Since then, other studies have explored differences in brain structure and function between individuals with different sexual orientations. These studies suggest that sexual preference is at least partially influenced by brain structure and function. Several studies have explored brain structure and function differences between individuals with different sexual orientations. Progesterone can also affect sexual function and desire, although its role is not as well understood as testosterone and estrogen . Low levels of testosterone can lead to decreased sexual desire and dysfunction. The hypothalamus also plays a crucial role in regulating hormone production, including releasing testosterone and oestrogen, which are essential for sexual function . More recently, attention has shifted toward understanding the role of androgens, with growing evidence suggesting testosterone may influence pathogenesis and modulate symptom severity and frequency of primary headache disorders. Steroid hormones have been implicated in demyelinating diseases such as MS, as it is more common in women and as its course differs between women and men . Through their ability to regulate gene expression of many downstream effector genes, steroid hormones and their NRs are involved in various physiological functions, such as development, metabolism, reproduction, behavior and cell homeostasis. These classical steroid receptors are present in different isoforms throughout the nervous system of both sexes 63,69,72,73,74. Similarly, the expression of the steroidogenic enzymes, such as the P450 side chain cleavage (P450scc, CYP11A1), which converts cholesterol into pregnenolone, and the 3-beta-hydroxysteroid dehydrogenase (3β-HSD), which converts pregnenolone to progesterone, are well documented in the CNS 69,70. Although, these cells are post-mitotic, non-migratory, and unable to remyelinate upon transplantation into demyelinated lesions 55,56,57. Testosterone supplementation can have potential adverse events when used at a supratherapeutic level, and prenatal testosterone exposure is believed to contribute to the pathogenesis of neurodevelopmental 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. Additionally, understanding the cellular and molecular mechanisms of these steroid hormones in the remyelination processes may contribute to the development of new and safer treatments for MS patients of both sexes. As long-term testosterone treatment has been proven safe, and outcomes of a first clinical trial in men with relapsing-remitting MS have been very encouraging, further clinical trials are desirable. The use of their potent synthetic analogs, i.e., nestorone and MENT, with proven efficacy, to minimize the potential undesirable side effects, may offer enhanced benefits for myelin repair in demyelinating diseases. The smaller size of progesterone and testosterone and their natural presence within the circulation, de-novo synthesis within neural tissue and enhanced permeability across the blood–brain barrier point to their high therapeutic potential. The nervous system, in addition to be a target for steroid hormones, is the source of a variety of neuroactive steroids, which are synthesized and metabolized by glial cells and neurons. The first clinical trial by Voskuhl’s team, giving 10 men with relapsing-remitting MS a testosterone gel treatment, showed a shift in peripheral lymphocyte composition by decreasing the percentage of CD4+ T cells (TH1 phenotype) and by increasing natural killer (NK) cells 146,147,148. Recent data also suggest a protective role of testosterone through its action on mast cells by favoring the production of IL-33, a cytokine that promotes a T-helper (Th2) protective response . This androgen is responsible for masculine features and fertility in males while having positive effects on bone density, lean mass, mood, and libido in females. Testosterone is the most potent androgen, produced primarily by the Leydig cells in the testis. Androstenedione has moderate androgenic activity, is produced by adrenal glands and gonads, and is derived from DHEA. These conditions can affect the brain and nervous system, leading to changes in sexual desire, arousal, and performance. In addition to these specific disorders, other conditions such as depression, anxiety, and stress can significantly impact sexual function. Some studies suggest that HSDD may be linked to changes in brain chemistry, particularly in the neurotransmitters dopamine and serotonin, which regulate mood and motivation . Other factors, such as social and cultural influences, genetic factors, and individual experiences, also play a role in developing sexual orientation. However, it is essential to note that sexual orientation is complex and multifaceted and cannot be reduced to differences in brain structure alone. LeVay compared the brains of homosexual and heterosexual men and found differences in the size of the anterior hypothalamus . AMPA and NMDA receptors are two ionotropic glutamate receptors involved in glutamatergic neurotransmission and essential to learning and memory via long-term potentiation. Variations in both the BDNF and BDNF-AS genes are important factors to consider, given their potential to alter BDNF function and contribute to multiple human phenotypes influencing disease susceptibility and treatment outcomes. In the human neocortex, regions with increased activity and BDNF expression exhibit reduced BDNF-AS expression. Activation of dopamine receptor D5 also promotes expression of BDNF in prefrontal cortex neurons. NMDA receptor activation triggers the release of the regulatory inhibitor, allowing for BDNF exon IV upregulation to take place in response to the activity-initiated calcium influx. The expression of reelin by Cajal–Retzius cells goes down during development under the influence of BDNF. It plays a role in the regulation of sexual behaviour and the formation of sexual preferences. It also plays a role in the formation of sexual memories and the regulation of sexual behaviour . The amygdala is responsible for processing emotional information and plays a role in regulating sexual desire and arousal.
