Upload
others
View
0
Download
0
Embed Size (px)
Citation preview
ISSN 2044-903810.2217/CPR.12.49 © 2012 Future Medicine Ltd 565
part of
Clin. Pract. (2012) 9(5), 565–578
Review
Gender differences in treatment
recommendations for sleep apnea
Francisco Campos-Rodríguez*1, Miguel A Martínez-García2 & Josep M Montserrat3
Practice Points � Obstructive sleep apnea (OSA) is between two- and five-times less prevalent in
women than in men. Gender differences in terms of pathogenesis, clinical presentation
and severity of this sleep disorder have been advocated to explain this disparity in
prevalence.
� Most of the research in the field of OSA treatment has been conducted exclusively or
predominantly in male populations. Since studies addressing gender differences in the
treatment of OSA are scarce, the management options for this disorder in women are
therefore unclear.
� Continuous positive airway pressure (CPAP) is the treatment of choice for OSA patients,
and can effectively reverse most of the consequences associated with OSA. However,
few studies have investigated whether this kind of treatment is also effective in women.
A recent study has reported that CPAP therapy may decrease cardiovascular mortality in
women.
� Gender differences have not been assessed in non-CPAP therapies such as weight loss,
mandibular advancement devices, surgery, exercise training and hypoglossal nerve
stimulation.
� Hormone-replacement therapy in the management of postmenopausal women with OSA
yields conflicting results.
� Future research should assess the effectiveness of CPAP and other therapies in women
with OSA.
1Sleep-Disordered Breathing Unit, Respiratory Department, Valme University Hospital, Ctra Cadiz S/N, 41014, Sevilla, Spain 2Respiratory Department, La Fe University & Polytechnic Hospital, Valencia, Spain3Respiratory Department, IDIBAPS, Clinic Hospital, Barcelona, Spain*Author for correspondence: Tel.: +34 955015780; [email protected]
Clin. Pract. (2012) 9(5)566 future science group
Review | Campos-Rodríguez, Martínez-García & Montserrat
summary Obstructive sleep apnea (OSA) is a common disorder with gender differences
with respect to prevalence, clinical complaints, physiopathology and, possibly, cardiovascular
and healthcare outcomes. To date, most of the treatment recommendations for OSA patients
are supported by research conducted in men, while there is a scarcity of studies specifically
designed to investigate the role of different treatment options, including continuous positive
airway pressure (CPAP), in women’s health. Nevertheless, recent studies have shed some light
on this topic, showing that CPAP treatment may decrease cardiovascular mortality and most of
the clinical complaints associated with OSA in women. The role of non-CPAP therapies such
as weight loss, surgery, mandibular advancement devices and hormone-replacement therapy
has not been adequately assessed in women, or yields conflicting results.
Obstructive sleep apnea (OSA) is a frequent condition characterized by repetitive episodes of upper airway obstruction during sleep that provoke frequent arousals, sleep fragmentation and oxygen desaturation. Women have consist-ently been reported to have a lower prevalence of this sleep disorder than men, with a male:female ratio of 2–5:1 [1–4]. This lower prevalence raises the question of whether women manifest OSA differently to men, or whether they may be pro-tected by a distinct physiopathology. It has been postulated that women do not show the classic symptomatology of snoring, witnessed apneas and daytime hypersomnolence, and thus may be underdiagnosed. Some studies have reported that the positive correlation between apnea–hypop-nea index (AHI) and the Epworth Sleepiness Scale was not affected by gender [5], whereas other researchers have shown that this scale may be a more sensitive measure of subjective sleepi-ness in men than in women [6]. Snore features also seem to be different in both genders, which may impact in the clinical suspicion [7]. However, studies comparing the clinical complaints and presentation of men and women with OSA show that the prevalence of most of these symptoms are similar in both genders but, unlike men, women more frequently present ‘atypical’ symptoms such as depression, anxiety, insomnia, headache and fatigue, which may contribute to decreased disease recognition and misdiagnosis [8–11]. A dis-tinct pathogenesis of this sleep disorder is also thought to play a role in the difference in gen-der prevalence. For example, women with OSA tend to be more obese than males with the same severity of the disorder, although it seems that fat distribution (central obesity seen in males, as opposed to peripheral obesity in women) rather
than BMI may be more important in determin-ing the risk of OSA [9,12]. Data regarding whether upper airway collapsibility differs in both genders and to what extent it may explain different OSA prevalence are controversial [13–16]. Hormones also play an important role in the pathogenesis of OSA. There is strong evidence that menopause increases the risk of developing OSA in women by 3.5–4-times and, in fact, most women with OSA are post menopausal [17,18]. Several differ-ent mechanisms have been proposed to explain how hormones would affect the propensity of female gender towards OSA. Sexual hormones may affect the distribution of body fat, the upper airway dilatory muscle function and cen-tral and neural respiratory control mechanisms. These data suggest that either the higher levels of progesterone/estrogen or the lower levels of testosterone in women may protect them against the development of OSA. All of these different characteristics of OSA in both genders may explain why women usually have less-severe sleep disorder in polysomnographic studies, with a lower AHI than men, as well as a ten-dency toward a clustering of apneic events during rapid eye movement sleep [3]. These gender dif-ferences may have an impact on cardiovascular and other health outcomes. Some studies have shown that, compared with men with similar OSA severity, women had lower perceived health status and quality of life, in addition to overuse of psychoactive drugs, and were heavier users of healthcare resources. In women, the presence of OSA was associated with greater healthcare uti-lization and costs than in men [19,20]. Conflicting data exist regarding differences in cardiovascular outcomes. Whereas some authors have reported an association between OSA and hypertension
567future science group www.futuremedicine.com
Gender differences in treatment recommendations for sleep apnea | Review
restricted to men, others have found that this relationship is more evident in elderly women [8,21]. Data from the Sleep Heart Health Study cohort [22–24] could not find any association between severe OSA and mortality or other inci-dent cardiovascular outcomes in approximately 3000 women followed-up for more than 8 years. However, severe OSA accounted for only 3% of all the women sampled in this study, which may have biased the results.
