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Objectives. To quantify semen quality in the Greenlandic population. Study design. A cross-sectional study including recently proven fertile men from four regions including nine municipalities and one settlement in Greenland. Methods. The samples were analysed for sperm cell concentrations and motility using standard methods. Results. In total 201 semen samples were collected. The median sperm cell concentration of fertile men in Greenland was 53 x106 sperm cells/ml, with a median sperm cell volume of 3.2 ml, a total sperm count of 185.6 x106 sperm cells and a median motility of 60 %. Regionally there were no statistical significant difference in sperm counts, but the sperm cell motility differed among regions, with the lowest sperm cell motility found in semen samples collected on the east coast. Overall sperm cell concentration and total sperm count in Greenland seems to be in the lower range compared to studies from Europe, USA and Japan. Conclusion. Within Greenland the sperm cell concentration appears to be similar in different regions, but sperm cell motility tends to be lower in men from the east coast. This may be related to the higher organochlorine exposure level previously demonstrated in this population. Keywords: Sperm count, Greenland, biopersistent organochlorines, PCB, DDE

The effects of estrogenic compounds on the development of sexual characteristics in juvenile guppies (Poecilia reticulata) were examined. After exposure for 3 months, the sex ratio was female biased in guppies exposed to 0.5 microg/L 17beta-estradiol (E2) or higher but unaffected by exposure to 4-tert-octylphenol (OP). When exposed to 100 microg/L OP, the male guppy sexual behavior and sperm count were increased. In contrast, the male sperm count was markedly reduced after exposure to a high concentration of E2. The length of the gonopodium (copulatory organ) was increased when exposed to 100 microg/L OP and at all the tested concentrations of E2. Similar concentrations of OP and E2 reduced the gonad weight of the females. The results demonstrate that the development of sexual characteristics in guppies can be disturbed by environmentally realistic concentrations of E2 but higher concentrations of OP are needed to induce similar alterations.

Previous laboratory studies have demonstrated that estrogenic and antiandrogenic chemicals can alter several sexual characteristics in male poeciliid fishes. Whether similar disturbances occur under field conditions remains to be confirmed. Lake Apopka, Florida, is contaminated with numerous chemicals, some of which possess endocrine-disrupting activity. Male mosquitofish (Gambusia holbrooki) were collected monthly from December 2000 through May 2001 from Lake Apopka and two nearby reference lakes, Orange Lake and Lake Woodruff National Wildlife Refuge. Selected sexual characteristics were compared temporally and among lakes during the collection period. Male fish from Lake Apopka had slightly shorter gonopodia and on average 32 and 47% fewer sperm cells per milligram testis, when compared with the fish collected from Orange Lake and Lake Woodruff, respectively. The testes weights increased markedly during spring, with significantly smaller testes in fish from Lake Apopka than from Orange Lake, but surprisingly, the smallest testes occurred in males obtained from the Lake Woodruff population. The highest liver weights were found in the Lake Apopka population. Whole-body concentrations of testosterone and estradiol varied among months; the peak testosterone concentration occurred in January and was significantly lower in male fish from Lake Apopka compared with Orange Lake. The intensity of male courtship behavior was highly correlated to body testosterone concentration, but no statistically significant differences in sexual behavior among the lakes were found. We conclude that sexual characteristics of relevance to male reproductive capacity are altered in the Lake Apopka mosquitofish population, and we discuss the presence of chemicals with antiandrogenic effects in Lake Apopka as a possible cause of the observed alterations.

Low-level exposure to polychlorinated biphenyl-153 (PCB-153) and dichlorodiphenyldichloroethylene (p-p′-DDE) can impair fetal growth; however, the exposure–response relationship and effect modifiers of such association are not well established. This study is an extension of an earlier European meta-analysis. Our aim was to explore exposure–response relationship between PCB-153 and p-p′-DDE and birth outcomes; to evaluate whether any no exposure–effect level and susceptible subgroups exist; and to assess the role of maternal gestational weight gain (GWG). We used a pooled dataset of 9377 mother–child pairs enrolled in 14 study populations from 11 European birth cohorts. General additive models were used to evaluate the shape of the relationships between organochlorine compounds and birth outcomes. We observed an inverse linear exposure–response relationship between prenatal exposure to PCB-153 and birth weight [decline of 194 g (95% CI −314, −74) per 1 μg/L increase in PCB-153]. We showed effects on birth weight over the entire exposure range, including at low levels. This reduction seems to be stronger among children of mothers who were non-Caucasian or had smoked during pregnancy. The most susceptible subgroup was girls whose mothers smoked during pregnancy. After adjusting for absolute GWG or estimated fat mass, a reduction in birth weight was still observed. This study suggests that the association between low-level exposure to PCB-153 and birth weight exists and follows an inverse linear exposure–response relationship with effects even at low levels, and that maternal smoking and ethnicity modify this association. Keywords: Biomarkers of exposure, Persistent organic pollutants, Polychlorinated biphenyls (PCBs), Dichlorodiphenyldichloroethylene (DDE), Birth weight

STUDY QUESTION: Is overweight associated with impaired sperm DNA integrity?SUMMARY ANSWER: High body mass index (BMI) is not associated with impaired sperm DNA integrity as assessed by the DNA Fragmentation Index (DFI).WHAT IS KNOWN ALREADY: Previous studies, based on fewer subjects and including mainly subfertile men, have shown conflicting results regarding the influence of overweight and obesity on sperm DNA integrity.STUDY DESIGN, SIZE, DURATION: This cross-sectional study was based on semen samples from 1503 men from the general population.PARTICIPANTS/MATERIALS, SETTING, METHODS: We included two cohorts (cohort A and B) of military recruits (n = 275, n = 304, respectively), one group (cohort C) of fertile men and men without known fertility problems (n = 724), and one group (cohort D) of men between 19 and 40 years without known fertility problems (n = 200). In all cohorts, data were available on BMI, DFI as measured by the sperm chromatin structure assay (SCSA), standard semen characteristics, and potential confounders (age, abstinence time, smoking habits). The subjects were categorized according to BMI into four groups: underweight ( 20% and DFI > 30%, were calculated for the other groups. Calculations were made for the material as a whole and after exclusion of cohort C which included proven fertile men.MAIN RESULTS AND THE ROLE OF CHANCE: We found that normal-weight men had significantly higher DFI than overweight men, with a mean difference of 1.13% (95% CI: 1.05-1.22%); P = 0.001). Overweight men had a reduced risk of having DFI ≥ 20% and DFI ≥ 30%, compared with normal-weight men; adjusted odds ratio (OR) = 0.61 (95% CI: 0.42-0.88; P < 0.01) and adjusted OR = 0.48 (95% CI: 0.28-0.84; P < 0.01), respectively. When excluding cohort C, the statistical significance was lost. Regarding standard semen parameters, we found that obese men had a higher percentage of progressive motile spermatozoa than normal-weight men; mean difference 1.15% (95% CI: 1.02-1.30%, P < 0.05) but the significance was lost when excluding cohort C. All other standard semen parameters were unaffected by BMI.LIMITATIONS, REASONS FOR CAUTION: A main limitation might be the cross-sectional nature of the data. Furthermore our study included a significant proportion of men with proven fertility (75% of cohort C, n = 550), and could therefore be biased toward fertility.WIDER IMPLICATIONS OF THE FINDINGS: Our study indicates that overweight per se is not associated with a higher level of sperm DNA damage.STUDY FUNDING/COMPETING INTERESTS: This research has been given grants from the following: EU 5th and 7th framework program (Inuendo and Clear projects, [Contracts no. QLK4-CT-2001-00202 and FP7-ENV-2008-1-226217)]), the Swedish Research Council (Grants No. 2007-2590, 521-2004-6072 and 521-2002-3907); the Swedish Governmental Funding for Clinical Research, Skåne county council's research and development foundation, MAS Funds, University Hospital MAS Foundation in Malmö, Crafoordska Fund, Ove Tulefjords Fund, Foundation for Urological Research, Fundacion Federico SA, and Gunnar Nilssons Cancer Fund. The authors declare that there are no conflicts of interest.

