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Andrology Mar 2024Despite its efficacy for treating androgenetic alopecia, finasteride, an inhibitor of 5α-reductase (i.e., the enzyme converting testosterone, T, into...
Despite its efficacy for treating androgenetic alopecia, finasteride, an inhibitor of 5α-reductase (i.e., the enzyme converting testosterone, T, into dihydrotestosterone, DHT), is associated with several side effects including sexual dysfunction (e.g., erectile dysfunction). These side effects may persist after drug suspension, inducing the so-called post-finasteride syndrome (PFS). The effects of subchronic treatment with finasteride (i.e., 20 days) and its withdrawal (i.e., 1 month) in rat corpus cavernosum have been explored here. Data obtained show that the treatment was able to decrease the levels of the enzyme 5α-reductase type II in the rat corpus cavernosum with increased T and decreased DHT levels. This local change in T metabolism was linked to mechanisms associated with erectile dysfunction. Indeed, by targeted metabolomics, we reported a decrease in the nitric oxide synthase (NOS) activity, measured by the citrulline/arginine ratio and confirmed by the decrease in NO levels, and a decrease in ornithine transcarbamylase (OTC) activity, measured by citrulline/ornithine ratio. Interestingly, the T levels are negatively correlated with NOS activity, while those of DHT are positively correlated with OTC activity. Finasteride treatment also induced alterations in the levels of other molecules involved in the control of penile erection, such as norepinephrine and its metabolite, epinephrine. Indeed, plasma levels of norepinephrine and epinephrine were significantly increased and decreased, respectively, suggesting an impairment of these mediators. Interestingly, these modifications were restored by suspension of the drug. Altogether, the results reported here indicate that finasteride treatment, but not its withdrawal, affects T metabolism in the rat corpus cavernosum, and this alteration was linked to mechanisms associated with erectile dysfunction. Data here reported could also suggest that the PFS sexual side effects are more related to dysfunction in a sexual central control rather than peripheral compromised condition.
Topics: Male; Humans; Rats; Animals; Finasteride; Erectile Dysfunction; Citrulline; Dihydrotestosterone; Epinephrine; Norepinephrine; 5-alpha Reductase Inhibitors
PubMed: 37621185
DOI: 10.1111/andr.13515 -
Biochemical Pharmacology Sep 2023Bitter taste receptors (TAS2R) are found in numerous extra-oral tissues, including smooth muscle (SM) cells in both vascular and visceral tissues. Upon activation, TAS2R...
Bitter taste receptors (TAS2R) are found in numerous extra-oral tissues, including smooth muscle (SM) cells in both vascular and visceral tissues. Upon activation, TAS2R stimulate the relaxation of the SM. Nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling pathway is involved in penile erection, and type 5 phosphodiesterase (PDE5) inhibitors, a cGMP-specific hydrolase are used as first-line treatments for erectile dysfunction (ED). Nevertheless, PDE5 inhibitors are ineffective in a considerable number of patients, prompting research into alternative pharmacological targets for ED. Since TAS2R agonists regulate SM contractility, this study investigates the role of TAS2Rs in rat corpus cavernosum (CC). We performed immunohistochemistry to detect TAS2R10, isometric force recordings for TAS2R agonists denatonium and chloroquine, the slow-release HS donor GYY 4137, the NO donor SNAP, the β-adrenoceptor agonist isoproterenol and electrical field stimulation (EFS), as well as measurement of endogenous hydrogen sulfide (HS) production. The immunofluorescence staining indicated that TAS2R10 was broadly expressed in the CC SM and to some extent in the nerve fibers. Denatonium, chloroquine, SNAP, and isoproterenol cause potent dose-dependent SM relaxations. HS production was decreased by NO and HS synthase inhibitors, while it was enhanced by denatonium. In addition, denatonium increased the relaxations induced by GYY 4137 and SNAP but failed to modify EFS- and isoproterenol-induced responses. These results suggest neuronal and SM TAS2R10 expression in the rat CC, where denatonium induces a strong SM relaxation per se and promotes the HS- and NO-mediated inhibitory gaseous neurotransmission. Thus, TAS2R10 might represent a valuable therapeutic target in ED.
Topics: Male; Animals; Rats; Taste; Isoproterenol; Chloroquine; Cyclic GMP
PubMed: 37597814
DOI: 10.1016/j.bcp.2023.115754 -
Acta Biomaterialia Oct 2023The tunica albuginea (TA) of the penis is an elastic layer that serves a structural role in penile erection. Disorders affecting the TA cause pain, deformity, and...
