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EMAS position statement: Predictors of premature and early natural menopause

      Highlights

      • A family history of premature or early menopause, being a multiple-birth child and some specific genetic variants are strong genetic predictors–.
      • Early menarche, nulliparity, cigarette smoking and being underweight are strong reproductive and lifestyle predictors.
      • Current clinical guidelines recommend early initiation of hormone therapy and continued use until the average age at menopause (50–52 years).
      • Ethnicity-specific age at menopause should be considered in the assessment for the timing of cessation of hormone therapy.

      Abstract

      Introduction

      While the associations of genetic, reproductive and environmental factors with the timing of natural menopause have been extensively investigated, few epidemiological studies have specifically examined their association with premature (<40 years) or early natural menopause (40–45 years).

      Aim

      The aim of this position statement is to provide evidence on the predictors of premature and early natural menopause, as well as recommendations for the management of premature and early menopause and future research.

      Materials and methods

      Literature review and consensus of expert opinion.

      Results and conclusions

      Strong genetic predictors of premature and early menopause include a family history of premature or early menopause, being a child of a multiple pregnancy and some specific genetic variants. Women with early menarche and nulliparity or low parity are also at a higher risk of experiencing premature or early menopause. Cigarette smoking (with a strong dose–response effect) and being underweight have been consistently associated with premature and early menopause. Current guidelines for the management of premature and early menopause mainly focus on early initiation of hormone therapy (HT) and continued treatment until the woman reaches the average age at menopause (50–52 years). We suggest that clinicians and health professionals consider the age at menopause of the relevant region or ethnic group as part of the assessment for the timing of HT cessation. In addition, there should be early monitoring of women with a family history of early menopause, who are a child of a multiple pregnancy, or who have had early menarche (especially those who have had no children). As part of preventive health strategies, women should be encouraged to quit smoking (preferably before the age of 30 years) and maintain optimal weight in order to reduce their risk of premature or early menopause.

