Combined therapy with testosterone and phosphodiesterase type 5 inhibitors in patients with erectile dysfunction

Oral therapy with inhibitors of the phosphodiesterase type 5, e.g. sildenafil, varde-nafil, and tadalafil, is highly effective for therapy of erectile dysfunction (Shabsigh and Anastasiadis 2003). However, in placebo-controlled phase III clinical trials and post-marketing evaluation approximately 15 to 40% of patients do not respond to this medication. There is some evidence that patients with erectile dysfunction and testosterone deficiency respond poorly to therapy with phosphodiesterase type 5 inhibitors (Guay etal. 2001; Shabsigh 2003).

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Fig. 11.2 Blood flow parameters of the cavernous arteries assessed by duplex sonography after a standardized pharmacostimulation of erection with 10 ^g prostaglandin E1. PSV, peak systolic velocity; EDV, end diastolic velocity; RI, resistance index; open bars, baseline values; grey bars, placebo plus sildenafil group; filled bars, testosterone plus sildenafil group (modified with permission from Aversa etal. 2003, copyright 2003, Blackwell Publishing).

Two prospective, randomized placebo-controlled studies have been performed recently to test whether testosterone substitution can improve the response to sildenafil in patients with erectile dysfunction and testosterone serum levels in the low-normal or hypogonadal range. The first study included 20 patients with arte-riogenic erectile dysfunction as diagnosed by dynamic colour duplex ultrasound. These men had normal sexual desire, serum levels of total and free testosterone in the lower quartile of the normal range and had not responded to the highest dose of sildenafil (100 mg) on six consecutive attempts (Aversa etal. 2003). Patients were randomized to transdermal non-scrotal testosterone patches (5 mg/d; n = 10) or placebo patches (n = 10), and received 100 mg sildenafil tablets on demand. Dynamic colour duplex ultrasound revealed a significant increase of arterial inflow to cavernous arteries of the penis in the testosterone-treated men, whereas this parameter remained unchanged in the placebo-group (Fig. 11.2). Effects on erectile function were assessed by the International Index of Erectile Function (IIEF) questionnaire (Rosen etal. 1997). Compared to placebo plus sildenafil, treatment with testosterone and sildenafil resulted in a significantly increased score of the erectile function domain, the intercourse satisfaction domain, and the overall satisfaction domain of the IIEF. The scores of the sexual desire domain and orgasmic function domain remained unchanged, indicating that the treatment effect of testosterone was not only due to central effects on sexual desire. The Global Assessment Question (GAQ) "Has the treatment you received . . . improved your erections" was positively affirmed by 80% of men in the testosterone/sildenafil group compared to 10% in the placebo/sildenafil group at the end of treatment (Aversa etal. 2003).

This pilot study was followed by a randomized, double-blind, placebo-controlled 12-week multicentre study in 70 men with low or low-normal serum testosterone (morning levels before 10 a.m.: < 400 ng/dl) and non-responders to 100 mg of sildenafil during a four-week run-in period (Shabsigh et al. 2003). Patients were randomly assigned to therapy with placebo gel and sildenafil (group I, n = 33) or 5 g/d of testosterone gel and sildenafil (group II, n = 37). While the severity of erectile dysfunction was similar in both groups at baseline, the erectile function domain as well as the orgasmic function domain of the IIEF improved significantly in group II at study week 4, and scores remained at this level up to the end of the study. However, it should be noted that the difference between both groups lost significance following week 4 because of improvement of the total IIEF score and score of the erectile function domain in group I. In addition, no control group treated only with testosterone and oral placebo was included in this study.

One further, however not properly controlled study in patients with diabetes mellitus and erectile dysfunction not responding to sildenafil therapy showed similar results (Kalinchenko et al. 2003). 120 diabetic patients, aged 43 to 73 years, with low testosterone levels and erectile dysfunction who had failed to respond to 100 mg sildenafil at least three times were given 80-120 mg/d of oral testosterone undecanoate and sildenafil for four to six weeks. Androgen replacement in combination with sildenafil medication significantly improved erectile function and libido as assessed by the IIEF. After cessation of testosterone therapy, scores of the IIEF decreased to baseline within two weeks.

The two randomized, placebo-controlled studies provide preliminary evidence that patients with erectile dysfunction and low-normal or subnormal testosterone levels who do not respond to high-dose sildenafil therapy might benefit from a combined therapy with testosterone and phosphodiesterase type 5 inhibitors. However, further large-scale studies are needed to test the long-term benefit of this interesting combination therapy for erectile dysfunction.

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