Spotlight on Research for 2005

July 2005 (historical)

Hormone Replacement Not Associated with Severe Lupus Flares

Women with systemic lupus erythematosus (lupus) - a disease in which the body's immune system mistakenly attacks and damages healthy tissues of the skin, joints and internal organs - may experience the benefits of postmenopausal hormone replacement therapy (HRT) without an increased risk of severe disease flares, according to a major study funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), part of the Department of Health and Human Services' National Institutes of Health (NIH).

In the 16-center study of 351 menopausal women, those taking a standard regimen of hormone replacement therapy (0.625 mg conjugated estrogens daily plus 5 mg medroxyprogestrone for 12 days per month) had no statistically significant increased risk of severe flares compared to those taking a placebo. A severe flare was defined by several criteria, including the presence of new or worsening central nervous system involvement; inflammation of the blood vessels (vasculitis), kidneys (nephritis) and/or muscles (myositis); and/or blood abnormalities, including low platelet count (thrombocytopenia) and destruction of the red blood cells (hemolytic anemia); hospitalization for lupus activity; the addition of new immunosuppressive agents or extremely high doses of steroids.

Women in the HRT group were, however, approximately 20 percent more likely to have a mild-to-moderate flare, which included new or worsening skin rashes, mouth ulcers, hair loss, aching (arthralgia) or inflammation of the joints (arthritis), or fluid around the heart or lungs. None of these mild-to-moderate flares resulted in the need for high-dose steroids or hospitalizations.

In recent years, long-term use of HRT has fallen out of favor due to uncovered risks of cardiovascular disease and some estrogen-dependent cancers. Yet short-term therapy is still widely used and beneficial for hot flashes, vaginal dryness, and urethritis and other unpleasant effects of menopause, as well as for preventing osteoporosis.

"Women with lupus who are taking cyclophosphamide (a drug that suppresses damaging inflammation of the disease, but also can lead to premature ovarian failure) are especially prone to early and severe effects of menopause that can be a source of emotional and physical dysfunction," Jill Buyon, M.D., professor of medicine at New York University School of Medicine and the study's co-leader. As such, HRT can provide a particular benefit for these women, she says. HRT is also proven to be useful for preserving bone density, a particular concern for women with lupus who take corticosteroid medications to control disease inflammation. Bone loss is a serious side effect of the medications.

Traditionally, doctors have not prescribed hormone replacement therapy in women with lupus for fear that increasing the level of female hormones in the body might increase disease activity. This fear arose in part from the fact that lupus is far more common in women (women with the disease outnumber men 10 to 1) and that it typically begins during the childbearing years (after the onset and before the cessation of menstruation) when female hormone levels are at their peak. In addition, some murine models of lupus have shown detrimental effects of estrogens.

"While long-term use of HRT is no longer advised for most postmenopausal women, this does not reduce the importance of establishing the safety of HRT in women with SLE for whom disease treatment may precipitate early and particularly severe menopausal symptoms," says Stephen I. Katz, M.D., Ph.D., NIAMS Director. "As with any drug, doctors and patients must carefully weigh the expected benefits of HRT against the possible risks."

The authors say the study has provided important reassurances, but further investigation of HRT is needed to determine the most appropriate candidates for therapy. "Some women may be biologically predisposed to flares in response to hormones," says Dr. Buyon. "In the future there may be ways to determine who's at greatest risk of flares before initiating treatment."

Michelle Petri, M.D., M.P.H., of Johns Hopkins University was the co-leader of the study.

In addition to NIAMS' support, funds for the work came from NIH's National Center for Research Resources, Office of Research on Women's Health and National Center on Minority Health and Health Disparities.

The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases, the training of basic and clinical scientists to carry out this research, and the dissemination of information on research progress in these diseases. For additional information, call NIAMS's Clearinghouse toll free at 1-877-22-NIAMS, or visit the NIAMS Web site at

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Buyon JP et al.The effect of combined estrogen and progesterone hormone replacement therapy on disease activity in systemic lupus erythematosus: a randomized trial. Ann Intern Med 2005; 42(12):953-962.