Maternal age at menarche and reproductive health in young adult men: a cohort study.

STUDY QUESTION: Is maternal age at menarche associated with reproductive health in sons measured by semen quality, testes volume and reproductive hormone levels? SUMMARY ANSWER: Later maternal age at menarche was associated with impaired semen characteristics, lower testes volume and altered levels of reproductive hormones, while earlier maternal age at menarche was not strongly associated with reproductive outcomes in sons. WHAT IS KNOWN ALREADY: Both earlier and later maternal age at menarche may be associated with altered male reproductive health outcomes. This is the first study to investigate the potential association between maternal age at menarche and semen quality, testes volume and reproductive hormone levels in sons. STUDY DESIGN, SIZE, DURATION: In this population-based cohort study, we used data from the Fetal Programming of Semen Quality Cohort nested within the Danish National Birth Cohort. In total, 5697 sons born in 1998-2000 were invited to participate in the cohort in 2017-2019. PARTICIPANTS/MATERIALS, SETTING, METHODS: In total, 1043 (18% of the invited) young men with information on maternal age at menarche provided a semen and blood sample, measured their testes volume, and filled in a questionnaire on health behavior and pubertal development. Maternal age at menarche was reported by the mothers during pregnancy and examined categorically (as earlier, at the same time or later than their peers), continuously and modeled as splines. We estimated relative percentage differences in the reproductive outcomes using negative binomial regression models. Further, we did a mediation analysis to investigate the potential mediating role of timing of the sons' pubertal development. MAIN RESULTS AND THE ROLE OF CHANCE: Sons whose mothers had age at menarche later than peers had 15% lower (95% CI: -27%; 0%) sperm concentration, 14% lower (95% CI: -28%; 1%) total sperm count, 7% higher (95% CI: 0%; 14%) proportion of nonprogressive or immotile spermatozoa, 6% lower (95% CI: -11%; 0%) testes volume, 6% lower (95% CI: -12%; 1%) luteinizing hormone, 6% lower (95% CI: -12%; 1%) sex hormone-binding globulin and 5% lower (95% CI: -9%; 0%) testosterone levels compared with sons whose mothers had age at menarche at the same time as peers. Our study did not suggest that earlier maternal age at menarche was strongly associated with semen quality, testes volume or reproductive hormones in sons. However, the spline analyses indicated a potential inverted U-shaped association for sperm concentration and testes volume, and levels of sex hormone-binding globulin and testosterone. We found no strong evidence of mediation by timing of the sons' own pubertal development. LIMITATIONS, REASONS FOR CAUTION: There was a rather low participation rate in the Fetal Programming of Semen Quality Cohort and we tried to counter it by applying selection weights. Maternal age at menarche was recalled during pregnancy, which may introduce misclassification, most likely nondifferential. Inaccuracy of the sons' recalled pubertal development years after the event may result in underestimation of the possible mediating role of pubertal timing. WIDER IMPLICATIONS OF THE FINDINGS: Our findings may represent a degree of shared heritability of reproductive health or be a result of an underlying epigenetic profile or unknown shared environmental, cultural or dietary exposure, causing both altered age at menarche and impaired reproductive health outcomes in sons. However, the exact mechanism for the investigated association remains unknown. STUDY FUNDING/COMPETING INTEREST(S): This article is part of the ReproUnion collaborative study, cofinanced by the European Union, Intereg V ÖKS (20200407). The FEPOS project was further funded by the Lundbeck Foundation (R170-2014-855), the Capital Region of Denmark, Medical doctor Sofus Carl Emil Friis and spouse Olga Doris Friis's Grant, Axel Muusfeldt's Foundation (2016-491), A.P. Møller Foundation (16-37), the Health Foundation and Dagmar Marshall's Fond. Additionally, this study received funding from Aarhus University. There are no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Health perspectives and handling of PFAS contamination in Denmark.

Per- and polyfluorinated alkyl substances (PFAS) are a group of man-made extremely persistent chemicals that have been spread worldwide since the 1950s due to their properties as effective water- and grease-repellent and heat- and temperature-resistant. They are associated with an increasing number of health effects including immune and hormonal disturbances and some types of cancer. We present a review of PFAS pollution in Denmark, the current human exposure, suspected health effects, and patient management in environmental medicine.

