Objectives: Hypogonadism is often associated with diabetes mellitus and both conditions represent major risk factors for erectile dysfunction (ED). The aim of this study was to evaluate the effect of diabetes-induced hypogonadism on ED using two distinct animal models: alloxan-rabbits and streptozotocin (STZ)-rats.
Methods: A subgroup of diabetic animals was Testosterone (T) replaced. After 8 weeks from induction of diabetes, erectile function was evaluated by in vitro contractility studies (rabbit) and in vivo cavernous nerve electro-stimulation (ES, rat).
Results: In both models of chemical diabetes an overt hypogonadism was observed, as derived by the reduced T plasma concentrations and by atrophy of the androgen-dependent accessory glands (prostate and seminal vesicles). In diabetic animals, T substitution completely reverted hypogonadism and diabetes-induced penile hyposensitivity to in vitro (acetylcholine, rabbit) or in vivo (ES, rat) relaxant stimuli. Moreover, T replacement was able to restore nitric oxide synthase (nNOS) expression, which was reduced (P<0.05) in STZ-rats. In diabetic animals, T substitution reinstated sildenafil-induced enhancement of both in vitro nitric oxide-donor (NCX 4040) relaxant effect (rabbit) and in vivo ES-induced erection (rat). The abolishment of the sildenafil effect on erectile response in diabetic animals might be due to the hypogonadism-induced PDE5 deficiency. Accordingly, PDE5 resulted reduced in diabetic STZ-rats (P<0.05) and normalized by T. In STZ-rats, intracavernous injection of sodium nitroprusside (SNP) induced a more sustained erection than in control rats, which was no further enhanced by sildenafil. T substitution normalized both hyper-responsiveness to SNP and sildenafil efficacy along with PDE5 expression.
Conclusion: In conclusion, in two experimental models of diabetes T deficiency underlies biochemical alterations leading to ED. Normalizing T in diabetes restores nNOS and PDE5, and reinstates either sensitivity to relaxant stimuli and responsiveness to sildenafil.