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Frontiers in Neuroendocrinology Oct 2019Hormonal contraceptives are frequently prescribed drugs among women, mainly for their reversible contraceptive purposes but also for beneficial effects in some... (Review)
Review
Hormonal contraceptives are frequently prescribed drugs among women, mainly for their reversible contraceptive purposes but also for beneficial effects in some gynecological pathologies. Despite extensive studies aimed at elucidating the physical effects of hormonal contraceptives and ameliorating some unwanted outcomes, little is known yet about the effects of these drugs on brain function and related behavior, which are known to be modulated by endogenous steroid hormones. We describe the current literature on preclinical studies in animals undertaken to investigate effects of hormonal contraceptives on brain function and behavior. These studies suggest that hormonal contraceptives influence neurohormones, neurotransmitters, neuropeptides, and emotional, cognitive, social and sexual behaviors. Animals allow examination of the basic biological mechanisms of these drugs, devoid of the psychological aspect often associated to hormonal contraceptives' use in women. Understanding the neurobiological effects of these drugs may improve women's health and may help women making informed choices on hormonal contraception.
Topics: Animals; Anxiety; Behavior, Animal; Brain; Contraceptive Agents, Hormonal; Depression; Female; Humans; Learning; Neuropeptides; Neurosteroids; Pregnanolone; Sexual Behavior; Social Behavior; Stress, Psychological; Synaptic Transmission
PubMed: 31614151
DOI: 10.1016/j.yfrne.2019.100799 -
Pharmacology & Therapeutics Nov 2018Neurosteroids are neuroactive brain-born steroids. They can act through non-genomic and/or through genomic pathways. Genomic pathways are largely described for steroid... (Review)
Review
Neurosteroids are neuroactive brain-born steroids. They can act through non-genomic and/or through genomic pathways. Genomic pathways are largely described for steroid hormones: the binding to nuclear receptors leads to transcription regulation. Pregnenolone, Dehydroepiandrosterone, their respective sulfate esters and Allopregnanolone have no corresponding nuclear receptor identified so far whereas some of their non-genomic targets have been identified. Neuroplasticity is the capacity that neuronal networks have to change their structure and function in response to biological and/or environmental signals; it is regulated by several mechanisms, including those that involve neurosteroids. In this review, after a description of their biosynthesis, the effects of Pregnenolone, Dehydroepiandrosterone, their respective sulfate esters and Allopregnanolone on their targets will be exposed. We then shall highlight that neurosteroids, by acting on these targets, can regulate neurogenesis, structural and functional plasticity. Finally, we will discuss the therapeutic potential of neurosteroids in the pathophysiology of neurological diseases in which alterations of neuroplasticity are associated with changes in neurosteroid levels.
Topics: Animals; Dehydroepiandrosterone; Humans; Nervous System Diseases; Neurogenesis; Neuronal Plasticity; Neurotransmitter Agents; Pregnanolone; Pregnenolone
PubMed: 29953900
DOI: 10.1016/j.pharmthera.2018.06.011 -
The Journal of Steroid Biochemistry and... Jun 2016Elevated levels of neurosteroids during late gestation protect the fetal brain from hypoxia/ischaemia and promote neurodevelopment. Suppression of allopregnanolone... (Review)
Review
Elevated levels of neurosteroids during late gestation protect the fetal brain from hypoxia/ischaemia and promote neurodevelopment. Suppression of allopregnanolone production during pregnancy leads to the onset of seizure-like activity and potentiates hypoxia-induced brain injury. Markers of myelination are reduced and astrocyte activation is increased. The placenta has a key role in maintaining allopregnanolone concentrations in the fetal circulation and brain during gestation and levels decline markedly after both normal and preterm birth. This leads to the preterm neonate developing in a neurosteroid deficient environment between delivery and term equivalence. The expression of 5α-reductases is also lower in the fetus prior to term. These deficiencies in neurosteroid exposure may contribute to the increase in incidence of the adverse patterns of behaviour seen in children that are born preterm. Repeated exposure to glucocorticoid stimulation suppresses 5α-reductase expression and allopregnanolone levels in the fetus and results in reduced myelination. Both fetal growth restriction and prenatal maternal stress lead to increased cortisol concentrations in the maternal and fetal circulation. Prenatal stress results in reduced expression of key GABAA receptor subunits that normally heighten neurosteroid sensitivity. These stressors also result in altered placental allopregnanolone metabolism pathways. These findings suggest that reduced neurosteroid production and action in the perinatal period may contribute to some of the adverse neurodevelopmental and behavioural outcomes that result from these pregnancy compromises. Studies examining perinatal steroid supplementation therapy with non-metabolisable neurosteroid analogues to improve these outcomes are warranted.
