Testosterone products are prescribed to males for a variety of possible health benefits, but causal effects are unclear. Evidence from randomized trials are difficult to obtain, particularly regarding effects on long-term or rare outcomes. Mendelian randomization analyses were performed to infer phenome-wide effects of free testosterone on 461 outcomes in 161,268 males from the UK Biobank study. Lifelong increased free testosterone had beneficial effects on increased bone mineral density, and decreased body fat; adverse effects on decreased HDL, and increased risks of prostate cancer, androgenic alopecia, spinal stenosis, and hypertension; and context-dependent effects on increased hematocrit and decreased C-reactive protein. No benefit was observed for type 2 diabetes, cardiovascular or cognitive outcomes. Mendelian randomization suggests benefits of long-term increased testosterone should be considered against adverse effects, notably increased prostate cancer and hypertension. Well-powered randomized trials are needed to conclusively address risks and benefits of testosterone treatment on these outcomes.
Keywords: Mendelian randomization; UK Biobank; genetics; genome-wide association study; genomics; human; hypertension; medicine; prostate cancer; testosterone.
Men experience a gradual decline in their testosterone levels as they grow older. However, the effects of testosterone and the consequences of supplementation on the human body have been unclear. Scientists use so-called randomized controlled trials to establish cause-and-effect and to reduce bias. In these experiments, participants are randomly assigned to a either a treatment group (that receives the intervention being tested) or a control group (that either receives an alternative intervention, a dummy or placebo, or no intervention at all). Randomization ensures that both groups are balanced, and any resulting differences can be attributed to the treatment. However, randomized controlled trials are time-consuming and expensive, so trials of testosterone have had relatively small numbers of participants and short follow-up periods. This makes it difficult to draw conclusions about any potential effects of testosterone administration on less common diseases in men. Now, Paré et al. investigated the effects of naturally produced testosterone using Mendelian randomization, which mimics randomized trials by exploiting the fact that parents randomly pass on their unique genetic variants to their children at conception. This random assignment of genetic variants leads to its informal namesake, “nature’s clinical trial”, and provides the ability to study cause-and-effect for any genetically determined factors, such as testosterone levels. Paré et al. studied the long-term effects of testosterone on 22 diseases previously explored in randomized controlled trials, and hundreds of other traits and diseases that have not been investigated in any randomized controlled trials yet. The Mendelian randomization analysis made it possible to examine the effects of lifelong naturally elevated testosterone levels on 469 traits and diseases. Paré et al. found that testosterone increased the density of bone mineral and decreased body fat. However, it also increased the risks of prostate cancer, high blood pressure, baldness and a condition affecting the spine. It also increased the number of red blood cells and decreased a marker of inflammation, which may be beneficial or detrimental depending on the context. This shows that genetic analyses can be powerful methods to prioritize the allocation of limited resources towards investigating the most pressing clinical questions. The results of this study may help inform physicians and patients about the effects of long-term testosterone use. Ultimately, large randomized controlled trials are needed to conclusively address the cause-and-effect on these diseases.
© 2020, Mohammadi-Shemirani et al.