17 Alpha-Estradiol: a Less-Feminizing Estrogen

Abstract

Alzheimer’s disease (AD) is a major neurodegenerative disorder in the elderly and is the most common form of dementia. Approved AD drugs like donepezil and memantine provide some cognitive benefits to a subset of patients. However, the cost burden of AD will continue to increase in the absence of more effective drugs that treat its symptoms and ultimately slow its progression or delay or prevent its onset. A substantial number of studies report that 17β-estradiol (E2; estrogen), a potent endogenous feminizing hormone, is neuroprotective. Unfortunately, negative results from the Women’s Health Initiative (WHI) and its ancillary Memory Study (WHIMS) have overshadowed the positive data collected over several decades. Importantly, there are a number of reasons why the WHIMS results should not be generalized to less- or non-feminizing estrogens. For the sake of argument, consider “non-hormonal” or non-feminizing estrogens to be worthwhile drug development candidates for AD and other neurodegenerative conditions because they have the potential to retain the positive neuroprotective activities of E2 while reducing the potential complications associated with feminizing hormones. Because the literature comparing estrogenicity of various estrogens is complex and spans multiple decades, we summarize herein the available hormonal comparisons of a common less-feminizing estrogen, 17α-estradiol (17αE2), with E2. 17αE2 is less feminizing than E2 in every published study where reasonable comparisons can be made. One-half of these studies report a difference of two orders of magnitude or greater. In practice, compounds like 17αE2 may prove to be largely non-feminizing at doses to be explored in human clinical trials. Moreover, other novel E2 analogues have been identified that are essentially devoid of feminizing actions. If the positive effects of feminizing estrogens on neurodegeneration prove useful in treating neurodegenerative diseases, less-feminizing and non-feminizing estrogen analogues may be even more effective, safer, and better tolerated.