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| Names | |
|---|---|
| IUPAC name Estra-1,3,5(10)-triene-3,16α,17β-triol | |
| Systematic IUPAC name (1R,2R,3aS,3bR,9bS,11aS)-11a-Methyl-2,3,3a,3b,4,5,9b,10,11,11a-decahydro-1H-cyclopenta[a]phenanthrene-1,2,7-triol | |
| Other names Oestriol; E3; Estratriol; Theelol; Trihydroxyestrin; Trihydroxyoestrin; 16α-Hydroxyestradiol | |
| Identifiers | |
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3D model (JSmol) | |
| ChEBI | |
| ChEMBL | |
| ChemSpider | |
| ECHA InfoCard | 100.000.021 |
| KEGG | |
| UNII | |
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| Properties | |
| C18H24O3 | |
| Molar mass | 288.387 g/mol |
Except where otherwise noted, data are given for materials in theirstandard state (at 25 °C [77 °F], 100 kPa). | |
Estriol (E3), also spelledoestriol, is asteroid, a weakestrogen, and a minor femalesex hormone.[1][2] It is one of three majorendogenous estrogens, the others beingestradiol andestrone.[1] Levels of estriol in women who are notpregnant are almost undetectable.[3] However, during pregnancy, estriol is synthesized in very high quantities by theplacenta and is the most produced estrogen in the body by far,[3][4] although circulating levels of estriol are similar to those of other estrogens due to a relatively high rate ofmetabolism andexcretion.[4][5] Relative to estradiol, both estriol and estrone have far weaker activity as estrogens.[1]
In addition to its role as a natural hormone, estriol is used as amedication, for instance inmenopausal hormone therapy; for information on estriol as a medication, see theestriol (medication) article.
Estriol is an estrogen, specifically anagonist of theestrogen receptorsERα andERβ.[1][6][7] It is a far lesspotent estrogen than is estradiol, and as such is a relatively weak estrogen.[1][7][8][9] According to onein vitro study, therelative binding affinity (RBA) of estriol for the human ERα and ERβ was 11.3% and 17.6% of that of estradiol, respectively, and therelative transactivational capacity of estriol at the ERα and ERβ was 10.6% and 16.6% of that of estradiol, respectively.[7] According to anotherin vitro study however, the RBA of estriol for the ERα and ERβ were 14% and 21% of those of estradiol, respectively,[10] suggesting that unlike estradiol and estrone, estriol may have preferentialaffinity for ERβ.[6]
Although estriol is anefficacious agonist of the ERs, it is reported to have mixedagonist–antagonist (partial agonist) activity at the ER; on its own, it is weakly estrogenic, but in the presence of estradiol, it isantiestrogenic.[8][9] Given bysubcutaneous injection in mice, estradiol is about 10-fold more potent than estrone and about 100-fold more potent than estriol.[11][12] It is notable that unlike estriol, estrone can bemetabolized into estradiol, and most of its potencyin vivo is in fact actually due to conversion into estradiol.[1]
In addition to acting as an agonist of thenuclear ERs, estriol at high concentrations (~1,000–10,000 nM) also acts as anantagonist of theGPER, amembrane estrogen receptor where, conversely, estradiol acts as an agonist.[13][8][6][14] Estradiol increasesbreast cancer cell growth via activation of the GPER (in addition to the ER), and estriol has been found to inhibit estradiol-induced proliferation oftriple-negative breast cancer cells through blockade of the GPER.[14]
| Estrogen | ERTooltip Estrogen receptorRBATooltip relative binding affinity (%) | Uterine weight (%) | Uterotrophy | LHTooltip Luteinizing hormone levels (%) | SHBGTooltip Sex hormone-binding globulinRBATooltip 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.ERRBA =Relative binding affinity toestrogen receptors of ratuterinecytosol. Uterine weight = Percentage change in uterine wet weight ofovariectomized rats after 72 hours with continuous administration of 1 μg/hour viasubcutaneously implantedosmotic 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., notendogenous).b = Atypical uterotrophic effect which plateaus within 48 hours (estradiol's uterotrophy continues linearly up to 72 hours).Sources:[15][16][17][18][19][20][21][22][23] | |||||
In women who are not pregnant estriol is produced in only very small quantities, and circulating levels are barely detectable.[3] Unlike estradiol and estrone, estriol is not synthesized in or secreted from the ovaries,[25] and is instead derived mainly if not exclusively from 16α-hydroxylation of estradiol and estrone bycytochrome P450enzymes (e.g.,CYP3A4) mainly in theliver.[26][27] Estriol is cleared from thecirculation rapidly in non-pregnant women, and so circulating levels are very low, but concentrations of estriol in theurine are relatively high.[26]
Although circulating levels of estriol are very low outside of pregnancy,parous women have been found to have levels of estriol that are to some degree higher than those ofnulliparous women.[8]
