The flawed beneficial effects of hormone replacement therapy
11 October 2012
Schierbeck and colleagues suggested that “initiation of hormone replacement therapy in women early after menopause significantly reduces the risk of the combined endpoint of mortality, myocardial infarction, or heart failure” . However, after a closer look at their study, the results do not appear so straightforward.
Indeed, after a mean duration of 10.1 years of randomised treatment in 1006 women, the primary endpoint occurred in 17 fewer subjects (33 vs 16) in treated group than in control group. However, women in the control group were 0.47 years (about 5.7 months) older than those in the treated group .
In the cardiovascular secondary prevention trial Cholesterol and Recurrent Events (CARE) , patients were randomized to 40 mg daily of the cholesterol-lowering drug pravastatin or placebo. In the 4159 participants, statin therapy was associated with 97 fewer revascularizations . It has been calculated that the average delay of revascularization was 0.09 years (33 days) over 5 years . Although it is difficult to make a similar calculation for the study by Schierbeck and colleagues , it seems unlikely that the projected delay on 10 years of the events defined in the primary endpoint would be longer. In other words, although the authors adjusted the composite endpoint’s results for age, the apparent significant beneficial results may have been seriously flawed.
Furthermore, the assumption that heart protection in fertile women is mediated by premenopausal levels of female hormones is not consistent with epidemiological findings that premenopausal hysterectomy essentially cancels the protection, even in cases with preservation of functioning ovaries . On the contrary, these data  suggest that an intact uterus has an important role in the protection of premenopausal women, and likely this is related to the beneficial effect of iron depletion in menstruating women  (i.e., the iron hypothesis suggested by Sullivan more than 30 years ago ).
If you torture numbers enough they will say anything you want.
Luca Mascitelli, MD
Comando Brigata alpina “Julia”, Udine 33100, Italy
Mark R. Goldstein, MD, FACP
NCH Healthcare Group, Naples, FL, USA
1. Schierbeck LL, Rejnmark L, Tofteng CL, Stilgren L, Eiken P, Mosekilde L, Køber L, Jensen JE. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial. BMJ 2012; 345: e6409.
2. Sacks FM, Pfeffer MA, Moye LA, et al, for the Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996; 335: 1001–9.
3. Bassan M, Panush N. Treating hypercholesterolemia—without the hype. Am J Cardiol 1997; 79: 1001–3.
4. Kannel WB, Levy D. Menopause, hormones, and cardiovascular vulnerability in women. Arch Intern Med 2004; 164: 479-81.
5. Mascitelli L, Goldstein MR, Pezzetta F. Explaining sex difference in coronary heart disease: is it time to shift from the oestrogen hypothesis to the iron hypothesis? J Cardiovasc Med (Hagerstown) 2011; 12: 64-5.
6. Sullivan JL. Iron and the sex difference in heart disease risk. Lancet 1981; 1: 1293-4.
Competing interests: None declared
Comando Brigata alpina Julia, 8, via S. Agostino, Udine 33100, Italy
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