Sex Difference in Chronic Obstructive Lung Disease. Does it Matter? A Concise Review

ABSTRACT

Chronic obstructive lung disease (COPD) primarily affects men; however, its epidemiology has been changing because more women have become smokers. Recently, investigators found that although women and men were exposed to the same amount of smoke fume, women tended to have more severe disease and higher mortality rate. They also complain of more dyspnoea and may experience more severe exacerbations than men. This led to the question of whether sex has an impact on COPD course and whether women have a higher susceptibility to smoke fumes than men. That may be explained by multiple complex factors highlighting the relationship between sex, epidemiology, method of diagnostics and the clinical course of the disease.

In this review, sex differences in epidemiology, clinical presentation, exacerbation, co-morbidities and treatment are covered.

KEYWORDS:

• COPD
• gender
• female
• clinical presentation
• exacerbation
• treatment

Introduction

Chronic obstructive pulmonary disease (COPD) is expected to be the third cause of mortality and morbidity in the world in 2020 (1). Smoking is the best known etiological factor in COPD. Although, in general, smoking rate is diminishing due to the stop smoking campaigns throughout the world, it is still increasing among women, especially in the developing countries (2). Therefore, it is expected that COPD prevalence is increasing among women. Hence, other possible etiologies such as passive smoking, biomass fume exposure, malnutrition and infections affect mostly women in poor countries (2–6).

There might be clinical differences based on sex. Whilst women are more likely to develop chronic bronchitis, emphysema appears more common among men (5). Women declare much dyspnoea than men. Exacerbations may result in different outcomes and the treatment adherence may be different according to the sex (2–5).

In this review, we discuss the relationship between COPD and female sex based on the current literature.

Epidemiology

Historically, COPD is known as smoking-related disease that mainly affects men, because men have smoked more than women worldwide (7). However, COPD has been increasingly prevalent in women and now has similar mortality in the USA ((3,8). During the interval between first National Health and Nutrition Examination Survey (NHANES I) to NHANES III, the prevalence of moderate COPD increased by approximately 8 per 1000 women and decreased by 33.8 per 1000 men (3,9). During 1980 to 2000, the annual mortality rate for COPD in women increased by 291% 1). In the year 2000, for the first time, COPD deaths in women exceeded the deaths in men in the USA (3). In 2000, in Canada, the prevalence of COPD was found to be 8.2% in women smokers and 3.5% in men smokers (10). During 2000 to 2010, current smokers had similar relative risks for mortality from COPD in male (26.6) and females (22.6). These rates were almost double compared to 1982–1988 (3). During 1994 to 2010, in the European Union, the mortality rate in men decreased from 90.1 to 61.3; however, in women, these rates were 27.0 in 1994 and 25.15 in 2010 (3).

Outside the Western countries, current epidemiological studies coming from countries such as China, India and Turkey showed that the prevalence is still higher in men than in women ((11,12). The Burden of Obstructive Lung Disease “BOLD” study showed that in Sydney, COPD prevalence was approximately 8% in men and 12% in women, whereas in Manila, it was 18% in men and 7% in women. In Adana (a city of Turkey), it was 15% in men and 6% in women 13). The BOLD group also reported that COPD mortality was higher in countries with a low level of gross national income per capita (14). While smoking rates in women have largely stabilized in developed countries, the rates are continuing to climb in developing countries; therefore, one can expect that there may be a change in prevalence and mortality in women similar to that seen in developed countries. There are about 200 million women in the world who smoke. In developed countries, approximately 22% of women smoke. In developing countries, approximately 9% of women smoke, but because most women live in developing countries, there are more women smokers in developing countries than in developed countries. The prevalence of women smokers in developing countries, if effective anti-tobacco initiatives and action plans are not implemented, is predicted to rise to 20% by 2025. This would mean that there could be 532 million women smokers worldwide by 2025 (2,3,15).

