Researchers at the Intermountain Medical Center Heart Institute in Murray, Utah, which is the flagship facility for the Intermountain Healthcare system, studied 5,695 men between the ages of 53 and 71. The men, all patients at Intermountain Healthcare hospitals, had initial low testosterone levels.

Researchers found that men who received testosterone supplementation to achieve normal or high testosterone levels had reduced overall rates of major adverse cardiac events at one and three years after their initial low levels of testosterone were measured, compared to other men who had persistently low levels of testosterone. The lower rate of cardiac events included a reduction in the adjusted risk of death and a reduction in heart attacks.

The Intermountain Medical Center Heart Institute research team will report their findings at the 2014 American Heart Association in Chicago at 8:30 am, MST, on Tuesday, Nov. 18.

The study comes at an important time, as the U.S. Federal Drug Administration is evaluating the safety of testosterone supplementation and whether it is a risk to the health of older men.

According to the FDA, 1.3 million patients received a prescription for testosterone therapy in 2010. By 2013, the number rose to 1.3 million patients, with men ages 40 to 64 making up 70% of the prescriptions.

Smaller studies have been conducted on testosterone replacement therapy and its cardiovascular effects in men, with different results. While it is known that low levels of testosterone pose an increased cardiovascular risk, the risks versus benefits of supplementation have not been clearly identified.

The new findings that testosterone therapy is generally safe and does not increase the risk of major adverse cardiac events for men with low levels of testosterone, provides assurance to physicians across the country to use it when it's needed with less concern about its effect on their patients' heart health, say researchers.

"Testosterone therapy has become very popular in the United States in recent years," said Jeffrey Anderson, MD, a cardiologist at the Intermountain Medical Center Heart Institute, and lead researcher for the study. "With this study we are getting closer to defining the true associations between testosterone treatment and cardiovascular risks or benefits."

During clinical follow-up, men in the study were categorized as having persistently low testosterone levels (only 14% had been given supplements), normal levels or high levels (all were supplemented). All of the men had at least three years of subsequent follow-up observation. Researchers than assessed the impact on death, heart attack, or stroke of supplementation to normal or high levels after one and three years by reviewing electronic medical records.

"While this study provides reassurance about the safety of using supplementation to move from low to normal levels of testosterone, more studies, particularly large randomized studies, are needed," said Dr. Anderson.

Testosterone replacement therapy does not increase cardiovascular risks in men with low testosterone levels -- ScienceDaily

The study also found that men who were treated but did not attain normal levels did not see the same benefits as those whose levels did reach normal.

The study was published online Aug. 6, 2015, in the European Heart Journal.

Mixed results in past studies

The findings may sway the ongoing debate over testosterone therapy's benefits and risks, especially for the heart. Studies over the past few years have yielded mixed results, although part of that might stem from differing patient populations and research methods.

For example, the new VA study excluded men with a history of heart attacks or strokes, although it did include those with existing heart disease. A much-cited VA database study that was published in JAMA in 2013 looked specifically at men with coronary artery disease; about 20 percent of the total study group of around 8,700 men had suffered a prior heart attack.

So far, the medical community lacks results from any definitive clinical trial that might provide clear guidance. Meanwhile, the Food and Drug Administration issued guidance earlier in 2015 advising clinicians about the over-use of testosterone therapy, and pointing to a possible increased risk of heart attack and stroke.

Right dose critical for benefits

The new VA study is likely to draw attention because of its large size and relatively long follow-up period. Dr. Rajat Barua, the paper's corresponding author, says the study is also noteworthy because of its finding that administering the right dose is critical: Treating "low T" but not restoring levels to normal doesn't appear to impart much benefit, at least in terms of cardiovascular risk. Testosterone isn't prescribed with the goal of improving heart health, but that is a consideration in many cases.

"It is the first study to demonstrate that significant benefit is observed only if the dose is adequate to normalize the total testosterone levels," Barua and his coauthors wrote. "Patients who failed to achieve the therapeutic range after testosterone replacement therapy did not see a reduction in or stroke and had significantly less benefit on mortality."

