Low Testosterone Levels Linked With Higher Risk for Depression

Pauline Anderson

March 06, 2008

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March 6, 2008 — Researchers have uncovered a link between low testosterone and depression. Their study, which appears in the March issue of the Archives of General Psychiatry, shows that older men with abnormally low free testosterone levels, or hypogonadism, were on average 271% more likely to display clinically significant signs of depression than men with higher testosterone levels.

"Importantly, these results could not be explained by increasing age, education level, smoking, obesity, or poor physical health — all factors that are known to dampen testosterone and that are associated with depression," said lead author Dr. Osvaldo P. Almeida, MD, PhD, director of research at the Western Australian Centre for Health and Ageing, and professor and chair of geriatric psychiatry, School of Psychiatry and Clinical Neurosciences, at the University of Western Australia, in Perth.

The results of this study could have important implications for treatment of depression in certain males, he said. "Older men with depression should be assessed for hypogonadism, and older hypogonadal men who fail to respond to standard antidepressant therapy may benefit from testosterone replacement," said Dr. Almeida.

Results Independent of Physical Health

The study sample of 3987 men aged 71 to 89 years was taken from a community sample of older male residents of Perth, Australia, who were part of the larger prospective Health in Men Study.

To determine their physical health, the researchers used the weighted Charlson index, which takes into account 17 common medical conditions — including myocardial infarction, congestive heart failure, peripheral arterial disease, cerebrovascular disease, and chronic pulmonary disease. They retrieved linked data for all participants from the Health in Men Study. As well, the participants used the 36-item Short Form Health Survey to rate their own health.

The men were screened for cognitive impairment and depression, completing the Standardized Mini-Mental State Examination and the 15-item Geriatric Depression Scale (GDS-15). In the sample, 203 (5.1%) had a total GDS-15 score within the depression range (scores of 7 or more). Men with depression were older than their nondepressed counterparts, had lower education levels, and were more likely to be former or current smokers and to have a body-mass index (BMI) of 30 or greater.

Researchers took blood samples to test serum concentrations of total and free testosterone and divided the men into quintiles according to these concentrations. Compared with men in the highest quintile, the odds ratio for depression in men in the lowest quintile for total testosterone was 1.94. However, the association between depression and total testosterone became nonsignificant after the analysis was adjusted for age, educational level, smoking, BMI, and other factors.

Link With Free Testosterone Remained Significant When Adjusted

When they looked at free testosterone, the researchers found that men in the lowest quintile also had increased risk for depression in relation to men in the highest quintile (odds ratio, 3.12). But this association remained significant after the analysis was adjusted for age, education level, smoking, BMI, and other factors (odds ratio, 2.71).

"The findings of this study are compelling in suggesting a causal relationship between low free testosterone and depression in older men," Dr. Almeida told Medscape Psychiatry in an emailed comment. "The association is biologically plausible; there is evidence from lab work that testosterone may increase the bioavailability of serotonin and noradrenaline in the brain and this could explain its antidepressogenic effect."

Current evidence suggests that it is free testosterone, or testosterone that is not bound to the proteins albumin and sex-hormone-binding globulin, that is biologically active (also called "bioavailable" testosterone). "In other words, if we wish to clarify what testosterone does, we need to look at free testosterone," said Dr. Almeida.

In Men Over 70 Years, 20% Develop Hypogonadism

The study results do not mean that all older men should receive testosterone replacement therapy, but they do suggest that this therapy should be considered for the significant number of older men with low male hormone levels, said Dr. Almeida. "The association between depression and free testosterone is limited to hypogonadal men, or men with abnormally low free testosterone. After age 70 years, approximately 20% of men develop hypogonadism. This particular group may benefit from testosterone replacement."

Dr. Almeida added that randomized trials are now needed to determine whether testosterone replacement is effective and safe to treat depression in this group.

He stressed that the association between free testosterone and depression is a "risk" association rather than a cause-consequence effect. "Not all older men with depression are hypogonadal, and not all hypogonadal men have depression. But there is a dramatic increase in the risk of depression among hypogonadal men."

As the population ages, there is likely to be an increase in the number of men with hypogonadism, said Dr. Almeida.

He noted, too, that while depression is more prevalent among women, the gap between the sexes "all but disappears" later in life. "Our findings may partly explain why that is so," he said.

The study was supported by grants from the National Health and Medical Research Council of Australia. Biochemical analyses were funded by a Sylvia and Charles Viertel Charitable Foundation Clinical Investigator Award.

The authors report no conflicts of interest.

Arch Gen Psychiatry. 2008;65:283-289. Abstract