparison of serum unconjugated estriol and estetrol in normal and complicated pregnancies, Obstet. Gynecol. 58 (1981) 276-281.</ref>
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 |last=Fruzzetti |first=Franca |last2=Fidecicchi |first2=Tiziana |last3=Montt Guevara |first3=Maria Magdalena |last4=Simoncini |first4=Tommaso |date=2021 |title=Estetrol: A New Choice for Contraception |url=https://www.mdpi.com/2077-0383/10/23/5625 |journal=Journal of Clinical Medicine |language=en |volume=10 |issue=23 |pages=5625 |doi=10.3390/jcm10235625 |issn=2077-0383 |pmc=PMC8658652 |pmid=34884326}}</ref> due to the large intra- and inter-individual variation in maternal estetrol plasma levels during pregnancy.<ref>J. Heikkilä, T. Luukkainen, Urinary excretion of estriol and 15a-hydroxyestriol in complicated pregnancies, Am. J. Obstet. Gynecol. 110 (1971) 509-521.</ref><ref>D. Tulchinsky, F.D. Frigoletto, K.J. Ryan, J. Fishman, Plasma estetrol as an index of fetal well-being, J. Clin. Endocrinol. Metab. 40 (1975) 560-567</ref><ref>A.D. Notation, G.E. Tagatz, Unconjugated estriol and 15a-hydroxyestriol in complicated pregnancies, Am. J. Obstet. Gynecol. 128 (1977) 747-756.</ref><ref>N. Kundu, M. Grant, Radioimmunoassay of 15a-hydroxyestriol (estetrol) in pregnancy serum, Steroids 27 (1976) 785-796.</ref><ref>N. Kundu, M. Wachs, G.B. Iverson, L.P. Petersen, Comparison of serum unconjugated estriol and estetrol in normal and complicated pregnancies, Obstet. Gynecol. 58 (1981) 276-281.</ref>


==Biological activity==
==Biological activity==
Estetrol is an [[agonist]] of the [[estrogen receptor]]s (ERs), and hence is an [[estrogen]].<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 Suppl 1 | pages = 47–58 | date = 2008 | pmid = 18464023 | doi = 10.1080/13697130802073425 | s2cid = 24003341 }}</ref><ref name="pmid19167495" /> It has moderate [[affinity (pharmacology)|affinity]] for [[ERα]] and [[ERβ]], with K<sub>i</sub> values of 4.9&nbsp;nM and 19&nbsp;nM, respectively.<ref name="pmid18464023" /><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 Suppl 1 | pages = 64–8 | date = 2008 | pmid = 18464025 | doi = 10.1080/13697130802050340 | s2cid = 11027782 }}</ref> As such, estetrol has 4- to 5-fold preference for the ERα over the ERβ.<ref name="pmid18464023" /><ref name="pmid18464025" /> The estrogen has low affinity for the ERs relative to estradiol, and both estetrol and the related estrogen [[estriol]] require substantially higher concentrations than estradiol to produce similar effects to estradiol.<ref name="pmid18464023" /> The affinity of estetrol for the ERs is about 0.3% (rat) to 6.25% (human) of that of estradiol, and its ''[[in vivo]]'' [[potency (pharmacology)|potency]] in animals is about 2 to 3% of that of estradiol.<ref name="pmid18464023" /> Estetrol shows high [[binding selectivity|selectivity]] for the ERs.<ref name="pmid18464023" /><ref name="pmid18464025" />
<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 Suppl 1 | pages = 47–58 | date = 2008 | pmid = 18464023 | doi = 10.1080/13697130802073425 | s2cid = 24003341 }}</ref><ref name="pmid19167495" /> 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" /><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 Suppl 1 | pages = 64–8 | 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 E4 has a low risk of non-specific side effects.


