Table 2 summarises the various TRT preparations and their side effects. 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 . 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. Placebo-controlled trials are necessary to ascertain the role and safety of TRT in men with epilepsy. There is no evidence supporting the role of TRT for management of epilepsy. TOTEM-RRMS is an ongoing phase II, multicenter, placebo-controlled, double-blind trial studying MS progression in testosterone deficient men with TRT . Further clinical trials studying the effect of TRT on gray matter volume in patients with RRMS reinforced the benefit of TRT-induced remyelination by demonstrating arrest of gray matter loss when exposed to testosterone . If such association exists, then we will investigate the effect of testosterone replacement therapy on correcting these abnormalities. Indeed, many of these regions that show sexually dimorphic expression of the AR are also involved in metabolic homeostasis, which will later be discussed in detail.43 The role of central AR activation in metabolism in adults will be discussed below. Although the available evidence clearly demonstrates that AR is not necessary for organizational effects on behavior in rodents, this is not the case in primates. The adrenal gland is activated almost simultaneously, via the sympathetic nervous system, and releases the hormone epinephrine. The reaction begins in the amygdala, which triggers a neural response in the hypothalamus. Efferent vagal fibers originating from the nucleus ambiguous fire in parallel to the respiratory system, decreasing the vagal cardiac parasympathetic tone. While the sympathetic nervous system is activated, the parasympathetic nervous system decreases its response. It activates the adrenal medulla, releasing catecholamines that amplify the sympathetic response. Those patients with primary diagnosis of prostate cancer and normal serum testosterone levels will be evaluated a second time after confirmation of low testosterone, as described above. The primary goal of this pilot study is to investigate the association between testosterone deficiency and the presence of abnormalities in the function of the autonomic nervous system. Parkinson disease (PD), is observed twice as frequently in men than women, typically affecting males in their fifth or sixth decade of life . Preclinical models have demonstrated decreased adipose infiltration in DMD muscles and improved muscle function in female mice treated with oral selective AR modulators . Overall, the connection between androgens, ARs, and ALS remains complex and unclear, with evidence suggesting that sex-based differences might play a role 30–32. 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. It fully manifests in men, typically in their third to fifth decades of life, while women with homozygous mutation have a subclinical disease course, indicating a role of androgen in pathogenesis as opposed to solely the mutant AR . Some neuromuscular conditions exhibit a higher prevalence in men, suggesting a potential pathological role of sex hormones . Hyperhomocysteinemia has been observed in women with polycystic ovary syndrome, who are known to have elevated testosterone levels. Given the impact of chronic stress and SNS activation on testosterone levels, natural testosterone boosters can play a role in supporting hormonal balance. While cortisol is necessary for our survival, chronic high levels can have detrimental effects on health, including a negative impact on testosterone production. The sympathetic nervous system and testosterone are two critical components of the body’s response to stress and danger. Therefore, it is possible that increasing testosterone levels through the use of testosterone boosters could enhance the body’s "fight or flight" response. While research directly examining the effects of testosterone boosters on the SNS is limited, studies have shown that testosterone can influence sympathetic activity. There are several regions of the brain that regulate glucose and energy homeostasis and also express AR.39-42 Only the most likely regions for androgen action on metabolism will be discussed here. It is also unclear if the phenotype is due to AR in the CNS and if the effects of androgen are organizational or activational. The central effects of testosterone deficiency in men are summarized in (Figure 2). However, it is uncertain if the effects of AR in the brain are due to organizational or activational effects, as AR deletion may lead to developmental defects that are revealed in adulthood. However, in many of these models, AR is deleted developmentally, making it hard to differentiate the organizational effects from the activational effects of androgen. Within the brain, testosterone is aromatized (to estradiol), which is the principal active hormone for developmental influences. Estrogen and progesterone bind to their cognate nuclear hormone receptors, which translocate to the cell nucleus and interact with regions of DNA known as hormone response elements (HREs) or get tethered to another transcription factor's binding site. For instance, males of most species prefer the odor and appearance of females over males, which is instrumental in stimulating male sexual behavior. The hypothalamus receives many inputs from the brainstem, the most notable from the nucleus of the solitary tract, the locus coeruleus, and the ventrolateral medulla. It synthesizes and secretes certain neurohormones, called releasing hormones or hypothalamic hormones, and these in turn stimulate or inhibit the secretion of hormones from the pituitary gland. The hypothalamus has the function of regulating certain metabolic processes and other activities of the autonomic nervous system. After the fight or flight response, the parasympathetic system's main function is to activate the "rest and digest" response and return the body to homeostasis.
