IJE Advance Access originally published online on February 21, 2006
International Journal of Epidemiology 2006 35(3):787-795; doi:10.1093/ije/dyl024
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Published by Oxford University Press 2006
Article |
Risk factors for cryptorchism among populations at differing risks of testicular cancer
1 Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Rockville, MD, USA
2 National Institute of Child Health and Human Development, NIH, DHHS, Rockville, MD, USA
3 National Institute of Environmental Health Sciences, NIH, DHHS, Research Triangle Park, NC, USA
* Corresponding author. Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, 6120 Executive Boulevard, EPS-7060, Rockville, MD 20852, USA. E-mail: mcglynnk{at}mail.nih.gov
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Abstract |
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Background Cryptorchism is strongly associated with the development of testicular germ cell tumours (TGCTs), possibly owing to a common aetiology. However, while TGCT incidence varies greatly between white and black men, little variability has been reported between the two groups in cryptorchism prevalence. This may suggest that cryptorchism risk factors differ by ethnicity.
Methods To examine this hypothesis, a prospective analysis was conducted among black and white participants in the US Collaborative Perinatal Project. White participants included 238 cryptorchid sons and 12 296 non-cryptorchid sons, while black participants included 188 cryptorchid sons and 11 942 non-cryptorchid sons.
Results While cryptorchism was significantly more common among white sons (1.90% vs 1.55%; P = 0.04), the difference was incompatible with the 5-fold difference in TGCT rates. The principal maternal risk factors among white sons were age (P = 0.03), hypertension/proteinuria (P = 0.006), and length of time to become pregnant (P = 0.055), while major maternal risk factors among black sons were age (P = 0.06), height (P = 0.007), weight (P = 0.06), and radiation exposure (P = 0.02). Only maternal height, however, had a different relationship with risk among black and white sons. Neonatal associations with risk (shorter gestational age, lower birthweight, shorter length) were similar in the two groups.
Conclusions These results do not support the hypothesis that the risk factors for cryptorchism vary dramatically by ethnicity but may suggest that cryptorchism is not as closely linked to TGCT among black men as among white men.
Keywords Cryptorchism, testicular cancer, ethnicity, risk factor
Accepted 30 January 2006
Cryptorchism is one of the most common congenital anomalies among males1 and is strongly associated with the development of testicular germ cell tumours (TGCTs).2 It has been suggested that both conditions, as well as hypospadias and poor semen quality, are part of a testicular dysgenesis syndrome (TDS) that originates in utero.3 The aetiology of the TDS disorders is currently unknown, although in utero exposure to an oestrogenic milieu, an anti-androgenic milieu, or to placental abnormalities have all been suggested as possibilities.4–7
TGCTs are notable for their early age of onset (15–35 years) and for the disparity in incidence rates between different countries and different ethnic groups living in the same country. In the US, the incidence among white men, which has been increasing for at least 50 years, is five times greater than the incidence among black men.8 This difference in TGCT rates suggests that a similar difference in the prevalence of cryptorchism may exist. It is not clear, however, that this is the case. While some studies have reported that white males have a significantly higher risk of cryptorchism than black males,9 other studies have reported no difference in risk.10–13 In addition, many of the suggested risk factors for cryptorchism, such as low birthweight, short gestational age, and being born small-for-gestational age, are reported to be more common among US black babies,14 indicating that the relationship between these factors and cryptorchism might not be the same in white and black babies. Previous studies, however, have not specifically determined whether cryptorchism risk factors differ by ethnicity. Therefore, the present study was undertaken to examine risk factors for cryptorchism in a large, multiethnic cohort study.
