2026 Volume 90 Issue 5 Pages 549-558
Background: Previous clinical studies reported that testosterone replacement therapy unexpectedly increased cardiovascular (CV) events in elderly men, through an unknown underlying mechanism. Because nitric oxide (NO) production is reduced in elderly men, we hypothesized that testosterone exerts harmful CV effects under reduced NO production, and examined this hypothesis using a 2/3 nephrectomized triple neuronal/inducible/endothelial NO synthases (NOS)-knockout (NX-TKO) mouse model that causes death from myocardial infarction (MI).
Methods and Results: The survival rate was markedly worse in male NX-TKO mice than in male NX-wild-type (NX-WT) mice. Orchiectomy (ORX) significantly aggravated the survival rate in NX-WT mice, but significantly improved it in NX-TKO mice. In the NX-TKO-ORX mice, long-term subcutaneous treatment with testosterone significantly deteriorated the survival rate, the incidence of MI, and CV risk factors. Furthermore, testosterone-induced aortic relaxations were significantly more impaired in the TKO than in the WT mice. RNA sequencing in the hearts of TKO-ORX mice without and with testosterone treatment indicated possible involvements of immunity- and inflammation-mediated mechanisms in the harmful CV effects of testosterone.
Conclusions: These results provide the first evidence that testosterone exerts harmful CV effects, including shorter survival, increased incidence of MI, impaired arterial relaxation, and exacerbated cardiovascular risk factors, in the absence of NOS in mice. Our findings may explain in part why testosterone replacement therapy increases CV events in elderly men.
