Sex and Gender in Lung Disease and Sleep Disorders

Abstract

The terms sex and gender often are used interchangeably, but have specific meaning when it comes to their effects on lung disease. Ample evidence is now available that sex and gender affect the incidence, susceptibility, presentation, diagnosis, and severity of many lung diseases. Some conditions are more prevalent in women, such as asthma. Other conditions are seen almost exclusively in women, like lymphangioleiomyomatosis. Some life stages—such as pregnancy—are unique to women and can affect the onset and course of lung disease. Clinical presentation may differ as well, such as higher number of exacerbations experienced by women with COPD and greater cardiovascular morbidity in women with sleep-disordered breathing. In addition, response to therapy and medication safety may also differ by sex, and yet, pharmacogenomic factors often are not addressed adequately in clinical trials. Various aspects of lung and sleep biology and pathobiology are impacted by female sex and female reproductive transitions. Differential gene expression or organ development can be impacted by these biological differences. Understanding these differences is the first step in moving toward precision medicine for women. This article is a state-of-the-art review of specific effects of sex and gender focused on epidemiology, disease presentation, risk factors, and management of lung diseases. Pathobiological mechanisms explaining sex differences in these diseases are beyond the scope of this article. We review the literature and focus on recent guidelines about using sex and gender in research. We also review sex and gender differences in lung diseases.

Investigations of the interaction and impact of sex and gender on respiratory disorders are lacking. Only in the last decade have these differences been explored in more detail in respiratory diseases and sleep disorders. A search on PubMed of lung and sex or gender reveals more articles published on this important topic in each of the past decades. However, heart and sex or gender outpaces the lung search (Fig 1). Despite advances in clinical medicine, genetics, and proteomics, we are in the nascency of using these advances for directed screening, diagnosis, and treatment in women. Clear sex differences exist in the incidence and prevalence of respiratory diseases (Fig 2A-2C).^{1, 2, 3, 4, 5} Despite knowledge regarding different presentations of diseases in the sexes, disease in women continues to be underdiagnosed, and women may not receive appropriate timely therapies.^{6, 7, 8} Therapies tested only in men have been extrapolated for use in women. To provide precision medicine tailored to women, we need to understand sex-dependent disease drivers and, specifically, to develop dedicated therapies and management strategies. We need to understand the difference between sex and gender, to use appropriate terminology, and to understand the physiologic and anatomic differences between the sexes that may contribute to respiratory diseases throughout the lifespan (Table 1).⁹ Changes in sex hormones throughout development, puberty, pregnancy, and menopause influence lung function and health, as well as sleep. This article aims to provide a state-of-the-art review of appropriate terminology for sex and gender and how these constructs impact specific respiratory diseases and sleep disorders (Table 2).^{10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28} We chose to focus on COPD, asthma, lung cancer, interstitial lung disease, and OSA as the most common respiratory disorders to impact women. Pulmonary hypertension, cystic fibrosis, and sarcoidosis have a large sex and gender body of literature, and it was not feasible to do them justice in this article. Similarly, an in-depth analysis of the impact of pregnancy is beyond the scope of this article.

Figure 1.

Bar graph showing studies indexed in PubMed over the time frame using the search terms “lung and (sex or gender)” and “heart and (sex or gender).”

Figure 2.

A-C, Bar graphs showing the prevalence of airway disease by sex (A), the prevalence of ILD by sex (B), and incidence of lung cancer by sex (C). ILD = interstitial lung disease.

Table 1.

Anatomic and Physiological Differences Between the Sexes

Lower in Women	Higher in Women	Equal in Both Sexes
TLC (corrected for height)	Expiratory flow limitation	Respiratory rate
Tidal volume (corrected for height), minute ventilation (corrected for height)	Resistive work of breathing	Viscoelastic work of breathing
Peak inspiratory flow (corrected for height), peak expiratory flow (corrected for height)	Dyspnea rating (for given minute ventilation)	No. of alveoli per unit volume
Airway size (height matched)	. . .	. . .
Tracheal diameter (matched for TLC)	. . .	. . .
Pharyngeal airway length	. . .	. . .

