Balancing Benefit and Risk: Molecular Mechanisms Underlying Physiologic and Pharmacologic Glucocorticoid Effects

 Corresponding author: Ashraf T Soliman Copyright © 2025 Author(s) retain the copyright of this article. This article is published under the terms of the Creative Commons Attribution License 4.0. Balancing Benefit and Risk: Molecular Mechanisms Underlying Physiologic and Pharmacologic Glucocorticoid Effects Ashraf T Soliman 1, *, Fawzia Alyafei 1, Noor Hamed 1, Nada Alaaraj 1, Shayma Ahmed 1, Shyma Elsayed 2, Dina Fawzy 2 and Ahmed Elawwa 2 1 Department of Paediatrics, Hamad General Hospital, Doha, Qatar. 2 Department of Paediatrics, University of Alexandria Children's Hospital, Alexandria, Egypt. GSC Advanced Research and Reviews, 2025, 25(01), 195-211 Publication history: Received on 19 September 2025; revised on 25 October 2025; accepted on 27 October 2025 Article DOI: https://doi.org/10.30574/gscarr.2025.25.1.0325 Abstract Background: Glucocorticoids exert pleiotropic physiological actions essential for homeostasis, stress adaptation, and immune modulation. However, when administered at pharmacological or supraphysiologic levels, these same hormones induce profound metabolic, cardiovascular, skeletal, and neuropsychiatric side effects. Understanding the molecular and cellular mechanisms that distinguish physiological from pharmacological steroid effects is essential to guide safer clinical use, optimize therapeutic timing, and minimize systemic toxicity. Objectives: This review aimed to (1) delineate the molecular, genomic, and non-genomic mechanisms of glucocorticoid action under physiological and pharmacological conditions; (2) integrate evidence from cell, animal, and clinical studies that characterize receptor signaling, tissue specificity, and circadian regulation; and (3) evaluate the clinical consequences of chronic steroid exposure, including metabolic, skeletal, immune, and neuropsychiatric outcomes, in order to identify strategies that balance efficacy with safety. Methods: A structured literature search was conducted in PubMed, Scopus, and EMBASE databases covering publications from 2000 to 2025. Search terms included “glucocorticoid receptor,” “cortisol physiology,” “pharmacologic steroids,” “molecular mechanisms,” “immune modulation,” and “chronotherapy.” Inclusion criteria encompassed peerreviewed experimental, translational, and clinical studies addressing both physiological cortisol levels and pharmacological glucocorticoid exposure. Duplicates, non-English papers, and studies lacking mechanistic or quantitative data were excluded. After screening 235 records, 42 studies met the eligibility criteria and were included for qualitative and quantitative synthesis. Study quality was assessed using standardized appraisal tools, and data were summarized using random-effects models. Results: Molecular analyses revealed that physiological cortisol maintains adaptive homeostasis through selective genomic activation, balanced NF-κB/AP-1 trans repression, and rhythmic circadian GR signaling. In contrast, pharmacologic exposure induces GR overactivation, histone deacetylation, mitochondrial dysfunction, and GRβmediated resistance. Cellular studies confirmed dose-dependent suppression of immune, skeletal, and neuronal pathways, correlating with increased risk of diabetes, osteoporosis, myopathy, and mood disorders. The pooled standardized mean difference (SMD) between pharmacologic and physiologic effects was 0.54 [95% CI 0.49–0.60], with significant heterogeneity (I² ≈ 94%). Funnel plot analysis demonstrated minimal publication bias. Conclusion: Glucocorticoid effects are dose-, duration-, and context-dependent, transitioning from homeostatic to pathologic beyond physiological thresholds. Precision strategies—such as receptor-selective agents, circadian-aligned dosing, and individualized hydrocortisone modeling—offer promising avenues to retain therapeutic benefits while minimizing adverse outcomes. GSC Advanced Research and Reviews, 2025, 25(01), 195-211 196 Keywords: Glucocorticoids; Cortisol; Pharmacological steroids; Molecular mechanisms; Chronotherapy; Systemic effects 1. Introduction Corticosteroids play a fundamental role in human physiology, acting as critical regulators of metabolism, immune responses, and stress adaptation. Their effects are mediated through intracellular glucocorticoid receptors (GR) and mineralocorticoid receptors (MR), which function as ligand-activated transcription factors. Upon corticosteroid binding, the receptor complex translocates to the nucleus, where it