Respiratory health in women: from menarche to menopause

Abstract

Gender differences in respiratory health have, in recent years, been the focus of considerable scientific effort. This paper reviews recent literature on respiratory health in women in relation to age at menarche, menstrual cycle, irregular menstruation, polycystic ovarian syndrome, menopause and exogenous sex hormones. This literature provides substantial evidence that hormonal status plays an important role for respiratory health in women. Effects of hormonal status on the airways often appear to be heterogeneous and recent literature in particular suggests that the interplay between hormonal and metabolic factors is important. A view to developmental factors may also be relevant for the understanding of respiratory health according to hormonal status in women. Further knowledge of respiratory health in women holds interesting potential for intervention and personalized treatment.

Keywords::

• allergy
• asthma
• chronic obstructive pulmonary disease
• hormonal replacement therapy
• irregular menstruation
• lung function
• menarche
• menopause
• menstrual cycle
• metabolic syndrome
• metabolism
• oral contraceptive
• polycystic ovarian syndrome
• sex hormones

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Release date: 28th March 2012; Expiration date: 28th March 2013

Learning objectives

• • Assess the effect of the timing of menarche on respiratory health

• • Evaluate how polycystic ovary disease and oral contraceptive pills affect respiratory health

• • Analyze the effects of menopause and hormone therapy on respiratory health

• • Distinguish possible metabolic and inflammatory pathways associated with respiratory health during a woman’s lifetime

Financial & competing interests disclosure

EDITOR

Elisa Manzotti,Editorial Director, Future Science Group, London, UK;Disclosure:Elisa Manzotti has disclosed no relevant financial relationships.

CME AUTHOR

Charles P Vega,Health Sciences Clinical Professor; Residency Director, Department of Family Medicine, University of California, Irvine, CA, USA;Disclosure:Charles P. Vega, MD, has disclosed no relevant financial relationships.

AUTHORS

Ferenc Macsali,Haukeland University Hospital, Bergen, Norway;Disclosure:Ferenc Macsali has disclosed no relevant financial relationships.

Cecilie Svanes,University of Bergen, Bergen, Norway;Disclosure:Cecilie Svanes has disclosed no relevant financial relationships.

Line Bjørge,Haukeland University Hospital, Bergen, Norway;Disclosure:Line Bjørge has disclosed no relevant financial relationships.

Ernst R Omenaas,University of Bergen, Bergen, Norway;Disclosure:Ernst R Omenaas has disclosed no relevant financial relationships.

Francisco Gómez Real,Haukeland University Hospital, Bergen, Norway;Disclosure:Francisco Gómez Real has disclosed no relevant financial relationships.

Figure 1. Changing hormonal status along women’s life-span.

PCOS: Polycystic ovarian syndrome.

Redrawn with permission from [201].

Figure 2. Idealized scheme of the hormonal and body temperature changes during the menstrual cycle.

FSH: Follicle-stimulating hormone; LH: Luteinizing hormone.

Modified with permission from [26].

As early as the 19th century, the surgeon John Hutchinson pointed to the differences in respiratory health between men and women. He carried out extensive observations of 2104 men and 26 women, and showed differences in breathing movements between the genders [1].

Gender differences are related to the reproductive functions of men and women. The differences involve sex hormones and metabolic factors in close interplay in order to promote reproduction. Hormonal and metabolic factors influence almost every process in the organism and the last few decades have brought increasing knowledge about the role of reproductive factors in chronic disease, with most focus on cardiovascular disease. Much attention has been paid to thromboembolism as a side-effect of oral contraceptives and to cancer risk following use of hormone substitution at menopause. At the same time, the importance of polycystic ovarian syndrome (PCOS) as a predictor for chronic diseases such as cardiovascular disease and diabetes has been recognized. However, the understanding of hormonal and metabolic factors in relation to respiratory diseases has been limited.

The Global Initiative for Asthma 2010 has estimated that 300 million people suffer from asthma [2], and chronic obstructive pulmonary disease (COPD) is projected to be the fourth leading cause of death worldwide by 2030 [3,4]. In spite of its importance and the extensive research performed during the last decades, many aspects of female lung health still remain in the dark.

A gender shift in asthma incidence around puberty has been known for decades. Boys have more asthma than girls but when reaching puberty this relationship reverses and from puberty onwards women have more asthma than men [5–7]. It has also been shown that women experience more severe asthma than men and are more often hospitalized for asthma exacerbations [7,8]. Gender differences in asthma incidence and presentation suggest both genetic and hormonal components in asthma.

Hormonal factors are closely linked with metabolic factors and obesity. The populations of both developing and developed nations are converging towards a more sedentary lifestyle. According to the WHO, 1.5 billion adults over 20 years of age are overweight and 0.5 billion are obese [9]. Both increased weight and less physical activity fuel insulin resistance, a major risk contributor to common chronic diseases. The importance of the global obesity epidemic for respiratory health is not fully known. Due to the close interplay with hormonal factors, metabolic factors are highly relevant when investigating the relation of hormonal factors to airway diseases.

The present review describes current respiratory health in relation to aspects of hormonal status in women. However, hormonal status in interplay with metabolic factors might possibly have wider consequences, with effects on health and disease of the offspring generation. Barker hypothesized that development of chronic diseases starts at conception and in intrauterine life [10]. Low birthweight and low gestational age have been found to be associated with many aspects of adult health, one important aspect being insulin resistance and development of metabolic syndrome. There is also evidence for effects on adult respiratory disease and lung function [10–12].

The literature on lung health in women is confusing and sometimes contradictory, not surprising given that women are hormonally heterogeneous and less investigated than men (Figure 1). The gender ratio of the Hutchinson study including 2104 men and 26 women is not entirely untypical two centuries later. However, although investigating respiratory health in women is particularly challenging, considerable advances have been made in recent years.

