The studies reviewed here demonstrate that testosterone acts in the CNS to differentially impact glucose homeostasis and energy balance in males and females. Female global ARKO mice display normal metabolic phenotypes on a chow diet, yet they develop insulin resistance, glucose intolerance, and obesity when on a high-fat diet relative to normal mice on a high-fat diet.87 However, the authors did not explore if this obesity was due to increased food intake or decreased energy expenditure. In these mice, androgen excess decreased hypothalamic POMC messenger RNA expression. In female mice with chronic androgen excess during adulthood, leptin fails to reduce body weight, leading to obesity. Testosterone action is probably mediated at least in part via the AR, as men that have AR variants with low transcriptional activity exhibit hyperinsulinemia and obesity69 However, ERs are also involved in testosterone's metabolic effect in men, as treatment with an aromatase inhibitor blocked the ability of testosterone replacement to suppress adiposity in men.70 More direct evidence for the role of the AR in metabolic homeostasis can be gathered from androgen-receptor knockout (ARKO) mouse models. Androgens bind to these receptors and operate via genomic (DNA binding) or nongenomic pathways (non-DNA binding) that influence multiple signaling cascades essential for CNS function and neuroprotection. Following androgen binding, they convert to a nuclear receptor which influences gene expression through binding at specific DNA sequences. Testosterone is converted into dihydrotestosterone (DHT) by the action of 5-alpha reductase in the prostate and skin. Testosterone is the most potent androgen, produced primarily by the Leydig cells in the testis. Androstenedione acts as the precursor for both testosterone and estrogen. 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. 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. However, the impact of androgens on oxidative stress as well as the negative modulation of neurotrophins growth factors may have counterproductive detrimental effects 12, 13. Conversely, DHEA has the opposite effect than testosterone on brain development, possibly counteracting the effects of testosterone. We also discuss how the metabolic effect of testosterone is centrally mediated via the androgen receptor. In men, testosterone plays a pivotal role in maintaining the health and function of these neural pathways. 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. 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 . Future studies should deepen our understanding of TRTs’ effects on MS in men with testosterone deficiency and those with normal levels along with optimizing therapeutic strategies across a broader spectrum of demyelinating diseases. This data highlights the potential protective effects of androgens in demyelinating disorders. However, the precise role of androgens in the pathogenesis of these disorders and their potential use in treatment remains largely unexplored . This has led people to calling it the "fight, flight, freeze" response, "fight-flight-freeze-fawn" or "fight-flight-faint-or-freeze", among other variants. Originally understood as the "fight-or-flight" response in Cannon's research, the state of hyperarousal results in several responses beyond fighting or fleeing. This response is recognised as the first stage of the general adaptation syndrome that regulates stress responses among vertebrates and other organisms. His theory states that animals react to threats with a general discharge of the sympathetic nervous system, preparing the animal for fighting or fleeing. Nevertheless, there is extensive evidence that prenatal androgen excess alters metabolism via central actions. Interestingly, the same group showed that XY animals on a chow diet show increased fat mass and impaired glucose tolerance relative to XX animals.34 These results suggest that the X chromosome may only contribute to impaired metabolism in conditions of nutrient excess. The role of central AR in masculinizing the brain with respect to metabolism will be discussed below. Quantitative assessments have provided valuable insights into the extent of neural dysfunction and the potential benefits of testosterone replacement therapy. Additionally, personalized medicine approaches, tailored to the specific needs and responses of individual patients, could revolutionize the management of testosterone-deficient neuropathy. Future studies should focus on elucidating the mechanisms by which testosterone influences neural pathways and exploring novel therapeutic strategies to enhance nerve regeneration and function. These findings position androgens and ARs as promising targets for the therapeutic management of various neurological diseases. In neonatal life, gonadal steroids are thought to influence the development of the hypothalamus. Estrogen receptor (ER) has been shown to transactivate other transcription factors in this manner, despite the absence of an estrogen response element (ERE) in the proximal promoter region of the gene. Estrogen and progesterone can influence gene expression in particular neurons or induce changes in cell membrane potential and kinase activation, leading to diverse non-genomic cellular functions. Most nerve fibres within the hypothalamus run in two ways (bidirectional). The hypothalamus controls body temperature, hunger, important aspects of parenting and maternal attachment behaviours, thirst, fatigue, sleep, circadian rhythms, and is important in certain social behaviors, such as sexual and aggressive behaviors. The hypothalamus is located below the thalamus and is part of the limbic system. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. According this view, the lateral hypothalamus is "a unique arbitrator of learning capable of shifting behavior toward or away from important events". Lesions in this nucleus abolish passive defensive behavior, like freezing and the "on-the-back" posture. Moreover, the premammillary nucleus also is mobilized, the dorsomedial part but not the ventrolateral part. Fos-labeled cell analysis showed that the PMDvl is the most activated structure in the hypothalamus, and inactivation with muscimol prior to exposure to the context abolishes the defensive behavior. The medial zone of hypothalamus is part of a circuitry that controls motivated behaviors, like defensive behaviors. Further lesion of the lateral part of the ventromedial nucleus in the same animal produces complete cessation of food intake. Bilateral lesion of the medial part of the ventromedial nucleus causes hyperphagia and obesity of the animal.
