This study aimed to explore the association between growth differentiation factor-15 (GDF-15), a stress-induced factor, and sex hormones in male patients with coronary artery disease (CAD). In this study, we recruited 253 male patients with CAD and 205 male controls. Patients were divided into three groups in accordance with GDF-15 tertiles. Serum levels of GDF-15, testosterone, estradiol and other biochemical variables were measured. Serum levels of GDF-15 were significantly increased and serum testosterone and testosterone/estradiol ratio (T/E2 ratio) were significantly decreased in CAD patients compared with controls. Patients with high GDF-15 levels had lower testosterone (203.97, 95% CI 154.67–328.30 vs. 303.98, 95% CI 246.93–345.66; P = 0.001) and T/E2 ratio (8.82, 95% CI 5.77–11.41 vs. 11.07, 95% CI 7.91–14.32; P = 0.013). Correlation analyses showed that serum GDF-15 levels inversely correlated with testosterone levels (r = −0.339) and T/E2 ratio (r = −0.365) (both P < 0.001). In multivariate regression analyses, the association between GDF-15 and T/E2 ratio was maintained (B=-0.442, 95% CI -99.568 to -6.991, P = 0.015). Furthermore, in vitro studies showed a synergistic effect of testosterone and estradiol on GDF-15 secretion, and demonstrated that testosterone association with estradiol decreased GDF-15 secretion through androgen receptor/estrogen receptor-mediated pathways. Together, these results suggest that upregulation of GDF-15 in the presence of low and imbalanced sex hormone levels may contribute to CAD. Thus, restoring the balance of testosterone and estradiol may inhibit the effects of GDF-15 and serve as a promising therapeutic strategy for the treatment of CAD.