Tattoo exposure and biomarkers of male fecundity: A cross-sectional study among young Danish males.

To investigate if timing of puberty is associated with semen characteristics, testicular volume, and reproductive hormone levels. Cohort study. The Danish National Birth Cohort (DNBC) and its sub-cohort, the Fetal Programming of Semen Quality (FEPOS) cohort of 1,058 young men. Self-reported information on timing (younger, same age, older than peers) of the pubertal markers: voice break (primary exposure), pubic hair growth, regular shaving, and axillary hair growth. We estimated the relative differences with 95% confidence intervals (CI) 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 [LH], sex hormone-binding globulin [SHBG], testosterone, estradiol, free androgen index [FAI]) obtained at a median age of 19.2 years according to timing of pubertal development. Compared to 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 lower proportion of non-progressive 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 (24% [-1%, 55%]), higher SHBG (7% [0%, 15%]), lower estradiol (-14% [-23%, -5%]) and lower FAI (-8% [-14%, -1%]), whereas voice break 'younger than peers' tended to have higher LH (4% [-2%, 11%]), higher testosterone (5% [0%, 11%]), higher estradiol (17% [6%, 29%]) and higher FAI (4% [-2%, 11%]). When the categorical pubertal markers were analyzed as a linear term to assess for dose-dependency, older age at pubertal development were associated with higher FSH, higher SHBG, lower testosterone, lower estradiol and lower FAI for most pubertal markers. 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.

ABSTRACTBackgroundAtopic dermatitis (AD) may be associated with male reproductive health. However, epidemiological studies are yet to explore this hypothesis.ObjectivesTo investigate whether AD in childhood is associated with poorer reproductive health in young men from the general population.MethodsThis study is based on the Danish National Birth Cohort (DNBC) and its sub‐cohort, the Fetal Programming of Semen Quality cohort (FEPOS), which consists of young men born between 1998 and 2000 and whose mothers were included in the DNBC. In total, 5697 young men were invited during the recruitment period from 2017 to 2019, where 1058 were enroled and completed a comprehensive questionnaire regarding health and lifestyle, provided semen and blood samples and self‐measured their testicular volume. Information on maternal‐reported doctor‐diagnosed AD was obtained from the DNBC during childhood. The associations of semen characteristics, testicular volume and reproductive hormone levels with the occurrence of AD were analyzed using negative binomial and linear regression models.ResultsIn total, 220 (21%) young men had childhood AD. Men with childhood AD had slightly higher sperm concentration compared to those without (17%, 95% confidence intervals (CI): 3% to 33%), and lower FSH (−9%, 95% CI: −17% to 0%) and LH (−8%, 95% CI: −14% to −1%). Testosterone and estradiol levels and the remaining reproductive health outcomes were comparable between men with and without childhood AD.ConclusionsThis study indicates that childhood AD might not have a clinically significant negative association with semen quality or reproductive hormone levels in young adulthood.

Maternal fever during pregnancy has been associated with an increased risk of genital malformations, but the implication for long-term reproductive health in the offspring is unknown. To investigate associations between timing, duration, and temperature of fetal exposure to maternal fever and sons' semen quality, testicular volume, and levels of reproductive hormones in early adulthood. Further, to examine whether concurrent use of antipyretics and/or antibiotics modified the effect. We used the Fetal Programming of Semen Quality cohort consisting of men born to women enrolled in the Danish National Birth Cohort. Self-reported information on maternal fever was collected twice during pregnancy (median 16 and 31 pregnancy weeks) and categorized as any fever during pregnancy, fever during early pregnancy (weeks 1-15), and fever exclusively during late pregnancy (weeks 16-42). Semen quality and concentrations of reproductive hormones were measured at a clinical examination at the age of 18.9 years. We used negative binomial regression to examine the associations, adjusting for maternal age at birth, maternal smoking, family occupational status, and precision variables related to semen quality and hormonal levels, for example, abstinence time. 986 men were included in the study, of which 23% had mothers reporting at least one episode of fever. We found no strong indications of associations between maternal fever during pregnancy and male reproductive health in young men. Concurrent use of antipyretics and antibiotics did not modify the association. Strengths include the large sample size, prospectively collected data, and the adjustment for maternal factors during pregnancy and important precision variables. A limitation is the crude self-reported information on maternal fever. We found no evidence to support that timing, duration, or temperature of maternal fever during pregnancy has a long-term impact on semen characteristics, testicular volume, or level of reproductive hormones in male offspring.

