Cell therapy for male sexual dysfunctions: systematic review and position statements from the European Society for Sexual Medicine.

Background: Cell therapy (CT) is a form of regenerative medicine under investigation for the management of male sexual dysfunction (MSD). Aim: We sought to perform a systematic review of published information on CT for MSD and provide an official position statements for the European Society for Sexual Medicine. Methods: A comprehensive bibliographic search on the MEDLINE, Web of Science, Scopus, and Cochrane Library databases was conducted in February 2023. Articles were selected based on the Population, Intervention, Comparator, Outcome, Study design (PICOS) model if they included male patients (P) undergoing CT (I) with or without comparison with other treatments (C) and evaluated the impact of CT on sexual function (O). Quantitative data were reported as found in the original studies (S). Level of evidence and grade of recommendation according to the Oxford Centre for Evidence-Based Medicine were assigned to each statement. Outcomes: Outcomes were determined based on assessment of erectile function, ejaculatory function, orgasmic function, sexual desire, and penile curvature. Results: A total of 19 studies and 421 patients were included. Most articles (n = 12, 63%) were case series, whereas a minority of papers (n = 6, 32%) had a comparative group; only 2 articles reported randomized controlled trials (RCTs) and 1 article reported a post hoc analysis of RCTs. Most articles (16, 84%) investigated patients with erectile dysfunction (ED). Improvements in the International Index of Erectile Function-Erectile Function Domain (IIEF-EF) or the IIEF 5-item version (IIEF-5) were found in 11/15 (73%) studies, with mean increases in IIEF-EF, mean IIEF-5, and median IIEF-EF between 8 and 14 points, 2 and 9 points, and 4.5 and 6 points, respectively. Two papers (20%) evaluated men with Peyronie's disease (PD). In both ot these articles penile curvature improvement and plaque volume reduction were described in all patients (n = 16, 100%). Objective measurements were performed in 1 study, which showed 10°-120° (15%-100%) curvature improvement and 90%-100% plaque reduction. Mild transient adverse events at the donor or administration sites were found in 7/16 (44%) papers on ED. Priapism was reported in one case (20%) and mild penile skin complications were reported in the majority of patients after CT for PD. No severe adverse events were described. Clinical Implications: Although high-quality evidence is lacking, CT appears to have potential benefits from application in patients with ED or PD. Strengths and Limitations: This report is to our knowledge the most comprehensive and up-to-date systematic review on the topic of CT for the management of MSD, including the position statements of the European Society for Sexual Medicine. Overall the assessment of available studies demonstrated low quality and significant heterogeneity. Conclusion: Preliminary findings support potential efficacy and safety of CT in patients with ED or PD. Low-quality papers, high methodological heterogeneity, uncertainty about the magnitude of the beneficial effects, and lack of long-term data limit the available evidence.

The Possible Role of Prescribing Medications, Including Central Nervous System Drugs, in Contributing to Male-Factor Infertility (MFI): Assessment of the Food and Drug Administration (FDA) Pharmacovigilance Database.

BACKGROUND: A wide range of medications may have a possible role in the development of male-factor infertility (MFI), including various antineoplastic agents, testosterone/anabolic steroids, immunosuppressive drugs/immunomodulators, glucocorticosteroids, non-steroidal anti-inflammatory drugs, opiates, antiandrogenic drugs/5-alpha-reductase inhibitors, various antibiotics, antidepressants, antipsychotics, antiepileptic agents and others. We aimed at investigating this issue from a pharmacovigilance-based perspective. METHODS: The Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database was queried to identify the drugs associated the most with MFI individual reports. Only those drugs being associated with more than 10 MFI reports were considered for the disproportionality analysis. Proportional Reporting Ratios (PRRs) and their confidence intervals were computed for all the drugs identified in this way in January 2023. Secondary, 'unmasking', dataset analyses were carried out as well. RESULTS: Out of the whole database, 955 MFI reports were identified, 408 (42.7%) of which were associated with 20 medications, which had more than 10 reports each. Within this group, finasteride, testosterone, valproate, diethylstilbestrol, mechloretamine, verapamil, lovastatin and nifedipine showed significant levels of actual disproportionate reporting. Out of these, and before unmasking, the highest PRR values were identified for finasteride, diethylstilbestrol and mechloretamine, respectively, with values of 16.0 (12.7-20.3), 14.3 (9.1-22.4) and 58.7 (36.3-95.9). CONCLUSIONS: A variety of several medications, a number of which were already supposed to be potentially linked with MFI based on the existing evidence, were associated with significant PRR levels for MFI in this analysis. A number of agents which were previously hypothesized to be associated with MFI were not represented in this analysis, suggesting that drug-induced MFI is likely under-reported to regulatory agencies. Reproductive medicine specialists should put more effort into the detection and reporting of these adverse drug reactions.

