Anna Maria Andersson

Are Environmental Levels of Bisphenol A Associated with Reproductive Function in Fertile Men

Background Rodent and in vitro studies have demonstrated the estrogenicity of bisphenol A (BPA). However, few studies have examined the relationship between human exposure to BPA and male reproductive function. Objectives We investigated the relationships between environmental BPA exposure and reproductive parameters, including semen quality and male reproductive hormones, in prospectively recruited fertile men. Methods Participants (n = 375) were partners of pregnant women who participated in the Study for Future Families in four U.S. cities, and all of the men provided blood, semen, and urine samples. BPA was measured in urine. Serum samples were analyzed for reproductive hormones, including follicle-stimulating hormone, luteinizing hormone (LH), testosterone, inhibin B, estradiol, and sex hormone–binding globulin (SHBG), as well as the free androgen index (FAI). Semen analyses were performed according to World Health Organization criteria. Pearson correlations were used for unadjusted analyses, and multiple linear regression analyses were used to examine associations controlling for age, body mass index, smoking, ethnicity, urinary creatinine concentration, time of sample collection, and duration of abstinence. Results After multivariate adjustment, we observed no significant associations between any semen parameter and urinary BPA concentration. However, a significant inverse association was found between urinary BPA concentration and FAI levels and the FAI/LH ratio, as well as a significant positive association between BPA and SHBG. Conclusions Our results suggest that, in fertile men, exposure to low environmental levels of BPA may be associated with a modest reduction in markers of free testosterone, but any effects on reproductive function are likely to be small, and of uncertain clinical significance.

Male Reproductive Disorders, Diseases, and Costs of Exposure to Endocrine-Disrupting Chemicals in the European Union

INTRODUCTION Increasing evidence suggests that endocrine-disrupting chemicals (EDCs) contribute to male reproductive diseases and disorders. PURPOSE To estimate the incidence/prevalence of selected male reproductive disorders/diseases and associated economic costs that can be reasonably attributed to specific EDC exposures in the European Union (EU). METHODS An expert panel evaluated evidence for probability of causation using the Intergovernmental Panel on Climate Change weight-of-evidence characterization. Exposure-response relationships and reference levels were evaluated, and biomarker data were organized from carefully identified studies from the peer-reviewed literature to represent European exposure and approximate burden of disease as it occurred in 2010. The cost-of-illness estimation utilized multiple peer-reviewed sources. RESULTS The expert panel identified low epidemiological and strong toxicological evidence for male infertility attributable to phthalate exposure, with a 40-69% probability of causing 618,000 additional assisted reproductive technology procedures, costing €4.71 billion annually. Low epidemiological and strong toxicological evidence was also identified for cryptorchidism due to prenatal polybrominated diphenyl ether exposure, resulting in a 40-69% probability that 4615 cases result, at a cost of €130 million (sensitivity analysis, €117-130 million). A much more modest (0-19%) probability of causation in testicular cancer by polybrominated diphenyl ethers was identified due to very low epidemiological and weak toxicological evidence, with 6830 potential cases annually and costs of €848 million annually (sensitivity analysis, €313-848 million). The panel assigned 40-69% probability of lower T concentrations in 55- to 64-year-old men due to phthalate exposure, with 24 800 associated deaths annually and lost economic productivity of €7.96 billion. CONCLUSIONS EDCs may contribute substantially to male reproductive disorders and diseases, with nearly €15 billion annual associated costs in the EU. These estimates represent only a few EDCs for which there were sufficient epidemiological studies and those with the highest probability of causation. These public health costs should be considered as the EU contemplates regulatory action on EDCs.

Urinary Concentrations of Di(2-ethylhexyl) Phthalate Metabolites and Serum Reproductive Hormones: Pooled Analysis of Fertile and Infertile Men

Urinary concentrations of metabolites of the anti-androgenic xenobiotic di-(2-ethylhexyl) phthalate (DEHP) were previously shown to be weakly associated with serum levels of several hormones in 2 disparate US populations: partners of pregnant women participating in the Study for Future Families and partners in infertile couples from Massachusetts General Hospital infertility clinic. The observed associations between phthalate metabolites and reproductive hormones were robust and insensitive to the characteristics of the subpopulation or the laboratory in which the hormones were measured, despite the fact that these 2 populations span a range of fertility, urinary phthalate metabolites, and reproductive hormone levels. We therefore examined associations between urinary metabolites of DEHP and reproductive hormones-follicle-stimulating hormone, luteinizing hormone, testosterone (T), inhibin B, and estradiol (E(2))-and sex hormone-binding globulin (SHBG) in the pooled population. The magnitude of the associations seen were similar to those reported for each population separately, but effect estimates were more precise because of the increased sample size and the greater range of phthalate metabolite concentrations and hormone levels. Urinary concentrations of 3 metabolites of DEHP [mono(2-ethylhexyl) phthalate (MEHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), and mono(2-ethyl-5-oxohexyl) phthalate (MEOHP)] were inversely associated with the free androgen index (FAI = T/SHBG) and calculated free testosterone. Urinary concentrations of MEHHP and MEOHP were positively associated with SHBG, and MEHP was inversely associated with E(2). No other phthalate metabolites were associated with serum hormones, consistent with results in each population. Our results in this diverse population suggest that DEHP exposure is robustly associated with some male sex steroid hormones.

