Testosterone, Cognition, Ageing, and Cancer

The primary aim of the study is - in a prospective controlled design - to examine whether treatment-induced decreases in testosterone acts as a mechanism of cancer-related cognitive impairment (CRCI) in testicular and prostate cancer patients.

Secondary aims are 1) to explore whether decreases in testosterone interacts with increasing age to cause more severe CRCI in older patients, 2) to explore underlying neurophysiological (brain morphology) mechanisms of CRCI, and 3) to evaluate selected genetic variants as possible moderators of CRCI.

The study will include three groups with a total of 120 participants: A) Forty testicular cancer patients will be included and examined 1) shortly after orchiectomy and prior to any further treatment and 2) at 6 months' follow- up. B) Forty prostate cancer patients will be included and examined at two time-points: 1) prior to initiation of medical castration and radiotherapy and 2) at 6 months' follow- up. C) Forty age- and education-matched healthy controls will be included and assessed at a similar time-interval, i.e., at an initial examination and at a 6 month follow-up. Measures include a battery of neuropsychological/ cognitive tests, questionnaires, blood samples, and Magnetic Resonance Imaging (MRI).

Primary hypothesis

1. Treatment-induced decreases in testosterone will be associated with decline in global cognitive functioning from baseline to 6 months' follow- up in both testicular and prostate cancer patients.

   Secondary hypotheses
2. Treatment-induced decreases in testosterone will be associated with decline in individual cognitive domains (i.e., processing speed, attention, verbal fluency, executive functioning, working memory, verbal learning and memory, visuospatial learning and memory, and visuospatial ability) from baseline to 6 months' follow- up in both testicular and prostate cancer patients.
3. Decline in cognitive functioning from baseline to 6 months' follow- up in both testicular and prostate cancer patients will correspond to changes in grey matter as measured by T1-weighted MRI.
4. Decline in cognitive functioning from baseline to 6 months' follow- up in both testicular and prostate cancer patients will correspond to changes in brain white matter as measured with diffusion-weighted MRI.
5. Treatment-induced decreases in testosterone will be more strongly associated with decline in cognitive functioning in prostate cancer patients compared with testicular cancer patients due to more advanced age in the former group.
6. Treatment-induced decreases in testosterone will be more strongly associated with decline in cognitive functioning in both testicular and prostate cancer patients carrying the the Apolipoprotein E (APOE) ε4 allele, the Val catechol-O-methyltranferase (COMT) allele, the Val/Val Brain- derived neurotrophic factor (BDNF) genotype, and a short polymorphic CAG repeat length of the Androgen Receptor (AR) gene.
7. Treatment-induced decreases in testosterone will be associated with increases in neurobehavioral symptoms (i.e., apathy, executive dysfunction, and disinhibition) from baseline to 6 months' follow- up in both testicular and prostate cancer patients.
8. Treatment-induced decreases in testosterone will be associated with decreases in health-related quality of life from baseline to 6 months' follow- up in both testicular and prostate cancer patients.
9. Treatment-induced decreases in testosterone will be associated with decreases in perceived cognitive functioning from baseline to 6 months' follow- up in both testicular and prostate cancer patients.

Eligibility Criteria:
Inclusion Criteria:

* Confirmed diagnosis of testicular cancer
* Confirmed diagnosis of prostate cancer and prescription of medical castration and radiotherapy

Exclusion Criteria:

* Previous cancer disease
* Previous central nervous system disease
* Brain metastases
* Severe psychiatric disease (e.g., schizophrenia, major depressive disorder)
* Insufficient Danish proficiency for neuropsychological testing