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. In 2014, a meta-analysis of six studies of testosterone treatment in eugonadal and hypogonadal men, including the above three studies, concluded that TRT improved mood and decreased depressive symptoms in men with low to hypogonadal levels of total testosterone . Three early interventional studies of TRT using testosterone gel or intramuscular testosterone undecanoate in men with hypogonadism based on mean total testosterone levels ranging from 230 to 300 ng/dl (7.97–10.40 SI units) reported a significant reduction in depressive symptoms 80–82. This important new finding indicates inhibiting androgen receptor signaling in brain regions regulating mood generates a stronger depressogenic action than inducing very low testosterone levels with ADT in men with prostate cancer. The impact of chronic stress and the subsequent activation of the SNS on testosterone levels is well-documented. In times of stress, the body prioritizes the production of cortisol over testosterone, leading to a decrease in testosterone levels. While cortisol is necessary for our survival, chronic high levels can have detrimental effects on health, including a negative impact on testosterone production. 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. Testosterone boosters, such as Prime Male, are supplements designed to naturally increase 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 . This includes ongoing research exploring the potential therapeutic targets involving the androgen signaling pathway for management of neurological disorders. Despite the above findings, there is no established indication of TRT or androgen-blocking medication in neurological disorders. Additionally, androgen-blocking agents could increase the risk of neurodegenerative conditions, such as Parkinson disease and Alzheimer disease. On the other hand, androgen-blocking treatments may help alter disease progression in spinal and bulbar muscular atrophy. Although limited to experimental use, testosterone replacement therapy (TRT) may serve potential benefits in the management of multiple sclerosis, epilepsy, headache, Duchenne muscular dystrophy, amyotrophic lateral sclerosis, and Parkinson disease. This interplay between testosterone and the SNS could have significant implications for how individuals respond to stress and engage in risk-taking behaviors.
