This data highlights the potential protective effects of androgens in demyelinating disorders. This male predominance, particularly among those with testosterone deficiency, has sparked research into the potential role of androgens in PD pathogenesis and as a therapeutic target. Although considerable attempts have been made to assess the effects of TRT in men and MCI, there is a notable lack of research on the role of androgens in the development of neurodegenerative disease in women or comparing these effects across genders. A study examining testosterone reactivity during skydiving, a quintessential sensation-seeking activity, found that testosterone reactivity was significantly greater than basal day measurements. This hormone, primarily known for its role in male sexual development and function, also has significant effects on the SNS and the body’s response to stress. There are some evidences supporting the hypothesis that testosterone may act protectively in neurodegenerative disorders, e.g. Chromosome idiogram map of gene variants that have significant genome-wide association with testosterone. Research on male twins has provided heritability estimates of 57–58% for total testosterone 125, 126. In preclinical research, androgen receptor signaling in brain regions regulating mood has been reported to have anti-stress and antidepressant effects . The androgen receptor may not have important roles in the susceptibility to depression or the positive response to TRT if the androgen receptor has less sensitivity to testosterone due to longer CAG repeats 104, 106–108. The TRAVERSE trial is now being completed to determine whether testosterone replacement therapy provides significant benefit in clinical disorders including depression. Randomized, placebo-controlled clinical trials have evaluated the benefit of testosterone treatment in men with major depressive disorder. The mood effect of testosterone treatment has been extensively investigated and meta-analyzed in eugonadal and hypogonadal men with depressive symptoms or major depressive disorder with inconclusive results 20, 26, 35, 50, 75–79. The influence of androgens on brain development may begin during fetal development. In this article, we discuss the different forms of endogenous androgen, their function in the CNS, the evolving understanding of the role of androgen in various CNS disorders, and the therapeutic use of androgen supplementation for CNS pathologies. The body of evidence highlighting the involvement of androgens and androgen receptors (ARs) in pathogenesis of neurological diseases is growing. This review highlights the increasing recognition of testosterone and androgen signaling in various neurological conditions, with evidence of both protective and harmful effects depending on dosage and context. This article explores the intricate relationship between androgens, androgen receptors, and the central nervous system. Natural testosterone boosters, like Prime Male, can support healthy testosterone levels, but should be used as part of a comprehensive health strategy. This could indirectly influence testosterone levels, as poor sleep has been linked to lower testosterone levels. Androgen deprivation therapy (ADT) is the first line treatment for advanced, metastatic, and recurrent prostate cancer due to its ability to dramatically reduce circulating testosterone. Other research has shown that testosterone may exert an antidepressant action by activating androgen receptor MAPK-ERK2 signaling in the hippocampus . Increasing testosterone levels have been found to inhibit hypothalamic GnRH release via classical negative feedback thereby reducing anterior pituitary secretion of LH and FSH and their stimulation of testosterone steroidogenesis . Furthermore, using a logistic regression, this study found that high depression scores were present in 61% of men with hypogonadism compared to only 14% of eugonadal men . Androgen receptor expression has been found to be decreased by 2.7-fold in hypothalamus of men with major depressive disorder compared to male controls . Testosterone and DHT binding to the ligand binding domain stimulates the androgen receptor protein to assume an active conformation. The androgen receptor protein consists of a transcriptional regulation domain at the N-terminus that activates or represses target genes, the highly conserved DNA binding domain with two zinc fingers that bind promoter or enhancer DNA consensus sequences of target genes, a small hinge region, and a ligand binding domain at the C-terminus 88, 89. Furthermore, meta-analyses have shown that TRT has a more consistent antidepressant effect in men with less severe, subclinical depression 20, 75, 78, 79, 87. It is important to note that the Testosterone Trials found that TRT improved mood and decreased depressive symptoms in hypogonadal men. In contrast, transdermal options—such as gels and patches—provide more stable hormone levels and are linked to the lowest cardiovascular risk. This is attributed to the increased access to hormonal supplements via online shops, increased awareness around presentation of hypogonadism, and marketing of TRT for cosmetic indications or as an anti-aging supplement. Further prospective clinical trials are warranted to understand safety of TRT and identify patient population that will benefit from TRT use for management of their primary headache disorders. The mechanism behind the protective effects of androgen on epilepsy remains unclear. 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. 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.
