By Jeffrey T. Jensen, MD

Leon Speroff Professor and Vice Chair for Research, Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland

Dr. Jensen reports he is a consultant for Teva Pharmaceuticals, Microchips, and Evofem; is a consultant for and receives grant research support from Bayer Healthcare, Merck, Agile Pharm, Population Council, AbbVie, ContraMed, and FHI360; and receives grant/research support from HRA Pharma and Medicines 360.

SYNOPSIS: A meta-analysis suggests that early menopause increases the risk of cardiovascular disease and all-cause mortality.

SOURCE: Muka T, Oliver-Williams C, Kunutsor S, 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; Sep. 14. Doi: 10.1001/jamacardio.2016.2415 [Epub ahead of print].

The existing literature supports that menopause increases the risk of cardiovascular disease. However, whether early-onset menopause increases this risk further is controversial. Muka et al conducted a systematic review to identify studies evaluating age of menopause (exposure) and cardiovascular disease risk or mortality (outcomes). The search strategy identified 9,439 unique citations. After excluding reviews, letters, case reports, in vitro or animal studies, and studies without the proper exposure or outcomes, the authors screened 68 full-text manuscripts for eligibility and identified 33 pertinent articles reflecting the results of 32 (24 prospective cohort, two case-control, six cross-sectional) unique studies with data on 342,284 women. All but one of the included studies evaluated cardiovascular disease risk in relation to the age at onset of menopause, and four studies evaluated the risk in relation to time since onset of menopause.

In the pooled meta-analysis, compared to women with onset of menopause at age 45 years or beyond, those with very early onset of menopause younger than 45 years had a significant increase in coronary heart disease risk (adjusted relative risk [RR], 1.50; 95% confidence interval [CI], 1.28-1.76), cardiovascular disease mortality (RR, 1.11; 95% CI, 1.03-1.20), and all-cause mortality (RR, 1.19; 95% CI, 1.08-1.31), but not in stroke risk (RR, 1.23; 95% CI, 0.98-1.53) or stroke mortality (RR, 0.99; 95% CI, 0.92-1.07). In contrast, onset of menopause in the late 40s (45-49 years of age) compared with 50-54 years of age did not significantly increase risk in any of these categories. The results support premature or early-onset menopause as a risk factor for coronary heart disease, cardiovascular disease mortality, and overall mortality.


Meta-analysis offers many advantages to the investigator, but few rewards to the reader. Combining the results of previous studies yields impressive numbers of subjects and events that can provide statistical significance without the high costs associated with subject recruitment and follow-up in prospective studies, or drudgery of data cleaning and selection of appropriate controls for a case-control study. The routine disclaimer associated with meta-analysis applies to this paper — interpret these results with caution!

Although the paper by Muka et al received some press, the primary references already supported a relationship between early menopause and coronary heart disease risk. Lokkegaard et al used the Danish Nurse Cohort study to obtain data on age at menopause and cardiovascular disease.1 These authors found that menopause before both age 40 years and 45 years was associated with an increased risk of ischemic heart disease, with the greatest risk seen in women with early oophorectomy. In the U.S. Multi-Ethnic Study of Atherosclerosis cohort of 2,509 women, surgical or natural menopause at age < 46 years of age increased the risk of both coronary heart disease (HR, 2.08; 95% CI, 1.17-3.70) and stroke (RR, 2.19; 95% CI, 1.11-4.32).2 The meta-analysis extends this work by showing a significant increase in cardiovascular disease mortality and all-cause mortality among women with a very young age (< 45 years) of menopause. Keep in mind that these risk estimates are extremely small (11% for cardiovascular disease death and 19% for all-cause mortality).

So why focus on this paper at all? I presented evidence in last month’s OB/GYN Clinical Alert from De Kat et al that a high-risk cardiovascular profile may develop during the perimenopause.3 If so, early menopause may accelerate the progression of disease in women who accumulate cardiovascular risk factors during the perimenopause. Although we should not over-interpret the significance of the findings, death is a very serious outcome.

How should we counsel women with early menopause regarding hormone replacement therapy? In the Danish Nurse Cohort study, ever-use of hormone replacement therapy reduced the risk of cardiovascular disease, but only among those women with very early surgical menopause.1 However, ever-use is a weak indicator of exposure, and may not reflect the benefit or risk associated with consistent longitudinal exposure. So more studies are needed to confirm benefit. In my practice, I counsel healthy postmenopausal women to strongly consider hormonal therapy, since delaying initiation may allow atherosclerotic changes to develop, increasing the risk of myocardial infarction and stroke.4 Estrogens reduce the risk of atherosclerotic plaque formation.5 As I have previously mentioned, as estrogen levels decline, this protection diminishes, and plaque accumulates, particularly in women with unfavorable lipid profiles and other cardiovascular risk factors. Age matters and so does progestogen exposure. The combined data from both the combined (conjugated equine estrogen [CEE]/medroxyprogesterone acetate) and estrogen-only (CEE) arms of the Women’s Health Initiative study showed a nonsignificant reduction in risk of myocardial infarction (RR, 0.76; 95% CI, 0.50-1.16) for women who initiated therapy less than 10 years post-menopause compared to the significant elevation of 1.28 (95% CI, 1.03-1.58) for women who began treatment 20 or more years post-menopause.6 We also know that women 50-59 years of age randomized to CEE alone in the Women’s Health Initiative showed a lower incidence of cardiovascular disease and all-cause mortality than those who received placebo.7 Although a reduction in these risks was not observed in older women randomized to CEE only, there was no significant increase in risk.

The great reluctance of primary care physicians to recommend hormone replacement therapy for any women makes our jobs as gynecologists difficult. I feel we have sufficient evidence to strongly recommend hormonal therapy for healthy menopausal women. For our youngest patients experiencing early menopause, we must be even more strident in our messaging.


  1. Lokkegaard E, Jovanovic Z, Heitmann BL, et al. The association between early menopause and risk of ischaemic heart disease: Influence of hormone therapy. Maturitas 2006;53:226-233.
  2. Wellons M, Ouyang P, Schreiner PJ, et al. Early menopause predicts future coronary heart disease and stroke: The Multi-Ethnic Study of Atherosclerosis. Menopause 2012;19:1081-1087.
  3. de Kat AC, Verschuren WM, Eijkemans MJ, et al. The association of low ovarian reserve with cardiovascular disease risk: A cross-sectional population-based study. Hum Reprod 2016;31:1866-1874.
  4. Hodis HN, Mack WJ, Henderson VW, et al. Vascular effects of early versus late postmenopausal treatment with estradiol. N Engl J Med 2016;374:1221-1231.
  5. Miller VM, Clarkson TB, Harman SM, et al. Women, hormones, and clinical trials: A beginning, not an end. J Appl Physiol 2005;99:381-383.
  6. Rossouw JE, Prentice RL, Manson JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 2007;297:1465-1477.
  7. LaCroix AZ, Chlebowski RT, Manson JE, et al. Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: A randomized controlled trial. JAMA 2011;305:1305-1314.