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.

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.

Examining Male Predominance of Severe COVID-19 Outcomes: A Systematic Review.

Although not universal, many epidemiological data sources signal that a higher proportion of males than females with confirmed Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infections have adverse outcomes, such as intensive care unit (ICU) admission and death. Though likely multifactorial, the various hypotheses that have been proposed as underlying factors behind this trend are related to greater smoking prevalence among males, testosterone (T) deficiency causing an inflammatory storm, androgen-driven pathogenesis of SARS-CoV-2, a protective effect of estrogen in females, and inborn errors of cytokine immunity. This review aims at examining the evidence and at assessing the likelihood that the factors being investigated are contributory to the reported trend of male predominance of severe COVID-19 cases. Sources were obtained using the PubMed database and were selected based on their relevance to one of the primary hypotheses attempting to explain the strong male sex bias of severe SARS-CoV-2 infections. Emphasis was placed on meta-analyses and population-based studies. Sources are current through February 22, 2022. A severe COVID-19 case or outcome is defined in this review as a progression of the SARS-CoV-2 virus that results in either admission to an ICU for management of symptoms and clinical stabilization or which leads to death. Although the trend of male predominance of severe COVID-19 cases is likely multifactorial, the hypothesis of T deficiency causing an inflammatory storm has support from many studies with limited conflicting evidence. An inborn error in cytokine immunity is also well supported, but it needs more studies to add support to the hypothesis. The immunologic protective effect of estrogen is supported by multiple studies, but it also has conflicting evidence. It appears less likely that the trend is caused solely by an increased prevalence of smoking among males or an androgen-driven pathogenesis, based on the extent of conflicting evidence.

Risk of Postoperative Thromboembolism in Men Undergoing Urological Prosthetic Surgery: An Assessment of 21,413 Men.

PURPOSE: We assessed venous thromboembolism (VTE) and associated risk factors following artificial urinary sphincter (AUS) and inflatable penile prosthesis (IPP) surgery. MATERIALS AND METHODS: Using IBM® MarketScan, a commercial claims database, patients undergoing AUS and IPP surgery were identified using CPT® and ICD (International Classification of Diseases)-10 procedure codes between 2008 and 2017. ICD-9 and -10 codes were used to identify health care visits associated with lower extremity deep vein thrombosis (DVT) and pulmonary embolism (PE) within 90 days of surgery. Covariates were assessed using a multivariable model to determine association with outcome of DVT and/or PE. RESULTS: A total of 21,413 men underwent AUS (4,870) or IPP (16,543) surgery between 2008 and 2017 with a median age of 62 years and 68 years, respectively. DVT and PE events following AUS and IPP surgery occurred in 1.54% and 1.04%, respectively. A history of varicose veins (HR 2.76; 95% CI 1.11-6.79), prior history of DVT (HR 13.65; 95% CI 7.4-25.19), or PE (HR 7.65; 95% CI 4.01-14.6) in those undergoing AUS surgery was highly associated with development of postoperative VTE. Likewise, prior history of DVT (HR 12.6; 95% CI 7.99-19.93) and PE (HR 8.9; 95% CI 5.6-14.13) was strongly associated with a VTE event following IPP surgery. CONCLUSIONS: In a large cohort of men undergoing AUS and IPP surgery, 1.54% and 1.04% of men experienced a VTE event within 90 days of surgery, respectively. Prior history of varicose veins, DVT, and PE was associated with an increased likelihood of developing a postoperative DVT or PE.

Seasonal variation in semen quality is not associated with fecundity in the Utah Population Database.

We determine whether a suspected seasonal variability in semen quality affect subsequent live birth rates. This is a retrospective, cohort analysis of men who provided semen analyses as part of fertility workup through a large andrology lab between 1996 and 2013 and corresponding birth rates using the Utah Population Database (UPDB). Semen parameters were analysed including total motile count (TMC), total sperm count, sperm concentration and progressive motility. Corresponding live births reflect those born in the state of Utah and were derived from birth certificate data available in the UPDB. Descriptive statistics were reported along with linear regression analysis with mixed effected models to test for an interaction between seasonal variation in semen quality and birth rates, accounting for age at the time of the semen analysis and abstinence time. A total of 11,929 patients and 14,765 semen samples were included. Only 3597 men (39% of men) had one or more values outside the World Health Organization reference range for their semen parameters. Linear regression demonstrated a consistent U-shaped relationship between TMC, total sperm count, and sperm concentration and season, with spring and winter yielding the highest values with a decline in the summer and fall. 7319 of these males had recorded live births for a total of 13,502 live births during the study period after a median follow-up of 7.2 years (IQR: 3.9-11.0). We did not find a significant interaction between specific semen parameters for a specific season and subsequent live births. Semen quality was the highest in the spring and winter, however there was no interaction between seasonal variability in semen quality and subsequent births. This is one of the largest studies describing seasonal variation in semen quality in humans.