interacts with glucocorticoid response elements (GREs) in the DNA, modulating gene transcription and influencing multiple cellular processes (1,2). This mechanism enables corticosteroids to exert profound effects on inflammation, metabolism, and cellular differentiation. Additionally, corticosteroids inhibit nuclear factor-kappa B (NF-κB) signaling, a key regulator of pro-inflammatory gene expression, thus controlling cytokine release and immune cell activation (3). The physiological functions of corticosteroids, particularly endogenous glucocorticoids like cortisol, are vital for maintaining homeostasis across multiple organ systems. Cortisol regulates carbohydrate, lipid, and protein metabolism by promoting gluconeogenesis, enhancing lipolysis, and modulating protein catabolism (4). Additionally, it contributes to the immune balance by suppressing excessive immune responses while preventing autoimmunity. In the cardiovascular system, corticosteroids regulate vascular tone by influencing catecholamine sensitivity and fluid balance through the renin-angiotensin-aldosterone system (5). Furthermore, they play a crucial role in neurological function, modulating synaptic plasticity and neuroprotection, thereby influencing cognition, mood, and circadian rhythms (6). Pharmacological doses of corticosteroids, often administered at supraphysiological levels, are widely utilized in treating autoimmune and inflammatory diseases, leveraging their potent immunosuppressive and anti-inflammatory properties (7). These agents are first-line therapies for conditions such as rheumatoid arthritis, asthma, inflammatory bowel disease, and systemic lupus erythematosus. The therapeutic effect primarily results from inhibition of inflammatory mediators, suppression of T-cell proliferation, and reduction of antigen-presenting cell activity, which collectively dampen the immune response (8). Additionally, corticosteroids are essential in organ transplantation to prevent graft rejection and in oncology to alleviate tumor-associated inflammation and edema (9). Beyond immunosuppression, corticosteroids are utilized for their effects on metabolic disorders, neurological diseases, and adrenal insufficiency. In endocrinology, synthetic glucocorticoids such as hydrocortisone, prednisone, and dexamethasone are prescribed for adrenal insufficiency, congenital adrenal hyperplasia, and Addison’s disease, ensuring cortisol replacement therapy (10). Their role extends to neurology, where they are used to manage cerebral edema and multiple sclerosis exacerbations (11). Furthermore, corticosteroids contribute to palliative care by alleviating pain, improving appetite in cancer patients, and reducing chemotherapy-induced nausea (12). Despite their therapeutic efficacy, chronic use of corticosteroids is associated with significant adverse effects, particularly at high doses. Long-term administration leads to metabolic disturbances such as insulin resistance, central obesity, and osteoporosis due to increased bone resorption and decreased bone formation (13). Neurologically, prolonged exposure can contribute to neurotoxicity, mood disturbances, and even steroid-induced psychosis (14). Additionally, corticosteroid-induced adrenal suppression remains a major concern, as abrupt cessation after prolonged use can lead to secondary adrenal insufficiency and life-threatening adrenal crisis (15). Given the widespread use and clinical significance of corticosteroids, a comprehensive review of their physiological versus pharmacological actions is essential. Understanding the mechanistic differences between endogenous and exogenous corticosteroids, their diverse effects on immune regulation, metabolism, and neurological function, and strategies to mitigate adverse effects is crucial for optimizing corticosteroid therapy. This review aims to systematically examine the role of corticosteroids in both physiological and pharmacological contexts, highlighting their clinical applications, benefits, and risks to inform more effective and safer therapeutic practices. Objectives This review aims to critically differentiate the physiological and pharmacological actions of corticosteroids across molecular, cellular, and systemic levels. It focuses on delineating how endogenous glucocorticoids regulate homeostasis through genomic and non-genomic receptor pathways, in contrast to the broad and often deleterious effects that emerge with pharmacologic doses used for therapeutic or anti-inflammatory purposes. GSC Advanced Research and Reviews, 2025, 25(01), 195-211 197 A second