Because of increased incidence of depression at critical hormonal transition phases such as postpartum and perimenopause, much speculation has taken place about estrogen's role as a precipitant. Recent studies have found increased incidence of depressive symptoms and major depression during the menopause transition (Cohen et al. 2006; Freeman et al. 2006). The initial findings of Freeman et al. (2004) in regard to estrogen were that both high and low estrogen levels were associated with depression. More recently, the data suggest that variability in estrogen levels may drive depression. A model of differential sensitivity to estrogen has been proposed for premenstrual dysphoric disorder (PMDD) and also by Cohen et al. (2006) to explain the findings of increased depression during the menopause transition. Increased FSH, suggesting ovarian aging, and overall low or variable estrogen were also found to be strongly associated with depression (Freeman et al. 2006). And in the Freeman et al. study, PMDD was associated with depression during the menopause transition. Furthermore, the central effects of estrogen are intriguing and lend credence to a possible role of estrogen in modulating critical neuronal systems involved in depression. Studies in nonhuman primates have confirmed that estrogen increases tryptophan hydroxylase, the rate-limiting step in serotonin synthesis (Bethea et al. 2002). Estrogen also decreases serotoninia (5-HTia) autoreceptor binding, which would serve to increase serotonin levels at the synapse (Bethea et al. 2002). Estrogen modulates the serotonin transporter, leading to decreases in the transporter mRNA but increases in the transporter expression in the hypothalamus (Bethea et al. 2002). Estrogen also decreases monoamine oxidase A activity, which would potentiate actions of norepinephrine in the synapse, and increases tyrosine hydroxylase, the critical first enzyme for synthesis of norepinephrine (Bethea et al. 2002). However, use of estrogen as a treatment has produced mixed results, perhaps because not all studies have targeted women with changing estrogen levels. Early studies found an effect of high-dose estrogen augmentation on response to antidepressants (Klaiber et al. 1979; Shapira et al. 1985). In situations of recent-onset estrogen deficiency such as postpartum and perimenopause, estrogen has been demonstrated to be an effective treatment for depression in randomized, controlled trials (Gregoire et al. 1996; Schmidt et al. 2000; Soares et al. 2001). However, randomized, controlled trials examining the effects of estrogen on mood in postmenopausal women have been negative (Hlatky et al. 2002; Morrison et al. 2004), suggesting a loss of beneficial mood response to estrogen following prolonged periods without estrogen. Finally, if data on estrogen's role in inhibiting the HPA axis in normal women are correct, then lower estradiol in depressed women would result in exacerbation of the HPA axis abnormalities seen in major depression, and these may need to be corrected along with changing the ovarian hormone milieu.
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