Mast cell function in prostate inflammation, fibrosis, and smooth muscle cell dysfunction.

Intraurethral inoculation of mice with uropathogenic Escherichia coli (CP1) results in prostate inflammation, fibrosis, and urinary dysfunction, recapitulating some but not all of the pathognomonic clinical features associated with benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS). In both patients with LUTS and CP1-infected mice, we observed increased numbers and activation of mast cells and elevated levels of prostate fibrosis. Therapeutic inhibition of mast cells using a combination of a mast cell stabilizer, cromolyn sodium, and the histamine 1 receptor antagonist cetirizine di-hydrochloride in the mouse model resulted in reduced mast cell activation in the prostate and significant alleviation of urinary dysfunction. Treated mice showed reduced prostate fibrosis, less infiltration of immune cells, and decreased inflammation. In addition, as opposed to symptomatic CP1-infected mice, treated mice showed reduced myosin light chain-2 phosphorylation, a marker of prostate smooth muscle contraction. These results show that mast cells play a critical role in the pathophysiology of urinary dysfunction and may be an important therapeutic target for men with BPH/LUTS.NEW & NOTEWORTHY LUTS-associated benign prostatic hyperplasia is derived from a combination of immune activation, extracellular matrix remodeling, hyperplasia, and smooth muscle cell contraction in prostates of men. Using a mouse model, we describe the importance of mast cells in regulating these multiple facets involved in the pathophysiology of LUTS. Mast cell inhibition alleviates both pathology and urinary dysfunction in this model, suggesting the potential for mast cell inhibition as a therapeutic that prevents and reverses pathology and associated symptomology.

Sperm retrieval and intracytoplasmic sperm injection outcomes in men with cystic fibrosis disease versus congenital bilateral absence of the vas deferens.

Recent data suggest that cystic fibrosis transmembrane conductance regulator (CFTR) gene alterations negatively impact male fertility beyond obstruction. We sought to compare gene alterations, sperm retrieval rates, and intracytoplasmic sperm injection (ICSI) outcomes among men with cystic fibrosis (CF) disease and congenital bilateral absence of the vas deferens (CBAVD) only. We retrospectively evaluated all men who underwent surgical sperm retrieval at two academic, high-volume andrology centers from 2010 to 2018. Only men with documented CFTR alterations and obstructive azoospermia from either CBAVD or CF were included. Differences between groups for CFTR abnormality, sperm retrieval, and ICSI outcomes were statistically analyzed. Overall, 39 patients were included with 10 in the CF and 29 in the CBAVD groups. Surgical sperm retrieval rates were significantly lower in the CF group for sperm concentration (14.8 × 10[6] ml-1 vs 61.4 × 10[6] ml-1, P = 0.02) and total motile sperm count (2.9 million vs 11.4 million, P = 0.01). This difference was only predicted by homozygous delta F508 CFTR mutations (P < 0.05). The CF group also demonstrated a significantly higher rate of rescue testicular sperm extraction (70.0% vs 27.6%, P < 0.03) and lower fertilization rate with ICSI (32.5% vs 68.9%, P < 0.01). In conclusion, those with CF demonstrated lower sperm quality, greater difficulty with sperm retrieval, and worse ICSI outcomes compared with CBAVD-only patients. Homozygous delta F508 CFTR mutations appear to significantly impair spermatogenesis and sperm function.

Risk factors for hypogonadism in young men with erectile dysfunction.

