Research Article| Volume 128, P22-28, October 2019

Reproductive history and risk of cognitive impairment in Japanese women


      • Reproductive history was associated with cognitive impairment.
      • A longer reproductive period was associated with a lower risk of cognitive impairment.
      • The findings suggest that longer exposure to endogenous estrogen may have a protective effect against cognitive impairment.



      While exposure to endogenous estrogen may be associated with better cognitive performance, it is still unclear whether it has an association with mild cognitive impairment (MCI) or dementia. The aim of this study was to clarify the effects of reproductive history, as a surrogate marker of exposure to endogenous estrogen, on the risk of cognitive impairment (MCI or dementia) in women.

      Study design

      A total of 747 women aged 40–59 years in the Saku area (Nagano Prefecture) were followed as part of the Japan Public Health Center-based Prospective (JPHC) Study, which started in 1990. Participants had undergone a mental health examination in 2014–2015.

      Main outcome measures

      We used multiple logistic regression to analyze the association between reproductive history, obtained at baseline and 10-year follow-up, with current cognitive impairment diagnosed by a trained psychiatrist, adjusting for various lifestyle factors.


      Among 670 eligible women, current cognitive impairment was diagnosed in 227, 196 of whom had MCI and 31 dementia. A longer reproductive period had a significantly inverse association with cognitive impairment (P-trend = 0.032). In particular, women with a reproductive period ≥38 years compared with ≤33 years had a significantly lower risk of cognitive impairment (multivariable adjusted odds ratio=0.62, 95% confidence interval=0.40–0.96).


