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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 -
International Journal of Impotence... Sep 2022Men with Stuttering Priapism (SP) and sleep-related painful erections (SRPE) experience bothersome nocturnal painful erections resulting in poor sleep. The aim of this...
Men with Stuttering Priapism (SP) and sleep-related painful erections (SRPE) experience bothersome nocturnal painful erections resulting in poor sleep. The aim of this study is to observe common features and differences between men with SP and SRPE based on polysomnography, nocturnal penile tumescence (NPT), and penile doppler ultrasound (PDU). This is a prospective cohort study of 20 participants divided into two groups (Group 1 = SP [n = 12]; Group 2 = SRPE [n = 8]) with bothersome painful nocturnal erections. All participants were referred to the sleep disorder clinic to be assessed and consented for overnight polysomnography with simultaneous NPT recording and to complete validated sleep, sexual dysfunction and health-related quality of life questionnaires. Unstimulated PDU was also performed. Abnormal Polysomnographic findings (reduced sleep efficiency, total sleep time, and awake after sleep onset) were identified in both groups suggesting poor sleep. Men with SP had significantly longer erections (60.0 vs 18.5; p = 0.002) and took longer to detumesce once awake (25.7 vs 5.4 min; p = 0.001) than men with SRPE. They also had significantly higher peak systolic and end diastolic velocities on unstimulated PDU with an abnormal low resistance waveform identified. No sleep pathology was identified in men with SP. This implies a local (penile) etiology in men with SP. Men with SRPE had a normal resting PDU and abnormal sleep architecture with REM awakenings and significantly more Periodic limb movements (p = 0.04) than men with SP suggesting a central (sleep-related) cause in men with SRPE. Sexual dysfunction and poor HR-QoL was identified on validated questionnaires in both groups. SP and SRPE are rare entities that share similar symptoms (painful nocturnal erections and poor sleep) but dissimilar features of nocturnal erection onset, duration and resolution with different polysomnographic features which may allude to a different pathophysiology.
Topics: Humans; Male; Pain; Penile Erection; Priapism; Prospective Studies; Quality of Life; REM Sleep Parasomnias; Stuttering; Ultrasonography, Doppler
PubMed: 34389802
DOI: 10.1038/s41443-021-00462-3 -
Frontiers in Physiology 2022Erectile dysfunction (ED) is the most common male sexual dysfunction by far and the prevalence is increasing year after year. As technology advances, a wide range of... (Review)
Review
Erectile dysfunction (ED) is the most common male sexual dysfunction by far and the prevalence is increasing year after year. As technology advances, a wide range of physical diagnosis tools and therapeutic approaches have been developed for ED. At present, typical diagnostic devices include erection basic parameter measuring instrument, erection hardness quantitative analysis system, hemodynamic testing equipment, nocturnal erection measuring instrument, nerve conduction testing equipment, At present, the most commonly used treatment for ED is pharmacological therapy represented by phosphodiesterase five inhibitors (PDE5i). As a first-line drug in clinical, PDE5i has outstanding clinical effects, but there are still some problems that deserve the attention of researchers, such as cost issues and some side effects, like visual disturbances, indigestion, myalgia, and back pain, as well as some non-response rates. Some patients have to consider alternative treatments. Moreover, the efficacy in some angiogenic EDs (diabetes and cardiovascular disease) has not met expectations, so there is still a need to continuously develop new methods that can improve hemodynamics. While drug have now been shown to be effective in treating ED, they only control symptoms and do not restore function in most cases. The increasing prevalence of ED also makes us more motivated to find safer, more effective, and simpler treatments. The exploration of relevant mechanisms can also serve as a springboard for the development of more clinically meaningful physiotherapy approaches. Therefore, people are currently devoted to studying the effects of physical therapy and physical therapy combined with drug therapy on ED. We reviewed the diagnosis of ED and related physical therapy methods, and explored the pathogenesis of ED. In our opinion, these treatment methods could help many ED patients recover fully or partially from ED within the next few decades.
PubMed: 36699684
DOI: 10.3389/fphys.2022.1096741 -
The Journal of Sexual Medicine Apr 2021Current treatments for erectile dysfunction (ED) are ineffective in prostatectomy and diabetic patients due to cavernous nerve (CN) injury, which causes smooth muscle...
BACKGROUND
Current treatments for erectile dysfunction (ED) are ineffective in prostatectomy and diabetic patients due to cavernous nerve (CN) injury, which causes smooth muscle apoptosis, penile remodeling, and ED. Apoptosis can occur via the intrinsic (caspase 9) or extrinsic (caspase 8) pathway.
AIM
We examined the mechanism of how apoptosis occurs in ED patients and CN injury rat models to determine points of intervention for therapy development.
