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CME

Dihydrotestosterone May Not Affect Prostate Growth But May Reduce BMD

  • Authors: News Author: Laurie Barclay, MD
    CME Author: Charles P. Vega, MD
  • CME Released: 11/16/2010
  • THIS ACTIVITY HAS EXPIRED
  • Valid for credit through: 11/16/2011
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Target Audience and Goal Statement

This article is intended for primary care clinicians, urologists, endocrinologists, and other specialists who care for middle-aged and older men.

The goal of this activity is to provide medical news to primary care clinicians and other healthcare professionals in order to enhance patient care.

Upon completion of this activity, participants will be able to:

  1. Analyze the physiologic effects of testosterone.
  2. Evaluate the effects of dihydrotestosterone treatment in healthy older men.


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Author(s)

  • Laurie Barclay, MD

    Freelance writer and reviewer, Medscape, LLC

    Disclosures

    Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.

Editor(s)

  • Brande Nicole Martin

    CME Clinical Editor, Medscape, LLC

    Disclosures

    Disclosure: Brande Nicole Martin has disclosed no relevant financial relationships.

CME Author(s)

  • Charles P. Vega, MD

    Associate Clinical Professor, Residency Program Director, Prime-LC, University of California-Irvine, Orange, California; Department of Family Medicine, University of California-Irvine, Orange, California

    Disclosures

    Disclosure: Charles P. Vega, MD, has disclosed no relevant financial relationships.

CME Reviewer(s)

  • Sarah Fleischman

    CME Program Manager, Medscape, LLC

    Disclosures

    Disclosure: Sarah Fleischman has disclosed no relevant financial relationships.


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CME

Dihydrotestosterone May Not Affect Prostate Growth But May Reduce BMD

Authors: News Author: Laurie Barclay, MD CME Author: Charles P. Vega, MDFaculty and Disclosures
THIS ACTIVITY HAS EXPIRED

CME Released: 11/16/2010

Valid for credit through: 11/16/2011

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November 16, 2010 — Dihydrotestosterone (DHT) treatment for 24 months does not affect prostate growth but causes a decrease in spinal, but not hip, bone mineral density (BMD), according to the results of a randomized, placebo-controlled, parallel-group trial reported in the November 16 issue of the Annals of Internal Medicine.

"Benign prostatic hypertrophy increases with age and can result in substantially decreased quality of life for older men," write Amanda Idan, BSc, MHSc, from Concord Hospital, ANZAC Research Institute, University of Sydney, Sydney, Australia, and colleagues. "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."

At an ambulatory care research center, 114 healthy men older than 50 years without known prostate disease were randomly assigned to receive transdermal DHT (70 mg) or placebo gel daily for 2 years. Every 6 months, blood samples and questionnaires were collected, prostate volume was measured with ultrasonography, and BMD and body composition were measured with dual-energy x-ray absorptiometry. Data were analyzed by mixed-model analysis for repeated measures.

With time on study, there was an increase during 24 months in total prostate volume (29%; 95% confidence interval [CI], 23% - 34%), central prostate volume (75%; 95% CI, 64% - 86%; P < .01), and serum prostate–specific antigen level (PSA; 15%; 95% CI, 6% - 24%). However, DHT had no effect on these changes (P > .2).

Compared with placebo, DHT reduced lumbar spine BMD (1.4%; 95% CI, 0.6% - 2.3%; P < .001) at 24 months but not hip BMD (P > .2) and increased serum aminoterminal propeptide of type I procollagen in the second year of the study. In the DHT group, levels of serum DHT and its metabolites were increased, whereas serum testosterone, estradiol, luteinizing hormone, and follicle-stimulating hormone levels were suppressed. DHT increased hemoglobin levels (7%; 95% CI, 5% - 9%), serum creatinine levels (9%; 95% CI, 5% - 11%), and lean mass (2.4%; 95% CI, 1.6% - 3.1%) but reduced fat mass (5.2%; 95% CI, 2.6% - 7.7%; P < .001 for all).

DHT was not associated with any serious adverse effects but did cause some protocol-specific discontinuations. These were asymptomatic increased hematocrit levels in 8 patients, which resolved after treatment was stopped, and increased PSA levels in 3 patients, none of whom had prostate cancer.

"Negative findings on prostate growth cannot exclude adverse effects on the natural history of prostate cancer," the study authors write. "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."

In an accompanying editorial, Ronald S. Swerdloff, MD, from Harbor–University of California, Los Angeles, and Christina Wang, MD, from David Geffen School of Medicine at the University of California, Los Angeles, note that this study was not adequately powered to definitively answer the question of long-term safety of testosterone use.

