For Peer Review Only - NaturDoctor.com 2010 - Premenstrual Asthma a… · For Peer Review Only...

For Peer Review O

nly

Premenstrual Asthma and Symptoms Related to

Premenstrual Syndrome

Journal: Journal of Asthma

Manuscript ID: LJAS-2010-0101.R1

Manuscript Type: Original

Date Submitted by the Author:

19-May-2010

Complete List of Authors: Pereira-Vega, Antonio; Juan Ramón Jiménez, Neumología Sánchez, José L; Huelva University, Department of Nursing Gil, Francisco L; Hospital Juan Ramón Jiménez, Neumología Maldonado, Jose A; Hospital Juan Ramón Jiménez, Neumología Bravo, Jose M; Hospital Juan Ramón Jiménez, Neumología Ignacio, Jose M; Hospital Comarcal de la Serranía de Ronda, Pneumology Section Vázquez, Rosa; Hospital Infanta Elena, Pneumology Section Álvarez, Francisco; Hospital Virgen del Rocío, Pneumology Section Romero, Pedro; Hospital de Baza, Pulmonary Section Sánchez, Inmaculada; Hospital Juan Ramón Jiménez, Pulmonary Section

Keywords: Asthma, Menstruation, Premenstrual syndrome

URL: http://mc.manuscriptcentral.com/ljas

Journal of Asthma

For Peer Review O

nly

Title

Premenstrual Asthma and Symptoms Related to Premenstrual Syndrome

Authors

Antonio Pereira-Vega1 MD, PhD ([email protected]).

José L Sánchez2 MD, PhD ([email protected])

Francisco L Gil1 MD, ([email protected])

José A Maldonado1 MD, ([email protected])

José M Bravo1 MD ([email protected])

José M Ignacio3 MD, PhD ([email protected])

Rosa Vázquez4 MD, PhD ([email protected])

Francisco Álvarez5 MD, PhD ([email protected])

Pedro Romero6 MD, PhD ([email protected])

Inmaculada Sánchez1 MD ([email protected])

1 Pneumology Section. Hospital Juan Ramón Jiménez, Huelva (Spain).

2 Department of Nursing. University of Huelva.

3 Pneumology Section. Hospital Comarcal de la Serranía de Ronda (Málaga).

4. Pneumology Section. Hospital Infanta Elena (Huelva)

Page 1 of 38


Journal of Asthma

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

mailto:[email protected]










For Peer Review O

nly

5 Pneumology Service. Hospital Virgen del Rocío (Sevilla)

6 Pneumology Section. Hospital de Baza (Granada)

Author contribution

Antonio Pereira-Vega: lead researcher, coordinator and writer of the manuscript.

José L Sánchez: researcher, supervisor of statistics and writer of the manuscript.

Francisco L Gil: researcher at Hospital Juan Ramón Jiménez (Huelva).

José A Maldonado: writer and researcher at Hospital Juan Ramón Jiménez (Huelva).

José M Bravo: researcher at Hospital Juan Ramón Jiménez.

José M Ignacio: study coordinator at Hospital Comarcal de la Serranía de Ronda (Málaga).

Rosa Vázquez: study coordinator at Hospital Infanta Elena (Huelva).

Francisco Álvarez: study coordinator at Hospital Vírgen del Rocío (Sevilla).

Pedro Romero: study coordinator at Hospital de Baza (Granada).

Inmaculada Sánchez: researcher at Hospital Juan Ramón Jiménez (Huelva).

Corresponding Author: Antonio Pereira Vega. Pneumology Section.

Hospital Juan Ramón Jiménez. Ronda Norte, S/N. Huelva 21005

[email protected] Tel.:/Fax: 00 34 959016060

Page 2 of 38


Journal of Asthma

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


For Peer Review O

nly

This study was carried out on patients from five hospitals: Hospital Juan Ramón

Jiménez, (Huelva); Hospital Comarcal de la Serranía de Ronda (Málaga); Hospital

Infanta Elena (Huelva); Hospital Virgen del Rocío (Sevilla); Hospital de Baza (Granada).

This Study was supported by grants from Neumosur (7/2003); and the Health Ministry

of the Regional Autonomous Government of Andalusia in 2005 (0074/2005).

Conflict of interest statements:

Antonio Pereira-Vega has no conflicts of interest to disclose.

José L Sánchez has no conflicts of interest to disclose.

Francisco L Gil has no conflicts of interest to disclose.

José A Maldonado has no conflicts of interest to disclose.

José M Bravo has no conflicts of interest to disclose.

José M Ignacio has no conflicts of interest to disclose.

Rosa Vázquez has no conflicts of interest to disclose.

Francisco Álvarez has no conflicts of interest to disclose.

Pedro Romero has no conflicts of interest to disclose.

Inmaculada Sánchez has no conflicts of interest to disclose.

Page 3 of 38


Journal of Asthma

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

Abstract

BACKGROUND: It is unclear whether premenstrual asthma is associated with

premenstrual syndrome. The objective of this study is to compare premenstrual

symptoms among asthmatic women according to whether they have premenstrual

asthma or not.

METHODS: A questionnaire on respiratory symptoms during a single menstrual cycle

was drawn up for asthmatics of fertile age, together with another on symptoms related

to premenstrual syndrome. These included dysphoric-psychiatric symptoms (anxiety,

depression, fatigue, irritability and mood swings), oedematous symptoms (abdominal

and mammary tension, swelling, acne and migraine), and other symptoms (leg pains,

nausea, sweating, vomiting and tiredness). Morning and evening peak flow scores were

collected to evaluate lung function. Premenstrual asthma was determined to be a ≥ 20%

objective exacerbation in the premenstrual phase over the preovulatory phase in terms

of both respiratory symptoms and/or peak flow. The intensity of the change in

symptoms was evaluated according to the effect size.

