BACKGROUND: Hormones of the hypothalamic-pituitary-gonadal (HPG), hypothalamic-pituitary-adrenal (HPA), and hypothalamic-pituitary-somatotropic (HPS) axes are potentially involved in major depressive disorder (MDD), but these hormones have not been simultaneously investigated in male patients with MDD. We investigated the association between male MDD symptoms and estradiol, testosterone, cortisol, dehydroepiandrosterone sulfate (DHEAS), and insulin-like growth factor 1 (IGF1). METHODS: Serum estradiol, testosterone, cortisol, DHEAS, and IGF1 levels were measured in 54 male patients with MDD and 37 male controls and were compared with clinical factors. We investigated the associations between hormone levels and Hamilton Depression Rating Scale (HAM-D) scores. The correlations among hormones were also investigated. RESULTS: Patients had significantly lower estradiol levels than controls (22.4 ± 8.4 pg/mL vs. 26.1 ± 8.5 pg/mL, P = 0.040). Serum estradiol levels were negatively correlated with HAM-D scores (P = 0.000094) and positively correlated with Global Assessment of Functioning scores (P = 0.000299). IGF1 levels and the cortisol:DHEAS ratio were higher in patients than in controls (IGF1: 171.5 ± 61.8 ng/mL vs. 144.1 ± 39.2 ng/mL, P = 0.011; cortisol:DHEAS ratio: 0.07 ± 0.05 vs. 0.04 ± 0.02, P = 0.001). DHEAS levels were lower in patients than in controls (227.9 ± 108.4 μg/dL vs. 307.4 ± 131.2 μg/dL, P = 0.002). IGF1, cortisol:DHEAS ratio, and DHEAS were not significantly correlated with HAM-D scores. Cortisol and testosterone levels were not significantly different between patients and controls. Serum estradiol levels were positively correlated with DHEAS levels (P = 0.00062) in patients, but were not significantly correlated with DHEAS levels in controls. CONCLUSION: Estradiol may affect the pathogenesis and severity of patients with MDD in men, and other hormones, such as those in the HPA and HPS axes, may also be involved in male MDD. Additionally, a correlation between estradiol and DHEAS may affect the pathology of MDD in men.