TLC = total lung capacity.

Table 2.

Sex and Gender Differences in Common Respiratory Diseases

Disease	Sex Differences		Gender Differences, Women vs Men
	Male Sex	Female Sex
COPD	Higher prevalence	Early onset with less tobacco exposure, majority of nonsmoking COPD, high exacerbation rates, immune dysregulation, higher annual decline in DLCO, decline in lung function at menopause, more anxiety and depression, poorer QoL	Increased advertisements aimed at women in the 1960s; increased smoking rates; often misdiagnosed; presence of comorbid conditions, anxiety, and depression
Asthma	Higher prevalence before puberty	Higher prevalence after puberty, perimenstrual asthma, less likely to receive pharmacotherapy, worse perception of symptoms, worse QoL despite similar baseline severity, potentially improves after menopause, HRT has conflicting results on asthma incidence during menopause	Occupational exposures may worsen asthma features, more obesity, and GERD; often misdiagnosed; prescribed psychotropic medications more often
Lung cancer	Higher incidence and mortality; some studies suggest better response to immunotherapy, but not consistent	Potentially more susceptible to cigarette smoke; represent most cancers in nonsmokers; underrepresented in screening studies; may need different screening guidelines; may have more benefit from screening; better overall response to therapy; overall better survival after adjusting for tumor type, age, and smoking status	Targeted smoking campaigns, increased smoking rates, more difficulty in quitting smoking, exposure to second- and third-hand smoke, higher exposure in certain occupations, potentially higher environmental exposure, misdiagnosis or later diagnosis
ILD	IPF is more common, mortality higher, more prone to fibrosis developing in CTD-ILD and poorer prognosis	Hypersensitivity pneumonitis and sarcoidosis are more common, CTD-ILD more common, less fibrosis in CTD-ILD, IPF mortality lower, lymphangioleiomyomatosis occurs almost exclusively	Report more dyspnea for same severity of disease in IPF, dyspnea impacts emotional health-related QoL more in women with IPF, poorer QoL in sarcoidosis, poorer QoL in RA-ILD, time to treatment initiation for IPF and other ILD longer
OSA	Higher overall AHI, lower oxygen saturation	REM predominant OSA, worsens with age and menopause, more frequent arousals from sleep, incidence increased in menopause (especially if not receiving HRT)	Fatigue and insomnia, rather than snoring and sleepiness may be predominant symptoms; screening questionnaires such as STOP-BANG favor men; very limited data on response to different treatments between men and women

AHI = apnea hypopnea index; CTD-ILD = connective tissue disease-related interstitial lung disease; DLCO = diffusion capacity of the lung for carbon monoxide; GERD = gastroesophageal reflux disease; HRT = hormone replacement therapy; ILD = interstitial lung disease; IPF = idiopathic pulmonary fibrosis; QoL = quality of life; RA-ILD = rheumatoid arthritis-associated interstitial lung disease; REM = rapid eye movement; STOP-BANG = snoring, tired, observed apnea, pressure, BMI, age, neck circumference, gender.

Sex and Gender Terminology

Sex and gender influence epidemiologic data, disease pathogenesis and pathophysiologic features, clinical manifestations, response to treatment, access to care, and health outcomes. Hence, sex and gender should be considered in all types of research, clinical practice, and educational curricula.

