Remarkably, PRs are broadly expressed throughout the brain and can be detected in neural cell type 63,93,96,97. Progesterone can be converted into 5α-dihydroprogesterone (5α-DHP) by the 5α-reductases and subsequently 5α-DHP can be reduced to 3α,5α-tetrahydroprogesterone (3α,5α-THP) by the enzyme 3α-hydroxysteroid oxidoreductase 63,92,93,94. However, recent studies have also reported contradictory results concerning the steroid status in MS patients.
ARs are also found in the dorsal horn of the spinal cord and various brain stem locations, predominating in the area postrema, motor nucleus of the vagus nerve, dorsal raphe nucleus, periaqueductal gray, retrorubral nucleus, retrotrapezoid nucleus, and substantia nigra. Notably, ARs have been identified in the forebrain, thalamus, hypothalamus, amygdala, hippocampus, and olfactory bulb. Figure 1 provides a simplified representation of androgen signaling pathways in the CNS. It is responsible for formation of external male genitalia in fetus, prostate growth, and plays a role in male pattern baldness. Testosterone is converted into dihydrotestosterone (DHT) by the action of 5-alpha reductase in the prostate and skin. Androstenedione acts as the precursor for both testosterone and estrogen.
A randomized, controlled, double-blind trial conducted in 1989 studied the effects of TRT in 40 men with myotonic dystrophy and ultimately demonstrated increased muscle mass but without positive impact on overall strength . Progressive testicular atrophy causing oligospermia is seen in 80% of men with DM1 along with reduced adrenal androgen synthesis . Furthermore, testosterone supplementation along with exercise in patients with IBM led to an additional decrease in inflammatory response when compared to exercise alone .
Several studies including ours convincingly show that progesterone and testosterone play a key role in the process of myelination and remyelination. We have recently shown that the sex differences in oligodendrocyte density and myelin proteins, previously observed by Cerghet et al. , are determined by the postnatal increase in testosterone levels and AR expression in male mice . Thus, testosterone depletion results in an increased risk of dysfunction and disease in androgen-responsive tissues, including the brain 121,122,123. On the contrary, medroxyprogesterone acetate (MPA), another synthetic progestin that binds not only to PR but also to glucocorticoid receptors (GR) and has anti-estrogenic effects, had no effect on myelination or on oligodendrocyte lineage progression . In particular, recent findings from our laboratory indicate that progesterone and testosterone not only regulate proliferation and differentiation of myelinating cells (Figure 1B), two key events in MS disease, but may also modulate the vulnerability of the myelin sheaths and neurons to toxic insults.
As for astrocytes, microglia/macrophages play a crucial role in both developmental and repairing oligodendrogenesis and myelination. Astrocytes contribute to the formation and functioning of the blood–brain barrier (BBB) and the disruption of BBB seems to be an essential step in triggering CNS inflammation and subsequent tissue injury . They produce several growth factors, such as platelet-derived growth factor, brain-derived neurotrophic factor or ciliary neurotrophic factor to promote OPC development and CNS myelination and they aid in the removal of myelin debris 20,21,22,23,24,25. Astrocytes form stellate cells with multiple processes and occupy about 25% to 50% of brain volume.
Indeed, neuroactive steroids exert key physiological roles in the PNS acting on the glial 8–16 and neuronal compartments 17–19. However, more recent results have indicated that the peripheral nervous system (PNS) also synthesizes and metabolizes neuroactive steroids and is a target for these molecules. Moreover, pharmacological tools able to increase the synthesis of neuroactive steroids might represent new interesting therapeutic strategy to be applied in case of peripheral neuropathy. Indeed, neuroactive steroids have been recently proposed as therapies for different types of peripheral neuropathy, like for instance those occurring during aging, chemotherapy, physical injury and diabetes.
Several neurotransmitters play essential roles in sexual function, including dopamine, serotonin, and norepinephrine . Medications such as antidepressants and blood pressure medications can also affect sexual function by altering hormone levels. Low levels of estrogen can lead to decreased sexual desire and dysfunction. The neurological pathway for sexual behaviour is a complex process involving multiple brain regions, hormone production, and the peripheral nervous system. During sexual activity, signals from the brain activate the sympathetic nervous system, causing rhythmic contractions of the genital muscles and ejaculation in men.
Later on, a second wave from the dorsal regions in the spinal cord and lateral ganglionic eminence in the brain replace or facilitate the whole spread 9,10,11. Importantly, they have limited potential of regeneration in response to any damage to their processes or myelin sheath 2,3,4. Thus, as per the requirement of their role, oligodendrocytes are more distributed along the axonal tracks as compared to grey matter regions. Neuronal cell bodies and dendrites are concentrated in the gray matter, where information is received, processed and integrated, while white matter consists of bundles of axons insulated by a multi-layer lipid structure called myelin. LXR, liver X receptor; RXR, retinoic X receptor; TSPO, translocator protein-18 kDa; NCV, nerve conduction velocity. Indeed, these therapeutic strategies are extremely intriguing given the many situations in which there are no effective treatments that can prevent, arrest or reverse peripheral nerve damage. Moreover, at least in diabetic animals, activation of LXR seems to be particularly interesting, because at variance to that of TSPO , did not induce significant changes of neuroactive steroid levels in plasma.

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