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There is growing evidence that a of pulmonary diseases affect women differently and with a greater degree of severity than men.

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The causes for such sex disparity is the focus of this Blue Conference Perspective review, which explores basic cellular and molecular mechanisms, life stages, and clinical outcomes based on environmental, sociocultural, occupational, and infectious scenarios, as well as medical health beliefs. Owing to the breadth of issues related to women and lung disease, we present examples of both basic and clinical concepts that may be the cause for pulmonary disease disparity in women.

These examples include those diseases that predominantly affect women, as well as the rising incidence among women for diseases traditionally occurring in men, such as chronic obstructive pulmonary disease. Sociocultural implications of pulmonary disease attributable to biomass burning and infectious diseases among women in low- to middle-income countries are reviewed, as are disparities in respiratory health among sexual minority women in high-income countries.

The implications of the use of complementary and alternative medicine by women to influence respiratory disease are examined, and future directions for research on women and respiratory health are provided. Some pulmonary diseases occur disproportionately or almost exclusively in women. These diseases may be underdiagnosed by clinicians, either due to their relative rarity or to clinical manifestations that mimic those seen with other respiratory diseases. One patient M. My story begins 31 years ago on the day I was ladies seeking sex stevens village with a profile of someone who has a spontaneous pneumothorax.

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I had several episodes of respiratory disease events that were not elucidated until a lung biopsy through bronchoscopy 19 years later confirmed the diagnosis of LAM, a disease almost exclusively found in women. My LAM remains in the high-moderate range, and I do not require oxygen unless I go to higher altitudes.

Fatigue is frequently a problem for those with LAM, but now that I am retired, I am better able to manage my issues with fatigue.

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My LAM has been managed appropriately, my progression has been very slow, and I continue to live a full and satisfying life. As a patient, I wish my disease had been diagnosed appropriately sooner. It is important that physicians are aware of this rare disease to help women like me manage their life accordingly.

Other respiratory conditions that impact women nearly exclusively include pulmonary hypertension 1catamenial diseases 2and pregnancy-associated asthma exacerbation 3. Although rare, bloody pleural effusions can occur with endometriosis or with ectopic endometrium in the chest during the menstrual cycle 2. There are more respiratory disorders common to women, such as autoimmune lung disease especially lupusthan men 1.

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The development and progression of certain common respiratory diseases has been found to differ by sex. One such disease is chronic obstructive pulmonary disease COPDwhich is now the third leading cause of death in the United States 4. The increased prevalence of COPD in women is believed due to changing smoking patterns and women taking on more traditional male occupations. However, growing evidence supports ificant sex-based differences in the disease 7. For example, of never-smokers who develop COPD, women are 1.

Women are also twice as likely to have COPD with the chronic bronchitis form rather than ladies seeking sex stevens village emphysema form as men 8. New research on sex differences in COPD development is focusing on hormonal aling and the immune system proteome 9 All people, regardless of sex, deserve a timely and correct diagnosis.

As more knowledge is gained about sex-specific symptoms of respiratory disease, it is hoped that the rate of misdiagnosis, such as occurred in the LAM story described above, will decrease. One North American study found that physicians presented with a clinical vignette suggestive of COPD were ificantly less likely to diagnose COPD when the patient was described as female compared with male A similar study found that differences in the rates of diagnosis disappeared when spirometry data were presented 12underscoring the importance of obtaining spirometry in patients with symptoms suggestive of COPD.

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Currently, only approximately one-third of patients with a diagnosis of COPD in the United States have undergone confirmatory spirometry Correct diagnosis and treatment is important to improve quality of life. Women with COPD report a lower frequency of phlegm production than men 14 but similar or higher frequency of cough and more severe dyspnea Increased rates of COPD exacerbations have also been documented in women in large clinical trials 15 — 17 ; however, it is unknown whether the increased rates are due to differences in reporting thresholds or disease biology.

Respiratory-related deaths in the TORCH study were the most frequent cause of death, and the causes of death were similarly distributed across both sexes. Basic differences in anatomy and physiology between men and women no doubt influence both the course of respiratory disease and response to treatment. A metaanalysis of 11 longitudinal studies suggests that women experienced a greater rate of lung function decline than men when adjusted for the amount ladies seeking sex stevens village tobacco smoked In the Lung Health Study, lung function decline in women who continued to smoke was more rapid than in men An important clinical question going forward with many respiratory diseases is whether men and women should be treated differently.

Nonetheless, smoking cessation products may differ in effectiveness based on sex. Researchers have recently shown that dopamine activation during smoking differs in women and men 22with men being more responsive to nicotine and women more responsive to the taste and sensory effects of smoking.

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This may be why the use of nicotine patches to quit smoking is more effective in men than women, whereas other non—nicotine-based pharmacologic therapies, including bupropion and varenicline, appear to be equally effective. Further research is needed to delineate optimal, sex-specific treatment approaches. Women may be protected from certain age-related biological processes by producing lower levels of reactive oxidant species, important drivers of pathology in age-related pulmonary disease 23and by having a slower rate of telomere shortening and longer telomeres than men 24 — One popular hypothesis is that the action of estrogen on an estrogen response element present in telomerase reverse transcriptase stimulates telomerase activity and the addition of telomere repeats to the ends of chromosomes The development and progression of the age-related diseases is dependent on mechanisms associated with cellular senescence that may be triggered by telomere shortening, which in women occurs at a slower rate than in men.

Does telomere shortening versus cigarette smoking affect the susceptibility of women to COPD? Sex ladies seeking sex stevens village in respiratory disease may also arise from early life exposures that occur in a broad window of time extending from lung growth and maturation during the fetal period through young adulthood 27 — Many stressors can impact lung development and lung disease, including indoor and outdoor air pollution, stress both anxiety and that associated with socioeconomic statusaccess to health care, genetics and epigenetics, and diet.

