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Original Research |

Long-Term Effects of Dihydrotestosterone Treatment on Prostate Growth in Healthy, Middle-Aged Men Without Prostate Disease: A Randomized, Placebo-Controlled Trial

Amanda Idan, BSc, MHSc; Kaye A. Griffiths, AMS, DMU; D. Tim Harwood, PhD; Markus J. Seibel, MD, PhD; Leo Turner, MMed, RN; Ann J. Conway, MBBS; and David J. Handelsman, MBBS, PhD
[+] Article and Author Information

From Concord Hospital, ANZAC Research Institute, University of Sydney, Sydney, Australia.


Acknowledgment: The authors are grateful for the skilled management of participants by the Andrology and Endocrinology Department staff and to the participants whose commitment made the study possible. The authors also thank the Data Safety and Monitoring Committee: Drs. Michael Boyer (Chair), Ken Ho, and Val Gebski, as well as Dr. Elisabeth Le Nestour (formerly of Besins) and Neta Nelson (BHR Pharma) for their invaluable support of the study.

Grant Support: By BHR Pharma.

Potential Conflicts of Interest: Ms. Idan: Provision of writing assistance, medicines, equipment, or administrative support: BHR Pharma. Employment: BHR Pharma. Ms. Griffiths: Provision of writing assistance, medicines, equipment, or administrative support: BHR Pharma. Mr. Turner: Other relationships: Member of the human research ethics committee, which did not take part in the review of this study. Ms. Conway: Payment for lectures, including service on speakers bureaus: Bayer Schering. Dr. Handelsman: Grants received/pending: Ascend/Besins and BayerSchering. Provision of writing assistance, medicines, equipment, or administrative support: Ascend/Besins. Consultancy: Radius and Clarus Therapeutics. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M10-1059.

Reproducible Research Statement:Study protocol and data set: Available from Dr. Handelsman (e-mail, djh@anzac.edu.au). Statistical code: Not available.

Requests for Single Reprints: David J. Handelsman, MBBS, PhD, ANZAC Research Institute, Sydney, New South Wales 2139, Australia; e-mail, djh@anzac.edu.au.

Current Author Addresses: Ms. Idan, Ms. Griffiths, Mr. Turner, and Dr. Conway: Department of Andrology, Concord Hospital, Sydney, New South Wales 2139, Australia.

Dr. Harwood: Cawthron Institute, 98 Halifax Street East, Nelson 7010, New Zealand.

Dr. Seibel: Department of Endocrinology, Concord Hospital and ANZAC Research Institute, Sydney, New South Wales 2139, Australia.

Dr. Handelsman: ANZAC Research Institute, Sydney, New South Wales 2139, Australia.

Author Contributions: Conception and design: L. Turner, A.J. Conway, D.J. Handelsman.

Analysis and interpretation of the data: K.A. Griffiths, D.T. Harwood, M.J. Seibel, A.J. Conway, D.J. Handelsman.

Drafting of the article: A. Idan, D.T. Harwood, M.J. Seibel, D.J. Handelsman.

Critical revision of the article for important intellectual content: M.J. Seibel, D.J. Handelsman.

Final approval of the article: M.J. Seibel, A.J. Conway, D.J. Handelsman.

Provision of study materials or patients: K.A. Griffiths.

Statistical expertise: D.J. Handelsman.

Obtaining of funding: D.J. Handelsman.

Administrative, technical, or logistic support: A. Idan, K.A. Griffiths, D.T. Harwood, M.J. Seibel, L. Turner, A.J. Conway, D.J. Handelsman.

Collection and assembly of data: A. Idan, K.A. Griffiths, D.T. Harwood, M.J. Seibel.


Ann Intern Med. 2010;153(10):621-632. doi:10.7326/0003-4819-153-10-201011160-00004
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Background: Benign prostatic hypertrophy increases with age and can result in substantially decreased quality of life for older men. Surgery is often required to control symptoms. It has been hypothesized that long-term administration of a nonamplifiable pure androgen might decrease prostate growth, thereby decreasing or delaying the need for surgical intervention.

Objective: To test the hypothesis that dihydrotestosterone (DHT), a nonamplifiable and nonaromatizable pure androgen, reduces late-life prostate growth in middle-aged men.

Design: Randomized, placebo-controlled, parallel-group trial. (Australian New Zealand Clinical Trials Registry number: ACTRN12605000358640)

Setting: Ambulatory care research center.

Participants: Healthy men (n = 114) older than 50 years without known prostate disease.

Intervention: Transdermal DHT (70 mg) or placebo gel daily for 2 years.

Measurements: Prostate volume was measured by ultrasonography; bone mineral density (BMD) and body composition were measured by dual-energy x-ray absorptiometry; and blood samples and questionnaires were collected every 6 months, with data analyzed by mixed-model analysis for repeated measures.

