Respiratory Medicine 119 (2016) 155e159

Contents lists available at ScienceDirect

Respiratory Medicine
journal homepage: www.elsevier.com/locate/rmed

Review article

Coexistence of asthma and polycystic ovary syndrome: A concise

review
Louise Zierau a, b, *, Elisabeth Juul Gade a, Svend Lindenberg b, Vibeke Backer a,
Simon Francis Thomsen c, d
a
Respiratory Research Unit, Department of Respiratory Medicine, Bispebjerg University Hospital, Copenhagen, Denmark
b
Copenhagen Fertility Center, Copenhagen, Denmark
c
Department of Dermatology, Bispebjerg University Hospital, Copenhagen, Denmark
d
Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

a r t i c l e i n f o a b s t r a c t

Article history: Asthma may be associated with polycystic ovary syndrome (PCOS), and possibly patients with PCOS have
Received 19 April 2016 a more severe type of asthma. The purpose of this systematic literature review is to summarize evidence
Received in revised form of a coexistense of PCOS and asthma using the available literature. The search was completed on
23 August 2016
01.01.2016. English language articles were retrieved using the search terms Asthma AND PCOS,
Accepted 24 August 2016
Available online 26 August 2016
Asthma AND systemic inammation, Asthma AND metabolic syndrome, asthma AND gynaecology,
PCOS AND systemic inammation, PCOS AND metabolic syndrome, PCOS AND allergy. Five papers
meeting prespecied search criteria were found of which two were registry studies of relevance. The
Keywords:
Asthma
current literature supports a coexistense of PCOS and asthma and gives us an indication of the causes for
Polycystic ovary syndrome (PCOS) the possible link between PCOS and asthma. Further research in the area must be conducted to deter-
Inammation mine the exact nature and magnitude of the association.
2016 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
2. Evidence of a co existence of PCOS and asthma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
3. Supporting evidence of a coexistence of PCOS and asthma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
3.1. Other aspects of female reproduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
3.2. The metabolic syndrome and obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
3.3. Systemic inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158

1. Introduction endocrine disorder among women of fertile age affecting approx-

imately 6e7% [1]. PCOS is a multifactorial heterogeneous condition
Polycystic ovary syndrome (PCOS) is the most common characterized by anovulation, infertility, hyperandrogenism, hir-
sutism, insulin resistance, bleeding disorders (absence of men-
struations >3 months), polycystic ovaries (seen by ultrasound) [2],
heart and lung diseases and overweight [3]. A strong overlap is seen
* Corresponding author. Respiratory Research Unit, Department of Respiratory between PCOS and the metabolic syndrome with insulin resistance,
Medicine, Bispebjerg Hospital, Bispebjerg Bakke 23, DK-2400, Copenhagen NV,
hypertension, dyslipidaemia and overweight being central aspects
Denmark. Tel.: 45 22434353.
E-mail address: L_zierau@hotmail.com (L. Zierau). of the conditions. Therefore, PCOS is perceived as a metabolic

