Hormonal Dysregulation in Major Depressive Disorder: A Systematic Review

Background: Major Depressive Disorder (MDD) is a leading cause of global disability, affecting approximately 280 million people worldwide and exhibiting a two- to three‐fold higher prevalence in women (World Health Organization, 2023). Neuroendocrine systems—including the hypothalamic–pituitary–adrenal (HPA), –thyroid (HPT), –gonadal (HPG), metabolic, and somatotropic axes—modulate mood via genomic and rapid non‐genomic mechanisms. Although individual hormonal contributions to MDD have been studied, a unified, up‐to‐date synthesis is lacking.Methods: In January 2025, we conducted PRISMA‐guided searches of PubMed, Embase, Web of Science, and PsycINFO (January 2015–April 2025) using terms for cortisol, thyroid hormones, estrogen, testosterone, insulin, leptin, growth hormone, IGF-1, and neuropeptides, combined with “major depressive disorder” or “depression.” Two independent reviewers screened 1 500 records, removed 300 duplicates, and assessed 120 full texts, of which 35 met inclusion criteria (human clinical, animal, or cellular studies with hormonal assays and mood outcomes). Data (sample, design, hormone measures, mood scales, interventions) were extracted; study quality was appraised via Newcastle–Ottawa and Cochrane tools. Heterogeneity precluded meta‐analysis, so we synthesized findings narratively.Results:1.HPA‐Axis. MDD consistently associates with elevated basal and evening cortisol, flattened diurnal slopes, and exaggerated stress reactivity (standardized mean difference ≈ 1.18, p < .00001) (Arinami et al., 2023). Endogenous Cushing’s syndrome yields ~ 90 % depression prevalence, whereas Addison’s disease features fatigue and low mood, underscoring cortisol’s bidirectional role (Arinami et al., 2023; Pruessner et al., 2017).2.HPT‐Axis. Both overt and subclinical hypothyroidism raise depression risk (odds ratio 1.30–1.77), particularly in women; up to 5 % of MDD patients have undiagnosed hypothyroidism. Adjunctive T3 (25–50 µg/day) accelerates SSRI response in treatment‐resistant depression (Molendijk, Schmidt, & van der Hart, 2021).3.HPG‐Axis. Female estrogen/progesterone fluctuations around perimenopause, menstrual cycle, and postpartum increase vulnerability, with estradiol therapy reducing HAM-D scores by ≥ 30 % (Chafkin et al., 2021). Male hypogonadism responds to adjunct testosterone (50–200 mg/week), lowering depressive symptoms (Chafkin et al., 2021). Elevated serum G protein–coupled estrogen receptor 1 (GPER1) in drug‐naïve MDD (0.28 ± 0.02 ng/mL) correlates with HAM-D (r ≈ 0.67), offering a novel biomarker (Fındıklı et al., 2017).4.Metabolic Hormones. Atypical depression shows hyperinsulinemia (↑ fasting insulin, ↑ HOMA-IR) during acute episodes (70 studies; N ≈ 240 700), normalizing in remission. Insulin sensitizers (metformin, GLP-1 agonists) and lifestyle yield 20–35 % HAM-D reductions (Wulsin, Singla, & Teal, 2023). Leptin elevation links to blunted ventral striatal reward activation (Straub & Cutolo, 2018).5.Somatotropic Axis. Acromegaly patients’ depression scores decrease significantly post‐tumor resection in parallel with IGF-1 normalization; in rodents, IGF-1 deficiency induces depression‐like behavior reversible by exogenous IGF-1 (Chopra, Dworkin, & Tandon, 2021).6.Neuropeptides. CRH overactivity drives HPA dysregulation; reduced neuropeptide Y exacerbates stress responses; galanin and neuropeptide S receptors emerge as therapeutic targets (Rana et al., 2022).Conclusion. MDD is a systemic neuroendocrine disorder. Routine endocrine screening (cortisol, TSH/free T4, sex steroids, insulin sensitivity, neuropeptides) and targeted augmentations (T3, sex steroids, insulin sensitizers, neurosteroids) promise precision treatments. Longitudinal endocrine–genetic subtyping and RCTs of novel modulators (e.g., GPER1 agonists) should be research priorities.