It is well known that some female patients with asthma experience an exacerbation of asthma symptoms during the premenstrual or menstrual phase of their cycle. This has been described using the term menstrual or perimenstrual asthma (PMA). After Frank's first report on PMA in 1931,1 many studies focused on the relationship between menstruation and asthmatic symptoms.2, 3 In the 1980s, the characterization of PMA was well established, including peak expiratory flow (PEF) abnormalities in addition to increases in asthmatic symptoms during the perimenstrual phase in PMA patients.4 Recent studies have highlighted the causes of PMA, such as the role of hormones.5, 6

Because bronchial asthma is one of the most common diseases, management of bronchial asthma, including medical interviews, can play an important role in actual clinical settings. During the medical interview, it is very important for the physician to note predictive factors of asthma exacerbation, such as menstruation. However, there is likely to be a discrepancy between studies of PMA and the perception of PMA by physicians in practice and the relationship between asthma exacerbation and menstruation may not receive adequate attention. Although around 30% to 40% of women with asthma report perimenstrual worsening of symptoms,7-10 many physicians tend to think that the rate of PMA is much lower. This is because both female patients and their physicians have paid little attention to PMA.11 It is clear that adequate information about PMA, including characteristic symptoms, hyperresponsiveness and respiratory dysfunction,12-15 pathogenesis5, 6 and therapy,12, 16 are well documented. However, there are few studies that compare PMA patients with non-PMA patients using a questionnaire survey, include all patients with asthma, and are administered in an actual clinical setting. Hence, we designed a study of PMA in actual practice. The prevalence of the conception that PMA is not widely accepted in an actual clinical setting can improve the management of asthma.

A questionnaire survey was administered by the Niigata Asthma Treatment Study Group; the survey took problems regarding asthma management into consideration. The subjects in this survey were adult patients with bronchial asthma who visited medical institutions in Niigata Prefecture, starting in 1998. The attending physicians of these patients were included in the survey. Based on these surveys, we have reported the clinical characteristics of adult bronchial asthma patients,17 the characteristics of elderly bronchial asthma18 and near fatal asthma,19 the relationship between smoking and gender in asthma patients20 and changes in asthma management.21, 22 At the beginning of this survey (1998), there were no questions about the relationship between asthma symptoms and the menstrual phase: these questions were added in 2004 for the reasons mentioned above. In this paper, the analysis was based on the results obtained from surveys conducted from 2004 onwards in order to examine PMA in an actual clinical setting.

The questionnaire used in this study was administered in Niigata Prefecture, Japan, under the Ethical Principles for Medical Research Involving Human Subjects, Declaration of Helsinki. The institutions involved were 28 large hospitals (200 beds or more), 15 small hospitals (<200 beds) and 35 clinics (no beds). Three thousand six hundred and fifty questionnaires were prepared and 2,865 were answered (response rate: 78.5%). The contents of the questionnaire are shown in Table 1 (originally in Japanese). The questionnaire was carried out over 2 months from September to October 2004. Subjects were adult patients (aged 16 years and over) with bronchial asthma who regularly visited the participating institutes for asthma management (typically once or twice per month). The recruited patients were asked to complete the questionnaire by themselves. Therefore, the understanding of technical terms such as "attack" or "unconsciousness" in the questionnaire (Table 1) depended upon the individual patients.

