Combination clomiphene citrate and anastrozole duotherapy improves semen parameters in a multi-institutional, retrospective cohort of infertile men.

In men with impaired semen parameters, empiric medical therapies such as clomiphene citrate, a selective estrogen receptor modulator (SERM), and anastrozole, a selective aromatase inhibitor, are often employed. The effects of jointly administering these agents on semen parameters are not well understood. Here, we describe the findings of our multi-center, retrospective cohort study of men with idiopathic primary or secondary infertility. Twenty-one men were treated with combination therapy (anastrozole and clomiphene) and 69 men were treated with monotherapy (anastrozole). Patients with pre-treatment normozoospermia and recent or current exogenous testosterone therapy were excluded. Baseline and post-treatment semen and sex hormone parameters were compared among groups. The median follow-up duration was 91 days [interquartile range (IQR), 64-117 days]. Following treatment, 43% of men in the combination therapy group demonstrated normozoospermia, compared to 25% in the monotherapy group. Furthermore, men in the combined group demonstrated marked improvements in total motile sperm count (TMSC) [11.3 vs. 2.1 million (M), P=0.03]. There were no significant differences in hormone levels among the two groups following treatment. Combination therapy with clomiphene citrate and anastrozole was associated with modest benefits in post-treatment semen parameters, when compared to anastrozole monotherapy. These benefits may contribute to improvements in pregnancy outcomes with less invasive assisted reproductive technologies, such as intrauterine insemination (IUI). Future investigations with larger sample sizes and prospective study designs are necessary.

The effect of red blood cell disorders on male fertility and reproductive health.

Male infertility is defined as a failure to conceive after 12 months of unprotected intercourse owing to suspected male reproductive factors. Non-malignant red blood cell disorders are systemic conditions that have been associated with male infertility with varying severity and strength of evidence. Hereditary haemoglobinopathies and bone marrow failure syndromes have been associated with hypothalamic-pituitary-gonadal axis dysfunction, hypogonadism, and abnormal sperm parameters. Bone marrow transplantation is a potential cure for these conditions, but exposes patients to potentially gonadotoxic chemotherapy and/or radiation that could further impair fertility. Iron imbalance might also reduce male fertility. Thus, disorders of hereditary iron overload can cause iron deposition in tissues that might result in hypogonadism and impaired spermatogenesis, whereas severe iron deficiency can propagate anaemias that decrease gonadotropin release and sperm counts. Reproductive urologists should be included in the comprehensive care of patients with red blood cell disorders, especially when gonadotoxic treatments are being considered, to ensure fertility concerns are appropriately evaluated and managed.

The Diversity of Vasectomy Reversal Providers and Their Web-based Advertising Habits in the United States.

OBJECTIVE: To better understand the internet advertising material published on clinician websites for the 30,000 men who undergo evaluation for vasectomy reversal (VR), which is a technically demanding procedure requiring microsurgical expertise. METHODS: Internet search trends for "vasectomy" and "vasectomy reversal" from 2004 to 2022 were assessed using Google Trends. Search engines were then queried on a state-by-state basis for physicians performing VR and the available information aggregated and analyzed using standard statistical approaches. RESULTS: VR search volume consistently represented roughly one-tenth of the search volume for vasectomy. One hundred and ninety reversal clinics were identified in 44 of 50 states with the highest number identified in the southeast region and an overall median price of $6500. Ninety percent of physicians were male and completed residencies in urology. Other specialties included obstetrics and gynecology, general surgery, family medicine and orthopedic surgery. Forty-two percent of urologists had completed infertility fellowships. Sixty percent of physicians utilized a microscope, and 4.7% of physicians explicitly stated they did not perform vasoepididymostomy even when indicated. Fifty two percent of clinics reported VR success rates as high as 100%, and 34% of clinics reported pregnancy outcomes. Twenty-five percent of clinics reported out-of-pocket VR pricing and 26% discussed possible complications. CONCLUSION: VR is a technically demanding cash-pay procedure being performed by physicians with a wide array of backgrounds and outcomes. Urologists should strive to lead by example and report their training, personal experiences, and expected outcomes to enable optimal medical decision making for each patient.

