estetrol

Estetrol
	IUPAC name (8R,9S,13S,14S,15R,16R,17R)-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3,15,16,17-tetrol
Identifiers
CAS number	15183-37-6
PubChem	27125
ChemSpider	25245
Jmol-3D images	Image 1; Image 2
	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 Oc1cc3c(cc1)[C@H]2CC[C@@]4([C@@H](O)[C@H](O)[C@H](O)[C@H]4[C@@H]2CC3)C ;
	InChI 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 InChI=1/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-NYLIRDPKBD ;
Properties
Molecular formula	C18H24O4
Molar mass	304.38 g/mol
	(verify) (what is: /?); Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
	Infobox references

エステトロール

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2012/11/07 22:57:27」(JST)

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[Wiki en表示]

Estetrol (E4), or 15α-hydroxyestriol, is an estrogen steroid hormone, found in detectable levels in maternal serum at around week 20.^[1]

Estetrol is a human steroid, produced by the fetal liver during pregnancy only. This natural hormone was discovered in urine of pregnant women by Diczfalusy and coworkers in 1965.^[2] Estetrol has the structure of an estrogenic steroid with four hydroxyl groups which explains the acronym E4. Estetrol is synthesized in the fetal liver from estradiol (E2) and estriol (E3) by the two enzymes 15α- and 16α-hydroxylase.^[3]^[4]^[5] After birth the neonatal liver rapidly looses its capacity to synthesize E4 because these two enzymes are no longer expressed.

Estetrol reaches the maternal circulation through the placenta and was already detected at nine weeks of pregnancy in maternal urine.^[6]^[7] During the second trimester of pregnancy high levels were found in maternal plasma, with steadily rising concentrations of unconjugated E4 to about 1 ng/mL (> 3 nmol/L) towards the end of pregnancy.^[8]^[9] So far the physiological function of E4 is unknown. The possible use of E4 as a marker for fetal well-being has been studied quite extensively. However, due to the large intra- and inter-individual variation of maternal E4 plasma levels during pregnancy this appeared not to be feasible.^[10]^[11]^[12]^[13]^[14]

Since 2001 E4 has been studied extensively. High oral absorption and bioavailability with a 2–3 hours elimination half-life in the rat has been established.^[15] In the human E4 showed a high and dose-proportional oral bioavailability and a long terminal elimination half-life of about 28 hours.^[16]

Results from in vitro studies showed that E4 binds highly selective to the estrogen receptors with preference for the ERα form of the receptor unlike ethinyl estradiol (EE) and 17β-estradiol (E2).^[17] Also in contrast with EE and especially with E2, E4 does not bind to sex hormone binding globulin (SHBG) and does not stimulate the production of SHBG in vitro.^[18]

The properties of E4 have also been investigated in a series of highly predictive, well validated pharmacological in vivo rat models. In these models, E4 exhibited estrogenic effects on the vagina, the uterus (both myometrium and endometrium), body weight, bone mass, bone strength, hot flushes and on ovulation (inhibition).^[19]^[20]^[21]^[22] All these effects of E4 were dose-dependent with maximal effects at comparable dose levels. Surprisingly, E4 prevented tumour development in a DMBA mammary tumour model to an extent and at a dose level similar to the anti-estrogen tamoxifen and to ovariectomy.^[23] This anti-estrogenic effect of E4 in the presence of E2 has also been observed in in vitro studies using human breast cancer cells [in-house data Pantarhei Bioscience B.V., The Netherlands].

The data indicate that E4 may be suitable for use in several indications e.g. contraception, hormone replacement therapy (both vasomotor symptoms and vulvar vaginal atrophy), breast cancer and osteoporosis. Estetrol is being developed as estrogenic component in the oral contraceptive pill by Estetra (Belgium). Pantarhei Bioscience B.V. (The Netherlands) is developing estetrol for hormone replacement therapy, breast cancer and osteoporosis.

