Free Testosterone May Help Diagnose Hypogonadism

Becky McCall

May 19, 2015

DUBLIN — Measuring free testosterone together with total testosterone may provide a more accurate picture than measuring total-testosterone levels alone when it comes to diagnosing deficiency of this male hormone, a new study indicates.

There is concern that, under current clinical guidelines, some men are misdiagnosed with testosterone deficiency and receive inappropriate therapy, while others who should get treatment don't receive it, Dr Leen Antonio (University of Leuven, Belgium) explained when presenting her research here at the European Congress of Endocrinology (ECE) 2015.

"I think it would be preferable to use free testosterone rather than total testosterone to measure deficiency, especially in men who have borderline total-testosterone levels. Our results suggest that free testosterone is more informative than total testosterone," she told attendees.

Currently, total-testosterone levels are used as a measure of testosterone deficiency or hypogonadism. However, only free testosterone, unbound by sex-hormone–binding globulin (SHBG), can enter and activate androgen receptors in cells, resulting in testosterone-mediated effects, she explained.

Asked to comment, Dr Alvin Matsumoto (VA Puget Sound Health Care System, Seattle, Washington) said he agrees with Dr Antonio's conclusion, which supports US Endocrine Society guidelines issued in 2010.

These suggest the additional measurement of free-testosterone level in some men in whom total-testosterone concentrations are near the lower limit of the normal range and/or in whom alterations in SHBG are suspected.

"Advanced age and obesity [and] other comorbidities may…alter SHBG concentrations. Obesity is a particularly common cause of low total testosterone but normal free testosterone and of misdiagnosis of hypogonadism," he explained in an email.

Dr Jean-Marc Kaufman (Ghent University Hospital, Belgium) agrees: "The results from the…study presented by Leen Antonio confirm and formally demonstrate what was already suggested for a long time by indirect evidence. When total-testosterone levels are borderline [and] in situations where important variations of SHBG can be expected, total testosterone can lead to overdiagnosis of hypogonadism (such as in obese men, or men treated with glucocorticoids who have lower SHBG) or to underdiagnoses (eg, in older men or men with thyroid hyperfunction, situations with higher SHBG)."

Unfortunately, Dr Matsumoto noted, accurate methods to detect free testosterone are not routinely available in most clinical laboratories.

Accurate Diagnosis Key to Avoid Overuse of Testosterone

Accurately diagnosing true testosterone deficiency has become increasingly important as, in recent years, a rapidly increasing number of aging men have been treated with testosterone for male hypogonadism; the rate of testosterone supplementation has nearly quadrupled in the United States. The issue is less of problem in Europe, but prescriptions for testosterone have also increased there, by 30% in the United Kingdom, for example.

Such treatment remains controversial, as concern has emerged about the potential for cardiovascular side effects with the use of testosterone therapy, particularly in older men. The US Food and Drug Administration recently issued a warning about this, although the European Medicines Agency did not find sufficient evidence to draw the same conclusion.

Free Testosterone: A More Accurate Diagnostic Tool?

Dr Antonio and her colleagues set out to determine whether free testosterone or total testosterone is more closely associated with hypogonadal signs and symptoms and whether free testosterone might potentially be a more accurate diagnostic tool for testosterone deficiency, given the backdrop of the 2010 US Endocrine Society guidelines.

They assessed approximately 3000 community-dwelling men participating in the European Male Ageing Study (EMAS), the largest-ever study of aging in men in the world, running across eight European countries — the men assessed were aged 40 to 79 years, and median follow-up time was 4.5 years.

They compared three groups of men: those with both normal total testosterone (>10.5 nmol/L) and normal calculated (using an algorithm as opposed to direct measurement) free testosterone (>220 pmol/L) as the reference group (n = 2540); men with normal total testosterone and low free testosterone (group 1, n = 261); and men with low total testosterone and normal free testosterone (group 2, n = 92).

Men in group 1, but not group 2, were in poorer health and had lower hemoglobin; after adjustment for confounders, men in group 1 had less frequent morning erections (P = .012), more erectile dysfunction (P < .001), and more physical symptoms (limited vigorous activity (P = .011), and more trouble walking 1 km (P = .026) and bending (P = .005) than those in the reference group.

The lower hemoglobin levels of men with low free testosterone might suggest anemia or androgen deficiency, according to Dr Antonio.

"They may have signs and symptoms that suggest hypogonadism — sexual and physical — but their testosterone levels might indicate that there is no problem," she explained to Medscape Medical News.

In contrast, men with low total testosterone but normal free testosterone (group 2) were younger and showed fewer differences compared with the referent group for health status, although they had the highest body mass index (BMI), and 60% had metabolic syndrome, compared with just 20% of the reference group.

This supports the concept outlined by Dr Matsumoto, whereby obesity is a common cause of misdiagnosis of hypogonadism.

"This is a clinically important study that supports the 'free-hormone hypothesis,' in that isolated low free testosterone was associated with symptoms of androgen deficiency, while isolated total testosterone was not," Dr Matsumoto observed.

"Clinicians should look at free-testosterone level as well as total level, especially if the patient has signs and symptoms of testosterone deficiency," Dr Antonio emphasized.

Important to Use Correct Method to Detect Free Testosterone

Dr Matsumoto cautioned, however, that the free-testosterone measurements done routinely in most laboratories are direct immunoassays and as such are inaccurate and affected by alterations in SHBG.

"Therefore, although they are routinely available, [they] should be not used to assess free testosterone in clinical practice," he stressed.

Measuring free testosterone by the gold-standard equilibrium dialysis method is much more accurate, he says, or free testosterone can be calculated from measurements of total testosterone and SHBG, but neither of these is routinely available in most clinical laboratories; they are usually confined to commercial reference laboratories or specialized laboratories. "So there is an additional practitioner burden in sending samples to these laboratories and also an added expense," he observed.

But "some practitioners measure total testosterone and SHBG levels that are routinely available in local laboratories and use formulae available online to calculate free testosterone."

The European Male Ageing Study is funded by the Commission of the European Communities Fifth Framework Programme Quality of Life and Management of Living Resources. Drs Antonio, Matsumoto, and Kaufman have declared no relevant financial relationships.

European Congress of Endocrinology 2015. May 17, 2015; Dublin, Ireland. Abstract 37OC2.4


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