http://dx.doi.org/10.1016/j.rmed.2016.08.025
0954-6111/ 2016 Elsevier Ltd. All rights reserved.
156 L. Zierau et al. / Respiratory Medicine 119 (2016) 155e159
syndrome [4,5].
It is estimated that as many as 50% of all patients with PCOS are
overweight but how weight affects the pathogenesis is still un-
known [6]. A weight loss of 5% improves the endocrinological
prole and thereby the chance of ovulation and pregnancy [7].
Weight loss can be achieved primarily by lifestyle changes through
diet and exercise. If overweight patients with PCOS reduce their
diet to 1200e1500 kcal/day combined with moderate exercise
(30 min a day) 5 days a week they will improve their metabolic-,
endocrine- and fertility-prole [8,9].
PCOS is associated with low-grade systemic inammation. This
inammation causes an elevation of certain biomarkers such as
CRP, interleukin-18 (IL-18), monocyte chemo attractant protein-1
and leucocytes. Furthermore, endothelial dysfunction and
increased oxidative stress are seen [10,11].
Asthma is a complex and chronic inammatory disorder of the
airways characterized by local and systemic inammation, revers-
ible airway obstruction, airway hyperresponsiveness and increased
mucus production. Immunologically asthma is characterized by a T-
helper cell 2 (Th2)-immune response with a resulting increased IgE
formation and eosinophilia. A number of cytokines (IL-4, -5, -13, -17
-22, and TNF) are activated during the Th2 immune response. These
cytokines induce the inammatory histological changes seen in the
epithelium of the respiratory tract [12]. In addition to the local
inammation of the respiratory tract, asthma is also associated
with elevated systemic inammation seen by for example elevated
CRP levels, which is deteriorated by obesity [13]. A majority of adult
patients with asthma are women and many are obese [14]. Both
men and women experience an improvement in their respiratory
symptoms after weight loss [15]. As with obesity a higher preva-
lence of the metabolic syndrome is seen among patients with
asthma [16,17].
PCOS and asthma share many common features regarding
metabolic control, systemic inammation, allergy, menstrual cycle
and female sex hormones. Both conditions are aggravated by
obesity and improved by weight loss. Therefore we hypothesize
that a coexistence of PCOS and asthma is present.
By clarifying a possible link between PCOS and asthma, we will
be able to target the treatment of both conditions and stress the
importance of a multidisciplinary approach. Herein we review the
evidence for a coexistence of PCOS and asthma.
2. Evidence of a co existence of PCOS and asthma
A systematic literature search was performed using the PubMed
database, Google Scholar, Embase, Web of Science, SCOPUS, and
Cochrane library retrieving papers from 1938 to 2015. Search terms
were: Asthma AND PCOS, Asthma AND systemic inammation,
Asthma AND metabolic syndrome, asthma AND gynaecology, PCOS
AND systemic inammation, PCOS AND metabolic syndrome, PCOS
AND allergy. Cross-references were scrutinized to identify addi-
tional studies. We were interested in original studies, case reports,
cohort studies, controlled trials, and review articles. Five articles
were found. Among those two registry studies were of relevance.
A recent population-based retrospective cohort study using data
linkage in a Australian statewide hospital morbidity database
including 2566 patients with PCOS (ICD-10: E28.2; polycystic ovary
syndrome or ICD-9: 256.4; polycystic ovaries) and a control group
of 25,660 women without the PCOS diagnosis determined the
prevalence of all hospitalizations from 15 years of age until a me-
dian age of 35.8 years. The study showed that 10.6% of patients with
PCOS were admitted to hospital because of asthma compared to
only 4.5% among the control group. Furthermore, a higher preva-
lence of respiratory diseases in general (22.8 vs. 14.2%) was seen
among the patients with PCOS [18]. This indicates an association
between PCOS and respiratory diseases in general, but especially
asthma, which possibly is more severe among PCOS patients.
These observations were conrmed in a Danish national
registry-based study including 19,199 patients with PCOS, and
57,483 age-matched controls. The PCOS patients were divided into
two groups according to the diagnostic criteria of inclusion [19]. In
all 1217 women with PCOS who fullled the Rotterdam criteria (2
out of 3): 1. oligo- and/or anovulation, 2. clinical and/or biochemical
signs of hyperandrogenism, and 3. polycystic ovaries and exclusion
of other etiologies (congenital adrenal hyperplasias, androgen-
secreting tumours, Cushing's syndrome) [20] or had clinical and/
or biochemical hyperandrogenism were included (group A). The
rest of the women with PCOS included had the ICD:10 diagnosis of
PCOS or hirsutism (L680, E28.2) (group B). This registry-based
study showed a higher prevalence of asthma and a greater usage
of asthma and allergy medications among patients with PCOS. In
total 3.2% (group A)/3.0% (group B) of patients with PCOS had
asthma in contrast to 2.2% of a population-based matched control
group. Moreover, 19.5% (group A)/19.2% (group B) of the patients
with PCOS had used asthma medication at some point in their lives
compared to 14.1% in the control group; within the last year these
rates were 6.4% (group A)/6.5% (group B) and 4.7% for the control
group, respectively. The same tendency was seen in regards to use
of corticosteroids and allergy-related medicine (ATC codes R06A,
H02AB); 28.1% (group A)/30.6% (group b) of the PCOS patients had
used these medications at some point, which was only seen in
23.2% of the control group. Within the last year 8.9% (group A)/9.1%
(group B) of the PCOS patients versus 6.3% of the control subjects
had used these medications.
The two studies above uses different diagnostic criteria to select
the PCOS populations. This leads to the possibility of a slightly
different group of women with PCOS in the two studies.
By using the ICD:9 diagnosis patients with polycystic ovaries are
included - and they may not have polycystic ovary syndrome and
therefore it can interfere with the observations made. The ICD:10
diagnosis on the other hand insures patients with polycystic ovary
syndrome. Finally, by using the international accepted Rotterdam
criteria to select the PCOS patients the selection bias is minimize.
In spite of the use of different diagnostic criteria, these studies
underline the possibility of a link or a coexistence of PCOS and
asthma seen through the rate of admission and the usage of asthma
and allergy medication.
3. Supporting evidence of a coexistence of PCOS and asthma
3.1. Other aspects of female reproduction
Asthma and the female reproduction interact in several aspects
(Table 1). Asthma has been associated with irregular menstruation
and sex hormones, as seen in patients with PCOS. The association
between asthma and female sex hormones has been known since
1938 [21] when a study associated worsening of asthma symptoms
with the female menstruation cycle. These cyclic deteriorations of
asthma symptoms during the luteal phase and/or during the rst
days of menstruation are termed premenstrual asthma (PMA). PMA
is dened as a decrease of 20e40% in the peak expiratory ow
(PEF) and is experienced by 30e40% of all female asthma patients
[22]. PMA is associated with a more severe type of asthma char-
acterized by an increase in asthma symptoms and a greater usage of
rescue medicine [23]. Among women admitted because of asthma
attacks as many as 46% were in their premenstrual phase of their
cycle [24]. Additionally, the concentration of female sex hormones
in sputum changes through the menstrual cycle, showing a raised
level of testosterone in the luteal phase [25].
Irregular menstruations have also been associated with asthma.
 L. Zierau et al. / Respiratory Medicine 119 (2016) 155e159 157

