Non-feminizing estrogens: A novel neuroprotective therapy

• Estrogen therapy is associated with an increased incidence of stroke and breast cancer.
• Numerous experimental studies support the neuroprotective role of estrogens.
• Non-feminizing estrogens may offer an alternative strategy with minimal side effects.
• Non-feminizing estrogens are protective in experimental models of stroke, AD, and TBI.

While the conflict between basic science evidence for estrogen neuroprotection and the lack of effectiveness in clinical trials is only now being resolved, it is clear that strategies for estrogen neuroprotection that avoid activation of ERs have the potential for clinical application. Herein we review the evidence from both in vitro and in vivo studies that describe high potency neuroprotection with non-feminizing estrogens. We have characterized many of the essential chemical features of non-feminizing estrogens that eliminate or reduce ER binding while maintaining or enhancing neuroprotection. Additionally, we provide evidence that these non-feminizing estrogens have efficacy in protecting the brain from AD neuropathology and traumatic brain injury. In conclusion, it appears that the non-feminizing estrogen strategy for neuroprotection is a viable option to achieve the beneficial neuroprotective effects of estrogens while eliminating the toxic off-target effects of chronic estrogen administration.