Marijn M. Brouwers

Hypospadias: risk factor patterns and different phenotypes.

Study Type – Aetiologic (case‐referent)
Level of Evidence 2a

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

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.

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.

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 17β-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.