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Sexual dimorphism: Is it relevant to steroid resistance or asthma control?

  • Gary M. Hunninghake
    Affiliations
    Division of Pulmonary, Critical Care and Sleep Medicine, and Channing Laboratory, Department of Medicine, Brigham and Women's Hospital; and Harvard Medical School, Boston, Mass
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  • Diane R. Gold
    Correspondence
    Reprint requests: Diane R. Gold, MD, MPH, Channing Laboratory, 181 Longwood Ave, Boston, MA 02115-5804.
    Affiliations
    Division of Pulmonary, Critical Care and Sleep Medicine, and Channing Laboratory, Department of Medicine, Brigham and Women's Hospital; and Harvard Medical School, Boston, Mass
    Search for articles by this author

      Key words

      Suboptimal asthma control was more prevalent among inhaled corticosteroid users, particularly females from a population of 501 adult subjects with asthma evaluated in a cross-sectional French study published in this issue of the Journal.
      • Siroux V.
      • Boudier A.
      • Bousquet J.
      • Bresson J.-L.
      • Cracowski J.-L.
      • Ferran J.
      • et al.
      Phenotypic determinants of uncontrolled asthma.
      Optimal asthma control was not achieved in the majority of study participants. Although this study has limitations, its results challenge us to review the potential sources of corticosteroid resistance and to examine the evidence for sexual dimorphism
      • Ober C.
      • Loisel D.A.
      • Gilad Y.
      Sex-specific genetic architecture of human disease.
      in steroid responsiveness for asthma and chronic obstructive pulmonary disease (COPD). Limitations of the study include potential confounding by indication, less well validated measures of asthma control, and potential disease misclassification. Subjects with asthma with more persistent or severe symptoms were more likely to be prescribed inhaled corticosteroids (confounding by indication). Classification of asthma control using Global Initiative for Asthma Guidelines
      • Bousquet J.
      Global initiative for asthma (GINA) and its objectives.
      may not be as well validated an approach as the Asthma Control Test, a tool discussed in the article by Schatz et al that also appears in this issue of the Journal.
      • Schatz M.
      • Kosinski M.
      • Yarias A.S.
      • Hanlon J.
      • Watson M.E.
      • Jhingran P.
      The minimally important difference of the Asthma Control Test.
      In addition, the higher prevalence of cough and phlegm in patients with poorly controlled asthma on inhaled corticosteroids suggests possible disease misclassification or overlap of asthma with COPD
      • Panhuysen C.I.
      • Bleecker E.R.
      • Koeter G.H.
      • Meyers D.A.
      • Postma D.S.
      Characterization of obstructive airway disease in family members of probands with asthma: an algorithm for the diagnosis of asthma.
      in this population. Finally, this study did not formally assess its participants for steroid resistance. One definition used for asthma research requires a <15% increment in the FEV1 (percent of predicted value) after 2 weeks of treatment with 40 mg oral prednisolone, despite demonstrating a >15% reversibility to an inhaled β2-agonist.
      • Barnes P.J.
      • Greening A.P.
      • Crompton G.K.
      Glucocorticoid resistance in asthma.
      This may be too limiting in evaluating change in FEV1, in that a steroid response may occur even if the response to β2-agonists is suboptimal. In the study by Siroux et al,
      • Siroux V.
      • Boudier A.
      • Bousquet J.
      • Bresson J.-L.
      • Cracowski J.-L.
      • Ferran J.
      • et al.
      Phenotypic determinants of uncontrolled asthma.
      variable participant compliance or dosage may have influenced symptom responsiveness.
      Nevertheless, most
      • Convery R.P.
      • Leitch D.N.
      • Bromly C.
      • Ward R.J.
      • Bartlett G.
      • Hendrick D.J.
      Effect of inhaled fluticasone propionate on airway responsiveness in treatment-naive individuals—a lesser benefit in females.
      • Dijkstra A.
      • Vonk J.M.
      • Jongepier H.
      • Koppelman G.H.
      • Schouten J.P.
      • ten Hacken N.H.
      • et al.
      Lung function decline in asthma: association with inhaled corticosteroids, smoking and sex.
      The ENFUMOSA cross-sectional European multicentre study of the clinical phenotype of chronic severe asthma. European Network for Understanding Mechanisms of Severe Asthma.
