Time to pregnancy and life expectancy: a cohort study of 18 796 pregnant couples.

STUDY QUESTION: Is fecundity, measured as time to pregnancy (TTP), associated with mortality in parents? SUMMARY ANSWER: Prolonged TTP is associated with increased mortality in both mothers and fathers in a dose-response manner. WHAT IS KNOWN ALREADY: Several studies have linked both male and female fecundity to mortality. In women, infertility has been linked to several diseases, but studies suggest that the underlying conditions, rather than infertility, increase mortality. STUDY DESIGN, SIZE, DURATION: A prospective cohort study was carried out on 18 796 pregnant couples, in which the pregnant women attended prophylactic antenatal care between 1973 and 1987 at a primary and tertiary care unit. The couples were followed in Danish mortality registers from their child's birth date until death or until 2018. The follow-up period was up to 47 years, and there was complete follow-up until death, emigration or end of study. PARTICIPANTS/MATERIALS, SETTING, METHODS: At the first antenatal visit, the pregnant women were asked to report the time to the current pregnancy. Inclusion was restricted to the first pregnancy, and TTP was categorised into <12 months, ≥12 months, not planned, and not available. In sub-analyses, TTP ≥12 was further categorized into 12-35, 36-60, and >60 months. Information for parents was linked to several Danish nationwide health registries. Survival analysis was used to estimate the hazard ratios (HRs) with a 95% CI for survival and adjusted for age at the first attempt to become pregnant, year of birth, socioeconomic status, mother's smoking during pregnancy, and mother's BMI. MAIN RESULTS AND THE ROLE OF CHANCE: Mothers and fathers with TTP >60 months survived, respectively, 3.5 (95% CI: 2.6-4.3) and 2.7 (95% CI: 1.8-3.7) years shorter than parents with a TTP <12 months. The mortality was higher for fathers (HR: 1.21, 95% CI: 1.09-1.34) and mothers (HR: 1.29, 95% CI: 1.12-1.49) with TTP ≥12 months compared to parents with TTP <12 months. The risk of all-cause mortality during the study period increased in a dose-response manner with the highest adjusted HR of 1.98 (95% CI: 1.62-2.41) for fathers and 2.03 (95% CI: 1.56-2.63) for mothers with TTP >60 months. Prolonged TTP was associated with several different causes of death in both fathers and mothers, indicating that the underlying causes of the relation between fecundity and survival may be multi-factorial. LIMITATIONS, REASONS FOR CAUTION: A limitation is that fecundity is measured using a pregnancy-based approach. Thus, the cohort is conditioned on fertility success and excludes sterile couples, unsuccessful attempts and spontaneous abortions. The question used to measure TTP when the pregnant woman was interviewed at her first attended prophylactic antenatal care: 'From the time you wanted a pregnancy until it occurred, how much time passed?' could potentially have led to serious misclassification if the woman did not answer on time starting unprotected intercourse but on the start of wishing to have a child. WIDER IMPLICATIONS OF THE FINDINGS: We found that TTP is a strong marker of survival, contributing to the still-emerging evidence that fecundity in men and women reflects their health and survival potential. STUDY FUNDING/COMPETING INTEREST(S): The authors acknowledge an unrestricted grant from Ferring. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication. M.L.E. is an advisor to Ro, VSeat, Doveras, and Next. TRIAL REGISTRATION NUMBER: N/A.

Preconception sleep duration, non-daytime work schedules, and incidence of spontaneous abortion: a prospective cohort study.

