The human infertility single-cell testis atlas (HISTA): an interactive molecular scRNA-Seq reference of the human testis.

BACKGROUND: Single-cell RNA-seq (scRNA-Seq) has been widely adopted to study gene expression of the human testis. Several datasets of scRNA-Seq from human testis have been generated from different groups processed with different informatics pipelines. An integrated atlas of scRNA-Seq expression constructed from multiple donors, developmental ages, and fertility states would be widely useful for the testis research community. OBJECTIVE: To describe the generation and use of the human infertility single-cell testis atlas (HISTA), an interactive web tool for understanding human spermatogenesis through scRNA-Seq analysis. METHODS: We obtained scRNA-Seq datasets derived from 12 donors, including healthy adult controls, juveniles, and several infertility cases, and reprocessed these data using methods to remove batch effects. Using Shiny, an open-source environment for data visualization, we created numerous interactive tools for exploring the data, some of which support simple statistical hypothesis testing. We used the resulting HISTA browser and its underlying data to demonstrate HISTA's value for testis researchers. RESULTS: A primary application of HISTA is to search by a single gene or a set of genes; thus, we present various analyses that quantify and visualize gene expression across the testis cells and pathology. HISTA also contains machine-learning-derived gene modules ("components") that capture the entire transcriptional landscape of the testis tissue. We show how the use of these components can simplify the highly complex data in HISTA and assist with the interpretation of genes with unknown functions. Finally, we demonstrate the diverse ways HISTA can be used for new data analysis, including hypothesis testing. DISCUSSION AND CONCLUSIONS: HISTA is a research environment that can help scientists organize and understand the high-dimensional transcriptional landscape of the human testis. HISTA has already contributed to published testis research and can be updated as needed with input from the research community or downloaded and modified for individual needs.

Describing patterns of familial cancer risk in subfertile men using population pedigree data.

