Exposure to maternal hormones (during pregnancy), particularly estrogen (DES), is associated with testicular germ‐cell cancer risk, 2000
The present case-control study was undertaken to investigate the association between exposure to maternal hormones and risk of testicular germ-cell cancer (TGCC) by histologic subgroups.
Cases were males, aged 16 to 59 years, diagnosed with testicular germ-cell cancer in Ontario between 1987 and 1989.
Histologic review was performed on all eligible cases for the purpose of categorizing cases as seminoma or non-seminoma (the latter classified 2 ways, with and without tumors containing seminoma). Risk factor data were collected on 502 cases, 346 case mothers, 975 age-matched controls, and 522 control mothers.
Exogenous hormone exposure was associated with elevated risk (OR = 4.9, 95% CI 1.7-13.9). Several additional risk factors were associated with risk of testicular cancer: bleeding and threatened miscarriage (OR = 0.6, 95% CI 0.3-1.0), maternal cigarette smoking (12+ cigarettes/day OR = 0.6, 95% CI 0. 4-1.0). pre-term birth (OR = 1.6, 95% CI 1.0-2.5), and treatment for undescended testicle (OR = 8.0, 95% CI 3.2-20.0). First births were associated with elevated risk (OR = 1.7, 95% CI 1.0-2.8) among mothers below the age of 24 years at conception. There was little evidence that risk factors differed by histologic subgroup. We found evidence that exposure to maternal hormones, particularly estrogens, is associated with testicular germ-cell cancer risk. Not only does exposure to elevated levels (exogenous hormone use, pre-term birth, and first births among young mothers) increase risk but also exposure to relatively lower levels (heavy cigarette consumption and, perhaps, bleeding and threatened miscarriage) may decrease cancer risk.
The early age at incidence of testicular germ‐cell cancer suggests that childhood exposures, possibly even those occurring in utero, may be important, including exposure to maternal hormones, from exogenous and endogenous sources.
A number of case‐control studies have interpreted results based on the hypothesis that exposure to maternal hormones elevates risk of testicular cancer (see 1980 study, 1983 study, 1986 study) however, their results have not been entirely consistent with this hypothesis.
The present case‐control study was undertaken to examine the association of maternal hormone exposure, from both exogenous and endogenous sources, and risk of testicular germ‐cell cancer. The study also included histological review of all eligible cases, to further investigate the association according to the major histological subgroups, seminoma and non‐seminoma (the latter classified 2 ways, with and without tumors containing seminoma).
Definition of exposure variables
Exogenous hormone exposure was determined from the mother’s reported use of prescription hormones [e.g., diethylstilbestrol (DES) or premarin], prescription medication for conditions associated with threatened miscarriage, injections or pills to determine pregnancy, and use of oral contraceptives around the time of conception. Because reported exposures to exogenous hormones were uncommon, these exposures were combined into a dichotomous variable, coded “yes” if the mother reported exposure to any of the sources of exogenous hormones and “no” if she reported exposure to none of them.
Early population‐based case‐control studies reported that exogenous hormone exposure, in the form of pregnancy tests and hormone use for threatened miscarriage, elevated risk for testicular cancer (see 1979 study, 1980 study, 1983 study), while later studies failed to confirm the association (see 1986 study, 1988 study). Despite the fact that the present study provides evidence of an association in both histological subgroups, caution should be used in interpreting the results: DES has been associated with adverse health effects in both male and female offspring, exposure status was not validated in the current study, and participation rates among case mothers were higher than among control mothers. Potential recall bias has been reported in other studies, and such bias could be expected to operate in both histological subgroups.
In conclusion, our results support the hypothesis that exposure to maternal hormones, particularly estrogen, is associated with testicular germ‐cell cancer risk. Not only does exposure to elevated levels of maternal hormones (exogenous hormone use and pre‐term birth) appear to increase cancer risk, but exposure to relatively lower levels of maternal hormones (heavy cigarette consumption and, perhaps, bleeding and threatened miscarriage), as measured by indices of exposure to maternal hormones, appears to decrease cancer risk. Future studies should consider direct measurement of these exposures, to further explore the association between maternal estrogen exposure and risk of testicular germ‐cell cancer.
Evidence that risk factors differ by histological subgroup has been difficult to interpret. Our results support the conclusion of Møller and Skakkebæk that the causes of seminoma and non‐seminoma are likely the same. Furthermore, there is little convincing evidence to support the need to distinguish between non‐seminomatous tumors containing seminoma and those not containing seminoma. However, caution should be used in interpreting these results because small numbers in the histological subgroup analysis resulted in limited statistical power to detect differences. Since the evidence for possible differences comes from studies looking at maternal age and parity, an understanding of the mechanisms underlying histological differences may come with a better understanding of how maternal age and parity themselves are associated with risk of testicular germ‐cell cancer.
DES DIETHYLSTILBESTROL RESOURCES