RESULTS: The study examined 103 patients of fertile age, 46 of whom (44.7%)

presented with premenstrual asthma. Practically all of the monitored symptoms increased

in the premenstrual phase with respect to the preovulatory phase. This increase was

greater in women with premenstrual asthma, especially for abdominal tension (effect size

0.88 against 0.33; p=0.009) and mammary tension (0.95 against 0.49; p=0.018).

CONCLUSIONS: A clear link was found between premenstrual asthma and the

premenstrual exacerbation of dysphoric symptoms, and certain oedematous symptoms

such as abdominal and mammary tension as well as a swelling sensation.

Page 4 of 38


Journal of Asthma

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

ABREVIATIONS LIST:

(GINA 2005): Global Initiative for Asthma 2005

(PMA): Premenstrual asthma

(D/s): Difference between the means/Joint Standard Deviation.

(NO): Nitric Oxide

Page 5 of 38


Journal of Asthma

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

Introduction

Premenstrual syndrome is defined as the cyclical recurrence of physical or

psychological symptoms that appear after ovulation in the luteal phase of the cycle1 and

disappear a few days after the start of the next menstruation2. More than 150 clinical

manifestations have been attributed to the syndrome3, 4, 5, mainly congestive

oedematous symptoms in terms of the physical point of view, and mood swings in the

psychological.

The luteal phase displays an exacerbation of pre-existing illnesses, such as

bronchial asthma, acne, porphyria, epilepsy, migraine, Behçet syndrome and

myasthenia gravis6. Premenstrual asthma (PMA), defined as an exacerbation of the

respiratory symptoms and/or the peak flow scores, affects more than 30% of asthmatic

women7, 8, 9.

Studies have been performed on the relationship between asthmatic symptoms,

premenstrual symptoms (physical and psychological)10 and lung function. Agarwal et

al.8 reported that the exacerbation of asthma during the perimenstrual phase is due to

increased resistance in the airway, not just to a heightened perception of symptoms. In

healthy non-asthmatic women, the variations in peak flow in relation to the menstrual

cycle are minimal11. Ensom et al.10 found a significant correlation between respiratory

and premenstrual symptoms during the menstrual cycle in the majority of women with

PMA, and another important link, between peak flow scores and premenstrual

symptoms, in 43% of these women. They analyzed all of the symptoms associated with

premenstrual syndrome (physical and psychological), applying to them a single global

score.

Page 6 of 38


Journal of Asthma

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

The aim of our study is to compare premenstrual symptoms (dysphoric-

psychiatric, oedematous and others) among asthmatic women according to whether

they have PMA or not.

Methods and Materials

The general methodology and the partial results of this study that refer to the

prevalence of premenstrual asthma based on the applied definition have been published

previously 9. We concluded from the prior analysis of our data that clinical behavior

was equivalent if we used one or two cycles, so it is probably sufficient to base the

PMA definition on one cycle only. The methodology involves a daily record of

respiratory symptoms and peak flow in asthmatic women of fertile age during the

menstrual cycle taken at outpatient clinics at five hospitals in Andalusia, Spain. The

exclusion criteria were pregnancy or lactation. After informed consent was given, data

was collected on asthma severity, on whether the patient perceived an exacerbation in

her asthma during the menstrual cycle and if she was taking oral contraceptives.

Women taking oral contraceptives were omitted from the analysis. Patients were asked

to note respiratory symptoms (cough, dyspnoea, wheezing and tightness across the

chest) and morning and evening peak flow scores.

We defined PMA from the semi-objective point of view based partly on the

methodology of Eliasson7 and Ensom10. The daily presence of the symptoms studied

was catalogued from zero to three, zero being: absence of symptoms; one - mild

symptoms (slight interference with normal activity); two - moderate symptoms

(interference with normal activity without impeding work or school attendance); three -

Page 7 of 38


Journal of Asthma

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

severe symptoms (interference with normal activity leading to absence at work, school

or cancellation of appointments). A daily score index was calculated, along with an

average of score indexes over two six-day periods: from 5th to 10th day (the first day

being the start of menstruation), which would correspond to the follicular or

preovulatory phase; and the last five days of the cycle, including the first day of

menstruation, corresponding to the premenstrual phase. The difference between these

two values was considered significant if above 20%. PMA is also considered to be when

premenstrual deterioration is higher than 20% of PF values.

In addition, a questionnaire validated by Mortola et al.12, 10 was completed for

the same menstrual cycle that covered dysphoric-psychiatric symptoms (anxiety,

depression, fatigue, irritability and mood swings), oedematous symptoms (abdominal

and mammary tension, swelling, acne and cephalalgia), and other symptoms (leg pains,

nausea, sweating, vomiting and tiredness). The interpretation of each group of

symptoms was made in the same way as for the respiratory symptoms, on a scale of 0

to 3, with the mean calculated for each symptom in the preovulatory and premenstrual

phases. To compare the changes in each symptom, the effect size was calculated as the

quotient between the difference in the means of the two phases and the joint standard

deviation (D/s)13.

