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Frontiers in Neuroendocrinology Jul 2021Neurosteroids, steroid hormones synthesized locally in the nervous system, have important neuromodulatory and neuroprotective effects in the central nervous system.... (Review)
Review
Neurosteroids, steroid hormones synthesized locally in the nervous system, have important neuromodulatory and neuroprotective effects in the central nervous system. Progress in neurosteroid research has led to the successful translation of allopregnanolone into an approved therapy for postpartum depression. However, there is insufficient evidence to support the assumption that steroidogenesis is exactly the same between the nervous system and the periphery. This review focuses on CYP11A1, the only enzyme currently known to catalyze the first reaction in steroidogenesis to produce pregnenolone, the precursor to all other steroids. Although CYP11A1 mRNA has been found in brain of many mammals, the presence of CYP11A1 protein has been difficult to detect, particularly in humans. Here, we highlight the discrepancies in the current evidence for CYP11A1 in the central nervous system and propose new directions for understanding neurosteroidogenesis, which will be crucial for developing neurosteroid-based therapies for the future.
Topics: Animals; Brain; Central Nervous System; Cholesterol Side-Chain Cleavage Enzyme; Female; Humans; Pregnanolone; Pregnenolone
PubMed: 34015388
DOI: 10.1016/j.yfrne.2021.100925 -
International Journal of Molecular... Dec 2023Steroid hormone production via the adrenal cortex, gonads, and placenta (so-called glandular steroidogenesis) is responsible for the endocrine control of the body's... (Review)
Review
Steroid hormone production via the adrenal cortex, gonads, and placenta (so-called glandular steroidogenesis) is responsible for the endocrine control of the body's homeostasis and is organized by a feedback regulatory mechanism based on the hypothalamus-pituitary-steroidogenic gland axis. On the other hand, recently discovered extraglandular steroidogenesis occurring locally in different tissues is instead linked to paracrine or autocrine signaling, and it is independent of the control by the hypothalamus and pituitary glands. Bone cells, such as bone-forming osteoblasts, osteoblast-derived osteocytes, and bone-resorbing osteoclasts, respond to steroid hormones produced by both glandular and extraglandular steroidogenesis. Recently, new techniques to identify steroid hormones, as well as synthetic steroids and steroidogenesis inhibitors, have been introduced, which greatly empowered steroid hormone research. Based on recent literature and new advances in the field, here we review the local role of steroid hormones in regulating bone homeostasis and skeletal lesion formation. The novel idea of extraglandular steroidogenesis occurring within the skeletal system raises the possibility of the development of new therapies for the treatment of bone diseases.
Topics: Pregnancy; Female; Humans; Steroids; Adrenal Cortex Hormones; Gonads; Adrenal Cortex; Bone and Bones
PubMed: 38139309
DOI: 10.3390/ijms242417482 -
Current Drug Metabolism 2022Cytochrome P450s are a widespread and vast superfamily of hemeprotein monooxygenases that metabolize physiologically essential chemicals necessary for most species'... (Review)
Review
Cytochrome P450s are a widespread and vast superfamily of hemeprotein monooxygenases that metabolize physiologically essential chemicals necessary for most species' survival, ranging from protists to plants to humans. They catalyze the synthesis of steroid hormones, cholesterol, bile acids, and arachidonate metabolites and the degradation of endogenous compounds, such as steroids, fatty acids, and other catabolizing compounds as an energy source and detoxifying xenobiotics, such as drugs, procarcinogens, and carcinogens. The human CYP17A1 is one of the cytochrome P450 genes located at the 10q chromosome. The gene expression occurs in the adrenals and gonads, with minor amounts in the brain, placenta, and heart. This P450c17 cytochrome gene is a critical steroidogenesis regulator which performs two distinct activities: 17 alpha-hydroxylase activity (converting pregnenolone to 17- hydroxypregnenolone and progesterone to 17-hydroxyprogesterone; these precursors are further processed to provide glucocorticoids and sex hormones) and 17, 20-lyase activity (which converts 17-hydroxypregnenolone to DHEA). Dozens of mutations within CYP17A1 are found to cause 17-alpha-hydroxylase and 17, 20-lyase deficiency. This condition affects the function of certain hormone-producing glands, resulting in high blood pressure levels (hypertension), abnormal sexual development, and other deficiency diseases. This review highlights the changes in CYP17A1 associated with gene-gene interaction, drug-gene interaction, chemical-gene interaction, and its biochemical reactions; they have some insights to correlate with the fascinating functional characteristics of this human steroidogenic gene. The findings of our theoretical results will be helpful to further the design of specific inhibitors of CYP17A1.