STUDY QUESTION: To what extent do self-reported sleep duration and non-daytime work schedules in either partner affect the rate of spontaneous abortion (SAB)? SUMMARY ANSWER: Incidence of SAB had little association with female sleep duration and a modest positive association with male short sleep duration, female work at night, and discrepant work schedules among partners. WHAT IS KNOWN ALREADY: Several studies have reported an association between short sleep duration in either partner and reproductive health outcomes, including fecundability. Moreover, certain types of female occupational exposures during pregnancy have been associated with an increased risk of SAB. No studies have evaluated SAB risk in relation to male sleep and work schedules, or joint exposures within a couple. STUDY DESIGN, SIZE, DURATION: This prospective cohort study included 9357 female participants and 2602 of their male partners residing in North America (June 2013 to April 2023). PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants enrolled when they were attempting pregnancy and completed self-administered baseline questionnaires about their average sleep duration and work schedules. Among those who conceived, we ascertained SAB and gestational age at loss via follow-up questionnaires. We used multivariable Cox proportional hazards models with gestational weeks as the time scale to estimate hazard ratios (HRs) and 95% CIs relating SAB with sleep duration and non-daytime work schedules for female and male participants, and the couple. We used inverse probability weighting to account for potential selection bias due to the possibility of differential participation of male partners with respect to the exposures. MAIN RESULTS AND THE ROLE OF CHANCE: Compared to female participants with recommended sleep (7-8.9 h), those reporting short sleep duration (<6 h) did not have a higher rate of SAB (HR 0.88, 95% CI 0.69, 1.13). Short self-reported sleep duration among male participants was modestly associated with a higher rate of SAB (adjusted and weighted HR 1.30, 95% CI 0.96, 1.75). Female night work at night (adjusted HR 1.19, 95% CI 1.02, 1.38) and male non-daytime work (adjusted and weighted HR 1.26, 95% CI 1.00, 1.59) were associated with modestly higher rates of SAB, whereas female rotating shift work was not (adjusted HR 0.91, 0.78, 1.05) compared with daytime workers. Couples in which work schedules were discrepant had an elevated rate of SAB if the male partner worked a non-daytime shift (adjusted and weighted HR 1.46, 95% CI 1.13, 1.88) compared with couples in which both members worked during the day. The corresponding HR if only the female partner worked a non-daytime shift was 1.21 (95% CI 0.92, 1.58). LIMITATIONS, REASONS FOR CAUTION: Data on sleep duration and work schedules were based on self-report, which is vulnerable to misclassification, particularly since participants were asked to report their average sleep duration during the past month. Work exposures were heterogeneous, as many different types of employment may require night and shift work and may have different associations with SAB. WIDER IMPLICATIONS OF THE FINDINGS: Our findings are consistent with previous research indicating that some types of female employment schedules may be associated with SAB incidence. This is the first study to indicate a relationship between SAB and male employment schedules, indicating that discrepant work schedules within a couple might be relevant. STUDY FUNDING/COMPETING INTEREST(S): This work was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development grants R01HD105863 (PIs: L.A.W. and M.L.E.), R01HD086742 (PIs: L.A.W. and E.E.H.), and R21HD072326 (PI: L.A.W.). PRESTO has received in-kind donations from Swiss Precision Diagnostics and Kindara.com for primary data collection. L.A.W. is a consultant for AbbVie, Inc. and the Gates Foundation. M.L.E. is an advisor for and holds stock in Ro, Hannah, Dadi, Underdog, Vseat, & Doveras. The other authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: N/A.

The relationship between klotho, testosterone, and sexual health parameters among US adult men.

BACKGROUND: Klotho is a pleotropic hormone involved in a multitude of biological processes necessary for healthy aging, and affords protection from adverse events such as cardiovascular disease, inflammation, and various cancers. Emerging evidence suggests that klotho is also an important component of biochemical pathways that regulate hormone balance, which may include those pathways governing testosterone production and men's sexual health, though data are limited and results are mixed. OBJECTIVE: Using a cohort of 767 men from the NHANES 2015-2016 survey cycle, we set out to quantify the association between serum klotho levels and serum testosterone levels, as well as clinical markers of men's sexual health (e.g., testosterone:estrogen ratio, bioavailable testosterone, and free testosterone). METHODS: Multivariable linear and logistic regression models while controlling for potential confounders were constructed to quantify the relationship between serum klotho and testosterone, as well as between serum klotho and odds of low testosterone (serum testosterone < 300 ng/dL). RESULTS: A positive association was observed between serum klotho and testosterone (ß = 0.18, p = 0.04). Serum klotho levels were also stratified into quartiles, and we observed statistically significant increases in testosterone for increasing quartile level of klotho using the first quartile as the reference group (ß = 90.51, p = 0.001, ß = 106.93, p = 0.002, ß = 95.33, p = 0.03 for quartiles 2, 3, and 4, respectively). The average testosterone values by quartiles of klotho were 306.9 ng/dL, 390 ng/dL, 409.3 ng/dL, and 436.6 ng/dL, respectively. We modeled important proxies for sexual health including bioavailable and free testosterone, the testosterone:estradiol ratio, and C-reactive protein. Men in the second quartile of klotho had a significantly lower odds of an abnormal testosterone:estradiol ratio compared to the first quartile [OR = 0.18, 95% CI = (0.03, 0.98)].We observed null associations between continuous serum klotho and odds of low testosterone [OR = 1.0, 95% CI = (1.0, 1.0)], and when stratified by quartile, we observed a significant decrease in the odds of low testosterone for individuals in the second quartile of klotho compared to the first quartile [OR = 0.21, 95% CI = (0.05, 0.91)]. In addition, C-reactive protein was inversely associated with testosterone in men (ß = - 4.65, p = 0.001), and inversely associated with quartiles of klotho (ß = - 2.28, p = 0.04, ß = - 2.22, p = 0.04, ß = - 2.28, p = 0.03, for quartiles 2, 3, and 4, respectively). CONCLUSION: Our findings support previous studies suggesting a role for klotho in testosterone levels and sexual function among men. Future studies are warranted to corroborate these findings, determine clinical significance, and elucidate potential mechanisms underlying these associations.

Investigating the prevalence of erectile dysfunction among men exposed to organophosphate insecticides.

