EMAS position statement: Predictors of premature and early natural 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
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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.
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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.
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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.
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