Patients' attitude with surgery for Peyronie's disease: results from a multicentric European study.

BACKGROUND: Despite the existence of conservative therapies for Peyronie's disease (PD), surgery is commonly utilized for the treatment of bothersome curvatures due to its potential effectiveness, although it carries intrinsic risks and may not universally lead to satisfactory outcomes. AIM: To explore the rate and factors influencing patients' willingness to undergo surgery for PD. METHODS: Data were prospectively collected in 5 European academic centers between 2016 and 2020. Data included age, time from PD onset, penile pain, curvature degree, difficulty at penetration, hourglass deformity, erectile dysfunction (ED), and previous treatments. All patients were offered conservative treatments, either medications or injections. Tunical shortening or lengthening procedures were offered as an alternative to conservative treatments, when indicated. Penile prosthesis was offered to those with concomitant ED. Patients' attitudes with surgery were recorded. Logistic regression analyses tested the profile of patients who were more likely to be willing to undergo surgery. OUTCOMES: Patients' willingness to undergo surgery for PD. RESULTS: This study included 343 patients with a median age of 57.3 years (IQR, 49.8-63.6) and a median penile curvature of 40.0° (IQR, 30.0°-65.0°). Overall, 161 (47%) experienced penetration difficulties and 134 (39%) reported ED. Additionally, hourglass deformity and penile shortening were reported by 48 (14%) and 157 (46%), respectively. As for previous treatments, 128 (37%) received tadalafil once daily; 54 (16%) and 44 (13%), intraplaque verapamil and collagenase injections; and 30 (9%), low-intensity shock wave therapy. Significant curvature reduction (≥20°) was observed in 69 (20%) cases. Only 126 (37%) patients were open to surgery for PD when suggested. At logistic regression analysis after adjusting for confounders, younger age (odds ratio [OR], 0.97; 95% CI, 0.95-1.00; P = .02), more severe curvatures (OR, 1.04; 95% CI, 1.03-1.06; P < .0001), and difficulty in penetration (OR, 1.88; 95% CI, 1.04-3.41; P = .03) were associated with a greater attitude to consider surgical treatment. CLINICAL IMPLICATIONS: The need for effective nonsurgical treatments for PD is crucial, as is comprehensive patient counseling regarding surgical risks and benefits, particularly to younger males with severe curvatures. STRENGTHS AND LIMITATIONS: Main limitations are the cross-sectional design and the potential neglect of confounding factors. CONCLUSIONS: Patients with PD, having a lower inclination toward surgery, emphasize the need for effective nonsurgical alternatives and accurate counseling on the risks and benefits of PD surgery, particularly for younger men with severe curvatures.

Risk of unfavorable outcomes after penile prosthesis implantation - results from a national registry (INSIST-ED).

Like all surgeries, penile prosthesis implantation (PPI) has the potential for both postoperative complications and suboptimal patient satisfaction. In order to assess risk factors for poor satisfaction, we reviewed patients who had been prospectively recruited in a national multi-institutional registry of penile prostheses procedures (INSIST-ED) from 2014 to 20121. Patient baseline characteristics and postoperative complications were recorded. The primary endpoint of this study was unfavorable outcomes after inflatable PPI, defined as significant postoperative complications (Clavien-Dindo ≥2) and/or Sexuality with Quality of Life and Sexuality with Penile Prosthesis (QoLSPP) scores below the 10th percentile. A total of 256 patients were included in the study. The median age was 60 years (IQR 56-67). The most common cause of erectile dysfunction (ED) was organic (42.2%), followed by pelvic surgery/radiotherapy (39.8%) and Peyronie's disease (18.0%). Postoperative complications were recorded in 9.6%. High-grade complications (Clavien ≥2) occurred in 4.7%. At 1-year follow-up, the median QoLSPP total score was 71 (IQR 65-76). In all, 14.8% of patients were classified as having experienced unfavorable outcomes because of significant postoperative complications and/or QoLSPP scores below the 10th percentile. Logistic regression analysis demonstrated patient age to be non-linearly associated with the risk of experiencing unfavorable outcomes. A U-shaped correlation showed a lower risk for younger and older patients and a higher risk for middle-aged men. ED etiology and surgical volume were not associated with PPI outcomes. Physicians should, therefore, be aware that middle-aged men may be at higher risk of being unsatisfied following PPI compared to both younger and older patients.

European Society of Sexual Medicine consensus statement on the use of animal models for studying Peyronie's disease.

