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.

Surgical Management and Oncologic Outcomes of Renal Cell Carcinoma and Inferior Vena Caval Thrombi With Aggressive Histologic Variants.

OBJECTIVE: To characterize the surgical management, perioperative, and cancer-specific outcomes, and the influence of aggressive histologic variants (AHV) on operative management among patients with renal cell carcinoma (RCC) and inferior vena cava (IVC) thrombus. RCC with rhabdoid and/or sarcomatoid differentiation, which we defined as AHV, portends a worse prognosis. AHV can be associated with a desmoplastic reaction which may complicate resection. METHODS: We reviewed patients undergoing radical nephrectomy and IVC thrombectomy between 1990 and 2020. Comparative statistics were employed as appropriate. Survival analysis was performed according to the Kaplan-Meier method, and intergroup analysis performed with log-rank statistics. Multivariable cox proportional hazards regression was used to assess the effect of AHV, age, thrombus level, vena cavectomy, metastases, and medical comorbidities on recurrence and overall survival (OS). RESULTS: Ninety-four of 403 (23.3%) patients had AHV, including 43 (46%) rhabdoid, 39 (41%) sarcomatoid, and 12 (13%) with both. AHV were more likely to present with advanced disease; however, increased perioperative complications or decreased OS were not observed. Median (IQR) survival was 16.7 (4.8-47) months without AHV and 12.6 (4-29) months with AHV (P = .157). Sarcomatoid differentiation was independently associated with worse OS (HR = 2.016, CI 1.38-2.95, P <.001), whereas rhabdoid alone or with sarcomatoid demonstrated similar OS (P = 0.063). CONCLUSION: RCC and IVC thrombus with AHV are more likely to present with metastatic disease, and sarcomatoid differentiation is associated with a worse OS. Resection of tumors with and without AHV have similar perioperative complications, suggesting that surgery can be safely accomplished in patients with RCC and IVC thrombus with AHV.

Surgical management of National Institutes of Health category II chronic bacterial prostatitis: a case series and scoping review of the literature.

Background: National Institutes of Health (NIH) category II prostatitis refractory to antibiotic therapy can be challenging to treat. We present the outcomes from a case series of men who have undergone various surgical therapies to treat this condition. Additionally, we performed a scoping review of studies describing the characteristics and outcomes of patients surgically treated for chronic bacterial prostatitis (CBP). Methods: This is a single-center retrospective case series of adult patients at Cleveland Clinic Glickman Urological and Kidney Institute with refractory NIH category II prostatitis managed with surgical intervention. PubMed was queried and all resulting articles were analyzed for relevance and parallel study designs. Results: Twelve subjects underwent endoscopic procedures. Two of 12 (16.7%) subjects had CBP recurrence with E. Coli at 12 and 60 months; both patients initially had prostatic stones. One patient with CBP recurrence developed a urethral stricture. Seven subjects were treated with nerve-sparing robotic radical prostatectomy of whom two had concomitant prostate cancer. Three subjects had prostate stones, two of which extended beyond the surgical capsule. E. coli was the isolated pathogen for six patients with two of these being multi-drug resistant (MDR) E. coli. One patient in this group experienced recurrent urinary tract infections (UTIs) despite the surgery. Scoping review of available articles consistently failed to mention definitive diagnosis of CBP with prostatic secretion cultures or even urine cultures prior to surgical intervention and no studies were found on the curative outcomes of surgical intervention. Conclusions: Our study provides one of the first single-center retrospective case series of patients with antibiotic refractory NIH category II CBP managed with surgical intervention. Overall, rate of cure between all surgical modalities was 84% (n=16). When disease is confined to the surgical capsule, endoscopic management is likely sufficient. Radical prostatectomy expectedly increased rates of postoperative erectile dysfunction and stress urinary incontinence compared to endoscopic intervention. However, in patients with disease beyond the capsule and/or concomitant prostate cancer, prior endoscopic treatment, or life-threatening UTI, radical prostatectomy may be justified.

Elevated periprostatic venous testosterone correlates with prostate cancer progression after radical prostatectomy.

