Interestingly, in two randomized, double-blind, placebo-controlled clinical trials completed in 2009, testosterone treatment of men with dysthymic disorder, which is a milder, but persistent depressive disorder characterized by an early, insidious onset and a chronic course, had a stronger antidepressant effect 84, 85. In the Testosterone Trials cohort of hypogonadal men were characterized as having two morning total testosterone levels less than 275 ng/dl (9.53 nmol/L SI units), sexual dysfunction, and diminished physical functioning including low vitality. The Testosterone Trials consisting of seven double-blind, placebo-controlled trials has been the largest investigation to date of the efficacy and benefits of testosterone replacement therapy (TRT) in men older than 65 years who have developed age-related hypogonadism based on strict clinical criteria 15, 70–72. The significant association of ADT with depression held when the meta-analysis was restricted to studies of localized prostate cancer or a clinical diagnosis of a depressive disorder rather than a depressive inventory by a physician or patient self-report. Androgen deprivation therapy has been reported to provoke depressive symptoms and increase the incidence of major depressive episodes in many but not all studies. In conclusion, various neurological disorders exhibit male predominance, while some demonstrate reduced disease severity in men. Ongoing clinical trials are investigating the use of TRT in the context of neurological conditions as outlined in the preceding sections of this review. At present, there are no established guidelines recommending the use of TRT for the treatment of neurological conditions. It is worth noting that clinical guidelines surrounding the use of TRT focus primarily on its cardiovascular safety and benefit. Table 2 summarises the various TRT preparations and their side effects. It is advised to do an individualized risk assessment along with shared decision making with each patient 76, 77. ADT results in many adverse physiological effects, far more frequent and intense than occurring in clinical hypogonadism, which includes severe fatigue, increased adiposity and obesity, dyslipidemia, insulin resistance, cardiovascular dysregulation, sarcopenia, osteoporosis and fractures, sexual dysfunction, and increased inflammation 47, 48. Because circulating levels of gonadotropins do not change when pituitary androgen receptors are knocked out in transgenic mice, gonadotrophs in the anterior pituitary do not appear to be a site for testosterone negative feedback . These meta-analyses further strengthen the concept that clinical hypogonadism confers a high risk for depression in men. When hypogonadotropic hypogonadal men were treated with testosterone replacement therapy, their Beck depression score decreased by 90% and was similar to normal male controls . Men with normal total testosterone levels had a considerably longer depression-free survival period . The cross-sectional Health in Men Study (HIMS) in Australia reported that the risk of depression increased threefold in men with free testosterone level below 60 pg/ml compared to men with a free testosterone level above 100 pg/ml . In 2018, the Endocrine Society Clinical Practice Guideline established criteria for hypogonadism requiring that two morning serum testosterone levels are below 280–300 ng/dl (9.7–10.4 nmol/L SI units) . A genetically informed precision medicine approach using genes regulating testosterone levels and androgen receptor sensitivity will likely be essential in gaining critical insight into the role of testosterone in depression. However, studies on the interaction of testosterone levels with depression and the antidepressant effect of testosterone replacement therapy in hypogonadal men with depression have been inconclusive. Therefore, the benefits of testosterone replacement therapy on major depressive disorder in men with clinically defined hypogonadism remains uncertain and will hopefully be elucidated by the TRAVERSE Trial and other ongoing research. Furthermore, the Testosterone Trials and other studies have reported that testosterone replacement therapy may only be beneficial in men with dysthymic disorder or subsyndromal depression that does not meet criteria for major depressive syndrome. This latter finding suggests that men with an androgen receptor having higher sensitivity and transcription activity due to shorter CAG repeats is more strongly impacted by higher testosterone levels and will be more responsive to testosterone replacement therapy. These findings suggest that hypogonadal levels of testosterone dysregulate mood and induce depressive symptoms that can be ameliorated by testosterone treatment, but TRT is unlikely to be an antidepressant treatment for major depressive disorder. Testosterone activated androgen receptor signaling in the hippocampus has been shown to upregulate neurogenesis, which may promote antidepressant responses in depression . Testosterone can also promote synaptic plasticity and synaptic remodeling in limbic brain neurons expressing the androgen receptor and regulating mood 112–114. In addition to the slower genomic actions of the cytosolic AR after translocating to the nucleus, androgen receptors expressed on the cell surface have rapid, non-genomic actions by signaling via downstream calcium, Akt, MAPK-ERK kinase, and protein kinase pathways (Fig. 1), which can regulate synaptic plasticity and have other brain actions 88, 94, 95. After binding testosterone or DHT, the cytosolic androgen receptor assumes an active confirmation, dissociates from these cytoplasmic proteins, and translocates to the nucleus where the activated AR dimerizes and functions as a ligand-dependent nuclear transcriptional regulator (Fig. 1). In the central nervous system, androgen receptors are highly expressed in the arcuate nucleus and other medial basal region of the hypothalamus, the bed nucleus of the stria terminalis and amygdala in limbic pathway, the hippocampus, and the temporal lobe, which are brain regions regulating mood and cognitive function 91, 92. Testosterone binds to the androgen receptor with a low nanomolar affinity, while the stronger biological action of DHT is mediated by its two-fold higher affinity and five-fold lower rate of dissociation from the AR compared to testosterone. A study reviewing the effects of AR antagonism in presymptomatic SOD1- G93A male mice, noted an earlier onset of myofiber atrophy when compared with female mice. Therefore, studies have explored androgen antagonists as a potential therapeutic strategy to modify disease progression. SBMA is caused by CAG expansion at the first exon of the androgen receptor gene. The specific relationship between androgens and hemorrhagic stroke remains under-investigated. Thus, the direct relation between androgen level and homocysteine may act as a potential mechanism for increased cardiovascular events through accelerated atherosclerosis and thromboembolism 18, 19.
