Disfiguring skin diseases refer to skin diseases that significantly affect one's appearance. The development of disfiguring skin diseases is multifactorial, such as genetic, immune, and endocrine factors. However, recent research suggests that emotional distress (such as anxiety, depression, and sleep disorders) has been implicated as a key contributing factor to the onset and progression of disfiguring skin diseases, including acne, rosacea, and vitiligo; in turn, the psychosocial burden imposed by these conditions exacerbates emotional disturbances, thereby creating a self-perpetuating vicious cycle. Therefore, understanding the relationship between emotional distress and disfiguring skin diseases is essential. In recent years, the proposed concept of the "brain-skin axis" has framed the nervous, endocrine, and immune systems as an intricate regulatory network, highlighting the multilayered connections between the brain and the skin. Within the mechanistic framework of the brain-skin axis, emotional distress may alter neural and endocrine signaling, potentially disrupt normal skin homeostasis, exacerbate inflammatory responses and immune dysregulation, and impair skin barrier function; based on experimental and observational evidence, these changes may elevate susceptibility to disfiguring skin diseases. In this review, we examined the complex relationship between emotional distress and three disfiguring skin diseases (acne, rosacea, and vitiligo) from the perspective of the brain-skin axis. We also discussed the potential value of various psychosomatic interventions, including psychotherapy, pharmacotherapy and integrated therapy in improving both dermatological symptoms and psychiatric comorbidities. Understanding the interactions and mechanisms linking emotional distress and disfiguring skin diseases through the lens of the brain-skin axis can provide new insights into the diagnosis and treatment of these skin conditions.
Aging and alcohol exert marked effects on the endocrine system - in particular the hypothalamic-pituitary-gonadal (HPG) and hypothalamic-pituitary-adrenal (HPA) axes. The aging female brain represents a unique substrate for alcohol effects, given that both the HPG and HPA undergo significant changes with aging in women, making this demographic notably different from both males and younger females. Little attention has been directed at alcohol effects in this group but changing trends in women's drinking have brought these issues to the forefront. Major gaps in our understanding of aging females include how stressors common to middle and older aged women impact alcohol consumption, and how alcohol consumption in older women impacts brain health and aging. Thus, here we review the current state of knowledge concerning the unique neuroendocrinology of aging females, their stressors and pharmacokinetic reactions to alcohol, and their interactions as causes and neurotoxic consequences of excessive alcohol drinking. We highlight the role of the neuroimmune system at the intersection of aging, alcohol and stress effects, and brain endocrine systems. We conclude that therapeutic interventions should be aimed at managing alcohol-induced neuroimmune responses and their downstream effects on vulnerable white matter. In addition, mid-life represents a window of opportunity in which to introduce strategies to limit alcohol consumption and its consequences for the aging female brain. As so little is known about how alcohol intake impacts brain health in females, let alone in aging females, we assert the need for further investigation of middle-aged and aged females in human and preclinical studies.
The neuropeptides orexin-A (OXA) and orexin-B (OXB), central orchestrators of arousal and energy homeostasis, are increasingly recognized as key neuromodulators within the vertebrate retina. This review synthesizes current evidence demonstrating a broad extra-hypothalamic expression of the orexin system across retinal neurons, including photoreceptors, bipolar (BCs), amacrine (ACs), and ganglion cells (GCs). We detail a sophisticated, cell-type-specific signaling framework where orexins exert complex, often antagonistic, presynaptic and postsynaptic actions via orexin 1 (OX1R) and orexin 2 (OX2R) receptors. These actions fine-tune signal transmission by potentiating glutamate release from BCs while suppressing GABAergic inhibition from ACs, ultimately modulating retinal output. A central theme emerging is the system's pivotal role in non-image-forming visual functions: OXA enhances the pupillary light reflex (PLR) by increasing the excitability of specific intrinsically photosensitive retinal ganglion cells (M2 ipRGCs), while OXB potentiates scotopic (dim-light) sensitivity by disinhibiting rod bipolar circuits. Furthermore, pharmacological inhibition of orexin receptors affects circadian rhythms in both the retina and hypothalamus. However, the field is marked by intriguing paradoxes, such as the stimulatory effects of receptor antagonists and significant species differences in OX2R expression. We critically evaluate evidence for a tonically active retinal orexin system that interfaces with dopaminergic signaling and circadian photic input. By integrating molecular, cellular, and behavioral findings, this review clarifies how retinal orexinergic modulation serves as a potential crucial interface between light detection, circadian physiology, and systemic arousal, while highlighting critical translational gaps and future research directions.
