Testosterone replacement to normal levels in middle-aged and elderly hypogonadal men significantly improved all components of the metabolic syndrome at 24 months, according to research presented here at the International Diabetes Federation World Diabetes Congress 2011.
Positive effects were maintained for at least 60 months, reported Farid Saad, PhD, from Bayer Schering Pharma in Berlin, Germany, which sponsored the prospective observational study.
“The long-term data are intriguing and the magnitude of changes came as a surprise, even to many experts who have been working with testosterone for decades,” Dr. Saad told Medscape Medical News. “The findings are more than promising, especially when it comes to obesity, for which neither medicine nor the pharmaceutical industry has found a good answer.”
A total of 147 hypogonadal men from 38 to 83 years of age participated in the study, all of whom had presented at a urology clinic with testosterone levels between 0.14 and 3.51 ng/mL.
The men were treated with 1000 mg parenteral testosterone undecanoate (Nebido, Bayer Schering Pharma) injected once every 3 months for at least 48 months. (The product is not approved in the United States, but is licensed to Endo Pharmaceuticals. It has been approved since 2004 in Europe, Latin America, and parts of Asia and the Middle East.)
At the end of the 48-month study period, the average reduction in waist circumference was “quite substantial,” at 8.0 cm, and showed “consistent and progressive decline” as far out as 60 months in some cases, he said.
In addition, body weight was reduced by 12.9 kg, from an average of 106.6 to 93.7 kg.
In terms of percent weight change, subjects lost around 5% of their initial weight after about 15 months, and about 10% after 3.5 to 4.0 years of treatment, he added.
“We were surprised to see these data when we first analyzed them because short-term studies of testosterone replacement suggest there’s a shift of fat mass to lean mass. People who are on treatment for 1 year may gain 4.5 to 5.0 kg of lean mass and lose 5.0 to 6.0 kg of fat mass — but the overall effect on weight is moderate. These 4-year data were a surprise when we saw people lost 12.9 kg, and the 60-month data suggest this continues — we have not yet reached the plateau, the weight is still declining,” he said.
Both systolic and diastolic blood pressure were also significantly reduced (by 15.2 and 13.3 mm Hg, respectively), dropping from 155/94 to 140/80.8 mm Hg at 48 months.
There was a significant improvement in lipid profiles, with total serum cholesterol dropping from 297.7 to 194.5 mg/dL, triglycerides dropping from 290.4 to 194.2 mg/dL, and low-density-lipoprotein cholesterol dropping from 160.4 to 118.3 mg/dL.
“With HDL [high-density lipoprotein], we saw a phenomenon that we cannot yet explain,” said Dr. Saad. “There was a rise in HDL during the first 24 months of treatment and then a drop. We don’t know how this came about, but maybe it was related to a massive drop in total cholesterol in some of the men who had levels between 350 and 400 mg/dL at baseline.”
He said it is possible that cholesterol levels improved with the help of other medications. “This study was done in a urology office. It is possible that once these patients were diagnosed with severe dyslipidemia, they were referred back to internal medicine practitioners and put on other medication.”
There was also an initial significant decrease in levels of liver enzymes, with aspartate aminotransferase dropping from 43.9 to 22.0 U/L and alanine aminotransferase dropping from 46.6 to 22.8 U/L over the first 24 months, and then leveling off. These decreases likely indicate an improvement of nonalcoholic fatty liver disease, said Dr. Saad.
Additionally, there was a “marked reduction” in C-reactive protein levels over the 4-year period, from 7.1 to 1.6 mg/L, which was not surprising because “testosterone has recently been shown in a number of studies to be an anti-inflammatory agent,” he said.
Finally, mean plasma glucose levels declined from 105.8 to 97.0 mg/dL over the 4-year period. “Without separating those with elevated glucose from those with normal glucose at baseline, we saw a mean reduction in the first 1.5 years, and then the levels stabilized,” he said.
Dr. Saad said that epidemiologic studies consistently suggest that testosterone deficiency are found in about 50% of men with type 2 diabetes. In this context, he said, screening of diabetic men “may be justified, but in the world of diabetes treatment, testosterone deficiency is still not well known.”
In terms of perceived risks associated with testosterone replacement, the study found no rise in prostate-specific antigen; although there was a slight increase in prostate volume, it was considered to be a result of aging, he said. In addition, there was a decline in the International Prostate Symptom Score, a measure of urinary function, indicating an improvement.
“These are probably the longest-term data that I’ve seen,” Arya Sharma, MD, PhD, cochair of the session, toldMedscape Medical News.
Dr. Sharma, who is professor of medicine and chair in obesity research and management at the University of Alberta, in Edmonton, Canada, said he does not currently screen diabetic men for low testosterone, but “in terms of biological plausibility, there are a lot of good arguments for why testosterone therapy could work in these patients.”
“I’d like to see a prospective randomized trial. There’s good rationale why it would and could work, but I think we would certainly want to see a randomized controlled trial.”
The study was sponsored by Bayer Schering Pharma. Dr. Saad is an employee of Bayer Schering Pharma. Coauthor L.J. Gooren reports receiving lecture honoraria from Organon, Bayer Schering Pharma, and Haider; and receiving travel grants from Bayer Schering Pharma and Takeda. Dr. Sharma has disclosed no relevant financial relationships.
International Diabetes Federation (IDF) World Diabetes Congress 2011. Abstract O-0535. Presented December 7, 2011.