Given the aforementioned differences in prevalence, severity, pathogenesis and clinical manifestation and outcomes of OSA, it can be speculated that there may also be gender dif-ferences regarding treatment options for this sleep disorder. Unfortunately, few studies have been specifically designed to assess whether the therapies that have been shown to be effective in men are also useful in women, so treatment recommendations in this large population are unclear. Most of the knowledge regarding these topics is supported by studies conducted pre-dominantly or exclusively in men; many others involving mixed samples do not stratify their results by gender. Given that OSA seems to have distinct characteristics in the two genders, it is possible that our present knowledge about effi-cacy, side effects or compliance, based on studies c onducted in men, may not apply to women.
Gender differences in treatment recommendations for OSA: continuous positive airway pressure therapyContinuous positive airway pressure (CPAP) is the treatment of choice for many patients with OSA, including those with severe, symptomatic OSA or concomitant cardiovascular disorders. Although this kind of therapy has been shown to reverse most of the clinical complaints associated with this sleep disorder and counterbalance car-diovascular outcomes, most of the research has been conducted in males. Therefore, evidence about the effectiveness of CPAP treatment on the many consequences of OSA in women is lacking.
� Effect of CPAP on sleepiness, quality of life & healthcare useCPAP improvement in functional status, day-time sleepiness and mood disturbances has been well documented in clinical trials conducted in predominantly male samples with OSA. These studies have failed to examine gender differences in outcomes, and most of them enrolled no more
than 15–20 women with OSA, accounting for only 10–15% of the overall samples. Consequently, it remains unclear whether women’s responses to treatment are similar to those of men [25–28].
Among the few studies that have analyzed a possible gender effect (Table 1), Ye and col-leagues compared CPAP effectiveness in func-tional status, daytime sleepiness, mood distur-bance, apnea symptoms and neurobehavioral performance in 152 men and 24 women with OSA after 3 months of CPAP treatment [11]. The patients presented with severe OSA (mean AHI: 63.9 ± 29.4) and were obese (mean BMI: 38.0 ± 8.2 kg/m2). Despite similarities in age, OSA severity and obesity, women with OSA showed greater impairment of daytime functioning and more symptoms than men at baseline. 3 months of CPAP treatment significantly improved func-tional status and relieved symptoms for both men and women, and gender differences disap-peared in all of the clinical outcomes assessed. There was no significant difference between gen-ders in response to CPAP treatment. This study suggests that CPAP treatment can be equally effective in reversing a wide range of clinical out-comes associated with OSA in both men and women, although the small number of women enrolled may have impeded the detection of any statistically significant difference in treatment response by gender.
Banno and colleagues compared 414 women with OSA and 1404 matched women from the general population [29]. Women with OSA were treated with CPAP or weight loss counseling. The healthcare cost in the 2 years prior to the diagnosis of OSA increased by US$123, and then dropped in the 2 years after treatment by $37 (p < 0.001), whereas the control group did not show any significant change in health-care expenses. The authors also found that the number of outpatient visits increased in the 2 years before diagnosis by 2.3 ± 0.4 and then decreased over the next 2 years after diagnosis by 1.4 ± 0.4 (p < 0.0001), whereas the control group did not have a significant change in medical vis-its. This study suggests that diagnosis and treat-ment of OSA may reduce the use of h ealthcare resources by women.
� Effect of CPAP on cardiovascular outcomesRecent research has consistently demonstrated that CPAP therapy is useful to prevent fatal and
Clin. Pract. (2012) 9(5)568 future science group
Review | Campos-Rodríguez, Martínez-García & MontserratTa
ble
1. S
tudi
es th
at h
ave
anal
yzed
con
tinu
ous
posi
tive
air
way
pre
ssur
e tr
eatm
ent i
n w
omen
.
Stud
y (y
ear)
Char
acte
rist
ics
of th
e st
udy
Qua
lity
of d
ata
Type
of t
reat
men
tKe
y fin
ding
sRe
f.
Ye e
t al.
(201
0)15
2 m
en a
nd 2
4 w
omen
with
OSA
. G
ende
r diff
eren
ces
in re
spon
se to
CP
AP
wer
e ex
amin
ed w
ith re
spec
t to
func
tiona
l sta
tus,
day
time
slee
pine
ss,
moo
d di
stur
banc
e, a
pnea
sym
ptom
s an
d ne
urob
ehav
iora
l per
form
ance
Pros
pect
ive,
ob
serv
atio
nal
stud
y
CPA
P tr
eatm
ent f
or
3 m
onth
s �
Aver
age
CPA
P us
e in
wom
en w
as n
ot d
iffer
ent f
rom
men
(4
.2 ±
2.4
vs
4.8
± 2.