      Keywords

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      References

        • Shifren J.L.
        • Gass M.L.
        • Nams Recommendations for Clinical Care of Midlife Women Working Group
        The North American Menopause Society recommendations for clinical care of midlife women.
        Menopause. 2014; 21: 1038-1062
        • Mishra G.D.
        • Chung H.F.
        • Pandeya N.
        • Dobson A.J.
        • Jones L.
        • Avis N.E.
        • et al.
        The InterLACE study: design, data harmonization and characteristics across 20 studies on women’s health.
        Maturitas. 2016; 92: 176-185
        • InterLACE Study Team
        Variations in reproductive events across life: a pooled analysis of data from 505,147 women across ten countries.
        Hum. Reprod. 2019; (Epub ahead of print)https://doi.org/10.1093/humrep/dez015
        • Mendoza N.
        • Julia M.D.
        • Galliano D.
        • Coronado P.
        • Diaz B.
        • Fontes J.
        • et al.
        Spanish consensus on premature menopause.
        Maturitas. 2015; 80: 220-225
        • Mishra G.D.
        • Pandeya N.
        • Dobson A.J.
        • Chung H.F.
        • Anderson D.
        • Kuh D.
        • et al.
        Early menarche, nulliparity and the risk for premature and early natural menopause.
        Hum. Reprod. 2017; 32: 679-686
        • Muka T.
        • Oliver-Williams C.
        • Kunutsor S.
        • Laven J.S.
        • Fauser B.C.
        • Chowdhury R.
        • et al.
        Association of age at onset of menopause and time since onset of menopause with cardiovascular outcomes, intermediate vascular traits, and all-cause mortality: a systematic review and meta-analysis.
        JAMA Cardiol. 2016; 1: 767-776
        • Anagnostis P.
        • Christou K.
        • Artzouchaltzi A.M.
        • Gkekas N.K.
        • Kosmidou N.
        • Siolos P.
        • et al.
        Early menopause and premature ovarian insufficiency are associated with increased risk of type 2 diabetes: a systematic review and meta-analysis.
        Eur. J. Endocrinol. 2019; 180: 41-50
        • Gallagher J.C.
        Effect of early menopause on bone mineral density and fractures.
        Menopause. 2007; 14: 567-571
        • Faubion S.S.
        • Kuhle C.L.
        • Shuster L.T.
        • Rocca W.A.
        Long-term health consequences of premature or early menopause and considerations for management.
        Climacteric. 2015; 18: 483-491
        • Anagnostis P.
        • Siolos P.
        • Gkekas N.K.
        • Kosmidou N.
        • Artzouchaltzi A.M.
        • Christou K.
        • et al.
        Association between age at menopause and fracture risk: a systematic review and meta-analysis.
        Endocrine. 2019; 63: 213-224
        • Georgakis M.K.
        • Thomopoulos T.P.
        • Diamantaras A.A.
        • Kalogirou E.I.
        • Skalkidou A.
        • Daskalopoulou S.S.
        • 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; 73: 139-149
        • Ryan J.
        • Scali J.
        • Carriere I.
        • Amieva H.
        • Rouaud O.
        • Berr C.
        • et al.
        Impact of a premature menopause on cognitive function in later life.
        BJOG. 2014; 121: 1729-1739
        • Georgakis M.K.
        • Kalogirou E.I.
        • Diamantaras A.A.
        • Daskalopoulou S.S.
        • Munro C.A.
        • Lyketsos C.G.
        • et al.
        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
        • De Vos M.
        • Devroey P.
        • Fauser B.C.
        Primary ovarian insufficiency.
        Lancet. 2010; 376: 911-921
        • Zhu D.
        • Chung H.F.
        • Pandeya N.
        • Dobson A.J.
        • Cade J.E.
        • Greenwood D.C.
        • et al.
        Relationships between intensity, duration, cumulative dose, and timing of smoking with age at menopause: a pooled analysis of individual data from 17 observational studies.
        PLoS Med. 2018; 15: e1002704
        • Zhu D.
        • Chung H.F.
        • Pandeya N.
        • Dobson A.J.
        • Kuh D.
        • Crawford S.L.
        • et al.
        Body mass index and age at natural menopause: an international pooled analysis of 11 prospective studies.
        Eur. J. Epidemiol. 2018; 33: 699-710
        • Murabito J.M.
        • Yang Q.
        • Fox C.
        • Wilson P.W.
        • Cupples L.A.
        Heritability of age at natural menopause in the Framingham Heart Study.
        J. Clin. Endocrinol. Metab. 2005; 90: 3427-3430
        • Treloar S.A.
        • Do K.A.
        • Martin N.G.
        Genetic influences on the age at menopause.
        Lancet. 1998; 352: 1084-1085
        • Snieder H.
        • MacGregor A.J.
        • Spector T.D.
        Genes control the cessation of a woman’s reproductive life: a twin study of hysterectomy and age at menopause.
        J. Clin. Endocrinol. Metab. 1998; 83: 1875-1880