Topics: Animals; Brain; Female; Fetus; Humans; Infant, Newborn; Neurotransmitter Agents; Pregnancy; Pregnanolone; Premature Birth; Receptors, GABA-A; Signal Transduction; Stress, Physiological
PubMed: 26365557
DOI: 10.1016/j.jsbmb.2015.09.012 -
Current Psychiatry Reports Apr 2021To provide an overview of existing studies on alterations in gonadal and neuroactive steroids (NASs) and mood symptoms among women with polycystic ovary syndrome (PCOS). (Review)
Review
PURPOSE OF REVIEW
To provide an overview of existing studies on alterations in gonadal and neuroactive steroids (NASs) and mood symptoms among women with polycystic ovary syndrome (PCOS).
RECENT FINDINGS
Recent studies have demonstrated a previously underappreciated association between PCOS and comorbid depression and anxiety. However, most studies on affective symptoms among women with PCOS have been cross-sectional, limiting our knowledge about fluctuations in symptoms over the menstrual cycle and reproductive lifespan for women with PCOS, as well as the potential interplay between NAS alterations and mood symptoms. Changes in the NAS allopregnanolone (ALLO) have been implicated in several reproductive-related psychiatric disorders (e.g., premenstrual dysphoric disorder (PMDD) and postpartum depression (PPD)) as well as in normal reproductive functioning, warranting further investigation for its potential role in the psychiatric symptoms observed in women with PCOS. Prospective studies evaluating associations between psychiatric symptoms and NAS are needed to elucidate the biological causes of the increased rates of psychiatric symptoms among women with PCOS and inform clinical treatment. ALLO, with its role in normal reproductive function, menstrual dysregulation among women with PCOS, and reproductive-related psychiatric conditions, makes it a particularly intriguing candidate for future investigation.
Topics: Affective Symptoms; Cross-Sectional Studies; Female; Humans; Neurosteroids; Polycystic Ovary Syndrome; Pregnanolone; Prospective Studies
PubMed: 33881645
DOI: 10.1007/s11920-021-01244-w -
Journal of Neuroendocrinology Feb 2022GABA is the main inhibitory neurotransmitter in the brain and GABAergic transmission has been shown to be of importance for regulation of mood, memory and food intake.... (Review)
Review
GABA is the main inhibitory neurotransmitter in the brain and GABAergic transmission has been shown to be of importance for regulation of mood, memory and food intake. The progesterone metabolite allopregnanolone (Allo) is a positive GABA receptor modulating steroid with potent effects. In humans, disorders such as premenstrual dysphoric disorder (PMDD), hepatic encephalopathy and polycystic ovarian syndrome are associated with elevated Allo levels and increased negative mood, disturbed memory and increased food intake in some individuals. This is surprising because Allo shares many properties with benzodiazepines and is mainly considered to be anxiolytic and anti-depressant. However, it is well established that, in certain individuals, GABA receptor activating compounds could have paradoxical effects and thus be anxiogenic in low physiological plasma concentrations but anxiolytic at high levels. We have demonstrated that isoallopregnanolone (Isoallo), the 3β-OH sibling of Allo, functions as a GABA receptor modulating steroid antagonist (GAMSA) but without any effects of its own on GABA receptors. The antagonistic effect is noted in most GABA subtypes investigated in vitro to date. In vivo, Isoallo can inhibit Allo-induced anaesthesia in rats, as well as sedation or saccadic eye velocity in humans. Isoallo treatment has been studied in women with PMDD. In a first phase II study, Isoallo (Sepranolone; Asarina Pharma) injections significantly ameliorated negative mood in women with PMDD compared with placebo. Several GAMSAs for oral administration have also been developed. The GAMSA, UC1011, can inhibit Allo induced memory disturbances in rats and an oral GAMSA, GR3027, has been shown to restore learning and motor coordination in rats with hepatic encephalopathy. In humans, vigilance, cognition and pathological electroencephalogram were improved in patients with hepatic encephalopathy on treatment with GR3027. In conclusion GAMSAs are a new possible treatment for disorders and symptoms caused by hyperactivity in the GABA system.
