Expert Review of Respiratory Medicine

ISSN: 1747-6348 (Print) 1747-6356 (Online) Journal homepage: http://www.tandfonline.com/loi/ierx20

Risk factors for Premenstrual Asthma. A

systematic review and meta-analysis.

JL Sanchez, A Pereira-Vega, F Alvarado-Gómez, JA Maldonado, C Svanes & F

Real

To cite this article: JL Sanchez, A Pereira-Vega, F Alvarado-Gómez, JA Maldonado, C Svanes &

F Real (2016): Risk factors for Premenstrual Asthma. A systematic review and meta-analysis.,
Expert Review of Respiratory Medicine

To link to this article: http://dx.doi.org/10.1080/17476348.2017.1270762

Accepted author version posted online: 09

Dec 2016.

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Download by: [University of Regina] Date: 13 December 2016, At: 11:11

Publisher: Taylor & Francis

Journal: Expert Review of Respiratory Medicine

DOI: 10.1080/17476348.2017.1270762
REVIEW

Risk factors for Premenstrual Asthma. A systematic review and meta-analysis.

Authors:

Sánchez-Ramos JLa, Pereira-Vega Ab, Alvarado-Gómez Fc,d, Maldonado-Pérez JAb, Svanes

Ce,f, Gómez-Real Fg,h.

Antonio Pereira-Vega and José Luis Sánchez-Ramos contributed equally to this work.

Affiliations:

a
University of Huelva. Spain

b
Pneumology Service, Juan Ramón Jiménez Hospital, Huelva, Spain

c
Library, Juan Ramón Jiménez Hospital, Huelva, Spain

d
Andalusian Health Service e-Library, Seville, Spain

e
Centre for International Health, University of Bergen, Norway

f
Department of Occupational Medicine, Haukeland University Hospital, Bergen, Norway

g
Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway

h
Department of Clinical Science, University of Bergen, Bergen, Norway

Correspondence:

José Luis Sánchez-Ramos

Department of Nursing. University of Huelva. Huelva

Avenida Tres de Marzo, s/n. 21071 Huelva, Spain

1
2
Abbreviations:

BMI: Body Mass Index

CINAHL: Cumulative Index to Nursing and Allied Health Literature

CRD: Centre for Reviews and Dissemination

DLCO: Diffusing capacity of the Lung for Carbon monoxide

EGEA: Epidemiological study on the Genetics and Environment of Asthma

FSH: Follicle-Stimulating Hormone

GM-CSF Granulocyte Macrophage Colony-Stimulating Factor

GSTT1: Glutathione S Transferase Theta 1

IL: Interleukin

LH: Luteinizing Hormone

LILACS: Literatura Latinoamericana y del Caribe en Ciencias de la Salud (Latin-American and

Caribbean Center on Health Sciences Information)

LTC: Leukotriene C

NOx: Nitric Oxide

NSAID: Non Steroid Anti-inflammatory Drugs

OC: Oral Contraceptives

PF: Peak Flow

PMA: Premenstrual Asthma

PMS: Premenstrual Syndrome

PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analysis

3
SUMMARY

Introduction:

Asthma in women can deteriorate in specific phases during the menstrual cycle. Deterioration in

the premenstrual phase (increase in symptoms or deterioration in peak flow measurements) is

known as premenstrual asthma. The etiology remains mostly unknown.

Areas covered:

This paper systematically reviews risk factors for premenstrual asthma. Medline, Embase,

CINAHL, Scopus, Web of Science, LILACS and secondary sources were searched. The

selection criteria were met by 20 articles.

Expert commentary:

Women with pre-menstrual asthma are older, have more severe asthma, a higher body-mass

index, a longer duration of asthma and a greater likelihood of aspirin sensitive asthma. They

more often have dysmenorrhea, premenstrual syndrome, shorter menstrual cycles, and longer

menstrual bleeding. The role of hormone levels and systemic inflammation remains unclear.

Key words:

Asthma; Risk Factors; Sex Hormones; Women’s Health; Phenotypes.

4
1. NTRODUCTION
1.1 Rationale

Asthma among women presents different characteristics from asthma in men [1]. This is

possibly due to differences in factors related to reproduction, such as genetic, hormonal and

metabolic features. Asthma among some fertile women is known to deteriorate at a specific

point in the menstrual cycle. Various authors [2-6] describe a cyclical deterioration of asthma in

the premenstrual or perimenstrual phase as “premenstrual asthma” (PMA).The perimenstrual

phase in the menstrual cycle is the phase in which asthma deteriorates most frequently, and the

phase most frequently studied in the literature [7]. However, cyclical exacerbations may also

occur in the periovulatory phase [8,9] or in the middle of the preovulatory or luteal phase [10,11].

This study will only address cyclical exacerbations in the perimenstrual phase.

PMA can be defined as asthma with a cyclical deterioration during the premenstrual phase

and/or during the first days of menstruation. Eliasson et al. [5] recorded asthma deterioration in

the premenstrual phase only in 10% of women with PMA, in 16% during the menstrual period

and in 74% during both periods. Some authors investigated one menstrual cycle only [12] while

others investigated various consecutive cycles [13]. Murphy et al. [14] found that only 4 of their

12 patients presented with PMA in the majority of the consecutive cycles studied (between 2

and 4).

Balzano et al. [15] raised doubts about whether the exacerbation of asthma in the perimenstrual

phase could be considered objective or whether it was due to a heightened perception of

symptoms caused by a particular psychological state occurring prior to menstruation. However,

later studies have identified objective changes in lung function (variations in peak flow and

bronchial hyperreactivity to methacholine or to physical exercise [16]) or in inflammation

parameters (levels of Nitric Oxide –NOx- or sputum eosinophilia) [17] during the perimenstrual

phase.

Definitions of premenstrual asthma might be based firstly on the patient’s subjective experience

of premenstrual asthma worsening; secondly, on systematically collected data on symptoms,

and finally, on objective criteria such as lung function or inflammation markers in the

premenstrual phase. Our research group [18] categorizes these three possible PMA definitions

5
as “PMA from the subjective viewpoint”, “semi-objective PMA” and “PMA defined by objective

criteria”.

This systematic review focuses on PMA as a suggested phenotype of asthma, as investigated

by various authors [2, 5, 12, 19]. Reported prevalence of premenstrual asthma varies between

11 to 45% [5, 6, 18, 20, 21].

The etiology and pathophysiology of PMA remains mostly unknown [22-27]. There are no

evidence-based guidelines for treatment, although therapeutic interventions have been

proposed [28-34]. Many studies have evaluated the effects of hormonal replacement therapy

involving different combinations of estrogens and/or progesterone in women with PMA [12, 28-

30, 32] and, although the results were sometimes contradictory, the majority showed positive

outcomes with a clinical improvement in peak flow values and a reduction in the number of

exacerbations. These data support the possible role of female sex hormones in PMA.

1.2 Objectives

The objective of this systematic review is to clarify the risk factors of PMA. Where sufficient data

is available, the effect sizes of individual risk factors are pooled and summarized.

6
2. METHODS

This systematic review was carried out in accordance with the recommendations of the PRISMA

declaration [35,36], although the protocol was not registered. Appendix A includes a PRISMA

checklist.

2.1 Eligibility criteria

The search for literature was carried out until December 31, 2015, with no limitation on dates

prior to that or the language in which the articles were written. Studies considered eligible were

those that referred to the etiology or risk factors of premenstrual asthma, regardless of study

design (cross-sectional, case-controls or cohorts studies, reviews of all types of risk factors on

humans or animals, in vivo or in vitro). Studies with focus on PMA etiology or comparing

asthmatic women with and without PMA were selected for the review.

