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Coexistence of asthma and polycystic ovary syndrome: A concise review
Respiratory Medicine 119 (2016) 155e159
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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 Copenhagen Fertility Center, Copenhagen, Denmark Department of Dermatology, Bispebjerg University Hospital, Copenhagen, Denmark d Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 19 April 2016 Received in revised form 23 August 2016 Accepted 24 August 2016 Available online 26 August 2016
Asthma may be associated with polycystic ovary syndrome (PCOS), and possibly patients with PCOS have a more severe type of asthma. The purpose of this systematic literature review is to summarize evidence of a coexistense of PCOS and asthma using the available literature. The search was completed on 01.01.2016. English language articles were retrieved using the search terms ‘Asthma’ AND ‘PCOS’, ‘Asthma’ AND ‘systemic inflammation’, ‘Asthma’ AND ‘metabolic syndrome’, ‘asthma’ AND ‘gynaecology’, ‘PCOS’ AND ‘systemic inflammation’, ‘PCOS’ AND ‘metabolic syndrome’, ‘PCOS’ AND ‘allergy’. Five papers meeting prespecified search criteria were found of which two were registry studies of relevance. The current literature supports a coexistense of PCOS and asthma and gives us an indication of the causes for the possible link between PCOS and asthma. Further research in the area must be conducted to determine the exact nature and magnitude of the association. © 2016 Elsevier Ltd. All rights reserved.
Keywords: Asthma Polycystic ovary syndrome (PCOS) Inflammation
Contents 1. 2. 3.
4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155 Evidence of a co existence of PCOS and asthma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156 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 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158 Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
1. Introduction Polycystic ovary syndrome (PCOS) is the most common
* Corresponding author. Respiratory Research Unit, Department of Respiratory Medicine, Bispebjerg Hospital, Bispebjerg Bakke 23, DK-2400, Copenhagen NV, Denmark. Tel.: þ45 22434353. E-mail address: [email protected] (L. Zierau). http://dx.doi.org/10.1016/j.rmed.2016.08.025 0954-6111/© 2016 Elsevier Ltd. All rights reserved.
endocrine disorder among women of fertile age affecting approximately 6e7% [1]. PCOS is a multifactorial heterogeneous condition characterized by anovulation, infertility, hyperandrogenism, hirsutism, insulin resistance, bleeding disorders (absence of menstruations >3 months), polycystic ovaries (seen by ultrasound) [2], heart and lung diseases and overweight [3]. A strong overlap is seen between PCOS and the metabolic syndrome with insulin resistance, hypertension, dyslipidaemia and overweight being central aspects of the conditions. Therefore, PCOS is perceived as a metabolic
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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 unknown [6]. A weight loss of 5% improves the endocrinological profile 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-profile [8,9]. PCOS is associated with low-grade systemic inflammation. This inflammation 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 inflammatory disorder of the airways characterized by local and systemic inflammation, reversible airway obstruction, airway hyperresponsiveness and increased mucus production. Immunologically asthma is characterized by a Thelper 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 inflammatory histological changes seen in the epithelium of the respiratory tract [12]. In addition to the local inflammation of the respiratory tract, asthma is also associated with elevated systemic inflammation 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 prevalence of the metabolic syndrome is seen among patients with asthma [16,17]. PCOS and asthma share many common features regarding metabolic control, systemic inflammation, 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.
between PCOS and respiratory diseases in general, but especially asthma, which possibly is more severe among PCOS patients. These observations were confirmed 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 fulfilled 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, androgensecreting 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.
2. Evidence of a co existence of PCOS and asthma 3. Supporting evidence of a coexistence 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 inflammation, Asthma AND metabolic syndrome, asthma AND gynaecology, PCOS AND systemic inflammation, PCOS AND metabolic syndrome, PCOS AND allergy. Cross-references were scrutinized to identify additional 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 median 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 prevalence of respiratory diseases in general (22.8 vs. 14.2%) was seen among the patients with PCOS [18]. This indicates an association
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 first days of menstruation are termed premenstrual asthma (PMA). PMA is defined as a decrease of 20e40% in the peak expiratory flow (PEF) and is experienced by 30e40% of all female asthma patients [22]. PMA is associated with a more severe type of asthma characterized 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.
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Table 1 Key studies. Symptoms PCOS and Asthma
Authors Ref.