For an evaluation of asthma control, patients were asked about their mean expiratory peak flow value (PEFV) and the incidence of asthma attacks during the 2 weeks prior to answering the questionnaire. During the year prior to the questionnaire, the patients were also asked about their asthma by choosing one of the following three answers: "few attacks," "seasonal attacks," and "frequent attacks." They were also asked about asthma-related work or school absences. The questionnaires asked about asthma-related symptoms in the 2 weeks prior to the questionnaire, including cough and sputum in the morning and at night, and sleep disturbances. The questionnaire also inquired about asthma-related emergencies, including ambulance use, emergency department visits and hospitalization, and life-threatening events such as unconsciousness during asthma attacks, attacks requiring respirator management, and asthma attacks induced by an anti-inflammatory agent (aspirin intolerant asthma, AIA). The subjects were required to answer "yes" or "no" to the following five questions: "Have you ever been hospitalized due to asthma?" "Have you ever been taken by ambulance or visited an emergency room due to an attack?" "Have you ever used a respirator due to an asthma attack?" "Have you ever been unconscious due to an asthma attack?" and "Have you ever had an attack induced by anti-inflammatory drugs including painkillers, antipyretics, or cold medicines?" To evaluate problems in asthma management and treatment related to normal activity levels, the questionnaires asked patients about their satisfaction in daily life. The subjects answered by choosing 1 of 5 answers: "very satisfied," "fairly satisfied," "mediocre," "slightly dissatisfied, "and "dissatisfied."

In addition to the patients' completing the questionnaire, their physicians were asked to supply details of current treatment, primarily identifying control medication, the type of asthma (atopic or nonatopic) in accordance with the elevation of serum total IgE or detection of specific IgE for allergens, and the severity of asthma in accordance with the Japanese Society of Allergology guideline for the diagnosis and management of bronchial asthma. The definition of severity of asthma is essentially the same as that used by the Global Initiative for Asthma.

Among all female patients who were menstruating during the survey period, patients who reported asthma exacerbation related to menstruation were allocated to the PMA group and those who did not were allocated to the non-PMA group.

The results are expressed as arithmetic means (±SD) for continuous variables. The differences between dichotomous variables were analyzed by chi-square test. The Kruskal-Wallis test was used to test for the equality of distributions of continuous variables. The pairwise year-to-year comparison was performed by chi-square test and Wilcoxon's rank sum test with Bonferroni's correction for the significance level. All statistical analyses were performed with the statistical software BMDP 3S (BMDP, Los Angeles, CA, USA) and Statxact (Cytel Software Co., Cambridge, MA, USA).

Of the female patients who were menstruating during the study period, 56 were classified as being in the PMA group and 424 were classified as being in the non-PMA group. Of the PMA patients, 37 (66.1%) reported that menstruation sometimes influenced their asthmatic symptoms, and 19 (33.9%) reported that menstruation always influenced their asthma. Asthmatic symptoms worsened in 51 patients (91.1%) with PMA; there were no reports of improved symptoms during menstruation. Asthma symptoms were affected in 30 patients (53.6%) before, in 9 patients (16.1%) before/during and in 14 patients (25.0%) during menstruation. The backgrounds of patients in the PMA and non-PMA groups are summarized in Table 2. The proportion of patients with step 3 and 4 disease severity was significantly higher in the PMA group than in the non-PMA group. The proportion of non-smokers was also significantly higher in the PMA group than in the non-PMA group. There were no significant differences in age, disease duration, type of asthma, or in the number of PEF users between the groups.

In terms of medication (Table 3), there was a significantly higher usage of leukotriene receptor antagonists (LTRA), oral corticosteroids (OCS), long-acting beta2 agonists (LABA) and oral sustained-released theophylline (OSRT) among patients in the PMA group compared with the non-PMA group. A tendency towards higher usage of salmeterol in the PMA group was noted but was not significant.

There were no significant differences between the two groups in asthma control and symptoms during the 2 weeks prior to answering the survey, except that there was a higher rate of asthma attacks among patients in the PMA group compared with the non-PMA group (Table 4-a). During the 1-year period prior to answering the survey, the proportion of respondents who reported 'frequent' asthma attacks was significantly higher in the PMA group than in the non-PMA group, despite no significant differences in asthma-related work or school absences (Table 4-b).