2.2 Information sources

The online bibliographical search consisted of three phases. In the first phase, we consulted

Health Technology Assessment, the Centre for Reviews and Dissemination (CRD),

Tripdatabase, the Cochrane Library and the clinical trials register of the U.S. National Institute

for Health http://www.clinicaltrials.gov/. We also consulted databases for clinical trials in Latin

America as well as the UptoDate clinical information resource.

In the second phase, we consulted bibliographical databases combining search subjects that

referred to premenstrual asthma. The databases included Medline, Embase, CINAHL, Scopus,

Web of Science and LILACS; we used a range of terms and expressions in order to identify as

many articles as possible.

7
In the third phase, we applied a pre-configured methodological filtering system proposed by

Wilczynski et al. [37] in order to identify studies on etiology.

2.3 Search strategies

We included synonymous and polysemic terms frequently used to describe either premenstrual

asthma or manifestations of asthma associated with the menstrual cycle. We searched for

articles that related to premenstrual asthma (menstrual cycle or hormonal activity AND asthma,

as well as articles relating to premenstrual or perimenstrual asthma). We further added other

terms when searching for studies on etiological factors: risk, cohort studies, between group,

search, meta-analysis, review or associated. Table 1 presents the search strategy for the

Medline and Embase databases via OvidSP. The search strategy was adapted to each phase.

2.4 Study selection

We conducted a review of all abstracts of the studies identified in the initial search (n=263). The

selected studies complied with the following requirements: 1) referral to the pathogenesis of

premenstrual asthma; 2) referral to risk factors such as atopy, sex and other hormones,

leukotrienes, cytokines, psychological factors and others; 3) inclusion of humans or animals, in

vivo or in vitro.

Two researchers (APV, JLSR) independently carried out the selection process. The results were

then pooled. Discrepancies were solved by using a consensus list including the predefined

criteria. The complete text of the selected studies (n=90) was then reviewed, and 70 articles

were rejected.

2.5 Data extraction process

We used the Mendeley bibliographical reference manager to process the results and eliminate

duplicates (http://www.mendeley.com). Relevant data was extracted from the selected papers

and entered into a task-specific database.

8
2.6 Data list

The data extracted from each study included: author and year, risk factor, number of

participants, age, length of follow-up, design and inclusion/exclusion criteria. As quality

parameters, we registered sample origin, definition of PMA, definition of exposures and study

quality evaluation. Results from each study were grouped according to the risk factors studied,

the level of the factor measured in women with or without PMA, and the statistical significance

of the associations, as reported in the publications or calculated according to the information

available in each study.

2.7 Risk of bias in individual studies

Potential bias in the included papers was evaluated by assessing the overall quality of the study,

samples origin (selection bias), PMA definition (classification bias), and definition of exposure

(classification bias). The Critical Appraisal Skills Programme [38] templates were used to

evaluate case-control studies, and the tool developed by Berra et al. [39] for the cross-sectional

studies.

2.8 Summary measures

Results from the selected studies were presented in terms of exposures and characteristics of

asthmatic women with and without premenstrual asthma.

2.9 Synthesis of results

When more than one article provided information on one risk factor, we performed a meta-

analysis to integrate numerical results. We assessed heterogeneity using graphical methods

(forest plot), Q statistic and coefficient of heterogeneity I2. Based on the heterogeneity, either

fixed or random effect models were chosen for the numerical synthesis of effect size. The

9
software used was MetaEasy (www.statanalysis.co.uk). Continuous outcomes were expressed

as standardized mean differences with 95% confidence intervals (95% CI).

2.10 Risk of bias across studies

There is presently no clear consensus concerning assessment of bias in publications regarding

etiological studies, unlike intervention studies. Although it is expected that etiological studies

with negative results are less likely to be published, we have not been able to evaluate

publication bias.

3. RESULTS

3.1 Study selection

The results of the selection process according to the reviewed sources (registers identified in

the search, reviewed abstracts, full articles reviewed and final list of articles included) are shown

in the flow diagram (Figure 1). The secondary sources, the CINAHL and LILACS databases,

provided a small number of references, and no additional information to that provided by the

main bibliographical databases.

3.2 Study characteristics

Table 2 shows the characteristics of the 20 studies that were selected. The majority (n=17) are

cross-sectional studies with a relatively small sample size.

The risk factors studied included: general factors (age, marital status, genotype, BMI, use of

aspirin or non steroid anti-inflammatory drugs (NSAIDs) to treat premenstrual syndrome),

asthma characteristics (age of onset, duration and severity of disease, aspirin sensitivity),

menstrual cycle characteristics (duration, days of bleeding, dysmenorrhea, use of oral

contraceptives), presence and severity of premenstrual syndrome, hormones (estradiol,

progesterone, Luteinizing Hormone (LH), Follicle-Stimulating Hormone (FSH), measures of

10
atopy (skin prick tests, total and specific IgEs), and inflammation-related metabolites

(eosinophilia, leukotrienes, interleukins, prostaglandins, histamine, GM-CSF and Platelet

Activating Factor).

The studies recorded between 1 and 6 complete menstrual cycles, some of the studies did not

record symptoms throughout the cycle. Several studies excluded pregnant or breast-feeding

women or women taking oral contraceptives (OC).

3.3 Risk of bias within studies

Concerning the possible risk of selection bias, most studies were conducted on asthmatic

women attending specialized outpatient clinics or general practices, although some studies

included patients hospitalized or participating in a Severe Asthma Research Program.

A possible source of classification bias was that definitions of PMA differed between studies.

Most of the studies (12) defined PMA from the subjective assessment of women (“Does your

asthma get worse in the premenstrual phase?”). Six other defined PMA as the premenstrual

deterioration of ≥ 20% in the recorded intensity of respiratory symptoms throughout the

menstrual cycle. Finally, one study defined PMA based on objective criteria such as

premenstrual deterioration of ≥ 40% in peak flow measurements. The assessment of exposition

to risk factors was based on either questionnaires or clinical measurements, and the methods

were not similar across studies (different questionnaires, RIE/ELISA, specific IgE/Prick test).

The quality of the included studies was medium-to-low (Table 3; See Tables 3.1.S and 3.2.S in

the Online Repository).

3.4 Results from the individual studies

Table 4 shows the most relevant results of the 20 selected studies, including a total of 2164

asthmatic women of whom 425 were defined as having premenstrual asthma. The most

common asthmatic symptoms were cough, wheeze, tightness in the chest and dyspnea [5, 6].

3.4.1 General characteristics of the patients

Various authors have analyzed general characteristics of asthmatic women with PMA (Table 4).

Shames et al. [50] and Rao et al. [48] suggested that these women were older than asthmatic

11
women without PMA. This was not addressed in two studies [6, 42]. Meta-analysis of these data

(Figure 2) shows some heterogeneity and an effect size (standardised mean difference) of 0.42

(95%CI 0.03-0.82) (this means that the age difference between women with and without

premenstrual asthma was 0.42 times higher than than the standard deviation). This value is

considered moderate.

Gorovenko et al. [42] found that women with PMA more frequently (100% vs 69%, p=0.0001)

possessed the genotype with the Glutathione S Transferase T1 (GST-T1) functional allele.