Introduction: Animal models are frequently used for translational research in Peyronie's disease (PD). However, due to lack of availability of guidelines, there is some heterogeneity in study design, data reporting, and outcome measures. Aim: This European Society for Sexual Medicine consensus statement aims to provide guidance in utilization of animal models in PD research in a standardized and uniform fashion. Methods: PubMed was searched for studies using animal models for PD. The following search terms were used: ("Peyronie's disease" OR "penile fibrosis" OR "penile curvature" OR "induration penis plastica" OR "erectile dysfunction") AND ("rodent" OR "mouse" OR "mice" OR "rat" OR "rabbit"). Outcomes: This European Society for Sexual Medicine statement describes best practice guidelines for utilization of animals in PD research: power calculation, details of available models, surgical procedures, and measurement techniques, while highlighting possible pitfalls and translational limitations of the models. Results: In total, 2490 studies were retrieved and 2446 articles were excluded. A total of 44 studies were included, of which 40 studies used rats, 1 study used both rats and mice, 1 study used a genetic mouse model, and 2 studies used rabbits. A significant number of the studies (70.5%) used transforming growth factor ß 1 for induction of fibrosis. Oxford 2011 Levels of Evidence criteria could not be applied due to the nature of the studies. Conclusion: Despite certain limitations of PD animal models presented, we aimed to provide guidance for their appropriate use in translational research, with the purpose of improving study quality and reproducibility as well as facilitating interpretation of reported results and conclusions.

A review on pharmacological options for the treatment of erectile dysfunction: state of the art and new strategies.

INTRODUCTION: Erectile dysfunction (ED) affects between 12.9% and 28.1% of men worldwide, presenting a strong aged-correlated prevalence. Several pharmacological treatments are currently available for ED, which can be classified into oral, injection, and topical/intraurethral therapies. AREAS COVERED: Extensive research on PubMed/MEDLINE until February 2023 was performed. For each of the aforementioned drug classes, available molecules, and formulations, their efficacy and most common adverse events as well as general guidelines on prescription were investigated and extensively described. A glimpse into future directions regarding ED pharmacotherapy is also present. EXPERT OPINION: In recent years, there have been significant developments in pharmacological treatments for ED. It is essential for physicians to identify the best treatment option for patients based on their preferences and sexual habits. The treatment approach for ED has shifted from a sequential to a parallel paradigm, where all treatment options are available as first-line therapies. While there are promising regenerative therapies for ED, such as shockwaves and platelet-rich plasma injections, pharmacological treatment is still the most effective option for most patients.

Outcomes following radical inguinal lymphadenectomy for penile cancer using a fascial-sparing surgical technique.

PURPOSE: To describe our surgical technique and report the oncological outcomes and complication rates using a fascial-sparing radical inguinal lymphadenectomy (RILND) technique for penile cancer patients with cN+ disease in the inguinal lymph nodes. METHODS: Over a 10-year period, 660 fascial-sparing RILND procedures were performed in 421 patients across two specialist penile cancer centres. The technique used a subinguinal incision with an ellipse of skin excised over any palpable nodes. Identification and preservation of the Scarpa's and Camper's fascia was the first step. All superficial inguinal nodes were removed en bloc under this fascial layer with preservation of the subcutaneous veins and fascia lata. The saphenous vein was spared where possible. Patient characteristics, oncologic outcomes and perioperative morbidity were retrospectively collected and analysed. Kaplan-Meier curves estimated the cancer-specific survival (CSS) functions after the procedure. RESULTS: Median (interquartile range, IQR) follow-up was 28 (14-90) months. A median (IQR) number of 8.0 (6.5-10.5) nodes were removed per groin. A total of 153 postoperative complications (36.1%) occurred, including 50 conservatively managed wound infections (11.9%), 21 cases of deep wound dehiscence (5.0%), 104 cases of lymphoedema (24.7%), 3 cases of deep vein thrombosis (0.7%), 1 case of pulmonary embolism (0.2%), and 1 case of postoperative sepsis (0.2%). The 3-year CSS was 86% (95%Confidence Interval [95% CI] 77-96), 83% (95% CI 72-92), 58% (95% CI 51-66), respectively, for the pN1, pN2 and pN3 patients (p < 0.001), compared to a 3-year CSS of 87% (95% CI 84-95) for the pN0 patients. CONCLUSION: Fascial-sparing RILND offers excellent oncological outcomes whilst decreasing the morbidity rates. Patients with more advanced nodal involvement had poorer survival rates, emphasizing the need for adjuvant chemo-radiotherapy.

Holmium Laser Enucleation of the Prostate Is Associated with Complications and Sequelae Even in the Hands of an Experienced Surgeon Following Completion of the Learning Curve.