Alcohol and male reproductive health: a cross-sectional study of 8344 healthy men from Europe and the USA

STUDY QUESTION Is there an association between alcohol intake and semen quality and serum reproductive hormones among healthy men from the USA and Europe? SUMMARY ANSWER Moderate alcohol intake is not adversely associated with semen quality in healthy men, whereas it was associated with higher serum testosterone levels. WHAT IS KNOWN ALREADY High alcohol intake has been associated with a wide range of diseases. However, few studies have examined the correlation between alcohol and reproductive function and most have been conducted in selected populations of infertile men or have a small sample size and the results have been contradictory. STUDY DESIGN, SIZE, DURATION A coordinated international cross-sectional study among 8344 healthy men. A total of 1872 fertile men aged 18-45 years (with pregnant partners) from four European cities and four US states, and 6472 young men (most with unknown fertility) aged 18-28 years from the general population in six European countries were recruited. PARTICIPANTS/MATERIALS, SETTING, METHODS The men were recruited using standardized protocols. A semen analysis was performed and men completed a questionnaire on health and lifestyle, including their intake of beer, wine and liquor during the week prior to their visit. Semen quality (semen volume, sperm concentration, percentage motile and morphologically normal sperm) and serum reproductive hormones (FSH, LH, testosterone, sex hormone-binding globulin, and inhibin B and free testosterone) were examined. MAIN RESULTS AND THE ROLE OF CHANCE The participation rate for our populations was 20-30%. We found no consistent association between any semen variable and alcohol consumption, which was low/moderate in this group (median weekly intake 8 units), either for total consumption or consumption by type of alcohol. However, we found a linear association between total alcohol consumption and total or free testosterone in both groups of men. Young and fertile men who consumed >20 units of alcohol per week had, respectively, 24.6 pmol/l (95% confidence interval 16.3-32.9) and 19.7 pmol/l (7.1-32.2) higher free testosterone than men with a weekly intake between 1 and 10 units. Alcohol intake was not significantly associated with serum inhibin B, FSH or LH levels in either group of men. The study is the largest of its kind and has sufficient power to detect changes in semen quality and reproductive hormones. LIMITATIONS, REASONS FOR CAUTION The participation rate was low, but higher than in most previous semen quality studies. In addition, the study was cross-sectional and the men were asked to recall their alcohol intake in the previous week, which was used as a marker of intake up to 3 months before. If consumption in that week differed from the typical weekly intake and the intake 3 months earlier, misclassification of exposure may have occurred. However, the men were unaware of their semen quality when they responded to the questions about alcohol intake. Furthermore, we cannot exclude that our findings are due to unmeasured confounders, including diet, exercise, stress, occupation and risk-taking behavior. WIDER IMPLICATIONS OF THE FINDINGS Our study suggests that moderate alcohol intake is not adversely associated with semen quality in healthy men, whereas it was associated with higher serum testosterone levels which may be due to a changed metabolism of testosterone in the liver. Healthy men may therefore be advised that occasional moderate alcohol intake may not harm their reproductive health; we cannot address the risk of high alcohol consumption of longer duration or binge drinking on semen quality and male reproductive hormones. STUDY FUNDING/COMPETING INTERESTS All funding sources were non-profitable and sponsors of this study played no role in the study design, in data collection, analysis, or interpretation, or in the writing of the article. The authors have no conflicts of interest.

Serum inhibin-b in fertile men is strongly correlated with low but not high sperm counts: a coordinated study of 1,797 European and US men

OBJECTIVE To describe associations between serum inhibin-b and sperm counts, adjusted for effect of time of blood sampling, in larger cohorts than have been previously reported. DESIGN Cross-sectional studies of spermatogenesis markers. SETTING Four European and four US centers. PATIENT(S) Fertile men (1,797) were included and examined from October 1996-February 2005. INTERVENTION(S) The study was observational and therefore without any intervention. MAIN OUTCOME MEASURE(S) Associations between inhibin-b and semen variables controlled for time of blood sampling and other covariates. RESULT(S) Inhibin-b decreased about 2.00% per hour from 8 am-12 pm and then about 3.25% per hour from 12 pm-4 pm. There was a strong positive association between inhibin-b levels less than 150 pg/mL and both sperm concentration and total sperm count (slopes of the regression lines were β=0.011 and β=0.013 for natural logarithm-transformed sperm concentration and total sperm count, respectively). For inhibin-b levels of 150-300 pg/mL the associations were not as steep (β=0.002), but still significant. For inhibin-b levels more than 300 pg/mL there was little association to the sperm counts. Neither sperm motility nor morphology was significantly related to inhibin-b level in any group. CONCLUSION(S) Serum inhibin-b levels decrease nonlinearly during the daytime, and are positively correlated with sperm counts, but the predictive power is best when inhibin-b is low.

