Five Years of Testosterone Ameliorates Metabolic Syndrome in Hypogonadal Men

Selected by Pietro Cazzola

TestosteroneA new observational study following men with hypogonadism taking testosterone for 5 years — the longest treatment duration to date — showed improvements in lipids, blood pressure, and blood glucose levels, thereby ameliorating a number of components of the metabolic syndrome.
"Men with hypogonadism, or testosterone deficiency, do get reasonable benefit from testosterone treatment, in a very subtle way," lead author Adulmaged M Traish, PhD, from Boston University School of Medicine, Massachusetts, toldMedscape Medical News. "They lose a bit of weight, it reduces hyperglycemia and insulin resistance, and, although it was a surprise to me, testosterone certainly normalizes the lipid profile."
The long duration of this new trial strengthens the findings, said Dr. Traish. "If this were a 3-week or 6-week observational study, I would have my personal doubts, but once you pass the third or fourth year and it stays consistent, it's beginning to tell us that there is something obviously there."
Dr. Traish and colleagues report their findings in their study published online October 15 in the International Journal of Clinical Practice.
"This hormone is with us, it kicks in after adrenarche [puberty] and it is an important metabolic hormone; it regulates our sugar metabolism and our muscle metabolism among other things, and when we don't have enough of this hormone, we are going to go into imbalance, " he noted.
Dr. Traish stressed, however, that testosterone is a reasonable treatment only for men with proven deficiency, "not as an overall drug to make miracles." A recent study showed testosterone use in the United States has tripled over a 10-year period, from 2001 to 2011, and critics have blamed this on aggressive marketing by the companies that produce testosterone-replacement therapies.
"We are simply bringing testosterone back to within the physiological range in men who are deficient," he stressed. But what constitutes testosterone deficiency is a subject of some debate, he acknowledged.

Testosterone Improves Cholesterol Over 5 Years
In their study, Dr. Traish and colleagues followed 255 men, aged 33 to 69 years of age, who had been diagnosed with subnormal plasma total testosterone levels (mean 9.93 nmol/L; range, 5.89–12.13 nmol/L) as well as at least mild symptoms of testosterone deficiency assessed by the Aging Males' Symptom scale.
All the subjects had sought urological consultation for various medical conditions (eg, erectile dysfunction or decreased libido) or had been referred to a urologist by another specialist, such as some men with osteoporosis suspected of having testosterone deficiency.
All men received treatment with parenteral testosterone undecanoate 1000 mg (Nebido, Bayer Pharma, Berlin, Germany) administered at baseline and 6 weeks and thereafter every 12 weeks up to 60 months.
Measurements of height, weight, and waist circumference were performed at baseline, and at each visit weight and waist circumference were assessed and blood samples drawn.
Testosterone levels improved from a mean of 9.9 nmol/L at the beginning of therapy to about 18 nmol/L within the first 12 months of therapy ( < .0001), then they reached a plateau and remained constant, at physiological levels, throughout the course of treatment, approaching 5 years.
Testosterone therapy reduced waist circumference by an average of 8.5 cm over the course of the study, and body weight fell by a mean of 15.35 kg ( < .0001 for both). These effects of testosterone on anthropometric parameters have been previously reported, say the researchers.
They also examined whether testosterone affects the components of the metabolic syndrome. Testosterone treatment resulted in a gradual and consistent decline in total-cholesterol levels, which was significant as early as 12 months of therapy and reached a plateau at 24 months. At baseline, the mean total cholesterol was 7.3 mmol/L (282 mg/dL), and this was reduced to about 4.9 mmol/L (188 mg/dL) by 24 months of therapy, remaining low throughout the remaining period of therapy.
Similarly, there were marked and significant gradual and consistent decreases in LDL-cholesterol levels, from 4.2 mmol/L (164 mg/dL) to 2.8 mmol/L (110 mg/dL), significant within the first year of treatment (P < .0001) and at 24 months (P < .0001 vs 12 months) and stable thereafter over the course of the 5-year period.
HDL-cholesterol levels slightly but significantly increased and remained elevated over the 5-year period of treatment. The total/HDL-cholesterol ratio, thought to predict the risk of cardiovascular disease and, in particular, ischemic heart disease, also improved considerably in these patients, from 5.44 to 3.49 (P< .0001) "suggesting a favorable change in the lipid profile and a potential reduction in CVD risk," the authors observe.

