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Hormones for Perimenopausal and Postmenopausal Depression

(PSYCHIATRIC TIMES) - Estrogen and progesterone are believed to play a role in the regulation of mood and well-being. Several mechanisms have been proposed for this effect, including the hormones' influence on monoamine oxidase (MAO) metabolism. Estrogen inhibits MAO, thereby diminishing the degradation of norepinephrine and serotonin and thus increasing their activity, while progesterone has the reverse impact on MAO (Chakravorty and Halbreich, 1997; Luine and Rhodes, 1983). Allopregnanolone, a metabolite of progesterone, is a potent neuroactive steroid that modulates g-aminobutyric acid (GABA) receptors and may be anxiolytic (Majewska et al., 1986).


Estrogen's influence on mood has been studied significantly more than that of progesterone. While estrogen's mood-elevating effect is generally acknowledged, the clinical magnitude of this effect remains unclear. Unfortunately, many studies examining this question have been uncontrolled or retrospective or have used populations with only mild levels of depression. A meta-analysis of research done between 1970 and 1995 (mostly involving conjugated equine estrogen [Premarin]) reported moderate-to-large mood-elevating effects from estrogen administration, which diminished following addition of a progestogen (Zweifel and O'Brien, 1997). Interestingly, in this meta-analysis, perimenopausal women appeared more likely to benefit than postmenopausal women. The authors, however, cautioned that methodological shortcomings limited the generalizability of several of the studies.

Three controlled studies evaluated the use of estrogen for perimenopausal and postmenopausal women with major and minor depression. The first, which evaluated the effect of transdermal estrogen (17-ß estradiol) in a group of 31 women and used the Hamilton Rating Scale for Depression (HAM-D) and Center for Epidemiologic Studies, Depression Scale (CES-D), reported that 80% of subjects experienced a response to estradiol compared to 22% of the placebo group (Schmidt et al., 2000). The second study, which comprised 50 perimenopausal depressed women on transdermal estrogen, reported a 68% remission rate among the estradiol group compared to 20% in the placebo group as measured with the Montgomery-Asberg Depression Rating Scale (MADRS) (Soares et al., 2001). A third study, also using transdermal estrogen, reported remission of depression in six of nine (66.7%) perimenopausal women but only two of 11 (18%) postmenopausal women, as defined by ratings on the MADRS, Beck Depression Inventory (BDI) and Clinical Global Impression (CGI) scale (Cohen et al., 2003). In all three studies, the mood effect was independent of estrogen's relief of vasomotor symptoms. Most recently, the Women's Health Initiative evaluated 16,609 postmenopausal women with a brief rating scale composed of items from the CES-D and Diagnostic Interview Schedule (DIS) and reported no improvement of depressive symptoms from equine estrogen. These inconsistent findings may result from different formulations of estrogen (Table 1), different menopausal status (perimenopausal versus postmenopausal), different methods of assessment of mood and/or different levels of depression among the subjects (major versus minor depression).

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