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Effect of Testosterone Replacement Therapy on Prostate Tissue in Men With Late-Onset HypogonadismA Randomized Controlled Trial FREELeonard S. Marks, MD; Norman A. Mazer, MD, PhD; Elahe Mostaghel, MD, PhD; David L. Hess, PhD; Frederick J. Dorey, PhD; Jonathan I. Epstein, MD; Robert W. Veltri, PhD; Danil V. Makarov, MD; Alan W. Partin, MD, PhD; David G. Bostwick, MD; Maria Luz Macairan, MD; Peter S. Nelson, MD
[+] Author Affiliations (http://jama.jamanetwork.com/article.aspx?articleid=204163#)
JAMA. 2006;296(19):2351-2361. doi:10.1001/jama.296.19.2351.
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ABSTRACTABSTRACT (http://jama.jamanetwork.com/article.aspx?articleid=204163#Abstract) | METHODS (http://jama.jamanetwork.com/article.aspx?articleid=204163#METHODS) | RESULTS (http://jama.jamanetwork.com/article.aspx?articleid=204163#RESULTS) | COMMENT (http://jama.jamanetwork.com/article.aspx?articleid=204163#COMMENT) | ARTICLE INFORMATION (http://jama.jamanetwork.com/article.aspx?articleid=204163#ArticleInformation) |REFERENCES (http://jama.jamanetwork.com/article.aspx?articleid=204163#References)




Context Prostate safety is a primary concern when aging men receive testosterone replacement therapy (TRT), but little information is available regarding the effects of TRT on prostate tissue in men.
Objective To determine the effects of TRT on prostate tissue of aging men with low serum testosterone levels.
Design, Setting, and Participants Randomized, double-blind, placebo-controlled trial of 44 men, aged 44 to 78 years, with screening serum testosterone levels lower than 300 ng/dL (<10.4 nmol/L) and related symptoms, conducted at a US community-based research center between February 2003 and November 2004.
Intervention Participants were randomly assigned to receive 150 mg of testosterone enanthate or matching placebo intramuscularly every 2 weeks for 6 months.
Main Outcome Measures The primary outcome measure was the 6-month change in prostate tissue androgen levels (testosterone and dihydrotestosterone). Secondary outcome measures included 6-month changes in prostate-related clinical features, histology, biomarkers, and epithelial cell gene expression.
Results Of the 44 men randomized, 40 had prostate biopsies performed both at baseline and at 6 months and qualified for per-protocol analysis (TRT, n = 21; placebo, n = 19). Testosterone replacement therapy increased serum testosterone levels to the mid-normal range (median at baseline, 282 ng/dL [9.8 nmol/L]; median at 6 months, 640 ng/dL [22.2 nmol/L]) with no significant change in serum testosterone levels in matched, placebo-treated men. However, median prostate tissue levels of testosterone (0.91 ng/g) and dihydrotestosterone (6.79 ng/g) did not change significantly in the TRT group. No treatment-related change was observed in prostate histology, tissue biomarkers (androgen receptor, Ki-67, CD34), gene expression (including AR, PSA, PAP2A, VEGF, NXK3, CLU [Clusterin]), or cancer incidence or severity. Treatment-related changes in prostate volume, serum prostate-specific antigen, voiding symptoms, and urinary flow were minor.
Conclusions These preliminary data suggest that in aging men with late-onset hypogonadism, 6 months of TRT normalizes serum androgen levels but appears to have little effect on prostate tissue androgen levels and cellular functions. Establishment of prostate safety for large populations of older men undergoing longer duration of TRT requires further study.
Trial Registration clinicaltrials.gov Identifier: NCT00161304 (http://clinicaltrials.gov/show/NCT00161304)


Testosterone replacement therapy (TRT) in aging men is a widespread, growing practice. According to pharmaceutical industry estimates, more than 1.8 million prescriptions for testosterone products were written in the United States in 2002, a 30% increase over the previous year and a 170% increase over the previous 5 years1 (http://jama.jamanetwork.com/article.aspx?articleid=204163#REF-JPC60008-1); in 2005, a total of 2.3 million prescriptions were written.2 (http://jama.jamanetwork.com/article.aspx?articleid=204163#REF-JPC60008-2)


