The goal of this study was to assess the influence of sex steroid hormone suppression on performance on tests of prefrontal cortex (PFC) and working memory function (WM) in premenopausal women. Twenty-five women were treated with leuprolide acetate depot (LAD), a gonadotropin releasing hormone (GnRH) analog that chemically suppressed ovarian function as treatment of various benign gynecologic disorders. Performance on tests of PFC and WM of the LAD-treated women was assessed at pretreatment baseline and, again, following 4 weeks of treatment and their performance was compared to that of 25 healthy, control participants matched on age, education, and general intelligence. Following 4 weeks of LAD treatment, estrogen levels decreased to the postmenopausal range whereas progesterone levels fell to the lower limit of the menstrual cycle range of values. Furthermore, the LAD-treated women also experienced a significant deterioration in mood, in health-related symptoms and in performance on two tests of WM following 4 weeks of treatment. It was determined that only the post-treatment declines in estrogen, but not those in progesterone, in mood, or in health-related symptoms were associated with the worsening of performance on the WM tests. These findings provide new evidence that estrogen is influential in the maintenance of WM processes in premenopausal women.