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| CASNo = 15183-37-6
| CASNo = 15183-37-6
| CASNo_Ref = {{cascite|correct|CAS}}
| CASNo_Ref = {{cascite|correct|CAS}}
⚫
| UNII_Ref = {{fdacite|correct|FDA}}
⚫
| UNII = ENB39R14VF
| ChEBI = 142773
| ChEBI = 142773
| PubChem = 27125
| ChEMBL = 1230314
| ChemSpiderID = 25245
| DrugBank = DB12235
| EC_number = 840-340-4
| KEGG = D11513
| 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
| 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
}}
}}
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=== Differences vs SERMs ===
=== 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 }}</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" />
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 ===
=== ERα activation ===
Line 77: Line 83:


===Distribution===
===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 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 = 41–46 | 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="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" />
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===
===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 = 31 December 2022 }}</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]])''
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===
===Excretion===
Line 92: Line 98:


===Synthesis===
===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 Suppl 1 | pages = 59–63 | date = 2008 | pmid = 18464024 | doi = 10.1080/13697130802054078 | s2cid = 42017011 }}</ref> without contaminants.
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==
==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.[1][2] 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.
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 ==
== References ==
Line 109: Line 115:
[[Category:Hormones of the pregnant female]]
[[Category:Hormones of the pregnant female]]
[[Category:Human female endocrine system]]
[[Category:Human female endocrine system]]
[[Category:Phenols]]
[[Category:Hydroxyarenes]]
[[Category:Polyols]]
[[Category:Polyols]]
[[Category:Sex hormones]]
[[Category:Sex hormones]]
[[Category:Orphan drugs]]
[[Category:Orphan drugs]]
[[Category:Tetrols]]

Latest revision as of 10:35, 22 December 2024

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
IUPAC name
Estra-1,3,5(10)-triene-3,15α,16α,17β-tetrol
Systematic 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
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.276.707 Edit this at Wikidata
EC Number
  • 840-340-4
KEGG
UNII
  • InChI=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
    Key: AJIPIJNNOJSSQC-NYLIRDPKSA-N
  • 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.[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 detectable 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). 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

[edit]

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]

Biological activity

[edit]

Estetrol has a moderate affinity for estrogen receptors alpha (ERα) and beta (ERβ), with Ki values of 4.9 nM and 19 nM, respectively.[8][9] As such, estetrol has 4- to 5-fold preference for ERα over ERβ.[8][9] 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][8] Estetrol displays a highly selective binding to its primary targets ERα and ERβ,[8][9] which ensures that estetrol 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

[edit]

Tissue-selective effect

[edit]

Estetrol shows selective estrogenic, neutral or anti-estrogenic activities in certain cell types and tissues.[9][10][11] In rodent models, estetrol has shown to elicit potent estrogenic activity on ovulation,[12] brain,[13] bone tissue,[14] cardiovascular system,[15] and uterus, associated with ovulation inhibition, prevention of bone demineralization, cardioprotective effects and maintenance of uterovaginal tissues, respectively.[15][16]

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.[11][17] This property of estetrol is associated with antagonistic effects on breast cell proliferation, migration and invasion in the presence of estradiol.[11][18]

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.[19]

Estetrol can therefore be described as the first Native Estrogen with Selective Tissue activity (NEST).[20][21]

Differences vs SERMs

[edit]

The selective tissue activity of estetrol is different from the effects of selective estrogen receptor modulators (SERMs), like tamoxifen and raloxifene.[22] 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.[22] Estetrol recruits the same co-regulators as other estrogens, while SERMs recruit other co-regulators.[21]

ERα activation

[edit]

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.[15]

Biochemistry

[edit]

Biosynthesis

[edit]

In the fetal liver, estetrol is synthesized from estradiol (E2) and estriol (E3) by two fetal liver enzymes, 15α- and 16α-hydroxylase, through hydroxylation.[23][24][25][26] Estetrol can be detected in maternal urine from the 9th week of gestation.[2][27][28] 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

[edit]

In terms of plasma protein binding, estetrol displays moderate binding to albumin, and shows no binding to SHBG.[29][30] The overall low plasma protein binding results in a ~50% free active fraction.[29] This compares to a 1% active form for EE and ~2% for estradiol.[31] Estetrol is equally distributed between red blood cells and plasma.[3]

Metabolism

[edit]

Cytochrome P450 (CYP) enzymes do not play a major role in the metabolism of estetrol.[8] Instead, estetrol undergoes extensive phase 2 metabolism in the liver to form glucuronide and sulphate conjugates.[8][10][32][33] The two main metabolites, estetrol-3-glucuronide and estetrol-16-glucuronide, have negligible estrogenic activity.[32][33] (see Drospirenone/estetrol)

Excretion

[edit]

Estetrol is mainly excreted in urine.[8][10] Estetrol is an end-stage product of metabolism, which is not converted back into active metabolites like estriol, estradiol or estrone.[9][29]

Chemistry

[edit]
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).[8][34] It is structurally different from the other estrogens because of the presence of four hydroxyl groups, which explains the abbreviation E4.[8][34]

Synthesis

[edit]

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%)[35] without contaminants.

History

[edit]

Estetrol was first described in 1965 by Egon Diczfalusy and coworkers at the Karolinska Institute in Stockholm, Sweden,[36][23][24][37] 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.[1][2] 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.[1][2] 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,[1] resulting in the introduction of E4 as the estrogenic component of a combined oral contraceptive in 2021.

References

[edit]
  1. ^ a b c d e f g h Holinka CF, Diczfalusy E, Coelingh Bennink HJ (May 2008). "Estetrol: a unique steroid in human pregnancy". The Journal of Steroid Biochemistry and Molecular Biology. 110 (1–2): 138–143. doi:10.1016/j.jsbmb.2008.03.027. PMID 18462934. S2CID 28007341.
  2. ^ a b c d e Yen SS, Jaffe RB, eds. (1991). Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management (3rd ed.). Copyright Elsevier/Saunders. pp. 936–981.
  3. ^ a b Fruzzetti F, Fidecicchi T, Montt Guevara MM, Simoncini T (November 2021). "Estetrol: A New Choice for Contraception". Journal of Clinical Medicine. 10 (23): 5625. doi:10.3390/jcm10235625. PMC 8658652. PMID 34884326.
  4. ^ Heikkilä J, Luukkainen T (June 1971). "Urinary excretion of estriol and 15 alpha-hydroxyestriol in complicated pregnancies". American Journal of Obstetrics and Gynecology. 110 (4): 509–21. doi:10.1016/0002-9378(71)90692-2. PMID 5582006.
  5. ^ Tulchinsky D, Frigoletto FD, Ryan KJ, Fishman J (April 1975). "Plasma estetrol as an index of fetal well-being". The Journal of Clinical Endocrinology and Metabolism. 40 (4): 560–7. doi:10.1210/jcem-40-4-560. PMID 805156.
  6. ^ Kundu N, Grant M (June 1976). "Radioimmunoassay of 15alpha-hydroxyestriol (estetrol) in pregnancy serum". Steroids. 27 (6): 785–96. doi:10.1016/0039-128x(76)90138-0. PMID 941193. S2CID 54373667.
  7. ^ Kundu N, Wachs M, Iverson GB, Petersen LP (September 1981). "Comparison of serum unconjugated estriol and estetrol in normal and complicated pregnancies". Obstetrics and Gynecology. 58 (3): 276–81. PMID 7266946.
  8. ^ a b c d e f g h i 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.
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