This was a cohort study from a UK Biobank  50 to 69-year-old residents of the UK, postmenopausal at the time of study enrolment between 2006 and 2010, were followed through to 2016. The participants had experienced either spontaneous POI or surgical POI before age 40; the data were compared to a reference group of postmenopausal women without premature menopause. A composite primary outcome measure was chosen of coronary artery disease, heart failure, aortic stenosis, mitral regurgitation, atrial fibrillation, ischemic stroke, peripheral artery disease, and venous thromboembolism. Of the 144 260 included in the study (mean age at enrolment 59.9 SD [5.4]), 4904(3.4%) had spontaneous POI, and 644(0.4%) had surgical POI. The primary outcome occurred in 292(6.0%) women with spontaneous POI (8.78/1000 woman-years) and 49(7.6%) women with surgical POI (11.27/1000 woman-years) compared to 5415(3.9%) women without POI (5.70/1000 woman-years). For the primary outcome, spontaneous and surgical POI was associated with HRs of 1.36(95% CI 1.19-1.56; p<0.001) and 1.87(95% CI 1.36-2.58; p<0.001) respectively after adjusting for cardiovascular disease risk factors and MHT usage. Comparing the hazards associated with spontaneous and surgical POI, there was no significant difference for the primary outcome in fully adjusted post hoc models.
It is well recognised that premature ovarian insufficiency is associated with an increased incidence of cardiovascular and cerebrovascular disease. This study confirmed a statistically significant relationship between age of menopause and the primary cardiovascular outcome measure. However, the absolute risk differences between the POI groups and the reference group were relatively small, probably because the number of cardiovascular cases was low in this relatively healthy cohort.
Only a few studies [1-3] have attempted to examine the difference in the risks between spontaneous and surgical POI. These studies have not conclusively shown a significant difference in cardiovascular risks between these types of POI. This may be because a difference does not exist, or more likely that limitations in numbers of cases studied, and methodology may have led to false-negative outcomes.
In an even larger study, data have been harmonised and pooled from 15 observational studies across 5 countries and regions from 301 438 women, which support the findings from the UK Biobank on cardiovascular disease risk. Compared with women who had menopause at 50-51 years, the risk of cardiovascular disease (coronary heart disease or stroke) was greater in women with POI (HR 1.55, 95% CI 1.38-1.73; p<0.0001) with an almost linear dose-response relationship. Each year of decrease in age at menopause was associated with a 3% increased risk of cardiovascular disease.
It is universally accepted that the increased risk of cardiovascular disease in POI is due to the potential for a prolonged hypoestrogenic state if left untreated. Meta-analyses have shown that women with POI who used MHT for longer than 10 years had the lowest risk of cardiovascular disease when compared with women who did not use MHT . Although POI studies have shown that MHT, particularly when used for more than 10 years, is associated with a lower cardiovascular risk, this was not found in some studies [1-3]. It is difficult to fully assess the relationship of cardiovascular risk in POI with MHT in cohort studies because accurate data are not always available regarding the i) timing of initiation, ii) dosage, iii) type, and iv) duration of use of MHT. A long term prospective randomised trial would be ideal, but in the absence of this, good quality prospectively collated global registry data (in progress) should provide useful information.
It is important to emphasise that younger age of menopause is not only associated with an increased risk of cardiovascular disease but also other serious conditions. A recent study in 11 258 Australian women has shown that women with POI had almost three times higher odds of developing multimorbidity in their 60s, adjusted for several chronic conditions at baseline and related risk factors . The 11 conditions studied included osteoporosis, arthritis, depression, diabetes, hypertension, and asthma.
The growing public health importance of studies that demonstrate the risks of POI to long term conditions [1-5] has been illustrated by a recent meta-analysis examining the global prevalence of POI and early menopause (EM) . This study demonstrated that the prevalence of spontaneous POI is considerably higher (3.7%) than the often-quoted prevalence of POI (1%), particularly in medium and low human development index countries.
The findings of the UK biobank and other recent cohort studies demonstrate clearly that women with spontaneous and surgical POI and early menopause are at significantly greater risk of cardiovascular and other chronic conditions than women going through menopause at the average age of 51 years. It should, therefore, be a public health priority that healthcare professionals are given adequate education and resources to identify these women at risk at an early stage. Preventive measures such as optimising lifestyle, diet, and exercise, and advice regarding MHT will have the greatest impact if instituted at the earliest stage possible.
Queen Charlotte's & Chelsea and Westminster Hospitals
Imperial College London
General Secretary International Menopause Society
Director, International Centre for Hormone Health
Honigberg MC, Zekavat SM, Aragam K, Finneran P, Klarin D, Bhatt DL, Januzzi JL Jr, Scott NS, Natarajan P. Association of Premature Natural and Surgical Menopause With Incident Cardiovascular Disease. JAMA. 2019 Nov 18.
Muka T, Oliver-Williams C, Kunutsor S, Laven JS, Fauser BC, Chowdhury R, Kavousi M, Franco OH. 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 Oct 1;1(7):767-776.
Ley SH, Li Y, Tobias DK, Manson JE, Rosner B, Hu FB, Rexrode KM. Duration of Reproductive Life Span, Age at Menarche, and Age at Menopause Are Associated With Risk of Cardiovascular Disease in Women. J Am Heart Assoc. 2017 Nov 2;6(11).
Zhu D, Chung HF, Dobson AJ, Pandeya N, Giles GG, Bruinsma F, Brunner EJ, Kuh D, Hardy R, Avis NE, Gold EB, Derby CA, Matthews KA, Cade JE, Greenwood DC, Demakakos P, Brown DE, Sievert LL, Anderson D, Hayashi K, Lee JS, Mizunuma H, Tillin T, Simonsen MK, Adami HO, Weiderpass E, Mishra GD. Age at natural menopause and risk of incident cardiovascular disease: a pooled analysis of individual patient data. Lancet Public Health. 2019 Nov;4(11):e553-e564.
Xu X, Jones M, Mishra GD. Age at natural menopause and development of chronic conditions and multimorbidity: results from an Australian prospective cohort. Hum Reprod. 2020 Jan 1;35(1):203-211.
Golezar S, Ramezani Tehrani F, Khazaei S, Ebadi A, Keshavarz Z. The global prevalence of primary ovarian insufficiency and early menopause: a meta-analysis. Climacteric. 2019 Aug;22(4):403-411.