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University Department of Growth and Reproduction Rigshospitalet (K.A.B., M.C., I.M.S., C.M.K., I.N.D., A.-M.S., J.T., N.E.S., K.M.M.), DK-2100 Copenhagen, Denmark; and Departments of Physiology and Paediatrics (A.-M.S., J.T.), University of Turku, FIN-20520 Turku, Finland
Address all correspondence and requests for reprints to: Katharina M. Main, M.D., Ph.D., University Department of Growth and Reproduction, GR-5064 Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. E-mail: katharina.main{at}rh.hosp.dk.
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Abstract |
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Objective: The aim of the study was to investigate the prevalence of hypospadias in Denmark and evaluate the relationship to anthropometrical measurements at birth and reproductive hormone levels at 3 months of age.
Design: A prospective cohort study was conducted with 3-yr follow-up (1997–2004).
Setting: The population-based study was conducted at the University Hospital of Copenhagen.
Participants: A total of 1072 Danish boys were consecutively recruited antenatally, with 74.4% completing the study.
Main Outcome Measures: The study examined the position of the urethral meatus, anthropometrical measurements, placental weight, and reproductive hormone levels.
Results: The Danish birth prevalence of hypospadias was significantly higher than in a concomitant Finnish study (1.03 vs. 0.27%; P = 0.012). At 3 yr, the true prevalence was found to be 4.64% because additional mild cases were detected when physiological phimosis dissolved. Weight for gestational age (percentage deviation from expected mean) (–5.00 vs. –0.59%; P = 0.030) and placental weight (567 vs. 658 g; P = 0.023) were significantly lower, and FSH was significantly higher (1.48 vs. 1.15 IU/liter; P = 0.007) in boys with hypospadias, compared with healthy boys.
Conclusions: We found a surprisingly high total rate of hypospadias of 4.6% in this large prospective cohort study. Seventy-two percent of the cases were apparent only after the prepuce could be retracted. Hypospadias were associated with elevated serum FSH levels at 3 months. We also confirmed an association between fetal growth impairment and hypospadias; however, it is yet unknown whether this indicates a causal relationship or a shared pathogenic factor.
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Introduction |
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During recent decades, several reports have indicated that Danish males carry a higher risk of testicular cancer and subfertility than Finnish males (7). We have previously reported also a significantly higher birth prevalence of cryptorchidism in Danish boys, compared with Finnish boys (8). The clinical and epidemiological associations among cryptorchidism, subfertility, and testicular cancer suggest the existence of etiological and pathogenic links, possibly due to a testicular dysgenesis syndrome (TDS). The clinical symptoms of TDS differ in severity and prevalence and may also include hypospadias (7).
The aim of this prospective cohort study was to describe the current birth rate of hypospadias in Denmark to assess whether it follows the same regional pattern as other features of TDS. The relationship between hypospadias and anthropometrical measurements at birth (as a marker of intrauterine growth) and reproductive hormone levels at 3 months of age was evaluated in boys with hypospadias in comparison with healthy boys.
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Subjects and Methods |
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The study was conducted as a prospective cohort study at the University Hospital of Copenhagen in Denmark from 1997–2004. The recruitment, study design, and ascertainment of urogenital malformations were performed in close collaboration with a Finnish study group and have previously been described (8).
Eligible women residing in the hospital referral area were consecutively recruited during the first trimester of pregnancy. To obtain a genetically and geographically well-defined population, only families who met the following criteria were included: both parents and grandparents of the unborn child had to be born and raised in Denmark with a maximum residence abroad of 3 yr for the mother and 10 yr for the father and grandparents.
The boys were examined shortly after birth and at 3, 18, and 36 months of age. In case of preterm birth, all examinations were postponed according to the expected date of delivery. Gestational age was based on routine ultrasonography in pregnancy wk 18–20, when available. In the remaining cases (2.1%), the last menstrual period was used. Birth weight (grams), birth length (centimeters), and head circumference (centimeters) were obtained from birth records. Weight for gestational age (WGA) was expressed as percentage deviation from the expected mean WGA using a gender-specific equation (9). Small for gestational age (SGA) was defined as less than –22% WGA approximate to –2 SD. Placentas were collected by midwives and stored at –20 C. They were subsequently weighed frozen at our department on a digital scale (Baby-Scale model; Solotop Oy, Vantaa, Finland) to the nearest 0.005 kg. At all subsequent examinations of the boys, weight was measured on a digital scale (Solotop Oy, Baby-Scale model) to the nearest 0.005 kg. Length was measured with the child supine on a portable infantometer (Kiddimeter, Raven Equipment Limited, Essex, UK) to the nearest 0.01 cm. At the age of 3 yr, an electronic stadiometer was used (Force Technology, Brøndby, Denmark). Head circumference was measured with a tape lasso (Lasso, Child Growth Foundation, London, UK) to the nearest 0.01 cm. For all above variables, the mean of three measurements was calculated.