A database was designed from which, after the inclusion of data on symptoms

and the peak flow scores on the days studied, it was determined whether the patient met

the clinic (semi-objective) or functional criteria, or both, for PMA (an increase ≥20% in

symptoms or peak flow). In order to avoid the 0 denominator in the percentage

computation, which would impair the calculation of variability, the constant 0.01 was

added to the denominator in all cases.

Page 8 of 38


Journal of Asthma

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

The patients were distributed among the various groups according to the

GINA 2005 scale of severity. We also evaluated the patient’s perception of

exacerbation in her asthma based on a Yes answer to the question: “Does your asthma

get worse before menstruation?” This question enabled us to classify the patients’

asthma as worse/not worse from the subjective standpoint.

The changes between the preovulatory and premenstrual phases were analyzed

in all the asthmatic women using the paired Student t test. The increase in symptoms

between both phases was compared for women with or without premenstrual asthma

via the Student t test for independent samples in the case of similar variance, and with

the Welch test for different variance. The relation between the premenstrual increase in

symptoms and asthma severity was explored using the non-parametric Kruskal-Wallis

test. A p value < 0.05 was considered significant. SPSS v.17 was used for all analysis.

Results

There were originally 141 asthmatic patients of fertile age, 25 of whom did not

register their symptoms and were excluded from the study. Of the 116 remaining patients

who filled in the questionnaires on the complete menstrual cycle, 13 were omitted from

the analysis as they were taking oral contraceptives. The baseline characteristics of the

definitive 103 patients (age, weight and spirometer rates) are shown in Table 1.

Those presenting with PMA criteria were 44.7% (46/103; IC95%: 35.3%-54.3%).

Changes in the peak flow scores between the preovulatory and premenstrual phases are

shown in Table 2. Although women with PMA exhibited worse peak flow scores in the

premenstrual phase (347.14 L/min) than in the preovulatory phase (365.3 L/min, p <

Page 9 of 38


Journal of Asthma

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

0.001), only three patients deteriorated by more than 20% in the premenstrual phase, and

they all fulfilled the PMA criteria for clinical exacerbation of their respiratory symptoms,

so the peak flow analysis, at least on this criterion, did not provide evidence for new PMA

cases.

One aim of our study was to examine the evolution of symptoms related to

premenstrual syndrome, comparing the intensity of change between the preovulatory and

premenstrual phases. Overall, asthmatic women experience a premenstrual increase in

almost all of the analyzed symptoms related to premenstrual syndrome (Figure 1), in

particular oedematous symptoms such as mammary and abdominal tension as well as a

sensation of swelling.

We also aimed to check whether this increase occurred in a different way in

asthmatic women who had PMA and in those who did not. For those women with

premenstrual asthma, there was clearly a greater increase in dysphoric symptoms (Figure

2), oedematous symptoms (Figure 3) and other symptoms (Figure 4). The exacerbation of

the majority of symptoms, especially those in the oedematous group, was significantly

greater in the PMA group, particularly abdominal tension (effect size D/s: 0.88 against

0.33; p=0.003), sensation of swelling (D/s: 0.82 versus 0.33; p=0.009) and mammary

tension (D/s: 0.95 against 0.49; p=0.018).

The subjective appreciation of the worsening of asthma, presented by 45 of the

103 women (47.3%), as indicated by an affirmative response to the question “Does your

asthma get worse before menstruation?”, is closely associated with the exacerbation of

specific premenstrual symptoms, particularly dysphoric-psychiatric symptoms such as

anxiety and depression, abdominal tension and others (Table 3). The increases in

premenstrual symptoms were similar for all levels of asthma severity (Table 4). Although

Page 10 of 38


Journal of Asthma

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

the premenstrual increase in abdominal tension was different at the various levels of

asthma severity, there was no linear relation to asthma severity.

Discussion

During the premenstrual phase, the majority of women of fertile age experience

physical and/or psychological symptoms related to premenstrual syndrome. Likewise,

some women with bronchial asthma suffer an exacerbation of their asthmatic symptoms

and/or lung function in the luteal phase of the menstrual cycle, especially in the days

leading up to menstruation and/or the days immediately after it starts, constituting what is

known as PMA. However, PMA is not considered to be indicative of premenstrual

syndrome1.

The definition of PMA varies according to studies. While some authors require

only a Yes answer to the question “Does your asthma get worse after menstruation?”

(subjective criteria)8, 14, 15, 16, others insist on a methodology for interpreting the data on

symptoms reported by patients (semi-objective criteria)7, 10, and still others demand

premenstrual exacerbation be demonstrated via objective criteria, such as peak flow or

NO17, 18 (objective criteria). In addition, fulfillment of criteria can be required for one8, 10,

19, 20 or several cycles4. Our study defines PMA by the fulfillment of semi-objective

criteria in a single menstrual cycle9.

Few studies have investigated the relationship between bronchial asthma and

premenstrual syndrome. Skrzypulec et al.21 determined the incidence of premenstrual

syndrome in girls from 12 to 19, with or without bronchial asthma, finding values of

20% and 46.67% respectively, data that suggest that bronchial asthma is associated

Page 11 of 38


Journal of Asthma

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

with a diminution of the prevalence of premenstrual syndrome in girls. Their study

found no link between the severity of symptoms, bronchial asthma duration, treatment

with glucocorticoids and the diagnosis and intensity of premenstrual syndrome. The

authors stated that their results could not be compared to either Ensom’s10, who found a

high frequency of premenstrual syndrome in women with PMA, or to Dorhofer’s22,

who reported greater anxiety and psychological distress in asthmatic women, as these

two studies analyzed different age groups, all of which suggests that more studies are

needed to clarify these results.

