Management of Male Infertility with Coexisting Sexual Dysfunction: A Consensus Statement and Clinical Recommendations from the Asia-Pacific Society of Sexual Medicine (APSSM) and the Asian Society of Men's Health and Aging (ASMHA).

Male infertility (MI) and male sexual dysfunction (MSD) can often coexist together due to various interplay factors such as psychosexual, sociocultural and relationship dynamics. The presence of each form of MSD can adversely impact male reproduction and treatment strategies will need to be individualized based on patients' factors, local expertise, and geographical socioeconomic status. The Asia Pacific Society of Sexual Medicine (APSSM) and the Asian Society of Men's Health and Aging (ASMHA) aim to provide a consensus statement and practical set of clinical recommendations based on current evidence to guide clinicians in the management of MI and MSD within the Asia-Pacific (AP) region. A comprehensive, narrative review of the literature was performed to identify the various forms of MSD and their association with MI. MEDLINE and EMBASE databases were searched for the following English language articles under the following terms: "low libido", "erectile dysfunction", "ejaculatory dysfunction", "premature ejaculation", "retrograde ejaculation", "delayed ejaculation", "anejaculation", and "orgasmic dysfunction" between January 2001 to June 2022 with emphasis on published guidelines endorsed by various organizations. This APSSM consensus committee panel evaluated and provided evidence-based recommendations on MI and clinically relevant MSD areas using a modified Delphi method by the panel and specific emphasis on locoregional socio-economic-cultural issues relevant to the AP region. While variations exist in treatment strategies for managing MI and MSD due to geographical expertise, locoregional resources, and sociocultural factors, the panel agreed that comprehensive fertility evaluation with a multidisciplinary management approach to each MSD domain is recommended. It is important to address individual MI issues with an emphasis on improving spermatogenesis and facilitating reproductive avenues while at the same time, managing various MSD conditions with evidence-based treatments. All therapeutic options should be discussed and implemented based on the patient's individual needs, beliefs and preferences while incorporating locoregional expertise and available resources.

Clinical recommendations on penile reconstructive and prosthetic surgery: a consensus statement from the Asia-Pacific Society of Sexual Medicine.

Introduction: Penile reconstructive and prosthetic surgery remains a highly specialized field where potential complications can be devastating, and unrealistic patient expectations can often be difficult to manage. Furthermore, surgical practice can vary depending on locoregional expertise and sociocultural factors. Methods: The Asia Pacific Society of Sexual Medicine (APSSM) panel of experts reviewed contemporary evidence regarding penile reconstructive and prosthetic surgery with an emphasis on key issues relevant to the Asia-Pacific (AP) region and developed a consensus statement and set of clinical practice recommendations on behalf of the APSSM. The Medline and EMBASE databases were searched using the following terms: "penile prosthesis implant," "Peyronie's disease," "penile lengthening," "penile augmentation," "penile enlargement," "buried penis," "penile disorders," "penile trauma," "transgender," and "penile reconstruction" between January 2001 and June 2022. A modified Delphi method was undertaken, and the panel evaluated, agreed, and provided consensus statements on clinically relevant penile reconstructive and prosthetic surgery, namely (1) penile prosthesis implantation, (2) Peyronie's disease, (3) penile trauma, (4) gender-affirming (phalloplasty) surgery, and (5) penile esthetic (length and/or girth enlargement) surgery. Main outcome measures: Outcomes were specific statements and clinical recommendations according to the Oxford Centre for Evidence-Based Medicine, and if clinical evidence is lacking, a consensus agreement is adopted. The panel provided statements on clinical aspects of surgical management in penile reconstructive and prosthetic surgery. Results: There is a variation in surgical algorithms in patients based on sociocultural characteristics and the availability of local resources. Performing preoperative counseling and obtaining adequate informed consent are paramount and should be conducted to discuss various treatment options, including the pros and cons of each surgical intervention. Patients should be provided with information regarding potential complications related to surgery, and strict adherence to safe surgical principles, preoperative optimization of medical comorbidities and stringent postoperative care are important to improve patient satisfaction rates. For complex patients, surgical intervention should ideally be referred and performed by expert high-volume surgeons to maximize clinical outcomes. Clinical implications: Due to the uneven distribution of surgical access and expertise across the AP region, development of relevant comprehensive surgical protocols and regular training programs is desirable. Strengths and Limitations: This consensus statement covers comprehensive penile reconstructive and prosthetic surgery topics and is endorsed by the APSSM. The variations in surgical algorithms and lack of sufficient high-level evidence in these areas could be stated as a limitation. Conclusion: This APSSM consensus statement provides clinical recommendations on the surgical management of various penile reconstructive and prosthetic surgeries. The APSSM advocates for surgeons in AP to individualize surgical options based on patient condition(s) and needs, surgeon expertise, and local resources.