Forbes et al. [41] found that among women with PMA 36.8% used acetylsalicylic acid and non-

steroidal anti-inflammatory drugs (NSAIDs) in the premenstrual period, as compared to 40.9% in

women without PMA. Rao et al. [48] recorded higher BMI (32.5 vs 29.8, p=0.03) in asthmatic

women with PMA compared to asthmatics without PMA.

3.4.2 General characteristics of asthma

Agarwal et al. [6] reported that women with PMA had asthma onset at an earlier age than

asthmatic women without PMA (18.2 vs 21.8 years, p=0.05), although Rao et al. [48] and our

meta-analysis of these two studies (Figure 2) failed to confirm a significant association with age

of -onset of asthma. Meta-analysis of data from Agarwal et al. [6] and Shames et al. [50]

showed that women with PMA had a significantly longer duration of asthma (standardised mean

difference 0.81, 95%CI 0.41-1.20).

According to Rao et al. [48], the severity of asthma was usually greater in women with PMA,

although Pereira et al. [18] did not find evidence of a linear relation between asthma severity

and PMA but that PMA could occur among women with any degree of asthma. In the study of

Agarwal et al. [6], women with PMA visited emergency rooms more often and were hospitalized

more frequently than women without menstrual-linked asthma.

Suzuki et al. [52] and Rao et al. [48] found that PMA was associated with a greater sensitivity to

and more frequent intolerance to acetylsalicylic acid. Meta-analysis of these data (Figure 2)

showed a significant stardardised mean difference of 0.44 (95%CI: 0.25-0.62).

3.4.3 Menstrual cycle

12
The duration of the menstrual cycle among women with PMA was reported to be slightly shorter

(27.8 vs 30.2 days, p<0.01) [43], with more days of bleeding (6.6 vs 5.5, p=0.05) [4], and higher

frequency of dysmenorrhea (12.5 vs 7.9%, p=0.019) [5].

3.4.5 Premenstrual syndrome

PMA was related to symptoms of premenstrual syndrome in studies by Rees [4], Eliasson et al.

[5], Agarwal et al. [6] and Murphy et al. [14]. Meta-analysis showed an effect size of 0.73

(95%CI: 0.45-1). Pereira et al. [45] also reported more anxiety in addition to symptoms of

premenstrual syndrom (abdominal tension, mammary tension, sensation of swelling) (Table 4).

3.4.6 Hormones

Pasaoglu et al. [34] and Pereira et al. [46] found that serum levels of estrogen and progesterone

did not differ significantly between women with and without PMA (Table 4). Pasaoglu et al.

suggested higher levels of FSH (13.3 vs 3.3) in asthmatic women with PMA,although statistical

significance was not provided.

3.4.7 Atopic sensitisation

Gorovenko et al. [42] and Rao et al. [48] found that women with PMA had significantly less

atopy measured as positive skin prick tests to common aeroallergens (Table 4). However, Rees

[4] found that allergic factors very often triggered asthma attacks in women with PMA (88 vs

58%, p=0.05). Our research group [44] found higher levels of total IgE, but not specific IgEs, in

women with PMA. Meta-analysis of four studies (Nakasato et al. [33], Pereira et al. [44], Rao et

al. [48] and Siroux et al. [51]) found no statistically significant differences in total IgE between

women with and without PMA (Figure 2).

3.4.8 Metabolites related to inflammation

Nakasato et al. [33] noted that LTC4 values in serum of patients with RMA were significantly

higher in the premenstrual period than in the preovulatory period. Our group [47] has analyzed

variations in leukotriene (LTC4) levels in the preovulatory and premenstrual periods in women

with and without PMA, finding no clear differences between the groups. Siroux et al. [51] found

higher levels of eosinophils in women with PMA (330 vs 190 eosinophils/mm3, p=0.01). Results

concerning other inflammation markers as interleukins, prostaglandin F2α, histamine,

13
granulocyte-macrophage colony-stimulating factor, platelet activating factor or Fractional

exhaled nitric oxide (FeNO) were also inconclusive (Table 4).

4. DISCUSSION

4.1 Summary of evidence

A large body of literature contribute to present pre-menstrual asthma as a specific phenotype of

asthma with particular characteristics. The literature suggests that women with pre-menstrual

asthma are older, have more severe asthma, a higher body-mass index, a longer duration of

asthma and a higher frequency of aspirin sensitive asthma. Further, women with PMA appear to

more often have dysmenorrhea, premenstrual syndrome, shorter menstrual cycles, and longer

menstrual bleedings. The literature on potential mechanisms of PMA is limited, and the role of

hormone levels and systemic inflammation remains unclear.

In this systematic review, we found that the definition of PMA varied across studies, and that

many studies defined PMA exclusively based on subjective criteria. In general, the quality of the

studies was medium-to-low with regard to the aims of the present review. Few studies had the

specific aim of determining the etiology of PMA, as the main objective for most studies was to

describe the clinical characteristics of PMA. We searched also such studies in order to identify

potential data that could contribute to assess the etiology of PMA. Few studies directly

compared asthmatic women with and without PMA, and some studies did not describe inclusion

and/or exclusion criteria. The number of women with PMA was low in many studies.

The literature suggested a wide range of potential risk factors for premenstrual asthma,

including hormonal factors [28, 32, 49, 53-54], atopy [44, 56-58], variations during the menstrual

cycle in levels of catecholamines, LTC4 leukotrienes [33], F2α prostaglandin [40] and cytokines

[59], psychological factors, lower defenses against infection, and an increase in bronchial

hyperreactivity [5, 60,61].

With regard to general characteristics, the studies generally agreed that women with PMA

were generally older, had a greater BMI, and were more often Glutathione S Transferase Theta

1 genotype (GSTT1) positive. This genetic trait is related to metabolism of prostaglandins (PG),

14
leukotrienes (LTC) and sex hormones. Obesity is a modifiable risk factor, and reducing obesity

might be a public health strategy to lower disease burden of PMA.

Acetylsalicylic acid and NSAIDs might be used to mitigate symptoms related to premenstrual

syndrome (PMS) such as abdominal pains or headaches. According to Forbes et al. [Error!

Bookmark not defined.], although 41% of the women with mild-moderate asthma analyzed

were taking such medication in the premenstrual period, there was no evidence that the

widespread use of NSAIDs for menstrual symptoms was causing substantial morbidity in

women with mild asthma.

The now classic study by Rees [4] extensively investigated a range of risk factors related to

personality traits and mental illnesses, without finding any significant differences between

women with or without PMA.

The general characteristics of asthma differed between women with and without PMA.

Several studies found that women with PMA suffered a greater number and more severe crises

of asthma immdediately before and on the first day of menstruation [9, 57, 63], and one study.

[64] showed that the number of emergency visits was higher in the preovulatory period. Meta-

analysis suggested higher asthma related to aspirin sensitivity in women with PMA.

With regard to menstrual cycle characteristics, PMA was associated with slightly shorter

menstrual cycles [43], longer menstrual bleedings [4] and more frequent dysmenorrhea [5].

Several studies [4] [6] [45] found greater frequency of premenstrual syndrome symptoms

among women with PMA. However, other authors could not confirm such relationship [5, 14].

Premenstrual syndrome severity was significantly greater among uncontrolled asthmatic women

than among patients with unchanged asthma symptoms in the perimenstrual period [65].

