By Robert W. Rebar, MD
Founding Chair Emeritus and Professor, Department of Obstetrics and Gynecology, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, MI
Dr. Rebar reports no financial relationships relevant to this field of study.
SYNOPSIS: Natural and surgical menopause appear to be associated with an increased risk for cardiovascular disease.
SOURCE: Honigberg MC, Zekavat SM, Aragam K, et al. Association of premature natural and surgical menopause with incident cardiovascular disease. JAMA 2019;322:2411-2421.
Even though cardiovascular disease is the leading cause of death among women worldwide, sex-specific risk factors are poorly appreciated.1 Because recent guidelines from the American College of Cardiology/American Heart Association indicate the need to use a history of premature menopause (defined as menopause prior to age 40 years) to refine cardiovascular risk assessments,2,3 investigators analyzed data from the observational cohort UK (United Kingdom) Biobank to assess whether early natural or surgical menopause increased the risk for cardiovascular disease. A total of 144,260 postmenopausal women (95.5% white) between the ages of 40 and 69 years (mean age 59.9 ± 5.4 standard deviation [SD] years) were recruited between 2006 and 2010 and followed through August 2016. Of these, 4,904 (3.4%) had natural premature menopause and 644 (0.4%) had surgical premature menopause. In the analyses, those postmenopausal women without premature menopause served as the reference group. The mean (± SD) age at menopause was 50.3 ± 4.2 years among women without premature menopause, 35.4 ± 3.9 years among women with natural premature menopause, and 34.2 ± 4.2 years among women with surgical premature menopause (P < 0.001). It is important to note that women with natural and surgical premature menopause were significantly more likely than women without premature menopause to have prevalent cardiovascular risk factors, to have smoked tobacco, and to have used menopausal hormone therapy (MHT) at enrollment. Participants were followed for a median of seven years (interquartile range 6.3-7.7).
A total of 5,415 women (3.9%) without premature menopause, 292 (6.0%) with natural premature menopause, and 49 (7.6%) with surgical premature menopause developed one or more incident cardiovascular diseases during follow-up. The incidence rate for the primary outcome (a composite of coronary artery disease, heart failure, aortic stenosis, mitral regurgitation, atrial fibrillation, ischemic stroke, peripheral artery disease, and venous thromboembolism) was 5.70 per 1,000 woman-years for women without premature menopause, 8.78 per 1,000 woman-years for natural premature menopause, and 11.27 per 1,000 woman-years for surgical premature menopause (both P < 0.001 vs. women without premature menopause). After adjustment for conventional cardiovascular risk factors as well as ever use of MHT, both natural premature menopause (hazard ratio [HR], 1.36; 95% confidence interval [CI], 1.19-1.56; P < 0.001) and surgical premature menopause (HR, 1.87; 95% CI, 1.36-2.58;
P < 0.001) were independently associated with incident cardiovascular disease. Associations of premature menopause with incident cardiovascular disease remained similar after incorporating ever use of MHT, current MHT use, duration of MHT use, and delayed initiation of MHT use five or more years after menopause.
These important findings are not easy to interpret because they are somewhat at odds with prior prospective cohort studies. In a study of 121,700 U.S. women 30 to 55 years of age who were followed from 1976 to 1982, women who had undergone bilateral oophorectomy and who had never taken estrogens had an increased risk (rate ratio [RR], 2.2; 95% CI, 1.2-4.2) of coronary heart disease as compared to normal premenopausal women.4 The use of estrogens in the postmenopausal period appeared to eliminate the increased risk among these women as compared to premenopausal women (RR, 0.9; 95% CI, 0.6-1.6). These earlier data suggested that, in contrast to natural menopause, bilateral oophorectomy increased the risk of coronary heart disease, with the increased risk prevented by estrogen therapy. A much more recent subgroup analysis of the Women’s Health Initiative (WHI) estrogen-alone trial of 9,939 women aged 50 to 79 years at the initiation of the study treated with conjugated equine estrogens (0.625 mg or placebo daily for a median of 7.2 years and followed for 18 years) indicated that women with bilateral oophorectomy had an estrogen-associated reduction in all-cause mortality.5
In addition, experimental data in cynomolgus monkeys support a beneficial effect of estrogen on the cardiovascular system when the estrogen is begun shortly following bilateral oophorectomy but not when it is begun far removed from the loss of ovarian function.6 A series of experiments have demonstrated that early and continued estrogen treatment can prevent the development of atherosclerotic plaques in the coronary vessels as well as stabilize further plaque development as documented by histological assessment of the vessels themselves. Experimental studies also have suggested that when initiated late in the atherosclerotic process, estrogen plus progestin (as is administered to women with a uterus) can have adverse effects, destabilizing existing plaques and potentially leading to a coronary heart disease event.
How, then, do we reconcile these disparate findings? It is important to note that the associations reported in the current study from the UK were modest at best. Moreover, associations are precisely that: associations only. Associations cannot establish causality. Large cohort studies such as this one from the UK rely on patient recall regarding the age of menopause and may be subject to recall bias. The reasons for bilateral oophorectomy were not available to the investigators but admittedly were unlikely the result of cardiovascular etiologies. The investigators themselves noted that the UK Biobank has a “healthy participant” selection bias, and the number of resulting cases of incident cardiovascular disease was relatively small. The small number of women in the UK study who had premature menopause also makes establishing associations more difficult with larger confidence intervals. No single study should be considered alone; the data in the entire field should be considered together.
Although the initial report of the WHI findings established that estrogens should not be provided to prevent cardiovascular disease,7 subsequent analysis of the data indicated that estrogen alone did not increase the risks for women when begun shortly after menopause onset.8 Subsequent analysis of data from 27,347 postmenopausal women aged 50 to 79 years and randomized to conjugated equine estrogens and medroxyprogesterone acetate for a median of 5.6 years or to conjugated equine estrogens alone (for women without a uterus) for 7.2 years found no increased risk for all-cause, cardiovascular, or cancer mortality in both arms together or individually during 18 years of cumulative follow-up.9
Taken together, then, these data imply to me that women with premature menopause should be offered estrogen therapy at least until the expected age of natural menopause if there are no contraindications to its use. However, whether provided estrogen or not, women with premature menopause should be counseled that they may be at increased risk for cardiovascular disease and should pursue a healthy lifestyle and a healthy diet. When all is said and done, isn’t that what we should recommend to all our patients?
- Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics — 2016 update: A report from the American Heart Association. Circulation 2016;133:e38-e360.
- Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019;73:e285-e350.
- Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2019;140:e596-e646.
- Colditz GA, Willett WC, Stampfer MJ, et al. Menopause and the risk of coronary heart disease in women. N Engl J Med 1987;316:1105-1110.
- Manson JE, Aragaki AK, Bassuk SS, et al. Menopausal estrogen-alone therapy and health outcomes in women with and without bilateral oophorectomy: A randomized trial. Ann Intern Med 2019; Sept 10. doi:10.7326/M19-0274. [Online ahead of print].
- Clarkson TB, Appt SE. Controversies about HRT – lessons from monkey models. Maturitas 2005;51:64-74.
- Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321-333.
- Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: The Womenʼs Health Initiative randomized controlled trial. JAMA 2004;291:1701-1712.
- Manson JE, Aragaki AK, Rossouw JE, et al. Menopausal hormone therapy and long-term all-cause and cause-specific mortality: The Womenʼs Health Initiative randomized trials. JAMA 2017;318:927-938.