INTRODUCTION

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Available information suggests that women are more frequently and more severely affected by asthma. From 1982 to 1992, the prevalence of asthma among U.S. women increased by 82% (from 2.9% to 5.4%) compared with an increase of 29% among U.S. men (from 4.0% to 5.1%) (1). During these same years, asthma mortality increased among women by 59% versus a 34% increase among men. Seventy-five percent of adult patients admitted to hospitals for asthma are women (2). The reason for these sex differences in asthma remain unclear. It has been hypothesized that hormonal fluctuations during the menstrual cycle play a significant role in the pathophysiology of asthma, resulting in periodic worsening of disease severity in adult females (3). A recent study found that almost 50% of emergency department (ED) visits occur during the perimenstrual phase (10). The purpose of our study was to further evaluate the relation between the phase of menstrual cycle and ED visits for acute asthma as well as the relation between the phase of menstrual cycle at ED presentation and markers of acute and chronic asthma severity.

	METHODS

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This study combined data from three prospective cohort studies performed during 1997-1998, as part of the Multicenter Airway Research Collaboration (MARC) (http://healthcare.partners.org/marc). Using a standardized protocol, investigators at 64 EDs in 22 U.S. states and two Canadian provinces provided 24-h per day coverage for a median of 2 wk. Repeat visits by individual subjects were excluded. Potential asthma visits with lost medical records (n = 4) were excluded because a diagnosis of asthma could not be confirmed. All patients were managed at the discretion of the treating physician. Inclusion criteria were physician diagnosis of acute asthma, age 12 to 54 yr, and the ability to give informed consent. Of 1,302 eligible male and female patients, 932 (72%) patients with acute asthma were enrolled. The institutional review board at each of the 64 participating hospitals approved the study, and informed consent was obtained for all participants.

We excluded women from analysis for this study who were pregnant, on hormonal therapy, postmenopausal or status post hysterectomy, had incomplete reproductive data, or whose ED visit fell more than 28 d after their last menstrual period. For analysis, the idealized menstrual cycle was divided into four intervals: preovulatory (Days 5 to 11), periovulatory (Days 12 to 18), postovulatory (Days 19 to 25), and perimenstrual (Days 26 to 4), with Day 1 being onset of menstruation.

Data Collection

The ED interview assessed patients' demographic characteristics, menstrual history, asthma history, and details of their current asthma exacerbation. Adults (age 18 to 54), but not children (age 12 to 17), were asked about their usual asthma triggers (e.g., menstruation) and to identify the trigger of the index visit. Data on ED management and disposition were obtained by chart review. All forms were reviewed by site investigators before submission to the MARC Coordinating Center in Boston, where they underwent further review by trained personnel and then double data entry.

Peak expiratory flow rate (PEFR) is expressed as a percentage of patient's predicted value, based on race, age, sex, and height (11). Changes in PEFR are expressed as the absolute change in percent predicted (e.g., an improvement from 40% predicted to 70% predicted would be expressed as a change of 30%).

Statistical Analysis

All analyses were performed using STATA 5.0 (StataCorp, College Station, TX). Density of ED visits was plotted as a function of day of menstrual cycle using Splus 4.0 (Mathsoft Inc., Seattle, WA). Data are presented as proportions (with 95% confidence intervals [CI] and means with standard deviation [SD]). The association between menstrual phase and other factors was examined using chi-square goodness of fit test and one-way analysis of variance, as appropriate. All p values are two-tailed, with p < 0.05 considered statistically significant.

	RESULTS

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The overall participation rate for women in this study was approximately 71%. Of the 550 women enrolled in the study, 288 met criteria for analysis. Of the 262 excluded from analysis, 18 were pregnant, 15 had not reached menarche, 72 received hormonal therapy, 65 were postmenopausal or status post hysterectomy, 42 had incomplete reproductive data, and 50 reported their last menstrual period more than 28 d before the ED visit. Regular menstrual cycles were reported by 228 participants (79%), and 60 (21%) reported irregular cycles. Demographic and asthma factors are shown in Table 1. Menstrual regularity was not related to several markers of chronic or acute asthma.

Figure 1 shows the density of ED asthma visits plotted as a function of day of menstrual cycle for all 288 participants. ED visits for acute asthma were most common during the preovulatory phase. For women with regular cycles (n = 228), ED asthma visits were classified as follows: preovulatory, 76 (33%); periovulatory, 56 (25%); postovulatory, 48 (21%); or perimenstrual, 48 (21%); p = 0.03. Although statistical power was limited, similar results were found among women with irregular cycles (n = 60): 32%, 30%, 18%, and 20%, respectively; p = 0.34. When we restricted the analysis to subjects with severe asthma exacerbations (initial PEFR < 50% predicted), a similar pattern was observed.

View larger version (12K): [in this window] [in a new window]   Figure 1.   ED visits for asthma. Timing of emergency department visit for acute asthma (upper panel ) in relation to blood hormone levels in idealized menstrual cycle (lower panel ).

