Background There is substantial evidence to support that sex hormone (SH) activity in the brain may result in some degree of neuroprotection through a genomic mechanism. Furthermore, it has been postulated that a decline in plasma and CSF SH levels (as is seen with aging) can lead to the loss of neuro-protective factors in the CNS. The loss of these trophic and protective factors could enhance the risk for neural degeneration (ND) frequently seen in elderly patients. Therefore, the SH mediated neuroprotection pathways in brain can be important potential pharmacologic targets for treating or mitigating age-related ND. Lee and McEwen (2001) proposed four possible mechanisms of SH action: (1) direct genomic, (2) indirect genomic, (3) nongenomic, and (4) antioxidant.
Objective To systematically review the literature to evaluate the evidence supporting each of the four proposed mechanisms of SH action in the CNS and to determine if any of these mechanisms provide neuroprotection to CNS cells.
Methods A literature synthesis was conducted to evaluate the potential mechanisms of SH action in the CNS.
Data Sources A database from 1966 to 2005 of published manuscripts was compiled using MEDLINE, PubMed, Web of Science, Cochrane Register, and by manual search. Key words used in the search included SH, estrogen, testosterone, neuroprotection, neurodegeneration, brain, aging, steroid, and neurotrophic.
Selection Criteria (1) Studies investigating either human or animal models, studying CNS neurons; (2) studies with quantitative data; (3) studies reporting sufficient methodological and descriptive information for systematic analysis; and (4) studies published in English.
Data Synthesis Descriptive and quantitative outcome variables from 17 manuscripts published between 1994-2005 were systematically summarized and graphically displayed. In addition, animal and human CNS neuronal cell line models were incorporated into a meta-model.
Conclusions The results of this review suggest that the direct genomic, indirect genomic and nongenomic mechanisms of SH action likely occur in vivo; however, there is little evidence to support that the antioxidant mechanism of SH action occurs endogenously. Further research is needed to determine if the indirect genomic and non-genomic mechanisms provide protection against toxic insults to CNS cells. Once this knowledge is obtained, it will provide insight for future research in targeted pharmacotherapy that can be designed to mimic endogenous SH concentrations to prevent/treat age-related ND.
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