Review of the Effects of 17 Alpha-Estradiol in Humans: a Less Feminizing Estrogen with Neuroprotective Potential

Abstract

17α-Estradiol is a less feminizing isomer of the potent hormonal estrogen, 17β-estradiol. 17α-Estradiol is an orally active small molecule with conflicting reports of efficacy in preclinical models of degenerative diseases. A number of studies suggest neuroprotective potential in human neurodegenerative disorders, including Alzheimer’s disease (AD) and Parkinson’s disease. Several studies have established an antioxidant effect of 17α-estradiol in humans. The sodium salt of 17α-estradiol 3-sulfate is a minor component (2.5–9.5%) of several widely marketed estrogen hormone replacement products, such as Premarin^®, that are approved by the U.S. Food and Drug Administration and have been prescribed and studied in women and men for more than 65 years. Most of the more than 100 published reports on the neurological effects of feminizing estrogens found positive responses in at least one measure relating to cognition or prevention and treatment of AD, notwithstanding the negative results in the Women’s Health Initiative studies. Whether these limited, and often not statistically significant, findings are clinically meaningful remains unknown. In many in vitro and in vivo preclinical neuroprotection and related studies, 17α-estradiol and 17β-estradiol are active at similar concentrations and doses. However, 17α-estradiol is less pleiotropic than 17β-estradiol, and thus its potential toxicity might be lower. Given decades of mixed reports regarding the potential efficacy and safety of strongly feminizing hormones in neurodegenerative diseases, the weakly feminizing 17α-estradiol might be a suitable candidate for clinical testing of the neuroprotective potential of this chemical class because it avoids, or significantly reduces, the adverse effects of potent hormonal compounds. Drug Dev Res 70:1–21, 2009. © 2009 Wiley-Liss, Inc.