Long-term testosterone therapy sustainably lowers weight, improves metabolic parameters, and has a large effect on mortality in men with low levels of the hormone in addition to obesity, a long-term study has shown. 

Farid Saad, DVM, PhD, an andrology and endocrinology specialist who recently retired from Medical Affairs Andrology, Bayer, Berlin, Germany, presented the work as an oral poster at this year's virtual European and International Congress on Obesity (ECOICO 2020).

Over 11 years, men with obesity who took testosterone therapy lost a mean of 23 kg (51 lb) compared with a gain of 6 kg (13 lb) in those who did not take testosterone. Waist circumference decreased by a mean of 13 cm (5 inches) in those receiving testosterone, while it increased by 7 cm (2.7 inches) in the control group.

"The weight loss surprised us most," remarked Saad. "When we started out, we didn't really realize the potential effects because the weight loss was so subtle. The effects first became apparent at 4 years, and now we are pleased to see this weight loss has been sustained."

Testosterone therapy stands apart from many other weight loss interventions because most of those result in patients regaining lost weight at some point, he noted. "We don't see this with testosterone," said Saad, who is also an honorary professor at Gulf Medical University, Ajman, United Arab Emirates.

Commenting on the work, Geoffrey Hackett, MD, consultant in urology and sexual health medicine at University Hospitals Birmingham Foundation Trust, UK, says other studies support these findings.

"Other randomized studies have found loss of visceral fat and increase in lean muscle mass [with testosterone therapy]," he told Medscape Medical News.  

Hackett himself was involved in a study in which 200 obese men with type 2 diabetes were treated with testosterone therapy and followed for 4 years. "We found modest weight loss of about 2 kg versus placebo but they lost fat from around the waist and improved other aspects of their health."

The T4DM study from Australia, recently presented at the virtual American Diabetes Association (ADA) 80th Scientific Sessions, "showed a 40% reduction in progression to type 2 diabetes for testosterone versus placebo," Saad said. And as reported by Medscape Medical News in 2018, in a subset of his patients, Saad also found an effect on this outcome, with 22% of men with type 2 diabetes and hypogonadism achieving diabetes remission with testosterone.

Hackett added that, "Unfortunately, diabetes and obesity specialists have chosen to ignore these data and persist with lifestyle interventions as the sole basis of management despite clear evidence that they are losing the battle."

Hugh Jones, MD, professor of andrology at the University of Sheffield, UK, also praised the study for being well conducted and generating long-term evidence.

"Short-term studies of testosterone therapy, up to 1 year, have shown either a small or no weight loss as there is an increase in muscle as well as fat loss. But this study has provided exciting positive information that testosterone replacement over many years of treatment results in a progressive and very significant weight loss," Jones emphasized.

Slow, Steady, and Effective Weight Loss

Beginning in 2004, Saad's prospective, registry-based study at a urological practice in Bremerhaven, Germany, aimed to monitor the safety and effectiveness of a novel, long-acting testosterone injection given every 3 months.

In total, 61% (471 out of 773) of the men had obesity, and of these, 276 men received testosterone therapy comprised of testosterone undecanoate (TU) as a 1000-mg injection administered in the clinic every 3 months for up to 11 years. The remaining 195 men chose not to receive testosterone treatment, thereby serving as a control group. Compliance was excellent because the therapy was clinic-administered.

The researchers evaluated changes in weight, waist circumference, body mass index (BMI), visceral fat, major cardiovascular events, and mortality over time between those receiving and not receiving testosterone therapy.

A total of 4059 patient-years were analyzed, with the scientists adjusting for baseline differences between groups in terms of age, weight, waist circumference, fasting glucose, blood pressure, and lipids, as well as quality of life.

At baseline, the average patient age was 60.6 years in the testosterone group and 63.5 years in the control group. Also, 56.6% of the testosterone group and 63.6% of the control group had type 2 diabetes; 9.8% and 2.1% had prediabetes (A1c 5.7-6.4%), respectively.

