Importantly, recent research has shown that genetic factors can regulate the trajectory of testosterone during aging 21–23. Furthermore, it is well established that the rate of testosterone decline can be accelerated by modifiable lifestyle factors including obesity and alcohol consumption. Furthermore, gonadotropin secretion was upregulated and the testosterone/ luteinizing hormone ratio was decreased indicating declining Leydig cell function despite these men being young. Synthesis of testosterone and dihydrotestosterone (DHT) by the testis is stimulated by LH activating G protein-coupled LH receptors in Leydig cells. Testosterone secreted by the testis exerts negative feedback control of hypothalamic GnRH release, while estradiol formed by 5α-reductase conversion of testosterone exerts negative feedback control of anterior pituitary luteinizing hormone (LH) secretion. This article does not contain any studies with human or animal subjects performed by any of the authors.
Their interplay influences how individuals react to stressful situations and engage in risk-taking behaviors. The sympathetic nervous system and testosterone are two critical components of the body’s response to stress and danger. While they can offer benefits, they can also have side effects and may not be suitable for everyone.
These effects are also observed in women with catamenial epilepsy who experience decreased seizure frequency during the follicular phase of the menstrual cycle and improved seizure control in men who received testosterone supplements 64, 65. TOTEM-RRMS is an ongoing phase II, multicenter, placebo-controlled, double-blind trial studying MS progression in testosterone deficient men with TRT . The study demonstrated promising results with reversal of myelin damage and stimulation of myelin formation following testosterone use in mice that had neural AR.
Subsequent research, however, has discovered that androgens have more extensive physiological actions regulating cardiovascular, metabolic, hepatic, and immune systems and, importantly, the central nervous system 6–10 (Fig. 1). Other classical, well-established roles of testosterone include stimulation of erythropoiesis and maintenance of muscular strength and volumetric bone density mass 4, 5 (Fig. 1). Testosterone and the more biological active androgen, dihydrotestosterone (DHT), formed by conversion of testosterone by 5α-reductase, act as the primary sex hormones in men regulating male sexual development during puberty and spermatogenesis and sexual function in adulthood 1–3 (Fig. 1). Furthermore, polygenic mechanisms are likely to be critical to the biological heterogeneity that influences testosterone-depression interactions. These findings position androgens and ARs as promising targets for the therapeutic management of various neurological diseases. Emerging evidence from preclinical models, observational studies, and small-scale prospective studies have demonstrated the potential link between AR signaling in the pathogenesis of these conditions. Food and Drug Administration issued a black box warning for TRT due to the increased risk of cardiovascular events, like ischemic stroke or myocardial infarction .
In 2003, a small RCT study reported that the mean Hamilton score (21.8) in younger men (mean age 46.9 years) with hypogonadism and major depressive disorder refractory to antidepressant medications decreased by ~ 60% when their total testosterone levels were increased from 293 to 789 ng/dl (10.16–27.36 nmol/L SI units) by TRT compared to placebo treatment . However, a study using a logistic regression analysis with stratification for AR CAG repeat length found that the risk for depression was significantly lower in men with a highly sensitive androgen receptor due to short CAG repeats if their testosterone levels were high . When clinical criteria for hypogonadism are used, consistent  increases in depressive symptomatology and incidence of clinical depression  have been reported in hypogonadal men with confirmed testosterone deficiency compared to eugonadal men with testosterone levels in the normal physiological range. The benefits of testosterone replacement therapy in men with major depressive disorder and low testosterone levels in the clinically defined hypogonadal range remain uncertain and require further investigation. Considering that the brain serotonergic neuronal system has a critical role in depression and antidepressant treatment, the interaction of testosterone and kisspeptin neurotransmission may have an unrecognized role in major depressive disorder. Subsequently, observational, cross-sectional, or longitudinal studies reported an inverse relationship of depression scores in men with circulating testosterone levels in the low physiological and hypogonadal ranges, while other studies did not find a relationship of depressive symptoms and testosterone levels 20, 25, 26.
Hypogonadal men frequently experience a depressed mood, anhedonia, fatigue, and cognitive impairment, which are four of the five diagnostic criteria A specified for major depressive disorder in the Fifth Edition of the Diagnostic and Statistical Manual of Mental Disorders . A smaller number of longitudinal studies reported a greater rate of testosterone decline during aging with total testosterone decreasing by 1–2% per year 15, 16. In young, healthy men, circulating levels of total testosterone range from 300–1000 ng/dl (10.4–34.7 nmol/L SI units) with 0.5% to 3.0% being free testosterone unbound to sex hormone binding globulin (SHBG) or albumin 1, 2. The focus of this review will assess the role of testosterone in mood regulation regarding the above important issues. In contrast, rapid, non-genomic actions result for membrane androgen receptors signaling via downstream Akt and ERK-MAP kinase pathways. The slower genomic actions resulting from classical, canonical androgen receptor signaling involve dissociation of cytosolic AR from heat shock proteins, translocation of AR with chaperones to the nucleus, and then binding of AR and co-regulators to androgen response elements on target genes to activate or repress their expression. Testosterone and DHT secreted by the testis bind to and activate the androgen receptor (AR) expressed in peripheral organs and the central nervous system.
This suggests that testosterone and the SNS are closely linked, with testosterone potentially enhancing the body’s "fight or flight" response. There are also evidences against the neuroprotective action of testosterone. Alzheimer's disease (AD), mild cognitive impairment (MCI) or depression. One of the less known testosterone actions is neuroprotection. Testosterone -- the gonadal sex steroid hormone plays an important role in the central nervous system (CNS) development.
Elevated levels of homocysteine are responsible for accelerated atherosclerotic plaques due to oxidative stress, endothelial injury, and increased thrombosis . Dose-dependent effects of testosterone and association with ischemic stroke have been established. The ability of androgens to facilitate formation, growth, and modulation of neural networks may represent a target for neural recovery following an insult to the CNS. A deeper understanding of the complex relationship between testosterone, DHEA, and neurodevelopment is essential to determining clinical applications. DHEA leads to increased cortical thickness and has positive effects on areas of visual attention and working memory .