Persistent organochlorine pollutants (POPs) are ubiquitous, bioaccumulative compounds with potential endocrine-disrupting effects. They cross the placental barrier thereby resulting inin uteroexposure of the developing fetus. The objective of this study was to investigate whether maternal serum concentrations of polychlorinated biphenyls (PCBs) andp,p′-dichlorodiphenyldichloroethylene (p,p′-DDE) during pregnancy are associated with son's semen quality and reproductive hormone levels. During 2008–2009, we recruited 176 male offspring from a Danish cohort of pregnant women who participated in a study in 1988–1989. Each provided semen and blood samples that were analyzed for sperm concentration, total sperm count, motility, and morphology, and reproductive hormone levels, respectively. The maternal blood samples were collected in pregnancy week 30 and were analyzed for the concentrations of six PCBs (PCB-118, -138, -153, -156, -170, and -180) andp,p′-DDE. The potential associations betweenin uteroexposure to ΣPCBs (pmol/ml), Σdioxin like-(DL) PCBs (PCB-118 and -156) (pmol/ml), andp,p′-DDE and semen quality and reproductive hormone levels were investigated using multiple regression. Maternal median (range) exposure levels of ΣPCB, ΣDL-PCB, andp,p′-DDE were 10.0 (2.1–35.0) pmol/ml, 0.8 (0.2–2.7) pmol/ml, and 8.0 (0.7–55.3) pmol/ml, respectively, reflecting typical background exposure levels in the late 1980s in Denmark. Results suggested thatin uteroexposure to ΣPCB, ΣDL-PCB, andp,p′-DDE was not statistically significantly associated with semen quality measures or reproductive hormone levels. Thus, results based on maternal PCB andp,p′-DDE concentrations alone are not indicative of long-term consequences for male reproductive health; however, we cannot exclude that these POPs in concert with other endocrine-modulating compounds may have adverse effects.

BACKGROUND: Prenatal exposure to phthalates may pose a threat to human male reproduction. However, additional knowledge about the in vivo effect in humans is needed, and reported associations with genital abnormalities are inconclusive. We aimed to study prenatal di(2-ethylhexyl) phthalate (DEHP) and diisononyl phthalate (DiNP) exposure in relation to cryptorchidism, hypospadias, and human fetal Leydig cell function.METHODS: We studied 270 cryptorchidism cases, 75 hypospadias cases, and 300 controls. Second-trimester amniotic fluid samples were available from a Danish pregnancy-screening biobank (n = 25,105) covering 1980-1996. We assayed metabolites of DEHP and DiNP (n = 645) and steroid hormones (n = 545) by mass spectrometry. We assayed insulin-like factor 3 by immunoassay (n = 475) and analyzed data using linear or logistic regression.RESULTS: Mono(2-ethyl-5-carboxypentyl) phthalate (5cx-MEPP, DEHP metabolite) was not consistently associated with cryptorchidism or hypospadias. However, we observed an 18% higher (95% confidence interval [CI] = 5%-33%) testosterone level, and a 41% lower (-56% to -21%) insulin-like factor 3 level in the highest 5cx-MEPP tertile compared with the lowest. Mono(4-methyl-7-carboxyheptyl) phthalate (7cx-MMeHP, DiNP metabolite) showed elevated odds ratio point estimates for having cryptorchidism (odds ratio = 1.28 [95% CI = 0.80 to 2.01]) and hypospadias (1.69 [0.78 to 3.67]), but was not consistently associated with the steroid hormones or insulin-like factor 3.CONCLUSIONS: Data on the DEHP metabolite indicate possible interference with human male fetal gonadal function. Considering the DiNP metabolite, we cannot exclude (nor statistically confirm) an association with hypospadias and, less strongly, with cryptorchidism.

The present dissertation focuses on the reproductive health effects in humans from four diverse populations, including an Inuit population from Greenland, a Swedish population of fishermen and fishermen's wives, and urban populations from the cities of Warsaw in Poland and Kharkiv in Ukraine, representing populations with considerable variations in organochlorine exposure levels due to differences in the consumption of contaminated food items and the period since banning the use of the organochlorines selected in the present study. Due to bioaccumulation and their long half-lives in humans, these compounds are still ubiquitously detected in humans. The study included a total of 2,269 women who provided information via detailed questionnaires and 798 men who provided semen samples. Time to pregnancy varied between the populations included, whereas semen quality was remarkably similar with only minor differences in motility between countries and within regions in Greenland. An extensive quality control programme ensured a low level of variation between analysers in the evaluation of semen quality during semen sample collection. Sperm concentration and morphology were not associated with PCB-153 or DDE exposure, but sperm motility was consistently associated with PCB-153 exposure across populations. Xeno-estrogen, -androgen and dioxin-like activity in serum samples were not consistently associated with semen quality measures, indicating that the associations observed with sperm motility were not caused via direct effects on these receptors. The sperm chromatin structure assay showed a higher level of DNA fragmentation under higher PCB-153 exposure levels in the European populations, but not in the Greenlandic population. Disturbances in the female menstrual cycle were not consistently associated with PCB-153 or DDE exposure across the countries, but our results suggested a higher probability of ever having a spontaneous abortion among women with high PCB-153 or DDE exposure levels. Overall, the results suggest that PCB-153, but probably not DDE, may affect aspects of male and female reproductive functioning in European and Arctic populations at the levels of exposure currently experienced in these populations, although the associations observed did not seem to be a major cause of reduced human fertility.