Men With Chronic Orchialgia Exhibit Differential Neuroinflammatory Gene Expression Relative to Asymptomatic Controls.

OBJECTIVE: To identify differences in neuroinflammatory gene expression in individuals with chronic orchialgia (CO) compared to asymptomatic controls. METHODS: Vas deferens, spermatic cord fascia, blood, and urine were collected from 9 men with CO at time of microscopic spermatic cord denervation and 7 asymptomatic controls at time of vasectomy. RNA was isolated and analyzed with the NanoString Human Neuroinflammation panel. Data were normalized, gene expression fold changes and enriched pathways relative to asymptomatic controls were determined. Gene expression was considered significantly different if there was a >2-fold change and P-value <.05 relative to controls. RESULTS: Mean patient age was 51 years and median symptom duration 12 months. There were 26 genes with significantly differential expression in vas deferens. cFos, a marker of nociceptive pain, had the greatest difference (30.2-fold change, P <.000001). Enriched pathways in vas deferens included nerve function, matrix remodeling, and innate immune responses. In fascia, cFos also had the greatest differential expression (38-fold, P = .000002), followed by S100A12 (11-fold, inducer of innate immune response). Enriched pathways in fascia included nerve function and inflammation. In blood, there were no differentially expressed genes, and in urine there were 95 differentially expressed genes. CONCLUSION: Men with CO have a diverse set of neuroinflammatory genes with differential expression in tissue and urine relative to healthy controls. These findings confirm pathologic changes in tissue targeted by denervation surgery, and suggest molecular changes in neuropathic pain that could lead to biomarker identification and novel treatment.

Male-specific late effects in adult hematopoietic cell transplantation recipients: a systematic review from the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation.

Male-specific late effects after hematopoietic cell transplantation (HCT) include genital chronic graft-versus-host disease (GvHD), hypogonadism, sexual dysfunction, infertility, and subsequent malignancies. They may be closely intertwined and cause prolonged morbidity and decreased quality of life after HCT. We provide a systematic review of male-specific late effects in a collaboration between transplant physicians, endocrinologists, urologists, dermatologists, and sexual health professionals through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research, and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. The systematic review summarizes incidence, risk factors, screening, prevention and treatment of these complications and provides consensus evidence-based recommendations for clinical practice and future research.

The Impact of Race and Gender on 30-Day Urologic Surgery Complications.

OBJECTIVE: To assess the effect of race and gender on complications after urologic surgeries. MATERIALS AND METHODS: The American College of Surgeons' National Surgical Quality Improvement Program data was utilized for patients undergoing urologic surgeries. Patient demographics and comorbidities were analyzed. Postoperative complications occurring in a 30-day postoperative period were noted and classified per the Clavien-Dindo classification. RESULTS: From 2008-2018, 284,050 patients underwent urologic surgery. The majority were men (80%) and identified as non-Hispanic white (80%). Complications occurred in 12%, including 9% minor, 5% major, and mortality in 0.6%. Univariate analysis found female gender, non-Hispanic black and Native American race, and patient comorbidities (hypertension, diabetes, heart failure, lung disease, chronic kidney disease) to be associated with increased risk of complications. Female gender remained a significant predictor on multivariable logistic regression, and Hispanic race was found to be an independent negative predictor of postoperative complications, although these results did not appear clinically significant. On exclusion of gender-specific urologic surgeries, female gender was associated with higher likelihood of minor complications, but male gender was associated with higher likelihood of major complications or mortality. CONCLUSION: Race was not associated with postoperative complication rate. Patient comorbidities are associated with an increased risk of 30-day postoperative complications. Females were more likely to have minor and males were more likely to major complications. Optimizing patient comorbidities preoperatively is key to improving postoperative outcomes.

Male-Specific Late Effects in Adult Hematopoietic Cell Transplantation Recipients: A Systematic Review from the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation.

