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Testosterone therapy may benefit men with diabetes and obesity, but remains controversial
Endocrine Today | An increasing number of studies are reporting that testosterone therapy may not only normalize testosterone levels for men, but may also provide cardiometabolic benefits. Nearly 20 years ago, researchers discovered a link between low testosterone in men and the prevalence of...
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An increasing number of studies are reporting that testosterone therapy may not only normalize testosterone levels for men but may also provide cardiometabolic benefits.
Nearly 20 years ago, researchers discovered a link between low testosterone in men and the prevalence of diabetes. In a study published in 2004, researchers analyzed blood samples from 103 men with type 2 diabetes and discovered one-third of the cohort had hypogonadism. Paresh Dandona, MD, Ph.D., SUNY distinguished professor and chief of endocrinology at the University of Buffalo, New York, an Endocrine Today Editorial Board Member and co-author on the study, described the condition as hypogonadotropic hypogonadism and said the paper was pivotal in advancing the understanding of how testosterone levels are linked with cardiometabolic disorders.
Around the same time in the U.K., a group of researchers also observed associations between low testosterone levels for men with diabetes and cardiovascular disease. This was the impetus for a randomized controlled trial assessing the effects of testosterone therapy for men with type 2 diabetes and low testosterone.
“We looked at a population of 355 men with type 2 diabetes in Barnsley and found that 42% of the men had symptomatic low testosterone with diabetes. This is a lot of men with diabetes with low testosterone,” T. Hugh Jones, MD, consultant physician and endocrinologist at Barnsley Hospital, honorary professor of andrology at the University of Sheffield and honorary consultant endocrinologist at Royal Hallamshire Hospital in Sheffield, U.K., told Endocrine Today. “We were treating the men, with the majority having improved well-being and sexual function. Furthermore, our study in 2013 found men with low testosterone had double the risk of death (19.2%) compared to diabetic men who had normal testosterone (9%), whereas those on testosterone therapy had increased survival (8.4%) over a mean follow-up of 6 years.”
Over the past decade, numerous studies found testosterone therapy could have benefits for men with hypogonadism who also have diabetes, obesity, and other cardiometabolic disorders. However, this use of testosterone among endocrinologists remains low in the U.S.
There is also the question of whether to measure testosterone levels to screen for hypogonadism among men with cardiometabolic disorders. Gary Wittert, MBBCh, MD, FRACP, professor of medicine and director of the Freemason's Centre for Male Health and Wellbeing at the University of Adelaide in Australia, said the vast majority of men with metabolic syndrome who have a low serum testosterone concentration do not have pathological hypogonadism, but rather the low testosterone is caused by obesity or metabolic syndrome and is reversible with weight loss; comorbid conditions, such as depression; and concomitant medication use, such as opioids.
“The low testosterone is a bystander of something else that’s taking place,” Wittert told Endocrine Today.
Research on the link between testosterone and diabetes began in the late 1990s. Dandona said he began seeing men with diabetes in his practice who were prescribed sildenafil for erectile dysfunction but were not responding to the medication. He measured testosterone in these patients and discovered about one-third of men with type 2 diabetes had low testosterone levels.
In an update published in 2010, Dandona and colleagues linked low testosterone levels to obesity as well as type 2 diabetes. In that study, low testosterone was observed among 35% of men with diabetes and 25% of men with obesity without diabetes.
“Clearly, testosterone is not only a sex hormone, but it’s also a metabolic hormone,” Dandona said.
The next question researchers asked was whether testosterone therapy could have a beneficial effect on diabetes and obesity. In a study published in 2016, 44 men with hypogonadotropic hypogonadism were randomly assigned to 250 mg intramuscular testosterone or placebo every 2 weeks for 24 weeks. Compared with 50 men who were eugonadal at baseline, those with hypogonadism had interference with four insulin-signaling genes in the adipose tissue. At 24 weeks, the men receiving testosterone had increases in insulin sensitivity and lean mass and a decrease in subcutaneous fat that were not observed in the placebo group.
“When we treat these people with testosterone for 6 months, the insulin resistance mathematically reverses, and those four sites at which insulin-signaling behaviors are interfered with are also reversed,” Dandona said. “That made it quite clear that there is a clear-cut correlation of testosterone with insulin resistance and type 2 diabetes.”
Similar findings were also being observed in the U.K. In 2006 and 2011, Jones and colleagues published findings, first in a small study and then from the Times2 study, which then examined the impact of testosterone replacement in hypogonadal men on reducing insulin resistance, the central biochemical defect in type 2 diabetes and metabolic syndrome. The pilot study was the first to show that testosterone improved insulin resistance, glycemic control, and waist circumference.