After 11 years of follow-up, weight decreased by a mean of 23 kg (from 114 kg initially) in men taking testosterone compared with a loss of 6 kg in the control group, equating to a 20% and 6% loss in body weight, respectively.

Waist circumference decreased by a mean 13 cm in those taking testosterone but increased by 7 cm in the control group.

BMI fell by 7.6 points in the testosterone group (from 36.8 to 28.8 mg/kg² before adjustment, and to 27.9 mg/kg² after adjustment), while it increased by 2 points in the control group.

Measurements of visceral fat were also lower in the testosterone group. The so-called visceral adiposity index decreased by 2.7 points in the testosterone group and increased by 3.1 points in the control group.

Testosterone Leads to Tissue Remodeling, Which Takes Time

Saad explained why the long-term use of testosterone is an important aspect of this weight intervention. "If you only take testosterone for a short time you are likely to miss most of the benefits, because testosterone leads to tissue remodeling, which takes time."

The study did not look at body composition but other studies have.

"With testosterone therapy, a man might lose 4-6 kg of fat in the first year or so, but they gain lean muscle mass, which is more metabolically active and uses more calories, contributing to further weight loss," Saad pointed out.  

"Also, with increased muscle mass, patients are more likely to exercise more because it is easier and more enjoyable. Patients want to continue this therapy because they have so much more energy and feel so much better."

There was also a significant mortality difference between groups: 21 patients (7.6%) died in the testosterone group and 63 patients (32.3%) in the control group.

Some men in the control group experienced heart attack (28%) and stroke (27.2%), whereas there were no major cardiovascular events in men receiving testosterone therapy.

All the deaths in the testosterone group were related to traffic and sport accidents, or postsurgical infections, however.

A further 43 patients (22.1%) developed type 2 diabetes during the study, meaning 85% of control patients had type 2 diabetes after 11 years of follow-up. No patients, in addition to those with a diagnosis at baseline in the testosterone group, developed type 2 diabetes.

Regarding side effects, Saad said in the case of these patients, testosterone normalizes a hormone that is lacking.

"There used to be concerns around prostate cancer but that has long gone and we see more prostate cancer in the control group. Otherwise, we really don't see anything of concern. In the past there were concerns that hematocrit goes up but this is transient without clinical implication."

Comparable to Bariatric Surgery

Saad also presented a poster he said helps with comparison of testosterone therapy and bariatric surgery. He concluded that long-term testosterone therapy in men with hypogonadism and class III obesity (BMI ≥ 40 kg/m²) resulted in profound and sustained weight loss of a magnitude comparable to that achieved with metabolic surgery.

Study participants in the analysis all had class III obesity and hypogonadism. Typically, three quarters of patients with this degree of obesity have hypogonadism, something that "is often overlooked," said Saad.

"In very obese men you are very likely to find low testosterone."

"These patients with class III obesity lose weight in the range of bariatric surgery, so 30 kg or more, but this is over years rather than suddenly. I believe that the side-effect profile with testosterone is preferable to that of bariatric surgery," and the former "is a real alternative to...surgery," he asserted.

Bariatric surgery can have a number of complications and might not suit all patients. "It is not for everyone, and we have seen, albeit rarely, cases of osteoporosis due to malabsorption of nutrients. Lifelong supplements are also required with bariatric surgery while testosterone is quite the opposite in improving bone density and structure," he explained.

Currently, testosterone is not frequently used in weight loss clinics.

"People are only starting to use this now. Two years ago it entered the guidelines of the American Association of Clinical Endocrinologists, but it is not yet widely accepted because we need large randomized controlled trials which would take many years," Saad concluded.

Saad has reported being a consultant for Bayer and a stock/shareholder in Bayer, AbbVie, and CRISPR Therapeutics. Hackett has reported being a speaker for Bayer and Besins. Jones has declared that his institution has received research grants and he has received honoraria for nonpromotional educational lectures and advisory boards from Bayer Healthcare.

ECO-ICO 2020. Presented September 2, 2020. Oral abstract AD17-05, poster EP-524.

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Cite this: Testosterone: An Option for Weight Loss in Obesity With Hypogonadism - Medscape - Sep 08, 2020.