The evidence was never unanimous in favor of the "estrogen hypothesis." Awkward findings were swept under the rug under the influence of a strong paradigm (prevailing view) in favor of the hormonal explanation.  For example in the gold standard classic observational study of heart disease, The Framingham Study, women who had natural menopause, simple hysterectomy, or hysterectomy + oophorectomy all underwent a doubling in heart disease risk within 2 years after cessation of menses.  This increase in risk happened no matter what age the woman was when she stopped having periods. If only the uterus is removed in a premenopausal woman, her ovaries continue to cycle just as if the uterus was still present.  In this case, the woman continues to produce her "protective" hormones, however, according to Framingham, she suffers just as much disease increase as her sisters who have had their ovaries removed.  

There is a good bit of additional evidence against the estrogen hypothesis that remains essentially invisible when looked at from the point of view of the prevailing paradigm.  Such evidence includes the observation that men with serious heart disease who are given estrogen actually have a higher death rate than matched controls taking placebo.  The new randomized prospective study results together with the findings in men raise the possibility that young women are protected in some way from heart disease, not because of female sex hormones, but IN SPITE OF THEM.

In the various scholarly and media accounts, there has been no apparent interest in the obvious question posed by the new data:  if estrogen is not protective, what on earth could explain the virtually complete immunity against heart attacks enjoyed by young women?

I proposed such an alternative in 1981 in the British medical journal Lancet.  I suggested that menstruating women are protected by their continual loss of iron in menstrual blood.  This is now termed "the iron hypothesis.  One of several superficial arguments against the iron hypothesis was that no explanation was needed for the low heart disease rates in young women, because it was a "fact" that they were protected by their hormones.

After a long period of controversy, the iron hypothesis has now become much more acceptable to scientists and clinicians in this country as well as in Europe.  Recent findings are recognized as being strongly supportive.

The current status of the iron hypothesis is presented in the abstract of a recent review by 2 Dutch scientists (see text below).  The implications of new HRT findings have only briefly been mentioned in print (see text below of my letter to JAMA re HERS.

Jerome L. Sullivan, MD, PhD

RECENT REVIEW OF THE IRON HYPOTHESIS:
Iron, Atherosclerosis, and Ischemic Heart Disease [Abstract]

B. de Valk, MD; J. J. M. Marx, MD, PhD 

Objective: To review the epidemiological and experimental data concerning iron and the development of atherosclerosis and ischemic heart disease. 

Data Sources: The English-language literature was searched from 1981 through 1998 manually and using MEDLINE and Current Contents.   Important references in the articles that were found were also included in this review. 

Results: There is growing epidemiological evidence for a relationship between iron levels and cardiovascular disease. Some experimental data support the role of iron in the process of lipid peroxidation, the first step in the formation of atherosclerotic lesions. Macrophages and endothelial cells are involved in this process, but the exact mechanism and the sites of the interactions between these cells, iron, and low-density lipoprotein are still unknown. 

Conclusions: Strong epidemiological evidence is available that iron is an important factor in the process of atherosclerosis. Epidemiological studies, eg, prospective follow-up studies in blood donors, may clarify the  cardiovascular benefits of iron depletion. Knowledge of the molecular mechanism of iron-related cardiovascular disease is still limited. We speculate that catalytically active iron species modify low-density lipoprotein levels to interact with the macrophage oxidized low-density lipoprotein receptor. Both nontransferrin-bound plasma iron and  hemoglobin are candidates for such interactions.

Arch Intern Med. 1999;159:1542-1548

JAMA 1999;281:795 

To the Editor: The belief that HRT protects against heart disease is rooted not only in observational studies,[1] but also in a conviction that female hormones are the protective factor in menstruating women. Many physicians embraced the conclusions of the observational studies because these studies seemed to confirm the "fact" of hormonal protection in young women. The notion that estrogen protects has achieved the status of a largely unquestioned myth despite serious unresolved issues[2] and the absence of definitive trial data addressing this important question. If hormonal influences explain the virtual absence of MI in menstruating women, some discernible impact of HRT would be expected. The HERS study[3] shows no cardiovascular benefit of HRT in older women with heart disease. The study is thus relevant to the mystery of the sex difference in heart disease rates. 

The HERS findings[3] weaken the case for direct hormonal effects and focus attention on other hypotheses that may explain menstruating women's remarkable protection against MI. One such hypothesis is the suggestion that young women are protected by their continual loss of iron in menstrual blood.[2,4] The hypothesis has considerable explanatory power.[2,4] The plausibility of the hypothesis has been strengthened recently by studies confirming one of its key predictions, that volunteer blood donation is associated with a reduction in coronary events.[5] 

The iron hypothesis may account for the possible decrease in coronary  risk in the later years of observation during HERS.[3] Participation was restricted to women who had not undergone hysterectomy. Uterine bleeding associated with HRT may have caused a significant and progressive decline in stored iron level. For the average participant, HRT-associated uterine bleeding undoubtedly caused less blood and iron loss than that associated with menstruation. However, during the many months of the study, significant unmeasured decreases in stored iron level could have occurred in many subjects without causing anemia. If frozen serum samples are available from the time of entry into the study and at the conclusion of the study, it may be possible by measurement of serum ferritin to document stored iron loss in the participants taking HRT. Monitoring of serum ferritin levels is advisable during the remaining years of observation. 

Jerome L. Sullivan, MD, PhD 
Winter Park, Fla 

1. Petitti DB. Hormone replacement therapy and heart disease prevention: experimentation trumps observation. JAMA. 1998;280:650-652. 

2. Sullivan JL. Iron vs cholesterol: perspectives on the iron and heart disease debate. J Clin Epidemiol. 1996;49:1345-1352. 

3. Hulley S, Grady D, Bush T, et al, for the Heart and Estrogen/ progestin Replacement Study (HERS) Research Group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA. 1998;280:605-613. 

4. Sullivan JL. Iron and the sex difference in heart disease risk. Lancet. 1981;1:1293-1294. 

5. Tuomainen TP, Salonen R, Nyyssonen K, Salonen JT. Cohort study of relation between donating blood and risk of myocardial infarction in 2682 men in eastern Finland. BMJ.  1997;314:793-794.