Menarche

Age at menarche signals the start of a women’s reproductive life and is determined by environmental and genetic factors [13,14]. Children closer to the equator, at lower altitudes, those in urban areas and mildly obese children have earlier menarche than those at northern latitudes, those who live higher above sea levels, those who live in cities and those with normal weight [13]. Records from different countries, particularly from Nordic countries, have shown that during the 100-year period until the middle of the 20th Century, age of menarche decreased from 16–17 years to slightly less than 13 years [13,15]. Increased body fat is related to earlier menarche, and leptin secreted in adipose tissue has been identified as an important link between body fat and timing of menarche; higher levels of leptin signal earlier menarche [16,17]. There are differences in age at menarche between different ethnic groups, implying heritable components. African–Americans and Mexican–Americans have menarche earlier than Americans of European descent [18]. Menarche, in turn, signals closure of the epiphyses and termination of length growth [13].

Early menarche is associated with later general health. Increased risk of breast cancer and increased risk for developing metabolic syndrome, including obesity, Type 2 diabetes and cardiovascular disease later in life, have been observed [19]. A Chinese study demonstrated early menarche to be associated with higher risk of metabolic syndrome, raised blood pressure, raised fasting glucose and higher triglyceride levels [20].

There is evidence of an association of menarche with asthma and lung function. In a study from Varraso et al. an association between early menarche, increased BMI and asthma severity was found. Clinical asthma severity in the last 12 months was assessed by a score (0–7) based on the frequency of asthma attacks, persisting symptoms between attacks and hospitalization. Asthma severity, which was unrelated to sex, increased with BMI in women (p = 0.0001). The association remained after adjustment for age, forced expiratory volume in 1 s (FEV₁), smoking habits and BMI-adjusted dyspnea, and taking into account familial dependence (p = 0.0001). The association between BMI and severity was stronger in women with early menarche than in women without early menarche (p-interaction = 0.02) [21]. In the Tucson Children’s Respiratory Study, Guerra et al. followed a birth cohort longitudinally, in which an association between increasing BMI and a significant increase in unremitting asthma and wheezing at ages 11 and 16 years was shown [22]. This investigation also demonstrated that children with unremitting wheezing or asthma had significantly earlier onset of puberty [22]. Another study from Al-Sahab et al. showed that onset of early menarche (<11.56 years of age) predicted postmenarcheal incidence of asthma; girls who matured early had more than twice the risk of developing asthma during early adulthood than girls who matured at an average age (odds ratio [OR]: 2.34; CI: 1.19–4.59) [23]. Onset of puberty in girls was defined based on parental reports of the child’s pubic and/or underarm hair, breast development or menstruation. This definition has limitations as these three events normally occur over a time span of approximately 2 years from a mean of 10.5 years for breast development, pubic hair at 11.0 years and menarche at 12.8 years [13]. A study of adult women by Salam et al. showed an association of early age at menarche with increased risk of asthma, women with menarche at 12 years of age or earlier had a 2.08-fold (95% CI: 1.05–4.12) risk of asthma after puberty [24]. In a European population study of adults, Macsali et al. found that women reporting menarche before age 11 years, compared with women with menarche at age 13 years (reference category), had lower lung function (FEV₁: adjusted difference -113 ml; 95% CI: -196 to -33 ml); forced vital capacity (FVC; -126 ml 95% CI: -223 to -28 ml); and FEV₁ % predicted (-3.28% 95% CI -6.25 to -0.30%); FVC percent predicted (-3.63% 95% CI: -6.64 to -0.62%). Women with early menarche also had more asthma symptoms (OR 1.80; 95% CI: 1.09–2.97), asthma with bronchial hyper-reactivity (BHR; OR: 2.79; 95% CI: 1.06–7.34) and higher asthma symptom score (mean ratio 1.58; 95% CI: 1.12–2.21). The findings were consistent across Europe, suggesting a biological rather than sociocultural explanation [25].

Macsali et al. found no relationship with age of menarche with FEV₁/FVC ratio, but the population was relatively young for investigating COPD (age 25–55 years) [25]. Salam et al.[24] and Guerra et al.[22] did not address COPD in their analyses of very young populations. In the case–control study of asthma by Varraso et al.[21], investigation of COPD was not feasible due to the study design.

In summary, the literature consistently shows an association between early menarche and higher risk of asthma and asthma symptoms. Only one study investigates lung function, and the finding of lower lung function in women with early menarche was consistent in a multicultural population and seemed rather convincing. There is no evidence to conclude a possible association of COPD with age of menarche, mostly because investigation of respiratory health and menarche is mostly performed in younger cohorts.

The finding that women with early menarche subsequently have more asthma and lower lung function may be explained by two different types of mechanisms, and a combination of the two seems plausible. First, there may be common developmental, metabolic and hormonal factors determining both early menarche and poorer respiratory health. These could be factors such as unfavorable metabolic profile, insulin resistance or poor intrauterine development, sometimes reflected in low birthweight. Second, early menarche itself might induce changes in airway function. Insulin resistance and an unfavorable metabolic situation are factors that could be predictors of early menarche as well as asthma. For instance, it seems plausible that the termination of growth signaled by menarche would also affect lung growth.

Menstrual cycle

The course and timing of menstruation is steered through a complex endocrine interplay between hormones originating from the hypothalamus, the pituitary gland and the ovaries. Extensive physiological changes take place during the menstrual cycle. Figure 2 shows an idealized scheme of the variations in sex hormones and body temperature during the menstrual cycle [26].

Many diseases are influenced by the menstrual cycle. Diseases as varied as migraine, epilepsy, bipolar disorder, inflammatory bowel disease and rheumatoid arthritis are known to show menstrual cyclicity [27–29].

