Early Menopause Linked to Later Depression

Nancy A. Melville

January 06, 2016

The risk for postmenopausal depression is decreased with later age at menopause, supporting evidence of potential antidepressive effects associated with longer exposure to endogenous estrogens, a new meta-analysis suggests.

"Our analysis showed that overall, increasing age at menopause by 2 years decreases the postmenopausal risk by 2% (per 2-year increment)," lead author Eleni Th Petridou, MD, PhD, of the National and Kapodistrian University of Athens, in Greece, told Medscape Medical News.

"Considering that age at menopause may differ among women up to 20 years, the cumulative protective effect becomes quite sizeable."

The findings were published online January 6 in JAMA Psychiatry.

The meta-analysis included 14 studies involving 67,714 women; results showed that increasing age at menopause was linked with a reduction in the odds ratio (OR) for depression per 2-year increment (OR, 0.98; 95% confidence interval [CI], 0.96 - 0.99 in 13 studies). Similar reductions were seen with a longer duration of the reproductive period (OR, 0.98; 95% CI, 0.96 - 0.99 in five studies).

In looking at three studies involving severe depression, which included 52,736 participants, the effect was greater: there was a 5% decrease in the risk for severe depression with each 2-year increase in age at menopause. Three studies that controlled for past depression also showed decreases in subsequent depression with older age at menopause (OR, 0.98; 95% CI, 0.96 - 1.00).

Four studies, involving 3033 participants, showed that menopause at age 40 years or later was associated with a 50% decreased risk for depression compared with menopause occurring in women younger than 40 years.

Studies that included women with surgically induced menopause were not included in the meta-analysis, but the authors said the findings were "in accordance with previous studies reporting that early menopause due to oophorectomy increases the risk of depression later in life."

Importantly, the association of increased postmenopausal depression with earlier menopause remained consistent after controlling for use of hormone replacement therapy (HRT) ― in the seven studies (56,813 cases) in the analysis that included HRT data, the proportion of patients having ever received HRT varied between 20% and 45%. There were no significant differences in the results in those patients.

"It seems that HRT use does not offset the odds of depression," Dr Petridou said. "It should be noted, however, that other endogenous sex hormones, such as progesterone, might also be implicated in the protection conferred against postmenopausal depression."

The findings appear to underscore a neuroprotective role of circulating estradiol, which some studies have shown "acts in neurons and glial cells via the intracellular estrogen receptors α and β, as well as [having] antiatherogenic actions including enhancement of endothelial function, blockage of smooth muscle cell proliferation, and inhibition of inflammation," the authors write.

In terms of prevention of the potential loss of those benefits as a result of early menopause, clinicians should monitor those patients, and research should continue to focus on refining HRT, Dr Petridou said.

"The findings of the current meta-analysis point to women with a premature menopause as a high-risk group for selective depression screening and close mental follow-up to identify depressive symptomatology earlier and treat it more effectively," Dr Petridou said.

Furthermore, randomized, controlled studies should be aimed at preventing postmenopausal depression with new and targeted sex HRTs, she added.

"The significant differences of exogenously administered sex hormones should be seriously considered in new studies to come up with safer HRT conferring also antidepressive protection of endogenous sex hormones."

In an editorial that accompanied the study, Hadine Joffe, MD, director of the Division of Women's Health, Brigham and Women's Hospital, in Boston, Massachusetts, and Joyce T. Bromberger, PhD, of the University of Pittsburgh, note that early menopause has been associated in previous research with a variety of nonpsychiatric diseases, including cardiovascular disease, cognitive decline, and dementia, and that the new analysis underscores the risk for depression.

"The current article adds postmenopausal depression to that list, with findings that show similarly that the effect of a slightly early natural menopause is small, while the effect of premature menopause is much stronger," they say.

Important limitations of the study include the fact that the overall risk observed was not necessarily large and the possibility of past depression as a potential confounder was not well addressed, Dr Joffe told Medscape Medical News.

"It is important to note that the magnitude of the effect is very small," Dr Joffe said.

"Also, past depression was not adjusted for in most studies, and that is likely to be the primary predictor of any subsequent depression — that is the primary risk factor for women, and clinicians to be aware of as a risk factor for depression after menopause."

In the editorial, Dr Joffe and Dr Bromberger caution that consideration should be given to a host of potential confounders that have been independently associated with the risk for depression as well as earlier menopause.

"These risk factors include sleep difficulties, stress, functioning in work and relationships, and early-life adverse exposures (eg, socioeconomic disadvantage, childhood maltreatment)," they write.

"This meta-analysis is a commendable effort to expand thinking about the role of lifetime exposure to reproductive hormones in the occurrence of postmenopausal depression and to shift our research focus to explore a new paradigm," the editorialists conclude.

The authors of the study have disclosed no relevant financial relationships. Dr Joffe has received research funding from Merck and Cephalon/Teva and is a consultant/advisor to Mitsubishi-Tanabe, Merck, and Noven. Dr Joffe's and Dr Bromberger's work was supported by grants from the National Institutes of Health.

JAMA Psychiatry. Published online January 6, 2016. Full text, Editorial

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