Short-term Testosterone Replacement for 'Male Menopause' Appears Safe

LOS ANGELES, Nov. 15 -- Six months of testosterone replacement therapy in aging men restored serum values to normal without apparent harmful effects to the prostate, according to preliminary data from a small study.

The results of the study seemed to contradict suggestions that when given to older men with late-onset hypogonadism, exogenous testosterone accumulates in the prostate, converts to dihydrotestosterone, and causes biological changes including the risk of prostate cancer, said Leonard Marks, M.D., of the University of California Los Angeles, and colleagues.

Preliminary data from this study, they reported in the Nov. 15 issue of the Journal of the American Medical Association, suggested that six months of testosterone replacement have little effect on prostate tissue, androgen levels and cellular functions and should not entail substantial risks of stimulating occult prostate disease.

Aspects of late-onset hypogonadism, sometimes called male menopause or male climacteric, may be eased with testosterone replacement therapy, the researchers said. Low-testosterone changes include depression, sexual dysfunction, diminished lean body mass, diminution in muscle volume and strength, and reduced bone-mineral density.

However, most testosterone prescriptions are written for men older than 45 years, a group in which prostate disease is most common, Dr. Marks said.

The prostate-gland findings came from a six-month randomized, double-blind, placebo-controlled trial that included 40 men, ages 44 to 78 years, with screening serum testosterone levels lower than 300 ng/dL (<10.4 nmol/L) and related symptoms. The study was conducted at a Los Angeles community-based research center from 2003 to 2004.

All 40 men had prostate biopsies at baseline and at six months. Twenty-one were randomized to testosterone therapy, and 19 served as the placebo arm.

Testosterone replacement therapy increased serum testosterone levels from a baseline median of 282 ng/dL (9.8 nmol/L) to the midnormal median range at six months of 640 ng/dL (22.2 nmol/L). There was no significant change in serum testosterone levels in matched, placebo-treated men, the investigators reported.

However, in prostate tissue, testosterone increased median androgen concentrations only slightly and not significantly compared with baseline levels or between the two groups, the investigators found.

In the intervention group, median prostate tissue levels of testosterone were 0.91 ng/g at baseline and 1.55 ng/g post-treatment. Dihydrotestosterone levels were 6.79 ng/g at baseline and 6.82 ng/g post-treatment (P=0.29).

Prostate volume was not significantly changed by treatment, and changes in serum prostate-specific antigen (PSA), voiding symptoms, and urinary flow were minor, the researchers reported.

No treatment-related change was observed in prostate histology, including stroma-epithelial ratio, percentage of atrophic glands, or in measurements of biomarkers for cell proliferation (Ki-67), androgen receptor, or angiogenesis (CD34).

Overall, no statistically significant changes in gene expression changes were associated with treatment. Known androgen-regulated genes (AR, PSA, NXK.13, PAP2A) were unchanged and genes related to cell stress (CLU) or angiogenesis (VEGF) were no different from expression in the placebo group.

As for prostate cancer, there were no treatment-related changes, the researchers reported. Six of 40 men who completed the trial were found to have prostate cancer at six months: four of 19 in the placebo group and two of 21 in the treatment group. These six men probably had cancer throughout the trial, the investigators said.

From these data, testosterone cannot be implicated as a cancer stimulus, the researchers concluded. Nevertheless, they said, a longer, appropriately powered study is needed to determine whether the rate of PSA increase can help identify men who would be at special risk.

Discussing the limitations of the study, the researchers said that the small sample size, short duration, and lack of power for secondary endpoints suggest that the present study does not establish complete safety for large populations of men receiving testosterone treatment. At the population level, it would require a trial with 6,000 men.

However, in certain clinical situations, short-term testosterone therapy might be useful. For example, perioperative testosterone appears to accelerate the post-surgery recovery of elderly men from knee replacement, or therapy might help modify the profound muscle catabolism associated with severe burn injuries. Furthermore the benefits for patients with metabolic syndrome have been shown to extend even after the end of treatment.

The prostate risk of men undergoing testosterone treatment "may not be as great as once believed, especially if the results of the pretreatment biopsy are negative," Dr. Marks said. However, he added, the establishment of prostate safety for large populations of older men undergoing longer testosterone replacement therapy requires further study.

Among the unrestricted education grants to support this study were those from Watson Laboratories in Salt Lake City and Solvay Pharmaceuticals in Marietta, Ga. Dr. Marks reported serving as a paid consultant/advisor to Slovay Pharmaceuticals and Watson Laboratories, and serving as an investigator for Watson Laboratories in an unrelated trial. Peter Nelson, M.D., also served as a paid consultant/advisor to Solvay Pharmaceuticals.