SAN FRANCISCO-- Use of hormone replacement therapy (HRT) may increase the risk of adult-onset asthma in women, according to research presented at CHEST 2000. The data suggest that HRT may predispose women to asthma--but it does not appear to worsen chronic obstructive pulmonary disease (COPD).

Randomized clinical trials have suggested that HRT increases markers of inflammation, such as C-reactive protein levels, by up to 85%. Studies have also shown that HRT has anti-inflammatory effects in that it reduces E-selectin levels. Because increased C-reactive proteins have been linked to asthma and reduced E-selectin levels have been associated with worsened COPD, the study was designed to determine if HRT increases the risk of asthma or COPD development.

R. Graham Barr, MD, MPH, and colleagues examined data from the longitudinal Nurses' Health Study, which includes 121,701 female registered nurses who were age 30 to 55 years when the study was started in 1976. The researchers prospectively followed women who became menopausal during the study.

"By 1996, just about the whole population had become menopausal," explained Dr. Barr, who is a research fellow in Pulmonary Epidemiology at the Channing Laboratory at Brigham and Women's Hospital in Boston.

Every two years, the study participants were sent a questionnaire on HRT use, menopausal status, medical history, and smoking habits. Subjects who reported a physician diagnosis of asthma or COPD from 1986 to 1996 were sent a supplemental questionnaire in 1998 to confirm the diagnosis. Use of an asthma medication was required for women to be categorized as asthmatic. The definition of COPD required that subjects not only report recent respiratory symptoms but also have demonstrated spirometric or radiographic abnormalities.

ESTROGEN USE LINKED TO ASTHMA

From 1984 to 1996, the researchers found that 756 women had new physician diagnoses of asthma, 409 had new physician diagnoses of COPD, and 345 had new physician diagnoses of both diseases. As shown in Table 1 (see below), HRT users had an 80% higher risk of asthma than did never users. The effect was similar among women who took conjugated estrogen only and among those who received estrogen plus progestin. The association between HRT and asthma risk increased in magnitude with higher doses of estrogen and with longer duration of estrogen use.

A similar association was found for women who developed both asthma and COPD. In contrast, "There was basically no association between HRT use and the subsequent diagnosis of COPD," according to Dr. Barr. "We think that HRT may worsen inflammation or bronchospasm, [thus] leading to adult-onset asthma, but does not appear to contribute to irreversible lung function changes that are characteristic of COPD."

IMPLICATIONS

While the findings suggest that women taking HRT are more likely to develop asthma than are never users, "the chance of developing asthma in this age range is not terribly high--about 1% or less," Dr. Barr explained. "So, although the 80% increase is quite a large difference, the absolute risk of developing this disease is quite low."

He also added that the beneficial effects of HRT on bone density (and possibly cardiovascular health) may outweigh the potential negative effects of HRT on asthma risk. "Many more women are at risk of osteoporosis or cardiovascular events than of developing asthma in this age range," Dr. Barr said.

Dr. Barr and colleagues are currently analyzing the study data to determine if HRT worsens preexisting asthma, as determined by the number of urgent physician visits, emergency department visits, and hospitalizations. Their preliminary findings do not support this idea. "We are not seeing a large worsening of asthma with HRT among women who already have a physician diagnosis of asthma," Dr. Barr explained. Thus, HRT appears to only predispose women to asthma.

--Kristin Della Volpe

The Reproductive Cycle and Asthma

Further support for a link between changes in female reproductive hormones and asthma was presented by Gordon T. Ford, MD, at CHEST 2000. Asthma epidemiology indicates that the condition is less common in girls in early childhood; by menarche, though, the gender ratio is equal. Asthma incidence increases throughout the reproductive years, changing again at menopause, he explained. In addition, changes in asthma severity have been found perimenstrually, with the use of oral contraceptives, during pregnancy, and at menopause (regardless of whether hormone replacement therapy is used). "I think all of these data are extraordinarily compelling … to suggest that there is a relationship between reproductive hormones and asthma in women," explained Dr. Ford, who is a Professor of Medicine in the Division of Respiratory Medicine at the University of Calgary, Alberta, Canada. "What are the potential mechanisms?" he continued. "Mast cell activation and degranulation have been shown to be common features in the functional layer of the endometrium perimenstrually in healthy women. Animal studies have demonstrated estrogen receptors on purified rat peritoneal mast cells. Estradiol augments nonspecific mast cell degranulation in these cells in vitro," according to Dr. Ford. "Thus, we have fluctuations in reproductive hormones during the menstrual cycle, which may cause systemic activation of mast cells in the endometrium," he speculated. These mast cells may release cellular mediators, including leukotrienes and interleukins. Dr. Ford suspects that the cyclical release of these inflammatory mediators may be responsible for causing perimenstrual airway inflammation. --Kristin Della Volpe