There was no significant difference in satisfaction in daily life between the two groups (Table 5). The results regarding asthma-related emergency episodes are summarized in Table 6. Higher rates of hospitalization, ambulance or emergency department visits were reported by patients in the PMA group compared with those in the non-PMA group. The rates of asthma attacks with unconsciousness and AIA episodes were also significantly higher in the PMA group than in the non-PMA group.

In this study, we reported on the characteristics of PMA based on responses to a questionnaire survey. The first problem when proposing a study of PMA is defining what PMA is. In spite of many studies on PMA, no standard definition of PMA has been established. In many of these studies, exacerbation of asthmatic symptoms in association with menstruation was used as the definition of PMA,2, 4, 7-10, 23, 24 although decreases in forced expiratory flow (FEV1) or in PEF, scoring of symptoms and frequency of rescue medication for attacks were sometimes used instead. Note that the definition of PMA used in this report was retrospective self-reports of exacerbation of asthma symptoms based on responses to the questionnaire.

Regarding the rate of PMA, there was an interesting discrepancy between previous studies and our results. In western countries, the rate of PMA in menstruating female patients has been reported to be 30-40%. However, the PMA rate found in this study was only 11.3%. It is well known that some patients with PMA cannot recognize exacerbations of their asthmatic symptoms or decreases in respiratory function.4, 10 Chandler et al. showed that only 5 patients with PMA recognized the exacerbation of their asthmatic symptoms by themselves, even though decreases in FEV1 of more than 20% were associated with menstruation in all 20 patients.12 This may be the reason for the low rate of PMA found in our study. In fact, a previous study in Europe, which similarly used self-reports of exacerbated symptoms in response to a questionnaire to define PMA, showed only an 8.2% PMA rate,11 suggesting that the observed differences in the incidence of PMA are not due to race but to study design. However, both physicians and female asthma patients should pay attention to the current lack of patient knowledge relating to PMA because predictive factors of asthma exacerbation, such as menstruation, are, in practice, very important in the management of female patients with asthma.

Because our questionnaire survey only addressed limited clinical features of asthma, it is impossible to compare these results with the clinical characteristics of PMA that were discussed previously, namely, the associations with duration and cycle of menstruation, use of contraceptives and PMA-specified symptoms. However, there were some obvious clinical features of PMA in this study. Regarding the severity of asthma, including the frequency of asthma attacks and symptoms (shown in Tables 2, 4), patients in the PMA group suffered more severe asthma than patients in the non-PMA group, similar to results from previous studies.8, 9, 16, 24-26 Therefore, more aggressive patient management, including increased oral corticosteroid use, was used with patients in the PMA group than in the non-PMA group (Table 3). The rates of emergency episodes in the PMA group, including hospitalization, ambulance or emergency department visits, were higher than in the non-PMA group. These were also similar to those reported in previous studies.27-31

Among the clinical features of PMA outlined in this report, it is very interesting to note that there was a significantly greater proportion of AIA (25.5%) among patients in the PMA group compared with the non-PMA group (8.4%). This may indicate a significant association between PMA and AIA. Moreover, the characteristics of AIA reported previously are very similar to those of PMA.19, 32, 33 LTRA have been reported to be effective in asthma control in both PMA25 and AIA.34, 35 The use of nonsteroidal anti-inflammatory drugs in PMA might not cause this relation, because Forbes et al. reported that there was no association between the use of nonsteroidal anti-inflammatory drugs and PMA.11 These results may indicate that a shared dysfunction of leukotriene and prostaglandin metabolism may be involved in PMA and AIA. Although there is no established cause of PMA, this similarity may contribute to the elucidation of the mechanism of PMA and may present a new strategy not only for PMA but also for AIA.

In summary, using a questionnaire survey conducted in Japan, we compared the clinical features of PMA with those reported previously. The lower rate of PMA found in this study is likely due to the study method used, namely self-reports of PMA. Both physicians and their female asthma patients should pay attention to the current lack of patient knowledge relating to PMA. An interesting observation in this study was that there was a significant increase in the incidence of AIA among patients in the PMA group compared with the non-PMA group, indicating that the clinical similarity between PMA and AIA may provide a new insight into the mechanism of PMA.

