Testosterone and dihydrotestosterone tissue levels in recurrent prostate cancer.
OBJECTIVE
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.


METHODS
Prostate specimens from 36 men were procured preserving blood flow to prevent ischemia and cyropreserved immediately. Recurrent prostate cancer specimens from 18 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.
Titus
Mark A
MA
Department of Pathology, UNC Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, 27599-7295, USA. matitus@med.unc.edu
Schell
Michael J
MJ
Lih
Fred B
FB
Tomer
Kenneth B
KB
Mohler
James L
JL
D000368:Aged; D000369:Aged, 80 and over; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D013196:Dihydrotestosterone / Q000032:analysis*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D011863:Radioimmunoassay / Q000379:methods; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods; D016019:Survival Analysis; D013739:Testosterone / Q000032:analysis*
D013196:Dihydrotestosterone; D013739:Testosterone