Numerous observational studies have linked anti-androgen therapy, commonly used in prostate cancer, with an elevated risk of AD and other neurodegenerative diseases, like Parkinson disease . The following section highlights our current understanding of the role of androgens in certain CNS disorders and their potential therapeutic role across neurological domains. A deeper understanding of the mechanisms involved in neuroplasticity could guide therapeutic interventions with androgens such as testosterone replacement therapy (TRT) in neurological recovery in neurodegenerative diseases. The relationship between androgens and brain development highlights the need to understand their role in neuroplasticity. We examine the role of physiologically derived androgens and androgenic supplements in neurodevelopment and neuroplasticity and delve into the involvement of androgen pathways in the pathogenesis of various neurological disorders. Some studies suggest that fenugreek may help to increase testosterone levels by reducing the enzymes that convert testosterone into estrogen. Given the impact of chronic stress and SNS activation on testosterone levels, natural testosterone boosters can play a role in supporting hormonal balance. Larger placebo-controlled trials are essential to establish the safety and efficacy of TRT in patients with RRMS along with expanding research to include patients with NMO, MOGAD, and other related disorders. Conversely, a retrospective analysis of five men with PD and testosterone deficiency did show significant improvement of refractory non-motor PD symptoms following TRT . These considerations conflict with an open label trial that found no statistical difference in the improvement of both motor and non-motor symptoms of PD following use of TRT in men with concomitant PD and hypogonadism. Post-menopausal women account for 60% of patients with AD, with female gender being an independent risk factor for development of AD. As of March 2025, there are no ongoing clinical trials investigating TRT in patients with myotonic dystrophy, likely due to a limited patient population. Progressive testicular atrophy causing oligospermia is seen in 80% of men with DM1 along with reduced adrenal androgen synthesis . After research indicated GnRH neurons do not express androgen receptors, kisspeptin and its G protein-coupled receptor KISS1R were discovered as important regulators of GnRH neurons . Androgen regulation of the hypothalamic-pituitary–gonadal (HPG) axis is critical for homeostatic regulation of synthesis and secretion of testosterone and the most potent androgen dihydrotestosterone (DHT) by the testis (Fig. 1). Dysregulation of the hypothalamic-pituitary–gonadal (HPG) axis has been observed in patients with major depressive episodes. Likewise, in an adjusted linear regression analysis, the prospective Longitudinal Aging Study Amsterdam observed greater depressive symptoms in men with the lowest quartile of calculated free testosterone compared to men in the highest free testosterone quartile . Notably, ARs have been identified in the forebrain, thalamus, hypothalamus, amygdala, hippocampus, and olfactory bulb. Although the exact location and function of ARs in the adult brain remain under investigation, animal models have demonstrated the presence of ARs at multiple CNS locations. Figure 1 provides a simplified representation of androgen signaling pathways in the CNS. The study also found that testosterone reactivity to skydiving was predicted by increased cortisol, increased sympathetic activity (heart rate), and reduced parasympathetic activity1. Genome-wide association studies (GWAS) from the UK Biobank and other large cohorts have identified the SNP-based heritability for total testosterone to be ~ 20% and free testosterone to be ~ 15% 21–23, 127. Testosterone can also regulate monoamine oxidase and catechol-o-methyl transferase in amygdala, hippocampus, and other limbic brain areas involved in depression and mediating antidepressant responses 12, 122, 123. Increasing synaptic levels of serotonin with selective serotonin reuptake in inhibitors contributes to antidepressant responses in depression . Functional neuroimaging studies (fMRI and PET) have found that testosterone can regulate cerebral blood flow and neuronal activity in the amygdala, hippocampus, and frontal and temporal cortex 109–111. The non-canonical actions of membrane androgen receptors may be coordinated with the canonical actions of androgen receptors in the nucleus. AR transcriptional regulation is modulated by co-regulators that bind to activated androgen receptors in a ligand-dependent manner to co-activate or co-repress target genes. However, it is important to note that the use of testosterone boosters should be approached with caution. They typically contain ingredients like D-Aspartic Acid, Vitamin D, and Zinc, which have been shown to support testosterone production. Given the relationship between testosterone and the SNS, it is plausible that testosterone boosters could influence the functioning of the SNS. 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 . Androgens have antiseizure effects, which are further augmented when used with an aromatase inhibitor that decreases the conversion of androgen into the proconvulsant estradiol and increases levels of androgen . 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 . Meta-analysis studying the effects of menopausal hormonal therapy found improvement in overall cognitive function after estrogen-only therapy and decline in cognitive scores with estrogen-progesterone therapy when compared to controls 49, 50. A study of the effects of pubertal induction with monthly testosterone injections in young boys aged 12 to 17 years receiving glucocorticoids demonstrated no effects on bone density or bone age advancement but improved muscle strength. 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. 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 .
