The efficacy of estrogen replacement therapy (ERT) for mood disturbances associated with menopause has yet to be firmly established. The objective of this study was to investigate the efficacy of ERT for improving mood and anxiety of non-depressive postmenopausal women. This double-blind, randomized, placebo-controlled study involved two treatment groups: one receiving conjugated equine estrogens (CEEs; 0.625 mg/day) and the other placebo, for six cycles of 28 days each. Subjects were hysterectomized, healthy, non-depressive (according to Schedule for Affective Disorders and Schizophrenia, Life Time Version [SADS-L]) women. Depressive and anxiety symptoms were assessed with the Beck Depression Inventory (BDI), and the Hamilton Anxiety Scale (HAMA), respectively. The Profile of Mood States (POMS) and other scales were used to characterize symptoms. In both groups, BDI scores were significantly lower at cycles 1, 2, 3, and 6, compared with baseline assessments (p<0.01). Anxiety scores for both groups significantly improved from cycle 3 to study endpoint. The only significant difference favoring the active group occurred at cycle 1. POMS scores were significantly improved at the end of cycles 1, 2, 3 and 6 among treated subjects and at the end of cycles 2, 3, and 6 among placebo subjects. ERT is not associated with improvements in mood or anxiety symptoms in non-depressive, hysterectomized, postmenopausal women.

This study aimed to evaluate the effect of estrogen replacement therapy on verbal cognitive performance of middle-aged postmenopausal women. Middle-aged (40 to 59 years) hysterectomized, oligosymptomatic women receiving 0.625 mg/day of conjugated equine estrogens (N = 27) or placebo (N = 32) in a double-blind parallel group design were compared according to their performance on a verbal memory battery before and after six 28-day cycles of treatment. Both groups had similar age and educational level. The estrogen group performed better on digit span-forward and on the recall of the easy stimuli on the verbal-paired associates test regardless of age, education, physical symptoms, number of years of menopause, or blood estradiol levels. However, the small magnitude of difference in the effect on attentional span suggests that the estrogen-related improvement is unlikely to be of clinical relevance. Estrogen replacement therapy did not improve verbal memory in middle-aged, hysterectomized, postmenopausal, asymptomatic women.

Methyltestosterone 2.5 mg had the highest effect size compared with placebo, but the high dropout rate prevented its efficacy from being determined. Estrogen plus medroxyprogesterone, combined with methyltestosterone or otherwise, demonstrated a trend toward increased efficacy of venlafaxine. Further larger-scale clinical trials are needed to elucidate the findings of this pilot study.