INTRODUCTION: Erectile dysfunction (ED) poses a significant disease morbidity and contributor to male infertility, where an estimated 20-40% of men are affected annually. While several risk factors have been identified in the etiology of ED (e.g., aging, heart disease, diabetes, and obesity), the complete pathogenesis remains to be elucidated. Over the last few decades, the contribution of environmental exposures to the pathogenesis of ED has gained some attention, though population studies are limited and results are mixed. Among environmental contaminants, organophosphate (OP) insecticides represent one of the largest chemical classes, and chlorpyrifos is the most commonly used OP in the U.S. OP exposure has been implicated in driving biological processes, including inflammation, reactive oxygen species production, and endocrine and metabolism disruption, which have been demonstrated to adversely affect the hypothalamus and testes and may contribute to ED. Currently, studies evaluating the association between OPs and ED within the U.S. general population are sparse. METHODS: Data were leveraged from the National Health and Nutrition Examination Survey (NHANES), which is an annually conducted, population-based cross-sectional study. Urinary levels of 3,5,6-trichloro-2-pyridinol (TCPy), a specific metabolite of the most pervasive OP insecticide chlorpyrifos, were quantified as measures of OP exposure. ED was defined by responses to questionnaire data, where individuals who replied "sometimes able" or "never able" to achieve an erection were classified as ED. Chi-square, analysis of variance (ANOVA), and multivariable, weighted linear and logistic regression analyses were used to compare sociodemographic variables between quartiles of TCPy exposure, identify risk factors for TCPy exposure and ED, and to analyze the relationship between TCPy and ED. RESULTS: A total of 671 adult men were included in final analyses, representing 28,949,379 adults after survey weighting. Approximately 37% of our cohort had ED. Smoking, diabetes, aging, Mexican-American self-identification, and physical inactivity were associated with higher ED prevalence. Analysis of TCPy modeled as a continuous variable revealed nonsignificant associations with ED (OR = 1.02 95% CI [0.95, 1.09]). Stratification of total TCPy into quartiles revealed increased odds of ED among adults in the second and fourth quartiles, using the first quartile as the reference (OR = 2.04 95% CI [1.11, 3.72], OR = 1.51 95% CI [0.58, 3.93], OR = 2.62 95% CI [1.18, 5.79], for quartiles 2, 3, and 4, respectively). CONCLUSIONS: The results of our study suggest a potential role for chlorpyrifos and other OPs the pathogenesis of ED. Future studies are warranted to validate these findings, determine clinical significance, and to investigate potential mechanisms underlying these associations.

The association between 2,4-D and serum testosterone levels: NHANES 2013-2014.

BACKGROUND: Previous studies have investigated associations between herbicides such as 2,4-Dichlorophenoxyacetic acid (2,4-D) and dyshormonogenesis, specifically low testosterone, in human, rodent, and cell models, but results have been conflicting and inconclusive. METHODS: Using data from a cross-sectional study of 456 adult men in the 2013-2014 NHANES survey cycle, we examined the relationship between urinary concentrations of 2,4-D and serum testosterone levels. RESULTS: Multivariable regression models adjusting for potential confounders revealed a significant, negative association between urinary 2,4-D and mean serum testosterone among U.S. adult males (ß = - 11.4 ng/dL, p = 0.02). Multivariable logistic regression models using a cutoff defining abnormally low testosterone (i.e., serum testosterone < 300 ng/dL) revealed no significant associations between 2,4-D and the odds of low testosterone. CONCLUSION: These findings expand on previous literature implicating a role for 2,4-D in the etiology of low testosterone and dyshormonogenesis. Future studies are warranted to corroborate these findings, determine clinical significance, and to investigate the proposed potential biological mechanisms underlying this association.

Impaired fecundity as a marker of health and survival: a Danish twin cohort study.

