The epidemiology of hormones and prostate cancer

Prostate cancer is the most common cancer in men in the UK. However, there are no well-established modifiable risk factors. Testosterone and insulin-like growth factor-I (IGF-I) are hormones which may be involved in prostate cancer risk, but the totality of the evidence is not clear. This thesis aimed to investigate the epidemiology and associations of circulating testosterone, IGF-I and other factors with prostate cancer risk.
The cross-sectional associations of a range of anthropometric, sociodemographic, and behavioural factors with circulating sex hormone and IGF concentrations were investigated using the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group (EHNBPCCG), an international consortium of prospective studies. These analyses used individual participant data from up to 25 studies and 16,000 men free from prostate cancer and observed that age, adiposity and racial/ethnic group generally had large magnitudes of associations with these hormone concentrations. This enhances the understanding of how these factors may affect disease risk and may offer insights for prostate cancer prevention.
The association between free testosterone (the testosterone which is considered biologically active) and prostate cancer risk was investigated in the context of a possible threshold association. The EHNBPCCG contains individual participant data from 20 prospective studies including 7,000 prostate cancer cases and 12,000 controls with free testosterone data. Men with very low circulating free testosterone concentrations had a lower risk of prostate cancer, but possibly a higher risk of high-grade tumours. This analysis provides the first large-scale prospective epidemiological evidence of an association between circulating free testosterone concentrations and prostate cancer risk.
The possible associations of clinically low testosterone (diagnosis of Klinefelter’s syndrome, testicular hypofunction and hypopituitarism) and clinically high IGFI (acromegaly) with subsequent risk of prostate cancer diagnosis and mortality were examined using English national hospital admission and death records. Men diagnosed with any hypogonadal disease had a lower risk of prostate cancer mortality. Men diagnosed with acromegaly had an increased risk of prostate cancer diagnosis and possibly prostate cancer mortality. These results support the roles of both testosterone and IGF-I in prostate cancer risk.
Possible haematological risk factors for prostate cancer were investigated in the UK Biobank in 210,000 men (5,700 prostate cancer cases). Higher red blood cell and platelet counts, and lower measures of red blood cell size were associated with an increased prostate cancer risk. Higher white blood cell and neutrophil counts were associated with an increased risk of prostate cancer mortality. These findings were consistent with the possible roles of testosterone, inflammation and/or infection in prostate cancer risk.
In conclusion, research from this thesis supports the roles of testosterone, IGF-I and infection/inflammation in prostate cancer risk and identified potential anthropometric, sociodemographic and behavioural factors which may affect prostate cancer risk through alterations in these physiological characteristics.

Keywords: prostate cancer
hormones
pooled data
epidemiology
IGF-I
UK Biobank
testosterone
Advisor: Key, T
Perez-Cornago, A
Travis, R