||Researchers from the University
of Pennsylvania School of Medicine found in a database study
of women heart patients that COX inhibitors such as traditional
nonsteroidal anti-inflammatory drugs (NSAIDs) may undermine
any purported protection against heart disease in participants
taking estrogen therapy.
||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
||The results were described this week
in PLoS Medicine.
(PHILADELPHIA) – Researchers from the University
of Pennsylvania School of Medicine found in a database study of women heart patients
that COX inhibitors such as traditional nonsteroidal
anti-inflammatory drugs (NSAIDs) may undermine any purported protection against heart
disease in participants taking estrogen
therapy. The results were
described this week in PLoS Medicine.
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
de Investigación Farmacoepidemiológica (Madrid),
and was partially funded by the National
Heart, Lung, and Blood Institute. Karine Egan, Penn, was also a co-author.
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