References

^ Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management, 3rd ed., SSC Yen and RB Jaffe (eds.), pp. 936–981, Copyright Elsevier/Saunders 1991
^ A.A. Hagen, M. Barr, E. Diczfalusy, Metabolism of 17b-oestradiol-4-14C in early infancy, Acta Endocrinol. 49 (1965) 207-220.
^ 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
^ J. Schwers, M. Govaerts-Videtsky, N. Wiqvist, E. Diczfalusy, Metabolism of oestrone sulphate by the previable human foetus, Acta Endocrinol. 50 (1965) 597-610.
^ 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.
^ J. Heikkilä, H. Adlercreutz, A method for the determination of urinary 15α-hydroxyestriol and estriol, J. Steroid Biochem. 1 (1970) 243-253
^ J. Heikkilä, Excretion of 15α-hydroxyestriol and estriol in maternal urine during normal pregnancy, J. Steroid Biochem. 2 (1971) 83-93.
^ C.F. Holinka, E. Diczfalusy, H.J.T. Coelingh Bennink, Estetrol: a unique steroid in human pregnancy, J. Steroid Biochem. Mol. Biol. 110 (2008) 138-143
^ F. Coelingh Bennink, C.F. Holinka, M. Visser, H.J.T. Coelingh Bennink, Maternal and fetal estetrol levels during pregnancy, Climacteric 11 (Suppl 1) (2008) 69-72.
^ J. Heikkilä, T. Luukkainen, Urinary excretion of estriol and 15a-hydroxyestriol in complicated pregnancies, Am. J. Obstet. Gynecol. 110 (1971) 509-521.
^ 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
^ A.D. Notation, G.E. Tagatz, Unconjugated estriol and 15a-hydroxyestriol in complicated pregnancies, Am. J. Obstet. Gynecol. 128 (1977) 747-756.
^ N. Kundu, M. Grant, Radioimmunoassay of 15a-hydroxyestriol (estetrol) in pregnancy serum, Steroids 27 (1976) 785-796.
^ 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.
^ H.J.T. Coelingh Bennink, A.M. Heegaard, M. Visser, C.F. Holinka, C. Christiansen, Oral bioavailability and bone-sparing effects of estetrol in an osteoporosis model, Climacteric 11 (Suppl 1) (2008) 2-14.
^ M. Visser, C.F. Holinka, H.J.T. Coelingh Bennink, First human exposure to exogenous oral estetrol in early postmenopausal women, Climacteric 11 (Suppl 1) (2008) 31-40.
^ M. Visser, J.-M. Foidart, H.J.T. Coelingh Bennink, In vitro effects of estetrol on receptor binding, drug targets and human liver cell metabolism, Climacteric 11 (Suppl 1) (2008) 64-68.
^ G. Hammond, K. Hogeveen, M. Visser, H.J.T. Coelingh Bennink, Estetrol does not bind sex hormone binding globulin or increase its production by human HepG2 cells. Climacteric 11 (Suppl 1) (2008) 41-46.
^ C.F. Holinka, M. Brincat, H.J.T. Coelingh Bennink, Preventive effect of oral estetrol in a menopausal hot flush model, Climacteric 11 (Suppl 1) (2008) 15-21.
^ A.M. Heegaard, C.F. Holinka, P. Kenemans, H.J.T. Coelingh Bennink, Estrogenic uterovaginal effects of oral estetrol in the modified Allen-Doisy test, Climacteric 11 (Suppl 1) (2008) 22-28.
^ H.J.T. Coelingh Bennink, S. Skouby, P. Bouchard, C.F. Holinka, Ovulation inhibition by estetrol in an in vivo model, Contraception 77(3) (2008) 186-190.
^ H.J.T. Coelingh Bennink, S. Skouby, P. Bouchard, C.F. Holinka, Ovulation inhibition by estetrol in an in vivo model, Climacteric 11 (Suppl 1) (2008) 30 (a summary from Contraception 77(3) (2008) 186-190).
^ H.J.T. Coelingh Bennink, Singer C, Simoncini T, Genazzani AR, Holinka CF, Kubista E, Estetrol, a pregnancy-specific human steroid, prevents and suppresses mammary tumor growth in a rat model. Climacteric 11 (Suppl 1) (2008) 29.

English Journal

Vasorelaxing effects of estetrol in rat arteries.

Hilgers RH, Oparil S, Wouters W, Coelingh Bennink HJ.SourceDivision of Cardiovascular Disease, Department of Medicine, Vascular Biology and Hypertension Program, University of Alabama at Birmingham, Birmingham, Alabama 35294-0007, USA.
The Journal of endocrinology.J Endocrinol.2012 Oct;215(1):97-106. doi: 10.1530/JOE-12-0009. Epub 2012 Jul 13.
This study compared ex vivo relaxing responses to the naturally occurring human hormone estetrol (E(4)) vs 17β-estradiol (E(2)) in eight different vascular beds. Arteries were mounted in a myograph, contracted with either phenylephrine or serotonin, and cumulative concentration-response curves (CRC
PMID 22798015

Temperature-controlled micro-TLC: a versatile green chemistry and fast analytical tool for separation and preliminary screening of steroids fraction from biological and environmental samples.

Zarzycki PK, Slączka MM, Zarzycka MB, Bartoszuk MA, Włodarczyk E, Baran MJ.SourceSection of Toxicology and Bioanalytics, Department of Civil and Environmental Engineering, Koszalin University of Technology, Śniadeckich 2, 75-453 Koszalin, Poland. pkzarz@wp.pl
The Journal of steroid biochemistry and molecular biology.J Steroid Biochem Mol Biol.2011 Nov;127(3-5):418-27. doi: 10.1016/j.jsbmb.2011.05.007. Epub 2011 Jun 6.
This paper is a continuation of our previous research focusing on development of micro-TLC methodology under temperature-controlled conditions. The main goal of present paper is to demonstrate separation and detection capability of micro-TLC technique involving simple analytical protocols without mu
PMID 21669284

Japanese Journal

エストロゲン--エストロン(E1),エストラジオール(E2),エストリオール(E3)およびエステトロール(E4) (広範囲血液・尿化学検査免疫学的検査(第7版・4)その数値をどう読むか) -- (内分泌学的検査性線・胎盤関係)

