Volume 124, Issue 4, Pages 688-690 (October 2009)

20 of 57

FULL TEXT

FULL-TEXT PDF (87 KB)

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

Received 17 August 2009; accepted 18 August 2009.

Refers to article:

Phenotypic determinants of uncontrolled asthma , 10 August 2009
Valérie Siroux, Anne Boudier, Jean Bousquet, Jean-Louis Bresson, Jean-Luc Cracowski, Joane Ferran, Frédéric Gormand, Jocelyne Just, Nicole Le Moual, Sophie Morange, Rachel Nadif, Marie-Pierre Oryszczyn, Christophe Pison, Pierre Scheinmann, Raphaëlle Varraso, Daniel Vervloet, Isabelle Pin, Francine Kauffmann, Epidemiological Study on the Genetics and Environment of Asthma
The Journal of Allergy and Clinical Immunology
October 2009 (Vol. 124, Issue 4, Pages 681-687.e3)
Abstract | Full Text | Full-Text PDF (333 KB)

Key words: Sex, gender, asthma, allergy, chronic obstructive pulmonary disease, steroid, inhaled steroid, corticosteroid, glucocorticoid, steroid resistance

Article Outline

• References

• Copyright

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.1 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 dimorphism2 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 Guidelines3 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.4 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 COPD5 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.6 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,1 variable participant compliance or dosage may have influenced symptom responsiveness.

Nevertheless, most7, 8, 9, 10 but not all11 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,1 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,12 medication compliance,13 treatment of women by physicians, stress,14 home allergens, smoke exposure, and/or home cooking exposures.

Much has been written about the molecular basis for steroid resistance,15 and an exhaustive review is beyond the scope of this editorial. Suggested mechanisms include decreased expression or binding affinity of the glucocorticoid receptor,16 increased phosphorylation of the glucocorticoid receptor,17 dysregulation of the transcription factor activator protein 1 (AP-1),18 reduction and activity of histone deacetylase 2,19, 20 and vitamin D3 deficiency resulting in diminished IL-10 production from T-regulatory cells.21 Additional epidemiologic associations with steroid resistance include cigarette smoking22 (which can reduce histone deacetylase 2 expression)23, 24 and obesity25 (which may operate through the mitogen-activated protein kinase pathway).26

There is little doubt that sex has a major impact on age-associated asthma prevalence27, 28 and asthma severity.29, 30 Sex appears to influence the heritability of and genetic susceptibility to asthma-related intermediate phenotypes like IgE.31, 32 Life cycle hormonal changes have been posited to be partially responsible for some of these sex differences,33, 34 and sex and life cycle–specific changes in glucocorticoid and estrogen metabolism may represent pathways influencing sex-specific asthma expression and steroid responsiveness.35 The degree of glucocorticoid receptor expression has been shown to be sex-dependent in some human studies,36, 37 consistent with findings suggesting that glucocorticoid responsiveness differs by sex in rodents.38, 39 Although vitamin D levels have been shown to be lower in female subjects than in male subjects in the general population,40 this has not been demonstrated in patients with asthma.41 However, sex has been shown influence the numbers of IL-10–producing T-regulatory cells, with female subjects having lower counts.42 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.43 The correlation with obesity and asthma per se has been noted to be stronger among female subjects than male subjects.44, 45, 46, 47 In addition, evidence shows that 17B-estradiol can regulate the mitogen-activated protein kinase pathway in some cell types in female rats only.48

The molecular, physiologic, and radiologic evidence for sex differences in COPD expression, and in responsiveness to steroids in COPD, is less consistent.49, 50 Although female subjects do not typically exhibit increased smoking behavior compared with men, the pathophysiologic response to smoking may differ.51, 52 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.51, 53, 54 Early-onset severe COPD may be female-predominant.55

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

1. 1Siroux 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. Abstract | Full Text | Full-Text PDF (332 KB) | CrossRef

2. 2Ober C, Loisel DA, Gilad Y. Sex-specific genetic architecture of human disease. Nat Rev Genet. 2008;9:911–922. CrossRef

3. 3Bousquet J. Global initiative for asthma (GINA) and its objectives. Clin Exp Allergy. 2000;30(suppl 1):2–5. CrossRef

4. 4Schatz M, Kosinski M, Yarias AS, Hanlon J, Watson ME, Jhingran P. The minimally important difference of the Asthma Control Test. J Allergy Clin Immunol. 2009;124:719–723. Abstract | Full Text | Full-Text PDF (400 KB) | CrossRef

5. 5Panhuysen CI, Bleecker ER, Koeter GH, Meyers DA, Postma DS. 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.

6. 6Barnes PJ, Greening AP, Crompton GK. Glucocorticoid resistance in asthma. Am J Respir Crit Care Med. 1995;152:S125–S140.