        • de Bruin J.P.
        • Bovenhuis H.
        • van Noord P.A.
        • Pearson P.L.
        • van Arendonk J.A.
        • te Velde E.R.
        • et al.
        The role of genetic factors in age at natural menopause.
        Hum. Reprod. 2001; 16: 2014-2018
        • van Asselt K.M.
        • Kok H.S.
        • Pearson P.L.
        • Dubas J.S.
        • Peeters P.H.
        • Te Velde E.R.
        • et al.
        Heritability of menopausal age in mothers and daughters.
        Fertil. Steril. 2004; 82: 1348-1351
        • Cramer D.W.
        • Xu H.
        • Harlow B.L.
        Family history as a predictor of early menopause.
        Fertil. Steril. 1995; 64: 740-745
        • Gosden R.G.
        • Treloar S.A.
        • Martin N.G.
        • Cherkas L.F.
        • Spector T.D.
        • Faddy M.J.
        • et al.
        Prevalence of premature ovarian failure in monozygotic and dizygotic twins.
        Hum. Reprod. 2007; 22: 610-615
        • Ruth K.S.
        • Perry J.R.
        • Henley W.E.
        • Melzer D.
        • Weedon M.N.
        • Murray A.
        Events in early life are associated with female reproductive ageing: a UK Biobank Study.
        Sci. Rep. 2016; 6: 24710
        • Treloar S.A.
        • Sadrzadeh S.
        • Do K.A.
        • Martin N.G.
        • Lambalk C.B.
        Birth weight and age at menopause in Australian female twin pairs: exploration of the fetal origin hypothesis.
        Hum. Reprod. 2000; 15: 55-59
        • de Bruin J.P.
        • Nikkels P.G.
        • Bruinse H.W.
        • van Haaften M.
        • Looman C.W.
        • te Velde E.R.
        Morphometry of human ovaries in normal and growth-restricted fetuses.
        Early Hum. Dev. 2001; 60: 179-192
        • Stolk L.
        • Zhai G.
        • van Meurs J.B.
        • Verbiest M.M.
        • Visser J.A.
        • Estrada K.
        • et al.
        Loci at chromosomes 13, 19 and 20 influence age at natural menopause.
        Nat. Genet. 2009; 41: 645-647
        • He C.
        • Kraft P.
        • Chen C.
        • Buring J.E.
        • Pare G.
        • Hankinson S.E.
        • et al.
        Genome-wide association studies identify loci associated with age at menarche and age at natural menopause.
        Nat. Genet. 2009; 41: 724-728
        • Stolk L.
        • Perry J.R.
        • Chasman D.I.
        • He C.
        • Mangino M.
        • Sulem P.
        • et al.
        Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways.
        Nat. Genet. 2012; 44: 260-268
        • Elzaiat M.
        • Todeschini A.L.
        • Caburet S.
        • Veitia R.A.
        The genetic make-up of ovarian development and function: the focus on the transcription factor FOXL2.
        Clin. Genet. 2017; 91: 173-182
        • Weinberg-Shukron A.
        • Rachmiel M.
        • Renbaum P.
        • Gulsuner S.
        • Walsh T.
        • Lobel O.
        • et al.
        Essential role of BRCA2 in ovarian development and function.
        N. Engl. J. Med. 2018; 379: 1042-1049
        • Murray A.
        • Bennett C.E.
        • Perry J.R.
        • Weedon M.N.
        • Jacobs P.A.
        • Morris D.H.
        • et al.
        Common genetic variants are significant risk factors for early menopause: results from the Breakthrough Generations Study.
        Hum. Mol. Genet. 2011; 20: 186-192
        • Wood M.A.
        • Rajkovic A.
        Genomic markers of ovarian reserve.
        Semin. Reprod. Med. 2013; 31: 399-415
        • Laven J.S.
        Genetics of early and normal menopause.
        Semin. Reprod. Med. 2015; 33: 377-383
        • Whitcomb B.W.
        • Purdue-Smithe A.
        • Hankinson S.E.
        • Manson J.E.
        • Rosner B.A.
        • Bertone-Johnson E.R.
        Menstrual cycle characteristics in adolescence and early adulthood are associated with risk of early natural menopause.
        J. Clin. Endocrinol. Metab. 2018; 103: 3909-3918
        • Wang M.
        • Gong W.W.
        • Hu R.Y.
        • Wang H.
        • Guo Y.
        • Bian Z.
        • et al.
        Age at natural menopause and associated factors in adult women: findings from the China Kadoorie Biobank study in Zhejiang rural area.
        PLoS One. 2018; 13: e0195658
        • Li L.
        • Wu J.
        • Pu D.
        • Zhao Y.
        • Wan C.
        • Sun L.
        • et al.
        Factors associated with the age of natural menopause and menopausal symptoms in Chinese women.
        Maturitas. 2012; 73: 354-360
        • Perez-Alcala I.
        • Sievert L.L.
        • Obermeyer C.M.
        • Reher D.S.
        Cross cultural analysis of factors associated with age at natural menopause among Latin-American immigrants to Madrid and their Spanish neighbors.
        Am. J. Hum. Biol. 2013; 25: 780-788
        • Parazzini F.
        • Progetto Menopausa Italia Study Group