The skin functions as a neuro-immuno-endocrine organ with an extensive microbial interface capable of bidirectional signaling with the central nervous system. While the gut-brain axis is well established, the skin-microbiota-brain (SMB) axis remains underexplored, particularly with respect to affective symptom dimensions (depression, anxiety, stress) that commonly co-occur with chronic inflammatory dermatoses. This review synthesizes evidence across clinical, translational, and experimental studies and organizes it by strength (associational findings, mechanistic plausibility, and limited interventional signals). We outline a systems-level model in which cutaneous microbial dysbiosis is associated with brain-relevant pathways via immune, neuropeptide, and metabolic routes. Candidate mediators include cytokines (IL-6, IL-17, TNF-α), neuropeptides (e.g., substance P, CGRP), and microbial-derived metabolites (e.g., SCFA-like compounds and tryptophan catabolites). These signals are hypothesized to influence neuroimmune tone and neurovascular signaling based largely on broader systemic inflammation and stress biology; direct causal evidence specifically attributing affective outcomes to skin microbiome perturbations in humans remains limited. In parallel, top-down neuroendocrine signaling via hypothalamic-pituitary-adrenal (HPA) axis activation, cortisol-related signaling, and sympathetic outflow can alter skin barrier function, antimicrobial peptide expression, and microbial ecology, potentially contributing to symptom-maintaining loops (e.g., itch-sleep disruption-stress). Importantly, we consider counterarguments (psychosocial burden, reverse causality, treatment effects, and the localized nature of lesions) and identify research priorities required to test causality (longitudinal sampling, mechanistic biomarker panels, and preregistered interventional studies with affective endpoints and mediation analyses). By integrating dermatological, microbiological, and neuroimmunological evidence within a symptom-centered framework, the SMB axis is positioned as a biologically plausible but still evolving model that may help explain affective symptom burden in subsets of patients with inflammatory skin disease and guide mechanism-informed translational research.
Emerging evidence demonstrates that insulin has a modulating effect on metabolic and cognitive function in the brain, highlighting the potential role of aberrant brain insulin signaling in the pathogenesis of various neuropsychiatric illnesses. Neuroimaging paradigms using intranasal insulin (INI) as a pharmacological challenge have allowed us to study the effects of insulin in the human brain. In this scoping review, we conducted a systematic database search to identify relevant research studies that employed an INI-based neuroimaging assay of brain insulin signaling. Thirty-six studies met inclusion criteria for this review. INI was found to significantly modulate activity and cerebral blood flow in brain regions related to homeostatic/hedonic control of food intake, as well as cognition. This review highlights the putative role of insulin signaling in the brain and the potential therapeutic value of INI in patients with mental health, addiction, and co-morbid metabolic disorders.
Progesterone is a highly lipophilic gonadal hormone that can influence behavior and mental health through its receptors in the brain. Fluctuations in progesterone levels across critical periods of a females life are associated with increased susceptibility to mental conditions. This review highlights the effects of progestagens, including progesterone and synthetic progestins, on the brain, mood, stress, and cognition in females. The primary focus is on experimental pharmacological research that teases out the distinct effects of progestagens from those of estrogens. Additionally, the key literature on puberty, the menstrual cycle, pregnancy, perimenopause, hormonal contraceptives, and menopausal hormone therapy is reviewed, although conclusions are limited by the nested effects of progestagens and estrogens. Single study-findings suggest an influence of progesterone on amygdala reactivity related to processing of emotional stimuli and memory. In patients with premenstrual dysphoric disorder, progesterone receptor modulation improves premenstrual mood symptoms and potentially enhances fronto-cingulate control over emotion processing. The interaction between progestagens and the systems involved in the regulation of stress seems to influence subjective experiences of mood and stress. Sparse studies investigating the effects of progestin-only contraceptives suggest effects of progestagens on the brain, mood, and stress. Progesterone and progestins used for contraception can influence neural processes as myelination and neuroprotection, exerting protective effects against stroke. Concerning menopausal hormonal therapy, the effects of progestins are largely unknown. Levels of progesterone as well as type, administration route, timing, dose regimen, metabolism, and intracellular activity of progestins in hormonal contraceptives and menopausal hormonal therapy are factors whose effects remain to be elucidated. Altogether, current knowledge highlights the potential role of progestagens in females health but also calls for well-designed pharmaco-behavioral studies disentangling the effects of progestagens from those of estrogens.