The tunica albuginea (TA) of the penis is an elastic layer that serves a structural role in penile erection. Disorders affecting the TA cause pain, deformity, and erectile dysfunction. There is a substantial clinical need for engineered replacements of TA, but data are scarce on the material properties and biochemical composition of healthy TA. The objective of this study was to assess tissue organization, protein content, and mechanical properties of porcine TA to establish structure-function relationships and design criteria for tissue engineering efforts. TA was isolated from six pigs and subjected to histomorphometry, quantification of collagen content and pyridinoline crosslinks, bottom-up proteomics, and tensile mechanical testing. Collagen was 20 ± 2%/wet weight (WW) and 53 ± 4%/dry weight (DW). Pyridinoline content was 426 ±131 ng/mg WW, 1011 ± 190 ng/mg DW, and 45 ± 8 mmol/mol hydroxyproline. Bottom-up proteomics identified 14 proteins with an abundance of >0.1% of total protein. The most abundant collagen subtype was type I, representing 95.5 ± 1.5% of the total protein in the samples. Collagen types III, XII, and VI were quantified at 1.7 ± 1.0%, 0.8 ± 0.2%, and 0.4 ± 0.2%, respectively. Tensile testing revealed anisotropy: Young's modulus was significantly higher longitudinally than circumferentially (60 ± 18 MPa vs. 8 ± 5 MPa, p < 0.01), as was ultimate tensile strength (16 ± 4 MPa vs. 3 ± 3 MPa, p < 0.01). Taken together, the tissue mechanical and compositional data obtained in this study provide important benchmarks for the development of TA biomaterials. STATEMENT OF SIGNIFICANCE: The tunica albuginea of the penis serves an important structural role in physiologic penile erection. This tissue can become damaged by disease or trauma, leading to pain and deformity. Treatment options are limited. Little is known about the precise biochemical composition and biomechanical properties of healthy tunica albuginea. In this study, we characterize the tissue using proteomic analysis and tensile testing to establish design parameters for future tissue engineering efforts. To our knowledge, this is the first study to quantify tissue anisotropy and to use bottom-up proteomics to characterize the composition of penile tunica albuginea.
Topics: Male; Humans; Animals; Swine; Penile Induration; Anisotropy; Proteomics; Tissue Engineering; Penis; Collagen; Structure-Activity Relationship
PubMed: 37579910
DOI: 10.1016/j.actbio.2023.08.017 -
International Journal of Molecular... Jul 2023This study aimed to investigate the mechanism underlying social stress (SS)-induced erectile dysfunction (ED) and evaluate the effects of a single subanesthetic dose of...
This study aimed to investigate the mechanism underlying social stress (SS)-induced erectile dysfunction (ED) and evaluate the effects of a single subanesthetic dose of ketamine on SS-related ED. Male FVB mice were exposed to retired male C57BL/6 mice for 60 min daily over a 4-week period. In the third week, these FVB mice received intraperitoneal injections of either saline (SSS group) or ketamine (SSK group). Erectile function was assessed by measuring the intracavernosal pressure (ICP) during electrical stimulation of the major pelvic ganglia. Corpus cavernosum (CC) strips were utilized for wire myography to assess their reactivity. Both SSS and SSK mice exhibited significantly lower ICP in response to electrical stimulation than control mice. SS mice showed increased contractility of the CC induced by phenylephrine. Acetylcholine-induced relaxation was significantly reduced in SSS and SSK mice. Sodium nitroprusside-induced relaxation was higher in SSS mice compared to control and SSK mice. Nicotine-induced neurogenic and nitric oxide-dependent relaxation was significantly impaired in both SSS and SSK mice. An immunohistochemical analysis revealed co-localization of tyrosine hydroxylase and neuronal nitric oxide synthase-immunoreactive fibers in the CC. These findings highlight the complex nature of SS-related ED and suggest the limited efficacy of ketamine as a therapeutic intervention.
Topics: Humans; Male; Mice; Animals; Erectile Dysfunction; Ketamine; Mice, Inbred C57BL; Penile Erection; Penis; Synaptic Transmission
PubMed: 37569356
DOI: 10.3390/ijms241511973 -
BMC Urology Aug 2023An arteriovenous fistula is an abnormal communication between an artery and a vein. Traumatic penile arteriospongious fistula is a rare complication and has been... (Review)
Review
BACKGROUND
An arteriovenous fistula is an abnormal communication between an artery and a vein. Traumatic penile arteriospongious fistula is a rare complication and has been described as a cause of erectile dysfunction. Clinical evaluation of patients with erectile dysfunction after penile trauma includes a thorough history, physical examination, vascular assessment, and other complementary exams. Treatment consists of endovascular embolization, surgical ligation, or a combination of both techniques.
CASE PRESENTATION
A 40-year-old man presented with erectile dysfunction that had persisted since suffering blunt trauma a few months ago. He reported problems with short duration of erection and insufficient penile tumescence. Due to high suspicion of an arteriovenous fistula, he was referred to angiography, which confirmed the diagnosis of an abnormal connection between the pudendal vessels. The patient was treated with the coil embolization technique and the symptoms were successfully resolved after endovascular treatment.
