Toward the effective surveillance of hypospadias.

Dolk, Helen; Vrijheid, Martine; Scott, J. E.; Addor, Marie‐Claude; Botting, Bev; Vigan, Catherine De; Walle, Hermien Ek de; Garne, Ester; Loane, Maria; Pierini, Anna; García‐Miñaúr, Sixto; Physick, Nigel; Tenconi, Romano; Wiesel, Awi; Calzolari, Elisa; Stone, D.A.

doi:10.1289/ehp.6398

Cited by 84 publications

(68 citation statements)

References 28 publications

(37 reference statements)

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“…For example, the definition of hypospadias has changed over the years (Dolk et al, 2004) and registered rates for cryptorchidism are difficult to compare due to the complexities related to its assessment. Nevertheless, the results of the sensitivity analyses conducted either by selection of registries including only cases of cryptorchidism diagnosed before 1 year of age, or using data from prospective clinical studies of male newborns confirm the correlations observed in all registries except for a decrease in the statistical power in some instances.…”

Section: Discussionmentioning

confidence: 99%

International geographic correlation study of the prevalence of disorders of male reproductive health

et al. 2013

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what is known already: Some associations between these outcomes have been shown in studies focusing on individuals and mainly in Nordic European countries. These associations, together with histological evidence of a dysgenesis pattern in testicular tissue specimens, have generated the concept of the existence of a 'testicular dysgenesis syndrome' originating in utero. study design, size, duration: This is a geographical correlation study using cancer, malformations rates and sperm quality data collected between the years 1998 and 2005.participants/materials, setting, methods: Incidence rates of testicular cancer were extracted from International Agency for Research on Cancer registries and Globocan, while cryptorchidism and hypospadias prevalence rates were obtained from EUROCAT and International Clearinghouse for Birth Defects Surveillance and Research registries. Sperm concentration data were extracted from recent studies using standardized methodology. A total of 39 registries and 9 sperm studies were selected. Non-parametric Spearman correlation tests were used to test the association between these four disorders. Correlations were computed for all registries together, for registries with high-quality matching coverage only and by continents. Sensitivity analyses were also conducted using data from prospective clinical studies to take into account potential bias related mainly to ascertainment of malformation rates.main results and the role of chance: We found positive correlations between testicular cancer and hypospadias (r ¼ 0.32, P ¼ 0.05) and between hypospadias and cryptorchidism (r ¼ 0.70, P ¼ 0.008). Stronger correlations were observed when using registries with high-quality matching coverage. Among these registries, differences between Europe and the rest of the world appeared (the positive correlation between testicular cancer and cryptorchidism was stronger outside Europe, r ¼ 0.83, P ¼ 0.01 compared with 0.40, P ¼ 0.60 for European registries). A negative correlation between testicular cancer and sperm concentration was observed (r ¼ 20.88, P ¼ 0.002). These correlations support our initial hypothesis but remain only suggestive due to the intrinsic limitations in the study design (i.e. geographical correlation study) and do not allow causal inference.limitations, reasons for caution: Differences in the ascertainment of malformations rates (definition, length of follow-up) make the international comparison difficult. The small number of registries for some conditions (cryptorchidism) or of studies (for sperm quality) and the absence of information about major risk factors such as ethnicity and socioeconomic status in the registries are also limitations.wider implications of the findings: Our findings are in agreement with results of studies focusing on individuals and suggest that shared risk factors are present in the populations studied. † These authors contributed equally to this work.

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Section: Discussionmentioning

confidence: 99%

International geographic correlation study of the prevalence of disorders of male reproductive health

et al. 2013

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“…The prevalence of hypospadias is approximately 4 to 6 in 1,000 male children (Dolk et al 2004;Paulozzi 1999 ; Paulozzi et al 1997 ) . The external genitalia originate from the genital tubercle (GT) by gathering mesenchymal cells at the border of the cloacal membrane.…”

Section: Introductionmentioning

confidence: 99%

Di-n-butyl phthalate induced hypospadias relates to autophagy in genital tubercle via the PI3K/Akt/mTOR pathway

