Background: Radical prostatectomy (RP) and radiation treatment are standard options for localized prostate cancer. Even though nerve-sparing techniques have been increasingly utilized in RP, erectile dysfunction (ED) due to neuropraxia remains a frequent complication. Erectile function recovery rates after RP remain unsatisfactory, and many men still suffer despite the availability of various therapies. Objective: This systematic review aims to summarize the current treatments for post-RP-ED, assess the underlying pathological mechanisms, and emphasize promising therapeutic strategies based on the evidence from basic research. Method: Evaluation and review of articles on the relevant topic published between 2010 and 2021, which are indexed and listed in the PubMed database. Results: Phosphodiesterase type 5 inhibitors, intracavernosal and intraurethral injections, vacuum erection devices, pelvic muscle training, and surgical procedures are utilized for penile rehabilitation. Clinical trials evaluating the efficacy of erectogenic drugs in this setting are conflicting and far from being conclusive. The use of androgen deprivation therapy in certain scenarios after RP further exacerbates the already problematic situation and emphasizes the need for effective treatment strategies. Conclusion: This article is a detailed overview focusing on the pathophysiology and mechanism of the nerve injury developed during RP and a compilation of various strategies to induce cavernous nerve regeneration to improve erectile function (EF). These strategies include stem cell therapy, gene therapy, growth factors, lowintensity extracorporeal shockwave therapy, immunophilins, and various pharmacological approaches that have induced improvements in EF in experimental models of cavernous nerve injury. Many of the mentioned strategies can improve EF following RP if transformed into clinically applicable safe, and effective techniques with reproducible outcomes.

Purpose: This study aimed to assess the possible healing effect of combination treatment with a hydrogen sulfide (H2S) donor, sodium hydrosulfide (NaHS) plus tadalafil on partial bladder outlet obstruction (PBOO)-induced bladder dysfunction. Materials and Methods: A total of 75 male Sprague-Dawley rats aged 10-wk and 300-350g were divided into five groups; control; PBOO; PBOO+NaHS (5.6mg/kg/day, i.p., 6-wk); PBOO+tadalafil (2mg/kg/day, oral, 6-wk) and PBOO+NaHS+tadalafil. PBOO was created by partial urethral ligation. 6 weeks after obstruction, the in vitro contractile responses of the detrusor muscle and Western blotting, H2S and malondialdehyde assay were performed in bladder tissues. Results: There was an increase in bladder weight(p<0.001) and a decrease in contractile responses to KCl (p<0.001), carbachol (p<0.01), electrical field stimulation (p<0.05) and ATP (p<0.001) in the detrusor smooth muscle of obstructed rats which was normalized after the combination treatment. Cystathionine γ-lyase and cystathionine γ-synthase, and nuclear factor kappa B protein levels did not significantly differ among groups. The obstruction induced decrement in 3-mercaptopyruvate sulfur transferase protein expression(p<0.001) and H2S levels(p<0.01) as well as increment in protein expressions of neuronal nitric oxide synthase (NO, p<0.001), endothelial NOS (p<0.05), inducible NOS(p<0.001), hypoxia-inducible factor 1-alpha (p<0.01), and malondialdehyde levels (p<0.01), when combined treatment entirely normalized. Conclusions: Combination therapy has beneficial effects on bladder dysfunction via regulating both H2S and nitric oxide pathways as well as downregulation of oxidative stress and hypoxia. The synergistic effect of H2S and nitric oxide is likely to modulate bladder function, which supports the combined therapy for enhancing clinical outcomes in men with BPH/LUTS.