Significant familial clustering of Peyronie's disease in close and distant relatives.

BACKGROUND: Peyronie's disease (PD) has previously been observed to co-aggregate in a small number of first-degree relative pairs (e.g., father-son). However, the familial aggregation of PD in more distant relatives, as well as the aggregation of Dupuytren's disease (DD) in probands and relatives, has not been thoroughly investigated. OBJECTIVE: This study explored the evidence for familial clustering of PD and DD in close and distant relatives. MATERIALS AND METHODS: The Utah Population Database, which includes genealogy information linked to electronic medical records (available since 1995), was used to identify men and their relatives with PD and DD based on ICD9/10 codes. All cases were required to have high-quality genealogy data. We estimated relative risk (RR) of PD and DD in first- through fifth-degree relatives compared to matched population rates of disease. We also investigated the average relatedness of cases compared to the average relatedness of sets of matched controls. Outcome measures include estimation of relative risk and excessive relatedness as measured by a Genealogical Index of Familiality (GIF) analysis. RESULTS: We analyzed 307 individuals with PD, and their first- through fifth-degree relatives. Approximately 0.12% of the population had PD, 95% of these were diagnosed over the age of 30 years (age range: 10-92 years), and 1.3% of PD probands had a comorbid diagnosis of DD. RR estimates for PD were significant for first- and fifth-degree relatives. RR estimates for DD were significant only for probands. The average relatedness of cases was significantly greater than matched controls, even after removing first- and second-degree relatives. We also found that 74.9% of identified PD probands belonged to pedigrees with a statistical excess of PD. CONCLUSION: Despite the low prevalence of PD in our healthcare records, the results provide evidence that support a genetic contribution to at least a subset of PD cases.

Hypogonadism Associated With Higher Rate of Penile Prosthesis Infection: An Analysis of United States Claims Data.

OBJECTIVE: To understand the relationship between hypogonadism and penile prosthesis infection risk. METHODS: We performed a retrospective analysis using IBM MarketScan Commercial Claims and Encounters database. We identified men with ED diagnosis who underwent penile prosthesis placement from 1/1/2008 to 12/31/2017. Comorbidities and risk factors were identified along with a diagnosis of hypogonadism. After placement of penile prosthesis, men were followed until date of surgery of penile prosthesis explant due to infection. Cox proportional hazards models from time of penile prosthesis surgery to date of infection adjusting for various known confounding factors were run. RESULTS: We identified 16,660 men who had received penile prosthesis during the study period. 4,832 (29.0%) men had a hypogonadism diagnosis at the time of their initial surgery date. There were 421 (2.5%) device infections requiring explanation. Descriptively, a higher percentage of infections were noted for removal and replacement surgeries compared to primary implants. Hypogonadism was independently associated with a 25.8% higher risk of penile prosthesis infection (HR: 1.258, 95% CI: 1.024-1.546). Among those men who received testosterone therapy for hypogonadism (prescription data within 0-30 days and within 0-90 days of their initial implant surgery), the effect of hypogonadism on infection risk was no longer significant. CONCLUSIONS: Untreated hypogonadism was associated with a 26% higher risk of penile prosthesis infection. This association was most pronounced in men undergoing removal and replacement surgery, which likely drives this association. This suggests a possible benefit to testosterone therapy in testosterone deficient men prior to penile implant, specifically in men undergoing revision.

Disorders of Ejaculation: An AUA/SMSNA Guideline.

PURPOSE: Men who ejaculate before or shortly after penetration, without a sense of control, and who experience distress related to this condition may be diagnosed with premature ejaculation (PE), while men who experience difficulty achieving sexual climax may be diagnosed with delayed ejaculation (DE). The experience of many clinicians suggest that these problems are not rare and can be a source of considerable embarrassment and dissatisfaction for patients. The role of the clinician in managing PE and DE is to conduct appropriate investigation, to provide education, and to offer available treatments that are rational and based on sound scientific data. MATERIALS AND METHODS: The systematic review utilized to inform this guideline was conducted by a methodology team at the Pacific Northwest Evidence-based Practice Center. A research librarian conducted searches in Ovid MEDLINE (1946 to March 1, 2019), the Cochrane Central Register of Controlled Trials (through January 2019) and the Cochrane Database of Systematic Reviews (through March 1, 2019). An update search was conducted on September 5, 2019. Database searches resulted in 1,851 potentially relevant articles. After dual review of abstracts and titles, 223 systematic reviews and individual studies were selected for full-text dual review, and 8 systematic reviews and 59 individual studies were determined to meet inclusion criteria and were included in the review. RESULTS: Several psychological health, behavioral, and pharmacotherapy options exist for both PE and DE; however, none of these pharmacotherapy options have achieved approval from the United States Food and Drug Administration and their use in the treatment of PE and DE is considered off-label. CONCLUSION: Disturbances of the timing of ejaculation can pose a substantial impediment to sexual enjoyment for men and their partners. The Panel recommends shared decision-making as fundamental in the management of disorders of ejaculation; involvement of sexual partner(s) in decision making, when possible, may allow for optimization of outcomes.