4.1.1 Female sex hormones and premenstrual asthma

Asthma is associated to premenarche [66], premature menarche [67,68], fertility [69], pregnancy

[70], premenopause [71] and menopause [72]. During a woman’s fertile age, sex hormones

undergo important changes along the menstrual cycle. In the premenstrual period, levels of

estrogen and progesterone increase significantly, to be followed by a sharp fall just before

menstruation begins. Rubio et al. [49] found that asthmatic women had lower premenstrual

15
levels of progesterone than healthy women. Although they made no comparison between

women with or without PMA, all those with PMA belonged to a group of women who had very

low concentrations of progesterone at the 21st day of the cycle. Experimental studies have

described contradictory pro- and anti-inflammatory effects both for estrogens [73-77] and

progesterone [78,79]. Townsend et al. [80] reported that the role of estrogens in inflammation

could vary depending on the target organ and the levels of hormones. Mechanisms behind the

association of sex hormones with premenstrual deterioration of asthma might be related to

airway inflammation [81]. Several authors observed greater bronchial hyperreactivity in the

premenstrual phase [53, 54, 61, 82]. Ackerman [83] stated that the estrogen/androgen balance

could modulate the inflammatory response, and that androgens could act as protectors in the

development of allergic inflammation. Women with PMA presented similar levels of LH to other

asthmatic women in the premenstrual period, while FSH was slightly higher. D´Agostino et al.

[84,85] cited testosterone as a cause of the premenstrual exacerbation of bronchial

hyperreactivity in asthmatic women. There is not sufficient evidence for a clear etiological role of

sex hormones in PMA [34].

Clinical observations do not seem to confirm the hypothesis that patients with PMA have

different sex hormone levels from women without PMA. However, studies of the serum levels of

sex hormones might not reflect the potential role of these hormones in PMA, as these hormones

can act through other circulating or local mediators increasing angiogenesis and the capacity for

diffusion in the respiratory tract without any clear relation to serum hormone levels.

Other factors controlled by sex hormones would be the abnormal cyclical beta2-adrenoreceptor

regulation [28, 86-90], the mast cell degranulation occurred in the endometrium in the days

before and during menstruation [74, 91], and metalloproteases like angiotensin converting

enzyme and neutral endopeptidase [92].

4.1.2 Atopic sensitisation

A tendency to higher levels of IgE was suggested in women with PMA. However, the

relationship between PMA and atopy was highly heterogeneous, and the measures of atopy

varied greatly between the studies.

16
Skoczynsky et al. [93] also found significantly higher total IgE in women with PMA. Martínez

Moragón et al. [57] discovered that asthmatic women who had a life-threatening crisis on the

first day of menstruation, as opposed to those who had one on the other days of the cycle, had

double the level of total IgE. However, our findings were not consistent with this results.

Roby et al. [58] found higher levels of IgG, IgM and IgE antibodies against progesterone and

estrogens in patients with symptoms of asthma, migraines and pain related to hormonal

variations, when compared to healthy women.

4.1.3 Metabolites related to inflammation

Other factors related to PMA are inflammatory mediators like eosinophils, leukotrienes or

cytokines that emerge as a result of mast cell degranulation. In the EGEA study, Siroux et al.

[51] reported higher levels of peripheral eosinophilia.

Several studies [33] [100,101] suggest higher values of LTC4 in PMA patients and that LTC4

leukotrienes have a relevant role in PMA etiopathogeny. This suggests a possibility of using

anti-leukotriene treatment in PMA. Likewise, Pasaoglu et al. [34] noted an improvement in

premenstrual symptoms and peak flow levels in 11 women with PMA when taking a anti-

leukotriene. Our group [47] has found no clear differences between in leukotriene (LTC4) levels

in the preovulatory and premenstrual period in women with and without PMA. These

observationsdo not support the possible involvement of leukotrienes in the pathogenesis of

PMA of moderate intensity or the use of anti-leukotrienes as specific therapy in PMA.

Other inflammatory mediators related to PMA etiopathogeny are prostaglandins [40] and

cytokines [59]. Hernández-Colín et al. [102] related the high levels of prostaglandin 2 alpha

often found in the last phase of the menstrual cycle with progesterone levels which were also

elevated in this period, and secondarily with the possible appearance of PMA.

There has been much interest in recent years in the involvement of cytokines in the

etiopathogeny of bronchial asthma [103,104] and their possible use in future treatments

[105,106]. The level of pro-inflammatory cytokines IL-1β, IL-6, IL-8 were 1.5 to 3 times greater

during menstruation than the late follicular phase, this being associated to lesser concentrations

of estradiol and progesterone. Variability during the menstrual cycle and the correlations to sex

17
hormone levels would seem to support the role of cytokines in the menstrual cycle [107].

Bertone-Johnson et al. [108] found a relation between certain cytokines and premenstrual

syndrome.

Nakasato et al. [33] found no differences in cytokines levels (IL-1ß, IL-4, IL-5, IL-6 and GM-

CSF) between two phases of the menstrual cycle, or in any of the other markers analyzed

(LTB4, the activating factor of platelets and histamine) in asthmatic women with or without PMA.

Agarwal et al. [59] related a deterioration in asthma before menstruation to a cytokine imbalance

in women with PMA (a rise in IL-10 and a fall in Interferon gamma). Skoczynski et al. [93] found

more elevated levels of IL-4 and eotaxin in the sputum of women with PMA when compared to

asthmatics without PMA both in the follicular and luteal phases, although no changes were

registered in IL-1β or IL-10.

5. Limitations

The studies included in this article were generally weak in providing scientific evidence on PMA

etiology, and some of them have a very small number of patients. Further, most were cross-

sectional studies, precluding the possibility to establish a clear causal relationship. PMA was

also often subjectively defined based on whether the patient’s asthma worsened at some point

during the menstrual cycle. Moreover, most of the studies asked specifically whether a

deterioration had occurred in the premenstrual period, which could lead to selection bias. Some

studies included specific questions on the influence of the menstrual cycle on the intensity of

asthma symptoms. Only a few studies actually used a daily record of the intensity of asthma

symptoms or peak flow for one or various cycles. In addition, some studies did not make a clear

distinction between asthmatic women with and without PMA, which made it difficult to draw

conclusions on its etiology.

The search strategy involved two researchers independently selecting articles for the review,

however, there is still a possibility for a biased selection of literature. A weakness of the review

was the limited data available for the meta-analyses, which were performed based on a small

number of studies with small sample sizes. The results should thus be interpreted with caution.

One strength of this review is that we did not limit the search with regard to language. A number

18
of the publications about premenstrual asthma are from clinical environment that have published

their finding in various languages.

6. Conclusions

Premenstrual asthma is a phenotype of asthma with specific characteristics. This phenotype is

relevant due to its frequency, clinical importance and potential for personalized treatment.

Although there is no generally accepted definition, criteria based on standardized recording of

respiratory symptoms and peak flow levels during the menstrual cycle can be considered valid

for detecting this condition.

The etiology of PMA remains unclear. Women with PMA are older, more obese and have a

higher frequency of GSST1 functional genotype. Women with PMA have longer duration of

asthma, more severe asthma and more often asthma related to acetylsalicylic acid. PMA is also

associated with dysmenorrhea, shorter duration of cycles, longer menstrual bleedings and

presence of the premenstrual syndrome. However, there are discrepancies in the literature as to

the understanding of the role of atopic sensitisation and levels of female sex hormones.

Published results concerning inflammation markers are also inconclusive. The relationship

between the hormonal changes through the menstrual cycle and premenstrual asthma is not

well understood, but we specualte that this may hold a key to further understanding. There is a

need to explore complex relationships including intermediate mechanisms, for example cyclical

variations in cytokines and leukotrienes, in turn influenced by hormonal variations.