Sex- and gender-based medicine is a relatively new field and spans across medical disciplines. Although some limited data are available on sex- and gender-based influences in respiratory disease, the data are fraught with use of incorrect terminology. Sex and gender are used interchangeably or incorrectly in many publications. Sex is a biological construct, whereas gender is a social construct (Fig 3). Hence, the term sex indicates an animal’s or a person’s biological status. This status is defined by a combination of anatomic features, genetics, sex organs, and hormones. It also has been suggested that sex characteristics be considered as a spectrum, rather than as a binary construct.²⁹ However, gender is considered to be a psychological and social construct that reflects the behaviors, attitudes, and feelings of a person in the context of their historical and cultural milieu. Gender encompasses factors such as societal roles, work roles, environmental exposures, and social support. Thus, it has been recommended that sex be used to describe the biological differences and influences observed in female individuals compared with male individuals. Gender should be used when describing psychological and social differences between men and women.³⁰ Health ultimately is impacted by an interaction of both sex and gender, where influences of both sex and gender are observed in individual patients and circumstances in both health and disease. Representative examples of the way terminology should be used would be the following. Sex differences are inherent in lung structure and function in utero, at puberty, and during pregnancy and menopause. Hormonal influences on asthma manifestation around puberty, pregnancy, and menopause are related to female sex. The impact of biomass fuel on lung physiology and disease in women in low-income countries is related to women’s societal role, and therefore is a gender effect. Although previous guidelines have defined sex and gender primarily for researchers,^31,32 their correct use should be incorporated into clinical medicine.

Figure 3.

Diagram showing the domains through which sex and gender impact respiratory disease. Sex and gender also interact with each other at various points of development, diagnosis, and management of respiratory diseases.

The Food and Drug Administration has required that both male and female animals be included in preclinical studies for decades. After decades of underrepresentation of women in research studies, the National Institutes of Health now requires the consideration of sex as a biological variable when designing research studies on human subjects and vertebrate animals. However, many published methods sections do not distinguish the sex of animals or do not combine sexes without distinguishing differences in male and female responses. In 2018, an National Institutes of Health expert panel reported on the importance of an increased understanding of biological, pathophysiologic, and behavioral mechanisms underlying sex and gender differences in lung and sleep health and disease, which can lead to better health.³³ The panel also identified key areas for future research. In this review, although we advocate the use of the correct use of sex and gender when discussing data from the existing literature, we used the same terminology used in the published manuscripts, even when terminology was used incorrectly, to avoid misrepresenting the cited studies. Many of the studies assume that biological sex is the same as the gender with which an individual identifies.

COPD

COPD is no longer only a disease of men. Unfortunately, a survey of 368 physicians in 2017 suggested a persistent gap in knowledge about the prevalence of COPD in women.³⁴ Although mortality rates for COPD overall have been trending down, rates are not falling as rapidly in women as compared with men. Between 2005 and 2014, women accounted for a higher proportion of COPD hospitalizations and in-hospital deaths at all time points examined.³⁵ A recent study found that women with COPD have lower diffusion capacity of the lung for carbon monoxide values, despite a higher FEV₁ percent predicted as compared with men. In addition, women with COPD showed a steeper annual decline in diffusion capacity of the lung for carbon monoxide.³⁶

COPD in women may be underdiagnosed. Reasons for underdiagnosis or a delay in diagnosis may be lack of a formal evaluation with spirometry,⁶ women seeking care later in the course of disease, physician bias, or associated fatigue or depression misdirecting diagnostic strategies.⁷ Underdiagnosis may be associated with psychological distress and worse health-related quality of life.³⁷

The increase in smoking rates for women in the 1960s and 1970s often has been cited as the reason for the global increase in COPD rates in women. However, larger pulmonary function impairment for the same level of tobacco exposure in female smokers compared with male smokers¹¹ and higher exposure to biomass fuels in women in developing countries³⁸ may be responsible. For the same amount of exposure to tobacco smoke, women are likely to demonstrate more severe airflow limitation at an earlier age than men and to experience more exacerbations.¹² Currently, the reasons why women differ from men in cigarette smoke susceptibility largely are unknown. Higher levels of cigarette smoke metabolites, such as polycyclic aromatic hydrocarbon adducts, have been found in lungs of female smokers compared with male smokers,³⁹ and increased small airways remodeling in female subjects in animal models may be important contributors.⁴⁰ Airways of women who smoke and have COPD exhibit higher wall area percentage, narrowed airway lumens, and thickened airway walls compared with those of men.⁴¹

Opportunities to understand better the sex- and gender-specific treatment outcomes in COPD have been missed, and guidance in offering tailored sex- or gender-focused pharmacologic treatment of COPD are lacking. A better understanding of biological differences in susceptibility and the COPD phenotype will lead to sex-specific therapeutic targets.