      A longer reproductive period was associated with a lower risk of cognitive impairment, which suggests that a longer exposure to endogenous estrogen may have a protective effect against cognitive impairment.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Maturitas
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Ohara T.
        • Hata J.
        • Yoshida D.
        • Mukai N.
        • Nagata M.
        • Iwaki T.
        • Kitazono T.
        • Kanba S.
        • Kiyohara Y.
        • Ninomiya T.
        Trends in dementia prevalence, incidence, and survival rate in a Japanese community.
        Neurology. 2017; 88: 1925-1932
      1. Annual Report on the Aging Society.
        Cabinet Office, Government of Japan, 2016
        • Winblad B.
        • Palmer K.
        • Kivipelto M.
        • Jelic V.
        • Fratiglioni L.
        • Wahlund L.O.
        • Nordberg A.
        • Backman L.
        • Albert M.
        • Almkvist O.
        • Arai H.
        • Basun H.
        • Blennow K.
        • de Leon M.
        • DeCarli C.
        • Erkinjuntti T.
        • Giacobini E.
        • Graff C.
        • Hardy J.
        • Jack C.
        • Jorm A.
        • Ritchie K.
        • van Duijn C.
        • Visser P.
        • Petersen R.C.
        Mild cognitive impairment--beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment.
        J. Intern. Med. 2004; 256: 240-246
        • Cooper C.
        • Sommerlad A.
        • Lyketsos C.G.
        • Livingston G.
        Modifiable predictors of dementia in mild cognitive impairment: a systematic review and meta-analysis.
        Am. J. Psychiatry. 2015; 172: 323-334
        • Laws K.R.
        • Irvine K.
        • Gale T.M.
        Sex differences in cognitive impairment in Alzheimer’s disease.
        World J. Psychiatry. 2016; 6: 54-65
        • Mielke M.M.
        • Vemuri P.
        • Rocca W.A.
        Clinical epidemiology of Alzheimer’s disease: assessing sex and gender differences.
        Clin. Epidemiol. 2014; 6: 37-48
        • Iwata A.
        • Iwatsubo T.
        • Ihara R.
        • Suzuki K.
        • Matsuyama Y.
        • Tomita N.
        • Arai H.
        • Ishii K.
        • Senda M.
        • Ito K.
        Effects of sex, educational background, and chronic kidney disease grading on longitudinal cognitive and functional decline in patients in the Japanese Alzheimer’s Disease neuroimaging Initiative study.
        Alzheimer’s Dementia. 2018;
        • Luine V.N.
        Estradiol and cognitive function: past, present and future.
        Horm. Behav. 2014; 66: 602-618
        • Georgakis M.K.
        • Kalogirou E.I.
        • Diamantaras A.A.
        • Daskalopoulou S.S.
        • Munro C.A.
        • Lyketsos C.G.
        • Skalkidou A.
        • Petridou E.T.
        Age at menopause and duration of reproductive period in association with dementia and cognitive function: A systematic review and meta-analysis.
        Psychoneuroendocrinology. 2016; 73: 224-243
        • Geerlings M.I.
        • Launer L.J.
        • de Jong F.H.
        • Ruitenberg A.
        • Stijnen T.
        • van Swieten J.C.
        • Hofman A.
        • Witteman J.C.
        • Pols H.A.
        • Breteler M.M.
        Endogenous estradiol and risk of dementia in women and men: the Rotterdam Study.
        Ann. Neurol. 2003; 53: 607-615
        • Tsugane S.
        • Sawada N.
        The JPHC study: design and some findings on the typical Japanese diet.
        Jpn. J. Clin. Oncol. 2014; 44: 777-782
        • Nagata C.
        • Matsushita Y.
        • Shimizu H.
        Prevalence of hormone replacement therapy and user’s characteristics: a community survey in Japan.
        Maturitas. 1996; 25: 201-207
        • Nagata C.
        • Matsushita Y.
        • Inaba S.
        • Kawakami N.
        • Shimizu H.
        Unapproved use of high-dose combined pills in Japan: a community study on prevalence and health characteristics of the users.
        Prev. Med. 1997; 26: 565-569
        • Elwood R.W.
        The Wechsler Memory Scale-Revised: psychometric characteristics and clinical application.
        Neuropsychol. Rev. 1991; 2: 179-201
        • Agrell B.
        • Dehlin O.
        The clock-drawing test.
        Age Ageing. 1998; 27: 399-403
        • Hughes C.P.
        • Berg L.
        • Danziger W.L.
        • Coben L.A.
        • Martin R.L.
        A new clinical scale for the staging of dementia.
        Br. J. Psychiatry. 1982; 140: 566-572
        • Radloff L.S.
        The CES-D scale:a self-report depression scale for research in the general population.
        Appl. Psychol. Meas. 1977; 1: 385-401
        • Kroenke K.
        • Spitzer R.L.
        • Williams J.B.
        The PHQ-9: validity of a brief depression severity measure.
        J. Gen. Intern. Med. 2001; 16: 606-613
        • Fujishima M.
        • Kawaguchi A.
        • Maikusa N.
        • Kuwano R.
        • Iwatsubo T.
        • Matsuda H.
        I. Japanese alzheimer’s disease neuroimaging, I. Japanese alzheimer’s disease neuroimaging, sample size estimation for alzheimer’s disease trials from japanese ADNI serial magnetic resonance imaging.
        J. Alzheimers Dis. 2017; 56: 75-88
        • Petersen R.C.
        • Smith G.E.
        • Waring S.C.
        • Ivnik R.J.
        • Tangalos E.G.
        • Kokmen E.
        Mild cognitive impairment: clinical characterization and outcome.
        Arch. Neurol. 1999; 56: 303-308
        • Sugishita M.
        • Koshizuka Y.
        • Sudou S.
        • Sugishita K.
        • Hemmi I.
        • Karasawa H.
        • Ihara M.
        • Asada T.
        • Mihara B.
        The validity and reliability of the japanese version of the mini-mental state examination (MMSE-J) with the original procedure of the attention and calculation task.
        Japanese J. Cogn. Neurosci. 2001; 20 (in Japanese with an abstract in English): 91-110
        • American Psychiatric Association
        Diagnostic and Statistical Manual of Mental Disorders. 4th ed. American Psychiatric Association, Washington, DC2000
        • Iwatsubo T.
        • Iwata A.
        • Suzuki K.
        • Ihara R.
        • Arai H.
        • Ishii K.
        • Senda M.
        • Ito K.
        • Ikeuchi T.
        • Kuwano R.
        Japanese and North American Alzheimer’s Disease Neuroimaging Initiative studies: harmonization for international trials.
        Alzheimer’s & Dementia. 2018; 14: 1077-1087
        • Petersen R.C.
        • Caracciolo B.
        • Brayne C.
        • Gauthier S.
        • Jelic V.
        • Fratiglioni L.
        Mild cognitive impairment: a concept in evolution.
        J. Intern. Med. 2014; 275: 214-228
        • Rocca W.
        • Bower J.
        • Maraganore D.
        • Ahlskog J.
        • Grossardt B.
        • de Andrade M.
        • Melton L.
        Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause.
        Neurology. 2007; 69: 1074-1083
      2. Obesity: Preventing and Managing the Global Epidemic. WHO Technical Report Series no. 894.
        WHO, Geneva2000 (p. 9)
        • McLay R.N.
        • Maki P.M.
        • Lyketsos C.G.
        Nulliparity and late menopause are associated with decreased cognitive decline.
        J. Neuropsychiatry Clin. Neurosci. 2003; 15: 161-167
        • Li F.D.
        • He F.
        • Chen T.R.
        • Xiao Y.Y.
        • Lin S.T.
        • Shen W.
        • Wang X.Y.
        • Zhai Y.J.
        • Shang X.P.
        • Lin J.F.
        Reproductive history and risk of cognitive impairment in elderly women: a cross-sectional study in eastern China.
        J. Alzheimers Dis. 2016; 49: 139-147
        • Geerlings M.I.
        • Ruitenberg A.
        • Witteman J.C.
        • van Swieten J.C.
        • Hofman A.
        • van Duijn C.M.
        • Breteler M.M.
        • Launer L.J.
        Reproductive period and risk of dementia in postmenopausal women.
        Jama. 2001; 285: 1475-1481
        • Fox M.
        • Berzuini C.
        • Knapp L.A.
        Cumulative estrogen exposure, number of menstrual cycles, and Alzheimer’s risk in a cohort of British women.
        Psychoneuroendocrinology. 2013; 38: 2973-2982
        • Ryan J.
        • Carriere I.
        • Scali J.
        • Ritchie K.
        • Ancelin M.L.
        Life-time estrogen exposure and cognitive functioning in later life.
        Psychoneuroendocrinology. 2009; 34: 287-298
        • Kaye S.A.
        • Folsom A.R.
        • Soler J.T.
        • Prineas R.J.
        • Potter J.D.
        Associations of body mass and fat distribution with sex hormone concentrations in postmenopausal women.
        Int. J. Epidemiol. 1991; 20: 151-156