STUDY QUESTION: Can we simultaneously assess risk for multiple cancers to identify familial multicancer patterns in families of azoospermic and severely oligozoospermic men? SUMMARY ANSWER: Distinct familial cancer patterns were observed in the azoospermia and severe oligozoospermia cohorts, suggesting heterogeneity in familial cancer risk by both type of subfertility and within subfertility type. WHAT IS KNOWN ALREADY: Subfertile men and their relatives show increased risk for certain cancers including testicular, thyroid, and pediatric. STUDY DESIGN, SIZE, DURATION: A retrospective cohort of subfertile men (N = 786) was identified and matched to fertile population controls (N = 5674). Family members out to third-degree relatives were identified for both subfertile men and fertile population controls (N = 337 754). The study period was 1966-2017. Individuals were censored at death or loss to follow-up, loss to follow-up occurred if they left Utah during the study period. PARTICIPANTS/MATERIALS, SETTING, METHODS: Azoospermic (0 × 106/mL) and severely oligozoospermic (<1.5 × 106/mL) men were identified in the Subfertility Health and Assisted Reproduction and the Environment cohort (SHARE). Subfertile men were age- and sex-matched 5:1 to fertile population controls and family members out to third-degree relatives were identified using the Utah Population Database (UPDB). Cancer diagnoses were identified through the Utah Cancer Registry. Families containing ≥10 members with ≥1 year of follow-up 1966-2017 were included (azoospermic: N = 426 families, 21 361 individuals; oligozoospermic: N = 360 families, 18 818 individuals). Unsupervised clustering based on standardized incidence ratios for 34 cancer phenotypes in the families was used to identify familial multicancer patterns; azoospermia and severe oligospermia families were assessed separately. MAIN RESULTS AND THE ROLE OF CHANCE: Compared to control families, significant increases in cancer risks were observed in the azoospermia cohort for five cancer types: bone and joint cancers hazard ratio (HR) = 2.56 (95% CI = 1.48-4.42), soft tissue cancers HR = 1.56 (95% CI = 1.01-2.39), uterine cancers HR = 1.27 (95% CI = 1.03-1.56), Hodgkin lymphomas HR = 1.60 (95% CI = 1.07-2.39), and thyroid cancer HR = 1.54 (95% CI = 1.21-1.97). Among severe oligozoospermia families, increased risk was seen for three cancer types: colon cancer HR = 1.16 (95% CI = 1.01-1.32), bone and joint cancers HR = 2.43 (95% CI = 1.30-4.54), and testis cancer HR = 2.34 (95% CI = 1.60-3.42) along with a significant decrease in esophageal cancer risk HR = 0.39 (95% CI = 0.16-0.97). Thirteen clusters of familial multicancer patterns were identified in families of azoospermic men, 66% of families in the azoospermia cohort showed population-level cancer risks, however, the remaining 12 clusters showed elevated risk for 2-7 cancer types. Several of the clusters with elevated cancer risks also showed increased odds of cancer diagnoses at young ages with six clusters showing increased odds of adolescent and young adult (AYA) diagnosis [odds ratio (OR) = 1.96-2.88] and two clusters showing increased odds of pediatric cancer diagnosis (OR = 3.64-12.63). Within the severe oligozoospermia cohort, 12 distinct familial multicancer clusters were identified. All 12 clusters showed elevated risk for 1-3 cancer types. An increase in odds of cancer diagnoses at young ages was also seen in five of the severe oligozoospermia familial multicancer clusters, three clusters showed increased odds of AYA diagnosis (OR = 2.19-2.78) with an additional two clusters showing increased odds of a pediatric diagnosis (OR = 3.84-9.32). LIMITATIONS, REASONS FOR CAUTION: Although this study has many strengths, including population data for family structure, cancer diagnoses and subfertility, there are limitations. First, semen measures are not available for the sample of fertile men. Second, there is no information on medical comorbidities or lifestyle risk factors such as smoking status, BMI, or environmental exposures. Third, all of the subfertile men included in this study were seen at a fertility clinic for evaluation. These men were therefore a subset of the overall population experiencing fertility problems and likely represent those with the socioeconomic means for evaluation by a physician. WIDER IMPLICATIONS OF THE FINDINGS: This analysis leveraged unique population-level data resources, SHARE and the UPDB, to describe novel multicancer clusters among the families of azoospermic and severely oligozoospermic men. Distinct overall multicancer risk and familial multicancer patterns were observed in the azoospermia and severe oligozoospermia cohorts, suggesting heterogeneity in cancer risk by type of subfertility and within subfertility type. Describing families with similar cancer risk patterns provides a new avenue to increase homogeneity for focused gene discovery and environmental risk factor studies. Such discoveries will lead to more accurate risk predictions and improved counseling for patients and their families. STUDY FUNDING/COMPETING INTEREST(S): This work was funded by GEMS: Genomic approach to connecting Elevated germline Mutation rates with male infertility and Somatic health (Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): R01 HD106112). The authors have no conflicts of interest relevant to this work. TRIAL REGISTRATION NUMBER: N/A.

Transgenerational effects of paternal exposures: the role of germline de novo mutations.

Germline de novo mutations (DNMs) refer to spontaneous mutations arising during gametogenesis, resulting in genetic changes within germ cells that are subsequently transmitted to the next generation. While the impact of maternal exposures on germline DNMs has been extensively studied, more recent studies have begun to highlight the increasing importance of the effects of paternal factors. In this review, we have summarized the existing literature on how various exposures experienced by fathers affect the germline DNM burden in their spermatozoa, as well as their consequences for semen analysis parameters, pregnancy outcomes, and offspring health. A growing body of literature supports the conclusion that advanced paternal age (APA) correlates with a higher germline DNM rate in offspring. Furthermore, lifestyle choices, environmental toxins, assisted reproductive techniques (ART), and chemotherapy are associated with the accumulation of paternal DNMs in spermatozoa, with deleterious consequences for pregnancy outcomes and offspring health. Ultimately, our review highlights the clear importance of the germline DNM mode of inheritance, and the current understanding of how this is affected by various paternal factors. In addition, we explore conflicting reports or gaps of knowledge that should be addressed in future research.

Untreated hypogonadism and testosterone replacement therapy in hypogonadal men are associated with a decreased risk of subsequent prostate cancer: a population-based study.