1 h/
day;
p =
0.2
65)
�CP
AP
trea
tmen
t sig
nific
antly
impr
oved
func
tiona
l sta
tus
and
relie
ved
OSA
sym
ptom
s fo
r bot
h m
en a
nd w
omen
. The
re w
as
no s
igni
fican
t diff
eren
ce b
etw
een
gend
ers
in re
spon
se to
CP
AP
trea
tmen
t, an
d ge
nder
diff
eren
ces
in C
PAP
adhe
renc
e w
ere
not o
bser
ved
[11]
Bann
o et
al.
(200
6)41
4 w
omen
with
OSA
and
140
4 m
atch
ed
wom
en fr
om th
e ge
nera
l pop
ulat
ion
Hea
lthca
re u
tiliz
atio
n 2
year
s af
ter
diag
nosi
s w
as a
naly
zed
in w
omen
w
ith O
SA
Retr
ospe
ctiv
e,
obse
rvat
iona
l co
hort
stu
dy
322
wom
en w
ere
trea
ted
with
CPA
P an
d 92
wer
e on
ly re
com
men
ded
wei
ght l
oss
�Th
ere
was
an
incr
ease
in fe
es o
f US$
123.
43 ±
25.
01 in
the
2 ye
ars
befo
re d
iagn
osis
and
a re
duct
ion
in fe
es o
f $37
.96
± 21
.35
in th
e 2
year
s af
ter d
iagn
osis
(p <
0.0
001)
�Th
e nu
mbe
r of c
linic
vis
its in
crea
sed
in th
e 2
year
s be
fore
di
agno
sis
by 2
.32
± 0.
43 a
nd d
ecre
ased
ove
r the
nex
t 2 y
ears
by
1.4
8 ±
0.42
vis
its (p
< 0
.000
1)
[29]
Mor
rish
et a
l. (2
008)
292
men
and
47
wom
en w
ith O
SA
The
stud
y co
mpa
red
the
mor
talit
y ris
k in
bo
th g
ende
rs
Retr
ospe
ctiv
e st
udy
All
patie
nts
wer
e tr
eate
d w
ith C
PAP
�M
orta
lity
risk
was
com
para
ble
in m
en a
nd w
omen
with
OSA
tr
eate
d w
ith C
PAP,
whe
n th
e re
sults
wer
e ad
just
ed fo
r sev
eral
co
nfou
nder
s, in
clud
ing
the
Char
lson
sco
re (O
R: 0
.95;
95%
CI
: 0.3
9–2.
29)
[37]
Cam
pos-
Rodr
igue
z et
al.
(201
2)
1116
wom
en re
ferr
ed fo
r OSA
sus
pici
on.
Card
iova
scul
ar m
orta
lity
was
com
pare
d w
ith a
con
trol
gro
up w
ithou
t OSA
Pros
pect
ive,
ob
serv
atio
nal
coho
rt s
tudy
278
non-
OSA
con
trol
gr
oup,
155
wom
en w
ith
mild
-to-
mod
erat
e O
SA
(AH
I 10–
30) w
ith C
PAP
(com
plia
nce
of a
t lea
st
4 h/
day)
, 421
with
sev
ere
OSA
(AH
I >30
) with
CPA
P,
167
with
unt
reat
ed
mild
-to-
mod
erat
e O
SA (w
ithou
t CPA
P or
av
erag
e ad
here
nce
<4 h
/day
) and
95
with
un
trea
ted
seve
re O
SAM
edia
n fo
llow
-up
of
72 m
onth
s
�Co
mpa
red
with
the
cont
rol g
roup
with
out O
SA, w
omen
w
ith u
ntre
ated
sev
ere
OSA
had
an
incr
ease
d ca
rdio
vasc
ular
m
orta
lity
risk
(HR:
3.5
0; 9
5% C
I: 1.
23–9
.98)
, whe
reas
wom
en
with
sev
ere
OSA
trea
ted
with
CPA
P ha
d a
sim
ilar m
orta
lity
risk
to th
e co
ntro
l gro
up (H
R: 0
.55;
95%
CI:
0.17
–1.7
4) �
Wom
en w
ith m
ild-t
o-m
oder
ate
OSA
(eith
er C
PAP
trea
ted
or
untr
eate
d) h
ad a
sim
ilar m
orta
lity
risk
com
pare
d w
ith th
e no
n-O
SA c
ontr
ol g
roup
�CP
AP
com
plia
nce
mea
sure
d in
hou
rs p
er d
ay w
as
inde
pend
ently
ass
ocia
ted
with
low
er c
ardi
ovas
cula
r mor
talit
y ris
k (H
R: 0
.72;
95%
CI:
0.63
–0.8
3)
[38]
Jaya
ram
an
et a
l. (2
011)
56 w
omen
and
39
men
with
OSA
D
iffer
ence
s in
CPA
P pr
essu
re re
quire
men
ts
wer
e as
sess
ed
Retr
ospe
ctiv
e st
udy
CPA
P tr
eatm
ent
�CP
AP
pres
sure
requ
irem
ent w
as h
ighe
r in
men
than
in w
omen
(1
2.7
vs 1
0.2
cm H
2O; p
< 0
.000
1) �
The
effec
t of g
ende
r on
CPA
P re
quire
men
t was
foun
d to
be
sign
ifica
nt e
ven
afte
r cor
rect
ing
for s
ever
ity
of O
SA
[39]
Sin
et a
l. (2
002)
296
patie
nts
with
OSA
(81.
1% m
en)
Pred
icto
rs o
f CPA
P co
mpl
ianc
e at
6 m
onth
s w
ere
asse
ssed
Pros
pect
ive,
lo
ngitu
dina
l co
hort
stu
dy
CPA
P fo
r 6 m
onth
s �
Wom
en, o
n av
erag
e, u
sed
CPA
P m
ore
freq
uent
ly th
an m
en b
y 0.
