|Year : 2013 | Volume
| Issue : 1 | Page : 15-18
Parental risk factors associated with hypospadias
Bindhu Suma Shekar, Ramakrishna Avadhani
Department of Anatomy, Yenepoya Medical College, Mangalore, Karnataka, India
|Date of Web Publication||21-Jun-2013|
Bindhu Suma Shekar
Department of Anatomy, Yenepoya Medical College, Mangalore, Karnataka
Source of Support: None, Conflict of Interest: None
Introduction: Hypospadias is one of the most common congenital anomalies of male external genitalia. It occurs in approximately 1 in 250 newborn. Hypospadias can be defined as an abnormal urethral orifice under surface of the penis with or without chordee and with or without dorsal hood. Hypospadias may be an isolated defect or a phenotypical component of a more complex condition such as an intersex state. The only treatment is surgery. Thus, prevention is imperative. To accomplish this, it is necessary to determine the etiology of hypospadias. Objective: To identify risk factors for hypospadias, with a focus on potential endocrine disruption, in parental demography, diet, and occupation. Materials and Methods: In a case-control study nested within a cohort of 3246 male births, we compared 17 hypospadias cases with 68 controls. Through questionnaire proforma, information was collected on pregnancy aspects and personal characteristics. Result: Our findings indicate that parental pesticide exposure and smoking were associated with hypospadias, maternal occupational exposure, diet and life style were not associated with hypospadias. The prevalence rate of hypospadias in our study was 0.05%. Conclusion: Since the paternal pesticide exposure and smoking were significantly associated with hypospadias, paternal exposure should be included in further studies on hypospadias risk factors.
Keywords: Endocrine disruption, hypospadias, phenotypical
|How to cite this article:|
Shekar BS, Avadhani R. Parental risk factors associated with hypospadias. Arch Med Health Sci 2013;1:15-8
| Introduction|| |
Hypospadias is one of the most common congenital anomaly of male external genitalia. It occurs in approximately 1 in 250 newborn.  Hypospadias can be defined as an abnormal urethral orifice under surface of the penis with or without chordee and with or without dorsal hood. Hypospadias may be an isolated defect or a phenotypical component of a more complex condition such as an intersex state. Hypospadias in boys is defined as an association of three anomalies of the penis: (1) an abnormal ventral opening of the urethral meatus that may be located anywhere from the ventral aspect of the glans penis to the perineum, (2) an abnormal ventral curvature of the penis (chordee), and (3) an abnormal distribution of foreskin with a "hood" present dorsally and deficient foreskin ventrally.  The second and third characteristics are not present in all cases. Hypospadias is typically diagnosed at new born physical examination.
Hypospadias is a result of arrested development of the urethra, foreskin, and ventral surface of the penis where the urethral opening may be anywhere along the shaft, within the scrotum, or in the perineum. The only treatment is surgery. Thus, prevention is imperative. To accomplish this, it is necessary to determine the etiology of hypospadias.
Development of external genital organ is similar in males and females in indifferent stage up to eighth week of intrauterine life.  After this stage, the development precedes either in male or female direction. The male hormone testosterone secreted by fetal testis is responsible for development of external genitalia in male direction. During the 3 rd week of development, mesenchymal cells originating in the region of primitive streak migrate around cloacal membrane to form a pair of slightly elevated folds, the cloacal folds. Cranial to the cloacal membrane, the folds unite to form the genital tubercle. The urogenital sinus is divided into pelvic part and phallic part. The phallic part is closed by urogenital membrane. The mesoderm on either side of it is soon heaped up to form two longitudinal elevations called primitive urethral folds. In addition to these folds, three other elevations of mesoderm are soon apparent. These are genital tubercle and right and left genital swellings. From this stage onwards, development in male and female is different. The genital tubercle enlarges and now is called the phallus.  It undergoes great enlargement to form the penis. A urethral groove is established by the development of urethral folds on the ventral side of the phallic portion of urogenital sinus on either side of the urethral plate. These folds are covered by surface epithelium and is suggested that the groove between them be called primary urethral groove.  A secondary urethral groove develops at approximately 8 th week, as a result of disintegration of the roof of the primary groove. Continuation of this process eventually establishes the definitive urethral groove. At approximately the 11 th week of development, when the Leydig cells of the testis increase in number, size, and function, the urethral folds begin to fuse ventrally in the midline to form the urethra. Via similar process, the proximal portion of glanular urethra forms shortly thereafter and thus derived from urethral plate (endodermal origin). The distal portion of glanular urethra is formed by lamellar in growth of the surface epithelium (ectodermal origin) that grows toward the distal extent of urethral plate, becoming stratified squamous epithelium at the completion of development. 
