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. 2019 Dec 24;322(24):2411-2421.
doi: 10.1001/jama.2019.19191.

Association of Premature Natural and Surgical Menopause With Incident Cardiovascular Disease

Michael C Honigberg  1   2   3   4 , Seyedeh Maryam Zekavat  3   4   5 , Krishna Aragam  1   2   3   4 , Phoebe Finneran  1   4 , Derek Klarin  3   6 , Deepak L Bhatt  7 , James L Januzzi Jr  1   2 , Nandita S Scott  1   2 , Pradeep Natarajan  1   2   3   4
Affiliations

Association of Premature Natural and Surgical Menopause With Incident Cardiovascular Disease

Michael C Honigberg et al. JAMA. .

Abstract

Importance: Recent guidelines endorse using history of menopause before age 40 years to refine atherosclerotic cardiovascular disease risk assessments among middle-aged women. Robust data on cardiovascular disease risk in this population are lacking.

Objective: To examine the development of cardiovascular diseases and cardiovascular risk factors in women with natural and surgical menopause before age 40 years.

Design, setting, and participants: Cohort study (UK Biobank), with adult residents of the United Kingdom recruited between 2006 and 2010. Of women who were 40 to 69 years old and postmenopausal at study enrollment, 144 260 were eligible for inclusion. Follow-up occurred through August 2016.

Exposures: Natural premature menopause (menopause before age 40 without oophorectomy) and surgical premature menopause (bilateral oophorectomy before age 40). Postmenopausal women without premature menopause served as the reference group.

Main outcomes and measures: The primary outcome was a composite of incident coronary artery disease, heart failure, aortic stenosis, mitral regurgitation, atrial fibrillation, ischemic stroke, peripheral artery disease, and venous thromboembolism. Secondary outcomes included individual components of the primary outcome, incident hypertension, hyperlipidemia, and type 2 diabetes.

Results: Of 144 260 postmenopausal women included (mean [SD] age at enrollment, 59.9 [5.4] years), 4904 (3.4%) had natural premature menopause and 644 (0.4%) had surgical premature menopause. Participants were followed up for a median of 7 years (interquartile range, 6.3-7.7). The primary outcome occurred in 5415 women (3.9%) with no premature menopause (incidence, 5.70/1000 woman-years), 292 women (6.0%) with natural premature menopause (incidence, 8.78/1000 woman-years) (difference vs no premature menopause, +3.08/1000 woman-years [95% CI, 2.06-4.10]; P < .001), and 49 women (7.6%) with surgical premature menopause (incidence, 11.27/1000 woman-years) (difference vs no premature menopause, +5.57/1000 woman-years [95% CI, 2.41-8.73]; P < .001). For the primary outcome, natural and surgical premature menopause were associated with hazard ratios of 1.36 (95% CI, 1.19-1.56; P < .001) and 1.87 (95% CI, 1.36-2.58; P < .001), respectively, after adjustment for conventional cardiovascular disease risk factors and use of menopausal hormone therapy.

