Estriol

Estriol (E3), also spelled oestriol, is a steroid, a weak estrogen, and a minor female sex hormone.<ref name="pmid16112947">Template:Cite journal</ref><ref name="Puri2005">Template:Cite book</ref> It is one of three major endogenous estrogens, the others being estradiol and estrone.<ref name="pmid16112947" /> Levels of estriol in women who are not pregnant are almost undetectable.<ref name="IIIBarbieri2013">Template:Cite book</ref> However, during pregnancy, estriol is synthesized in very high quantities by the placenta and is the most produced estrogen in the body by far,< name="IIIBarbieri2013" /><ref name="Goodman2003">Template:Cite book</ref> although circulating levels of estriol are similar to those of other estrogens due to a relatively high rate of metabolism and excretion.<ref name="Goodman2003" /><ref name="(Prof.)2001" /> Relative to estradiol, both estriol and estrone have far weaker activity as estrogens.<ref name="pmid16112947" />

In addition to its role as a natural hormone, estriol is used as a medication, for instance in menopausal hormone therapy; for information on estriol as a medication, see the estriol (medication) article.

Biological activity

Estriol is an estrogen, specifically an agonist of the estrogen receptors ERα and ERβ.<ref name="pmid16112947" /><ref name="JaouenSalmain2015">Template:Cite book</ref><ref name="pmid16554039">Template:Cite journal</ref> It is a far less potent estrogen than is estradiol, and as such is a relatively weak estrogen.<ref name="pmid16112947" /><ref name="pmid16554039" /><ref name="LappanoRosano2010" /><ref name="Becker2001">Template:Cite book</ref> According to one in vitro study, the relative binding affinity (RBA) of estriol for the human ERα and ERβ was 11.3% and 17.6% of that estradiol, respectively, and the relative transactivational capacity of estriol at the ERα and ERβ was 10.6% and 16.6% of that of estradiol, respectively.<ref name="pmid16554039" /> According to another in vitro study however, the RBA of estriol for the ERα and ERβ were 14% and 21% of those of estradiol, respectively,<ref name="RubanyiKauffman2003">Template:Cite book</ref> suggesting that unlike estradiol and estrone, estriol may have preferential affinity for ERβ.<ref name="JaouenSalmain2015" />

Although estriol is an efficacious agonist of the ERs, it is reported to have mixed agonist–antagonist (partial agonist) activity at the ER; on its own, it is weakly estrogenic, but in the presence of estradiol, it is antiestrogenic.<ref name="LappanoRosano2010">Template:Cite journal</ref><ref name="Becker2001" /> Given by subcutaneous injection in mice, estradiol is about 10-fold more potent than estrone and about 100-fold more potent than estriol.<ref name="Labhart2012">Template:Cite book</ref><ref name="Blackburn2014">Template:Cite book</ref> It is notable that unlike estriol, estrone can be metabolized into estradiol, and most of its potency in vivo is in fact actually due to conversion into estradiol.<ref name="pmid16112947" />

In addition to acting as an agonist of the nuclear ERs, estriol at high concentrations (~1,000–10,000 nM) also acts as an antagonist of the GPER, a membrane estrogen receptor where, conversely, estradiol acts as an agonist.<ref name="pmid26023144">Template:Cite journal</ref><ref name="LappanoRosano2010" /><ref name="JaouenSalmain2015" /><ref name="GirgertEmons2014">Template:Cite journal</ref> Estradiol increases breast cancer cell growth via activation of the GPER (in addition to the ER), and estriol has been found to inhibit estradiol-induced proliferation of triple-negative breast cancer cells through blockade of the GPER.<ref name="GirgertEmons2014" />

Biochemistry

File:Steroidogenesis.svg

Human steroidogenesis, showing estriol at bottom right.<ref name="HäggströmRichfield2014">Template:Citation</ref> In essence, it follows the pathway from dehydroepiandrosterone or DHEA (at left), but with a modified DHEA with an additional OH-group.

Biosynthesis

In non-pregnant women

In women who are not pregnant estriol is produced in only very small quantities, and circulating levels are barely detectable.<ref name="IIIBarbieri2013" /> Unlike estradiol and estrone, estriol is not synthesized in or secreted from the ovaries,<ref name="JaypeeBrothers2006">Template:Cite bookTemplate:Dead link</ref> and is instead derived mainly if not exclusively from 16α-hydroxylation of estradiol and estrone by cytochrome P450 enzymes (e.g., CYP3A4) mainly in the liver.<ref name="HendersonPonder2003" /><ref name="Assali2013">Template:Cite book</ref> Estriol is cleared from the circulation rapidly in non-pregnant women, and so circulating levels are very low, but concentrations of estriol in the urine are relatively high.<ref name="HendersonPonder2003" />

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 of nulliparous women.<ref name="LappanoRosano2010" />

In pregnant women

Estriol is produced in quantities that are notable only during pregnancy.<ref name="IIIBarbieri2013" /> Levels of estriol increase 1,000-fold during pregnancy,<ref name="LappanoRosano2010" /> whereas levels of estradiol and estrone increase 100-fold,<ref name="Blackburn2014" /> and estriol accounts for 90% of the estrogens in the urine of pregnant women.<ref name="(Prof.)2001">Template:Cite book</ref> At term, the daily production of estriol by the placenta is 35 to 45 mg,<ref name="Blackburn2014" /> and levels in the maternal circulation are 8 to 13 ng/dL.<ref name="IIIBarbieri2013" />

