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Background: Prenatal exposures to xenobiotics during the masculinization programming window are suggested to impact male fecundity later in life. Frequently used nitrosatable drugs, such as penicillins and beta2-agonists, contain amines or amides that may form teratogenic compounds in reaction with nitrite., Objectives: We explored whether maternal nitrosatable drug use during gestation was associated with biomarkers of male fecundity in adulthood; moreover, the potential modifiable effect of nitrate and vitamin intake was investigated., Method: We performed a cohort study in the Fetal Programming of Semen Quality cohort that includes semen characteristics, reproductive hormone concentrations, and measures of testis size on 1058 young adult sons in the Danish National Birth Cohort. Information on maternal use of nitrosatable drugs was obtained from questionnaires and interviews around gestational weeks 11 and 16. A multivariable negative binomial regression model was used to obtain relative differences in biomarkers of male fecundity for those whose mothers used nitrosatable drugs compared to those without such maternal use. In sub-analyses, the exposure was categorized according to nitrosatable drug type: secondary amine, tertiary amine, or amide. We investigated dose dependency by examining the number of weeks with intake and explored potential effect modification by low versus high maternal nitrate and vitamin intake from diet and nitrate concentration in drinking water. We added selection weights and imputed values of missing covariates to limit the risk of selection bias., Results: In total, 19.6% of the study population were born of mothers with an intake of nitrosatable drugs at least once during early pregnancy. Relative differences in biomarkers related to male fecundity between exposed and unexposed participants were negligible. Imputation of missing covariates did not fundamentally alter the results. Furthermore, no sensitive subpopulations were detected., Conclusions: The results suggest that maternal use of nitrosatable drugs does not have a harmful influence on the male fecundity of the offspring., (© 2024 The Authors. Andrology published by Wiley Periodicals LLC on behalf of American Society of Andrology and European Academy of Andrology.)

Background: Poor male fecundity is of concern and warrants the identification of potential modifiable risk factors. Short and long sleep duration might be risk factors for poor male fecundity although evidence in this research field is inconsistent., Objectives: To investigate the association between sleep duration and biomarkers of male fecundity in young men., Materials and Methods: We conducted a cross-sectional study of 1,055 young men from the Fetal Programming of Semen Quality (FEPOS) cohort, Denmark, 2017-2019. Sleep duration was obtained from an online survey answered by the participants prior to the clinical visit, where semen and blood samples were obtained, and testis volume was self-assessed using an Orchidometer. Percentage differences in semen characteristics, testes volume, and reproductive hormone levels were analysed according to sleep duration using multivariable negative binomial regression models. Sleep duration was dichotomised (recommended (6-9 h/night) versus deviant sleep) and visualised continuously as restricted cubic spline plots., Results: Deviation from recommended sleep duration was associated with higher high DNA stainability (HDS) of 5% (95% CI: -1%; 13%), higher testosterone of 3% (95% CI: 0%; 7%) and higher free androgen index (FAI) of 6% (95% CI: 0%; 13%). The spline plots overall supported these results, suggesting u-shaped associations between sleep duration and HDS, testosterone and FAI, a linear association between sleep duration and semen volume and sex hormone binding globulin (SHBG) and an inverse u-shaped association with normal morphology., Discussion: Information on sleep duration was obtained by self-report in broad categories with at least 3 h intervals. We were not able to investigate short or long sleep duration separately, since only few participants reported this., Conclusion: Sleep duration was associated with some biomarkers of fecundity in young men. Maintaining a recommended sleep duration may thus be beneficial for young men with regard to reproductive health., (© 2023 American Society of Andrology and European Academy of Andrology.)

