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Comment & Response
January 04, 2017

Effect of Iron Levels on Women After Premature or Early-Onset Menopause

Author Affiliations
  • 1Medical Service, Comando Brigata Alpina “Julia,” Multinational Land Force, Udine, Italy
  • 2NCH Physician Group, Naples, Florida
JAMA Cardiol. Published online January 4, 2017. doi:10.1001/jamacardio.2016.5083

To the Editor Muka et al1 found a higher risk of adverse cardiovascular outcomes in women who experience premature or early-onset menopause. This detrimental association is usually thought to be associated with the early loss of the ovarian function through menopause. However, the estrogen hypothesis is not consistent with epidemiological findings that premenopausal hysterectomy essentially cancels the protection even in patients with preserved functioning ovaries.2 Of note, healthy premenopausal women are largely protected from coronary heart disease; remarkably, so are women with heterozygous familial hypercholesterolemia.3 Despite a genetically determined, grossly unfavorable lipid phenotype, cardiovascular protection suggests not only that the protective factor is powerful but also that it does not operate through a lipid-related mechanism. Therefore, it has been proposed that an intact uterus has an important role in the protection of premenopausal women, and this is likely associated with the beneficial effect of iron depletion in menstruating women, ie, the iron hypothesis suggested by Sullivan4 in 1981.

During late adolescence, men begin a steady accumulation of stored iron with age, but women fail to acquire significant iron stores because of their continual losses of iron in menstrual blood, pregnancies, and deliveries. A protective effect of iron depletion that may have multiple beneficial consequences is decreased availability of redox-active iron, which may participate in the generation of powerful oxidant species, such as hydroxyl radical, and in lipid peroxidation and in turn induce atherosclerotic plaque vulnerability.

A recent trial5 found that phlebotomy of 1 unit of whole blood twice a year among predominantly white middle-aged and elderly men with peripheral arterial disease resulted in a significant decrease in overall mortality, myocardial infarction, and stroke over a several-year period compared with the control group not phlebotomized. Interestingly, average menstrual blood loss each year (780 mL) approximates two 500-mL units of whole blood. Therefore, higher body iron stores might be involved in determining the higher risk of adverse cardiovascular outcomes in women who experience premature or early-onset menopause.

Future studies should be conducted to find out the exact role of iron depletion in the prevention of atherosclerosis progression and plaque destabilization in women with premature menopause.

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Article Information

Corresponding Author: Luca Mascitelli, MD, Medical Service, Comando Brigata Alpina “Julia,” Multinational Land Force, 8 Via S, Agostino, Udine 33100, Italy (lumasci@libero.it).

Published Online: January 4, 2017. doi:10.1001/jamacardio.2016.5083

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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;1(7):767-776.
Kannel  WB, Levy  D.  Menopause, hormones, and cardiovascular vulnerability in women. Arch Intern Med. 2004;164(5):479-481.
Hill  JS, Hayden  MR, Frohlich  J, Pritchard  PH.  Genetic and environmental factors affecting the incidence of coronary artery disease in heterozygous familial hypercholesterolemia. Arterioscler Thromb. 1991;11(2):290-297.
Sullivan  JL.  Iron and the sex difference in heart disease risk. Lancet. 1981;1(8233):1293-1294.
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(5):949-957.e1.