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As CYP mono\u2010oxygenases activity is frequently altered during disease, we tested our hypothesis that CYP mono\u2010oxygenase expression and testosterone metabolism are altered in cardiac hypertrophy. We investigate major CYP mono\u2010oxygenase isoforms and other steroid\u2010metabolizing enzymes and the androgen receptor in normal, hypertrophic, and assist device\u2010supported human hearts and in spontaneously hypertensive rats (SHR). We show increased and idiosyncratic metabolism of testosterone in hypertrophic heart and link these changes to altered CYP mono\u2010oxygenase expression. We show significant induction of 5\u2010alpha steroid reductase and P450 aromatase gene expression and enhanced production of dihydrotestosterone, which can be inhibited by the 5\u2010alpha reductase inhibitor finasteride. We show increased gene expression of the androgen receptor and increased levels of lipid peroxidation in diseased hearts, the latter being markedly inhibited by CYP mono\u2010oxygenase inactivation. We show alpha\u2010MHC to be significantly repressed in cardiac hypertrophy and restored to normal on testosterone supplementation. We conclude that heart\u2010specific steroid metabolism is of critical importance in cardiac hypertrophy.\u2014Thum, T., Borlak, J. 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