      • Bacharier L.B.
      • Guilbert T.W.
      • Zeiger R.S.
      • Strunk R.C.
      • Morgan W.J.
      • Lemanske Jr., R.F.
      • et al.
      Patient characteristics associated with improved outcomes with use of an inhaled corticosteroid in preschool children at risk for asthma.
      but not all
      • Rogers A.J.
      • Tantisira K.G.
      • Fuhlbrigge A.L.
      • Litonjua A.A.
      • Lasky-Su J.A.
      • Szefler S.J.
      • et al.
      Predictors of poor response during asthma therapy differ with definition of outcome.
      previous reports agree with the findings of this French study, suggesting that female subjects with asthma may derive less benefit from inhaled steroids. In the study by Siroux et al,
      • Siroux V.
      • Boudier A.
      • Bousquet J.
      • Bresson J.-L.
      • Cracowski J.-L.
      • Ferran J.
      • et al.
      Phenotypic determinants of uncontrolled asthma.
      the reduced response to inhaled corticosteroids in females may have been a result of biologic/molecular differences between the sexes, or unmeasured gender differences in the technique of administration of inhalers,
      • Redline S.
      • Gold D.
      Challenges in interpreting gender differences in asthma.
      medication compliance,
      • Gamble J.
      • Stevenson M.
      • McClean E.
      • Heaney L.G.
      The prevalence of non-adherence in difficult asthma.
      treatment of women by physicians, stress,
      • Wright R.J.
      Stress and acquired glucocorticoid resistance: a relationship hanging in the balance.
      home allergens, smoke exposure, and/or home cooking exposures.
      Much has been written about the molecular basis for steroid resistance,
      • Barnes P.J.
      • Adcock I.M.
      Glucocorticoid resistance in inflammatory diseases.
      and an exhaustive review is beyond the scope of this editorial. Suggested mechanisms include decreased expression or binding affinity of the glucocorticoid receptor,
      • Sher E.R.
      • Leung D.Y.
      • Surs W.
      • Kam J.C.
      • Zieg G.
      • Kamada A.K.
      • et al.
      Steroid-resistant asthma: cellular mechanisms contributing to inadequate response to glucocorticoid therapy.
      increased phosphorylation of the glucocorticoid receptor,
      • Irusen E.
      • Matthews J.G.
      • Takahashi A.
      • Barnes P.J.
      • Chung K.F.
      • Adcock I.M.
      p38 Mitogen-activated protein kinase-induced glucocorticoid receptor phosphorylation reduces its activity: role in steroid-insensitive asthma.
      dysregulation of the transcription factor activator protein 1 (AP-1),
      • Loke T.K.
      • Mallett K.H.
      • Ratoff J.
      • O'Connor B.J.
      • Ying S.
      • Meng Q.
      • et al.
      Systemic glucocorticoid reduces bronchial mucosal activation of activator protein 1 components in glucocorticoid-sensitive but not glucocorticoid-resistant asthmatic patients.
      reduction and activity of histone deacetylase 2,
      • Barnes P.J.
      • Ito K.
      • Adcock I.M.
      Corticosteroid resistance in chronic obstructive pulmonary disease: inactivation of histone deacetylase.
      • Ito K.
      • Yamamura S.
      • Essilfie-Quaye S.
      • Cosio B.
      • Ito M.
      • Barnes P.J.
      • et al.
      Histone deacetylase 2-mediated deacetylation of the glucocorticoid receptor enables NF-kappaB suppression.
      and vitamin D3 deficiency resulting in diminished IL-10 production from T-regulatory cells.
      • Xystrakis E.
      • Kusumakar S.
      • Boswell S.
      • Peek E.
      • Urry Z.
      • Richards D.F.
      • et al.
      Reversing the defective induction of IL-10-secreting regulatory T cells in glucocorticoid-resistant asthma patients.
      Additional epidemiologic associations with steroid resistance include cigarette smoking
      • Chaudhuri R.
      • Livingston E.
      • McMahon A.D.
      • Thomson L.
      • Borland W.
      • Thomson N.C.
      Cigarette smoking impairs the therapeutic response to oral corticosteroids in chronic asthma.
      (which can reduce histone deacetylase 2 expression)
      • Ito K.