Results: Over 24 months, there was an increase in total (29% [95% CI, 23% to 34%]) and central (75% [CI, 64% to 86%]; P < 0.01) prostate volume and serum prostate-specific antigen level (15% [CI, 6% to 24%]) with time on study, but DHT had no effect (P > 0.2). Dihydrotestosterone treatment decreased spinal BMD (1.4% [CI, 0.6% to 2.3%]; P < 0.001) at 24 months but not hip BMD (P > 0.2) and increased serum aminoterminal propeptide of type I procollagen in the second year of the study compared with placebo. Dihydrotestosterone increased serum DHT levels and its metabolites (5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol) and suppressed serum testosterone, estradiol, luteinizing hormone, and follicle-stimulating hormone levels. Dihydrotestosterone increased hemoglobin levels (7% [CI, 5% to 9%]), serum creatinine levels (9% [CI, 5% to 11%]), and lean mass (2.4% [CI, 1.6% to 3.1%) but decreased fat mass (5.2% [CI, 2.6% to 7.7%]) (P <0.001 for all). Protocol-specific discontinuations due to DHT were asymptomatic increased hematocrit (n = 8), which resolved after stopping treatment, and increased prostate-specific antigen levels (n = 3; none with prostate cancer) in the DHT group. No serious adverse effects due to DHT occurred.

Limitation: Negative findings on prostate growth cannot exclude adverse effects on the natural history of prostate cancer.

Conclusion: Dihydrotestosterone treatment for 24 months has no beneficial or adverse effect on prostate growth but causes a decrease in spinal but not hip BMD. These findings have important implications for the wider use of nonsteroidal pure androgens in older men.

Primary Funding Source: BHR Pharma.

Figures

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Figure 1.
Study flow diagram.

DHT = dihydrotestosterone.

* For details of adverse events, see the Results section.

† Participants excluded from the intention-to-treat analysis received the randomly allocated intervention but did not provide any efficacy end point data.

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Figure 2.
Serum DHT, testosterone, estradiol, and LH levels during the study.

Data are expressed as means and 95% CIs of changes from pretreatment baseline for men who received DHT and placebo. Treatment period is indicated by the thick line along the x-axis. Total participants are indicated at each time point. The dashed line indicates the reference range (upper limit for serum DHT level and lower limit for serum testosterone level). To convert estradiol values to pg/mL, divide by 3.671. To convert testosterone values to ng/dL, divide by 0.0347. DHT = dihydrotestosterone; LH = luteinizing hormone.

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Appendix Figure 1.
Serum 3α-diol, 3β-diol, FSH, and SHBG levels during the study.

Data are expressed as means and 95% CIs of changes from pretreatment baseline for men who received DHT and placebo. Treatment period is indicated by the thick line along the x-axis. Total participants are indicated at each time point. 3α-diol = 5α-androstane-3α,17β-diol; 3β-diol = 5α-androstane-3β,17β-diol; DHT = dihydrotestosterone; FSH = follicle-stimulating hormone; SHBG = sex hormone–binding globulin.

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Appendix Figure 2.
Total lean mass, hemoglobin level, total fat mass, and serum PSA level during the study.

Data are expressed as means and 95% CIs of changes from pretreatment baseline for men who received DHT and placebo. Treatment period is indicated by the thick line along the x-axis. Total participants are indicated at each time point. The dashed line indicates no change from baseline. DHT = dihydrotestosterone; PSA = prostate-specific antigen.

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Figure 3.
Total and central prostate volumes during the study.

Data are expressed as means and 95% CIs of changes from pretreatment baseline for men who received DHT and placebo. Treatment period is indicated by the thick line along the x-axis. Total participants are indicated at each time point. The dashed line indicates no change from baseline. DHT=dihydrotestosterone.

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Figure 4.
Lumbar (L2–4) spine and femoral neck BMD during the study.

Data are expressed as means and 95% CIs of changes from pretreatment baseline for men who received DHT and placebo. Treatment period is indicated by the thick line along the x-axis. Total participants are indicated at each time point. The dashed line indicates no change from baseline. BMD = bone mineral density; DHT = dihydrotestosterone.

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Appendix Figure 3.
Serum PINP and urinary NTX levels during the study.

Data are expressed as means and 95% CIs of changes from pretreatment baseline for men who received DHT and placebo. Treatment period is indicated by the thick line along the x-axis. Total participants are indicated at each time point. DHT = dihydrotestosterone; NTX = aminoterminal cross-linked telopeptide of collagen type I; PINP = aminoterminal propeptide of type I procollagen.

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Summary for Patients

Daily Application of Dihydrotestosterone Gel Does Not Prevent Age-Related Growth of the Prostate Gland

The summary below is from the full report titled “Long-Term Effects of Dihydrotestosterone Treatment on Prostate Growth in Healthy, Middle-Aged Men Without Prostate Disease. A Randomized, Placebo-Controlled Trial.” It is in the 16 November 2010 issue of Annals of Internal Medicine (volume 153, pages 621-632). The authors are A. Idan, K.A. Griffiths, D.T. Harwood, M.J. Seibel, L. Turner, A.J. Conway, and D.J. Handelsman.

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