New well-designed studies with a sufficiently large sample size are needed in order to

understand the etiology of PMA and in order to elaborate guidelines for diagnosis and treatment

of premenstrual asthma. Like Skoczynsky et al. [109], we believe that interdisciplinary

collaboration could shed light on this subject. There is also a need for an international

consensus on a definition of premenstrual asthma, and future studies should take into account

modifiable risk factors such as BMI, smoking and socioeconomic status.

19
7. Expert commentary:

Pre-menstrual asthma is a specific phenotype of asthma. Women with pre-menstrual asthma

are older, have more severe asthma, a higher body-mass index, a longer duration of asthma

and a greater likelihood of aspirin sensitive asthma. They more often have dysmenorrhea,

premenstrual syndrome, shorter menstrual cycles, and longer menstrual bleedings. The role of

hormone levels and systemic inflammation remains unclear.

8. Five-year view:

While the characteristics of premenstrual asthma are reasonably well described in the literature,

there is a need for future research with the objective of determining the etiology of premenstrual

asthma. New studies should include sufficient sample size and use standardized methodology.

In particular, it is important to define premenstrual asthma clearly, preferably based on

symptoms and peak flow, while comparing asthmatic women of fertile age with and without

premenstrual worsening of asthma. In the coming years, interdisciplinary collaboration will be

needed to understand the complex interrelationship of hormonal, metabolic and inflammatory

factors in order to elucidate the mechanisms behind premenstrual asthma.

9. Key issues

• Premenstrual asthma is a relevant phenotype of asthma due to its frequency, clinical

importance and potential for personalized treatment.

• Premenstrual asthma is generally defined as the cyclical deterioration of asthma during

the premenstrual phase. A consensus with regard to the precise definition of

premenstrual asthma would be useful for further research.

• Standardized recording of respiratory symptoms and peak flow levels during the

menstrual cycle are valid tools for diagnosing the condition.

• The literature is limited by cross-sectional study design and small sample size.

• The etiology and pathophysiology of premenstrual asthma remains mostly unknown.

20
• Women with premenstrual asthma are older, more obese and have a higher frequency of

GST-T1 functional genotype.

• Premenstrual asthma can occur at any level of severity of the disease, although usually it

is associated with greater asthma severity.

• Women with premenstrual asthma had longer duration of asthma, and more often had

asthma related to acetylsalicylic acid administration.

• Women with premenstrual asthma more often had dysmenorrhea, shorter menstrual

cycles and longer menstrual bleedings. Premenstrual asthma is related to symptoms of

the premenstrual syndrome.

Funding

This paper was not funded.

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity

with a financial interest in or financial conflict with the subject matter or materials discussed in

the manuscript. This includes employment, consultancies, honoraria, stock ownership or options,

expert testimony, grants or patents received or pending, or royalties.

21
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103. Lemanske RF and Busse WW. Asthma: clinical expression and molecular mechanisms. J

Allergy Clin Immunol 2010; 125:S95-102.

104. Broide DH, Finkelman F, Bochner BS and Rothenberg ME. Advances in mechanisms of

asthma, alergy and immunology in 2010. J Allergy Clin Immunol 2011;127:689-95.

105. Corren J. Cytokine inhibition in severe asthma:current knowlledge and future directions.

Current Opinion in Pulmonary Medicine 2011;17:29-33.

106. Desay D and Brightling C. Cytokines and cytokines-specific therapy in asthma.Adv Clin

Chem 2012;57:57-97.

107. Whitcomb BW, Mumford SL, Perkins NJ, Wactawski-Wende J, Bertone-Johnson ER,

Lynch KE and Schisterman EF. Urinary cytokine and chemokine profiles across the

menstrual cycle in healthy reproductive-aged women. Fertility and Sterility 2014; 101 (5):

1383-1391.

33
108. Bertone-Johnson ER, Ronnenberg AG, Houghton SC, Nobles C, Zagarins SE, Takashima-

Uebelhoer BB, Faraj JL and Whitcomb BW. Association of inflammation markers with

menstrual symptom severity and premenstrual syndrome in young women. Human

Reproduction, 2014; 29 (9): 1987–1994.

109. Skoczynsky S, Semik-Orzech A, Szanecki W, Majewski M, Kolodziejczyk K, Sozanska E,

Witek A, Pierzchala W. Perimenstrual Asthma as a Gynecological and Pulmonological

Clinical Problem. Adv Clin Exp Med 2014; 23 (4): 665-668.

Medline Embase Cochrane, Others (LILACS, CINAHL,

(n=61) (n=92) clinical trials WOS, Scopus)
(n=4) (n=162)
↓ ↓ ↓ ↓
Registers identified in the search → Duplicated
(n=319) registers
(n = 66)
↓
Reviewed abstracts of potentially relevant articles → Rejected
(n = 253) abstracts
(n = 163)
↓
Full articles reviewed and deemed eligible (n = 90) → Rejected articles
(n = 70)
↓
Final list of articles included (n = 20)

Figure 1. Flow diagram of information obtained from the bibliographical review

LILACS: Literatura Latinoamericana y del Caribe en Ciencias de la Salud (Latin-American and Caribbean Center on
Health Sciences Information); CINAHL: Cumulative Index to Nursing and Allied Health Literature; WOS: Web of
Science.

34
Figure 2. Meta-analysis of risk factors for premenstrual asthma

Horizontal axis represents Effect: Standardized Mean Difference, or Standardized Difference in Exposition* (dichotomous); I2: Coefficient of Heterogeneity; p: significance for Q statistic

35
Table 1. Search strategy for Embase and Medline via OvidSP

Query Search strategies

1 premenstrual asthma.ab,ti.
2 perimenstrual asthma.ab,ti.
3 asthma.ab,ti.
4 asthma.sh.
5 menstrual cycle.ab,ti.
6 hormonal activity.ab,ti.
7 3 or 4
8 5 or 6
9 7 and 8
10 1 or 2 or 9
risk:.mp. or exp cohort studies/ or between group:.tw. or search:.tw. or meta
11
analysis.mp,pt. or review.pt. or associated.tw.
12 10 and 11

Field search abbreviations: ab: abstract; ti: title; sh: subheading; mp: default fields; tw: text word; pt: publication type

Table 2. Characteristics of the comparative studies selected

Author, Risk factors Sample size Age Duration of monitoring Design Inclusion/exclusion
year, (cycles) criteria
reference
Agarwal Age; 100 asthmatic women in 15-45 PF registered in 20 Cross-sectional Excluded: pregnancy,
1997 [6] Marital status; India asthmatic women during study lactation, taking OC or
Age of asthma onset and (23% with subjective 2 cycles oral corticosteroids in
duration of ashtma PMA). PF is measured in the 4 previous weeks
10 participants in each
group
Eliasson Serum 13-14-diOH-15- 24 PMA, 4 with asthma Mean ages: PMA: PF measured in 1 cycle Cross-sectional NA
1986a [40] keto-prostaglandin F2 but no PMA and 4 healthy 31.9; asthmatic study
alpha women. Study of the level women without
of PG F2αα in follicular PMA: 39; healthy
and luteal phases women: 30.8
Eliasson PMS; 57 asthmatic women, PMA: 37.1 No daily register (global Cross-sectional Excluded:
1986b [5] dysmenorrhea 19 (33%) with PMA No PMA: 35 questionnaire) study postmenopausal
38 no PMA women