Among asthmatics, fluctuations in symptoms can be caused by for instance infections, pollen levels and work-related exposures. However, for a large number of asthmatic women the causes of variations in disease over time are not known. It seems plausible that hormonal and metabolic variations during the menstrual cycle could influence the airways.

There has been a considerable scientific effort to describe variations in asthma during the menstrual cycle. Respiratory symptoms [30–32], peak expiratory flow rate [33–37], asthma exacerbations [31,38], hospital admissions [39,40], BHR [41] and fractional exhaled nitric oxide [32] have all been found to vary during the menstrual cycle. Gibbs et al. followed 114 asthmatic women attending an outpatient clinic and 30–40% reported premenstrual deterioration [34]. Eliasson et al. conducted a survey among asthmatics and found that 33% of women had significantly higher symptom scores during the premenstrual phase. In these women, worsening of respiratory symptoms correlated with dysmenorrhea and premenstrual syndrome [30]. Most of these studies are based on samples of asthmatic women; however, Dratva et al.[41] investigated bronchial hyper-responsiveness in a large population-based sample of women. This study found that women had increased BHR in the perimenstrual phase and a tendency to a periovulatory peak, with an OR for being hyper-responsive to metacholin in the perimenstrual period of 2.3 (1.27–4.29) [41]. This analysis also showed that the cyclical variations in BHR were smaller among women taking oral contraceptives. Another analysis of a large general population sample showed great fluctuations in respiratory symptoms during the menstrual cycle. Symptoms were more prevalent during the midluteal to midfollicular stages, often with a dip near time of ovulation; however, peaks varied between subgroups with different cyclical patterns according to asthma status, smoking status and BMI [42].

A major methodological problem when investigating menstrual cyclicity is the use of predefined cut-off points (i.e., investigating the perimenstrual or the prementrual period). Biological cyclicity does not advocate this, and such categorization implies a risk of losing important information and bias the identification of peaks. Statistical methodology designed to investigate chronobiological rhythmicity is an important alternative. Most of the above cited analyses relate to predefined menstrual periods, with the exceptions of the study by Dratva et al. that applied trigonometric functions in the analysis of bronchial hyper-responsiveness [41] and the study by Macsali et al.[42] that used methods for investigating chronobiological rhythmicity as developed by Mojon et al.[43] and further developed by Koukkari and Sothern [26]. Another important source of error is the assessment of self-reported worsening of asthma in relation to the menstrual cycle, which may lead to differential recall bias in several studies.

Taking into account the methodological problems, the literature is still convincing with regard to the presence of menstrual cycle variation in asthma, as consistently demonstrated in a number of studies with different designs and methodology. However, the literature is inconsistent and possibly biased when it comes to the identification of specific periods of the menstrual cycle when symptoms or disease are more prevalent or severe. There has been particular focus on pre- or peri-menstrual asthma and some focus on periovulatory changes, but most studies have not used methodology assigned to freely identify patterns. On the other hand, the identification of peaks may be of less importance for practical purposes; as the study of Macsali et al.[42] indicates differences in pattern between subgroups, each asthmatic woman could identify their own cyclical pattern and adapt treatment thereafter.

To our knowledge, possible variations in COPD exacerbations during the menstrual cycle have not been investigated. Relatively few women with COPD are in the fertile age; however, for these few women the question might be relevant.

The biological mechanisms underlying the menstrual cyclicity in asthma and airway hyper-responsiveness are not well understood. Estrogens are likely to be of importance [44,45], as well as progesterone [46]. A study by Mandhane et al.[47] showed that increased fractional exhaled nitric oxide as a marker of airway inflammation was inversely related to estrogen in the menstrual cycle, while the opposite was true for progesterone. A recent study by Jain et al.[48] showed progesterone receptors on the proximal region of the cilia of airway epithelia. If exposed to progesterone, the cilia beat frequency was decreased. However, no consistent results have been found when measuring sex hormones against various clinical outcomes. This is not surprising given the large individual variations of sex hormones within a woman and between women, as well as the complexity of hormonal and physiological changes during the menstrual cycle. It seems unlikely that one or two hormones alone can explain the cyclicity of asthma.

Irregular menstruation & PCOS

Irregular menstruation is a main feature in PCOS, and will usually reflect PCOS in women of fertile age [49]. The prevalence of PCOS among women of fertile age might be as high as 15% depending on how it is defined [50]. It is the most common endocrinological disturbance among women of fertile age, with both hormonal and metabolic components. PCOS is an important cause of subfertility. PCOS is also associated with an increased risk for diabetes mellitus and cardiovascular diseases and it is strongly related to obesity. The main pathological feature of PCOS is insulin resistance with systemic inflammation. PCOS is sometimes considered a variation of metabolic syndrome expressed in women of fertile age. Hyperandrogenism is another main feature, and whether this is a cause or consequence of insulin resistance is not fully understood. There is a developmental link from impairment in intrauterine development through low birthweight, childhood disadvantage such as catch-up growth, prepubertal obesity and early menarche. PCOS is further linked to subfertility, and in the case of pregnancy, to preeclampsia and gestational diabetes (Figure 1).

Despite its relevance for chronic inflammatory diseases, the literature on irregular menstruation and PCOS in relation to respiratory health is limited to two articles based on cross-sectional analyses. In analysis of a postal survey of a large Northern European general population including 8588 women aged 26–42 years, Svanes et al.[51] showed irregular menstruation to be associated with higher risk of asthma (OR: 1.54; CI: 1.11–2.13), asthma symptoms (OR: 1.47; 95% CI: 1.16–1.86), and asthma with hayfever (OR: 1.95; CI: 1.30–2.96). This was also observed when excluding women taking asthma medication, and the findings were adjusted for BMI. In an analysis of 1631 women aged 28–44 years participating in the European Community Respiratory Health Survey, Real et al.[52] showed irregular menstruation to be associated with lower FVC (adjusted difference: 63 ml; 95% CI: -124 to -1), more asthma symptoms (OR: 1.76; CI: 1.29–2.40), and more asthma with atopic sensitization (OR: 2.46; CI: 1.43–4.23). The lung function deficit demonstrated among women with irregular menstruation was relatively large. There was an inverse U-shaped association of lung function with BMI, showing maximal lung function at BMI of approximately 24–25 kg/m². Irregular menstruation and BMI showed additive effects on asthma and FVC. The FEV₁/FVC ratio was not significantly different between women with regular and irregular menstruation, and there was no indication of a relationship with COPD in this young age group.