Table 1
Key studies.

Symptoms Authors Ref. Study design Main ndings

PCOS and Asthma Hart, R., 2014 Registry Women with PCOS has a higher prevalence of asthma and uses more asthma medicine than non-PCOS
Glintborg, D., 2015 studies women.
Bleeding disorders Svanes, C. et al., Clinical study 9% of women with irregular menstruations have asthma.
2005 Women with irregular menstruations have a lower forced vital capacity (FVC)
Real, F.G. et al.,
2007
Premenstrual Asthma Claude, R., 1938 Review 20-40% decrease in the peak expiratory ow
(PMA) Vrieze, A., 2003 Clinical
Shames, RS., 1998
Menarche Liebeoth, S., 2014, Registry Menarche before the age of 12 almost doubles the risk of developing asthma.
2015 studies
Al-Sahab 2011
Infertility Gade EJ., 2014, Clinical study Asthma patients experience a longer time to pregnancy and less often become pregnant than non-asthmatics.
2016
Obesity Haldar, P., 2008 Clinical study Asthma and PCOS symptoms increase with obesity. Obesity increases the risk of developing asthma e
Lergos RS. 2000 especially among women.
Metabolic syndrome Velez MS. 2014 Review The metabolic syndrome is present in many patients PCOS or Asthma.
Brumpton BM. Registry
2013
Systemic inammation Duleba, AJ., 2012 Clinical study Raised levels of systemic inammation is seen both among patients with PCOS and asthma.
Makoto, K., 2013

