Estriol

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Estriol
Estriol.svg
Estriol-3D-model.png
Clinical data
Pronunciation /ˌɛstrl/ ES-TRYE-ohl[citation needed]
Trade names Ovestin, others[1]
Synonyms 16α-Hydroxyestradiol; Estra-1,3,5(10)-triene-3,16α,17β-triol
Routes of
administration
Oral, vaginal
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Biological half-life 5 hours[2]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.000.021
Chemical and physical data
Formula C18H24O3
Molar mass 288.39 g·mol−1
3D model (JSmol)
  (verify)

Estriol (E3), also spelled oestriol, is a steroid, a weak estrogen, and a minor female sex hormone.[3][4] It is one of three major endogenous estrogens, the others being estradiol and estrone.[3] Levels of estriol in women who are not pregnant are almost undetectable.[5] However, during pregnancy, estriol is synthesized in very high quantities by the placenta and is the most produced estrogen in the body by far,[5][6] although circulating levels of estriol are similar to those of other estrogens due to a relatively high rate of metabolism and excretion.[6][7] Relative to estradiol, both estriol and estrone have far weaker activity as estrogens.[3] Although it is less commonly used than other estrogens, estriol is available for medical use throughout the world in a variety of formulations, including for oral and vaginal administration.[3]

Biological activity[edit]

Estriol is an estrogen, specifically an agonist of the estrogen receptors ERα and ERβ.[3][8][9] It is a far less potent estrogen than is estradiol, and as such is a relatively weak estrogen.[3][9][10][11] 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 estrone at the ERα and ERβ was 10.6% and 16.6% of that of estradiol, respectively.[9] 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,[12] suggesting that unlike estradiol and estrone, estriol may have preferential affinity for ERβ.[8]

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 estradiol, it is antiestrogenic.[10][11] Relative to estradiol, the esstrogenic potency of estriol and estrone have been reported to be 80- and 12-fold lower than that of estradiol, respectively.[13] 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.[3]

In addition to acting as an agonist of the nuclear ERs, estriol also acts as an antagonist of the GPER at high concentrations, a membrane estrogen receptor where, conversely, estradiol acts as an agonist.[10][8][14] 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.[14]

Biochemistry[edit]

Human steroidogenesis, showing estriol at bottom right.[15] In essence, it follows the pathway from dehydroepiandrosterone or DHEA (at left), but with a modified DHEA with an additional OH-group.

Biosynthesis[edit]

In women who are not pregnant estriol is produced in only very small quantities, and circulating levels are in fact barely detectable.[5] Unlike estradiol and estrone, estriol is not synthesized in or secreted from the ovaries,[16] 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.[17][18] 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.[17]

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.[10]

In pregnant women[edit]

Estriol is produced in quantities that are notable only during pregnancy.[5] Levels of estriol increase 1,000-fold during pregnancy,[10] whereas levels of estradiol and estrone increase 100-fold,[13] and estriol accounts for 90% of the estrogens in the urine of pregnant women.[7] At term, the daily production of estriol by the placenta is 35 to 45 mg,[13] and levels in the maternal circulation are 8 to 13 ng/dL.[5]

The placenta produces pregnenolone and progesterone from circulating cholesterol.[6] 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).[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.[5][19] 16α-OH-DHEA-S is then taken up by the placenta.[5] Due to high expression of steroid sulfatase in the placenta, 16α-OH-DHEA-S is rapidly cleaved into 16α-OH-DHEA.[5] 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),[20] which is subsequently converted into estriol by 17β-hydroxysteroid dehydrogenase and then secreted predominantly into the maternal circulation.[5][17] Approximately 90% of precursors in estriol formation originate from the fetus.[17]

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.[7] As such, target tissues are likely to be exposed to similar amounts of free estriol, estradiol, and estrone during pregnancy.[7]

