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“Dihydrotestosterone (DHT) treatment for 24 months does not affect prostate growth, but causes a decrease in spinal, but not hip, bone mineral density (BMD)," Australian researchers found after evaluating 114 men for two years. "Every six 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," according to the paper in the Annals of Internal Medicine. "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."
Dihydrotestosterone May Not Affect Prostate Growth But May Reduce BMD
Medscape: Medscape Access
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.
Idan A, Griffiths KA, Harwood DT, et al.
Long-Term Effects of Dihydrotestosterone Treatment on Prostate Growth in Healthy, Middle-Aged Men Without Prostate Disease. Annals of Internal Medicine 2010;153(10):621-32.
Long-Term Effects of Dihydrotestosterone Treatment on Prostate Growth in Healthy, Middle-Aged Men Without Prostate Disease — Ann Intern Med
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.
Commentary: Swerdloff RS, Wang C.
Dihydrotestosterone: Hormone or Autocrine-Paracrine Signal? Annals of Internal Medicine 2010;153(10):678-9.
A few excerpts:
Because
testosterone affects prostate growth, it has been postulated that androgens that are not 5 alpha-reducible or that result in lower intraprostatic dihydrotestosterone (
DHT) levels would spare the prostate and might prevent prostate enlargement and prostate cancer. Thus, synthetic non–5 alpha-reducible androgens might be promising approaches to late-onset hypogonadism or andropause. Surprisingly, studies show that DHT, a potent androgen that cannot be aromatized, has minimal and perhaps inhibitory effects on prostate size and symptoms associated with benign prostatic hypertrophy. This led to the speculation that DHT might be a favorable way to treat late-onset hypogonadism. Because most studies were short in duration, long-term data on prostate size and lower urinary tract symptoms are needed.
Further concern is that nonaromatizable DHT could reduce BMD by lowering serum and tissue estradiol levels.
Idan and colleagues confirmed that increasing serum DHT levels about 10-fold markedly suppressed serum luteinizing hormone, testosterone, and estradiol levels.
In normal men, serum DHT levels are approximately 10% of the serum testosterone levels, whereas intraprostatic DHT levels are much higher than serum levels, with the intraprostatic DHT–testosterone ratio being 7 to 8. Marks and colleagues demonstrated that administration of testosterone to mildly testosterone-deficient men increased serum testosterone levels but did not increase either prostatic DHT or testosterone concentrations. Thus, it seems that the amplifying 5 alpha-reductase system is so efficient in regulating intraprostatic DHT levels that substrate (for example, testosterone) concentrations are limiting only at very low levels. Furthermore, the ability of the 5 alpha-reductase system to produce high tissue levels of DHT in organs, such as the prostate, indicates that even high levels of DHT in the blood remain much lower than the levels reached in the prostate and thus have little influence on prostate growth. In contrast, high levels of DHT in the blood will act as a hormone and thus produce real effects in tissues with less dominant testosterone to DHT-amplifying systems, such as muscle, fat, and bone marrow.
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.