Evidence‐based neuroprotective potential of nonfeminizing estrogens: In vitro and in vivo studies

Menopause weakens the brain's structural integrity and increases its susceptibility to a range of degenerative and mental illnesses. 17β estradiol (17βE2) exhibits potent neuroprotective properties. Exogenous estrogen supplementation provides neuroprotection, but the findings presented by the Million Women Study (MWS) and the Women's Health Initiative (WHI), as well as the increased risk of endometrial cancer, breast cancer and venous thromboembolism associated with estrogen use, have cast doubt on its clinical use for neurological disorders. Thus, the objective of our review article is to compile all in vitro and in vivo studies conducted till date demonstrating the neuroprotective potential of nonfeminizing estrogens. This objective has been achieved by gathering various research and review manuscripts from different records such as PubMed, Embase, Scopus, Google Scholar, Web of Science and OVID, using different terms like ‘estrogen deficiency, 17β estradiol, non‐feminising estrogens, and brain disorder’. However, recent evidence has revealed the contribution of numerous non‐estrogen receptor‐dependent pathways in neuroprotective effects of estrogen. In conclusion, synthetic nonfeminizing estrogens that have little or no ER binding but are equally powerful (and in some cases more potent) in delivering neuroprotection are emerging as viable and potential alternatives. Menopause weakens the brain's structural integrity and increases its susceptibility to a range of degenerative and mental illnesses. 17β estradiol (17βE2) exhibits potent neuroprotective properties. Exogenous estrogen supplementation provides neuroprotection, but the findings presented by the Million Women Study (MWS) and the Women's Health Initiative (WHI), as well as increased risk of endometrial cancer, breast cancer and venous thromboembolism associated with estrogen use, have casted doubt on its clinical use for neurological disorders. Large number of in vitro and few in vivo studies clearly demonstrate receptor‐independent neuroprotective effect of nonfeminizing estrogens ZYC23, ZYC26, prolame, 17αE2, Ent‐17βE2 and so forth. These nonfeminizing estrogens did not affect peripherally hence may prove to be safe alternative of estrogen therapies (17β estradiol), which acts via binding with estrogen receptors.