"These data do show that a 10-fold increase in serum DHT levels had no significant effects on prostate size, serum DHT, and International Prostate Symptom Score, suggesting that the modest increases of serum DHT seen after testosterone treatment may not have a clinically significant effect on prostate health," Drs. Swerdloff and Wang write. "Idan and colleagues argue that their findings provide insight about the potential efficacy of future synthetic androgen receptor modulators that will likely share (with DHT) the anabolic effects on muscle and fat, as well as the sparing effects on the prostate. However, we caution that each synthetic androgen-receptor modulator could have a different target organ profile. We conclude that DHT acts as a hormone in tissues without high concentrations of 5α-reductase enzymes but mainly in an autocrine–paracrine manner in tissues like the prostate, in which 5α-reductase is abundant."

BHR Pharma supported this study. Some of the study authors have disclosed various financial relationships with BHR Pharma, Bayer Schering, Ascend/Besins, and/or Radius and Clarus Therapeutics. Drs. Swerdloff and Wang have disclosed no relevant financial relationships.

Ann Intern Med. 2010;153:621-632, 678-679.

Clinical Context

Testosterone has multiple effects throughout the body, including the prostate. The prostate contains abundant amounts of 5α-reductase, which converts testosterone into DHT. In doing so, the prostate amplifies the effects of testosterone, which leads to prostate enlargement. However, DHT cannot be amplified, and it may even prevent prostate growth via negative feedback on the production of endogenous androgens as well as interaction with an estrogen receptor in the prostate. Short trials have suggested that exogenous administration of DHT can indeed slow the rate of prostate growth, but this phenomenon has not been confirmed in longer trials. The current study addresses this issue.

Study Highlights

  • Men eligible for study participation were at least 50 years old and were free of prostate disease or severe, uncontrolled illness at the time of enrollment.
  • Participants were randomly assigned to receive DHT 70 mg daily transdermally or placebo. The study was double blinded.
  • Study outcomes were measured at baseline and at 3, 6, 12, 18, and 24 months. The main study outcome was total prostate volume at 2 years, as measured by ultrasound examination. Researchers also followed serum PSA levels, BMD at the hip and spine by dual-energy x-ray absorptiometry, carotid intima-media thickness by ultrasonography, muscular strength by hand grip dynamometry, and several measures of quality of life.
  • 114 men underwent randomization. The mean age of participants was 60.5 years, and baseline characteristics were well matched between the DHT group and the placebo group. The mean total prostate volume was approximately 29 mL at baseline.
  • Adherence to study therapy and follow-up procedures exceeded 95% in both groups.
  • DHT therapy increased serum levels of DHT to approximately 10 times of baseline values while also suppressing testosterone, estradiol, luteinizing hormone, and follicle-stimulating hormone levels to castrate levels. Placebo treatment was not associated with any change in hormone levels.
  • At 2 years, the average prostate volume increased by 29% (95% CI, 23% - 34%), and serum PSA levels increased by a mean of 15% (95% CI, 6% - 24%). However, DHT did not have a significant effect on these outcomes vs placebo, and prostate symptom scores were similar in comparing the 2 treatment groups.
  • DHT was associated with a more significant BMD loss at the lumbar spine (mean, −1.4%; 95% CI, 0.6% - 2.3%; P < .001) vs placebo (no significant change from baseline). However, DHT did not promote BMD loss at the hip (P > .2).
  • Serum levels of aminoterminal propeptide of type I procollagen, a marker of bone turnover, was significantly elevated during year 2 of treatment with DHT. However, another marker, urine aminoterminal cross-linked telopeptide of collagen type I, was not.
  • Lean body mass increased (2.4%; 95% CI, 1.6% - 3.1%), and fat mass decreased (5.2%; 95% CI, 2.6% - 7.7%) by a mean of 1.0 kg to 1.5 kg each during treatment with DHT, but there was no change in body composition in the placebo group. Grip strength improved in the DHT group vs the placebo group, but there was no difference between groups in abdominal, mid-thigh, or mid-arm circumference.
  • DHT did not increase carotid intima-media thickness vs placebo. DHT did promote a slight increase in systolic blood pressure and pulse but also failed to significantly alter serum lipid levels.
  • General quality of life, satisfaction with physical activity, and psychosexual function were not improved with DHT vs placebo.
  • DHT therapy increased hematocrit and creatinine levels vs baseline values.
  • 13 men in the DHT group and 5 men in the placebo group discontinued treatment. 8 men stopped DHT because of polycythemia, which resolved on cessation of therapy, and 3 men treated with DHT discontinued therapy because of elevated PSA values.
  • Rates of overall adverse events and serious adverse events were otherwise similar in comparing the DHT group vs the placebo group.

Clinical Implications

  • The prostate amplifies the effects of endogenous testosterone, which leads to prostate enlargement. However, DHT cannot be amplified, and it may even prevent prostate growth via negative feedback on the production of endogenous androgens as well as interaction with an estrogen receptor in the prostate.
  • The current study found that DHT treatment did not significantly affect prostate size or serum PSA levels vs placebo among healthy older men. However, DHT was associated with bone loss at the lumbar spine. DHT did not alter measurements of atherosclerosis or quality of life.

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