METHODS AND OUTCOMES
Immunohistochemical and western analyses for caspase 3-cleaved, caspase-8 and caspase-9 (pro and active forms) were performed in corpora cavernosal tissue from Peyronie's, prostatectomy and diabetic ED patients (n = 33), penis from adult Sprague Dawley rats that underwent CN crush (n = 24), BB/WOR diabetic and control rats (n = 8), and aged rats (n = 9).
RESULTS
Caspase 3-cleaved was observed in corpora cavernosa from Peyronie's patients and at higher abundance in prostatectomy and diabetic tissues. Apoptosis takes place primarily through the extrinsic (caspase 8) pathway in penis tissue of ED patients. In the CN crushed rat, caspase 3-cleaved was abundant from 1-9 days after injury, and apoptosis takes place primarily via the intrinsic (caspase 9) pathway. Caspase 9 was first observed and most abundant in a layer under the tunica, and after several days was observed in the lining of and between the sinuses of the corpora cavernosa. Caspase 8 was initially observed at low abundance in the rat corpora cavernosa and was not observed at later time points after CN injury. Aged and diabetic rat penis primarily exhibited intrinsic mechanisms, with diabetic rats also exhibiting mild extrinsic activation.
CLINICAL TRANSLATION
Knowing how and when to intervene to prevent the apoptotic response most effectively is critical for the development of drugs to prevent ED, morphological remodeling of the corpora cavernosa, and thus, disease management.
STRENGTHS AND LIMITATIONS
Animal models may diverge from the signaling mechanisms observed in ED patients. While the rat utilizes primarily caspase 9, there is a significant flux through caspase 8 early on, making it a reasonable model, as long as the timing of apoptosis is considered after CN injury.
CONCLUSIONS
Apoptosis takes place primarily through the extrinsic caspase 8 dependent pathway in ED patients and via the intrinsic caspase 9 dependent pathway in commonly used CN crush ED models. This is an important consideration for study design and interpretation that must be taken into account for therapy development and testing of drugs, and our therapeutic targets should ideally inhibit both apoptotic mechanisms. Martin S, Harrington DA, Ohlander S, et al. Caspase Signaling in ED Patients and Animal Models. J Sex Med 2021;18:711-722.
Topics: Animals; Caspases; Diabetes Mellitus, Experimental; Disease Models, Animal; Erectile Dysfunction; Hedgehog Proteins; Humans; Male; Penile Erection; Penis; Rats; Rats, Sprague-Dawley
PubMed: 33707045
DOI: 10.1016/j.jsxm.2021.01.175 -
Frontiers in Immunology 2020Experimental autoimmune prostatitis (EAP) is a well-established model induced by an autoimmune response to prostate antigen. The symptomatic, pathological, and...
Experimental autoimmune prostatitis (EAP) is a well-established model induced by an autoimmune response to prostate antigen. The symptomatic, pathological, and immunological characteristics of EAP animals are highly consistent with human chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), which makes EAP an ideal model for this disease. Here, we investigate the influence of EAP on male rat sexual function and the efficacy of anti-inflammatory therapy with celecoxib. EAP rat models were established using male Wistar rats. Rats were randomly assigned to a normal control group, an EAP model group, or an EAP model with celecoxib treatment group (celecoxib group). Behavioral changes, sexual behavioral changes, and erectile function were estimated using an open-field test, a sucrose consumption test, mating experiments, and by intracavernous pressure/mean arterial pressure ratio (ICP/MAP). Histological changes in the prostate were observed by HE staining, and the serum inflammatory factors IL-1β and TNF-α levels were measured by enzyme-linked immunosorbent assay. In addition, serotonin (5-hydroxytryptamine, 5-HT), 5-HT receptor, 5-HT receptor, and serotonin transporter (SERT) expression levels in the hippocampus and spinal cord (T13-L1, L5-S2) were examined by immunohistochemistry and western blot analysis. Results showed that EAP rats exhibited characteristics of depression, decreased sexual drive, premature ejaculation, and increased threshold of penile erection. Moreover, all these changes were effectively alleviated by celecoxib. Significant increases in prostatic interstitial infiltration by inflammatory cells and in serum IL-1β and TNF-α levels were observed in EAP rats, and these were partially reduced by celecoxib. Additionally, the expression pattern of serotonin system regulators in the hippocampus and spinal cord were altered in EAP model rats, including a decrease in 5-HT levels and an increase in 5-HT receptor levels. In conclusion, autoimmune prostatitis impaired rat sexual function, and this was effectively prevented by anti-inflammatory therapy with celecoxib. Moreover, a serotonin system disorder in the central nervous system was likely mediated via inflammation in EAP rats.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Autoimmune Diseases; Celecoxib; Depression; Disease Models, Animal; Erectile Dysfunction; Hippocampus; Inflammation; Interleukin-1beta; Male; Prostate; Prostatitis; Rats; Rats, Wistar; Serotonin; Sexual Behavior; Treatment Outcome
PubMed: 33013933
DOI: 10.3389/fimmu.2020.574212 -
International Orthopaedics Oct 2021Pelvic ring injuries, frequently caused by high energy trauma, are associated with high rates of morbidity and mortality (5-33%), often due to significant blood loss and... (Review)
Review
INTRODUCTION
Pelvic ring injuries, frequently caused by high energy trauma, are associated with high rates of morbidity and mortality (5-33%), often due to significant blood loss and disruption of the lumbosacral plexus, genitourinary system, and gastrointestinal system. The aim of the present study is to perform a systematic literature review on male and female sexual dysfunctions related to traumatic lesions of the pelvic ring.