Barua is with the Kansas City (Mo.) VA Medical Center. He's also an assistant professor of medicine at the University of Kansas.

The study team looked at national data on more than 83,000 men with documented low testosterone, all age 50 or above, who received care in VA between 1999 and 2014.

The researchers divided the men into three clinical groups: those who were treated to the point where their total testosterone levels returned to normal (Group 1); those who were treated but without reaching normal (Group 2); and those who were untreated and remained at low levels (Group 3).

Study compared similar groups of men

Importantly, all three groups were "propensity matched" so the comparisons would be between men with similar health profiles. The researchers took into account a wide array of factors that might affect cardiovascular and overall risk. They included, for example, age, body mass index, various chronic diseases, LDL cholesterol levels, and the use of aspirin, beta blockers, and statins.

The average follow-up across the groups ranged from 4.6 to 6.2 years.

The sharpest contrast emerged between Group 1 (those who were treated and attained normal levels) and Group 3 (those whose low testosterone went untreated). The treated men were 56 percent less likely to die during the follow-up period, 24 percent less likely to suffer a heart attack, and 36 percent less likely to have a stroke.

The differences between Group 1 and Group 2 (those who were treated but did not attain normal levels) were similar but less pronounced.

Little difference emerged between Groups 2 and 3, except for a slight benefit in survival for those who were treated.

'Off-label' use remains a concern

Barua and colleagues say they don't know the exact reasons for testosterone's apparent benefits for the heart and overall survival. "The mechanisms for these effects remain speculative," they write. Possible explanations, they say, could involve body fat, insulin sensitivity, lipids, blood platelets, inflammation, or other biological pathways. More research is needed, they say, to clarify how testosterone affects the cardiovascular system.

While the new study results do seem to advocate for testosterone replacement therapy, Barua stresses the need for "appropriate screening, selection, dosing, and follow-up of patients to maximize the benefit of testosterone therapy."

The authors also caution that "off-label" use remains a concern. In other words, doctors should not write a prescription simply because an older man is complaining of symptoms such as low energy and low sex drive. According to the FDA, "Testosterone products are FDA-approved only for use in men who lack or have low testosterone levels in conjunction with an associated medical condition. Examples of these conditions include failure of the testicles to produce testosterone because of reasons such as genetic problems or chemotherapy...None of the FDA-approved testosterone products are approved for use in men with low testosterone levels who lack an associated medical condition."

Study of 83,000 Veterans finds cardiovascular benefits to testosterone replacement

Testosterone and men's quality of life - PubMed (nih.gov)

The investigators restored testosterone to normal levels in 255 hypogonadal men and the treatment lasted for up to five years, with injections given at day 1, after 6 weeks, and then every 12 weeks after that. Patients did not follow a controlled diet or standard exercise program but received advice to improve their lifestyle habits.

On average, the men weighed 236 pounds before beginning testosterone treatment and 200 pounds after treatment (106.2 vs. 90.07 kg). Weight loss was reportedly continuous, with an average reduction in body weight ranging from about 4% after one year of treatment to more than 13% after five years. Men lost an average of nearly 3.5 inches (8.8 cm) around their waist.  The study showed that waist circumference declined from 107.24 to 98.46 cm.  In addition, body mass index (BMI) declined from 33.93 to 29.17 kg/m². The mean weight loss after one, two, three, four, and five years was 4.12%, 7.47 %, 9.01%, 11.26%, and 13.21%, respectively.

Overall, 95% of the patients lost weight; 31% lost 20 kg or more, and 77% lost 10% or more of their initial body weight. A total of 97% of the patients experienced a reduction in waist circumference.

“There was no intention to make them lose weight,” Dr. Saad told Renal & Urology News. “The weight loss was never expected. This was found as a side effect of treatment. Some of the men came in for erectile dysfunction treatment.”

