Testosterone Restores Diabetes-Induced Erectile Dysfunction and Sildenafil Responsiveness in Two Distinct Animal Models of Chemical Diabetes
Article first published online: 20 FEB 2006
The Journal of Sexual Medicine
Volume 3, Issue 2, pages 253–266, March 2006
How to Cite
Zhang, X.-H., Filippi, S., Morelli, A., Vignozzi, L., Luconi, M., Donati, S., Forti, G. and Maggi, M. (2006), Testosterone Restores Diabetes-Induced Erectile Dysfunction and Sildenafil Responsiveness in Two Distinct Animal Models of Chemical Diabetes. Journal of Sexual Medicine, 3: 253–266. doi: 10.1111/j.1743-6109.2006.00207.x
- Issue published online: 20 FEB 2006
- Article first published online: 20 FEB 2006
Vol. 3, Issue 3, 573, Article first published online: 20 APR 2006
- Experimental Diabetes;
Introduction. Hypogonadism is often associated with diabetes and both conditions represent major risk factors for erectile dysfunction (ED).
Aim. To investigate the role of hypogonadism on phosphodiesterase type 5 (PDE5) expression and sildenafil responsiveness in diabetes.
Methods. Two different models of experimental diabetes were used: (i) alloxan-induced diabetic rabbit; and (ii) streptozotocin (STZ)-induced diabetic rat. In both experimental models, animals were separated into three groups: control, diabetic, diabetic supplemented with testosterone (T) enanthate. Rabbits were used for “in vitro” experiments. Conversely, each rats group was further subdivided: no further treatment or acute sildenafil dosing (25 mg/kg, 1 hour before “in vivo” electrical stimulation [ES]).
Main Outcome Measure. Erectile capacity was evaluated either by “in vitro” contractility study (alloxan-induced diabetic rabbit) and “in vivo” evaluation of erectile response elicited by ES of cavernous nerve (STZ-induced diabetic rats). Also endothelial nitric oxide synthase, neural nitric oxide synthase (nNOS), and PDE5 protein (Western blot) and mRNA (quantitative real-time reverse transcriptase polymerase chain reaction [RT-PCR]) expression were measured in rat penile samples of each group.
Results. In both models, hypogonadism was observed, characterized by reduced T and atrophy of androgen-dependent accessory glands. T substitution completely reverted hypogonadism and diabetes-induced penile hyposensitivity to “in vitro” (acetylcholine, rabbit) or “in vivo” (ES, rat) relaxant stimuli, along with 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). PDE5 was reduced in diabetic STZ rats (P < 0.05) and normalized by T. In STZ rats, sodium nitroprusside (SNP) intracavernous injection 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.
Conclusion. In two models of diabetes T deficiency underlies biochemical alterations leading to ED. Normalizing T in diabetes restores nNOS and PDE5, and reinstates sensitivity to relaxant stimuli and responsiveness to sildenafil. Zhang X-H, Filippi S, Morelli A, Vignozzi L, Luconi M, Donati S, Forti G, and Maggi M. Testosterone restores diabetes-induced erectile dysfunction and sildenafil responsiveness in two distinct animal models of chemical diabetes. J Sex Med 2006;3:253–266.