Further research should also explore alternatives to oestradiol therapy. In addition to new SERMs that may activate the multiple neuroprotective mechanisms of action of ERs, another promising therapeutic avenue for brain diseases is the development of selective neuroprotective ERα, ERβ and GPER ligands139,140. In addition, as local oestradiol synthesis in the brain is neuroprotective, studies should be directed to understand the mechanisms that regulate aromatase expression in the brain. The human aromatase gene promoter region is highly complex, with promoters that are used with tissue specificity141. Thus, aromatase tissue-specific regulation by natural or synthetic compounds opens the possibil¬ity for selective modulation of oestrogen biosynthesis within the human brain142.