The median onset of the asthma exacerbation before ED arrival was approximately 18 h. When classifying phase of menstrual cycle based on the onset of asthma symptoms rather than date of ED presentationwe again found no evidence of a perimenstrual peak. For all 288 participants, 83 (29%) were preovulatory, 68 (24%) were periovulatory, 58 (20%) were postovulatory, and 78 (27%) were perimenstrual (p = 0.18). Similar results were found among subgroups defined by menstrual regularity.

Only 13% (95% CI, 9 to 18%) of adult women reported reproductive factors as a personal asthma trigger. We found no significant association between phase of menstrual cycle at ED presentation and reproductive factors as asthma triggers in the past or for the current exacerbation (Table 2). Furthermore, there was no significant association between phase of menstrual cycle at ED presentation and several markers of chronic and acute asthma severity.

	DISCUSSION

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Our data suggest that ED visits for asthma exacerbations in women are more frequent during the preovulatory menstrual phase (Days 5 to 11). Few women reported that reproductive factors, such as menses, were important triggers of their asthma exacerbation. In addition, the phase of the menstrual cycle on presentation to the ED had no relationship to acute or chronic asthma severity.

These findings challenge the significance of hormonal changes as a common factor for asthma exacerbations in women. Previous survey studies of women with stable asthma reported 30 to 40% had worsening of symptoms immediately prior to or at the time of menstruation (3, 9). Recall bias is inherent to questionnaire studies but may have been greater in these studies because only the relation of menses and asthma was explored. Our patients were asked to identify all exacerbating factors from a comprehensive list and menses was selected by only 13%. Thus, the proportion of women with perimenstrual worsening of asthma may be overestimated, or truly worsening symptoms may not lead to exacerbations requiring acute medical care.

Our study also contradicts a more comparable study which noted an increased frequency of ED asthma visits by women during the perimenstrual phase (Days 26 to 4) (10). Several differences exist, however, between the current study and that of Skobeloff and coworkers. Our study consists of a larger number of women (288 versus 182) from more than 10 times as many sites. More importantly, our study involved consecutive enrollment rather than a convenience sample. Another potentially relevant difference was that Skobeloff and coworkers used onset of asthma symptoms to assign the menstrual phase, whereas our primary analysis used date of ED presentation. However, reanalysis of our data using the symptom approach did not demonstrate a perimenstrual peak for patient presentation.

Objective evaluations of airway function during the menstrual cycle in women with stable asthma have yielded inconsistent results. Some studies have noted worsening symptoms and decreases in PEFR in the premenstrual and menstrual period (3, 5, 7, 8, 12), whereas others found no changes in symptoms or spirometric parameters (13). One report found a marked decrease in PEFR coinciding with ovulation (14). Other studies found a discordance between symptoms and spirometric measurements during the menstrual cycle (6, 7). Even if one considers that airway function worsens in the perimenstrual period, our data suggest that it does not result in more asthma exacerbations requiring acute medical care.

The pathophysiology of menstrual variability in asthmatic women is unknown. The effects of the menstrual cycle on the expression of asthma have been attributed to changes in progesterone and/or estradiol levels that affect airway function or inflammatory processes. Current evidence does not allow identification of the responsible hormone or hormones, or whether absolute levels or changes in hormone levels are most important. Both exogenous progesterone and estradiol administration have been reported to improve asthma in women (8, 14). Estradiol administration has been demonstrated to decrease symptoms, cyclic variability in PEFR, and airway reactivity in premenopausal asthmatic women (8, 17). However, estrogen replacement therapy is associated with a greater risk of developing asthma in postmenopausal nonasthmatic women and worsening of disease activity in postmenopausal asthmatics (18, 19).

If hormonal changes in the perimenstrual period are significant factors in asthma exacerbations, our study suggests that clinical deterioration requiring acute medical care is delayed until the preovulatory phase. Alternatively, hormonal alterations in the preovulatory phase may be responsible for asthma exacerbations. Our findings also suggest that hormonal factors have little influence on the severity of asthma or response to therapy once an exacerbation has begun. As noted by other investigators (10), we found no association between menstrual phase on ED presentation and acute asthma severity, as measured by PEFR or admission status. A recent ED study also found no correlation of estradiol concentrations with the severity of bronchospasm or need for hospitalization (20).

A potential limitation of our current study is the self- reporting of menstrual as well as asthma histories. We did not attempt to verify phase of the menstrual cycle with measurements of estradiol or progesterone. In addition, 50 women were excluded from analysis because their last menstrual period fell more than 28 d before their ED visit; we did not ascertain the onset of menses after the ED visit for these women. Nonetheless, even if all 50 patients were added to the perimenstrual group, our study would not demonstrate a statistically significant peak in ED asthma visits during the perimenstrual phase.

Despite these potential limitations, our data raise considerable doubt about prior findings of an increased frequency of ED asthma visits during the perimenstrual phase. Furthermore, our data suggest that observations of decreased airway function in the perimenstrual period in patients with stable asthma may not translate into exacerbations of sufficient severity to require ED care. Further investigation into possible hormonal influences on asthma exacerbations in women is warranted.