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

== Mode of Action ==

=== '''Tissue-selective effects of Estetrol''' ===
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 |last=Gérard |first=C. |last2=Blacher |first2=S. |last3=Communal |first3=L. |last4=Courtin |first4=A. |last5=Tskitishvili |first5=E. |last6=Mestdagt |first6=M. |last7=Munaut |first7=C. |last8=Noel |first8=A. |last9=Gompel |first9=A. |last10=Péqueux |first10=C. |last11=Foidart |first11=J. M. |date=2015 |title=Estetrol is a weak estrogen antagonizing estradiol-dependent mammary gland proliferation |url=https://pubmed.ncbi.nlm.nih.gov/25359896/ |journal=The Journal of Endocrinology |volume=224 |issue=1 |pages=85–95 |doi=10.1530/JOE-14-0549 |issn=1479-6805 |pmid=25359896}}</ref> In rodent models, estetrol has shown to elicit potent estrogenic activity on ovulation<ref>{{Cite journal |last=Bennink |first=Herjan J. T. Coelingh |last2=Skouby |first2=Sven |last3=Bouchard |first3=Philippe |last4=Holinka |first4=Christian F. |date=2008-03-01 |title=Ovulation inhibition by estetrol in an in vivo model |url=https://www.contraceptionjournal.org/article/S0010-7824(07)00515-X/abstract |journal=Contraception |language=English |volume=77 |issue=3 |pages=186–190 |doi=10.1016/j.contraception.2007.11.014 |issn=0010-7824}}</ref>, brain<ref>{{Cite journal |last=Pluchino |first=N. |last2=Santoro |first2=A. N. |last3=Casarosa |first3=E. |last4=Giannini |first4=A. |last5=Genazzani |first5=A. |last6=Russo |first6=M. |last7=Russo |first7=N. |last8=Petignat |first8=P. |last9=Genazzani |first9=A. R. |date=2014-09-01 |title=Effect of estetrol administration on brain and serum allopregnanolone in intact and ovariectomized rats |url=https://www.sciencedirect.com/science/article/pii/S0960076014000971 |journal=The Journal of Steroid Biochemistry and Molecular Biology |language=en |volume=143 |pages=285–290 |doi=10.1016/j.jsbmb.2014.04.011 |issn=0960-0760}}</ref>, bone tissue<ref>{{Cite journal |last=Coelingh Bennink |first=H. J. T. |last2=Heegaard |first2=A.-M. |last3=Visser |first3=M. |last4=Holinka |first4=C. F. |last5=Christiansen |first5=C. |date=2008-01-01 |title=Oral bioavailability and bone-sparing effects of estetrol in an osteoporosis model |url=https://doi.org/10.1080/13697130701798692 |journal=Climacteric |volume=11 |issue=sup1 |pages=2–14 |doi=10.1080/13697130701798692 |issn=1369-7137 |pmid=18464016}}</ref>, cardiovascular system<ref name=":2">{{Cite journal |last=Abot |first=Anne |last2=Fontaine |first2=Coralie |last3=Buscato |first3=Mélissa |last4=Solinhac |first4=Romain |last5=Flouriot |first5=Gilles |last6=Fabre |first6=Aurélie |last7=Drougard |first7=Anne |last8=Rajan |first8=Shyamala |last9=Laine |first9=Muriel |last10=Milon |first10=Alain |last11=Muller |first11=Isabelle |date=2014 |title=The uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor α modulation, uncoupling nuclear and membrane activation |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4287935/ |journal=EMBO Molecular Medicine |volume=6 |issue=10 |pages=1328–1346 |doi=10.15252/emmm.201404112 |issn=1757-4676 |pmc=4287935 |pmid=25214462}}</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 |last=Benoit |first=Thibaut |last2=Valera |first2=Marie-Cecile |last3=Fontaine |first3=Coralie |last4=Buscato |first4=Melissa |last5=Lenfant |first5=Francoise |last6=Raymond-Letron |first6=Isabelle |last7=Tremollieres |first7=Florence |last8=Soulie |first8=Michel |last9=Foidart |first9=Jean-Michel |last10=Game |first10=Xavier |last11=Arnal |first11=Jean-Francois |date=2017-11-01 |title=Estetrol, a Fetal Selective Estrogen Receptor Modulator, Acts on the Vagina of Mice through Nuclear Estrogen Receptor α Activation |url=https://ajp.amjpathol.org/article/S0002-9440(17)30361-9/abstract |journal=The American Journal of Pathology |language=English |volume=187 |issue=11 |pages=2499–2507 |doi=10.1016/j.ajpath.2017.07.013 |issn=0002-9440 |pmid=28827141}}</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 |last=Gallez |first=Anne |last2=Blacher |first2=Silvia |last3=Maquoi |first3=Erik |last4=Konradowski |first4=Erika |last5=Joiret |first5=Marc |last6=Primac |first6=Irina |last7=Gérard |first7=Céline |last8=Taziaux |first8=Mélanie |last9=Houtman |first9=René |last10=Geris |first10=Liesbet |last11=Lenfant |first11=Françoise |date=2021 |title=Estetrol Combined to Progestogen for Menopause or Contraception Indication Is Neutral on Breast Cancer |url=https://www.mdpi.com/2072-6694/13/10/2486 |journal=Cancers |language=en |volume=13 |issue=10 |pages=2486 |doi=10.3390/cancers13102486 |issn=2072-6694 |pmc=PMC8160902 |pmid=34065180}}</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 |last=Giretti |first=Maria Silvia |last2=Montt Guevara |first2=Maria Magdalena |last3=Cecchi |first3=Elena |last4=Mannella |first4=Paolo |last5=Palla |first5=Giulia |last6=Spina |first6=Stefania |last7=Bernacchi |first7=Guja |last8=Di Bello |first8=Silvia |last9=Genazzani |first9=Andrea Riccardo |last10=Genazzani |first10=Alessandro D. |last11=Simoncini |first11=Tommaso |date=2014-05-26 |title=Effects of Estetrol on Migration and Invasion in T47-D Breast Cancer Cells through the Actin Cytoskeleton |url=http://journal.frontiersin.org/article/10.3389/fendo.2014.00080/abstract |journal=Frontiers in Endocrinology |volume=5 |doi=10.3389/fendo.2014.00080 |issn=1664-2392 |pmc=PMC4033260 |pmid=24904530}}</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 |last=Klipping |first=Christine |last2=Duijkers |first2=Ingrid |last3=Mawet |first3=Marie |last4=Maillard |first4=Catherine |last5=Bastidas |first5=Adriana |last6=Jost |first6=Maud |last7=Foidart |first7=Jean-Michel |date=2021 |title=Endocrine and metabolic effects of an oral contraceptive containing estetrol and drospirenone |url=https://linkinghub.elsevier.com/retrieve/pii/S0010782421000020 |journal=Contraception |language=en |volume=103 |issue=4 |pages=213–221 |doi=10.1016/j.contraception.2021.01.001}}</ref>