76 ±
0.3
2 h
�In
the
mul
tivar
iate
, adj
uste
d an
a lys
is, f
emal
e ge
nder
was
in
depe
nden
tly a
ssoc
iate
d w
ith b
ette
r CPA
P co
mpl
ianc
e (p
= 0
.020
)
[40]
AH
I: A
pnea
–hyp
opne
a in
dex;
CPA
P: C
ontin
uous
pos
itive
airw
ay p
ress
ure;
HR:
Haz
ard
ratio
; NS:
Non
sign
ifica
nt; O
R: O
dds
ratio
; OSA
: Obs
truc
tive
slee
p ap
nea;
RR:
Rel
ativ
e ris
k.
569future science group www.futuremedicine.com
Gender differences in treatment recommendations for sleep apnea | ReviewTa
ble
1. S
tudi
es th
at h
ave
anal
yzed
con
tinu
ous
posi
tive
air
way
pre
ssur
e tr
eatm
ent i
n w
omen
(con
t.).
Stud
y (y
ear)
Char
acte
rist
ics
of th
e st
udy
Qua
lity
of d
ata
Type
of t
reat
men
tKe
y fin
ding
sRe
f.
Pelle
tier-
Fleu
ry
et a
l. (2
001)
136
men
and
27
wom
en w
ith O
SA
Pred
icto
rs o
f CPA
P co
mpl
ianc
e w
ere
asse
ssed
. Bad
adh
eren
ce w
as d
efine
d as
CP
AP
drop
out o
r use
<3
h/da
y
Pros
pect
ive,
ob
serv
atio
nal
coho
rt s
tudy
All
patie
nts
wer
e tr
eate
d w
ith C
PAP
(med
ian
follo
w-u
p 88
7 da
ys)
�In
the
mul
tivar
iate
, adj
uste
d an
a lys
is, f
emal
e ge
nder
was
in
depe
nden
tly a
ssoc
iate
d w
ith p
oore
r CPA
P co
mpl
ianc
e (R
R: 2
.8; 9
5% C
I: 1.
4–5.
4; p
= 0
.002
)
[41]
Woe
hrle
et a
l. (2
011)
4821
pat
ient
s w
ith O
SA (8
2% m
en a
nd 1
8%
wom
en)
Patt
erns
of u
se w
ere
com
pare
d in
bot
h ge
nder
s
Retr
ospe
ctiv
e st
udy
All
patie
nts
wer
e tr
eate
d w
ith C
PAP.
Co
mpl
ianc
e da
ta w
ere
regi
ster
ed fo
r the
last
6
mon
ths
of u
se
�M
en h
ad s
igni
fican
tly h
ighe
r ave
rage
CPA
P us
e in
min
utes
per
ni
ght (
377
± 94
vs
370
± 96
min
; p <
0.0
5) a
nd d
ays
per w
eek
(6.1
± 1
.4 v
s 6.
0 ±
1.3
days
; p <
0.0
5) th
an w
omen
[42]
Ant
tala
inen
et
al.
(200
7)23
3 ag
e- a
nd B
MI-m
atch
ed m
ale–
fem
ale
pairs
with
par
tial u
pper
airw
ay o
bstr
uctio
n.
CPA
P ad
here
nce
was
stu
died
Retr
ospe
ctiv
e st
udy
CPA
P tr
eatm
ent f
or
1 ye
ar �
CPA
P ad
here
nce
was
60.
5% in
wom
en a
nd 5
6.9%
in m
en
(p =
NS)
[43]
Budh
iraja
et a
l. (2
007)
65 m
en a
nd 3
5 w
omen
with
OSA
Th
e au
thor
s an
alyz
ed th
e im
pact
of g
ende
r an
d ea
rly u
se in
com
plia
nce
at 3
0 da
ys
Retr
ospe
ctiv
e st
udy
CPA
P tr
eatm
ent f
or
1 m
onth
�Th
e au
thor
s di
d no
t find
any
diff
eren
ces
in th
e av
erag
e da
ily
CPA
P us
age
time
(5.0
± 1
.9 v
s 5.
0 ±
2.2
h/da
y; p
= 0
.9) i
n w
omen
and
men
, res
pect
ivel
y �
Long
-ter
m a
dher
ence
to C
PAP
ther
apy
can
be p
redi
cted
as
early
as
3 da
ys a
fter
CPA
P in
itiat
ion
[44]
AH
I: A
pnea
–hyp
opne
a in
dex;
CPA
P: C
ontin
uous
pos
itive
airw
ay p
ress
ure;
HR:
Haz
ard
ratio
; NS:
Non
sign
ifica
nt; O
R: O
dds
ratio
; OSA
: Obs
truc
tive
slee
p ap
nea;
RR:
Rel
ativ
e ris
k.
Clin. Pract. (2012) 9(5)570 future science group
Review | Campos-Rodríguez, Martínez-García & Montserrat
nonfatal cardiovascular outcomes associated with OSA. This finding, however, is supported by studies conducted predominantly or exclu-sively in male populations. Evidence regarding potential gender differences in the response to cardiovascular outcomes with CPAP therapy is scarce [30–35].