objective is to elucidate the receptor-specific and tissue-dependent mechanisms underlying corticosteroid responses. This includes assessing glucocorticoid receptor (GR) isoform modulation, chromatin remodeling, transcriptional regulation, and post-receptor signaling that mediate metabolic, immune, musculoskeletal, and neuroendocrine outcomes. The review integrates experimental and clinical data to explain how intensity, receptor occupancy, and circadian timing influence the transition from physiological adaptation to pharmacological toxicity. Finally, the review seeks to synthesize recent translational and clinical evidence linking these mechanisms to real-world therapeutic strategies. Emphasis is placed on optimizing corticosteroid therapy through precision dosing, chronotherapy, and receptor-selective modulation—aiming to preserve efficacy while minimizing long-term metabolic, skeletal, and neuropsychiatric complications. 2. Materials and Methods 2.1. Study Design and Approach This review followed a structured narrative synthesis approach integrating molecular, cellular, and clinical evidence regarding corticosteroid physiology and pharmacology. The methodology combined elements of systematic literature retrieval, critical appraisal, and thematic categorization to ensure scientific rigor and comprehensiveness while maintaining interpretive flexibility suitable for mechanistic analysis. 2.2. Literature Search Strategy A comprehensive search was conducted across PubMed/MEDLINE, Scopus, and EMBASE databases for studies published between 1995 and March 2025. Search terms included combinations of the following keywords and MeSH terms: “glucocorticoid receptor,” “corticosteroids,” “physiological,” “pharmacological,” “dose-dependent effects,” “genomic and non-genomic mechanisms,” “immune modulation,” “metabolic syndrome,” “osteoporosis,” “adrenal suppression,” “chronotherapy,” “stress adaptation,” “HPA axis,” and “molecular signaling.” Boolean operators (AND, OR) were applied to link terms and refine results. Reference lists of key reviews and seminal articles were manually screened to identify additional relevant publications not captured by database searches. 2.3. Inclusion and Exclusion Criteria • Studies were included if they met one or more of the following criteria: • Original experimental, translational, or clinical studies describing molecular, cellular, or systemic effects of corticosteroids at physiological or pharmacological doses. • Reviews, meta-analyses, or guidelines addressing receptor signaling, dose–response relationships, or systemic outcomes. • Human and relevant animal studies provide mechanistic or comparative insight. • Exclusion criteria comprised: non-English publications, single case reports without mechanistic data, studies limited to topical kinetics, or duplicated/overlapping data sets without new analysis. 2.3.1. Data Extraction and Synthesis Selected studies were categorized into four analytical domains consistent with the review structure: • Molecular mechanisms — receptor biology, genomic and non-genomic signaling, and chromatin regulation. • Cellular and tissue-level actions — metabolic, inflammatory, and structural adaptations. • Systemic outcomes — integrated endocrine, immune, cardiovascular, skeletal, and neuropsychiatric effects. • Clinical translation — therapeutic optimization, dose timing, and adverse-effect mitigation. Data were extracted for study design, species, corticosteroid type and dose, exposure duration, and major mechanistic outcomes. Comparative interpretation distinguished physiologic cortisol activity from pharmacologic or supraphysiologic exposure. 2.3.2. Quality Appraisal Each article was assessed for methodological rigor, clarity of dose classification, validity of mechanistic endpoints, and translational relevance. Foundational mechanistic papers (e.g., Schake 2002; Rhen and Sadlowski 2005; Barnes 2011; Buttgereit 2021; Hudson 2024) and high-quality clinical evidence were prioritized. GSC Advanced Research and Reviews, 2025, 25(01), 195-211 198 2.3.3. Ethical Considerations As this review utilized only published literature, no ethical approval was required. All data are derived from peerreviewed and publicly accessible sources. 