Background Androgen deprivation therapy (ADT) has been associated with adverse effects on the brain. ADT alters testosterone levels via its action on the hypothalamus‐pituitary‐gonadal axis and may influence hypothalamic functions. Given the wide regional connectivity of the hypothalamus and its role in regulating cognition and behavior, we assessed the effects of ADT on hypothalamic resting state functional connectivity (rsFC) and their cognitive and clinical correlates. Methods In a prospective observational study, 22 men with nonmetastatic prostate cancer receiving ADT and 28 patients not receiving ADT (controls), matched in age, years of education, and Montreal Cognitive Assessment score, participated in N‐back task and quality of life (QoL) assessments and brain imaging at baseline and at 6 months. Imaging data were processed with published routines and the results of a group by time flexible factorial analysis were evaluated at a corrected threshold. Results ADT and control groups did not differ in N‐back performance or QoL across time points. Relative to controls, patients receiving ADT showed significantly higher hypothalamus‐right mid‐cingulate cortex (MCC) and precentral gyrus (PCG) rsFC during follow‐up versus baseline. Further, the changes in MCC and PCG rsFC were correlated positively with the change in QoL score and 0‐back correct response rate, respectively, in patients with undergoing ADT. Conclusion Six‐month ADT affects hypothalamic functional connectivity with brain regions critical to cognitive motor and affective functions. Elevated hypothalamic MCC and PCG connectivity likely serve to functionally compensate for the effects of ADT and sustain attention and overall QoL. The longer‐term effects of ADT remain to be investigated.

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