sirolimus and Erectile-Dysfunction

The immunosuppressive agents target of rapamycin inhibitors (TOR-I) (sirolimus, and everolimus) have been widely used in kidney transplantation for >10 years. Up to 40% of men receiving a kidney transplant are younger than 50, and fertility as well as erectile function are major concerns. In this review, we provide a synopsis of past studies focusing on gonadal function in men treated with TOR-I, mainly sirolimus, to establish what impact they have on male gonads, and which pathophysiological pathways are involved. A PubMed search for the years 1990-2006 selected articles that focused on the gonadal impact of TOR-I. Primary outcome measures were testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) levels. Secondary outcome measures were sexual function, fertility status and sperm parameters. Treatment with TOR-I results in a decrease in testosterone level, and an opposite increase in LH. Moreover, spermatogenesis seems to be disrupted by TOR-I and FSH levels are increased. Sirolimus and everolimus inhibit the activity of mammalian targets of rapamycin, a serine/threonine kinase involved in numerous cell-growth processes. Molecular mechanisms of action of TOR-I on the testis involve inhibition of a stem cell factor/c-kit-dependant process in spermatogonia. Preliminary results appear to show that TOR-I treatment has deleterious actions on the testis and impairs gonadal function after renal transplantation, but the impact of these effects are unknown.

Topics: Adult; Erectile Dysfunction; Everolimus; Heart Transplantation; Humans; Immunosuppressive Agents; Infertility, Male; Kidney Transplantation; Male; Protein Kinases; Sirolimus; Spermatogenesis; Testosterone; TOR Serine-Threonine Kinases

This study sought to evaluate the safety and feasibility of zotarolimus-eluting stent implantation in focal atherosclerotic lesions of the internal pudendal arteries among men with erectile dysfunction (ED) and a suboptimal response to phosphodiesterase-5 inhibitors.. ED, a common condition, is often mediated by atherosclerosis. Current treatment options are limited.. Male subjects with atherosclerotic ED and a suboptimal response to phosphodiesterase-5 inhibitors were enrolled in this prospective, multicenter, single-armed safety and feasibility trial. A novel combination of clinical, duplex ultrasound, and invasive angiographic factors were used to determine eligibility for stent therapy. The primary safety endpoint was any major adverse event 30 days after the procedure. The primary feasibility end point was improvement in the International Index of Erectile Function (Erectile Dysfunction Domain) score ≥ 4 points in ≥ 50% of subjects at 3 months. We report 6-month follow-up results, including duplex ultrasound and angiography.. Forty-five lesions were treated with stents in 30 subjects. Procedural success was 100% with no major adverse events through follow-up. The primary feasibility endpoint at 6 months was achieved by 59.3% of intention-to-treat subjects (95% confidence interval: 38.8% to 77.6%) and 69.6% of per-protocol subjects (95% confidence interval: 47.1% to 86.8%). Duplex ultrasound peak systolic velocity of the cavernosal arteries increased from baseline by 14.4 ± 10.7 cm/s at 30 days and 22.5 ± 23.7 cm/s at 6 months. Angiographic binary restenosis (≥ 50% lumen diameter stenosis) was reported in 11 (34.4%) of 32 lesions.. Among patients with ED and limited response with pharmacologic therapy, percutaneous stent revascularization of the internal pudendal artery is feasible and is associated with clinically meaningful improvement in both subjective and objective measures of erectile function.

