INTRODUCTION: Over the past decade, the global burden of depression has increased and remains higher in women than in men. Emerging evidence suggests that low testosterone is linked to depressive symptoms in both sexes, raising important questions about its causal role and potential as a therapeutic target. OBJECTIVE: To provide a narrative review of the literature on the relationship between testosterone and depression across both sexes, examine underlying neurobiological mechanisms, and assess the efficacy and risks of testosterone replacement therapy (TRT) as a treatment for depressive symptoms. METHODS: We conducted a narrative review of PubMed, Medline, and Google Scholar for articles published between 1980 and 2024. Eligible sources included primary research articles, systematic reviews, meta-analyses, and narrative reviews that examined the relationship between testosterone levels, depression, and the effects of TRT on mood regulation. Search terms include low testosterone, hypogonadism, depression, mood disorders, androgen deficiency, TRT, neurotransmitters, and mental health. RESULTS: Low testosterone is associated with depressive symptoms, particularly in hypogonadal men. Testosterone modulates serotonergic, dopaminergic, and GABAergic systems and acts on brain regions involved in mood regulation, including the prefrontal cortex, amygdala, and hippocampus. TRT improves mood, energy, and libido in hypogonadal men, though evidence in eugonadal men and women is mixed. Ethnic and genetic factors, such as androgen receptor Cytosine, Adenine, Guanine (CAG) repeat length, may influence susceptibility and treatment response. Risks of TRT include erythrocytosis, prostate-specific antigen elevation, cardiovascular events, and metabolic changes. CONCLUSION: Testosterone may play a significant role in mood regulation, and its deficiency may contribute to depressive symptoms. TRT is a promising treatment option for select patients, though it must be personalized and closely monitored to balance therapeutic benefits with potential risks.
Abadom et al. (Wed,) studied this question.