Asthma

Sex and gender differences in asthma are noted throughout the lifespan. During the teenage years, boys have a higher prevalence of asthma compared with girls, but women show a far higher prevalence compared with men.³ A gap in asthma mortality by sex remains, with a higher prevalence of deaths resulting from asthma in women.¹⁴

Women have a more severe asthma phenotype, tend to be overrepresented in severe asthma cohorts, and have higher health care use, hospitalizations, and ED visits.¹³ Obesity and gastroesophageal reflux are more common comorbidities in women, and women tend to have a non-type 2 endotype profile more often.¹³ Asthma frequently is underdiagnosed in women, and women with a diagnosis of asthma are less likely to receive therapy as compared with men.⁸ Women receive psychopharmaceuticals more frequently than men as compared with inhaled corticosteroids. Among patients with asthma who are never smokers and use inhaled corticosteroids, the increase in FEV₁ relative to vital capacity is significantly higher in men.⁴² In a study evaluating omalizumab efficacy, women demonstrated worse perception of asthma (Brief Illness Perception Questionnaire) at every visit and believed that the asthma they experienced was more symptomatic as compared with that of men. Despite having similar baseline severity and obtaining a similar level of control (Asthma Control Questionnaire), women experienced a greater impact on their quality of life.¹⁵

Asthma is the most common chronic respiratory disease in pregnancy, affecting 3% to 12% of women.⁴³ Maternal and fetal complication risk increases slightly with asthma, and these risks are magnified with uncontrolled asthma.⁴⁴ Asthma course during pregnancy can be variable, with about one-third of patients experiencing worsening.⁴⁵ Lack of adherence to controller medication use may contribute to clinical worsening.⁴⁶ Women seeking answers about the safety of these medications throughout pregnancy and breastfeeding need to be reassured by their health care providers. A treatment strategy that seeks to normalize fractional exhaled nitric oxide may be better than a symptom-guided approach for the health of the mother and the child.⁴⁷ Available safety profiles of budesonide, beclomethasone, and fluticasone propionate during pregnancy make them the preferred molecules.⁴⁸ In most cases, risk of disease outweighs the risk of medications.

Menopause transition may increase respiratory symptoms, and new-onset asthma may develop. Whether hormone replacement therapy increases the risk of new-onset asthma remains unclear.^16,49,50 However, in patients with established asthma, use of hormone replacement therapy was associated with increased risk of severe asthma exacerbations⁵¹ and an increased risk of hospital admission. These results demonstrate the need for prospective longitudinal studies to understand asthma characteristics better, such as lung function and underlying inflammation around menopause transition, menopause, and in relationship to hormonal therapy.

Lung Cancer

An epidemic of lung cancer in women is occurring globally. Once believed to be a disease of men, in 1987, lung cancer became the leading cause of cancer deaths in women in the United States. The World Health Organization estimated that nearly 600,000 women died of lung cancer globally in 2019.⁵² Cigarette smoking is the dominant risk factor for lung cancer in both men and women. This section highlights what is known about sex and gender differences in lung cancer, but a recent publication provides an in-depth review of the topic.⁵³

Lung cancer screening using low-dose CT imaging of the chest for early detection initially was recommended by the United States Preventive Services Task Force in 2013.⁵⁴ Based on new evidence, lung cancer screening is now recommended by the United States Preventive Services Task Force for individuals 50 to 80 years of age who have at least 20 pack-years of smoking and currently are smoking or quit within the previous 15 years.¹⁷ Although women were underrepresented in trials of low-dose CT imaging, results suggest that screening for lung cancer results in a larger mortality reduction for women compared with men.¹⁹

Whether women are more susceptible to the effects of carcinogens from tobacco use is a hypothesis that has received much attention and remains under investigation. Case control studies initially suggested that with the same exposure to tobacco, women showed a 1.5 to 2 times increased risk of lung cancer developing.¹⁸ Some studies suggest that lung cancer in women occurs at a younger age and with less cigarette exposure compared with men.⁵⁵ However, in prospective studies, incidence rates and hazard ratios of lung cancer were no different in women and men.⁵⁶ The hypothesis that women are more susceptible to the development of tobacco-related lung cancer remains unproven. A recent surgeon general report on the health consequences of smoking notes that studies addressing sex-associated differences in lung cancer risk are two to three decades old and were performed in older cohorts smoking cigarettes that have less lung cancer risk than those currently on the market.⁵⁷ Further research is needed in this area.

