The Testicular Dysgenesis Syndrome: Associated Maternal Exposures and Future Burden of Testicular Germ Cell Tumors in the US
Open AccessBackgroundTesticular germ cell tumors (TGCT) are rare tumors in the general population but are the most commonly occurring cancer among men between the ages of 15 and 44 years in many countries, including the United States (US). While non-Hispanic white men have the highest incidence of TGCT in the US, the rate of increase over time has slowed, while the rates among other racial/ethnic groups, particularly Hispanics, have increased. Whether incidence rates among men from other racial/ethnic groups will ever approach the rates among non-Hispanic whites is unclear. Despite the well-documented increase in rates, the etiology of TGCT remains uncertain, although evidence suggests that it is initiated in-utero. TGCT is known to be associated with other male reproductive disorders, including two manifest at birth (cryptorchidism, hypospadias) and one manifest in adulthood (impaired spermatogenesis). Collectively, the four disorders (TGCT, cryptorchidism, hypospadias, impaired spermatogenesis) make up the Testicular Dysgenesis Syndrome (TDS). Understanding factors that are related to any of the TDS conditions may better help to understand the etiology of all the conditions, including TGCT. As the in-utero hormonal milieu is critical to the development of the male phenotype, factors that affect hormone levels may play key roles in determining TDS. Two important factors could be proper placental functioning and maternal exposure to endocrine disrupting chemicals (EDCs). ObjectivesThis dissertation investigated future trends in TGCT incidence, explored certain placental characteristics and risk of cryptorchidism and hypospadias, and examined personal care product use during pregnancy and TGCT risk in sons. The study aims were to 1) forecast trends in TGCT incidence by race/ethnicity to determine the future burden of TGCT in the US, 2) to evaluate the association between placental characteristics (placental thickness, placental infarcts, type of umbilical cord insertion, neutrophils in the amnion of placental surface, hemorrhage of maternal surface of placenta, laceration of maternal surface of placenta, intervillous thrombosis, calcification of the placenta, and presence of macrophages in the amniotic fluid) and risk of two congenital anomalies (cryptorchidism and hypospadias), and 3) to evaluate the association between personal care product use during pregnancy and risk of TGCT in sons.MethodsThe first study in this dissertation utilized incidence data from population-based cancer registries from the Cancer Incidence in North America (CiNA) analytic file provided by the North American Association of Central Cancer Registries (NAACCR). Cancer incidence data that meet high-quality standards from the Surveillance, Epidemiology and End Results program of the National Cancer Institute and the Centers for Disease Control and Prevention’s National Program of Cancer Registries are included in the CiNA analytic data set. For the first study, age-period-cohort (APC) models were used to observe TGCT incidence rates by racial/ethnic group. A forecasting model was developed from the APC models which was used to calculate age-specific forecasts of future TGCT incidence rates. The forecasting model was also used to calculate age-specific forecasts of future TGCT burden by the corresponding US population projections (provided by the US Census Bureau). The second study utilized data from the Collaborative Perinatal Project (CPP), a prospective maternal-child study conducted by National Institute of Neurologic Diseases and Stroke (NINDS). Between 1959 and 1965, the CPP enrolled 48,917 pregnant women who received prenatal care from 12 medical centers in the US. Placental measures and characteristics were collected from study participants according to a protocol prepared specifically for the CPP. Unconditional logistic regression adjusting for identified covariates was used to calculate adjusted odds ratios and their 95% confidence intervals (CIs) for the association between selected placental characteristics and risk of two congenital anomalies (cryptorchidism and hypospadias). The third study utilized data from The US Servicemen’s Testicular Tumor Environmental and Endocrine Determinants study, a case-control study of testicular germ cell tumors among military servicemen conducted by the NCI and the Department of Defense. Unconditional logistic regression adjusting for identified covariates was used to calculate adjusted odds ratios and their 95% CIs for the association between selected maternal factors and TGCT risk.ResultsBetween 1999 and 2012, TGCT incidence rates, overall and by histology, were highest among NHWs, followed by Hispanics, Asian/Pacific Islanders, and non-Hispanic blacks. Between 2013 and 2026, rates among Hispanic men were forecast to increase by 3.96% annually, the highest rate of increase of any racial/ethnic group. By 2026, the highest TGCT rates in the US will be among Hispanics, due to increases in both seminoma and nonseminoma. Rates among NHWs will increase slightly, while rates among other racial/ethnic groups will decrease slightly. In the second study, the analysis of cryptorchidism found that lower placental weight was associated with increased risk (p-trend: <0.01). In categorical analyses in which the middle tertile was the reference group, cryptorchidism was inversely associated with placental weight in the highest tertile (OR: 0.66, 95% CI: 0.46-0.94) among white boys, and positively associated with placental weight in the lowest tertile among black boys (OR: 1.70, 95% CI: 1.11-2.59). Additionally, cryptorchidism was significantly associated with circummarginate (OR: 1.90, 95% CI: 1.18-3.05) umbilical cord insertion among white boys. The analysis of hypospadias found that boys born in pregnancies in which there was calcification on the maternal surface of the placenta were at significantly higher risk (OR: 1.52. 95% CI: 1.04-2.20). In the third study, maternal use of face lotion more than one time per week was associated with a significantly increased risk of TGCT (OR: 1.42, 95% CI: 1.09-1.86, p-trend: 0.01). None of the other products examined (perfume, hairspray, nail polish, hair dye, permanent wave, body lotion, deodorant, sunscreen) were associated with TGCT risk.ConclusionBy 2026, Hispanics will have the highest rate of TGCT of any racial/ethnic group in the US because of the rising incidence among recent birth cohorts. Reasons for the increase in rates and trends are unclear, but could be related to as yet unidentified varying exposures, place of birth, country of ancestry and/or length of residence in the US. The increasing rates among Hispanic men suggest an area where future public health prevention efforts and education should be targeted. The results from the second study suggest that placental insufficiency may be related to risk of cryptorchidism and hypospadias. Additionally, our significant findings with cirummarginate umbilical cord insertion and placental calcification suggest possible clinical implications. It may prove fruitful for clinicians to not overlook these conditions as they may be clinically relevant in both cryptorchidism and hypospadias risk. Further studies examining the association of placental insufficiency with these anomalies are warranted. The results from the third study suggest that exposure to some personal care products during pregnancy may affect TGCT risk in sons. Further investigation is warranted concerning specific chemicals in personal care products that might influence TGCT risk as well as combinations of chemicals, as a majority of women in the current study reported using more than one type of product. Future studies would benefit from a more detailed assessment of personal care product use during pregnancy and breastfeeding and also among a more racially/ethnically diverse population.
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