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Skeletal formula of estetrol
Ball-and-stick model of the estetrol molecule
IUPAC name
Other names
Oestetrol; E4; 15α-Hydroxyestriol; Estra-1,3,5(10)-triene-3,15α,16α,17β-tetrol
3D model (JSmol)
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).
Infobox references

Estetrol (E4), or oestetrol, is a weak estrogen steroid hormone which is found in detectable levels only during pregnancy.[1][2] It is produced exclusively by the fetal liver.[1] Estetrol is closely related to estriol, which is also a weak estrogen that is found in high quantities only during pregnancy.[1][2] Along with estradiol (E2), estrone (E1), and estriol (E3), estetrol is a major estrogen in the body, although only during pregnancy.[1]

In addition to its role as a natural hormone, estetrol is under clinical development for use as a medication, for instance in menopausal hormone therapy; for information on estetrol as a medication, see the estetrol (medication) article.

Biological function

Estetrol is an estrogen and has estrogenic effects in various tissues.[1] 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.[3][4][5][6][7]

Biological activity

Estetrol is an agonist of the estrogen receptors (ERs), and hence is an estrogen.[8][9] It has moderate affinity for the ERα and ERβ, with Ki values of 4.9 nM and 19 nM, respectively.[8][10] As such, estetrol has 4- to 5-fold preference for the ERα over the ERβ.[8][10] 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.[8] 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 in animals is about 2 to 3% of that of estradiol.[8] Estetrol shows high selectivity for the ERs.[8][10]



Estetrol is synthesized during pregnancy only in the fetal liver from estradiol (E2) and estriol (E3) by the two enzymes 15α- and 16α-hydroxylase.[11][12][13] Alternatively, estetrol is synthesized with 15α-hydroxylation of 16α-hydroxy-DHEA sulfate as an intermediate step.[14] It appears in maternal serum at around week 9 of pregnancy.[2] After birth the neonatal liver rapidly loses its capacity to synthesize estetrol 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.[15][16] During the second trimester of pregnancy high levels were found in maternal plasma, with steadily rising concentrations of unconjugated estetrol to about 1 ng/mL (>3 nM) towards the end of pregnancy.[1]


In terms of plasma protein binding, estetrol is moderately bound to albumin, and is not bound to sex hormone-binding globulin (SHBG).[17][18]


Estetrol is metabolized minimally, if at all.[8] It is conjugated via glucuronidation and to a lesser extent sulfation and then excreted.[8][19]


Estetrol is excreted mostly or completely in urine.[19][8]


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 a naturally occurring estrane steroid and derivative of estrin (estratriene).[8][9] It has four hydroxyl groups, which explains the abbreviation E4.[8][9]


Chemical syntheses of estetrol have been published.[20]


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.[8][21]


  1. ^ a b c d e f 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.
  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. ^ J. Heikkilä, T. Luukkainen, Urinary excretion of estriol and 15a-hydroxyestriol in complicated pregnancies, Am. J. Obstet. Gynecol. 110 (1971) 509-521.
  4. ^ 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
  5. ^ A.D. Notation, G.E. Tagatz, Unconjugated estriol and 15a-hydroxyestriol in complicated pregnancies, Am. J. Obstet. Gynecol. 128 (1977) 747-756.
  6. ^ N. Kundu, M. Grant, Radioimmunoassay of 15a-hydroxyestriol (estetrol) in pregnancy serum, Steroids 27 (1976) 785-796.
  7. ^ 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.
  8. ^ a b c d e f g h i j k l 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.
  9. ^ 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.
  10. ^ a b c 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.
  11. ^ 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
  12. ^ J. Schwers, M. Govaerts-Videtsky, N. Wiqvist, E. Diczfalusy, Metabolism of oestrone sulphate by the previable human foetus, Acta Endocrinol. 50 (1965) 597-610.
  13. ^ 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.
  14. ^ Jerome Frank Strauss; Robert L. Barbieri (2009). Yen and Jaffe's Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management. Elsevier Health Sciences. pp. 262–. ISBN 1-4160-4907-X.
  15. ^ J. Heikkilä, H. Adlercreutz, A method for the determination of urinary 15α-hydroxyestriol and estriol, J. Steroid Biochem. 1 (1970) 243-253
  16. ^ J. Heikkilä, Excretion of 15α-hydroxyestriol and estriol in maternal urine during normal pregnancy, J. Steroid Biochem. 2 (1971) 83-93.
  17. ^ Visser M, Holinka CF, Coelingh Bennink HJ (2008). "First human exposure to exogenous single-dose oral estetrol in early postmenopausal women". Climacteric. 11 Suppl 1: 31–40. doi:10.1080/13697130802056511. PMID 18464021.
  18. ^ Hammond GL, Hogeveen KN, Visser M, Coelingh Bennink HJ (2008). "Estetrol does not bind sex hormone binding globulin or increase its production by human HepG2 cells". Climacteric. 11 Suppl 1: 41–6. doi:10.1080/13697130701851814. PMID 18464022.
  19. ^ a b Mawet M, Maillard C, Klipping C, Zimmerman Y, Foidart JM, Coelingh Bennink HJ (2015). "Unique effects on hepatic function, lipid metabolism, bone and growth endocrine parameters of estetrol in combined oral contraceptives". Eur J Contracept Reprod Health Care. 20 (6): 463–75. doi:10.3109/13625187.2015.1068934. PMC 4699469. PMID 26212489.
  20. ^ Warmerdam EG, Visser M, Coelingh Bennink HJ, Groen M (2008). "A new route of synthesis of estetrol". Climacteric. 11 Suppl 1: 59–63. doi:10.1080/13697130802054078. PMID 18464024.
  21. ^ Hagen AA, Barr M, Diczfalusy E (June 1965). "Metabolism of 17-beta-oestradiol-4-14-C in early infancy". Acta Endocrinol. 49: 207–20. doi:10.1530/acta.0.0490207. PMID 14303250.