BACKGROUND: Holmium laser enucleation of the prostate (HoLEP) is considered a challenging procedure even for surgeons who have completed the learning curve. OBJECTIVES: To assess outcomes and complications following HoLEP performed by a highly experienced surgeon. DESIGN, SETTING, AND PARTICIPANTS: This was a single-institution prospective study (NCT03583034) performed at a tertiary referral centre that included 243 consecutive patients with lower urinary tract symptoms (LUTS) due to benign prostatic enlargement (BPE) treated with HoLEP by a single experienced surgeon (>1600 cases). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Patients were assessed using validated questionnaires and uroflowmetry at baseline and several follow-up dates. Intraoperative and postoperative complications were recorded. Kaplan-Meier analysis was used to estimate recovery rates for urinary continence and erectile function. Logistic regression models were constructed to assess predictors of postoperative complications. RESULTS AND LIMITATIONS: Of the 243 patients, 78 (32.1%) had an indwelling urethral catheter. The median prostate volume (PV) was 87 cm3 (interquartile range 60-115) and 146 patients (59.8%) had PV >80 cm3. At 3-mo follow-up, 219 patients (90.1%) had a peak flow rate >20 ml/s and 182 (74.9%) had no postvoid residual urine. The improvement in subjective symptoms was significant at 1-mo follow-up and was maintained until 12 mo after surgery. Urinary continence recovery was slow, with an estimated rate of 68% (95% confidence interval [CI] 62-74%) at 1 mo and 94% (95% CI 91-97%) at 12 mo after HoLEP. The recovery rate for erectile function was 53% (95% CI 46-61%) at 1 mo and 85% (95% CI 77-90%) at 12 mo. Postoperative complications occurred in 36 patients (14.8%) during their hospital stay, in 34 (14%) within 1 mo following discharge from hospital, and in ten (4.1%) at later follow-up dates. Clinically significant complications (Clavien-Dindo ≥2) were observed in 44 cases (18%) and were more common for patients with an indwelling catheter at baseline (odds ratio 5.05; p = 0.006). CONCLUSIONS: HoLEP is an effective procedure for treating LUTS due to BPE, although it is not devoid of complications and sequelae, even in the hands of a highly experienced surgeon. PATIENT SUMMARY: Holmium laser treatment of the prostate to reduce its size has positive results for urinary function when performed by an experienced surgeon, even in complex cases, although there can be complications.

The Application of Hyaluronic Acid Injections in Functional and Aesthetic Andrology: A Narrative Review.

Hyaluronic acid (HA) is a glycosaminoglycan widely utilised in different fields of medicine. We aimed to provide a comprehensive overview of the scientific evidence on the use of HA in andrology. A review of the literature to identify pertinent studies concerning the use of HA in andrology was carried out on the Medline, EMBASE, and the Cochrane databases, with no time restriction up to December 2022. Penile girth enlargement (PGE) using HA proved to be safe and effective in enhancing the diameter of the penis, with durable and satisfactory outcomes in long-term follow-up. Injection of HA in the glans seems to represent an alternative treatment option for those patients with premature ejaculation (PE) who fail to respond to conventional medications. HA intra-plaque injections represent a valid option which may contribute to restore sexual activity in patients with Peyronie's disease (PD). The adoption of HA filler injections should always be tailored to the patient's peculiar anatomy and underlying condition. More robust evidence is required to achieve a uniformed consensus regarding the use of HA in andrology, and further efforts should continue to improve the current injection techniques and HA products.

Clinical parameters associated with altered sperm DNA fragmentation index among primary infertile men: Findings from a real-life cross-sectional study.

