Thus, it is hypothesized that alterations of ARs or androgen interactions with ARs located in the CNS may play a role in various neurological diseases and serve as a target for disease management. 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. These hormones not only play an important role in the development of secondary sexual characteristics and fertility but are increasingly recognized for their role in the development and function of the CNS. Androstenediol is an androgen that is converted into testosterone and estrogen in peripheral tissue. In this article, we discuss the different forms of endogenous androgen, their function in the CNS, the evolving understanding of the role of androgen in various CNS disorders, and the therapeutic use of androgen supplementation for CNS pathologies. This review highlights the increasing recognition of testosterone and androgen signaling in various neurological conditions, with evidence of both protective and harmful effects depending on dosage and context. This article does not contain any studies with human or animal subjects performed by any of the authors. 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. In conclusion, various neurological disorders exhibit male predominance, while some demonstrate reduced disease severity in men. Table 2 summarises the various TRT preparations and their side effects. Data so far obtained indicate that the levels of several neuroactive steroids are affected in peripheral neuropathy. Therefore, consistent with the effects exerted on the proteins of peripheral myelin, PROG stimulates the synthesis of myelin membranes accelerating the time of initiation and enhancing the rate of myelin synthesis in Schwann cells co-cultured with DRG neurons 19,58. Among the physiological effects of neuroactive steroids in the PNS, the regulation of the myelination program has been investigated extensively. Neuroactive steroids may exert their effects by classical steroid receptors as well as non-classical steroid receptors. This suggests BDNF is not only capable of initiating synapse formation through its effects on NMDA receptor activity, but it can also support the regular every-day signaling necessary for stable memory function. Thus, it appears BDNF can upregulate the expression and synaptic localization of AMPA receptors, as well as enhance their activity through its postsynaptic interactions with the NR2B subunit. Additionally, castration of male mice has shown deleterious effects on the susceptibility and severity of EAE and treatment with testosterone resulted in the attenuation of symptoms and reduced inflammation 139,140,141. An implication of testosterone in the susceptibility to autoimmune diseases has indeed been suggested by several studies 137,138. Additionally, we established that sex differences in myelin are already present at postnatal day 10 (P10) and the postnatal treatment by testosterone or 5α-DHT showed their long-lasting masculinizing effects on the density of oligodendrocytes and the structure of the myelin sheaths. All these results highlight the role of testosterone, signaling via the neural AR, in the proliferation of OPCs and their differentiation into myelinating oligodendrocytes (same results as presented in Figure 2). Our previous studies have provided evidence that testosterone, its natural metabolites or synthetic derivatives, stimulate the proliferation of OPCs as well as their differentiation into myelinating oligodendrocytes via AR. Testosterone can exert its effects on target cells via multiple mechanisms and the neural AR was identified as a key target for its remyelinating effects. Furthermore, the review delves into the neural correlates of sexual arousal, elucidating the role of various brain regions in the perception and processing of sexual stimuli. These findings position androgens and ARs as promising targets for the therapeutic management of various neurological diseases. 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 .
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