During the 4 th month of intra-uterine life, the ectodermal cells from the tip of the glans penetrate inward and form a short epithelial cord, which is called external urethral meatus. The genital swellings fuse with each other in the midline to form the scrotal sac. It is the 'testes determining factor' present on Y chromosome, which is responsible for development of testes. Fetal testes secrete testosterone, which influences the development of genital ducts and external genitalia. Also, Sertoli cells in the fetal testes produce a non-steroidal substance known as Mullerian inhibiting substance (MIS) or Anti-mullerian hormone (AMH) that causes regression of para mesonephric ducts. 
The characteristic defects of hypospadias may result from one or more of the following: Abnormal androgen production by the fetal testis, limited androgen sensitivity in the target tissue of the developing external genitalia and/or premature cessation of androgenic stimulation secondary to premature involution of Leydig cells of the fetal testis.  Other possible causes include insufficient testosterone and/or dihydrotestosterone synthesis, presumably defective or deficient 5α reductase enzyme activity and or defective androgen-receptor quality or quantity.
| Objectives|| |
To identify risk factors for hypospadias, with a focus on potential endocrine disruption, in parental demography, diet, and occupation.
| Materials and Methods|| |
The present study was a case-control study carried out from July 2008 to July 2011 at KLE Hospital Belgaum. The database labor registries of our hospital indicated that there were total 3243 male births during this period. All examined for presence /absence of hypospadias by attending pediatrician. Hypospadias was detected in 17 male newborns. Control cases comprised of 68 male newborns without hypospadias of similar gestational age and birth weight collected by cluster sampling.
Once hypospadias was identified, the neonate was examined in detail to identify other anomalies, weight at birth, and gestational age. The mother of the study neonate was subjected to answer a questionnaire after obtaining consent. This questionnaire consisted of present and past obstetric history, information related to diet, medications, occupation, and smoking. The controls were also examined in detail, and their mothers similarly answered a questionnaire after consent.
Data was compiled and analyzed by descriptive analysis; comparison of risk factors was done using student t test. P value < 0.05 was considered as significant.
| Result|| |
Total number of male birth during the study period was 3243, in that, 17 children born with hypospadias. The incidence of hypospadias in our hospital was 0.52%. General characteristics of the study population are shown [Table 1] and dietary pattern in [Table 2]. [Table 1] presents the risk factors for hypospadias related to mother and father. Significant risk factors were related to intrauterine growth (smoking and occupation). Mothers with better general health showed less risk of hypospadias.
General characteristics of parents during indexed pregnancy
Maternal age was statistically significant, but it was not higher in mothers of hypospadias children (23.64 ± 2.71 yrs vs. 25.61 ± 2.74 yrs, P-0.02). We could not find out any association with parity and hypospadias; 47% of mothers were primiparous in hypospadias group and 51% of mothers in control group. None of the mothers in the study group underwent fertility treatment. None of the mothers in both the groups had consanguineous marriage. BMI in the normal range is 20-24. In our study, BMI was (27.03 ± 1.33) in mothers of hypospadias children and in control was (25.60 ± 1.15).