A very recent study with 37 severe OSA patients showed that CPAP therapy on the first night improved heart rate variability similarly in both men and women [36]. Morrish and col-leagues retrospectively analyzed 292 men and 47 women diagnosed with OSA and treated with CPAP and found that women had a 3.44 greater mortality risk than men, but these dif-ferences disappeared when the results were adjusted for confounding variables, including the Charlson score (odds ratio [OR]: 0.95; 95% CI: 0.39–2.29), suggesting that the greater comorbidity recorded in women explained most of the difference between the mortality risk for women and men in this study (Table 1) [37].
A very recent paper by Campos-Rodriguez and colleagues has reported an increased mor-tality risk in women with untreated, severe OSA, and a reduction in this risk in those adequately treated with CPAP [38]. This study is the first to address the role of CPAP treatment in car-diovascular mortality on a large clinic sample composed exclusively of women, and with a long-term follow-up. In this prospective, obser-vational study, 1116 women referred for suspicion of OSA underwent a diagnostic sleep study and were followed for a median period of 72 months. Compared with the control group without OSA (defined as an AHI <10), women with severe, untreated OSA (AHI ≥30, CPAP not prescribed or compliance lower than 4 h/day) were 3.5-times more likely to die from cardiovascular causes (95% CI: 1.23–9.98), whereas those with CPAP-treated, severe OSA (compliance with CPAP of 4 h/day or greater) had a similar mortality risk to women in the control group (hazard ratio [HR]: 1.60; 95% CI: 0.52–4.90). The authors also investigated the role of CPAP adherence in these outcomes, and found that adherence meas-ured as the average number of hours of CPAP use per day was independently associated with lower cardiovascular mortality risk (HR: 0.72; 95% CI: 0.63–0.83). The results of this study suggest that adequate CPAP treatment can effec-tively reverse mortality risk in women with severe OSA, as is the case with men.
� Gender differences in CPAP requirements & complianceGiven that women usually have a less severe OSA than men and apneic events tend to cluster in REM sleep, it can therefore be hypothesized that pressure requirements may differ in the two genders, and that women would need lower pressures to avoid upper airway obstruction. One retrospective study carried out in 56 women and 39 men with OSA who were started on CPAP treatment found that the pressure requirement was higher in men than in women (12.7 vs 10.2 cm H
2O; p < 0.0001) [39]. The effect of
gender on CPAP requirement was found to be significant even when confounding variables were accounted for by using linear regression.
The effectiveness of CPAP therapy greatly depends on consistent use, so any differences between men and women in the patterns of adherence to OSA treatment may be important. However, the influence of gender on CPAP adher-ence has not been clarified and several studies have reported conflicting results. Female gender has been identified as an independent risk factor for both inadequate and good CPAP compliance, whereas other studies have not found gender to be a predictive factor for adherence. Sin and col-leagues prospectively assessed compliance in 296 OSA patients who started CPAP therapy [40]. At 6 months, average adherence to the device was 5.8 h/day and 88.5% of the sample use it at least 3.5 h/day. In the multiple regression ana lysis, female gender was independently associated with better adherence (p = 0.020) and, on average, women used CPAP more frequently than men by 0.76 ± 0.32 h. By contrast, Pelletier-Fleury and colleagues prospectively followed 163 OSA patients treated with CPAP for a median period of 2.43 years [41]. After adjusting for confounders, female gender was a predictive factor for noncom-pliance (adjusted HR: 2.8; 95% CI: 1.4–5.4), defined as CPAP dropout or usage of less than 3 h/day. The authors hypothesized that lower perceptions of health and quality of life in women would be responsible for this worse compliance. Similarly, data from another large population of 4281 patients treated with CPAP showed that men had significantly higher average CPAP use in minutes per night (377 ± 94 vs 370 ± 96 min; p < 0.05) and days per week (6.1 ± 1.4 vs 6.0 ± 1.3 days; p < 0.05) than women, in the last 6 months of registration [42]. In this study, how-ever, many clinical data were lacking, for example,
571future science group www.futuremedicine.com
Gender differences in treatment recommendations for sleep apnea | Review
primary diagnosis, BMI, Epworth Scale and how many patients stopped therapy. Furthermore, the statistically significant gender differences may not have any clinical interest and may simply be due to the large sample size. Finally, other authors have not found gender to be an inde-pendent predictor of adherence. Anttalainen and colleagues retrospectively reviewed 233 age- and BMI-matched male–female pairs with partial upper airway obstruction treated with CPAP for 1 year and found no gender differences in adher-ence [43]. Likewise, Budhiraja and colleagues, in a retrospective study of 100 patients started on CPAP therapy, did not find any differences in the average daily CPAP usage time (5.0 ± 1.9 vs 5.0 ± 2.2 h/day; p = 0.9) in women and men, respectively [44]. Ye and colleagues also reported a similar adherence to the device in 24 women and 152 men after 3 months of CPAP treat-ment (4.2 ± 2.4 vs 4.8 ± 2.1 h/day; p = 0.26) [11]. The higher prevalence of REM-related OSA in women compared with men may influence CPAP compliance. However, a very recent study in 1019 consecutive adults with OSA observed no sig-nificant difference in CPAP adherence between patients with REM-related OSA and nonstage-specific OSA [45].