Forbes AAS or AINEs in the 461 asthmatic women, 38 20-29 No daily register (global Cross-sectional Women with mild
2000 [41] premenstrual phase for PMA (8.2 %) questionnaire) study asthma prescribed
PMS symptoms 423 no PMA inhaled b-agonists
during the 2 years
before the survey.
Gorovenko Genotype (GSTT1); 74 asthmatic women: NA No daily register (global Cross-sectional NA
2005 [42] Allergy (prick tests); Age 9 PMA (12.16 %); questionnaire) study
65 no PMA
Hanley Duration of the cycle 102 asthmatic women 16-55 PF in 2-3 cycles Cross-sectional Asthmatic women
1981 [43] (36 PMA) study
PF in 13 of those with
PMA and 12 with no
PMA.
Murphy OC 28 asthmatics 21-48 Daily register 2-4 months. Cross-sectional Premenopausal
2008 [14] PMS 16 PMA study women, regular
12 no PMA periods
Author, Risk factors Sample size Age Duration of monitoring Design Inclusion/exclusion
year, (cycles) criteria
reference
Nakasato LTC4, IL-1β, 5 PMA, 5 asthmatic 18-42 3 cycles Age-matching NA
1999 [33] IL-4, IL-5, IL-6, GM-CSF, women with no PMA case control
histamine, LTB4, and study
platelet-activating
factor
Pasaoglu Estrogens; 24 with mild asthma: 25-47 A study of 3 cycles: Pre/post study Excluded: regular use
2008 [34] Progesterone; 11 PMA 1st inhaled corticosteroids (cross-sectional of oral corticosteroids
LH; 13 no PMA (IC) only; for analysis of
FSH 2nd IC + placebo; hormones)
3rd IC + Montelukast
Pereira Total IgE, specific IgE; 31 PMA, 14-44 1 cycle Cross-sectional Excluded: lactation,
2010ª [44]Phadiatop 28 no PMA study pregnancy and OC
Pereira Premenstrual symptoms 46 PMA, 14-47 1 cycle Cross-sectional Excluded: lactation,
2010b [45] 57 no PMA study pregnancy and OC
Pereira Asthma severity (GINA) 46 PMA, 14-47 1 cycle Cross-sectional Excluded: lactation,
2010c [18] 57 no PMA study pregnancy and OC
Pereira Estrogens, Progesterone 31 PMA, 14-44 1 cycle Cross-sectional Excluded: lactation,
2012ª [46]and quotient 28 no PMA study pregnancy and OC
Pereira LTC4 Leukotrienes 34 PMA 14-44 1 cycle Cross-sectional Excluded: lactation,
2012b [47] 24 No PMA study pregnancy and OC
Rao 2013 Age, BMI 483 asthmatics 13-50 NA Cross-sectional Excluded: < 12 years
[48] Asthma characteristics; 92 (17%) PMA study and > 50 years
Atopy; Total IgE; 391 no PMA
Aspirin-Intolerant Asthma
Rees 1963 Personality disorders, 81 16-50 Register of daily Age, marital Of fertile age (between
[4] neurotic symptoms, 27 PMA (33 %) symptoms over a number status, parity menarche and
allergy or infection 27 No PMA of cycles and socio- menopause)
factors, psychological economic
factors; menstrual status,
function (age of matching case-
menarche, length and control study
regularity of menstrual
cycle, severity of
psychological changes
related to PM age at
which asthma started).
Rubio Estrogens, 30 asthmatic women and 20-37 1 cycle Case-controlOf fertile age, regular
Ravelo Progesterone, 15 control participants. study cycles.
1988 [49] Cortisone Excluded: OC,
glucocorticoids taken
in the previous 2
months
Shames Age, nº years with 32 asthmatic women 18-50 6 cycles; PF measured in Cross-sectional Regular cycles (26-35
1998 [50] asthma, severity 9 (28.2%) with PMA 2 cycles, and study days)
methacholine in PO and Excluded: pregnant,
PM phases menopause, chronic
cardiopulmonary
illnesses, use of anti-
inflammatory drugs or
OC
Siroux 2007 Allergy: 16 PMA; NA No daily register (global Cross-sectional NA
[51] eosinophils, 86 no PMA questionnaire) study
Total IgE, (EGEA study)
Nº prick tests +
Suzuki Severity: 54 PMA (11.3%) >16 2 cycles Cross-sectional Asthmatic women of
2007 [52] Aspirin-Intolerant Asthma 422 no PMA study fertile age

PMA: Premenstrual asthma; PF: Peak flow; OC: Oral contraceptives; PG: Prostaglandin; NA: Not available; PMS: Premenstrual syndrome;

AAS: Acetyl-salicylic acid; NSAIDs: Non-steroidal anti-inflammatory drugs; GSTT1: Glutathione S Transferase Theta 1; LTC4: Leukotriene C4;

IL: Interleukine; GM-CSF: Granulocyte-macrophage colony-stimulating factor; PO: Preovulatory; PM: Premenstrual.
Table 3. Quality parameters of the observational studies

Author Selection bias: Classification bias: Classification bias: Study quality evaluation
Sample origin Definition of PMA Definition of exposure
Agarwal Women consecutively Subjective General questionnaire Medium
1997 [6] attending outpatient clinic
Eliasson NA Subjective Blood samples: radioimmunoassay Low
1986a [40] 20/24 objective, with ↓ PF 8 of the asthmatic women (7 with PMA) Significance of the differences
were taking CO found not discussed
Eliasson Women consecutively PMA subjective (premenstrual Global questionnaire for RS and PMS Low/Medium
1986b [5] attending outpatient clinicand menstrual) PMA definition subjective. No
Deteriorating premenstrual 10%; register of symptoms
Menstrual 16% and in both
phases: 74%
Forbes 24 general practices in South Questionnaire: `Does your General questionnaire Low/Medium
2000 [41] London asthma vary with the time of your PMA definition subjective. No
monthly cycle?' register of symptoms
Gorovenko NA Questionnaires: Blood samples: Low/Medium
2005 [42] PCR for genes Highlights role of genotype
Prick test although PMA definition is
subjective only
Hanley Hospital 16; Questionnaire: Does your General questionnaire Low
1981 [43] Outpatients clinic 13; asthma deteriorate or improve Doubts as to whether this is a
By letter: 158 during menstruation, or is there representative sample
no change?