Topics: Humans; Lyases; Pregnenolone; Progesterone; Steroid 17-alpha-Hydroxylase; Steroids
PubMed: 35366770
DOI: 10.2174/1389200223666220401093833 -
The Journal of Headache and Pain Mar 2021Neurosteroids affect the balance between neuroexcitation and neuroinhibition but have been little studied in migraine. We compared the serum levels of pregnenolone...
BACKGROUND
Neurosteroids affect the balance between neuroexcitation and neuroinhibition but have been little studied in migraine. We compared the serum levels of pregnenolone sulfate, pregnanolone and estradiol in women with menstrually-related migraine and controls and analysed if a correlation existed between the levels of the three hormones and history of migraine and age.
METHODS
Thirty women (mean age ± SD: 33.5 ± 7.1) with menstrually-related migraine (MM group) and 30 aged- matched controls (mean age ± SD: 30.9 ± 7.9) participated in the exploratory study. Pregnenolone sulfate and pregnanolone serum levels were analysed by liquid chromatography-tandem mass spectrometry, while estradiol levels by enzyme-linked immunosorbent assay.
RESULTS
Serum levels of pregnenolone sulfate and pregnanolone were significantly lower in the MM group than in controls (pregnenolone sulfate: P = 0.0328; pregnanolone: P = 0.0271, Student's t-test), while estradiol levels were similar. In MM group, pregnenolone sulfate serum levels were negatively correlated with history of migraine (R = 0.1369; P = 0.0482) and age (R = 0.2826, P = 0.0025) while pregnenolone sulfate levels were not age-related in the control group (R = 0.04436, P = 0.4337, linear regression analysis).
CONCLUSION
Low levels of both pregnanolone, a positive allosteric modulator of the GABAA receptor, and pregnenolone sulfate, a positive allosteric modulator of the NMDA receptor, involved in memory and learning, could contribute either to headache pain or the cognitive dysfunctions reported in migraine patients. Overall, our results agree with the hypothesis that migraine is a disorder associated with a loss of neurohormonal integrity, thus supporting the therapeutic potential of restoring low neurosteroid levels in migraine treatment.
Topics: Aged; Estradiol; Female; Humans; Migraine Disorders; Pregnanolone; Pregnenolone
PubMed: 33757421
DOI: 10.1186/s10194-021-01231-9 -
Frontiers in Neuroendocrinology Oct 2019The pregnenolone-progesterone-allopregnanolone pathway is receiving increasing attention in research on the role of neurosteroids in pathophysiology, particularly in... (Review)
Review
The pregnenolone-progesterone-allopregnanolone pathway is receiving increasing attention in research on the role of neurosteroids in pathophysiology, particularly in stress-related and drug use disorders. These disorders involve an allostatic change that may result from deficiencies in allostasis or adaptive responses, and may be downregulated by adjustments in neurotransmission by neurosteroids. The following is an overview of findings that assess how pregnenolone and/or allopregnanolone concentrations are altered in animal models of stress and after consumption of alcohol or cannabis-type drugs, as well as in patients with depression, anxiety, post-traumatic stress disorder or psychosis and/or in those diagnosed with alcohol or cannabis use disorders. Preclinical and clinical evidence shows that pregnenolone and allopregnanolone, operating according to a different or common pharmacological profile involving GABAergic and/or endocannabinoid system, may be relevant biomarkers of psychiatric disorders for therapeutic purposes. Hence, ongoing clinical trials implicate synthetic analogs of pregnenolone or allopregnanolone, and also modulators of neurosteroidogenesis.
Topics: Alcoholism; Animals; Marijuana Use; Neurosteroids; Pregnanolone; Pregnenolone; Progesterone; Signal Transduction; Stress, Psychological
PubMed: 31525393
DOI: 10.1016/j.yfrne.2019.100789 -
Reproductive Biology and Endocrinology... Jun 2022According to current definitions of Polycystic Ovary Syndrome (PCOS), hyperandrogenism is considered as a key element in the pathogenesis of this common endocrinopathy....