We sought to understand the relationship between hypogonadism and testosterone replacement therapy (TRT) in hypogonadal men on the risk of developing localized and metastatic prostate cancer. We used the Merative MarketScan database of commercial claims encounters to identify men diagnosed with hypogonadism. These men were matched to eugonadal men who served as controls. Multivariate negative binomial regression analysis of prostate cancer diagnoses, hypogonadism, and TRT in hypogonadal men adjusting for various known confounding factors was used to understand the impact of hypogonadism and TRT on prostate cancer risk. We identified 3,222,904 men who met inclusion criteria, of which 50% were diagnosed with hypogonadism (1,611,452) and each were matched to a control (1,611,452). The incidence of prostate cancer was 2.16%, 1.55%, and 1.99% in eugonadal controls, hypogonadal men on TRT, and hypogonadal men without TRT, respectively (p < 0.001). Untreated hypogonadism was independently associated with a decreased risk of localized prostate cancer (IRR 0.46, 95% CI 0.43-0.50, p < 0.001) compared to eugonadal controls. Hypogonadal men on TRT also had a significantly decreased risk of localized prostate cancer (IRR 0.49, 95% CI 0.45-0.53, p < 0.001). Furthermore, hypogonadal men on TRT (IRR 0.21, 95% CI 0.19-0.24, p < 0.001) or without TRT (IRR 0.20, 95% CI 0.18-0.22, p < 0.001) both had significantly decreased risk of metastatic prostate cancer, respectively. Our population-based analysis suggests that untreated hypogonadism in men is associated with a 50% decreased incidence of localized prostate cancer and an 80% decreased incidence of metastatic prostate cancer. TRT in hypogonadal men was also associated with a decreased risk of subsequent prostate cancer. Further research is needed to better understand the relationship between hypogonadism and TRT in hypogonadal men on the risk of subsequent prostate cancer.

Cost and utilization analysis of concurrent versus staged testicular prosthesis implantation for radical orchiectomy.

PURPOSE: American Urological Association guidelines recommend testicular prosthesis discussion prior to orchiectomy. Utilization may be low. We compared outcomes and care utilization between concurrent implant (CI) and staged implant (SI) insertion after radical orchiectomy. MATERIALS & METHODS: The MarketScan Commercial claims database (2008-2017) was queried for men ages >18 years who underwent radical orchiectomy for testicular mass, stratified as orchiectomy with no implant, CI, or SI. 90-day outcomes included rate of reoperation, readmission, emergency department (ED) presentation, and outpatient visits. Regression models provided rate ratio comparison. RESULTS: 8803 patients (8564 no implant, 190 CI, 49 SI; 2.7% implant rate) were identified with no difference in age, Charlson Comorbidity Index, insurance plan, additional cancer treatment, or metastasis. Median perioperative cost at orchiectomy (+/- implant) for no implant, CI, and SI were $5682 (3648-8554), $7823 (5403-10973), and $5380 (4130-10521), respectively (p<0.001). Median perioperative cost for SI at implantation was $8180 (4920-14591) for a total cost (orchiectomy + implant) of $13650 (5380 + 8180). CI patients were more likely to have follow-up (p = 0.006) with more visits (p = 0.030) compared to the SI group post-implantation but had similar follow-up (p = 0.065) and less visits (p = 0.025) compared to the SI patients' post-orchiectomy period. Overall explant rates were 4.7% for CI and 14.3% for SI (p = 0.04) with a median time to explant of 166 (IQR: 135-210) and 40 days (IQR: 9.5-141.5; p = 0.06). Median cost of removal was $2060 (IQR: 967-2880). CONCLUSIONS: CI placement has less total perioperative cost, lower explant rate, and similar postoperative utilization to SI.

Single-cell multi-omics analysis of human testicular germ cell tumor reveals its molecular features and microenvironment.

Seminoma is the most common malignant solid tumor in 14 to 44 year-old men. However, its molecular features and tumor microenvironment (TME) is largely unexplored. Here, we perform a series of studies via genomics profiling (single cell multi-omics and spatial transcriptomics) and functional examination using seminoma samples and a seminoma cell line. We identify key gene expression programs share between seminoma and primordial germ cells, and further characterize the functions of TFAP2C in promoting tumor invasion and migration. We also identify 15 immune cell subtypes in TME, and find that subtypes with exhaustion features were located closer to the tumor region through combined spatial transcriptome analysis. Furthermore, we identify key pathways and genes that may facilitate seminoma disseminating beyond the seminiferous tubules. These findings advance our knowledge of seminoma tumorigenesis and produce a multi-omics atlas of in situ human seminoma microenvironment, which could help discover potential therapy targets for seminoma.