STUDY QUESTION: Is fecundity, measured as self-reported time to first pregnancy (TTP), a marker for subsequent health and survival? SUMMARY ANSWER: Long TTP was a marker for increased mortality among women and higher hospitalization rates for both women and men. WHAT IS KNOWN ALREADY: Poor semen quality has been linked to increased mortality and morbidity from a wide range of diseases. Associations among fecundity, health and survival among women are still uncertain and studies on actual measures of fecundity and health outcomes are rare. STUDY DESIGN, SIZE, DURATION: We performed a prospective cohort study of 7825 women and 6279 men, aged 18 and above with measures on first TTP, who participated in one of the Danish nation-wide twin surveys in 1994 (twins born 1953-1976) and 1998 (twins born 1931-1952). They were followed-up for mortality and hospital admissions from the interview until 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: Twins were identified in the Danish Twin Registry and linked to Danish registers. TTP was restricted to the first pregnancy as a categorical outcome with cut-off points at 2, 10 and 18 months. We analysed the association between TTP and survival using a Cox proportional hazards model estimating hazards ratios (HRs) with 95% confidence intervals (CIs). Fine-Gray survival models were used to estimate sub-hazard ratios for specific causes of death allowing for competing risks. Using negative binomial regression, we estimated incidence rate ratios (IRRs) with 95% CIs for all-cause and cause-specific hospitalizations. All analyses were stratified by sex and adjusted for age at interview, birth cohorts, age at first attempt to become pregnant, smoking, years in school and BMI. MAIN RESULTS AND THE ROLE OF CHANCE: In the total study population, 49.9% of women and 52.7% of men reported a TTP of less than 2 months, 30.8% of women and 29.6% of men reported a TTP of 2-9 months, 6.6% of women and 5.7% of men reported a TTP of 10-17 months, and 13.3% of women and 12.0% of men reported a TTP of 18 months or more. Among 1305 deaths, we found a higher mortality for women (HR = 1.46; 95% CI 1.15, 1.87) with a TTP of ≥18 months relative to those with a TTP of <2 months, while the highest mortality was indicated for men with a TTP of 10-17 months (HR = 1.31; 95% CI 0.98, 1.74). Among 53 799 hospitalizations, we found an increased hospitalization rate among women (HR = 1.21; 95% CI 1.0-1.41) and men (HR = 1.16; 95% CI 1.00-1.35) with a TTP of ≥18 months, and for men with a TTP of 2-9 months (HR = 1.14; 95% CI 1.01-1.30). A dose-response relationship was found for women regarding both mortality (P = 0.022) and hospitalizations (P = 0.018). Impaired fecundity was associated with a wide range of diseases and some causes of death, indicating a multi-factorial causal influence on fecundity, especially among women. LIMITATIONS, REASONS FOR CAUTION: A major limitation was that fecundity depends on both partners, which was not considered in this study. Moreover, we could not obtain information on a number of potential confounders. WIDER IMPLICATIONS OF THE FINDINGS: Fecundity seems positively correlated with overall health and may be a universal marker of future health and survival. These results add knowledge to the limited findings showing that reduced fecundity in women and poor semen quality in men may reflect worse health and a shorter life, particularly among women. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by NIH grant HD096468 (M.L.E., T.K.J. and R.L.J.). The authors declare that they have no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Male cellular telephone exposure, fecundability, and semen quality: results from two preconception cohort studies.

STUDY QUESTION: To what extent is exposure to cellular telephones associated with male fertility? SUMMARY ANSWER: Overall, we found little association between carrying a cell phone in the front pants pocket and male fertility, although among leaner men (BMI <25 kg/m2), carrying a cell phone in the front pants pocket was associated with lower fecundability. WHAT IS KNOWN ALREADY: Some studies have indicated that cell phone use is associated with poor semen quality, but the results are conflicting. STUDY DESIGN, SIZE, DURATION: Two prospective preconception cohort studies were conducted with men in Denmark (n = 751) and in North America (n = 2349), enrolled and followed via the internet from 2012 to 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS: On the baseline questionnaire, males reported their hours/day of carrying a cell phone in different body locations. We ascertained time to pregnancy via bi-monthly follow-up questionnaires completed by the female partner for up to 12 months or until reported conception. We used proportional probabilities regression models to estimate fecundability ratios (FRs) and 95% confidence intervals (CIs) for the association between male cell phone habits and fecundability, focusing on front pants pocket exposure, within each cohort separately and pooling across the cohorts using a fixed-effect meta-analysis. In a subset of participants, we examined selected semen parameters (semen volume, sperm concentration and sperm motility) using a home-based semen testing kit. MAIN RESULTS AND THE ROLE OF CHANCE: There was little overall association between carrying a cell phone in a front pants pocket and fecundability: the FR for any front pants pocket exposure versus none was 0.94 (95% CI: 0.0.83-1.05). We observed an inverse association between any front pants pocket exposure and fecundability among men whose BMI was <25 kg/m2 (FR = 0.72, 95% CI: 0.59-0.88) but little association among men whose BMI was ≥25 kg/m2 (FR = 1.05, 95% CI: 0.90-1.22). There were few consistent associations between cell phone exposure and semen volume, sperm concentration, or sperm motility. LIMITATIONS, REASONS FOR CAUTION: Exposure to radiofrequency radiation from cell phones is subject to considerable non-differential misclassification, which would tend to attenuate the estimates for dichotomous comparisons and extreme exposure categories (e.g. exposure 8 vs. 0 h/day). Residual confounding by occupation or other unknown or poorly measured factors may also have affected the results. WIDER IMPLICATIONS OF THE FINDINGS: Overall, there was little association between carrying one's phone in the front pants pocket and fecundability. There was a moderate inverse association between front pants pocket cell phone exposure and fecundability among men with BMI <25 kg/m2, but not among men with BMI ≥25 kg/m2. Although several previous studies have indicated associations between cell phone exposure and lower sperm motility, we found few consistent associations with any semen quality parameters. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the National Institutes of Health, grant number R03HD090315. In the last 3 years, PRESTO has received in-kind donations from Sandstone Diagnostics (for semen kits), Swiss Precision Diagnostics (home pregnancy tests), Kindara.com (fertility app), and FertilityFriend.com (fertility app). Dr. L.A.W. is a fibroid consultant for AbbVie, Inc. Dr. H.T.S. reports that the Department of Clinical Epidemiology is involved in studies with funding from various companies as research grants to and administered by Aarhus University. None of these studies are related to the current study. Dr. M.L.E. is an advisor to Sandstone Diagnostics, Ro, Dadi, Hannah, and Underdog. Dr. G.J.S. holds ownership in Sandstone Diagnostics Inc., developers of the Trak Male Fertility Testing System. In addition, Dr. G.J.S. has a patent pending related to Trak Male Fertility Testing System issued. TRIAL REGISTRATION NUMBER: N/A.

