BOSTON, Massachusetts—Women who have surrogate markers indicating increased estrogen exposure are twice as likely to develop systemic lupus erythematosus (SLE) as women without such exposure. The high-risk markers are early age at both menarche and menopause, use of oral contraceptives, and use of postmenopausal hormone therapy. New data from the Nurses' Health Study suggest a causative role for estrogen in SLE and appear in the April issue of Arthritis & Rheumatism.¹ Lupus experts warn against overgeneralizing from these data, however.

"Placing excessive blame for the initiation or exacerbation of SLE on the use of exogenous hormones or on the timing of physiologic hormonal events is a concern," write Michael D. Lockshin, MD, director of the Barbara Volcker Center for Women and Rheumatic Diseases with the Hospital for Special Surgery, and Jill P. Buyon, MD, a rheumatologist at the New York Hospital for Joint Diseases, both in New York City, in an accompanying editorial.² "Even less understandable, except perhaps if one is devoted to the notion of an excessive influence of estrogen, is the insistence that the secondary effects of estrogen explain the sex ratio differences."

Data from two cohort studies used to identify risk factors

Researchers prospectively followed 238,308 women from the Nurses' Health Study (NHS) and NHSII cohorts. When the study began, the older women (in the NHS cohort) were 30 to 55 years of age, the younger women (in the NHSII cohort) 25 to 42 years of age. Womens' self-reported SLE diagnoses were confirmed by medical chart review. There were 262 incident cases of SLE between the two cohorts.

Women 10 years of age or younger at menarche had slightly more than double the risk of developing SLE (confidence interval [95% CI] 1.4-3.2). Oral contraceptive use (pooled RR 1.5, 95% CI 1.1-2.1) and use of postmenopausal hormones (RR 1.9, 95% CI 1.2-3.1) also significantly increased the risk of SLE, the study showed. The study showed no relation between the type or the potency of estrogen or progestin and the risk of developing SLE.

"[T]he risk of SLE remained elevated for more than 10 years after the cessation of oral contraceptives and at least 5 years after the cessation of postmenopausal hormones," conclude the researchers led by Karen H. Costenbader, MD, MPH, of Brigham and Women's Hospital, in Boston, Massachusetts.

An elevation of SLE risk was observed among postmenopausal women primarily after surgical menopause (RR 2.3, 95% CI 1.2-4.5) and among women with earlier age at natural menopause (P <.05). Women who developed SLE were 51.6 years of age, whereas women who did not develop SLE were an average age of 52.7 at the onset of menopause. The study showed that the younger a woman was when she entered menopause, the greater her risk of developing SLE.

The researchers found that women who entered menopause before age 47 were more than twice as likely to develop SLE as were their counterparts who experienced natural menopause at age 53 or older.

Menstrual irregularity was also associated with an increased risk of SLE among women in the NHSII cohort. Parity, age at first birth, and total duration of breastfeeding did not appear to increase the risk of developing SLE, the study found.

Many questions remain on estrogen's role in SLE

"The predominance of women with autoimmune diseases like lupus remains an enigma for everyone," said Robert G. Lahita, MD, PhD, professor of medicine at Mount Sinai Medical School, in New York, and chairman of medicine at the Jersey City Medical Center, in New Jersey. "As [Drs.] Lockshin and Buyon say in their editorial, the true meaning of the pathophysiology of many female-predominant diseases will become evident when we understand the gender ‘underpinnings' of the disease SLE," he told CIAOMed.

"Some of the issues raised here argue more for the molecular effects of estrogens on the receptors for this hormone on cells like T-cells and possibly B-cells," he said. "Various polymorphisms have been described for the differential effects of estrogen on the cells of those women with lupus. Moreover, the effects of early menarche, the use of oral contraceptives, and the age of onset of menopause are all factors that require further research and must have physiological meaning," he added.

There are other theories. "The absence of androgens could be one major issue in these women, not estrogens—a finding that has not been explained and is a constant in most men who suffer with diseases like SLE," Dr. Lahita said. "However, the data point to estrogens since the discussion centers about oral hormone use, menarche, menopause, etc," he noted.

"I would agree that estrogens may not be the ‘cause of the disease' nor may it be the sole sex determinant of SLE, but it has a pivotal role in immune function that has to be important in diseases like SLE," Dr. Lahita said. "Molecular studies are needed and further analysis of other factors related to female reproduction is needed to explain the remarkable facts brought forth in the Costenbader study."

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References

1. Costenbader KH, Feskanich D, Stampfer MJ, Karlson EW. Reproductive and menopausal factors and risk of systemic lupus erythematosus in women. Arthritis Rheum. 2007;56:1251-1262.
2. Lockshin MD, Buyon JP. Estrogens and lupus: bubbling cauldron or another overrated witches' brew? Arthritis Rheum. 2007;56:1048-1050.