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Material and methods |
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Study participants
The study participants were enrolled in the US Collaborative Perinatal Project (CPP), a prospective study of pregnant women and the children they delivered.15 The women were recruited between 1959 and 1965 at 12 US study centres [in Baltimore, Boston, Buffalo, Memphis, Minneapolis, New Orleans, New York (two), Philadelphia, Portland, Providence, and Richmond]. Eleven study centres recruited patients from the participating University Hospital's prenatal clinic, while one study centre recruited patients from 13 participating private practices. Women were ineligible if they were incarcerated, if they were planning to leave the area or to place the child for adoption, or if they gave birth on the day they were recruited into the study. Approximately 42 000 women were enrolled, and 55 000 children were born in the study. The children were examined at scheduled intervals for birth defects and other outcomes through age 7 years. During the first year of life, the children were assessed three times; in the delivery room, at age 4 months, and at age 12 months.
For the present study, only male babies born to black or white mothers were eligible for inclusion. Other eligibility criteria were: (i) gestation between 26 and 48 weeks, (ii) birthweight 
500 g, and (iii) baby lived at least 1 year. Limits were placed on gestational age and birthweight because values outside the stated limits were likely to be data errors, given that the births took place in the 1960s. While gestational ages equal to or greater than 44 weeks were almost certainly inaccurate, as well, babies with those gestational ages were not excluded as it is highly likely that they were full-term.16 As the analysis plan included gestational age only as a dichotomous variable (pre-term, not pre-term), the exclusion of babies in the 44–48 weeks gestational age range was not deemed necessary. The criterion that the children had to live at least a year was included because diagnoses of cryptorchism in the delivery room are unreliable, as testes frequently descend after birth.17 Research indicates, however, that most testes that spontaneously descend will do so within the first 6 months of life.18 As the CPP did not have a physical examination between the 4th and 12th months of life, however, only boys who lived until the 12 month exam were included in the current study. Boys first observed to be cryptorchid after the first year of life were not included because it was impossible, in those cases, to distinguish true cryptorchism from retractile testes.
Variables selected for evaluation included ones that were specifically maternal in nature, as well as those that were classified as neonatal. The maternal variables included age, pre-pregnancy weight, weight gain during pregnancy, height, marital status, socioeconomic status, length of time to become pregnant, gravidity, last prior pregnancy outcome, prior pregnancy loss, infertility history, blood type, Rh factor, age at menarche, DES use, all oestrogen use, progestin use, viral infections, bacterial infections, live vaccines, smoking status at enrolment, radiation exposure preceding pregnancy, hypertension/proteinuria, diabetes, hypothyroidism, hyperthyroidism, hyperemesis gravidarum, vaginal bleeding, and vomiting by trimester. One paternal variable, age of the father, was also examined. The socioeconomic index calculated for subjects in the CPP was the mean of three percentile scores (for education, occupation, and family income), where education was for the head of the household, occupation was for the head of the household or chief wage earner, and the score used to calculate the percentile for an occupation was based on the percentiles of education and income among those with the same occupation.19
Neonatal variables examined included gestational age, birthweight, small-for-gestational age, chest circumference, head circumference, body length, season of birth, multiple birth, method of delivery, hydramnios, inguinal hernia, hypospadias, chordee, other external abnormalities of the genitalia, genetic syndromes, and placental weight. Small-for-gestational-age was determined by comparing birthweights for each gestational age in the CPP to the 10th percentile of birthweight for gestational age developed for California non-Hispanic white births between 1970 and 1976.20 The 10th percentiles of birthweight for gestational age for black births were obtained directly from R.L. Williams (personal communication).
Statistical methods
The proportions of unilateral and bilateral cryptorchism by ethnicity were compared using chi-squared tests of independence. For the examination of the relationship between maternal variables and cryptorchism, race-specific univariate logistic regression analyses were used to compute relative risks (RRs) and 95% confidence intervals (95% CIs) for each variable. For these analyses, most continuous variables were categorized based on their distribution in the whole study population. In the next step, race-specific multivariable logistic regression models of maternal variables that included variables found to be statistically significant in the univariate analyses were examined. Next, a multivariable logistic regression model that included the maternal variables from both the black and white analyses was examined. The model also included a term for race. Finally, a series of multivariable logistic regression models were examined that included interaction terms between race and each maternal variable.