      • Lim S.
      • Caramori G.
      • Chung K.F.
      • Barnes P.J.
      • Adcock I.M.
      Cigarette smoking reduces histone deacetylase 2 expression, enhances cytokine expression, and inhibits glucocorticoid actions in alveolar macrophages.
      • Adenuga D.
      • Yao H.
      • March T.H.
      • Seagrave J.
      • Rahman I.
      Histone deacetylase 2 is phosphorylated, ubiquitinated, and degraded by cigarette smoke.
      and obesity
      • Sutherland E.R.
      • Lehman E.B.
      • Teodorescu M.
      • Wechsler M.E.
      Body mass index and phenotype in subjects with mild-to-moderate persistent asthma.
      (which may operate through the mitogen-activated protein kinase pathway).
      • Sutherland E.R.
      • Goleva E.
      • Strand M.
      • Beuther D.A.
      • Leung D.Y.
      Body mass and glucocorticoid response in asthma.
      There is little doubt that sex has a major impact on age-associated asthma prevalence
      • Almqvist C.
      • Worm M.
      • Leynaert B.
      Impact of gender on asthma in childhood and adolescence: a GA2LEN review.

      Current Asthma Prevalence Percents by Age, United States: National Health Interview Survey; 2006. Available from http://www.cdc.gov/asthma/nhis/06/table4-1.htm. Accessed September 2009.

      and asthma severity.
      • Sears M.R.
      • Greene J.M.
      • Willan A.R.
      • Wiecek E.M.
      • Taylor D.R.
      • Flannery E.M.
      • et al.
      A longitudinal, population-based, cohort study of childhood asthma followed to adulthood.
      • Tantisira K.G.
      • Colvin R.
      • Tonascia J.
      • Strunk R.C.
      • Weiss S.T.
      • Fuhlbrigge A.L.
      Airway responsiveness in mild to moderate childhood asthma: sex influences on the natural history.
      Sex appears to influence the heritability of and genetic susceptibility to asthma-related intermediate phenotypes like IgE.
      • Hunninghake G.M.
      • Lasky-Su J.
      • Soto-Quiros M.E.
      • Avila L.
      • Liang C.
      • Lake S.L.
      • et al.
      Sex-stratified linkage analysis identifies a female-specific locus for IgE to cockroach in Costa Ricans.
      • Raby B.A.
      • Soto-Quiros M.E.
      • Avila L.
      • Lake S.L.
      • Murphy A.
      • Liang C.
      • et al.
      Sex-specific linkage to total serum immunoglobulin E in families of children with asthma in Costa Rica.
      Life cycle hormonal changes have been posited to be partially responsible for some of these sex differences,
      • Weiss S.
      • Speizer F.E.
      Bronchial asthma mechanisms and therapeutics.
      • Farha S.
      • Asosingh K.
      • Laskowski D.
      • Hammel J.
      • Dweik R.A.
      • Wiedemann H.P.
      • et al.
      Effects of the menstrual cycle on lung function variables in women with asthma.
      and sex and life cycle–specific changes in glucocorticoid and estrogen metabolism may represent pathways influencing sex-specific asthma expression and steroid responsiveness.
      • Troisi R.J.
      • Speizer F.E.
      • Willett W.C.
      • Trichopoulos D.
      • Rosner B.
      Menopause, postmenopausal estrogen preparations, and the risk of adult-onset asthma: a prospective cohort study.
      The degree of glucocorticoid receptor expression has been shown to be sex-dependent in some human studies,
      • Tsai B.S.
      • Watt G.
      • Koesnadi K.
      • Townley R.G.
      Lymphocyte glucocorticoid receptors in asthmatic and control subjects.
      • Joyner J.M.
      • Hutley L.J.
      • Cameron D.P.
      Glucocorticoid receptors in human preadipocytes: regional and gender differences.
      consistent with findings suggesting that glucocorticoid responsiveness differs by sex in rodents.
      • Kant G.J.
      • Lenox R.H.
      • Bunnell B.N.
      • Mougey E.H.
      • Pennington L.L.
      • Meyerhoff J.L.
      Comparison of stress response in male and female rats: pituitary cyclic AMP and plasma prolactin, growth hormone and corticosterone.
      • Chisari A.
      • Carino M.
