PURPOSE: We compare the efficacy of testosterone gel (T-gel) versus placebo as adjunctive therapy to tadalafil in hypogonadal men with erectile dysfunction who do not respond to tadalafil alone. We have recently shown that, in men with erectile dysfunction (ED), free testosterone (FT) directly correlates with penile arterial inflow. Laboratory experiments indicate that the nitric oxide erectile pathway is testosterone-dependent. Castration induces erectile dysfunction (ED) and reduction in nitric oxide synthase and in phosphodiesterase type 5 (PDE5) in the erectile tissue. Furthermore, castration causes apoptosis adversely affecting smooth muscle content and penile hemodynamics leading to veno-occlusive dysfunction. Testosterone therapy reverses these structural, biochemical, and physiological changes. In humans, testosterone therapy improves erectile function in men with hypogonadism. However, the efficacy of testosterone monotherapy may not be adequate because of the multifactorial nature of the pathophysiology of ED.This led us to further investigate the effect(s) of androgen administration on cavernous arteries in patients failing tadalafil treatment.

MATERIALS AND METHODS: A randomized, placebo controlled, double-blind, parallel group, multicenter study was performed. All patients with arteriogenic ED as evaluated by dynamic colour duplex ultrasound (D-CDU) studies, normal sexual desire but testosterone (T) and FT in the lower quartile of normal range (low-normal), not responding to tadalafil treatment (10mg) on six consecutive attempts.

MEASUREMENTS: All patients had D-CDU, hormonal [LH, prostate-specific antigen (PSA), total and free testosterone, sex hormone-binding protein (SHBG), oestradiol], biochemical [haematocrit, low-density lipoprotein (LDL) and HDL cholesterol, triglycerides], and sexual evaluations [International Index of Erectile Function (IIEF)] before and after 1 month of therapy with transdermal testosterone (5 mg/day, n = 10) or placebo along with tadalafil treatment on demand. Measurement of flow parameters by D-CDU on cavernous arteries was the primary endpoint of the study. Improvement of erectile function was assessed using the IIEF questionnaire and the Global Assessment Question (GAQ).  A total of 75 hypogonadal men (18 to 80 years old, morning serum total testosterone 400 ng/dl or less) with confirmed lack of response to tadalafil monotherapy were randomized (1:1) to receive a daily dose of 1% T-gel or 5 gm placebo gel as adjunctive therapy to 10 mg tadalafil during a 12-week period. Subjects were evaluated for sexual function, primarily based on the International Index of Erectile Function (IIEF), quality of life and serum testosterone levels at baseline and weeks 4, 8 and 12.

 RESULTS: Testosterone treated subjects had greater improvement in erectile function compared to those who received placebo, reaching statistical significance at week 4 (4.4 vs 2.1, p = 0.029, 95.1% CI 0.3, 4.7). Similar trends were observed for improvements in orgasmic function, overall satisfaction, total IIEF score and percentage of IIEF responders. T-gel significantly (p < or =0.004) increased total and free testosterone levels throughout the study, although no significant correlations were made between testosterone levels and the IIEF at end point. In addition testosterone administration induced a significant increase in arterial inflow to cavernous arteries measured by D-CDU (32 +/- 3.6 vs. 25.2 +/- 4 cm/s, P < 0.05), with no adverse effects. Also, a significant improvement in erectile function domain score at IIEF was found in the androgen but not in the placebo-treated patients (21.8 +/- 2.1 vs. 14.4 +/- 1.4, P < 0.05) which was associated with significant changes in the GAQ score (80%vs. 10%, P < 0.01).

CONCLUSIONS: T-gel taken with tadalafil may be beneficial in improving erectile function in hypogonadal men with erectile dysfunction who are unresponsive to tadalafil alone. In patients with arteriogenic ED and low-normal androgen levels, short-term testosterone administration increases T and FT levels and improves the erectile response to tadalafil likely by increasing arterial inflow to the penis during sexual stimulation. It is important to screen all men with ED for hypogonadism, especially those with a history of inadequate response to prior PDE5 inhibitors. The combination of testosterone plus PDE5 inhibitors may be considered for the treatment of ED in men with low to low-normal testosterone levels, who had inadequate response to prior treatment with PDE5 inhibitors alone. So, in hypogonadal patients with ED, androgen supplementation is first-line therapy. If patients are unresponsive to androgen alone or tadalafil alone, combined use may improve erectile function and enhance the therapeutic effect of PDE-5 inhibitors.

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