Synthesis and Actions of 5α-Reduced Metabolites of Testosterone in the Nervous System

The document discusses the role of testosterone and its metabolites, produced by enzymes 5α-reductase (5α-Rs) and 3α/3β-hydroxysteroid oxidoreductases (3α/3β-HSORs), in the central nervous system. These metabolites act as neuroactive signaling steroid molecules, modulating physiological processes like myelination, neurotransmission, and stress response. They are expressed in GABAergic output neurons and modulate gamma-aminobutyric acid (GABA) function at GABA-A receptors. The levels of these metabolites are influenced by circulating levels and gonadectomy, and are altered in psychiatric and neurodegenerative diseases. The metabolites have shown neuroprotective effects in models of Parkinson's disease, spinal cord injury, and traumatic brain injury, among others. They also decrease neuropathic pain associated with diabetes mellitus. However, 5α-R inhibitors used for androgenetic alopecia have been associated with endocrine and neuropsychiatric side effects in some male patients. The document concludes that understanding the actions of testosterone and its metabolites in the nervous system could have important clinical implications for the treatment of neurological disorders.