Diagnoses and medications associated with delayed ejaculation.

Background: Delayed ejaculation (DE) is a disorder that can cause significant distress for sexually active men. The etiology of DE is largely idiopathic, with even less being known about clinical factors associated with the condition. Aim: We sought to use data mining techniques to examine a broad group of health conditions and pharmaceutical treatments to identify factors associated with DE. Methods: Using an insurance claims database, we evaluated all men with a diagnosis of DE and matched them to a cohort (1:1) of men with other male sexual disorders of urologic origin (ie, erectile dysfunction [ED] and Peyronie's disease [PD]). Given the low prevalence of DE, we incorporated the random forest approach for classification of DE vs controls, with a plethora of predictors and cross-validation with the least absolute shrinkage and selection operator (LASSO). We used both a high-performance generalized linear model and a multivariate logistic model. The area under the curve was reported to demonstrate classifier performance, and odds ratios were used to indicate risks of each predictor. We also evaluated for differences in the prevalence of conditions in DE by race/ethnicity. Outcomes: Clinical factors (ie, diagnoses and medications) associated with DE were identified. Results: In total, 11 602 men with DE were matched to a cohort of men with PD and ED. We focused on the 20 factors with the strongest association with DE across all models. The factors demonstrating positive associations with DE compared to other disorders of male sexual dysfunction (ie, ED and PD) included male infertility, testicular dysfunction, anxiety, disorders of lipid metabolism, alpha adrenergic blocker use, anemia, antidepressant use, and psychoses such as schizophrenia or schizoaffective disorder. In addition, the prevalence of several conditions varied by race/ethnicity. For example, male infertility was present in 5% of Asian men compared to <2% of men of other races. Clinical Implications: Several medical conditions and pharmacologic treatments are associated with DE, findings that may provide insight into the etiology of DE and offer treatment options. Strengths and Limitations: This study is to our knowledge the first to use using data mining techniques to investigate the association between medical conditions/pharmacologic agents and the development of subsequent DE. The generalizability of our findings is limited given that all men were commercially insured. Conclusion: DE is associated with multiple medical conditions, a finding that may help identify the etiology for this disorder.

5-alpha reductase inhibitors (5-ARi) with or without alpha-blockers (α-B) for Benign Prostatic Hyperplasia do NOT lower the risk of incident Bladder Cancer: United States insurance claims data.

BACKGROUND: Chemoprotective effect of 5-alpha reductase inhibitors (5-ARi) on bladder cancer (BCa) risk in men with Benign Prostatic Hyperplasia (BPH) has been explored with conflicting results. We sought to examine the effect of 5-ARi on new BCa diagnoses in a large US database. METHODS: Men ≥ 50 y/o with a prescription for 5-ARi after BPH diagnosis were identified in the IBM® Marketscan® Research de-identified Databases between 2007 and 2016 and matched with paired controls. Incident BCa diagnoses were identified after BPH diagnosis and/or pharmacologic treatment. Multivariable regression modeling adjusting for relevant factors was implemented. Sub-group analyses by exposure risk were performed to explore the association between 5-ARi and BCa over time. Administration of alpha-blockers (α-B) w/o 5-ARi was also examined. RESULTS: In total, n = 24,036 men on 5-ARi, n = 107,086 on 5-ARi plus alpha-blockers, and n = 894,275 without medical therapy for BPH were identified. The percentage of men diagnosed with BCa was 0.8% for the 5-ARi, 1.4% for the 5-ARi + α-B, and 0.6% for the untreated BPH group of incident BCa (adjusted hazard ratio [aHR], 0.90, 95% confidence interval [CI] 0.56 - 1.47), and 1.08, 95%CI 0.89 - 1.30, respectively). This was also true at both shorter (≤ 2 yr) and longer-term (> 2 yr) follow up. In addition, α-B alone had no change in BCa risk (HR 1.06, 0.86-1.30). CONCLUSIONS: We did not find any diminished risk of new BCa in men treated with 5-ARi (i.e., chemoprotective effect). The current report suggests that 5-ARi do not change a man's bladder cancer risk.

Association between priapism and HIV disease and treatment.