Lung cancers in never smokers are more common in women. This observation suggests that sex- and gender-related differences exist in carcinogenesis influenced by hormonal, genetic, and environmental factors. In the United States, approximately 15% to 20% of lung cancers in women occur in never smokers compared with 7% to 9% in men.²⁰ Globally, 53% of women and 15% of men with lung cancer are never smokers.⁵⁸ In addition, occupational and environmental exposure may vary by gender. Women are more likely to be exposed to smoke and byproducts of burning of coal or biomass fuels for heating and cooking. A meta-analysis examined the association of solid fuel use and lung cancer and found an increased risk in women (OR, 1.81; 95% CI, 1.54-2.12), but not in men (OR, 1.16; 95% CI, 0.79-1.69).⁵⁹

Studies have demonstrated better lung cancer outcomes in women compared with men. For every stage of cancer, survival rates for women are significantly higher than for men. This survival benefit was independent of race, stage, histologic findings, or treatment and was most marked in patients older than 50 years.^21,60

Lung cancer is the leading cancer killer among women. Sex- and gender-related differences likely exist, but more work needs to be done to understand the mechanisms of carcinogenesis, the factors that impact survival in women, and whether differential screening strategies should be performed.

Interstitial Lung Disease

Sex, sex hormones, and age may contribute to the development of several types of interstitial lung disease (ILD). Idiopathic pulmonary fibrosis (IPF) commonly is considered a male-predominant disease (1.5 to 2 times more frequent than in women).²² Men older than 65 years have the highest mortality and disease prevalence.⁶¹ Currently, IPF is considered a disease of aging because of the association of disease with a reduction in telomere length and premature grey hair color. Men tend to have a worse prognosis for IPF and other non-IPF ILDs, with lower transplant-free survival rates.⁶² Kawano-Dourado et al²³ reviewed studies using the gender, age, physiology score, highlighting that men have a worse prognosis in IPF and in non-IPF ILDs. Overall mortality rates of IPF for men were 1.63 times that of women in a review of US claims data.⁶³ However, women may have significantly lower risks of both ILD-related and non-ILD-related hospitalizations.⁶⁴ Current management includes antifibrotics that have not shown sex differences in response to treatment.

Familial forms of ILD that occur in patients with IPF can demonstrate mutations in telomere-related gene mutations. In these cases, men usually are younger than women (54 years vs 63 years, respectively) at diagnosis,⁶⁵ and the prevalence of ILD increases with age.⁶⁵ In a recent review, Kawano-Dourado et al²³ noted that telomere length was significantly shorter in diseased men, indicating that women may be protected from telomere shortening in a study of patients with familial pulmonary fibrosis.⁶⁶

In the United States, hypersensitivity pneumonitis (HP) predominately is a disease of women (58%).⁶⁷ However, more men demonstrate HP in other countries, including Denmark (57%).⁶⁸ Although many cases are associated with an occupational exposure, these cases are not associated by sex. Men seem more likely than women to demonstrate HP as a result of farming or metal-working fluid exposures.⁶⁹ Bird exposure accounts for most cases of HP in men and women.²⁴