The population-attributable fraction for smoking as a cause of COPD ranged from 9.7 to 97.9%, and is less than 80% of COPD in most studies (16). This shows the fact that a significant burden of disease is attributable to non-smoking risk factors, such as specifically genetic syndromes, occupational exposure, traffic and other outdoor pollution, indoor air pollution, second-hand smoke, outdoor and indoor biomass smoke, dietary factors, chronic asthma and tuberculosis ((16,17). According to the World Health Organization (WHO), it has been estimated that about 2.4 billion people (about 50% of world's population) and 90% of people living in rural areas use biomass fuel as the primary energy source for domestic purposes (18,19). Women, spending more time indoors for cooking, are more exposed to biomass fuel combustion products than men. A meta-analysis has shown that biomass smoke exposure was a risk factor for developing COPD in both women and men (17,20,21). Among non-smoker COPD population, 80% were women 3). In Malatya, a large city of Turkey, the female-to-men COPD ratio was 1:4. Biomass exposure was the sole reason for COPD in 54.6% of the women. In the same area, the smoking rate was 25.5% in women and 57.2% in men (21). In China, biomass fuel exposure was 75.3% in women when compared to men, in whom it was still 31.5% (22). In China, in never smokers, airflow obstruction was found in 5% in females and 5.1% in males (mean age was approximately 50 years). The odds ratio was positively associated with cooking with coal, lower household income, prior tuberculosis, less education, rural region and lower body mass index (23). A case–control study showed that women who were exposed to wood smoke had a fivefold higher risk of developing COPD (24,25).

Exposure to second-hand smoking is another important risk factor. The relative risk for having COPD from second-hand smoking is 1.31 in China, where second-hand smoking has been extremely prevalent. About 49.2% of Chinese non-smokers are exposed to second-hand smoking; and of those, 51.3% of women and 12.1% of men were exposed to second-hand smoking at home. At work, the rates were around 26% for both sexes (18,26).

It has long been speculated that autoimmunity would be another risk factor for non-smoking COPD. Women have a propensity for autoimmunity. In a study that was done in 25 non-smoker COPD subjects, females were more prevalent. Two pathologic sub-types of inflammation were identified as eosinophilic and neutrophilic and those may be associated with organ-specific autoimmune disease (27). Another less mentioned possible etiologic factor for COPD is malnutrition. An estimated 20–45% of women of childbearing age in the developing world do not eat the WHO recommended 2250 calories a day. Underweight newborns who are delivered by unhealthy mothers are also at risk. All those factors are mostly related with low socioeconomic status associated with poverty, which disproportionately affects women (2,28,29).

Biological reasons for susceptibility

The increased prevalence and mortality in women lead questions about biological and sex-specific genetic factors (3). An early meta-analysis of eight population-based observational studies that includes a great variety of general health characteristics failed to support the hypothesis of widespread differences in the effects of cigarette smoking on lung function between sex and racial subgroups (30). However, more recent studies have showed contrasting results ((7,8,31–34). In a study that included 330 COPD patients, Caucasians had less loss of lung function per pack-year smoked than African Americans and men less than women (Susceptibility index: 0.98% vs. −1.21%, p = 0.001) 31). Silverman et al. found elevated prevalence of COPD (71.4%) in females among the early-onset COPD probands. Female first-degree relatives had significantly lower forced expiratory volume in one second/forced vital capacity (FEV₁/FVC), with greater bronchodilator responsiveness. Female first-degree relatives who smoked had significantly greater risk of FEV₁<40% (OR: 3.56) (35). In the COPD Gene Study, severe, early-onset COPD subjects were predominantly female (66%) ((3,4). Recently, Jordan et al. 36) raised a potential explanation for this controversy. In their cross-sectional analysis of data from Health Survey for England, the COPD prevalence was calculated as 16.1%, 7% and 9% using different diagnostic criteria [Global Initiative for Obstructive Lung Disease (GOLD), National Institute for Health and Clinical Excellence (NICE), and lower limit of normal (LLN)], respectively. Based on the GOLD and NICE criteria, men (OR 1.46) had significant independent risks of COPD compared with women (OR 1.30). However, with LLN, the effect was removed (OR 0.96). They found that when using the GOLD and NICE definitions, women appeared to have a significantly greater susceptibility to COPD for the same level of smoke exposure, but this was not seen when using the LLN criteria. This study showed that female susceptibility depended on using the GOLD definition of COPD, which has been the definition used in many other studies (36).

