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The increased prevalence of depression in women during perimenopause and postmenopause has led to several studies examining estrogen replacement and augmentation therapy for women during these stages of life. Perimenopause is the phase before menopause, which continues until menstruation has ceased for 12 consecutive months. Common symptoms include hot flashes, decreased libido, sleep disruption, and depression. In one study, perimenopausal women with major depression, dysthymic disorder, or minor depressive disorder received transdermal patches of 17[b]-estradiol (100 mg) or placebo in a 12-week study (336). Sixty-eight percent of women treated with estradiol had remission of depression compared to 20% in the placebo group (336). An earlier study also found that estrogen was superior to placebo in reducing depressive symptoms in perimenopausal women (337). A small study of 16 perimenopausal women found that estrogen replacement therapy was effective in treating depression (338). Other studies have found that both transdermal patches and sublingual estradiol improved mood in women with premenstrual dysphoric disorder and postpartum depression (339-341). Other studies have not found efficacy of estrogen replacement therapy for depression (342-344). In a review of the literature, Epperson and associates (345) reported that five studies found estrogen replacement therapy more effective than placebo in a mixed group of perimeno-pausal and postmenopausal women and 5 found it as effective as placebo. One study (346) found that estrogen was superior to placebo in perimenopausal, but not postmenopausal women. In an early study, estrogen 5-25 mg/day, which is 5-25 times the replacement dose, was more effective than placebo in the treatment of women with depression that were unresponsive to antidepressants (347). A more recent study in postmenopausal Chinese women did not find differences between 1 and 2 mg of oral estradiol and placebo on symptoms of anxiety and depression (348).

In addition to estrogen replacement as a monotherapy, it has also been used as an augmentation strategy in women with menopausal depression. Fluoxetine in combination with estrogen replacement therapy proved superior to fluoxetine alone in a single study (349). On the other hand, Oppenheim and colleagues did not find estrogen augmentation effective when administered with imipramine (345, 350).

In summary, data are conflicting regarding the efficacy of estrogen replacement therapy in perimenopausal or postmenopausal women with depression. Some investigators have attributed inconsistent findings to the use of poorly bioavailable oral preparations, failure to use laboratory measures to confirm menopausal status, and wide variability of diagnostic and outcome measures (336). The mechanism of action of estrogen is unknown; however, a substantial body of evidence indicates that it influences monoamine and GABA systems. There is little evidence to support the use of estrogen augmentation with cyclic antidepressants, although some evidence supports its value in combination with fluoxetine. Its use as an augmentation agent is also limited by the risks of toxicity when used in combination with imipramine, which is most likely a consequence of a pharmacokinetic interaction. Increased risk of carcinoma and cardiovascular disease may be associated with estrogen replacement (351-354).

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