Gender differences in treatment recommendations for OSA: non-CPAP therapies � Behavioral therapy for OSA: obesity,
exercise training, smoking habit, alcohol intake & sedativesObesity is the most important modifiable risk factor for OSA, and it has been well documented that weight reduction has a positive impact on this disorder. Peppard and colleagues, in a population-based, prospective cohort study, showed that a 10% weight loss predicted a 26% (95% CI: 18–34) decrease in the AHI, whereas a 10% weight gain predicted an approximate 32% (95% CI: 20–45) increase in the AHI [46]. Toumilehto and colleagues, in a prospec-tive, randomized, controlled study conducted in overweight patients with mild OSA, found that 1 year of a lifestyle intervention program, including a very low calorie diet that effectively decreased BMI by 3.5 ± 2.1 kg/m2, significantly reduced the AHI (-4.0 vs 0.3; p = 0.017) and achieved a higher rate of OSA resolution (defined as an AHI <5) compared with the control group (61 vs 32%; p = 0.019) [47]. Unfortunately, these
studies did not separately analyze their results in both genders, so it is unclear whether these beneficial effects of weight reduction are equally relevant in men and women. By contrast, data from the Sleep Heart Health Study on 2698 par-ticipants determined that men were more likely than women to have an increase in the respira-tory disturbance index with a given increase in weight and, similarly, weight reductions had a more favorable impact on OSA in men than in women (Table 2) [48]. These findings concurred with other studies, which have reported that OSA is more closely related to weight in men than in women, who tend to develop OSA only at much higher levels of obesity and tend to have a lower AHI at every level of BMI when compared with men of the same BMI [49,50]. These find-ings suggest that weight reduction might have a greater impact on OSA in men than in women because the latter have an anatomically more sta-ble upper airway, which would be less affected by changes in weight, whereas men have a higher proportion of central body fat, which is more closely related to obstruction of the upper airway.
Bariatric surgery is an effective treatment in morbidly obese patients, and a recent meta-ana lysis has shown that weight reduction after surgery decreased the AHI by 38.2 events/h (95% CI: 31.9–44.4) [51]. In most of the stud-ies included in the meta-ana lysis, however, the number of women was either very small or unreported.
Novel treatments for OSA, including exercise training, oropharyngeal exercise and hypo glossal nerve stimulation, appear to improve AHI in patients with mild-to-moderate OSA [52,53], but a possible gender effect has not been investigated.
Although there is a pathophysiological hypoth-esis to explain why smoking can be a risk factor for OSA (it has been suggested that irritation, inflammatory changes and swelling contribute to increased upper airway resistance), there is no definitive evidence about the association between these two disorders. We also lack any evidence to show that smoking cessation improves OSA sever-ity [54]. Likewise, alcohol intake can increase the frequency and duration of respiratory events, but it has not been clearly shown that it provokes sleep apnea in subjects who otherwise do not snore or have sleep apnea [55]. The benefits of alcohol ces-sation on OSA have not been assessed. The effects of sedatives and hypnotics on the development and worsening of OSA remain uncertain, and
Clin. Pract. (2012) 9(5)572 future science group
Review | Campos-Rodríguez, Martínez-García & MontserratTa
ble
2. S
tudi
es th
at h
ave
anal
yzed
non
cont
inuo
us p
osit
ive
airw
ay p
ress
ure
trea
tmen
t in
wom
en.
Stud
y (y
ear)
Char
acte
rist
ics
of th
e st
udy
Qua
lity
of d
ata
Type
of t
reat
men
tKe
y fin
ding
sRe
f.
Bixl
er e
t al.
(200
1)10
00 w
omen
rand
omly
sel
ecte
d fr
om g
ener
al p
opul
atio
n un
derw
ent o
ne n
ight
of s
leep
la
bora
tory
eva
luat
ion.
Pre
vale
nce
of O
SA a
nd it
s re
latio
nshi
p w
ith
men
opau
se w
ere
asse
ssed
Cros
s-se
ctio
nal
stud
ySo
me
wom
en w
ere
unde
rgoi
ng H
RT �
The
prev
alen
ce o
f OSA
(defi
ned
as A
HI >
15) f
or p
rem
enop
ausa
l w
omen
was
0.6
%, c
ompa
red
with
3.9
% fo
r pos
tmen
opau
sal w
omen
�Pr
eval
ence
of O
SA in
pos
tmen
opau
sal w
omen
with
HRT
was
sim
ilar
to th
at o
f pre
men
opau
sal w
omen
(1.1
vs
0.6%
; RR
= 1.
9 [0
.4–1
0.1]
; p
= 0.
40).
By c
ontr
ast,
post
men
opau
sal w
omen
with
out H
RT h
ad a
hi
gher
pre
vale
nce
of O
SA c
ompa
red
with
pre
men
opau
sal w
omen
(5.5
vs
0.6
%; R
R =
9.3
[2.6
–25.
8]; p
= 0
.003
) �
In th
e m
ultiv
aria
te a
naly
sis,
pos
tmen
opau
sal s
tatu
s w
ith H
RT w
as n
ot
asso
ciat
ed w
ith a
hig
her r
isk
of O
SA (O
R: 0
.9 [0
.1–5
.8];
p =
0.89
)
[17]
New
man
et
al.
(200
5)13
42 m
en a
nd 1
626
wom
en fr
om
the
Slee
p H
eart
Hea
lth S
tudy
.RD
I and
BM
I wer
e as
sess
ed a
t ba
selin
e an
d af
ter 5
yea
rs o
f fo
llow
-up
Pros
pect
ive,
lo
ngitu
dina
l co
hort
stu
dy
Effec
t of c
hang
es in
wei
ght
�Th
e eff
ect o
f wei
ght c
hang
e w
as g
reat
er fo
r men
than
wom
en.
