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The increasing prevalence of obesity adds another dimension to the pathophysiology of testosterone (TEST) deficiency (TD) and potentially impairs the therapeutic efficacy of classical TEST replacement therapy. We investigated the therapeutic effects of selective androgen receptor modulation with trenbolone (TREN) in a model of TD with the metabolic syndrome (MetS). Male Wistar rats (n=50) were fed either a control standard rat chow (CTRL) or a high-fat/high-sucrose (HF/HS) diet. After 8 weeks of feeding, rats underwent sham surgery or an orchiectomy (ORX). Alzet miniosmotic pumps containing either vehicle, 2-mg/kg·d TEST or 2-mg/kg·d TREN were implanted in HF/HS+ORX rats. Body composition, fat distribution, lipid profile, and insulin sensitivity were assessed. Infarct size was quantified to assess myocardial damage after in vivo ischaemia reperfusion, before cardiac and prostate histology was performed. The HF/HS+ORX animals had increased sc and visceral adiposity; circulating triglycerides, cholesterol, and insulin; and myocardial damage, with low circulating TEST compared with CTRLs. Both TEST and TREN protected HF/HS+ORX animals against sc fat accumulation, hypercholesterolaemia, and myocardial damage. However, only TREN protected against visceral fat accumulation, hypertriglyceridaemia, and hyperinsulinaemia and reduced myocardial damage relative to CTRLs. TEST caused widespread cardiac fibrosis and prostate hyperplasia, which were less pronounced with TREN. We propose that TEST replacement therapy may have contraindications for males with TD and obesity-related MetS. TREN treatment may be more effective in restoring androgen status and reducing cardiovascular risk in males with TD and MetS.