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This study underscores the importance of stress management and regular physical activity in maintaining healthy testosterone levels. Meghana S. Pagadala (MSP) provided important information about gene variants regulating testosterone that were identified in the GWAS of morning testosterone levels she completed. Recent GWAS research has identified significant associations of GCKR, BAIAP2L1, JMJD1C, FKBP4, SERPINA1, SHBG, FAM9B, and other gene variants with total testosterone levels 21–23, 127 (Fig. 2). Important considerations are that major depressive disorder is a clinically heterogeneous phenotype with depressed individuals differing in inherited polygenic determinants, onset and clinical course, symptom complexes, and comorbidities that contribute to potential multifactorial differences in pathophysiology. The studies reviewed here also suggest that a substantial deficiency in testosterone can cause a depressive-like state that can  respond to TRT. Using PET imaging, a recent study has reported that testosterone regulates hippocampal serotonin 5-HT4 receptors and increases brain serotonergic  function . Other research has found that testosterone promotes an antidepressant response by activating androgen receptor signaling via the MAPK-ERK2 cascade in the hippocampus 12, 117.
The findings of these two studies indicate that men with prostate cancer and a history of depression are especially vulnerable to the depressogenic effect of ADT. Recently, however, three studies with large sample sizes and statistical control of variables have shown a strong association of ADT with a depression diagnosis. Other small, cross-sectional prostate cancer studies, however, have found no statistical difference in self-reported depressive symptomatology between ADT-treated men compared to men not receiving ADT 50, 57, 63, 64. In an Asian cohort, the rate of incident depression over a three-year period was 13.9% in men with prostate cancer treated with ADT who had no prior diagnosis of a depressive disorder . These systemic changes can lead to coronary artery disease, type 2 diabetes, and dyslipidemia, and increase the risk of developing depression 49–51.
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.
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.
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.
However, there are no guidelines advocating the use of TRT in men with hypogonadism for stroke prevention. Testosterone at therapeutic level leads to protective effects against ischemic stroke and cardiovascular events. The higher incidence of ischemic stroke in men, especially with hypogonadism, as well as in post-menopausal women suggests involvement of sex hormones in the pathogenesis of ischemic stroke. Additionally, it has been shown to increase neurogenic output of excitatory progenitors in human brain organoids 10–12. Neuroplasticity is the ability of the brain to adapt in response to stimuli and is of distinct interest in stroke rehabilitation and cognitive recovery . Elevations in prenatal testosterone have additionally demonstrated an inverse relationship with the development of pathways responsible for social communication and cognition 6, 7. ARs are also found in the dorsal horn of the spinal cord and various brain stem locations, predominating in the area postrema, motor nucleus of the vagus nerve, dorsal raphe nucleus, periaqueductal gray, retrorubral nucleus, retrotrapezoid nucleus, and substantia nigra.
Testosterone treatment upregulates serotonin transporter expression and increases the firing rate of serotonergic dorsal raphe neurons 119, 120 which has been proposed to promote an antidepressant action. In men, CAG repeat length is normally distributed with an average of 22 repeats and has been shown to be identical in peripheral leukocytes and brain regions regulating mood and cognitive function . Missense mutations in the AR ligand binding result in complete or partial androgen insensitivity syndrome, although mutations in the N-terminal domain encoded by exon 1 have recently been shown to induce resistance to androgen actions .

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