BACKGROUNDGenerally, clinical assessment of gonadal testosterone (T) in human physiology is determined using concentrations measured in peripheral blood. Prostatic T exposure is similarly thought to be determined from peripheral T exposure. Despite the fact that androgens drive prostate cancer, peripheral T has had no role in the clinical evaluation or treatment of men with localized prostate cancer.METHODSTo assess the role of local androgen delivery in prostate cancer, we obtained blood from the (periprostatic) prostatic dorsal venous complex in 266 men undergoing radical prostatectomy from July 2014 to August 2021 and compared dorsal T (DT) levels with those in circulating peripheral blood (PT) and prostatic tissue. Comprehensive targeted steroid analysis and unbiased metabolomics analyses were performed. The association between the DT/PT ratio and progression-free survival after prostatectomy was assessed.RESULTSSurprisingly, in some men, DT levels were enriched several-fold compared with PT levels. For example, 20% of men had local T concentrations that were at least 2-fold higher than peripheral T concentrations. Isocaproic acid, a byproduct of androgen biosynthesis, and 17-OH-progesterone, a marker of intratesticular T, were also enriched in the dorsal vein of these men, consistent with testicular shunting. Men with enriched DT had higher rates of prostate cancer recurrence. DT/PT concentration ratios predicted worse outcomes even when accounting for known clinical predictors.CONCLUSIONSThese data suggest that a large proportion of men have a previously unappreciated exposure to an undiluted and highly concentrated T supply. Elevated periprostatic T exposure was associated with worse clinical outcomes after radical prostatectomy.FUNDINGNational Cancer Institute (NCI), NIH grants R01CA172382, R01CA236780, R01CA261995, R01CA249279, and R50CA251961; US Army Medical Research and Development Command grants W81XWH2010137 and W81XWH-22-1-0082.

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.

Management of prostatosymphyseal fistula following photoselective vaporization of the prostate: Case series and systematic review of the literature.

Background: This study is aimed to describe our institutional experience and review the literature to date on prostatosymphyseal fistula (PSF), or puboprostatic fistula, following bladder outlet procedures such as transurethral resection of the prostate (TURP) or laser photoselective vaporization of the prostate (PVP). Materials and methods: We retrospectively queried our institutional experience for management of PSF following PVP performed for symptomatic benign prostatic hyperplasia. We also performed a systematic literature review for PSF following PVP or TURP. Finally, we describe our surgical approach to the management of this challenging condition. Results: We identified 7 cases of PSF following PVP from our institution, as well as an additional 7 cases following PVP and 9 cases following TURP from literature review. The diagnosis of PSF was made between 0.5 and 24 months following PVP, and the most specific symptoms were pubic pain and difficulty ambulating. Most patients requiring several evaluations before the diagnosis was made using appropriate imaging studies. Seventy percent of patients required surgical intervention including fistula repair or prostatectomy. Our surgical approach has evolved, and we now routinely perform robotic fistula repair with Y-V plasty and interposition flap with excellent results. Conclusions: Puboprostatic fistula is a rare and poorly described complication of PVP or TURP. To the best of our knowledge, this case series of PSF following PVP represents the largest series to date and doubles the number of reported cases in the literature. Robotic fistula repair with interposition of either peritoneal or perivesical fat flaps appears to be a viable management strategy.

Extensive dystrophic calcification of eroded artificial urinary sphincter cuff-a rare cause of urethral obstruction: a case report.

Background: Despite a high technical success rate and satisfaction, complications of an artificial urinary sphincter (AUS) can occasionally occur and vary in severity from transient urinary retention to unrecognized urethral injury or urethral erosion. Infection usually occurs when urine comes into contact with the device and necessitates explant of the cuff followed by delayed device replacement. In rare cases, however, the device can remain in contact with urine for long periods of time without the sequelae normally associated with acute infection. Case Description: Here we present a case report of two patients with intraurethral migration of AUS cuffs associated with calcification resulting in urethral obstruction precluding catheterization. With extensive calcification around the cuff and longstanding complete erosion into the urethra, the urologist can expect obliteration of normal tissue planes and intense fibrosis during cuff explantation. Following excision of the cuff and stones, assessment of the urethral lumen should be performed to determine whether repair of the urethra is required. After surgery, urinary diversion with a urethral catheter is important to allow for urethral healing. Prior to considering AUS replacement, cystoscopic assessment of the urethra is critical to assess for stricture or other abnormality. Conclusions: Extensive calcification following AUS erosion into the urethra requires the expertise of a urologist with experience in urethral surgery in order to optimize outcomes. Urologists should be aware of this uncommon, but dramatic presentation of urethral obstruction due to a chronically eroded AUS cuff.

First Report of Testicular Replantation Following Wrong-Site Surgery.

