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Estriol ( E3), also spelled oestriol, is a steroid, a weak estrogen, and a minor female sex hormone. It is one of three major endogenous estrogens, the others being estradiol and estrone. Levels of estriol in women who are not pregnancy are almost undetectable. However, during pregnancy, estriol is synthesized in very high quantities by the placenta and is the most produced estrogen in the body by far, although circulating levels of estriol are similar to those of other estrogens due to a relatively high rate of metabolism and excretion. Relative to estradiol, both estriol and estrone have far weaker activity as estrogens.
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.
Although estriol is an efficacy 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 . Given by subcutaneous injection in mice, estradiol is about 10-fold more potent than estrone and about 100-fold more potent than estriol. It is notable that unlike estriol, estrone can be metabolism into estradiol, and most of its potency in vivo is in fact actually due to conversion into estradiol.
In addition to acting as an agonist of the nuclear receptor 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. 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.
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 nulliparity women.
The placenta produces pregnenolone and progesterone from circulating cholesterol. Pregnenolone is taken up by the fetal and converted into dehydroepiandrosterone (DHEA), which is then sulfation by steroid sulfotransferase into dehydroepiandrosterone sulfate (DHEA-S). DHEA-S is hydroxylation 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. 16α-OH-DHEA-S is then taken up by the placenta. Due to high expression of steroid sulfatase in the placenta, 16α-OH-DHEA-S is rapidly cleaved into 16α-OH-DHEA. 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), which is subsequently converted into estriol by 17β-hydroxysteroid dehydrogenase and then secreted predominantly into the maternal circulation. Approximately 90% of precursors in estriol formation originate from the fetus.
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. As such, target tissues are likely to be exposed to similar amounts of free estriol, estradiol, and estrone during pregnancy.
Estrone and estradiol are also produced in the placenta during pregnancy. 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. Then, placental 17β-hydroxysteroid dehydrogenase interconverts estrone and estradiol and the two hormones are secreted into the maternal circulation. DHEA-S that is taken up by the placenta is mainly produced by the fetal adrenal glands.
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.
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