Hormonal Dysregulation in Major Depressive Disorder: A Systematic Review

Abstract

Major Depressive Disorder (MDD) involves widespread hormone imbalances across the HPA, HPT, HPG, metabolic, and somatotropic axes. We performed a PRISMA-guided systematic review (2015–2025) of clinical and preclinical studies examining neuroendocrine contributions to MDD. Thirty-five studies met inclusion (N ≈ 250,000). Key findings: HPA-axis overactivity is nearly universal in acute MDD (meta-analytic SMD ≈ 1.18 for cortisol elevations). Thyroid dysfunction (especially overt hypothyroidism) modestly increases depression risk (OR ≈ 1.30 overall; OR ≈ 1.77 for overt cases). Sex steroid fluctuations (perimenstrual, postpartum, perimenopausal) heighten female vulnerability; estradiol therapy and adjunctive testosterone show benefit in selected trials/meta-analyses. Insulin resistance commonly accompanies “atypical” MDD, insulin-sensitizing agents (pioglitazone, metformin, GLP-1 agonists) produce moderate antidepressant benefits in trials and meta-analyses. GH/IGF-1 dysregulation (both excess and deficiency) associates with depressive symptoms. Neuropeptide modulation is an emerging target: intranasal neuropeptide Y (NPY) showed rapid MADRS improvement vs placebo in a randomized trial, while CRH1 antagonists (e.g., CP-316,311) failed in RCTs. Overall, MDD is best conceptualized as a systemic neuroendocrine disorder in many patients. Routine endocrine screening (cortisol, TSH/free T4, sex steroids, fasting insulin/HOMA-IR, and targeted neuropeptides where available) could enable precision augmentations (e.g., liothyronine, sex hormones, metformin, neurosteroids) tailored to endocrine subtypes. (Key metaanalytic and trial sources cited in Results/References).