Testosterone treatment in aging men

Issue: June 2008

ByGlenn R. Cunningham, MD

More than 20% of men aged 65 years and older have low total testosterone levels and a higher percentage have low free testosterone levels.

A recent report from the BACH survey indicates that these older men are likely to have symptoms consistent with testosterone deficiency. Recently reviewed in Endocrine Today is the report from Laughlin et al, which showed that men with testosterone levels in the lowest quartile had a 40% increased risk of mortality during a 20-year follow-up, independent of multiple risk factors and pre-existing medical conditions. Nonetheless, men aged older than 65 years only accounted for about 13% of the prescriptions written for testosterone in the United States.

There are multiple reasons why fewer men aged older than 65 years are prescribed testosterone replacement therapy as compared with testosterone deficient men aged 65 years and younger. First, most of the older men do not have congenital or anatomical disease involving hypothalamus, pituitary or testes. Second, total and free testosterone levels (calculated or accurately measured) are more likely to be equivocal or only mildly reduced. Third, the potential benefits of testosterone treatment may be less certain. Finally, the potential risks, particularly prostate cancer, are perceived to be greater.

Glenn R. Cunningham, MD
Glenn R. Cunningham

Clinical data reviewed

Evidence-based medicine requires that clinical trial data are used to make clinical decisions. The largest clinical trial of testosterone replacement therapy involved only 400 patients, and fewer than 25% of these men were aged 65 years and older. Thus, most clinical trials have not been powered to address either the potential benefits or the potential risks of treating older men. Snyder et al randomly assigned 108 men aged 65 years and older to testosterone or placebo treatment, but many of his patients did not have low testosterone levels.

Placebo-controlled trials of testosterone replacement therapy by Amory et al and by Kenny et al involved fewer older men. These studies have consistently demonstrated some improvement in body composition (eg, reduced fat mass and increased lean body mass) and bone mineral density. However, they have not demonstrated consistent improvement in functional measures. The studies were underpowered to address many of the potentially beneficial effects — sexual function, vitality or fatigue, physical activity, bone fractures or cognition. Snyder et al have proposed a one-year testosterone trial that would involve 1,200 men aged 65 years and older. This study has been reviewed, revised, re-reviewed and is now awaiting funding. If funded, it could provide definitive data on the efficacy of testosterone replacement therapy in older men.

Concerns arise

Concern about prostate cancer is the major reason why more older men are not treated with testosterone replacement therapy. We know that prostate growth occurs at puberty as testosterone levels increase, and that men with 5-alpha-reductase type 1 develop only rudimentary or no prostate. We also know that medical or surgical castration causes metastatic prostate cancer to regress until it becomes androgen-independent. Prostate cancer is a disease of older men. It is estimated that there will be 186,320 new cases of prostate cancer diagnosed in the United States this year, and that there will be 28,660 deaths caused by prostate cancer. Prostate cancer is the most common non-skin malignancy in men, accounting for 25% of malignancies. It is second only to lung and bronchial cancers as a cause of death, accounting for 10% of cancer deaths in men. Moreover, at least 50% of men aged 65 years and older will have occult prostate cancer at autopsy. Most of these cancers do not become clinical cancers. A recent meta-analysis of 18 prospective studies concluded that higher serum testosterone and free testosterone levels do not predict increased risk of prostate cancer. Most authorities do not think that testosterone causes prostate cancer, but it may facilitate its growth.

It is not known if raising the serum testosterone level into the eugonadal range will increase the risk for these small occult cancers to become clinical prostate cancers. We estimated that it will require a five-year study involving 6000 men to detect a 30% increase in clinical prostate cancers. A study of this magnitude would be very expensive. Marks randomly assigned 40 men with testosterone levels lower than 300 ng/dL to testosterone enanthate (150 mg by intramuscular injection every two weeks) or placebo injections for six months. He performed prostate biopsies at baseline and six months. Although serum levels of testosterone and dihydrotestosterone increased, prostatic levels of these hormones were not altered significantly. Furthermore, expression of multiple cancer-related genes in the prostate was not affected by testosterone treatment.

The study proposed by Snyder et al is not powered to provide a definitive answer regarding prostate cancer, but it would add greatly to our knowledge of potential side effects of testosterone replacement therapy in this age group. Rosen et al have proposed a registry of men with low testosterone levels who are being treated with testosterone therapy. A registry also could provide valuable information even though it would not be as definitive as a large clinical trial.

There are many older men with low serum testosterone levels and symptoms similar to those of younger hypogonadal men. Most of these men are not being treated for valid concerns. Although many clinical investigators are attempting to contribute to a better understanding of the benefit–risk ratio, realistically it will be at least six to eight years before definitive information is available.

In the interim, clinicians and patients will need to weigh the potential benefits and risks of treatment when serum levels of testosterone are low on multiple determinations. When a decision is made to treat with replacement doses of testosterone, the symptoms and signs associated with testosterone deficiency, the hematocrit, lower urinary tract symptoms, digital rectal examination of the prostate and the prostate specific antigen must be monitored periodically.

For more information:

Amory JK, Watts NB, Easley KA, et al. Exogenous testosterone or testosterone with finasteride increases bone mineral density in older men with low serum testosterone. J Clin Endocrinol Metab. 2004;89:503-510.

Araujo AB, Esche GR, Kupelian V, et al. Prevalence of symptomatic androgen deficiency in men. J Clin Endocrinol Metab. 2007;92:4241-4247.

Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in adult men with androgen deficiency syndromes: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2006;91:1995-2010.

Endogenous Hormones, Prostate Cancer Collaborative Group, Roddam AW, Allen NE, et al. Endogenous sex hormones and prostate cancer: a collaborative analysis of 18 prospective studies. J Natl Cancer Inst. 2008;100:170-183.

Harman SM, Metter EJ, Tobin JD, et al. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab. 2001;86:724-731.

Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin. 2008;58:71-96.

Kenny AM, Prestwood KM, Gruman CA, et al. Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels. J Gerontol A Biol Sci Med Sci. 2001;56:M266-M272.

Laughlin GA, Barrett-Connor E, Bergstrom J. Low serum testosterone and mortality in older men. J Clin Endocrinol Metab. 2008;93:68-75.

Marks LS, Mazer NA, Mostaghel E, et al. Effect of testosterone replacement therapy on prostate tissue in men with late-onset hypogonadism: a randomized controlled trial. JAMA. 2006;296:2351-2361.

Snyder PJ, Peachey H, Hannoush P, et al. Effect of testosterone treatment on body composition and muscle strength in men over 65 years of age. J Clin Endocrinol Metab. 1999;84:2647-2653.

Glenn R. Cunningham, MD, is Professor of Medicine and Professor of Molecular and Cellular Biology at Baylor College of Medicine, Houston, Medical Director of St. Luke’s Episcopal Hospital Diabetes Program, and is a member of the Endocrine Today Editorial Board.