Testicular replantation represents a unique circumstance. There are very few reports documenting their experience with testicle replantation and to the best of the authors' knowledge, this is the first case that has been reported in the peer-reviewed literature following a wrong site surgery. Therefore, we detail our technique and outcome when faced with such a rare event. In addition we review the literature, in order to compare and report the experience of others. This case highlights the value of applied microsurgical knowledge and the importance of cross-disciplinary efforts to improve patient outcomes.

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.

Chronic Scrotal Content Pain: a Review of the Literature and Management Schemes.

PURPOSE OF REVIEW: Chronic scrotal content pain (CSCP) is a complex condition with multiple etiologies that requires a thorough understanding of its pathophysiology, workup, and treatment options. We performed a comprehensive and contemporary review to augment our current understanding of CSCP. RECENT FINDINGS: We discuss new advances in CSCP-specific pain questionnaires, modern studies of microscopic spermatic cord denervation and its variations, and novel techniques including electric nerve stimulation and cryoablation in addition to randomized control trials with significant negative findings. We also present literature focusing on the prevention of CSCP secondary to surgical iatrogenic causes. The constantly evolving literature of CSCP has led to the significant evolution in its diagnosis and treatment, from oral medications to salvage options after microscopic spermatic cord denervation. With each advance, we come closer to developing a more thorough, evidence-based algorithm to guide urologists in treatment of CSCP.

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.

Diagnostic Accuracy of Prostate Biopsy for Detecting Cribriform Gleason Pattern 4 Carcinoma and Intraductal Carcinoma in Paired Radical Prostatectomy Specimens: Implications for Active Surveillance.

PURPOSE: Prostatic adenocarcinoma with cribriform morphology and/or intraductal carcinoma has higher recurrence and mortality rates after radiation and surgery. While the prognostic impact of these features is well studied, concordance with cribriform morphology and/or intraductal carcinoma on biopsy and prostatectomy has only recently gained attention. Our primary objective was to evaluate the diagnostic performance of biopsy to detect cribriform morphology and/or intraductal carcinoma in paired biopsy and prostatectomy specimens in a large contemporary cohort. MATERIALS AND METHODS: Patients who underwent prostate biopsy or had biopsies reviewed prior to prostatectomy at a tertiary hospital between November 2017 and November 2018 were included in study. Sensitivity and specificity were calculated to assess concordance with cribriform morphology and/or intraductal carcinoma on biopsy and prostatectomy. The association of biopsy diagnosed with cribriform morphology and/or intraductal carcinoma with adverse pathology was assessed by multivariable regression. RESULTS: Of the 455 men who underwent prostatectomy 216 (47.5%) had biopsy identified with cribriform morphology and/or intraductal carcinoma. For cribriform morphology and/or intraductal carcinoma the sensitivity and specificity of biopsy was 56.5% and 87.2%, respectively. In men eligible for active surveillance sensitivity was 34.1% and specificity was 88.1%. Magnetic resonance imaging targeted biopsies did not improve sensitivity (53.5%). Cribriform morphology and/or intraductal carcinoma identified on prostatectomy correlated with adverse pathological findings. However, compared to cribriform morphology and/or intraductal carcinoma negative biopsies, biopsies identified with cribriform morphology and/or intraductal carcinoma were not independently associated with adverse pathology. This was likely due to biopsy low sensitivity. CONCLUSIONS: In this cohort biopsy was not sensitive for detecting cribriform morphology and/or intraductal carcinoma and this was not improved by magnetic resonance imaging fusion. However, specificity was high, suggesting that when present on biopsy, cribriform morphology and/or intraductal carcinoma may be considered in treatment planning algorithms.

Herniated Kidney.

Postoperative incisional hernia is a relatively common complication following abdominal surgery. Herniation of the kidney is a less common entity and typically occurs as a congenital or acquired diaphragmatic defect, and rare case reports have demonstrated partial flank or lumbar herniation of the kidney. Herein we present a unique case of a postoperative incisional hernia containing the entire right kidney.

Contemporary management of advanced renal cell carcinoma.

Kidney cancer is the eighth most commonly diagnosed cancer in the United States, and nearly one-third of patients have locally advanced or metastatic disease at presentation. Historically, survival outcomes for patients with advanced disease have been poor. In recent years, several novel targeted agents have emerged for the management of advanced renal cell carcinoma that have changed treatment paradigms. At the same time, surgical therapy continues to have a critical role in the management of selected patients. Recent medical and surgical advances have improved the prognosis for patients with a diagnosis of advanced disease. This review provides an overview of the current treatment landscape for patients with advanced renal cell carcinoma.