Several studies have searched the biological background of possible susceptibility to cigarette smoke in women. Women could be genetically more predisposed to smoking-induced lung damage, and there might be a greater dose-dependent effect in women smokers. Women have smaller airways so this could cause more exposure with a comparatively smaller amount of smoke (3). In a recent mouse model, the excess risk of small airways disease in female mice after chronic smoke exposure was found to be associated with increased oxidative stress and transforming growth factor beta (TGFβ1) signalling, and related to the effects of female sex hormones (37). Cigarette smoke metabolism might be different in women, depending on hormonal factors ((3,33). Sex hormones affect lung growth and development, airway hyper-responsiveness and detoxification of tobacco smoke. The pubertal switch in asthma from a male-predominant disease to a female-predominant disease may be a manifestation of such effects. Estrogen can induce differentiation and maturation of the lung. It may also be involved in the production of cytokines, triggering a TH2-dominant immune response. Menopause, which is age related and associated with the decline in estrogen and progesterone, is an important cause of accelerated alveolar loss 33).

Growing evidence indicates that estrogen may delay the loss of lung function, with maintenance of alveolar structure and the number of alveolar attachments to small conducting airways, cilia beat and epithelial nitric oxide ((22,33). In a recent study on biomarkers in COPD, by Torres et al., cytokines such as interleukin 16 (IL-16), pulmonary and activation-regulated chemokine (PARC) and vascular endothelial growth factor (VEGF) were independently associated with female sex 38).

COPD-specific outcomes

As a result of growing epidemiological data, the prevalence of COPD in women is getting more attention, but many other aspects may be also affected by sex. Diagnosis, symptoms, health-related quality of life (HRQoL), co-morbidities, management, natural course, disease progression and mortality could all be influenced by sex. These might be a reflection of anatomical and physiological differences between the sexes and cultural and sex-related social factors (9).

A. Diagnosis

Women are more likely to be diagnosed with asthma by physicians. There is a perception that COPD is not a woman's disease. Therefore, even though women present with COPD symptoms, they are less likely to receive spirometry ((3,39,40). In a recent study, in 3,500 subjects from Spain, 73% of the patients with spirometric COPD criteria were underdiagnosed, and this percentage was unevenly distributed by sex, being over a quarter times more frequent in women (86.0%) than in men (67.6%) (3,41). Physicians should think that if the symptoms are compatible with COPD, one should order spirometry regardless of sex. However, data show that only 22% of the physicians request a spirometry 8) and without spirometry, physicians think of asthma more than COPD in women. In a study of 397 COPD subjects (52% women), self-reported COPD was common among men, and co-diagnosis of COPD with asthma was more common among women (p > 0.05) (42).

There may be a sex disparity in using health resources and patients' perception about their illness and health resource availability. In a cross-sectional prospective study of 46,587 ICU admissions in 91 units across England, Wales and Northern Ireland, no sex differences were found on admission or mortality rate in several diagnoses including COPD (43). However, in the USA, a study evaluating patients' perceptions in COPD showed that more women than men reported an annual household income <$30,000, but there were no significant sex differences in frequency of health insurance, physician visits or having spirometry. In adjusted models (7), women were more likely to report COPD diagnostic delay (OR: 1.66), difficulty reaching their physician (OR: 2.54) and reported that time spent with their physician was insufficient (44).

B. Clinical features

There have^{Table 1} been several studies which suggest that COPD clinical presentation is different in women. Women are more likely to report dyspnoea and less likely to report phlegm. A Japanese study showed that women were more dyspnoeic, had worse quality of life (SGRQ and SF-36) and scores worse on the Morale Scale that measures subjective well-being (45). In the French Initiatives BPCO real-world cohort, women were matched with men and for a given age and the level of airflow obstruction, women with COPD had higher body weight, obstruction and dyspnoea (BOD) scores due to more dyspnoea and lower body mass index (BMI) (46). In a Swedish study, similar proportions of women and men experienced fatigue, and that was associated with a 6-minute walk distance (6MWD) and body weight, obstruction, dyspnoea and exercise (BODE) index in both sexes (47). A recent USA study showed that similar numbers of women and men reported dyspnoea, but women reported less phlegm and rated their health as poor/very poor (44). In the European Respiratory Society study on chronic obstructive pulmonary disease (EUROSCOP) study, men and women reported similar symptoms; however, men had more wintertime phlegm production. Symptoms were only correlated with baseline FEV₁ in men but not in women (48).

