Risk factors for different phenotypes of hypospadias: results from a Dutch case-control study.

UNLABELLED: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: The various phenotypes of hypospadias may result from disturbances of dissimilar embryonic processes in different time windows, suggesting aetiological heterogeneity; however, only a few studies have investigated the risk factors for the different hypospadias phenotypes. The study confirmed that genetic predisposition possibly plays a role in anterior and middle hypospadias, as shown by the large effect estimates for familial occurrence of these forms of hypospadias. By contrast, the posterior phenotype was more often associated with pregnancy-related factors, such as primiparity, preterm delivery, and being small for gestational age. New findings were that hormone-containing contraceptive use after conception increased the risk of middle and posterior hypospadias, while multiple pregnancies were associated with the posterior form in particular. OBJECTIVE: To identify specific risk factors for different phenotypes of hypospadias that may arise as a result of dissimilar embryonic processes in different time windows. PATIENTS AND METHODS: A total of 405 hypospadias cases and 627 male controls were included in a Dutch case-control study. Medical records of cases were reviewed to determine the anatomical location of the urethral opening, while demographic, lifestyle and pregnancy-related risk factor data were obtained from self-administered questionnaires. Multivariable and multinomial logistic regression analyses were used to calculate effect estimates for the group containing all cases of hypospadias and for the different hypospadias phenotypes. RESULTS: Cases were subdivided into anterior (glandular and coronal; 59%), middle (penile; 29%) and posterior (penoscrotal, scrotal and perineal; 12%) hypospadias. Being a twin/triplet, primiparity, preterm delivery, and being small for gestational age were associated with hypospadias, particularly in posterior cases. Family history of hypospadias increased the risk of hypospadias, an effect that seemed to be more predominant in anterior and middle forms. Maternal obesity seemed to increase the risk of hypospadias in general, and hormone-containing contraceptive use during pregnancy especially increased the risk of middle and posterior hypospadias. CONCLUSIONS: Our study provides some indications for aetiological heterogeneity of hypospadias, separating anterior and middle phenotypes from posterior hypospadias. Future research should continue to try to establish which specific risk factors and mechanisms may differ according to hypospadias phenotype.

Exploration of gene-environment interactions, maternal effects and parent of origin effects in the etiology of hypospadias.

PURPOSE: Hypospadias is a common congenital malformation of the male external genitalia. Association studies for single nucleotide polymorphisms in genes encoding steroid 5alpha-reductase, estrogen receptors 1 and 2, and activating transcription factor 3 have been equivocal. We examined whether nonreplication of findings for 4 single nucleotide polymorphisms in these genes could be due to interaction with environmental exposures. MATERIALS AND METHODS: We genotyped 712 Dutch hypospadias case-parent triads for the 4 single nucleotide polymorphisms, used questionnaire information to determine exposures and performed association tests using the log-linear approach. We studied gene-environment interactions for the 4 single nucleotide polymorphisms with exposure to estrogens, cytokines or cigarette smoke, multiple birth, being born small for gestational age, maternal hypertension or preeclampsia, high body mass index or primiparity. In addition, the presence of maternal genetic and parent of origin effects was tested. RESULTS: Gene-environment interactions were identified for rs523349 in SRD5A2 with estrogen exposure and maternal hypertension or preeclampsia, as well as for rs11119982 in ATF3 with exposure to cytokines. Both single nucleotide polymorphisms seemed to influence hypospadias risk only in exposed cases. For rs6932902 in ESR1 only maternally derived alleles appeared to increase hypospadias risk in offspring. CONCLUSIONS: Interactions between genetic and environmental factors may help to explain nonreplication in genetic studies of hypospadias.

Risk factors for undescended testis.

OBJECTIVE: To contribute to the understanding of the etiology of undescended testis (UDT), by exploring a wide range of potential risk factors in a case-referent study. PATIENTS AND METHODS: Cases and referents were recruited at five hospitals and included 200 boys with surgically corrected UDT and 629 boys with persistent middle ear effusion. Risk factor data were obtained by postal questionnaires to both parents. Clinical data were collected from medical files. Adjusted odds ratios (OR) with 95% confidence intervals (CI) were estimated using logistic regression. RESULTS: The main findings include associations between UDT and familial occurrence of the disorder: OR 3.1 (95%CI 1.9-4.9), low birth weight: 2.2 (1.1-4.3), twinning: 2.2 (0.9-5.4), gestational preeclampsia: 1.9 (0.8-4.4), use of oral contraceptives after conception: 3.6 (1.0-12.5), in vitro fertilization/intracytoplasmic sperm injection treatment: 2.2 (0.8-6.0), paternal subfertility: 1.8 (0.8-4.1), and maternal occupational exposure to cosmetics: 3.0 (0.9-10.0). Subgroup analyses indicated differences in ORs for several factors between cases with (n = 92) and without (n = 103) inguinal hernia or hydrocele. CONCLUSION: The findings point towards a role for genetic predisposition, placental insufficiency, and possibly exposure to specific endocrine disrupting substances in the etiology of UDT. Further research should take into account potential etiologic differences between subgroups of cases with UDT.

