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

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: Slide 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) { { { { { { { {

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

Agefrequent persistent episodic Age and asthma - male : female ratio Clough Cl Exp All 1993

Male Female Rate per 100,000 population year Age-adjusted death rate due to asthma in USA Source:National Center for Health Statistics

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

Treatment of asthma: age 7-12 wheeze allergen exercise morning symptoms symptoms tightness Male Female 0 Percentage treated Kuhni et al Ped Pulm 1995 ** *

Airway obstruction! Before 10 minutes after allergen inhalation

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

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)

OVA-specific IgE in serum PBSOVAPBSOVA |------Male------| |-----Female----| *** *** ***

Cytokines in lung tissue IL-5RANTES PBSOVAPBSOVA |------Male------| |-----Female----| ****** PBSOVAPBSOVA |------Male------| |-----Female----| ** Post-hoc analysis: ** p<0.01 *** p<

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

Airway Branching Morphogenesis MMPS & ADAMs Growth factors

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

Males Females CCCTTTCCCTTT p=0.01 p=0.04 ns Exon T/C Mean annual decline in FEV 1 (ml/year) n= Genotype ESR1 and lung function decline Dijkstra et al J All CLin Imm 2006

Gender effect of inhaled corticosteroids? Convery et al ERJ Male Female Doubling dose increase in PD20 methacholine *

Mean annual FEV 1 decline in asthma Inhaled steroids - + P < 0.01 Dijkstra et al 2005 submitted male female

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

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