STUDY QUESTION Is age of menarche (AOM) associated with subfecundity and/or infertility in adulthood? STUDY ANSWER A late onset of menarche was associated with a slightly increased risk of subfecundity and infertility. WHAT IS KNOWN ALREADY Abnormal age at onset of menarche is a risk factor for several diseases later in life, but the effect on infertility is unknown. STUDY DESIGN, SIZE AND DURATION A cohort study of 73 107 pregnant Danish women enrolled in the Danish National Birth Cohort (DNBC) between 1996 and 2002 with self-reported data on AOM and waiting time to pregnancy (TTP). PARTICIPANTS/MATERIALS, SETTING AND METHODS Information on AOM and TTP was collected through a computer-assisted telephone interview scheduled in pregnancy Week 12. We estimated adjusted odds ratios (ORs) with 95% confidence intervals (CIs) using multivariate logistic regression with TTP categorized as subfecundity (TTP ≥6 months) and infertility (TTP >12 months). Multiple imputation was performed to account for missing data. MAIN RESULTS AND THE ROLE OF CHANCE We found trends towards higher odds of subfecundity and infertility with increasing age of menarche, using 13 years as the starting point. Among women reaching menarche at 15 years, the odds for subfecundity were 1.09 (95% CI: 1.03-1.15), and 1.17 (95% CI: 1.09-1.25) for women reaching menarche later than 15 years compared with the reference group of girls reaching menarche at 13 years. Additionally, women reaching menarche older than 15 years had an OR of infertility of 1.18 (95% CI: 1.08-1.29). Women younger than 11 years at menarche had lower odds of subfecundity. The results were generally attenuated when adjusting for women's age of pregnancy, but the significant positive trend of higher OR for subfecundity persisted, as did the higher OR for subfecundity among women experiencing menarche older than 15 years. LIMITATIONS, REASONS FOR CAUTION We used retrospectively collected self-reported information on AOM and TTP. Information on male factors was limited in this cohort. We only included pregnant women and have therefore no data on women with untreated and unsuccessfully treated infertility, limiting the generalizability to women who became pregnant. WIDER IMPLICATION OF THE FINDINGS This study indicates that the onset of menarche at 15 years or later is associated with subfecundity and infertility. STUDY FUNDING/COMPETING INTERESTS The Danish National Research Foundation has established the Danish Epidemiology Science Centre that initiated and created the DNBC. The cohort is furthermore a result of a major grant from this Foundation. Additional support for the DNBC is obtained from the Pharmacy Foundation, the Egmont Foundation, the March of Dimes Birth Defects Foundation, the Augustinus Foundation and the Health Foundation. This specific study was supported by a scholarship from the Ministry of Science and Innovation. No conflict of interest declared.

Persistent organic pollutants (POPs) may affect male reproductive function. Many dioxin-like POPs exert their effects by activation of the aryl hydrocarbon receptor (AHR) signalling pathway. We analysed whether gene-environment interactions between polymorphisms in AHR (R554K) and AHR repressor (AHRR P185A) and serum levels of markers of POP exposure 1,1-bis-(4-chlorophenyl)-2,2-dichloroethene (p,p'-DDE) and 2,2',4,4',5,5'-hexachlorobiphenyl (CB-153) are associated with 21 parameters of male reproductive function in 581 proven-fertile European and Greenlandic men. In Greenlandic men, AHR variants significantly modified the association between serum levels of both p,p'-DDE and CB-153 and inhibin B levels, sperm chromatin integrity, and seminal zinc levels. In the total cohort, interactions between AHRR variants and serum levels of CB-153 were associated with sperm chromatin integrity and the expression of the pro-apoptotic marker protein Fas. The data indicate that susceptibility to adverse effects of POP exposure on male reproductive function is dependent on polymorphisms in genes involved in AHR signalling. © 2014 Elsevier Inc.

Purpose: To evaluate whether manganese dipyridoxyl diphosphate (MnDPDP) or its metabolite manganese dipyridoxyl ethyldiamine (MnPLED) reduces post-ischemic myocardial injury. Material and Methods: Left anterior descending artery (LAD) in anesthetized pigs was occluded (30 min) followed by reperfusion (120 min) during hemodynamic monitoring and infarct assessment. Three μmol/kg MnDPDP, 1 μmol/kg MnPLED (or a mixture of both) or saline was injected i.v. 10 min before reperfusion followed by infusion of either 3 μmol/kg/h MnDPDP, 1 μmol/kg/h MnPLED (or a mixture of both) or saline. The plasma concentrations of MnDPDP, MnPLED and other metabolites (e.g., ZnDPDP and ZnPLED) were analyzed. Results: Femoral blood flow was reduced by 60% during early reperfusion in controls, whereas only 23 and 31% reductions were seen in animals treated with MnDPDP and MnPLED. During that time, +LV/dP and -LV/dP (maximum rate of left ventricular isovolumic contraction and relaxation, respectively), systolic pressure and diastolic pressure fell significantly less in animals treated with MnDPDP or MnPLED. Three out of 5 control animals experienced ventricular fibrillation (VF) during reperfusion, whereas VF was not seen in any of the pigs treated with MnPLED or/and MnDPDP. The infarct sizes in saline- and MnPLED-treated animals were 39±6 and 16±5%, respectively, of the occluded areas. MnDPDP did not reduce the infarct size. A mixture of MnDPDP and MnPLED significantly reduced infarct size (10±4%). When reperfusion started and throughout reperfusion, almost all injected MnDPDP was present as Zn-metabolites. Conclusion: MnPLED seems to reduce reperfusion-induced cardiac dysfunction and infarct size in pigs. MnDPDP does not reduce infarct size in the pig, probably because of the rapid exchange of Mn2+ for Zn2+ taking place in the pig.

Purpose: Evaluation of the tissue distribution of manganese (Mn) and general safety in normal and cholestatic male beagle dogs after i.v. administration of mangafodipir trisodium (MnDPDP, Teslascan). Material and Methods: Male beagle dogs, with or without surgical obstruction of the common bile duct, received a single i.v. bolus injection of saline (control), or MnDPDP at doses of 10 or 50 μmol/kg b.w. and were sacrificed 1 or 7 days after treatment. Tox-icity was assessed and tissue concentrations of Mn were measured. Results: Increased tissue Mn concentrations were found in all dogs treated with MnDPDP and were greatest in those with biliary obstruction. Although Mn concentrations decreased with time in most tissues in each of the treated groups, this was not the case for the brain and adrenal glands in dogs with total biliary obstruction in which further increases in Mn concentrations were seen at the later time point. This suggested a re-distribution of Mn from the major body depots such as the liver. There were no effects of MnDPDP on clinical sign/behaviour, organ weights, histomorphology or clinical biochemistry. Conclusion: These findings indicate that a single clinical dose of 5 μmol/kg MnDPDP is likely to be well tolerated in patients with cholestasis.

