Interview conducted by April Cashin-Garbutt, BA Hons (Cantab)
Please could you give a brief introduction to testicular cancer?
This is a set of malignancies that arise in germ cells of the testicles, the specialized cells that produce sperm. Taken together, testicular cancers are the most common form of malignancy that occurs in young men (approximately 15 to 35 years of age).
Fortunately, most men who are diagnosed with this cancer respond very well to therapy and are eventually cured. However, they are so young that they must live for decades with any so-called late effects such as increased risks of an additional testicular cancer, other cancers, heart disease, infertility, and sexual problems.
Researchers are therefore very interested in finding environmental causes that may provide routes to preventing testicular cancer. This was the objective of Dr. Leslie Bernstein, who designed and ran our study, when she decided to investigate recreational drugs as possible causes of testicular cancer.
What factors were previously known to increase the risk of testicular cancer?
It has long been know that a personal history of congenitally undescended testicles (cryptorchidism) is associated with approximating four-fold increased risk, while family history of testicular cancer can be associated with even higher risk if the affected relative is a brother.
More recently, several genetic variants have been identified that are also related to risk, and the biological mechanism whereby these work is now being investigated.
Some environmental risk factors, such as exposure to organochloride pesticides, have also been suggested by recent research, and this is an area of active study.
Your research showed that recreational marijuana use increased the risk of developing testicular cancer. Please could you explain how you define “recreational marijuana use”?
We are referring to use of marijuana for reasons other than medical care.
Did your research show that recreational marijuana use increased the risk of all types of testicular cancer, or only some?
Detailed analysis of the data indicated that almost all of the elevated risk pertained to non-seminoma, a form of testicular cancer that tends to occur at earlier ages and to require more aggressive treatment.
How did you demonstrate this relationship?
The study used the well-described case-control approach to investigating risk factors among human participants. Men diagnosed with testicular cancer in Los Angeles County were invited to participate, and for those who accepted, unaffected men of similar age and racial/ethnic heritage were asked to participate as unaffected controls. These control men provide reference information allowing us to learn whether the men who developed testicular cancer had been exposed more often (or less often) to each of the various factors that the study investigated. Information about history of exposure was provided by each man during an in-person interview.
We analyzed reported histories of using various recreational drugs in relation to testis cancer risk, accounting for known risk factors such as age, history of cryptorchidism and family history. There was no obvious difference in the frequency with which men with testicular cancer and the unaffected controls reported using most drugs. However, those with testis cancer more frequently reported having used marijuana.
Did your research show that the relationship was a causative one, i.e. can marijuana use be said to cause testicular cancer, or could this be a coincidental association?
I would hesitate to call the association causal at this point. What we can say with confidence is that all three studies that have addressed this question have found the same very specific result: a reported history of using marijuana is associated with elevated risk of non-seminoma testicular cancer.
These findings are unlikely to be due to chance, given the statistical properties of the estimates from each study, and the consistency of the results between studies. However, the possibility remains that men who use marijuana are strongly inclined to have some risk factor that has not yet been discovered, and that was not measured in any of these studies. However, if this were the case, the effect of this hypothetical risk factor would have to be even stronger than the effect of marijuana, and no such factor has been postulated.
By what mechanism do you think recreational marijuana use could cause testicular cancer?
Two scenarios seem plausible based on what is known about physiologic effects of marijuana and testicular biology.
First, marijuana smoke may interfere with hormonal signaling that is required for proper development and function of the testicle. In animals studied in controlled experiments, both marijuana smoke and the marijuana constituent Δ9-Tetrahydrocannabinol (called “THC”) have been shown to suppress androgen levels in male mice. Similarly in humans, men who smoke marijuana have been found to have lower levels of androgens circulating in their blood. So perhaps elevated risk of seminoma occurs as a result of marijuana’s suppression of androgens below levels required by the testicles for optimal health.
A second possibility is that THC from marijuana specifically interferes with other biological processes, which are carried out by the so-called endocannabinoid system. This is a network of signaling molecules produced by the body that bind the same cellular receptors as THC. These receptors are present in testicular tissue, and it has been suggested that THC from marijuana may bind these receptors, keeping them from carrying out their usual function and thereby damaging testicles in a way that predisposes to non-seminoma. It was this possibility that motivated Dr. Janet Daling, a member of the research team that first reported the marijuana-nonseminoma association, to investigate marijuana use as a possible contributor to testicular cancer risk.
Did your research show a relationship between any other drugs and an increased risk of testicular cancer?
No. However, we did see an association between reported use of cocaine and reduced risk of all testicular cancer (not just non-seminoma). Cocaine appears to destroy testicular germ cells in both humans and laboratory animals, so we suspect that any protective effect of cocaine results from loss of germ cells, which would be expected to damage or destroy a man’s fertilty.
What impact do you think your research will have?
Since this is the third study to reveal the same specific association between marijuana use and nonsemionoma risk, I hope that the scientific community will now investigate possible mechanisms so that we can draw more definitive causal inferences. In the meanwhile, I feel that young men deserve to be aware of these findings so that they can make informed decisions about using marijuana.
How do you think the future of research into testicular cancer will develop?
I anticipate that some scientist will focus their attention on biological mechanisms whereby both marijuana and recently identified genetic variants operate to influence risk.
Do you have any plans for further research into this area?
I am interested in studying marijuana use in more detail, to learn whether there are particular ages at which a man’s use of marijuana is particularly harmful, and to understand the biological processes through which risk is influenced. This information should allow us to begin formulating more specific interventions.
Where can readers find more information?
All three reports on this topic have been published in the journal Cancer. The work discussed above can be accessed online at http://onlinelibrary.wiley.com/doi/10.1002/cncr.27554/abstract
About Victoria Cortessis
Victoria Cortessis, PhD, is a faculty member in the Norris Comprehensive Cancer Center and departments of Preventive Medicine and Obstetrics and Gynecology at the Keck School of Medicine of the University of Southern California.
She directs a program of research using methods of epidemiology, genetics and molecular biology to understand causes of congenital and malignant conditions of the urological system.
Recent results from her research group include identification of genetic determinants of cryptorchidism, testicular cancer and bladder cancer risk, as well as learning that women who complete at least one pregnancy or use estrogen plus progestin in the perimenopausal period experience reduced bladder cancer risk.