      • Perone M.
      • Gaillard R.C.
      • Spinedi E.
      Sex and strain variability in the rat hypothalamo-pituitary-adrenal (HPA) axis function.
      Although vitamin D levels have been shown to be lower in female subjects than in male subjects in the general population,
      • Ginde A.A.
      • Liu M.C.
      • Camargo Jr., C.A.
      Demographic differences and trends of vitamin D insufficiency in the US population, 1988-2004.
      this has not been demonstrated in patients with asthma.
      • Brehm J.M.
      • Celedon J.C.
      • Soto-Quiros M.E.
      • Avila L.
      • Hunninghake G.M.
      • Forno E.
      • et al.
      Serum vitamin D levels and markers of severity of childhood asthma in Costa Rica.
      However, sex has been shown influence the numbers of IL-10–producing T-regulatory cells, with female subjects having lower counts.
      • Jartti T.
      • Burmeister K.A.
      • Seroogy C.M.
      • Jennens-Clough M.L.
      • Tisler C.J.
      • Salazar L.P.
      • et al.
      Association between CD4(+)CD25(high) T cells and atopy in children.
      In addition, although little evidence links sex with histone deacetylase 2 expression specifically, histone deacetylase 2 binds to the estrogen receptor α, and 17B-estradiol results in its disassociation.
      • Itoh Y.
      • Hayashi H.
      • Miyazawa K.
      • Kojima S.
      • Akahoshi T.
      • Onozaki K.
      17beta-Estradiol induces IL-1alpha gene expression in rheumatoid fibroblast-like synovial cells through estrogen receptor alpha (ERalpha) and augmentation of transcriptional activity of Sp1 by dissociating histone deacetylase 2 from ERalpha.
      The correlation with obesity and asthma per se has been noted to be stronger among female subjects than male subjects.
      • Seidell J.C.
      • de Groot L.C.
      • van Sonsbeek J.L.
      • Deurenberg P.
      • Hautvast J.G.
      Associations of moderate and severe overweight with self-reported illness and medical care in Dutch adults.
      • Shaheen S.O.
      • Sterne J.A.
      • Montgomery S.M.
      • Azima H.
      Birth weight, body mass index and asthma in young adults.
      • Coogan P.F.
      • Palmer J.R.
      • O'Connor G.T.
      • Rosenberg L.
      Body mass index and asthma incidence in the Black Women's Health Study.
      • Beckett W.S.
      • Jacobs Jr., D.R.
      • Yu X.
      • Iribarren C.
      • Williams O.D.
      Asthma is associated with weight gain in females but not males, independent of physical activity.
      In addition, evidence shows that 17B-estradiol can regulate the mitogen-activated protein kinase pathway in some cell types in female rats only.
      • McMillan J.
      • Fatehi-Sedeh S.
      • Sylvia V.L.
      • Bingham V.
      • Zhong M.
      • Boyan B.D.
      • et al.
      Sex-specific regulation of growth plate chondrocytes by estrogen is via multiple MAP kinase signaling pathways.
      The molecular, physiologic, and radiologic evidence for sex differences in COPD expression, and in responsiveness to steroids in COPD, is less consistent.
      • Watson L.
      • Schouten J.P.
      • Lofdahl C.G.
      • Pride N.B.
      • Laitinen L.A.
      • Postma D.S.
      Predictors of COPD symptoms: does the sex of the patient matter?.
      • Soriano J.B.
      • Sin D.D.
      • Zhang X.
      • Camp P.G.
      • Anderson J.A.
      • Anthonisen N.R.
      • et al.
      A pooled analysis of FEV1 decline in COPD patients randomized to inhaled corticosteroids or placebo.
      Although female subjects do not typically exhibit increased smoking behavior compared with men, the pathophysiologic response to smoking may differ.
      • Martinez F.J.
      • Curtis J.L.
      • Sciurba F.
      • Mumford J.
      • Giardino N.D.
      • Weinmann G.
      • et al.
      Sex differences in severe pulmonary emphysema.
      • Gan W.Q.
      • Man S.F.
      • Postma D.S.
      • Camp P.
      • Sin D.D.
      Female smokers beyond the perimenopausal period are at increased risk of chronic obstructive pulmonary disease: a systematic review and meta-analysis.