Among women with regular menstruations 6% have asthma in
contrast to 9% among women with irregular menstruations [26].
Moreover, menstrual irregularity and/or oligomenorrhea, which is
a hallmark of PCOS, has a detrimental effect on lung function.
Particularly, women with menstrual irregularity and/or oligome-
norrhea are known to have a signicantly lower forced vital ca-
pacity (FVC) and more often have allergic asthma than women with
regular menstruations.
In addition, the lung function is affected by BMI. At BMI 25 (kg/
m2) FVC and FEV1 (forced expiratory volume during the rst sec-
ond) were at their maximum. Higher or lower BMI is associated
with a lower FVC and FEV1 among women with irregular men-
struations [27]. This underlines the association between asthma,
high BMI and irregular menstruations.
Early menarche also affects the risk of developing asthma. In a
group of girls with menarche before the age of 12, 7.4% had asthma
compared to only 4.5% in the group of girls where menarche
occurred after 12 years of age [28]. This is supported by another
study showing how early menarche more than doubles the risk of
developing asthma in early adulthood. Girls with menarche before
12 years of age had a 19.2% risk of asthma compared with 6.2% in
the group of girls with menarche after 12 years of age [29]. To end
with, a systematic review of population studies found a 37%
increased risk of asthma among girls with early menarche (i.e.
before 12 years of age) compared with girls with lather menarche
[30].
Asthma and allergy often co-occur [31]. Allergy has been asso-
ciated with the endometriosis. Among patients with endometriosis
the risk of allergy is 57% and the risk of asthma 9%. In contrast, the
risk of allergy is only 23% whereas the risk of asthma is 4% among
women without endometriosis [32]. This underlines an association
between the female reproduction and allergy.
It is known that as many as 27% of patients with asthma have a
waiting time to pregnancy of more than 12 months in comparison
to only 21.6% among patients without asthma. Moreover, women
with well-treated asthma experience a shorter time to conception
[33]. A newly published clinical prospective study further supports
this issue, in that female asthmatics have a longer time to preg-
nancy and less often become pregnant than non-asthmatic women
[34]. This suggests that asthma not only has a local detrimental
effect on the respiratory organs but also a systemic effect on the
whole body and the reproductive organs.
3.2. The metabolic syndrome and obesity
The metabolic syndrome constitutes a cluster of cardio-
metabolic risk factors involving dyslipidemia, hypertension, insu-
lin resistance, and abdominal obesity. Other traits associated with
the metabolic syndrome are gestational diabetes, type 2 diabetes,
systemic inammation and endothelial dysfunction. It is estimated
that around half of all PCOS patients suffer from the metabolic
syndrome [35]. This leads to increasing PCOS symptoms and
obesity [36,37]. Among these women weight loss improves the
endocrine prole and thereby increases the chances of pregnancy
[38,39,40].
The same trend is seen among patients with asthma. Asthma
symptoms worsen with obesity. Obese individuals have a higher
risk of developing asthma over time, and have a poorer response to
asthma treatment. At the same time weight loss improves the
symptoms of asthma in these patients [41].
Not only is asthma connected to obesity, it is also connected to
the metabolic syndrome. As with obesity a higher prevalence of
metabolic syndrome is seen among asthma patients [42]. The
metabolic syndrome is a well-documented part of both asthma and
PCOS and could therefore have an important role in the develop-
ment of asthma among patients with PCOS.
3.3. Systemic inammation
PCOS is associated with chronic low-grade inammation
measured primarily by raised levels of CRP, IL-6, TNF, neutrophils,
lymphocytes, monocyte chemoattractant protein-1, as well as
endothelial dysfunction and increased oxidative stress [43,44]. One
of the best-documented markers of the low-grade systemic
inammation in patients with PCOS is hs-CRP. High levels of hs-CRP
are found in both lean and obese patients with PCOS compared to
BMI-matched controls [45]. IL-18 is another cytokine of importance