Fetal exposure to endocrine-disrupting chemicals (EDCs) has been associated with reduced male fecundity, but with few studies considering chemical mixtures. We assessed the association between fetal exposure to a mixture of EDCs and biomarkers of male fecundity in young adulthood. The study population comprised 841 young adult males enrolled in the Fetal Programming of Semen Quality cohort, established as a male offspring sub-cohort within the Danish National Birth Cohort. Maternal blood samples were analyzed for concentrations of per- and polyfluoroalkyl substances (PFAS), phthalate metabolites, and triclosan. We used quantile g-computation to estimate the change in semen characteristics, testicular volume, and reproductive hormone levels with 95% confidence intervals (CI) per one-quartile increase in all chemicals within three chemical mixtures; an overall chemical mixture, a PFAS mixture, and a non-persistent chemical mixture. Fetal exposure to a one-quartile increase in the overall chemical mixture was associated with 4.0million/mL lower sperm concentration (95% CI: -9.1, 1.1), 16.1 million lower total sperm count (95% CI: -33.8, 1.6), 0.5mL smaller testicular volume (95% CI: -1.2, 0.3), 5% higher proportion of non-progressive and immotile spermatozoa (95% CI: 0.99, 1.11), and 7% higher concentration of FSH (95% CI: 0.99, 1.16), but with limited precision. Effect sizes were greatest in magnitude for sperm concentration and total sperm count. We observed somewhat similar associations for the PFAS mixture and no associations for the non-persistent chemical mixture. Results suggest that fetal exposure to an overall mixture of EDCs may be adversely associated with several biomarkers of male fecundity, but findings are also compatible with null associations. These associations, if true, appeared to be driven by PFAS, but misclassification due to a single measurement of the phthalate metabolites and triclosan may have attenuated the results.

Is maternal age at menarche associated with reproductive health in sons measured by semen quality, testes volume and reproductive hormone levels? 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. 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. 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. 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. 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. 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. 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. 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. N/A.

To study the associations between parental subfecundity, assessed by time to pregnancy and use of medically-assisted reproduction, and reproductive health of young men. Cohort study. Denmark. A total of 1,058 men in the Fetal Programming of Semen quality cohort, a subcohort of the Danish National Birth Cohort. 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. 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). 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 invitro 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. 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.

BackgroundPer- and polyfluoroalkyl substances (PFAS) are a large family of persistent industrial chemicals with endocrine disrupting properties. ObjectivesTo examine biomarkers of reproductive function in young adult males according to current environmental exposure to single and combined PFAS. MethodsThe study population consisted of young men (n = 1041, age 18–21) from the Fetal Programming of Semen Quality (FEPOS) cohort. These men were recruited from pregnancies included in the Danish National Birth Cohort (DNBC) between 1996 and 2002. From 2017 to 2019, participants answered an online questionnaire, completed a clinical examination and provided a blood and a semen sample. Exposure to 15 PFAS was measured in plasma. Six compounds were quantified above the limit of detection in at least 80% of the participants. We applied negative binomial regression and weighted quantile sum (WQS) regression models to assess associations between single and combined exposure to PFAS and measures of semen quality, testicular volume and reproductive hormones among the young men. ResultsWe found no consistent associations between plasma concentrations of PFAS, semen quality and testicular volume. Higher levels of single and combined PFAS were associated with slightly higher levels of follicle-stimulating hormone (FSH) (WQS 4% difference, 95% confidence interval: 0, 9). Perfluorooctanoic acid (PFOA) was the main contributor to this finding with positive signals also from perfluorodecanoic acid (PFDA) and perfluorohexane sulfonic acid (PFHxS). DiscussionWe examined exposure to a range of common PFAS in relation to biomarkers of male reproductive function and found an association with higher levels of FSH among young men from the general population in Denmark. Further studies on especially combined exposure to PFAS are needed to expand our understanding of potential endocrine disruption from both legacy and emerging compounds in relation to male reproductive function.