Paternal prescription medication before conception: A retrospective cohort study of all births in Denmark 1997-2017.

AIM: To study what medication fathers are being prescribed in the months preceding conception. METHODS: A retrospective cohort study of Danish national registries, comprising all births in Denmark 1997-2017 (1.3 million births). Time trends and absolute levels of paternal prescription medication in the 6 months prior to conception were assessed. While all medications were examined (N = 1335), we focused on the main medication groups, medications that have increased in use over time, and medications for which previous evidence exists of an effect on sperm quality. RESULTS: The average number of prescriptions increased over the study period (from 0.75 prescriptions to 0.82 per birth). Polypharmacy (three or more prescriptions) increased from less than 8% to 10% of fathers. The use of pain medication, proton-pump inhibitors, selective serotonin reuptake inhibitors and some inhalants have all increased markedly over the last 20 years. CONCLUSIONS: Potential harm to the offspring done by paternal medication may present an increasing problem. As paternal medication exposure is increasing, examination of generational effects, such as major birth defects, is necessary.

Disease burden in offspring is associated with changing paternal demographics in the United States.

BACKGROUND: Average paternal age in the United States has increased substantially in the last few decades. Children of advanced age fathers have a higher incidence of early onset cancer and neuropsychiatric disease. OBJECTIVES: To quantify the number of population adjusted cases of early-onset cancer and neuropsychiatric disease in children attributable to increasing paternal age in the United States. METHODS: Paternal age in the United States from 1972 to 2015 was collected using the National Vital Statistics System (NVSS). Population attributable fraction and paternal age-specific cumulative incidence rates of several cancers and neuropsychiatric disorders were obtained from peer-reviewed publications. Paternal age-specific birth rates were correlated with paternal age-specific cumulative incidence rates to determine the number of attributable cases of disease caused by advancing age of fathers in the United States. RESULTS: The 2015 birth cohort in the United States is estimated to expect 9.2% more cases of acute lymphoblastic leukemia (ALL) diagnosed before 16 years of age (157 additional cases), 13.2% more cases of embryonal tumors in children <5 years of age (209 additional cases), and 13.0% more cases of breast cancer in females younger than 40 years old (424 additional cases) compared to the 1972 birth cohort. We can estimate to expect 10.5% more cases of schizophrenia diagnosed before 21 years of age (2864 additional cases), 6.3% more cases of autism spectrum disorder (ASD) in adolescents <17 years of age (2934 additional cases), 4.5% more cases of anorexia nervosa (AN) in females 8-30 years old (620 additional cases), and 9.2% more cases of bipolar disorder in young patients 16-25 years old (252 additional cases) in the 2015 birth cohort compared to the 1972 birth cohort. CONCLUSION: Increasing paternal age in the United States is associated with a substantial increase in the number of cases of early-onset cancer and neuropsychiatric disease in offspring.

Vasectomy and the risk of prostate cancer in a prospective US Cohort: Data from the NIH-AARP Diet and Health Study.

BACKGROUND: Several studies have linked vasectomy with the risk of prostate cancer; however, this association has been attributed to selection bias. Since vasectomy is a common and effective form of contraception, these implications are significant. Therefore, we sought to test this association in a large observational cohort. OBJECTIVE: To evaluate the potential association between prior vasectomy and the risk of developing prostate cancer. MATERIALS AND METHODS: We evaluated the relationship between vasectomy and prostate cancer in the NIH-AARP Diet and Health Study. Of the 111,914 men, prostate cancer was identified in 13,885 men and vasectomies were performed in 48,657. We used multivariate analysis to examine the relationship between prostate cancer and vasectomy. We also performed propensity score-adjusted and propensity score-matched analysis. RESULTS: Men utilizing vasectomy were more likely to be ever married, fathers, educated, white, and screened for prostate cancer. During 4,251,863 person-years of follow-up, there was a small association between vasectomy and incident prostate cancer with a hazard ratio of 1.05 (95% CI, 1.01-1.11). However, no significant association was found when looking separately at prostate cancer by grade or stage. Conclusions were similar when using propensity adjustment and matching. Importantly, a significant interaction between vasectomy and PSA screening was identified. DISCUSSION: Estimates of the association between vasectomy and prostate cancer are sensitive to analytic method underscoring the tenuous nature of the connection. Given the differences between men who do and do not utilize vasectomy, selection bias appears likely to explain any identified association between vasectomy and prostate cancer. CONCLUSIONS: With over 20 years of follow-up, no convincing relationship between vasectomy and prostate cancer of any grade was identified.