Other studies showed that women were more likely to have depression, anxiety, fatigue, lower BMI and fat-free mass and more exacerbations than men ((3,37,49,50). Data from the Toward a Revolution in COPD Health (TORCH) study showed that women (n = 1481) had higher FEV₁ (47% vs. 44% predicted), worse St George's Respiratory Questionnaire (SGRQ), and worse Medical Council Research Score (MRC) than men (n = 4631). After adjusting for differences in baseline factors, the risk of mortality was 16% higher in men than in women, although this was not statistically significant. Causes of deaths were similar in both sexes. Exacerbations were 25% higher in women 50).

Recent data from Spain showed that women COPD patients were significantly younger, had better pulmonary function tests, smoked less but had worse quality of life measured using the EQ-5D and Airways Questionnaire 20 (AQ20), higher anxiety and depression (51). In a very recent study conducted in 19,260 women and 23,893 men in Quebec, men had significantly worse survival and significantly increased risk of rehospitalisation for COPD (52). In a meta-analysis, studying 55,709 participants, the authors reported that female current smokers had a significantly faster annual decline in FEV₁% predicted than male current smokers. Age did not materially affect the rate of decline in FEV₁% predicted in male and female former and never smokers (53).

Martinez et al. examined the computed tomography (CT) data from the National Emphysema Treatment Trial (NETT). Women had less emphysema, smaller airways, and thicker airway walls. Women were younger and exhibited lower BMI, shorter smoking history, less severe airflow obstruction, lower carbon monoxide diffusion lung capacity (DLCO) and arterial partial oxygen pressure (PO₂), higher arterial partial carbon dioxide pressure (PCO₂), shorter 6MWD, and lower maximal wattage during oxygen-supplemented cycle-ergometer (54). Recently COPDGene Study has investigated if sex-specific differences in emphysema persists within different subgroups; i.e., 1) different GOLD spirometric severity, 2) early-onset COPD (<55 years old) and 3) advanced emphysema (>25% emphysema). Compared with females, males had higher emphysema. Females with early-onset COPD, severe emphysema and GOLD grade-IV COPD had similar emphysema as males but markedly fewer pack-years smoking history (55).

In a 7-year prospective cohort study composed of outpatient COPD subjects (184 women and 251 men) who were referred to long-term oxygen therapy (LTOT), females were at a significantly higher risk for death (hazard ratio: 1.54) (56).

The reason why women experience more dyspnoea is unclear. Dyspnoea has several dimensions such as physical, affective and cognitive dimensions. Patients' response to dyspnoea has been affected by patients' emotional response and interpretation of the dyspnoeic sensation. Neurobiological studies showed that women had higher intrinsic sensitivity to somatic sensations including dyspnoea. Women also demonstrate greater attention to somatic sensations (57).

As discussed, the mortality data are conflicting, and there has been a need for further studies in which the confounders are more rigorously controlled. Women may live longer because they have different co-morbidity profile than men, and there has been some evidence that pulmonary hypertension is less severe and right heart functions are better preserved in women with COPD. On the other hand, women may be more likely to die from COPD because they have a different co-morbidity profile and have time to survive with the disease, and as a result may die from it, instead of being dead because of co-morbidities, particularly cardiovascular disease (56,58). Sex differences in clinical features and mortality have been summarized in Tables 1 and 2.