      It has been posited that women respond to smoke exposure with more airway disease, and men with more emphysema, but the evidence for this is mixed.
      • Martinez F.J.
      • Curtis J.L.
      • Sciurba F.
      • Mumford J.
      • Giardino N.D.
      • Weinmann G.
      • et al.
      Sex differences in severe pulmonary emphysema.
      • Camp P.G.
      • Coxson H.O.
      • Levy R.D.
      • Pillai S.
      • Anderson W.
      • Vestbo J.
      • et al.
      Sex differences in emphysema and airway disease in smokers.
      • Kim W.J.
      • Silverman E.K.
      • Hoffman E.
      • Criner G.J.
      • Mosenifar Z.
      • Sciurba F.C.
      • et al.
      CT metrics of airway disease and emphysema in severe COPD.
      Early-onset severe COPD may be female-predominant.
      • Silverman E.K.
      • Weiss S.T.
      • Drazen J.M.
      • Chapman H.A.
      • Carey V.
      • Campbell E.J.
      • et al.
      Gender-related differences in severe, early-onset chronic obstructive pulmonary disease.
      Further research is needed to ascertain the relative importance of biology (sex) and behavior (gender) in explaining male:female differences in asthma or COPD, including differences in responsiveness to inhaled corticosteroids. Given the large numbers of patients with airways disease worldwide, therapies tailored to sexual dimorphism in response to diet or pharmacologic therapy could have a major impact.

      References

        • Siroux V.
        • Boudier A.
        • Bousquet J.
        • Bresson J.-L.
        • Cracowski J.-L.
        • Ferran J.
        • et al.
        Phenotypic determinants of uncontrolled asthma.
        J Allergy Clin Immunol. 2009; 124: 681-687
        • Ober C.
        • Loisel D.A.
        • Gilad Y.
        Sex-specific genetic architecture of human disease.
        Nat Rev Genet. 2008; 9: 911-922
        • Bousquet J.
        Global initiative for asthma (GINA) and its objectives.
        Clin Exp Allergy. 2000; 30: 2-5
        • Schatz M.
        • Kosinski M.
        • Yarias A.S.
        • Hanlon J.
        • Watson M.E.
        • Jhingran P.
        The minimally important difference of the Asthma Control Test.
        J Allergy Clin Immunol. 2009; 124: 719-723
        • Panhuysen C.I.
        • Bleecker E.R.
        • Koeter G.H.
        • Meyers D.A.
        • Postma D.S.
        Characterization of obstructive airway disease in family members of probands with asthma: an algorithm for the diagnosis of asthma.
        Am J Respir Crit Care Med. 1998; 157: 1734-1742
        • Barnes P.J.
        • Greening A.P.
        • Crompton G.K.
        Glucocorticoid resistance in asthma.
        Am J Respir Crit Care Med. 1995; 152: S125-S140
        • Convery R.P.
        • Leitch D.N.
        • Bromly C.
        • Ward R.J.
        • Bartlett G.
        • Hendrick D.J.
        Effect of inhaled fluticasone propionate on airway responsiveness in treatment-naive individuals—a lesser benefit in females.
        Eur Respir J. 2000; 15: 19-24
        • Dijkstra A.
        • Vonk J.M.
        • Jongepier H.
        • Koppelman G.H.
        • Schouten J.P.
        • ten Hacken N.H.
        • et al.
        Lung function decline in asthma: association with inhaled corticosteroids, smoking and sex.
        Thorax. 2006; 61: 105-110
      1. The ENFUMOSA cross-sectional European multicentre study of the clinical phenotype of chronic severe asthma. European Network for Understanding Mechanisms of Severe Asthma.
        Eur Respir J. 2003; 22: 470-477
        • Bacharier L.B.
        • Guilbert T.W.
        • Zeiger R.S.
        • Strunk R.C.
        • Morgan W.J.
        • Lemanske Jr., R.F.
        • et al.
        Patient characteristics associated with improved outcomes with use of an inhaled corticosteroid in preschool children at risk for asthma.
        J Allergy Clin Immunol. 2009; 123: 1077-1082
        • Rogers A.J.
        • Tantisira K.G.
        • Fuhlbrigge A.L.
        • Litonjua A.A.
        • Lasky-Su J.A.
