Neurosteroid Biosynthesis in the Human Brain and Its Clinical Implications

Abstract

This paper summarizes the current knowledge concerning the biosynthesis of neurosteroids in the human brain, the enzymes mediating these reactions, their localization, and the putative effects of neurosteroids. The presence of the steroidogenic enzymes cytochrome P450(SCC), aromatase, 5alpha-reductase, 3alpha-hydroxysteroid dehydrogenase, and 17beta-hydroxysteroid dehydrogenase in the human brain has now been firmly established by molecular biological and biochemical studies. Their presence in the cerebral cortex and in the subcortical white matter indicates that various cell types, either neurons or glial cells, are involved in the biosynthesis of neuroactive steroids in the brain. The following functions are attributed to specific neurosteroids: modulation of GABA(A), N-methyl-d-aspartate (NMDA), nicotinic, muscarinic, serotonin (5-HT(3)), kainate, glycine and sigma receptors, neuroprotection and induction of neurite outgrowth, dendritic spines, and synaptogenesis. We still do not know whether and how the steroidogenic enzymes are involved in the pathophysiology of the nervous system. The first clinical investigations in humans produced evidence for an involvement of neuroactive steroids in conditions such as fatigue during pregnancy, premenstrual syndrome, postpartum depression, catamenial epilepsy, and depressive disorders. Further and improved knowledge of the biochemical pathways of neurosteroidogenesis and their actions on the brain may enable new perspectives in the understanding of the physiology of the human brain as well as in the pharmacological treatment of its disturbances.

The transcription of steroidogenic genes in the human cerebellum and hippocampus: a comparative survey of normal and Alzheimer's tissue

“…However, they detected CYP11A1, HSD3B2 and CYP21B transcription in pooled hippocampi and cerebella, in agreement with the findings here. Their detection of CYP17 mRNA contrasts with its absence from any of our hippocampal or cerebellar samples, although Stoffel-Wagner (2003) was similarly unable to detect it. Stoffel-Wagner (2003) also alludes to an unpublished study where CYP11A1 and CYP11B2 mRNAs could not be detected in human hippocampus.…”

“…Their detection of CYP17 mRNA contrasts with its absence from any of our hippocampal or cerebellar samples, although Stoffel-Wagner (2003) was similarly unable to detect it. Stoffel-Wagner (2003) also alludes to an unpublished study where CYP11A1 and CYP11B2 mRNAs could not be detected in human hippocampus. The absence of CYP17 transcription would obviate de novo synthesis of sex steroids; any synthesis within the CNS would instead have to rely on the conversion of circulating steroid precursors.…”

Inhibitory effects of pharmacological doses of melatonin on aromatase activity and expression in rat glioma cells

“…Steroids or their precursors can be metabolised in the CNS to derivates which can affect brain function and may have an important clinical significance (Weidenfeld and Schiller, 1984). Previous studies have shown that human brain and human neuronal cell lines secrete oestrogens (Stoffel-Wagner, 2001, 2003.…”

Functional significance of the rapid regulation of brain estrogen action: Where do the estrogens come from?

“…Under normal conditions, aromatase expression in the avian and mammalian central nervous system is restricted to specific neuronal populations. These neuronal groups are mainly located in the hypothalamic/preoptic (medial preoptic nucleus, ventromedial nucleus) and limbic system (bed nucleus of stria terminalis, amygdala, hippocampus, septum, etc), but more scattered populations of aromatase expressing neurons are also present in the cerebral cortex [24,160,215,216,252,271]. In zebra finches and canaries, aromatase is also detected in high concentrations in parts of the nidopallium adjacent to the song control nucleus HVC [14,166,222].…”