Table 1. Clinical characteristics associated with sex differences.

	n	Design	Aim	Result
Katsura et al.^41	156 (117 men, 39 women)	Prospective, cohort study Anthropometric variables, pulmonary function test, exercise capacity, degree of dyspnoea, subjective well-being and both generic and disease-specific HRQoL were measured.	Sex differences in dyspnoea and HRQoL in patients with COPD.	Women had significantly higher SGRQ scores for activity (p < 0.001), impact (p < 0.001) and total score (P < 0.001) than male patients. Sex differences exist in dyspnoea and HRQoL in patients with COPD.
Dales et al.^36	1,034 (550 men, 484 women)	Prospective cohort study Respiratory symptom questionnaires and spirometry	Sex differences in the clinical expression, clinical diagnoses and management of airway diseases in a primary-care setting.	Females reported dyspnoea (p = 0,008) and wheeze (p = 0.031) more frequently than men.
Tödt et al^42	121 (54 men, 67 women)	Cross-sectional study. Experience of fatigue (frequency, duration, and severity) and physical capacity (lung function, 6-minute walk distance [6MWD], grip strength, and timed-stand test) were assessed. BMI and BODE index were calculated.	The main purpose of this study was to examine the relationship between the experience of fatigue and factors of physical capacity and disease severity separately in men and women with COPD.	Exercise capacity and disease severity were associated with fatigue in both men and women. In women, leg fatigue was strongly associated with fatigue.
Watson et al^43	642 (178 women, 464 men)	Randomised double-blind, placebo-controlled study		Respiratory Symptoms were associated with reduced baseline FEV1 in men with COPD but not in women.
Celli et al^45
	6,112 (1,481 women 4,631 men)	Multi-centre, randomised, double-blind parallel-group, placebo-controlled study	Determine sex differences in survival, causes of death, and patient-centred outcomes in the 3-year Toward a Revolution in COPD Health (TORCH) study.	Women reported more exacerbations, worse dyspnoea and worse health status scores than men.
Roche et al^46	688 (146 women)	INITIATIVES BPCO cohort (multi-centre study)	Determine sex differences in the clinical features for a given age and level of airflow obstruction.	Women with COPD had higher BOD scores due to more pronounced dyspnoea and lower BMI.

HRQoL: Health-related quality of life; SGRQ: St George Respiratory Questionnaire; BMI: body mass index; BODE: body mass index, obstruction, dyspnoea, exercise capacity; BOD: body weight, obstruction, dyspnoea.

Table 2. Mortality.

	N	Study design	Patient characteristics	Results
Raine et al.^39	Number of patients: 46, 587 COPD patients: Number of men 494 Number of women 454	Prospective study. Data from 91 voluntarily contributing units across England, Wales, and Northern Ireland.	All patients were admitted to ICU (acute myocardial infarction, asthma, chronic obstructive airway disease, pneumonia, self-poisoning, seizures, primary brain injury, ventricular failure, cardiac arrhythmias, neurological bleeding)	COPD patients had no significant sex differences with respect to age, acute physiology score, past medical history, APACHE II score, or mortality
Sunyer et al.^61	Number of patients 15,517 COPD patients: Number of men 8,331 Number of women 2,631	A population-based cohort study	Asthma or COPD patients. (Older than 14 years)	Mortality rates in both males and females who visited emergency rooms for COPD or asthma were significantly higher than the expected rates in the general population. These relative increases in the mortality rates were significantly higher in females than in males for both causes of death, COPD (age-adjusted female/male ratio = 2.39) and asthma (ratio = 3.95).
Gonzalez et al.^47	43,153 COPD patients (19,260 women, 23,893 men)	Prospective cohort study	Aged >66 years who received 3 prescriptions for respiratory medications in any 1-year period.	Mean survival and time to rehospitalisation for obstructive airway disease are significantly better for female patients.
Machado et al.^50	435 COPD patients (184 women, 251 men)	Prospective cohort study	Baseline data were collected on enrollment into oxygen therapy, when patients were clinically stable.	Among patients with COPD on LTOT, women were more likely to die than men.

LTOT: Long-term oxygen therapy.

C. Co-morbidities

Sex differences in co-morbidities are understudied. The Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) study showed that, in females, cardiovascular co-morbidity and diabetes mellitus were less prevalent, whereas osteoporosis, inflammatory bowel disease, reflux and depression were more prevalent ((3,49,59). In a Spanish study, females had more heart failure, osteoporosis and diabetes mellitus but less co-morbidity compared with men (1.8 vs 3.7). The mean Charlson co-morbidity index score was 2.7 and not different between the sexes 60).

