Transcript Gender differences in COPD

Gender differences in asthma: unsolved puzzles
Dirkje Postma
University Medical Center
Groningen
Groningen Research Institute for
Asthma and COPD
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
Finland 1966
(Haahtela et al) { 1989
Sweden
(Aberg et al)
Japan
(Nakagomi et
al)
Scotland
(Rona et al)
{ 1979
1991
{ 1982
1992
{ 1982
1992
UK { 1989
(Omran et al) 1994
USA { 1982
(NHIS) 1992
New Zealand 1975
(Shaw et al) { 1989
Australia 1982
(Peat et al) { 1992
0
5
10 15 20 25
Prevalence, %
30
35
Available at: http://www.ginasthma.com. Slide 21. 2003.
Asthma: a benign disease?
•
•
•
•
sudden attacks of
breathlesness and/or cough
allergy (generally)
reversible airway obstruction
hyperresponsiveness
Age and asthma - male : female ratio
Age
frequent
persistent
episodic
7
2.1
3.8
14
2.1
4.0
21
1.5
1.5
28
1.3
1.8
Clough Cl Exp All 1993
Age-adjusted death rate due to asthma in USA
1.8
Female
Male
1.6
1.4
1.2
1.0
0.8
1979
1983
1987
1991
1995 1997
year
Source:National Center for Health Statistics
Childhood asthma - boy:girl ratio
Underdiagnosis in females
-girls
-parents
-doctor
Especially in low-income group
Treatment of asthma: age 7-12
100
*
80
*
*
Male
Female
60
40
20
0
wheeze
allergen
exercise
morning
symptoms symptoms tightness
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
2.5
***
***
2.0
***
1.5
1.0
0.5
0.0
PBS
OVA
|------Mal e------|
PBS
OVA
|-----F e mal e----|
Cytokines in lung tissue
-
-
IL-5
RANTES
***
***
**
20 00
300
15 00
200
10 00
100
50 0
0
PBS
OVA
|------Male------|
PBS
OVA
|-----Female----|
Post-hoc analysis:
** p<0.01
0
PBS
OVA
|------Male------|
*** p<0.001
PBS
OVA
|-----Female----|
Progression of asthma into (partial) irreversible
airway obstruction
Acute
inflammation
Steroid
response
Chronic inflammation
Structural changes
Time
Barnes PJ
Airway Branching Morphogenesis
MMPS & ADAMs
Growth factors
Lung growth in children
2 years
puberty
girls have larger airways in proportion to lung
volume than boys
Genotype ESR1 and lung function decline
Mean annual decline in FEV1
(ml/year)
Males
20
Females
p=0.01
p=0.04
ns
ns
10
0
-10
-20
-30
-40
-50
-60
n= 19 35 18
CC CT TT
10 29 9
CC CT TT
Exon 1 +30 T/C
Dijkstra et al J All CLin Imm 2006
Gender effect of inhaled corticosteroids?
Doubling dose increase in PD20 methacholine
2.5
2.0
*
Male
Female
1.5
1.0
0.5
0
Convery et al ERJ 2000
Mean annual FEV1 decline in asthma
0
P < 0.01
-10
male
female
-20
-30
-40
-50
+
-
+
Inhaled steroids
Dijkstra et al 2005 submitted
Conclusions on asthma
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?