Early Menopause Raises Risk of Postmenopausal Depression

MedicalResearch.com Interview with:
Eleni Petridou, MD, MPH, PhD
Marios K. Georgakis, MD
Department of Hygiene, Epidemiology and Medical Statistics
School of Medicine
National and Kapodistrian University of Athens
Athens, Greece

Medical Research: What is the background for this study?

Response: Previous epidemiologic studies have shown that women during their reproductive life are more vulnerable (by a factor of two) to depression than men; this has been particularly evident during peaks of intense fluctuations of ovarian hormones, like the premenstrual, perimenopausal and postpartum periods. Endogenous (natural) female sex hormones, however, have been shown in various experimental studies to possess neuroprotective and anti-depressive properties. Production of these hormones is diminished after menopause; therefore, age at menopause can be used as a proxy of the lifetime exposure to endogenous hormones. Our research hypothesis was whether longer exposure to endogenous sex hormones has a cumulative anti-depressive action, i.e., whether later age at menopause decreases the risk for postmenopausal depression.

Medical Research: What are the main findings?

Response: We identified 14 relevant studies comprising the postmenopausal experience of almost 68 000 individual cases of women after screening some 13,000 published scientific articles. Following synthesis of the data we showed that overall increasing age at menopause or longer duration of the reproductive period from menarche to menopause decreases the postmenopausal risk for depression. Specifically, we quantified the magnitude of the protection effect to +2% for every two years increase in the age at menopause or the duration of reproductive period. Considering that age at menopause may differ among women up to 20 years the protective effect becomes quite sizeable. The effect is even more evident for women with very premature menopause (before 40 years of age), who have been found to have a 2-fold increased risk of depression compared to women with menopause after 40 years. In addition, the risk was higher for women suffering severe depression, among whom increase of age at menopause by 2 years increased risk for severe depression by 5%. Interestingly, when either the effect of premenopausal depression or the history of hormonal replacement treatment (HRT) was taken into account, the effect on the examined association between age at menopause and depression remained practically unchanged.

Medical Research: What should clinicians and patients take away from your report?

Response: Fortunately, only one percent of women have natural menopause before the age of 40 years. According to the findings of the current meta-analysis, women with a premature menopause are, however, a prime target for selective screening regarding postmenopausal depression and close mental health follow-up thereafter; in this sense, it is hoped to identify depressive symptomatology at an earlier stage and thereafter, treat it more effectively. Nevertheless, given the high incidence of postmenopausal depression and the linear nature of the association, it may be prudent that guidelines regarding monitoring of all women for postmenopausal depression development by general practitioners are developed.

History of HRT does not seem to modify the postmenopausal depression risk, possibly due to the fact that these drugs are not essentially of the same composition as the naturally produced endogenous female gender hormones.

Medical Research: What recommendations do you have for future research as a result of this study?

Response: The study has synthesized findings from cross-sectional studies using gross proxies of the lifelong exposure to endogenous female sex hormonal environment with self-reported rather than medically assessed depression. Ideally, the findings should be replicated in large prospective studies assessing female sex hormonal levels at different time intervals and depression via psychiatric examination to allow also to possibly identifying which of these hormones may be causally associated with postmenopausal depression risk.

The debate is already hot about different specimens of HRT, available in the market in variable prices, depending on how well they imitate the natural hormonal environment after menopause. It seems that clinical research should focus on whether women could be benefitted from HRT also targeted for prevention of depression. The largest to date RCTs have shown that side effects including thrombosis and stroke outbalance potential beneficial actions of HRT and have limited their use. These studies included only women who initiated HRT late after menopause in their 60s and 70s. It has been, however, reported in later research that if HRT is initiated in a critical time period soon after menopause the protective actions possibly outbalance the side effects. Interestingly, experimental research is ongoing on the development of estrogen agonists targeting specifically receptors of these hormones in the brain and limiting potential side effects from other systems that arise by receptors mediating other actions. To this end, the significant differences of exogenously administered sex hormones should be seriously considered in the new studies as to come up with safer HRT conferring also the anti-depressive protection of endogenous sex hormones.


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. Published online January 06, 2016. doi:10.1001/jamapsychiatry.2015.2653.

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Eleni Petridou, MD, MPH, PhD, & Marios K. Georgakis, MD (2016). Early Menopause Raises Risk of Postmenopausal Depression 

Last Updated on January 8, 2016 by Marie Benz MD FAAD