Introduction Radical prostatectomy for prostate cancer has a significant potential role in inducing cavernous nerve injury (CNI). Increasing hypoxia and fibrosis induces destructive changes within cavernous vasculature. Adipose-derived stem cells (ADSCs) can maintain self-renewal and enhanced multi-differentiation potential through the release of a variety of paracrine factors and extracellular vesicles, allowing to repair damaged tissues. Considerable attention has increasingly been paid to their application in tissue engineering and regeneration. In addition, ADSCs can be obtained with a minimally invasive procedure and easily expanded in vitro with low immunogenicity. Nitric oxide (NO) is synthesized from the amino acid L-arginine by a family of enzymes, the nitric oxide synthases (NOS). Orally administered L-arginine enhances the erectile response presumably by stimulating NO production by the corporal tissues increasing cGMP production. Objective To evaluate the efficacy and tolerability of ADSCs and daily oral L-arginine alone or combination in treating rats with bilateral CNI (BCNI)-induced ED. Methods Adult Sprague-Dawley rats (n = 35) were divided into five groups: 1) control; 2) BCNI (4-wk); 3) BCNI+ADSCs (1 × 106 cells by intracavernosal injection); 4) BCNI+ L-arginine (4wk,10 mg/kg/day, oral); and 5) combination treatment with ADSCs and L-arginine in BCNI. Rats in the ADSCs treatment groups were subjected to intracavernosal injection after BCNI. In vivo erectile response was measured by CN stimulation. The relaxant and contractile responses were also detected on in vitro preparations of corpus cavernosum (CC) strips. The expression and localization of neuronal (nNOS), endothelial NOS (eNOS) as well as hypoxia (hypoxia-inducible factor-1α, HIF-1α), fibrosis [transforming growth factor-beta 1 (TGF- β1)]and apoptosis (Bax and Bcl-2) markers were determined using Western blotting and immunohistochemistry. The relative area of smooth muscle to collagen was measured using Masson trichrome staining. Results Rats with CNI had the lowest ICP/MAP ratio at 63% and total ICP at 55% for 7.5 V (P &lt; .001 vs controls) as well as in vitro electrical field stimulation-induced relaxant response at 10% (P &lt; .05 vs controls) and endothelium-dependent acetylcholine-caused relaxation at 56% (P &lt; .001 vs controls). The combined treatment showed more significantly improved erectile and relaxant responses more effectively than ADSCs or L-arginine treatment alone. Increased in the expressions of nNOS, HIF-1α, Bax, and Bcl-2 in the BCNI group were restored by all treatment regiments. eNOS and TGF- β1 protein expressions were similar among groups. Mono-treatment partially improved decreased smooth muscle mass while combined therapy completely recovered. Conclusions The intracavernous injection of ADSCs and oral administration of L-arginine, and, importantly, their combination could effectively protect against hypoxia-induced neurotoxicity, via their increasing endothelial cell function and smooth muscle content, anti-inflammatory, anti-apoptotic, anti-fibrotic properties in addition to reversing erectile function in the BCNI rat model. HIF-1α overexpression by the inhibition of the apoptotic pathway with the Bcl-2 family may have protective effects on the survival of cavernosal neurons. Disclosure No

Introduction The endocrine disease frequently interrupts sexual function, and sexual dysfunction may signal serious endocrine disease. Recent studies have claimed an association with hypothyroidism, low testosterone (T) levels and erectile dysfunction (ED), but causality is unclear. There is no study on the experimental model of hypothyroidism that was induced in rats by administration of propylthiouracil (PTU). Objective The purpose of this study was to investigate the deleterious effects of PTU-induced hypothyroidism on ED and T levels. In addition, Levothyroxine is known worldwide as the most common and least effective drug for controlling hypothyroidism. Methods Adult Sprague-Dawley rats (n = 35) were divided into five groups; control, PTU-induced hypothyroidism, PTU+ Levothyroxine, PTU+ Sustanon (a mixture of 4 types of T: propionate, phenylpropionate, isocaproate, decanoate) and PTU+ Levothyroxine + Sustanon. PTU was given in drinking water (0.05%) for 6 weeks. 