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OBJECTIVE: Despite reports of estradiol’s therapeutic efficacy in perimenopausal depression, the relationship between ovarian function and mood in perimenopausal depression remains unclear. The purpose of this study was to examine changes in mood and pituitary-ovarian axis function in women exhibiting perimenopausal depression. METHOD: Depression ratings (from the Center for Epidemiologic Studies—Depression Scale [CES-D Scale]) and follicle-stimulating hormone (FSH) plasma levels of depressed perimenopausal women (N=110) attending a menopause clinic were obtained at baseline and after a 6-week screening period. RESULTS: Eighteen women experienced an improvement in depression (50% decline in CES-D Scale scores) at week 6, which was associated with a significant decrease in FSH plasma levels (baseline: mean=73.3 IU/liter [SD=42.0]; week 6: mean=42.2 IU/liter [SD=28.6]). Similarly, those subjects experiencing a 50% drop in FSH plasma levels had significant decreases in CES-D Scale scores (baseline: mean=23.3 [SD=6.8]; week 6: mean=18.1 [SD=10.9]). However, between women with CES-D Scale scores ≥15 and those with CES-D Scale scores <15, no significant differences in FSH levels were observed either at baseline (mean=65.5 IU/liter [SD=35.7] and 60.9 IU/liter [SD=34.9], respectively) or at week 6 (mean=56.2 IU/liter [SD=36.6] and 51.5 IU/liter [SD=34.2]). CONCLUSIONS: Mood variability in women with perimenopausal depression may reflect episodic alterations in ovarian function that are best detected by longitudinal study designs.