Review
It's all about sex: gender, lung development and lung disease

https://doi.org/10.1016/j.tem.2007.08.003Get rights and content

Accumulating evidence suggests that gender affects the incidence, susceptibility and severity of several lung diseases. Gender also influences lung development and physiology. Data from both human and animal studies indicate that sex hormones might contribute to disease pathogenesis or serve as protective factors, depending on the disease involved. In this review, the influence of gender and sex hormones on lung development and pathology will be discussed, with specific emphasis on pulmonary fibrosis, asthma and cancer.

Introduction

Lung disease kills over 349 000 Americans every year and more than 35 million Americans have chronic lung disease [American Lung Association (ALA) lung disease data 2006 (www.lungusa.org)]. Substantial epidemiological evidence suggests that gender affects the incidence, susceptibility and severity of several lung diseases. Many studies have addressed the role of hormones in the gender disparities of pulmonary conditions. Some studies point to developmental and physiological differences playing roles. We will first review evidence for gender differences in lung development and then address gender differences in the prevalence and severity of several lung diseases using data from both human and animal studies.

Section snippets

Lung development

Sex hormones appear to exert regulatory effects on human lung development before and during the neonatal period. The androgen receptor is expressed in mesenchymal and epithelial cells of the lung throughout the human lifespan [1], and branching morphogenesis of human lung might be regulated in part by androgens [1]. Estrogen receptors α and β (ERα and ERβ) are also expressed in human lung [2]. Gender differences are also manifested in the expression of key genes. For example, surfactant

Interstitial lung diseases and idiopathic pulmonary arterial hypertension

There are gender differences in the prevalence of interstitial lung diseases. Idiopathic pulmonary fibrosis (see Glossary) is more prevalent in men than in women 14, 15 (Figure 1a), but whether this difference is directly due to or modified by sex hormone effects is unclear. Lymphangiomyomatosis (LAM) is a rare pulmonary condition primarily affecting young women of childbearing age [16]. Various anti-estrogen strategies have been used in the treatment of LAM and, currently, progesterone is the

Asthma

Evidence from several studies suggests a role for sex hormones in the pathogenesis of asthma. Among the general population, asthma prevalence is higher in women than in men [27]. However, several clinical studies point to distinctive changes in the prevalence and severity of asthma with age. Male children have asthma more frequently than do female children 28, 29. However, in and around the time of puberty, there is a reversal of this incidence leading to a female predominance [29]. Later in

Lung cancer

While lung cancer mortality in men appears to have reached a plateau, the mortality rate in women has increased considerably in the past 30 years, increasing fourfold since 1970 [55]. However, rates of diagnoses and deaths from lung cancer are still greater in men than in women (Figure 1c). Although cigarette smoking is certainly the primary cause of lung cancer, an estimated 15 000 lung cancer deaths per year occur in individuals who have never smoked [56]. Among these individuals who have

Summary

Gender plays a major role in both the healthy and diseased lung from very early life onwards. As summarized in Figure 2, sex hormones exert regulatory effects on lung development, physiology and pathology. Gender also affects airway inflammation and the prevalence and severity of many major lung diseases including pulmonary fibrosis, asthma and lung cancer (Figure 2). The gender differences discussed in this review highlight the importance of considering sex hormones in the prevention,

Acknowledgements

The authors would like to thank Drs Michael Fessler and Patricia Chulada for helpful comments during the preparation of this manuscript. This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. J.W.C. is the recipient of a Senior Research Training Fellowship from the American Lung Association of North Carolina.

Glossary

Airway hyperresponsiveness
an increased sensitivity of the airways to an inhaled constrictor agonist and a characteristic feature of asthma
Bleomycin
an antibiotic produced by the bacterium Streptomyces verticillus used as an anti–cancer agent. The most serious complication of bleomycin is pulmonary fibrosis. It is used to induce experimental fibrosis in laboratory animals.
COPD
chronic obstructive pulmonary disease (COPD) is a group of diseases characterized by limitation of airflow that is not

References (70)

  • S.A. Nadji

    Relationship between lung cancer and human papillomavirus in north of Iran, Mazandaran province

    Cancer Lett

    (2007)
  • Y.W. Cheng

    Gender difference in human papillomarvirus infection for non–small cell lung cancer in Taiwan

    Lung Cancer

    (2004)
  • Y. Kimura

    Expression of androgen receptor and 5alpha-reductase types 1 and 2 in early gestation fetal lung: a possible correlation with branching morphogenesis

    Clin. Sci. (Lond.)