Hart, R., 2014 Glintborg, D., 2015 Bleeding disorders Svanes, C. et al., 2005 Real, F.G. et al., 2007 Premenstrual Asthma Claude, R., 1938 (PMA) Vrieze, A., 2003 Shames, RS., 1998 Menarche Liebeoth, S., 2014, 2015 Al-Sahab 2011 Infertility Gade EJ., 2014, 2016 Obesity Haldar, P., 2008 Lergos RS. 2000 Metabolic syndrome Velez MS. 2014 Brumpton BM. 2013 Systemic inflammation Duleba, AJ., 2012 Makoto, K., 2013
Study design Main findings Registry Women with PCOS has a higher prevalence of asthma and uses more asthma medicine than non-PCOS studies women. Clinical study 9% of women with irregular menstruations have asthma. Women with irregular menstruations have a lower forced vital capacity (FVC)
Review Clinical
20-40% decrease in the peak expiratory flow
Registry studies
Menarche before the age of 12 almost doubles the risk of developing asthma.
Clinical study Asthma patients experience a longer time to pregnancy and less often become pregnant than non-asthmatics. Clinical study Asthma and PCOS symptoms increase with obesity. Obesity increases the risk of developing asthma e especially among women. Review The metabolic syndrome is present in many patients PCOS or Asthma. Registry Clinical study Raised levels of systemic inflammation is seen both among patients with PCOS and asthma.
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 oligomenorrhea are known to have a significantly lower forced vital capacity (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 first second) were at their maximum. Higher or lower BMI is associated with a lower FVC and FEV1 among women with irregular menstruations [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 associated 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 pregnancy 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 cardiometabolic risk factors involving dyslipidemia, hypertension, insulin resistance, and abdominal obesity. Other traits associated with the metabolic syndrome are gestational diabetes, type 2 diabetes, systemic inflammation 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 profile 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 development of asthma among patients with PCOS. 3.3. Systemic inflammation PCOS is associated with chronic low-grade inflammation 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 inflammation 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 inflammation of the adipose tissue [47],as others have suggested [48]. The levels of IL-18 are unchanged when the patient is treated with metformin
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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 inflammation among patients with PCOS [50,51]. In contrast to PCOS, the pathways of systemic inflammation in asthma are better explored. The inflammation 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 inflammatory histological 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 inflammation in the airways of asthma. They activate the naïve T cells that activate Th1 and Th2 cells. The Th1 pathway stimulates Interferon gamma (IFNgamma) and Th-17. This activation leads to stimulation and induction of neutrophilic inflammation. 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 secretion 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 patients. A high level of TNF is seen among patients with severe asthma and lower levels are seen among patients with mild asthma. These findings were correlated to the level of circulating cytokines and IL-8 [54]. As seen in PCOS, CRP is related to the low grade systemic inflammation in asthma. The level of CRP in steroidnaïve 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 defined in regards to menstrual irregularity, menarche and female hormonal disturbances. Menstrual irregularity and female hormonal disturbances are both corner stones in PCOS and also associate with asthma. Systemic inflammation is likely the most evident explanation of the coexistence of PCOS and asthma. The systemic inflammation plays an important role in the pathogenesis of both conditions and the overlap of affected biomarkers underlines their possible coexistence. The inflammation is further triggered by the degree of metabolic syndrome, which again affects the level of female sex hormones as seen in PCOS. The high prevalence of hospitalization because of asthma attacks among patients with PCOS could be explained by the prolonged 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. Conflicts of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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L. Zierau et al. / Respiratory Medicine 119 (2016) 155e159 [28] S. Lieberoth, E. Gade, K.O. Kyvik, V. Backer, S.F. Thomsen, Early menarche is associated with increased risk of asthma: prospective population-based study of twins, Respir. Med. (2015). [29] B. Al-Sahab, M.J. Hamadeh, C.I. Ardern, H. Tamim, Early menarche predicts incidence of asthma in early adulthood, Am. J. Epidemiol. 173 (2011) 64e70. [30] S. Lieberoth, E.J. Gade, J. Brok, V. Backer, S.F. Thomsen, Age at menarche and risk of asthma: systematic review and meta-analysis, J. Asthma 51 (2014) 559e565. [31] R.K. Rowe, M.A. Gill, Asthma: the interplay between viral infections and allergic diseases, Immunol. Allergy Clin. North Am. 35 (2015) 115e127. [32] I. Matalliotakis, H. Cakmak, M. Matalliotakis, D. Kappou, A. Arici, High rate of allergies among women with endometriosis, J. Obstet. Gynaecol. 32 (2012) 291e293. [33] E.J. Gade, S.F. Thomsen, S. Lindenberg, K.O. Kyvik, S. Lieberoth, V. Backer, Asthma affects time to pregnancy and fertility: a register-based twin study, Eur. Respir. J. 43 (2014) 1077e1085. [34] E.J. Gade, S.F. Thomsen, S. Lindenberg, V. Backer, Fertility outcomes in asthma: a clinical study of 245 women with unexplained infertility, Eur. Respir. J. (2016). [35] L.M. Velez, A.B. Motta, Association between polycystic ovary syndrome and metabolic syndrome, Curr. Med. Chem. 21 (2014) 3999e4012. [36] R.S. Legro, The genetics of obesity. Lessons for polycystic ovary syndrome. Department of obstetrics and gynecology, Pennsylvania state university college of medicine, hershey 17033, USA, Ann. N. Y. Acad. Sci. 900 (2000) 193e202. [37] A. Badawy, A. Elnashar, Treatment options for polycystic ovary syndrome. Department of obstetrics and gynecology, mansoura university, mansoura, Egypt, Int. J. Womens Health. 