Genital malformations and retractability of the prepuce were noted at all examinations. Only one boy was circumcised due to medical reasons. The location of the urethral meatus was described if visible, and hypospadias was graded as glandular, coronal, penile, penoscrotal, scrotal, or perineal according to the anatomical position (Fig. 1
). Cases of isolated malformed foreskin without hypospadias were not included as cases.
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Venous blood samples were obtained at the 3-month examination. Serum was stored at –20 C and later analyzed. Serum concentrations of FSH, LH, SHBG, testosterone, and inhibin B were measured. All analyses were done blinded at the laboratory at the University Department of Growth and Reproduction. Serum FSH, LH, and SHBG were measured by time-resolved immunofluorometric assays (Delfia; Wallac Inc., Turku, Finland) with detection limits of 0.06 and 0.05 U/liter for FSH and LH, respectively, and 0.23 nmol/liter for SHBG. Intra- and interassay coefficients of variation (CVs) were less than 5% in both gonadotropin assays and less than 6% in the SHBG assay. Serum testosterone was measured by RIA (Coat-a-Count; Diagnostic Products Corp., Los Angeles, CA) with a detection limit of 0.23 nmol/liter and intra- and interassay CVs less than 10%. Serum inhibin B was analyzed by a double-antibody enzyme immunometric assay using a monoclonal antibody raised against the inhibin ßB-subunit in combination with labeled antibody raised against the 
-subunit (Oxford Bio-Innovation, Oxford, UK). The detection limit was 20 pg/ml, and intra- and interassay CVs were less than 15% and less than 20%, respectively.
Analyses of the androgen receptor
DNA was isolated from EDTA-stabilized blood samples. All exons and part of the flanking introns were PCR amplified using the primers described by Batch et al. (10). The PCR products were scanned for mutations by single-strand conformation analysis. Products with an aberrant single-strand conformation analysis pattern were sequenced and subsequently sequenced using the Sequenase kit (version 2.0; USB Corp., Cleveland, OH) (11).
Participants
Of 2095 live-born children, 1072 boys entered the study. A total of 1052 boys were examined at birth or the expected date of delivery; 971 of these were reexamined 3 months later. The remaining 81 families were lost to follow-up. Twenty boys were seen only at 3 months and the subsequent examinations because they either left the hospital before being examined neonatally or the examination was postponed due to medical problems. Eight hundred ninety boys were reexamined at 18 months of age and 798 boys at 3 yr of age, whereas 101 and 92 families, respectively, were lost to follow-up.
Statistical analysis
Statistical analyses were performed using SPSS for Windows 11.0 (SPSS, Inc., Chicago, IL). Prevalences are given as cases per boys examined in the study. The prevalence at 3 months of age is also given as cases per total number of live-born births, including girls. Ninety-five percent confidence intervals (CIs) on prevalence rates were calculated using R (12) and given in parentheses. 
2 statistics, based on 2 x 2 cross-tabulations, were used for comparison of hypospadias rates between countries. All anthropometrical measurements followed normal distribution, and differences between groups were tested with unpaired t test. Univariate general linear regression models tested linear trends in the anthropometrical measurements. Reproductive hormones did not follow normal distribution and were described by median and 95% prediction intervals. Differences were tested using the Mann-Whitney U test.
Ethics
The study was conducted according to the Helsinki II Declaration and was approved by the local Danish ethics committee [(KF) 01-030/97] and the Danish Data Protection Agency (1997-1200-074). The parents gave written informed consent.
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Results |
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There were eight cases of hypospadias at birth [0.75% (95% CI 0.32–1.47%)]. The prepuce was malformed in all cases. Glandular hypospadias was diagnosed in one case; the boy suffered from additional cleft palate and congenital hypothyroidism. Coronal hypospadias was found in four cases, and three cases were distal penile. In two of the latter, additional cryptorchidism was present, in one boy combined with atresia of the tricuspid valves of the heart. The third boy with penile hypospadias suffered from atrial and ventricular septal defects. We found normal male karyotype (46,XY) and no androgen receptor mutations in these three boys. Numbers of CAG repeats were 21, 22, and 25, respectively. The normal range in Denmark is 14–33, median 21 (13). Isolated malformation of the foreskin without hypospadias was detected in four boys.