Estetrol can therefore be described as the first Native Estrogen with Selective Tissue activity (NEST).<ref>{{Cite journal |last=Gérard |first=C. |last2=Jost |first2=M. |last3=Oligschläger |first3=Y. |last4=Foidart |first4=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 |last=Gérard |first=Céline |last2=Arnal |first2=Jean-François |last3=Jost |first3=Maud |last4=Douxfils |first4=Jonathan |last5=Lenfant |first5=Françoise |last6=Fontaine |first6=Coralie |last7=Houtman |first7=René |last8=Archer |first8=David F. |last9=Reid |first9=Robert L. |last10=Lobo |first10=Rogerio A. |last11=Gaspard |first11=Ulysse |date=2022-02-01 |title=Profile of estetrol, a promising native estrogen for oral contraception and the relief of climacteric symptoms of menopause |url=https://www.tandfonline.com/doi/full/10.1080/17512433.2022.2054413 |journal=Expert Review of Clinical Pharmacology |language=en |volume=15 |issue=2 |pages=121–137 |doi=10.1080/17512433.2022.2054413 |issn=1751-2433}}</ref>

=== '''Estetrol is different from selective estrogen receptor modulators (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 |last=Garefalakis |first=Maria |last2=Hickey |first2=Martha |date=2008-03-07 |title=Role of androgens, progestins and tibolone in the treatment of menopausal symptoms: a review of the clinical evidence |url=https://www.dovepress.com/role-of-androgens-progestins-and-tibolone-in-the-treatment-of-menopaus-peer-reviewed-fulltext-article-CIA |journal=Clinical Interventions in Aging |language=English |volume=3 |issue=1 |pages=1–8 |doi=10.2147/CIA.S1043 |pmc=PMC2544356 |pmid=18488873}}</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" />