REFERENCES

1
Frank RT. The hormonal cause of premenstrual tension. Arch. Neurol. Psychiatry 1931; 26: 1053-1057.

2
Rees L. An aetiological study of premenstrual asthma. J. Psychosom. Res. 1963; 7: 191-197.

3
Wulfsohn NL, Politzer WM. Bronchial asthma during menses and pregnancy. S. Afr. Med. J 1964; 38: 173.
 

4
Pauli BD, Reid RL, Munt PW, Wigle RD, Forkert L. Influence of the menstrual cycle on airway function in asthmatic and normal subjects. Am. Rev. Respir. Dis. 1989; 140: 358-362.
 

5
Faas M, Bouman A, Moesa H, Heineman MJ, de Leij L, Schuiling G. The immune response during the luteal phase of the ovarian cycle: a Th2-type response? Fertil. Steril. 2000; 74: 1008-1013.
 

6
Tan KS. Premenstrual asthma: epidemiology, pathogenesis and treatment. Drugs 2001; 61: 2079-2086.
 

7
Hanley SP. Asthma variation with menstruation. Br. J. Dis. Chest 1981; 75: 306-308.
 

8
Shames RS, Heilbron DC, Janson SL, Kishiyama JL, Au DS, Adelman DC. Clinical differences among women with and without self-reported perimenstrual asthma. Ann. Allergy Asthma Immunol. 1998; 81: 65-72.
 

9
Agarwal AK, Shah A. Menstrual-linked asthma. J. Asthma 1997; 34: 539-545.
 

10
Juniper EF, Kline PA, Roberts RS, Hargreave FE, Daniel EE. Airway responsiveness to methacholine during the natural menstrual cycle and the effect of oral contraceptives. Am. Rev. Respir. Dis. 1987; 135: 1039-1042.
 

11
Forbes L, Jarvis D, Bumey P. Is pre-menstrual asthma related to the use of aspirin or non-steroidal anti-inflammatory drugs? Respir. Med. 2000; 94: 828-829.
 

12
Chandler MH, Schuldheisz S, Phillips BA, Muse KN. Premenstrual asthma: the effect of estrogen on symptoms, pulmonary function, and beta 2-receptors. Pharmacotherapy 1997; 17: 224-234.
 

13
Weinmann GG, Zacur H, Fish JE. Absence of changes in airway responsiveness during the menstrual cycle. J. Allergy Clin. Immunol. 1987; 79: 634-638.
 

14
Tan KS, McFarlane LC, Lipworth BJ. Modulation of airway reactivity and peak flow variability in asthmatics receiving the oral contraceptive pill. Am. J. Respir. Crit. Care Med. 1997; 155: 1273-1277.
 

15
Tan KS, McFarlane LC, Lipworth BJ. Loss of normal cyclical beta 2 adrenoceptor regulation and increased premenstrual responsiveness to adenosine monophosphate in stable female asthmatic patients. Thorax 1997; 52: 608-611.
 

16
Eliasson O, Densmore MJ, Scherzer HH, DeGraff AC Jr. The effect of sodium meclofenamate in premenstrual asthma: a controlled clinical trial. J. Allergy Clin. Immunol. 1987; 79: 909-918.
 

17
Suzuki E, Hasegawa T, Koya T et al. Questionnaire-based Analysis of Current Status of Adult Bronchial Asthma in Niigata Prefecture. Comparison with the Asthma Guideline. Acta Medica. Biologica. 2002; 50: 135-143.

18
Suzuki E, Hasegawa T, Koya T et al. Questionnaire-based Characterization of Bronchial Asthma in Elderly. Analysis in Niigata Prefecture, Japan. Allergol. Int. 2002; 51: 241-248.