        Determinants of age at menopause in women attending menopause clinics in Italy.
        Maturitas. 2007; 56: 280-287
        • Hernandez-Angeles C.
        • Castelo-Branco C.
        Early menopause: a hazard to a woman’s health.
        Indian J. Med. Res. 2016; 143: 420-427
        • Sullivan S.D.
        • Sarrel P.M.
        • Nelson L.M.
        Hormone replacement therapy in young women with primary ovarian insufficiency and early menopause.
        Fertil. Steril. 2016; 106: 1588-1599
        • Torrealday S.
        • Kodaman P.
        • Pal L.
        Premature ovarian insufficiency—an update on recent advances in understanding and management.
        F1000Res. 2017; 6: 2069
        • van Kasteren Y.M.
        • Schoemaker J.
        Premature ovarian failure: a systematic review on therapeutic interventions to restore ovarian function and achieve pregnancy.
        Hum. Reprod. Update. 1999; 5: 483-492
        • Parente R.C.
        • Faerstein E.
        • Celeste R.K.
        • Werneck G.L.
        The relationship between smoking and age at the menopause: a systematic review.
        Maturitas. 2008; 61: 287-298
        • Schoenaker D.A.
        • Jackson C.A.
        • Rowlands J.V.
        • Mishra G.D.
        Socioeconomic position, lifestyle factors and age at natural menopause: a systematic review and meta-analyses of studies across six continents.
        Int. J. Epidemiol. 2014; 43: 1542-1562
        • Gold E.B.
        The timing of the age at which natural menopause occurs.
        Obstet. Gynecol. Clin. North Am. 2011; 38: 425-440
        • Hyland A.
        • Piazza K.
        • Hovey K.M.
        • Tindle H.A.
        • Manson J.E.
        • Messina C.
        • et al.
        Associations between lifetime tobacco exposure with infertility and age at natural menopause: the Women’s Health Initiative Observational Study.
        Tob. Control. 2016; 25: 706-714
        • van Asselt K.M.
        • Kok H.S.
        • van Der Schouw Y.T.
        • Grobbee D.E.
        • te Velde E.R.
        • Pearson P.L.
        • et al.
        Current smoking at menopause rather than duration determines the onset of natural menopause.
        Epidemiology. 2004; 15: 634-639
        • Baron J.A.
        • La Vecchia C.
        • Levi F.
        The antiestrogenic effect of cigarette smoking in women.
        Am. J. Obstet. Gynecol. 1990; 162: 502-514
        • Khaw K.T.
        • Tazuke S.
        • Barrett-Connor E.
        Cigarette smoking and levels of adrenal androgens in postmenopausal women.
        N. Engl. J. Med. 1988; 318: 1705-1709
        • Ruan X.
        • Mueck A.O.
        Impact of smoking on estrogenic efficacy.
        Climacteric. 2015; 18: 38-46
        • Tao X.
        • Jiang A.
        • Yin L.
        • Li Y.
        • Tao F.
        • Hu H.
        Body mass index and age at natural menopause: a meta-analysis.
        Menopause. 2015; 22: 469-474
        • Bluher S.
        • Mantzoros C.S.
        Leptin in reproduction.
        Curr. Opin. Endocrinol. Diab. Obes. 2007; 14: 458-464
        • Mitchell M.
        • Armstrong D.T.
        • Robker R.L.
        • Norman R.J.
        Adipokines: implications for female fertility and obesity.
        Reproduction. 2005; 130: 583-597
        • Jungari S.B.
        • Chauhan B.G.
        Prevalence and determinants of premature menopause among Indian women: issues and challenges ahead.
        Health Soc. Work. 2017; 42: 79-86
        • Master-Hunter T.
        • Heiman D.L.
        Amenorrhea: evaluation and treatment.
        Am. Fam. Phys. 2006; 73: 1374-1382
        • Schwartz D.B.
        Malnutrition in chronic obstructive pulmonary disease.
        Respir. Care Clin. N. Am. 2006; 12: 521-531
        • Sarac F.
        • Oztekin K.
        • Celebi G.
        Early menopause association with employment, smoking, divorced marital status and low leptin levels.
        Gynecol. Endocrinol. 2011; 27: 273-278
        • Szegda K.L.
        • Whitcomb B.W.
        • Purdue-Smithe A.C.
        • Boutot M.E.
        • Manson J.E.
        • Hankinson S.E.
        • et al.
        Adult adiposity and risk of early menopause.
        Hum. Reprod. 2017; 32: 2522-2531
        • Sadrzadeh S.
        • Verschuuren M.
        • Schoonmade L.J.
        • Lambalk C.B.
        • Painter R.C.
        The effect of adverse intrauterine conditions, early childhood growth and famine exposure on age at menopause: a systematic review.
        J. Dev. Orig. Health Dis. 2018; 9: 127-136
        • Cresswell J.L.
        • Egger P.
        • Fall C.H.
        • Osmond C.
        • Fraser R.B.
        • Barker D.J.
        Is the age of menopause determined in-utero?.
        Early Hum. Dev. 1997; 49: 143-148
        • Tom S.E.
        • Cooper R.
        • Kuh D.
        • Guralnik J.M.
        • Hardy R.
        • Power C.
        Fetal environment and early age at natural menopause in a British birth cohort study.
