Hormone replacement therapy and NSAIDs

I’ll get back to glucagon regulation in a bit. I just got around to reading the latest articles published by PLoS Medical and wanted to mention the findings of an observational study that looked into potential interactions between hormone replacement therapy and traditional nonsteroidal anti-inflammatory drugs (NSAID). (Traditional NSAIDs include things like ibuprofen and naproxen, but aspirin was excluded. Selective NSAIDs like Vioxx were also excluded because they apparently weren’t available in the United Kingdom during the period studied.)

You might recall that hormone replacement therapy made the news in 2002 when a study by the Women’s Health Initiative (WHI) was shut down early because of unacceptable increases in breast cancer. I think there was concern about breast cancer going into the study, however. A more surprising finding was that coronary heart disease (CHD) was higher in women undergoing hormone replacement than those taking a placebo. This was surprising because pre-menopausal women have a much lower risk of heart disease than men, and this difference is thought to be due to some cardioprotective action of estrogen. If estrogen provides cardioprotection, then why were post-menopausal women on hormone replacement at a slightly greater risk for coronary heart disease than women taking a placebo?

One reason, known (or at least suspected) for some time, was that progesterone opposes the cardiovascular benefits of estrogen. (Progesterone – as medroxyprogesterone – was increasingly added to the hormone replacement mix because of an increased risk of uterine cancer. However, a 2002 editorial in the Journal of the American Medical Association cited statistics that in 2000, twice as many prescriptions were written for a pill with just estrogen than a pill with both estrogen and progesterone.)

The article in PLoS Medicine outlines another possibility. This study, which was not a randomized and controlled trial, searched a British database and looked at risks for heart attacks among women who had received (or were still receiving) hormone replacement therapy and those who hadn’t versus a group of “control” patients. This group isn’t really a true control, they were just randomly drawn from some population and matched to the study group by some criteria. They also looked at the use of NSAIDs for those same women.

So, we’ve got two groups of women: our study group and the controls. The authors compared the risk of heart attack (acute MI – myocardial infarction – to be fancy) for women that had undergone hormone therapy (HT) and those that hadn’t, as well as whether they took NSAIDs or not. The relative risks are shown in the table below (as odds ratios). An odds ratio of 1 indicates equal risk; less than one, less risk; and greater than one, a greater risk. The data indicate that the risk of heart attack is reduced for women currently undergoing hormone replacement, but that risk increases for women that are currently undergoing hormone replacement therapy and also taking NSAIDs.

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Enough statistics. What’s the physiological reasoning behind this? Like most everything else, it comes down to proteins. Specifically, enzymes known as cyclooxygenases. There are 3 kinds: COX-1, COX-2, and COX-3. The enzyme of prime interest is the COX-2 protein. This enzyme catalyzes a reaction that produces a molecule called prostacyclin (PGI₂). This molecule is a prostaglandin. PGI tends to decrease platelet activity (platelets play a role in blood clotting) and increase the diameter of blood vessels (vasodilation). Estrogen increases the amount of prostacyclin by activating the COX-2 enzyme. Traditional NSAIDs inhibit cyclooxygenases. Inhibiting COX-2 directly opposes the action of estrogen.

This doesn’t mean that women going through menopause should run out and start hormone replacement therapy. The authors of the study are quick to note its limitations. Chiefly, it wasn’t a randomized controlled trial. The data they analyzed wasn’t collected with this issue in mind, it was just a database of patient information. In other words, these data are suggestive but require more controlled studies to draw more definitive conclusions. In any case, hormone replacement therapy still increases risk of breast cancer, so any potential benefits related to minimizing the symptoms of menopause, heart disease or osteoporosis have to be weighed against the risks.

References:

1. Garcia Rodriguez, et al. (2007). “Traditional Nonsteroidal Anti-Inflammatory Drugs and Postmenopausal Hormone Therapy:A Drug–Drug Interaction?” PLoS Medicine
2. Writing Group (2002). “Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results from the Women's Health Initiative Randomized Controlled Trial” JAMA 288(3): 321-333. Available free with registration.
3. Fletcher and Colditz (2002). “Failure of estrogen plus progestin therapy for prevention.” JAMA 288(3): 366-368. July 17. Available free with registration.