Timing of puberty in relation to semen characteristics, testicular volume, and reproductive hormones: a cohort study.

OBJECTIVE: To investigate whether the timing of puberty is associated with semen characteristics, testicular volume, and reproductive hormone levels. DESIGN: Cohort study. SETTING: Not applicable. PATIENTS: The Danish National Birth Cohort and its subcohort, the Fetal Programming of Semen Quality cohort of 1,058 young men. INTERVENTION(S): Self-reported information on the timing (younger, same age, older than peers) of the pubertal markers: voice break (primary exposure), pubic hair growth, regular shaving, and axillary hair growth. MAIN OUTCOME MEASURES(S): We estimated the relative differences with 95% confidence intervals for semen characteristics (semen volume, sperm concentration, total sperm count, sperm motility, percentage of morphologically normal spermatozoa), testicular volume, and reproductive hormones (follicle stimulating hormone [FSH], luteinizing hormone, sex hormone-binding globulin [SHBG], testosterone, estradiol, and free androgen index [FAI]) obtained at a median age of 19.2 years according to timing of pubertal development. RESULT(S): Compared with men reporting voice break "same age as peers," men reporting voice break "older than peers" tended to have lower total sperm count (-12% [-25%, 4%]) and lower percent morphologically normal spermatozoa (-10% [-20%, 2%]), whereas men reporting voice break "younger than peers" tended to have a lower proportion of nonprogressive and immotile spermatozoa (-6% [-13%, 1%]) and larger testicular volume (7% [1%, 13%]). The pattern was less consistent for the other pubertal markers. For reproductive hormones, voice break "older than peers" tended to have higher FSH levels (24% [-1%, 55%]), higher SHBG levels (7% [0, 15%]), lower estradiol levels (-14% [-23%, -5%]), and lower FAI (-8% [-14%, -1%]), whereas voice break "younger than peers" tended to have higher luteinizing hormone levels (4% [-2%, 11%]), higher testosterone levels (5% [0%, 11%]), higher estradiol levels (17% [6%, 29%]), and higher FAI (4% [-2%, 11%]). When the categorical pubertal markers were analyzed as a linear term to assess dose dependence, older age at pubertal development was associated with higher FSH levels, higher SHBG levels, lower testosterone levels, lower estradiol levels, and lower FAI for most pubertal markers. CONCLUSION(S): These results lend weak support to the hypothesis that older age at pubertal development is associated with markers of reduced male fecundity, especially reproductive hormone levels, although associations with semen characteristics and testicular volume were statistically insignificant.

Semen quality and reproductive hormones in sons of subfertile couples: a cohort study.

OBJECTIVE: To study the associations between parental subfecundity, assessed by time to pregnancy and use of medically-assisted reproduction, and reproductive health of young men. DESIGN: Cohort study. SETTING: Denmark. PATIENT(S): A total of 1,058 men in the Fetal Programming of Semen quality cohort, a subcohort of the Danish National Birth Cohort. INTERVENTION(S): From 2017-2019, men were recruited and provided semen and blood samples. Information on parental time to pregnancy and use of medically-assisted reproduction (including type of treatment) as well as demographic, health, and lifestyle factors were available. We estimated the crude and adjusted relative percentage differences with 95% confidence intervals (CIs) in the outcomes according to time to pregnancy and use of medically-assisted reproduction, using multiple adjusted negative binomial regression analysis. MAIN OUTCOME MEASURE(S): Semen characteristics (semen volume, sperm concentration, total sperm count, sperm motility, and morphology), testicular volume, and reproductive hormone levels (follicle stimulating hormone, luteinizing hormone, testosterone, estradiol, sex hormone-binding globulin, and free androgen index). RESULT(S): Overall, semen quality and levels of reproductive hormones were not lower among sons of subfecund parents reporting a time to pregnancy >6 months or use of intrauterine insemination. Sons conceived after in vitro fertilization or intracytoplasmic sperm injection, had a higher semen concentration (29%; 95% CI, -7%-79%) and a higher percentage of sperm with normal morphology (20%; 95% CI, -8%-56%), but with 95% CI overlapping the null. Moreover, these sons had slightly higher estradiol levels (30%; 95% CI, 7%-57%). The absolute differences seen were small, and the clinical significance of these differences are unknown. CONCLUSION(S): We found no major difference in semen quality or reproductive hormones in sons conceived by subfertile couples or with the use of medically-assisted reproduction.

