These may include reduced libido, diminished energy, decreased life satisfaction, and the onset of symptoms such as weakness, irritability, and, notably, depression, one of the leading causes of disability worldwide.1,2
Although depression is more prevalent in women than in men (8.3% vs 4.6%), there is no significant gender difference in the prevalence of clinically significant depression in older adults (8.6% of men vs 7.9% of women). As men age, both the prevalence of depression and the incidence of hypogonadism increase.2
Research has demonstrated that men living with depression tend to have lower testosterone levels, particularly in cases that are severe or resistant to treatment. In such cases, >40% of men are found to have hypogonadism.1
This pattern is observed not only in elderly men but also in those with co-existing conditions such as HIV or chronic sleep deprivation. Interestingly, testosterone levels in depressed men are often low regardless of changes in body weight or physical activity.1
In healthy young men, total testosterone levels typically range from 10.4nmol/L to 34.7nmol/L, with only 0.5% to 3.0% being free testosterone (unbound to sex hormone-binding globulin [SHBG] or albumin).3
As men age, levels fall into the hypogonadal range (< 9.72nmol/L–10.41nmol/L) as early as age 40. Early studies suggested a steady decline of 0.4% per year after age 40, and free testosterone levels drop even faster due to an age-related increase in SHBG.3
Recent research shows that testosterone levels decline even in healthy, young men. For instance, a study of men aged 34 found no baseline age effect on testosterone trajectories over a 12-year period, but it did highlight declining Leydig cell function.3
Factors such as obesity, alcohol consumption, and certain chronic conditions like type 2 diabetes have been shown to accelerate testosterone decline, often more significantly than age itself.3
The decline in testosterone is driven by a variety of mechanisms, including impaired luteinizing hormone receptor signaling, oxidative stress-induced dysfunction in mitochondrial cholesterol transport, and the loss of Leydig cells. Genetic factors also play a role in how testosterone levels change over time.3
The link between TD and depression
There is compelling evidence that links testosterone deficiency (TD) to increased depressive symptoms. A 2004 study using Veterans Affairs data found that men with testosterone levels <6.93nmol/L had a 21.7% incidence of major depressive disorder over two years, compared to eugonadal men.3
Similarly, a 2005 study found that men with testosterone levels <8.67nmol/L were at greater risk of depression, with an adjusted hazard ratio of 2.1. Other studies have also supported this link.3
A 2006 Canadian study found significantly lower testosterone levels in middle-aged men with depression, while the Health in Men Study showed that men with free testosterone levels <60pg/ml were three times more likely to experience depression. Long-term studies have further confirmed that low testosterone levels predict a higher risk of developing depression over time.3
Can TRT improve depression in hypogonadal men?
Several studies have investigated the potential of testosterone replacement therapy (TRT) to alleviate depressive symptoms in men with hypogonadism. The evidence suggests that TRT can improve depression by enhancing brain function, particularly in older men and those experiencing age-related testosterone decline (often referred to as andropause).1
One of the earliest studies demonstrating the potential benefits of TRT in treating depression was conducted by Pope et al (2003), who carried out an eight-week randomised, placebo-controlled study to assess the effects of testosterone transdermal gel in men with refractory depression and low or borderline testosterone levels.4
Participants with hypogonadism were randomly assigned to receive either 1% testosterone gel (10g/day) or a placebo while continuing their existing antidepressant treatment. At the end of the trial, those receiving testosterone gel showed significantly greater improvement in Hamilton Depression Rating Scale (HAM-D) scores compared to the placebo group.4
In their meta-analysis, Zarrouf et al (2009) assessed TRT for depression and found that individuals treated with TRT showed a 50% reduction in HAM-D scores compared to those on placebo. Subgroup analyses revealed that TRT was particularly effective in men with hypogonadism, showing a significant reduction in depression, while the effects were less pronounced in eugonadal participants. TRT was effective in individuals living with HIV as well as their HIV-negative counterparts.1
Vartolomei et al (2018) analyzed 15 randomized controlled trials (RCTs) involving 1586 men with late-onset testosterone deficiency (TD) to assess the impact of TRT on depression.5
Their findings indicated that TRT reduced depressive symptoms in men with mild pre-treatment depression, but the effect was not significant in men with major depressive disorder. Among men without pre-treatment depression, TRT led to a reduction in depressive symptoms, though the clinical significance of this reduction remains uncertain.5
Khera et al (2012) conducted a 12-month observational study to evaluate the long-term effects of TRT on depression symptoms in hypogonadal men.