BACKGROUND: The objective of this study is to evaluate the hormone profile of young men with the chief complaint of erectile dysfunction (ED) and determine the comorbidities in this population. METHODS: A retrospective chart review of men aged 18 to 40 years who presented with ED and had a hormone evaluation but without prior medication for hormone manipulation from 2002 to 2016 was performed at a tertiary care institution. Data were obtained on demographics, comorbidities, medications, and hormonal evaluations. RESULTS: A total of 2292 men with ED were identified and 2130 of them received testosterone level evaluation. The most common comorbidities that men were actively being treated for were depression (22.3%), anxiety (16.1%), hypertension (15.6%), diabetes (7.2%), cancer (6.2%), and cardiovascular disease (3.3%). The average total testosterone level was 368 ± 160 ng/dL; 10.7% of men had hypogonadism. Multivariate analysis demonstrated age, body mass index (BMI), depression, and cancer predicted a hypogonadal status. Patients with BMI > 28.2 kg/m, age > 34 years, cancer diagnosis, or depression were 3.350-fold, 1.447-fold, 2.317-fold, or 1.420-fold more likely to be diagnosed hypogonadal than nonoverweight, age ≤ 34 years, noncancer, or nondepressive patients. CONCLUSION: The majority of men under the age of 40 with ED exhibit a normal hormonal milieu. Young ED men with BMI > 28.2 kg/m, age >34 years, cancer diagnosis, or depression are at risk for hypogonadism.

Cannabis and Male Fertility: A Systematic Review.

PURPOSE: With cannabis consumption on the rise and use prominent among males of reproductive age it is essential to understand the potential impact of cannabis on male fertility. We reviewed the literature regarding the effects of cannabis on male fertility. MATERIALS AND METHODS: We performed a literature search using PubMed®/MEDLINE® to identify relevant studies of the effects of cannabis on male fertility. Relevant studies were identified and reviewed. RESULTS: The strongest evidence of cannabis induced alterations in male fertility is in the category of semen parameters. Research supports a role for cannabis in reducing sperm count and concentration, inducing abnormalities in sperm morphology, reducing sperm motility and viability, and inhibiting capacitation and fertilizing capacity. Animal models demonstrate a role for cannabis in testicular atrophy, and reduced libido and sexual function but to our knowledge these results have not yet been replicated in human studies. Studies of hormonal changes suggest inconclusive effects on testosterone levels, lowered luteinizing hormone levels and unchanged follicle-stimulating hormone levels. CONCLUSIONS: Current research suggests that cannabis may negatively impact male fertility. Further studies are needed to validate that robust findings in animal models will carry over into human experience. Clinicians should be aware of these potential effects when prescribing medical marijuana therapies to men of reproductive age, and they should consider the degree of cannabis use as a possible component of a complete male infertility workup.

Uropathogenic Escherichia coli-induced fibrosis, leading to lower urinary tract symptoms, is associated with type 2 cytokine signaling.

Chronic inflammation and prostate fibrosis have been identified as contributors to lower urinary tract symptoms (LUTS) pathophysiology in humans. It has been shown that transurethral infection of an Escherichia coli strain named CP1, which was isolated from a patient with chronic prostatitis, can lead to the develop of differential chronic inflammation and pain in certain mouse strains. Therefore, we hypothesized that differential inflammation would influence fibrotic response in the prostate. This study showed that while prostatic infection by CP1 causes the development of chronic tactile allodynia in NOD/ShiltJ (NOD) but not C57BL/6 (B6) mice, both mice developed evidence of prostate inflammation, prostate fibrosis, and urinary dysfunction. Fibrosis was confirmed by the upregulation of fibrosis-associated messenger RNAs (mRNAs), α-smooth muscle actin immunohistochemistry, and collagen staining with picrosirius red. These findings were mainly focused on the dorsolateral lobes of the prostate. Both mouse strains also developed smaller, more frequent voiding patterns postinfection, examined via cystometry. B6 mice responded to CP1 infection with type 2 cytokines (IL-4 and IL-13), while NOD mice did not, which may explain the differing tactile allodynia responses and level of collagen deposition. When mice lacking signal transducer and activator of transcription 6 (STAT6), a transcription factor known to be important for the production and signaling of IL-4 and IL-13, were infected with CP1, fibrosis was attenuated. This study provides a potential model for studying the development of infection-induced prostatic fibrosis and LUTS. This study also demonstrates that CP1-induced prostate fibrosis has a STAT6-dependent mechanism in B6 mice.

Inconsistent Adoption of World Health Organization V (2010) Semen Analysis Reference Ranges in the United States Eight Years After Publication.