Our study has examined asthmatic women of fertile age whose mean age was

28.24 years. Like Ensom and Dohofer, we found an increase in practically all of the

symptoms related to premenstrual syndrome (Figure 1). However, we have not studied

non-asthmatic women, and here we differ from the Skrzypulec study21.

Regarding the link between PMA and symptoms of premenstrual syndrome,

Ensom et al.10 analyzed the connection between the latter, respiratory function and

asthmatic symptoms in 14 women of fertile age who were diagnosed with light chronic

bronchial asthma and presented with moderate PMA criteria. Premenstrual syndrome

was detected in 50% of the women with PMA. The authors show a significant link

between symptoms for asthma and premenstrual syndrome in 10 of the women, and an

important connection between peak flow and symptoms of premenstrual syndrome in

six of them. Our study divides the symptoms related to premenstrual syndrome into

three groups2, 5: dysphoric/psychiatric, oedematous and others of different origin. PMA

was related to these symptoms in all three groups. The connection to

dysphoric/psychiatric symptoms can be explained by the known relationship between

Page 12 of 38


Journal of Asthma

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

asthma and psychosomatic factors, with PMA considered both from the semi-objective

(Figures 2-4) and subjective perspectives (Table 3).

On the other hand, we believe that the link found between PMA and the

oedematous group of symptoms may originate in the generalized oedema seen in the

luteal phase of the menstrual cycle. In the case of PMA, an oedema of the bronchial

mucus may occur, which would imply an exacerbation of the asthma in the

premenstrual phase.

Dorhofer and Sigmon22 have analyzed the link between asthma severity and the

symptoms related to premenstrual syndrome. The authors demonstrated a greater

incidence of anxiety and psychological changes in women whose asthma symptoms

and/or peak flow deteriorate in the premenstrual phase. Our study, however, found no

relation between asthma severity and the symptoms of premenstrual syndrome (Table

4).

The limits of our research are typical of transverse studies, as it analyses

relationships but cannot differentiate between cause and effect. Although we have not

included tobacco consumption, its effects on the symptoms would occur throughout the

entire menstrual cycle and not just in the premenstrual phase. Neither have we included

the use of aspirin and non-steroidal anti-inflammatory medication. The use of these as

treatment for premenstrual symptoms could exacerbate respiratory symptoms.

However, Eliasson et al23 show that this theoretical effect would occur in the

preovulatory phase but not in the premenstrual phase. Nor have we defined

premenstrual syndrome; instead, during the course of the cycle we closely examined

the evolution of some of the symptoms that form part of it. This methodology does not

allow us to compare our study to others published previously, and there no common

Page 13 of 38


Journal of Asthma

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

definition of premenstrual syndrome in studies on the links to asthma. The method used

to record the symptoms related to premenstrual syndrome is validated, and is reliable as

an instrument applicable to clinical and some research settings12. The influence of

potential allergens as triggers to justify the symptoms is not fully known. However, the

study was conducted over an extended period of time, and not at a specific time, so that

the influence of a particular allergen should not be decisive.

The treatment of asthma could be a confounding factor that impedes

clarification in the study of the relation between PMA and premenstrual symptoms. A

confounding factor must meet three criteria: a) the treatment is a factor associated to

PMA; b) the treatment is a risk factor in premenstrual symptoms; c) the treatment is not

a link in the “causal” chain between PMA and premenstrual symptoms. With regard to

the first point, the treatment would be the same a priori for women with or without

PMA, except in the use of stronger rescue medication during the premenstrual phase.

The level of asthma severity (GINA), which would condition the base treatment, is not

associated to PMA9 neither premenstrual symptoms. The second point is more

controversial. The possible effect of treatment as a factor that increases premenstrual

symptoms would be limited to the possible increase in irritability linked to a greater use

of Beta-2. This symptom is not significantly associated to PMA. In terms of anxiety,

there are doubts about whether this is caused by the medication or precisely because of

the increase in the respiratory symptomatology. The use of Beta-2 would not justify the

other associations detected: abdominal tension, sweating, mammary tension,

cephalalgia or tiredness. Therefore, we believe that the treatment of asthma is not a

confounding factor in this context.

Page 14 of 38


Journal of Asthma

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

Our conclusion is that there exists a relation between PMA and symptoms

associated with premenstrual syndrome. We have found a clear link between PMA and

the psychopathological sphere, as shown by symptoms such as depression and anxiety,

and certain oedematous symptoms, such as abdominal tension, mammary tension and

the sensation of swelling. Our data suggest a common ethiopathogeny for both sets of

clinical symptoms; in this case, a future line of investigation could be the study of this

mechanism regarding a common treatment for the two sets of symptoms.

Page 15 of 38


Journal of Asthma

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

ACKNOWLEDGMENTS

We wish to thank the following medical personnel for their help in performing the field

study: Evangelina Maldonado and Jose Antonio Bernal Rodríguez (Huelva), Maria José

Chocrón Giráldez and Magdalena Pinto Tenorio (Ronda), Patricia Calvo Tudela (Baza)

and Pablo Pérez Navarro (Sevilla).

Page 16 of 38


Journal of Asthma

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

Figure 1: Effect size: change in the average of each symptom between the

preovulatory and premenstrual phases in relation to the standard deviation of

variance.