BACKGROUND: Priapism, a urologic emergency, has known associations with certain medical conditions. Many cases are idiopathic, suggesting an opportunity to identify novel risk factors. AIM: We sought to identify medical conditions and pharmaceutical treatments that are associated with priapism using data-mining techniques. METHODS: Using deidentified data in a large insurance claims database, we identified all men (age ≥20 years) with a diagnosis of priapism from 2003 to 2020 and matched them to cohorts of men with other diseases of male genitalia: erectile dysfunction, Peyronie disease, and premature ejaculation. All medical diagnoses and prescriptions used prior to first disease diagnosis were examined. Predictors were selected by random forest, and conditional multivariate logistic regressions were applied to assess the risks of each predictor. OUTCOMES: We identified novel relationships of HIV and some HIV treatments with priapism and confirmed existing associations. RESULTS: An overall 10 459 men with priapism were identified and matched 1:1 to the 3 control groups. After multivariable adjustment, men with priapism had high associations of hereditary anemias (odds ratio [OR], 3.99; 95% CI, 2.73-5.82), use of vasodilating agents (OR, 2.45; 95% CI, 2.01-2.98), use of HIV medications (OR, 1.95; 95% CI, 1.36-2.79), and use of antipsychotic medications (OR, 1.90; 95% CI, 1.52-2.38) as compared with erectile dysfunction controls. Similar patterns were noted when compared with premature ejaculation and Peyronie disease controls. CLINICAL IMPLICATIONS: HIV and its treatment are associated with priapism, which may affect patient counseling. STRENGTHS AND LIMITATIONS: To our knowledge, this is the first study to identify risk factors for priapism utilizing machine learning. All men in our series were commercially insured, which limits the generalizability of our findings. CONCLUSION: Using data-mining techniques, we confirmed existing associations with priapism (eg, hemolytic anemias, antipsychotics) and identified novel relationships (eg, HIV disease and treatment).

Worldwide Temporal Trends in Penile Length: A Systematic Review and Meta-Analysis.

PURPOSE: Normative male genital measurements are clinically useful and temporal changes would have important implications. The aim of the present study is to characterize the trend of worldwide penile length over time. MATERIALS AND METHODS: A systematic review and meta-analysis using papers from PubMed, Embase, and Cochrane Library from inception to April 2022 was performed. PRISMA guidelines were used for abstracting data and assessing data quality and validity. Pooled means and standard deviations for flaccid, stretched, and erect length were obtained. Subgroup analyses were performed by looking at differences in the region of origin, population type, and the decade of publication. Metaregression analyses were to adjusted for potential confounders. RESULTS: Seventy-five studies published between 1942 and 2021 were evaluated including data from 55,761 men. The pooled mean length estimates were flaccid length: 8.70 cm (95% CI, 8.16-9.23), stretched length: 12.93 cm (95% CI, 12.48-13.39), and erect length: 13.93 cm (95% CI, 13.20-14.65). All measurements showed variation by geographic region. Erect length increased significantly over time (QM=4.49, df=2, p=0.04) in several regions of the world and across all age groups, while no trends were identified in other penile size measurements. After adjusting for geographic region, subject age, and subject population; erect penile length increased 24% over the past 29 years. CONCLUSIONS: The average erect penis length has increased over the past three decades across the world. Given the significant implications, attention to potential causes should be investigated.

Congenital male genital malformations and paternal health: An analysis of the US claims data.

OBJECTIVE: To investigate the potential association between paternal health and male genital malformations in the offspring. MATERIALS AND METHODS: We analyzed data from 2007 to 2016 derived from the IBM MarketScan Research database, which reports on reimbursed private healthcare claims in the United States. The association between paternal comorbidities (defined as individual and combined measures) and genital malformations in male offspring was analyzed. RESULTS: Of 376,362 male births, 22% of fathers had at least one component of metabolic syndrome (≥1) prior to conception. Totals of 2880 cases of cryptorchidism (0.77%) and 2651 cases of hypospadias (0.70%) were identified at birth. While 0.76% of sons born to fathers with no metabolic syndrome components were diagnosed with cryptorchidism, 0.82% of sons with fathers with multiple metabolic syndrome components had cryptorchidism. Similarly, 0.69% versus 0.88% of sons had hypospadias when fathers had 0 or 2+ components of metabolic syndrome. After adjusting for maternal and paternal factors, the odds of a son being diagnosed with hypospadias increased with two or more paternal metabolic syndrome components (Odds ratio [95% confidence interval]: 1.27 [1.10-1.47]). Specific components of paternal metabolic syndrome were not generally more associated with a son's genital malformations. When we performed a subgroup analysis where genital malformations were defined based on surgical correction, the association with hypospadias persisted. CONCLUSIONS: Fathers with multiple components of metabolic syndrome in the preconception period were observed to be at increased risk for having sons born with hypospadias. The results support the association between a man's andrological and overall health.

The Association between Monthly, Yearly, and Lifetime Cannabis Use, and Semen Parameters in Asian-American Men.