    (2003)
  • B. Fleisher

    Lung profile: sex differences in normal pregnancy

    Obstet. Gynecol.

    (1985)
  • C.F. Doershuk

    Specific airway resistance from the perinatal period into adulthood. Alterations in childhood pulmonary disease

    Am. Rev. Respir. Dis.

    (1974)
  • R.H. Perelman

    Discordance between male and female deaths due to the respiratory distress syndrome

    Pediatrics

    (1986)
  • W.M. Thurlbeck

    Postnatal human lung growth

    Thorax

    (1982)
  • V. Hoffstein

    Relationship between lung volume, maximal expiratory flow, forced expiratory volume in one second, and tracheal area in normal men and women

    Am. Rev. Respir. Dis.

    (1986)
  • T.R. Martin

    Airway size is related to sex but not lung size in normal adults

    J. Appl. Physiol.

    (1987)
  • M.A. Carey

    The impact of sex and sex hormones on lung physiology and disease: lessons from animal studies

    Am. J. Physiol Lung Cel. Mol. Physiol.

    (2007)
  • C.E. Dammann

    Androgen regulation of signaling pathways in late fetal mouse lung development

    Endocrinology

    (2000)
  • G.D. Massaro

    Sexual dimorphism in the architecture of the lung's gas-exchange region

    Proc. Natl Acad. Sci. U. S. A.

    (1995)
  • D. Massaro et al.

    Estrogen receptor regulation of pulmonary alveolar dimensions: alveolar sexual dimorphism in mice

    Am. J. Physiol. Lung Cell. Mol. Physiol.

    (2006)
  • C. Patrone

    Regulation of postnatal lung development and homeostasis by estrogen receptor beta

    Mol. Cell. Biol.

    (2003)
  • J. Gribbin

    The incidence and mortality of idiopathic pulmonary fibrosis and sarcoidosis in the UK

    Thorax

    (2006)
  • A.L. Olson

    Mortality from pulmonary fibrosis increased in the United States from 1992 to 2003

    Am. J. Respir. Crit. Care Med.

    (2007)
  • (1999) NHLBI Workshop Summary. Report of workshop on lymphangioleiomyomatosis.national heart, lung, and blood...
  • S.R. Johnson

    Lymphangioleiomyomatosis

    Eur. Respir. J.

    (2006)
  • A.B. Varkey

    Chronic obstructive pulmonary disease in women: exploring gender differences

    Curr. Opin. Pulm. Med.

    (2004)
  • S.S. Birring

    Clinical, radiologic, and induced sputum features of chronic obstructive pulmonary disease in nonsmokers: a descriptive study

    Am. J. Respir. Crit. Care Med.

    (2002)
  • D. Gu

    Cigarette smoking and exposure to environmental tobacco smoke in China: the international collaborative study of cardiovascular disease in Asia

    Am. J. Public Health

    (2004)
  • S.H. Jee

    Effects of husbands’ smoking on the incidence of lung cancer in Korean women

    Int. J. Epidemiol.

    (1999)
  • A.M. Hackman et al.

    Pharmacotherapy for idiopathic pulmonary arterial hypertension during the past 25 years

    Pharmacotherapy

    (2006)
  • A.M. Smith

    The influence of sex hormones on pulmonary vascular reactivity: possible vasodilator therapies for the treatment of pulmonary hypertension

    Curr. Vasc. Pharmacol.

    (2006)
  • T.H. March

    Modulators of cigarette smoke-induced pulmonary emphysema in A/J mice

    Toxicol. Sci.

    (2006)
  • Cited by (316)

    • Sex specificity in neonatal diseases

      2023, Principles of Gender-Specific Medicine: Sex and Gender-Specific Biology in the Postgenomic Era
    View all citing articles on Scopus
    View full text