Evaluating incidence, prevalence, and treatment trends in adult men with hypogonadism in the United States.

No extensive studies have investigated current diagnosis and treatment trends of hypogonadism (HG) in adult men in the United States. Using a comprehensive commercial insurance database, we surveyed current trends in incidence, prevalence, and treatment of hypogonadism in the United States. We analyzed insurance claims data from 2008-2017 using the IBM MarketScan™ Commercial Claims and Encounters database for men ≥18. Overall, we estimated annual incidence at 16.1 cases per 100,000 person-years, with the highest incidence seen among men 35-44 years at 21.5 cases per 100,000 person-years (IRR 1.83; 95% CI 1.63, 2.06, p < 0.001) and among those living in the Southern United States at 22.6 cases per 100,000 person-years (IRR 1.96; 95% CI 1.76, 2.18, p < 0.001). The prevalence of HG across the study period increased from 0.78% to 5.4%, while treatment rates decreased from 32.9% to 20.8%. These study findings provide a large-scale view of current diagnosis rates and treatment of hypogonadism in adult men in the United States. Despite the increase in prevalence of disease, there is an observed decline in treatment rates after diagnosis. Further investigations are needed to identify factors driving the observed decline in healthcare utilization among men with hypogonadism.

Genetics and erectile dysfunction: leveraging early foundations for new discoveries.

There is considerable interest in understanding the genetics of erectile dysfunction (ED). Since early twin studies that suggested a genetic component to ED, multiple candidate gene studies have identified genetic variants that may be associated with ED. Genome-wide association studies (GWAS) have overcome some of the criticism of the candidate gene approach. Two recent GWAS studies have identified loci near SIM1 that may be associated with ED and have renewed interest in the leptin melanocortin signaling pathway. We review the current literature on the genetic basis of ED by highlighting several candidate genes and genetic variants associated with ED.

Regional variation in the incidence and prevalence of Peyronie's disease in the United States-results from an encounters and claims database.

In recent years there have been more studies dedicated to Peyronie's disease (PD). However, prevalence and incidence are likely underestimated, with limited information on regional variation in the rate of diagnosis. In this study, we sought to estimate age and regional variation of the annual incidence and prevalence of PD in the United States. We reviewed data from the IBM MarketScan™ Claims and Encounters database between 2008-2017 for men ≥18 years. Inclusion required ≥1 medical claim with PD, identified by ICD-9 and ICD-10 codes or ≥1 claim for intralesional injection for PD, identified by Current Procedure Terminology (CPT) code. Overall average annual incidence was estimated at 20.9 cases per 100,000, with the highest rate of 41.6 cases per 100,000 observed in men 55-64 years (RR = 8.2; p < 0.0001). Geographically, the highest incidence rate was observed in the South (23.9 cases per 100,000 men; RR = 1.30; p < 0.0001). Across all ages, overall prevalence of PD showed a general upward trend, from 0.052% in 2008 to 0.096% in 2017. Our findings suggest men in the southern U.S. are diagnosed more with PD compared to other regions. Identification of associated factors may allow for a more proactive approach to diagnosis and management.

Is treatment of hypogonadism safe for men after a solid organ transplant? Results from a retrospective controlled cohort study.

Male solid organ transplant patients are at increased risk of hypogonadism and the safety of treating these patients for hypogonadism is unknown. We sought to evaluate the safety of treating hypogonadism in the solid organ transplant recipient. To accomplish this, we performed a retrospective review between 2009 and 2017 of patients treated at a single academic urology clinic. Men who underwent a solid organ transplant with a diagnosis of hypogonadism (Testosterone <350 ng/dl) were included. In total, 87 hypogonadal transplant recipients were included (29 no treatment; 58 treated). Treatment modalities included non-testosterone therapies (human chorionic gonadotropin, clomiphene), topical, injectable, and subcutaneous T preparations. There was no difference between groups for baseline characteristics including age, length of follow-up since transplant, baseline testosterone, and transplant type. There was no difference in prostate cancer diagnoses, erythrocytosis, rejection, infections, number of unplanned admissions per patient. While there was no difference in the proportion of deaths in untreated (21%; n = 6) and treated transplant recipients (7%; n = 4; p = 0.08), the median survival was longer in men treated with T (p = 0.03). Treatment of hypogonadism in solid organ recipients did not increase the risk for adverse effects related to treatment of hypogonadism or solid organ transplant.