=== '''Estetrol activates ERα differently than other estrogens''' ===
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==
==Biochemistry==


===Biosynthesis===
===Biosynthesis===
Estetrol is synthesized during pregnancy only in the [[fetus|fetal]] [[liver]] from [[estradiol]] (E2) and [[estriol]] (E3) by the two [[enzyme]]s 15α- and 16α-hydroxylase.<ref>J. Schwers, G. Eriksson, N. Wiqvist, E. Diczfalusy, 15a-hydroxylation: A new pathway of estrogen metabolism in the human fetus and newborn, Biochim. Biophys. Acta. 100 (1965) 313-316</ref><ref>J. Schwers, M. Govaerts-Videtsky, N. Wiqvist, E. Diczfalusy, Metabolism of oestrone sulphate by the previable human foetus, Acta Endocrinol. 50 (1965) 597-610.</ref><ref>S. Mancuso, G. Benagiano, S. Dell’Acqua, M. Shapiro, N. Wiqvist, E. Diczfalusy, Studies on the metabolism of C-19 steroids in the human foeto-placental unit, Acta Endocrinol. 57 (1968) 208-227.</ref> Alternatively, estetrol is synthesized with 15α-hydroxylation of [[16α-hydroxy-DHEA sulfate]] as an intermediate step.<ref name="StraussBarbieri2009">{{cite book|author1=Jerome Frank Strauss|author2=Robert L. Barbieri|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> It appears in maternal urine at around week 9 of pregnancy.<ref name="YenJaffe1991" /> After birth the neonatal liver rapidly loses its capacity to synthesize estetrol because these two enzymes are no longer expressed.
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=":5">J. Schwers, G. Eriksson, N. Wiqvist, E. Diczfalusy, 15a-hydroxylation: A new pathway of estrogen metabolism in the human fetus and newborn, Biochim. Biophys. Acta. 100 (1965) 313-316</ref><ref name=":6">J. Schwers, M. Govaerts-Videtsky, N. Wiqvist, E. Diczfalusy, Metabolism of oestrone sulphate by the previable human foetus, Acta Endocrinol. 50 (1965) 597-610.</ref><ref>S. Mancuso, G. Benagiano, S. Dell’Acqua, M. Shapiro, N. Wiqvist, E. Diczfalusy, Studies on the metabolism of C-19 steroids in the human foeto-placental unit, Acta Endocrinol. 57 (1968) 208-227.</ref> Alternatively, estetrol is synthesized with 15α-hydroxylation of [[16α-hydroxy-DHEA sulfate]] as an intermediate step.<ref name="StraussBarbieri2009">{{cite book|author1=Jerome Frank Strauss|author2=Robert L. Barbieri|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 9<sup>th</sup> week of gestation.<ref name="YenJaffe1991" /><ref>J. Heikkilä, H. Adlercreutz, A method for the determination of urinary 15α-hydroxyestriol and estriol, J. Steroid Biochem. 1 (1970) 243-253</ref><ref>J. Heikkilä, Excretion of 15α-hydroxyestriol and estriol in maternal urine during normal pregnancy, J. Steroid Biochem. 2 (1971) 83-93.</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" />

Estetrol reaches the maternal circulation through the placenta and was already detected at nine weeks of pregnancy in maternal urine.<ref>J. Heikkilä, H. Adlercreutz, A method for the determination of urinary 15α-hydroxyestriol and estriol, J. Steroid Biochem. 1 (1970) 243-253</ref><ref>J. Heikkilä, Excretion of 15α-hydroxyestriol and estriol in maternal urine during normal pregnancy, J. Steroid Biochem. 2 (1971) 83-93.</ref> During the second trimester of pregnancy high levels were 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.<ref name="pmid18462934" />


