Older Age At Menopause, Longer Reproductive Period May Decrease Risk for Depression

Older age at menopause and a longer reproductive period may be associated with a lower risk for depression later in life, according to research published in JAMA Psychiatry.

Estrogens have been known to have antidepressive effects, but associations between reduced endogenous estrogens and depression have not been examined in postmenopausal women. Therefore, researchers examined how menopause at an advanced age, which would indicate longer exposure to endogenous estrogen, could lead to decreased risk for depression.

“These findings indicate that a shorter exposure to endogenous estrogens that is linked to a longer duration of estrogen deficiency, assessed through proxy variables, increases the risk for subsequent late-life depression and emphasizes the importance of the neuroprotective and antidepressive properties of the endogenous estrogens,” the researchers wrote.

In this meta-analysis, a pair of reviewers scanned a total of 12 323 articles from the MEDLINE database. Fourteen studies including 67 714 women were included in the analysis. Additional pairs of reviewers extracted information based on the participants’ characteristics and the method that researchers used to ascertain depression.

Among 67 434 unique participants from 13 studies, the researchers found  an inverse association between depression and increasing age at menopause in postmenopausal women, with an odds ratio (OR) of 0.98 (95% CI of 2-year increments, 0.96-0.99).

Among 3033 unique participants from 4 different studies, menopause after age 40 was associated with a 50% decreased risk for depression when compared with premature menopause.

Pooled analysis of 3 studies including 52 736 unique participants that examined severe depression revealed a 5% decrease in risk for severe depression with increasing age at menopause.

The researchers also conducted a sensitivity analysis of 3 studies involving 48 894 unique participants that controlled for past depression, which revealed similar patterns for age at menopause (OR=0.98; 95% CI, 0.96-1.00).

The researchers concluded based on the data that health care professionals could recognize the extent of depression in the menopausal group and plan for treatment accordingly.

“If confirmed in prospective and culturally diverse studies controlling for potential confounders and assessing depression via psychiatric evaluation, these findings could have a significant clinical effect by allowing for the identification of a group of women at higher risk for depression who may benefit from psychiatric monitoring or estrogen-based therapies,” they concluded.

In an accompanying editorial, Hadine Joffe, MD, MSc, of Brigham & Women’s Hospital and the Dana Farber Cancer Institute in Boston, and Joyce T. Bromberger, PhD, of the University of Pittsburgh, placed these findings in context.

They noted that the average age of women included in most of the studies analyzed was approximately 5 years older than the average age at menopause.

“Therefore, this meta-analysis does not address depression associated with the gonadal steroid fluctuations of the perimenopause or recent estradiol withdrawal of the immediate postmenopause,” they wrote. “Rather, the analysis applies to depression in older women whose brains have not recently been exposed to estradiol or other reproductive hormones and for whom hormonal risk factors have previously been considered less relevant.”

Even so, the study’s findings offer a novel way of understanding the effects of female reproductive hormones on the central nervous system, Drs Joffe and Bromberger noted, particularly because gonadal steroids may have a neuroprotective effect that lasts beyond menopause.

“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,” they concluded.

“The literature in this area would benefit from prospective studies that investigate the incidence of diagnostically confirmed depression episodes during and after the menopausal transition.”

However, Drs Joffe and Bromberger also highlighted several limitations, including the limited number of studies controlling for past depression, the small effect size, issues with self-reported scales of depression as well as self-reported age at menopause, the inclusion of women who were using or had used hormone therapy, and the need to account for potential confounders.

“Given the small effect size and limitations of the studies used in this analysis, more direct evidence supporting a sustained and delayed neuroprotective effect of extended exposure to estradiol, cyclic progestins, and their neurosteroid derivatives is required to support the use of hormonal therapy as a therapeutic approach to protecting against postmenopausal depression,” they concluded.

References

1. Georgakis MK, Thomopoulos TP, Diamantaras A, et al. Association of Age at Menopause and Duration of Reproductive Period with Depression After Menopause: A Systematic Review and Meta-analysis. JAMA Psychiatry. 2016;. doi: 10.1001/jamapsychiatry.2015.2653.
2. Joffe H, Bromberger JT. Shifting Paradigms About Hormonal Risk Factors for Postmenopausal Depression: Age at Menopause as an Indicator of Cumulative Lifetime Exposure to Female Reproductive Hormones. JAMA Psychiatry. 2016;doi:10.1001/jamapsychiatry.2015.2701.