The placenta produces pregnenolone and progesterone from circulating cholesterol.<ref name="Goodman2003"/> Pregnenolone is taken up by the fetal adrenal glands and converted into dehydroepiandrosterone (DHEA), which is then sulfated by steroid sulfotransferase into dehydroepiandrosterone sulfate (DHEA-S).Template:Citation needed DHEA-S is hydroxylated by high CYP3A7 expression and activity into 16α-hydroxy-DHEA-S (16α-OH-DHEA-S) in the fetal liver and to a limited extent in the fetal adrenal glands.<ref name="IIIBarbieri2013" /><ref name="Yamazaki2014">Template:Cite book</ref> 16α-OH-DHEA-S is then taken up by the placenta.<ref name="IIIBarbieri2013" /> Due to high expression of steroid sulfatase in the placenta, 16α-OH-DHEA-S is rapidly cleaved into 16α-OH-DHEA.<ref name="IIIBarbieri2013" /> Then, 16α-OH-DHEA is converted by 3β-hydroxysteroid dehydrogenase type I (3β-HSD1) into 16α-hydroxyandrostenedione (16α-OH-A4) and 16α-OH-A4 is converted by aromatase into 16α-hydroxyestrone (16α-OH-E1),<ref name="AcademicPress2005">Template:Cite book</ref> which is subsequently converted into estriol by 17β-hydroxysteroid dehydrogenase and then secreted predominantly into the maternal circulation.<ref name="IIIBarbieri2013" /><ref name="HendersonPonder2003">Template:Cite book</ref> Approximately 90% of precursors in estriol formation originate from the fetus.<ref name="HendersonPonder2003" />

During pregnancy, 90 to 95% of estriol in the maternal circulation is conjugated in the form of estriol glucuronide and estriol sulfate, and levels of unconjugated estriol are slightly less than those of unconjugated estradiol and similar to those of unconjugated estrone.<ref name="(Prof.)2001" /> As such, target tissues are likely to be exposed to similar amounts of free estriol, estradiol, and estrone during pregnancy.<ref name="(Prof.)2001" />

Estrone and estradiol are also produced in the placenta during pregnancy.<ref name="IIIBarbieri2013" /> However, in the case of estrone and estradiol, DHEA-S is taken up by the placenta and cleaved by steroid sulfatase into dehydroepiandrosterone (DHEA), DHEA is converted by 3β-hydroxysteroid dehydrogenase type I into androstenedione, and androstenedione is aromatized into estrone.<ref name="IIIBarbieri2013" /> Then, placental 17β-hydroxysteroid dehydrogenase interconverts estrone and estradiol and the two hormones are secreted into the maternal circulation.<ref name="IIIBarbieri2013" /> DHEA-S that is taken up by the placenta is mainly produced by the fetal adrenal glands.<ref name="IIIBarbieri2013" />

Distribution

Estriol is poorly bound to sex hormone-binding globulin (SHBG),<ref name="Buchsbaum2012">Template:Cite book</ref> with much lower binding affinity for this protein, relative to estradiol, and hence a greater fraction available for biological activity.<ref name="LorenzoHorowitz2015">Template:Cite book</ref>

Metabolism

Estriol is metabolized via glucuronidation and sulfation.<ref name="OettelSchillinger2012" /><ref name="MuseyKirdani1973" />

Excretion

The main urinary metabolites of exogenous estriol administered via intravenous injection in baboons have been found to be estriol 16α-glucuronide (65.8%), estriol 3-glucuronide (14.2%), estriol 3-sulfate (13.4%), and estriol 3-sulfate 16α-glucuronide (5.1%).<ref name="OettelSchillinger2012">Template:Cite book</ref><ref name="MuseyKirdani1973">Template:Cite journal</ref> The metabolism and excretion of estriol in these animals closely resembled that which has been observed in humans.<ref name="MuseyKirdani1973" /> 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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Medical use

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Estriol is used as a medication, primarily in hormone therapy for menopausal symptoms.<ref name="pmid16112947" />

Chemistry

Estriol, also known as 16α-hydroxyestradiol or as estra-1,3,5(10)-triene-3,16α,17β-triol, is a naturally occurring estrane steroid with double bonds between the C1 and C2, C3 and C4, and C5 and C10 positions and hydroxyl groups at the C3, C16α, and C17β positions.<ref name="Elks2014">Template:Cite book</ref><ref name="IndexNominum2000">Template:Cite book</ref> The name estriol and the abbreviation E3 were derived from the chemical terms estrin (estra-1,3,5(10)-triene) and triol (three hydroxyl groups).

History

Estriol was discovered in 1930.<ref name="Josimovich2013">Template:Cite book</ref><ref name="SartorelliJohns2013">Template:Cite book</ref> It was isolated and purified from the urine of pregnant women by Marrian and colleagues.<ref name="Josimovich2013" /><ref name="SartorelliJohns2013" />

Use in screening

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 like Down syndrome or Edward's syndrome. It is included as part of the triple test and quadruple test<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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 a nonstress test. Conditions which can create false positives and false negatives in estriol testing for fetal distress include preeclampsia, anemia, and impaired kidney function.<ref name="isbn0-323-05747-0">Template:Cite book</ref>

Further reading

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