Erectile dysfunction after COVID-19 recovery: A follow-up study.

OBJECTIVES: Several studies confirm multiple complications after COVID-19 infection, including men's sexual health, which is caused by both physical and psychological factors. However, studies focusing on long-term effects among recovered patients are still lacking. Therefore, we aimed to investigate the erectile function at three months after COVID-19 recovery along with its predicting factors. METHODS: We enrolled all COVID-19 male patients, who were hospitalized from May to July 2021, and declared to be sexually active within the previous two weeks. Demographic data, mental health status, and erectile function were collected at baseline and prospectively recollected three months after hospital discharge. To determine changes between baseline and the follow-up, a generalized linear mixed effect model (GLMM) was used. Also, logistic regression analysis was used to identify the associating factors of erectile dysfunction (ED) at three months. RESULTS: One hundred fifty-three men with COVID-19 participated. Using GLMM, ED prevalence at three months after recovery was 50.3%, which was significantly lower compared with ED prevalence at baseline (64.7%, P = 0.002). Declination of prevalence of major depression and anxiety disorder was found, but only major depression reached statistical significance (major depression 13.7% vs. 1.4%, P < 0.001, anxiety disorder 5.2% vs. 2.8% P = 0.22). Logistic regression, adjusted for BMI, medical comorbidities, and self-reported normal morning erection, showed a significant association between ED at three months and age above 40 years and diagnosis of major depression with adjusted OR of 2.65, 95% CI 1.17-6.01, P = 0.02 and 8.93, 95% CI 2.28-34.9, P = 0.002, respectively. CONCLUSION: Our study showed a high ED prevalence during the third month of recovery from COVID-19. The predicting factors of persistent ED were age over 40 years and diagnosis of major depression during acute infection.

COVID Pandemic Impact on Healthcare Provision and Patient Psychosocial Distress: A Multi-National Cross-Sectional Survey among Asia-Pacific Countries.

PURPOSE: COVID pandemic significantly affected the delivery and maintenance of healthcare system, resulting in greater utilization of digital health interventions. MATERIALS AND METHODS: This multi-national cross-sectional survey was administered to clinicians working in major Asia-Pacific cities during the mandatory social lockdown period in June 2020. Clinical demographics and professional data, delivery of Andrology-related healthcare services, and patient distress based on validated questionnaires such as Depression and Anxiety Stress Scales (DASS) and Decisional Engagement Scale (DES) were collected. RESULTS: Telehealth medicine was instituted in all the centres with the majority of centres (92.9%) reported a 50% or more reduction in out-patient related services. The numbers of phone calls, emails correspondence and educational webinars have significantly increased. Despite the provision of reasons for changes in healthcare service and delay in surgery, more than half of the patients (57.1%) rated 2 on the DASS score for the item on patients over-react to situations, while a third of the patients (35.7%) scored a 2 for DASS item on patients being more demanding or unreasonable. The DES scores were more positive with most patients reported a score above 7 out of 10 in terms of items on accepting current arrangement (85.7%), confident in clinician decision-making about treatment (92.9%) and comfortable that the decision is consistent with their preferences (71.4%). Most patients (85.7%) indicated their preferences for more detailed information on healthcare provision. CONCLUSIONS: Our study showed telehealth services were integrated early and successfully during the COVID pandemic and patients were generally receptive with minimal psychosocial distress.

Erectile dysfunction among Thai patients with COVID-19 infection.

