Pam Harrison

November 10, 2016

For hypogonadal men, long-term treatment with an injectable form of testosterone improves sexual and urinary function, and, in hyopogonadal men with type 2 diabetes, it also improves glycemic control, registry data out to 8 years indicate.

In addition, it leads to striking changes in body composition, including reductions in waist circumference, body mass index (BMI), and body weight, and increases in lean muscle mass.

"Testosterone is one of the most beneficial — and at the same time, the most underestimated and under-rated — treatment modalities for hypogonadal men," said Farid Saad, MD, honorary professor at Gulf Medical University in Ajman, United Arab Emirates, and therapeutic area head of global medical affairs andrology at Bayer AG in Berlin.

"It's just amazing what it does, and it certainly does not deserve the bad reputation it has," he told Medscape Medical News.

"We need to do our best to convince healthcare professionals and the authorities that testosterone is actually a very beneficial treatment that confers many health benefits on these men, including less cardiovascular disease and fewer cardiovascular events," he explained.

Dr Saad presented his team's findings at the Sexual Medicine Society of North America Fall 2016 Scientific Meeting in Scottsdale, Arizona.

Erectile and Urinary Function

The prospective registry from which Dr Saad and his colleagues collected their data was initiated in 2004 by two urologists who wanted to track the progress of their patients who were being treated with an injectable form of testosterone administered once every 3 months (Nebido, Bayer Schering Pharma AG).

At the time, the registry was not supported by industry, but it was later championed by Dr Saad as a project that needed some form of financial backing because 4 to 5 years into the registry's existence, the data were beginning to look extremely tantalizing.

Dr Saad's team used the registry to identify a group of men diagnosed with hypogonadism who received a testosterone injection every 3 months, and a control group of men diagnosed with hypogonadism who chose not to be treated with testosterone, matched for age, waist circumference, and BMI.

The researchers used propensity-matched 8-year data on 82 men in each group for their analysis. Mean age of the 164 men was 61.6 years, and median follow-up was 7 years.

To assess urinary symptoms, the self-administered International Prostate Symptom Score (IPPS) was used, as was residual voiding volume.

"Both the IPPS and the residual bladder volumes increased over 8 years in the untreated group. This is not surprising because we know urinary function doesn't improve with age," Dr Saad noted.

Over 8 years, testosterone not only improves urinary function, it also halts the progression of urinary problems.

In contrast, "we saw a remarkable, steady, consistent, and sustained improvement in both subjective and objective parameters of urinary function in the testosterone-treated group. Over 8 years, testosterone not only improves urinary function, it also halts the progression of urinary problems. It seems to essentially preserve urinary function that would otherwise deteriorate," he reported.

The same pattern of change over time was observed on the erectile function domain of the International Index of Erectile Function (IIEF-EF); erectile function improved in the testosterone group but worsened in the control group.

Prostate volume increased slightly in the testosterone group, but not to any clinically meaningful degree, and stayed virtually unchanged in the control group.

Table 1. Change From Baseline in Urinary Symptoms and Erectile Function at 8-Year Follow-up

  Testosterone Group Control Group  
Measure Baseline 8-Year Follow-up Baseline 8-Year Follow-up P Value
IPPS 7.4 2.0 4.3 7.0 <.0001
Residual urine volume 50.6 mL 14.0 mL 45.7 mL 66.6 mL <.0001
IIEF-EF score 19.5 25.8 20.2 12.4 <.0001
Prostate volume 31.4 mL 33.2 mL 33.4 mL 33.6 mL <.0001
Aging Males' Symptoms score 53.8 17.2 40.6 46.0 <.0001


Of the 21 deaths that occurred in the control group, 19 were from cardiovascular causes. There were only two deaths in the testosterone group, and neither was related to treatment.

There were no major adverse cardiovascular events in the testosterone group, but there were 28 nonfatal strokes and 25 nonfatal myocardial infractions in the control group.