in PCOS. IL-18 is known to stimulate TNF, IL-6 and CRP. IL-18 and
CRP levels are raised in PCOS patients with cardiovascular disease,
high BMI and insulin resistance (via the correlation to waist to hip
ratio and fasting insulin levels) e as seen in PCOS [46]. In patients
with PCOS the IL-18 levels are independent of BMI - indicating that
the elevated levels are caused by PCOS and not by the inammation
of the adipose tissue [47],as others have suggested [48]. The levels
of IL-18 are unchanged when the patient is treated with metformin
158 L. Zierau et al. / Respiratory Medicine 119 (2016) 155e159
or oral contraceptives. In contrast, the level of IL-6 decreased in
parallel with the increase in insulin sensitivity when patients are
treated with metformin [49]. Moreover IL-17 and TNF are well
known markers of low grade systemic inammation among pa-
tients with PCOS [50,51].
In contrast to PCOS, the pathways of systemic inammation in
asthma are better explored. The inammation characteristic of
asthma creates a reversible obstruction of the airways and local
hyperactivity with increased production of mucus. Asthma is
characterized by a Th2-immunereaction with high levels of IgE and
eosinophilia. The Th2-response is characterized by upregulation of
various cytokines. These cytokines induce inammatory histologi-
cal changes in the epithelia in the airways. The paradigm of classical
asthma as an eosinophilic type has been challenged and asthma is
now described as a heterogeneous disease. This heterogeneity
manifests in different phenotypes; eosinophil, non-eosinophil,
neutrophil, and mixed types. The Th2 cell-activation is lead
through an activation of dendritic cells. These cells play a role in
initiation and maintenance of the allergic inammation in the
airways of asthma. They activate the nave T cells that activate Th1
and Th2 cells. The Th1 pathway stimulates Interferon gamma (IFN-
gamma) and Th-17. This activation leads to stimulation and in-
duction of neutrophilic inammation. The Th2 pathway leads to
further activation of goblet cells through IL-4 and Il-13. Moreover,
the emission of IL-5, one of the key cytokines in maturation, growth
and activation of eosinophils, is activated through the Th2 pathway.
Lastly, the activation of mast cells through IL-9 leads to the secre-
tion of histamine [52,53]. Release of TNF is predominately done by
macrophages but also by other immune cells and stromal cells.
These cell types are found at higher concentrations in asthma pa-
tients. A high level of TNF is seen among patients with severe
asthma and lower levels are seen among patients with mild
asthma. These ndings were correlated to the level of circulating
cytokines and IL-8 [54]. As seen in PCOS, CRP is related to the low
grade systemic inammation in asthma. The level of CRP in steroid-
nave asthma patients has been proven to correlate positively with
the level of eosinophils in sputum and negatively to the lung
function [55].
4. Conclusion
The association of gynecological disorders and asthma is well
dened in regards to menstrual irregularity, menarche and female
hormonal disturbances. Menstrual irregularity and female hor-
monal disturbances are both corner stones in PCOS and also asso-
ciate with asthma. Systemic inammation is likely the most evident
explanation of the coexistence of PCOS and asthma. The systemic
inammation plays an important role in the pathogenesis of both
conditions and the overlap of affected biomarkers underlines their
possible coexistence. The inammation is further triggered by the
degree of metabolic syndrome, which again affects the level of fe-
male sex hormones as seen in PCOS.
The high prevalence of hospitalization because of asthma at-
tacks among patients with PCOS could be explained by the pro-
longed and irregular intermenstrual periods seen in PCOS. This
irregularity is caused by hormonal imbalances such as higher levels
of testosterone. This could be the reason for the increased number
of asthma attacks seen among patients with PCOS. In conclusion,
further research is needed to determine the exact mechanisms
underlying the coexistence of PCOS and asthma.
Conicts of interest
The authors report no conicts of interest. The authors alone are
responsible for the content and writing of the paper.
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