In the EPIDEPOC study of 10,711 patients in Spain, hypertension, diabetes, anxiety and depression were higher in women, whilst ischemic heart disease was more common in men (61). In a Swedish study, men had more lung cancer, ischemic heart disease and renal failure and women had more osteoporosis, hypertension, rheumatoid arthritis, osteoporosis and mental disease ((3,62). A study evaluating sex differences in the prevalence of psychiatric disorders and psychological distress in COPD showed that women had significantly higher anxiety sensitivity and depressive symptoms compared to men, but did not report more limitations in psychological functioning. Women also reported being less confident in their ability to control respiratory symptoms, and more daily physical limitations compared to men, despite having comparable COPD severity, dyspnoea scores and exacerbation rates (3,54,63). In another study conducted in Italy, women had more anxiety, depression and dyspnoea than men. Dyspnoea was more strongly correlated with depression in women than in men 64). Details of co-morbidities in different sexes are summarized in Table 3.

Table 3. Co-morbidities.

	n	Study design	Results
Naberan et al.^46	4574 (740 female)	Multi-centre, cross-sectional observational study	Women showed poorer quality of life, a higher rate of anxiety and depression (p < 0.001).
Almagro et al.^54	398 (45 female)	Multi-centre, cross-sectional study	Women had lower prevalence of ischemic heart disease (p < 0.008) and alcoholism (p < 0.03), but more frequently presented with chronic heart failure (p < 0.03), osteoporosis (p < 0.007) and diabetes mellitus without complications (p < 0.02).
Carrasco-Garrido et al.^55	10,711 (2613 female)	An observational and descriptive epidemiological study (EPIDEPOC study)	The frequency of hypertension, diabetes, anxiety and depression was greater in women.
Di Marco et al.58	202 (47 female)	Prospective study	Female patients had higher levels of anxiety and depression and worse symptom-related quality of life.

D. Exacerbations

There might be differences in COPD exacerbations between women and men. A cross-sectional study utilizing the 1996 Nationwide Inpatient Sample that included 71,130 patients with COPD exacerbations, the in-hospital mortality due to COPD exacerbation was higher in men (65). In a study conducted in patients admitted with an exacerbation, men (n = 191) had more sputum production and cough during the exacerbation, but there was no difference between them in breathlessness and co-morbidity conditions when stable. Although women (n = 206) had a higher level of education than men, and they had similar household income and health insurance as compared with men, they were less likely to seek emergency care within 24 hours prior to emergency room (ER) admission (42). During a two-week follow-up period after ER admission, men tended to have more relapses than women, but women were less likely to self-medicate ((3,42). In a study from Singapore, conducted in 186 COPD patients, Cao et al. found that men had a greater readmission risk for COPD exacerbation in univariate analysis, but that was not confirmed with multivariate regression model (disease duration >5 years, FEV₁ <50% predicted, use of psychotropic drugs and vaccination status) 66). Increased rehospitalisation risks for women COPD patients could be related to anxiety and different co-morbidity profile (57). In a study conducted in exacerbated patients in our centre, women tended to have more severe exacerbations, higher number of hospitalisations and different co-morbidity profile than men (67). In a UK study conducted in 91 ICUs with 46,587 cases, there were no sex differences in in-hospital mortality (43). In Spain, 9,918 males and 5,598 females who were admitted to ER with diagnosis of COPD or asthma during the period from 1985 to 1989, vital status of patients was followed to the end of 1995 to evaluate the mortality differences in both sexes. Female COPD patients had 2.39 times more risk than males (68). Studies in sex differences in exacerbations are summarized in Table 4.

Table 4. Exacerbations.

	N	Patient characteristics	Study design	Results
Cydulka et al.^38	397 (206 females)	55 years or older who presented with exacerbation of COPD	Prospective, cohort study	During the exacerbation, women initiated less home therapy and were less likely to seek emergency care within the first 24 hours of symptom onset (25% vs. 36%; p<0.01).
Patil et al.^59	71.124 (40.085 females)	40 years or older with an acute exacerbation of COPD at hospital discharge	Cross-sectional study	In-hospital mortality for patients with an acute exacerbation of COPD was 2.5%. Multivariate analyses identified male sex as independent risk factor for in-hospital mortality.
Cao et al.^60	186 (31 females)	Moderate-to-severe COPD patients with one or more admissions for acute exacerbations	Cross-sectional study	Univariate analysis showed that male sex significantly associated with frequent past readmissions.