OBJECTIVE: To determine the percentage of laboratories in the United States that have adopted the World Health Organization 2010 (WHO 5) semen analysis (SA) reference values 6years after their publication. METHODS: Laboratories were identified via 3 approaches: using the Clinical Laboratory Improvement Amendments (CLIA) website, the CDC's 2015 Assisted Reproductive Technology Fertility Clinical Success Rate Report, and automated web searches. Laboratories were contacted by phone or email to obtain de-identified SA reports and reference ranges. RESULTS: We contacted 617 laboratories in 46 states, of which 208 (26.7%) laboratories in 45 states were included in our analysis. 132 (63.5%) laboratories used WHO 5 criteria, 57 (27.4%) used WHO 4 criteria, and 19 (9.1%) used other criteria. WHO 5 criteria adoption rates varied by geographic region, ranging from 87.5% (35/40) in the Midwest to 50.0% (33/66) in the West. There was a greater adoption rate of WHO 5 reference values in academic affiliated (23/26, 88.5%) compared to non-academic affiliated laboratories (110/182, 60.4%) (P = .028). CONCLUSION: While the majority of laboratories have adopted WHO 5 criteria following its release 6years ago, a large percentage (36.5%) use what is now considered outdated criteria. This variability could result in the characterization of a male's semen values as being "within reference range" at one center and "outside of reference range" at another. This inconsistency in classification may result in confusion for the both patient and physician and potentially shift the burden of infertility evaluation and treatment to the female partner.

Role of gram-positive bacteria in chronic pelvic pain syndrome (CPPS).

INTRODUCTION: Chronic pelvic pain syndrome (CPPS) is a complex disorder that affects a large proportion of all men. A limited understanding of its etiology and pathogenesis is reflected by the absence of effective therapies. Although CPPS is deemed clinically non-infectious with no well-defined etiological role for microbes, bacteria is readily isolated from both healthy and patient prostate secretion and urine samples. Our laboratory has previously demonstrated that a specific gram-negative bacterial isolate can induce CPPS-like symptoms in mice. Here we aimed to expand on these findings examining the role of gram-positive patient-derived bacteria in CPPS. METHODS: A retrospective analysis of bacterial cultures from CPPS patients from a single center was performed. Gram-positive bacteria were isolated from the expressed prostatic secretion (EPS) of three CPPS-patients (pain inducers, PI) and one from a healthy volunteer (non-pain inducer, NPI). These bacteria were inoculated intra-urethrally in two mouse backgrounds and analyzed for their ability to induce tactile allodynia, voiding dysfunction, and colonize the murine prostate. Host immune responses to bacterial instillation were analyzed by flow cytometry. RESULTS: PI strains (Staphylococcus haemolyticus 2551, Enterococcus faecalis 427, and Staphylococcus epidermidis 7244) induced and maintained tactile allodynia responses (200% increase above baseline) for 28 days in NOD/ShiLtJ mice. Conversely the healthy subject derived strain (Staphylococcus epidermidis NPI) demonstrated no significant pelvic allodynia induction. Intra-urethral inoculation of the four bacterial strains into C57BL/6 mice did not induce significant increases in pain responses. Infected NOD/ShiLtJ displayed significant voiding dysfunction compared to their control counterparts. Colony counts of prostate tissues from both NOD/ShiLtJ and C57BL/6 mice at day 28 demonstrated that bacterial strains colonized equally well, including NPI. We also determined that mechanistically, the patient-isolates induced prostate inflammation specifically involving T-cells and monocytes. CONCLUSIONS: Gram-positive isolates from CPPS patients showed enhanced ability to induce tactile allodynia compared to a single taxonomically similar gram-positive strain isolated from a healthy control. Responses were shown to be dependent on host genetic background and not on colonization differences between strains.

Selective Androgen Receptor Modulators: Current Knowledge and Clinical Applications.

