Sex Steroid Signaling in the Airway

  • Y. S. PrakashEmail author
  • Venkatachalem Sathish
  • Elizabeth A. Townsend


The influence of sex hormones (estrogen, progesterone, testosterone) in the biology and pathophysiology of various organ systems is being increasingly recognized. While sex steroid effects, especially estrogens, on the cardiovascular system have been well studied, clinical and emerging bench research evidence exists for the role of sex hormones in airway and lung physiology and in diseases such as asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis. In this chapter, we briefly define what sex differences exist in airway or lung structure and function under normal conditions, the potential role of sex steroids at different time points in life and in specific disease states, setting the stage to explore whether and how sex hormone signaling mechanisms may be contributory. We focus on the mechanisms by which estrogens, progresterone, and testosterone influence airway smooth muscle and epithelium in regulating airway tone and the potential contribution of these hormones in airway remodeling.


Lung disease Asthma Female Gender Estrogen 



This research was supported by the Flight Attendants Medical Research Institute (FAMRI; VS), a Small Grants Program by the Clinical Translational Science Activities (CTSA) of the Mayo Clinic (YSP), and an NIGMS T32 Institutional Training grant to the Columbia University Department of Anesthesiology (EAT).


  1. 1.
    No authors (2010) Putting gender on the agenda. Nature 465:665. doi:  10.1038/465665a
  2. 2.
    Miller VM (2010) Sex-based differences in vascular function. Womens Health (Lond Engl) 6:737–52. doi:  10.2217/whe.10.53 CrossRefGoogle Scholar
  3. 3.
    Hepper PG, Shannon EA and Dornan JC (1997) Sex differences in fetal mouth movements. Lancet 350:1820.PubMedCrossRefGoogle Scholar
  4. 4.
    Seaborn T, Simard M, Provost PR, Piedboeuf B and Tremblay Y (2010) Sex hormone metabolism in lung development and maturation. Trends Endocrinol Metab 21:729–38.PubMedCrossRefGoogle Scholar
  5. 5.
    Becklake MR and Kauffmann F (1999) Gender differences in airway behaviour over the human life span. Thorax 54:1119–38.PubMedCrossRefGoogle Scholar
  6. 6.
    Carey MA, Card JW, Voltz JW, Arbes SJ, Jr., Germolec DR, Korach KS and Zeldin DC (2007) It’s all about sex: gender, lung development and lung disease. Trends Endocrinol Metab 18:308–13.PubMedCrossRefGoogle Scholar
  7. 7.
    Abramovich DR (1974) Human sexual differentiation–in utero influences. J Obstet Gynaecol Br Commonw 81:448–53.PubMedCrossRefGoogle Scholar
  8. 8.
    Kimura Y, Suzuki T, Kaneko C, Darnel AD, Akahira J, Ebina M, Nukiwa T and Sasano H (2003) 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) 105:709–13.CrossRefGoogle Scholar
  9. 9.
    Martin JA, Hamilton BE, Sutton PD, Ventura SJ, Menacker F and Kirmeyer S (2006) Births: final data for 2004. Natl Vital Stat Rep 55:1–101.Google Scholar
  10. 10.
    Townsend EA, Miller VM and Prakash YS (2012) Sex differences and sex steroids in lung health and disease. Endocr Rev 33:1–47. doi:  10.1210/er.2010-0031 PubMedCrossRefGoogle Scholar
  11. 11.
    Melgert BN, Ray A, Hylkema MN, Timens W and Postma DS (2007) Are there reasons why adult asthma is more common in females? Curr Allergy Asthma Rep 7:143–50.PubMedCrossRefGoogle Scholar
  12. 12.
    Postma DS (2007) Gender differences in asthma development and progression. Gend Med 4 Suppl B:S133–46.PubMedCrossRefGoogle Scholar
  13. 13.