CONCLUSIONS
The appearance of a post-traumatic arteriospongious fistula is a rare complication with almost non-existent literature reported. Rapid development in endovascular techniques, in which we use embolic agents to block anomalous blood flow, has allowed safe, effective and less invasive alternative to surgery. Our case demonstrates that endovascular approach is a successful treatment for post-traumatic arteriospongious fistula since the symptoms were resolved, and normal erectile function was regained after the intervention.
Topics: Male; Humans; Adult; Erectile Dysfunction; Penis; Penile Erection; Arteriovenous Fistula; Angiography; Embolization, Therapeutic
PubMed: 37558999
DOI: 10.1186/s12894-023-01305-7 -
Asian Journal of Andrology Jan 2024Hyperlipidemia is a major risk factor for erectile dysfunction (ED). Oxidative stress and phenotypic modulation of corpus cavernosum smooth muscle cells (CCSMCs) are the...
N-acetylcysteine ameliorates erectile dysfunction in rats with hyperlipidemia by inhibiting oxidative stress and corpus cavernosum smooth muscle cells phenotypic modulation.
Hyperlipidemia is a major risk factor for erectile dysfunction (ED). Oxidative stress and phenotypic modulation of corpus cavernosum smooth muscle cells (CCSMCs) are the key pathological factors of ED. N-acetylcysteine (NAC) can inhibit oxidative stress; however, whether NAC can alleviate pathological variations in the corpus cavernosum and promote erectile function recovery in hyperlipidemic rats remains unclear. A hyperlipidemia model was established using 27 eight-week-old male Sprague-Dawley (SD) rats fed a high-fat and high-cholesterol diet (hyperlipidemic rats, HR). In addition, 9 male SD rats were fed a normal diet to serve as controls (NC). HR rats were divided into three groups: HR, HR+normal saline (NS), and HR+NAC (n = 9 for each group; NS or NAC intraperitoneal injections were administered daily for 16 weeks). Subsequently, the lipid profiles, erectile function, oxidative stress, phenotypic modulation markers of CCSMCs, and tissue histology were analyzed. The experimental results revealed that erectile function was significantly impaired in the HR and HR + NS groups, but enhanced in the HR + NAC group. Abnormal lipid levels, over-activated oxidative stress, and multi-organ lesions observed in the HR and HR + NS groups were improved in the HR + NAC group. Moreover, the HR group showed significant phenotypic modulation of CCSMCs, which was also inhibited by NAC treatment. This report focuses on the therapeutic effect of NAC in restoring erectile function using a hyperlipidemic rat model by preventing CCSMC phenotypic modulation and attenuating oxidative stress.
Topics: Male; Animals; Hyperlipidemias; Oxidative Stress; Erectile Dysfunction; Acetylcysteine; Rats, Sprague-Dawley; Rats; Penis; Myocytes, Smooth Muscle; Phenotype; Penile Erection
PubMed: 37534881
DOI: 10.4103/aja202324 -
International Urology and Nephrology Nov 2023We aimed in the current study to identify the predictive factors of ED occurrence in healthy individuals following penile fracture surgical repair as well as the effect...
Role of penile rehabilitation through daily intake of 5 mg tadalafil on erectile dysfunction after different presentations of penile fracture: a prospective case-control study.
PURPOSE
We aimed in the current study to identify the predictive factors of ED occurrence in healthy individuals following penile fracture surgical repair as well as the effect of penile rehabilitation in the form of daily tadalafil 5 mg intake for 1 month for patients who suffered from ED after penile fracture incident.
METHOD
The current study was a prospective case-control study. Twenty-five patients were enrolled into the study starting from January (2022) to February (2023). Furthermore, time of presentation was determined, and length of tear intra-operative was measured, and then, a follow-up 1 week postoperatively in the outpatient clinic was conducted. All patients were instructed to start intercourse at least 2 weeks after the first visit provided that the wound epithelialized. Potent patients returned back home. A rehabilitation course of daily tadalafil 5 mg for 1 month was prescribed for patients who started complaining of ED that was confirmed by evaluation with the Arabic validated version of the international index of erectile function (ArIIEF-5). The rehabilitation therapy was terminated by resumption of normal erectile function. Thus, re-evaluation with the ArIIEF-5 was determined according to their response to therapy. Also, the patients were evaluated by hospital anxiety and depression scale (HADS) before and after penile fracture repair.
RESULTS
The current study had demonstrated that a 1% increase in age determines an increase in odds ratio for post-penile fracture ED with 73.6% and 1 cm increase in the length of tear determines an increase in odds ratio for post-penile fracture ED with 20.04 times.