        • Szefler S.J.
        • et al.
        Predictors of poor response during asthma therapy differ with definition of outcome.
        Pharmacogenomics. 2009; 10: 1231-1242
        • Redline S.
        • Gold D.
        Challenges in interpreting gender differences in asthma.
        Am J Respir Crit Care Med. 1994; 150: 1219-1221
        • Gamble J.
        • Stevenson M.
        • McClean E.
        • Heaney L.G.
        The prevalence of non-adherence in difficult asthma.
        Am J Respir Crit Care Med. 2009 July 30; ([Epub ahead of print])
        • Wright R.J.
        Stress and acquired glucocorticoid resistance: a relationship hanging in the balance.
        J Allergy Clin Immunol. 2009; 123: 831-832
        • Barnes P.J.
        • Adcock I.M.
        Glucocorticoid resistance in inflammatory diseases.
        Lancet. 2009; 373: 1905-1917
        • Sher E.R.
        • Leung D.Y.
        • Surs W.
        • Kam J.C.
        • Zieg G.
        • Kamada A.K.
        • et al.
        Steroid-resistant asthma: cellular mechanisms contributing to inadequate response to glucocorticoid therapy.
        J Clin Invest. 1994; 93: 33-39
        • Irusen E.
        • Matthews J.G.
        • Takahashi A.
        • Barnes P.J.
        • Chung K.F.
        • Adcock I.M.
        p38 Mitogen-activated protein kinase-induced glucocorticoid receptor phosphorylation reduces its activity: role in steroid-insensitive asthma.
        J Allergy Clin Immunol. 2002; 109: 649-657
        • Loke T.K.
        • Mallett K.H.
        • Ratoff J.
        • O'Connor B.J.
        • Ying S.
        • Meng Q.
        • et al.
        Systemic glucocorticoid reduces bronchial mucosal activation of activator protein 1 components in glucocorticoid-sensitive but not glucocorticoid-resistant asthmatic patients.
        J Allergy Clin Immunol. 2006; 118: 368-375
        • Barnes P.J.
        • Ito K.
        • Adcock I.M.
        Corticosteroid resistance in chronic obstructive pulmonary disease: inactivation of histone deacetylase.
        Lancet. 2004; 363: 731-733
        • Ito K.
        • Yamamura S.
        • Essilfie-Quaye S.
        • Cosio B.
        • Ito M.
        • Barnes P.J.
        • et al.
        Histone deacetylase 2-mediated deacetylation of the glucocorticoid receptor enables NF-kappaB suppression.
        J Exp Med. 2006; 203: 7-13
        • Xystrakis E.
        • Kusumakar S.
        • Boswell S.
        • Peek E.
        • Urry Z.
        • Richards D.F.
        • et al.
        Reversing the defective induction of IL-10-secreting regulatory T cells in glucocorticoid-resistant asthma patients.
        J Clin Invest. 2006; 116: 146-155
        • Chaudhuri R.
        • Livingston E.
        • McMahon A.D.
        • Thomson L.
        • Borland W.
        • Thomson N.C.
        Cigarette smoking impairs the therapeutic response to oral corticosteroids in chronic asthma.
        Am J Respir Crit Care Med. 2003; 168: 1308-1311
        • Ito K.
        • Lim S.
        • Caramori G.
        • Chung K.F.
        • Barnes P.J.
        • Adcock I.M.
        Cigarette smoking reduces histone deacetylase 2 expression, enhances cytokine expression, and inhibits glucocorticoid actions in alveolar macrophages.
        FASEB J. 2001; 15: 1110-1112
        • Adenuga D.
        • Yao H.
        • March T.H.
        • Seagrave J.
        • Rahman I.
        Histone deacetylase 2 is phosphorylated, ubiquitinated, and degraded by cigarette smoke.
        Am J Respir Cell Mol Biol. 2009; 40: 464-473
        • Sutherland E.R.
        • Lehman E.B.
        • Teodorescu M.
        • Wechsler M.E.
        Body mass index and phenotype in subjects with mild-to-moderate persistent asthma.
        J Allergy Clin Immunol. 2009; 123: 1328-1334
        • Sutherland E.R.
        • Goleva E.
        • Strand M.
        • Beuther D.A.
        • Leung D.Y.
