Sildenafil increases serum testosterone levels by a direct action on the testes.

Phosphodiesterase-5-inhibitors, such as sildenafil, increase intracavernosal cyclic guanosine monophosphate levels, which results in corporal smooth muscle relaxation and penile erection. Here, we determined the effects of sildenafil administration on the hypothalamic-pituitary-gonadal axis in men with erectile dysfunction and low testosterone levels. The Testosterone and Erectile Dysfunction trial (ClinicalTrials.gov # NCT00512707) initially administered an optimized dose of sildenafil to 140 men, aged 40-70 years with erectile dysfunction, low serum total testosterone (<11.4 nmol/L; 330 ng/dL) and/or free testosterone (<173 pmol/L; 50 pg/mL) over 3-7 weeks. Sex steroids and gonadotropins were measured at baseline and after sildenafil optimization in a longitudinal study without a separate control group. Serum testosterone, dihydrotestosterone (DHT) and oestrogens were measured using liquid chromatography-tandem mass spectrometry. Administration of an optimized dose of sildenafil was associated with mean increases of 3.6 nmol/L (103 ng/dL; p < 0.001) and 110 pmol/L (31.7 pg/mL; p < 0.001) in total and free testosterone levels respectively. This was accompanied by parallel increases in serum DHT (0.17 nmol/L; 4.9 ng/dL; p < 0.001) and oestradiol (14 pmol/L; 3.7 pg/mL; p < 0.001) and significant suppression of luteinizing hormone (change -1.3 units/L; p = 0.003) levels, suggesting a direct effect at the testicular level. Androstenedione and oestrone increased by 1.3 nmol/L (38 ng/dL; p = 0.011) and 10.7 pmol/L (2.9 pg/mL; p = 0.012), respectively, supporting a possible effect of sildenafil on adrenal steroidogenesis. In conclusion, sildenafil administration was associated with increased testosterone levels likely ascribable to a direct effect on the testis.

The effect of testosterone on mood and well-being in men with erectile dysfunction in a randomized, placebo-controlled trial.

The relationship between testosterone, well-being and mood is poorly understood. We investigated the effect of testosterone supplementation on mood, well-being, and self-reported health in men with erectile dysfunction (ED) and low serum testosterone levels. This was a randomized, double-blind, placebo-controlled trial (ClinicalTrials.gov registration number NCT00512707), in which 140 men, 40-70 years, with ED and low serum testosterone levels were first optimized on sildenafil alone for 3-7 weeks and then randomized to receive either sildenafil plus testosterone gel (n = 70) or sildenafil plus placebo (n = 70) gel for 14 weeks. Using multiple imputations and generalized linear regression, we compared psychological changes in well-being, evaluated by the Psychological General Well-Being Index, and mood, evaluated by Derogatis Affects Balance Scale. Mood and well-being scores were similar between the two groups at baseline and did not substantially change during the administration of sildenafil or after randomization to testosterone. Our findings show that the addition of testosterone to sildenafil in men with ED and low serum testosterone levels was not associated with improvement in either well-being or mood.