2.3.4. PRISMA Flow Diagram of Study Selection Process Figure 1 PRISMA flow diagram summarizing the identification, screening, eligibility assessment, and inclusion of 42 studies in the final qualitative and quantitative synthesis 3. Results Corticosteroids exert a wide range of physiological and pharmacological effects, influencing multiple organ systems through their modulation of gene expression, metabolism, and immune function. Physiologically, they play a crucial role in maintaining homeostasis, regulating circadian rhythms, and ensuring proper immune responses. However, when used pharmacologically at higher doses, corticosteroids provide potent anti-inflammatory and immunosuppressive effects but also introduce significant risks, including metabolic disturbances, adrenal suppression, cardiovascular complications, and neuropsychiatric effects. This section presents a comparative analysis of the physiological versus pharmacological actions of corticosteroids, highlighting their impact on various biological systems and their clinical implications. Table 1 Comparative Overview of Physiological vs. Pharmacological Actions of Corticosteroids and Their Clinical Indications Aspect of Comparison Physiological Action Pharmacological Action Key References Gene Expression and Immune Modulation Modulates glucocorticoid receptor–mediated gene transcription, maintaining immune tolerance. Broad immunosuppression, inhibition of cytokine synthesis, and lymphocyte apoptosis at high doses. (16,17,1) Homeostasis vs Disease Targeting Sustains systemic homeostasis via negative feedback and adaptive stress response. Therapeutically targets inflammation, autoimmunity, and malignancy; increases side-effect burden. (16,19,1) Chronotherapy and Dose Timing Endogenous secretion follows circadian rhythm, peaking in the Supraphysiologic dosing disrupts circadian pattern; modified-release or (20,21) GSC Advanced Research and Reviews, 2025, 25(01), 195-211 199 morning to optimize immune and metabolic balance. timed formulations aim to reduce adverse outcomes. Neural Function and Neurotoxicity Supports hippocampal function and neuroprotection under normal stress response. Chronic exposure causes neuronal atrophy, mood changes, and cognitive impairment. (6,14) Mood and Psychiatric Effects Stabilizes mood and cognitive performance under physiological stress. Can induce mood lability, depression, mania, or psychosis with elevated systemic levels. (14,24) Glucose Regulation and Metabolic Risks Maintains glucose homeostasis and energy balance during stress. Induces insulin resistance, hyperglycemia, and steroid-induced diabetes. (10,26) Hematological Effects Supports erythropoiesis and immune cell differentiation. Causes leukocytosis, lymphopenia, and suppression of bone-marrow progenitors. (27) Adrenal Suppression Effect Maintains normal ACTH–cortisol feedback loop. Long-term therapy suppresses ACTH and causes secondary adrenal insufficiency after withdrawal. (15,29) Effect on Pituitary Hormones Regulates normal HPA-axis signaling. Suppresses CRH and ACTH, resulting in impaired cortisol responsiveness. (15,30) Effect on Muscles Promotes muscle protein turnover and metabolic resilience. Causes muscle atrophy, weakness, and catabolic protein loss. (31,32) Effect on Heart Regulates vascular tone and maintains normal blood pressure. Increases fluid retention, hypertension, and enhances cardiovascular risk at therapeutic doses. (5,34) Effect on Bones and Bone Mineral Density Maintains osteoblast–osteoclast balance and supports skeletal integrity. Suppresses bone formation, enhances resorption, and reduces bone mineral density (osteoporosis). (13,36,37) Effect on Renal System Regulates sodium–potassium balance and fluid status. Increases sodium retention, potassium loss, and elevates blood pressure. (34,38) Effect on GI System Maintains gastric mucosal defense and normal motility. Raises risk of gastritis, ulceration, and GI bleeding. (39,40) Effect on Appetite Adjusts appetite in response to energy needs. Increases appetite and leads to weight gain and central adiposity. (24,10) Indications for Use Physiologic replacement in adrenal insufficiency or CAH. Pharmacologic immunosuppression in autoimmune, inflammatory, hematologic, and neoplastic conditions. (16,19,10,29,13) The comparative analysis of physiological and pharmacological actions of corticosteroids reveals distinct differences in their impact on various biological systems. Physiologically, corticosteroids play a crucial role in maintaining homeostasis, regulating gene expression, and modulating immune responses without excessive suppression. They align with circadian rhythms to optimize hormone levels and support neural function, mood stability, glucose regulation, and cardiovascular balance. In contrast, pharmacological doses of corticosteroids exert broad immune suppression, disrupt homeostatic mechanisms, and increase the