8 (3) (Feb 2011) 25e35. [38] R. Pasquali, A. Gambineri, D. Biscotti, V. Vicennati, L. Gagliardi, D. Colitta, S. Fiorini, G.E. Cognini, M. Filicori, A.M. Morselli-Labate, Effect of long-term treatment with metformin added to hypocaloric diet on body composition, fat distribution, and androgen and insulin levels in abdominally obese women with and without the polycystic ovary syndrome, J. Clin. Endocrinol. Metab. 85 (2000) 2767e2774. [39] T.M. Barber, M.I. McCarthy, J.A. Wass, S. Franks, Obesity and polycystic ovary syndrome. Diabetes research laboratories, oxford centre for diabetes, endocrinology and metabolism, oxford university, oxford, UK, Clin. Endocrinol. (Oxf). 65 (2) (Aug 2006) 137e145. [40] D. Panidis, K. Tziomalos, E. Papadakis, C. Vosnakis, P. Chatzis, I. Katsikis, Lifestyle intervention and anti-obesity therapies in the polycystic ovary syndrome: impact on metabolism and fertility. Division of endocrinology and human reproduction, second department of obstetrics and gynecology, aristotle university of thessaloniki, hippokration hospital, thessaloniki, Greece, Endocrine (Apr 27. 2013). €rvi, Effects of weight loss on peak flow [41] K. Hakala, B. Stenius-Aarniala, A. Sovija variability, airways obstruction, and lung volumes in obese patients with asthma, Chest 118 (2000) 1315e1321.
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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 Copenhagen Fertility Center, Copenhagen, Denmark Department of Dermatology, Bispebjerg University Hospital, Copenhagen, Denmark d Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 19 April 2016 Received in revised form 23 August 2016 Accepted 24 August 2016 Available online 26 August 2016
Asthma may be associated with polycystic ovary syndrome (PCOS), and possibly patients with PCOS have a more severe type of asthma. The purpose of this systematic literature review is to summarize evidence of a coexistense of PCOS and asthma using the available literature. The search was completed on 01.01.2016. English language articles were retrieved using the search terms ‘Asthma’ AND ‘PCOS’, ‘Asthma’ AND ‘systemic inflammation’, ‘Asthma’ AND ‘metabolic syndrome’, ‘asthma’ AND ‘gynaecology’, ‘PCOS’ AND ‘systemic inflammation’, ‘PCOS’ AND ‘metabolic syndrome’, ‘PCOS’ AND ‘allergy’. Five papers meeting prespecified search criteria were found of which two were registry studies of relevance. The current literature supports a coexistense of PCOS and asthma and gives us an indication of the causes for the possible link between PCOS and asthma. Further research in the area must be conducted to determine the exact nature and magnitude of the association. © 2016 Elsevier Ltd. All rights reserved.
Keywords: Asthma Polycystic ovary syndrome (PCOS) Inflammation
Contents 1. 2. 3.
4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155 Evidence of a co existence of PCOS and asthma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156 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 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158 Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
1. Introduction Polycystic ovary syndrome (PCOS) is the most common
* Corresponding author. Respiratory Research Unit, Department of Respiratory Medicine, Bispebjerg Hospital, Bispebjerg Bakke 23, DK-2400, Copenhagen NV, Denmark. Tel.: þ45 22434353. E-mail address: [email protected] (L. Zierau). http://dx.doi.org/10.1016/j.rmed.2016.08.025 0954-6111/© 2016 Elsevier Ltd. All rights reserved.
endocrine disorder among women of fertile age affecting approximately 6e7% [1]. PCOS is a multifactorial heterogeneous condition characterized by anovulation, infertility, hyperandrogenism, hirsutism, insulin resistance, bleeding disorders (absence of menstruations >3 months), polycystic ovaries (seen by ultrasound) [2], heart and lung diseases and overweight [3]. A strong overlap is seen between PCOS and the metabolic syndrome with insulin resistance, hypertension, dyslipidaemia and overweight being central aspects of the conditions. Therefore, PCOS is perceived as a metabolic
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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 unknown [6]. A weight loss of 5% improves the endocrinological profile 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-profile [8,9]. PCOS is associated with low-grade systemic inflammation. This inflammation 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 inflammatory disorder of the airways characterized by local and systemic inflammation, reversible airway obstruction, airway hyperresponsiveness and increased mucus production. Immunologically asthma is characterized by a Thelper 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 inflammatory histological changes seen in the epithelium of the respiratory tract [12]. In addition to the local inflammation of the respiratory tract, asthma is also associated with elevated systemic inflammation 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 prevalence of the metabolic syndrome is seen among patients with asthma [16,17]. PCOS and asthma share many common features regarding metabolic control, systemic inflammation, 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.
between PCOS and respiratory diseases in general, but especially asthma, which possibly is more severe among PCOS patients. These observations were confirmed 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 fulfilled 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, androgensecreting 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.