The perinatal period is characterized by extreme shifts in hormones, neurochemistry, and life experiences that drive significant changes in the brain, known as maternal plasticity. Due to rising maternal health conditions, such as postpartum depression, there is a critical need to investigate factors, such as engagement in physical activity and exercise, that may mitigate susceptibility to maladaptive maternal plasticity. This scoping review aims to analyze exercise interventions and maternal brain outcomes during reproduction. A systematic search was completed in Medline, Embase, CINAHL, PsycINFO, SportDiscuss. The key concepts of the search were (i) brain plasticity, (ii) maternal reproductive period including pre-conception, pregnancy, and postpartum, and (iii) exercise interventions. Due to the limited amount of evidence available on this topic, the review findings were discussed using a combined scoping and narrative review approach. The search produced 2,167 unique articles after removing 2588 duplicates. Covidence software was used for the screening procedure. Following title and abstract screening, 2160 articles were deemed irrelevant and removed. Seven articles moved forward to full-text screening. One article was excluded during full-text screening for wrong outcomes, leaving six papers for extraction. Extraction revealed that four out of six studies were conducted in the rodent alone, one was conducted in humans alone and one was conducted in both a human and a rodent model. The methodological inconsistencies in the limited number of studies within this field highlight the need for standardization, which motivated the development of the Consensus on Exercise Reporting Template for animal research. Moreover, the present review highlights future directions and knowledge gaps, emphasizing the critical need for high-quality research to address the many unanswered questions regarding the impact of exercise on the maternal brain.
There is a lack of understanding of the neural mechanisms regulating the rewarding effects of social interactions. A significant contributor to this lack of clarity is the diversity of social behaviors and animal models utilized to investigate mechanisms. Other sources of the lack of clarity are the diversity of brain regions that can regulate social reward and the diversity of signaling pathways that regulate reward. To provide some clarity into the mechanisms of social reward, this review focused on the brain region most implicated in reward for multiple stimuli, the nucleus accumbens, and surveyed (systematically reviewed) studies that investigated the relationship between social interaction and five signaling systems implicated in the regulation of reward and social behavior: oxytocin, vasopressin, serotonin, opioids and endocannabinoids. Moreover, all of these studies were organized by the type of social behavior studied: affiliative interactions, play behavior, aggression, social defeat, sex behavior, pair-bonding, parental behavior and social isolation. From this survey and organization, this review concludes that oxytocin, endocannabinoids and mu-opioid receptors in the nucleus accumbens positively regulate the rewarding social behaviors, and kappa-opioid receptors negatively regulate the rewarding social behaviors. The opposite profile is observed for these signaling systems for the aversive social behaviors. More studies are needed to investigate the directional role of the serotonin system in the nucleus accumbens in the regulation of many types of social behaviors, and vasopressin likely does not act in the nucleus accumbens in the regulation of the valence of social behaviors. Many of these different signaling systems are also interdependent of one another in the regulation of different types of social behaviors. Finally, the interaction of these signaling systems with dopamine in the nucleus accumbens is briefly discussed.
As fundamental primary processes in maintaining the body's health, sleep and eating habits influence reciprocally, and this relationship is also modulated by circadian rhythms. Consistently, the literature reports various levels of alterations in sleep parameters and circadian preferences among individuals exhibiting dysfunctional eating behaviors. The present review aims to provide an up-to-date overview of case-control studies conducted to date on this topic. A systematic literature search was conducted to detect case-control studies investigating both subjective and objective sleep parameters and circadian preferences in individuals with eating disorders. Thirty-three articles published between 1980 and 2025 were included. Patients with eating disorders show reduced sleep efficiency, prolonged sleep onset latency, and increased arousal levels. Specifically, individuals with anorexia nervosa experience more frequent and longer nighttime awakenings, as well as reductions in both slow-wave sleep and REM sleep. In contrast, findings related to bulimia nervosa and binge eating disorder are quite inconsistent, partly due to the limited number of studies available. Overall, individuals with eating disorders tend to exhibit a preference for evening chronotypes. This review supports the existence of an association between eating disorders and alterations in sleep and circadian rhythms. Nonetheless, current research does not provide a consistent picture of the nature, characteristics, or causality of these dysfunctions. Several factors - such as body mass index, the severity of eating disorder symptoms, and orexin levels - appear to be involved. Further investigation into these relatively understudied areas could inform the development of more effective rehabilitation strategies.
