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. It prepares the body to respond effectively to potentially threatening situations by increasing heart rate, constricting blood vessels, and dilating the pupils, among other physiological responses. 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. The sympathetic nervous system transfers signals from the dorsal hypothalamus, which activates the heart, increases vascular resistance, and increases blood flow, especially to the muscle, heart, and brain tissues. The sympathetic nervous system originates in the spinal cord and its main function is to activate the arousal responses that occur during the fight-or-flight response. The hormones estrogen, testosterone, and cortisol, as well as the neurotransmitters dopamine and serotonin, also affect how organisms react to stress. 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.
