Testosterone is a major regulator of sexual desire, spontaneous sexual thoughts, motivation, attentiveness to erotic stimuli, and sexual activity in men. Experimental studies show that testosterone regulates penile nitric oxide synthase and blood flow. These data lead to speculation that, in men with erectile dysfunction (ED), normal testosterone level is necessary to achieve an optimum response to phosphodiesterase type 5 (PDE5) inhibitors.
This randomized, parallel group trial was performed in 140 men aged 40 to 70 with ED and low levels of total or free testosterone levels (<330 ng/dl or <50 pg/ml, respectively). First, dose of sildenafil was optimized for 3 to 7 weeks (25-100 mg/d). Then, participants were randomized (1:1) to testosterone (Testim, Auxilium Pharmaceuticals, Malvern) or placebo gel. Men were treated for 14 weeks and testosterone was adjusted on the basis of testosterone measurements. During the treatment, erectile and sexual functions as well as ED-related quality of life were assessed using standardized and validated questionnaires.
During the first phase, sildenafil administered alone increased testosterone levels by ~100 ng/dl. Later on, in the testosterone-treated group, testosterone levels increased further to the average level of 649 ng/dl. Sildenafil alone induced a substantial increase in all domains of the International Index of Erectile Function (IIEF) such as erectile function, sexual desire, orgasmic function, or intercourse satisfaction. Sildenafil alone also improved substantially all domains of the Sexual Encounter Profile (SEP), e.g. frequency of sexual encounters, vaginal penetration or ejaculation. Further, sildenafil also improved the ED-related quality of life. Importantly, there was no difference between men who did or did not take testosterone (in addition to sildenafil) as concerns the evaluated parameters of sexual function. The analysis limited to men who completed 14 weeks of treatment provided similar results. The effect of testosterone on ED did not vary by the testosterone levels, age or body mass index.
Thus, sildenafil plus testosterone did not improve sexual function compared with sildenafil plus placebo. This may seem surprising in light of preclinical data. However, sildenafil may have increased testosterone levels higher than the upper limit of dose-response relationship of testosterone for erectile function. Testosterone and sildenafil may share common mechanistic pathways and the optimized dose of sildenafil may have maximally induced these pathways. The results are not related to methodological problems: this was a randomized, double-blind and placebo-controlled trial, dropout rate was low, patients responded robustly to sildenafil, duration of testosterone treatment was sufficient to induce a therapeutic response.
Thus, in summary, these results do not support the routine addition of testosterone therapy for improving erectile response to selective PDE5 inhibitors in men with ED who have low testosterone levels.
Reference: Spitzer M, Basaria S, Travison TG, Davda MN, Paley A, Cohen B, Mazer NA, KNapp PE, Hanka S, Lakshman KM, Ulloor J, Zhang A, Orwoll K, Eder R, Collins L, Mohammed N, Rosen RC, DeRogatis L, Bhasin S. Effect of testosterone replacement on response to sildenafil citrate in men with erectile dysfunction: a parallel, randomized trial. Ann Intern Med. 2012 157(10):681-91.