Elsevier

Maturitas

Volume 123, May 2019, Pages 82-88
Maturitas

EMAS position statement: Predictors of premature and early natural menopause

https://doi.org/10.1016/j.maturitas.2019.03.008Get rights and content

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.

Introduction

Timing of menopause is an indicator of ovarian function and has important health implications. Natural menopause is commonly defined as the time when a woman has experienced 12 consecutive months of amenorrhoea without obvious cause [1], such as removal of both ovaries (bilateral oophorectomy), chemotherapy or radiotherapy for cancer. The International collaboration on the Life course Approach to reproductive health and Chronic disease Events (InterLACE) [2] recently reported that the average age at natural menopause across 21 studies from 10 countries ranged from 47 to 53 years, varying across ethnic groups from 48 years for women of South Asian background to 50 years for Caucasian women living in Australia and Europe, and 52 years for Japanese women [3]. These results are primarily obtained from women living in high-income countries, hence the average age at menopause for women in low- and middle-income countries may lie outside this range.

Menopause before the age of 40 is commonly referred to as premature menopause, although primary ovarian insufficiency (POI) is currently considered the most apposite term to denote the loss of ovarian function as it does not specify definitive failure [4]. Menopause that occurs between 40 and 45 years is termed early menopause. Data from the InterLACE consortium indicate that in the general female population of high-income countries, the prevalence of premature menopause is 2% (range 1–3%) and of early menopause is 7.6% (range 5–10%), suggesting that almost one in 10 women have premature or early menopause [5]. Recent reviews have concluded that premature or early menopause is associated with an increased risk of all-cause mortality, cardiovascular disease, type 2 diabetes, depression, osteoporosis and fracture [[6], [7], [8], [9], [10], [11]]. There is some evidence that premature menopause is associated with greater than average cognitive decline in later life [12], but current studies do not support a consistent association between early menopause and dementia risk [13].

Premature menopause is often idiopathic, but there are some genetic and autoimmune links, with X chromosome defects being the most common genetic contributors [14]. Few epidemiological studies have specifically examined the associations of non-genetic factors with premature and early menopause [5,15,16]. This position statement highlights the genetic, reproductive, lifestyle, and early-life and social/environmental factors associated with premature and early natural menopause. As findings in relation to premature menopause are limited, we focus on early menopause but include evidence specific to premature menopause where it is available.

Section snippets

Heritability

Heritability estimates of age at menopause in mothers, daughters and sisters provide evidence for the contribution of genetic factors to the timing of menopause. The Framingham Heart Study reported that the heritability estimate for the adjusted age at natural menopause for the pooled sample of original and offspring cohorts was 0.52 [17]. This suggests that genetic effects explain at least half of the inter-individual variation in age at natural menopause. Cross-national heritability estimates

Recommendations

Women with POI or early menopause experience an extended period of time with loss of ovarian hormone activity, and have increased risks of persistent vasomotor menopausal symptoms, cognitive or affective disorders, heart disease, stroke, bone loss and overall mortality [81]. The most recent recommendations are set out in the 2017 hormone therapy position statement of the North American Menopause Society (NAMS) [81]. This identifies women with POI or early natural or induced menopause or who

Summary

  • Premature menopause (also known as primary ovarian insufficiency or POI) is defined as menopause before the age of 40, while early menopause is defined as menopause between the ages of 40 and 45.

  • Genetic factors contribute to around 50% of the variation in age at natural menopause. A family history of premature or early menopause, being a child of a multiple pregnancy and some specific genetic variants have been identified as risk factors for premature and early menopause.

  • Early menarche,

Contributors

Gita D. Mishra and Hsin-Fang Chung prepared the initial draft, which was circulated to all other named authors (EMAS board members) for comments and approval; production was coordinated by Irene Lambrinoudaki and Margaret Rees.

Conflict of interest

Gita D. Mishra, none declared.

Hsin-Fang Chung, none declared.

Antonio Cano, none declared.

Peter Chedraui, none declared.

Dimitrios G. Goulis, none declared.

Patrice Lopes, none declared.

Alfred Mueck, in the past 5 years, has received research funding from various pharmaceutical companies that produce and/or sell products used as hormone therapy in peri- and postmenopausal women; as well as lecture fees from various pharmaceutical companies for lectures on hormone therapy or other issues of

Funding

No funding was received for the preparation of this position statement.