4 weeks after the beginning of PTU treatment, Levothyroxine (20 mg/kg/day, oral) and Sustanon (10 mg/kg, I.M., once/week) were given for 2 weeks. Serum levels of total T, triiodothyronine (T3) and thyroxine (T4) were determined. The ratio of intracavernosal pressure (ICP) to mean arterial pressure (MAP) and total ICP were measured by cavernous nerve stimulation. The relaxant and contractile responses were evaluated on in vitro preparations of corpus cavernosum (CC) strips. The expression and localization of neuronal (nNOS), endothelial NOS (eNOS) and phosphodiesterase type 5 (PDE5​) were determined using Western blotting and immunohistochemistry. The relative area of smooth muscle to collagen was measured using Masson trichrome staining. Results The rat model of hypothyroidism showed a significant decline in serum levels of total T, T3 and T4. Levothyroxine increased T3 and T4 levels while Sustanon normalized only total T levels. In addition, combined treatment of Levothyroxine and Sustanon enhanced all hormone levels. Rats with hypothyroidism displayed the lowest ICP/MAP ratio and total ICP for 7.5 V (P &lt; .001 vs controls). Combined treatment returned reduced ICP/MAP and total ICP responses, while partial amelioration was observed after Levothyroxine and Sustanon treatment alone. In vitro endothelium-dependent acetylcholine-caused relaxation at 1 nM (P &lt; .001 vs controls), electrical field stimulation-induced relaxant response at 20 Hz (P &lt; .001 vs controls) and sildenafil-induced relaxation at 10 µM (P &lt; .05 vs controls) were decreased in the CC strips from hypothyroid rats. The treatment with Levothyroxine and Sustanon increased the reduction in relaxation responses. Decreased in the expressions of eNOS and nNOS and increased in the expressions of PDE5 in the hypothyroid group were restored by Levothyroxine and Sustanon. Mono-treatment partially enhanced reduced smooth muscle mass while combined therapy completely recovered. Conclusions These results show that hypothyroidism adversely affects T levels and erectile responses via decreasing neurogenic and endothelium-dependent relaxation responses which were reversed by the combination therapy with Levothyroxine and Sustanon. Even though the associated alterations in T levels, ED and its reversibility indicate an exact role of thyroid hormones in the erection physiology. Disclosure Work supported by industry: no.

Background Sexual dysfunction may indicate severe endocrine diseases. Recent research has suggested a link between hypothyroidism, low testosterone (T) levels, and erectile dysfunction (ED); however, the exact cause is unknown. Aim We sought to investigate possible beneficial effects of levothyroxine and T alone or in combination on ED in propylthiouracil (PTU)-induced hypothyroid rats. Methods Adult Wistar rats (n = 35) were divided into 5 groups: control, PTU-induced hypothyroidism, PTU + levothyroxine, PTU + Sustanon (a mixture of 4 types of T: propionate, phenylpropionate, isocaproate, and decanoate) and PTU + levothyroxine + Sustanon. PTU was given in drinking water for 6 weeks. Four weeks after PTU administration, levothyroxine (20 μg microgram kg/day, oral) and Sustanon (10 mg/kg/week, intramuscular) were given for 2 weeks. Serum levels of total T, triiodothyronine (T3), and thyroxine (T4) were determined. In vivo erectile response and in vitro relaxant responses were measured. Localization of neuronal nitric oxide synthase (nNOS), endothelial NOS (eNOS), and phosphodiesterase type 5 (PDE5) were determined using immunohistochemical analysis. The relative area of smooth muscle to collagen was measured using Masson trichrome staining. Outcomes Outcome variables included in vivo erectile function, in vitro relaxant and contractile responses of corpus cavernosum (CC) strips; protein localization of eNOS, nNOS, and PDE5; and smooth muscle content in penile tissue. Results The rat model of hypothyroidism showed a significant decline in serum levels of total T, T3, and T4. Levothyroxine increased T3 and T4 levels, whereas Sustanon normalized only total T levels. Combined treatment enhanced all hormone levels. Rats with hypothyroidism displayed the lowest erectile response (P &lt; 