Male-specific late effects after hematopoietic cell transplantation (HCT) include genital chronic graft-versus-host disease (GVHD), hypogonadism, sexual dysfunction, infertility, and subsequent malignancies, such as prostate, penile, and testicular cancer. These effects may be closely intertwined and cause prolonged morbidity and decreased quality of life after HCT. Here we provide a systematic review of male-specific late effects in a collaboration among transplantation physicians, endocrinologists, urologists, dermatologists, and sexual health professionals through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. We used a systematic review methodology to summarize incidence, risk factors, screening, prevention, and treatment of these complications and provide consensus evidence-based recommendations for clinical practice and future research. Most of the evidence regarding male GVHD is still based on limited data, precluding strong therapeutic recommendations. Therefore, we recommend systematic screening for male genital GVHD regularly and reporting of cases to large registries to allow for a better understanding. Future research also should address treatment, given the little published evidence currently available. Male-specific endocrine consequences of HCT include hypogonadism, which also may affect bone health. Given the scanty evidence, current recommendations for hormone substitution and/or bone health treatment are based on similar principles as for the general population. Following HCT, sexual health decreases, and this topic should be addressed at regular intervals. Future studies should focus on interventional strategies to address sexual dysfunction. Infertility remains prevalent in patients having undergone myeloablative conditioning, warranting the offer of sperm preservation for all HCT candidates. Most studies on fertility rely on descriptive registry analysis and surveys, underscoring the importance of reporting post-HCT conception data to large registries. Although the quality of evidence is low, the development of cancer in male genital organs does not seem more prevalent in HCT recipients compared with the general population; however, subsequent malignancies in general seem to be more prevalent in males than in females, and special attention should be given to skin and oral mucosa. Male-specific late effects, which likely are more underreported than female-specific complications, should be systematically considered during the regular follow-up visits of male survivors who have undergone HCT. Care of patients with male-specific late effects warrants close collaboration between transplantation physicians and specialists from other involved disciplines. Future research should be directed toward better data collection on male-specific late effects and on studies about the interrelationships among these late effects, to allow the development of evidence-based effective management practices.

Functional and Taxonomic Dysbiosis of the Gut, Urine, and Semen Microbiomes in Male Infertility.

BACKGROUND: Little is known about the role of the genitourinary and gastrointestinal microbiota in the pathogenesis of male infertility. OBJECTIVE: To compare the taxonomic and functional profiles of the gut, semen, and urine microbiomes of infertile and fertile men. DESIGN, SETTING, AND PARTICIPANTS: We prospectively enrolled 25 men with primary idiopathic infertility and 12 healthy men with proven paternity, and we collected rectal swabs, semen samples, midstream urine specimens, and experimental controls. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We performed comprehensive semen analysis, 16S rRNA sequencing for quantitative high-resolution taxonomy, and shotgun metagenomics with a median of 140 million reads per sample for functional metabolic pathway profiling. RESULTS AND LIMITATIONS: We identified a diverse semen microbiome with modest similarity to the urinary microbiome. Infertile men harbored increased seminal α-diversity and distinct ß-diversity, increased seminal Aerococcus, and decreased rectal Anaerococcus. Prevotella abundance was inversely associated with sperm concentration, and Pseudomonas was directly associated with total motile sperm count. Vasectomy appeared to alter the seminal microbiome, suggesting a testicular or epididymal contribution. Anaerobes were highly over-represented in the semen of infertile men with a varicocele, but oxidative stress and leukocytospermia were associated with only subtle differences. Metagenomics data identified significant alterations in the S-adenosyl-L-methionine cycle, which may play a multifaceted role in the pathogenesis of infertility via DNA methylation, oxidative stress, and/or polyamine synthesis. CONCLUSIONS: This pilot study represents the first comprehensive investigation into the microbiome in male infertility. These findings provide the foundation for future investigations to explore causality and identify novel microbiome-based diagnostics and therapeutics for men with this complex and emotionally devastating disease. PATIENT SUMMARY: We explored the resident populations of bacteria living in the gut, semen, and urine of infertile and fertile men. We found several important bacterial and metabolic pathway differences with the potential to aid in diagnosing and treating male infertility in the future.