        Body mass and glucocorticoid response in asthma.
        Am J Respir Crit Care Med. 2008; 178: 682-687
        • Almqvist C.
        • Worm M.
        • Leynaert B.
        Impact of gender on asthma in childhood and adolescence: a GA2LEN review.
        Allergy. 2008; 63: 47-57
      2. Current Asthma Prevalence Percents by Age, United States: National Health Interview Survey; 2006. Available from http://www.cdc.gov/asthma/nhis/06/table4-1.htm. Accessed September 2009.

        • Sears M.R.
        • Greene J.M.
        • Willan A.R.
        • Wiecek E.M.
        • Taylor D.R.
        • Flannery E.M.
        • et al.
        A longitudinal, population-based, cohort study of childhood asthma followed to adulthood.
        N Engl J Med. 2003; 349: 1414-1422
        • Tantisira K.G.
        • Colvin R.
        • Tonascia J.
        • Strunk R.C.
        • Weiss S.T.
        • Fuhlbrigge A.L.
        Airway responsiveness in mild to moderate childhood asthma: sex influences on the natural history.
        Am J Respir Crit Care Med. 2008; 178: 325-331
        • Hunninghake G.M.
        • Lasky-Su J.
        • Soto-Quiros M.E.
        • Avila L.
        • Liang C.
        • Lake S.L.
        • et al.
        Sex-stratified linkage analysis identifies a female-specific locus for IgE to cockroach in Costa Ricans.
        Am J Respir Crit Care Med. 2008; 177: 830-836
        • Raby B.A.
        • Soto-Quiros M.E.
        • Avila L.
        • Lake S.L.
        • Murphy A.
        • Liang C.
        • et al.
        Sex-specific linkage to total serum immunoglobulin E in families of children with asthma in Costa Rica.
        Hum Mol Genet. 2007; 16: 243-253
        • Weiss S.
        • Speizer F.E.
        Bronchial asthma mechanisms and therapeutics.
        3rd ed. Little, Brown, Boston1993
        • Farha S.
        • Asosingh K.
        • Laskowski D.
        • Hammel J.
        • Dweik R.A.
        • Wiedemann H.P.
        • et al.
        Effects of the menstrual cycle on lung function variables in women with asthma.
        Am J Respir Crit Care Med. 2009; 180: 304-310
        • Troisi R.J.
        • Speizer F.E.
        • Willett W.C.
        • Trichopoulos D.
        • Rosner B.
        Menopause, postmenopausal estrogen preparations, and the risk of adult-onset asthma: a prospective cohort study.
        Am J Respir Crit Care Med. 1995; 152: 1183-1188
        • Tsai B.S.
        • Watt G.
        • Koesnadi K.
        • Townley R.G.
        Lymphocyte glucocorticoid receptors in asthmatic and control subjects.
        Clin Allergy. 1984; 14: 363-371
        • Joyner J.M.
        • Hutley L.J.
        • Cameron D.P.
        Glucocorticoid receptors in human preadipocytes: regional and gender differences.
        J Endocrinol. 2000; 166: 145-152
        • Kant G.J.
        • Lenox R.H.
        • Bunnell B.N.
        • Mougey E.H.
        • Pennington L.L.
        • Meyerhoff J.L.
        Comparison of stress response in male and female rats: pituitary cyclic AMP and plasma prolactin, growth hormone and corticosterone.
        Psychoneuroendocrinology. 1983; 8: 421-428
        • Chisari A.
        • Carino M.
        • Perone M.
        • Gaillard R.C.
        • Spinedi E.
        Sex and strain variability in the rat hypothalamo-pituitary-adrenal (HPA) axis function.
        J Endocrinol Invest. 1995; 18: 25-33
        • Ginde A.A.
        • Liu M.C.
        • Camargo Jr., C.A.
        Demographic differences and trends of vitamin D insufficiency in the US population, 1988-2004.
        Arch Intern Med. 2009; 169: 626-632
        • Brehm J.M.
        • Celedon J.C.
        • Soto-Quiros M.E.
        • Avila L.
        • Hunninghake G.M.
        • Forno E.
        • et al.
        Serum vitamin D levels and markers of severity of childhood asthma in Costa Rica.
        Am J Respir Crit Care Med. 2009; 179: 765-771
        • Jartti T.