E. Management

E.1. Smoking cessation

As mentioned in the epidemiology section, females are an attractive group of people for the tobacco industry to capture. That is most true for developing countries where there is still struggle of sex disparity in many social issues and women need to show their independence as they get more power economically.

Studies showed that women tended to quit smoking less frequently and less successfully. In a study conducted in Southern Cape-Karoo Region in South Africa, female smokers experienced more nicotine dependence, more depressive mood and withdrawal symptoms (69). However, in developed nations, there was little difference in success rate according to the sex. A meta-analyses found that although bupropion was an effective aid to smoking cessation in both sexes, men were more successful in long-term smoke cessation and women were less committed to quitting ((70,71). Beside possible physiological factors such as sex hormones, many behavioral and psychological factors such as fear of weight gain, need for social support, depression, low self-efficacy would be reason of worse outcome in women 72). Many social factors are related to the success rate: women are less likely to quit when they live alone or live with a smoker partner (71). The Lung Health Study (LHS) showed that women who became sustained quitters had an average improvement in FEV₁% predicted in the first year that was 2.5 times as great as the improvement in men (73). Therefore, although women have more difficulties quitting smoke cigarettes, they may have more benefit if they are successful.

E.2. Pharmacological therapy

There are scarce data regarding whether and how pharmacologic agents act differently in women and men. More importantly, the possible difference on adverse events has not been studied extensively. One study found that women with COPD received more prescription than men (65).

Until recently, most of the participants in large clinical trials were mainly males and were not designed for evaluation of sex-based outcomes and safety issues. In a case–control study using the General Practice Research Database, which composes of 79% of females with hip fracture and individually matched pairs, it was shown that there was a dose–response relationship between inhaled steroids and hip fracture (Odds ratio: 1.26) (74). A budesonide study conducted on COPD subjects (27% were females) who continued to smoke showed that the vertebral fracture rate was not different between budesonide and placebo and women and men (75). One study showed that fluticasone/salmeterol acted similarly in both women and men across several outcome measures, and there were no differences in adverse events (3,76). Another study showed that women deteriorated more than men after cessation of inhaled steroids (3,77).

E.3. Inhaler technique

There may also be sex differences in treatment compliance and device preferences. Sestini et al. found that men were more prescribed “new” dry powder inhalers versus metered dose inhalers (3,78). In a study in 1994, only 4% of women compared with 43% of men used metered dose inhalers correctly (3,79). In a study from Pakistan, there was no sex difference in using correct inhaler technique (3,80).

E.5 Pulmonary rehabilitation

There might be a sex difference regarding the effect of pulmonary rehabilitation. In a study in which 54% were females, rehabilitation produced better improvement in mastery, emotion and psychosocial subscales of Chronic Respiratory Disease Questionnaire (CRQ) and pulmonary functional status in total in women ((3,81). However, Foy et al. came to the conclusion that extended exercise therapy (18 months versus 3 months) provided beneficial effect in subscales of CRQ in men but not in women 82).

Conclusion

The prevalence and mortality of smoking are increasing in women across the world. As a result, increasing numbers of women are developing COPD. Women are also predisposed to a greater risk from non-smoking etiologies, such as biomass exposure, more than men. Recent evidence suggests that there may be enhanced susceptibility to cigarette smoke in women compared to men. Women present with more dyspnoea, different co-morbidities and worse quality of life. Exacerbations may result in different outcomes and frequent rehospitalisation. Treatment effects and adverse events are not systematically investigated in women but they may be under-treated.

Since using the GOLD diagnostic criteria of FEV₁/FVC <0.70 could potentially cause a sex bias, the previous work should be interpreted cautiously. Therefore, future studies should use LLN and z-scores as well as the GOLD criteria to make comparisons between the sexes in order to help clarify whether there truly are differences in COPD between the sexes.

Declaration of interest

The authors have stated explicitly that there are no conflicts of interest in connection with this article.