“Incomplete Recovery of Erectile Function in Rats after Discontinuation of Dual 5-Alpha Reductase Inhibitory Therapy”
Çetin Volkan Öztekin MD, Serap Gur PhD, Nour A. Abdulkadir PhD, Utku Lokman MD, Alp Özgür Akdemir MD, Mesut Cetinkaya MD, Wayne J.G. Hellstrom MD, FACS
May 8, 2012 – The Journal of Sexual Medicine
5-alpha reductase inhibitors (5ARIs) are often prescribed to treat benign prostatic hyperplasia (BPH)/lower urinary tract infections (LUTS). These medications work by inhibiting the conversion of testosterone to dihydrotestosterone, which has a greater androgen effect on the prostate. The drugs can reduce prostate volume size by 30% and improve LUTS, urinary flow rate, and quality of life. Patients who take 5ARIs are often less likely to have acute urinary retention and less likely to need surgery.
Sexual side effects, including erectile dysfunction (ED), ejaculatory dysfunction, and decreased libido, are common among men who take 5ARIs. Some men continue to have sexual side effects after they stop 5ARI therapy. A previous study had shown that the in vivo erectile response in rats declined after administration of dutasteride, a type of 5ARI.
Relaxation of cavernous smooth muscle tissue is a crucial part of the erection process. Both endothelium-dependent and independent relaxant responses must occur and nitric oxide (NO) plays an important role:
Nitric oxide (NO) that is originated by the parasympathetic nonadrenergic, noncholinergic (NANC) neurons and endothelial cells switches a molecular cascade that results in the relaxation of cavernosal smooth muscle cells. NO catalyzed by NO synthase (NOS) is both the principle neurotransmitter and endothelium-derived relaxing factor regulating the cavernosal smooth muscle relaxation. Neurogenic NO synthesized by neuronal NOS (nNOS) is critical for immediate relaxation of penile vessels and the corpus cavernosum whereas endothelium-generated NO synthesized by endothelial NOS plays a major role in maintaining an erection. NO acts by stimulating guanylyl cyclase to produce cyclic-guanosine monophosphate (GMP), which consequently causes cavernosal smooth muscle to relax. The inorganic compound sodium nitroprusside (SNP) is an agent that releases NO in biological systems and induces endothelium-dependent relaxations.
Androgens increase NOS expression in the penile corpus cavernosum of rats, and DHT has a more powerful effect on NOS expression. A recent study reported on significant deterioration of in vivo erectile response in rats after dutasteride administration. Although 4-week dutasteride therapy reduced relaxant response in corpus cavernosum smooth muscle (CCSM), the contractile response was augmented, causing an overall detrimental effect on erectile function.
The aim of the current study was to investigate how long-term 5ARI therapy affected erectile function in rats.
For humans, the washout period for dutasteride is between 0.5 and 1 year. It was determined that the comparable washout period for rats would be about 12 days. For the purposes of this study, a washout period of two weeks was considered acceptable.
Twenty-six adult male Sprague-Dawley rats were used in this study. They were divided into three groups. Group 1 (control group, 10 rats) were given normal drinking water. Group 2 (8 rats) were given dutasteride in their drinking water for 8 weeks. Group 3 (8 rats) were given dutasteride in their drinking water for 6 weeks. All of the rats were evaluated 8 weeks after the study began, which allowed for a 2-week washout period for Group 3.
To assess in vivo erectile function, the rats were anesthetized and tubes and transducers were implanted to measure mean arterial pressure (MAP) and intracavernosal pressure (ICP). A stainless steel bipolar hook stimulating electrode was placed around the cavernosal nerve. MAP and ICP were continuously measured. The cavernosal nerve was stimulated at a voltage of 5 Hz.
To measure isometric tension in corpus cavernosum smooth muscle (CCSM) strips, the rats’ penises were removed (after anesthesia) and strips were dissected off for evaluation.(in vitro)
Researchers found that even after a 2-week washout, rats treated with dutasteride had changes in erectile function. Their in vivo ICP and MAP and total ICP measurements had decreased. A decrease in NANC relaxation that was seen after 8 weeks of treatment was not seen after 6 weeks of treatment and a 2-week washout period.
Both groups treated with dutasteride had diminished endothelium-dependent and independent relaxant responses. Washout seemed to restore endothelium-independent responses, but not endothelium-dependent relaxations.
Dutasteride treatment (regardless of washout) caused diminished in vivo erectile response to cavernous nerve stimulation. However, washout normalized this drop in the in vitro setting.
For rats, long-term 5ARI treatment increases the risk of ED because of changes in relaxant and contractile responses of penile tissue. The current results suggest that some of the changes in CCSM function are persistent and may be irreversible. More studies are warranted, as men of various ages take 5ARIs for a variety of conditions.