Wom
en w
ith w
eigh
t los
s w
ere
less
like
ly to
sho
w a
dec
line
in R
DI t
han
men
with
wei
ght l
oss
�M
en w
ho re
duce
thei
r wei
ght b
y >1
0 kg
wer
e 5.
4-tim
es (C
I: 1.
6–17
.2)
mor
e lik
ely
to re
duce
thei
r RD
I by
15 u
nits
, whe
reas
wom
en w
ere
only
1.
8-tim
es (C
I: 0.
4–7.1
) mor
e lik
ely
(non
sign
ifica
nt)
[48]
Mar
klun
d et
al.
(200
4)49
0 m
en a
nd 1
20 w
omen
with
O
SA (A
HI ≥
10 in
the
supi
ne o
r la
tera
l pos
ition
) or s
norin
g. T
he
stud
y an
alyz
ed to
lera
bilit
y an
d pr
edic
tors
of s
ucce
ssfu
l tre
atm
ent
with
MA
D
Pros
pect
ive,
ob
serv
atio
nal
stud
y
MA
D fo
r at l
east
1 y
ear
�Fe
mal
e ge
nder
pre
dict
ed tr
eatm
ent s
ucce
ss, d
efine
d as
an
AH
I <10
in
both
the
supi
ne a
nd la
tera
l pos
ition
s (O
R: 2
.41;
CI:
1.19
–4.8
7; p
= 0
.01)
, co
mpa
red
with
men
�In
wom
en, m
ild O
SA (A
HI <
20) p
redi
cted
trea
tmen
t suc
cess
(OR:
12.
1,
CI: 1
.51–
97.8
; p =
0.0
19),
whe
reas
com
plai
nts
of n
asal
obs
truc
tion
wer
e as
soci
ated
with
ther
apy
failu
re (O
R: 0
.11; C
I: 0.
02–0
.79;
p =
0.0
28)
�W
omen
with
non
supi
ne-d
epen
dent
OSA
wer
e si
x-tim
es m
ore
likel
y to
ha
ve s
ucce
ss th
an m
en w
ith n
onsu
pine
-dep
ende
nt O
SA
[60]
Batt
agel
et
al.
(199
9)45
men
and
13
wom
en w
ith m
ild-
to-m
oder
ate
OSA
. Effe
cts
of M
AD
in
cha
nges
in a
irway
and
hyo
id
posi
tion
Pros
pect
ive,
ob
serv
atio
nal
stud
y
MA
D
�D
espi
te s
mal
ler f
aces
and
nar
row
er p
hary
nx, w
omen
enl
arge
thei
r ph
aryn
x m
ore
durin
g m
andi
bula
r adv
ance
men
t tha
n m
en in
diff
eren
t m
easu
rem
ents
of p
rotr
usio
n
[61]
Man
ber e
t al.
(200
3)Si
x po
stm
enop
ausa
l wom
en w
ith
mild
-to-
mod
erat
e O
SA.
The
effec
t of H
RT o
n O
SA w
as
anal
yzed
With
in-s
ubje
cts,
pr
oges
tero
ne
plac
ebo-
cont
rolle
d tr
ial
HRT
. 7–1
2 da
ys o
n es
trog
en
plus
pla
cebo
follo
wed
by
7–13
day
s on
est
roge
n pl
us
prog
este
rone
�Es
trog
en m
onot
hera
py w
as a
ssoc
iate
d w
ith a
sig
nific
ant r
educ
tion
in
the
mea
n A
HI f
rom
bas
elin
e (2
2.7
± 13
.2 v
s 12
.2 ±
8.1
; p <
0.0
5), b
ut th
e A
HI r
educ
tion
on e
stra
diol
plu
s pr
oges
tero
ne re
lativ
e to
bas
elin
e w
as
not s
tatis
tical
ly s
igni
fican
t (22
.7 ±
13.
2 vs
16.
2 ±
13.4
; p =
NS)
�
Sim
ilarly
, onl
y es
trog
en a
chie
ved
a re
duct
ion
in ti
me
spen
t with
SaO
2
< 90
% fr
om b
asel
ine
(6.7
± 8
.5 v
s 0.
6 ±
0.9;
p <
0.0
1)
[71]
Pick
ett e
t al.
(198
9)N
ine
ovar
ihys
tere
ctom
ized
w
omen
. The
aim
was
to
dete
rmin
e w
heth
er c
ombi
ned
HRT
dec
reas
ed O
SA in
hea
lthy
post
men
opau
sal w
omen
Cont
rolle
d tr
ial
with
cro
ssov
er
desi
gn
1 w
eek
of tr
eatm
ent w
ith
plac
ebo
or c
ombi
ned
prog
estin
and
est
roge
n
�Co
mbi
ned
HRT
redu
ced
the
aver
age
AH
I per
sub
ject
from
15
± 4
to
3 ±
1 (p
< 0
.005
) �
The
dura
tion
of h
ypop
neas
als
o de
crea
sed
with
HRT
[72]
AH
I: A
pnea
–hyp
opne
a in
dex;
CPA
P: C
ontin
uous
pos
itive
airw
ay p
ress
ure;
HRT
: Hor
mon
e-re
pla
cem
ent t
hera
py; M
AD
: Man
dibu
lar a
dvan
cem
ent d
evic
e; N
S: N
onsi
gnifi
cant
; OR:
Odd
s ra
tio; O
SA: O
bstr
uctiv
e sl
eep
apne
a;
RDI:
Resp
irato
ry d
istu
rban
ce in
dex;
RR:
Rel
ativ
e ris
k.