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Evaluations of the impact of environmental factors on respiratory disease often overlook everyday chemicals. These ubiquitous chemicals can impact respiratory health in unexpected ways The lung has hormone receptors that have been implicated in disease Furthermore, the lung plays a ificant role in xenobiotic metabolism, and many of these systems mature in the postnatal period. The lung has two primary routes of exposure to injurious compounds: via inhalation and via cardiac output and blood circulation.

Chemicals that can be metabolized and impact the respiratory tract differentially by sex and age include products of combustion, such as naphthalene 3233smoke 34vehicle exhaust—related air pollution 35and the ubiquitous component of plastics, bisphenol A BPA Early-life exposure to BPA is linked to both allergic sensitization and decrements in lung function, including wheeze, in children 303738 and alterations in fetal lung maturation in experimental animals More information is needed on how early exposure to ubiquitous chemicals like BPA affects the pulmonary health of women later in life.

These studies underscore several key points regarding environmental exposures and sex differences in lung disease: 1 there is a shifting steady state as the lung and individual grows and develops, 2 exposures can have both toxic and conditioning effects on the lung where exposure does not exhibit a phenotype at time of exposure but displays a phenotype when subsequently challenged, 3 the lag between exposure and health outcome can be substantial even multigenerationaland 4 interactions between exposures as well as cumulative effects from many exposures can be present.

Because these effects may differ by sex, it is critically important to include both sexes in research Women lead different lives than men. That intuitively obvious statement carries with it a sense of disparity in opportunity, whether one lives in New Ladies seeking sex stevens village City or in the most remote village on the planet. It may also indicate a health disparity based on differences in risk related to the roles of women in the household and within society.

Of course, the greatest source of ladies seeking sex stevens village disparity for either sex is the level of household income.

In the context of respiratory diseases, one global environmental exposure that has particular relevance for women is household ladies seeking sex stevens village pollution HAP that from indoor burning of solid fuels biomass and coal for cooking and heating. HAP exposure is associated with approximately 4 million deaths each year, predominantly from COPD, cardiovascular diseases, acute pneumonia in children under age 5 years, and lung cancer 41 The vast majority of HAP-related deaths and disabilities occur in low- and middle-income countries among those households living in severe poverty Women and children have the highest exposure to HAP due to their domestic roles Households typically have limited access to fuels, so wood, charcoal, animal dung, coal, or crop residues are used for cooking using either open fires or traditional unvented stoves.

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The daily breathing of filthy air that exceeds World Health Organization air quality standards by to fold has obvious health risks, as noted above. Women often have the domestic responsibility for cooking and for childcare, and are thus, along with children, particularly exposed to very unhealthy air to breathe.

Women and children are also at risk for two related injuries: 1 burns and scalds; and 2 sex-based violence, as women and children are often tasked with fuel gathering, miles from the safety of their villages and communities The good news is that cleaner cooking solutions, such as highly efficient cookstoves or effective ventilation of stoves by well-maintained chimneys, can ificantly ladies seeking sex stevens village household ladies seeking sex stevens village and save children from dying of acute pneumonia, as shown in a recently reported randomized controlled trial from Guatemala There is also an increasing global awareness of the challenge ahead and the need to improve and implement cleaner cooking solutions that are accepted by households and communities in the very different social and cultural settings around the world.

The scale of the problem is daunting, with a need to reach hundreds of millions of households and to find the best solutions and the best mechanisms to implement such strategies. The consensus-based research priorities to reduce the global burden of diseases from HAP and its burden on women and children are clear and many relate to the reduction of adverse respiratory outcomes Variability in diagnostic and treatment efficacy for tuberculosis TB in Kenya has been noted among HIV-positive and -negative pregnant women.

Biological differences based on sex

Reduction of TB transmission, morbidity, and mortality relies largely on intensified case finding, with early initiation of adequate treatment. Screening and diagnosis remains a challenge in resource-limited settings, especially among women due to pregnancy, poverty, and low levels of empowerment.

Diagnosing TB among pregnant women remains a challenge in Kenya. Kosgei and colleagues 47 found TB symptom screening questionnaires to be less useful than chest X-rays to identify TB suspects in both symptomatic and asymptomatic women.

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Physiological changes associated with pregnancy, as well as women living with HIV, may mask the symptoms of TB. These findings emphasize sex imbalances in resource-limited settings mostly biased toward women mainly due to socioeconomic and biologic factors, thus calling for a need to include sex in the core of TB management.

Even in high-income countries, disparities in respiratory risk and disease are documented among certain subpopulations of women, such as sexual minority women SMW. Nonsmoking SMW are also ificantly more likely to exhibit physiological evidence of secondhand smoke exposure These disparities arise from a multifactorial etiology.

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SMW experience minority stress or stress associated with being part of a stigmatized minority To cope, some SMW may adapt maladaptive behaviors, like smoking. In the case of asthma, minority stress likely also plays a direct role in disease pathophysiology 54 The tobacco industry actively targets sexual minorities, such as through in sexual minority media ladies seeking sex stevens village SMW often have limited access to health care due to a lack of health insurance and financial barriers 5558 In large part, these disparities stem from inequities in employer-sponsored health insurance for same-sex couples 63 Deficiencies in cultural competency among providers further impede the delivery of quality care to SMW.

Substantial proportions of SMW worry that there are not enough providers trained to work with sexual minorities, fear being treated differently if they disclose their sexual orientation, and express concern that their provider assumes them to be heterosexual 65 This discomfort can manifest in high rates of health care avoidance: one state survey found that approximately one-third of sexual minority individuals report not seeking health services because of their sexual orientation 65 ,