0.001 vs controls). Combined treatment returned reduced responses, while partial amelioration was observed after levothyroxine and Sustanon treatment alone. Acetylcholine (P &lt; 0.01 vs controls), electrical field stimulation (P &lt; 0.001 vs controls), and sildenafil-induced relaxant responses (P &lt; 0.05 vs controls) were decreased in the CC strips from hypothyroid rats. The combined treatment increased the reduction in relaxation responses. Levothyroxine and Sustanon restored decreases in eNOS and nNOS expression in the hypothyroid group. There was no significant difference in PDE5 expression among groups. Monotreatment partially enhanced reduced smooth muscle mass, while combined therapy completely recovered. Clinical Implications The combination of thyroid hormones and T is likely to be a therapeutic approach for treatment of hypothyroidism-induced ED in men. Strengths and Limitations Beneficial effects of levothyroxine and Sustanon treatment were shown in vitro and in vivo in PTU-induced hypothyroid rats. The main limitation of the study was the lack of measurement of androgen-sensitive organ weights and luteinizing hormone, follicle-stimulating hormone, and prolactin levels. Conclusion These findings demonstrate that neurogenic and endothelium-dependent relaxation responses are reduced by hypothyroidism, which is detrimental to T levels and erectile responses. Levothyroxine and Sustanon combination medication was able to counteract this effect.

Introduction Radical prostatectomy causes nerve injury-related erectile dysfunction (ED), which results in a poor response to phosphodiesterase 5 inhibitors. Hydrogen sulfide (H2S), an endogenous gasotransmitter, is produced by cystathionine-β-synthase (CBS), cystathionine-γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST) and participates in erectile physiology. Adipose-derived stem cells (ADSCs) represent a promising cell source for cell replacement therapy in several degenerative diseases because of its self-renewal properties and multi-differentiation potential with low immunogenicity. Objective The current study was to evaluate the effects of H2S donor, sodium hydrogen sulfide (NaHS), and transplantation of ADSCs per se and their combination treatment on bilateral cavernous nerve injury (BCNI)-induced erectile dysfunction (ED). Methods A total of 35 Sprague-Dawley rats were divided into 5 groups, including sham-operated (Sham), BCNI (4-wk), BCNI treated with NaHS (5.6 mg/kg/day, i.p.), BCNI treated with ADSCs (1x106 cells by intracavernosal injection) and BCNI treated with NaHS and ADSCs groups. Rats in the ADSCs treatment groups were subjected to intracavernosal injection after BCNI. Erectile function was evaluated by the ratio of intracavernous pressure (ICP)/mean arterial pressure (MAP) and total ICP. The relaxant and contractile responses of corpus cavernosum (CC) were measured from in vitro studies. Protein expression and localization of nitric oxide synthases (NOS) and H2S synthesis enzymes were analyzed by Western blotting and immunohistochemistry. The smooth muscle/collagen ratio was determined using Masson trichrome staining. Results Rats with BCNI displayed significantly reduced ICP/MAP and total ICP (p&lt;0.001 vs controls) when were partially restored by NaHS and ADSCs treatments alone. Interestingly, combined treatment completely enhanced decreased in vivo erectile responses (p&lt;0.001 vs the NC group). Relaxation responses to acetylcholine and electrical field stimulation (EFS) as well as contractile responses to phenylephrine and EFS in the CN group were less than in controls (p&lt; 0.05), which was normalized after all treatments groups. The combined treatment modulated changes of protein expressions and reduced ratio of smooth muscle to collagen in rats with BCNI. Conclusions The current data indicated that the combination treatment with NaHS and ADSCs is more successful than monotherapies in reversing BCNI-induced ED. H2S and cell-based therapy most probably may have a synergistic effect on erectile function via controlling molecular regulation and morphological penile alterations, which supports combined treatment for expanding clinical outcomes radical prostatectomy-induced ED. Disclosure Work supported by industry: no.