| Summary: | High hepcidin is linked to low-grade inflammation and lower iron levels. The consequences of testosterone replacement therapy (TRT) on inflammation and the risk of cardiovascular disease (CVD) are undetermined. We investigate the effect of TRT on the inflammatory cardiovascular risk markers hepcidin-iron, fibroblast growth factor 23 (FGF23)-phosphate-klotho, and calprotectin pathways. Methods: A randomized, placebo-controlled, double-blinded study at an academic tertiary-care medical center. Interventions were testosterone gel (TRT, <i>n</i> = 20) or placebo gel (<i>n</i> = 19) for 24 weeks. We included 39 men (50–70 years) with type 2 diabetes (T2D) on metformin monotherapy with bioavailable testosterone levels <7.3 nmol/L. Body composition was assessed with DXA- and MRI-scans; the main study outcomes were serum hepcidin-iron, FGF23, phosphate, klotho, and calprotectin. Results: Hepcidin levels decreased during TRT (β = −9.5 ng/mL, <i>p</i> < 0.001), lean body mass (β = 1.9 kg, <i>p</i> = 0.001) increased, and total fat mass (β = −1.3 kg, <i>p</i> = 0.009) decreased compared to placebo. Delta hepcidin was not associated with changes in lean body mass or fat mass. Iron and the pathways of FGF23-phosphate-klotho and calprotectin were unchanged during TRT. Conclusions: During TRT, the reduction in hepcidin was not associated with circulating iron levels, lean body mass, or fat mass; these findings suggested a direct anti-inflammatory effect of TRT and no indirect effect mediated through these factors.
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