BACKGROUND: Recurrent pregnancy loss and unexplained infertility are the current indications to test sperm DNA fragmentation according to the European Association of Urology Guidelines on sexual and reproductive health. OBJECTIVE: To identify a novel and better performing model to diagnose primary infertile men presenting with altered sperm DNA fragmentation and to outline its predictive ability in respect to current European Association of Urology Guidelines' recommendations. MATERIALS AND METHODS: Data from the latest 515 consecutive primary infertile men as for World Health Organization criteria were analyzed. Semen analysis, sperm DNA fragmentation (according to sperm chromatin structure assay), and serum hormones were considered in every patient. Altered sperm DNA fragmentation was defined with levels greater than 30%. Descriptive statistics was applied to compare patients with normal versus SDF > 30%. The new predicting model was identified through logistic regression analysis exploring potential predictors of SDF > 30% at first clinical presentation. Diagnostic accuracy between the two predictive models (European Association of Urology Guidelines vs. new) was assessed, and decision curve analyses tested their clinical benefit. RESULTS: Of 515, 268 (51.9%) patients had SDF > 30% at clinical presentation. Patients with SDF > 30% were older (median [interquartile range] 39 [35-43] vs. 37 [34-41] years), had lower mean testicular volume (Prader 15 [12-20] vs. 17.5 [13.5-20] and lower total motile sperm count (1.80 [0.7-13.2] vs. 11.82 [4.2-44.5] × 106 ), all p < 0.001. No other clinical differences were depicted. The two groups showed similar rates of history of recurrent pregnancy loss and unexplained infertility. At multivariable logistic regression analysis, age more than 38 years (odds ratio: 2.43) and baseline total motile sperm count less than 20 × 106 (odds ratio: 3.72) were associated with SDF > 30%, after adjusting for Prader < 15, history of miscarriages and unexplained infertility, all p < 0.0001. The newly identified model (unexplained infertility + history of poli-abortions + Prader < 15 + age ≥38 years + total motile sperm count <20 × 106 ) showed higher accuracy to identify SDF > 30% at baseline in respect to European Association of Urology Guidelines (area under the curve: 72.1 vs. 52.7), with superior clinical net benefit use. CONCLUSIONS: The application of the European Association of Urology sexual and reproductive health guidelines does not ensure proper identification of primary infertile men with pathological sperm DNA fragmentation. We propose a novel and better performing predictive model to identify the infertile men with altered sperm DNA fragmentation at first clinical assessment. DISCUSSION: As altered sperm DNA fragmentation has been widely linked with the inability to conceive, this second-level test could be further implemented over the diagnostic workup of a broader subset of patients presenting for male factor infertility. We propose a better performing model to identify this specific category of patients.

Infertile men with semen parameters above WHO reference limits at first assessment may deserve a second semen analysis: Challenging the guidelines in the real-life scenario.

OBJECTIVES: To investigate which infertile men with semen parameters above WHO reference limits at first semen analysis deserve a second semen test. MATERIALS AND METHODS: Data from 1358 consecutive infertile men were analysed. Patients underwent two consecutive semen analyses at the same laboratory. Descriptive statistics and logistic regression models tested the association between clinical variables and semen parameters. A new predicting model was identified through logistic regression analysis exploring potential predictors of semen parameters below WHO reference limits after a previously normal one. Diagnostic accuracy of the new model was compared with AUA/ASRM and EAU guidelines. Decision curve analyses (DCA) tested their clinical benefit. RESULTS: Of 1358, 212 (15.6%) infertile men had semen parameters above WHO reference limits at first analysis. Of 212, 87 (41.0%) had a second semen analysis with results above WHO reference limits. Men with sperm parameters below reference limits at second analysis had higher FSH values, but lower testicular volume (TV) (all p<0.01) compared to men with a second semen analysis above WHO limits. At multivariable logistic regression analysis, lower TV (OR 0.9, p = 0.03), higher FSH (OR 1.2, p<0.01), and lower total sperm count (OR 0.9, p<0.01) were associated with second semen analyses below WHO limits. DCA showed the superior net benefit of using the new model, compared to both AUA/ASRM and EAU guidelines to identify those men with a second semen sample below WHO limits after a previously normal one. CONCLUSIONS: Approximately 60% of infertile men with a first semen analysis above WHO limits have a second analysis with results below limits. The newly identified risk model might be useful to select infertile men with initial semen results above WHO limits who deserve a second semen analysis.

Are finasteride-related penile curvature/Peyronie's disease Adverse Event Reports worthy of further clinical investigation? Disproportionality analysis based on both the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) pharmacovigilance databases.

A limited number of studies have described patients on finasteride showing findings which were consistent with Peyronie's disease (PD). We aimed to detect a pharmacovigilance signal of possible association between finasteride and PD-related clinical features. The Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database was queried to identify the ten drugs which were associated the most with the adverse drug reactions (ADRs) recorded as "penile curvature" and/or "Peyronie's disease". A similar analysis, including the same drugs, was carried out for the EMA (European Medicines Agency) EudraVigilance (EV) database. Descriptive data have been analyzed, and Proportional Reporting Ratios (PRRs) have been computed against the other nine drugs of the database. Overall, 860 reports of "penile curvature" and/or "Peyronie's disease", were identified in the FAERS database, 214 of which (24.9%) were associated with finasteride. Most reports (56.9%) were submitted by healthcare professionals. Where a treatment-indication was stated, the vast majority of reports (176/210; 83.8%) were associated with androgenetic alopecia. The outcome of most ADRs was "serious" (82.2%), with 96 ADRs resulting in levels of permanent disability. For 97/214 individual cases, penile curvature/PD reports were not part of a syndromic cluster suggestive of post-finasteride syndrome (PFS). The PRR resulted 6.6 (95% CI: 5.6-7.8) and 11.8 (95% CI: 9.08-15.33), respectively, in the FAERS and in the EV databases. Notwithstanding the related limitations and biasing factors of pharmacovigilance studies based on spontaneous reporting, the PRR values here identified should be interpreted as strong signals of disproportionality. These findings, per se, are however not useful to confirm any causal association. Clinical studies are needed to investigate on the possible role for finasteride in causing PD-related clinical features, an hypothesis which remains highly speculative due to the very questionable quality of present data.