In a separate study also presented at this meeting, testosterone replacement therapy was found to significantly improve symptoms of metabolic syndrome associated with testosterone deficiency.  Investigators started collecting data in 2004 from 261 patients with late-onset hypogonadism at a single center in Germany. Patients received 1,000 mg of testosterone undecanoate on the first day of the study, at week 6, and then every three months. At each visit, investigators measure subjects’ hormone, glucose, and lipid levels, as well as blood pressure (BP).

The mean follow-up was 4.25 years. The prevalence of metabolic syndrome dropped from 56% to 30% after 57 months of treatment. Triglyceride levels decreased in 77% of patients, glucose levels decreased in 67% of patients, and mean arterial pressure decreased in 78% of patients. The average waist circumference shrank by 11 cm.

“When indicated, testosterone treatment is both essential and safe in elderly patients with symptomatic late-onset hypogonadism,” said lead author Aksam Yassin, MD, PhD, Chairman of the Institute of Urology & Andrology in Norderstedt-Hamburg, Germany. “Further analysis is needed to confirm if our findings are due to a direct effect of restoring physiologic testosterone levels.”

Previous research has linked metabolic syndrome to testosterone deficiency. In addition, testosterone deficiency is associated with individual components of metabolic syndrome.

To determine the presence of metabolic syndrome among study participants, investigators used the definition from the International Diabetes Federation. All subjects were diagnosed with the syndrome if they displayed central obesity combined with at least two of the following risk factors: elevated triglycerides levels, decreased high-density lipoproteins, high BP, and excessive blood sugar concentrations.

“Testosterone investigation in elderly patients with health problems is an essential part of men’s health practice,” Dr. Yassin said.

Testosterone undecanoate is not yet available in the United States, but it is marketed in Europe, Latin America, Australia, and parts of Asia and Africa.  Dr. Saad is an employee of Bayer Pharma, which makes a brand of testosterone undecanoate. Bayer Pharma partially funded Dr. Saad’s study in its final two years.

Study Shows Health Benefits of Testosterone Replacement - Renal and Urology News

After 5 years of treatment, the average weight of participants dropped from 104.2 kg at baseline to 92.5 kg. 96.3% of participants lost weight with 80.2% having lost ≥ 5 kg, 51.2% having lost ≥10 kg, 31.5% having lost ≥ 15 kg, and 14.2% having lost ≥ 20 kg.

Statistically significant decrease in waist circumference was seen in addition to improvements in both lipid profiles and blood pressure. The waist circumference of study participants decreased from a baseline average of 108.6 cm down to 99.0 cm. Average total cholesterol dropped from 264 to 212 mg/dL. The average low-density lipoprotein cholesterol (LDL-C) dropped from162.3 mg/dL to 126.4 mg/dL; and the average triglyceride level dropped from 261mg/dL to 199 mg/dL. Further, HDL-C increased from 40.1 mg/dL up to 55.6 mg/dL.

Average systolic and diastolic blood pressure decreased from 140 to 122.3 mmHg and 81.6 to 77.6 mmHg, respectively. In addition, mean fasting glucose levels decreased from 112.7 to 99.0 mg/dL and mean glycated hemoglobin (HbA1c) values decreased from 6.7% to 5.6%.

Overall, individuals in this study experienced an average drop in their BMI from 33.1 down to 29.4.

• A statistically significant drop in body weight and waist circumference was seen in participants using testosterone undecanoate for testosterone replace therapy
• Testosterone replacement therapy may have additional beneficial effects on glucose, lipids, and blood pressure, in hypogonadal obese men
• Additional studies are needed evaluating risks verses benefits in subpopulations of patients

Yassin DJ, Doros G, Hammerer PG, Yassin AA. Long-Term Testosterone Treatment in Elderly Men with Hypogonadism and Erectile Dysfunction Reduces Obesity Parameters and Improves Metabolic Syndrome and Health-Related Quality of Life. J Sex Med. 2014.

Multiple Benefits of Long-Term Testosterone Replacement Therapy for Diabetes Patients (diabetesincontrol.com)