Epigenetic determinants of reproductive potential augment the predictive ability of the semen analysis.

OBJECTIVE: To investigate the power of DNA methylation variability in sperm cells in assessing male fertility potential. DESIGN: Retrospective cohort. SETTING: Fertility care centers. PATIENTS: Male patients seeking infertility treatment and fertile male sperm donors. INTERVENTION: None. MAIN OUTCOME MEASURES: Sperm DNA methylation data from 43 fertile sperm donors were analyzed and compared with the data from 1344 men seeking fertility assessment or treatment. Methylation at gene promoters with the least variable methylation in fertile patients was used to create 3 categories of promoter dysregulation in the infertility treatment cohort: poor, average, and excellent sperm quality. RESULTS: After controlling for female factors, there were significant differences in intrauterine insemination pregnancy and live birth outcomes between the poor and excellent groups across a cumulative average of 2-3 cycles: 19.4% vs. 51.7% (P=.008) and 19.4% vs. 44.8% (P=.03), respectively. Live birth outcomes from in vitro fertilization, primarily with intracytoplasmic sperm injection, were not found to be significantly different among any of the 3 groups. CONCLUSION: Methylation variability in a panel of 1233 gene promoters could augment the predictive ability of semen analysis and be a reliable biomarker for assessing intrauterine insemination outcomes. In vitro fertilization with intracytoplasmic sperm injection appears to overcome high levels of epigenetic instability in sperm.

Male infertility.

Clinical infertility is the inability of a couple to conceive after 12 months of trying. Male factors are estimated to contribute to 30-50% of cases of infertility. Infertility or reduced fertility can result from testicular dysfunction, endocrinopathies, lifestyle factors (such as tobacco and obesity), congenital anatomical factors, gonadotoxic exposures and ageing, among others. The evaluation of male infertility includes detailed history taking, focused physical examination and selective laboratory testing, including semen analysis. Treatments include lifestyle optimization, empirical or targeted medical therapy as well as surgical therapies that lead to measurable improvement in fertility. Although male infertility is recognized as a disease with effects on quality of life for both members of the infertile couple, fewer data exist on specific quantification and impact compared with other health-related conditions.

Incidence and Risk Factors for Postoperative Venous Thromboembolism After Gender Affirming Vaginoplasty: A Retrospective Analysis of a Large Insurance Claims Database.

OBJECTIVES: To investigate the incidence and associated risk factors of venous thromboembolism (VTE) after gender affirming vaginoplasty. METHODS: We searched International Business Machines Corporation (IBM) Marketscan, a commercial claims database, for Current Procedural Terminology and International Classification of Diseases (ICD) procedure codes to identify patients who underwent gender affirming vaginoplasty from 2011-2020. We quantified deep venous thrombosis and pulmonary embolism using ICD-9 and ICD-10 codes found within 90 days after surgery. Univariate and multivariate analyses were performed to establish association between VTE events and age, residency location, and comorbidities. RESULTS: We identified 1588 patients who underwent gender affirming vaginoplasty. Overall, 1.1% of patients experienced a VTE within 90 days following surgery. Patients who experienced postoperative VTE were older, more likely to have had a prior VTE, less likely to be from an urban area, and more likely to have a higher Charlson Comorbidity Index score. Among patients with postoperative VTE, 47.1% had previous VTE. Among patients without a postoperative VTE, 1.3% had previous VTE. CONCLUSION: In patients undergoing gender affirming vaginoplasty, the incidence of postoperative VTE was 1.1%. Older age, rurality, increased comorbidities, and prior VTE were associated with increased risk of postoperative VTE. Current guidelines do not recommend cessation of gender affirming hormone therapy (GAHT) prior to vaginoplasty. Further research is needed to evaluate if certain high-risk patients would benefit from perioperative adjustment of GAHT or perioperative VTE prophylaxis.

Tissue-specific DNA methylation variability and its potential clinical value.

