Neurosteroid biosynthesis: Enzymatic pathways and neuroendocrine regulation by neurotransmitters and neuropeptides

Laboratory of Cellular and Molecular Neuroendocrinology, European Institute for Peptide Research (IFRMP 23), Regional Platform for Cell Imaging (PRIMACEN), University of Rouen, 76821 Mont-Saint-Aignan, France
Frontiers in Neuroendocrinology (Impact Factor: 7.04). 08/2009; 30(3):259-301. DOI: 10.1016/j.yfrne.2009.05.006
Source: PubMed


Neuroactive steroids synthesized in neuronal tissue, referred to as neurosteroids, are implicated in proliferation, differentiation, activity and survival of nerve cells. Neurosteroids are also involved in the control of a number of behavioral, neuroendocrine and metabolic processes such as regulation of food intake, locomotor activity, sexual activity, aggressiveness, anxiety, depression, body temperature and blood pressure. In this article, we summarize the current knowledge regarding the existence, neuroanatomical distribution and biological activity of the enzymes responsible for the biosynthesis of neurosteroids in the brain of vertebrates, and we review the neuronal mechanisms that control the activity of these enzymes. The observation that the activity of key steroidogenic enzymes is finely tuned by various neurotransmitters and neuropeptides strongly suggests that some of the central effects of these neuromodulators may be mediated via the regulation of neurosteroid production.