BACKGROUND
According to current definitions of Polycystic Ovary Syndrome (PCOS), hyperandrogenism is considered as a key element in the pathogenesis of this common endocrinopathy. However, until now, studies about ovarian androgen profile in women are very rare. Our aim was then to characterise the expression profile of the androgens in follicular fluid of 30 PCOS patients, and compare it to those of 47 Control women and 29 women with only polycystic ovary morphology on ultrasounds (ECHO group).
METHODS
A retrospective, single-centre cohort study was performed. The intrafollicular concentrations of the key androgens were assessed and correlated with the intrafollicular levels of some adipokines of interest. Androgens were quantified by mass spectrophotometry combined with ultra-high-performance liquid chromatography, while adipokine concentrations were measured by ELISA assays.
RESULTS
In PCOS patients, the intrafollicular concentrations of the androgens synthesised by ovarian theca cells, i.e., 17OH-pregnenolone, dehydroepiandrosterone, Δ4-androstenedione and testosterone, were significantly higher than those of the androgens of adrenal origin, and positively correlated with the main PCOS clinical and biological features, as well as with the adipokines mostly expressed in the follicular fluid of PCOS patients, i.e. resistin, omentin, chemerin and apelin. Conversely, Control women showed the highest levels of 17OH-progesterone, deoxycorticosterone and 11-deoxycortisol. Confirming these results, apelin levels were negatively associated with pregnenolone and deoxycorticosterone concentrations, while visfatin levels, which were higher in the Control group, negatively correlated with the Δ4-androstenedione and testosterone ones.
CONCLUSIONS
PCOS is characterised by a selective increase in the intrafollicular levels of the androgens synthesised by theca cells, strengthening the hypothesis that ovarian hyperandrogenism plays a central role in its pathogenesis. Further, the significant correlation between the intrafollicular concentrations of the androgens and most of the adipokines of interest, including apelin, chemerin, resistin and omentin, confirms the existence of a close relationship between these two hormonal systems, which appear deeply involved in ovarian physiology and PCOS physiopathology.
Topics: Adipokines; Androgens; Androstenedione; Apelin; Cohort Studies; Desoxycorticosterone; Female; Follicular Fluid; Humans; Hyperandrogenism; Polycystic Ovary Syndrome; Pregnenolone; Resistin; Retrospective Studies; Testosterone
PubMed: 35701786
DOI: 10.1186/s12958-022-00959-6 -
Journal of Neuroendocrinology Feb 2023Steroids and endocannabinoids are part of two modulatory systems and some evidence has shown their interconnections in several functions. Homeostasis is a common... (Review)
Review
Steroids and endocannabinoids are part of two modulatory systems and some evidence has shown their interconnections in several functions. Homeostasis is a common steady-state described in the body, which is settled by regulatory systems to counterbalance deregulated or allostatic set points towards an equilibrium. This regulation is of primary significance in the central nervous system for maintaining neuronal plasticity and preventing brain-related disorders. In this context, the recent discovery of the shutdown of the endocannabinoid system (ECS) overload by the neurosteroid pregnenolone has highlighted new endogenous mechanisms of ECS regulation related to cannabis-induced intoxication. These mechanisms involve a regulatory loop mediated by overactivation of the central type-1 cannabinoid receptor (CB1R), which triggers the production of its own regulator, pregnenolone. Therefore, this highlights a new process of regulation of steroidogenesis in the brain. Pregnenolone, long considered an inactive precursor of neurosteroids, can then act as an endogenous negative allosteric modulator of CB1R. The present review aims to shed light on a new framework for the role of ECS in the addictive characteristics of cannabis with the novel endogenous mechanism of ECS involving the neurosteroid pregnenolone. In addition, this new endogenous regulatory loop could provide a relevant therapeutic model in the current context of increasing recreational and medical use of cannabis.
Topics: Endocannabinoids; Cannabis; Neurosteroids; Brain; Pregnenolone; Receptor, Cannabinoid, CB1
PubMed: 36043319
DOI: 10.1111/jne.13191 -
The Journal of Steroid Biochemistry and... Oct 2020Gastrointestinal function is known to be regulated by steroid molecules produced by the gonads, the adrenal glands and the gut microbiota. However, we have a limited...