7. 7Convery RP, Leitch DN, Bromly C, Ward RJ, Bartlett G, Hendrick DJ. Effect of inhaled fluticasone propionate on airway responsiveness in treatment-naive individuals—a lesser benefit in females. Eur Respir J. 2000;15:19–24. MEDLINE | CrossRef

8. 8Dijkstra A, Vonk JM, Jongepier H, Koppelman GH, Schouten JP, ten Hacken NH, et al. Lung function decline in asthma: association with inhaled corticosteroids, smoking and sex. Thorax. 2006;61:105–110. MEDLINE | CrossRef

9. 9The 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. MEDLINE | CrossRef

10. 10Bacharier LB, Guilbert TW, Zeiger RS, Strunk RC, Morgan WJ, Lemanske RF, 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. Abstract | Full Text | Full-Text PDF (128 KB) | CrossRef

11. 11Rogers AJ, Tantisira KG, Fuhlbrigge AL, Litonjua AA, Lasky-Su JA, Szefler SJ, et al. Predictors of poor response during asthma therapy differ with definition of outcome. Pharmacogenomics. 2009;10:1231–1242. CrossRef

12. 12Redline S, Gold D. Challenges in interpreting gender differences in asthma. Am J Respir Crit Care Med. 1994;150:1219–1221.

13. 13Gamble J, Stevenson M, McClean E, Heaney LG. The prevalence of non-adherence in difficult asthma. Am J Respir Crit Care Med. 2009 July 30;[Epub ahead of print].

14. 14Wright RJ. Stress and acquired glucocorticoid resistance: a relationship hanging in the balance. J Allergy Clin Immunol. 2009;123:831–832. Full Text | Full-Text PDF (60 KB) | CrossRef

15. 15Barnes PJ, Adcock IM. Glucocorticoid resistance in inflammatory diseases. Lancet. 2009;373:1905–1917. Abstract | Full Text | Full-Text PDF (429 KB) | CrossRef

16. 16Sher ER, Leung DY, Surs W, Kam JC, Zieg G, Kamada AK, et al. Steroid-resistant asthma: cellular mechanisms contributing to inadequate response to glucocorticoid therapy. J Clin Invest. 1994;93:33–39. MEDLINE | CrossRef

17. 17Irusen E, Matthews JG, Takahashi A, Barnes PJ, Chung KF, Adcock IM. 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. Abstract | Full Text | Full-Text PDF (228 KB) | CrossRef

18. 18Loke TK, Mallett KH, Ratoff J, O'Connor BJ, 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. Abstract | Full Text | Full-Text PDF (254 KB) | CrossRef

19. 19Barnes PJ, Ito K, Adcock IM. Corticosteroid resistance in chronic obstructive pulmonary disease: inactivation of histone deacetylase. Lancet. 2004;363:731–733. Abstract | Full Text | Full-Text PDF (91 KB) | CrossRef

20. 20Ito K, Yamamura S, Essilfie-Quaye S, Cosio B, Ito M, Barnes PJ, et al. Histone deacetylase 2-mediated deacetylation of the glucocorticoid receptor enables NF-kappaB suppression. J Exp Med. 2006;203:7–13. MEDLINE | CrossRef

21. 21Xystrakis E, Kusumakar S, Boswell S, Peek E, Urry Z, Richards DF, 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. MEDLINE | CrossRef

22. 22Chaudhuri R, Livingston E, McMahon AD, Thomson L, Borland W, Thomson NC. Cigarette smoking impairs the therapeutic response to oral corticosteroids in chronic asthma. Am J Respir Crit Care Med. 2003;168:1308–1311. CrossRef

23. 23Ito K, Lim S, Caramori G, Chung KF, Barnes PJ, Adcock IM. Cigarette smoking reduces histone deacetylase 2 expression, enhances cytokine expression, and inhibits glucocorticoid actions in alveolar macrophages. FASEB J. 2001;15:1110–1112. MEDLINE

24. 24Adenuga D, Yao H, March TH, 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. CrossRef

25. 25Sutherland ER, Lehman EB, Teodorescu M, Wechsler ME. Body mass index and phenotype in subjects with mild-to-moderate persistent asthma. J Allergy Clin Immunol. 2009;123:1328–1334. Abstract | Full Text | Full-Text PDF (133 KB) | CrossRef

26. 26Sutherland ER, Goleva E, Strand M, Beuther DA, Leung DY. Body mass and glucocorticoid response in asthma. Am J Respir Crit Care Med. 2008;178:682–687. CrossRef

27. 27Almqvist C, Worm M, Leynaert B. Impact of gender on asthma in childhood and adolescence: a GA2LEN review. Allergy. 2008;63:47–57.

28. 28Current 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.

29. 29Sears MR, Greene JM, Willan AR, Wiecek EM, Taylor DR, Flannery EM, et al. A longitudinal, population-based, cohort study of childhood asthma followed to adulthood. N Engl J Med. 2003;349:1414–1422. CrossRef

30. 30Tantisira KG, Colvin R, Tonascia J, Strunk RC, Weiss ST, Fuhlbrigge AL. Airway responsiveness in mild to moderate childhood asthma: sex influences on the natural history. Am J Respir Crit Care Med. 2008;178:325–331. CrossRef

31. 31Hunninghake GM, Lasky-Su J, Soto-Quiros ME, Avila L, Liang C, Lake SL, 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. CrossRef

32. 32Raby BA, Soto-Quiros ME, Avila L, Lake SL, 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. MEDLINE | CrossRef

33. 33Weiss S, Speizer FE. Bronchial asthma mechanisms and therapeutics. 3rd ed.. Boston: Little, Brown; 1993;.

