In the absence of controlled intervention studies and in view of the conflicting data presented above, it is difficult to predict the net effects of testosterone on cardiovascular disease. Further difficulties arise from the fact that associations found in observational studies do not prove causal relationships and that in theory several effects of testosterone on intermediate phenotypes can be exerted via either non-genomic or genomic mechanisms, the latter being mediated either directly via testosterone and dihydrotestosterone or indirectly via estradiol. Genetic studies on the associations or effects of genetic variation in the androgen receptor and estrogen receptors may answer these questions. In addition, variations in these genes as well in genes or enzymes (e.g. aromatase and 5a-reductase) and transport proteins (e.g. sex hormone binding globulin) regulating the bioavailability of these hormones may modulate the effects of testosterone.
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