K. M. Main

Difference in prevalence of congenital cryptorchidism in infants between two Nordic countries.

BACKGROUNDnSeveral investigators have shown striking differences in semen quality and testicular cancer rate between Denmark and Finland. Since maldescent of the testis is a shared risk factor for these conditions we undertook a joint prospective study for the prevalence of congenital cryptorchidism.nnnMETHODSn1068 Danish (1997-2001) and 1494 Finnish boys (1997-99) were consecutively recruited prenatally. We also established prevalence data for all newborns at Turku University Central Hospital, Finland (1997-99, n=5798). Testicular position was assessed by a standardised technique. All subtypes of congenital cryptorchidism were included, but retractile testes were considered normal.nnnFINDINGSnPrevalence of cryptorchidism at birth was 9.0% (95% CI 7.3-10.8) in Denmark and 2.4% (1.7-3.3) in Finland. At 3 months of age, prevalence rates were 1.9% (1.2-3.0) and 1.0% (0.5-1.7), respectively. Significant geographic differences were still present after adjustment for confounding factors (birthweight, gestational age, being small for gestational age, maternal age, parity, mode of delivery); odds ratio (Denmark vs Finland) was 4.4 (2.9-6.7, p<0.0001) at birth and 2.2 (1.0-4.5, p=0.039) at three months. The rate in Denmark was significantly higher than that reported 40 years ago.nnnINTERPRETATIONnOur findings of increasing and much higher prevalence of congenital cryptorchidism in Denmark than in Finland contribute evidence to the pattern of high frequency of reproductive problems such as testicular cancer and impaired semen quality in Danish men. Although genetic factors could account for the geographic difference, the increase in reproductive health problems in Denmark is more likely explained by environmental factors, including endocrine disrupters and lifestyle.

Nordic consensus on treatment of undescended testes

Aim: To reach consensus among specialists from the Nordic countries on the present state‐of‐the‐art in treatment of undescended testicles.

Changes in Anti-Müllerian Hormone (AMH) throughout the Life Span: A Population-Based Study of 1027 Healthy Males from Birth (Cord Blood) to the Age of 69 Years

CONTEXTnAnti-Müllerian hormone (AMH), which is secreted by immature Sertoli cells, triggers the involution of the fetal Müllerian ducts. AMH is a testis-specific marker used for diagnosis in infants with ambiguous genitalia or bilateral cryptorchidism.nnnAIMnThe aim of the study was to describe the ontogeny of AMH secretion through life in healthy males.nnnSETTINGnThis was a population-based study of healthy volunteers.nnnPARTICIPANTSnPARTICIPANTS included 1027 healthy males from birth (cord blood) to 69 yr. A subgroup was followed up longitudinally through the infantile minipuberty [(in cord blood, and at 3 and 12 months), n=55] and another group through puberty [(biannual measurements), n=83].nnnMAIN OUTCOME MEASURESnSerum AMH was determined by a sensitive immunoassay. Serum testosterone, LH, and FSH were measured, and pubertal staging was performed in boys aged 6 to 20 yr (n=616).nnnRESULTSnSerum AMH was above the detection limit in all samples with a marked variation according to age and pubertal status. The median AMH level in cord blood was 148 pmol/liter and increased significantly to the highest observed levels at 3 months (P<0.0001). AMH declined at 12 months (P<0.0001) and remained at a relatively stable level throughout childhood until puberty, when AMH declined progressively with adults exhibiting 3-4% of infant levels.nnnCONCLUSIONnBased on this extensive data set, we found detectable AMH serum levels at all ages, with the highest measured levels during infancy. At the time of puberty, AMH concentrations declined and remained relatively stable throughout adulthood. The potential physiological role of AMH and clinical applicability of AMH measurements remain to be determined.

Adverse trends in male reproductive health: we may have reached a crucial ‘tipping point’

Healthy men produce an enormous number of sperms, far more than necessary for conception. However, several studies suggest that semen samples where the concentration of sperms is below 40 mill/mL may be associated with longer time to pregnancy or even subfertility, and specimens where the concentration of sperms is below 15 mill/mL may carry a high risk of infertility. Historic data from the 1940s show that the bulk of young men at that time had sperm counts far above 40 mill/mL with averages higher than 100 mill/mL. However, recent surveillance studies of young men from the general populations of young men in Northern Europe show that semen quality is much poorer. In Denmark approximately 40 percent of the men have now sperm counts below 40 mill/mL. A simulation assuming that average sperm count had declined from 100 mill/mL in ‘old times’ to a current level close to 40 mill/mL indicated that the first decline in average sperm number of 20–40 mill/mL might not have had much effect on pregnancy rates, as the majority of men would still have had counts far above the threshold value. However, due to the assumed decline in semen quality, the sperm counts of the majority of 20 year old European men are now so low that we may be close to the crucial tipping point of 40 mill/mL spermatozoa. Consequently, we must face the possibility of more infertile couples and lower fertility rates in the future.

