COX Inhibitors May Weaken Protective Qualities Of Estrogen Hormone Therapy

Premenopausal women are less susceptible to heart attack and stroke than are males of the same age group, an advantage that is lost after menopause. However, why this happens physiologically is unclear. Despite the cardiovascular advantage of premenopausal women, it has been difficult to identify a cardioprotective effect of taking estrogen in postmenopausal women. The Penn research group recently found in mice that estrogen acts via COX-2–dependent prostacyclin, a fat that has a role in limiting blood clotting. Estrogen in this animal model acts via prostacyclin to decrease clotting and oxidative stress in cells and to limit hardening of the arteries.

“We were prompted to perform these studies while exploring the mechanism by which NSAIDs confer a cardiovascular hazard, that is suppression of COX-2 derived prostacyclin,” says lead author Garret FitzGerald, MD, Director of the Institute for Translational Medicine and Therapeutics at Penn.

Inhibition of COX-2 by NSAIDs prevents production of prostacyclin. However, as estrogen acts to increase production of prostacyclin, the researchers surmise that the possible positive effects of estrogen therapy on the cardiovascular system may be counteracted by the COX-inhibiting NSAIDs.

To ascertain whether the failure to detect a benefit from estrogen might be partly attributable to a pharmacological interaction between inhibitors of COX-2 and estrogen, the researchers examined the medical records of 1,673 women between 50 and 84 from the United Kingdom’s General Practice Research Database who had heart attacks or who died from coronary heart disease and compared them with 7,005 control participants.

The researchers found that use of estrogen replacement therapy was associated with a significantly lower risk of heart attack than non-use. However, in women who used NSAIDs, such as ibuprofen, which inhibit COX-1 and COX-2, at the same time as hormone replacement therapy, this protective effect was lost.

Whether taking estrogen actually confers cardioprotection remains controversial. It seems likely that benefit is conferred only on women who commence estrogen close to the time of menopause; such women were the object of this study, explain the researchers. If estrogen is started some years after the onset of menopause it may actually confer risk itself.

“These provocative observations should not be regarded as a basis for clinical decisions,” says FitzGerald. “However, they are mechanistically plausible and should stimulate further research."

This work was performed in collaboration with Luis Alberto García Rodríguez, from the Centro Español de Investigación Farmacoepidemiológica (Madrid), and was partially funded by the National Heart, Lung, and Blood Institute. Karine Egan, Penn, was also a co-author. The results were described this week in PLoS Medicine.