Serum levels of testosterone decline with age,3 (http://jama.jamanetwork.com/article.aspx?articleid=204163#REF-JPC60008-3) and in many aging men with low levels of the hormone, alterations such as depression, sexual dysfunction, diminished lean body mass, diminution in muscle volume and strength, and reduced bone mineral density may develop. Such changes, in association with low testosterone levels, have been called “male menopause,” which is also known as male climacteric,4 (http://jama.jamanetwork.com/article.aspx?articleid=204163#REF-JPC60008-4)andropause,5 (http://jama.jamanetwork.com/article.aspx?articleid=204163#REF-JPC60008-5) androgen deficiency of the aging male syndrome,6 (http://jama.jamanetwork.com/article.aspx?articleid=204163#REF-JPC60008-6) or late-onset hypogonadism.7 (http://jama.jamanetwork.com/article.aspx?articleid=204163#REF-JPC60008-7) Aspects of the syndrome may be ameliorated with TRT,8 (http://jama.jamanetwork.com/article.aspx?articleid=204163#REF-JPC60008-8)- 10 (http://jama.jamanetwork.com/article.aspx?articleid=204163#REF-JPC60008-8) and most testosterone prescriptions are currently written for men older than 45 years,1 (http://jama.jamanetwork.com/article.aspx?articleid=204163#REF-JPC60008-1) a demographic in which prostate disease is most common. Between 2 and 4 million men, nearly all in this “prostatic age group,” may be candidates for treatment.11 (http://jama.jamanetwork.com/article.aspx?articleid=204163#REF-JPC60008-11)


Prostate growth, both normal and abnormal, is dependent on the presence of androgens. Without androgenic stimulation, the prostate fails to develop.12 (http://jama.jamanetwork.com/article.aspx?articleid=204163#REF-JPC60008-12)- 14 (http://jama.jamanetwork.com/article.aspx?articleid=204163#REF-JPC60008-12) After development of the gland in adults, reduction in testosterone levels causes regression of both benign and malignant prostatic overgrowth.15 (http://jama.jamanetwork.com/article.aspx?articleid=204163#REF-JPC60008-15),16 (http://jama.jamanetwork.com/article.aspx?articleid=204163#REF-JPC60008-16)Conversely, in men with advanced prostate cancer, testosterone administration often exacerbates the disease, causing increased bone pain, urinary obstruction, and even death.17 (http://jama.jamanetwork.com/article.aspx?articleid=204163#REF-JPC60008-17),18 (http://jama.jamanetwork.com/article.aspx?articleid=204163#REF-JPC60008-18)


Thus, when aging men receive supplemental testosterone, a primary concern is prostate safety. Even in men with no sign of prostate cancer, the possibility of stimulating growth in subclinical disease exists. Instances of prostate cancer in men receiving testosterone supplementation have been reported.19 (http://jama.jamanetwork.com/article.aspx?articleid=204163#REF-JPC60008-19)- 21 (http://jama.jamanetwork.com/article.aspx?articleid=204163#REF-JPC60008-19) When TRT is prescribed, careful monitoring for prostate disease is considered mandatory.11 (http://jama.jamanetwork.com/article.aspx?articleid=204163#REF-JPC60008-11) However, screening and follow-up of serum levels of prostate-specific antigen (PSA) may be problematic because PSA is directly regulated by androgens and might increase in the absence of disease.


Clinical trials to date have shown no evidence of any overt carcinogenicity or nonphysiological effect on prostatic growth when TRT is used in otherwise healthy aging men.22 (http://jama.jamanetwork.com/article.aspx?articleid=204163#REF-JPC60008-22),23 (http://jama.jamanetwork.com/article.aspx?articleid=204163#REF-JPC60008-23) Attempts to relate endogenous serum testosterone levels to the development of prostate cancer or benign prostatic hyperplasia, with occasional exception,24 (http://jama.jamanetwork.com/article.aspx?articleid=204163#REF-JPC60008-24),25 (http://jama.jamanetwork.com/article.aspx?articleid=204163#REF-JPC60008-25) have been inconclusive.26 (http://jama.jamanetwork.com/article.aspx?articleid=204163#REF-JPC60008-26) Experimentally, testosterone administration in laboratory animals when used alone serves only as a weak carcinogen at most.27 (http://jama.jamanetwork.com/article.aspx?articleid=204163#REF-JPC60008-27) One estimate suggests that to detect a 30% increase in treatment-related prostate cancers from TRT, a randomized controlled trial involving more than 6000 older men and having follow-up for at least 5 years would be required28 (http://jama.jamanetwork.com/article.aspx?articleid=204163#REF-JPC60008-28); however, an expert panel of the Institute of Medicine recommended that short-term efficacy trials should be completed to justify a larger safety trial.1 (http://jama.jamanetwork.com/article.aspx?articleid=204163#REF-JPC60008-1)


We conducted a randomized controlled trial to assess the effects of TRT on the prostate with a focus on prostate tissue. The hypothesis tested in this serial biopsy study is that exogenous testosterone accumulates in the prostate, converts to dihydrotestosterone, and affects biological change in the gland.