Trends in treatment of Peyronie's disease in adult men in the United States from 2008 to 2017-results from an encounter and claims database.

Treatments for Peyronie's Disease (PD) include oral medications, intralesional injections, and surgery. Collagenase Clostridium histolyticum (CCh) is the only FDA-approved treatment for PD. We sought to examine current trends in treatment of PD across the United States. Using data in the MarketScan Database, we conducted a retrospective study of men with PD in the United States. Cases were identified by ICD-9 and 10 codes, and treatments were identified using NDC and CPT codes. Treatment rates were analyzed using a linear regression model, and a Cox proportional hazard function test was performed for time-to-treatment analysis. About 27.8% of men with PD were treated within a year of diagnosis. The annual treatment rate increased from 23.2 to 35.4%, and intralesional injection was the most used treatment. Over the study period, the percentage of men receiving treatment with oral medication increased from 0.66 to 20.5%, while the use of intralesional injection and surgery decreased. Increased odds of treatment were observed in men 45-54 years (odds ratio [OR] 1.35; 95% confidence interval [CI], 1.21-1.50; p = 0) and in the southern region (OR 1.48; 95% CI, 1.39-1.56; p = 0). Trends in treatment of PD have changed over time. Intralesional injection remains the most used treatment option for men with PD.

Effects of SARS CoV-2, COVID-19, and its vaccines on male sexual health and reproduction: where do we stand?

Since severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first discovered, there have been questions surrounding the effects of coronavirus disease 2019 (COVID-19), and more recently the COVID-19 vaccine, on men's health and fertility. Significant research has been conducted to study viral tropism, potential causes for gender susceptibility, the impact of COVID-19 on male sexual function in the acute and recovery phases, and the effects of the virus on male reproductive organs and hormones. This review provides a recent assessment of the literature regarding the impact of COVID-19 and its vaccine on male sexual health and reproduction.

Pharmacokinetics of testosterone therapies in relation to diurnal variation of serum testosterone levels as men age.

BACKGROUND: To improve symptoms associated with testosterone deficiency, many testosterone therapies are available that aim to restore serum testosterone (T) levels to the normal physiologic range. The magnitude, frequency, and duration between peak and trough T concentrations vary with route of administration, and none reflect normal endogenous daily diurnal T variations. OBJECTIVE: To compare pharmacokinetic profiles of serum T from approved T formulations with endogenous diurnal T variations in young and older men, and to consider whether there may be value in mimicking the diurnal T rhythmicity with exogenous testosterone therapies as men age. MATERIALS AND METHODS: A literature search of studies examining the diurnal variation of endogenous T in healthy men and men with testosterone deficiency was performed using PubMed in January 2020. Additional searches for serum T pharmacokinetic profiles of various testosterone therapy formulations were also conducted. Prescribing information for various T formulations was also reviewed. DISCUSSION AND CONCLUSION: Endogenous diurnal T variation is well described and appears to be blunted naturally as men age. Men with testosterone deficiency lack diurnal T variation and exhibit a flatter T profile compared with eugonadal men. Some T replacement options provide intraday T level variations similar to normal circadian secretion, and others provide a flatter exposure profile reflective of depot release. Others provide profiles that exceed the frequency and physiologic range of the natural diurnal variation of T. All exogenous T replacement dosing targets an increase in average T levels to within the normal physiologic range and improves symptoms associated with low T, but no single testosterone therapy can exactly mimic the normal diurnal T patterns seen in younger men and the blunted circadian T secretion of older men.

Lower female partner live birth rate in male cancer survivors: An age-matched cohort analysis of the Utah Population Database.

We determine the time to first live birth for female partners of males after a cancer diagnosis. Our group performed a retrospective, population-based, age-matched cohort study of Utah male residents diagnosed with cancer at age 18 years or later between 1956 and 2013 (exposed) matched to male Utah residents without cancer diagnosis (unexposed). Using stratified Cox proportional hazard models, we adjusted for race, ethnicity and number of live births prior to cancer diagnosis, to estimate the effect of time to a partner live birth following cancer diagnosis. Our study cohort included 19,303 men diagnosed with cancer (exposed) and 93,608 age-matched men without cancer diagnoses (unexposed). Exposed men were less likely to have a live birth prior to first cancer diagnosis (60.7% vs. 65.4%, p < 0.001) and after first cancer diagnosis (10.9% vs. 12.2%, p < 0.001) compared to unexposed men. Exposed men had a fertility hazard rate that was 31% lower after cancer diagnosis date than unexposed men (HR: 0.69; 95% CI: 0.65-0.72). This was most profound for men aged 18-30 years (HR: 0.59, 95% CI: 0.55-0.63). Male cancer survivors have a 31% lower female partner live birth rate after cancer diagnosis. These findings are important for patient counselling regarding fertility preservation at the time of cancer diagnosis.