Manganese(II) dipyridoxyl diphosphate (MnDPDP) is the active component of mangafodipir trisodium injection (Teslascan), a new contrast medium for magnetic resonance imaging. A high performance liquid chromatography (HPLC) method was developed for the simultaneous determination of MnDPDP and its five major metabolites in human plasma, i.e. the dephosphorylation products MnDPMP (manganese(II) dipyridoxyl monophosphate) and MnPLED (manganese(II) dipyridoxyl ethylenediamine diacetate) and the corresponding substances obtained after transmetallation with zinc (ZnDPDP, ZnDPMP and ZnPLED). Heparinized blood samples from patients receiving mangafodipir trisodium injection were immediately mixed with solid trisodium phosphate dodecahydrate to obtain pH 10.0 +/- 0.2 in order to inhibit further in vitro dephosphorylation and transmetallation. The plasma thus obtained was ultrafiltrated prior to HPLC analysis. The chromatographic separation was obtained using a mixed-bed resin with both anion exchange and reversed-phase functions (OmniPac PAX-500) using isocratic elution and UV detection at 310 nm. With an injection volume of 50 microliters, the limit of quantitation (LOQ) values were 0.8-2.3 microM for the Mn compounds and 0.1-0.8 microM for the Zn compounds. The between-run accuracy of spiked plasma samples was in the range 97.5-106.7% with a precision in the range 3.1-9.0%. The best fit calibration curves were obtained using non-linear regression according to the equation Y = A + BXM in the concentration range from LOQ to 100 microM. Long-term storage of spiked plasma samples for three months at -20 degrees C demonstrated the required stability with recovery values within 85-115% of MnDPDP and its five metabolites.

Purpose: To study the metabolism and pharmacokinetics of mangafodipir trisodium injection, 0.01 mmol/ml (Teslascan), in healthy male volunteers. Material and Methods: Eight volunteers received mangafodipir trisodium as an infusion over 20 min, and 5 received it as an injection (≤ min). Both groups received 5 and 10 μmol/kg b.w. with a wash-out period of 3 weeks between doses. Metabolites were measured in plasma, total manganese and zinc were measured in plasma and urine and total manganese was measured in faeces. Results: The parent compound MnDPDP (manganese dipyridoxyl diphosphate) and 5 metabolites; MnDPMP (manganese dipyridoxyl monophosphate), MnPLED (manganese dipyridoxyl ethylenediamine) and the corresponding zinc compounds ZnDPDP, ZnDPMP and ZnPLED, were detected in plasma. ZnPLED was the only detectable metabolite 8 h after dosing. The apparent volume of distribution of manganese exceeded the interstitial body fluids. The volume of distribution of the ligand indicated distribution to the extracellular fluid only, with the plasma clearance close to the glomerular filtration rate. The manganese was incompletely excreted during the 4 days after treatment with the major part in faeces and less than 20% of the dose in the urine. Conclusion: Dephosphorylation and simultaneous transmetallation with zinc are the main metabolic pathways of MnDPDP in man.

Does moderate alcohol intake affect menstrual cycle characteristics among women in the Danish population?Levels of alcohol exposure as seen in this study do not substantially affect the menstrual cycle.Animal studies indicate alcohol-induced disruptions of the reproductive system, but previous epidemiological studies addressing the possible association between alcohol intake and the menstrual cycle are sparse.A cross-sectional study with retrospectively collected data including 82 146 pregnant Danish women in the Danish National Birth Cohort (DNBC) enrolled during the years 1996-2002.Information on weekly alcohol consumption and menstrual cycle characteristics before pregnancy was obtained through a computer-assisted telephone interview in pregnancy Week 12-16. The associations between weekly alcohol consumption and menstrual cycle irregularity (≥7 days difference between cycles) and length (short cycle: ≤24 days, long cycle: ≥32 days) were analysed using logistic regression with weekly alcohol intake categorized into abstainers (0 drinks per week), low (0.5-2.0 drinks per week), moderate (2.5-14.0 drinks per week) and high (14.0-86.5 drinks per week). Estimates are given as adjusted odds ratios with 95% confidence intervals.The overall participation rate was 60% of the women invited. We found that a high weekly alcohol consumption was not associated with menstrual cycle disturbances. We observed higher odds of irregular and short cycles among abstainers when compared with women with a low weekly alcohol consumption, but found no trend of more cycle disturbances with higher alcohol consumption.Possible limitations in our study include a risk of selection bias due to the moderate participation rate and the use of retrospective information on alcohol exposure and menstrual cycle characteristics before getting pregnant. The higher odds of irregular and short cycles among abstainers may reflect other health problems in these women rather than an actual effect of alcohol on the menstrual cycle.The generalizability of the study results is restricted to women who manage to conceive and women who do not use oral contraceptives within 2 months before getting pregnant. This study suggests that the menstrual cycle is not substantially affected by higher alcohol consumption among the participating women.Supported by a scholarship from Aarhus University Research Foundation. The Danish National Research Foundation has established the Danish Epidemiology Science Centre that initiated and created the DNBC. The cohort is furthermore a result of a major grant from this Foundation. Additional support for the DNBC is obtained from the Pharmacy Foundation, the Egmont Foundation, the March of Dimes Birth Defects Foundation, the Augustinus Foundation and the Health Foundation. No conflict of interest declared.

Does perfluorooctane sulfonate (PFOS) and perfluorooctanate (PFOA) exposure disrupt the menstrual cyclicity?The female reproductive system may be sensitive to PFOA exposure, with longer menstrual cycle length at higher exposure.PFOS and PFOA are persistent man-made chemicals. Experimental animal studies suggest they are reproductive toxicants but epidemiological findings are inconsistent.A cross-sectional study including 1623 pregnant women from the INUENDO cohort enrolled during antenatal care visits between June 2002 and May 2004 in Greenland, Poland and Ukraine.Information on menstrual cycle characteristics was obtained by questionnaires together with a blood sample from each pregnant woman. Serum concentrations of PFOS and PFOA were measured by liquid chromatography tandem mass spectrometry. Multiple imputations were performed to account for missing data. The association between PFOS/PFOA and menstrual cycle length (short cycle: ≤24 days, long cycle: ≥32 days) and irregularities (≥7 days in difference between cycles) was analyzed using logistic regression with tertiles of exposure. Estimates are given as adjusted odds ratios (ORs) with 95% confidence intervals (CIs).Higher exposure levels of PFOA were associated with longer menstrual cycles in pooled estimates of all three countries. Compared with women in the lowest exposure tertile, the adjusted OR of long cycles was 1.8 (95% CI: 1.0; 3.3) among women in the highest tertile of PFOA exposure. No significant associations were observed between PFOS exposure and menstrual cycle characteristics. However, we observed a tendency toward more irregular cycles with higher exposure to PFOS [OR 1.7 (95% CI: 0.8; 3.5)]. The overall response rate was 45.3% with considerable variation between countries (91.3% in Greenland, 69.1% in Poland and 26.3% in Ukraine).Possible limitations in our study include varying participation rates across countries; a selected study group overrepresenting the most fertile part of the population; retrospective information on menstrual cycle characteristics; the determination of cut-points for all three outcome variables; and lacking information on some determinants of menstrual cycle characteristics, such as stress, physical activity, chronic diseases and gynecological disorders, thus confounding cannot be excluded.The generalizability of the study results is restricted to fertile women who manage to conceive and women who do not use oral contraceptives when getting pregnant or within 2 months before getting pregnant. To our knowledge only one previous epidemiological study has addressed the possible association between perfluorinated chemical exposure and menstrual disturbances. Though pointing toward different disturbances in cyclicity, both studies suggest that exposure to PFOA may affect the female reproductive function. This study contributes to the limited knowledge on effects of exposure to PFOA and PFOS on female reproductive function and suggests that the female reproductive system may be affected by environmental exposure to PFOA.Supported by a scholarship from Aarhus University Research Foundation. The collection of questionnaire data and blood samples was part of the INUENDO project supported by The European Commission (Contract no. QLK4-CT-2001-00 202), www.inuendo.dk. The Ukrainian part of the study was possible by a grant from INTAS (project 012 2205). Determination of PFOA and PFOS in serum was part of the CLEAR study (www.inuendo.dk/clear) supported by the European Commission's 7th Framework Program (FP7-ENV-2008-1-226217). No conflict of interest declared.