Treatment of Persistent or Recurrent Varicoceles: A Systematic Review.

CONTEXT: The outcomes and morbidity following treatment for persistent or varicocele recurrence remain controversial. OBJECTIVE: To conduct a systematic review relating to the outcomes following treatment (any surgical or radiological) for varicocele persistence/recurrence. EVIDENCE ACQUISITION: A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. Prospective and retrospective observational or interventional studies were included until March 2022. Outcomes were pregnancy rate, improvements in semen parameters after treatment compared with those at baseline, pain control, complication rates, and repeat treatment approach. Men of any age with any-grade persistent/recurrent varicoceles were included. EVIDENCE SYNTHESIS: Of 913 articles identified, 18 with 1073 patients were eligible for inclusion. The mean time between the first and repeat treatment ranged between 5.3 and 73.3 months. The indication for repeat treatment was infertility in eight and pain control in six out of 18 studies, whereas four did not provide details for the indication. Of the patients with recurrent/persistent varicoceles initially treated using a radiological intervention, 83.8% underwent another radiological procedure, whereas 16.2% underwent a surgical procedure. Of those initially treated with a surgical procedure, 77.8% underwent a further surgical procedure, whereas 22.2% underwent a radiological procedure. The rate of success of repeat treatment was 60-100%. The reported complications were as follows: hydrocele (up to 16%), testicular atrophy (up to 2%), scrotal hematoma (up to 1.6%), wound infection (up to 6.6%), chronic pain (up to 2.9%), injury to other organs (up to 10%), and thrombophlebitis (up to 5.8%). The rate of symptom resolution was >90% for pain control. Pregnancy rates were 17-58% at 12-month follow-up. Semen parameters improved after repeat treatment compared with that at baseline in 87.5% of studies. The main limitations are the high risk of bias according to the Newcastle and Ottawa Scale, heterogeneity of the included studies, and small simple size. CONCLUSIONS: Treating any grade of persistent/recurrent varicoceles has a good rate of success, pregnancy, and pain control, but there is still a risk of complications. Repeat treatment with the same interventional modality is feasible. The level of evidence is overall low. PATIENT SUMMARY: In this systematic review on persistent or recurrent varicoceles, we showed that repeat treatment with radiological or surgical procedures was feasible, with good success, pregnancy, and pain control rates at follow-up. However, repeat treatment was associated with a higher risk of complications than reported in the published literature relating to patients having their first intervention.

The symptomatic burden of Peyronie's disease at presentation according to patient age: A critical analysis of the Peyronie's disease questionnaire (PDQ) domains.

BACKGROUND: Peyronie's disease (PD) has a huge impact on patients' physical and psychological wellbeing. OBJECTIVES: To investigate whether patients' age has an impact on PD symptomatic burden at first presentation. MATERIALS AND METHODS: Data from 129 consecutive heterosexual patients seeking first medical attention for PD at a single andrological tertiary-referral centre were collected. All patients completed the International Index for Erectile Function (IIEF) and the PD questionnaire (PDQ). Descriptive statistics were used to compare clinical features between younger (≤40years) and older (>40 years) patients. Multivariable linear model assessed the impact of age, the degree of penile curvature and their impact on PDQ (total scores and its domains), after adjusting for PD duration and IIEF-erectile function domain scores. RESULTS: Of 129, 24 (18.6%) patients were ≤40 years old. Young patients presented with a less severe curvature than older patients (median [interquartile ranges] 20° [15-36] vs. 50° [40-80]; p = 0.04). However, younger age was associated with higher psychological and physical symptoms, PDQ-penile pain and PDQ-symptom bother scores (Coeff -0.11, -0.21 and -0.17, respectively) (all p < 0.05). Moreover, the greater the degree of curvature, the higher the PDQ-psychological and physical symptoms and the PDQ-symptom bother scores (Coeff. 0.21 and 0.22, respectively; all p < 0.05). CONCLUSION: Around one in five men seeking first medical help for PD is younger than 40 years at presentation in the real-life setting. PD-related distress varies according to patients' age, with younger men presenting with a greater risk of penile pain and symptom bother despite lower curvature.