At 3 months, two additional glandular and one coronal hypospadias were detected (Table 1); in none of these the prepuce was split. Thus, the prevalence of hypospadias among live-born boys was 1.03% (95% CI, 0.51–1.83) or 5.25 per 1000 live-born births (95% CI, 2.62–9.38/1000).
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). At birth, the prepuce could be retracted in 27% of boys, at 18 months of age in 53%. At 3 yr, the prepuce could be retracted in 62% of boys (in 2% status was not noted). In 4.64% (95% CI, 3.38–6.34%) of the 3-yr-old boys, displacement of the urethral meatus was present. In two of the boys with glandular hypospadias diagnosed at 3 yr, congenital cryptorchidism with spontaneous testicular descent before 3 months were present. In one case with delayed diagnosis of glandular hypospadias, testicular ascent (acquired cryptorchidism) was also present. If including only boys with retractable prepuce at 3 yr (n = 495), the prevalence of hypospadias was 7.5%. Anthropometrical data at birth
At birth, we found signs of impaired intrauterine growth in boys with hypospadias, irrespective of type and age at diagnosis. Mean (SD) weight for gestational age was significantly smaller [–5.00% (11.3) vs. –0.59% (12.4), P = 0.030] and placental weight was lower [567 g (108) vs. 658 g (142), P = 0.023], compared with boys with no urogenital malformations. However, only one boy with (penile) hypospadias was born SGA (WGA = –42.54%), whereas the rest of the cases were born with appropriate weight for gestational age (range –21.09 to 24.18).
In boys with coronal or penile hypospadias, birth weight (P = 0.027), length (P = 0.030), head circumference (P = 0.030), and WGA (P = 0.011) were smaller than in healthy boys (Table 2). We found a decreasing linear trend for birth weight (P = 0.005), birth length (P = 0.015), head circumference (P = 0.002), and weight for gestational age (P = 0.008) with more severe type of hypospadias (glandular-coronal-penile) (Fig. 2).
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Reproductive hormones
At 3 months of age, we found significantly higher levels of FSH and higher FSH to inhibin B ratios among boys with hypospadias, compared with healthy boys. No other reproductive hormone differed significantly between healthy boys and boys with hypospadias (Table 3). We also found elevated FSH levels [median (95% prediction interval)] in the group of boys with glandular hypospadias alone, compared with healthy boys [1.43 IU/liter (0.62–3.99) vs. 1.15 IU/liter (0.41–2.85), P = 0.033]. FSH to inhibin B ratio tended to be elevated in boys with glandular hypospadias, compared with healthy boys [0.34 (0.17–1.16) vs. 0.29 (0.08–1.02), P = 0.095].
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Discussion |
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We do not exclude that some of the mild cases of hypospadias diagnosed during childhood could represent normal variants of penile morphology. However, these boys showed a trend toward impaired intrauterine growth, and basal FSH levels at 3 months of age were significantly higher than in healthy boys. The latter may imply an impaired testicular function necessitating an increased gonadotropic drive. Thus, the present findings corroborate the hypothesis that these cases are true, but mild, disorders of male genital development. Because all boys with late-diagnosed hypospadias had normal-looking prepuce, these cases may easily be overlooked unless genital examination includes a gentle attempt to retract the foreskin and inspect the urethral meatus if visible, also after the neonatal period.
Even disregarding these late-diagnosed hypospadias the Danish prevalence is very high, compared with previous data (1, 2, 3), although a birth rate of hypospadias of 0.73% was reported from The Netherlands in a recent cross-sectional study of boys examined before the age of 6 months (14). A Finnish cohort study closely coordinated with our study revealed a significantly lower rate of hypospadias of 0.27% (P = 0.012) (15). Furthermore, the Danish cases detected at birth were in general more severe than those in Finland in which only glandular and coronal cases were found. Thus, the present study confirmed an interesting difference between these two Nordic countries with regard to male reproductive health symptoms and lends support to the assumption that Danish more often than Finnish males suffer from testicular dysgenesis syndrome, which besides hypospadias entails testicular cancer, cryptorchidism, and spermatogenetic failure. The etiology of this syndrome is not yet clarified but may include developmental exposure to endocrine disrupting chemicals and/or lifestyle factors in combination with genetic susceptibility (7).