The association between varicocoeles and vascular disease: an analysis of U.S. claims data.

S‪tudies have suggested an association between varicocele, hypogonadism, and elevated oxidative stress markers, but no other health risks have been associated with varicoceles. ‬‬‬‬We sought to determine the association between varicocele and incident medical comorbidities. ‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬Using the Truven Health MarketScan® claims database from 2001 to 2009, we identified 4459 men with varicoceles, and 100,066 controls based on ICD-9 and CPT codes, with an average follow-up of 3.1 person years. Men with varicoceles were classified as symptomatic or asymptomatic based on co-existing diagnoses. Men with medical comorbidities present before or within 1 year of index diagnosis were excluded. Metabolic and cardiovascular outcome variables were identified via ICD-9 codes. A Cox regression analysis was used to assess incident risk of metabolic and cardiovascular disease amongst the different groups. Men with varicoceles had a higher incidence of heart disease compared to men who underwent infertility testing (HR 1.22, 95% CI: 1.03-1.45), and men who underwent vasectomy (HR 1.32, 95% CI 1.13-1.54). The varicoceles group also had a higher risk of diabetes (HR 1.73, 95% CI: 1.37-2.18) and hyperlipidemia (HR 1.15, 95% CI: 1.03-1.28) compared to the vasectomy group. Furthermore, men with symptomatic varicoceles (n = 3442) had a higher risk of heart disease, diabetes, and hyperlipidemia following diagnosis, while men with asymptomatic varicoceles (n = 1017) did not. Given the prevalence of varicoceles, further research is needed to understand the implications of a varicocele to a man's overall health.

Male infertility is associated with altered treatment course of men with cancer.

This study aims to evaluate whether cancer treatments differ in infertile men compared to men who have undergone vasectomy and age-matched controls. We analyzed subjects from the Truven Health MarketScan Claims database from 2001 to 2009. Infertile men were identified through diagnosis and treatment codes. Comparison groups included vasectomized men and an age-matched cohort who were not infertile and had not undergone vasectomy. We considered cancer types previously associated with infertility that were diagnosed after the diagnosis of infertility. The treatment regimens were determined based on the presence of claims with CPT codes for chemotherapy (CTX), radiation (RTX) or surgical treatment (ST) for each entity in all study groups. Cases with multimodal treatments were also identified. As a result, CTX was similarly distributed among the infertile, vasectomized, and control groups. In contrast, RTX treatment length was shorter in infertile men. The frequency of multimodal treatment (i.e., radiation and chemotherapy) was twofold lower in men with infertility compared to other men. By focusing on treatment patterns for each cancer type among these groups, the duration of RTX and CTX was shorter in infertile men diagnosed with NHL compared to controls. We conclude that Infertile men diagnosed with cancer and specific cancer types experience different treatment courses, with shorter RTX and less combined RTX/CTX compared to fertile and vasectomized men. These differences could reflect differences in stage at presentation, biological behavior, or treatment responses in infertile men.

Increased risk of autoimmune disorders in infertile men: analysis of US claims data.

Aberrations in reproductive fitness may be a harbinger of medical diseases in men. Existing data suggest that female infertility is associated with autoimmune disorders; however, this has not been examined in men. As immune surveillance and hormonal factors can impact male fertility and autoimmunity, we sought to determine the association between male infertility and incident autoimmune disorders. We analyzed subjects from the Truven Health MarketScan claims database from 2001 to 2008. Infertile men were identified through diagnosis and treatment codes. We examined the most common immune disorders, which were identified by ICD9 diagnosis codes. Men diagnosed with an immune disorder at baseline or within 1 year of follow-up were excluded. Infertile men were compared to vasectomized men (i.e., men who are likely fertile) and to age-matched control (10 : 1) group using Cox regression analysis. A total of 33,077 infertile men (mean age of 33 years), 77,693 vasectomized men (mean age 35), and 330,770 age-matched control men (mean age 33) were assembled with a total follow-up of 1.49 M person-years. Overall, immune disorders were rare in the group with the individual conditions occurring in <0.1% of men. However, infertile men displayed the highest risk of many conditions. Infertile men had a higher risk of developing rheumatoid arthritis compared to both vasectomized men (HR 1.56, 95% CI 1.19-2.05) and age-matched controls (HR 1.29, 95% CI 1.02-1.62). Additionally, this higher risk was seen in general immune disorders (under which systemic lupus erythematosus is categorized) compared to vasectomized men (HR 3.11, 95% CI 2.00-4.86) and age-matched men (HR 2.12, 95% CI 1.52-2.96). This same risk trend was seen in psoriasis, when compared to vasectomized men (HR 1.28, 95% CI 1.09-1.50) and age-matched controls (HR 1.20, 95% CI 1.04-1.37). A similar trend was seen in the analysis comparing infertile men and vasectomized men in developing multiple sclerosis (HR 1.91, 95% CI 1.10-3.31) and Grave's disease (HR 1.46, 95% CI 1.10-1.92), as well as the higher risk of infertile men compared to the age-matched group at developing thyroiditis (HR 1.60, 95% CI 1.02-2.52). The current analysis shows that infertile men have a higher risk of developing certain autoimmune disorders in the years following an infertility evaluation. Specifically, infertile men had higher rates of developing rheumatoid arthritis, multiple sclerosis, psoriasis, thyroiditis, and Grave's disease. Given these findings, further research should focus on confirmation of these associations and elucidation of the pathways between fertility and immunity.