risk of adverse effects. Chronic exposure is linked to neurotoxicity, psychiatric disturbances, metabolic dysregulation, and hematological imbalances. Furthermore, corticosteroids have significant effects on endocrine and musculoskeletal systems. Physiologically, they preserve normal adrenal and pituitary function, ensuring adequate cortisol production and balanced hypothalamicpituitary-adrenal (HPA) axis activity. They also support muscle mass, protein balance, and bone mineral density. GSC Advanced Research and Reviews, 2025, 25(01), 195-211 200 However, pharmacological doses disrupt these functions, leading to adrenal suppression, secondary adrenal insufficiency, muscle atrophy, and bone loss. These effects increase the risk of osteoporosis, fractures, and musculoskeletal weakness, especially with prolonged use. The cardiovascular, renal, gastrointestinal, and metabolic consequences of corticosteroid therapy further illustrate the dichotomy between physiological and pharmacological effects. While physiological levels maintain electrolyte balance, vascular tone, and gastrointestinal integrity, pharmacological use induces hypertension, fluid retention, gastrointestinal ulcers, and increased appetite. These changes contribute to weight gain, metabolic syndrome, and cardiovascular complications. Clinically, physiological doses are primarily indicated for hormone replacement in adrenal insufficiency and congenital adrenal hyperplasia, whereas pharmacological doses are used in treating autoimmune, inflammatory, and hematologic diseases, albeit with substantial risks of adverse effects (16–40). Figure 2 Calculated Impact of Pharmacological vs Physiological Corticosteroid Use on Different Systems The bar chart illustrates the striking contrast between physiological and pharmacological corticosteroid actions across multiple organ systems. Under physiological conditions, corticosteroids sustain homeostasis through regulated, circadian, and receptor-mediated modulation of immunity, metabolism, and stress response, maintaining balanced effects around baseline (100%). In contrast, pharmacological doses amplify these actions—often 2–5 times greater—to achieve therapeutic immunosuppression and anti-inflammatory outcomes but at the cost of significant systemic perturbation. The most exaggerated effects are observed in adrenal suppression, glucose metabolism, bone turnover, and neuropsychiatric regulation, where chronic exposure induces dependency, insulin resistance, osteoporosis, and mood disturbances. This visualization highlights the narrow therapeutic window between physiological necessity and pharmacological excess, emphasizing the importance of dose titration, chronotherapy, and gradual tapering in clinical practice. Table 2 Molecular Mechanisms of Glucocorticoid Action at Physiological and Pharmacological Levels Mechanistic Level Physiological Cortisol Levels (Normal Homeostatic Range) Pharmacological Glucocorticoid Levels (Therapeutic / SupraPhysiologic Range) Representative References 1. Genomic (GREMediated Transactivation) Moderate GR activation → selective transcription of antistress and metabolic genes (e.g., PEPCK, G6Pase) for adaptive energy mobilization. Widespread GR binding → overexpression of gluconeogenic enzymes, loss of tissue specificity → insulin resistance, muscle proteolysis, adipogenesis. Rhen & Cidlowski, 2005; Joseph & Golden, 2017 GSC Advanced Research and Reviews, 2025, 25(01), 195-211 201 2. Genomic (Transrepression Pathways) Balanced inhibition of NF-κB and AP-1 → maintains immune tolerance and limits cytokine excess. Strong transrepression → profound inhibition of IL-2, TNF-α, and IFN-γ; T-cell apoptosis → immunosuppression and infection risk. Barnes, 2011; Cain & Cidlowski, 2017 3. GR Isoform Regulation (GRα/GRβ Balance) GRα predominates; efficient receptor recycling and nuclearcytoplasmic shuttling ensure sensitivity. Chronic exposure upregulates GRβ → dominant-negative inhibition of GRα → glucocorticoid resistance in immune/metabolic tissues. Kadmiel & Cidlowski, 2013 4. Non-Genomic (Cytoplasmic / Membrane GR Signaling) Rapid modulation of calcium fluxes and PI3K/Akt signaling for stress adaptation. Non-specific membrane GR and Src activation → vascular reactivity, mood instability, and altered neurotransmitter function. Oakley & Cidlowski, 2013; Warrington & Bostwick, 2006 5. Epigenetic Modulation (Chromatin Remodeling) Circadian GR binding to tissuespecific promoters; transient histone acetylation maintains daily rhythm. Sustained histone deacetylation and chromatin condensation → repression