Testosterone Improves BP, Blood Sugar, HbA1c, and CRP
Testosterone treatment also produced a marked and sustained gradual decrease in systolic blood pressure from a mean of 153.55 mm Hg to 137.72 mm Hg ( P < .0001); the decrease was significant and gradual over the first 2 years and remained low over the entire course of the 5 years of treatment. A similar pattern was recorded with diastolic blood pressure, which dropped from 93.49 to 79.59 mm Hg (P < .0001).
And there was a significant gradual decrease in fasting blood glucose from 5.74 mmol/L (103.35 mg/dL) to 5.41 mmol/L (97.56 mg/dL); again, the decrease was significant after 12 months (P < .0001), further declined after 24 months (P = .012 vs 12 months), and then reached a plateau.
This was paralleled by a marked decrease in HbA1c from 7.06% to 6.16%, which, in contrast to other parameters, was statistically significant after 12 months (P < .0001), between 24 and 12 months (P < .0001), between 36 and 24 months (P = .0036), between 48 and 36 months (P = .0049), and between 60 and 48 months (P = .0149).
The researchers also observed a marked and significant reduction in C-reactive protein (CRP), from 6.29 U/L to 1.03 U/L (< .0001), with a plateau after 36 months, which was accompanied by significant declines in aspartate transaminase and alanine transaminase, "suggesting a reduced inflammatory response and improvement in liver function," they note.
On a safety note, the incidence of prostate cancer, which was diagnosed in 3 men, provides reassurance with regard to the role of testosterone, say Dr. Traish and colleagues, who note that other recent reports have placed fears regarding testosterone therapy and prostate cancer incidence "in a more rational perspective."

Testosterone Deficiency: More Risk for CVD and Diabetes
Asked by Medscape about a recent review that found scant definitive evidence that testosterone supplementation affects the risk of cardiovascular disease, Dr. Traish said it suffered from all of the weaknesses inherent in any meta-analysis, with many of the included studies having considerable limitations.
And while he acknowledged that his new study is observational and "was not designed to specifically investigate the effects of testosterone on metabolic syndrome," nor did it select patients for specific comorbidities, it did at least represent patients "in a real-life setting with various symptoms, comorbidities, and conditions," he and his colleagues observe.
Dr. Traish said there are many issues to consider on this controversial topic.
"There are more men who are androgen deficient and are not treated, from this country and all around, for reasons that are beyond my understanding. In some countries it's because of the healthcare system. The argument is, 'Are we pushing this on men and asking them, should they check their T?' but if we are looking at quality of life, what's wrong with checking testosterone levels in the same way as we check cholesterol levels? If the testosterone is below the normal range, what's wrong with giving testosterone?
"Men who are deficient in testosterone have more risk for vascular disease, more risk for diabetes, and more risk of hypertension," he stressed.

Testosterone Deficiency Should Be More Than a Lab Test
He acknowledged, however, that there is disagreement on what constitutes hypogonadism. "We are complex organisms; my threshold may be 350 ng/dL [of testosterone], but someone else's threshold may be 450, so that person, once he goes below 450 he is deficient, but if we take my threshold as the universal one, he's cool."
Official guidelines from the US Endocrine Society guidelines indicate testosterone deficiency is anything below the range of 300 to 340 ng/dL, he said, "so if you are lower, you are hypogonadal. In Europe, the range is 8 to 11 nmol/L"
And he emphasized that the key to proper diagnosis of hypogonadism is "to use the range of testosterone [that indicates deficiency] plus a number of signs and symptoms. It should not just be a lab test. It should be a lab test plus symptoms such as fatigue, sexual dysfunction, and other indicators."
And finally, "Which testosterone? That I don't know — the injectable, the gel, the tablet, the inhaler…the spray. That becomes a preference of the patient and his physician to discuss which one is best for him," he concluded.

Dr. Traish has reported no relevant financial relationships; disclosures for the coauthors are listed in the article.

Int J Clin Pract . Published online October 15, 2013.

Lisa Nainggolan