Ischemic stroke involves two interrelated pathological processes: primary ischemic brain injury and secondary cerebral ischemia-reperfusion (CI/R) injury. This condition has become a global health issue; however, effective pharmacotherapies for ameliorating cerebral ischemia (CI) and CI/R injury remain critically lacking. Members of the vascular endothelial growth factor (VEGF) family, recognized as key signaling molecules, play pivotal roles in various physiological and pathological processes, including angiogenesis, neuroprotection, neuroinflammation, and vascular permeability. Recent studies have revealed that several members of the VEGF family may mitigate CI or CI/R injury through mechanisms such as promoting angiogenesis, inhibiting neuronal apoptosis, and counteracting neuroinflammation. Paradoxically, these molecules can also exacerbate ischemic and I/R-induced brain damage by promoting blood-brain barrier disruption and intensifying inflammatory responses post-stroke. This narrative review evaluates the dual roles of distinct VEGF family members in CI and I/R injury, focusing on elucidating their underlying mechanisms. The review aims to provide a theoretical framework for optimizing VEGF-targeted therapeutic strategies, thereby maximizing neuroprotective efficacy while minimizing adverse effects in stroke treatment.
Women exhibit greater nicotine use vulnerability than men. Common cessation treatments are less effective for women, suggesting unique contributors to women's smoking that are not fully characterized or targeted by available treatments. High estradiol is associated with enhanced smoking and cessation difficulty, whereas high progesterone is associated with reduced smoking and better cessation success. Hormonal contraceptives can produce similar or even outsized alterations in nicotine use outcomes. Despite clear effects of natural and synthetic sex steroid hormones on nicotine intake, the behavioral pathways by which hormones alter nicotine use outcomes remain unmapped. In this review paper, we propose that uncovering such mechanisms requires examining sex steroid hormone modulation of non-primary reinforcement factors in our animal models. Parallel effects of natural and synthetic sex steroid hormones on nicotine self-administration occur in animal models. Further, women's smoking is more influenced by environmental stimuli, such as the smell, taste, and visual cues associated with nicotine use than by the reinforcing effects of nicotine. In building our case, we first summarize research supporting the import of environmental factors in nicotine intake for women and translation to female rats. We also synthesize findings on how biological sex and sex steroid hormones influence these mechanisms in humans and rats. Lastly, we will detail promising directions for future research.
Acute cannabis exposure can transiently impair cognitive performance, increasing the risk of accidental injury and potentially disrupting activities of daily living. Although sex differences in responses to cannabis have been reported, no systematic review has examined whether these extend to acute cognitive effects. Our primary aim was to examine sex differences in the acute effects of cannabis (including isolated delta-9-tetrahydrocannabinol [THC]) on cognition in humans. Our secondary aim was to determine if sex differences in the acute effects of cannabis vary by cognitive domain, route of administration, or dosing paradigm. Following PRISMA guidelines, we conducted a comprehensive literature search across Embase, MEDLINE, APA PsycInfo, Cochrane Library, and Web of Science databases. Of 1,625 unique records, 169 underwent full-text screening, and 29 studies met inclusion criteria. Six of 29 articles (20.7 %), representing eight of 216 cognitive outcomes (3.7 %), found statistical evidence of sex differences in acute cognitive effects of cannabis/THC. All six found increased effects in female participants in at least one cognitive variable; one study additionally found increased effects in male participants, and one study found divergent cognitive effects in male and female participants. There were no clear patterns by cannabis dosing paradigm, route of administration, or cognitive domain. Overall, we found limited evidence that sex significantly influences the acute cognitive effects of cannabis, though methodological heterogeneity precludes any firm conclusions. Future studies should prioritize the measurement of sex-related factors, such as hormonal modulation of cannabinoid pharmacokinetics and pharmacodynamics.
Orexin-A and orexin-B are hypothalamic neuropeptides that coordinate arousal, metabolic, and reproductive functions through orexin receptor 1 (OX1R) and orexin receptor 2 (OX2R). This review synthesizes evidence from humans, experimental models, and domestic species to examine how orexin signaling modulates female physiology across the lifespan. Perinatally, orexin activation supports neonatal survival by stabilizing respiration, feeding, and sleep-wake organization. During puberty, orexins integrate metabolic and circadian cues to regulate gonadotropin-releasing hormone output and reproductive onset. In pregnancy and lactation, central and peripheral adaptations coordinate maternal metabolism, uteroplacental communication, and prolactin-dependent lactation. In aging, reduced orexin tone contributes to sleep fragmentation, metabolic dysregulation, and cognitive decline. Therapeutically, dual orexin receptor antagonists and intranasal orexin delivery illustrate stage-specific intervention strategies. Evidence across life stages derives from human, rodent, and large-animal models and must be interpreted within species-, sex-, and stage-specific biological constraints. Collectively, orexin signaling represents a conserved integrative network with health relevance.
