Female Sex and Gender in Lung/Sleep Health and Disease. Increased Understanding of Basic Biological, Pathophysiological, and Behavioral Mechanisms Leading to Better Health for Female Patients with Lung Disease

Abstract

Female sex/gender is an undercharacterized variable in studies related to lung development and disease. Notwithstanding, many aspects of lung and sleep biology and pathobiology are impacted by female sex and female reproductive transitions. These may manifest as differential gene expression or peculiar organ development. Some conditions are more prevalent in women, such as asthma and insomnia, or, in the case of lymphangioleiomyomatosis, are seen almost exclusively in women. In other diseases, presentation differs, such as the higher frequency of exacerbations experienced by women with chronic obstructive pulmonary disease or greater cardiac morbidity among women with sleep-disordered breathing. Recent advances in -omics and behavioral science provide an opportunity to specifically address sex-based differences and explore research needs and opportunities that will elucidate biochemical pathways, thus enabling more targeted/personalized therapies. To explore the status of and opportunities for research in this area, the NHLBI, in partnership with the NIH Office of Research on Women's Health and the Office of Rare Diseases Research, convened a workshop of investigators in Bethesda, Maryland on September 18 and 19, 2017. At the workshop, the participants reviewed the current understanding of the biological, behavioral, and clinical implications of female sex and gender on lung and sleep health and disease, and formulated recommendations that address research gaps, with a view to achieving better health outcomes through more precise management of female patients with nonneoplastic lung disease. This report summarizes those discussions.

Role of Estrogen Receptors α and β in a Murine Model of Asthma: Exacerbated Airway Hyperresponsiveness and Remodeling in ERβ Knockout Mice

“…In addition, MA challenged mice of all three populations (WT, ERa KO, and ERb KO) showed a significant decline in lung function compared to respective PBS treated mice. Here, female mice exposed to MA in all three study populations showed prominent decline compared to males, which corroborates with clinical data suggesting increased severity of asthma in females (Weiss and Gold, 1995;de Marco et al, 2000;Melgert et al, 2005;Vink et al, 2010;Han et al, 2018). In addition, the severity of MA induced AHR and remodeling was found to be more pronounced in ERb KO mice compared to WT and ERa KO.…”

“…Airway mechanics were determined using the forced oscillation technique (FOT) of the FlexiVent Fx1 module, which is an invasive endpoint technique that delivers parameters like airway resistance (Rrs), compliance (Crs), elastance (Ers), tissue elasticity (H) and tissue damping (G), which together depict the overall lung function (Aravamudan et al, 2012;Ambhore et al, 2019a). Our study shows that ERb KO mice show deteriorated lung function compared to WT and ERa KO in both the genders at baseline, with prominent changes observed in females compared to males, which correlates with earlier clinical findings suggesting females are susceptible to asthma (Weiss and Gold, 1995;Angele et al, 2000;de Marco et al, 2000;Caracta, 2003;Melgert et al, 2005;Carey et al, 2007b;Matsubara et al, 2008;Takeda et al, 2013;Han et al, 2018). Interestingly, ERa KO mice of either sex showed no changes in lung function compared to WT mice at baseline, which can be attributed to the protective role of ERb or detrimental role of ERa in the airways, especially in ASM (Ambhore et al, 2018;Ambhore et al, 2019a).…”

“…Akin to clinical data, sex differences and sex steroids play a crucial role in the incidence and severity of asthma (Clough, 1993;Redline and Gold, 1994;Weiss and Gold, 1995;Caracta, 2003;Carey et al, 2007c;Card and Zeldin, 2009;Antunes et al, 2010;Woods et al, 2010;Townsend et al, 2012a;Bonds and Midoro-Horiuti, 2013;Sathish et al, 2015b;Sathish and Prakash, 2016). Considering the fact that women are more prone to the occurrence of asthma than men (de Marco et al, 2000;Melgert et al, 2005;Carey et al, 2007b;Matsubara et al, 2008;Vink et al, 2010;Dursun et al, 2014;Fuseini and Newcomb, 2017;Pignataro et al, 2017;Han et al, 2018), identifying the role of sex steroids, especially estrogen in airways might shed some light on the pathology of asthma.…”

Clinical trials for COVID-19 should include sex as a variable

“…As long as drug trials jci.org hypoxic patients by using a combination of noninvasive ventilatory support devices and patient positioning (20). As there are sex-based differences in lung physiology including airway caliber, lung volumes, diaphragmatic excursion, accessory muscle mechanics, and abdominal fat distribution (21), sex-disaggregated outcome data on different invasive and noninvasive ventilatory modalities are crucial, but have not been included in preliminary studies.…”

Obstructive sleep apnoea and exercise functional capacity: time to move?

“…The interesting data reported by MENDELSON et al [11] have been collected from previously published clinical studies and therefore reflect some limitations found commonly in clinical research. Indeed, as it is often seen in cardiovascular and OSA studies [17][18][19][20][21], women and the elderly were under-represented [11]. This limitation is relevant because previous research has shown that the association of OSA with significant reductions in quality of life scores is independent of sleepiness and comorbidities in men less than 69 years old, but not in men older than 70 years [15].…”