Testosterone and Dihydrotestosterone Tissue Levels in Recurrent Prostate Cancer

Abstract

Purpose: Prostate cancer eventually recurs during androgen deprivation therapy despite castrate levels of serum androgens. Expression of androgen receptor and androgen receptor^regulated proteins suggests androgen receptor activation in recurrent prostate cancer. Many groups have pursued mechanisms of ligand-independent androgen receptor activation but we found high levels of testicular androgens in recurrent prostate cancer tissue using RIA. Experimental Designs: Prostate specimens from 36 men were procured preserving blood flow to prevent ischemia and cyropreserved immediately. Recurrent prostate cancer specimens from18 men whose cancer recurred locally during androgen deprivation therapy and androgen-stimulated benign prostate specimens from 18 men receiving no hormonal treatments were studied. Tissue levels of testosterone and dihydrotestosterone were measured in each specimen using liquid chromatography/electrospray tandem mass spectrometry.Testosterone and dihydrotestosterone levels were compared with clinical variables and treatment received. Results: Testosterone levels were similar in recurrent prostate cancer (3.75 pmol/g tissue) and androgen-stimulated benign prostate (2.75 pmol/g tissue,Wilcoxon two-sided, P = 0.30). Dihydrotestosterone levels decreased 91% in recurrent prostate cancer (1.25 pmol/g tissue) compared with androgen-stimulated benign prostate (13.7 pmol/g tissue; Wilcoxon two-sided, P < 0.0001) although dihydrotestosterone levels in most specimens of recurrent prostate cancer were sufficient for androgen receptor activation.Testosterone or dihydrotestosterone levels were not related to metastatic status, antiandrogen treatment, or survival (Wilcoxon rank sum, all P > 0.2).Conclusions: Recurrent prostate cancer may develop the capacity to biosynthesize testicular androgens from adrenal androgens or cholesterol. This surprising finding suggests intracrine production of dihydrotestosterone and should be exploited for novel treatment of recurrent prostate cancer.Prostate cancer recurs in almost all men receiving androgen deprivation therapy (ADT) and is the main cause of death in prostate cancer. Recurrent prostate cancer retains androgen receptor protein expression, with androgen receptor remaining active in growth signaling despite castrate levels of circulating androgens (1). Androgen receptor protein and androgen receptor -regulated proteins are expressed in prostate cancer that recurs during ADT in both the primary (2 -5) and bone metastases (6, 7). Androgen receptor activation in recurrent prostate cancer may occur by a variety of mechanisms that alter the sensitivity (8 -10) or specificity (11) of androgen receptor (reviewed in refs. 12 -14). Recent studies using androgenindependent prostate cancer cell lines (8, 9) and xenografts (9) showed that androgen receptor overexpression allowed recurrent prostate cancer growth in the presence of castrate levels of circulating androgens. However, androgen receptor mutations that prevented ligand-binding prevented recurrent growth; ove...

Fibroblasts prolong serum prostate-specific antigen decline after androgen deprivation therapy in prostate cancer

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Pro-survival and anti-apoptotic properties of androgen receptor signaling by oxidative stress promote treatment resistance in prostate cancer

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Differential androgen receptor signals in different cells explain why androgen-deprivation therapy of prostate cancer fails

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