Topics: Adult; Aged; Angiography; Dose-Response Relationship, Drug; Drug-Eluting Stents; Erectile Dysfunction; Feasibility Studies; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Middle Aged; Penile Erection; Phosphodiesterase 5 Inhibitors; Prospective Studies; Prosthesis Design; Sirolimus; Treatment Outcome; Ultrasonography, Doppler, Duplex

Conventional angioplasty balloon catheter, drug coated balloon (DCB), or angioplasty with drug eluting stent (DES) have been used on the percutaneous treatment of erectile dysfunction (ED). Currently available DCBs are paclitaxel eluting balloon (PEB), very recently, sirolimus eluting balloon (SEB). Although endovascular revascularization with balloon resulted in improvement of ED, there have been no prior reports on the feasibility of SEB treatment for ED.. We present an observational, retrospective-prospective multicentre registry in patients evaluating the use of SEB for the treatment of de novo stenosis in native internal pudendal arteries. We will include 100 patients affected by vasculogenic ED non responder to PDE5i with up to two lesions requiring treatment. ED patients should present a IIEF-5 Score<15, positive dynamic doppler (PSV <25 cm/s) and/or evidence at basal CT angiography. At 30 days, 180, 240, and 365 days following the index procedure, IIEF-5 score will be assessed, and medication regimen and adverse event monitoring will be assessed. At 8 months a dynamic Doppler will be performed. Patients will be followed up for 2 years. The primary endpoints are the Delta IIEF-5 Score and a Delta PSV between basal and 8 months follow-up. The secondary endpoint is the incidence of major adverse event (MAE), binary restenosis and late loss in patients who will repeat control angiography if clinically indicated.. Considering the limitations and safety concerns of PEB, POBA and DES used so far in ED clinical investigations, we hypothesize that sirolimus nanocarriers-coated balloon can potentially be an improved next-generation treatment for ED patients.

Topics: Drug-Eluting Stents; Erectile Dysfunction; Humans; Male; Prospective Studies; Registries; Retrospective Studies; Sirolimus; Treatment Outcome

Arteriogenic erectile dysfunction is a common disease oftentimes not satisfactory treatable with medical therapy.. To assess the safety and clinical success rate of endovascular revascularization of erection-related arteries with the angiolite BTK stent in patients with arteriogenic erectile dysfunction.. A total of 100 consecutive men (61.8 ± 10 years) with atherosclerotic lesions in erection-related arteries agreed to participate and were included into a single-center all-comers registry. Endovascular therapy with angiolite BTK drug-eluting stents was performed on a total of 211 lesions. Patients received a baseline International Index of Erectile Function (IIEF)-15 questionnaire at first presentation and 3 and 12 months after stenting. An improvement by 4 points in the erectile function domain consisting of 6 questions (IIEF-6) was defined as minimal clinically important difference. A total of 24 patients with 52 stented arterial lesions underwent angiographic follow-up of the initially treated arterial side during secondary revascularization of the contralateral side (angiographic sub-study).. Clinical improvement of erections in 100 patients undergoing endovascular revascularization of erection-related arteries.. No major adverse events occurred during endovascular revascularization or within 30 days thereafter. Technical success was achieved in all lesions and procedural success in all patients. At 1 year, 55 of 97 patients (56.7%) improved by at least 4 points in IIEF-6 score and thus achieved a clinically relevant improvement of erectile function.In the angiographic sub-study, arterial patency and binary restenosis were observed in 46 of 52 (88.5%) and in 8 of 52 (15.4%), respectively, after a mean follow-up of 9.6 ± 5.8 months.. In patients with arteriogenic erectile dysfunction, endovascular therapy with a novel thin-strut sirolimus eluting stent is a safe and feasible treatment option.. This real-world arterial revascularization registry included patients with a multitude of risk factors for ED, thereby representing the heterogeneity in patients in the clinical practice, which is one of its strengths but also one of its weaknesses. Another strength was the focus being laid on analyzing outcomes of patients with arteriogenic ED using only a single endovascular device. Further studies are warranted to better define subgroups of patients with impaired clinical outcomes.. Within the present all-comers registry, endovascular therapy of erectile dysfunction with the angiolite BTK stent was shown to be a safe and feasible treatment option resulting in clinical improvement rates comparable to earlier clinical trials although also showing that further research is warranted to define patient subgroups with particular benefits of endovascular therapy. Schönhofen J, Räber L, Knöchel J, et al. Endovascular Therapy for Arteriogenic Erectile Dysfunction With a Novel Sirolimus-Eluting Stent. J Sex Med 2021;18:315-326.