Gastrointestinal function is known to be regulated by steroid molecules produced by the gonads, the adrenal glands and the gut microbiota. However, we have a limited knowledge on the functional significance of local steroid production by gastrointestinal tract tissue. On this basis, we have here evaluated, as a first methodological approach, the expression of steroidogenic molecules and the local levels of key steroids in the male rat colon. Our findings indicate that the colon tissue expresses molecules involved in the early steps of steroidogenesis and in the consecutive synthesis and metabolism of steroid hormones, such as progesterone, testosterone and 17β-estradiol. In addition, the levels of the steroid hormone precursor pregnenolone and the levels of active metabolites of progesterone and testosterone, such as dihydroprogesterone, tetrahydroprogesterone, dihydrotestosterone and 17β-estradiol, were higher in colon than in plasma. Higher levels of the androgen metabolite 3α-diol were detected in the colon in comparison with another non-classical steroidogenic tissue, such as the cerebral cortex. These findings suggest the existence of local steroid synthesis and metabolism in the colon, with the production of active steroid metabolites that may impact on the activity of the enteric nervous system and on the composition of the gut microbiota.
Topics: Animals; Cerebral Cortex; Colon; Male; Rats, Sprague-Dawley; Steroids
PubMed: 32777355
DOI: 10.1016/j.jsbmb.2020.105732 -
Frontiers in Genetics 2021Forsythiae Fructus (Lianqiao in Chinese) is widely used in traditional Chinese medicine. The lipid components in Forsythiae Fructu are the basis of plant growth and... (Review)
Review
Forsythiae Fructus (Lianqiao in Chinese) is widely used in traditional Chinese medicine. The lipid components in Forsythiae Fructu are the basis of plant growth and active metabolism. Samples were collected at two growth stages for a comprehensive study. Transcriptome and lipidomics were performed by using the RNA-seq and UPLC-Q-TOF-MS techniques separately. For the first time, it was reported that there were 5802 lipid components in Lianqiao comprised of 31.7% glycerolipids, 16.57% phospholipids, 13.18% sphingolipids, and 10.54% fatty acids. Lipid components such as terpenes and flavonoids have pharmacological activity, but their content was low. Among these lipids which were isolated from Forsythiae Fructus, 139 showed significant differences from the May and July harvest periods. The lipids of natural products are mainly concentrated in pregnenolones and polyvinyl lipids. RNA-Seq analysis revealed 92,294 unigenes, and 1533 of these were differentially expressed. There were 551 differential genes enriched in 119 KEGG pathways. The synthesis pathways of terpenoids and flavonoids were explored. Combined with the results of lipidomics and transcriptomics, it is hypothesized that in the synthesis of abscisic acid, a terpenoid, may be under the dynamic regulation of genes EC: 1.1.1.288, EC: 1.14.14.137 and EC: 1.13.11.51 in balanced state. In the synthesis of gibberellin, GA20-oxidase (GA20ox, EC: 1.14.11.12), and GA3-oxidase (GA3ox, EC: 1.14.11.15) catalyze the production of active GAs, and EC: 1.14.11.13 is the metabolic enzymes of active GAs. In the synthesis of flavonoids, MF (multifunctional), PAL (phenylalanine ammonia-lyase), CHS (chalcone synthase), ANS (anthocyanidin synthase), FLS (flavonol synthase) are all key enzymes. The results of the present study provide valuable reference information for further research on the metabolic pathways of the secondary metabolites of
PubMed: 34764985
DOI: 10.3389/fgene.2021.758326 -
Zhurnal Nevrologii I Psikhiatrii Imeni... 2023Despite the proven importance of neurosteroids in many physiological processes, their role in the pathogenesis of the most of psychiatric disorders remains relatively... (Review)
Review
Despite the proven importance of neurosteroids in many physiological processes, their role in the pathogenesis of the most of psychiatric disorders remains relatively understudied. This article reviews the current clinical evidence on the effects of neurosteroids on the formation and treatment of anxiety disorder, depression, bipolar disorder, and schizophrenia. In particular, the article points out the ambivalent nature of the effects of neurosteroids on GABA- and other receptors. We are especially interested in the anxiolytic and anxiogenic effects of some neurosteroids, the antidepressant effect of allopregnanolone in treating postpartum and other forms of depression, and the nature of short- and long-term mechanisms of antidepressant effects of neurosteroids of different types. The currently unproven hypothesis about the effect of changes in the level of neurosteroids on the course of bipolar disorder is also discussed, with an analysis of the scientific evidence on the development of schizophrenic symptomatology in relation to changing neurosteroid levels in the context of positive and cognitive symptoms.
Topics: Female; Humans; Neurosteroids; Mental Disorders; Bipolar Disorder; Anxiety Disorders; Pregnanolone
PubMed: 37084362
DOI: 10.17116/jnevro202312304131