Testosterone improved the erectile dysfunction induced by anti-cancer agent doxolubicine in rats

Abstract

ABSTRACT Introduction Many chemotherapeutic agents are administered to cancer patients worldwide. We previously reported at the world meeting on Sexual Medicine 2018 that doxorubicin (DOX) increased the risk of erectile dysfunction (ED) according to our analyses of the US Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) database. We also reported that DOX decreased erectile function in a study using rats. DOX also decreased rat testosterone levels. These studies suggest a need for a new treatment method for ED associated with anticancer drug treatment. Objective To investigate the effect of testosterone administration on DOX-induced ED in rats. Methods Twelve-week-old male Wistar ST rats were separated into Control, DOX, and DOX+T groups. DOX (3 mg/kg) was intravenously administered on days 1, 8, 15, and 22 in the DOX and DOX+T groups. Testosterone undecanoate (25 mg/kg) was administered to DOX+T rats on day 1. Erectile function was tested using ICP measurements, and endothelial function was tested by assessing isometric tension. Oxidative stress (NADPH oxidase), inflammation (IL-6), and smooth muscle factor (α-SMA, Cavin-1, and Cavin-2) mRNA expression levels were tested using real-time PCR. Results After the 4-week observation period, the ICP/MAP ratio in the DOX group (0.32 ± 0.03) was significantly decreased compared to the Control group (0.72 ± 0.05) (P <0.01). The ICP/MAP ratio in the DOX + T group (0.61 ± 0.07) was increased significantly compared to the DOX group (P <0.01). According to isometric tension measurements, reactivity to acetylcholine was significantly lower in the DOX group (35.0 ± 5.1%) than in the control group (77.6 ± 7.9%), whereas reactivity in the DOX + T group (69.8 ± 8.5%) was significantly improved (P <0.05). NADPH oxidase-1 and IL-6 mRNA levels were increased in the DOX group compared to the Control group (P <0.01), and levels were decreased relative to the DOX group in the DOX+T group. α-SMA, Cavin-1, and Cavin-2 mRNA levels were decreased in the DOX group compered to the Control group. These levels were improved in the DOX+T group. Conclusions We have demonstrated in rats that androgen replacement therapy may mitigate ED induced by DOX administration. We hypothesize that administration of testosterone improves smooth muscle function and vascular endothelial cell function by suppressing oxidative stress and inflammatory response in the corpus cavernosum, and maintaining normal levels of caveolin-related factors. When androgen deficiency symptoms are observed due to administration of anticancer drugs such as DOX, androgen replacement therapy is expected to be one viable treatment option. Our study sheds light on possible treatment strategies for improving quality of life for cancer survivors. Disclosure Work supported by industry: no.