We observed a two-fold increased risk of TGCT associated with frequent marijuana use. In histologic specific analyses, the associations were limited to nonseminomas. These associations were independent of known risk factors for TGCT, age, race and prior cryptorchidism, as well as cigarette smoking and alcohol consumption. We also reported reduced risk of TGCT associated with infrequent and short-term use; however, these findings were not robust to sensitivity analyses and require further evaluation.
There is limited evidence that marijuana use may modulate TGCT risk. The only other published study to date examined the association of marijuana use and TGCT in a population-based case-control study in Western Washington State.10
Daling and colleagues reported that men with TGCT were significantly more likely than controls to be current marijuana users. The association was particularly strong among men who were frequent current users (at least weekly) or current users of long duration (ten years or more).10
In addition, the associations appeared to be limited to cases with nonseminoma or mixed germ cell tumors.10
Unlike the study in Western Washington State the results of our study are not supportive of an association between weekly marijuana use and TGCT; instead, our results are supportive of a substantially increased risk of TGCT with very frequent marijuana use, daily or greater. In addition, although we were not able to evaluate current use with our data (< 10% of our study population reported current marijuana use), our findings are supportive of the association between frequent and long-term marijuana use and nonseminoma.
Puberty may be a period of development during which environmental factors increase the risk of TGCT.17
Exposures during this time may be more relevant to nonseminoma TGCT risk, given that the peak occurrence of nonseminoma TGCT occurs ten-years earlier than seminoma TGCT, and within a biologically relevant time period after puberty. It is plausible that the use of marijuana during puberty perturbs the hypothalamic-pituitary-gonadal axis leading to altered levels of pituitary gonadotropins (follicle-stimulating hormone (FSH) and luteinizing hormone (LH)) and sex-steroid hormones and potentially increased risk of nonseminoma TGCT.
Studies have demonstrated that acute or chronic treatment of cannabis-extract in male mice and tetrahydrocannabinol (THC), the active ingredient in marijuana, in male rats can act centrally to affect circulating levels of testosterone, FSH, and LH.13;18-20
Two cannabinoid receptors exist in humans, the brain-type receptors (CB1) and the spleen-type receptors (CB2).21-23
These two major sub-types of cannabinoid receptors are part of the G-protein-coupled receptor family and influence a variety of biologic responses. CB1 and CB2 are expressed in the testes and sperm as well as in the brain, heart, uterus, embryo, spleen and immune cells.19
Laboratory evidence demonstrates that cannabis and cannabis-like compounds target cannabinoid receptors in Leydig and Sertoli cells and influence testosterone and pituitary gonadotropin release as well as Sertoli cell survival. Studies have shown that endogenous cannabinoid-like (endocannabinoid) lipid mediators (anandamide specifically) suppressed LH and testosterone levels in wild-type but not CB1 knockout mice, providing evidence that the endocannabinoid system acts to alter testosterone and pituitary gonadotropin concentrations.24
Further, there is evidence that cannabinoids can inhibit testosterone activity by impairing androgen binding to receptors.25
Although our results support the findings by Daling et al., there are several limitations to our study. The study relied on self-report of marijuana use, which is an illicit drug. Persons with a serious disease, such as cancer, may more accurately report the use of an illegal substance than individuals without a serious medical condition. To address this concern, we compared the marijuana use in the controls with publicly available national data and found no significant difference. The specificity of our finding, that the association between marijuana use and TGCT was primarily limited to nonseminoma, may be due to the limited numbers of seminoma and mixed germ cell tumors.
Use of friend controls as the referent group in any study raises the concern that controls are too similar to cases. If the controls, in fact, were too similar to cases in terms of their marijuana use patterns, then it is likely that our estimates of risk would have underestimated the true relationship between marijuana use and TGCT. In our study, however, the controls were older and reported higher incomes than cases, suggesting that over-matching was not present, at least for these factors. While we attempted to match on age, the cases tended to nominate friend controls who were generally older than they were, so we adjusted for age in all of our analyses. We also evaluated income as a potential confounding factor and found that it had no effect in a model adjusting for age, race, history of cryptorchidism, cigarette smoking and alcohol consumption. Thus, income was not included in the final models.
As the use of friend controls can bias the results of retrospective studies, we evaluated the extent to which reporting of marijuana use among the controls was consistent with data from the 1996 population-based National Survey on Drug Use and Health (NSDUH; known as the National Household Survey on Drug Abuse prior to 1999). We compared the observed number of controls who reported ever using marijuana with the expected number based on age- and race-specific proportions in the survey data26
; we did not find a significant difference, suggesting selection or reporting bias was not an explanation for the observed associations [among 128 white men of all ages in the control group, 68 reported any marijuana use compared with 70.9 expected based on NSDUH data (O/E ratio, 0.96; 95% CI, 0.74, 1.22)]. The NSDUH did not capture information on lifetime frequency of use; however, it did collect information on current frequency of use. Using the NSDUH variable on current frequency of use, we did not find a significant observed-to-expected difference when we compared the observed number of controls who reported daily marijuana use with the expected number based on age- and race- specific proportions of current daily use [among 123 white men of all ages in the control group, 32 reported any marijuana use compared with 32.5 expected based on NSDUH data (O/E ratio, 0.98; 95% CI, 0.67, 1.3)].
Our finding of an association between frequent marijuana use and TGCT, particularly among men with nonseminoma is consistent with the findings of a previous report.10
The biologically active components of marijuana may directly affect TGCT risk by altering gonadotropin and hormone levels during puberty; however, these components may function through pathways other than the endocannabinoid system. Additional studies of marijuana use and TGCT are warranted, especially studies evaluating the role of endocannabinoid signaling and cannabinoid receptors in TGCT.