May 28, 2008 — The use of hormone replacement therapy (HRT) does not appear to increase the short-term risk of coronary heart disease in women with a favorable lipid profile, a new analysis of the Women's Health Initiative (WHI) suggests [ color="blue">1].
The analysis, published in the June 1, 2008 issue of the American Journal of Cardiology, was conducted by a group led by Dr Paul Bray (Cardeza Foundation for Hematologic Research, Philadelphia, PA).
The National Heart, Lung, and Blood Institute (NHLBI)-sponsored WHI consisted of two trials--one assessing the effect of conjugated equine estrogen (CEE) alone in women without a uterus, and the other examining CEE plus medroxyprogesterone acetate (MPA) in postmenopausal women who had not undergone a hysterectomy. Overall results showed that neither therapy protected against coronary events, as had been suggested in earlier observational studies, and that the combined therapy was actually associated with an increased risk of CHD.
In the current case-control analysis, which was conducted only in women without baseline cardiovascular disease, the researchers examined whether levels of lipids and C-reactive protein (CRP) could be useful for predicting HRT-mediated CHD risk. Lipid and CRP levels at baseline and at one year were obtained from 271 patients who suffered an initial CHD event during in the first four years of follow-up of the study (cases) and from 707 controls matched for age at screening, randomization date, and hysterectomy status. All models were adjusted for age, year of randomization, history of hypertension, body-mass index, current smoking, cholesterol-lowering medication use, and diabetes.
Results showed that favorable lipid status at baseline tended to predict better CHD outcomes when using CEE with or without MPA. Several baseline lipid measurements, but especially the LDL/HDL-cholesterol ratio, interacted with CEE with or without MPA to modify the risk of CHD. Specifically, women with baseline LDL/HDL-cholesterol ratios of more than 2.5 were at increased CHD risk from hormone therapy, whereas there was no increased CHD risk from HRT when the baseline LDL/HDL-cholesterol ratio was below 2.5.
Odds Ratio for CHD With Hormone Use
| LDL/HDL ratio | OR for CHD with hormone use |
| <2.5 | 0.60 (0.34–1.06) |
| >2.5 | 1.73 (1.18–2.53) |
size="1">p for interaction=0.02
Baseline CRP levels added little or no additional value beyond the LDL/HDL-cholesterol biomarker for predicting CHD risk in women using hormone therapy.
Bray et al comment: "Importantly, we found no clear evidence that either form of hormone therapy posed a risk of coronary heart disease events for women with baseline HDL cholesterol above 50 mg/dL or LDL cholesterol, total/HDL-cholesterol ratio, and LDL/HDL-cholesterol ratio less than the median control value." They add that the results "emphasize the potential coronary heart disease safety of hormone therapy in women with a desirable 'healthy' lipid profile."
Possible Mechanism
On the possible mechanism behind these observations, the authors note that the cholesterol metabolite 27-hydroxycholesterol has been shown to compete with estrogen for binding to vascular estrogen receptors, blocking the beneficial effects of estrogen (nitric-oxide production and endothelial cell migration) on murine vascular cells, leading to the hypothesis that postmenopausal women with a poor lipid profile have increased 27-hydroxycholesterol, which disables a potential vascular benefit of estrogen. Conversely, the women with favorable lipids mightexperience no harm or even benefit from estrogen therapy if they have low 27-hydroxycholesterol, they add.
Bray et al point out that despite increasing information and understanding of clinical benefits and risks of hormone therapy, doctors are still challenged in making management choices for individual postmenopausal women. They caution that this report considered only risks and benefits associated with CHD outcomes, and the decision to use HRT must consider the totality of health risks and benefits, including stroke, thrombosis, and gallbladder disease. They add that women considering the use of postmenopausal hormone therapy should determine their overall cardiac risk and specifically their lipid profile. Noting that a previous WHI analysis has suggested that the absolute excess CHD risk is low or absent in younger postmenopausal women who use CEE with or without MPA, they conclude that the current analysis now suggests that this risk is also low in women with a favorable lipid profile.
NHLBI: New Results Help Benefit-Risk Decision
Commenting on the current analysis for heartwire , Dr Michael Lauer (director of the NHLBI division of prevention and population sciences) warned that the results need to be interpreted carefully because a case-control study is not as reliable as a randomized trial. "These results do suggest that at least for a short period of time, women with low cholesterol are not at increased risk of CHD from taking hormones. But this does not change the primary results of the WHI, which showed that neither form of hormone therapy reduces the risk of heart disease in healthy, postmenopausal women, and estrogen plus progestin increases the risk. In addition, both estrogen plus progestin and estrogen alone increase the risk of stroke and thromboembolism, serious cardiovascular conditions that the new analysis does not address, and combination hormone therapy also increases the risk of breast cancer," Lauer said.
He added: "These results can help women and their clinicians make better informed decisions about whether the benefits of hormone therapy outweigh the risks. I think we can say that short-term HRT use is an option for a woman who is experiencing severe menopausal symptoms, and if a woman has favorable cholesterol, we can now feel more comfortable about that decision." But he added: "In general, however, women should not take hormone therapy to prevent heart disease, and women who choose to use hormone therapy for menopausal symptoms should use the lowest possible dose for the shortest duration."
Bray PF, Larson JC, LaCroix AZ, et al. Usefulness of baseline lipids and C-reactive protein in women receiving menopausal hormone therapy as predictors of treatment-related coronary events. Am J Cardiol 2008; 101:1599–1605. Abstract.
face="Verdana" size="1">The complete contents of Heartwire , a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.
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Cite this: Sue Hughes. No Increased CHD Risk With HRT in Women With Favorable Lipid Profile? - Medscape - May 28, 2008.
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