Human urinary excretion of non-persistent environmental chemicals: an overview of Danish data collected between 2006 and 2012

Several non-persistent industrial chemicals have shown endocrine disrupting effects in animal studies and are suspected to be involved in human reproductive disorders. Among the non-persistent chemicals that have been discussed intensively during the past years are phthalates, bisphenol A (BPA), triclosan (TCS), and parabens because of their anti-androgenic and/or estrogenic effects. Phthalates are plasticizers used in numerous industrial products. Bisphenol A is the main component of polycarbonate plastics and epoxy resins. Parabens and TCS are antimicrobial preservatives and other phenols such as benzophenone-3 (BP-3) act as a UV-screener, while chlorophenols and phenyl phenols are used as pesticides and fungicides in agriculture. In spite of the widespread use of industrial chemicals, knowledge of exposure sources and human biomonitoring studies among different segments of the population is very limited. In Denmark, we have no survey programs for non-persistent environmental chemicals, unlike some countries such as the USA (NHANES) and Germany (GerES). However, we have analyzed the excretion of seven parabens, nine phenols, and the metabolites of eight different phthalates in urine samples collected over the past 6 years from four Danish cohorts. Here, we present biomonitoring data on more than 3600 Danish children, adolescents, young men, and pregnant women from the general population. Our study shows that nearly all Danes were exposed to the six most common phthalates, to BPA, TCS, and BP-3, and to at least two of the parabens. The exposure to other non-persistent chemicals was also widespread. Our data indicate decreasing excretion of two common phthalates (di-n-butyl phthalate and di-(2-ethylhexyl) phthalate) over time.

Current exposure of 200 pregnant Danish women to phthalates, parabens and phenols

Many phthalates, parabens and phenols are suspected to have endocrine-disrupting properties in humans. They are found in consumer products, including food wrapping, cosmetics and building materials. The foetus is particularly vulnerable and exposure to these chemicals therefore is of concern for pregnant women. We investigated current exposure to several commonly used phthalates, parabens and phenols in healthy, pregnant Danish women. A total of 200 spot urine samples were collected between 8 and 30 weeks of gestation and analysed for metabolites of ten phenols, seven parabens and 16 phthalate by liquid chromatography-tandem mass spectrometry representing 26 non-persistent compounds. The majority of analytes were present in the urine sample collected from most women who participated. Thus, in 174 of the 200 women, metabolites of more than 13 (>50%) of 26 compounds were detected simultaneously. The number of compounds detected per woman (either as the parent compound or its metabolite(s)) ranged from 7 to 21 with a median of 16. The majority of compounds correlated positively with each other within and between chemical groups, suggesting combined exposure sources. Estimated daily intakes (DIs) of phthalates and bisphenol A (BPA) were below their individual tolerable DI (TDI) and with hazard quotients below 1. In conclusion, we found detectable levels of phthalate metabolites, parabens and phenols in almost all pregnant women, suggesting combined multiple exposures. Although the estimated DI of phthalates and BPA for an individual was below TDI, our results still raise concern, as current toxicological risk assessments in humans do not take into account simultaneous exposure. The true cumulative risk for the foetus may therefore be underestimated.

Testicular dysgenesis syndrome comprises some but not all cases of hypospadias and impaired spermatogenesis

In 2001, when the testicular dysgenesis syndrome (TDS) concept was proposed, it suggested that impaired development of foetal testes could lead to increased risks of cryptorchidism, hypospadias, decreased spermatogenesis or testis cancer. The TDS concept links the pathogenesis of the four disorders together, but does not imply that all affected men develop all four symptoms. The least affected men may merely have a slightly reduced spermatogenic capacity, and only the most severely affected may present all symptoms. A majority of cases of testicular germ cell cancers (TGCC) and cryptorchidism are most likely caused by TDS. However, the frequency of the syndrome in the general population and to what extent poor semen quality and hypospadias are actually biologically related through a foetal mechanism remain unresolved. Hypospadias and impaired spermatogenesis can be classified as TDS if combined with cryptorchidism or TGCC. By contrast, recent studies demonstrated that among men with isolated hypospadias, only a fraction of cases are linked to TDS. There is no doubt that TDS contributes to impaired semen quality. This is most obvious for cases with visible dysgenetic features in testis histology, but in the majority of men with impaired semen quality as the only symptom, an association with TDS is less clear. Such cases have a very heterogeneous aetiology and may be caused by a host of other - often post-natal-factors. In conclusion, the TDS as a holistic concept has inspired new research activities and led to a better understanding of the early origin of male reproductive problems, but it clearly encompasses only a fraction of cases of hypospadias and impaired spermatogenesis.