The literature thus shows a link between respiratory health and PCOS. This relates to asthma and lung function, while COPD in relation to irregular menstruation has not been investigated. The time sequence between PCOS and asthma has also not been investigated. An association is plausible, as overweight, which is another marker of insulin resistance, is a well known risk factor for asthma and lower lung function. Furthermore, intrauterine development as reflected in low birthweight is related both to PCOS and impaired respiratory health; thus, common developmental factors may also be of importance for an association.

The few published studies suggest that the presence of PCOS or any of its clinical features should give a warning regarding possible impairment in respiratory health among women. Given that recommendations have been put forth to assess the risk of metabolic syndrome in all patients with PCOS, it seems plausible also to consider respiratory health in this context.

Oral contraceptives

Gestagens and estrogens combined in oral contraceptive pills (OCPs) have been in extensive use worldwide during the last 50 years. There has been great publicity concerning side effects of oral contraceptive, in particular with regard to cardiovascular events, but there is limited knowledge about potential influences on respiratory health.

Respiratory health has not been investigated in large controlled trials of OCPs, and so far there does not appear to be an intention of including this up on introduction of new OCPs. Publications on respiratory health in relation to OCP are thus based on observational studies, and current knowledge must be sought from careful analysis and interpretation of findings from imperfect study designs. In the Copenhagen City Heart Study, Lange et al. did not find any significant increase in wheezing (p = 0.997), asthma (p = 0.964), asthma medication (p = 0.448) or coughing at exertion (p = 0.866) among women using OCPs [53]. Forbes et al. showed that hormonal contraceptives had no influence on asthma severity in women with relatively mild asthma [54]. Salam et al.[55] showed that the OCP was associated with more wheeze among nonasthmatics (OR: 1.75; CI: 1.15–2.65) and less wheeze among asthmatics (OR: 0.18; CI: 0.06–0.56). An elevated asthma risk in past OCP users was observed in the Nurses Health Study (OR: 1.52; CI: 1.08–2.13) [56]. In the Tasmanian Asthma Survey, a 7% decrease in adult-onset asthma was indicated per year of OCP use [57]. This analysis is based on longitudinal data from a well-characterized population cohort. A cross-sectional analysis of the Respiratory Health in Northern Europe population-based study found an increased risk for asthma among women using oral contraceptive (OR: 1.43; CI: 1.09–1.86) [58]. However, when stratifying for BMI, this association was present only among normal (OR: 1.45; CI: 1.02–2.05) and overweight women (OR: 1.91; CI: 1.20–3.02) and a nonsignificant protective effect was indicated among lean women (OR: 0.41; CI: 0.12–1.40). This interplay with BMI seems biologically plausible, and is difficult to explain by confounding or bias. An analysis of BHR in a general population showed less variation during the menstrual cycle in BHR in women using OCP, but the study does not describe possible differences in BHR mean level according to OCP use [41]. It seems reasonable that some women with strong cyclical variation in their asthma could experience more stability when changing the hormonal profile with OCP. A possible association of oral contraceptive with COPD has to our knowledge not been examined.

Confounding by indication is a problem in the observational studies of OCP and respiratory health. Oral contraceptive is for example used as a treatment for PCOS, which appears to be related to asthma and lower lung function, as well as diabetes and cardiovascular disease. Hence, PCOS may possibly be an important confounding factor in the association of oral contraceptive with airways disease, a factor that has not been accounted for in the above mentioned studies. The issue is complicated by the fact that OCPs sometimes causes irregular menstruation.

Thus, the literature is methodologically problematic and apparently gives inconsistent results. The contents of OPCs has varied over time–presently used OCPs have a higher dose of progesterone relative to the estrogen content compared with OCPs that were used some years ago. Thus, there may be some differences in the exposure between the studies. Confounding by indication may differ between the study populations, as prevalence of OCP use varied considerably even among the northern European countries [58]. PCOS is not adequately accounted for in any of the above studies. Definition of reference category may contribute to discrepancies between studies, as may differences in BMI were present between the investigated populations.

In conclusion, it seems likely and biologically plausible that OCPs may affect the airways and that such effects could be heterogeneous. There are indications that asthma may be a side-effect of OCP in some women, but a solid longitudinal study indicates protective effects for adult-onset asthma. Differences according to BMI have been demonstrated, as well as differences in effect on respiratory symptoms between asthmatics and nonasthmatics. One large study showed reduced cyclical variability in BHR among OCP users. For clinical purposes, doctors should be aware of the possibility that exogenous hormones may affect respiratory health, and listen to the individual patients; further advice is not found in the literature.

The possibility for airways effects is, however, more than sufficient to strongly advocate that respiratory symptoms and disease are investigated when introducing new OCPs.

Menopause & hormone-replacement therapy

Menopause in women is defined as the cessation of menstruation for 12 months. The median age of menopause is 51 years [59]. In a large population study including the pan-European Community Respiratory Health Study and the Swiss SAPALDIA databases, Dratva et al. showed an increase in median age of menopause towards 54 years [60]. The single factor with the largest influence on age of menopause is smoking: menopause among smokers happens 1.5 years earlier, dependent on both numbers of cigarettes as well as duration of smoking [59,60].