        • Burmeister K.A.
        • Seroogy C.M.
        • Jennens-Clough M.L.
        • Tisler C.J.
        • Salazar L.P.
        • et al.
        Association between CD4(+)CD25(high) T cells and atopy in children.
        J Allergy Clin Immunol. 2007; 120: 177-183
        • Itoh Y.
        • Hayashi H.
        • Miyazawa K.
        • Kojima S.
        • Akahoshi T.
        • Onozaki K.
        17beta-Estradiol induces IL-1alpha gene expression in rheumatoid fibroblast-like synovial cells through estrogen receptor alpha (ERalpha) and augmentation of transcriptional activity of Sp1 by dissociating histone deacetylase 2 from ERalpha.
        J Immunol. 2007; 178: 3059-3066
        • Seidell J.C.
        • de Groot L.C.
        • van Sonsbeek J.L.
        • Deurenberg P.
        • Hautvast J.G.
        Associations of moderate and severe overweight with self-reported illness and medical care in Dutch adults.
        Am J Public Health. 1986; 76: 264-269
        • Shaheen S.O.
        • Sterne J.A.
        • Montgomery S.M.
        • Azima H.
        Birth weight, body mass index and asthma in young adults.
        Thorax. 1999; 54: 396-402
        • Coogan P.F.
        • Palmer J.R.
        • O'Connor G.T.
        • Rosenberg L.
        Body mass index and asthma incidence in the Black Women's Health Study.
        J Allergy Clin Immunol. 2009; 123: 89-95
        • Beckett W.S.
        • Jacobs Jr., D.R.
        • Yu X.
        • Iribarren C.
        • Williams O.D.
        Asthma is associated with weight gain in females but not males, independent of physical activity.
        Am J Respir Crit Care Med. 2001; 164: 2045-2050
        • McMillan J.
        • Fatehi-Sedeh S.
        • Sylvia V.L.
        • Bingham V.
        • Zhong M.
        • Boyan B.D.
        • et al.
        Sex-specific regulation of growth plate chondrocytes by estrogen is via multiple MAP kinase signaling pathways.
        Biochim Biophys Acta. 2006; 1763: 381-392
        • Watson L.
        • Schouten J.P.
        • Lofdahl C.G.
        • Pride N.B.
        • Laitinen L.A.
        • Postma D.S.
        Predictors of COPD symptoms: does the sex of the patient matter?.
        Eur Respir J. 2006; 28: 311-318
        • Soriano J.B.
        • Sin D.D.
        • Zhang X.
        • Camp P.G.
        • Anderson J.A.
        • Anthonisen N.R.
        • et al.
        A pooled analysis of FEV1 decline in COPD patients randomized to inhaled corticosteroids or placebo.
        Chest. 2007; 131: 682-689
        • Martinez F.J.
        • Curtis J.L.
        • Sciurba F.
        • Mumford J.
        • Giardino N.D.
        • Weinmann G.
        • et al.
        Sex differences in severe pulmonary emphysema.
        Am J Respir Crit Care Med. 2007; 176: 243-252
        • Gan W.Q.
        • Man S.F.
        • Postma D.S.
        • Camp P.
        • Sin D.D.
        Female smokers beyond the perimenopausal period are at increased risk of chronic obstructive pulmonary disease: a systematic review and meta-analysis.
        Respir Res. 2006; 7: 52
        • Camp P.G.
        • Coxson H.O.
        • Levy R.D.
        • Pillai S.
        • Anderson W.
        • Vestbo J.
        • et al.
        Sex differences in emphysema and airway disease in smokers.
        Chest. 2009, July 17; ([Epub ahead of print])
        • Kim W.J.
        • Silverman E.K.
        • Hoffman E.
        • Criner G.J.
        • Mosenifar Z.
        • Sciurba F.C.
        • et al.
        CT metrics of airway disease and emphysema in severe COPD.
        Chest. 2009; 136: 396-404
        • Silverman E.K.
        • Weiss S.T.
        • Drazen J.M.
        • Chapman H.A.
        • Carey V.
        • Campbell E.J.
        • et al.
        Gender-related differences in severe, early-onset chronic obstructive pulmonary disease.
        Am J Respir Crit Care Med. 2000; 162: 2152-2158

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