Serum IGF1 and insulin levels in girls with normal and precocious puberty

OBJECTIVE IGF1 plays an important role in growth and metabolism during puberty. IGF1 levels are increased in girls with central precocious puberty (CPP). However, the relationship with insulin before and during gonadal suppression is unknown. In addition, the influence of the exon 3-deleted GH receptor gene (GHRd3) on IGF1 levels was evaluated. DESIGN Nine hundred and eleven healthy and 23 early pubertal girls (15 with CPP) participated and were evaluated by dual-energy X-ray absorptiometry (DXA) scans, fasting and oral glucose-stimulated insulin levels, IGF1 levels, and GHR genotyping. Fifteen girls with early puberty (13 with CPP) were treated with GNRH agonists and reevaluated after 3 and 12 months. RESULTS IGF1 and insulin levels were higher in girls with CPP compared with healthy controls after adjustment for age, bone age, and breast development (all P≤0.02). IGF1 levels were only significantly positively correlated with insulin levels in girls with CPP at baseline (P≤0.03). During gonadal suppression, changes in IGF1 levels were inversely associated with changes in insulin levels (P=0.04). The GHRd3/d3 genotype was associated with significantly higher IGF1 levels (P=0.01) but not with earlier pubertal timing in healthy girls. The distribution of the GHRd3 genotypes among girls with CPP did not differ significantly from healthy girls (P=0.2). CONCLUSION The increased IGF1 and insulin levels in girls with CPP may be causally interrelated. In addition, the GHRd3 allele positively influences IGF1 levels in a copy number-response relationship but not pubertal timing in healthy girls.

Serum Inhibin A and Inhibin B in Central Precocious Puberty before and during Treatment with GnRH Agonists

Serum levels of the gonadal hormones inhibin A and inhibin B are undetectable or low in prepubertal girls, and rise during puberty. In girls with central precocious puberty (CPP) the hypothalamic-pituitary-gonadal axis is prematurely activated, if the girl is thereafter treated with GnRH agonists both gonadotropins and estradiol levels become suppressed. We therefore investigated serum levels of inhibin A and inhibin B in girls with CPP at diagnosis and during treatment in order to test the hypothesis that inhibin secretion would increase and decrease in parallel with the activation and suppression of the hypothalamic-pituitary-gonadal axis. Serum levels of inhibin A and inhibin B were significantly (p < 0.0005) elevated in 42 girls at diagnosis of CPP (inhibin A: 7 pg/ml (<7–139), inhibin B: 80 pg/ml (<20–294) (median, range)) compared to levels in age-matched healthy schoolgirls (inhibin A: all values <7 pg/ml, inhibin B: 21 pg/ml (<20–122) (median, range)), but were appropriate for Tanner stage. During treatment with GnRH agonist (intranasal buserelin and oral cyproterone acetate, treatment group 1, n = 23, or triptorelin depot injections, treatment group 2, n = 19) levels of both hormones fell significantly (p = 0.002). There was a significantly (p = 0.003) greater fall in inhibin B levels during treatment in group 2 compared to group 1, with inhibin B levels now lying below (group 2: <20 pg/ml (<20–68)) rather than within (group 1: 34.5 pg/ml (<20–93)) the age-appropriate range. It is concluded that levels of inhibin A and inhibin B are elevated and suppressed in concert with activation and suppression of the hypothalamo-pituitary-gonadal axis in girls with CPP, supporting the concept that ovarian inhibin secretion is dynamically regulated by gonadotropin stimulation.

The importance of a complete declaration of isothiazolinones in products beyond cosmetics

Anna M. Andersson1 , Morten S. Opstrup1,2, Claus Zachariae1, Ulrik F. Friis1,2, Jacob P. Thyssen1,2 and Jeanne D. Johansen1,2 1Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, 2900 Hellerup, Denmark and 2Department of Dermatology and Allergy, National Allergy Research Centre, Herlev and Gentofte Hospital, University of Copenhagen, 2900 Hellerup, Denmark

Update on Comorbidities in Psoriasis

Purpose of ReviewPsoriasis is a chronic inflammatory skin disease affecting approximately 3% of the general population. Over the past decades, psoriasis has been associated with a range of comorbidities. In the current review, we summarize epidemiological and pathophysiological traits of comorbidities in patients with psoriasis.Recent FindingsIn addition to psoriatic arthritis, studies have found increased prevalence of certain cancers, as well as cardiometabolic, neuropsychiatric, gastroenterologic and autoimmune diseases in patients with psoriasis. While the etiopathogenesis is likely multifactorial, psoriasis-associated systemic low-grade inflammation is believed to play an important role in the development and maintenance of a number of these concurring diseases.SummaryIn order to effectively manage patients with psoriasis, increased awareness and timely intervention on such comorbidities and modifiable risk factors are warranted by treating physicians. Since comorbidities may confer a substantial disease and healthcare burden, the importance of routine screening for high-prevalence and high-risk comorbidities in patients with psoriasis should be emphasized.