▀▀ : statistically significant increases

PMA: Premenstrual Asthma

Page 17 of 38


Journal of Asthma

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

Figure 2: Effect size and the dysphoric symptoms

Dysphoric symptoms

Effect size: D/s

0 0,1 0,2 0,3 0,4 0,5 0,6

Anxiety

Depression

Fatigue

Irritabil ity

Mood

PMA

No PMA

P=0.026


Page 18 of 38


Journal of Asthma

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

Figure 3: Effect size and the oedematous symptoms

Oedematous symptoms

Effect size: D/s

0 0,2 0,4 0,6 0,8 1

Abdominal tension

Swelling

Acne

Mammary tension

PMA

No PMA

P=0.003

P=0.009

P=0.018


Page 19 of 38


Journal of Asthma

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

Figure 4: Effect size and other symptoms

Other symptoms

Effect size: D/s

-0,2 -0,1 0 0,1 0,2 0,3 0,4 0,5

Cephalalgia

Pain

Nausea

Sweating

Vomiting

Tiredness

PMA

No PMA

P=0.033

P=0.032


Page 20 of 38


Journal of Asthma

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

Table 1: Baseline patient characteristics.

Global Premenstrual

asthma

No premenstrual

asthma

P

Age: mean

(typical deviation).

Age range

28.6

(8.8)

14-47

26.9

(6.5)

16-37

28.78

(9.93)

14-47

0.41

Weight: mean

(typical deviation)

63.23

(12.3)

63.65

(14..15)

62.97

(11.23)

0.84

FVC%: mean

(typical deviation)

93.69

(13.66)

91.25

(12.49)

95.22

(14.31)

0.31

FEV1%: mean

(typical deviation)

90.61

(18.1)

88.2

(15.9)

92.11

(19.4)

0.45

FEV1/FVC%: mean

(typical deviation)

79.98

(1.6)

80.2

(11.5)

79.8

(11.9)

0.92

Page 21 of 38


Journal of Asthma

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

Table 2: Preovulatory and premenstrual Peak Flow values, according to Premenstrual

Asthma

Peak Flow n Preovulatory

Mean (L/min)

Premenstrual

Mean (L/min)

p

Global 103 362.87 357.19 0.13

Yes 46 365.81 347.14 0.000 PMA

No 57 360.5 365.3 0.35


Page 22 of 38


Journal of Asthma

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

Table 3: Effect size (D/s) according to the subjective recognition of premenstrual

exacerbation of asthma

Symptoms Worse Not worse p

Anxiety 0.44 0.05 0.02

Depression 0.39 -0.04 0.03

Fatigue 0.30 0.08 0.21

Irritability 0.42 0.13 0.07

Dysphoric

Mood swings 0.50 0.28 0.16

Abdominal tension 0.77 0.40 0.02

Swelling 0.59 0.50 0.21

Acne 0.40 0.05 0.04

Oedematous

Mammary tension 0.72 0.69 0.12

Cephalalgia 0.30 0.00 0.08

Leg pains 0.58 0.11 0.01

Nausea 0.45 0.02 0.01

Sweating 0.19 0.06 0.40

Vomiting* -0.13 -0.04 0.41

Other

Tiredness 0.26 0.12 0.34

* A negative value means the symptom in the premenstrual phase was less intense; a

positive number means the opposite.

Page 23 of 38


Journal of Asthma

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

Table 4: Premenstrual increase in symptoms according to asthma severity (GINA 2005)

Total Intermittent

Light

persistent

Moderate

persistent

Severe

persistent p

Nº Patients 103 39 19 16 29

Anxiety 0.18 0.04 0.19 0.23 0.29 0.66

Depression 0.08 0.06 0.09 0.06 0.06 0.77

Fatigue* 0.11 0.07 0.23 -0.03 0.07 0.61

Irritability 0.19 0.18 0.18 0.11 0.13 0.98

Mood 0.24 0.17 0.37 0.21 0.19 0.42

Abdominal tension 0.37 0.23 0.61 0.2 0.41 0.035

Swelling 0.35 0.24 0.7 0.28 0.29 0.08

Acne 0.12 0.06 0.08 0.32 0.19 0.27

Mammary tension 0.43 0.37 0.51 0.29 0.51 0.58

Cephalalgia 0.13 0.11 0.05 0.09 0.08 0.96

Leg pain 0.19 0.06 0.35 0.27 0.14 0.41

Nausea 0.09 0.05 0.19 0.06 0.04 0.33

Sweating* 0.05 -0.02 0.13 -0.05 0.14 0.24

Vomiting* -0.01 -0.004 -0.009 0 -0.05 0.72

Tiredness* 0.15 0.12 0.31 0.03 -0.006 0.2



Page 24 of 38


Journal of Asthma

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

References:

1 Moline ML. Pharmacologic strategies for managing premenstrual syndrome. Clin

Pharm. 1993 Mar;12(3):181-96.

2 Korzekwa MI, Steiner M. Premenstrual syndromes. Clin Obstet Gynecol. 1997 Sep;40(3):564-76.

3 American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4ht ed. Washington, DC: American Psychiatric Association 1994:75-18.

4 Halbreich U, Endicott J. Methodological issues in studies of premenstrual changes. Psychoneuroendocrinology. 1985;10(1):15-32.

5 American College of Obstetricians and Gynecologist (ACOG). Premenstrual Syndrome. Washington, DC, ACOG, 2000.

6 Boggess KA, Williamson HO, Homm RJ. Influence of the menstrual cycle on systemic diseases. Obstet Gynecol Clin North Am. 1990 Jun;17(2):321-42.