CONCLUSION
The current study enhances the proper counseling of these patients prior to repairing the defect about the probability of ED occurrence as well as initiating early penile rehabilitation to help these patients resuming their normal sexual activity as soon as possible.
Topics: Male; Humans; Erectile Dysfunction; Tadalafil; Case-Control Studies; Penis; Penile Erection; Rupture; Treatment Outcome; Carbolines
PubMed: 37526789
DOI: 10.1007/s11255-023-03713-y -
Journal of Clinical Medicine Jul 2023Pediatric chronic myeloid leukemia (CML) is a very rare malignancy (age-related incidence 0.1/100,000) typically presenting with leucocyte counts >100,000/µL. However,... (Review)
Review
Pediatric chronic myeloid leukemia (CML) is a very rare malignancy (age-related incidence 0.1/100,000) typically presenting with leucocyte counts >100,000/µL. However, clinical signs of leukostasis are observed at diagnosis in only approximately 10% of all cases and among these, priapism is infrequent. Here, we analyze data from pediatric CML registries on the occurrence of priapism heralding diagnosis of CML in 16/491 (3.2%) boys (median age 13.5 years, range 4-18) with pediatric CML. In the cohort investigated, duration of priapism resulting in a diagnosis of CML was not reported in 5 patients, and in the remaining 11 patients, occurred as stuttering priapism over 3 months ( = 1), over 6 weeks ( = 1), over 1-2 weeks ( = 2), over several days ( = 2), or 24 h ( = 1), while the remaining 4 boys reported continuous erection lasting over 11-12 h. All patients exhibited splenomegaly and massive leukocytosis (median WBC 470,000/µL, range 236,700-899,000). Interventions to treat priapism were unknown in 5 patients, and in the remaining cohort, comprised intravenous fluids ± heparin ( = 2), penile puncture ( = 5) ± injection of sympathomimetics ( = 4) ± intracavernous shunt operation ( = 1) paralleled by leukocyte-reductive measures. Management without penile puncture by leukapheresis or exchange transfusion was performed in 3 boys. In total, 7 out 15 (47%) long-term survivors (median age 20 years, range 19-25) responded to a questionnaire. All had maintained full erectile function; however, 5/7 had presented with stuttering priapism while in the remaining 2 patients priapism had lasted <12 h until intervention. At its extreme, low-flow priapism lasting for longer than 24 h may result in partial or total impotence by erectile dysfunction. This physical disability can exert a large psychological impact on patients' lives. In a narrative review fashion, we analyzed the literature on priapism in boys with CML which is by categorization stuttering or persisting as mostly painful, ischemic (low-flow) priapism. Details on the pathophysiology are discussed on the background of the different blood rheology of hyperleukocytosis in acute and chronic leukemias. In addition to the data collected, instructive case vignettes demonstrate the diagnostic and treatment approaches and the outcome of boys presenting with priapism. An algorithm for management of priapism in a stepwise fashion is presented. All approaches must be performed in parallel with cytoreductive treatment of leukostasis in CML which comprises leukapheresis and exchange transfusions ± cytotoxic chemotherapy.
PubMed: 37510891
DOI: 10.3390/jcm12144776 -
Case Reports in Urology 2023Priapism is a prolonged involuntary erection that can have severe complications if left untreated. Ischaemic priapism is very rare in children and requires urgent...
Priapism is a prolonged involuntary erection that can have severe complications if left untreated. Ischaemic priapism is very rare in children and requires urgent intervention to prevent permanent erectile dysfunction and penile shortening. It can be caused by ischaemia in sickle cell anaemia, leukaemia, trauma, drugs, or idiopathy. Homocystinuria is a rare autosomal recessive disorder that can cause hyperhomocysteinemia and hypercoagulability. Very few reports suggested that priapism can be caused by hyperhomocysteinemia, and they were in adults. However, we present the first of such a case to the best of our knowledge of a prepubescent child who only had the MTHFR (C677T) mutation that causes homocystinuria and had ischaemic priapism. A nine-year-old Syrian Arab boy was presented with priapism that lasted for a few hours. Blood tests show normal blood count, film, and haemoglobin electrophoresis. However, prothrombin time, partial thromboplastin time, homocysteine level, and C-reactive protein were elevated. Other coagulation tests were within the normal range. Doppler ultrasonography found decreased cavernous blood flow, and warm 0.9% saline lavage of the cavernosa was indicated and successfully treated the priapism. Genetic testing for the homozygous MTHFR (C677T) mutation was later confirmed, and warfarin was indicated. In conclusion, homocystinuria is very rare in priapism, and this is the first case to report this phenomenon in a child. Ultrasonography in low-income countries is an essential tool that helps identify a wide variety of medical conditions such as priapism and can be successfully managed by aspiration with warm saline.
PubMed: 37485311
DOI: 10.1155/2023/2263341