Men at + 50, testosterone and mental health

Testosterone is a vital hormone that plays a key role in male health. And yes there is - as suspected - a direct pathway between the testes and the brain.

Testosterone is produced mainly in the testes and acts as the primary male sex hormone. Beyond these well-known sexual functions, testosterone is of importance in several other body systems like the cardiovascular, metabolic, and immune systems. 

Most notably, testosterone impacts the brain, particularly in regions involved in mood regulation, raising questions about its role in male mental health.

Testosterone declines with age
As men age, their testosterone levels naturally decline, which has been linked to several age-related health issues.

In healthy young men, testosterone levels typically range from 300 to 1000 ng/dl, but this gradually decreases with age.

This decline is particularly evident in men over the age of 40, where testosterone levels decrease by around 1% to 2% each year.

By the time men reach their 60s or 70s, many experience testosterone levels that are significantly lower than those in their younger years. 

The aging process, coupled with lifestyle factors such as obesity and chronic diseases like diabetes, further exacerbates the decrease in testosterone levels.

This decline in testosterone, often referred to as age-related hypogonadism, has been linked to several health issues, including reduced muscle mass, osteoporosis, and fatigue. Studies suggest that this testosterone decrease can also contribute to the development of depression.

Testosterone deficiency and depression in men
Research suggests that men with low testosterone levels are more likely to experience depressive symptoms.

In fact, men suffering from testosterone deficiency often report symptoms that resemble those of major depressive disorder. These include feelings of sadness, loss of interest in daily activities, and fatigue. 

This overlap has led scientists to investigate whether low testosterone could be a contributing factor to depression in men. 

Several studies have since found that men with testosterone levels below the normal range showed significantly higher depression scores compared to those with normal testosterone levels. And the lowest testosterone levels were associated with the most severe depressive symptoms. 

That was most apparent in older men. However, not all research supports this connection, indicating that other factors may also be at play.

Testosterone’s antidepressant mechanisms in the brain
Testosterone affects brain areas involved in regulating mood such as the limbic structures central to emotional processing and the regulation of depressive symptoms.

Research suggests that testosterone has neuroprotective and antidepressant-like effects in these brain regions. Especially testosterone’s impact on the hippocampus, which is critical for memory and emotional regulation, has been studied.

In the hippocampus, testosterone has been shown to activate androgen receptors, which can trigger signaling pathways that enhance neuroplasticity (our ability to adapt) and reduce the risk of depressive behavior.

One such pathway involves a signaling pathway (the mitogen-activated protein kinase), which is involved in brain cell growth and survival.  By activating this pathway, testosterone may help protect against the damage to brain cells often seen in depression.

Additionally, testosterone may influence the serotonin system, a key player in the regulation of mood. Research has shown that testosterone can enhance serotonin receptor sensitivity, thus improving serotonin signaling in the brain.

This interaction between testosterone and serotonin may explain why low testosterone levels are often associated with higher rates of depression in men, particularly those with age-related testosterone decline.

By influencing these brain regions, normal levels of testosterone help protect against the development of depression.

The role of the brain-testes axis in depression
A central aspect in understanding the link between testosterone and depression lies in the regulation of the specific and direct pathway between the brain and the testes; the hypothalamic-pituitary-gonadal axis.

This brain system controls the production and release of testosterone. It involves complex interactions between the brain and the gonads, ensuring the body maintains appropriate levels of testosterone.

Research has shown that disruptions in the axis can lead to low testosterone levels, depressive symptoms, and even the onset of depression. For instance, men with major depressive disorder often show altered testosterone secretion patterns (that are controlled by the brain), including lower daytime and nighttime testosterone levels. 

This dysregulation may result from impaired feedback mechanisms between the brain and the testes. That is especially true in aging men where the body’s typical hormonal responses to low testosterone become dysfunctional.

Interestingly, testosterone’s influence also involves interactions with kisspeptin neurons in the hypothalamus of the brain. Kisspeptin is a key regulator of the release of sex hormones, not only testosterone.

These interactions suggest that testosterone may play a critical role in modulating mood through the regulation of other sex hormone pathways.

Testosterone therapy and its effects on depression
Given the strong association between low testosterone levels and depression, testosterone replacement therapy has been explored as a potential treatment for men experiencing both conditions. 

This treatment has shown promising results, particularly in men with hypogonadism, where testosterone levels fall below 200 ng/dl. In some cases, men with clinically low testosterone levels who received testosterone showed significant improvements in depressive symptoms.

However, not all men respond equally to testosterone therapy, and the effectiveness of treating depression in men with testosterone is still under investigation. 

About the scientific paper:

First author: Richard L. Hauger, USA
Published: Reviews in Endocrine and Metabolic Disorders, November 2022
Link to paper: https://link.springer.com/article/10.1007/s11154-022-09767-0