BACKGROUND: Erectile dysfunction (ED) is suspected to be the symptom manifestation of COVID-19. However, scarce data was presented this day. Our study was conducted to determine the prevalence of ED and its associated factors among Thai patients with COVID-19. METHODS: Sexually active males with COVID-19, hospitalized between May and July 2021 at one university hospital in Bangkok, were screened for erectile dysfunction by the International Index of Erectile Function 5 (IIEF-5). Demographic data and COVID-19 treatment history were collected. Mental health status, including depression and anxiety, was evaluated with the Thai Patient Health Questionnaire 9 (PHQ-9) and the Generalized Anxiety Disorder Scale (GAD-7), respectively. The sample size was calculated, and logistic regression was used to analyze the association. RESULTS: One hundred fifty-three men with COVID-19 were recruited. ED prevalence was 64.7%, of which severity was mostly mild. Logistic regression, adjusted for age, BMI, and medical comorbidities, portrayed a significant association between ED and mental health status. Higher risk of ED was found in participants with major depression [adjusted OR 8.45, 95% CI: 1.01-70.96, P=0.049] and higher GAD-7 total score [adjusted OR 1.15, 95% CI: 1.01-1.31, P=0.039]. CONCLUSIONS: Thai patients with COVID-19 had high prevalence of ED, which was associated with mental disorders. Thus, screening for mental problems is recommended in individuals with COVID-19 and ED.

Provision of Sexual Medicine Services During the Coronavirus Disease-2019 Pandemic: An Asia Pacific Society of Sexual Medicine Position Statement.

The coronavirus disease-2019 (COVID-19) pandemic has caused an unprecedented healthcare crisis with various governmental healthcare policies enforced to redirect medical prioritization and minimize the spread of COVID19 infection. Recognizing that the COVID-19 crisis will be protracted, it is important that clinicians and the healthcare industry continue to adapt existing resources and review contingency plan amidst this uncertain and difficult times. The Asia Pacific Society of Sexual Medicine supports ongoing precautionary healthcare measures implemented by various institutions and governmental policies to contain and eliminate COVID19 infection. Clinicians are encouraged to modify and adapt various strategies that will continue to provide, support, and treat sexual health-related conditions in a safe and efficient manner. Chung E, Jiann BP, Nagao L, et al. Provision of Sexual Medicine Services During the Coronavirus Disease-2019 Pandemic: An Asia Pacific Society of Sexual Medicine Position Statement. J Sex Med 2020;8:325-326.

The Asia-Pacific Flexible Dose Study of Dapoxetine and Patient Satisfaction in Premature Ejaculation Therapy: The PASSION Study.

INTRODUCTION: Dapoxetine is a short-acting selective serotonin reuptake inhibitor for treatment of premature ejaculation (PE). AIM: To evaluate the efficacy and safety of dapoxetine 30 and 60 mg as needed in Asia-Pacific men with PE. METHODS: The study was a prospective, 12-week, open-label study to evaluate the efficacy and safety of flexible-dose dapoxetine in men with PE diagnosed by a Premature Ejaculation Diagnostic Tool score of at least 11, a self-estimated intravaginal ejaculation latency time (IELT) no longer than 2 minutes, and an International Index of Erectile Function erectile function domain score of at least 21. MAIN OUTCOME MEASURES: Percentage of subjects reporting their PE as at least "slightly better" using the Clinical Global Impression of Change (CGIC) question. RESULTS: Two hundred eighteen of 285 randomized subjects completed the study. The mean subject age was 45.9 years and 57.7% were Korean. Dosages 1 (30 mg), 2 (30 → 60 mg), and 3 (30 → 60 → 30 mg) were used in 141, 124, and 13 subjects, respectively. At study end, a PE CGIC rating of at least "slightly better" was reported by 77.3%, 92.8%, and 100% of subjects for dosages 1, 2, and 3, respectively (P = .49). At study end, a CGIC rating of "slightly better" was reported by 85.2% and 85.3% of subjects with lifelong PE and acquired PE, respectively (P = .50). At study end, a CGIC rating of "slightly better" was reported by 84.1% and 86.4% of subjects with an estimated baseline IELT no longer than and at least ≤1 minute, respectively (P = .16). The incidence of a CGIC rating of at least "slightly better" was lower in subjects reporting an adverse event of moderate or severe severity and in subjects who increased to and maintained a dapoxetine dose of 60 mg and higher in subjects older than 50 years and in subjects with a baseline estimated IELT of at least 1 minute. CONCLUSION: In this study, flexible dosing of dapoxetine (30 and 60 mg) appeared effective in the treatment of PE.

