Estetrol (E4), or oestetrol, is a weak estrogensteroid hormone which is found in detectable levels only during pregnancy. It is produced exclusively by the fetalliver. Estetrol is closely related to estriol, which is also a weak estrogen that is found in high quantities only during pregnancy. Along with estradiol (E2), estrone (E1), and estriol (E3), estetrol is a major estrogen in the body, although only during pregnancy.
Estetrol is an estrogen and has estrogenic effects in various tissues. 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.
Estetrol is an agonist of the estrogen receptors (ERs), and hence is an estrogen. It has moderate affinity for the ERα and ERβ, with Ki values of 4.9 nM and 19 nM, respectively. As such, estetrol has 4- to 5-fold preference for the ERα over the ERβ. 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. The affinity of estetrol for the ERs is about 0.3% (rat) to 6.25% (human) of that of estradiol, and its in vivopotency in animals is about 2 to 3% of that of estradiol. Estetrol shows high selectivity for the ERs.
Estetrol is synthesized during pregnancy only in the fetalliver from estradiol (E2) and estriol (E3) by the two enzymes 15α- and 16α-hydroxylase. Alternatively, estetrol is synthesized with 15α-hydroxylation of 16α-hydroxy-DHEA sulfate as an intermediate step. It appears in maternal serum at around week 9 of pregnancy. 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. 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.
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