STUDY QUESTIONIs maternal pre-pregnancy BMI associated with semen quality, testes volume, and reproductive hormone levels in sons?SUMMARY ANSWERMaternal pre-pregnancy BMI was associated with an altered reproductive hormone profile in young adult sons, characterized by higher levels of oestradiol, LH, and free androgen index (FAI) and lower levels of sex hormone-binding globulin (SHBG) in sons born of mothers with pre-pregnancy overweight and obesity.WHAT IS KNOWN ALREADYEvidence suggests that maternal pre-pregnancy BMI may influence reproductive health later in life. Only one pilot study has investigated the association between maternal pre-pregnancy BMI and reproductive health outcomes in sons, suggesting that a high BMI was associated with impaired reproductive function in the adult sons.STUDY DESIGN, SIZE, DURATIONA population-based follow-up study of 1058 young men from the Fetal Programming of Semen Quality (FEPOS) cohort nested within the Danish National Birth Cohort (DNBC), 1998–2019, was carried out.PARTICIPANTS/MATERIALS, SETTING, METHODSIn total, 1058 adult sons (median age 19 years, 2 months), born 1998–2000 by mothers included in the DNBC, participated in FEPOS. At a clinical examination, they provided a semen and blood sample, measured their testes volume, and had height and weight measured. Maternal pre-pregnancy BMI was obtained by self-report in early pregnancy. Semen characteristics, testes volume, and reproductive hormone levels were analysed according to maternal pre-pregnancy BMI categories and as restricted cubic splines using negative binomial and ordinary least square regression models. Mediation analyses examined potential mediation by the sons’ birthweight, pubertal timing, fat mass, and BMI. Additional analyses investigated the role of paternal BMI in the potential associations between maternal BMI and reproductive health outcomes.MAIN RESULTS AND THE ROLE OF CHANCEWe found no consistent associations between maternal pre-pregnancy BMI and semen characteristics or testes volume. Sons of mothers with higher pre-pregnancy BMI had higher oestradiol and lower SHBG levels, both in a dose-dependent manner. Sons of mothers with pre-pregnancy obesity (≥30 kg/m2) had higher LH levels and a higher FAI than sons born by mothers with normal pre-pregnancy BMI (18.5–24.9 kg/m2). The mediation analyses suggested that the effect of maternal pre-pregnancy BMI on higher levels of oestrogen, LH, and FAI was partly mediated by the sons’ birthweight, in addition to adult fat mass and BMI measured at the clinical examination, whereas most of the effect on lower levels of SHBG was primarily mediated by the sons’ own fat mass and BMI. Paternal BMI was not a strong confounder of the associations in this study.LIMITATIONS, REASONS FOR CAUTIONThis study was based in a population-based cohort with a low prevalence of overweight and obesity in both mothers and adult sons. Some men (10%) had blood for reproductive hormone assessment drawn in the evening. While several potential confounding factors were accounted for, this study's inherent risk of residual and unmeasured confounding precludes provision of causal estimates. Therefore, caution should be given when interpreting the causal effect of maternal BMI on sons’ reproductive health.WIDER IMPLICATIONS OF THE FINDINGSGiven the widespread occurrence of overweight and obesity among pregnant women, it is imperative to thoroughly examine the potential consequences for reproductive hormone levels in adult sons. The potential effects of maternal pre-pregnancy obesity on sons’ reproductive hormone profile may potentially be partly avoided by the prevention of overweight and obesity in the sons.STUDY FUNDING/COMPETING INTEREST(S)The project was 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), AP Møller Foundation (16-37), the Health Foundation, Dagmar Marshall's Fond, Aarhus University, Independent Research Fund Denmark (9039-00128B), and the European Union (ERC, BIOSFER, 101071773). Views and opinions expressed are, however, those of the authors only and do not necessarily reflect those of the European Union or the European Research Council. Neither the European Union nor the granting authority can be held responsible. The authors declare that they have no conflict of interest.TRIAL REGISTRATION NUMBERN/A.