There are changes in hormonal levels due to the approach of menopause. Among others, follicle-stimulating hormone and luteinizing hormone rises and estrogen actually increases before endocrine production ceases, while paracrine production of estrogen in fatty tissue is maintained and eventually increases [61,62]. Menstruation increasingly becomes irregular before it eventually disappears. A large proportion of women experience vasomotor symptoms. The average age for onset of the perimenopausal transition is 46 years with an average duration of 5 years [59]. A substantial proportion of women use hormone-replacement therapy (HRT) for shorter or longer periods, although the use of HRT has diminished due to a study from the Women’s Health Initiative [63].

The relationship between menopause and the menopausal transition to lung health is still not well understood. The reasons for this are several. There has been a great focus on HRT while the underlying condition – the menopausal transition – has been scarcely studied. In addition, study designs and populations have been heterogeneous. There is also the problem of which subgroups of women are really being compared. The single fact that HRT is possible represents a selection bias in population-based studies of the menopause.

Concerning menopause, longitudinal analysis of the Nurses’ Health Study from the USA by Troisi et al.[56] showed that postmenopausal women who were never users of replacement hormones had a significantly lower age-adjusted risk of asthma than premenopausal women (relative risk: 0.65; CI: 0.46–0.92).

In cross-sectional analyses of the multicentric and multinational European Community Respiratory Health Study, Real et al.[64] found that women not menstruating for the last 6 months (n = 432; 34%) had significantly lower FEV₁ values (-120 ml; 95% CI: -177 to -63), lower FVC values (-115 ml; 95% CI: -181 to -50) and more respiratory symptoms (OR: 1.82; 95% CI: 1.27–2.61), especially in relation to allergy (OR: 1.91; 95% CI: 1.03–3.53), than women of similar age menstruating regularly. Results were similar when restricting analyses to those who never smoked, suggesting that results could not be easily attributed to confusion with COPD, and no significant association with COPD was found (OR: 1.51, 95% CI: 0.88–2.59). Associations were significantly stronger among women with BMI of less than 23 kg/m² (respiratory symptoms: OR: 4.07; 95% CI: 1.88–8.80; FEV₁-adjusted differences: -166; 95% CI: -263 to -70) than among women with BMIs of 23–28 kg/m² (respiratory symptoms: OR: 1.10; CI: 0.61–1.97; p [interaction]: 0.04; FEV₁-adjusted difference: -54; 95% CI: -151 to 43; p [interaction] = 0.06). Strengths of this study were the use of objective data such as hormonal levels (estradiol, follicle-stimulating hormone and luteinizing hormone), lung function measurements and measurements of IgE.

Jarvis and Leynaert [65], in cross-sectional analyses of data from the Health Survey for England, found that menstrual cessation that was due to surgery was associated with the reporting of wheeze (OR: 1.55; CI: 1.09–2.20) even if women denied ever using HRT.

Concerning HRT and respiratory health, the literature shows puzzling results: while studies dealing with asthma and respiratory symptoms agree in an increased risk related to HRT, especially among nonsmokers and lean women, those studying lung function indicate either a beneficial or at least a neutral association with HRT.

Concerning asthma and respiratory symptoms, Troisi et al.’s [56] longitudinal analyses of The Nurses’ Health Study found that among naturally menopausal women, the age-adjusted relative risk of asthma for ever use of postmenopausal hormones was 1.49 (95% CI: 1.10–2.00); for current use of hormones (conjugated estrogens with or without progesterone), 1.50 (95% CI: 0.98–2.30); and for past use, 1.52 (95% CI: 1.08–2.13), compared with never use of hormones.

In cross-sectional analyses of the Copenhagen Heart Study, Lange et al.[53] found among postmenopausal women a weak but consistent association between HRT and self-reported asthma (OR: 1.42; 95% CI: 0.95–2.12), wheeze (OR: 1.29; 95% CI: 1.02–1.64), cough at exertion (OR: 1.34; 95% CI: 1.01–1.77)), and use of asthma medication (OR: 1.45; 95% CI: 0.97–2.18).

Analyzing The Nurses’ Health Study, Barr et al.[66] found that HRT was associated with newly diagnosed asthma (multivariate rate ratio [MRR]: 2.29; 95% CI: 1.59–3.29) but not with COPD. In the same study, an interaction of HRT with BMI on respiratory symptoms was also observed. HRT was more strongly associated with asthma among women with a BMI <25 kg/m² compared with those with a BMI >30 kg/m² (MRR: 3.09 vs 1.58).

Gomez Real et al.[67] observed in cross-sectional analyses of the multinational and multicentric Respiratory Health in Northern Europe study that HRT was associated with an increased risk for asthma (OR: 1.57; 95% CI: 1.07–2.30), wheeze (OR: 1.60; 95% CI: 1.22–2.10) and hay fever (OR: 1.48; 95% CI: 1.15–1.90). Furthermore, the associations with asthma and wheeze were significantly stronger among women with BMI in the lower tertile (asthma OR: 2.41; 95% CI: 1.21–4.77 and wheeze OR: 2.04; 95% CI: 1.23–3.36) than among heavier women (asthma: p (interaction) = 0.030; wheeze: p (interaction) = 0.042). Increasing BMI was associated with more asthma (OR: 1.08; 95% CI: 1.05–1.12 per kg/m²), but this effect was only found among women not taking HRT (OR: 1.10; 95% CI 1.05–1.14 per kg/m²) and no such association was detected among HRT users (OR: 1.00; 95% CI: 0.92–1.08) per kg/m²; p [interaction] = 0.046). Menopause was not significantly associated with asthma, wheeze or hay fever.

