Estetrol

Estetrol

Clinical data
Routes of administration	Oral
Legal status
Legal status	US: Investigational New Drug
Pharmacokinetic data
Biological half-life	28 hours
Identifiers
IUPAC name (8R,9S,13S,14S,15R,16R,17R)-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3,15,16,17-tetrol
Synonyms	E4; 15α-Hydroxyestriol; Estra-1,3,5(10)-triene-3,15α,16α,17β-tetrol; Donesta; Estelle
CAS Number	15183-37-6 Y
PubChem CID	27125
ChemSpider	25245 Y
UNII	ENB39R14VF
Chemical and physical data
Formula	C18H24O4
Molar mass	304.38 g/mol
3D model (JSmol)	Interactive image
SMILES C[C@]12CC[C@H]3[C@H]([C@@H]1[C@H]([C@H]([C@@H]2O)O)O)CCC4=C3C=CC(=C4)O
InChI InChI=1S/C18H24O4/c1-18-7-6-12-11-5-3-10(19)8-9(11)2-4-13(12)14(18)15(20)16(21)17(18)22/h3,5,8,12-17,19-22H,2,4,6-7H2,1H3/t12-,13-,14-,15-,16-,17+,18+/m1/s1 Y Key:AJIPIJNNOJSSQC-NYLIRDPKSA-N Y

Estetrol (E4) is a weak estrogen steroid hormone which is found in detectable levels only during pregnancy. It 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.

The data indicate that E4 may be suitable for use in several indications e.g. contraception, hormone replacement therapy (both vasomotor symptoms and vulvar vaginal atrophy), breast cancer, prostate cancer and osteoporosis. Estetrol is being developed as estrogenic component in the oral contraceptive pill (as estetrol/drospirenone) and for hormone replacement therapy by Mithra Pharmaceuticals (Belgium). Pantarhei Oncology B.V. (The Netherlands) is developing estetrol for the treatment of breast cancer and prostate cancer.

Estetrol is synthesized during pregnancy only in the fetal liver 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 E4 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 E4 to about 1 ng/mL (> 3 nmol/L) towards the end of pregnancy. So far the physiological function of E4 is unknown. The possible use of E4 as a marker for fetal well-being has been studied quite extensively. However, due to the large intra- and inter-individual variation of maternal E4 plasma levels during pregnancy this appeared not to be feasible.