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Men whose testosterone levels fall unusually high or unusually low for their age group face an increased risk of developing depression. A large study of middle-aged and older adults suggests that these hormonal imbalances serve as an indicator of mental health vulnerabilities, particularly for men in their early fifties. The findings were published in the Journal of Affective Disorders.

As men age, their reproductive systems undergo gradual physiological changes, most notably a steady decline in sex hormones. Research indicates that testosterone levels in men begin to decrease gradually around age 35. Total testosterone tends to drop by roughly half a percent each year. Other forms of the hormone can decline at a slightly faster rate of more than one percent annually.

Researchers Dan He, Huan Liu, Feng Zhang, and their colleagues at Xi’an Jiaotong University in China wanted to understand how this natural hormonal shift relates to psychological well-being. Past research has linked androgens to mood regulation because these hormones interact with brain chemicals like dopamine and serotonin. Most of that evidence has relied on data collected at a single moment in time. This makes it difficult to tell if hormonal changes actually precede the onset of mental health conditions.

The team focused on two specific measurements of the hormone. Total testosterone refers to all the testosterone currently circulating in the bloodstream. Most of this hormone is bound to proteins like albumin and sex hormone-binding globulin, rendering it largely inactive.

Free testosterone, on the other hand, is the tiny fraction that floats in the blood without binding to proteins. It usually makes up between one and three percent of a man’s total testosterone. Because it is unattached, free testosterone easily crosses cell membranes to bind with receptors and influence bodily functions directly. Many researchers consider it a more accurate measure of active hormones in the body.

To explore the connection between these hormone measures and mental health, the researchers analyzed health records from a massive database called the UK Biobank. The analysis included 133,733 men between the ages of 40 and 70. The researchers excluded anyone who already had a history of depression or anxiety at the beginning of the study.

The team also removed men who were taking anti-anxiety drugs, anti-depression medications, or any prescriptions known to alter testosterone levels. Men with pre-existing testicular dysfunction were excluded as well. This screening process helped ensure that the final analysis focused on individuals without pre-existing medical conditions that might skew the hormonal data.

The researchers looked at blood samples taken at the start of the project to determine each participant’s total and free testosterone levels. Rather than using a single threshold for high or low hormones, the team compared each man to other men in his specific five-year age bracket. They defined a hormonal imbalance as having levels substantially above or below the statistical average for that specific age group.

They then tracked the participants’ medical records over an average of nearly 11 years to see who eventually received a formal diagnosis of anxiety or depression. The researchers adjusted their statistical models to account for a wide variety of outside factors that can influence mood. These included body mass index, socioeconomic status, physical activity, smoking habits, alcohol consumption, and pre-existing conditions like heart disease, diabetes, chronic pain, and sleep issues.

Over the tracking period, 3,701 men developed depression and 3,398 developed anxiety. The researchers found that men with abnormally low and abnormally high total testosterone levels faced a greater risk of developing depression compared to men with average levels. High total testosterone carried an elevated risk, but the association was even stronger for the low end of the spectrum.

When looking at free testosterone, the link to depression was particularly pronounced. Men with unusually low free testosterone were about twice as likely to develop depression as those in the normal range. The researchers also found that low free testosterone was associated with a higher risk of developing both anxiety and depression simultaneously.

The researchers then broke the data down by specific age groups to see when these risks peaked. They observed that the link between hormonal imbalances and mood disorders was strongest in middle-aged men. For instance, in the 50 to 54 age group, low free testosterone was associated with roughly a fivefold increase in the risk of developing anxiety. In the 55 to 59 age group, low free testosterone was associated with more than triple the risk of depression.

The team mapped out the relationship visually and found a U-shaped curve for free testosterone in relation to mental health risks. This indicates that moving too far in either direction from the age-adjusted average carries an elevated risk for psychological issues. The researchers also noted that as men advanced into their late sixties, the association between high free testosterone and depression risk diminished.

In a separate analysis, the researchers looked at questionnaire scores that measure the severity of anxiety and depression symptoms. They found that low free testosterone was consistently associated with higher severity scores on both mental health assessments. These results suggest that free testosterone might serve as a sensitive biological marker for recognizing mood-related vulnerabilities during male aging.

The study relies on observational data, meaning it can only show a correlation. It does not prove that abnormal testosterone causes depression or anxiety. The hormone measurements were also only taken once at the beginning of the study. Because hormone levels naturally fluctuate throughout the day and over months or years, a single blood test might not capture a person’s long-term biological status.

The mental health diagnoses were based on hospital inpatient records. This reliance on official medical codes means the study might miss milder cases of depression or anxiety that are managed outside of clinical settings. The researchers also relied on self-reported questionnaires for lifestyle habits like smoking and drinking, which can sometimes introduce memory-related errors.

The deviations measured in the study represent statistical comparisons against a population average, not clinical diagnoses of testosterone deficiency. Experiencing a statistical imbalance does not mean a person requires medical treatment. The researchers emphasize that these results should not be used as a rationale for initiating testosterone replacement therapy. Such medical decisions rely on absolute clinical thresholds and the presence of physical symptoms, not just mathematical deviations from peer averages.

The researchers suggest that future studies with repeated hormone measurements could help map out long-term biological changes more accurately. They recommend that health professionals consider screening middle-aged men for mental health concerns if they exhibit signs of reproductive aging. Measuring free testosterone might offer an additional tool for identifying men who face a higher risk of mood disorders as they get older.

The study, “The complex relationship between testosterone imbalance and the risk of depression and anxiety in men,” was authored by Dan He, Yifan Gou, Wenming Wei, Chuyu Pan, Boyue Zhao, Jin Feng, Jingni Hui, Huan Liu, and Feng Zhang.