1. Gender differences in asthma: unsolved puzzles Dirkje Postma University Medical Center Groningen

2. The Burden of Asthma: increasing prevalence in children/adolescents Asthma is a significant burden not only in terms of health care costs, but also in lost productivity and reduced participation in family and social life The prevalence of asthma is increasing worldwide, especially among children Available at: http://www.ginasthma.com. Slide 21. 2003. Finland (Haahtela et al) Sweden (Aberg et al) Japan (Nakagomi et al) Scotland (Rona et al) UK (Omran et al) New Zealand (Shaw et al) Prevalence, % USA (NHIS) Australia (Peat et al) 05101520253035 1992 1982 1989 1975 1992 1982 1994 1989 1992 1982 1992 1982 1991 1979 1989 1966 { { { { { { { {

4. Asthma: a benign disease? sudden attacks of breathlesness and/or cough allergy (generally) reversible airway obstruction hyperresponsiveness

5. Agefrequent persistent episodic 7 2.1 3.8 14 2.1 4.0 21 1.5 1.5 28 1.3 1.8 Age and asthma - male : female ratio Clough Cl Exp All 1993

6. 1979 1.6 1.4 1.2 1.0 Male Female 19831987199119951997 1.8 0.8 Rate per 100,000 population year Age-adjusted death rate due to asthma in USA Source:National Center for Health Statistics

7. Underdiagnosis in females -girls -parents -doctor Especially in low-income group Childhood asthma - boy:girl ratio

8. Treatment of asthma: age 7-12 wheeze allergen exercise morning symptoms symptoms tightness 20 40 60 Male Female 0 Percentage treated 80 100 Kuhni et al Ped Pulm 1995 ** *

9. Airway obstruction! Before 10 minutes after allergen inhalation

10. Sex hormones Interaction between sex hormones and immune function Women are more susceptible to specific immunological disorders Better B cell mediated immunity Higher Ig levels Higher CD4 to CD8 ratios

11. Sex hormones and asthma In humans data remain inconclusive Mouse model: –Estrogen: increases BALF eosinophilia in oophorectomized rats with asthma (Ligeiro de Oliveira et al. 2004) –Progesterone: increases airway inflammation in male mice with asthma (Hellings et al. 2003) –Testosterone: Castration of male asthmatic mice increases BALF eosinophilia (Hayashi et al. 2003)

12. OVA-specific IgE in serum PBSOVAPBSOVA 0.0 0.5 1.0 1.5 2.0 2.5 |------Male------| |-----Female----| *** *** ***

13. Cytokines in lung tissue IL-5RANTES PBSOVAPBSOVA 0 500 1000 1500 2000 |------Male------| |-----Female----| ****** PBSOVAPBSOVA 0 100 200 300 |------Male------| |-----Female----| ** Post-hoc analysis: ** p<0.01 *** p<0.001 --

14. Barnes PJ Chronic inflammation Structural changes Acute inflammation Steroid response Time Progression of asthma into (partial) irreversible airway obstruction

15. Airway Branching Morphogenesis MMPS & ADAMs Growth factors

16. Lung growth in children girls have larger airways in proportion to lung volume than boys puberty 2 2 years

17. Males Females CCCTTTCCCTTT -60 -50 -40 -30 -20 -10 0 10 20 p=0.01 p=0.04 ns Exon 1 +30 T/C Mean annual decline in FEV 1 (ml/year) 19351810299n= Genotype ESR1 and lung function decline Dijkstra et al J All CLin Imm 2006

18. Gender effect of inhaled corticosteroids? Convery et al ERJ 2000 0.5 1.5 2.0 0 2.5 1.0 Male Female Doubling dose increase in PD20 methacholine *

19. -50 -40 -30 -20 -10 0 Mean annual FEV 1 decline in asthma Inhaled steroids - + P < 0.01 Dijkstra et al 2005 submitted male female

20. less prevalent in girls more prevalent in female adults due to airway and lung growth hormonal changes hyperresponsiveness immune development Conclusions on asthma

21. In females more severe higher mortality more and longer hospitalisations (except boys) less response to inhaled steroids? different interaction with genetic background? hormonal influence? Conclusions on asthma