Pluripotent stem cell derived cardiomyocytes for cardiac repair.

OPINION STATEMENT: The adult mammalian heart has limited capacity for regeneration, and any major injury such as a myocardial infarction results in the permanent loss of up to 1 billion cardiomyocytes. The field of cardiac cell therapy aims to replace these lost contractile units with de novo cardiomyocytes to restore lost systolic function and prevent progression to heart failure. Arguably, the ideal cell for this application is the human cardiomyocyte itself, which can electromechanically couple with host myocardium and contribute active systolic force. Pluripotent stem cells from human embryonic or induced pluripotent lineages are attractive sources for cardiomyocytes, and preclinical investigation of these cells is in progress. Recent work has focused on the efficient generation and purification of cardiomyocytes, tissue engineering efforts, and examining the consequences of cell transplantation from mechanical, vascular, and electrical standpoints. Here we discuss historical and contemporary aspects of pluripotent stem cell-based cardiac cell therapy, with an emphasis on recent preclinical studies with translational goals.

Cell-based delivery of dATP via gap junctions enhances cardiac contractility.

The transplantation of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) is a promising strategy to treat myocardial infarction and reverse heart failure, but to date the contractile benefit in most studies remains modest. We have previously shown that the nucleotide 2-deoxyadenosine triphosphate (dATP) can substitute for ATP as the energy substrate for cardiac myosin, and increasing cellular dATP content by globally overexpressing ribonucleotide reductase (R1R2) can dramatically enhance cardiac contractility. Because dATP is a small molecule, we hypothesized that it would diffuse readily between cells via gap junctions and enhance the contractility of neighboring coupled wild type cells. To test this hypothesis, we performed studies with the goals of (1) validating gap junction-mediated dATP transfer in vitro and (2) investigating the use of R1R2-overexpressing hPSC-CMs in vivo as a novel strategy to increase cardiac function. We first performed intracellular dye transfer studies using dATP conjugated to fluorescein and demonstrated rapid gap junction-mediated transfer between cardiomyocytes. We then cocultured wild type cardiomyocytes with either cardiomyocytes or fibroblasts overexpressing R1R2 and saw more than a twofold increase in the extent and rate of contraction of wild type cardiomyocytes. Finally, we transplanted hPSC-CMs overexpressing R1R2 into healthy uninjured rat hearts and noted an increase in fractional shortening from 41±4% to 53±5% just five days after cell transplantation. These findings demonstrate that dATP is an inotropic factor that spreads between cells via gap junctions. Our data suggest that transplantation of dATP-producing hPSC-CMs could significantly increase the effectiveness of cardiac cell therapy.

Contractility and kinetics of human fetal and human adult skeletal muscle.

Little is known about the contraction and relaxation properties of fetal skeletal muscle, and measurements thus far have been made with non-human mammalian muscle. Data on human fetal skeletal muscle contraction are lacking, and there are no published reports on the kinetics of either fetal or adult human skeletal muscle myofibrils. Understanding the contractile properties of human fetal muscle would be valuable in understanding muscle development and a variety of muscle diseases that are associated with mutations in fetal muscle sarcomere proteins. Therefore, we characterised the contractile properties of developing human fetal skeletal muscle and compared them to adult human skeletal muscle and rabbit psoas muscle. Electron micrographs showed human fetal muscle sarcomeres are not fully formed but myofibril formation is visible. Isolated myofibril mechanical measurements revealed much lower specific force, and slower rates of isometric force development, slow phase relaxation, and fast phase relaxation in human fetal when compared to human adult skeletal muscle. The duration of slow phase relaxation was also significantly longer compared to both adult groups, but was similarly affected by elevated ADP. F-actin sliding on human fetal skeletal myosin coated surfaces in in vitro motility (IVM) assays was much slower compared with adult rabbit skeletal myosin, though the Km(app) (apparent (fitted) Michaelis-Menten constant) of F-actin speed with ATP titration suggests a greater affinity of human fetal myosin for nucleotide binding. Replacing ATP with 2 deoxy-ATP (dATP) increased F-actin speed for both groups by a similar amount. Titrations of ADP into IVM assays produced a similar inhibitory affect for both groups, suggesting ADP binding may be similar, at least under low load. Together, our results suggest slower but similar mechanisms of myosin chemomechanical transduction for human fetal muscle that may also be limited by immature myofilament structure.