7 Eliasson O, Scherzer HH, DeGraff AC Jr. Morbidity in asthma in relation to the menstrual cycle. J Allergy Clin Immunol. 1986 Jan;77(1 Pt 1):87-94.

8 Agarwal AK, Shah A. Menstrual-linked asthma. J Asthma. 1997;34(6):539-45.

9 Pereira Vega A, Sánchez Ramos JL, Maldonado Pérez JA et al. Variability in the prevalence of premenstrual asthma. European Respiratory Journal (Eur Respir J. 2009 Nov 6. [Epub ahead of print] PMID: 19897559 [PubMed - as supplied by publisher])

10 Ensom MH, Chong E, Carter D. Premenstrual symptoms in women with premenstrual asthma. Pharmacotherapy. 1999 Apr;19(4):374-82.

11 Chong E, Ensom MH. Peak expiratory flow rate and premenstrual symptoms in healthy nonasthmatic women. Pharmacotherapy. 2000 Dec;20(12):1409-16.

12 Mortola JF, Girton L, Beck L, Yen SS. Diagnosis of premenstrual syndrome by a simple, prospective, and reliable instrument: the calendar of premenstrual experiences. Obstet Gynecol 1990;76:302-307.

13 Dunlop, W. P., Cortina, J. M., Vaslow, J. B., & Burke, M. J. (1996). Meta-analysis of experiments with matched groups or repeated measures designs. Psychological

Methods, 1, 170-177.

14 Rees L. An etiological study of premenstrual asthma. J. Psychosom Res 1963; 7: 191-7.

15 Hanley SP. Asthma variation with menstruation. Br J Dis Chest. .1981 Jul;75(3):306-8.

Page 25 of 38


Journal of Asthma

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

16 Gibbs CJ, Coutts II, Lock R, Finnegan OC, White RJ. Premenstrual exacerbation of asthma. Thorax. 1984. Nov;39(11):833-6.

17 Mandhane PJ, Hanna S, Inman M, et al. Changes in Exhaled Nitric Oxide Related to Estrogen and Progesterone During the Menstrual Cycle. Chest 2009; 136:1301-7.

18 Farha S, Asosingh K, Laskowski, D et al…Effects of the Menstrual Cycle on Lung Function Variables in Women with Asthma. Am J. Respir. Crit. Care Med. 2009 Jun 11. (E-published ahead of print) PubMed PMID: 19520904.

19 Ensom MH. Gender-based differences and menstrual cycle-related changes in specific diseases: implications for pharmacotherapy. Pharmacotherapy. 2000 May;20(5):523-39.

20 Pasaoglu G, Mungan D, Abadoglu O, Misirligil Z. Leukotriene receptor antagonists: a good choice in the treatment of premenstrual asthma?. J Asthma. 2008 Mar;45(2):95-9.

21 Skrzypulec V, Doniec Z, Drosdzol A et al. The influence of bronchial asthma on premenstrual syndrome prevalence among girls. Journal of Physiology and

Pharmacology 2007; 58 (suppl 5): 639-646.

22 Dorhofer DM, Sigmon ST. Physiological and psychological reactivity in women with asthma: the effects of anxiety and menstrual cycle phase. Behav Res Ther 2002; 40: 3-17.

23 Eliasson O, Longo M, Dore-Duffy P et al. Serum 13-14-diOH-15-keto-Prostaglandin F2alpha and Airway Response to Meclofenamate and Metaproterenol in Relation to the Menstrual Cycle. Journal of Asthma 1986; 23(6):309-319.

Page 26 of 38


Journal of Asthma

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

Dear Dr. Bernstein: Please find attached the revised version of our manuscript, which includes changes recommended by the reviewers, as well as the letter in which we give a detailed response to each of the comments made by the reviewers. Sincerely, Dr Antonio Pereira Vega. 12-May-2010 Dear Dr Pereira-Vega: Your manuscript entitled "Premenstrual Asthma and Symptoms Related to Premenstrual Syndrome" which you submitted to Journal of Asthma, has been reviewed. The reviewer comments are included at the bottom of this letter. The reviewer(s) would like to see some revisions made to your manuscript before publication. Therefore, I invite you to respond to the reviewer(s)' comments and revise your manuscript. When you revise your manuscript please highlight the changes you make in the manuscript by using the track changes mode in MS Word or by using bold or coloured text. To submit the revision, log into http://mc.manuscriptcentral.com/ljas and enter your Author Center, where you will find your manuscript title listed under "Manuscripts with Decisions." Under "Actions," click on "Create a Revision." Your manuscript number has been appended to denote a revision. Please enter your responses to the comments made by the reviewer(s) in the space provided. You can use this space to document any changes you made to the original manuscript. Please be as specific as possible in your response to the reviewer(s). IMPORTANT: Your original files are available to you when you upload your revised manuscript. Please delete any redundant files before completing the submission. Because we are trying to facilitate timely publication of manuscripts submitted to Journal of Asthma, your revised manuscript should be uploaded as soon as possible. If it is not possible for you to submit your revision in a reasonable amount of time, we may have to consider your paper as a new submission. Once again, thank you for submitting your manuscript to Journal of Asthma and I look forward to receiving your revision. Sincerely, Jonathan A. Bernstein, M.D. Editor in Chief Journal of Asthma [email protected]