Perfluoroalkyl substances (PFASs) are widely used in a variety of industrial processes and products, and have been detected globally in humans and wildlife. PFASs are suspected to interfere with endocrine signaling and to adversely affect human reproductive health. The aim of the present study was to investigate the associations between exposure to PFASs and sperm global methylation levels in a population of non-occupationally exposed fertile men. Measurements of PFASs in serum from 262 partners of pregnant women from Greenland, Poland and Ukraine, were also carried out by liquid chromatography tandem mass spectrometry. Perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS), and perfluorononanoic acid (PFNA) were detected in 97% of the blood samples. Two surrogate markers were used to assess DNA global methylation levels in semen samples from the same men: (a) average DNA methylation level in repetitive DNA sequences (Alu, LINE-1, Satα) quantified by PCR-pyrosequencing after bisulfite conversion; (b) flow cytometric immunodetection of 5-methyl-cytosines. After multivariate linear regression analysis, no major consistent associations between PFASs exposure and sperm DNA global methylation endpoints could be detected. However, since weak but statistically significant associations of different PFASs with DNA hypo- and hyper-methylation were found in some of the studied populations, effects of PFASs on sperm epigenetic processes cannot be completely excluded, and this issue warrants further investigation.

International audience; There are emerging concerns about potential effects on child health and development of early-life exposure to substances such as brominated flame retardants (BFRs), perfluorinated compounds (PFCs), phthalates and phenols (including bisphenol A (BPA)); pregnancy and birth cohort studies are ideally designed to study such concerns prospectively. As part of the ENRIECO project, we evaluated existing human biomonitoring data for these substances in European birth cohorts and develop recommendations for more harmonized methods that will enable combination and comparison of cohort data in the future. The ENRIECO inventory shows that 20 European birth cohorts have measured or are measuring BFRs (N=10), PFCs (N=11), phthalates (N=16) or phenols (N=8). Generally, samples were collected prenatally or at birth and measurements involved few subjects in each cohort (a few hundred maximum). Biological matrices, timing, and analytical methods of the measurements varied between cohorts. Few cohorts have measured at multiple time points or in children. In European cohorts, levels of BFRs were very low and at least 10-fold lower than in US; levels of PFCs and phthalates have decreased over the last decade since the phasing out of certain of these compounds; concentrations of phenols are comparable to those in the US. Although there is little published data in the cohorts now, many measurements are ongoing and we recommend that cohorts start working towards combined and comparison studies. Specific recommendations for use of existing data include the development of conversion models for the different media used for measurement of persistent chemicals, and inter-laboratory comparisons and calibrations. Recommendations for further data collection include more evaluation of exposure to these chemicals in children; repeated measurements of non-persistent chemicals; validation and harmonisation of questionnaires; and the development of mechanisms for fast European birth cohort response for the detection and prioritisation of new chemicals of concern.

Recently the dogma that there is an inverse linear association between androgen receptor (AR) CAG and GGN polymorphisms and receptor activity has been challenged. We analysed the pattern of association between 21 male reproductive phenotypes and AR CAG/GGN repeat lengths in 557 proven-fertile men.A linear association was only found between sperm DNA fragmentation index (DFI) and CAG length, and between inhibin B and GGN length. Men with longer CAG then the reference (22-24), had higher oestradiol levels, whereas men with shorter CAG stretches had a higher DFI and a higher proportion of Fas-positive germ cells. Subjects with either short or long CAG had increased seminal levels of prostate-specific antigen and neutral α-glucosidase activity. Compared to men with the median GGN length of 23, those with shorter GGN repeats had higher levels of inhibin B, higher proportions of normal and progressive sperm, and a higher fraction of Fas-positive sperm, while men with longer GGN had higher oestradiol levels.These data indicate that at least for some markers of male reproductive function the association with CAG or GGN repeat length is curvilinear. © 2013 Elsevier Ireland Ltd.

Environmental exposures during pregnancy and early life may have adverse health effects. Single birth cohort studies often lack statistical power to tease out such effects reliably. To improve the use of existing data and to facilitate collaboration among these studies, an inventory of the environmental exposure and health data in these studies was made as part of the ENRIECO (Environmental Health Risks in European Birth Cohorts) project. The focus with regard to exposure was on outdoor air pollution, water contamination, allergens and biological organisms, metals, pesticides, smoking and second hand tobacco smoke (SHS), persistent organic pollutants (POPs), noise, radiation, and occupational exposures. The review lists methods and data on environmental exposures in 37 European birth cohort studies. Most data is currently available for smoking and SHS (N=37 cohorts), occupational exposures (N=33), outdoor air pollution, and allergens and microbial agents (N=27). Exposure modeling is increasingly used for long-term air pollution exposure assessment; biomonitoring is used for assessment of exposure to metals, POPs and other chemicals; and environmental monitoring for house dust mite exposure assessment. Collaborative analyses with data from several birth cohorts have already been performed successfully for outdoor air pollution, water contamination, allergens, biological contaminants, molds, POPs and SHS. Key success factors for collaborative analyses are common definitions of main exposure and health variables. Our review emphasizes that such common definitions need ideally be arrived at in the study design phase. However, careful comparison of methods used in existing studies also offers excellent opportunities for collaborative analyses. Investigators can use this review to evaluate the potential for future collaborative analyses with respect to data availability and methods used in the different cohorts and to identify potential partners for a specific research question. This work was supported by ENRIECO (Environmental Health Risks in European Birth Cohorts), a project conducted within the European Union's 7th Framework Programme (Theme 6, Environment (Including Climate Change)) [Grant agreement number: 226285]

Several animal studies indicate that mercury is a male reproductive toxicant, but human studies are few and contradictory. We examined semen characteristics and serum levels of reproductive hormones in relation to environmental exposure to mercury. Blood and semen samples were collected from 529 male partners of pregnant women living in Greenland, Poland and Ukraine between May 2002 and February 2004. The median concentration of the total content of mercury in whole blood was 9.2 ng ml(-1) in Greenland (0.2-385.8 ng ml(-1)), 1.0 ng ml(-1) in Poland (0.2-6.4 ng ml(-1)) and 1.0 ng ml(-1) in Ukraine (0.2-4.9 ng ml(-1)). We found a significantly positive association between the blood levels of mercury and serum concentration of inhibin B in men from Greenland (β=0.074, 95% confidence interval (CI)=0.021 to 0.126) and in an analysis including men from all three regions (β=0.067, 95% CI=0.024 to 0.110). The association may be due to beneficial effects of polyunsaturated fatty acids (PUFAs), which are contained in seafood and fish. No significant association (P>0.05) was found between blood concentrations of mercury and any of the other measured semen characteristics (semen volume, total sperm count, sperm concentration, morphology and motility) and reproductive hormones (free androgen index (FAI), follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone and LH×testosterone) in any region. In conclusion, the findings do not provide evidence that environmental mercury exposure in Greenlandic and European men with median whole blood concentration up to 10 ng ml(-1) has adverse effects on biomarkers of male reproductive health.Asian Journal of Andrology advance online publication, 10 December 2012; doi:10.1038/aja.2012.121.

