New genetics and blood-based study links testosterone and insulin-like growth factor hormones to aggressive prostate cancer for the first time.
Prostate cancer is one of the world’s top cancer killers and the second most common cancer in men worldwide, with one in eight men in the UK diagnosed with the disease during their lifetime. There is an urgent need to better understand the factors that influence prostate cancer risk, particularly for the more aggressive forms of the disease.
Researchers from Oxford Population Health’s Cancer Epidemiology Unit (CEU) have contributed valuable evidence in this area, particularly on the link between hormones and prostate cancer risk. In particular, a previous study positive associations between high levels of free testosterone (not attached to any proteins) and insulin-like growth factor-I (IGF-I) and increased risks of prostate cancer. It is thought that the link between levels of these hormones and prostate cancer may be due to their role in regulating prostate cell growth, function and survival.
To date, the limited number of prostate cancer cases within cohort studies meant it was not possible to assess how IGF-1 and free testosterone affect the risk of different types of prostate cancer, particularly aggressive forms of the disease.
Furthermore, it was not clear whether these hormones directly increase prostate cancer risk, or if they are merely linked to a different factor which is the true cause. It was also possible that these associations were the result of reverse causation, where preclinical cancer symptoms caused the hormone levels to change before the disease was diagnosed.
To clarify these unknowns, CEU researchers led the largest study to date, using data from an international consortium: the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group. This worldwide database collates information from all prospective studies of hormonal factors and prostate cancer risk, and contains over 17,000 prostate cancer cases with measured hormone levels (including 2,300 aggressive cases) and 37,000 controls. They also obtained genetic data from the PRACTICAL consortium, which contains over 79,000 prostate cancer cases and 60,000 controls.
The researchers investigated the association between blood levels of IGF-1 and free testosterone and the risk of overall, aggressive and early-onset prostate cancer. In addition, they performed a genetic approach known as Mendelian randomisation (MR). This used genetic variants that have previously been associated with levels of IGF-1 and free testosterone to investigate whether those with higher genetically predicted hormone concentrations have an increased risk of prostate cancer. Because these genetic variants are randomly allocated and fixed before birth, MR studies are less likely to be affected by confounding factors or reverse causation than studies which directly measure hormone levels.
- In the blood-based analysis, levels of IGF-1 were positively associated with a greater risk of overall and aggressive prostate cancer. For each standard deviation increase, the risk rose by 9% for each.
- This was confirmed in the MR analysis: higher genetically predicted levels of IGF-1 were associated with a greater risk of overall, aggressive and early-onset prostate cancer. For each standard deviation increase in genetically predicted IGF-1, the risk increased by 7%, 10% and 13 % respectively.
- In the blood-based analysis, levels of free testosterone were positively associated with a greater risk of overall prostate cancer. For each standard deviation increase, the risk increased by 3%.
- In the MR study, higher genetically predicted levels of free testosterone were associated with a greater risk of overall, aggressive and early-onset prostate cancer. For each standard deviation increase in free testosterone, the risk increased by 20%, 23% and 37% respectively.
According to the researchers, the results suggest that reducing blood levels of both IGF-1 and free testosterone through lifestyle or drug interventions may be a strategy to decrease prostate cancer risk, although this needs further research.
Dr Eleanor Watts (formerly CEU, now at the National Cancer Institute), lead author for both studies, said: ‘This is the first analysis that has applied both blood-based and genetic approaches to investigate the association of these hormones with prostate cancer risk, using data from two large international consortia that represent almost all the available data worldwide. For the first time we show evidence that both IGF-I and free testosterone are important for aggressive, clinically relevant disease. These findings support the need for more research on the modifiable determinants of these hormones, and on whether interventions to lower levels of these hormones might reduce the risk of prostate cancer.’
The testosterone study was published in The International Journal of Cancer.
The IGF-1 study was published in International Journal of Epidemiology