Thai men's health and sexual attitude.

Men's health awareness, including the research and study of quality of life, sexual desires and risk factors, has increased worldwide. In Thailand, this advancement is made possible by cooperation, research and sponsorship from the local Thai community. This article aims to illustrate the sexual attitudes of Thai people, to determine the degree of erectile dysfunction (ED) and to investigate how to manage and cope with ED in a Thai community. We reviewed the relevant literature from Thai-based articles and surveys in regard to men's health, sexual attitudes, the prevalence of ED and common risk factors in the Thai community. The primary risk factor for ED in Thai men was age-related health decline and the presence of vascular disease. Most Thai men will seek consultation from their partner in regard to ED. The main presentation of metabolic disease in Thai patients was dyslipidemia. New selective serotonin reuptake inhibitors are not available for premature ejaculation in Thai communities. The debate in regard to malpractice compensation is an issue that should be closely monitored. There is currently a shortage of home care for the elderly in Thailand. The insights provided by the articles helped recruit the study patients and in turn, helped us gain knowledge that can be translated into improved men's health care in Thailand.

Angiomyeloproliferative lesions following autologous stem cell therapy.

Some reports suggest that autologous hematopoietic stem cell transplantation holds potential for treatment of renal diseases such as lupus nephritis, but the safety of delivering various stem cell types (hematopoietic, mesenchymal, and endothelial precursors) is not well established. Here, we report a case of lupus nephritis treated by direct renal injection of autologous stem cells recovered from peripheral blood. The patient developed masses at the sites of injection and hematuria. We suspected transitional cell carcinoma but nephrectomy revealed that the masses were angiomyeloproliferative lesions. We believe that this previously undescribed pathologic entity is stem cell-derived or -induced. The biologic potential, including the neoplastic potential, of this lesion is unknown. This case illustrates that the development of angiomyeloproliferative lesions is a possible complication of stem cell therapy.

Increased prevalence of erectile dysfunction (ED): results of the second epidemiological study on sexual activity and prevalence of ED in Thai males.

OBJECTIVE: The aim of this study is to investigate changes in sexual activity and the prevalence of erectile dysfunction (ED) in Thai males. In addition, the treatment-seeking behaviour of Thai patients suffering from ED is also investigated. MATERIALS AND METHODS: In a cross sectional study using a standardized questionnaire with a multi-stage stratified random sampling, 2,269 men aged 40-70 were interviewed. The questionnaire was designed to investigate the effects of socioeconomic factors, medical conditions and unhealthy lifestyles on the development of ED. Furthermore, the questionnaire was designed to characterize the treatment-seeking behaviour of Thai patients suffering from ED. RESULTS: Compared to the first report dated the year 2000, the prevalence of ED has increased from 37.5% to 42.18%. In terms of socioeconomic factors, the highest prevalence of ED was observed among unemployed men (78.51%). Prostatism and/or prostatitis (Odd ratios (OR) = 2.02) and long histories of smoking (more than 30 years, OR = 2.36) were identified as statistically significant risk factors for ED, with p-values of <0.001. It is important to notice that 38.78% of the ED patients wanted to discuss their problem with spouses or partners. Three quarters of the ED patients (74.54%) preferred oral medication as therapy. CONCLUSIONS: The epidemiology of ED in Thailand is changing. An increased prevalence of ED does require further epidemiological studies on a regular basis in order to better understand the etiology of ED and look for measures (such as education) to counter the disease.

Intracavernous growth differentiation factor-5 therapy enhances the recovery of erectile function in a rat model of cavernous nerve injury.