34. 34Farha S, Asosingh K, Laskowski D, Hammel J, Dweik RA, Wiedemann HP, 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. CrossRef

35. 35Troisi RJ, Speizer FE, Willett WC, 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.

36. 36Tsai BS, Watt G, Koesnadi K, Townley RG. Lymphocyte glucocorticoid receptors in asthmatic and control subjects. Clin Allergy. 1984;14:363–371. MEDLINE

37. 37Joyner JM, Hutley LJ, Cameron DP. Glucocorticoid receptors in human preadipocytes: regional and gender differences. J Endocrinol. 2000;166:145–152. MEDLINE | CrossRef

38. 38Kant GJ, Lenox RH, Bunnell BN, Mougey EH, Pennington LL, Meyerhoff JL. Comparison of stress response in male and female rats: pituitary cyclic AMP and plasma prolactin, growth hormone and corticosterone. Psychoneuroendocrinology. 1983;8:421–428. MEDLINE | CrossRef

39. 39Chisari A, Carino M, Perone M, Gaillard RC, Spinedi E. Sex and strain variability in the rat hypothalamo-pituitary-adrenal (HPA) axis function. J Endocrinol Invest. 1995;18:25–33. MEDLINE

40. 40Ginde AA, Liu MC, Camargo CA. Demographic differences and trends of vitamin D insufficiency in the US population, 1988-2004. Arch Intern Med. 2009;169:626–632. CrossRef

41. 41Brehm JM, Celedon JC, Soto-Quiros ME, Avila L, Hunninghake GM, 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. CrossRef

42. 42Jartti T, Burmeister KA, Seroogy CM, Jennens-Clough ML, Tisler CJ, Salazar LP, et al. Association between CD4(+)CD25(high) T cells and atopy in children. J Allergy Clin Immunol. 2007;120:177–183.

43. 43Itoh 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. MEDLINE

44. 44Seidell JC, de Groot LC, van Sonsbeek JL, Deurenberg P, Hautvast JG. Associations of moderate and severe overweight with self-reported illness and medical care in Dutch adults. Am J Public Health. 1986;76:264–269. MEDLINE | CrossRef

45. 45Shaheen SO, Sterne JA, Montgomery SM, Azima H. Birth weight, body mass index and asthma in young adults. Thorax. 1999;54:396–402. MEDLINE | CrossRef

46. 46Coogan PF, Palmer JR, O'Connor GT, Rosenberg L. Body mass index and asthma incidence in the Black Women's Health Study. J Allergy Clin Immunol. 2009;123:89–95. Abstract | Full Text | Full-Text PDF (148 KB) | CrossRef

47. 47Beckett WS, Jacobs DR, Yu X, Iribarren C, Williams OD. 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.

48. 48McMillan J, Fatehi-Sedeh S, Sylvia VL, Bingham V, Zhong M, Boyan BD, 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. MEDLINE

49. 49Watson L, Schouten JP, Lofdahl CG, Pride NB, Laitinen LA, Postma DS. Predictors of COPD symptoms: does the sex of the patient matter?. Eur Respir J. 2006;28:311–318. MEDLINE | CrossRef

50. 50Soriano JB, Sin DD, Zhang X, Camp PG, Anderson JA, Anthonisen NR, et al. A pooled analysis of FEV1 decline in COPD patients randomized to inhaled corticosteroids or placebo. Chest. 2007;131:682–689. MEDLINE | CrossRef

51. 51Martinez FJ, Curtis JL, Sciurba F, Mumford J, Giardino ND, Weinmann G, et al. Sex differences in severe pulmonary emphysema. Am J Respir Crit Care Med. 2007;176:243–252. CrossRef

52. 52Gan WQ, Man SF, Postma DS, Camp P, Sin DD. 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. CrossRef

53. 53Camp PG, Coxson HO, Levy RD, 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].

54. 54Kim WJ, Silverman EK, Hoffman E, Criner GJ, Mosenifar Z, Sciurba FC, et al. CT metrics of airway disease and emphysema in severe COPD. Chest. 2009;136:396–404. CrossRef

55. 55Silverman EK, Weiss ST, Drazen JM, Chapman HA, Carey V, Campbell EJ, et al. Gender-related differences in severe, early-onset chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2000;162:2152–2158.

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

Reprint requests: Diane R. Gold, MD, MPH, Channing Laboratory, 181 Longwood Ave, Boston, MA 02115-5804.

Disclosure of potential conflict of interest: D. R. Gold has received research support from the National Institutes of Health; G. M. Hunninghake has declared he has no conflicts of interest.

PII: S0091-6749(09)01312-8

doi:10.1016/j.jaci.2009.08.029

20 of 57