Neuroinflammatory gene expression analysis reveals potential novel mediators and treatment targets in interstitial cystitis with Hunner lesions.

BACKGROUND: We sought to study differential neuroinflammatory gene expression in men with interstitial cystitis (IC) with Hunner lesions compared with asymptomatic controls using NanoString, which uses barcoded probes to measure hundreds of genes. IC is a heterogenous condition lacking reliable biomarkers, and a subset of patients exhibits Hunner lesions, implicating the bladder as an inflammatory pain generator. METHODS: Blood, urine, and bladder biopsies were collected from 6 men with IC and Hunner lesions. 7 asymptomatic controls had blood and urine collected and 2 benign bladder biopsies were obtained from our tissue bank. RNA was isolated and analyzed with NanoString Human Neuroinflammation panel. Gene expression was considered significant if there was a >1.5-fold change and adjusted P value <0.05 compared with controls. RESULTS: Mean patient age was 61.5 years with 8 years median symptom duration. In bladder tissue, while many cytokine and chemokine genes had higher expression as expected (e.g., TNF, CXCL10), other significant genes included TRPA1 (1098-fold increased, expressed in pain sensing neurons) and TNFRSF17 (735-fold, B-cell related). In urine, there was 114-fold increase in S1PR4, which mediates pain via TRP-dependent pathways. A patient on cyclosporine had lower inflammatory gene expression levels relative to other IC patients, but no difference in TRPA1. CONCLUSIONS: Men with IC and Hunner lesions have a diverse set of neuroinflammatory genes with differential expression compared to controls. We identified genes linked to neuropathic pain through the TRP pathway and this expression was not reduced by cyclosporine. These findings open a new direction for biomarker and therapeutic discovery.

Prolactin-to-Testosterone Ratio Predicts Pituitary Abnormalities in Mildly Hyperprolactinemic Men with Symptoms of Hypogonadism.

PURPOSE: We aimed to identify predictor variables associated with pituitary abnormalities in hypogonadal men with mild hyperprolactinemia. We also sought to develop a decision-making aid to select patients for evaluation with pituitary magnetic resonance imaging. MATERIALS AND METHODS: We retrospectively examined men with mild hyperprolactinemia (15.1-50.0 ng/ml) who presented with symptoms of hypogonadism and underwent pituitary magnetic resonance imaging. Demographics, laboratory values and clinical data were obtained from the electronic medical record. Selected predictor variables were included in multivariable logistic regression and partitioning models. Cost avoidance analysis was performed on models achieving sensitivities ≥90%. RESULTS: A total of 141 men were included in the study, of whom 40 (28%) displayed abnormalities on pituitary magnetic resonance imaging. Patients with pituitary abnormalities exhibited higher prolactin (p=0.01), lower testosterone (p=0.0001) and lower luteinizing hormone (p=0.03) levels than those with normal anatomy, as well as higher prolactin-to-testosterone ratios (p <0.0001) and lower luteinizing hormone-to-follicle-stimulating hormone ratios (p=0.0001). These serological variables were identified as the best performing predictor variables. The partition incorporating a prolactin-to-testosterone ratio cutoff of 0.10 and prolactin cutoff of 25 ng/ml achieved 90% sensitivity and 48% specificity, and reduced diagnostic expenses by 28%. CONCLUSIONS: Hypogonadal men presenting with mild hyperprolactinemia and pituitary abnormalities declare themselves via endocrine studies routinely ordered to evaluate these conditions. The prolactin-to-testosterone ratio is the best independent predictor of finding a pituitary abnormality on magnetic resonance imaging, although sensitivity improves by referencing additional serological parameters. Significant cost avoidance may result from screening this population prior to ordering pituitary magnetic resonance imaging.