PURPOSE: Medicinal and recreational cannabis use has grown exponentially, however, its effect on testicular function and spermatogenesis remains uncertain. The aim of this study was to evaluate the association between cannabis use and semen parameters in a cohort of Asian-American men with unknown fertility. MATERIALS AND METHODS: Asian men were recruited to complete an online survey and submit a semen sample. Semen analysis, demographic data, lifestyle factors, and cannabis use habits were collected. Linear and logistic regression analyses were used to determine. RESULTS: Among the 112 men included in this study, 51 used cannabis at least once in their lifetime, 30 men used cannabis at least once in the last 12 months, and 26 men used cannabis at least once in the last 30 days. Adjusted linear regression analyses identified an association between cannabis use in the previous 30 days and worse sperm morphology (ß: -0.45, p=0.025) and sperm motility (ß: -1.64, p=0.016). However, when stratifying by subfertile semen quality (i.e., WHO criteria), no association was identified between semen quality and cannabis use. Lower sperm morphology and motility are partially associated with recent cannabis use, while all other semen parameters are not. CONCLUSIONS: We did not observe any consistent associations between cannabis use on any semen parameters in Asian-American men. Further studies within the field are needed to explore racial and ethnic differences in semen quality and lifestyle factors.

Preconception paternal comorbidities and offspring birth defects: Analysis of a large national data set.

BACKGROUND: Despite the fact that the father contributes half the genome to a child, associations between paternal factors and birth defects are poorly understood. OBJECTIVES: To investigate the association between preconception paternal health and birth defects in the offspring. MATERIALS AND METHODS: We conducted analysis of a national cohort study utilizing the IBM Marketscan Research Database, which includes data on reimbursed private healthcare claims in the United States from 2007 to 2016. The potential association between paternal comorbidities, as measured by the components of metabolic syndrome (MetS), and any birth defect in the offspring was analyzed. RESULTS: Of the 712,774 live births identified, 21.2% of children were born to fathers with at least one component of the metabolic syndrome (MetS ≥1) prior to conception. Compared to infants born to fathers with no components of the metabolic syndrome, a modestly higher percentage of infants with cardiac birth defects were born to fathers with more components of MetS (MetS = 1, OR [95% CI]: 1.07 [1.01-1.13]; MetS ≥2, 1.17 [1.08-1.26], in comparison to MetS = 0) after adjusting for maternal and paternal factors. Similarly, a higher percentage of infants with respiratory defects were born to fathers with two or more components of metabolic syndrome (MetS ≥2, OR [95% CI]: 1.45 [1.22-1.71]). DISCUSSION AND CONCLUSION: In this private insurance claims-based study, we found that fathers with metabolic syndrome-related diseases before conception were at increased risk for having a child affected by birth defects, especially cardiac and respiratory defects, and this association was not influenced by paternal age or assessed maternal factors.

The Risk of Cardiovascular and Cerebrovascular Disease in Men With a History of Priapism.

PURPOSE: Priapism is a debilitating condition that affects sexual function. As a majority of cases are idiopathic, investigators have hypothesized underlying vascular dysfunction which may predispose men to priapism. We sought to determine if men are at risk for other sequelae of vascular dysfunction such as cardiovascular and thromboembolic disease after a priapism event. MATERIALS AND METHODS: Using a large commercial insurance claims data warehouse, we evaluated all men (age ≥20) with a diagnosis of priapism from 2003-2020 and matched them to a cohort of men with other urological disorders of sexual dysfunction (erectile dysfunction, Peyronie's disease, and premature ejaculation). We identified incident disease (cardiovascular disease, heart disease, embolism, thrombosis, cerebrovascular disease) for all cohorts. RESULTS: A total of 10,459 men with priapism were identified and were matched to men with erectile dysfunction, Peyronie's disease, or premature ejaculation. The mean age was 51.1 years old. Men with priapism showed increased incidence of heart disease, both ischemic (HR 1.24, 95% CI 1.09-1.42) and other heart disease (HR 1.24, 95% CI 1.12-1.38) in the years following the priapism diagnosis. Incident cerebrovascular disease was also more likely in men with a history of priapism (HR 1.33, 95% CI 1.15-1.55). Men requiring treatment for ischemic priapism had a higher hazard of cardiovascular and cerebrovascular disease. In addition, men with more priapism episodes had a higher rate of cardiovascular disease and thromboembolic events. CONCLUSIONS: Men with priapism are at increased risk for cardiovascular and cerebrovascular events in the years following a priapism.

The association between organophosphate insecticides and blood pressure dysregulation: NHANES 2013-2014.