INTRODUCTION: Neurogenic erectile dysfunction remains a serious complication in the postprostatectomy population. Effective protective and regenerative neuromodulatory strategies are needed. AIM: To determine the effect of growth differentiation factor-5 (GDF-5) on erectile function and its mechanism in a rat model of cavernous nerve (CN) injury. MAIN OUTCOME MEASURES: Erectile function was assessed by CN electrostimulation at 4 weeks. Penile tissues were examined by real-time polymerase chain reaction (PCR) and immunohistochemical analyses. METHODS: Forty-eight male Sprague-Dawley rats were randomly divided into six equal groups: one group underwent sham operation (uninjured controls), while five groups underwent bilateral CN crush. Crush-injury groups were treated at the time of injury with intracavernous injection of a slow-release suspension of liquid microparticles containing no GDF-5 (vehicle), 0.4 microg (low concentration), 2 microg (intermediate concentration), or 10 microg GDF-5 (high concentration). One untreated group served as injured controls. RESULTS: GDF-5 enhanced erectile recovery and significantly increased intracavernous pressure in the low and intermediate-concentration groups vs. injured controls. Low-concentration GDF-5 demonstrated the best functional preservation, as the intracavernous pressure increase in this group did not differ significantly from uninjured controls. A dose-response relationship was confirmed for the effects of GDF-5 in penile tissue. Low-concentration GDF-5 showed better preservation of the penile dorsal nerves and antiapoptotic effects in the corpus cavernosum (P < 0.05 vs. injured controls). Although high concentration GDF-5 did not confer meaningful erectile recovery, this dose was more effective at decreasing transforming growth factor-beta than low-concentration GDF-5. CONCLUSIONS: Intracavernous injection of low (0.4 microg) or intermediate-concentration GDF-5 (2 microg) was effective in preserving erectile function in a rat model of neurogenic erectile dysfunction. The underlying mechanism appears to involve neuron preservation and antiapoptosis.

The potential of hormones and selective oestrogen receptor modulators in preventing voiding dysfunction in rats.

OBJECTIVE: To investigate whether oestrogen, selective oestrogen receptor modulators (SERMs), and growth hormone (GH) can prevent the development of voiding dysfunction in a postpartum postmenopausal rat model of voiding dysfunction. MATERIALS AND METHODS: Immediately after spontaneous delivery, nine primiparous Sprague-Dawley rats served as uninjured controls (sham group) and 54 underwent intravaginal balloon dilation. On day 7, the 54 subject rats underwent bilateral ovariectomy. A week later, six treatment groups of nine rats were randomized to receive: normal saline (injured control group), 17beta-oestradiol (E(2)), raloxifene, levormeloxifene, GH, or GH + E(2). The treatment groups received daily subcutaneous injections for 3 weeks. The effects of hormone treatment were examined by conscious cystometry at the end of the study. Voiding dysfunction was defined to include overactive bladder and sphincter deficiency. RESULTS: The sham rats had a mean (sd) voiding frequency of 3 (0.87) times in 10 min and a bladder capacity of 0.43 (0.13) mL with smooth cystometry curves. The number of rats in each treatment group (each group contained nine rats) that had voiding dysfunction was as follows: E(2), three; raloxifene, six; levormeloxifene, four; and controls, four (P > 0.05 among the groups). Only one rat in the GH-treated group and no rats in the GH + E(2)-treated group had voiding dysfunction, which was significantly less in the GH + E(2)-treated group than in the controls (P = 0.041). CONCLUSION: This functional data suggest that the development of voiding dysfunction can be prevented by short-term administration of GH and GH + E(2) in our rat model. SERMs and E(2) alone seem to have no therapeutic effect.

Neurturin enhances the recovery of erectile function following bilateral cavernous nerve crush injury in the rat.