Microscopic spermatic cord denervation for chronic orchialgia/chronic scrotal content pain: operative outcomes and predictors of failure.

BACKGROUND: To describe our institutional outcomes with microscopic spermatic cord denervation (MSCD) for chronic scrotal content paint (CSCP) and identify predictors of treatment failure. METHODS: Retrospective chart review was performed to identify all MSCD performed by two surgeons at a single institution from 2010-2019. Patient demographic data and operative outcomes were collected. Patients were excluded from analysis if no post-operative follow up was available. Success was defined as complete resolution of bothersome pain. Multivariable logistic regression was utilized to identify predictors of treatment failure. RESULTS: During the study period, 101 patients were identified in which 113 MSCD procedures were performed. Final analysis included 103 procedures across 93 patients. Mean age was 41.8 years (SD 13.2), mean BMI was 29.2 kg/m2 (SD 5.96) and median months of pain preceding surgery were 24 (range, 3-300 months). Overall, 75/103 (73%) MSCD were successful. Of the failures, 5 patients had recurrence of pain greater than 6 months after surgery. Only the presence of pelvic floor muscle spasm (PFMS) independently predicted MSCD failure (OR 3.95, P=0.02). 9 of 19 (47%) patients with PFMS experienced treatment failure, while 19 of 84 (23%) without PFMS experienced failure. CONCLUSIONS: MSCD offers a therapeutic option for patients with refractory CSCP. The presence of PFMS is associated with lower surgical success rates. Patients with pre-operatively identified PFMS should be counseled regarding a higher risk of treatment failure.

The effect of trainee involvement on surgical outcomes and complications of male infertility surgical procedures.

In this study, we sought to determine the effect of trainee (resident or fellow physician) involvement in male infertility surgical procedures on patient surgical outcomes and complications. The American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database was retrospectively reviewed for fertility surgical procedures from 2006 to 2012. The procedures included were as follows: epididymectomy, spermatocelectomy, varicocelectomy ± hernia repair, ejaculatory duct resection, vasovasostomy, vasoepididymostomy and 'unlisted procedure male genital system' (to capture sperm retrieval procedures). A variety of peri- and post-operative outcomes were examined. Trainee and nontrainee-involved groups were compared by Wilcoxon rank sum tests, followed by logistic regression, univariate and multivariate analyses. 924 cases were included: 309 with trainees and 615 without. The median post-graduate trainee year was 3 (range: 0-10). Patients in the trainee-involved cohort had higher rates of chronic obstructive pulmonary disease, steroid usage and black race. Mean operative time was 42.5% longer in trainee-involved cases, even after controlling for other covariates (76.2 vs. 49.5 min, p = .00). Hospital stay length was also longer in trainee-involved cases (0.41 vs. 0.35 days, p = .02). There were no differences in superficial infections (p = 1.00), deep wound infections (p = 1.00), urinary tract infections (p = .26), or reoperations (p = .23) with or without trainee involvement.

Fertility considerations in men with testicular cancer.

The modern approach to cancer management has evolved into a multidisciplinary initiative focused not only on cancer specific and overall survival, but also patient quality of life and survivorship. Future fertility is often a major concern for young patients undergoing cancer therapy. Fertility preservation has emerged as a viable but significantly underutilized option. Patients and families should be aware of the varying effects of antineoplastic therapy on their future fertility to allow for an informed decision regarding their fertility preservation options. In this review we discuss the epidemiology, pathophysiology, and management of fertility in the setting of testicular cancer diagnosis and treatment.

Sperm granuloma masquerading as a supernumerary testis.

Sperm granuloma is a common finding following vasectomy, with majority of the lesions located at the site of the vasectomy defect. Sperm granulomas are typically small and asymptomatic. We describe a case in which the nodule presented similarly to a supernumerary testis by radiographic features.

Development of a Clinically Relevant Men's Health Phenotype and Correlation of Systemic and Urologic Conditions.