In the Times2 study, researchers randomly assigned 220 participants to use a transdermal 2% testosterone gel or placebo for 6 months. The testosterone group had a greater reduction in insulin resistance and a 0.5% greater decrease in HbA1c compared with the placebo. Some men receiving testosterone also had improvements in lipid parameters.
“Testosterone replacement also improved symptoms of sexual function,” Jones said. “You have the benefit of the quality of life, and you have the benefit of the underlying problem of insulin resistance.”
Testosterone to prevent diabetes
During the past 5 years, multiple research groups have continued to examine the beneficial effects of testosterone therapy for men with hypogonadism and type 2 diabetes or obesity. A few studies have taken a step further to look at how testosterone may help slow or halt the progression from prediabetes to diabetes.
Data published in 2019 provided evidence that testosterone therapy may be able to prevent type 2 diabetes for men with hypogonadism and prediabetes. Researchers analyzed data from 316 men with prediabetes, defined as an HbA1c of 5.7% to 6.4%, and hypogonadism. Participants were treated with parenteral testosterone undecanoate or received no treatment. Over 8 years of follow-up, the testosterone group had a 0.39% decline in HbA1c, with 90% of the participants achieving an HbA1c of less than 5.7%, whereas the untreated group had a 0.1% increase in HbA1c and 40.2% had progression to type 2 diabetes with an HbA1c greater than 6.5%.
“The placebo group illustrates what happens when you don’t treat these patients,” W. Timothy Garvey, MD, MACE, MABOM, professor of medicine at the University of Alabama (UAB) at Birmingham, director of the UAB Diabetes Research Center and co-author on the 2019 study, told Endocrine Today. “The natural history of this is they deteriorate. This was a long-term study, it was 8 years of follow-up. Over that period, there was a significant deterioration in metabolism with respect to glycemic control, and more patients were diagnosed with type 2 diabetes. It’s not only the benefits, it’s what happens when you don’t treat.”
Similar findings were observed in a study published in 2020. In the study, men with hypogonadism and type 2 diabetes were treated with testosterone therapy. Testosterone was associated not only with the loss of adiposity and increase in insulin sensitivity but also with the reversal of diabetes itself for one-third of participants over a period of 8 years.
In a randomized controlled trial published in 2021, Wittert and colleagues looked further into the preventive effects of testosterone replacement, specifically for men without pathological hypogonadism. The T4DM trial enrolled men aged 50 to 74 years with a waist circumference of 95 cm or more and with impaired glucose tolerance or newly diagnosed type 2 diabetes. Participants had serum testosterone of 14 nmol/L or less. Men with no pathological hypogonadism were excluded. Participants were randomly assigned to 1,000 mg testosterone undecanoate or placebo at baseline, 6 weeks, and then every 3 months for 2 years. All also participated in a 2-year lifestyle program.
At 2 years, men who received testosterone had a 0.75 mmol/L greater decrease in 2-hour glucose compared with placebo, and the percentage of participants with a 2-hour glucose of 11.1 mmol/L or higher at 2 years was 12% in the testosterone group compared with 21% in the placebo group.
The researchers measured fat mass and lean mass using DXA scans and also analyzed glycemic and lipid markers to begin to uncover the mechanisms by which testosterone therapy worked.
“The major determinant was a decrease in fat mass,” Wittert said. “One of the surprises, given what we postulated, was an absence of effect in the increase of skeletal muscle mass or strength.”
Wittert noted the effect of testosterone to increase muscle mass was small in comparison with other studies of testosterone treatment. In the placebo group, muscle mass decreased, which is the usual consequence of weight loss. Testosterone treatment prevented this and induced a small increase in muscle mass and also an increase in muscle strength. Wittert said it is likely testosterone therapy alone, without lifestyle intervention, would result in a greater increase in muscle mass.
Controversy surrounding risks
While multiple studies have reported the benefits of testosterone therapy, uptake of the therapy has been slow in practice in part due to concerns surrounding CV risk.
A study published in JAMA in 2013 initially found that men in the Veterans Affairs health system from 2005 to 2011 who used testosterone therapy had increased risks for adverse outcomes, which were defined as a composite of all-cause mortality, myocardial infarction, and stroke.
“That study started the headlines, and what people heard about testosterone was the scare story that testosterone was associated with heart attacks, stroke, and death,” Abraham Morgentaler, MD, FACS, associate professor of surgery, part-time in the division of urology at Beth Israel Deaconess Medical Center, Harvard Medical School, told Endocrine Today. “We actually have no [strong] data that supports that. On the contrary, most of the data is either neutral about the risk or favorable.”