Page 27 of 38


Journal of Asthma

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

http://mc.manuscriptcentral.com/ljas

http://correo.uhu.es/src/compose.php?send_to=Jonathan.Bernstein%40uc.edu

For Peer Review O

nly

Reviewer(s)' Comments to Author: Reviewer: 1

Comments to the Corresponding Author The following observations are in the different sections: Material and methods: although you can intuit in the text, should be included that the use of contraceptives is exclusion’s criterion. It has now clearly stated in Material and Methods that those women taking oral contraceptives, though not strictly excluded from the study, were not included in the data analysis. Results: Table 1. Tiffeneau’s index is FEV1/VC and table’s data, neither in the materials nor the methods are specified the execution of a maneuver vital capacity, it should be replaced by FEV1/FVC%. This has been corrected in Table 1 Table 4: the correct classification is severe persistent no serious persistent. This has been corrected in Table 4 Discussion: PMA is present only answering “yes” to the question "does your asthma Worse Before menstruation?" and although the answer is yes in 46, there is only a 20% decline in three patients. Have authors considered other more objective methods like the asthma control test? It would be a good point to introduce into the discussion. This has been clarified in Material and Methods. We consider PMA to be a premenstrual exacerbation of more than 20% in the daily register of respiratory symptoms (semi-objective criteria) as well as a premenstrual exacerbation of more than 20% in PF. In Material and Methods, we have added that an affirmative answer to the question “Does your asthma get worse before menstruation? does NOT amount to PMA, but is a subjective perception of deterioration. This difference is also made clear in Table 3. In order to emphasise this definition of PMA, this paragraph has been shifted to the end of the Material and Methods section. In Results, it has been clarified that 45/103 women (43.7%) noted this deterioration.

In the Discussion, the original article already specified that we consider PMA to be based on semi-objective criteria. In Table 2 we refer to the 46 women who presented with PMA (not to the 45 women who perceived deterioration). The 46 showed a significant mean fall in PF (de 365.81 to 347.14 L/min). In effect, if we require a premenstrual fall of more than 20%, only three of these patients achieved that. These three women were already classified as PMA patients according to semi-objective criteria, so PF alone did not provide any new cases, even though it contributes to the definition of PMA. It is logical that PMA prevalence is varied according to the level of requirements for PMA definition. The 20% fall in PF criterion is probably too strict.

Answer yes to the question is subjective information. Dysphoric-psychiatric symptoms have been measured. Is there connection between affirmative answer and a higher score on this questionnaire? As we state in the Results:

Page 28 of 38


Journal of Asthma

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

The subjective appreciation of the worsening of asthma, presented by 45 of the 103 women (47.3%), as indicated by an affirmative response to the question “Does your asthma get worse before menstruation?”, is closely associated with the exacerbation of specific premenstrual symptoms, particularly dysphoric-psychiatric symptoms such as anxiety and depression, abdominal tension and others (Table 3). The average age is low; there must be involved allergen as triggers among patients. Perhaps they have the same effect as the tobacco, but we should discuss this aspect.

The following point has been added to the Discussion: The influence of potential allergens as triggers to justify the symptoms is not fully known. However, the study was conducted over an extended period of time and not at a specific time, so that the influence of a particular allergen should not be decisive.

A smaller sample in the study analysed 59 women who gave their consent to have blood extracted in order to determine their levels of total and specific IgE total and Phadiatop. The 35 who were positive for Phadiatop had specific IgE with no significant difference in any of the allergens among women with or without PMA.

Reviewer: 2

Comments to the Corresponding Author The manuscripts addresses an important clinical questions; however, the following limitations tempered the enthusiasm: 1. Classification of PMA seems quite subjective. It is unclear why peak flow data, while collected, were not used in PMA definition. We use PF in the definition of PMA. But only three women have a premenstrual decline of 20%, all of whom were already considered PMA under the criterion of registration of respiratory symptoms using the above method (semi-objective point of view). Table 2 shows that 46 women with PMA present a significant average decrease of PF (from 365.81 to 347.14 L/min). 2. It does not appear that any validated scales were utilized to measure anxiety, depression, mood, nausea, etc. The use of non-validated scales can significantly affect study results. References to the validation of premenstrual symptoms questionnaires have been included. This paragraph has been added to the Discussion: The method used to record the symptoms related to premenstrual syndrome is validated, and is reliable as an instrument applicable to clinical and some research settingsError! Bookmark not

defined.. 3. The effect of asthma therapy were not taken into account as a potential confounder. This is correct. In the study of the relation between PMA and premenstrual symptoms, if a patient presenting with PMA meant an increase in the treatment, this would make the link between the two less clear, if: The following has been added to the Discussion: 1. the treatment was a factor associated to PMA. 2. the treatment was a risk factor in premenstrual symptoms. 3. the treatment was not a link in the “causal” chain between PMA and premenstrual symptoms. .

Page 29 of 38


Journal of Asthma

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

The following has also been added to the Discussion:

The treatment of asthma could be a confounding factor that impedes clarification in the study of the relation between PMA and premenstrual symptoms. A confounding factor must meet three criteria: a) the treatment is a factor associated to PMA; b) the treatment is a risk factor in premenstrual symptoms; c) the treatment is not a link in the “causal” chain between PMA and premenstrual symptoms. With regard to the first point, the treatment would be the same a priori for women with or without PMA, except in the use of stronger rescue medication during the premenstrual phase. The level of asthma severity (GINA), which would condition the base treatment, is not associated to PMAError! Bookmark not defined.

neither premenstrual

symptoms. The second point is more controversial. The possible effect of treatment as a factor that increases premenstrual symptoms would be limited to the possible increase in irritability linked to a greater use of Beta-2. This symptom is not significantly associated to PMA. In terms of anxiety, there are doubts about whether this is caused by the medication or precisely because of the increase in the respiratory symptomatology. The use of Beta-2 would not justify the other associations detected: abdominal tension, sweating, mammary tension, cephalalgia or tiredness. Therefore, we believe that the treatment of asthma is not a confounding factor in this context.