2. Evidence of a co existence of PCOS and asthma 3. Supporting evidence of a coexistence 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 inflammation, Asthma AND metabolic syndrome, asthma AND gynaecology, PCOS AND systemic inflammation, PCOS AND metabolic syndrome, PCOS AND allergy. Cross-references were scrutinized to identify additional 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 median 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 prevalence of respiratory diseases in general (22.8 vs. 14.2%) was seen among the patients with PCOS [18]. This indicates an association
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 first days of menstruation are termed premenstrual asthma (PMA). PMA is defined as a decrease of 20e40% in the peak expiratory flow (PEF) and is experienced by 30e40% of all female asthma patients [22]. PMA is associated with a more severe type of asthma characterized 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.
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Table 1 Key studies. Symptoms PCOS and Asthma
Authors Ref.
Hart, R., 2014 Glintborg, D., 2015 Bleeding disorders Svanes, C. et al., 2005 Real, F.G. et al., 2007 Premenstrual Asthma Claude, R., 1938 (PMA) Vrieze, A., 2003 Shames, RS., 1998 Menarche Liebeoth, S., 2014, 2015 Al-Sahab 2011 Infertility Gade EJ., 2014, 2016 Obesity Haldar, P., 2008 Lergos RS. 2000 Metabolic syndrome Velez MS. 2014 Brumpton BM. 2013 Systemic inflammation Duleba, AJ., 2012 Makoto, K., 2013
Study design Main findings Registry Women with PCOS has a higher prevalence of asthma and uses more asthma medicine than non-PCOS studies women. Clinical study 9% of women with irregular menstruations have asthma. Women with irregular menstruations have a lower forced vital capacity (FVC)
Review Clinical
20-40% decrease in the peak expiratory flow
Registry studies
Menarche before the age of 12 almost doubles the risk of developing asthma.
Clinical study Asthma patients experience a longer time to pregnancy and less often become pregnant than non-asthmatics. Clinical study Asthma and PCOS symptoms increase with obesity. Obesity increases the risk of developing asthma e especially among women. Review The metabolic syndrome is present in many patients PCOS or Asthma. Registry Clinical study Raised levels of systemic inflammation is seen both among patients with PCOS and asthma.
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 oligomenorrhea are known to have a significantly lower forced vital capacity (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 first second) were at their maximum. Higher or lower BMI is associated with a lower FVC and FEV1 among women with irregular menstruations [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 associated 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 pregnancy 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 cardiometabolic risk factors involving dyslipidemia, hypertension, insulin resistance, and abdominal obesity. Other traits associated with the metabolic syndrome are gestational diabetes, type 2 diabetes, systemic inflammation 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 profile 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 development of asthma among patients with PCOS. 3.3. Systemic inflammation PCOS is associated with chronic low-grade inflammation 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 inflammation 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 inflammation of the adipose tissue [47],as others have suggested [48]. The levels of IL-18 are unchanged when the patient is treated with metformin
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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 inflammation among patients with PCOS [50,51]. In contrast to PCOS, the pathways of systemic inflammation in asthma are better explored. The inflammation 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 inflammatory histological 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 inflammation in the airways of asthma. They activate the naïve T cells that activate Th1 and Th2 cells. The Th1 pathway stimulates Interferon gamma (IFNgamma) and Th-17. This activation leads to stimulation and induction of neutrophilic inflammation. 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 secretion 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 patients. A high level of TNF is seen among patients with severe asthma and lower levels are seen among patients with mild asthma. These findings were correlated to the level of circulating cytokines and IL-8 [54]. As seen in PCOS, CRP is related to the low grade systemic inflammation in asthma. The level of CRP in steroidnaïve 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 defined in regards to menstrual irregularity, menarche and female hormonal disturbances. Menstrual irregularity and female hormonal disturbances are both corner stones in PCOS and also associate with asthma. Systemic inflammation is likely the most evident explanation of the coexistence of PCOS and asthma. The systemic inflammation plays an important role in the pathogenesis of both conditions and the overlap of affected biomarkers underlines their possible coexistence. The inflammation is further triggered by the degree of metabolic syndrome, which again affects the level of female sex hormones as seen in PCOS. The high prevalence of hospitalization because of asthma attacks among patients with PCOS could be explained by the prolonged 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. Conflicts of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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