Surgical tips in difficult penile prosthetic surgery: a narrative review.

Penile prosthesis implantation continues to represent a reliable solution to address erectile dysfunction when oral medications fail, are not tolerated or are contraindicated, and most typically is associated with excellent satisfaction rates and durable results. Despite the dramatic improvements in the prostheses' design, in the surgical instruments and techniques over the years, certain categories of patients still pose a significant surgical challenge. The aim of the current review is to provide a quick and useful practical guidance based on our expertise in the identification and management of the difficult penile prosthesis implantation cases. A narrative review design was here preferred to fulfil our purpose. The search strategy included a range of terms, e.g. penile prosthesis, corporal fibrosis, infection, ischaemic priapism, Peyronie's disease, radical prostatectomy, pelvic surgery. Extensive corporal fibrosis after explantation of an infected device or after prolonged ischaemic priapism may represent the most difficult situations to deal with in penile prosthesis implantation surgery. Penile prosthesis implantation in patients with Peyronie's disease and in those who previously underwent radical prostatectomy also presents with an increased risk of complications. Experienced surgeons need to be able to recognise promptly and manage urethral perforation, cylinder crossover, tunical perforation and erosion, as these complications are more common when dealing with difficult penile prosthesis implantation cases. Applying penile lengthening techniques and principles can be useful in selected cases to ensure better postoperative satisfaction rates, especially in those patients who have experienced a more significant degree of loss of length preoperatively. High-volume-implanting surgeons should always be involved in complex cases to minimise the risk of complications. A thorough preoperative counselling can set realistic patients' expectations in this context, further contributing to postoperative satisfaction.

The Effect of Varicocele Treatment on Fertility in Adults: A Systematic Review and Meta-analysis of Published Prospective Trials.

CONTEXT: The benefits and harms of varicocele treatment versus observation in adult infertile males are still controversial. OBJECTIVE: To systematically pool the evidence on outcomes of varicocele treatment (any surgical or radiological) versus observation in adult infertile men. EVIDENCE ACQUISITION: A systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. Only prospective randomized and nonrandomized studies were included until November 2021. The primary outcome was pregnancy rate; the secondary outcomes were improvements in sperm concentration, normal morphology, and progressive sperm motility after treatment compared to baseline. Men ≥18 yr of age with any-grade varicoceles were included. EVIDENCE SYNTHESIS: Of 557 articles identified, 12 were eligible for inclusion, involving 1357 patients. Varicoceles were treated surgically in ten and radiologically in four studies. Varicocele treatment improved pregnancy rates (odds ratio 1.29; 95% confidence interval [CI] 1.00-1.65; p = 0.048) and sperm concentration (mean difference 12.34 million/ml, 95% CI 3.49-21.18; p = 0.006) compared with observation. Proportions of spermatozoa with normal morphology and progressive motility were not statistically different from those with observation. However, considering treatment arm only, sperm concentration, progressive motility, and normal sperm morphology were improved compared with baseline. A subgroup analysis showed that the benefit of varicocele treatment is evident in men with an abnormal semen analysis. The main limitation is represented by the heterogeneity of the included studies, mostly in terms of study population, fertility of the partner, outcome evaluation, lack of long-term outcomes, and intermediate/high risk of bias. CONCLUSIONS: Treatment of any-grade varicoceles may improve pregnancy rates and sperm concentration in adult infertile men, while benefits in sperm motility and normal morphology are less clear. PATIENT SUMMARY: In this systematic review and meta-analysis of all published prospective trials on varicocele treatment, significant evidence emerged on its benefit in terms of improved pregnancy rates and sperm concentration, while benefits in sperm motility and morphology are less clear.

Is There a Relevant Clinical Impact in Differentiating Idiopathic versus Unexplained Male Infertility?