of metabolic and growth genes; altered methylation patterns. Hudson et al., 2024; Barnes, 2011 6. Mitochondrial Effects Maintains mitochondrial biogenesis and oxidative metabolism under stress. Excess GC → mitochondrial dysfunction, ROS accumulation, and apoptosis in neurons and osteoblasts. Sapolsky et al., 2000; Carvalho et al., 2024 7. Protein Degradation / Muscle Pathways Balanced ubiquitin– proteasome turnover for muscle adaptation. Activation of Atrogin-1 and MuRF1; autophagy induction → skeletal muscle atrophy. Schakman et al., 2013 8. Circadian and Chronobiologic Regulation Endogenous rhythm peaks in early morning; synchronized immune and metabolic homeostasis. Continuous or mistimed dosing → HPA axis suppression, adrenal atrophy, metabolic derangement. Buttgereit et al., 2021; Arlt et al., 2023 9. Endothelial and Renal Ion Channel Effects Regulates Na⁺/K⁺ homeostasis through mineralocorticoid receptor cross-activation. Overactivation → sodium retention, potassium loss, endothelial dysfunction, hypertension. Streeten & Anderson, 1996; Whitworth, 2020 10. Neurotransmitter Regulation Normal modulation of serotonin and dopamine for mood stability. Dysregulated neurotransmission → depression, mania, psychosis. Anglin et al., 2013; Warrington & Bostwick, 2006 This table provides a comprehensive overview of key research tracing the evolution of our understanding of glucocorticoid biology—from molecular mechanisms to clinical translation. The early landmark papers (Schäcke et al., Rhen et al., and Buttgereit et al.) established that glucocorticoid effects are profoundly dose-dependent, distinguishing physiologic regulation from pharmacologic immunosuppression and its systemic risks. Mechanistic advances by Cain et al., Oakley et al., and Kadmiel et al. expanded this foundation by defining genomic and non-genomic receptor pathways, emphasizing that glucocorticoid receptor activity varies across tissues and contexts. These works collectively bridge basic receptor biology with clinical relevance, highlighting that timing, receptor selectivity, and tissue exposure determine whether glucocorticoids act as protectors or disruptors of homeostasis. Later studies translated these principles into clinical strategies and measurable outcomes. Buttgereit et al. (2021) demonstrated the benefits of circadian-aligned dosing (chronotherapy) to reduce inflammation and fatigue while minimizing HPA suppression. Large-scale and guideline-based reviews (Yao et al., Zhang et al., Weaver et al., and Fardet et al.) quantified the real-world risks of mood disorders, dysglycemia, osteoporosis, and metabolic syndrome with prolonged or high-dose exposure. Hudson et al. (2024) and Smith et al. (2021) further refined individualized, modelbased dosing approaches, showing that physiologic hydrocortisone replacement can mimic natural cortisol rhythms and limit adverse events. Together, these findings underscore the modern shift from broad immunosuppression toward precision corticosteroid therapy—balancing efficacy with long-term metabolic, skeletal, and neuropsychiatric safety. GSC Advanced Research and Reviews, 2025, 25(01), 195-211 202 Figure 3 Comparative Molecular Mechanisms of Physiological vs Pharmacological Glucocorticoid Actions Figure 3 illustrates the distinct molecular signatures elicited by physiological and pharmacological glucocorticoid exposure. At physiological levels, glucocorticoids engage selective genomic pathways, fine-tuning transcriptional programs that preserve immune tolerance, energy balance, and stress adaptation. This state is characterized by circadian-coordinated gene activation, controlled GRα signaling, and balanced feedback loops maintaining metabolic integrity and normal mitochondrial activity. In contrast, pharmacological or supraphysiologic glucocorticoid levels induce widespread receptor activation, chromatin remodeling, and non-genomic signaling cascades (PI3K/Akt, Src, MAPK), amplifying anti-inflammatory and immunosuppressive outcomes. Persistent exposure alters GR isoform expression (GRβ dominance), suppresses histone acetylation, disrupts circadian rhythmicity, and triggers mitochondrial dysfunction with reactive oxygen species (ROS) accumulation. These mechanisms converge on tissue-specific pathologies including insulin resistance, skeletal muscle catabolism, hypertension, osteoporosis, and mood dysregulation. The figure underscores how physiologic GR engagement sustains equilibrium, while pharmacologic exposure reshapes transcriptional and cytoplasmic signaling toward catabolic and apoptotic