New Perspectives on Testosterone Therapy

Adult hypogonadism is a clinical syndrome complex in men often associated with pathological changes in metabolism, sexual functioning, cognition, body composition, physical strength, and/or energy. A recent survey of 10,000 men (average age 52 years) found that 80% had moderate or severe scores that were consistent with testosterone deficiency[i]. While testosterone replacement therapy has proven effective in treating many symptoms of adult hypogonadism, less than 10% of affected men seek treatment[ii]. A wider understanding of testosterone deficiency, as well as the potential health benefits of hormone replacement therapy, is needed. In an effort to further this objective, this paper reviews some of latest and most compelling findings in the areas of hormone research and adult hypogonadism treatment.

Metabolic Syndrome

Metabolic syndrome comprises a group of pathologies including abdominal fat accumulation, insulin resistance, hypertension, and dyslipidaemia (reduced HDL, elevated LDL and triglycerides). This syndrome is considered a strong risk factor for diabetes and cardiovascular disease (CVD). Research over the last five years has established a strong link between metabolic syndrome and hypogonadism. The interplay between the two is often described as a vicious cycle. As the process goes, reduced testosterone levels support the accumulation of fat around the abdominal region. The increased abdominal adiposity contributes to a host of adverse metabolic changes including insulin resistance, increased androgen-to-estrogen metabolism, and elevated inflammatory markers. Serum testosterone is further suppressed by these changes, which only propagates the cycle.

While links between metabolic syndrome and hypogonadism had been established prior, the past year has produced the most compelling research concerning the use of testosterone therapy to treat this disorder. For example, one study examined the effects of androgen supplementation in 184 men with combined hypogonadism and metabolic syndrome[iii]. The men were given parenteral testosterone (1000 mg testosterone undecanoate at 0, 6, and 18 weeks) or placebo, and monitored for 30 weeks. Androgen supplementation significantly reduced body mass index (BMI), waist circumference, and serum glucose compared to placebo. Serum insulin and leptin levels were also reduced, as were the inflammatory markers IL-1 beta, TNF-alpha, and C-reactive protein. Testosterone replacement therapy had significantly improved several markers of metabolic syndrome.

A second study followed 50 patients with both metabolic syndrome and hypogonadism for 24 months[iv]. It compared the effects of testosterone undecanoate (1,000 mg every 12 weeks) to placebo for the first 12 months, followed by 12 months of testosterone therapy for all patients. An analysis of the data found that testosterone supplementation significantly improved waist circumference, visceral fat mass, and insulin resistance, all key components of metabolic syndrome. After two years, only 35% or 58% of patients retained a positive diagnosis for metabolic syndrome as defined by NCEP-ATPIII and IDF criteria, respectively. Under the controlled experimental conditions, testosterone therapy reversed metabolic syndrome in a high percentage of patients.

CVD and Mortality

The favorable effects of testosterone therapy on metabolic syndrome have strong implications for cardiovascular health. Maintaining normal youthful hormone levels can thus be an effective strategy to improving CVD risk. More than that, however, our very understanding of the relationship between testosterone, cardiovascular health, and mortality has been changing. It has long been known that men are more likely to suffer from sudden cardiac arrest than women are. For many years, this tendency was attributed to the atheroprotective effects of estrogen, or negative influence of androgens. New evidence, however, suggests that testosterone has a direct atheroprotective effect, independent of its aromatization to estrogen[v]. Furthermore, the data is pointing to hypogonadism as a fundamental contributor to cardiovascular disease in men[vi].

One recurring finding this past year has been a link between hypogonadism and mortality from cardiovascular event. For example, one study followed 1,954 men aged 20-79 years for 7.2 years. Hormone levels were recorded at baseline and at the time of death for 195 participants[vii]. After controlling for factors such as waist circumference, smoking, alcohol use, and physical activity, low serum testosterone levels (< 250 ng/dL) were associated with increased rate of mortality from cardiovascular disease and cancer. Another study examined 126 male patients admitted to the hospital for myocardial infarction[viii]. Free testosterone, C-reactive protein, NT-pro-BNP, and hemoglobin levels were measured at the time of admission. The 30-day mortality rate was later analyzed. All of the men that died (n=16) had a testosterone level below 300 ng/dL. A third study followed 930 patients with coronary disease for two years[ix]. Once again, low testosterone (bioavailable) was associated with a significantly increased rate of mortality.

Testosterone replacement therapy in adult hypogonadism is now well understood to have favorable effects on many cardiovascular disease risk factors. It has previously been shown to improve lipid profiles, lower certain inflammatory markers, reduce abdominal fat stores, and enhance insulin sensitivity and glycemic control[x]. Testosterone therapy has also been shown to exert positive effects in some patients with cardiac ischemia, angina, and even chronic heart failure. These most recent findings only serve to further solidify a relationship between testosterone and cardiovascular health. Furthermore, they are forcing medicine to look even more closely at the potential atheroprotective value of hormone replacement therapy in aging men.

Alzheimer’s Disease

This past couple of years has also seen a stronger association established between low testosterone levels and Alzheimer’s disease. One recent paper concerns a one-year cohort study of 153 ambulatory community-living men aged 55 years and over (the mean age was 72.7 years)[xi]. None of the men had been previously diagnosed with Alzheimer’s disease. Various serum markers were taken at baseline including total and bioavailable testosterone. At their one-year follow up, the cognitive health of all subjects was re-evaluated. Ten subjects (6.5%) had developed Alzheimer’s disease during this time. After adjusting for age, education, BMI, fasting glucose, and HDL-cholesterol, bioavailable testosterone was found to be a strong independent predictor for the later development of Alzheimer’s disease.

A second study, published the year earlier, examined brain sex steroid levels in post-mortem tissue samples of men and women diagnosed with Alzheimer’s disease[xii]. In men aged 60-79 years at the time of death, testosterone levels (but not estrogens) were lower in cases where mild neuropathological changes or advanced AD neuropathology were present. There was also an inverse relationship between testosterone levels and soluble beta-amyloid (Abeta), the major constituent of amyloid plaque in Alzheimer’s. These studies add to earlier works suggesting a link between sex steroids and this disease[xiii]. While not conclusive, the data is promising. More research is clearly needed to determine if hormone replacement therapy in aging men can reduce the risk of developing Alzheimer’s disease.

Looking Forward

The past couple of years have brought fourth many compelling studies on the hormone testosterone. As we further review the results of hormone replacement therapy, we are finding significant potential in not only traditional treatment areas such as the loss of muscle mass with aging (sarcopenia) and sexual dysfunction, but in fundamental areas of metabolic, cardiovascular, and cognitive health. Cardiovascular disease remains the most common cause of death, and Alzheimer’s a growing concern in a population that seems to be growing older. While treatment rates below 10% for testosterone deficiency as discouraging, they also suggest great potential for medicine to change the health landscape for men given the proper education and support.