Occupational exposure to endocrine disruptors and time to pregnancy among couples in a large birth cohort study: the Generation R Study.

OBJECTIVE: To study the influence of occupational exposure to endocrine disruptors (EDs) on time to pregnancy (TTP). DESIGN: Cross-sectional analysis within a prospective, population-based cohort study. SETTING: Medical center. PATIENT(S): Mothers and fathers who filled out a questionnaire during mid-pregnancy (response 77% and 82% of enrollment, respectively) were selected if the pregnancy was planned and either parent performed paid employment. In total, 2,774 mothers and 2,728 partners were included in the statistical analyses. INTERVENTIONS(S): None. MAIN OUTCOME MEASURE(S): Self-reported TTP (months). RESULT(S): There was no correlation between maternal and paternal exposure, because κ values for agreement for all exposure categories ranged from 0.03 to 0.13. Paternal occupational exposure to heavy metals (hazard ratio of pregnancy 0.83; 95% confidence interval 0.71-0.97) and overall exposure to EDs (hazard ratio 0.85; 95% confidence interval 0.75-0.96) was statistically significantly associated with an increased TTP. Maternal occupational exposure to all categories of EDs showed prolonged TTP, but the decreased hazard ratios were not statistically significant. CONCLUSION(S): This birth cohort study provides indications for adverse effects of parental occupational exposure to EDs on TTP.

Estrogenic and androgenic activities in total plasma measured with reporter-gene bioassays: relevant exposure measures for endocrine disruptors in epidemiologic studies?

Measurements of estrogenic and androgenic activities in total plasma with Chemically Activated LUciferase gene eXpression (CALUX®) bioassays could provide biologically relevant measures for exposure to endocrine disruptors in epidemiologic studies. The objective of this study was to explore the effects of a variety of sources of potential endocrine disruptors on estrogenic and androgenic activities in total plasma measured by CALUX®. Plasma samples and interview data on sources of potential endocrine disruptors were collected from 108 men with different exposures profiles. CALUX® measurements (BioDetection Services) involved human U2-OS cell lines controlled by the estrogen receptor alpha and the androgen receptor. Mean differences (beta) in 17ß-estradiol equivalents (EEQs) and dihydrotestosterone equivalents (AEQs) between exposure groups were estimated using general linear models. Mean plasma AEQs and EEQs were 9.1×10(-1)ng/ml and 12.0pg/ml, respectively. Elevated AEQs were found in smokers (beta 1.9 (95%CI 0.1-3.6)×10(-1)ng/ml) and heavy drinkers (1.4 (0.2-3.1)×10(-1)ng/ml), and in men occupationally exposed to disinfectants (1.6 (0.3-3.5)×10(-1)ng/ml) or welding/soldering fumes (1.4 (-0.2-2.9)×10(-1)ng/ml). Occupational exposure to pesticides, disinfectants, and exhaust fumes seemed to be associated with increased plasma EEQs: 1.5 (-0.2-3.2)pg/ml, 2.1 (0.2-3.9)pg/ml, and 2.9 (0.6-5.2)pg/ml, respectively. Moderate to high plasma dioxin levels, measured in a subgroup by the dioxin-responsive CALUX®, were accompanied by a 20% increase in AEQs. This is the first study in which CALUX® was used to assess hormone activities in total plasma. Although the results are not yet readily interpretable, they indicate that these measurements can be valuable for epidemiologic studies on endocrine disruptors and give direction for further research.

Maternal and paternal risk factors for anorectal malformations: a Dutch case-control study.