Murphy NA Various definitions: RS, asthma Daily register of mood and physical Medium
2008 [14] treatment, PF symptoms
↑ RS or treatment with or without
↓ PF in at least 1 cycle
Nakasato Women consecutively >40% PF: a very restrictive Blood samples taken: Medium
1999 [33] attending outpatient clinic. definition IL: ELISA; Small simple, PMA
LTC4: RIA definition highly restrictive
Pasaoglu Mild asthma sufferers from Deteriorating premenstrual of the Blood samples taken: Low/Medium
2008 [34] outpatient department RS and PF for 3 months RIA: Estrogens, Progesterone, LH, FSH The study is designed to
evaluate a treatment rather than
investigate PMA etiology.
Pereira Specialist medical PMA: >20% deterioration of Blood samples taken: Medium/High
2010a [44] consultancy symptoms or PF RIA for Total and Specific IgE in PO and Directly compares asthmatic
PM phases women with PMA to those with
Phadiatop no PMA
Pereira Specialist medical PMA: >20% deterioration of Validated questionnaire on premenstrual Medium/High
2010b [45] consultancy symptoms or PF syndrome Directly compares asthmatic
women with PMA to those with
no PMA
Pereira Specialist medical PMA: >20% deterioration of GINA Medium/High
2010c [18] consultancy symptoms or PF Directly compares asthmatic
women with PMA to those with
no PMA
Pereira Specialist medical PMA: >20% deterioration of Blood samples taken: Medium/High
2012a [46] consultancy symptoms or PF RIA, Estrogens, Progesterone and their Directly compares asthmatic
quotient in PO and PM phases women with PMA to those with
no PMA
Pereira Specialist medical PMA: >20% deterioration of Blood samples taken: Medium/High
2012b [47] consultancy symptoms or PF RIA, LTC4 in the PO and PM phases Directly compares asthmatic
women with PMA to those with
no PMA
Rao 2013 Severe Asthma Research Screening questionnaire: menses Lung function, FeNO, Total IgE, Medium/High
[48] Program as a trigger for asthma symptom Questionnaire for symptoms A very complete study aimed at
onset or worsening Prick test studying PMA etiology
Rees 1963 Specialist medical Asthma attacks that occur Global self-reporting questionnaire Low
[4] consultancy preferentially in the PM phase Pioneering study, but with some
methodological deficiencies
Rubio Allergology outpatients clinic. PMA subjective. 20 asthmatic Global questionnaire Medium
Ravelo Groups determined by women were asked if their Blood samples taken: Not specifically aimed at
1988 [49] progesterone behaviour were asthma deteriorated in PM phase RIA, Estrogens, Progesterone, Cortisone studying PMA etiology
later established
Author Selection bias:
Sample origin
Shames Self-selection: this could
1998 [50] influence asthma severity and,
as a result, the prevalence of
PMA although, in principle, it
would not represent a
differential bias between PMA
and no PMA
Siroux 2007 Asthmatic women at a
[51] hospital doctor’s surgery
Suzuki Hospital and clinic outpatients Subjective: patients who reported Global self-reporting questionnaire
2007 [52]
Classification bias: Classification bias: Study quality evaluation
Definition of PMA Definition of exposure
Subjective Clinical questionnaire, RS, Low/Medium
Lung function with daily PF, Spirometry PMA evaluated subjectively,
and Methacholine PO and PM in 2 cycles possible self-selection bias
Asthma severity (treatment necessary,
work days lost, Emergency Service visits,
hospitalizations)
NA Global questionnaire Low/Medium
Blood samples taken: Only evaluates the global
Total IgE, questionnaire. Study controls
Prick test, age confusion, smoking and
Phadiatop asthma severity
Medium
asthma exacerbation related to Only evaluates subjective PMA;
menstruation no daily register

NA: Not Available; PF: Peak Flow; PMA: Premenstrual asthma; PMS: Premenstrual Syndrome; RS: Respiratory Symptoms; NSAIDs: Non-

steroidal anti-inflammatory drugs; ELISA: Enzyme-linked immunosorbent assay; RIA: Radioimmuno Analysis; LTC4: Leukotriene C4; PO:

Preovulatory; PM: Premenstrual. FeNO: Fractional exhaled nitric oxide.

Table 4. Results from the individual studies

Author Group factor Risk Factors PMA No PMA p

Agarwal 1997 [6] General Age (SD) 28 (7.8) 27.4 (8.2) NS
Gorovenko 2005 Age (SD) 44.95 (1.5) 44.47 (1.22) NS
[42]
Rao 2013 [48] Age (SD) 35.2 (9.3) 32.2 (9.9) 0.007
Shames 1998 [50] Age (SD) 40.2 (5.2) 31.4 (7.1) 0.0007
Agarwal 1997 [6] Marital status (% 70 70 NS
married)
Gorovenko 2005 Genotype (% GSTT1, 100 68.96 0.0001
[42] gene per PCR)
Forbes 2000 [61] Aspirin or NSAIDs in the 14/38 (36.8%) 172/421 (40.9%) NS
premenstrual phase for
PMS symptoms
Rao 2013 [48] BMI, kg/m2 32.5 (11.1) 29.8 (8.6) 0.03
Agarwal 1997 [6] Asthma Starting age (SD) 18.2 (8.4) 21.8 (9.4) 0.05
Rao 2013 [48] characteristics Starting age (SD) 12.9 (11.1) 13.1 (11.4) 0.73
Agarwal 1997 [6] Years with asthma (SD)9.8 (7.3) 5.6 (5.1) < 0.005
Shames 1998 [50] Years with asthma (SD)28 (15) 16 (11) 0.039
Pereira 2010c [18] Asthma severity (GINA)Mild intermittent 10 (21.7%) 29 (50.9%) Linear
Mild persistent 15 (32.6%) 4 (7%) association p-
Moderate persistent 8 (17.4%) 8 (14%) value 0.184
Severe persistent 13 (28.3%) 16 (28.1%)
Rao 2013 [48] Asthma severity (% Mild 31 (52%) 195 (50%) 0.0003
severe) Moderate 14 (14%) 80 (20%)
Severe 48 (52%) 116 (30%)
Shames 1998 [50] Asthma severity Multiple end points (rank sums) (rank sums) 0.07
Agarwal 1997 [6] Visits to Emergency (%) 14/23 (61%) 27/77 (35%) <0.05
Agarwal 1997 [6] Hospitalization (%) 11/23 (48%) 10/77 (13%) <0.05
Rao 2013 [48] Aspirin sensitivity 23/92 (30%) 36/391 (10%) <0.0001
Suzuki 2007 [52] AIA (%) 14/41 (25.5%) 35/380 (8.4%) <0.0001
Hanley 1981 [43] Menstrual cycle Duration of cycle 27.8 30.2 <0.01
Rees 1963 [4] Mean number days of 6.6 (1.81) 5.5 (1.7) 0.05
bleeding (SD)
Eliasson 1986b [5] Dysmenorrhoea 12.5 7.9 0.019
Murphy 2008 [13] OC (%) 6/16 (37.5 %) 5/12 (41.7 %) 0.99*
Rees 1963 [4] Premenstrual Premenstrual syndrome 100 65 <0.01
syndrome (%)
Agarwal 1997 [6] Premenstrual syndrome 21/23 (91%) 49/77 (64%) <0.05
(%)
Eliasson 1986b [5] Premenstrual syndrome 12.5 (Mean score) 8.8 0.07
Murphy 2008 [14] Premenstrual Median AUC: 3.45 2.33 0.26
syndrome: area under
curve (AUC) of
premenstrual symptoms
 Author Group factor Risk Factors PMA No PMA p
Pereira 2010b [45] Anxiety (Effect size, 0.46 0.06 0.026
D/s)
Pereira 2010b [14] Sensation of swelling 0.82 0.33 0.009
(Effect size, D/SD)
Pereira 2010b [45] Abdominal tension 0.88 0.33 0.003
(Effect size, D/S)
Pereira 2010b [45] Mammary tension 0.95 0.49 0.018
(Effect size, D/s)
Rees 1963 [4] Severity of None 0 35 0.003*
premenstrual syndrome Light or moderate 45 40
(%) Severe 55 25
Pasaoglu 2008 Hormones Estradiol PM: 89.3 pg/ml PM: 72 pg/ml NA
[34]
Pereira 2012a [46] Estrogens PO: 111.49 pg/ml PO: 131.31 pg/ml 0.845
PM: 95.9 PM: 123.83
Pasaoglu 2008 Progesterone PM: 7.3 ng/ml PM: 9.2 ng/ml NA
[34]
Pereira 2012a Progesterone PO: 0.83 ng/ml PO: 1.39 ng/ml 0.225
[46] PM: 6.82 PM: 6.31
Pereira 2012a [46] Estrogens/Progesterone PO: 219.26 PO: 356.6 0.865
PM: 35.53 PM: 355.22 0.371
Pasaoglu 2008 LH PM: 3.5 mU/ml PM: 4.9 mU/ml NA
[34]
Pasaoglu 2008 FSH PM: 13.3 mIU/ml PM: 3.3 mIU/ml NA
[34]
Gorovenko 2005 Atopic Allergy (% skin test) 44.45 83.07 0.027
[42] sensitisation
Rao 2013 [48] Atopy 60 (76%) 297 (88%) 0.01
Rees 1963 [4] Allergy (precipitated 88% 58% 0.05
most of the attacks)
Siroux 2007 [51] Skin Test + 1.86 1.65 0.65
Nakasato 1999 Total IgE 462 IU/ml 514 IU/ml NS*
[33]
Pereira 2010a [44] Total IgE (geometric 206.31 87.99 0.01
mean)
Pereira 2010a [44] Total IgE (% > 100kU/l) 84 43 0.001
Rao 2013 [48] Total IgE (SD) 208.4 (325.7) 292.2 (540.9) 0.06
Siroux 2007 [51] Total IgE 154 128 0.68
Pereira 2010a [44] Phadiatop (% +) 68 50 0.17
% peripheral
Rao 2013 [48] eosinophils 3.4 3.4 NS
Siroux 2007 [51] Eosinophils/mm3 330 194 0.01
Nakasato 1999 Metabolites Leukotriene C4 PO: 24.0 pg/ml PO: NA** NA
[33] related to PM: 69.0 pg/ml PM: NA**
Pereira 2012b [47] inflammation Leukotriene LTC4 PO: 1.5 ng/ml; PO: 1.4 ng/ml NS
PM: 1.31 PM: 1.29
Nakasato 1999 Interleukine IL-1β PO: 0.3 pg/mL PM: 0.4 NA NA
[33] IL-4 (not detectable) (serum levels of
IL-5 (not detectable) cellular mediators do
IL-6 PO: 0.8 pg/mL; PM: 0.4 not differ between
periods)
Eliasson 1986a Prostaglandin F2alpha Early cycle: 143 pg/0.1 ml 169.3 pg/0.1ml NS*
[40] Late cycle: 15.9 pg/0.1 ml 9.5 pg/0.1ml NS*
Nakasato 1999 Histamine PO: 0.1 ng/mL PM: 0.1 NA NA
[33]
Nakasato 1999 GM-CSF PO: Not detectable PO: NA NA
[33] PM: Not detectable PM: NA
Nakasato 1999 Platelet Activating PO: Not detectable PO: NA NA
[33] Factor PM: Not detectable PM: NA
Rao 2013 [48] log FeNO (SD) 1.4 (0.4) 1.4 (0.4) 0.84