Body fat throughout childhood in 2647 healthy Danish children: agreement of BMI, waist circumference, skinfolds with dual X-ray absorptiometry.

Background/Objectives:Total body fat percentage (%BF) evaluated by dual energy X-ray absorptiometry (DXA) scans (DXA %BF) is widely recognized as a precise measure of fatness. We aimed to establish national reference curves for DXA %BF, %BF calculated from skinfolds (SF %BF) and waist circumference (WC) in healthy children, and to compare agreement between the different methods.Subjects/Methods:Based on 11u2009481 physical examinations (anthropometry) and 1200 DXA scans from a longitudinal cohort of Danish children (n=2647), we established reference curves (LMS-method) for SF %BF, WC (birth to 14 years) and DXA %BF (8–14 years). Age- and sex-specific Z-scores for body mass index (BMI), WC and SF %BF were compared. Sensitivity and specificity were calculated for agreement of WC, SF %BF and BMI with DXA %BF to identify obese children (>+1 s.d.).Results:%BF differed with age, sex, pubertal stage and social class. SF %BF correlated strongly with DXA %BF (r=0.86). BMI and WC also correlated positively with DXA %BF (Z-scores; r= 0.78 and 0.69). Sensitivity and specificity were 79.5 and 93.8 for SF %BF, 75.9 and 90.3 for BMI and 59.2 and 95.4 for WC.Conclusions:SF %BF showed the highest correlation and best agreement with DXA %BF in identifying children with excess fat (+1 s.d.).

Sons conceived by assisted reproduction techniques inherit deletions in the azoospermia factor (AZF) region of the Y chromosome and the DAZ gene copy number

BACKGROUNDnDeletions in the azoospermia factor (AZF) region of the Y chromosome are frequent in infertile men. The clinical consequences and the mode of inheritance of these deletions are not yet clear.nnnMETHODSnY chromosome deletion mapping and quantitative PCR analysis of the DAZ-gene copy number, supplemented with haplogroup typing in deleted patients, were performed, in combination with clinical assessments in 264 fathers and their sons conceived by assisted reproduction techniques (ART), and in 168 fertile men with normal sperm concentration.nnnRESULTSnIn the ART fathers group, a complete AZFc deletion was detected in 0.4% (1/264). AZFc rearrangements/polymorphisms were found in 6.8% (18/264; 95% CI: 4.4-10.5), which was significantly more frequent (P = 0.021) than in the controls (3/168; 1.8%, 95% CI: 0.6-5.1). All deletions were transmitted to the sons, without any clinical symptoms in early childhood. In the fathers, there was no significant correlation between the DAZ copy number and the severity of spermatogenic failure.nnnCONCLUSIONSnAZFc rearrangements/polymorphisms are transmitted to sons and may represent a risk factor for decreased testis function and male subfertility, which needs confirmation in further studies in larger cohorts. However, deletions of two DAZ gene copies are compatible with normal spermatogenesis and fertility.

Semen quality, reproductive hormones and fertility of men operated for hypospadias

The testicular function of men previously operated for hypospadias has been sparsely investigated. Therefore, we investigated semen quality and reproductive hormones of 92 men with isolated hypospadias (IH) and 20 with hypospadias and additional genital disorders (HAGD) and compared with similar results from young men from the general Danish population. All participants lived the Copenhagen area of Denmark. Additionally, fertility information on 1083 men registered as operated for hypospadias was retrieved from national registries. The semen quality of men with IH did not differ from controls, but was reduced in men with HAGD. Median values for IH and HAGD were, respectively: sperm concentration 52 and 32 million (mill)/mL (p = 0.02), total sperm counts 173 and 101 mill (p = 0.03), motile spermatozoa 70 and 58% (p = 0.007) and morphological normal spermatozoa 9 and 4% (p = 0.004). Men with IH had a slight increase in follicle stimulating hormone and luteinizing hormone levels, whereas men with HAGD had more pronounced disturbances. 24.0% of the 1083 men operated for hypospadias were registered as fathers to at least one child, whereas the corresponding number in the general age-matched population was 29.4% (p < 0.01). In conclusion, the majority of men with IH had normal semen quality, whereas it was reduced for men with HAGD. However, reproductive hormone levels indicated a subtle impairment of testicular function also in men with IH. An observed lower number of fathers among men with hypospadias may be because of psychosocial aspects, sexual dysfunction or reduced semen quality or a combination of these factors. Our results should be reassuring for patients with mild forms of IH and their relatives. They can be informed that hypospadias in such cases is not generally associated with poor semen quality. Particularly among patients with HAGD, several may, however, need fertility treatment to reproduce.