Vitamin D is metabolised throughout the male reproductive system, suggesting a direct regulatory role of vitamin D in male reproduction. To investigate the association between plasma vitamin D levels at sperm ejaculation and during spermatogenesis and biomarkers of male fecundity in young men. From the Fetal Programming of Semen Quality cohort, Denmark, 2017-2019, 1047 young men provided a semen and a blood sample, and self-measured their testes volume at a clinical visit. Plasma levels of vitamin D (25(OH)D3) and reproductive hormones were measured in the blood sample. Relative percentage differences in semen characteristics, testes volume and reproductive hormone levels were analysed according to measured vitamin D levels (categorised, continuous and as restricted cubic splines) at sperm ejaculation. Additionally, we used the seasonal variation in endogenous vitamin D synthesis to estimate individual vitamin D levels 3 months prior to sperm ejaculation (at initiation of spermatogenesis) in addition to 2 and 1 month before. This was analysed following the same strategy. Compared to measured vitamin D levels >75nmol/L, levels <25nmol/L at sperm ejaculation were associated with lower total sperm count (‒15% [95% confidence interval: ‒33%; 8%]), and a higher proportion of non-progressive and immotile spermatozoa (11% [95% confidence interval: 0%; 24%]). Lower measured vitamin D levels were also associated with higher oestradiol, lower sex hormone-binding globulin and lower follicle-stimulating hormone, in dose-dependent manners. Vitamin D levels estimated before and during spermatogenesis yielded similar associations as vitamin D levels measured at sperm ejaculation. By using the seasonal variation in endogen vitamin D synthesis, we were able to estimate individual vitamin D levels during spermatogenesis. Lower vitamin D levels before and during spermatogenesis and at sperm ejaculation were associated with lower total sperm count and sperm motility and an altered reproductive hormone profile.

Maternal intake of paracetamol during pregnancy and biomarkers of male fecundity in young adult sons

Longitudinal Assessment of Pubertal Attainment and Testicular Function Following Pediatric Hematopoietic Stem Cell Transplantation: The Role of the Conditioning Regimen

This study was conducted to assess reproductive endocrine function, testicular volume, semen quality, and fertility in adult male patients after renal transplantation (RTx) during childhood or adolescence. Twenty-four RTx recipients (median age: 28.1 years) were examined at a median of 18.6 years after RTx. Reproductive hormone levels and semen samples were studied and compared to those of 56 age-matched controls (median age: 30.2 years). Eight RTx men (33%) had been treated with cyclophosphamide. Medical records were retrospectively reviewed and data on puberty, dialysis, and immunosuppressive medication were analyzed to evaluate the prospect of fertility and sexual health. The testicular volumes and total sperm counts of the RTx patients were smaller than those of the controls with a median of 11.4 versus 33.9 mL, P<0.001 and 1.3 versus 135.5 million, P<0.001, respectively. Only four (22%) of the RTx men had normospermia in semen sample. The reproductive hormone levels were normal in the majority of the RTx survivors, with only two survivors showing androgen deficiency. Patients without history of cyclophosphamide therapy had significantly smaller testes and total sperm counts (median: 12.5 mL and 16.3 million) in comparison with their healthy peers (P<0.001 in both), and those with previous cyclophosphamide treatment showed further worse outcome (8.5 mL and 0 million, respectively, P<0.001 in both). Testicular function is often impaired even years after transplantation and poor semen quality decreases the prospect of fertility in men after pediatric RTx.