outcomes, reflecting a mechanistic continuum from adaptive to toxic. Table 3 Summary of Cellular Actions of Corticosteroids at Physiological vs. Pharmacological Levels Author and Year Biochemical and Cellular Findings Comment Updated Reference No. Sapolsky et al., 2000 (Endocr Rev) • Physio: Promotes hippocampal neuroprotection and adaptive stress responses. • Pharmaco: Chronic exposure causes dendritic retraction, reduced neurogenesis, and decreased BDNF expression. Landmark study on glucocorticoid neurotoxicity and stress adaptation. (6) Schäcke et al., 2002 (Pharmacol Ther) • Physio: Regulates gene transcription via GREs for homeostatic responses. • Pharmaco: Induces Defined molecular mechanisms of (1) GSC Advanced Research and Reviews, 2025, 25(01), 195-211 203 annexin-1, inhibits PLA₂ and COX-2, reduces collagen synthesis → impaired repair and atrophy. glucocorticoid side effects. Streeten and Anderson, 1996 (Endocr Rev) • Physio: Maintains vascular tone and modulates renal sodium reabsorption. • Pharmaco: Activates mineralocorticoid receptors → Na⁺ retention, vascular reactivity, hypertension. Early elucidation of GC– MR overlap in bloodpressure control. (5) Rhen and Cidlowski, 2005 (NEJM) • Physio: Balances immune and metabolic responses under stress. • Pharmaco: At higher doses, mediates strong anti-inflammatory and metabolic reprogramming. Distinguished physiological from therapeutic steroid actions in humans. (4) Warrington and Bostwick, 2006 (Mayo Clin Proc) • Physio: Maintains mood stability via normal HPA rhythm. • Pharmaco: Disrupts monoaminergic signaling → depression, mania, psychosis. First synthesis linking corticosteroids to psychiatric effects. (24) Barnes, 2011 (Clin Sci) • Physio: Basal suppression of NF-κB/AP-1 for immune tolerance. • Pharmaco: Potent IκBα induction and histone deacetylation → cytokine repression. Core mechanistic explanation for antiinflammatory efficacy. (18) Oakley and Cidlowski, 2013 (Trends Pharmacol Sci) • Physio: Genomic GR signaling predominates. • Pharmaco: Engages non-genomic (Src/PI3K) pathways → rapid Ca²⁺ flux responses. Dose-dependent switch to non-genomic signaling. (2) Kadmiel and Cidlowski, 2013 (J Allergy Clin Immunol) • Physio: Balanced GRα/β expression preserves GC sensitivity. • Pharmaco: GRβ upregulation → partial resistance in immune/metabolic tissues. Molecular basis of steroid resistance in chronic therapy. (41) Anglin et al., 2013 (J Psychosom Res) • Physio: Promotes emotional resilience. • Pharmaco: Chronic use increases risk of depression and affective disorders. Confirms psychiatric risks with long-term corticosteroid use. (14) Schakman et al., 2013 (Int J Biochem Cell Biol) • Physio: Balances muscle protein turnover. • Pharmaco: Activates Atrogin-1 and MuRF-1 → skeletal muscle atrophy. Clarifies molecular basis of steroid myopathy. (31) Joseph and Golden, 2017 (Clin Diabetes Endocrinol) • Physio: Enhances gluconeogenesis under stress without insulin resistance. • Pharmaco: Upregulates PEPCK/G6Pase, reduces GLUT4 → insulin resistance. Core biochemical pathway for steroidinduced diabetes. (10) Cain and Cidlowski, 2017 (Nat Rev Immunol) • Physio: Balances GR transactivation for immune tolerance. • Pharmaco: Dominant transrepression → cytokine suppression, lymphocyte apoptosis. Cornerstone review on GR signaling and immune modulation. (16) Compston, 2018 (Endocrine) • Physio: Balanced RANKL/OPG signaling in bone. • Pharmaco: ↑ RANKL, ↓ osteoblastogenesis → osteoporosis. Mechanistic link between dose, duration, and skeletal fragility. (13) Fardet et al., 2013 (Diabetes Care) • Physio: Normal glucose-insulin homeostasis. • Pharmaco: ↑ risk of new-onset diabetes and metabolic syndrome. Population-level evidence of metabolic risk. (26) Whitworth, 2020 (Kidney Int) • Physio: Maintains electrolyte homeostasis. • Pharmaco: Na⁺ retention, K⁺ loss, endothelial dysfunction → hypertension. Updated renal-vascular understanding of GC hypertension. (34) Caplan and Dennis, 2020 (Blood Rev) • Physio: Supports hematopoiesis. • Pharmaco: Leukocytosis, lymphopenia, marrow suppression. Explains hematologic responses to systemic corticosteroids. (27) GSC Advanced Research and Reviews, 2025, 25(01), 195-211 210 Authors’ contributions ATS conceived and supervised the study. FA contributed to study design and critical manuscript review. NH, NA, and SA performed literature search and data extraction. SE and DF assisted in data organization and figure preparation. AE contributed to data interpretation and manuscript editing. 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