The same analysis strategy was repeated for the neonatal variables. Race-specific univariate models identified neonatal factors related to cryptorchism. Significant factors were then included in race-specific multivariable models. Finally, all neonatal data were included in a single model that included a term for race and, as a last step, the significance of interactions between race and each variable were examined in a series of models. Although the interpretation of such a model is not entirely clear, a final analysis included all variables, both neonatal and maternal, in a single model. All statistical tests were two-sided. Analyses were done using the SAS software package, version 8.0 (SAS Institute, Cary, NC).
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Results |
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Data from 24 664 male births were included in the analysis. 12 534 of the births (50.8%) occurred among white mothers and 12 130 (49.2%) occurred among black mothers. Among the sons of white mothers, there were 238 diagnoses of cryptorchism, resulting in a prevalence of 1.90%. The comparable prevalence among sons of black mothers, 1.55% (188/12 130), was significantly lower than the prevalence among the white sons (
2 = 4.42; P = 0.04). Among the sons with cryptorchism, 31% (74/238) of the white sons had bilateral cryptorchism, compared with 24% (45/188) of the black sons; a difference that was not statistically significant (2 = 2.67; P = 0.10). White and black mothers of cryptorchid sons were similar to mothers of non-cryptorchid sons with respect to maternal weight gain, marital status, socioeconomic status, smoking status at study enrolment, infertility history, gravidity/parity, prior pregnancy loss, last prior pregnancy outcome, diabetes, hyperemesis gravidarum, and DES use (Table 1). Case and control mothers also did not vary with respect to body mass index, blood type, Rh factor, history of dysmenorrhoea, age at menarche, any oestrogen use in pregnancy, progestin use in pregnancy, viral or bacterial infections, live vaccines received, hypothyroidism, hyperthyroidism, vaginal bleeding during pregnancy, vomiting during pregnancy, or having a previous child with a congenital malformation (data not shown).
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Among white mothers, variables significantly related to cryptorchism included older maternal age, longer duration of time trying to become pregnant, and gestational hypertension or pre-eclampsia (Table 1). Risk also increased with increasing paternal age, although the risk was not significant until the father's age reached 40 years (RR = 5.4; 95% CI 1.3–23.4). Among black mothers, height and radiation exposure were significantly associated with risk. Black mothers' risk also increased directly with age (P = 0.06) and weight (P = 0.06).
A multivariable analysis of the maternal risk factors that were univariately related to risk found that only older maternal age (P = 0.02) and hypertension/proteinuria (P = 0.002) remained significant among white mothers (Table 2). Among black mothers, only maternal height (P = 0.002) remained significantly associated with risk, while radiation in the previous 12 months remained of borderline significance (P = 0.054). The inclusion of medical centre into the models had no effect on the results.
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An examination of maternal variables in a single model that included the data of all mothers found that the only variable that remained significantly related to cryptorchism was hypertension/proteinuria (P = 0.04). The subsequent series of models that included interaction terms between race and each maternal variable found that only height had a different relationship to cryptorchism in blacks and whites (P = 0.02). While the black mothers had a U-shaped relationship between risk and height, there was no indication of any relationship among white mothers.
Neonatal variables that were significantly associated with risk among both black and white babies included lower birthweight, shorter body length, and smaller chest circumference (Table 3). Inguinal hernia, hypospadias, other external urogenital anomalies, and genetic syndromes were also significantly associated with risk in both ethnic groups. Among black babies, smaller head circumference (RR = 0.9; 95% CI 0.8–0.9) and placental weight (data not shown) were significantly associated with risk, while among white babies, hydramnios (RR = 2.1; 95% CI 1.1–3.9) and chordee (RR = 8.7; 95% CI 1.9–39.4) were significantly associated. Neither decreased gestational age (<37 weeks) nor being born small-for-gestational-age were formally associated with risk although decreased gestational age was of borderline significance (P = 0.055) in white babies, while being small-for-gestational-age was of borderline significance (P = 0.08) in black babies.