Lymphangioleiomyomatosis is almost exclusively a disease of young women, although reports of postmenopausal lymphangioleiomyomatosis are increasing.²⁵ Estrogens are believed to play a pathogenic role in lymphangioleiomyomatosis because it is restricted almost exclusively to women; is exacerbated by exogenous estrogen use, including oral contraceptives; worsens with the onset of menses⁷⁰ or pregnancy⁷¹; and is less aggressive in postmenopausal women.²⁵ About 46% of women with tuberous sclerosis (TSC) are found to have lymphangioleiomyomatosis-like lesions in the lungs. Loss of heterozygosity among TSC genes in lesions of different organs in women with lymphangioleiomyomatosis is consistent with the tumor suppressor gene model.⁷² Men with TSC also have been reported to demonstrate lymphangioleiomyomatosis-like lesions.⁷³ The TSC mutations that occur in lymphangioleiomyomatosis result in inappropriate and constitutive signaling through the rapamycin pathway. The Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus trial showed that sirolimus, an mammalian target of rapamycin complex 1 inhibitor, stabilized lung function (FEV₁) decline.⁷⁴ Hormonal-related treatment methods lack efficacy and are not recommended in expert guidelines.⁷⁵

Connective tissue-related ILD (CTD-ILD) is reported more frequently in younger women and never smokers. CTD-ILD is reported more frequently in women with systemic lupus erythematosus, systemic sclerosis, and Sjögren’s disease, with the largest sex difference of 7:1 to 10:1 in systemic lupus erythematosus.²⁶ Rheumatoid arthritis-associated ILD is reported more often in men than women, with the more aggressive usual interstitial pneumonia pattern occurring more commonly in men.⁷⁶ In systemic sclerosis,⁷⁷ rheumatoid arthritis,⁷⁸ and autoimmune inflammatory myopathy,²⁷ men seem to be at increased risk for more rapid disease progression and increased mortality. In a single-center study of 243 patients with CTD-ILD, men experienced increased mortality across diseases.⁷⁹ Treatment of CTD-ILD in pregnancy is complicated by concerns for teratogenicity for some drugs.

Men have a higher risk of primary exposure to silica, asbestos, hard metals, and occupational exposures associated with the development of silicosis, asbestosis, coal workers’ pneumoconiosis, and berylliosis.⁸⁰ Secondary or indirect exposures associated with ILD including asbestos and second-hand smoke are noted more often in women.⁸¹ Although women also may have a greater exposure to biomass fuels for cooking, the impact of domestic pollution on risk of ILDs has not been well studied.⁸²

OSA

Over the past two decades, our knowledge and awareness of OSA in women has increased dramatically. Once thought to be a disease only of middle-aged men, OSA clearly is a disease that affects women of all ages, but diagnosis and treatment for it lags behind that of men. Women with the same symptoms receive a diagnosis and are treated for OSA less often than men, although the consequences of the disease are similar or worse for women.²⁸ Although OSA is known to be more common in men, prevalence studies have varied since women were included. In the mid 1990s, the prevalence of OSA (apnea hypopnea index, ≥ 5-10+ symptoms) was reported as 4% in men and 2% in women.⁸³ Using more current scoring and diagnostic criteria, the reported prevalence of OSA for women varies by age: 24% in those 20 to 44 years of age, 56% in those 45 to 54 years of age, and up to 75% in those 55 to 70 years of age.⁸⁴ A notable difference between men and women is that the prevalence of OSA increases with age in both genders, but the disease severity increases dramatically in women after 50 years of age.^{85, 86, 87, 88} In a recent study, the prevalence in men was 50%, that in premenopausal women was 9%, and that in postmenopausal women was 30%.⁸⁹ The rise in OSA prevalence after menopause is likely in part the result of hormonal changes and increasing central obesity associated with menopause, but this is not completely clear yet.