        Hum. Reprod. 2010; 25: 791-798
        • Canavez F.S.
        • Werneck G.L.
        • Parente R.C.
        • Celeste R.K.
        • Faerstein E.
        The association between educational level and age at the menopause: a systematic review.
        Arch. Gynecol. Obstet. 2011; 283: 83-90
        • Yarde F.
        • Broekmans F.J.
        • van der Pal-de Bruin K.M.
        • Schonbeck Y.
        • te Velde E.R.
        • Stein A.D.
        • et al.
        Prenatal famine, birthweight, reproductive performance and age at menopause: the Dutch hunger winter families study.
        Hum. Reprod. 2013; 28: 3328-3336
        • Elias S.G.
        • van Noord P.A.H.
        • Peeters P.H.M.
        • Tonkelaar I.D.
        • Grobbee D.E.
        Caloric restriction reduces age at menopause: the effect of the 1944–1945 Dutch famine.
        Menopause. 2018; 25: 1232-1237
        • Mishra G.
        • Hardy R.
        • Kuh D.
        Are the effects of risk factors for timing of menopause modified by age? Results from a British birth cohort study.
        Menopause. 2007; 14: 717-724
        • Hardy R.
        • Kuh D.
        Does early growth influence timing of the menopause? Evidence from a British birth cohort.
        Hum. Reprod. 2002; 17: 2474-2479
        • Mishra G.D.
        • Cooper R.
        • Tom S.E.
        • Kuh D.
        Early life circumstances and their impact on menarche and menopause.
        Womens Health (Lond.). 2009; 5: 175-190
        • Hardy R.
        • Kuh D.
        Social and environmental conditions across the life course and age at menopause in a British birth cohort study.
        BJOG. 2005; 112: 346-354
        • Lawlor D.A.
        • Ebrahim S.
        • Smith G.D.
        The association of socio-economic position across the life course and age at menopause: the British Women’s Heart and Health Study.
        BJOG. 2003; 110: 1078-1087
        • Richards M.
        • Kuh D.
        • Hardy R.
        • Wadsworth M.
        Lifetime cognitive function and timing of the natural menopause.
        Neurology. 1999; 53: 308-314
        • Kuh D.
        • Butterworth S.
        • Kok H.
        • Richards M.
        • Hardy R.
        • Wadsworth M.E.
        • et al.
        Childhood cognitive ability and age at menopause: evidence from two cohort studies.
        Menopause. 2005; 12: 475-482
        • Whalley L.J.
        • Fox H.C.
        • Starr J.M.
        • Deary I.J.
        Age at natural menopause and cognition.
        Maturitas. 2004; 49: 148-156
        • Allsworth J.E.
        • Zierler S.
        • Lapane K.L.
        • Krieger N.
        • Hogan J.W.
        • Harlow B.L.
        Longitudinal study of the inception of perimenopause in relation to lifetime history of sexual or physical violence.
        J. Epidemiol. Commun. Health. 2004; 58: 938-943
        • Allsworth J.E.
        • Zierler S.
        • Krieger N.
        • Harlow B.L.
        Ovarian function in late reproductive years in relation to lifetime experiences of abuse.
        Epidemiology. 2001; 12: 676-681
        • Magnus M.C.
        • Anderson E.L.
        • Howe L.D.
        • Joinson C.J.
        • Penton-Voak I.S.
        • Fraser A.
        Childhood psychosocial adversity and female reproductive timing: a cohort study of the ALSPAC mothers.
        J. Epidemiol. Commun. Health. 2018; 72: 34-40
        • Chrousos G.P.
        • Torpy D.J.
        • Gold P.W.
        Interactions between the hypothalamic-pituitary-adrenal axis and the female reproductive system: clinical implications.
        Ann. Intern. Med. 1998; 129: 229-240
        • Prasad S.
        • Tiwari M.
        • Pandey A.N.
        • Shrivastav T.G.
        • Chaube S.K.
        Impact of stress on oocyte quality and reproductive outcome.
        J. Biomed. Sci. 2016; 23: 36
        • Wise L.A.
        • Krieger N.
        • Zierler S.
        • Harlow B.L.
        Lifetime socioeconomic position in relation to onset of perimenopause.
        J. Epidemiol. Commun. Health. 2002; 56: 851-860
        • Mishra G.D.
        • Chung H.F.
        • Gelaw Y.A.
        • Loxton D.
        The role of smoking in the relationship between intimate partner violence and age at natural menopause: a mediation analysis.
        Womens Midlife Health. 2018; 4: 1
        • The NAMS 2017 Hormone Therapy Position Statement Advisory Panel
        The 2017 hormone therapy position statement of the North American Menopause Society.
        Menopause. 2017; 24: 728-753
        • Vujovic S.
        • Brincat M.
        • Erel T.
        • Gambacciani M.
        • Lambrinoudaki I.
        • Moen M.H.
        • et al.
        EMAS position statement: managing women with premature ovarian failure.
        Maturitas. 2010; 67: 91-93
      1. NICE Guideline [NG23], Menopause: Diagnosis and Management, 2015. https://www.nice.org.uk/guidance/ng23. (Accessed 24 January 2019).