===Distribution===
===Distribution===
In terms of [[plasma protein binding]], estetrol is moderately bound to [[human serum albumin|albumin]], and is not bound to [[sex hormone-binding globulin]] (SHBG).<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 Suppl 1 | pages = 31–40 | date = 2008 | 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 Suppl 1 | pages = 41–6 | date = 2008 | pmid = 18464022 | doi = 10.1080/13697130701851814 | s2cid = 22715507 }}</ref>
In terms of [[plasma protein binding]], estetrol displays moderate binding to [[human serum albumin|albumin]], and shows no binding to SHBG.<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 Suppl 1 | pages = 31–40 | date = 2008 | 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 Suppl 1 | pages = 41–6 | date = 2008 | pmid = 18464022 | doi = 10.1080/13697130701851814 | s2cid = 22715507 }}</ref> The overall low plasma protein binding results in a ~50% free active fraction.<ref name="pmid18464021" /> This compares to a 1% active form for EE and ~2% for estradiol.<ref>{{Cite journal |last=Stanczyk |first=Frank Z. |last2=Archer |first2=David F. |last3=Bhavnani |first3=Bhagu R. |date=2013-06-01 |title=Ethinyl estradiol and 17beta-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment |url=https://www.contraceptionjournal.org/article/S0010-7824(12)01079-7/abstract |journal=Contraception |language=English |volume=87 |issue=6 |pages=706–727 |doi=10.1016/j.contraception.2012.12.011 |issn=0010-7824}}</ref> E4 is equally distributed between red blood cells and plasma.<ref name=":0" />


===Metabolism===
===Metabolism===
Estetrol undergoes no phase I metabolism by CYP P450 enzymes.<ref name="pmid18464023" /> It is [[conjugation (biochemistry)|conjugated]] via [[glucuronidation]] and to a lesser extent [[sulfation]] and then [[excretion|excreted]].<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 = Eur J Contracept Reprod Health Care | volume = 20 | issue = 6 | pages = 463–75 | date = 2015 | pmid = 26212489 | pmc = 4699469 | doi = 10.3109/13625187.2015.1068934 | doi-broken-date = 28 February 2022 }}</ref>
Cytochrome P450 (CYP) enzymes do not play a major role in the metabolism of E4.<ref name="pmid18464023" /> Instead, E4 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 = Eur J Contracept Reprod Health Care | volume = 20 | issue = 6 | pages = 463–75 | date = 2015 | pmid = 26212489 | pmc = 4699469 | doi = 10.3109/13625187.2015.1068934 | doi-broken-date = 28 February 2022 }}</ref> The two main metabolites, estetrol-3-glucuronide and estetrol-16-glucuronide, have negligible estrogenic activity. ''(see [[Drospirenone/estetrol]])''


===Excretion===
===Excretion===
Estetrol is [[excretion|excreted]] mostly or completely in [[urine]].<ref name="pmid26212489" /><ref name="pmid18464023" />
Estetrol is mainly [[excretion|excreted]] in [[urine]].<ref name="pmid18464023" /><ref name="pmid26212489" /> E4 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="pmid18464021" />


==Chemistry==
==Chemistry==
Line 71: Line 88:
{{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.}}
{{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 a [[natural compound|naturally occurring]] [[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 = J. Steroid Biochem. Mol. Biol. | volume = 114 | issue = 1–2 | pages = 85–9 | 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 has four [[hydroxyl group]]s, which explains the abbreviation E4.<ref name="pmid18464023" /><ref name="pmid19167495" />
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 = J. Steroid Biochem. Mol. Biol. | volume = 114 | issue = 1–2 | pages = 85–9 | 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===
===Synthesis===
[[Chemical synthesis|Chemical syntheses]] of estetrol have been published.<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 Suppl 1 | pages = 59–63 | date = 2008 | pmid = 18464024 | doi = 10.1080/13697130802054078 | s2cid = 42017011 }}</ref>
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 Suppl 1 | pages = 59–63 | date = 2008 | pmid = 18464024 | doi = 10.1080/13697130802054078 | s2cid = 42017011 }}</ref> without contaminants.