Glycemic Control and Weight Loss

In any cohort of middle-aged hypogonadal men, obesity is almost ubiquitous, and the registry cohort was no exception. "Almost all of the men were overweight or obese," Dr Saad reported.

Not surprisingly, approximately 35% of the men in both groups had type 2 diabetes. All were on antidiabetic treatment, largely metformin.

At baseline, the average level of glycosylated hemoglobin (HbA1c) in the men with diabetes was about 8%, meaning that the majority of men had poor glycemic control with standard diabetic treatment, said Dr Saad.

Table 2. Change From Baseline in Body Composition

Outcome Baseline 8-Year Follow-up P Value
Waist circumference (cm)      
   Testosterone group 106.1 98.3 <.0001
   Control group 106.0 107.7 <.005
Body mass index (kg/m²)      
   Testosterone group 30.7 26.6 <.0001
   Control group 30.5 31 ns


Over the 8 years, the men in the testosterone group lost more than 13% of their body weight, whereas the men in the control group gained 0.09%.

"With long-term testosterone, we see a reduction in waist circumference, which means that there is a reduction in visceral fat, we see a reduction in overall obesity, and we see tremendous reduction in body weight," Dr Saad confirmed.

"We also saw this amazing reduction in HbA1c, by approximately 2%, which is unbelievable because it's very difficult to achieve even a 1% reduction in HbA1c with any specific antidiabetic medication, especially over the long term," he added.

Over 90% of the treated group had an HbA1c level below 6.5% at their last measurement, he reported.

Another "unique effect" of testosterone is the fact that it "automatically" builds muscle mass — one of the main reasons it is abused when taken in supraphysiological doses.

With increasing muscle mass, "you increase your basal energy expenditure," Dr Saad explained.

"More muscle means more calorie consumption, and this is part of the reason men lose weight on testosterone," he said. The other part is that obese hypogonadal men not on testosterone are often typical "couch potatoes."

"When you restore testosterone to normal levels, behavior changes in a subtle manner. Anecdotally, men reported walking and cycling more and getting involved in sports, so they became more active than before," said Dr Saad.

"Testosterone goes far beyond being a sex hormone; it is very important in terms of both metabolic and cardiovascular disease, and you have tremendously beneficial effects on both," he noted.

Intriguing Data

These data are very intriguing, said Landon Trost, MD, head of andrology and male infertility at the Mayo Clinic in Rochester, Minnesota, who is a member of the American Urological Association guideline committee on hypogonadism.

"They really just need confirmation from an external group, and preferably one that does not have industry ties," Dr Trost told Medscape Medical News.

However, there is no incentive for any company to do a prospective long-term study on testosterone because the drug is not patent protected. These are "probably going to be the best long-term data we have, and there are shortcomings," he said.

For example, it is not clear how many men in the control group dropped out during the 8-year follow-up period because they were not getting any benefit, magnifying the benefits of treatment in the testosterone group over time.

"Nevertheless, all of this has been confirmed by other studies with much shorter follow-up, so they support the idea that, potentially, you get continued benefits over time," added Dr Trost.

He noted that most specialists who are familiar with the cardiovascular data, as they relate to testosterone, are very critical of studies that report an increased risk for cardiovascular events and of people who suggest that better, more critical analysis of this link shows that testosterone is likely protective against cardiovascular events.

"The majority of us who really keep up on these data are supportive of the concept that testosterone is beneficial in appropriately selected patients," Dr Trost said. "But that's not a man with normal testosterone who just wants a boost in life; it's men with low-testosterone symptoms and consistently low testosterone values who are most likely to benefit significantly from treatment."

Dr Saad is therapeutic area head of global medical affairs andrology at Bayer AG. Dr Trost has disclosed no relevant financial relationships.

Sexual Medicine Society of North America (SMSNA) Fall 2016 Scientific Meeting. Abstracts 016, 130, and 132. Presented November 3, 2016.


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