Objectives Pregnant hairdressers may be exposed to a mixture of chemicals in their working environment. The possible relationship between these chemical agents and male reproductive tract malformations has raised concern that the working environment of hairdressers might have adverse effects on fetal development. This study assessed the risk of cryptorchidism and hypospadias among boys of maternal hairdressers. Methods National population-based registers were used to determine maternal occupation and identify cases of cryptorchidism and hypospadias. The cohort comprised all children born in Denmark from 1980–2007. Using Cox regression, we estimated hazard ratios (HR) with 95% confidence intervals (95% CI) for hospitalization for cryptorchidism and hypospadias from 1980–2009. Results Boys of hairdressers were not at increased risk of cryptorchidism (134 cases, HR 0.91; 95% CI 0.77–1.08) or hypospadias (33 cases, HR 1.27; 95% CI 0.90–1.79) compared to children of mothers in other occupations (14 988 and 2556 cases of cryptorchidism and hypospadias, respectively). Additional analyses using children of shop assistants and receptionists as controls and restricted to (i) firstborns, (ii) cryptorchidism cases with corrective surgery, (iii) specific birth years, and (iv) women without social benefit payments in gestational weeks 8–14 produced consistent results of no increased risk. Conclusion Our nationwide cohort study shows that, despite exposure to a complex chemical milieu, hairdressers do not have an increased risk of having boys with cryptorchidism and hypospadias.

STUDY QUESTION: Does in utero exposure to constituents of cigarette smoke have a programming effect on daughters' age of menarche and markers of long-term reproductive health? SUMMARY ANSWER: In utero exposure to constituents of cigarette smoke was associated with earlier age of menarche and--to a lesser extent--changes in the testosterone profile of the young women. WHAT IS KNOWN ALREADY: Studies observe potential effects of in utero exposure to constituents of cigarette smoke on the intrauterine formation of female gonads, but the consequences on long-term reproductive health in daughters remain unclear. STUDY DESIGN, SIZE AND DURATION: A prospective cohort study was designed using data from 965 pregnant women enrolled prior to a routine 30th-week antenatal examination at a midwifery practice in Denmark from 1988 to 1989 and a follow-up of their 19-21-year-old daughters in 2008. PARTICIPANTS/MATERIALS, SETTING AND METHODS: The pregnant women provided information on lifestyle factors during pregnancy, including the exact number of cigarettes smoked per day during the first and the second trimesters. A total of 438 eligible daughters were asked to complete a web-based questionnaire on reproductive health and subsequently invited to participate in a clinical examination during 2008. Of the 367 daughters (84%) who answered the questionnaire, 267 (61%) agreed to further examination. Information on menstrual pattern was provided at examination, blood samples were drawn to be analyzed for serum levels of reproductive hormones [FSH, LH, estradiol (E(2)), sex hormone-binding globulin, anti-Müllerian hormone, dehydroepiandrosterone-sulphate (DHEAS), free testosterone and free E(2)] and number of follicles (2-9 mm) were examined by transvaginal ultrasound. The daughters were divided into three exposure groups according to the level of maternal smoking during first trimester [non-exposed (reference), low-exposed (mother smoking >0-9 cigarettes/day) and high-exposed (mother smoking ≥ 10 cigarettes/day)]. Data were analyzed by multiple regression analyses in which we adjusted for potential confounders. Both crude and adjusted test for trend were carried out using maternal smoking during the first trimester as a continuous variable. MAIN RESULTS AND THE ROLE OF CHANCE: We observed an inverse association between in utero exposure to constituents of cigarette smoke and age of menarche (P = 0.001). Daughters exposed to >0-9 cigarettes/day debuted with -2.7 [95% confidence interval (CI) -5.2 to -0.1] percentage earlier age of menarche, whereas daughters exposed to ≥ 10 cigarettes/day had -4.1 (95% CI: -6.6 to -1.5) percentage earlier age of menarche corresponding to 6.5 (95% CI: -10.7 to -2.2) months. There was a non-significant tendency towards lower levels of testosterone and DHEAS with increasing in utero exposure to constituents of cigarette smoke but no associations with follicle number, cycle length or serum levels of the other reproductive hormones were observed. LIMITATIONS AND REASONS FOR CAUTION: We collected information on age of menarche retrospectively but the recall time was relatively short (2-10 years) and the reported values were within the normal range of Caucasians. Analyses of reproductive hormones are presented only for the group of daughters who were non-users of hormonal contraceptives because users were excluded, leaving only a low number of daughters available for the analyses (n = 75), as reflected in the wide CIs. The analyses of hormones were further adjusted for menstrual phase at time of clinical examination (follicular, ovulation and luteal phase) because blood samples were not collected on a specific day of the menstrual cycle. WIDER IMPLICATIONS OF THE FINDINGS: This study supports the limited evidence of an inverse association between maternal smoking during pregnancy and age of menarche and further addresses to what extent reproductive capacity and hormones may be programmed by maternal smoking during pregnancy. A trend toward earlier maturation of females is suggested to have implications on long-term reproductive function. STUDY FUNDING/COMPETING INTEREST(S): Supported by a scholarship from The Lundbeck Foundation (R93-A8476). No conflict of interest declared.

This study investigated whether perfluorooctanoic acid (PFOA) and perfluorooctanesulfonate (PFOS), which exhibit reproductive toxicity in experimental animals, affect sperm sex chromosome ratio. The Y:X ratio was determined by fluorescence in situ hybridization. Serum concentrations of PFOA and PFOS were measured in 607 men from Greenland, Poland and Ukraine using liquid chromatography-tandem mass spectrometry. Data was analyzed by linear and nonlinear regression. We observed no associations between PFOA and Y:X ratio (p=0.845 in a linear model, p=0.296 in a nonlinear model). A positive nonlinear association between PFOS and Y:X ratio was observed (p=0.016), with no association in a linear model (p=0.118). Analyzing the populations separately, a negative trend between categorized PFOS exposure and Y:X ratio was observed for the Inuit (B=-0.002, p=0.044). In conclusion, there was a negative trend between Y:X ratio and PFOS in the Inuit, while there was no association between PFOA and the Y:X ratio in adult men.

