Effect of High Testosterone Levels on Endothelial Function in Aorta and Erectile Function in Rats

Background: Testosterone is an important hormone for the physical and mental health of men; however testosterone administration has also been suggested to adversely affect the cardiovascular system. Aim: To investigate the effects of excessive testosterone administration on vascular endothelial and erectile function in rats. Methods: A total of seventy-five 12-week-old rats were divided into the following groups: Sham, castrated (Cast), castrated with subcutaneous administration of 100 mg/kg/month testosterone (Cast + T1), and castrated with subcutaneous administration of 100 mg/kg/week testosterone (Cast + T4). To observe the changes in testosterone level after the administration, rats were further divided into the following groups: control; T(6.25), wherein the rats were subcutaneously injected with 6.25 mg/kg testosterone; T(25) per week, wherein the rats were subcutaneously injected with 25 mg/kg testosterone per week; and T(100), wherein the rats were subcuta-neously injected with 100 mg/kg testosterone per week. The relaxation responses of aorta were measured in these rats using standardized methods, and their erectile function was also evaluated. Statistical analysis of the obtained data was performed using two-way analysis of variance (ANOVA), Tukey-Kramer's multiple comparison test, or Student's t-test. Outcomes: At the end of the study period, endothelial function was evaluated through measurement of isomet-ric tension, while erectile function was assessed using intracavernosal pressure (ICP), mean arterial pressure (MAP), and the expression of endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), sirtuin 1 (Sirt1) and vascular endothelial growth factor A. Results: The ICP/MAP ratio in the Cast group (0.42 +/- 0.04) was significantly lower than that in the Sham group (0.79 +/- 0.07). The ICP/MAP ratio in the Cast + T1 group (0.73 +/- 0.06) was significantly higher than that in the Cast group (P < .01) and that of the Cast + T4 (0.38 +/- 0.01) group was unchanged (P > .05). The T (25) and T(100) groups exhibited significantly lower responses to ACh than the control group at 4 weeks (P < .01). Meanwhile, the ICP/MAP ratios in the T(25) group (0.44 +/- 0.07) and T(100) group (0.47 +/- 0.03) were significantly lower than that in the control group (0.67 +/- 0.05) at stimulation frequencies of 16 Hz (P < .05). The expression of androgen receptor, Sirt1, and eNOS were significantly lower while that of iNOS was higher in the T(25) group compared with the control group (P < .05). Clinical Translation: The results based on this animal model indicate that extremely high testosterone levels may affect endothelial and erectile function. Strengths and Limitations: We found that high-dose testosterone administration decreased endothelial function in aorta and erectile function in rats. A major limitation of this study is that the blood concentration may not be representative of that in humans, and further research is needed. Conclusion: The findings suggest that high doses of testosterone may cause endothelial dysfunction in the aorta and erectile dysfunction in rats and that the blood concentration should be monitored after testosterone administration. Copyright (C) 2022 The Authors. Published by Elsevier Inc. on behalf of the International Society for Sexual Medicine.