Perimenopausal depression and early menopause: cause or consequence?

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The menopause transition (MT) is accompanied by an increased risk for both first-time onset and recurrence of major depressive disorder compared with the premenopause,1-3 and, in some studies, compared with the postmenopause.4,5 Importantly, prospective community-based studies have documented that the majority of women are not at risk for the development of major or minor depression as they transition to the menopause. In those women who do develop depression during the MT, few risk factors have been identified that make some women more susceptible to perimenopausal depression (PMD) compared with others. Thus far, the strongest predictor is a history of depressive symptoms or past major depressive episodes.6,7
In this issue of Menopause, Marsh et al examined the hypothesis that prolonged estrogen (mainly estradiol) exposure during a woman's reproductive life (ie, years before menopause) reduced her risk for developing PMD.8 The authors characterized duration of estrogen exposure as follows: duration of reproductive years, operationally defined as the number of years between onset of menarche (based on a woman's recall) and the age of onset of the MT; duration of hormonal contraceptive (HC) use; or increased number of pregnancies and lactation, which would increase exposure (decrease risk) or decrease exposure to estrogen (increase risk), respectively. The authors employed data from the Study of Women's Health Across the Nation (SWAN) cohort, including a total of 1,306 women who were followed prospectively from pre- to postmenopause. Among them, 506 (39%) met Center for Epidemiological Studies Depression Scale (CES-D) score criteria for a depression during the early or late MT (CES-D ≥16)—a rate of depressive illness notably higher than the reported estimates of approximately a 20% lifetime prevalence of major depression in women.9 Marsh et al's univariate analysis findings suggested that just one additional year of reproductive life, older age at MT, or longer HC use, as well as greater social support decreased risk for depression during the MT, whereas there were no effects of parity or lactation. The univariate analysis, however, also suggested that other factors acted to increase PMD risk, including premenopausal depression, past antidepressant use, stressful life events, vasomotor symptoms, greater baseline weight (1 kg), smoking status, ethnicity, and education. A multivariate analysis, adjusted for most of these variables, but—importantly for this editorial—not age at MT, also showed a decreased risk of PMD for those with a longer duration of reproductive years and HC use, and more social support. Whereas, an increased risk of PMD was associated with a history of premenopausal depression, antidepressant use, stressful life events, and vasomotor symptoms. Marsh et al interpret their results to suggest that a longer history of naturally fluctuating estrogen levels, as well as stable elevated levels of exogenous estrogen, as experienced during HC use (ie, increased estrogen exposure), confer a protective benefit against the risk of PMD.
The findings of Marsh et al highlight the importance of understanding the effects of premenopausal hormone exposure on the risk for depression during the MT. PMD is thought to reflect alterations in ovarian hormone secretion during the MT, which suggests a possible role for changes in estradiol secretion accompanying the MT.10 Current data suggest that changes or extreme variability in estradiol secretion during the MT act to induce depressive symptoms in women at risk.11 Marsh et al are the first to report an association between lifetime duration of estrogen exposure and risk for PMD in a prospective sample.

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