Our findings may represent an increase in the incidence of hypospadias in Denmark, although results from previous studies are not directly comparable. Sorensen (16) made an extensive retrospective examination of case notes, 1910–1945. Among boys alive at discharge (10 d old), he found a prevalence of hypospadias of 0.33% (90 of 27,613). Although the exact prevalence of subtypes was not established, the author estimated that three quarters were distal (16).
The prevalence of hypospadias in Denmark (Odense County) in 1997–2001 was estimated to be 12.85 per 10,000 total births according to EUROCAT (www.eurocat.ulster.ac.uk/; a joint European surveillance study). However, glandular hypospadias were not included in this register, thus underestimating the prevalence. Furthermore, several studies have suggested a substantial underascertainment of hypospadias in registers (1, 2, 6, 14), rendering register-based studies unsuitable for evaluation of geographic differences and temporal trends.
We found lower mean WGA and placental weights in boys with hypospadias irrespective of the subtype or age at diagnosis compared with healthy boys. Boys with coronal or penile hypospadias had lower mean birth weight, shorter mean birth length, smaller mean head circumference, and lower mean WGA, compared with healthy boys. Two of the boys with penile hypospadias had additionally congenital heart malformations, which could possibly affect the anthropometrical measurements. Yet the trend toward lower WGA also was found for boys with glandular and coronal hypospadias. These findings are in line with previous studies reporting that being small for gestational age rather than absolute birth weight is the dominating risk factor for hypospadias (17, 18, 19).
Previous epidemiological studies have found a close relationship between low birth weight and hypospadias (5, 17, 20, 21, 22). In monozygotic twins discordant for hypospadias, the twin with the lower birth weight was the one with hypospadias (23), and boys with hypospadias have been shown to have lower birth weights than their healthy brothers (18).
Birth weight exhibits well-known gender-specific differences, assumed to be associated with differences in fetal androgen levels (24, 25). We have previously described anthropometrical measurements in girls from the same cohort (26). Interestingly, birth weight and weight for gestational age in boys with coronal or penile hypospadias was actually smaller than those in girls. At 18 and 36 months of life, this group of boys still tended to be smaller than the average. The reasons for the association of hypospadias and other genital abnormalities with intrauterine growth retardation are currently not known, but defects of placental function and endocrine dysregulation have been hypothesized to be involved in these disorders.
Previous reports on reproductive hormones in boys with hypospadias have shown conflicting results, most probably due to differences in severity of hypospadias, age of the included cases, and the applied hormone assays (27, 28). No studies have thus far evaluated basal hormone levels during the early postnatal surge of reproductive hormones. Although there was no significant difference in serum testosterone and LH levels between the groups, the higher FSH values represent an increased gonadotropin drive of testicular function indicating a primary testicular dysfunction. Prenatal growth restraint has been shown to lead to elevated serum FSH concentrations in infant boys (29). However, only one boy with hypospadias was born SGA in our material. The group of boys with hypospadias in this study may be too small to detect differences in serum LH and testosterone because these reproductive hormones have only a brief postnatal peak (30).
The etiology of hypospadias remains obscure in most cases (31). There is a clear genetic component in the etiology illustrated by familial cases, although only a small percentage has been linked to single gene mutations (32). We found no androgen receptor mutations in the boys with penile hypospadias, and the number of CAG repeats were within the limits of the normal range in the Danish population (13). We hypothesize that some cases may be due to intrauterine exposure to environmental factors and that this could at least partly explain the difference in the prevalence between Denmark and Finland. Hypospadias in male rodents have been found after maternal treatment with potent estrogens (e.g. diethylstilbestrol), 5-reductase inhibitors (e.g. finasteride), androgen receptor antagonists (e.g. vinclozolin; 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene; and prochloraz), and cytochrome P450 enzyme inhibitors (e.g. some fungicides) (33). Dietary exposure of pregnant rats to high levels of dibutyl phthalate also caused testicular dysgenesis, including hypospadias in the offspring (34).
In conclusion, in this large prospective cohort study we found a surprisingly high total rate of hypospadias of 4.6% in Denmark. Seventy-two percent of the cases were apparent in childhood only after the prepuce could be retracted. Hypospadias were associated with elevated serum FSH levels at 3 months. We also confirmed an association between fetal growth impairment and hypospadias; however, it is yet unknown whether this indicates a causal relationship or a shared pathogenic factor.
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Footnotes |
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First Published Online May 3, 2005
Abbreviations: CI, Confidence interval; CV, coefficient of variation; SGA, small for gestational age; TDS, testicular dysgenesis syndrome; WGA, weight for gestational age.
Received February 14, 2005.
Accepted April 22, 2005.
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, Outlier; *, extreme.