BACKGROUND: Organophosphate (OP) insecticides represent one of the largest classes of sprayed insecticides in the U.S., and their use has been associated with various adverse health outcomes, including disorders of blood pressure regulation such as hypertension (HTN). METHODS: In a study of 935 adults from the NHANES 2013-2014 cycle, we examined the relationship between systolic and diastolic blood pressure changes and urinary concentrations of three OP insecticides metabolites, including 3,5,6-trichloro-2-pyridinol (TCPy), oxypyrimidine, and para-nitrophenol. These metabolites correspond to the parent compounds chlorpyrifos, diazinon, and methyl parathion, respectively. Weighted, multivariable linear regression analysis while adjusting for potential confounders were used to model the relationship between OP metabolites and blood pressure. Weighted, multivariable logistic regression analysis was used to model the odds of HTN for quartile of metabolites. RESULTS: We observed significant, inverse association between TCPy on systolic blood pressure (ß-estimate = -0.16, p < 0.001) and diastolic blood pressure (ß-estimate = -0.15, p < 0.001). Analysis with para-nitrophenol revealed a significant, positive association with systolic blood pressure (ß-estimate = 0.03, p = 0.02), and an inverse association with diastolic blood pressure (ß-estimate = -0.09, p < 0.001). For oxypyrimidine, we observed significant, positive associations between systolic blood pressure (ß-estimate = 0.58, p = 0.03) and diastolic blood pressure (ß-estimate = 0.31, p < 0.001). Furthermore, we observed significant interactions between TCPy and ethnicity on systolic blood pressure (ß-estimate = 1.46, p = 0.0036). Significant interaction terms were observed between oxypyrimidine and ethnicity (ß-estimate = -1.73, p < 0.001), as well as oxypyrimidine and BMI (ß-estimate = 1.51 p < 0.001) on systolic blood pressure, and between oxypyrimidine and age (ß-estimate = 1.96, p = 0.02), race (ß-estimate = -3.81 p = 0.004), and BMI on diastolic blood pressure (ß-estimate = 0.72, p = 0.02). A significant interaction was observed between para-nitrophenol and BMI for systolic blood pressure (ß-estimate = 0.43, p = 0.01), and between para-nitrophenol and ethnicity on diastolic blood pressure (ß-estimate = 2.19, p = 0.006). Lastly, we observed a significant association between the odds of HTN and TCPy quartiles (OR = 0.65, 95% CI [0.43,0.99]). CONCLUSION: Our findings support previous studies suggesting a role for organophosphate insecticides in the etiology of blood pressure dysregulation and HTN. Future studies are warranted to corroborate these findings, evaluate dose-response relationships between organophosphate insecticides and blood pressure, determine clinical significance, and elucidate biological mechanisms underlying this association.

The association between caffeine intake and testosterone: NHANES 2013-2014.

BACKGROUND: Caffeine is one of the most commonly used psychoactive drugs in the world, and provides many health benefits including alertness, improved memory, and reducing inflammation. Despite these benefits, caffeine has been implicated in a number of adverse health outcomes possibly due to effects within the endocrine system, effects that may contribute to impaired reproductive function and low testosterone in men. Previous studies have investigated associations between caffeine consumption and testosterone levels in men, although the quantity and generalizability of these studies is lacking, and the results between studies are conflicting and inconclusive. METHODS: Using data from a cross-sectional study of 372 adult men in the 2013-2014 NHANES survey cycle, the researchers set out to characterize the association between serum testosterone levels, caffeine, and 14 caffeine metabolites. RESULTS: Multivariable, weighted linear regression revealed a significant inverse association between caffeine and testosterone. Multivariable, linear regression revealed significant, inverse associations between 6 xanthine metabolic products of caffeine and testosterone. Inverse associations were observed between 5-methyluric acid products and testosterone, as well as between 5-acetlyamino-6-amino-3-methyluracil and testosterone. A significant, positive association was observed for 7-methyl xanthine, 3,7-dimethyluric acid, and 7-methyluric acid. Logistic regression models to characterize the association between 2 biologically active metabolites of caffeine (theobromine and theophylline) and odds of low testosterone (< 300 ng/dL) were non-significant. CONCLUSIONS: These findings suggest a potential role for caffeine's contribution to the etiology of low testosterone and biochemical androgen deficiency. Future studies are warranted to corroborate these findings and elucidate biological mechanisms underlying this association.

Cost of Intralesional Collagenase Clostridium Histiolyticum Therapy Versus Surgery for the Management of Peyronie's Disease: A Claims-Based Analysis (2009-2019).