Estrone and estradiol are also produced in the placenta during pregnancy.[5] 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.[5] Then, placental 17β-hydroxysteroid dehydrogenase interconverts estrone and estradiol and the two hormones are secreted into the maternal circulation.[5] DHEA-S that is taken up by the placenta is mainly produced by the fetal adrenal glands.[5]

Distribution[edit]

Estriol is poorly bound to sex hormone-binding globulin (SHBG),[21] with much lower binding affinity for this protein, relative to estradiol, and hence a greater fraction available for biological activity.[22]

Metabolism and excretion[edit]

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%).[23][24] The metabolism and excretion of estriol in these animals closely resembled that which has been observed in humans.[24]

Medical use[edit]

Estriol is marketed widely in Europe and elsewhere throughout the world under the brand names Ovestin, Ortho-Gynest, and a variety of others.[1] It is available in oral tablet, vaginal cream, and vaginal suppository form, and is used in hormone replacement therapy for menopausal symptoms.[25] Estriol is also available in some countries as estriol succinate (brand name Synapause), a dosage-equivalent ester prodrug of estriol.[1][26][27] Estriol and estriol succinate are not approved for use in the United States and Canada, although they have been produced and sold by compounding pharmacies in North America for use as a component of bioidentical hormone replacement therapy.[citation needed] In addition, topical creams containing estriol are not regulated in the U.S. and are available over-the-counter.[citation needed]

Chemistry[edit]

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.[26][1] 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).

Analogues[edit]

A variety of analogues of estriol are known, including both naturally occurring isomers and synthetic substituted derivatives and esters.[26][1] 16β-Epiestriol, 17α-epiestriol, and 16β,17α-epiestriol are isomers of estriol that are endogenous weak estrogens.[26] Mytatrienediol (16α-methyl-16β-epiestriol 3-methyl ether) is a synthetic derivative of 16β-epiestriol that was never marketed.[26] Estriol diacetate benzoate, estriol succinate, estriol sodium succinate, and estriol tripropionate are synthetic esters of estriol that have been marketed for medical use, whereas estriol triacetate has not been introduced.[26][1] Quinestradol is the 3-cyclopentyl ether of estriol and has also been marketed.[26][1] These esters and ethers are prodrugs of estriol. Ethinylestriol and nilestriol are synthetic C17α ethynylated derivatives of estriol.[26][1] Ethinylestriol has not been marketed, but nilestriol, which is the 3-cyclopentyl ether of ethinylestriol and a prodrug of it, has been.[26][1]

History[edit]

Estriol was discovered in 1930.[28][29] It was isolated and purified from the urine of pregnant women by Marrian and colleagues.[28][29]

Society and culture[edit]

Generic name[edit]

Estriol is the generic name of estriol in American English and its INN, USP, BAN, DCF, and JAN.[26][1][30][31] It is pronounced /ˌɛstrl/ ES-TRYE-ohl.[citation needed] Estriolo is the name of estriol in Italian[31] and estriolum is its name in Latin, whereas its name remains unchanged as estriol in Spanish, Portuguese, French, and German.[31][1] Oestriol, in which the "O" is silent, was the former BAN of estriol and its name in British English,[26][30][1] but the spelling was eventually changed to estriol.[31]

Brand names[edit]

Estriol is or has been marketed under a variety of brand names throughout the world, including Aacifemine, Blissel, Colpogyn, Elinol, Estriel, Estriol, Estriosalbe, Estrokad, Evalon, Gelistrol, Gydrelle, Gynasan, Gynest, Incurin (veterinary), OeKolp, Oestro-Gynaedron, Orgestriol, Ortho-Gynest, Ovesterin, Ovestin, Ovestinon, Ovestrion, Pausanol, Physiogine, Sinapause, Synapause, Trophicreme, and Vacidox, among others.[1][31]

Use in screening[edit]

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 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.[32]

Research[edit]

Multiple sclerosis[edit]

Estriol was found in a study to noticeably reduce the symptoms of multiple sclerosis in pregnant women with the disease.[33]

References[edit]

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