    Schatz M, Dombrowski MP, Wise R, Thom EA, Landon M, Mabie W, Newman RB, Hauth JC, Lindheimer M, Caritis SN, Leveno KJ, Meis P, Miodovnik M, Wapner RJ, Paul RH, Varner MW, O’Sullivan M J, Thurnau GR, Conway D and McNellis D (2003) Asthma morbidity during pregnancy can be predicted by severity classification. J Allergy Clin Immunol 112:283–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Skobeloff EM, Spivey WH, St Clair SS and Schoffstall JM (1992) The influence of age and sex on asthma admissions. JAMA 268:3437–40.PubMedCrossRefGoogle Scholar
  15. 15.
    Carey MA, Card JW, Voltz JW, Germolec DR, Korach KS and Zeldin DC (2007) The impact of sex and sex hormones on lung physiology and disease: lessons from animal studies. Am J Physiol Lung Cell Mol Physiol %R 10.1152/ajplung.00174.2007 293:L272–278.Google Scholar
  16. 16.
    Dimitropoulou C, White RE, Ownby DR and Catravas JD (2005) Estrogen reduces carbachol-induced constriction of asthmatic airways by stimulating large-conductance voltage and calcium-dependent potassium channels. Am J Respir Cell Mol Biol 32:239–47.PubMedCrossRefGoogle Scholar
  17. 17.
    Matsubara S, Swasey CH, Loader JE, Dakhama A, Joetham A, Ohnishi H, Balhorn A, Miyahara N, Takeda K and Gelfand EW (2008) Estrogen determines sex differences in airway responsiveness after allergen exposure. Am J Respir Cell Mol Biol 38:501–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Ghayee HK and Auchus RJ (2007) Basic concepts and recent developments in human steroid hormone biosynthesis. Reviews in endocrine & metabolic disorders 8:289–300. doi:  10.1007/s11154-007-9052-2 CrossRefGoogle Scholar
  19. 19.
    Payne AH and Hales DB (2004) Overview of steroidogenic enzymes in the pathway from cholesterol to active steroid hormones. Endocr Rev 25:947–70.PubMedCrossRefGoogle Scholar
  20. 20.
    Luu-The V and Labrie F (2010) The intracrine sex steroid biosynthesis pathways. Prog Brain Res 181:177–92. doi: S0079-6123(08)81010-2 [pii] 10.1016/S0079-6123(08)81010-2Google Scholar
  21. 21.
    Miller VM and Duckles SP (2008) Vascular actions of estrogens: functional implications. Pharmacol Rev 60:210–41.PubMedCrossRefGoogle Scholar
  22. 22.
    Simoncini T and Genazzani AR (2003) Non-genomic actions of sex steroid hormones. Eur J Endocrinol 148:281–92.PubMedCrossRefGoogle Scholar
  23. 23.
    Tofovic SP (2010) Estrogens and Development of Pulmonary Hypertension – Interaction of Estradiol Metabolism and Pulmonary Vascular Disease. J Cardiovasc Pharmacol 56:696–708.PubMedCrossRefGoogle Scholar
  24. 24.
    Townsend EA, Thompson MA, Pabelick CM and Prakash YS (2010) Rapid effects of estrogen on intracellular Ca2+ regulation in human airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 298:L521 – 30.PubMedCrossRefGoogle Scholar
  25. 25.
    Valverde MA, Rojas P, Amigo J, Cosmelli D, Orio P, Bahamonde MI, Mann GE, Vergara C and Latorre R (1999) Acute activation of Maxi-K channels (hSlo) by estradiol binding to the beta subunit. Science 285:1929–31.PubMedCrossRefGoogle Scholar
  26. 26.
    Lambert JJ, Belelli D, Peden DR, Vardy AW and Peters JA (2003) Neurosteroid modulation of GABAA receptors. Prog Neurobiol 71:67–80.PubMedCrossRefGoogle Scholar
  27. 27.
    Townsend E, Meuchel L, Thompson M, Pabelick C and Prakash Y (2011) Estrogen increased nitric oxide production in human bronchial epithelium. J Pharmacol Exp Therap 339:815–824.CrossRefGoogle Scholar
  28. 28.
    Hamad AM, Clayton A, Islam B and Knox AJ (2003) Guanylyl cyclases, nitric oxide, natriuretic peptides, and airway smooth muscle function. Am J Physiol Lung Cell Mol Physiol 285:L973 – 83.PubMedGoogle Scholar
  29. 29.
    Folkerts G and Nijkamp FP (2006) Nitric oxide in asthma therapy. Curr Pharm Des 12:3221–32.PubMedCrossRefGoogle Scholar
  30. 30.
