Pharmacokinetics and pharmacodynamics of a novel estrogen Δ 8-estrone in postmenopausal women and men

Abstract

Recently a tenth equine estrogen, identified as the sulfate ester of Δ 8-estrone has been reported to be present in Premarin (a conjugated equine estrogen preparation), and because of its unique ring B unsaturated structure (conjugated double bond in the B ring), we have, in the present study, determined its pharmacokinetics in postmenopausal women and men, its interaction with uterine estrogen receptors and its uterotropic activity. After the administration of [ 14C]Δ 8-estrone, blood was drawn at various time intervals, and the plasma fractionated into the unconjugated sulfate and glucuronide fractions. The disappearance of radioactivity as Δ 8-estrone from plasma can be described as a function of two exponentials. The half-lives of the first and second components were 5±0.2 and 40.4 min, respectively. The mean metabolic clearance rate calculated (MCR), was 1711±252 l/d m 2. From the unconjugated fraction, Δ 8-17 β-estradiol was also isolated and identified. From the sulfate conjugated fraction, Δ 8-estrone sulfate and Δ 8-17 β-estradiol sulfate were isolated in almost equal amounts. No other metabolites of Δ 8-estrone was detectable in the plasma. Both Δ 8-estrone and Δ 8-17 β-estradiol bind with human endometrial and rat uterine estrogen receptors with high affinity. The binding affinities of Δ 8-17 β-estradiol for human endometrial and rat uterine cytoplasmic receptors were 4 and 25 times higher than those of the parent estrogen Δ 8-estrone, respectively. Administration of Δ 8-estrone and Δ 8-17 β-estradiol (2 μg/100 g body weight) to immature rats significantly ( P<0.05) increased the uterine weight compared to the controls. These data demonstrate that Δ 8-estrone has estrogenic activity, and that it is further metabolized in man to a single more potent estrogen, Δ 8-17 β-estradiol. The extent of this activation by 17 β-reduction appears to be greater than that observed with other estrogens. Both estrogens circulate as sulfate conjugates and are very slowly eliminated from the circulation. These data further suggest that Δ 8-estrone and its major metabolite Δ 8-17 β-estradiol can contribute to the overall in vivo biological effects of Premarin.