Jarvis et al.[65] found in cross-sectional analyses of data from the Health Survey for England that current use of HRT was associated with frequent wheeze, particularly among lean women (BMI <25; OR: 1.90; 95% CI: 1.17–3.05; BMI >25; OR: 1.02; 95% CI: 0.69–1.51).

In longitudinal analyses of a large database comprised mostly of French teachers, Romieu et al.[68] found an association of HRT with new cases of asthma (hazard ratio [HR]: 1.20; 95% CI: 0.98–1.46), especially of HRT consisting of estrogens only (HR: 1.54; 95% CI: 1.13–2.09), and particularly among never smokers (HR: 1.80; 95% CI: 1.15–2.80) and those reporting allergic disease prior to asthma onset (HR: 1.86; 95% CI: 1.18–2.93). The effect of menopausal status on asthma was not assessed.

Concerning HRT and lung function, Carlson et al.[69] found among postmenopausal women older than 65 years and participating in the Cardiovascular Health Study that HRT use was significantly associated with higher FEV₁ (p = 0.031) and with lower prevalence of obstruction (OR: 0.67; 95% CI: 0.48–0.95).

In a prospective crossover study involving 20 asthmatic women, Hepburn et al.[70] found that neither the discontinuation nor re-initiation of HRT in asthmatic postmenopausal women had any effect on objective measures of airway obstruction.

Pata [71] found in a randomized prospective study involving 75 women with no known pulmonary disease risk a significant increase in FVC and FEV₁ (p = 0.001 and p = 0.0001, respectively) after 3 months of HRT regardless of HRT type.

Mueller et al.[72] observed in an intervention study that 27 HRT users were less likely to show BHR compared with 58 nonusers (OR: 0.12; 95% CI: 0.03–0.55).

Cervrioglu et al.[73] found a statistically significant increase in FEV₁ and FVC levels among 23 postmenopausal women using continuous combined HRT for 3 months (p < 0.05) when compared with a control group of 25 postmenopausal women not using HRT, but no difference with 19 women using estrogen only.

The literature shows apparently contradicting results. This can be related to population differences in BMI, doctor’s practice concerning HRT use, the type and duration of HRT, self-selection in HRT use, as well as in methodological differences in study design or assessment of menopause. The main reason for different results is likely to be a difference in definition of reference groups. Furthermore, disentangling the effects of menopause itself from HRT is very complex, and will need large longitudinal studies as well as careful interpretation of findings, supported with better knowledge of biological mechanisms.

Biological mechanisms

As shown in this review, epidemiological data concerning the role of hormonal factors in obstructive respiratory diseases is complicated. The experimental data is even more complicated [44] and thus far do not explain the whole picture.

Much attention has been attached to estrogens, but estrogens alone do not fully explain the role of hormonal factors in respiratory health, as hormonal status among women varies greatly according to factors relating to reproduction, such as menarche, menstrual cycle and its regularity, pregnancy, lactation, proximity to menopause and use of exogenous hormones such as oral contraceptives or HRT (Figure 1). In addition, sex hormone levels and their effects may also vary according to the underlying metabolic condition as well as varying insulin sensitivity such as that seen in obesity, PCOS or degree of physical activity. Moreover, sex hormones and body fat mass are inter-related, and the levels of estrogens are closely related to body fat mass [74] and the subject’s metabolic status [75].

Hormonal factors in obstructive respiratory diseases should thus be studied in the perspective that gender differences exist in order to reproduce, reproduction requiring interacting correct hormonal, metabolic and immunological status. These components should not be studied separately.

The complexity with both pro- and anti-inflammatory effects of sex hormones in lung inflammation and asthma has been documented in clinical studies. Estrogen receptors are found on both vascular endothelial and smooth muscle cells being influenced by hormonal exposure [61,76], and thus may be of importance in the pathogenesis of asthma and allergy. It appears that estrogens have both pro- and anti-inflammatory effects, sometimes seemingly depending on whether they are endogenous or exogenous, and dosage, timing or length of administration [77–82]. Murine studies have shown a dual role of estrogen in the airways. In some studies it has been found that estrogen increases allergic inflammation [83–86]. On the other hand, estrogen decreases airways hyper-responsiveness [87,88].

The occurrence of asthma symptoms appears to be least frequent when serum estradiol levels are at a sustained high level in the menstrual cycle [89]. While asthma symptoms are low, levels of exhaled nitric oxide are high during mid-cycle when endogenous estrogen levels are at their highest [79,90].

Estrogen and progesterone receptors are observed on mast cells in the airways [91]. Eosinophils stimulated by a combination of the sex hormones β-estradiol and progesterone have shown significant degranulation, characteristic of an allergic reaction [92,93]. Progesterone is also found to increase BHR [93].

In general, estrogens suppress cellular immunity but stimulate humoral immunity [94]. Estrogen deficiency, however, promotes cellular (Th1-type) immunity. Progesterone stimulates a switch from Th1 to Th2-type immune responses [94]. Women using HRT had more B cells, higher T-cell proliferation and higher levels of TNF-α [95]. This represents a reversal of immune alterations associated with normal aging, suggesting that the use of HRT preserves or improves immune function [96]. Thus, both hormonal status and use of HRT can influence immunity and may be of importance in the pathogenesis of asthma and allergy.

C-reactive protein (CRP) is an inflammatory marker known to be related to smoking, obesity and cardiovascular disease [90]. Increased levels of CRP are significantly associated with respiratory symptoms, such as lower FEV₁, increased BHR [97] and nonallergic asthma [90], but not with allergic asthma [90]. Along with other markers of inflammation, CRP increases with use of oral preparations containing estrogens such as oral contraceptives and HRT [80,82,98,99].