Ethical statement

No ethical approval was required for the preparation of this position statement.

Provenance and peer review

This article is an EMAS position statement and was not externally peer reviewed.

References (83)

  • S.D. Sullivan et al.

    Hormone replacement therapy in young women with primary ovarian insufficiency and early menopause

    Fertil. Steril.

    (2016)
  • R.C. Parente et al.

    The relationship between smoking and age at the menopause: a systematic review

    Maturitas

    (2008)
  • E.B. Gold

    The timing of the age at which natural menopause occurs

    Obstet. Gynecol. Clin. North Am.

    (2011)
  • J.A. Baron et al.

    The antiestrogenic effect of cigarette smoking in women

    Am. J. Obstet. Gynecol.

    (1990)
  • J.L. Cresswell et al.

    Is the age of menopause determined in-utero?

    Early Hum. Dev.

    (1997)
  • D.A. Lawlor et al.

    The association of socio-economic position across the life course and age at menopause: the British Women’s Heart and Health Study

    BJOG

    (2003)
  • L.J. Whalley et al.

    Age at natural menopause and cognition

    Maturitas

    (2004)
  • G.D. Mishra et al.

    The role of smoking in the relationship between intimate partner violence and age at natural menopause: a mediation analysis

    Womens Midlife Health

    (2018)
  • S. Vujovic et al.

    EMAS position statement: managing women with premature ovarian failure

    Maturitas

    (2010)
  • J.L. Shifren et al.

    The North American Menopause Society recommendations for clinical care of midlife women

    Menopause

    (2014)
  • InterLACE Study Team

    Variations in reproductive events across life: a pooled analysis of data from 505,147 women across ten countries

    Hum. Reprod.

    (2019)
  • G.D. Mishra et al.

    Early menarche, nulliparity and the risk for premature and early natural menopause

    Hum. Reprod.

    (2017)
  • T. Muka 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)
  • P. Anagnostis 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)
  • J.C. Gallagher

    Effect of early menopause on bone mineral density and fractures

    Menopause

    (2007)
  • S.S. Faubion et al.

    Long-term health consequences of premature or early menopause and considerations for management

    Climacteric

    (2015)
  • P. Anagnostis et al.

    Association between age at menopause and fracture risk: a systematic review and meta-analysis

    Endocrine

    (2019)
  • M.K. Georgakis 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)
  • J. Ryan et al.

    Impact of a premature menopause on cognitive function in later life

    BJOG

    (2014)
  • D. Zhu 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)
  • D. Zhu et al.

    Body mass index and age at natural menopause: an international pooled analysis of 11 prospective studies

    Eur. J. Epidemiol.

    (2018)
  • J.M. Murabito et al.

    Heritability of age at natural menopause in the Framingham Heart Study

    J. Clin. Endocrinol. Metab.

    (2005)
  • H. Snieder et al.

    Genes control the cessation of a woman’s reproductive life: a twin study of hysterectomy and age at menopause

    J. Clin. Endocrinol. Metab.

    (1998)
  • J.P. de Bruin et al.

    The role of genetic factors in age at natural menopause

    Hum. Reprod.

    (2001)
  • R.G. Gosden et al.

    Prevalence of premature ovarian failure in monozygotic and dizygotic twins

    Hum. Reprod.

    (2007)
  • K.S. Ruth et al.

    Events in early life are associated with female reproductive ageing: a UK Biobank Study

    Sci. Rep.

    (2016)
  • S.A. Treloar et al.

    Birth weight and age at menopause in Australian female twin pairs: exploration of the fetal origin hypothesis

    Hum. Reprod.

    (2000)
  • L. Stolk et al.

    Loci at chromosomes 13, 19 and 20 influence age at natural menopause

    Nat. Genet.

    (2009)
  • C. He et al.

    Genome-wide association studies identify loci associated with age at menarche and age at natural menopause

    Nat. Genet.

    (2009)
  • L. Stolk et al.

    Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways

    Nat. Genet.

    (2012)
  • M. Elzaiat et al.

    The genetic make-up of ovarian development and function: the focus on the transcription factor FOXL2

    Clin. Genet.

    (2017)
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