    Kirsch EA, Yuhanna IS, Chen Z, German Z, Sherman TS and Shaul PW (1999) Estrogen acutely stimulates endothelial nitric oxide synthase in H441 human airway epithelial cells. Am J Respir Cell Mol Biol 20:658–66.PubMedCrossRefGoogle Scholar
  31. 31.
    Jain R, Ray JM, Pan JH and Brody SL (2012) Sex hormone-dependent regulation of cilia beat frequency in airway epithelium. Am J Respir Cell Mol Biol 46:446–53. doi:  10.1165/rcmb.2011-0107OC PubMedCrossRefGoogle Scholar
  32. 32.
    Ivanova MM, Mazhawidza W, Dougherty SM and Klinge CM (2010) Sex Differences in Estrogen Receptor Subcellular Location and Activity in Lung Adenocarcinoma Cells. Am. J. Respir. Cell Mol. Biol. 42:320–330.PubMedCrossRefGoogle Scholar
  33. 33.
    Pang JJ, Xu XB, Li HF, Zhang XY, Zheng TZ and Qu SY (2002) Inhibition of beta-estradiol on trachea smooth muscle contraction in vitro and in vivo. Acta Pharmacol Sin 23:273–7.PubMedGoogle Scholar
  34. 34.
    Jia S, Zhang X, He DZ, Segal M, Berro A, Gerson TG, Wang Z and Casale TB (2011) Expression and Function of a Novel Variant of Estrogen Receptor-ER-{alpha}36 in Mouse Airway. Am J Respir Cell Mol Biol. doi: 2010-0268OC [pii] 10.1165/rcmb.2010-0268OCGoogle Scholar
  35. 35.
    Foster PS, Goldie RG and Paterson JW (1983) Effect of steroids on beta-adrenoceptor-mediated relaxation of pig bronchus. Br J Pharmacol 78:441–5.PubMedCrossRefGoogle Scholar
  36. 36.
    Perusquia M, Hernandez R, Montano LM, Villalon CM and Campos MG (1997) Inhibitory effect of sex steroids on guinea-pig airway smooth muscle contractions. Comp Biochem Physiol C Pharmacol Toxicol Endocrinol 118:5–10.PubMedCrossRefGoogle Scholar
  37. 37.
    Hellings PW, Vandekerckhove P, Claeys R, Billen J, Kasran A and Ceuppens JL (2003) Progesterone increases airway eosinophilia and hyper-responsiveness in a murine model of allergic asthma. Clin Exp Allergy 33:1457–63.PubMedCrossRefGoogle Scholar
  38. 38.
    Kouloumenta V, Hatziefthimiou A, Paraskeva E, Gourgoulianis K and Molyvdas PA (2006) Non-genomic effect of testosterone on airway smooth muscle. Br J Pharmacol 149:1083–91.PubMedCrossRefGoogle Scholar
  39. 39.
    Bordallo J, de Boto MJ, Meana C, Velasco L, Bordallo C, Suarez L, Cantabrana B and Sanchez M (2008) Modulatory role of endogenous androgens on airway smooth muscle tone in isolated guinea-pig and bovine trachea; involvement of beta2-adrenoceptors, the polyamine system and external calcium. Eur J Pharmacol 601:154–62.PubMedCrossRefGoogle Scholar
  40. 40.
    Card JW, Carey MA, Bradbury JA, DeGraff LM, Morgan DL, Moorman MP, Flake GP and Zeldin DC (2006) Gender differences in murine airway responsiveness and lipopolysaccharide-induced inflammation. J Immunol 177:621–30.PubMedGoogle Scholar
  41. 41.
    Stewart AG, Fernandes D and Tomlinson PR (1995) The effect of glucocorticoids on proliferation of human cultured airway smooth muscle. Br J Pharmacol 116:3219–26.PubMedCrossRefGoogle Scholar
  42. 42.
    Stamatiou R, Paraskeva E, Papagianni M, Molyvdas PA and Hatziefthimiou A (2011) The mitogenic effect of testosterone and 17beta-estradiol on airway smooth muscle cells. Steroids 76:400–8. doi: S0039-128X(10)00299-0 [pii] 10.1016/j.steroids.2010.12.010Google Scholar

Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  • Y. S. Prakash
    • 1
    • 2
    Email author
  • Venkatachalem Sathish
    • 1
    • 2
  • Elizabeth A. Townsend
    • 3
  1. 1.Departments of Physiology and Biomedical EngineeringMayo ClinicRochesterUSA
  2. 2.Anesthesiology College of MedicineMayo ClinicRochesterUSA
  3. 3.Department of AnesthesiologyColumbia UniversityNew YorkUSA

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