Contradictory Findings During Menopause
April 20, 2017
To the BMJ Editor:
With regard to the report by Mytton and colleagues:
Mytton et al in an extensive data linked retrospective study reported that women who had hysterectomy with ovarian conservation exhibited a significantly lower risk of all-cause mortality and mortality from ischemic heart disease and cancer (1). They noted that removal of both ovaries protects against ovarian cancer while increasing the risk of cardiovascular mortality. Their observations contradict a detailed report of a cohort of 2873 Framingham Study female participants prospectively followed for 24 years (2). The 1978 study provided prospective evidence that menopause associates with a highly significant two-fold increase in the incidence of heart disease. Detailed data from the older study showed that cardiovascular protection diminished after surgical menopause regardless of whether or not oophorectomy had been performed.
Recently, Muka et al reported a higher risk of cardiovascular disease mortality and an overall mortality in women who experience premature or early on-set menopause (3). However, postmenopausal women on hormones had a doubled risk of coronary heart disease.
We suggest that observed considerable increases in serum ferritin levels at menopause marks a dramatic shift in iron metabolism possibly linked to increased iron stores or with heightened inflammatory responses (4). We invite investigators to consider that significantly increased risk of cardiovascular disease in postmenopausal women associates with altered iron homeostasis and potential increase in body iron stores after menstrual blood flow cessation (4).
The hypothesis that increased cardiovascular disease results from oxidative stress catalyzed by excess iron accumulation was tested in the VA Cooperative Study Trial 410, The Iron and Atherosclerosis Study (FeAST). The effects of phlebotomy on clinical outcomes were tested in peripheral arterial disease (PAD) with iron store reduction, estimated by serum ferritin; to levels approaching 25 ng/mL as occur in healthy menstruating women (5). Data from this prospective randomized study demonstrated that lower ferritin levels (76-78 ng/mL) predicted improved outcomes in younger men with (PAD) upon removal of an amount of iron represented by approximately a liter of blood. Lower ferritin levels strongly predicted improved clinical outcomes, regardless of randomization group, with a threshold for benefit below 76-78 ng/mL.
The striking relationship between menopause, whether surgical with or without oophorectomy, or natural, and coronary disease risk needs clarification. Dramatic changes during menopause in iron metabolism and hormone levels require prospective, granular studies to better understand and characterize the complex relationships occurring during this transition. One possibility is that iron in catalytic form stimulates inflammatory responses and leukocyte activity and associates with elevation of IL-6 and other inflammatory biomarkers based on our findings of direct associations (6) between elevated ferritin and inflammatory biomarkers, predominantly IL 6, and mortality.
Data from multiple sources support a need for additional studies testing the relationship between increased cardiovascular disease risk related to changing iron homeostasis, the role of inflammation and hormone status in women during and after surgical or natural menopause. Additionally, Gordon et al (2) reported unfavorable alterations in lipid metabolism with cessation of menses, most evident with bilateral oophorectomy plus hysterectomy. This risk factor may also play an important role. We recommend prospective serial measurements hormone replacement therapy (HRT) with estrogen and progestin or with estrogen alone, along with serial measures of hormone levels, lipid panels, ferritin, iron, hepcidin and inflammatory biomarkers in pre and postmenopausal women to better understand unique factors contributing to increased cardiovascular mortality. (4). An enhanced understanding of the biological basis for menopausal effects on cardiovascular disease offers important insights into prevention and treatment of cardiovascular disease generally.
Virginia W Hayes, MS, APN, BC: VA Sierra Nevada Health Care System, Reno Nevada
Ralph G DePalma, MD: VA Office of Research and Development, Washington, DC. Department of Surgery, Uniformed University of the Health Sciences, Bethesda, Maryland.
Leo R Zacharski, MD; VA White River Junction Health Care System, White River, Vermont.
The authors are employees of the Department of Veterans Affairs and report no financial conflicts or interests. The opinions expressed are those of the authors and not necessarily those of the Veterans Administration or the Government of the United States.
1. Mytton J, Evison F, Lilford, LJ. Removal of all ovarian tissue versus conserving ovarian tissue at time of hysterectomy in premenopausal patients with benign disease: study using routine data and data linkage. BMJ 2017;356:j372
2. Gordon, T, Kannel WB, Hjortland, C, McNamara PM. Menopause and the risk of cardiovascular disease. The Framingham Study. Ann Intern Med 1978; 89 (2): 157-161
3. 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: oi:10.1001/jamacardio.2016.2415
4. Hayes VW, DePalma RG, and Zacharski LR. Menstrual suppression, iron homeostasis, and disease risk. The Journal for Nurse Practitioners 2011; 7 (8): 660-664
5.. Zacharski LR, Shamayeva G, Chow, BK. Effect of controlled reduction of body iron stores on clinical outcomes in peripheral arterial Disease. Am Heart J 2011; 162: 949-957.
6. DePalma RG, Hayes VW, Chow BK, Shamayeva G, May PE, Zacharski LR. Ferritin levels, inflammatory biomarkers, and mortality in peripheral arterial disease: A sub study of the Iron (Fe) and Atherosclerosis Study (FeAST) Trial. J Vasc Surg. 2010; 51(6): 1498–1503
Competing interests: No competing interests