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Lifelong estradiol exposure and risk of depressive symptoms during the transition to menopause and postmenopause

Marsh, Wendy K. MD, MSc1; Bromberger, Joyce T. PhD2; Crawford, Sybil L. PhD3; Leung, Katherine MS4; Kravitz, Howard M. DO, MPH5; Randolph, John F. MD6; Joffe, Hadine MD, MSc7; Soares, Claudio N. MD, PhD, FRCPC, MBA8

doi: 10.1097/GME.0000000000000929
Original Articles

Objective: Depression risk increases during the menopausal transition (MT) and initial postmenopausal years—both times of significant fluctuations of estrogen. Research to date provides limited support for the hypothesis that estrogen fluctuations play a role in the greater susceptibility to midlife depression. Importantly, not all women report depressive symptoms during the MT, and recent reports suggest that duration of exposure to estradiol throughout the adult years may also play a role in vulnerability to depression. This study examines patterns of estrogen exposure during the reproductive years and risk of depression during the MT and early postmenopausal years.

Methods: A longitudinal, US community-based, multiethnic study of menopause. Data were collected at baseline and annually for 10 years, and included 1,306 regularly menstruating premenopausal women, aged 42 to 52 years at study entry. The main outcome was incidence of high level of depressive symptoms, Center for Epidemiological Studies Depression Scale (CES-D) score at least 16, in the MT and initial postmenopausal years, independent of premenopausal depression symptoms. Risk factors examined were duration of estrogen exposure (menarche to MT), duration of hormonal birth control use, pregnancies, and lactation.

Results: In a multivariate adjusted model, longer duration of estrogen exposure from menarche to MT onset was significantly associated with a reduced risk of depression (CES-D ≥16) during the MT and 10 years or less postmenopause (odds ratio 0.85, 95% confidence interval 0.78-0.92). Longer duration of birth control use was associated with a decreased risk of CES-D at least 16 (odds ratio 0.90, 95% confidence interval 0.83-0.98), but number of pregnancies or breastfeeding was not.

Conclusions: Patterns of reproductive lifetime exposure to estrogen are associated with risk of high depressive symptoms during the MT and initial postmenopausal years; longer exposure to estrogen seemed protective.

1Department of Psychiatry, University of Massachusetts Medical School, Worcester, MA

2Departments of Epidemiology and Psychiatry, University of Pittsburgh, Pittsburgh, PA

3Division of Preventive and Behavioral Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA

4Department of Obstetrics and Gynecology, University of Massachusetts Medical School, Worcester, MA

5Department of Psychiatry and Department of Preventive Medicine, Rush University Medical Center, Chicago, IL

6Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI

7Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA

8Department of Psychiatry, Queen's University School of Medicine, Kingston, Ontario, Canada.

Address correspondence to: Wendy K. Marsh, MD, MSc, Department of Psychiatry, University of Massachusetts Medical School, 55 Lake Avenue North, Ste3-301, Worcester, MA 01605. E-mail:

Received 23 December, 2016

Revised 3 April, 2017

Accepted 3 April, 2017

Author contributions: S.L.C., PhD, and K.L., MS, had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Funding/support: Funding was received from The Study of Women's Health Across the Nation (SWAN) has grant support from the National Institutes of Health (NIH), DHHS, through the National Institute on Aging (NIA), the National Institute of Nursing Research (NINR), and the NIH Office of Research on Women's Health (ORWH) (Grants U01NR004061; U01AG012505, U01AG012535, U01AG012531, U01AG012539, U01AG012546, U01AG012553, U01AG012554, and U01AG012495). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NIA, NINR, ORWH or the NIH. Supplemental funding obtained from The National Institute of Mental Health is also gratefully acknowledged.

Financial disclosure/conflicts of interest: First Author's time was covered on a KL2RR031981 Clinical Research Scholar Award. H.J. received research grants from Merck, Cephalon/Teva. Advisory/consulting: Noven, Merck, Mitsubishi Tanabe. Dr Joffe's R01 (R01MH082922) provided as the support for her time on this study. W.K.M., J.T.B., S.L.C., K.L., H.M.K., J.F.R., and C.N.S. report no conflicts of interest.

© 2017 by The North American Menopause Society.