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Low Testosterone
Levels Linked With Higher Risk for Depression
By Pauline Anderson
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.
Medscape Medical News 2008. © 2008 Medscape
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.
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