BACKGROUND: We study the role of gonadectomy on the response to unavoidable stress and the role of testosterone replacement on gonadectomy in the male Naval Medical Research Institute mice (30 ±5 g) were studied. For this purpose, the hormonal and metabolic changes were investigated. METHODS: In the experimental group, the gonads were surgically removed, and a cannula was inserted into the left lateral ventricle. For acute and chronic stress induction, animals were placed in the communication box for 30 min for one day and four consecutive days, respectively. The animals received different doses of intraventricular (ICV) testosterone (0. 01, 0. 05, 0. 1μg/mouse) 5 minutes or intraperitoneal (IP) testosterone (0. 05, 0. 01, 0. 1 mg/kg) 30 minutes before the stress induction. RESULTS: The results showed that acute and chronic stress increases plasma Cortisol concentration. IP testosterone injections of testosterone did not decrease Cortisol concentrations in response to acute stress, whereas ICV injections did reduce Cortisol concentrations. The stress reduced anorexia time, while the administration of testosterone increased anorexia time. In addition, acute stress reduced food intake in the gonadectomized mice. IP testosterone at 0. 01 and 0. 05 mg/kg increased food intake. Additionally, stress in gonadectomized mice reduced water intake, while the IP injection of testosterone in chronic stress further reduced water intake. Also, stress reduced the animals" brain/adrenal volumes, while the IP and ICV injection of testosterone at0. 01 mg/kg inhibited this effect. CONCLUSION: The results showed that the IP (0. 05, 0. 01, 0. 1 mg/kg) and ICV (0. 01, 0. 05, 0. 1 μg/mouse) administration of testosterone in the gonadectomized mice can modulate hormonal and metabolic changes induced by stress.