INTRODUCTION: Selective androgen receptor modulators (SARMs) differentially bind to androgen receptors depending on each SARM's chemical structure. As a result, SARMs result in anabolic cellular activity while avoiding many of the side effects of currently available anabolic steroids. SARMs have been studied in the treatment of breast cancer and cachexia and have also been used as performance-enhancing agents. Here, we evaluate and summarize the current literature on SARMs. AIM: To present the background, mechanisms, current and potential clinical applications, as well as risks and benefits of SARMs. METHODS: A literature review was performed in MEDLINE using the terms selective androgen receptor modulator, hypogonadism, cachexia, breast cancer, benign prostatic hyperplasia, libido, and lean muscle mass. Both basic research and clinical studies were included. MAIN OUTCOME MEASURE: To complete a review of peer-reviewed literature. RESULTS: Although there are currently no U.S. Food and Drug Agency-approved indications for SARMs, investigators are exploring the potential uses for these compounds. Basic research has focused on the pharmacokinetics and pharmacodynamics of these agents, demonstrating good availability with a paucity of drug interactions. Early clinical studies have demonstrated potential uses for SARMs in the treatment of cancer-related cachexia, benign prostatic hyperplasia (BPH), hypogonadism, and breast cancer, with positive results. CONCLUSION: SARMs have numerous possible clinical applications, with promise for the safe use in the treatment of cachexia, BPH, hypogonadism, breast cancer, and prostate cancer. Solomon ZJ, Mirabal JR, Mazur DJ, et al. Selective Androgen Receptor Modulators: Current Knowledge and Clinical Applications. Sex Med Rev 2019;7:84-94.

Infertility in the Aging Male.

PURPOSE OF REVIEW: In many countries, the average age of paternity is rising. The negative effect of older age on fertility in women is well documented; however, less is known about the impact of paternal age on fecundity. In this review, we summarize the current knowledge of how paternal age affects semen parameters, reproductive success, and offspring health. RECENT FINDINGS: Contemporary evidence confirms that aged men have worse semen parameters, including overall negative changes in sperm genetics. Reproductive outcomes with unassisted pregnancy tend to be worse with older fathers. While most current studies of assisted pregnancy do show a negative effect of paternal age, there are some conflicting results. Studies continue to show an overall increased risk of health problems, particularly neuropsychiatric conditions, in the offspring of older men. While men can often maintain fertility potential throughout a lifetime, increasing evidence indicates worsening of semen parameters, including sperm genetics, and potentially worse reproductive success. Older men should also be counseled on their offspring's possible increased risk of certain medical conditions.

Scrotal Ultrasound for Pain: Low Frequency of Absolute Surgical Indications.

OBJECTIVE: To examine the results of scrotal ultrasounds (US) conducted for scrotal or testicular pain and review the pathologic findings of orchiectomies done for lesions that were suspicious for malignancy on US. MATERIALS AND METHODS: We retrospectively reviewed the indications and findings of all scrotal US completed at our institution from 2002 to 2014. If a patient underwent an orchiectomy for an intratesticular lesion that was concerning for malignancy on US, the pathology report was also reviewed. RESULTS: There were 18,593 scrotal US performed, with 7,668 (41.2%) conducted for scrotal pain. Of the US performed for pain, 80.4% revealed benign or normal findings, and only 2.2% demonstrated a finding that is an absolute indication for surgery (intratesticular lesion suspicious for malignancy 0.8%, abscess 0.7%, torsion 0.6%, infiltrative process such as lymphoma 0.1%). For those patients undergoing an orchiectomy, 75% had malignancy on pathologic analysis. CONCLUSION: The majority of the 7668 US performed to evaluate scrotal or testicular pain reveal normal or benign findings. A low percentage demonstrates a finding that necessitates urgent or emergent surgery.

Physician Perceptions of Patient Health: A Comparative Analysis between Urologist and Hospitalist Perceptions of Need for Inpatient Hospitalist Comanagement Following Radical Cystectomy.

BACKGROUND/AIMS: The morbidity of radical cystectomy remains high. A multidisciplinary approach utilizing hospitalist comanagement may improve outcomes. It is unclear what factors should be considered to determine which patients might benefit from this approach. We sought to determine if there are differences between the perceived need for co-management between urologists and hospitalists. Preoperative variables were analyzed to determine which factors might be associated with need for comanagement. METHODS: A case-based survey was emailed to urologists and hospitalists at 3 academic institutions to investigate perceptions regarding need for inpatient medical comanagement of fictitious patients following cystectomy. Decisions were rated based on patient comorbidities, age, race, sex, cancer stage, neoadjuvant therapy, alcohol intake, performance status, and English literacy. A Wilcoxon rank sum test assessed each question for differences. A Mantel-Haenszel chi-square test was used to assess whether the proportion of respondents who advocated for comanagement increased as Charlson comorbidity score increased. RESULTS: The most significant determinant of need for postoperative comanagement was patients' comorbidities. Urologists and hospitalists did not differ significantly in beliefs regarding need for comanagement. CONCLUSION: The most important determining factor for comanagement was presence of comorbidities. Further studies are needed to evaluate the impact of this multidisciplinary approach.