Findings published in the European Heart Journal in 2015 ran contrary to CV concerns found in the JAMA study. Researchers analyzed data from more than 83,000 men with low testosterone treated at the Veterans Health Administration from 1999 to 2014. Compared with men who did not receive testosterone, men who received the therapy and whose testosterone levels returned to normal had a reduced risk for mortality, MI, and stroke.
Another concern providers should be aware of is an increased risk for prostate cancer with testosterone use, Garvey said.
“Good clinical practice is you do a rectal exam and see if there are any prostate nodules,” Garvey said. “If you find a dominant nodule or if the prostate-specific antigen is elevated, you wouldn’t use testosterone replacement in those folks.”
Jones said prostate cancer should be excluded before the use of testosterone therapy, and a urology review should be requested if an elevated PSA test or nodule causes concern. Testosterone therapy may unmask a prostate cancer, usually in the first year, but does not cause new prostate cancer, Jones said. He said that much of the concern surrounding prostate cancer risk with the use of testosterone therapy stems from a small study conducted by Charles B. Huggins, MD, in 1946.
“There were five patients in the paper with prostate cancer that importantly showed that castration shrank the tumor, whereas a patient given testosterone resulted in cancer,” Jones said. “Doctors will remember from medical school this association of testosterone with prostate cancer. It is widely accepted that there is no current evidence to link testosterone replacement with new development of prostate carcinoma.”
Questions surrounding screening
Guidance from medical societies varies on whether providers should measure testosterone levels in men diagnosed with type 2 diabetes or obesity. In the American Association of Clinical Endocrinology guidelines for medical care of patients with obesity, the authors recommend assessing all men with obesity or an increased waist circumference for a history of hypogonadism or testosterone deficiency. Testosterone therapy should be considered for those with true hypogonadism and obesity, according to the guideline. Additionally, the guideline recommends screening all men with type 2 diabetes to exclude testosterone deficiency.
In the 2022 American Diabetes Association Standards of Care, the authors cite the T4DM trial as evidence that testosterone therapy may help prevent the progression to diabetes in a specific population. The guideline advises providers to measure morning serum testosterone levels among men with diabetes and signs or symptoms of hypogonadism and acknowledges testosterone therapy could improve sexual function, well-being, muscle mass and strength, and bone density among men with symptoms of hypogonadism.
Dandona and Morgentaler both said they believe that a greater emphasis needs to be placed on testosterone screening for men diagnosed with type 2 diabetes.
“Every type 2 diabetic and every obese male should have his testosterone measured,” Dandona said. “Once the testosterone is found to be low, it should be replaced.”
“There’s no other blood test that will tell us so much about a man’s physical condition, about his prognosis, and also give an opportunity to treat and improve his quality of life in a variety of ways,” Morgentaler said.
Garvey said it is crucial for providers to assay free testosterone in addition to measuring total testosterone to confirm below-normal levels, as men with insulin resistance have low sex hormone-binding globulin levels, which can lead to lower circulating total testosterone. He added that if testosterone is prescribed, it is just one part of a treatment plan for men with hypogonadism and obesity.
“Just testosterone replacement may not be the full benefit you bring to these patients,” Garvey said. “You want to make sure that they have 10% or more weight loss as well to maximize the chances that they won’t get diabetes.”
Wittert said that simply measuring testosterone levels is not enough to diagnose pathological hypogonadism. Providers need to take a holistic approach and properly investigate the cause of low testosterone levels and remember that with weight loss and reversal of suboptimal lifestyle behaviors — for example, excess alcohol intake — testosterone will increase unless there is overt pathology of the hypothalamic-pituitary-testicular axis.
“If someone is overweight or obese and they have metabolic syndrome, and they’ve got a set of symptoms, don’t assume symptoms are due to the low testosterone,” Wittert said. “You owe that individual a thorough assessment to determine whether there is pathological hypogonadism present and identify concomitant health conditions, such as obstructive sleep apnea, depression, opioid and other drug use, and suboptimal lifestyle behaviors.”
Jones said testosterone therapy may become more common in practice if larger studies showing patient benefits are published. Additionally, Jones said he believes that future randomized controlled trials comparing testosterone with diabetes and obesity drugs are needed.
“If you have someone who has diabetes and hypogonadism, does the patient respond better on a combination of GLP-1 agonist and testosterone replacement than GLP-1 agonist alone?” Jones said. “Also, in the future, if you’ve got someone on that combination and you stop the GLP-1 agonist — which is more expensive than testosterone — do they maintain the weight they lost? It’s those sorts of longer studies [that are needed].”