Zhang

et al. 2017

Journal of Occupational Health

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Objective:To explore the mechanisms of hypospadias induced by in utero exposure to din-butyl phthalate (DBP ) . Methods : Timed-pregnant SpragueDawley rats were administered 750 mg / kg of DBP by gavage from GD (gestation days) 13 to GD 18, whereas control group received corn oil. Genital tubercles (GTs) and blood samples were collected from male fetuses on GD 19. The serum testosterone concentration, apoptosis activity, autophagosomes and their related proteins (light chain 3 (LC3-I, LC3-II) ), and sequestosomes (SQSTM1/ p62) in the GTs were then measured. Protein expression of protein kinase B (Akt), Beclin 1, phosphorylated Akt (p-Akt), p-S6, and phosphorylated mammalian target of rapamycin (p-mTOR) in the GTs were analyzed by Western blotting. Results: The incidence of hypospadias induced by DBP was 43.64% in male fetuses. The GT volume and GT volume/body weight of fetuses were significantly reduced in the hypospadias and the nonhypospadias groups. Apoptotic cell number was significantly decreased in the GTs of the hypospadias group, but unchanged in the non-hyposadias group. The ratio of LC3-II/LC3-I was higher in the GTs from DBP exposed fetuses compared to the control group. The ratio of LC3-II/LC3-I in the GTs was higher in the hypospadias group than in the non-hypospadias group. The number of autophagosomes was increased in the GTs of the hypospadias group. Protein expression of p-S6, p-mTOR, and p-Akt were significantly decreased in the GTs of hypospadiac rats. Conclusions: DBP-induced hypospadias might be associated with apoptosis and autophagy mediated by the PI3K/Akt/mTOR signaling pathway in the GT.

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“…This number could potentially increase further with age, as the prepuce could only be retracted in two-thirds of the boys at 3 years. The Danish prevalence, even at birth, was considerably higher than previously reported for Denmark or other countries (67)(68)(69)76), but due to the above-mentioned imprecision of registry data and differences in cohort study designs, no temporal trends could be determined with certainty. Again, the geographic difference in the prevalence of hypospadias between the two Nordic countries was in favor of Finland, and thus in line with data on congenital cryptorchidism, semen quality, and testicular cancer incidence.…”

Section: Prevalence Of Cryptorchidism and Hypospadiasmentioning

confidence: 63%

“…Hypospadias are another relatively common malformation with a reported prevalence of 0.7-1.8 out of 1000 newborn boys (67,68). Some reports suggest that there is a rise in the prevalence of hypospadias in several, but not all, regions (52,54,(69)(70)(71)(72)(73).…”

Section: Prevalence Of Cryptorchidism and Hypospadiasmentioning

confidence: 99%

Gonadal development and reproductive hormones in infant boys

Main¹,

Toppari²,

Skakkebæk³

2006

eur j endocrinol

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Background: The intrauterine milieu plays a crucial role for cardiovascular and metabolic diseases in adulthood, but little is known about its impact on gonadal development and reproduction. Impaired testis development in fetal life can lead to cryptorchidism, hypospadias, impaired semen quality, and testicular cancer, disorders that may present symptoms of a testicular dysgenesis syndrome. The prevalence of these disorders appears to increase in many areas, probably due to environmental factors acting in utero. Denmark has a significantly higher incidence of testicular cancer and lower sperm quality than Finland. Methods: We conducted a population-based study of newborn boys from Denmark and Finland, in order to examine whether this geographic difference was reflected in the reproductive health of newborns. Results: Danish boys had a lower testis volume at birth, a smaller testis growth up to 18 months of age and lower serum inhibin B and FSH levels at 3 months than Finnish. Danish boys also had a higher prevalence of both cryptorchidism and hypospadias than Finnish boys. In boys with cryptorchidism and hypospadias subtle changes in hormonal levels occurred, towards increased gonadotropins and lower inhibin B in cryptorchidism. Both types of congenital malformations were more frequent in children born small for gestational age, indicative of a relationship between growth and reproductive development. Conclusions: These early postnatal findings suggest that the previously observed population differences in reproductive health between young Danish and Finnish men are of fetal origin. The differences may originate as a result of gene-environment interactions, where endocrine disrupters may also play a role.

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Toward the effective surveillance of hypospadias.

Cited by 84 publications

References 28 publications

International geographic correlation study of the prevalence of disorders of male reproductive health

International geographic correlation study of the prevalence of disorders of male reproductive health

Di-n-butyl phthalate induced hypospadias relates to autophagy in genital tubercle via the PI3K/Akt/mTOR pathway

Gonadal development and reproductive hormones in infant boys

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