Topics: Drug-Eluting Stents; Endovascular Procedures; Erectile Dysfunction; Humans; Male; Sirolimus; Stents; Treatment Outcome

Erectile dysfunction (ED), which is common in patients with diabetes mellitus (DM), seriously affects quality of life. Previous studies on the treatment of DM-induced ED (DMED) involve autophagy, but the specific effect and mechanism of treatment are not yet clear.. To investigate the effect and mechanism of rapamycin, an autophagy inducer, in ameliorating DMED.. 45 male Sprague-Dawley rats (7 weeks old) were used in the experiment. 8 rats were randomly selected as the control group; the other rats were treated with streptozotocin to induce type 1 DM. After 10 weeks, an apomorphine test was used to confirm DMED. Rats with DMED were intraperitoneally injected with rapamycin or vehicle for 3 weeks. Rats in the control group were injected with saline. Erectile function in rats was measured by electrically stimulating the cavernous nerve. The penises were then harvested for histologic examinations, ribonucleic acid (RNA), and protein levels of related factors by immunohistochemistry, immunofluorescence, real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and Western blot.. Erectile function was evaluated by maximum intracavernous pressure and mean arterial pressure. Penile tissues were used to perform histologic examinations and to determine the RNA and protein levels.. Erectile function, which was impaired in rats with DMED, was significantly ameliorated in the DMED + rapamycin group. The nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway was inhibited in the DMED group, and rapamycin significantly reduced this inhibition. The DMED group showed increased autophagy and apoptosis level compared with the non-diabetic group, and rapamycin increased the autophagy level and decreased the apoptosis level in the penis. Penile fibrosis was more severe in the DMED group than in the control group and was partially but significantly improved in the DMED + rapamycin group compared with the DMED group. The adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin kinase (mTOR) and PI3K/AKT/mTOR pathways were activated, and the mTOR (regulatory associated protein of mTOR, complex 1 [raptor])/p70 ribosomal protein S6 kinase (p70S6K) pathway was inhibited in the DMED group. Compared with DMED group, rapamycin led to lower AMPK/mTOR and AKT/mTOR pathways expression, a higher degree of mTOR (raptor)/p70S6K pathway inhibition, and no change in the mTORC2-related pathway.. Rapamycin was effective in restoring erectile function in type 1 DMED models.. This study suggested for the first time that rapamycin, an autophagy inducer, is effective in restoring erectile function in rats with diabetes. However, the rat model might not represent the human condition.. Rapamycin improved erectile function in rats with DMED, likely by promoting autophagy, inhibiting apoptosis and fibrotic activity, and ameliorating endothelial function. These findings provide evidence of a potential treatment option for DMED. Lin H, Wang T, Ruan Y, et al. Rapamycin supplementation may ameliorate erectile function in rats with streptozotocin-induced type 1 diabetes by inducing autophagy and inhibiting apoptosis, endothelial dysfunction, and corporal fibrosis. J Sex Med 2018;15:1246-1259.

Topics: Animals; Apoptosis; Autophagy; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Disease Models, Animal; Erectile Dysfunction; Injections, Intraperitoneal; Male; Penile Erection; Rats; Rats, Sprague-Dawley; Sirolimus; Streptozocin

Topics: Drug-Eluting Stents; Erectile Dysfunction; Humans; Male; Penile Erection; Phosphodiesterase 5 Inhibitors; Sirolimus

Topics: Drug-Eluting Stents; Erectile Dysfunction; Humans; Male; Penile Erection; Phosphodiesterase 5 Inhibitors; Sirolimus

Topics: Drug-Eluting Stents; Erectile Dysfunction; Humans; Male; Penile Erection; Phosphodiesterase 5 Inhibitors; Sirolimus