This study involved 849 men prescribed 1% testosterone gel, with depressive symptoms assessed using the Patient Health Questionnaire-9 (PHQ-9).6
At baseline, 92.4% of participants reported depressive symptoms, with 17.3% having moderately severe to severe symptoms. Significant improvements in both total testosterone levels and PHQ-9 scores were observed by the third month of TRT.6
At 12 months, PHQ-9 scores showed a clinically meaningful average improvement of 5.62 points, and the percentage of men with moderately severe to severe symptoms dropped from 17.3% to 2.1%.6
Recent research: The TRAVERSE Depression Substudy
As part of the Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men (TRAVERSE) trial, Bhasin et al (2024) conducted a depression substudy to assess the effects of TRT on depressive symptoms in hypogonadal men, both with and without a history of depression.7
This substudy aimed to evaluate the potential of TRT to induce remission and improve depressive symptoms, energy, sleep, and cognition in middle-aged and older men with hypogonadism.7
Participants were divided into three groups: Men meeting rigorous criteria for low-grade persistent depressive disorder (LG-PDD), those with significant depressive symptoms (PHQ-9 > 4), and all participants enrolled in the parent trial. The study used a randomisation process where participants received either TRT (1.62% transdermal testosterone gel) or placebo gel.7
The primary outcome for the LG-PDD subgroup was the proportion of men achieving remission, defined by a PHQ-9 score of <4 and a Geriatric Depression Scale (GDS-15) score <5 at six-, 12-, and 24-months. Secondary outcomes assessed changes in depressive symptoms using the PHQ-9, GDS-15, and the Hypogonadism Impact of Symptoms Questionnaire (HIS-Q), which measured mood, energy, sleep, and cognition.7
Among the men who met the criteria for LG-PDD, the primary outcome revealed no significant difference in remission rates between the TRT and placebo groups. However, TRT showed numerically greater improvements in depressive symptoms, although these differences were not statistically significant.7
For the larger group of men with significant depressive symptoms (PHQ-9 > 4), TRT demonstrated more favourable outcomes. Testosterone-treated men showed greater reductions in depressive symptoms compared to those on placebo.7
The improvements in mood, as measured by the HIS-Q mood domain, were significant at six-, 12-, and 24-months (P=.008), and TRT was also associated with improved energy scores (P=.010). However, there were no significant differences in sleep or cognitive function scores between the TRT and placebo groups.7
In a post-hoc analysis of men with severe depressive symptoms (PHQ-9 ≥ 15), no significant changes were noted between the testosterone and placebo groups. In contrast, men with mild to moderate depressive symptoms (PHQ-9 scores between 5-14) showed substantial improvements in depressive symptoms on TRT (P = .012).7
Conclusion
TRT shows promise as an effective treatment for mild-to-moderate depression in men with low testosterone levels. Studies suggest that TRT can significantly reduce depressive symptoms, boosting mood and enhancing quality of life by restoring testosterone levels and supporting brain function.
References
- Zarrouf FA, et al. Testosterone and depression: Systematic review and meta-analysis. Journal of Psychiatric Practice, 2009.
- Mohit K. Patients with testosterone deficiency syndrome and depression. Archivos Españoles de Urología, 2013.
- Hauger RL, Saelzler UG, Pagadala MS, Panizzon MS. The role of testosterone, the androgen receptor, and hypothalamic-pituitary-gonadal axis in depression in ageing Men. Rev Endocr Metab Disord, 2022.
- Pope HG, Cohane GH, Kanayama G, et al. Testosterone gel supplementation for men with refractory depression: A randomized, placebo-controlled trial. Am J Psychiatry, 2003.
- Vartolomei MD, Kimura S, Vartolomei L, Shariat SF. Systematic Review of the Impact of Testosterone Replacement Therapy on Depression in Patients with Late-onset Testosterone Deficiency. European Urology Focus, 2018.
- Khera M, Bhattacharya RK, Blick G, et al. The effect of testosterone supplementation on depression symptoms in hypogonadal men from the Testim Registry in the US (TRiUS). Aging Male, 2012.
- Bhasin S, Seidman S, Travison TG. Depressive Syndromes in Men With Hypogonadism in the TRAVERSE Trial: Response to Testosterone-Replacement Therapy. The Journal of Clinical Endocrinology & Metabolism, 2024.