Complex diseases have multifactorial etiologies making actionable diagnostic biomarkers difficult to identify. Diagnostic research must expand beyond single or a handful of genetic or epigenetic targets for complex disease and explore a broader system of biological pathways. With the objective to develop a diagnostic tool designed to analyze a comprehensive network of epigenetic profiles in complex diseases, we used publicly available DNA methylation data from over 2,400 samples representing 20 cell types and various diseases. This tool, rather than detecting differentially methylated regions at specific genes, measures the intra-individual methylation variability within gene promoters to identify global shifts away from healthy regulatory states. To assess this new approach, we explored three distinct questions: 1) Are profiles of epigenetic variability tissue-specific? 2) Do diseased tissues exhibit altered epigenetic variability compared to normal tissue? 3) Can epigenetic variability be detected in complex disease? Unsupervised clustering established that global epigenetic variability in promoter regions is tissue-specific and promoter regions that are the most epigenetically stable in a specific tissue are associated with genes known to be essential for its function. Furthermore, analysis of epigenetic variability in these most stable regions distinguishes between diseased and normal tissue in multiple complex diseases. Finally, we demonstrate the clinical utility of this new tool in the assessment of a multifactorial condition, male infertility. We show that epigenetic variability in purified sperm is correlated with live birth outcomes in couples undergoing intrauterine insemination (IUI), a common fertility procedure. Men with the least epigenetically variable promoters were almost twice as likely to father a child than men with the greatest number of epigenetically variable promoters. Interestingly, no such difference was identified in men undergoing in vitro fertilization (IVF), another common fertility procedure, suggesting this as a treatment to overcome higher levels of epigenetic variability when trying to conceive.

Exogenous Testosterone Replacement Therapy Is Associated with Increased Risk for Vascular Graft Infections Among Hypogonadal Men.

BACKGROUND: Vascular graft infections (VGIs) are a major source of morbidity following vascular bypass surgery. Hypogonadal men may be at increased risk for impaired wound healing and infections, but it is unclear if testosterone replacement therapy (TRT) mitigates this risk. We designed this study to evaluate the relationship between hypogonadism and the use of testosterone replacement therapy (TRT) with subsequent risk for developing a VGI. METHODS: We performed a retrospective analysis of claims in the MarketScan database identifying men greater than 18 years of age who underwent placement of a prosthetic graft in the peripheral arterial circulation from January 2009 to December 2020. Patients were stratified based on diagnosis of hypogonadism and use of TRT within 180 days before surgery. The primary outcome was VGI and the need for surgical excision. The association between hypogonadism and TRT use on risk of VGI was analyzed using Kaplan-Meier plots and multivariate Cox proportional hazards models. RESULTS: We identified 18,312 men who underwent a prosthetic bypass graft procedure in the upper and lower extremity during the study period, of which 802 (5%) had diagnosis of hypogonadism. Among men with hypogonadism, 251 (31%) were receiving TRT. Patients on TRT were younger, more likely to be diabetic, and more likely develop a VGI during follow-up (14% vs. 8%; P < 0.001) that was in the lower extremity. At 5 years, freedom from VGI was significantly lower for hypogonadal men on TRT than patients not on TRT or without hypogonadism (Log rank P < 0.001). In Cox regression models adjusted for age, diabetes, obesity, smoking, corticosteroid use, and procedure type, hypogonadal men on TRT were at a significantly increased risk of graft infection (hazard ratio (HR):1.94, 95% confidence interval (CI):1.4-2.7; P < 0.001) compared to controls. CONCLUSIONS: This study demonstrates TRT among hypogonadal men is associated with an increased risk of prosthetic VGIs. Temporary cessation of TRT should be considered for men undergoing prosthetic graft implants, particularly those in the lower extremity.

Delayed placement of an inflatable penile prosthesis is associated with a high complication rate in men with a history of ischemic priapism.