==History==
==History==
Estetrol was discovered in 1965 by Egon Diczfalusy and coworkers at the Karolinska Institute in Stockholm, Sweden, via isolation from the [[urine]] of pregnant women.<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 Suppl 1 | pages = 47–58 | date = 2008 | pmid = 18464023 | doi = 10.1080/13697130802073425 | s2cid = 24003341 }}</ref><ref name="pmid14303250">{{cite journal | vauthors = Hagen AA, Barr M, Diczfalusy E | title = Metabolism of 17-beta-oestradiol-4-14-C in early infancy | journal = Acta Endocrinol. | volume = 49 | pages = 207–20 | date = June 1965 | issue = 2 | pmid = 14303250 | doi = 10.1530/acta.0.0490207 }}</ref>
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 17-beta-oestradiol-4-14-C in early infancy | journal = Acta Endocrinol. | volume = 49 | pages = 207–20 | date = June 1965 | issue = 2 | pmid = 14303250 | doi = 10.1530/acta.0.0490207 }}</ref><ref name=":5" /><ref name=":6" /><ref>{{Cite journal |last=Zucconi |first=G. |last2=Lisboa |first2=B. P. |last3=Simonitsch |first3=E. |last4=Roth |first4=L. |last5=Hagen |first5=A. A. |last6=Diczfalusy |first6=E. |date=1967 |title=ISOLATION OF 15α-HYDROXY-OESTRIOL FROM PREGNANCY URINE AND FROM THE URINE OF NEWBORN INFANTS |url=https://eje.bioscientifica.com/view/journals/eje/56/3/acta_56_3_006.xml |journal=Acta Endocrinologica |volume=56 |issue=3 |pages=413–423 |doi=10.1530/acta.0.0560413 |issn=0804-4643}}</ref> who identified and isolated this novel, native estrogen from late pregnancy urine and from the urine of newborn infants.


==References==
==References==

Revision as of 10:05, 12 April 2022

This article is about estetrol as a hormone. For its use as a medication, see Estetrol (medication).
For other uses, see Hydroxyestriol.
Estetrol
Skeletal formula of estetrol
Ball-and-stick model of the estetrol molecule
Names
Preferred IUPAC name
(1R,2R,3R,3aS,3bR,9bS,11aS)-11a-Methyl-2,3,3a,3b,4,5,9b,10,11,11a-decahydro-1H-cyclopenta[a]phenanthrene-1,2,3,7-tetrol
Other names
Oestetrol; E4; 15α-Hydroxyestriol; Estra-1,3,5(10)-triene-3,15α,16α,17β-tetrol
Identifiers
3D model (JSmol)
ChEBI
ECHA InfoCard 100.276.707 Edit this at Wikidata
KEGG
UNII
  • 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
Properties
C18H24O4
Molar mass 304.386 g/mol
1.38 mg/mL
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Estetrol (E4), or oestetrol, is one of the four natural estrogenic steroid hormones found in humans. Along with estrone (E1), estradiol (E2), and estriol (E3), estetrol is a major estrogen in the body, which is primarily found in humans.[1][2] In contrast to estrone and estradiol, estetrol is a native estrogen of fetal life. Estetrol is produced exclusively by the fetal liver[1] and is found in dectable levels only during pregnancy, with relatively high levels in the fetus and lower levels in the maternal circulation.[1][2]

In addition to its physiological role as a native hormone, estetrol can be used as a medication, see estetrol (medication). E4, in combination with drospirenone, has recently been approved as a new estrogenic component of a combined oral contraceptive (COC) and E4 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[3] due to the large intra- and inter-individual variation in maternal estetrol plasma levels during pregnancy.[4][5][6][7][8]

Biological activity

[9][10] Estetrol has a moderate affinity for estrogen receptors alpha (ERα) and beta (ERβ), with Ki values of 4.9 nM and 19 nM, respectively.[9][11] As such, estetrol has 4- to 5-fold preference for ERα over ERβ.[9][11] 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.[1][9] Estetrol displays a highly selective binding to its primary targets ERα and ERβ[9][11], which ensures that E4 has a low risk of non-specific side effects.