Semen quality associated with subsequent hospitalizations - Can the effect be explained by socio-economic status and lifestyle factors?

Semen quality is suggested to be a universal biomarker for future health. Previous studies have mostly been registry based excluding the possibility to address the importance of lifestyle, fertility status, health and socio-economic status. We aimed to investigate whether the association between semen quality and subsequent risk of hospitalization could be explained by differences in occupation, education, fertility, cryptorchidism, BMI or smoking; 1423 men with first semen sample at Fertility Clinic, Frederiksberg Hospital, Denmark, from 1977 to 2010 responded to a questionnaire in 2012 about current health, lifestyle, educational level and occupation. They were followed in the Danish National Patient Registry to first-time hospitalizations using ICD-8 and ICD-10 classification. Data were analysed by Cox proportional hazard regression models to adjust for the possible confounding factors. We found a significant higher risk of being hospitalized with decreasing sperm concentrations (0-15 mill/mL: HR1.78, 95% CI:1.51-2.09; 16-50 mill/mL: HR 1.37 95% CI: 1.17-1.60; 51-100 mill/mL: HR1.25 95% CI: 1.07-1.45). Same significant association of being hospitalized with decreasing total sperm counts was seen. The dose-response increase in risk in hospitalization with decreasing sperm concentration and total sperm count remained constant after further individual adjustment for occupation, marital status, fertility, cryptorchidism, BMI or smoking. The association between semen quality and subsequent morbidity was not explained by differences in lifestyle, behavioural or fertility status. We were unable to adjust for all possible confounders simultaneously due to limited sample size, and reverse causation is a possible explanation as information about education and lifestyle was obtained after semen analysis and hospitalizations occurred and may have changed as consequence of both. Semen quality may be a universal biomarker for future health not explained by lifestyle and socio-economic status, but this needs to be addressed further in future studies.

Decline in sperm count and motility in young adult men from 2003 to 2013: observations from a U.S. sperm bank.

Controversy exists regarding stability of semen quality over time with papers reporting decrease, increase or stable parameters in heterogeneous populations. The current study examined semen parameters of young adult men from 2003 to 2013 at an urban U.S. sperm bank. Semen parameters were analyzed before and after cryopreservation for a total of 9425 specimens from 489 individuals. Demographic information was obtained from a social and medical history questionnaire. Following 2-3 days abstinence, the specimens were collected at the laboratory and assessed by uniform technicians and techniques. The data were analyzed using generalized linear regression after adjustment for age, days of abstinence, for repeated samples, as well as by the Cochran-Armitage trend test. The within variability was accounted for by the repeated measures model. All p values were two-sided with p < 0.05 considered significant. There was a significant decline in sperm concentration (-3.55, 95% CI -4.87, -2.23; p < 0.001), total motility (-1.23, 95% CI -1.65, -0.82; p < 0.001), total count (-10.75, 95% CI -15.95, -5.54; p < 0.001) and total motile count (-9.43, 95% CI -13.14, -5.73; p < 0.001). There was no significant change in semen volume (0.03, 95% CI -0.02, 0.09; p = 0.2). The post-thaw total motility significantly (-2.30, 95% CI -2.72, -1.87; p < 0.001) decreased with time. Importantly, demographic and lifestyle factors were stable or improved over the study period. There was a decline in age (p(trend) = 0.003) and alcohol use (p(trend) = 0.005) and an increase in college GPA (Grade Point Average) (p(trend) = 0.02). BMI (p(trend) = 0.73), educational attainment (p(trend) = 0.2), race/ethnicity (p(trend) = 0.53), and lifestyle habits (weekly exercise, p(trend) = 0.21; smoking, p(trend) = 0.99; marital status, p(trend) = 0.85) remained constant. Uniform technicians and techniques over the study period make measurement bias unlikely. This report demonstrates a decline in semen quality among young adult men in the Boston area who were attending or completed a college education during the past 10 years, and requires further study.

Choice of underwear and male fecundity in a preconception cohort of couples.