Endothelin-1 is a strong vasoconstrictor [100] and broncho-constrictor with proinflammatory properties [101]. It is produced in endothelial cells, smooth muscle cells, airway epithelial cells and macrophages, and is consequently related to eosinophilic airway inflammation [102]. Estrogens are known to decrease plasma levels of endothelin-1 [103]. Estrogens may thus decrease inflammation in allergic asthma through this mechanism, and deficit of estrogens at some point in a women’s life may increase allergic asthma.

A dysfunctional endothelium may be a pathophysiological factor relating sex hormones to the airways. Inflammation due to dysfunctional endothelium is related to both asthma [104,105] and lung function [104,106]. Both sex hormones and insulin resistance influence this inflammation. Pulmonary function abnormalities, including reduction in gas transfer and lung function, may be related to impaired pulmonary microvasculature and injured alveolar epithelial basal lamina [106]. In addition, respiratory impairment is associated with cardiovascular risk [107]. A dysfunctional endothelium could contribute to comorbidity between obstructive airways diseases, cardiovascular diseases and obesity.

There is a growing awareness that asthma is a systemic disease and that systemic inflammation seems to be important in phenotypes of asthma [108]. In this way, inflammation related to metabolic dysfunction might be important in the development of obstructive lung diseases, although this issue is far from been understood. Androgens and estrogens have effects on lipid and carbohydrate metabolism in both men and women, as well as on vascular functions [109]. Women become more insulin resistant during the menopausal transition [110] with an increased risk for cardiovascular diseases [111,112]. Healthy menopausal women also have a certain degree of insulin resistance [113]. Estrogen appears to improve insulin sensitivity, while added gestagens may attenuate this beneficial effect [113,114]. Estrogens significantly reduce fasting serum glucose [115], but a lack of estrogens result in the development of insulin resistance and the metabolic syndrome [75,112,116]. There is even evidence of varying insulin levels and insulin sensitivity during the menstrual cycle due to estradiol and progesterone [117].

There is experimental evidence that sex steroids and insulin interact in their effects on tissues. At physiological levels testosterone and estradiol are considered to maintain normal insulin sensitivity, while outside the normal range they may promote insulin resistance [118]. In menopausal women and in men, estrogen is produced in a number of extragonadal sites, including the breast, bone, the vascular system and the brain. Within these sites, aromatases can locally generate high levels of estradiol without significantly affecting circulating levels [119]. Cytokines such as IL-6 and TNF-α play an important role in regulating estrogen synthesis in peripheral tissues [120]. Novel findings suggest that the IL-6 pathway links insulin resistance with inflammation by coordinating the interface between adaptive and natural immunity [121].

Obesity implies insulin resistance [122]. Increased BMI, obesity and insulin resistance are related to a state of inflammation [123], expressed as increased CRP [124] and adipokines, especially TNF-α and IL-6³¹[125–127], and decreased anti-inflammatory molecules such as adiponectin [123,128]. This state of inflammation is also expressed as chronic activation of the innate immune system [129]. Inflammation related to insulin resistance, the metabolic syndrome, obesity and cardiovascular diseases may be mediated by IL-6 and TNF-α [130], and appears to increase peripheral production of estrogens [120]. This is a possible mechanism explaining the relationship between BMI, inflammation and asthma, and allergy and sex hormones. The interaction of estrogens with the immune system and the inflammatory and immune responses may be central in explaining the effects of estrogens on the adipose/metabolic system and the cardiovascular system [130]. It seems plausible that this may be the case in the airways as well, but this has thus far not been extensively investigated.

Increasing BMI is related to higher risk of asthma [131–133] and lower lung function [134]. Furthermore, there is evidence linking insulin resistance to reduced lung function [135–140]. Oligomenorrhea and menstrual irregularity, an expression of insulin resistance and sex hormones disturbance, are also related to lower lung function and asthma. It is plausible that the airways can be affected by inflammation associated, with insulin resistance being seemingly related to both natural and allergic immunity, thus initiating asthma [117].

As pointed out by Lim et al.[44], the matter at hand is not easily explained by one single hormone or even experimental data only. For this reason, we have tried to focus on epidemiological data in order to outline the most recent findings. Findings from animal studies should be extrapolated with caution.

General methodological challenges

Why are there so diverse and often apparently inconsistent findings in the investigation of women’s lung health? Bias in assessment of hormonal status may be a problem, that is, menopause cannot be determined until 1 year after it actually happens, and is often made impossible to determine precisely due to the use of hormone substitution. At least it is reassuring that the literature suggests that women recall past and present hormonal and metabolic events fairly well [141,142]. The most important challenge is related to the fact that women differ greatly in hormonal profile during their lifespan and make a very heterogeneous study population (Figure 1). It is therefore of utmost importance for research in this field to investigate sufficient numbers of women, and with sufficient characterization of hormonal and metabolic status, to obtain adequate power for analysis of well-defined groups. The choice of reference category must be well founded and considered in order to interpret findings. Recently, several studies have pointed to an important interplay between hormonal and metabolic factors, also in the field of respiratory health in women. Future research needs to take into consideration metabolic status. Tobacco smoking has anti-oestrogen effects, and should also be considered in any analysis of respiratory health in women. The issue of asthma in relation to HRT is likely to be strongly influenced by smoking habits, BMI, doctor’s practice and self-selection, in a specific population at a specific time, and it is very plausible that even opposite conclusions may be reached in studies of different populations, defining the reference groups differently among others. This area is very complex, and comparing different entities is likely to account for most of the discrepancies in the literature.

Expert commentary

Hormonal factors influence respiratory health and disease throughout a woman’s life; the literature is rather convincing on this general aspect. There are some indications that such hormonal effects on the airways may be large. However, the understanding of the specific hormonal factors and possible biological mechanisms is limited. Most studies investigate asthma and asthma-related outcomes, some studies investigate lung function, hardly any studies address COPD. It seems relatively convincing that women with early menarche and irregular menstruation have more asthma and lower lung function. The literature consistently shows that asthma and respiratory symptoms vary during the menstrual cycle; this implies a therapeutic potential. Exogenous sex hormones appear to influence the airways, but the literature shows inconsistent results regarding the direction of the effects, both for OCPs and for HRT. Respiratory health should be included in clinical trials of such drugs. Changes in respiratory health around menopause seem likely, but are not well investigated and difficult to assess due to selection of HRT use.