BACKGROUND: The molecular mechanisms responsible for the survival and preservation of function for adult parasympathetic ganglion neurons following injury remain incompletely understood. However, advances in the neurobiology of growth factors, neural development, and prevention of cell death have led to a surge of clinical interest for protective and regenerative neuromodulatory strategies, as surgical therapies for prostate, bladder, and colorectal cancers often result in neuronal axotomy and debilitating loss of sexual function or continence. In vitro studies have identified neurturin, a glial cell line-derived neurotrophic factor, as a neuromodulator for pelvic cholinergic neurons. We present the first in vivo report of the effects of neurturin upon the recovery of erectile function following bilateral cavernous nerve crush injury in the rat. METHODS: In these experiments, groups (n = 8 each) consisted of uninjured controls and animals treated with injection of albumin (blinded crush control group), extended release neurotrophin-4 or neurturin to the site of cavernous nerve crush injury (100 mug per animal). After 5 weeks, recovery of erectile function (treatment effect) was assessed by cavernous nerve electrostimulation and peak aortic pressures were measured. Investigators were unblinded to specific treatments after statistical analyses were completed. RESULTS: Erectile dysfunction was not observed in the sham group (mean maximal intracavernous pressure [ICP] increase of 117.5 +/- 7.3 cmH2O), whereas nerve injury and albumin treatment (control) produced a significant reduction in ICP elevation of 40.0 +/- 6.3 cmH2O. Neurturin facilitated the preservation of erectile function, with an ICP increase of 55% at 62.0 +/- 9.2 cmH2O (p < 0.05 vs control). Extended release neurotrophin-4 did not significantly enhance recovery of erectile function with an ICP change of 46.9 +/- 9.6. Peak aortic blood pressures did not differ between groups. No significant pre- and post-treatment weight differences were observed between control, neurotrophin-4 and neurturin cohorts. All animals tolerated the five-week treatment course. CONCLUSION: Treatment with neurturin at the site of cavernous nerve crush injury facilitates recovery of erectile function. Results support further investigation of neurturin as a neuroprotective and/or neuroregenerative agent facilitating functional recovery after cavernous or other pelvic autonomic nerve injuries.

Isolated septal fibrosis or hematoma--atypical Peyronie's disease?

PURPOSE: Classically Peyronie's disease presents with penile curvature and/or pain, and is associated with a palpable penile plaque. We frequently examine patients with suspected Peyronie's disease ultrasonographically and have noted a subset of patients in whom we could identify only a circumscribed septal lesion. We identified characteristics of these patients. MATERIALS AND METHODS: Of our series of approximately 650 patients with Peyronie's disease 47 were identified with these lesions. RESULTS: Of the 47 patients 22 presented with penile curvature with or without accompanying or preceding pain. Of the 47 patients 17 had a significant history of trauma, although only had the classic stigmata of penile fracture. A total of 16 patients had no history of curvature, 7 presented with only penile shortening or focal lack of rigidity and 5 were incidentally found to have lesions during assessment for other complaints. Three patients presenting after trauma were noted to have septal liquefied hematomas, which we aspirated under ultrasound guidance. Followup ultrasound revealed minimal septal thickening. In 1 of these patients the hematoma was adjacent to more typical-appearing septal fibrosis. CONCLUSIONS: We theorize that these hematomas are due to septal fractures and may represent a forme fruste or possibly a precursor lesion of more typical septal fibrosis. Ultrasonographic evaluation may allow earlier identification and treatment of occult septal injuries or lesions and prevent subsequent fibrosis and its associated symptoms.

Upregulation of penile brain-derived neurotrophic factor (BDNF) and activation of the JAK/STAT signalling pathway in the major pelvic ganglion of the rat after cavernous nerve transection.

OBJECTIVES: Increasing attention is being focused on identifying novel approaches to recover cavernous nerve (CN) function after injury or secondary to disease states such as diabetes mellitus. We examined penile brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) expression, and activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) molecular pathway in the major pelvic ganglion (MPG) after CN injury in the rat. METHODS: Five groups of eight male Sprague-Dawley rats (4 mo, 250-300 g) were used in this study. The penis and MPG with attached CN segment were harvested at 0 h (controls), 12, and 24 h, as well as at 5 and 12 d after CN axotomy, for protein, messenger RNA (mRNA), and immunohistochemical analysis. RESULTS: mRNA and protein expression of BDNF was upregulated in the penis after injury (p<0.05). Levels of NT-3 were unchanged. The JAK/STAT pathway was activated in the MPG after transection, as evidenced by increased STAT1 (peak: 24 h) and STAT3 (peak: 5 d) phosphorylation (p<0.01 vs. controls). CONCLUSIONS: This study demonstrates increased expression of penile BDNF and upregulation of phosphorylated STAT1 and STAT3 in the MPG in response to CN transection. Activation of the JAK/STAT pathway after injury represents a promising new molecular target for modulating CN survival and regeneration.