OBJECTIVE: To develop a clinically relevant men's health phenotype and investigate the correlation between severity of urologic symptoms and systemic health conditions METHODS: Retrospective chart review was performed for men seeking care for benign prostatic hypertrophy, erectile dysfunction or chronic prostatitis or chronic pelvic pain syndrome. Urologic symptoms were assessed with the International Prostate Symptom Score, Sexual Health Inventory for Men, and National Institute of Health Chronic Prostatitis Symptom Score. Each was graded as absent or mild (0), moderate (1), or severe (2) and totaled for a urologic score (US). Seven comorbidities with known impact on urologic symptoms were similarly graded (0-2 for each) and totaled for a systemic score (SS). These domains were anxiety, cardiovascular, testosterone deficiency, insulin (diabetes), obesity, neurologic, and sleep apnea. RESULTS: The study included 415 men with median age of 53.8 (range 19-92). Mean total US was 2.1 (range 0-6) and mean SS was 4.1 (0-12). There was a strong correlation between US and SS (Spearman Rho = 0.37, P < .00001) which was consistent regardless of age. The hierarchy of systemic condition impact on US was cardiovascular> neurologic> diabetes> anxiety> sleep apnea> obesity> testosterone. By cluster analysis the tightest correlations were age with cardiovascular, anxiety with CPPS, and diabetes with erectile dysfunction. CONCLUSION: Systemic health conditions correlate strongly with urologic symptoms in men who present for urologic care. Phenotyping with ACTIONS (anxiety, cardiovascular, testosterone deficiency, insulin, obesity, neurologic, sleep apnea) can identify modifiable conditions that may impact urologic symptoms and outcome of interventions. Future validation in the general population is needed.

Biological therapy for non-obstructive azoospermia.

INTRODUCTION: Most male patients with non-obstructive azoospermia (NOA) have no therapeutic options outside of assisted reproductive techniques to conceive a biological child. If mature sperm cannot be obtained from the testes, these patients must rely on options of donor sperm or adoption. Several techniques are in the experimental stage to provide this patient population alternatives for conceiving. AREAS COVERED: This review discusses three of the experimental techniques for restoring fertility in men with NOA: spermatogonial stem cell transplantation, the use of adult and embryonic stem cells to develop mature gametes and gene therapy. After this discussion, the authors give their expert opinion and provide the reader with their perspectives for the future. EXPERT OPINION: Several limitations, both technical and ethical, exist for spermatogonial stem cell transplantation, the use of stem cells and gene therapy. Well-defined reproducible protocols are necessary. Furthermore, several technical barriers exist for all protocols. And while success has been achieved in animal models, future research is still required in human models.

Simple Operating Room Bundle Reduces Superficial Surgical Site Infections After Major Urologic Surgery.

OBJECTIVE: To reduce our superficial surgical site infection rate following major urologic surgery by implementing a simple operating room bundle. METHODS: A simple operating room bundle was applied to all major urologic cases (cystectomy, nephrectomy, and prostatectomy) at a single tertiary referral center. The bundle included allowing skin prep to dry appropriately, changing gloves before skin closure, irrigating the wound before skin closure, and using a new separate sterile closing instrument set for skin closure. Alcohol-based preps were also introduced hospital-wide 3 months into the study period. The SSI rate was obtained from the National Surgical Quality Improvement Program (NSQIP) database. RESULTS: The surgical site infection (SSI) rate was assessed after a 14-month study period for a total of 510 cases. Before instituting the alcohol-based prep, but after the bundle was implemented, 138 cases were analyzed over a 3-month period with an SSI rate of 0%. For the remaining 11 months with both the alcohol-based prep and the infection prevention bundle in place, the infection rate was 1.37% (7/510) as compared with 3.57% (22/615) for the 12-month period before bundle introduction, a statistically significant reduction (P = .023). CONCLUSION: The SSI rate after major urologic surgery at 1 center was reduced after the introduction of a simple, fast, low-cost, and easily reproducible bundle into the operating room. The use of this bundle reduces SSI, which is critical for the patient and the physician in this era of public reporting and reimbursement based on outcomes.