BACKGROUND: Anorectal malformations (ARM) are major congenital malformations that usually require a multitude of surgical procedures at a very early age and have a large impact on the lives of patients and their parents. The causes of ARM are still largely unknown, but they are assumed to have a multifactorial etiology. A few studies focused on environmental risk factors, but evidence is still scarce. METHODS: In this Dutch case-control study (1996-2008), we investigated the role of maternal and paternal risk factors in the etiology of ARM. Parents of 85 ARM cases and 650 controls filled in a questionnaire. Controls were children treated with ear ventilation tubes. RESULTS: A higher occurrence of fever during the first trimester of pregnancy was found for case mothers compared to control mothers (odds ratio [OR], 5.1; 95% Confidence Interval [CI], 0.9, 28.1). Maternal occupational exposure to industrial cleaning agents and solvents increased the risk of ARM three times (OR, 2.9; 95% CI, 0.9, 9.3). Overweight (Body Mass Index [BMI] > or = 25 kg/m(2)) before pregnancy also seemed to be associated with ARM (OR, 1.8; 95% CI, 1.1, 2.8), as well as maternal multivitamin use during pregnancy (OR, 1.6; 95% CI, 1.0, 2.7), paternal smoking (OR, 1.8; 95% CI, 1.1, 2.9), and paternal occupational exposure to exhaust fumes (OR, 1.9; 95% CI, 1.0, 3.6). Reported ARM in at least one first- or second-degree family member greatly increased the risk of having a child with an ARM (OR, 40.3; 95% CI, 4.8, 342.8). CONCLUSIONS: This study revealed potential risk factors for ARM, including fever during pregnancy, maternal overweight, use of multivitamins, paternal smoking, and occupational exposures, but a familial component seems important as well.

Hypospadias: risk factor patterns and different phenotypes.

OBJECTIVE: To obtain more insight into the origin of hypospadias by exploring a wide range of potential risk factors in a case-referent study in which a distinction was made between different phenotypes. PATIENTS AND METHODS: Cases and referents were 305 boys with hypospadias and 629 boys with middle ear effusion whose parents completed postal questionnaires. Hypospadias phenotype was classified as distal (195 boys), middle (67), and proximal (43). Adjusted odds ratios (OR) with 95% confidence intervals (CI) were estimated using logistic regression. RESULTS: Low birth weight, being a twin or triplet, mother being a diethylstilbestrol-daughter, fertility treatments, paternal subfertility, obesity, prescriptive drug use, and familial occurrence of hypospadias or testicular cancer were associated with hypospadias in general. For familial occurrence of hypospadias, there were high risk estimates for the distal and middle phenotypes with an OR (95%CI) of 10.4 (4.5-24.1) and 9.0 (3.1-26.0), but not for the proximal type at 1.8 (0.2-14.9). By contrast, the association with low birth weight (a proxy for placental dysfunction) seemed much stronger for proximal hypospadias with an OR (95%CI) of 9.1 (3.4-24.2) compared with distal and middle hypospadias at 2.6 (1.4-5.0) and 2.3 (0.8-6.5). There were similar estimates for pre-eclampsia. CONCLUSION: These findings indicate aetiological heterogeneity of hypospadias and provide indications for the possible mechanisms through which specific risk factors may interfere with penile development.

Risk factors for hypospadias.

Despite being one of the most common congenital defects in boys, the etiology of hypospadias remains largely unknown. In this case-referent study, we evaluated a wide spectrum of potential risk factors for hypospadias. Cases were identified from the hospital information system, and referents were recruited through the parents of the cases. Both parents of cases and referents completed written questionnaires that they received through the mail. Logistic regression analyses were used to assess the independent contribution of different factors to the risk of hypospadias. The final database included 583 cases and 251 referents. Hypospadias more often occurred in children whose father had hypospadias (OR=9.7; 95%CI: 1.3-74.0) and in children with a low birth weight (OR=2.3; 95%CI: 1.2-4.2). Indications for elevated risks were found when mothers were DES-daughters (OR=3.5; 95%CI: 0.8-15.6), fathers were subfertile (OR=1.8; 95%CI: 0.7-4.5), the parents had undergone fertility treatment (OR=2.3; 95%CI: 0.9-5.8), and in twin or triplet pregnancies (OR=2.0; 95%CI: 0.8-5.1). Maternal use of iron supplements (OR=2.2; 95%CI: 0.8-6.0), maternal smoking (OR=1.5; 95%CI: 1.0-2.4), paternal prescriptive drug use (OR=2.6; 95%CI: 1.1-6.6), and paternal exposure to pesticides (OR=2.1; 95%CI: 0.6-7.1) during the 3 months immediately prior to conception or in the first trimester of pregnancy also appeared to increase the risk of hypospadias. The associations found in this study support the hypothesis that genetic predisposition, placental insufficiency, and substances that interfere with natural hormones play a role in the etiology of hypospadias.