Selected biological properties of endogenous estrogens in rats
Estrogen ERTooltip Estrogen receptor RBATooltip relative binding affinity (%) Uterine weight (%) Uterotrophy LHTooltip Luteinizing hormone levels (%) SHBGTooltip Sex hormone-binding globulin RBATooltip relative binding affinity (%)
Control – 100 – 100 –
Estradiol (E2) 100 506 ± 20 +++ 12–19 100
Estrone (E1) 11 ± 8 490 ± 22 +++ ? 20
Estriol (E3) 10 ± 4 468 ± 30 +++ 8–18 3
Estetrol (E4) 0.5 ± 0.2 ? Inactive ? 1
17α-Estradiol 4.2 ± 0.8 ? ? ? ?
2-Hydroxyestradiol 24 ± 7 285 ± 8 +b 31–61 28
2-Methoxyestradiol 0.05 ± 0.04 101 Inactive ? 130
4-Hydroxyestradiol 45 ± 12 ? ? ? ?
4-Methoxyestradiol 1.3 ± 0.2 260 ++ ? 9
4-Fluoroestradiola 180 ± 43 ? +++ ? ?
2-Hydroxyestrone 1.9 ± 0.8 130 ± 9 Inactive 110–142 8
2-Methoxyestrone 0.01 ± 0.00 103 ± 7 Inactive 95–100 120
4-Hydroxyestrone 11 ± 4 351 ++ 21–50 35
4-Methoxyestrone 0.13 ± 0.04 338 ++ 65–92 12
16α-Hydroxyestrone 2.8 ± 1.0 552 ± 42 +++ 7–24 <0.5
2-Hydroxyestriol 0.9 ± 0.3 302 +b ? ?
2-Methoxyestriol 0.01 ± 0.00 ? Inactive ? 4
Notes: Values are mean ± SD or range. ER RBA = Relative binding affinity to estrogen receptors of rat uterine cytosol. Uterine weight = Percentage change in uterine wet weight of ovariectomized rats after 72 hours with continuous administration of 1 μg/hour via subcutaneously implanted osmotic pumps. LH levels = Luteinizing hormone levels relative to baseline of ovariectomized rats after 24 to 72 hours of continuous administration via subcutaneous implant. Footnotes: a = Synthetic (i.e., not endogenous). b = Atypical uterotrophic effect which plateaus within 48 hours (estradiol's uterotrophy continues linearly up to 72 hours). Sources: See template.

Mode of Action

Tissue-selective effects of Estetrol

Estetrol shows selective estrogenic, neutral or anti-estrogenic activities in certain cell types and tissues.[11][12][13] In rodent models, estetrol has shown to elicit potent estrogenic activity on ovulation[14], brain[15], bone tissue[16], cardiovascular system[17], and uterus, associated with ovulation inhibition, prevention of bone demineralization, cardioprotective effects and maintenance of uterovaginal tissues, respectively.[17][18]

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.[13][19] This property of estetrol is associated with antagonistic effects on breast cell proliferation, migration and invasion in the presence of estradiol.[13][20]

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.[21]

Estetrol can therefore be described as the first Native Estrogen with Selective Tissue activity (NEST).[22][23]

Estetrol is different from selective estrogen receptor modulators (SERMs)

The selective tissue activity of estetrol is different from the effects of selective estrogen receptor modulators (SERMs), like tamoxifen and raloxifene.[24] 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.[24] Estetrol recruits the same co-regulators as other estrogens, while SERMs recruit other co-regulators.[23]

Estetrol activates ERα differently than other estrogens

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.[17]

Biochemistry

Biosynthesis

In the fetal liver, estetrol is synthesized from estradiol (E2) and estriol (E3) by two fetal liver enzymes, 15α- and 16α-hydroxylase, through hydroxylation.[25][26][27] Alternatively, estetrol is synthesized with 15α-hydroxylation of 16α-hydroxy-DHEA sulfate as an intermediate step.[28] Estetrol can be detected in maternal urine from the 9th week of gestation.[2][29][30] 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 ng/mL (>3 nM) towards the end of pregnancy. Fetal plasma levels have been reported to be over 10 times higher than maternal plasma levels at parturition. [1]

Distribution

In terms of plasma protein binding, estetrol displays moderate binding to albumin, and shows no binding to SHBG.[31][32] The overall low plasma protein binding results in a ~50% free active fraction.[31] This compares to a 1% active form for EE and ~2% for estradiol.[33] E4 is equally distributed between red blood cells and plasma.[3]

