Dihydrotestosterone May Not Affect Prostate Growth But May Reduce BMD

Laurie Barclay, MD

November 16, 2010

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.