BACKGROUND: Corporal fibrosis is known to result from prolonged priapism; however, the impact of the timing of penile prosthesis placement after priapism on complication rates is poorly understood. AIM: We sought to evaluate the impact of timing of inflatable penile prosthesis (IPP) placement on complications in men with a history of ischemic priapism. METHODS: We performed a multicenter, retrospective cohort study of patients with a history of priapism undergoing IPP placement by 10 experienced implantation surgeons. We defined early placement as ≤6 months from priapism to IPP. We identified a 1:1 propensity-matched group of men without a history of priapism and compared complication rates between men who had early placement, late placement, and no history of priapism. OUTCOMES: Our primary outcome was postoperative noninfectious complications, and secondary outcomes included intraoperative complications and postoperative infection. RESULTS: A total of 124 men were included in the study with a mean age of 50.3 ± 12.7 years. A total of 62 had a history of priapism and 62 were matched control subjects. The median duration of priapism was 37 (range, 3-168) hours and the median time from ischemic priapism to IPP placement was 15 months (range, 3 days to 23 years). Fifteen (24%) men underwent early (≤6 months) IPP placement at a median time of 2 months (range, 3 days to 6 months) following the ischemic priapism event. The remaining 47 (76%) underwent placement >6 months following priapism at a median time of 31.5 months (range, 7 months to 23 years). The complication rate in the delayed placement group was 40.5% compared with 0% in the early placement group and control group. Cylinder-related complications such as migration or leak accounted for 8 (57%) of 14 of the postoperative noninfectious complications. Full-sized cylinders were used in all patients who had a cylinder related complication. CLINICAL IMPLICATIONS: Priapism patients should be referred to prosthetic experts early to decrease complication rates in those needing an IPP. STRENGTHS AND LIMITATIONS: This is a multicenter study from experienced prosthetic urologists but is limited by the retrospective nature and small number of patients in the early placement group. CONCLUSION: IPP complication rates are high in men with a history of ischemic priapism, especially when implantation is delayed beyond 6 months.

Abnormal Laboratory Values for Metabolic and Hormonal Syndromes Are Prevalent Among Patients Undergoing Rotator Cuff Repair.

Purpose: To determine the prevalence of systemic laboratory abnormalities among patients undergoing rotator cuff repair (RCR). Methods: Patients who underwent RCR at the authors' institution for 1 year between October 2021 to September 2022 were retrospectively identified. Preoperative laboratory values, including serum sex hormones, vitamin D, hemoglobin A1C, and a lipid panel, were obtained as part of our routine practice during the study period. Demographics and tear characteristics were compared in patients with laboratory data and those without. For included patients with laboratory data, mean laboratory values and percentage of patients with abnormal laboratory values were recorded. Results: During a 1-year period of time, 135 RCRs were performed, of which preoperative labs were obtained on 105. Of these, 67% were sex hormone deficient, 36% were vitamin D deficient, 45% had an abnormal hemoglobin A1C, and 64% had an abnormal lipid panel. In total 4% had "normal" labs. Conclusions: In this retrospective study, sex hormone deficiency is highly prevalent among patients undergoing RCR. Nearly all patients undergoing RCR have systemic laboratory abnormalities involving either sex hormone deficiency, vitamin D deficiency, dyslipidemia, and/or prediabetes. Level of Evidence: Level IV, prognostic case series.

Environmental exposure to industrial air pollution is associated with decreased male fertility.