Topics: Animals; Anti-Anxiety Agents; Clinical Trials, Phase II as Topic; Female; GABA-A Receptor Antagonists; Hepatic Encephalopathy; Humans; Pregnanolone; Premenstrual Dysphoric Disorder; Rats; Receptors, GABA-A; gamma-Aminobutyric Acid
PubMed: 34337790
DOI: 10.1111/jne.13013 -
Current Psychiatry Reports Aug 2018The purpose of this review is to provide a theoretical explanation and a review of the recent literature concerning the role of neuroactive steroids in perinatal... (Review)
Review
PURPOSE OF REVIEW
The purpose of this review is to provide a theoretical explanation and a review of the recent literature concerning the role of neuroactive steroids in perinatal depression, and to use this information to suggest future directions of research.
RECENT FINDINGS
The bulk of the evidence on neuroactive steroids in perinatal depression concerns allopregnanolone. Recent studies have been mixed, with some studies finding a direct correlation between lower levels of allopregnanolone and increased depressive symptoms but other studies finding no relationship. Evidence concerning other neuroactive steroids and perinatal depression is sparse. Additional research is needed with larger sample sizes and better characterization across the perinatal period (rather than cross-sectionally). Because some studies point to a lag between neuroactive steroid dysregulation and subsequent symptoms, future research should consider interactions with other aspects of neuroactive steroid physiology, such as synthetic enzymes or receptor plasticity.
Topics: Depression; Depression, Postpartum; Female; Humans; Pregnancy; Pregnancy Complications; Pregnanolone
PubMed: 30094520
DOI: 10.1007/s11920-018-0937-4 -
Psychiatry Research Jan 2024Major depressive disorder (MDD) and postpartum depression (PPD) are common and burdensome conditions. This study aims to evaluate the efficacy and safety of zuranolone,... (Meta-Analysis)
Meta-Analysis Review
Major depressive disorder (MDD) and postpartum depression (PPD) are common and burdensome conditions. This study aims to evaluate the efficacy and safety of zuranolone, a neuroactive steroid γ-aminobutyric acid type A receptors-positive allosteric modulator, in treating MDD and PPD. A comprehensive literature search was conducted until September 2023, identifying seven randomized controlled trials (RCTs). The results demonstrated that zuranolone significantly decreased Hamilton Rating Scale for Depression (HAM-D) scores in patients with PPD or MDD at day 15 (concluding the 14-day course) and day 42-45 (4 weeks after treatment cessation) compared with the placebo, albeit exhibiting a diminishing trend. Moreover, a higher percentage of patients with PPD or MDD achieved HAM-D response and remission with zuranolone treatment compared with placebo at day 15. However, zuranolone did not significantly increase the proportion of MDD patients achieving HAM-D remission at 42/43 days. Adverse events (AEs) such as somnolence, dizziness, and sedation were linked to zuranolone, with a higher but not statistically significant rate of discontinuation due to AEs in the zuranolone group. Overall, our findings support the rapid antidepressant effects of zuranolone in MDD and PPD, along with a relatively favorable safety and tolerability. Large-scale longitudinal RCTs are needed to evaluate the long-term efficacy of zuranolone.
Topics: Female; Humans; Depression; Antidepressive Agents; Pregnanolone; Depressive Disorder, Major; Treatment Outcome; Double-Blind Method
PubMed: 38029628
DOI: 10.1016/j.psychres.2023.115640 -
Endocrinology, Diabetes & Metabolism Apr 2021The neurosteroid allopregnanolone modulates oxytocin expression in the brain, and its effects arise from its action on the GABA receptor. Whether neurosteroid levels and...