Our objective was to investigate the relationship between male underwear-type worn during daytime/bedtime and male fecundity as measured by semen quality and time-to-pregnancy. We used data from a prospective preconception cohort conducted in 16 counties in Michigan and Texas, USA. 501 couples were enrolled and followed for 12 months of trying, which facilitated capture of time-to-pregnancy (in cycles), 6-cycle conception delay, and 12-month infertility. Male partners provided semen samples via in-home collection for next-day semen analysis comprised of 35 semen quality endpoints. At enrollment, men provided information on type of underwear worn during daytime and bedtime and were classified into 6 categories by underwear choice (n = 491): (i) briefs day/night, (ii) boxer-briefs day/night, (iii) boxers day/night, (iv) briefs day and boxers/none at night, (v) boxer-briefs day and boxers/none at night, (vi) boxers day and none at night. 473 (96%) men had semen analysis performed. Men switching from their usual daytime underwear to boxers/none for bed (groups 4, 5, 6) had the most evidence of change in semen quality endpoints (10 of 11 differences) relative to men wearing briefs day/night (group 1). Group 4 men had lower percent of sperm with coiled tail (ß = -0.18, 95% CI: -0.35, -0.01), higher percent round (ß = 0.22, 95% CI: 0.01, 0.42), number of immature sperm (ß = 0.44, 95% CI: 0.11, 0.77), and amplitude head displacement (ß = 0.57, 95% CI: 0.10, 1.03). Group 5 men had higher sperm head perimeter (ß=0.17, 95% CI: 0.002, 0.34), amplitude head displacement (ß = 0.47, 95% CI: 0.03, 0.91), percent cytoplasmic droplet (ß = 0.44, 95% CI: 0.11, 0.77) and high DNA stainability (ß=0.39, 95% CI: 0.01, 0.78). After false discovery rate control, no differences remained significant. No significant differences in time-to-pregnancy, conception delay, or infertility were observed. In summary, male underwear choice is associated with few differences in semen parameters; no association with time-to-pregnancy is observed providing reassurance to couples attempting pregnancy.

Comparability and reproducibility of adult male anogenital distance measurements for two different methods.

The distance from the genitals to the anus, anogenital distance, reflects androgen concentration during prenatal development in mammals. The use of anogenital distance in human studies is still very limited and the quality and consistency of measurements is an important methodological issue. The aim of this study was to assess the feasibility and reproducibility of adult male anogenital distance measurements by two different methods. All men were attending an outpatient clinic at a university hospital and underwent an andrological examination and completed a brief questionnaire. Two variants of anogenital distance [from the anus to the posterior base of the scrotum (AGDAS ) and to the cephalad insertion of the penis (AGDAP )] by two methods (lithotomy or frog-legged position) were assessed in 70 men. Within and between coefficient of variations, intra-class correlation coefficients, two-way repeated-measures analysis of variance, and scatter and Bland-Altman plots were calculated. The two methods produced similar values for AGDAP but different estimates for AGDAS . Nonetheless, the overall agreement (ICC ≥ 0.80) was acceptable for both measures. Therefore, both methods are internally consistent and adequate for epidemiological studies, and may be used depending on the available medical resources, clinical setting, and populations.

Testosterone therapy and mortality risk.

Recent data suggest an increased risk of cardiovascular events and mortality in men on testosterone therapy (TT). To date, there are no long-term, prospective studies to determine safety. In such cases, retrospective observational studies can be helpful. We examined our patient database to determine whether TT altered the risk of all-cause mortality in men. We queried our hormone database for all men with a serum testosterone level and then examined charts to determine testosterone status. In all, 509 men had charts available for review. We linked our patient records to the National Death Index to determine mortality. Of the 509 men who met inclusion criteria, 284 were on TT and 225 did not use testosterone. Age (mean 54 years) and follow-up time (mean 10 years) were similar for both groups. In all, 19 men died--10 (4.4%) men not on TT and 9 (3.2%) men on TT. After adjusting for age and year of evaluation, there was no significant difference in the risk of death based on TT (hazard ratio 0.92, 95% confidence interval 0.36-2.35, P=1.0). There appears to be no change in mortality risk overall for men utilizing long-term testosterone therapy.

The relationship between anogenital distance and age.

In humans, recent studies have correlated anogenital distance (AGD) in adult men to intrinsic testicular function. Although rodent studies suggest that AGD is determined in utero and remains constant in adult life, it is not certain if AGD remains constant across a man's adult life. We sought to determine if adult male AGD varies based on age. A cross-sectional study of men being evaluated at a men's health clinic. Anogenital distance (the distance from the posterior aspect of the scrotum to the anal verge) and penile length (PL) were measured using digital callipers. anova and linear regression were used to determine correlations between AGD, fatherhood status and age. In all, 473 men were included in the analysis with a mean age of 43 ± 13 years. The mean AGD for the group was 39 ± 13 mm. Anogenital distance did not vary between age categories for the entire group, for fathers, and for childless men. Moreover, penile length also remained constant across age categories. On adjusted analyses stratified by fatherhood status, there was no relationship between AGDp and age. The current cross-sectional study demonstrates that anogenital distance, defined as the distance from the posterior scrotum to the anal verge, is similar for men of different ages. As such, AGD may provide a measure for genital development and function throughout adult life. However, confirmation with longitudinal studies is needed.