Conclusions and relevance: Natural and surgical premature menopause (before age 40 years) were associated with a small but statistically significant increased risk for a composite of cardiovascular diseases among postmenopausal women. Further research is needed to understand the mechanisms underlying these associations.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Bhatt reported serving on advisory boards for Cardax, Cereno Scientific, Elsevier Practice Update Cardiology, Medscape Cardiology, PhaseBio, and Regado Biosciences; on the board of directors for Boston VA Research Institute, Society of Cardiovascular Patient Care, and TobeSoft; as a chair for the American Heart Association Quality Oversight Committee; on the data monitoring committees for Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards Lifesciences), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), and Population Health Research Institute; as site co-investigator for Biotronik, Boston Scientific, St Jude Medical (now Abbott), and Svelte; and as trustee for the American College of Cardiology. Dr Bhatt also reported receiving honoraria from the American College of Cardiology (senior associate editor, Clinical Trials and News, ACC.org; vice chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (editor in chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (editor in chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (guest editor; associate editor), Medtelligence/ReachMD (CME steering committees), Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (chief medical editor, Cardiology Today’s Intervention), and Society of Cardiovascular Patient Care (secretary/treasurer), WebMD (CME steering committees); other unfunded work with Clinical Cardiology (deputy editor), NCDR-ACTION Registry Steering Committee (chair), and VA CART Research and Publications Committee (chair); research funding from Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Idorsia, Ironwood, Ischemix, Eli Lilly, Medtronic, PhaseBio, Pfizer, Regeneron, Roche, Sanofi Aventis, Synaptic, and The Medicines Company; and royalties from Elsevier (editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease) and conducting unfunded research for FlowCo, Merck, Novo Nordisk, PLx Pharma, and Takeda. Dr Januzzi reported serving as a trustee of the American College of Cardiology; receiving grant support from Novartis Pharmaceuticals, Roche Diagnostics, Abbott, Singulex, and Prevencio; receiving consulting income from Abbott, Janssen, Novartis, Pfizer, Merck, and Roche Diagnostics; and participating in clinical end point committees/data safety monitoring boards for Abbott, AbbVie, Amgen, Boehringer Ingelheim, Janssen, and Takeda. Dr Natarajan reported receiving grant support from Amgen, Apple, and Boston Scientific; personal fees from Blackstone Life Sciences; and consulting income from Apple, all unrelated to this work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Creation of the Study Sample From Women in the UK Biobank
Postmenopausal women who were aged 40 to 69 years old at study enrollment were considered for inclusion. Exclusion criteria included unknown menopausal status, missing data on age at menopause, and prevalent diagnoses of coronary artery disease, heart failure, aortic stenosis, mitral regurgitation, atrial fibrillation, ischemic stroke, peripheral artery disease, venous thromboembolism, or congenital heart disease. aThe mean (SD) age at enrollment was 57.4 (7.8) years for the surgical premature menopause group, 58.9 (7.1) years for the natural premature menopause group, and 60.0 (5.4) years for the group without premature menopause.
Figure 2.
Figure 2.. Hazard Ratios and 95% CIs for Coronary Artery Disease, Aortic Stenosis, and Atrial Fibrillation Associated With Different Age at Menopause Thresholds
Groups are inclusive of all women with age at menopause below the listed cutoff. The reference group for all models is menopause at age 50 years or older. Hazard ratios and 95% CIs are derived from Cox proportional hazard models. A, Sparsely adjusted models are adjusted for age and race/ethnicity. B, Fully adjusted models are adjusted for age, race/ethnicity, prevalent type 2 diabetes, ever having smoked, systolic blood pressure, use of antihypertensive medication, non–high-density lipoprotein cholesterol, use of cholesterol-lowering medication, body mass index, C-reactive protein, and history of menopausal hormone therapy use.
Figure 3.
Figure 3.. Cumulative Incidence of Hypertension, Hyperlipidemia, and Type 2 Diabetes Among Women Without Each Condition at Enrollment
Women enrolled in the UK Biobank across a 3-decade range of ages. These cumulative incidence graphs depict the probability of developing hypertension, hyperlipidemia, and type 2 diabetes in women followed up to a given age, depicted on the x-axis, among those without each prevalent condition at study enrollment. Women with prevalent hypertension, hyperlipidemia, and type 2 diabetes were excluded from the respective cumulative incidence graph. In addition, at enrollment, 33.9% of women with surgical premature menopause, 30.7% with natural premature menopause, and 27.1% without premature menopause had hypertension; 15.2% with surgical premature menopause, 16.5% with natural premature menopause, and 11.9% without premature menopause had hyperlipidemia; and 2.0% with surgical premature menopause, 2.7% with natural premature menopause, and 1.4% without premature menopause had type 2 diabetes.
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