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Available from: Georges Pelletier,
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    • "While neurosteroids synthesis is widely documented in mammals, only few studies focused on de novo steroid synthesis in the brain of teleost fish [51] [52] [53] [54] [55] Such a feature raises the question of the origin, local and/or peripheral, of C19 androgens available for brain aromatization. Our laboratory recently demonstrated that the brain of adult zebrafish was able to de novo synthesize a wide variety of radiolabeled neurosteroids from [ 3 H]pregnenolone . "
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    ABSTRACT: Estrogens are known as steroid hormones affecting the brain in many different ways and a wealth of data now document effects on neurogenesis. Estrogens are provided by the periphery but can also be locally produced within the brain itself due to local aromatization of circulating androgens. Adult neurogenesis is described in all vertebrate species examined so far, but comparative investigations have brought to light differences between vertebrate groups. In teleost fishes, the neurogenic activity is spectacular and adult stem cells maintain their mitogenic activity in many proliferative areas within the brain. Fish are also quite unique because brain aromatase expression is limited to radial glia cells, the progenitor cells of adult fish brain. The zebrafish has emerged as an interesting vertebrate model to elucidate the cellular and molecular mechanisms of adult neurogenesis, and notably its modulation by steroids. The main objective of this review is to summarize data related to the functional link between estrogens production in the brain and neurogenesis in fish. First, we will demonstrate that the brain of zebrafish is an endogenous source of steroids and is directly targeted by local and/or peripheral steroids. Then, we will present data demonstrating the progenitor nature of radial glial cells in the brain of adult fish. Next, we will emphasize the role of estrogens in constitutive neurogenesis and its potential contribution to the regenerative neurogenesis. Finally, the negative impacts on neurogenesis of synthetic hormones used in contraceptive pills production and released in the aquatic environment will be discussed. Copyright © 2015. Published by Elsevier Ltd.
    The Journal of steroid biochemistry and molecular biology 07/2015; DOI:10.1016/j.jsbmb.2015.06.011 · 3.63 Impact Factor
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    • "It is an important organ of prereceptor androgen metabolism capable of both active androgen synthesis and inactivation regulating its exposure to androgens in an autocrine manner (O'Reilly et al. 2014). In addition, several steroids such as pregnenolone are synthesized in high concentrations in the brain, and these neurosteroids are involved in regulation of sexual behavior, feeding, aggressiveness, locomotion and stress (Baulieu 1997; Do Rego et al. 2009). "
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    ABSTRACT: The polar bear is an iconic Arctic species,threatened by anthropogenic impacts such as pollution and climate change. Successful reproduction of polar bears depends on a functioning steroid hormone system, which is susceptible to effects of persistent organic pollutants. The present study is the first study to report circulating concentrations of nine steroid hormones (i.e., estrogens, androgens and progestagens) in female polar bears (Ursus maritimus). The aim of the study was to investigate the effects of age, condition, location and reproductive status on steroid profile in female polar bears. Levels of pregnenolone (PRE), progesterone, androstenedione (AN), dehydroepiandrosterone (DHEA), testosterone, dihydrotestosterone, estrone (E1), 17a-estradiol (aE2) and 17b-estradiol (bE2) were quantified in blood (serum) of free-living female polar bears (n = 15) from Svalbard, Norway, by gas chromatography–tandem mass spectrometry (GC–MS/MS). Concentrations of androgens, estrogens and progestagens were in the range of 0.02–166, 0.01–1.49 and 0.16–17.1 nmol/L, respectively. A statistically significant negative correlation was found between E1 and DHEA, and a positive correlation between E1 and bE2. Additionally, negative relationships were found between body mass and cholesterol, contour body length and cholesterol, and head length and PRE, while a positive relationship was found between PRE and cholesterol. The steroid profile suggests that AN and the sex steroids are primarily synthesized through the D-4 pathway in polar bears, similar to rodents. The large individual variability in steroid levels reported here most likely reflects the differences in reproductive status of the female polar bears during mating season. The steroid data establish reference values of steroid hormones and may be applied in further studies on polar bears endocrine system and anthropogenic threats to polar bear reproduction.
    Polar Biology 03/2015; 38(8):1183-1194. · 1.59 Impact Factor
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    • "A peripheral source of androgens, such as dehydroepiandrosterone and androstenedione, comes from the adrenal glands in both sexes as well as the ovaries (Labrie et al., 2005), and in males estradiol can be synthesized from circulating testosterone by aromatase enzymes located in tissues throughout the body, including the brain (Simpson and Jones, 2006). In addition, the brain itself can be considered a steroidogenic organ, because it possesses the complement of steroid synthesizing enzymes, which enables synthesis of estrogens and androgens de novo, or by metabolism of peripherally derived precursors (Do Rego et al., 2009; Pelletier, 2010). These observations provide and infrastructure to explain why androgens in women (Miller et al., 2006) and estrogens in men (Cherrier et al., 2003) may influence mood and cognition, as well as vice-versa. "
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    ABSTRACT: The knowledge that diverse populations of dopaminergic neurons within the ventral tegmental area (VTA) can be distinguished in terms of their molecular, electrophysiological and functional properties, as well as their differential projections to cortical and subcortical regions has significance for key brain functions, such as the regulation of motivation, working memory and sensorimotor control. Almost without exception, this understanding has evolved from landmark studies performed in the male sex. However, converging evidence from both clinical and pre-clinical studies illustrates that the structure and functioning of the VTA dopaminergic systems are intrinsically different in males and females. This may be driven by sex differences in the hormonal environment during adulthood ('activational' effects) and development (perinatal and/or pubertal 'organizational' effects), as well as genetic factors, especially the SRY gene on the Y chromosome in males, which is expressed in a sub-population of adult midbrain dopaminergic neurons. Stress and stress hormones, especially glucocorticoids, are important factors which interact with the VTA dopaminergic systems in order to achieve behavioral adaptation and enable the individual to cope with environmental change. Here, also, there is male/female diversity not only during adulthood, but also in early life when neurobiological programing by stress or glucocorticoid exposure differentially impacts dopaminergic developmental trajectories in male and female brains. This may have enduring consequences for individual resilience or susceptibility to pathophysiological change induced by stressors in later life, with potential translational significance for sex bias commonly found in disorders involving dysfunction of the mesocorticolimbic dopaminergic systems. These findings highlight the urgent need for a better understanding of the sexual dimorphism in the VTA if we are to improve strategies for the prevention and treatment of debilitating conditions which differentially affect men and women in their prevalence and nature, including schizophrenia, attention/deficit hyperactivity disorder, autism spectrum disorders, anxiety, depression and addiction.
    Neuroscience 06/2014; 282. DOI:10.1016/j.neuroscience.2014.05.033 · 3.36 Impact Factor
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