TY - JOUR
T1 - Atorvastatin induces adrenal androgen downshift in men with prostate cancer
T2 - A post Hoc analysis of a pilot adaptive Randomised clinical trial
AU - Raittinen, Paavo V.H.
AU - Syvälä, Heimo
AU - Tammela, Teuvo L.J.
AU - Häkkinen, Merja R.
AU - Ilmonen, Pauliina
AU - Auriola, Seppo
AU - Murtola, Teemu J.
N1 - Funding Information:
The study was financially supported by Finnish Cultural Foundation, Finnish Cancer Society, Academy of Finland, and the Expert Responsibility Area of the Tampere University Hospital . UEF metabolomics laboratory is supported by Biocenter Finland and Biocenter Kuopio.
Funding Information:
Dr. Murtola reports grants from Finnish Cultural Foundation, Finnish Cancer Society, Academy of Finland, and Expert Responsibility Area of the Tampere University Hospital during the conduct of the study; personal fees from Astellas and Janssen, and other from Astellas and Bayer, outside the submitted work.
Publisher Copyright:
© 2021 The Authors
PY - 2021/6
Y1 - 2021/6
N2 - Background: Prostate cancer (PCa) progression depends on androgen receptor activity. Cholesterol is required for biosynthesis of all steroid hormones, including androgens. Impact of cholesterol-lowering statins on androgens is unknown. We explored atorvastatin influence on serum and prostatic tissue steroidomic profiles (SP) to expose novel pathways for limiting androgen concentration in men with PCa. Methods: This is a pre-planned post hoc analysis of ESTO-1 pilot randomised, double-blinded, clinical trial. Statin naïve men, scheduled for radical prostatectomy due to localised PCa, were randomised 1:1 to use daily 80 mg of atorvastatin or placebo before the surgery for a median of 28 days. Participants were recruited and treated at the Pirkanmaa Hospital District, Tampere, Finland. 108 of the 158 recruited men were included in the analysis based on sample availability for hormone profiling. Serum and prostatic tissue steroid profiles were determined using liquid chromatography mass spectrometry. Wilcoxon rank sum test and bootstrap confidence intervals (CI) were used to analyse the difference between placebo and atorvastatin arms. Findings: Most serum and prostatic steroids, including testosterone and dihydrotestosterone, were not associated with atorvastatin use. However, atorvastatin use induced serum SP changes in 11-ketoandrostenedione (placebo 960pM, atorvastatin 617.5pM, p-value <0.0001, median difference -342.5; 95% CI -505.23 – -188.98). In the prostatic tissue, atorvastatin was associated with plausible downshift in 11- ketodihydrotestosterone (placebo 25.0pM in 100 mg tissue/1 mL saline, atorvastatin 18.5pM in 100 mg tissue/1 mL saline, p-value 0.027, median difference -6.53; 95% CI -12.8 – -0.29); however, this association diminished after adjusting for multiple testing. No serious harms were reported. Interpretation: Atorvastatin was associated with adrenal androgen downshift in the serum and possibly in the prostate. The finding warrants further investigation whether atorvastatin could improve androgen deprivation therapy efficacy. Funding: Funded by grants from the Finnish Cultural Foundation, Finnish Cancer Society, Academy of Finland, and the Expert Responsibility Area of the Tampere University Hospital. Clinicaltrials.gov identifier: NCT01821404.
AB - Background: Prostate cancer (PCa) progression depends on androgen receptor activity. Cholesterol is required for biosynthesis of all steroid hormones, including androgens. Impact of cholesterol-lowering statins on androgens is unknown. We explored atorvastatin influence on serum and prostatic tissue steroidomic profiles (SP) to expose novel pathways for limiting androgen concentration in men with PCa. Methods: This is a pre-planned post hoc analysis of ESTO-1 pilot randomised, double-blinded, clinical trial. Statin naïve men, scheduled for radical prostatectomy due to localised PCa, were randomised 1:1 to use daily 80 mg of atorvastatin or placebo before the surgery for a median of 28 days. Participants were recruited and treated at the Pirkanmaa Hospital District, Tampere, Finland. 108 of the 158 recruited men were included in the analysis based on sample availability for hormone profiling. Serum and prostatic tissue steroid profiles were determined using liquid chromatography mass spectrometry. Wilcoxon rank sum test and bootstrap confidence intervals (CI) were used to analyse the difference between placebo and atorvastatin arms. Findings: Most serum and prostatic steroids, including testosterone and dihydrotestosterone, were not associated with atorvastatin use. However, atorvastatin use induced serum SP changes in 11-ketoandrostenedione (placebo 960pM, atorvastatin 617.5pM, p-value <0.0001, median difference -342.5; 95% CI -505.23 – -188.98). In the prostatic tissue, atorvastatin was associated with plausible downshift in 11- ketodihydrotestosterone (placebo 25.0pM in 100 mg tissue/1 mL saline, atorvastatin 18.5pM in 100 mg tissue/1 mL saline, p-value 0.027, median difference -6.53; 95% CI -12.8 – -0.29); however, this association diminished after adjusting for multiple testing. No serious harms were reported. Interpretation: Atorvastatin was associated with adrenal androgen downshift in the serum and possibly in the prostate. The finding warrants further investigation whether atorvastatin could improve androgen deprivation therapy efficacy. Funding: Funded by grants from the Finnish Cultural Foundation, Finnish Cancer Society, Academy of Finland, and the Expert Responsibility Area of the Tampere University Hospital. Clinicaltrials.gov identifier: NCT01821404.
KW - Clinical trial
KW - Prostate cancer
KW - Prostatic tissue adrenal androgens
KW - Serum adrenal androgens
KW - Statins
U2 - 10.1016/j.ebiom.2021.103432
DO - 10.1016/j.ebiom.2021.103432
M3 - Article
AN - SCOPUS:85107978684
VL - 68
M1 - 103432
ER -