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Among white babies, a multivariable analysis of the neonatal factors that were univariately associated with risk found that only low birthweight (P = 0.0005) remained significantly related to risk (Table 4). Shorter body length was related to risk, though the association was only of marginal significance (P = 0.06). Similarly, among black babies only low birthweight remained significantly associated with risk (P = 0.0003). The inclusion of medical centre into models did not affect the results. For both analyses of black and white babies, identical results were obtained whether forward or backward stepwise logistic regression was employed.
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In a final examination of the data, both maternal and neonatal variables were examined together in a single model. In a model that included the data of all mothers and sons, only maternal weight (P = 0.02), birthweight (P = 0.001), and race (P = 0.006) were significantly associated with risk of cryptorchism. The subsequent series of models that included interaction terms between race and each variable found that, again, only height had a different relationship with cryptorchism in blacks and whites (P = 0.01).
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Discussion |
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One of the most striking features of TGCT is the great difference in risk among various ethnic groups.8 As cryptorchism is one of the few well-established TGCT risk factors, it might be expected that the prevalence of cryptorchism would show a similar disparity. Most studies, however, have not reported a substantial difference in risk.10–12,21
One report to find a significantly higher prevalence of cryptorchism among white babies originated from the CPP.9 Defining cryptorchism differently than in the present study, the report noted that the prevalence among white babies was three times the prevalence among black babies. However, the findings were based on only 12 diagnoses of cryptorchism; nine among white and three among black babies. In contrast, three other reports from the CPP, using various definitions of cryptorchism, found no difference in prevalence by ethnicity,10,11,21 though one study did note a higher prevalence of bilateral cryptorchism among white (0.23%) vs black babies (0.15%).10 Studies of other US populations have not found a significant difference in prevalence between the two groups.12,13
The present study's finding of a significantly higher prevalence of cryptorchism among white sons is not inconsistent with these prior reports, given that the white prevalence (1.90%) is less than half a per cent higher than the black prevalence (1.55%). Such a small degree of difference cannot explain the 5-fold difference in TGCT incidence but may suggest that cryptorchism is not as closely linked to TGCT among black men. However, few data currently exist on the cryptorchism–TGCT relationship in black men, as most TGCT studies have been unable to include black participants. One study from South Africa, however, found that cryptorchism was significantly more common among black TGCT patients than among white.22 This finding is consistent with the alternative hypothesis that the cryptorchism-TGCT link is similar in both groups, but there are other unidentified risk factors that are more common among white populations. It is also possible that the higher risk among white populations is due to increased genetic susceptibility to an exposure equally common among blacks and whites.
In the current study, an examination of cryptorchism risk factors in black and white sons found no striking differences between the groups. The only factor that had a different relationship with risk by ethnicity was maternal height. Among black mothers, height was the single factor most significantly related to cryptorchism and had a U-shaped association with risk such that mothers shorter than 5'2'' or taller than 5'4'' had an increased risk. Though height has not been extensively examined in prior studies, one other study found a similar U-shaped association,7 and several studies reported body mass index associations with risk.11,12 In the present study, however, the association between weight and risk in black mothers disappeared when weight was examined in a multivariate model with height. When weight and height were replaced in the model with body mass index, there was no association with risk. Why height of black mothers would increase risk at the ends of the spectrum in not clear but is not likely explained by maternal hormones levels. In a companion study to the present one, height of black mothers was not associated with estradiol, estriol, or testosterone levels in either first or third trimester samples.23 As height was one of many variables examined in the current study, it is also possible that the association was a chance finding.
Other than that for maternal height, there were no significant differences in the distributions of the variables among the black and white participants. Among white mothers, but not black mothers, increased maternal age, a longer time trying to become pregnant, and increased risk among older primigravidas suggest that subfertility might be related to risk. Whether subfertility was more common among the white mothers is unclear, although the white mothers were slightly older than the black mothers and were more likely to be primigravidas. In addition, white mothers were more than twice as likely as black mothers to have a history of infertility (3.63% vs 1.29%). Prior studies of white mothers have also reported an association between cryptorchism and decreased fertility.7,24,25 Further speculation based on the current study is somewhat difficult, however, as the study did not ascertain whether any underlying subfertility was maternal or paternal in nature.
