In vivo and in vitro estrogenic profile of 17β-amino-1,3,5(10)estratrien-3-ol.

Abstract 17β-amino-1,3,5(10)estratrien-3-ol (17βAE 2 ), is the 17β-aminoestrogens prototype possessing anticoagulant activity, contrasting with the procoagulant effects of 17β-estradiol (17βE 2 ). Its estrogenicity profile has not been reported, and it was evaluated by uterotrophic assay, estrogen receptor binding affinity and its ability to induce gene transcription of the human estrogen receptor (hER)α mediated in a Saccharomyces cerevisiae yeast expression system. Additionally, 17βAE 2 and 17αAE 2 were compared with 17βE 2 in HeLa cells co-transfected with expression vectors for hERα or hERβ subtypes and for an estrogen-responsive reporter gene. Immature female CD1 mice and Wistar rats (21 days old) were treated for three days with 17βAE 2 (10–5000 μg/kg), 17βE 2 (0.001–1000 μg/kg) or vehicle (propylenglycol 10 ml/kg) and uterine weights were estimated. 17βAE 2 increased uterine weight in a dose-dependent manner. The effective dose (ED) 50 uterine weight values: 17βAE 2  = 552 and 764 μg/kg (17βE 2  = 4.8 and 16 μg/kg) and their relative uterotrophic potency were 0.86 and 2.1 (17βE 2  = 100) in mice and rats, respectively. 17βAE 2 competed with [ 3 H]E 2 for the estrogen receptor. The 17βAE 2 relative binding affinities (RBAs) were: 0.074; K i  = 2.2 × 10 −6  M (17βE 2  = 100; K i  = 1.6 × 10 −9  M); 0.029 and K i  = 3.8 × 10 −6  M (17βE 2  = 100; K i  = 1.1 × 10 −9  M) for mice and rats uteri respectively. 17βAE 2 activated hERα-mediated β-galactosidase transcription activity in the yeast system co-transfected with hERα gene. 17βAE 2 effective concentration (EC) 50  = 1.82 μM (17βE 2  = 2.14 nM) with a relative potency of 0.12 (17βE 2  = 100). These transactivation effects were abolished by the antagonist fulvestrant (ICI 182,780), similarly to 17βE 2 . 17βAE 2 and 17αAE 2 bind with low relative affinity to hERα and hERβ. Both induced hER-mediated reporter gene transactivation in a dose-response manner. The overall results provide evidence that 17βAE 2 has a weak agonist estrogenic action greatly mediated through the hERβ and to a lesser extent the hERα at genomic level.