It's time to reevaluate hormone replacement therapy (HRT) in menopausal women, according to Lawrence Phillips, M.D., a professor of medicine at the Emory University School of Medicine, Atlanta. Phillips and his colleague Robert Langer, M.D., MPH, director of the Outcomes Research Institute of Geisinger Health System's Center for Health Research & Rural Advocacy in Danville, Pa., developed a "unified hypothesis" to reconcile the data from animal and human observational studies with
the findings of randomized clinical trials such as the Women's Health Initiative (WHI) and the Heart and Estrogen/Progestin Replacement Study (HERS). Phillips discussed this unified hypothesis at The Endocrine Society Science Writer's Conference, held recently in New York.

As Phillips explained, observational studies indicated that HRT protected women against coronary heart disease (CHD), but the estrogen/progestogen and estrogen alone arms of WHI indicated increased CHD risk during the first year or two of therapy, then decreased CHD risk after several years of treatment. Younger women in the WHI also appeared to derive some CHD benefit from HRT, whereas older women seemed to be at particularly increased risk.

Oral estrogens are associated with the hepatic production of prothrombotic and proinflammatory factors, including C-reactive protein (CRP), an accepted marker of CHD risk, Phillips said. He noted that medroxyprogesterone acetate (MPA), the progestogen used in the WHI, tended to limit the potential vascular benefits of estrogens. However, results of observational studies using these agents suggest a cardioprotective benefit. These findings led Phillips and Langer to surmise that the discrepancy was due largely to the age of the study participants at the time HRT was initiated. Phillips explained that data from clinical trials where HRT was initiated years after menopause (the WHI model at an average age of 63 years; the HERS model at an average age of 67 years) were compared with data from observational studies where HRT was initiated right at the time of menopause.

Studies show that older women are significantly more likely than perimenopausal women to have coronary plaque, the thin fibrous cap and necrotic core of which make it vulnerable to inflammation-induced rupture, Phillips said. Animal studies also indicate that estrogens are less likely to limit the atherosclerotic process if plaque has already developed.

The unified hypothesis predicts that HRT initiated at the time of menopause should reduce CHD risk over time, Phillips said. However, HRT begun years after menopause should produce the biphasic effect of initial increase in CHD risk due to plaque rupture, followed by a cardioprotective benefit associated with the long-term prevention of plaque formation and remodeling of stable plaque.

Phillips and Langer also concluded that women who require progestogen for endometrial protection should derive greater CHD benefit from the use of an agent with less estrogen-antagonistic activity than MPA. It might help limit breast cancer risk to use a vaginal or intrauterine preparation, said Phillips. He and Langer published a paper, "Postmenopausal Hormone Replacement Therapy: Critical Reappraisal and a Unified Hypothesis," in the March 2005 issue of the journal Fertility and Sterility.

In her practice, Louise Parent-Stevens, Pharm.D., a clinical assistant professor of pharmacy practice at the University of Illinois in Chicago, follows the current guidelines. "For those women who want to take HRT, we are recommending as low a dose as possible, and we try to reduce the dose or discontinue it altogether every six to 12 months. We also try to educate them about the risks associated with HRT, as small as they may be."

Many women ask about bioidentical hormones, Parent-Stevens said. Pharmacists should understand that these are still estrogens, she cautioned. Another concern for women is the risk of breast cancer, she said. "We do know that it is related to the duration of therapy, which is why we encourage women not to stay on HRT for more than five years." She emphasized that "if the patient is aware of the risks associated with HRT, she can make an informed decision for herself."

THE AUTHOR is a clinical writer based in New Jersey.