Brain-derived neurotrophic factor (BDNF) acts primarily via the JAK/STAT pathway to promote neurite growth in the major pelvic ganglion of the rat: part I.

INTRODUCTION: Identification of the molecular mechanism of cavernous nerve regeneration is essential for future development of neuroprotective and regenerative strategies. AIM: To identify specific signal transduction pathway(s) associated with brain-derived neurotrophic factor (BDNF) enhanced cavernous nerve regeneration in an in vitro model. MATERIALS AND METHODS: Using 6-month-old male Fisher rats, inhibitors of four candidate signaling pathways were added to BDNF-treated explant cultures of major pelvic ganglia with attached cavernous nerve fragments. Study groups comprised of controls, BDNF alone at 50 ng/mL, or BDNF 50 ng/mL and inhibitors against MEK, PI3-K, PKA, and JAK/STAT pathways at increasing concentrations. MAIN OUTCOME MEASURE: The maximal neurite length for each tissue culture was measured and the mean maximal length +/- standard deviation was determined for all groups at 24, 36, and 48 hours. RESULTS: The JAK/STAT specific inhibitor AG490 significantly reduced BDNF-enhanced neurite growth. Maximum neurite lengths at 24, 36, and 48 hours for BDNF 50 ng/mL treated groups were 182.3, 348.1, and 528.1 microm, compared with AG490 at 25 microM (86.4, 165.1, 278.3 microm), 50 microM (78.8, 151.7, 235.3 microm), and 100 microM (71.83, 107.0, 219.6 microm) (P < 0.05). Neurite measures for BDNF with 25 and 50 microM U0126 (MEK pathway) were reduced to 402.0 and 424.3 microm at 48 hours, respectively (P < 0.05), likely reflecting an accessory molecular pathway. A similar observation was made for 100 uM LY294002 (PI3-K). No difference was observed for PKA inhibition. CONCLUSION: The JAK/STAT pathway is the major signal-transduction pathway of BDNF-enhanced cavernous nerve growth in an in vitro rat model.

The effect of intracavernosal growth differentiation factor-5 therapy in a rat model of cavernosal nerve injury.

OBJECTIVE: To determine whether the intracavernosal application of growth differentiation factor-5 (GDF-5) influences nerve regeneration and erectile function after cavernosal nerve injury in a rat model. MATERIALS AND METHODS: Thirty-two male Sprague-Dawley rats were randomly divided into four equal groups: eight had a sham operation (uninjured controls), while 24 had bilateral cavernosal nerve crush. The crush-injury groups were treated at the time of injury with an impregnated collagen sponge implanted into the right corpus cavernosum. The sponge contained no GDF-5 (injured controls), 2 microg (low concentration), or 20 microg GDF-5 (high concentration). Erectile function was assessed by cavernosal nerve electrostimulation at 8 weeks. Midshaft penile tissue samples were histochemically evaluated for neuronal nitric oxide synthase (nNOS)-containing fibres in the dorsal penile nerve. RESULTS: There was no erectile dysfunction in the uninjured control group, as shown by a mean (sem) maximal increase in intracavernosal pressure (ICP) of 149.5 (17.0) cmH(2)O on stimulation. By comparison, the ICP decreased in the injured control group, by 21.3 (6.7) cmH(2)O. After cavernosal nerve injury, the recovery of erectile function was greatest in the low-concentration GDF-5 group; the maximum ICP increase was 40.8 (13.3) cmH(2)O, vs 24.3 (5.9) cmH(2)O for 20 microg GDF-5. Histologically, the low-concentration group had significantly more nNOS-containing nerve fibres, at 163 (24.7), than the high-concentration group, at 76 (17.3), or injured controls, at 67 (23.8). By contrast, the uninjured controls had a mean of 538 (40.6) nerve fibres in the dorsal nerve. CONCLUSION: Bilateral cavernosal nerve crush resulted in erectile dysfunction with accompanying neurological changes in the rat. The intracavernosal application of GDF-5 enhanced the recovery of erectile function and n-NOS nerve preservation, with a 2-microg dose giving the most promising results.