INTRODUCTION
The neurosteroid allopregnanolone modulates oxytocin expression in the brain, and its effects arise from its action on the GABA receptor. Whether neurosteroid levels and the function of the GABA receptor are involved in the risk of preterm labour in pregnant women is unknown.
METHODS
Pregnant women with ( = 16) or without ( = 20) threatened preterm labour (TPL) in gestational week 33 + 6 days to 37 + 0 days were studied prospectively with procedures including foetal heart rate monitoring, vaginal examination, ultrasound examination and blood tests to determine allopregnanolone, progesterone and oxytocin levels. The GABA receptor function in both groups was measured with a saccadic eye velocity test (SEVT).
RESULTS
Plasma oxytocin levels were higher in the TPL group than in the control group (41.5 vs. 37.0 pmol/L, respectively, = .021). Although the allopregnanolone and progesterone levels in both groups did not differ, there was a negative association between blood oxytocin and allopregnanolone (as predictor) levels in the TPL group (B: -3.2, 95% confidence interval (CI): -5.5 to -0.9, = .012). As a predictor of TPL, progesterone was associated with cervix maturity (odds ratio: 1.02, 95% CI: 1.00-1.04, = .038). SEVT showed that the women in both groups had similar GABA receptor functions. In both groups, body mass index correlated with peak saccadic eye velocity ( = .34, = .044) and negatively with allopregnanolone ( = -.41, = .013).
CONCLUSIONS
Neurosteroid levels were unchanged in the peripheral blood of women with TPL, despite the increase in available oxytocin. Although the function of the GABA receptor was unchanged in women with TPL, to ensure reliable results, saccadic eye velocity should be investigated during a challenge test with a GABA receptor agonist.
Topics: Adolescent; Adult; Biomarkers; Body Mass Index; Brain; Female; Humans; Male; Obstetric Labor, Premature; Oxytocin; Pregnancy; Pregnanolone; Progesterone; Receptors, GABA-A; Risk; Saccades; Young Adult
PubMed: 33855217
DOI: 10.1002/edm2.216 -
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 -
The Journal of Steroid Biochemistry and... Jun 2016The hypothalamo-pituitary-adrenal (HPA) axis plays a critical role in regulating responses to stress and long term dysregulation of the HPA axis is associated with... (Review)
Review
The hypothalamo-pituitary-adrenal (HPA) axis plays a critical role in regulating responses to stress and long term dysregulation of the HPA axis is associated with higher rates of mood disorders. There are circumstances where the HPA axis is more or less responsive to stress. For example, during late pregnancy ACTH and corticosterone responses to stress are markedly suppressed, whereas in offspring born to mothers that experienced repeated stress during pregnancy, the HPA axis is hyper-responsive to stress. Neuroactive steroids such as allopregnanolone, tetrahydrodeoxycorticosterone (THDOC) and androstanediol can modulate HPA axis activity and concentrations of some neuroactive steroids in the brain are altered during pregnancy and following stress. Thus, here altered neurosteroidogenesis is proposed as a mechanism that could underpin the dynamic changes in HPA axis regulation typically observed in late pregnant and in prenatally stressed individuals. In support of this hypothesis, evidence in rats demonstrates that elevated levels of allopregnanolone in pregnancy induce a central inhibitory opioid mechanism that serves to minimize stress-induced HPA axis activity. Conversely, in prenatally stressed rodents, where HPA axis stress responses are enhanced, evidence indicates the capacity of the brain for neurosteroidogenesis is reduced. Understanding the mechanisms involved in adaptations in HPA axis regulation may provide insights for manipulating stress sensitivity and for developing therapies for stress-related disorders in humans.
Topics: Animals; Brain; Female; Humans; Hypothalamo-Hypophyseal System; Neurotransmitter Agents; Pituitary-Adrenal System; Pregnancy; Pregnanolone; Stress, Physiological
PubMed: 26259885
DOI: 10.1016/j.jsbmb.2015.08.003