* Significance calculation based on study data;

GSTT1: Glutathione S Transferase Theta 1; NSAIDs: Non-steroidal anti-inflammatory drugs; BMI: Body Mass Index; SD: Standard Deviation;

GINA: Global Initiative for Asthma; AIA: Aspirin Induced Asthma; OC: Oral Contraceptives; AUC: Area Under Curve; D/SD: Standardized Mean

Difference (Difference/Standard Deviation); PM: Premenstrual; PO: Preovulatory; LH: Luteinizing Hormone; FSH: Follicle-stimulating hormone;

LTC4: Leukotriene C4; GM-CSF: Granulocyte-macrophage colony-stimulating factor; FeNO: Fractional exhaled nitric oxide.
Appendix. Checklist of items to include when reporting a systematic review or meta-analysis1.

Section/Topic # Checklist Item Reported

on Page #
TITLE
Title 1 Identify the report as a systematic review, meta-analysis, or 1
both.
ABSTRACT
Structured 2 Provide a structured summary including, as applicable: 3
summary background; objectives; data sources; study eligibility
criteria, participants, and interventions; study appraisal and
synthesis methods; results; limitations; conclusions and
implications of key findings; systematic review registration
number.
INTRODUCTION
Rationale 3 Describe the rationale for the review in the context of what is 4-5
already known.
Objectives 4 Provide an explicit statement of questions being addressed 5
with reference to participants, interventions, comparisons,
outcomes, and study design (PICOS).
METHODS
Protocol and 5 Indicate if a review protocol exists, if and where it can be 6
registration accessed (e.g., Web address), and, if available, provide
registration information including registration number.
Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow- 6
up) and report characteristics (e.g., years considered,
language, publication status) used as criteria for eligibility,
giving rationale.
Information 7 Describe all information sources (e.g., databases with dates 6
sources of coverage, contact with study authors to identify additional
studies) in the search and date last searched.
Search 8 Present full electronic search strategy for at least one 7
database, including any limits used, such that it could be
repeated.
Study selection 9 State the process for selecting studies (i.e., screening, 7
eligibility, included in systematic review, and, if applicable,
included in the meta-analysis).
Data collection 10 Describe method of data extraction from reports (e.g., 7
process piloted forms, independently, in duplicate) and any
processes for obtaining and confirming data from
investigators.
Data items 11 List and define all variables for which data were sought 8
(e.g., PICOS, funding sources) and any assumptions and
simplifications made.
Risk of bias in 12 Describe methods used for assessing risk of bias of 8
individual studies individual studies (including specification of whether this was
done at the study or outcome level), and how this
information is to be used in any data synthesis.
Summary 13 State the principal summary measures (e.g., risk ratio, 8
measures difference in means).
Synthesis of 14 Describe the methods of handling data and combining 8-9
results results of studies, if done, including measures of
consistency (e.g., I2) for each meta-analysis.
Risk of bias 15 Specify any assessment of risk of bias that may affect the 9
across studies cumulative evidence (e.g., publication bias, selective
reporting within studies).
Additional 16 Describe methods of additional analyses (e.g., sensitivity or
analyses subgroup analyses, meta-regression), if done, indicating
which were pre-specified.
Section/Topic # Checklist Item Reported
on Page #
RESULTS
Study selection 17 Give numbers of studies screened, assessed for eligibility, 10
and included in the review, with reasons for exclusions at
each stage, ideally with a flow diagram.
Study 18 For each study, present characteristics for which data were 10
characteristics extracted (e.g., study size, PICOS, follow-up period) and
provide the citations.
Risk of bias 19 Present data on risk of bias of each study and, if available, 11
within studies any outcome-level assessment (see Item 12).
Results of 20 For all outcomes considered (benefits or harms), present, 11-13
individual studies for each study: (a) simple summary data for each
intervention group and (b) effect estimates and confidence
intervals, ideally with a forest plot.
Synthesis of 21 Present results of each meta-analysis done, including 11-13
results confidence intervals and measures of consistency.
Risk of bias 22 Present results of any assessment of risk of bias across
across studies studies (see Item 15).
Additional 23 Give results of additional analyses, if done (e.g., sensitivity
analysis or subgroup analyses, meta-regression [see Item 16]).
DISCUSSION
Summary of 24 Summarize the main findings including the strength of 14-19
evidence evidence for each main outcome; consider their relevance to
key groups (e.g., health care providers, users, and policy
makers).
Limitations 25 Discuss limitations at study and outcome level (e.g., risk of 19
bias), and at review level (e.g., incomplete retrieval of
identified research, reporting bias).
Conclusions 26 Provide a general interpretation of the results in the context 20
of other evidence, and implications for future research.
FUNDING
Funding 27 Describe sources of funding for the systematic review and 21
other support (e.g., supply of data); role of funders for the
systematic review.

1
Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009) Preferred Reporting Items for
Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(7): e1000097.
doi:10.1371/journal.pmed.1000097