The importance of understanding respiratory health in relation to these very factors is evident, as is the complexity in investigated hormonally heterogeneous women. Particular effort is needed to elucidate airway disease among women; the era for investigating respiratory health in 2000 men and 29 women has passed.

At present, the role of hormonal factors in respiratory health among women is sufficiently well documented for doctors to be aware of potential clinical manifestations in individual patients, but far from sufficient to found a basis for treatment strategies. Better understanding of this field has a realistic potential to enhance the knowledge of airways pathophysiology and to contribute to personalized treatment for asthma and COPD.

Five-year view

A multidisciplinary approach is needed to bring forward and integrate the understanding of sex hormones in respiratory health and disease. Clinical trials of exogenous sex hormones should include assessment of respiratory health. Epidemiological studies need large and well-characterized databases to tease out the complex inter-relationships between hormonal, metabolic and developmental influences. Experimental studies are needed to address the role of sex hormones in the lungs and interplay with local and systemic inflammation.

There is little knowledge of whether hormonal status influences COPD and COPD exacerbations. It seems plausible that airway effects of sex hormones also relate to COPD. Although COPD is relatively rare among women of fertile age, the disease is becoming more prevalent among women and the continuous increase in prevalence of overweight individuals might possibly contribute further to this trend. Thus, there is a need for research that sheds light on how hormonal and metabolic factors may influence COPD and possible variations in disease intensity.

The global increase in obesity is likely to be of importance for the association of hormonal status with respiratory health, and might even change the overall relationships of hormonal factors with respiratory disease. Research within this area should be alert to the close interplay between hormonal and metabolic factors.

We speculate that research efforts in this field during the next few years may lead to individualized treatment of asthma in relation to the menstrual cycle, to the inclusion of respiratory health in risk assessment for women with PCOS and to the identification of phenotypes such as ‘polycystic asthma’ or ‘menopausal asthma’.

The present review focuses on respiratory health in women from menarche to menopause; however, further understanding of this area may also be highly relevant for the understanding of how hormonal factors influence respiratory health in men.

Key issues

• • Early menarche is associated with more asthma and lower lung function in adult women.

• • This points to a link between developmental, metabolic and hormonal factors in respiratory health.

• • Menstrual cycle phase affects bronchial hyper-responsiveness, respiratory symptoms and asthma.

• • Women should be advised to monitor symptoms during the menstrual cycle and discuss individualized treatment with their doctor.

• • Irregular menstruation is associated with respiratory symptoms, asthma and lower lung function.

• • Recommended risk assessment in polycystic ovarian syndrome patients should include respiratory health.

• • The literature on oral contraceptives is not clear, while influence on the airways in some subgroups is suspected.

• • Clinical trials for new drugs should include assessment of asthma and respiratory disease.

• • Menopause appears to be associated with lower lung function; findings on asthma are contradictory. Hormone-replacement therapy appears to be associated with more asthma but improved lung function.

• • Further studies are needed to disentangle the effects of menopause and hormone-replacement therapy on lung health.

• • Hormonal and metabolic factors appear to interplay in relation to respiratory health.

• • Metabolic status needs to be taken into account in studies of hormonal factors.

• • The literature clearly shows that hormonal status is important for respiratory health in women, while understanding of specific factors and mechanisms is fragmentary.

• • A multidisciplinary approach is needed to bring the research field forward.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

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Respiratory health in women: from menarche to menopause

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Activity Evaluation: Where 1 is strongly disagree and 5 is strongly agree

	1	2	3	4	5
1. The activity supported the learning objectives.
2. The material was organized clearly for learning to occur.
3. The content learned from this activity will impact my practice.
4. The activity was presented objectively and free of commercial bias.

1. You are seeing a 16-year-old young woman who reports wheezing during gym class. Her only past medical history includes obesity and acne. Menarche occurred at age 11. As you evaluate this patient, what should you consider regarding the association between menarche and respiratory health?

• □ A Later menarche promotes a higher risk of asthma

• □ B Earlier menarche promotes a higher risk of asthma

• □ C Later menarche promotes reduced lung function

• □ D Earlier menarche promotes a higher risk of chronic obstructive pulmonary disease (COPD)

2. Ten years later, the patient from question # 1 returns to see you. She has been diagnosed with polycystic ovarian syndrome (PCOS), which is treated with an oral contraceptive pill (OCP). What should you consider regarding these factors and her respiratory health?

• □ A PCOS is related to higher risks of asthma but no change in lung function

• □ B PCOS can promote higher risks of asthma and reduced lung function

• □ C OCP should be avoided among women with asthma

• □ D OCP will probably increase this patient’s variability of asthma symptoms

3. The patient follows up with you again as she enters perimenopause. She wants to know how menopause and hormone therapy can affect her respiratory health. What can you tell her?

• □ A Menopause is associated with a higher risk of asthma

• □ B Menopause is associated with reduced lung function

• □ C Hormone therapy increases asthma symptoms while not affecting lung function

• □ D Hormone therapy usually improves both asthma symptoms and lung function

4. What should you consider regarding physiological mechanisms which have promoted changes in this patient’s respiratory health over time?

• □ A Estrogens act as potent anti-inflammatory agents in all tissues

• □ B Varying levels of estrogen alone can explain changes in obstructive pulmonary disease among women

• □ C Asthma symptoms are generally strongest when serum estradiol levels are high

• □ D C-reactive protein (CRP) levels increase with administration of exogenous estrogens