For Peer Review Only - NaturDoctor.com 2010 - Premenstrual Asthma a… · For Peer Review Only...
Transcript of 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
URL: http://mc.manuscriptcentral.com/ljas
Journal of Asthma
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
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
URL: http://mc.manuscriptcentral.com/ljas
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
URL: http://mc.manuscriptcentral.com/ljas
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
URL: http://mc.manuscriptcentral.com/ljas
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
URL: http://mc.manuscriptcentral.com/ljas
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
URL: http://mc.manuscriptcentral.com/ljas
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
URL: http://mc.manuscriptcentral.com/ljas
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
URL: http://mc.manuscriptcentral.com/ljas
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
URL: http://mc.manuscriptcentral.com/ljas
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
URL: http://mc.manuscriptcentral.com/ljas
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
URL: http://mc.manuscriptcentral.com/ljas
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
URL: http://mc.manuscriptcentral.com/ljas
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
URL: http://mc.manuscriptcentral.com/ljas
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
URL: http://mc.manuscriptcentral.com/ljas
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
URL: http://mc.manuscriptcentral.com/ljas
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
URL: http://mc.manuscriptcentral.com/ljas
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
URL: http://mc.manuscriptcentral.com/ljas
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
PMA: Premenstrual Asthma
Page 18 of 38
URL: http://mc.manuscriptcentral.com/ljas
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
PMA: Premenstrual Asthma
Page 19 of 38
URL: http://mc.manuscriptcentral.com/ljas
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
PMA: Premenstrual Asthma
Page 20 of 38
URL: http://mc.manuscriptcentral.com/ljas
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
URL: http://mc.manuscriptcentral.com/ljas
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
PMA: Premenstrual Asthma
Page 22 of 38
URL: http://mc.manuscriptcentral.com/ljas
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
URL: http://mc.manuscriptcentral.com/ljas
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
* A negative value means the symptom in the premenstrual phase was less intense; a
positive number means the opposite.
Page 24 of 38
URL: http://mc.manuscriptcentral.com/ljas
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
URL: http://mc.manuscriptcentral.com/ljas
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
URL: http://mc.manuscriptcentral.com/ljas
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
URL: http://mc.manuscriptcentral.com/ljas
Journal of Asthma
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
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
URL: http://mc.manuscriptcentral.com/ljas
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
URL: http://mc.manuscriptcentral.com/ljas
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
URL: http://mc.manuscriptcentral.com/ljas
Journal of Asthma
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
For Peer Review Only
Page 31 of 38
URL: http://mc.manuscriptcentral.com/ljas
Journal of Asthma
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
For Peer Review Only
Page 32 of 38
URL: http://mc.manuscriptcentral.com/ljas
Journal of Asthma
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
For Peer Review Only
Page 33 of 38
URL: http://mc.manuscriptcentral.com/ljas
Journal of Asthma
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
For Peer Review Only
Page 34 of 38
URL: http://mc.manuscriptcentral.com/ljas
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
URL: http://mc.manuscriptcentral.com/ljas
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
PMA: Premenstrual Asthma
Page 36 of 38
URL: http://mc.manuscriptcentral.com/ljas
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 37 of 38
URL: http://mc.manuscriptcentral.com/ljas
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
* A negative value means the symptom in the premenstrual phase was less intense; a
positive number means the opposite.
Page 38 of 38
URL: http://mc.manuscriptcentral.com/ljas
Journal of Asthma
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960