PURPOSE: Overall, male factor infertility (MFI) accounts for up to 50% of etiologies of couple's infertility, with almost 30% of MFI cases being idiopathic in nature. Idiopathic MFI does not support a tailored treatment work-up in clinical practice. To investigate rates of and characteristics of men presenting for idiopathic versus unexplained primary infertility as compared with same-ethnicity, age-comparable fertile men. MATERIALS AND METHODS: Demographic, clinical and laboratory data from 3,098 primary infertile men consecutively evaluated were analyzed and compared with those of 103 fertile controls. Idiopathic male infertility (IMI) was defined for abnormality at semen analysis with no previous history of diseases affecting fertility and normal findings on physical examination and genetic and laboratory testing. Unexplained male infertility (UMI) was defined as infertility of unknown origin with completely normal findings at semen analysis. Descriptive statistics and logistic regression models tested the association between clinical variables and idiopathic infertility status. RESULTS: Overall, 570 (18.5%) and 154 (5.0%) patients depicted criteria suggestive for either IMI or UMI, respectively. Groups were similar in terms of age, BMI, CCI, recreational habits, hormonal milieu, and sperm DNA fragmentation indexes. Conversely, testicular volume was lower in IMI (p<0.001). Vitamin D3 levels were lower in IMI vs. UMI vs. fertile controls (p=0.01). At multivariable logistic regression analysis only vitamin D3 deficiency (OR, 9.67; p=0.03) was associated with IMI. Characteristics suggestive for IMI versus UMI were observed in almost 20% and 5% of men, respectively. Overall, clinical differences between groups were slightly significant and certainly not supportive of a tailored management work-up. CONCLUSIONS: Current findings further support the urgent need of a more detailed and comprehensive assessment of infertile men to better tailoring their management work-up in the everyday clinical setting.

High serum alpha-fetoprotein levels in primary infertile men.

BACKGROUND: Alfa-fetoprotein (AFP) is a serum glycoprotein highly produced during fetal development. While AFP synthesis drops dramatically after birth, AFP production only persists or returns under specific pathological condition. OBJECTIVE: We sought to investigate the rate of and the potential meaning of high AFP serum levels in men seeking first medical attention for couple's primary infertility. MATERIALS AND METHODS: Socio-demographic and clinical data from 1803 non-Finnish, White-European primary infertile men were retrospectively analysed. AFP was routinely measured in each patient (high AFP was defined as >7 ng/ml). Men with history of liver diseases, testicular cancer, or other known causes of increased AFP levels were excluded from the final analysis. Semen analyses were based on the 2010 World Health Organization reference criteria. Descriptive statistics and logistic regression models tested the association between serum AFP and clinical variables. Possible nonlinear relationships were graphically explored with locally estimated scatterplot smoothing method. RESULTS: Overall, high serum AFP level was found in 29 (1.7%) patients. Normal versus high AFP levels patients were comparable in terms of body mass index (BMI), Charlson Comorbidity Index, waist circumference, smoking habits, history of cryptorchidism, testicular volume, and serum hormones (i.e., follicle-stimulating hormone, luteinizing hormone, and total testosterone). Conversely, men with higher AFP levels were older (p = 0.02), had lower sperm concentration (p = 0.003), and were more frequently oligozoospermic and azoospermic (all p ≤ 0.03). At multivariate analysis, high AFP levels were independently associated with oligozoospermia (OR 3.79; p = 0.033) and azoospermia (OR 3.29; p = 0.006). Likewise, if AFP levels increase, patients were found to be older, with higher BMI and to have more comorbidities (all p < 0.05). DISCUSSION: Unexplained high AFP levels account for almost 2% of cases in primary infertile patients without a previous history of associated disorders. Higher serum AFP levels are linked with aberrant sperm counts, older age, obesity, and a greater amount of comorbid conditions. CONCLUSION: Despite the need for additional validation, these data suggest that serum AFP measurement might have a multifaceted role over the diagnostic work-up of males presenting for couple's infertility.

Recreational Drug Misuse and Its Potential Contribution to Male Fertility Levels' Decline: A Narrative Review.

Recreational drug intake may be associated with a range of medical untoward consequences, including male infertility. However, as the related evidence is still limited, the main outcome of this review is to provide a better understanding of the existence of any association between recreational drug misuse and male fertility levels' decline. Whilst searching the MEDLINE/PubMed, a comprehensive overview of the literature regarding male infertility and substances of abuse (e.g., phytocannabinoids, opiates/opioids, stimulants, 'herbal highs', psychedelics, and 'novel psychoactive substances) was here undertaken. Due to the paucity of robust, high-quality, empirical, human studies, a narrative strategy was here preferred over a systematic approach. Relevant data are qualitatively analyzed and presented in a table. Although most available evidence is in support of a detrimental role of cannabis on human spermatogenesis, a few remaining studies failed to document any effect of this drug on seminal quality, and it is not clear to which extent this drug impacts fertility rates/time to pregnancy. The current understanding of the impact of opiate-, cocaine- and amphetamine/stimulant-misuse on human reproduction is widely unknown, and most studies dealing with this matter represent only an extrapolation of data derived from specific clinical circumstances. Although the message of 'no smoking, no alcohol and no street drugs' should always be offered as good health advice to all patients seeking medical help for fertility issues, robust scientific clinical evidence in support of a direct detrimental impact of recreational drugs on spermatogenesis is scant to date.