Aim To investigate whether sons of gardeners and building painters have increased risk of infertility in comparison with sons of bricklayers, carpenters and electricians. Methods Participants were men born 1965–1984 in Denmark whose fathers the year before birth had worked as gardeners, painters, bricklayers, carpenters or electricians ( N = 22,978). Cases of infertility were identified by Danish registers, and participants were followed-up for up to 24 years after their 20th birthday. Results Sons of gardeners did not have increased risk of infertility. Hazard ratios for sons of painters fluctuated around the null in main analyses but were 1.6 (98% CI: 1.0–2.5) and 1.7 (95% CI: 0.9–3.2) in the subset of participants with smallest risk of paternal exposure misclassification. Conclusions Working as gardener or building painter was not related to increased risk of infertility among the next generation of males in main analyses. However, inherent limitations in data may have attenuated true associations.

Perfluoroalkyl substances (PFASs) can interfere with male reproductive function, but evidence in humans is limited. Six hundred four fertile men (199 from Greenland, 197 from Poland and 208 from Ukraine) were enrolled in the study. We measured four PFASs in serum (PFOS, PFOA, PFNA and PFHxS) and concurrent DNA damage in spermatozoa by sperm chromatin structure assay (SCSA) and in situ terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay, apoptotic markers in semen (Fas-receptor and Bcl-xL), and reproductive hormones in serum. No association between PFASs and SCSA, apoptotic markers or reproductive hormones emerged. We observed a slight increase in SHBG and TUNEL-positivity with increased PFOA exposure in men from Greenland. Thus, consistent evidence that PFAS exposure interferes with sperm DNA fragmentation, apoptosis or reproductive hormones was not found.

BACKGROUND: Measures of prenatal environmental exposures are important, and amniotic fluid levels may directly reflect fetal exposures during hypothesized windows of vulnerability. OBJECTIVES: We aimed to detect various phthalate metabolites and perfluorooctanesulfonic acid (PFOS) in human amniotic fluid, to study temporal exposure trends, and to estimate potential associations with gestational week of amniocentesis and maternal age and parity at amniocentesis. METHODS: We studied 300 randomly selected second-trimester amniotic fluid samples from a Danish pregnancy-screening biobank covering 1980 through 1996. We used only samples from male offspring pregnancies. We assayed the environmental pollutants by liquid chromatography/triple quadrupole mass spectrometry and analyzed data using generalized linear regression models. RESULTS: We detected the di(2-ethylhexyl) phthalate (DEHP) metabolite mono(2-ethyl-5-carboxypentyl) phthalate (5cx-MEPP) at a median concentration of 0.27 ng/mL [interquartile range (IQR): 0.20-0.37 ng/mL], the diisononyl phthalate (DiNP) metabolite mono(4-methyl-7-carboxyheptyl) phthalate (7cx-MMeHP) at 0.07 ng/mL (IQR: 0.05-0.11 ng/mL), and PFOS at 1.1 ng/mL (IQR: 0.66-1.60 ng/mL). An increase of 1 calendar year was associated with 3.5% lower [95% confidence interval (CI): -4.8%, -2.1%] 5cx-MEPP levels and with 7.1% higher (95% CI: 5.3%, 9.0%) 7cx-MMeHP levels. For each later gestational week of amniocentesis, 5cx-MEPP was 9.9% higher (95% CI: 4.8%, 15.2%), 7cx-MMeHP was 8.6% higher (95: CI: 2.7%, 14.9%), and PFOS was 9.4% higher (95: CI: 3.3%, 15.9%). We observed no associations with maternal age or parity. CONCLUSIONS: Measured metabolite levels appeared to parallel decreasing DEHP exposure and increasing DiNP exposure during the study period. The environmental pollutant levels were positively associated with later gestational age at amniocentesis during pregnancy weeks 12-22. (Less)

Background Androgens are crucial for normal testicular descent. Studies show that some pesticides have estrogenic or antiandrogenic effects, and that female workers exposed to pesticides have increased risk of having a boy with cryptorchidism. The main objective of the present study was to investigate whether pregnant women exposed to pesticides due to their work in horticulture experience excess risk of having sons with cryptorchidism. Methods We conducted a cohort study of pregnant women working in horticulture using four cohorts including one cohort established with data from the departments of occupational medicine in Jutland and Funen and three existing mother-child cohorts (n = 1,468). A reference group was established from the entire Danish population of boys born in the period of 1986-2007 (n = 783,817). Nationwide Danish health registers provided information on birth outcome, cryptorchidism diagnosis and orchiopexy. The level of occupational exposure to pesticides was assessed by expert judgment blinded towards outcome status. Risk of cryptorchidism among exposed horticulture workers compared to the background population and to unexposed horticulture workers was assessed by Cox regression models. Results Pesticide exposed women employed in horticulture had a hazard ratio (HR) of having cryptorchid sons of 1.39 (95% CI 0.84; 2.31) and a HR of orchiopexy of 1.34 (0.72; 2.49) compared to the background population. Analysis divided into separate cohorts revealed a significantly increased risk of cryptorchidism in cohort 2: HR 2.58 (1.07;6.20) and increased risk of orchiopexy in cohort 4: HR 2.76 (1.03;7.35), but no significant associations in the other cohorts. Compared to unexposed women working in horticulture, pesticide exposed women had a risk of having sons with cryptorchidism of 1.34 (0.30; 5.96) and of orchiopexy of 1.93 (0.24;15.4). Conclusions The data are compatible with a slightly increased risk of cryptorchidism in sons of women exposed to pesticides by working in horticulture.

Background and Aims: The overall objective of the multi-center CLEAR project is to investigate the possible impact of climate change on human exposure to environmental contaminants and their impact...

Background and Aims: There are emerging concerns about potential effects on child health and development of early-life environmental exposure to substances such as brominated flame retardants (BFRs...

Background and Aims: Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) are man-made compounds found globally in humans. They are suspected to act as endocrine disrupters and since ...

Background and aims: Animal studies indicate that some phthalate metabolites may harm female reproductive function. The main objectives was to investigate associations between exposure to phthalate...

Objective To investigate the association between serum antimullerian hormone (AMH) and other reproductive parameters in young women. Design Cross-sectional study. Setting University hospital. Patient(s) Population-based cohort of 256 women: 180 were users and 76 were nonusers of hormonal contraceptives. Intervention(s) None. Main Outcome Measure(s) Antral follicles, androgens, age at menarche, and duration and regularity of menstrual cycle. Result(s) AMH levels were lower among users of hormonal contraceptives compared to nonusers. Among nonusers, women with AMH levels in the upper tertile had 55% (95% confidence interval [CI]: 22%–99%) higher levels of total T and 8% (95% CI=2%–15%) longer menstrual cycles than women with AMH levels in the lower tertile. An increase of 1 ng/mL in AMH was associated with 45% (95% CI=6%–97%) higher prevalence of irregular menstrual cycles. These associations were not seen among users of hormonal contraceptives. A strong relationship between AMH and follicle number was found in both users and nonusers. Conclusion(s) AMH measurements were found to be applicable in evaluation of the reproductive function of young women. However, there may be differences in the way that serum AMH levels can be interpreted depending on whether the woman uses hormonal contraceptives or not.