Oxytocin (OXT) plays a significant role in regulating social behaviour across various species, making it a key focus in neuroscience. Recent research has expanded beyond the established prosocial effects of OXT to explore its complex interplay with dopamine (DA), a key regulator of both reward processing and social behaviour. DA influences these behaviours both independently and in coordination with OXT. Emerging evidence highlights how psychostimulants disrupt OXT-DA interaction, exacerbating maladaptive social behaviours. This narrative review synthesises findings from pharmacological, optogenetic, and chemogenetic studies to elucidate mechanistic insights into OXT-DA crosstalk in both healthy and drug-compromised social functioning. We examined OXT-DA interaction in non-reproductive social behaviours, such as social approach and aggression, as well as reproductive behaviours, including parental care, offspring attachment, and pair bonding, both in the presence and absence of drugs of abuse. Understanding OXT-DA interaction offers important insights into the neurobiological mechanisms underlying both healthy and pathological social functioning.
Perimenopause represents a critical phase during which women are particularly susceptible to depression. Although fluctuations in estrogen levels resulting from ovarian aging and imbalances in the gut microbiota have been identified as contributing factors to the onset of depression, the interplay among these elements is frequently overlooked. Fluctuations in estrogen levels can further influence neurogenesis or apoptosis through effects on neurotransmitter balance, neuroinflammation, neuroendocrine regulation, and mitochondrial function. Meanwhile, dramatic shifts in estrogen levels can diminish microbial diversity and stability, thereby disrupting the homeostasis of metabolites and neurotransmitters via the gut-brain axis (GBA). Such disturbances may induce neuroinflammation, potentially leading to or exacerbating depressive symptoms. Additionally, the estrobolome (gut bacterial genes encoding estrogen-metabolizing enzymes) plays a regulatory role in the reabsorption, excretion, and systemic levels of estrogen through the modulation of β-glucuronidase activity, thereby affecting estrogen homeostasis. This review first examines the influence of fluctuations in estrogen levels on the composition and function of the gut microbiota, as well as the role of the gut microbiota in estrogen metabolism. It then discusses how estrogen deficiency and dysbiosis of the gut microbiota contribute to the pathogenesis of perimenopausal depression, discussing the potential for a vicious cycle mediated by the estrogen-gut microbiota axis that increases susceptibility to this condition. Finally, this review presents bioactive compounds derived from dietary sources or medicinal plants that exhibit estrogenic and prebiotic properties, which may offer diverse strategies for the prevention and management of perimenopausal depression through modulation of the estrogen-gut microbiota axis.
Schizophrenia spectrum disorders (SSD) are characterized by alterations in cortisol levels across various parameters, including stress reactivity, hair cortisol, and baseline levels, which may be influenced by antipsychotic treatment. To provide a comprehensive overview of cortisol dysregulation in SSD, we conducted meta-analyses assessing (1) the effects of antipsychotic treatment in SSD patients, and additionally comparing cortisol in SSD patients versus healthy controls (HC) (2) following stress induction (metabolic, physiological, psychological stressors), (3) in hair and (4) baseline levels. Systematic literature searches in PubMed, Web of Science, and PsycINFO (November 2024) identified 121 studies (9049 SSD patients) for inclusion. Meta-analytic results revealed that antipsychotic treatment significantly reduced cortisol levels in SSD (k = 16, g = -0.480, 95 % CI [-0.818, -0.142], p = 0.005). Additionally, compared to HC, SSD was associated with reduced cortisol suppression following dexamethasone exposure (k = 9, g = 0.299, 95 % CI [0.091, 0.507], p = 0.005) and with elevated baseline cortisol levels in the morning (k = 71, g = 0.38, 95 % CI [0.210, 0.546], p < 0.001) and evening (k = 11, g = 0.368, 95 % CI [0.076, 0.661], p = 0.014). However, there were no significant group differences in afternoon baseline cortisol, hair cortisol or cortisol reactivity to stress (p > 0.05). These findings offer a detailed understanding of cortisol alterations in SSD and improve our understanding of HPA axis dysregulation in SSD.