METHODS
Scopus, Cochrane Library MEDLINE via PubMed, and Embase were searched using the keywords: "Pelvic fracture," "Pelvic Ring Fracture," "Pelvic Ring Trauma," "Pelvic Ring injury," "Sexual dysfunction," "Erectile dysfunction," "dyspareunia," and their MeSH terms in any possible combination. The following questions were formulated according to the PICO (population (P), intervention (I), comparison (C), and outcome (O)) scheme: Do patients suffering from pelvic fracture (P) report worse clinical outcomes (C), in terms of sexual function (O), when urological injury occurs (I)? Is the sexual function (O) influenced by the type of fracture (I)?
RESULTS
After screening 268 articles by title and abstract, 77 were considered eligible for the full-text analysis. Finally 17 studies that met inclusion criteria were included in the review. Overall, 1364 patients (902 males and 462 females, M/F ratio: 1.9) suffering from pelvic fractures were collected.
DISCUSSION
Pelvic fractures represent challenging entities, often concomitant with systemic injuries and subsequent morbidity. Anatomical consideration, etiology, correlation between sexual dysfunction and genitourinary lesions, or pelvic fracture type were investigated.
CONCLUSION
There are evidences in the literature that the gravity and frequency of SD are related with the pelvic ring fracture type. In fact, patients with APC, VS (according Young-Burgess), or C (according Tile) fracture pattern reported higher incidence and gravity of SD. Only a week association could be found between GUI and incidence and gravity of SD, and relationship between surgical treatment and SD. Electrophysiological tests should be routinely used in patient suffering from SD after pelvic ring injuries.
Topics: Causality; Female; Fractures, Bone; Humans; Incidence; Lumbosacral Plexus; Male; Pelvic Bones; Retrospective Studies
PubMed: 34378143
DOI: 10.1007/s00264-021-05153-8 -
JAMA Network Open Feb 2023The human physiological sexual response is crucial for reward, satisfaction, and reproduction. Disruption of the associated neurophysiological pathways predisposes to... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
The human physiological sexual response is crucial for reward, satisfaction, and reproduction. Disruption of the associated neurophysiological pathways predisposes to low sexual desire; the most prevalent psychological form is hypoactive sexual desire disorder (HSDD), which affects 8% of men but currently has no effective pharmacological treatment options. The reproductive neuropeptide kisspeptin offers a putative therapeutic target, owing to emerging understanding of its role in reproductive behavior.
OBJECTIVE
To determine the physiological, behavioral, neural, and hormonal effects of kisspeptin administration in men with HSDD.
DESIGN, SETTING, AND PARTICIPANTS
This double-blind, 2-way crossover, placebo-controlled randomized clinical trial was performed at a single academic research center in the UK. Eligible participants were right-handed heterosexual men with HSDD. Physiological, behavioral, functional magnetic resonance imaging (fMRI), and hormonal analyses were used to investigate the clinical and mechanistic effects of kisspeptin administration in response to visual sexual stimuli (short and long video tasks). The trial was conducted between January 11 and September 15, 2021, and data analysis was performed between October and November 2021.
INTERVENTIONS
Participants attended 2 study visits at least 7 days apart, in balanced random order, for intravenous infusion of kisspeptin-54 (1 nmol/kg/h) for 75 minutes or for administration of a rate-matched placebo.
MAIN OUTCOMES AND MEASURES
Changes in (1) brain activity on whole-brain analysis, as determined by fMRI blood oxygen level-dependent activity in response to visual sexual stimuli during kisspeptin administration compared with placebo, (2) physiological sexual arousal (penile tumescence), and (3) behavioral measures of sexual desire and arousal.