Another possible explanation for the maternal age association in white mothers is that some studies have found that maternal estradiol26,27 and testosterone levels decline23,26 with age, though other studies have reported no association.28 In a CPP companion study to the present one, estradiol was not associated with age in either white or black mothers.23 In white mothers, however, a significant inverse association was found between testosterone levels and age, suggesting that the lower testosterone levels of older white mothers increase the risk of cryptorchism in their sons. This hypothesis was not supported in another companion CPP study, however, which found no relationship between maternal testosterone levels and cryptorchism in either white or black mothers.29
Similar to the maternal factors, associations between neonatal factors and cryptorchism did not vary greatly between black and white babies. Gestational age was more strongly associated with cryptorchism among white babies, while being small-for-gestational-age was more strongly associated in black babies. Neither variable, however, was formally significant. The lack of significance may have been due to the exclusion criteria, which limited study participation by length of gestation, birthweight, and vital status at 1 year.
Most measures of size of the baby (birthweight, chest circumference, and body length) were significantly related to risk among all babies, such that smaller, lighter babies were at higher risk than larger, heavier babies. Although the associations between body length and chest circumference with risk have not been widely examined in prior studies, their association with risk is not surprising given their relationship with birthweight and gestational age. Other genitourinary anomalies, such as inguinal hernia, hypospadias, and abnormalities of the genitalia were also, as anticipated from prior studies, significantly related to risk among all babies.7,12,13,24,30,31
Taken as a whole, the current study suggests that there are few differences in risk factors for cryptorchism among white and black babies. The relationship with maternal age in both white and black mothers and with time-to-pregnancy in white mothers may indicate that some aspect of maternal subfertility is related to cryptorchism. If this is the case, it might be expected that the prevalence of cryptorchism would have increased somewhat in the last 40 years as average maternal age has increased during this interval.14 Recent reports, however, have not found an increase in cryptorchism prevalence in the US though time trends have been difficult to estimate given temporal changes in definition.32 In support of the relationship between cryptorchism and maternal age are other recent reports that another TDS congenital disorder, hypospadias, also appears to be associated with maternal age.33–35
The major strengths of the current study were the prospective nature and focus on examination of the children over a number of years. This is an important consideration as full testicular descent is a late event in pregnancy, often not being completed until well after birth. The study was also quite large, including almost 25 000 births, was comprised of almost equal numbers of black and white babies, and included more black babies than any previously reported study. Although prior studies have included more than one ethnic group, most have not specifically examined whether there were differences in risk factors by ethnicity.
Given the size of the study, there was more than sufficient power to detect significant differences, even small differences that might contribute little to total risk. In that the study confirmed many previously reported associations, however, it is unlikely that the currently reported risk factors achieved significance only as a result of large numbers. The study also examined association with a large number of variables, which might increase the likelihood of finding statistically significant results. As a result, the findings were interpreted cautiously. Similarly, while the prospective nature of the study was an ideal design, it limited the number of cryptorchid cases that could be examined. Finally, the fact that the study took place in the 1960s may limit the ability to extrapolate findings to the present time.
In conclusion, the small difference in cryptorchism prevalence and the negligible differences in cryptorchism risk factors suggest that neither cryptorchism nor cryptorchism risk factors determine the difference in TGCT incidence among black and white men. Other, as yet, unidentified factors may be present among white populations, but not among black populations. It is difficult to know what these other factors might be as very few TGCT studies have included black men. Future efforts to include ethnic minorities in TGCT studies may prove helpful in elucidating why the rates vary greatly among different populations of men.
KEY MESSAGES
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Acknowledgments |
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This research was supported by the Intramural Research Program of the NIH, NCI, NIEHS, and NICHD.
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