OBJECTIVE: To understand how chronic exposure to industrial air pollution is associated with male fertility through semen parameters. DESIGN: Retrospective cohort study. PATIENTS: Men in the Subfertility, Health, and Assisted Reproduction cohort who underwent a semen analysis in the two largest healthcare systems in Utah from 2005-2017 with ≥1 measured semen parameter (N = 21,563). INTERVENTION(S): Residential histories for each man were constructed using locations from administrative records linked through the Utah Population Database. Industrial facilities with air emissions of nine endocrine-disrupting compound chemical classes were identified from the Environmental Protection Agency Risk-Screening Environmental Indicators microdata. Chemical levels were linked with residential histories for the 5 years before each semen analysis. MAIN OUTCOME MEASURES: Semen analyses were classified as azoospermic or oligozoospermic (< 15 M/mL) using World Health Organization cutoffs for concentration. Bulk semen parameters such as concentration, total count, ejaculate volume, total motility, total motile count, and total progressive motile count were also measured. Multivariable regression models with robust standard errors were used to associate exposure quartiles for each of the nine chemical classes with each semen parameter, adjusting for age, race, and ethnicity, as well as neighborhood socioeconomic disadvantage. RESULTS: After adjustment for demographic covariates, several chemical classes were associated with azoospermia and decreased total motility and volume. For exposure in the 4th relative to 1st quartile, significant associations were observed for acrylonitrile (ßtotal motility = -0.87 pp), aromatic hydrocarbons (odds ratio [OR]azoospermia = 1.53; ßvolume = -0.14 mL), dioxins (ORazoospermia = 1.31; ßvolume = -0.09 mL; ßtotal motility = -2.65 pp), heavy metals (ßtotal motility = -2.78pp), organic solvents (ORazoospermia = 1.75; ßvolume = -0.10 mL), organochlorines (ORazoospermia = 2.09; ßvolume = -0.12 mL), phthalates (ORazoospermia = 1.44; ßvolume = -0.09 mL; ßtotal motility = -1.21 pp), and silver particles (ORazoospermia = 1.64; ßvolume = -0.11 mL). All semen parameters significantly decreased with increasing socioeconomic disadvantage. Men who lived in the most disadvantaged areas had concentration, volume, and total motility of 6.70 M/mL, 0.13 mL, and 1.79 pp lower, respectively. Count, motile count, and total progressive motile count all decreased by 30-34 M. CONCLUSION(S): Several significant associations between chronic low-level environmental exposure to endocrine-disrupting compound air pollution from industrial sources and semen parameters were observed. The strongest associations were seen for increased odds of azoospermia and declines in total motility and volume. More research is needed to further explore additional social and exposure factors as well as expand on the risk posed to male reproductive health by the studied chemicals.

Prior COVID-19 infection associated with increased risk of newly diagnosed erectile dysfunction.

We sought to assess if COVID-19 infection recovery is associated with increased rates of newly diagnosed erectile dysfunction. Using IBM MarketScan, a commercial claims database, men with prior COVID-19 infection were identified using ICD-10 diagnosis codes. Using this cohort along with an age-matched cohort of men without prior COVID-19 infection, we assessed the incidence of newly diagnosed erectile dysfunction. Covariates were assessed using a multivariable model to determine association of prior COVID-19 infection with newly diagnosed erectile dysfunction. 42,406 men experienced a COVID-19 infection between January 2020 and January 2021 of which 601 (1.42%) developed new onset erectile dysfunction within 6.5 months follow up. On multivariable analysis while controlling for diabetes, cardiovascular disease, smoking, obesity, hypogonadism, thromboembolism, and malignancy, prior COVID-19 infection was associated with increased risk of new onset erectile dysfunction (HR 1.27; 95% CI 1.1-1.5; P = 0.002). Prior to the widespread implementation of the COVID-19 vaccine, the incidence of newly diagnosed erectile dysfunction is higher in men with prior COVID-19 infection compared to age-matched controls. Prior COVID-19 infection was associated with a 27% increased likelihood of developing new-onset erectile dysfunction when compared to those without prior infection.

Occurrence of pulmonary oil microembolism (POME) with intramuscular testosterone undecanoate injection: literature review.

Testosterone undecanoate injections (TU), an oil-based depot, is a universal hormonal-based treatment which has been associated with pulmonary oil microembolism (POME). However, the rate of POME during routine intramuscular (IM) TU injection is unknown. Here, we conduct a peer-reviewed literature review investigating POME incidents in the setting of TU injections. A total of 48 articles were selected in the literature review, which included 29 studies that used TU and reported its effects. Relatively few POME cases were reported across multiple published studies, including those that focused particularly on the occurrence rate of POME while administrating IM TU. Of the 29 individual studies, which included 7 978 patients, eight studies reported a total of 88 incidence of POME cases or cough. This included episodes of cough that were not originally declared as POME. One post market review reported 223 cases per 3,107,652 injections. When POME did occur, almost all cases resolved spontaneously within 60 min without intervention. Overall, POME was observed to be rare.

Evolution of the basic semen analysis and processing sperm.