RESULTS
Of the 37 men randomized, 32 completed the trial. Participants had a mean (SD) age of 37.9 (8.6) years and a mean (SD) body mass index of 24.9 (5.4). On viewing sexual videos, kisspeptin significantly modulated brain activity in key structures of the sexual-processing network on whole-brain analysis compared with placebo (mean absolute change [Cohen d] = 0.81 [95% CI, 0.41-1.21]; P = .003). Furthermore, improvements in several secondary analyses were observed, including significant increases in penile tumescence in response to sexual stimuli (by up to 56% more than placebo; mean difference = 0.28 units [95% CI, 0.04-0.52 units]; P = .02) and behavioral measures of sexual desire-most notably, increased happiness about sex (mean difference = 0.63 points [95% CI, 0.10-1.15 points]; P = .02).
CONCLUSIONS AND RELEVANCE
Collectively, this randomized clinical trial provides the first evidence to date showing that kisspeptin administration substantially modulates sexual brain processing in men with HSDD, with associated increases in penile tumescence and behavioral measures of sexual desire and arousal. These data suggest that kisspeptin has potential as the first pharmacological treatment for men with low sexual desire.
TRIAL REGISTRATION
isrctn.org Identifier: ISRCTN17271094.
Topics: Male; Humans; Adult; Penile Erection; Kisspeptins; Sexual Behavior; Sexual Dysfunctions, Psychological; Brain
PubMed: 36735255
DOI: 10.1001/jamanetworkopen.2022.54313 -
Scientific Reports Jun 2021Erectile dysfunction (ED) is mostly due to the lack of blood flow into the penis. In the past 20 years, near-infrared spectroscopy (NIRS) was used in measuring the... (Clinical Trial)
Clinical Trial
Erectile dysfunction (ED) is mostly due to the lack of blood flow into the penis. In the past 20 years, near-infrared spectroscopy (NIRS) was used in measuring the concentrations and temporal dynamics of different hemoglobin types. However, the dynamics of the light absorption (photoplethysmography; PPG) have not been applied to survey penile hemodynamics and erection quality. This paper compared the use of photoplethysmography (PPG) to study vascular ED with standard penile Doppler ultrasonography. Men diagnosed with vascular ED for at least 6 months and nominated for penile ultrasonography were included. PPG signals were collected during the ultrasound examination. All beat-to-beat PPG waveforms were aligned with the peak and averaged to one representative template waveform for feature analysis, including amplitude differences (APD) index, reflection time index (RTI), augmentation index (AI), and perfusion index (PI). An inverse correlation was found between end-erection amplitude and both erection hardness score (EHS) and resistive index (RI). APD index and EHS as well as the international index of erectile function-5 (IIEF) and RI were positively correlated. RTI and AI were inversely correlated to IIEF and RI. PI was positively correlated to RI. PPG may therefore be useful as a noninvasive, convenient, technique for sexual function evaluation.
Topics: Aged; Hemodynamics; Humans; Male; Middle Aged; Penile Erection; Penis; Photoplethysmography
PubMed: 34103629
DOI: 10.1038/s41598-021-91582-9 -
Sexual Medicine Jun 2021Penile fracture is a urologic emergency and is defined as the rupture of the tunica albuginea of the cavernous body in erection.
INTRODUCTION
Penile fracture is a urologic emergency and is defined as the rupture of the tunica albuginea of the cavernous body in erection.
AIM
Our study aims to evaluate patients with penile fracture and to identify the factors that may influence the sexual function after surgical repair.
METHODS
A total of 138 patients who were diagnosed with penile fracture between January, 1999 and December, 2018 were reviewed. Clinical features, perioperative assessment, time from injury to surgery, tunica defect properties, and presence of urethral injury were assessed.
MAIN OUTCOME MEASURES
Sexual function was evaluated by three parameters six months after surgical repair: International Index of Erectile Function-5 (IIEF-5) questionnaire, penile curvature and the presence of a painful intercourse. All factors that could potentially influence these parameters were analyzed.
RESULTS
The mean age was 31.2 years (19-55). Presentation delay ranged from 1 to 5 days (mean = 16.8 hours) while surgery delay was 14.3 hours ().The most common cause of penile fracture in our patients was forcefully bending of the erect penis to achieve detumescence in 62 cases (44.9%). On multivariate analysis, we found that the presentation delay and the fracture site located in the proximal shaft of the penis showed significant difference in the occurrence of postoperative ED (P = 0.03 and P = 0.015 respectively). Presentation delay, elective incision and tuncial leak located in the proximal shaft (P = 0.045; P = 0.018 and P = 0.022 respectively) were associated with higher penis curvature.
CONCLUSION
Immediate surgical repair and circumferential degloving incision for tunical leaks located in the proximal shaft of the penis are recommended in order to decrease the incidence of ED after surgical repair of penile fractures. Ouanes Y, Saadi MH, Alouene HH, et al. Sexual Function Outcomes After Surgical Treatment of Penile Fracture. Sex Med 2021;9:100353.
PubMed: 34062494
DOI: 10.1016/j.esxm.2021.100353