Reducing socioeconomic inequalities in COPD care in the hospital outpatient setting - A nationwide initiative.

OBJECTIVE: Socioeconomic differences in quality of care have been suggested to contribute to inequality in clinical prognosis of COPD. We examined socioeconomic differences in the quality of COPD outpatient care and the potential of a systematic quality improvement initiative in reducing potential socioeconomic differences. METHODS: A mandatory national quality improvement initiative has since 2008 monitored the quality of COPD care at all national pulmonary specialized outpatient clinics in Denmark using six evidence-based process performance measures. We followed patients aged ≥30 years with a first-ever outpatient contact for COPD during 2008-2012 (N = 23,741). Adjusted year-specific relative risks (RR) of fulfilling all relevant process performance measures was compared according to ethnicity, education, income, employment, and cohabitation using Poisson regression. RESULTS: Quality of care improved following the implementation of the clinical improvement initiative with 11% of COPD patients receiving optimal care in 2008 compared to 57% in 2012. Substantial socioeconomic differences were observed the first year: immigrants (RR 0.41, 95% CI 0.21-0.82), the unemployed (RR 0.37, 95% CI 0.18-0.74), disability pensioners (RR 0.63, 95% CI 0.46-0.87) and patients living alone (RR 0.80, 95% CI 0.60-0.97) were less likely to receive all relevant care processes, whereas those with highest education (RR 1.22, 95% CI 0.92-1.63) were more likely to receive these processes. These differences were eliminated during the study period. CONCLUSION: A systematic quality improvement initiative including regular audits, knowledge sharing, and detailed disease-specific recommendations for care improvement may increase the overall quality of care and considerably modify the substantial socioeconomic inequalities in COPD management.

Determinants of Smoking Cessation in Patients With COPD Treated in the Outpatient Setting.

BACKGROUND: The beneficial effects of smoking cessation on the progression of COPD are well established. Nevertheless, many patients with COPD continue to smoke. METHODS: In this nationwide hospital-based prospective follow-up study, we examined rates of smoking cessation and clinical and sociodemographic determinants of smoking cessation in 3,233 patients with COPD who smoked on outpatient contact during 2008 to 2012. Using multivariate Cox regression, we calculated hazard ratios (HRs) of quitting. RESULTS: Within 1 and 5 years from first outpatient contact, the probability of quitting was 19% and 45%, respectively. In adjusted analyses, patients were less likely to quit if they were younger, with an HR of 0.84 (95% CI, 0.71-0.99) for patients aged 50 to 69 years and 0.53 (95% CI, 0.37-0.76) for patients aged 30 to 49, compared with those aged 70 years or older, who had lower income (HR, 0.79; 95% CI, 0.67-0.94), lived alone (HR, 0.75; 95% CI, 0.64-0.88), were unemployed (HR, 0.70; 95% CI, 0.54-0.90), had milder COPD with an HR of 0.67 (95% CI, 0.53-0.84) for Global Initiative for Chronic Obstructive Lung Disease (GOLD) A and 0.61 (95% CI, 0.47-0.80) for GOLD B compared with GOLD D, had Medical Research Council (MRC) dyspnea scale score < 4 (HR 0.80, 95% CI 0.68-0.95), or no history of exacerbations treated on an outpatient basis. (HR, 0.80; 95% CI, 0.68-0.93). CONCLUSIONS: These findings reinforce that young and socioeconomically disadvantaged patients have more difficulties achieving timely smoking cessation. A novel finding is that patients with milder COPD are less likely to quit. The findings suggest a need for interventional studies focusing on these subgroups to ensure abstinence to halt disease progression.