Incidence of PIH, nausea, and vomiting during indexed pregnancy were not significantly different in mothers of children with hypospadias when compared with those of controls. Maternal education was not a relevant risk factor as the mothers in both the groups were educated at least up to high school level and well versed in reading and writing. None of the mothers in both the groups had consanguineous marriage, and none experienced or reported pregnancy-induced hypertension. Fifty-two percent of fathers in case groups were field workers and were exposed with pesticides, and 64% of fathers in case groups had smoking habits, and the mothers of the study group were passive smokers.
| Discussion|| |
Maternal primiparity, age 35 years or older, and BMI > 26 are factors known to be associated with increased risk of hypospadias among offspring, especially when present in combination. Two studies have suggested the combination of maternal age and parity, and both these studies have shown twofold to threefold higher risk of hypospadias among older primiparous women, as compared to younger multiparous women.  Carlson et al, 1995, have reported that advanced maternal age was associated with increased severity of hypospadias in their population.  Several explanations have been postulated for the finding of increased incidence and severity of hypospadias with increasing maternal age. Older mothers would potentially have longer exposure to endocrine disruptors than younger mothers and thus greater risk of hypospadias.  Maternal age was statistically significant, but it was not higher in mothers of hypospadias children (23.64 ± 2.71 yrs vs. 25.61 ± 2.74 yrs, P-0.02). We could not find out any association with parity and hypospadias: 47% of mothers were primiparous in hypospadias group and 51% of mothers in control group. Maternal sub-fertility has been proposed to contribute to higher risks of hypospadias observed among older and primiparous women.  Multiple births and fertility treatments, especially intra-cytoplasmic sperm injection, are associated with increased risk of hypospadias. None of the mothers in the study group underwent fertility treatment. None of the mothers in both the groups had consanguineous marriage. BMI in the normal range is 20-24. In our study, BMI was (27.03 ± 1.33) in mothers of hypospadias children and in control was (25.60 ± 1.15). None of the mothers in both the groups had consanguineous marriage. Nausea in early pregnancy is believed to be caused by the early surge of pregnancy hormones, particularly, hCG; the onset and peak of nausea and vomiting in early pregnancy parallel the hCG curve.  First-trimester nausea is considered to be a sign of a healthy pregnancy, because it is associated with lower risks of abortion and premature birth.  Incidence of PIH, nausea, and vomiting during indexed pregnancy were not significantly different in mothers of children with hypospadias when compared with those of controls. A previous study reported a maternal vegetarian diet as a risk factor for hypospadias and suggested a higher phytoestrogen intake as explanation.  Phytoestrogens are available in many food stuffs, although in low concentrations, with soya providing the richest source, if consumed in significant quantities, they may have substantial estrogenic effect which could contribute to the disruption of the developing fetus. A pregnancy diet lacking meat and fish appears to increase the risk of hypospadias in the offspring. Jenson et al, hypothesized that the detrimental changes in male reproductive health that are becoming more apparent may be caused by the developing fetus having an altered exposure to endocrine-disrupting chemicals with estrogenic effects. There are experimental findings suggesting that increased dietary intake of phytoestrogens have a protective effect on the risk of various hormone-related diseases. It has previously been suggested that the risk of genital anomalies in male offspring may be increased by intake of different soy proteins frequently ingested by vegetarians. Soybeans contain phytoestrogens that may produce estrogenic as well as anti-estrogenic effects via the estrogen receptor.  It has been suggested that phytoestrogens from soybeans, for instance, disrupt the musculanization of the male through interference with the pituitary-gonadal axis.  In our study, there were no differences in the proportion of hypospadias cases born to mothers consuming vegetarian diet. Previous studies have yielded conflicting results regarding parental smoking (preconception and/or during pregnancy) and the risk of hypospadias.  Parental smoking could have an effect through passive exposure of the mother. We found an association between hypospadias risk and exposure to passive smoking. Although there are mechanisms to explain an association with paternal smoking in the absence of an association with maternal smoking-for example, smoking may cause germ line mutations-the most likely explanation for the association with paternal smoking is perhaps chance variability. Several investigations have reported no associations between hypospadias risk and parental occupation.  The available literature pertaining to the relationship between hypospadias and parental gardening and farming is contradictory. Partly because of the secular increase in hypospadias rates observed in certain areas, a potential association between the defect and chemicals with estrogenic or anti-androgenic effects has been suggested.
| Conclusion|| |
Since the paternal pesticide exposure and smoking was significantly associated with hypospadias, paternal exposure should be included in further studies on hypospadias risk factors.
| Acknowledgement|| |
I thank Dr. R. B. Nerli, Professor & HOD of Urology, KLE hospital, KLE University, Belgaum, for his valuable advice and guidance.
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[Table 1], [Table 2]