Background: Perfluorinated alkyl acids (PFAAs), persistent chemicals with unique water-, dirt-, and oil-repellent properties, are suspected of having endocrine-disrupting activity. The PFAA compounds perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) are found globally in humans; because they readily cross the placental barrier, in utero exposure may be a cause for concern.Objectives: We investigated whether in utero exposure to PFOA and PFOS affects semen quality, testicular volume, and reproductive hormone levels.Methods: We recruited 169 male offspring (19–21 years of age) from a pregnancy cohort established in Aarhus, Denmark, in 1988–1989, corresponding to 37.6% of the eligible sons. Each man provided a semen sample and a blood sample. Semen samples were analyzed for sperm concentration, total sperm count, motility, and morphology, and blood samples were used to measure reproductive hormones. As a proxy for in utero exposure, PFOA and PFOS were measured in maternal blood samples from pregnancy week 30.Results: Multivariable linear regression analysis suggested that in utero exposure to PFOA was associated with lower adjusted sperm concentration (ptrend = 0.01) and total sperm count (ptrend = 0.001) and with higher adjusted levels of luteinizing hormone (ptrend = 0.03) and follicle-stimulating hormone (ptrend = 0.01). PFOS did not appear to be associated with any of the outcomes assessed, before or after adjustment.Conclusions: The results suggest that in utero exposure to PFOA may affect adult human male semen quality and reproductive hormone levels.

Persistent organic pollutants (POPs), such as polychlorinated biphenyls (PCBs), may interfere with hormonal processes. Knowledge about the effects of prenatal exposure to PCBs and their hydroxylated metabolites (OH-PCBs) on pubertal development is limited. Therefore, the aim of the current study was to determine whether prenatal environmental PCB and OH-PCB exposure are associated with reproductive hormone levels and pubertal characteristics in 13- to 15-year-old children. In this Dutch observational cohort study, 194 mother–infant pairs were included (1998–2002). Maternal pregnancy serum levels of PCBs, OH-PCBs, and other POPs were measured. At follow-up (2014–2016), we measured serum or plasma levels of reproductive hormones in their children. We assessed Tanner stages and testicular volume (by clinician or standardized self-assessment), and participants completed questionnaires on pubertal onset. In total, 101 adolescents (14.4 ± 0.8 years; 53.7% of invited) participated, and 55 were boys. In boys, higher prenatal PCB levels were associated with higher testosterone levels, higher pubic hair stage, larger testicular volume, and younger age at onset of growth spurt and voice break. In girls, higher prenatal PCB levels were associated with higher stages for breast development. In conclusion, higher prenatal PCB exposure could be associated with more advanced pubertal development in 13- to 15-year-old children.

To analyse the relationship between male infertility and chromosomal translocations, and the influence of different types of chromosomal translocations on semen quality, testicular volume and hormone levels. A retrospective cohort of infertile men was recruited for chromosomal analysis using standard Giemsa stain banding. Physical examinations, semen analysis, hormonal analysis and the detection of azoospermia factor (AZF) microdeletions were carried out. Men with normal fertility were used as controls. Among the 1056 infertile men, 22 had chromosomal translocations (2.1%), including seven with Robertsonian translocations (0.7%), 11 with autosome-autosome reciprocal translocations (1.0%) and four with gonosome-autosome reciprocal translocations (0.4%). Left and right testicular volumes of patients with chromosomal translocations were significantly smaller than those in the fertile control group. There were no significant differences in hormone levels between patients with chromosomal translocations and fertile controls, except for significantly lower testosterone levels in patients with Robertsonian and gonosome-autosome reciprocal translocations compared with the controls. All AZF microdeletion analyses showed normal results. Chromosomal translocations may cause reductions in testicular volume and testosterone level, which may impact spermatogenesis, resulting in azoospermia or oligozoospermia and male infertility.