4. Eliasson & Ensom methodology needs to be described in greater detail. This methodology is described in greater retail in Material and Methods: The daily presence of the symptoms studied was catalogued from zero to three, zero being: absence of symptoms, one: mild symptoms (slight interference with normal activity), two: moderate symptoms (interference with normal activity without impeding work or school attendance), three: severe symptoms (interference with normal activity leading to absence at work, school or cancellation of appointments). A daily score index was calculated, and an average of score indexes over two six-day periods: from 5

th to 10

th day (the first day being the

start of menstruation), which would correspond to the follicular or preovulatory phase, and the last five days of the cycle, including the first day of menstruation, corresponding to the premenstrual phase. The difference between these two values was considered significant if above 20%.

5. It is unclear when the questionnaire was administered during the cycle and whether recall bias could be present.

A recall bias is unlikely since all the symptoms, both respiratory as well as those associated to premenstrual syndrome, are recorded daily by the patients, who classify them according to a scale of intensity

Page 30 of 38


Journal of Asthma

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review Only

Page 31 of 38


Journal of Asthma

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Page 32 of 38


Journal of Asthma

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Page 33 of 38


Journal of Asthma

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Page 34 of 38


Journal of Asthma

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

Table 1: Baseline patient characteristics.

Global Premenstrual

asthma

No premenstrual

asthma

P

Age: mean

(typical deviation).

Age range

28.6

(8.8)

14-47

26.9

(6.5)

16-37

28.78

(9.93)

14-47

0.41

Weight: mean

(typical deviation)

63.23

(12.3)

63.65

(14..15)

62.97

(11.23)

0.84

FVC%: mean

(typical deviation)

93.69

(13.66)

91.25

(12.49)

95.22

(14.31)

0.31

FEV1%: mean

(typical deviation)

90.61

(18.1)

88.2

(15.9)

92.11

(19.4)

0.45

FEV1/FVC%: mean

(typical deviation)

79.98

(1.6)

80.2

(11.5)

79.8

(11.9)

0.92

Page 35 of 38


Journal of Asthma

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

Table 2: Preovulatory and premenstrual Peak Flow values, according to Premenstrual

Asthma

Peak Flow n Preovulatory

Mean (L/min)

Premenstrual

Mean (L/min)

p

Global 103 362.87 357.19 0.13

Yes 46 365.81 347.14 0.000 PMA

No 57 360.5 365.3 0.35


Page 36 of 38


Journal of Asthma

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

Table 3: Effect size (D/s) according to the subjective recognition of premenstrual

exacerbation of asthma

Symptoms Worse Not worse p

Anxiety 0.44 0.05 0.02

Depression 0.39 -0.04 0.03

Fatigue 0.30 0.08 0.21

Irritability 0.42 0.13 0.07

Dysphoric

Mood swings 0.50 0.28 0.16

Abdominal tension 0.77 0.40 0.02

Swelling 0.59 0.50 0.21

Acne 0.40 0.05 0.04

Oedematous

Mammary tension 0.72 0.69 0.12

Cephalalgia 0.30 0.00 0.08

Leg pains 0.58 0.11 0.01

Nausea 0.45 0.02 0.01

Sweating 0.19 0.06 0.40

Vomiting* -0.13 -0.04 0.41

Other

Tiredness 0.26 0.12 0.34



Page 37 of 38


Journal of Asthma

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review O

nly

Table 4: Premenstrual increase in symptoms according to asthma severity (GINA 2005)

Total Intermittent

Light

persistent

Moderate

persistent

Severe

persistent p

Nº Patients 103 39 19 16 29

Anxiety 0.18 0.04 0.19 0.23 0.29 0.66

Depression 0.08 0.06 0.09 0.06 0.06 0.77

Fatigue* 0.11 0.07 0.23 -0.03 0.07 0.61

Irritability 0.19 0.18 0.18 0.11 0.13 0.98

Mood 0.24 0.17 0.37 0.21 0.19 0.42

Abdominal tension 0.37 0.23 0.61 0.2 0.41 0.035

Swelling 0.35 0.24 0.7 0.28 0.29 0.08

Acne 0.12 0.06 0.08 0.32 0.19 0.27

Mammary tension 0.43 0.37 0.51 0.29 0.51 0.58

Cephalalgia 0.13 0.11 0.05 0.09 0.08 0.96

Leg pain 0.19 0.06 0.35 0.27 0.14 0.41

Nausea 0.09 0.05 0.19 0.06 0.04 0.33

Sweating* 0.05 -0.02 0.13 -0.05 0.14 0.24

Vomiting* -0.01 -0.004 -0.009 0 -0.05 0.72

Tiredness* 0.15 0.12 0.31 0.03 -0.006 0.2



Page 38 of 38


Journal of Asthma

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

For Peer Review Only - NaturDoctor.com 2010 - Premenstrual Asthma a… · For Peer Review Only...

Documents

Transcript of For Peer Review Only - NaturDoctor.com 2010 - Premenstrual Asthma a… · For Peer Review Only...