Update on Antibiotic Prophylaxis for Genitourinary Procedures in Patients with Artificial Joint Replacement and Artificial Heart Valves.

Infection of artificial joint replacements and heart valves is an uncommon but serious complication encountered anytime after the implantation of these prostheses. It is known that bacteremia can lead to infection of a prosthetic device. However, there is no strong evidence to correlate urologic procedures with the development of periprosthetic joint infection or prosthetic valve endocarditis. Therefore, antibiotic prophylaxis for the prevention of endocarditis is not recommended in patients undergoing urologic procedures. However, guidelines regarding prophylaxis to prevent infection of an artificial joint in the setting of a genitourinary procedure are more varied.

Simultaneous urethrocutaneous and urethrocavernous fistula after proximal corporospongiosal shunt for priapism.

Proximal corporospongiosal shunts are used for the most refractory cases of priapism. Here, we present the case of a 58-year-old man whose priapism was only partially responsive to phenylephrine injections and distal shunting. Proximal shunting was required, and he subsequently developed fistulization of the proximal penile urethra into the skin and the corpora cavernosa. The formation of simultaneous urethrocutaneous and urethrocavernous fistulae is a rare complication of proximal corporospongiosal shunts that can be initially managed with urinary diversion with a suprapubic tube.

Management of non-catheter-associated complicated urinary tract infection.

This article presents an overview of non-catheter-associated complicated urinary tract infection (UTI) from a urologic point of view. Discussion includes the evaluation and workup a complicated UTI through history, physical examination, laboratory analysis, and radiographic studies. Specific types of complicated UTI, such as urinary obstruction and renal abscess, are reviewed.

Influences of neuroregulatory factors on the development of lower urinary tract symptoms/benign prostatic hyperplasia and erectile dysfunction in aging men.

As men age, there is an increase in the frequency of pathologic diseases affecting the genitourinary tract. Most notable among these changes are the rising prevalence of lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH) and erectile dysfunction (ED). The pathogenesis of these conditions seems to be multifactorial and includes age-related changes in the nervous system and neuroregulatory factors, such as nitric oxide and RhoA/Rho-kinase. Various pharmacologic agents that target these pathways, such as α-blockers and PDE-5is, underscore the contribution of neuroregulatory factors on the development of LUTS/BPH and ED.

The polymorphism P315L of human toll-like receptor 1 impairs innate immune sensing of microbial cell wall components.

As a pattern recognition receptor, TLR1 mediates innate immune responses to a variety of microbial cell wall components including bacterial lipoproteins. We have previously shown that the central region of the extracellular domain of human TLR1, comprising leucine-rich repeat (LRR) motifs 9-12, is required for the sensing of bacterial lipopeptides. In this study, we have investigated three nonsynonymous single nucleotide polymorphisms (SNPs) located in this region of TLR1 by generating these variants and examining receptor function. We have found that a variant of TLR1 based upon the SNP P315L, located in the loop of LRR motif 11 (LRR11), is greatly impaired in mediating responses to lipopeptides and a variety of other bacterial agonists for this receptor. Despite normal cell surface expression, the P315L variant also fails to bind to GD2.F4, a commonly used anti-TLR1 mAb. Although a number of amino acid substitutions at position 315 impair receptor function, the leucine substitution has the strongest deleterious effect. GD2.F4 inhibits agonist-induced activation of TLR1, supporting a crucial role for the loop of LRR11 in receptor function. These results also suggest that the P315L SNP may predispose certain individuals to infectious diseases for which the sensing of microbial cell components by TLR1 is critical to innate immune defense.