The assessment of non-feminizing estrogens for use in neuroprotection.
Menopause is associated with a precipitous decline in circulating estrogens and a resulting loss of the neuroprotective actions of this steroid hormone. In view of the results of the Women's Health Initiative and the preceding knowledge that orally administered estrogens has a variety of adverse side effects, likely through actions on peripheral estrogen receptor alpha (ERα), we initiated a program of research to synthesis and assess a group of non-feminizing estrogens that lack ability to interact with ERs but retain much of the neuroprotective action of feminizing estrogens. This program of research is aimed at the identification of compounds which do not stimulate ERs but are potentially neuroprotective in vitro and in animal models of neuronal cell death. We discovered that the most effective non-feminizing estrogens were those with large bulky groups in the 2 and/or 4 carbon of the phenolic A ring of the steroid. These compounds were 8- to 114-fold more potent than 17 β-estradiol (βE2), but lacked ER binding capacity in vitro and feminizing effects in vivo. The success of this program of research suggests that strategies to optimize non-feminizing estrogens for use in postmenopausal women can be successful.
Institute for Aging and Alzheimer's Disease Research, Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
Kun Don
KD
Yi
Evelyn
E
Perez
Shaohua
S
Yang
Ran
R
Liu
Douglas F
DF
Covey
James W
JW
Simpkins
D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004958:Estradiol / Q000737:chemistry / Q000494:pharmacology; D004967:Estrogens / Q000737:chemistry* / Q000494:pharmacology*; D005260:Female; D006801:Humans; D018696:Neuroprotective Agents / Q000737:chemistry* / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000819:agonists / Q000502:physiology
D004967:Estrogens; D018696:Neuroprotective Agents; D011960:Receptors, Estrogen; D004958:Estradiol