In pregnancy, a condition unique to the female sex, OSA prevalence is estimated to be 8.5% in the first trimester and up to 19.7% in the third,⁹⁰ and higher in high-risk pregnancies. OSA in pregnancy is underdiagnosed and undertreated because of poor screening by obstetricians. The usual screening pregnancy questionnaires have poor predictive ability.⁹¹ The Home Sleep Apnea Test is validated in pregnancy, but can underestimate the degree of sleep-disordered breathing. Untreated OSA in pregnancy is associated with increased prevalence of gestational diabetes, hypertension, and pre-eclampsia.⁹²

At every stage of the patient experience (disease presentation, screening questionnaires, diagnostic testing, and treatment), bias against women is evident. Women are underrepresented in sleep laboratory referrals. This may be because of underreporting of classic OSA symptoms such as snoring and sleepiness.⁹³ Women are less likely to snore and report sleepiness compared with men and are more likely to report fatigue and insomnia.⁸⁶ However, even when women reported the same symptoms suggestive of OSA as men, women were less likely to be referred for a sleep evaluation.²⁸ Screening questionnaires that typically are used to identify those at risk of OSA have gender discrepancies as well. In a study comparing four of the more common questionnaires—snoring, tired, observed apnea, pressure referring to blood pressure (STOP), snoring, tired, observed apnea, pressure, BMI, age, neck circumference, gender (STOP-BANG), the Epworth sleepiness scale, and the Berlin questionnaire—in a group of men and women matched for the severity of OSA, the Epworth sleepiness scale was similar in both genders, STOP-BANG identified more men, and the Berlin questionnaire showed the highest sensitivity in both genders.⁹⁴ Changing some of the scoring of STOP-BANG to a score ≥ 5 instead of 3 improved specificity for predicting OSA in women and men, and adjusting the BMI cutoff to ≥ 30 or 31 kg/m² better predicted OSA in women. This indicates that these questionnaires can be useful, but perhaps the scoring and cutoffs need to be adjusted to improve the ability to identify the risk of OSA in women.⁹⁵

Diagnostic testing such as polysomnography has shown that women are more likely to experience most respiratory events (apneas and hypopneas) in rapid eye movement sleep and to have milder overall OSA when compared with men, and this held true across racial and ethnic groups.⁹⁶ Other studies have shown that younger women with rapid eye movement OSA tended to be more obese and were more likely to have depression compared with older women with rapid eye movement OSA.⁸⁷ The diagnostic criteria for OSA for many years included symptoms such as sleepiness. Women are less likely to report sleepiness, and instead use words like fatigue and poor sleep, potentially preventing them from receiving adequate diagnosing.

Outcomes and comorbidities associated with OSA also vary. Women with OSA are more likely to have hypertension and depression, but men are more likely to have ischemic heart disease and type II diabetes.⁹⁷ For many years, the cardiovascular consequences of untreated OSA were thought to be more prevalent in men. However, recent studies reveal worse markers of heart injury (high-sensitivity troponin) in women and the oxygen desaturation index (a marker of sleep-disordered breathing) associated more with adverse cardiovascular outcomes in women when compared with men.^88,98 Although these studies need to be replicated, they suggest that women with untreated OSA may be at higher risk of adverse cardiovascular outcomes than reported previously.

Even after women with OSA are identified and receive a diagnosis, they continue to face different challenges than men. Women are more likely to have more arousals from sleep and a lower apnea hypopnea index than men.⁹⁹ One study used autotitrating positive airway pressure with an algorithm designed specifically for women and compared it with a standard algorithm. When changes such as increased sensitivity to airflow limitation and lower pressure rise were used, women showed better control of OSA.¹⁰⁰ Despite years of knowing that significant differences exist between men and women with regard to OSA, a dearth of data are available comparing treatments. Additionally, the studies on alternative treatments for OSA such as oral appliances, surgery, or the hypoglossal nerve stimulator include a paucity of women treated with them. To enhance our understanding of sex and gender differences in OSA, research should be directed at dissecting the patient experience and response to interventions and therapy.

Conclusions

Various aspects of lung and sleep biology and pathobiology are impacted by sex and reproductive transitions. Differential gene expression or organ development can be impacted by these biological differences. The currently available data essentially are from cis-gender individuals. The literature is severely lacking for individuals whose gender does not match their biological sex. Understanding these differences is the first step in moving toward precision medicine for both men and women. These clinical differences between men and women further emphasize the importance of prompt recognition of possible cases, suitable diagnostic procedures, accurate assessment of the severity of the disease, and appropriate treatment.