19
Yoshimine F, Hasegawa T, Suzuki E et al. Contribution of Aspirin Intolerant Asthma to Near Fatal Asthma Based on Questionnaire Surveys in Niigata Prefecture, Japan. Respirology 2005; 10: 477-484.

20
Satoh H, Hasegawa T, Suzuki E et al. Gender Differences in Susceptibility of Asthma to Active Smoking. Questionnaire Based Analysis in the Niigata Prefecture, Japan. Allergol. Int. 2005; 54: 401-410.

21
Hasegawa T, Suzuki E, Muramatsu Y et al. Questionnaire-based analysis of the current level of asthma control and management in Niigata Prefecture, Japan: Changes from 1998 to 2000. Allergol. Int. 2004; 53: 135-144.

22
Hasegawa T, Suzuki E, Terada M et al. Improvement of Asthma Management in Actual Practice Consistent with Prevalence of Anti-inflammatory Agents. —Based on Questionnaire Surveys in Niigata Prefecture, Japan from 1998 to 2002—. Allergol. Int. 2005; 54: 555-563.

23
Gibbs CJ, Coutts II, Lock R, Finnegan OC, White RJ. Premenstrual exacerbation of asthma. Thorax 1984; 39: 833-836.
 

24
Eliasson O, Scherzer HH, DeGraff AC Jr. Morbidity in asthma in relation to the menstrual cycle. J. Allergy Clin. Immunol. 1986; 77: 87-94.
 

25
Nakasato H, Ohrui T, Sekizawa K et al. Prevention of severe premenstrual asthma attacks by leukotriene receptor antagonist. J. Allergy Clin. Immunol. 1999; 104: 585-588.
 

26
Peters SP, MacGlashan DW Jr, Schleimer RP, Hayes EC, Adkinson NF Jr, Lichtenstein LM. The pharmocologic modulation of the release of arachidonic acid metabolites from purified human lung mast cells. Am. Rev. Respir. Dis. 1985; 132: 367-373.
 

27
Eliasson O, Scherzer HH. Recurrent respiratory failure in premenstrual asthma. Conn. Med. 1984; 48: 777-778.
 

28
Murray RD, New JP, Barber PV, Shalet SM. Gonadotrophin-releasing hormone analogues: a novel treatment for premenstrual asthma. Eur. Respir. J. 1999; 14: 966-967.
 

29
Skobeloff EM, Spivey WH, Silverman R, Eskin BA, Harchelroad F, Alessi TV. The effect of the menstrual cycle on asthma presentations in the emergency department. Arch. Intern. Med. 1996; 156: 1837-1840.
 

30
Prescott E, Lange P, Vestbo J. Effect of gender on hospital admissions for asthma and prevalence of self-reported asthma: a prospective study based on a sample of the general population. Copenhagen City Heart Study Group. Thorax 1997; 52: 287-289.
 

31
Skobeloff EM, Spivey WH, St. Clair SS, Schoffstall JM. The influence of age and sex on asthma admissions. JAMA 1992; 268: 3437-3440.
 

32
Babu KS, Salvi SS. Aspirin and asthma. Chest 2000; 118: 1470-1476.
 

33
Szczeklik A, Stevenson DD. Aspirin-induced asthma: advances in pathogenesis, diagnosis, and management. J. Allergy Clin. Immunol. 2003; 111: 913-921.
 

34
Obase Y, Shimoda T, Tomari SY et al. Effects of pranlukast on chemical mediators in induced sputum on provocation tests in atopic and aspirin-intolerant asthmatic patients. Chest 2002; 121: 143-150.
 

35
Obase Y, Shimoda T, Tomari S et al. Effects of pranlukast on aspirin-induced bronchoconstriction: differences in chemical mediators between aspirin-intolerant and tolerant asthmatic patients. Ann. Allergy Asthma Immunol. 2001; 87: 74-79.