BACKGROUND: Collagenase Clostridium histolyticum (CCH), which was approved by the FDA for the treatment of Peyronie's disease (PD) in 2013, may obviate the need for surgery but its historically high cost must be considered when offering CCH vs surgical intervention to affected patients. AIM: To compare trends of intralesional injections vs surgical treatment for PD and assess the contemporary cost of treatment with CCH vs surgical intervention. METHODS: We reviewed 2009-2019 MarketScan Commercial Claims data to identify all men 18 years and older with PD. CPT and HCPCS codes were used to identify PD treatments for each patient. Associated insurance claims in USD were summed for each treatment type. OUTCOMES: Total and out-of-pocket costs, as well as frequencies, for treatments were calculated on a yearly basis and the Cochran-Armitage test was used to compare frequencies before and after FDA approval of CCH. RESULTS: Of 89,205 men diagnosed with PD, 21,605 (24.2%) underwent treatment; most required only intralesional injections, however 1,519 (7.0%) received only surgical therapy and 1,951 (9.0%) required medical and surgical therapy. Intralesional CCH use sharply increased after its FDA-approval in 2013 with a concomitant fall of intralesional verapamil use. The use of both surgical plication and plaque grafting decreased steadily from 2009 to 2019. The median cost per patient for all 3 treatments increased over the study time-period: $1,856 to $3,196 for plication, $2,233 to $3,631 for plaque grafting, and $6,940 to $8,895 per cycle for CCH. Out-of-pocket median patient contribution for plication, plaque grafting, and per cycle intralesional CCH injection were similar over the study period and never exceeded $300. CLINICAL IMPLICATIONS: CCH is significantly more expensive than any surgical treatment option, however, the out-of-pocket patient contribution for surgery and CCH are similar. STRENGTHS & LIMITATIONS: This study incorporated all procedure costs and is the most contemporary, comprehensive, and accurate reflection of overall and out-of-pocket costs to patients for surgical and intralesional PD therapies. We anticipate these data to allow for a more complete discussion between patients and providers regarding their care. The use of a commercial claims database prohibited assessment of post-procedural costs and treatment outcomes. CONCLUSION: CCH use has increased significantly since its FDA approval in 2013 with out-of-pocket patient contribution comparable to surgical therapy despite significantly higher total treatment costs. Walton EL, Quinn TP, Mulloy E, et al. Cost of Intralesional Collagenase Clostridium Histiolyticum Therapy Versus Surgery for the Management of Peyronie's Disease: A Claims-Based Analysis (2009-2019). Sex Med 2022;10:100517.

Medical Treatment of Disorders of Ejaculation.

Ejaculation and orgasm are complex phenomena within the male sexual response cycle. Disordered ejaculation commonly presents as premature or delayed ejaculation, although issues with painful ejaculation, retrograde ejaculation, or postorgasmic illness syndrome are also seen. This article will review the pathophysiology of these conditions as well as the current pharmacologic treatments available.

The association of impaired semen quality and pregnancy rates in assisted reproduction technology cycles: Systematic review and meta-analysis.

Some studies suggest a relationship between semen quality and pregnancy rates of assisted reproduction technologies (ART). Others have questioned the utility of semen quality as proxy for fertility in couples attempting to conceive with or without assistance. We aimed to investigate the current body of evidence which correlates semen parameters and clinical pregnancy among couples utilizing ART (i.e. in vitro fertilization [IVF], intracytoplasmic sperm injection [ICSI]) through a systematic review and meta-analysis of cross-sectional and retrospective cohort studies. Pooled Odd Ratio (OR) for oligo-, astheno- and teratospermic compared to normospermic number of ART cycles were calculated among. Meta-regression and sub-group analysis were implemented to model the contribution of clinical/demographic and laboratory standards differences among the studies. Overall, 17 studies were analysed representing 17,348 cycles were analysed. Pooled OR for impaired sperm concentration, motility and morphology was 1 (95%Confidence Interval [CI]: 0.97-1.03), 0.88 (95%CI: 0.73-1.03) and 0.88 (95%CI: 0.75-1) respectively. Further analysis on sperm morphology showed no differences with regard of IVF versus ICSI (p = 0.14) nor a significant correlation with rising reference thresholds (Coeff: -0.02, p = 0.38). A temporal trend towards a null association between semen parameters and clinical pregnancy was observed over the 20-year observation period (Coeff: 0.01, p = 0.014). The current analysis found no association between semen quality (as measured by concentration, motility or morphology) and clinical pregnancy rates utilizing ART. Future investigations are necessary to explore the association between semen parameters and other ART outcomes (e.g. fertilization, implantation, birth and perinatal health).