PURPOSE OF REVIEW: The sixth edition of the World Health Organization (WHO) laboratory manual for the examination and processing of human semen was recently published with specific step-by-step instructions for semen evaluation and sperm processing. Point-of-care (POC) testing for semen evaluation and microfluidics for sperm processing are rapidly evolving technologies that could impact how we evaluate and process sperm. Understanding the updated manual in the context of these novel technologies is important. RECENT FINDINGS: Proper standardization of semen evaluation and sperm processing will allow for consistent high-quality results among laboratories worldwide. POC testing could improve access to semen evaluations that generate referrals to male infertility specialists for further assessment. Microfluidics can select functional sperm with decreased DNA fragmentation in semen and testicular biopsy samples for assisted reproductive technology (ART). Clinical outcomes, such as pregnancy rates and live birth rates, have not been shown to be consistently improved with these technologies compared to conventional techniques, although high level evidence research in this area is limited. SUMMARY: POC testing and microfluidics have the potential to be combined with machine learning technologies to improve fertility care. If these technologies are appropriately optimized, they could change how we evaluate and process sperm, and potentially lead to improved ART outcomes.

AUA-recommended Antibiotic Prophylaxis for Primary Penile Implantation Results in a Higher, Not Lower, Risk for Postoperative Infection: A Multicenter Analysis.

PURPOSE: Our aim was to determine if the AUA-recommended prophylaxis (vancomycin + gentamicin alone) for primary inflatable penile prosthesis surgery is associated with a higher infection risk than nonstandard regimens. MATERIALS AND METHODS: We performed a multicenter, retrospective study of patients undergoing primary inflatable penile prosthesis surgery. Patients were divided into those receiving vancomycin + gentamicin alone and those receiving any other regimen. A Cox proportional-hazards model was constructed adjusted for major predictors. A subgroup analysis to identify the appropriate dosage of gentamicin was also performed. RESULTS: A total of 4,161 patients underwent primary inflatable penile prosthesis placement (2,411 received vancomycin + gentamicin alone and 1,750 received other regimens). The infection rate was similar between groups, 1% vs 1.2% for standard vs nonstandard prophylaxis. In the multivariable analysis, vancomycin + gentamicin (HR: 2.7, 95% CI: 1.4 to 5.4, P = .004) and diabetes (HR: 1.9, 95% CI: 1.03 to 3.4, P = .04) were significantly associated with a higher risk of infection. Antifungals (HR: 0.08, 95% CI: 0.03 to 0.19, P < .001) were associated with lower risk of infection. There was no statistically significant difference in infection rate between weight-based gentamicin compared to 80 mg gentamicin (HR: 2.9, 95% CI: 0.83 to 10, P = .1). CONCLUSIONS: Vancomycin + gentamicin alone for antibiotic prophylaxis for primary inflatable penile prosthesis surgery is associated with a higher infection risk than nonstandard antibiotic regimens while antifungal use is associated with lower infection risk. A critical review of the recommended antimicrobial prophylactic regimens is needed. Prospective research is needed to further elucidate best practices in inflatable penile prosthesis antimicrobial prophylaxis.

Diverse monogenic subforms of human spermatogenic failure.

Non-obstructive azoospermia (NOA) is the most severe form of male infertility and typically incurable. Defining the genetic basis of NOA has proven challenging, and the most advanced classification of NOA subforms is not based on genetics, but simple description of testis histology. In this study, we exome-sequenced over 1000 clinically diagnosed NOA cases and identified a plausible recessive Mendelian cause in 20%. We find further support for 21 genes in a 2-stage burden test with 2072 cases and 11,587 fertile controls. The disrupted genes are primarily on the autosomes, enriched for undescribed human "knockouts", and, for the most part, have yet to be linked to a Mendelian trait. Integration with single-cell RNA sequencing data shows that azoospermia genes can be grouped into molecular subforms with synchronized expression patterns, and analogs of these subforms exist in mice. This analysis framework identifies groups of genes with known roles in spermatogenesis but also reveals unrecognized subforms, such as a set of genes expressed across mitotic divisions of differentiating spermatogonia. Our findings highlight NOA as an understudied Mendelian disorder and provide a conceptual structure for organizing the complex genetics of male infertility, which may provide a rational basis for disease classification.

Fertility in the aging male: a systematic review.

The negative effect of advanced female age on fertility and offspring health is well understood. In comparison, much less is known about the implications of male age on fertility, with many studies showing conflicting results. Nevertheless, increasing evidence suggests that advanced paternal age has negative effects on sperm parameters, reproductive success, and offspring health. Herein, we summarize the current body of knowledge on this controversial topic, with the belief that this review will serve as a resource for the clinicians providing fertility counseling to couples with older male partners.