Reward system dysfunction is evident across neuropsychiatric conditions. Here we present data from a double-blinded pharmaco-fMRI study investigating the triggering of anhedonia and reward circuit activity in women. The hormonal states of pregnancy and parturition were simulated in euthymic women with a history of postpartum depression (PPD+; n = 15) and those without such a history (PPD−; n = 15) by inducing hypogonadism, adding back estradiol and progesterone for 8 weeks (“addback”), and then withdrawing both steroids (“withdrawal”). Anhedonia was assessed using the Inventory of Depression and Anxiety Symptoms (IDAS) during each hormone phase. Those who reported a 30 % or greater increase in IDAS anhedonia, dysphoria, or ill temper during addback or withdrawal, compared with pre-treatment, were identified as hormone sensitive (HS+) and all others were identified as non-hormone sensitive (HS−). The monetary incentive delay (MID) task was administered during fMRI sessions at pre-treatment and during hormone withdrawal to assess brain activation during reward anticipation and feedback. On average, anhedonia increased during addback and withdrawal in PPD+ but not PPD−. During reward feedback, both HS+ (n = 10) and HS− (n = 18) showed decreased activation in clusters in the right putamen (p < .031, FWE-corrected) and left postcentral and supramarginal gyri (p < .014, FWE-corrected) at the withdrawal scans, relative to pre-treatment scans. A modest sample size, stringent exclusion criteria, and relative lack of diversity in study participants limit the generalizability of results. Although results do not explain differential hormone sensitivity in depression, they demonstrate significant effects of reproductive hormones on reward-related brain function in women. •Estradiol and progesterone administration triggered depression symptoms in women with a history of postpartum depression.•Estradiol and progesterone administration also decreased activity in brain areas that respond to rewards.•Changes in brain activity in the reward network caused by pregnancy hormones did not explain why some women experience postpartum depression while others do not.