Estriol is produced in quantities that are notable only duringpregnancy.[3] Levels of estriol increase 1,000-fold during pregnancy,[8] whereas levels of estradiol and estrone increase 100-fold,[12] and estriol accounts for 90% of the estrogens in the urine of pregnant women.[5] At term, the daily production of estriol by the placenta is 35 to 45 mg,[12] and levels in the maternal circulation are 8 to 13 ng/dL.[3]
Theplacenta producespregnenolone andprogesterone from circulatingcholesterol.[4] Pregnenolone is taken up by the fetaladrenal glands and converted intodehydroepiandrosterone (DHEA), which is thensulfated bysteroid sulfotransferase intodehydroepiandrosterone sulfate (DHEA-S).[citation needed] DHEA-S ishydroxylated by highCYP3A7 expression and activity into16α-hydroxy-DHEA-S (16α-OH-DHEA-S) in the fetalliver and to a limited extent in the fetal adrenal glands.[3][28] 16α-OH-DHEA-S is then taken up by the placenta.[3] Due to high expression ofsteroid sulfatase in the placenta, 16α-OH-DHEA-S is rapidly cleaved into16α-OH-DHEA.[3] Then, 16α-OH-DHEA is converted by3β-hydroxysteroid dehydrogenasetype I (3β-HSD1) into16α-hydroxyandrostenedione (16α-OH-A4) and 16α-OH-A4 is converted byaromatase into16α-hydroxyestrone (16α-OH-E1),[29] which is subsequently converted into estriol by17β-hydroxysteroid dehydrogenase and then secreted predominantly into the maternal circulation.[3][26] Approximately 90% of precursors in estriol formation originate from the fetus.[26]
During pregnancy, 90 to 95% of estriol in the maternal circulation isconjugated in the form ofestriol glucuronide andestriol sulfate, and levels of unconjugated estriol are slightly less than those of unconjugated estradiol and similar to those of unconjugated estrone.[5] As such, target tissues are likely to be exposed to similar amounts of free estriol, estradiol, and estrone during pregnancy.[5]
Estrone andestradiol are also produced in the placenta during pregnancy.[3] However, in the case of estrone and estradiol, DHEA-S is taken up by the placenta and cleaved by steroid sulfatase intodehydroepiandrosterone (DHEA), DHEA is converted by3β-hydroxysteroid dehydrogenasetype I intoandrostenedione, and androstenedione is aromatized into estrone.[3] Then, placental17β-hydroxysteroid dehydrogenase interconverts estrone and estradiol and the two hormones are secreted into the maternal circulation.[3] DHEA-S that is taken up by the placenta is mainly produced by the fetal adrenal glands.[3]
Estriol is poorly bound tosex hormone-binding globulin (SHBG),[30] with much lowerbinding affinity for this protein, relative to estradiol, and hence a greater fraction available forbiological activity.[31]
Estriol ismetabolized viaglucuronidation andsulfation.[32][33]
The mainurinarymetabolites ofexogenous estriol administered viaintravenous injection inbaboons have been found to beestriol 16α-glucuronide (65.8%),estriol 3-glucuronide (14.2%),estriol 3-sulfate (13.4%), andestriol 3-sulfate 16α-glucuronide (5.1%).[32][33] Themetabolism andexcretion of estriol in these animals closely resembled that which has been observed in humans.[33] In non-pregnant women, estriol urinary excretion ranges between 0.02–0.1 mg every 24 hours. In comparison, in near-term pregnant women, estriol urinary excretion ranges from 50–150 mg every 24 hours.[34]
Estriol is used as amedication, primarily inhormone therapy formenopausalsymptoms.[1]
Estriol, also known as 16α-hydroxyestradiol or as estra-1,3,5(10)-triene-3,16α,17β-triol, is anaturally occurringestranesteroid withdouble bonds between the C1 and C2, C3 and C4, and C5 and C10 positions andhydroxyl groups at the C3, C16α, and C17β positions.[35][36] The nameestriol and the abbreviationE3 were derived from the chemical termsestrin (estra-1,3,5(10)-triene) andtriol (three hydroxyl groups).
Estriol was discovered in 1930.[37][38] It was isolated and purified from theurine of pregnant women by Marrian and colleagues.[37][38]
Estriol can be measured in maternal blood or urine and can be used as a marker of fetal health and well-being. If levels of unconjugated estriol (uE3 or free estriol) are abnormally low in a pregnant woman, this may indicate chromosomal or congenital anomalies likeDown syndrome orEdward's syndrome. It is included as part of thetriple test andquadruple test[39] for antenatal screening for fetal anomalies.
Because many pathological conditions in a pregnant woman can cause deviations in estriol levels, these screenings are often seen as less definitive of fetal-placental health than anonstress test. Conditions which can createfalse positives andfalse negatives in estriol testing for fetal distress includepreeclampsia,anemia, and impairedkidney function.[40]