Developmental transdiagnostic externalizing problems-including harmful substance use, conduct issues, oppositional-defiance, and ADHD-related hyperactivity-impulsivity-have significant societal impacts, contributing to high costs in areas such as incarceration, delinquency, unemployment, and relationship challenges. These issues also exhibit notable sex differences: males tend to show higher prevalence, while females, though less affected overall, often face more severe outcomes. Despite these public health and personal costs, research on externalizing problems in females remains limited, particularly regarding the biological and hormonal factors driving these sex differences. The current paper explores how female hormonal influences across developmental stages may affect externalizing behaviors, highlighting the role ovarian hormones may play in shaping these externalizing problems. During puberty, estradiol and progesterone shifts contribute to risk-taking behaviors in females, who show distinct vulnerability patterns from males. Other important and understudied reproductive periods include puberty, pregnancy and postpartum, and perimenopause and menopause, and the menstrual cycle, overall. However, most population-level studies overlook the role of ovarian hormone fluctuations. This review advocates for the integration of hormonal phases in assessments, as hormonal shifts may exacerbate symptoms or modify treatment responses. Cycle-aligned interventions and hormone stabilization strategies could improve treatment outcomes, addressing gaps in male-focused treatment models and enhancing care for females with these disorders.
Huntington's disease (HD) is increasingly recognized as a multisystem disorder in which perturbations of the gut microbiota may influence peripheral homeostasis and shape central neurodegeneration. Across human cohorts, HD is marked by reproducible β-diversity shifts, loss of butyrate-producing taxa, and disruptions in bile-acid and tryptophan-derived metabolites, indicating broad remodeling of microbiota-host metabolic interfaces. Integrating metabolomic evidence with mechanistic data from HD models, we delineate three convergent axes through which dysbiosis may modify disease biology: (i) short-chain fatty acids driven histone deacetylases and G-protein-coupled receptors pathways that impact transcriptional regulation and gut-brain endocrine signaling; (ii) bile acids dependent FXR/TGR5 circuits that couple metabolic stress to neuroinflammatory and mitochondrial vulnerability; and (iii) microbiota-regulated tryptophan metabolism, encompassing serotonin/melatonin rhythms, indole- aryl hydrocarbon receptor immunomodulation, and kynurenine-pathway neurotoxicity. Finally, we evaluate microbiota-targeted therapeutic strategies across these pathways and discuss their translational potential alongside central nervous system directed HTT-lowering approaches.
Hair cortisol concentration (HCC) is a crucial biomarker in psychoneuroendocrinological research, offering unique insights into long-term hypothalamic-pituitary-adrenal axis activity. Season has repeatedly shown associations with HCC. However, as of yet, no systematic attempt at quantifying season's influence on HCC has been undertaken. We conducted a systematic search of the bibliographic databases PubMed and PsycINFO. Twenty-nine between- and within-person studies fulfilled all eligibility criteria (N = 10,520 participants in total). Overall, 22 studies (76%) reported significant differences in HCC across seasons. Most between-personstudies reported lower HCC in winter/spring than in summer/autumn (10/15). This pattern was supported by 2/14 within-person studies, whereas others reported lower HCC in summer than in autumn (6/14). The remaining studies reported other patterns or no seasonal variations in HCC. In conclusion, there is accumulating evidence for seasonal variations in HCC, highlighting the need to consider the seasons in future research on HCC and health. Mechanisms related to meteorological, ecological, sociocultural, and lifestyle factors may underlie seasonal rhythmicity in cortisol secretion and accumulation in hair.
The thyroid-gut axis is a bidirectional system linking maternal endocrine function and gut microbiota, with important implications for fetal brain development. During pregnancy, maternal thyroid hormones (thyroxine and triiodothyronine) regulate neuronal growth, migration, myelination, and synapse formation. Maternal hypothyroidism, even in mild forms, can disrupt these processes, impairing neurogenesis, cortical development, and long-term cognitive outcomes in offspring. At the same time, maternal gut microbiota undergoes dynamic changes that influence thyroid hormone balance, nutrient absorption, and immune signaling through metabolites such as short-chain fatty acids, bile acids, and tryptophan derivatives. Dysbiosis may alter deiodinase activity, weaken intestinal barrier integrity, and promote inflammation, worsening thyroid dysfunction and increasing fetal vulnerability. Evidence suggests a feedback loop where microbiota affects thyroid homeostasis and thyroid hormones shape gut ecology. Emerging research indicates that microbiota-targeted therapies, diet, and environmental interventions may help restore balance, though key mechanistic gaps remain.