清水幸子
日本臨床 68(-) (982), 448-461, 2010-07
NAID 40017200784

胎児胎盤機能検査におけるDHAS負荷の臨床的意義に関する研究 : とくにDHASの胎児・胎盤系におけるestrogen代謝に及ぼす効果について

喜里山隆之
日本産科婦人科學會雜誌 38(5), 700-708, 1986-05-01
… Dehydroepiandrosterone-sulfate(DHAS)負荷時の胎児胎盤系におけるestrogen代謝に及ぼす影響を検討するために、妊娠末期正常妊婦および選択的帝王切開例を対象とし、DHAS100mg1回静注後の経時的母体静脈血(MV)、膀帯動脈血(UA)、膀帯静脈血(UV)および羊水(AF)中のunconjugatedestrone(E_1)、estradiol(E_2)、estriol(E_3)、estetrol(E_4)を測定し、以下の成績を得た。 …
NAID 110002221531

Related Pictures

[0] Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management, 3rd ed., SSC Yen and RB Jaffe (eds.), pp. 936–981, Copyright Elsevier/Saunders 1991

[1] A.A. Hagen, M. Barr, E. Diczfalusy, Metabolism of 17b-oestradiol-4-14C in early infancy, Acta Endocrinol. 49 (1965) 207-220.

[2] 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

[3] J. Schwers, M. Govaerts-Videtsky, N. Wiqvist, E. Diczfalusy, Metabolism of oestrone sulphate by the previable human foetus, Acta Endocrinol. 50 (1965) 597-610.

[4] 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.

[5] J. Heikkilä, H. Adlercreutz, A method for the determination of urinary 15α-hydroxyestriol and estriol, J. Steroid Biochem. 1 (1970) 243-253

[6] J. Heikkilä, Excretion of 15α-hydroxyestriol and estriol in maternal urine during normal pregnancy, J. Steroid Biochem. 2 (1971) 83-93.

[7] C.F. Holinka, E. Diczfalusy, H.J.T. Coelingh Bennink, Estetrol: a unique steroid in human pregnancy, J. Steroid Biochem. Mol. Biol. 110 (2008) 138-143

[8] F. Coelingh Bennink, C.F. Holinka, M. Visser, H.J.T. Coelingh Bennink, Maternal and fetal estetrol levels during pregnancy, Climacteric 11 (Suppl 1) (2008) 69-72.

[9] J. Heikkilä, T. Luukkainen, Urinary excretion of estriol and 15a-hydroxyestriol in complicated pregnancies, Am. J. Obstet. Gynecol. 110 (1971) 509-521.

[10] 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

[11] A.D. Notation, G.E. Tagatz, Unconjugated estriol and 15a-hydroxyestriol in complicated pregnancies, Am. J. Obstet. Gynecol. 128 (1977) 747-756.

[12] N. Kundu, M. Grant, Radioimmunoassay of 15a-hydroxyestriol (estetrol) in pregnancy serum, Steroids 27 (1976) 785-796.

[13] 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.

[14] H.J.T. Coelingh Bennink, A.M. Heegaard, M. Visser, C.F. Holinka, C. Christiansen, Oral bioavailability and bone-sparing effects of estetrol in an osteoporosis model, Climacteric 11 (Suppl 1) (2008) 2-14.

[15] M. Visser, C.F. Holinka, H.J.T. Coelingh Bennink, First human exposure to exogenous oral estetrol in early postmenopausal women, Climacteric 11 (Suppl 1) (2008) 31-40.

[16] M. Visser, J.-M. Foidart, H.J.T. Coelingh Bennink, In vitro effects of estetrol on receptor binding, drug targets and human liver cell metabolism, Climacteric 11 (Suppl 1) (2008) 64-68.

[17] G. Hammond, K. Hogeveen, M. Visser, H.J.T. Coelingh Bennink, Estetrol does not bind sex hormone binding globulin or increase its production by human HepG2 cells. Climacteric 11 (Suppl 1) (2008) 41-46.

[18] C.F. Holinka, M. Brincat, H.J.T. Coelingh Bennink, Preventive effect of oral estetrol in a menopausal hot flush model, Climacteric 11 (Suppl 1) (2008) 15-21.

[19] A.M. Heegaard, C.F. Holinka, P. Kenemans, H.J.T. Coelingh Bennink, Estrogenic uterovaginal effects of oral estetrol in the modified Allen-Doisy test, Climacteric 11 (Suppl 1) (2008) 22-28.

[20] H.J.T. Coelingh Bennink, S. Skouby, P. Bouchard, C.F. Holinka, Ovulation inhibition by estetrol in an in vivo model, Contraception 77(3) (2008) 186-190.

[21] H.J.T. Coelingh Bennink, S. Skouby, P. Bouchard, C.F. Holinka, Ovulation inhibition by estetrol in an in vivo model, Climacteric 11 (Suppl 1) (2008) 30 (a summary from Contraception 77(3) (2008) 186-190).

[22] H.J.T. Coelingh Bennink, Singer C, Simoncini T, Genazzani AR, Holinka CF, Kubista E, Estetrol, a pregnancy-specific human steroid, prevents and suppresses mammary tumor growth in a rat model. Climacteric 11 (Suppl 1) (2008) 29.

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