Metabolism

Cytochrome P450 (CYP) enzymes do not play a major role in the metabolism of E4.[9] Instead, E4 undergoes extensive phase 2 metabolism in the liver to form glucuronide and sulphate conjugates.[9][12] The two main metabolites, estetrol-3-glucuronide and estetrol-16-glucuronide, have negligible estrogenic activity. (see Drospirenone/estetrol)

Excretion

Estetrol is mainly excreted in urine.[9][12] E4 is an end-stage product of metabolism, which is not converted back into active metabolites like estriol, estradiol or estrone.[11][31]

Chemistry

See also: List of estrogens
Structures of major endogenous estrogens
Chemical structures of major endogenous estrogens
Estrone (E1)
Estriol (E3)
Estetrol (E4)
The image above contains clickable links
Note the hydroxyl (–OH) groups: 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 derivative of estrin (estratriene).[9][10] It is structurally different from the other estrogens because of the presence of four hydroxyl groups, which explains the abbreviation E4.[9][10]

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%)[34] without contaminants.

History

Estetrol was first described in 1965 by Egon Diczfalusy and coworkers at the Karolinska Institute in Stockholm, Sweden,[35][25][26][36] who identified and isolated this novel, native estrogen from late pregnancy urine and from the urine of newborn infants.

References

  1. ^ a b c d e Holinka CF, Diczfalusy E, Coelingh Bennink HJ (May 2008). "Estetrol: a unique steroid in human pregnancy". J. Steroid Biochem. Mol. Biol. 110 (1–2): 138–43. doi:10.1016/j.jsbmb.2008.03.027. PMID 18462934. S2CID 28007341.
  2. ^ a b c Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management, 3rd ed., SSC Yen and RB Jaffe (eds.), pp. 936–981, Copyright Elsevier/Saunders 1991
  3. ^ a b Fruzzetti, Franca; Fidecicchi, Tiziana; Montt Guevara, Maria Magdalena; Simoncini, Tommaso (2021). "Estetrol: A New Choice for Contraception". Journal of Clinical Medicine. 10 (23): 5625. doi:10.3390/jcm10235625. ISSN 2077-0383. PMC 8658652. PMID 34884326.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
  4. ^ J. Heikkilä, T. Luukkainen, Urinary excretion of estriol and 15a-hydroxyestriol in complicated pregnancies, Am. J. Obstet. Gynecol. 110 (1971) 509-521.
  5. ^ D. Tulchinsky, F.D. Frigoletto, K.J. Ryan, J. Fishman, Plasma estetrol as an index of fetal well-being, J. Clin. Endocrinol. Metab. 40 (1975) 560-567
  6. ^ A.D. Notation, G.E. Tagatz, Unconjugated estriol and 15a-hydroxyestriol in complicated pregnancies, Am. J. Obstet. Gynecol. 128 (1977) 747-756.
  7. ^ N. Kundu, M. Grant, Radioimmunoassay of 15a-hydroxyestriol (estetrol) in pregnancy serum, Steroids 27 (1976) 785-796.
  8. ^ N. Kundu, M. Wachs, G.B. Iverson, L.P. Petersen, Comparison of serum unconjugated estriol and estetrol in normal and complicated pregnancies, Obstet. Gynecol. 58 (1981) 276-281.
  9. ^ a b c d e f g h i j Coelingh Bennink HJ, Holinka CF, Diczfalusy E (2008). "Estetrol review: profile and potential clinical applications". Climacteric. 11 Suppl 1: 47–58. doi:10.1080/13697130802073425. PMID 18464023. S2CID 24003341.
  10. ^ a b c Visser M, Coelingh Bennink HJ (March 2009). "Clinical applications for estetrol" (PDF). J. Steroid Biochem. Mol. Biol. 114 (1–2): 85–9. doi:10.1016/j.jsbmb.2008.12.013. PMID 19167495. S2CID 32081001.
  11. ^ a b c d e Visser M, Foidart JM, Coelingh Bennink HJ (2008). "In vitro effects of estetrol on receptor binding, drug targets and human liver cell metabolism". Climacteric. 11 Suppl 1: 64–8. doi:10.1080/13697130802050340. PMID 18464025. S2CID 11027782.
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