DDT (dichlorodiphenyltrichloroethane) is an insecticide that was used worldwide in agriculture and for malaria vector control from the 1940s until its ban in many countries in 1970 and in subsequent years, mainly due to its biopersistence and adverse ecological effects. The main components of commercial DDT are its isomers (85%), although dichlorodiphenyldichloroethylene (DDE) and dichlorodiphenyldichloroethane (DDD) are present in small amounts. It has been demonstrated in several in vitro and in vivo studies that the DDT compounds have the potential to interfere with hormonal homeostasis, which has raised concern that the compound impacts human health. o,p′-DDT, which constitutes 15–20% of DDT, and to a lesser extent p,p′-DDT and o,p′-DDE are mimicking the action of the natural ligand, 17-β-estradiol, whereas p,p′-DDE, the main metabolite in living organisms, is antagonizing the natural action of androgens. There have been few studies investigating DDT effects on male reproductive function, but the evidence shows that men living in endemic malaria areas where DDT is still sprayed may have impaired reproductive function. Exposure to DDT has also been linked to early onset of puberty in girls, reduced or increased fertility among daughters, increased risk of spontaneous abortions, premature delivery, small-for-gestational age, and low birth weight, but generally, findings have not been consistent. For instance, an analysis of some 2400 children in the US Collaborative Perinatal Study found a highly significant steadily increasing risk for preterm birth with increasing DDE blood concentration above 10 ppb. Finally, there are reports linking blood DDE or measures of DDT body burden in adults with premature menopause, disturbance of menstrual cycle in terms of reduced luteal cycle length, and delayed conception as a measure of reduced fecundity.

Approximately 20% of all couples trying to become pregnant are not succeeding within the first year, and the proportion of children born after in vitro fertilization has risen. Whether the poor fertility can be prevented is a major issue that has been given considerable attention in the recent years. Several hypotheses for the apparent poor fertility have been put forward including lifestyle, such as smoking and obesity, occupational and environmental factors including chemicals with endocrine activity. None of these factors have had a major impact on the poor fertility although the available studies indicate that they all seem to contribute to some degree to fertility problems.

The purpose of this study was to investigate whether a nurse-led telephone session with patients suffering from breast cancer approximately ten days after final radiotherapy treatment affected their quality of life two to four weeks after radiotherapy. The study was conducted at the Radiotherapy ward at Vejle Hospital, Denmark between January and May 2010. The study population consisted of 100 patients, who were randomized with a 1:1 ratio to have either ordinary supportive conversations (control group), or ordinary supportive conversations and a supplementary nurse-led telephone session (intervention group). The quality of life was assessed using the questionnaires EORTC QLQ-C30 and EORTC QLQ-BR23. For statistical comparison of quality of life and for adjustment for covariates, multiple linear regression analysis was conducted. The mean [95 % CI] quality of life was 72.0 [66.4-77.6] in the control group and 69.9 [64.3-75.2] in the intervention group. Adjustment for covariates did not change the estimates. No statistically significant differences were found in the groups in either of the analyses. The nurse-led telephone session had no positive effect on the quality of life of patients with breast cancer two to four weeks after their final radiotherapy.

Background Sex hormones closely regulate development of the male genital organs during fetal life. The hypothesis that xenobiotics may disrupt endogenous hormonal signalling has received considerable scientific attention, but human evidence is scarce. Objectives We analyse occurrence of hypospadias and cryptorchidism according to maternal and paternal occupational exposure to possible endocrine disrupting chemicals. Methods We conducted a follow-up study of 45,341 male singleton deliveries in the Danish National Birth Cohort during 1997-2009. Information on work during pregnancy was obtained by telephone interviews around gestational week 16. Parents' job titles were classified according to DISCO-88. A job exposure matrix for endocrine disrupting chemicals (EDCs) was implemented to assess occupational exposures. The Medical Birth and National Hospital Register provided data on congenital anomalies diagnosed at birth or during follow-up, which ended in 2009. Crude and adjusted hazard ratios (HR) were obtained from Cox regression models. Results Among all pregnancies, 6.3% were classified as possibly or probably exposed to EDCs. The most prevalent occupations conferring possible exposure were cleaners, laboratory technicians, hairdressers and agricultural workers (58% of all potentially exposed). The final cumulative incidence of cryptorchidism in boys was 2.2% (1002 cases), and of hypospadias 0.6% (262 cases). The occurrence of hypospadias increased when mothers were probably [HRa = 1.8 (95% CI 1.0-2.6)] or possibly exposed to one or more EDCs [HRa = 2.6 (95% CI 1.8-3.4). Possible paternal exposure to heavy metals increased the risk of hypospadias [HRa 2.2 (95% CI: 1.0-3.4)] and cryptorchidism [HRa 1.9 (95% CI: 1.1-2.7)]. None of the exposure groups reached statistical significance. Conclusion The study provides some but limited evidence that occupational exposure to possible endocrine disrupting chemicals during pregnancy increases the risk of hypospadias.

The aim of the present study was to compare assessments of sperm concentration and sperm motility analysed by conventional semen analysis with those obtained by computer-assisted semen analysis (CASA) (Copenhagen Rigshospitalet Image House Sperm Motility Analysis System (CRISMAS) 4.6 software) using semen samples from 166 young Danish men. The CRISMAS software identifies sperm concentration and classifies spermatozoa into three motility categories. To enable comparison of the two methods, the four motility stages obtained by conventional semen analysis were, based on their velocity classifications, divided into three stages, comparable to the three CRISMAS motility categories: rapidly progressive (A), slowly progressive (B) and non-progressive (C+D). Differences between the two methods were large for all investigated parameters (P

background: According to the Rotterdam 2003 criteria, an ovary is defined as polycystic if 12 or more follicles of 2 –9 mm are present, when evaluating the ovary by ultrasonography on Days 3 –5 of the menstrual cycle in women not using hormonal contraceptives. The aim of this population-based study was to estimate the prevalence of polycystic ovaries (PCO) in a representative sample of young Danish women according to the Rotterdam criteria. methods: From a Danish pregnancy cohort established in 1988–1989, 267 (61%) young adult daughters agreed to participate in a clinical examination and 174 (40%) consented to vaginal ultrasound. Sufficient image quality in at least one ovary was obtained from 154 women. Both users and non-users of hormonal contraceptives were included and the examination was not restricted to a particular time of the menstrual cycle. results: The median (range) age was 20.1 (19.5 –21.0) years. The median follicle number per ovary was 14 (6 –30) and 12 or more follicles were counted in 104 of the 154 women. Thus, the prevalence was estimated to 68% [95% confidence interval (CI): 60– 74%]. PCO were present in 80% (95% CI: 65– 89%) of non-users (n ¼ 44) of hormonal contraceptives. Of the 104 women with PCO, 41% (95% CI: 32–51%) could be defined as having polycystic ovary syndrome. conclusions: A very large proportion of the young women had PCO according to the Rotterdam 2003 criteria. As the number of follicles is higher at a younger age, we believe the Rotterdam criteria should be revised, particularly to avoid misdiagnosis in this age group.