Background: High parental age is associated with adverse birth and genetic outcomes, but little is known about fecundity in male offspring., Objectives: We investigated if high parental age at birth was associated with biomarkers of male fecundity in a large population-based sample of young men., Materials and Methods: We conducted a study of 1057 men from the Fetal Programming of Semen Quality (FEPOS) cohort, a sub-cohort of sons born 1998-2000 into the Danish National Birth Cohort. Semen characteristics and reproductive hormone concentrations were measured in samples provided by the men 2017-2019. Testis volume was determined by self-measurement. Data on the parental age was drawn from registers. Adjusted relative difference in percentage with 95% confidence intervals were estimated for each outcome according to pre-specified maternal and paternal age groups (< 30 (reference), 30-34 and ≥ 35) as well as for combinations of parental age groups, using multivariable negative binomial regression models., Results: We did not observe consistent associations between parental age and biomarkers of fecundity, although sons of mothers ≥ 35 years had lower sperm concentration (-15% (95% CI: -30, 3)) and total sperm count (-10% (95% CI: -25, 9)). The analysis with parental age combinations showed lower sperm concentration with high age of the parents (both ≥ 35 years: -27%, 95% CI: -40, -19) when compared to the reference where both parents were below 30 years., Discussion and Conclusion: We found no strong association between higher parental age and biomarkers of fecundity in young men. However, we cannot exclude poorer semen characteristics in sons born by older mothers or with high age of both parents., (© 2023 The Authors. Andrology published by Wiley Periodicals LLC on behalf of American Society of Andrology and European Academy of Andrology.)

Background: Poor male fecundity is of concern, and a prenatal origin has been proposed. Folate, a methyl donor involved in DNA methylation, is essential for normal fetal development by regulating gene expression during different periods of fetal development. Thus, prenatal exposure to low maternal folate intake might have a programing function of the developing reproductive organs., Objectives: To examine the association between maternal intake of folate from diet and folic acid from supplements during pregnancy and markers of fecundity in young men., Materials and Methods: We conducted a follow-up study using a Danish mother-son cohort of 787 young men born 1998-2000. Percentage differences in semen characteristics, testes volume, and reproductive hormone levels were analyzed according to total folate calculated as dietary folate equivalents from diet and supplements in midpregnancy, using multivariable negative binomial regression models. Total folate was analyzed in quintiles, continuous per standard deviation decrease (SD: 318 μg/day) and as restricted cubic splines., Results: Low maternal intake of total folate was associated with lower total sperm count (-5% (95% confidence intervals [CI]: -11%; 2%)), a lower proportion of non-progressive and immotile spermatozoa (-5% [95% CI: -8%; -3%]), and lower testes volume (-4% [95% CI: -6%; -2%]) per SD decrease in total folate intake. Spline plots supported these findings., Discussion: The finding of a lower proportion of non-progressive and immotile spermatozoa, and hence a higher proportion of motile spermatozoa, in men of mothers with a lower intake of total folate in midpregnancy was surprising and may be a chance finding., Conclusion: Lower maternal intake of total folate in midpregnancy was associated with lower sperm count and lower testes volume, however, also with a lower proportion of non-progressive and immotile spermatozoa in adult men. Whether this actually affects the ability to obtain a pregnancy warrants further investigation., (© 2022 The Authors. Andrology published by Wiley Periodicals LLC on behalf of American Society of Andrology and European Academy of Andrology.)

Background: Paracetamol (acetaminophen) is a frequently used nonprescription analgesic with suggested endocrine-disrupting properties. Epidemiological evidence on the effect of paracetamol on male fecundity is sparse., Objectives: To investigate if the use of paracetamol as an oral nonprescription mild analgesic was associated with semen quality in young men., Materials and Methods: This cross-sectional study was based on data from the Fetal Programming of Semen Quality (FEPOS; 2017-2019) cohort of 1058 young men (18-21 years) included in the Danish National Birth Cohort. Participants completed a comprehensive online questionnaire on health behavior including analgesic use and provided a semen sample. Negative binomial regression models were used to estimate the percentage differences (adjusted mean ratios [aMR]) in semen quality characteristics according to paracetamol use (no; yes) and frequency of use (almost never; <1/month; ≥1/month; ≥1/week)., Results: In total, 28% of the 913 participants with available data reported the use of paracetamol within the last 6 months. We found a slightly higher total sperm count (aMR 1.13 95% CI [0.99-1.30]) in users compared to nonusers but other semen characteristics were unaffected. The frequency of use was suggestive of lower total sperm count and morphologically normal sperm cells primarily among users ≥1/week, however, CIs were wide., Discussion: We were unable to account for the underlying reason for paracetamol use, which may induce confounding by indication. Exposure misclassification due to recall is likely but probably nondifferential due to the participants' young age and unawareness of semen quality. Due to the rapid plasma half-life of paracetamol and few frequent users, it was not possible to conclude on potential high-dose effects., Conclusion: Our findings do not suggest any strong detrimental effect of paracetamol use on semen quality within this sample of young Danish men. However, the effects of high dose and frequent use cannot be excluded., (© 2021 American Society of Andrology and European Academy of Andrology.)