Use of androgen therapy for hypogonadism: Safe or not?

August 1, 2006

For the two to four million American men who suffer from hypogonadism or "andropause," is treatment with androgen replacement therapy safe, particularly in older men?

Atlanta-For the two to four million American men who suffer from hypogonadism or "andropause," is treatment with androgen replacement therapy safe, particularly in older men? That controversial question was tackled in a point-counterpoint debate during the AUA annual meeting here.

Andre T. Guay, MD, director of the Lahey Clinic Northshore Center for Sexual Function, Peabody, MA, argued in favor of androgen replacement therapy in men with clinical, symptomatic testosterone deficiency. Glenn R. Cunningham, MD, professor of medicine and molecular and cellular biology, Baylor College of Medicine, Houston, urged caution before prescribing such therapy.

Moderator J. Edson Pontes, MD, professor of urologic oncology and assistant dean, Wayne State University School of Medicine, Detroit, introduced the discussion by commenting on the topical nature of the issue in question. An estimated 10% to 30% of men between the ages of 40 and 79 years have low testosterone, Dr. Pontes said, and 10% to 70% have low bioavailable testosterone.

"In the aging population that we see in the offices now, especially with the baby boomers coming of age and with the attitude that we all have in this country of becoming healthy, quite often, patients come to me and ask the question, 'Is it safe to take androgen replacement' " Dr. Pontes said.

Dr. Guay argued that, although critics of testosterone replacement suggest that it may be associated with increased prostate cancer risk, scant evidence for this hypothesis is found in the scientific literature. He cited several epidemiologic studies demonstrating that testosterone treatment is safe in benign prostatic disease and is not associated with increased risk for prostate cancer. One such effort, the Massachusetts Male Aging Study, demonstrated a 4% incidence of prostate cancer after approximately 8 years of follow-up (Urology 2001; 57:930-5). PSA level was the only significant predictor of prostate cancer in this longitudinal study of 1,576 men; testosterone levels were unrelated to development of the disease.

Dr. Guay claimed that withholding testosterone therapy from men with hypogonadism, defined as a clinical condition characterized by low serum testosterone levels occurring in association with signs and symp-toms of androgen deficiency, may be unsafe. A study he cited of 77 men suggested that hypogonadism may actually be correlated with an increased risk for prostate cancer (JAMA 1996; 276:1904-6).

Dr. Guay highlighted three other studies showing low testosterone may be associated with markers of poor prognosis in prostate cancer, including higher pathologic and clinical stage, higher Gleason score, and an increased number of positive surgical margins and positive biopsy cores. He also cited evidence suggesting that men with hypogonadism may have higher rates of hyperlipidemia, cardiovascular disease, and osteoporosis.

Safety evidence "insufficient"
In his remarks, Dr. Cunningham emphasized the importance of practicing evidence-based medicine. He argued that the paucity of evidence supporting the safety of testosterone replacement therapy and calling for randomized clinical trials to address questions of safety for this therapy.

Dr. Cunningham challenged the claim that testosterone replacement therapy is safe by emphasizing that the evidence presented by Dr. Guay was from epidemiologic studies or from very small treatment trials.

"In order to be able to determine if testosterone replacement will increase clinical prostate cancer, we have estimated it will take a trial of 5 years and 6,000 men," Dr. Cunningham pointed out.

He also voiced concerns over the fact that the prevalence of occult prostate cancer increases as men age, raising the likelihood that men being treated with androgen replacement have occult prostate cancer. He conceded that the risk of such men developing clinical prostate cancer is unknown. He also urged urologists to use a new online prostate cancer risk calculator developed by Ian Thompson, MD, of the University of Texas Health Science Center at San Antonio, and colleagues.

"There are potential major risks with testosterone replacement therapy, so we need to be conservative about treatment until we have more information," Dr. Cunningham told Urology Times. "I am advocating treating selectively and monitoring aggressively."

"Life is not a clinical trial," Dr. Guay responded. "As experts, we are asked to make decisions based on less-than-ideal data."