573future science group www.futuremedicine.com
Gender differences in treatment recommendations for sleep apnea | ReviewTa
ble
2. S
tudi
es th
at h
ave
anal
yzed
non
cont
inuo
us p
osit
ive
airw
ay p
ress
ure
trea
tmen
t in
wom
en (c
ont.)
.
Stud
y (y
ear)
Char
acte
rist
ics
of th
e st
udy
Qua
lity
of d
ata
Type
of t
reat
men
tKe
y fin
ding
sRe
f.
Cist
ulli
et a
l. (1
994)
Six
post
men
opau
sal w
omen
with
m
ild–m
oder
ate
OSA
Th
e st
udy
asse
ssed
the
role
of H
RT
as a
trea
tmen
t for
OSA
Pros
pect
ive,
ob
serv
atio
nal
stud
y
HRT
with
eith
er e
stro
gen
alon
e (n
= 6
), or
inco
mbi
natio
n w
ith
prog
este
rone
(n =
9) f
or a
m
ean
of 5
0 ±
3 da
ys
�To
tal s
leep
tim
e, s
leep
arc
hite
ctur
e, p
erce
ntag
e of
rapi
d ey
e m
ovem
ent s
leep
, le
ngth
of a
pnea
s an
d bo
dy p
ositi
on w
ere
not
sign
ifica
ntly
diff
eren
t aft
er H
RT �
Com
pare
d w
ith b
asel
ine,
HRT
did
not
cha
nge
the
AH
I (43
± 9
vs
40
± 10
; p =
NS)
or t
he m
inim
um S
aO2 (7
9 ±
3% v
s 75
± 4
%; p
= N
S) �
HRT
onl
y ac
hiev
ed a
sig
nific
ant r
educ
tion
in th
e A
HI d
urin
g ra
pid
eye
mov
emen
t sle
ep (5
8 ±
6 vs
47
± 7;
p <
0.0
5)
[73]
Bloc
k et
al.
(198
1)21
pos
tmen
opau
sal w
omen
Th
e eff
ects
of H
RT o
n O
SA w
ere
eval
uate
d
Rand
omiz
ed,
doub
le-b
lind
cont
rolle
d st
udy
11 w
omen
rece
ived
m
edro
xypr
oges
tero
ne
30 m
g da
ily, a
nd te
n re
ceiv
ed p
lace
bo fo
r 1
mon
th
�In
the
plac
ebo-
trea
ted
grou
p, a
ll m
easu
red
varia
bles
of s
leep
and
br
eath
ing
wer
e id
entic
al a
t bas
elin
e an
d af
ter t
reat
men
t In
the
HRT
gro
up, o
nly
the
max
imum
dur
atio
n of
apn
ea w
as
sign
ifica
ntly
redu
ced
(p =
0.0
3)
[74]
Shah
ar e
t al.
(200
3)28
52 w
omen
, 50
year
s of
age
or
olde
r, w
ho p
artic
ipat
ed in
the
Slee
p H
eart
Hea
lth S
tudy
Th
e st
udy
exam
ined
the
rela
tions
hip
betw
een
the
use
of
HRT
and
the
prev
alen
ce o
f OSA
Cros
s-se
ctio
nal
stud
yA
tota
l of 9
07 w
omen
(32%
) w
ere
usin
g H
RT. 5
25 w
omen
w
ere
taki
ng e
stro
gen
alon
e an
d 38
2 w
ere
taki
ng
estr
ogen
and
pro
gest
eron
e.Th
e du
ratio
n of
med
icat
ion
use
was
not
reco
rded
�Th
e pr
eval
ence
of O
SA (d
efine
d as
an
AH
I ≥15
) am
ong
HRT
use
rs
was
app
roxi
mat
ely
half
the
prev
alen
ce a
mon
g no
nuse
rs (6
1/90
7 vs
286
/194
5) �
Mul
tivar
iate
adj
ustm
ent s
how
ed th
at, c
ompa
red
with
non
-HRT
use
rs,
the
prev
alen
ce o
f OSA
was
low
er a
mon
g w
omen
on
HRT
(adj
uste
d O
R: 0
.55;
CI:
0.41
–0.7
5)
�Bo
th w
omen
trea
ted
with
est
roge
n (O
R: 0
.53;
CI:
0.36
–0.7
6) a
nd th
ose
trea
ted
with
est
roge
n pl
us p
roge
ster
one
(OR:
0.6
0; C
I: 0.
38–0
.96)
sh
owed
a lo
wer
pre
vale
nce
of O
SA c
ompa
red
with
non
-HRT
use
rs
[70]
Saar
esra
nta
et a
l. (2
001)
Ten
post
men
opau
sal w
omen
w
ith p
redo
min
antly
par
tial u
pper
ai
rway
obs
truc
tion
durin
g sl
eep
The
stud
y as
sess
ed re
spira
tory
st
imul
atio
n ca
used
by
HRT
, and
al
so c
ompa
red
the
effec
ts o
f HRT
ag
ains
t CPA
P in
OSA
Pros
pect
ive,
ob
serv
atio
nal
stud
y
Wom
en w
ere
trea
ted
with
m
edro
xypr
oges
tero
ne
(60
mg/
day)
for 1
4 da
ys
They
wer
e al
so re
-eva
luat
ed
afte
r a 3
-wee
k w
asho
ut
perio
d A
fter
3 m
onth
s, s
ix o
f the
se
wom
en w
ere
also
eva
luat
ed
unde
r CPA
P tr
eatm
ent
�14
day
s of
HRT
impr
oved
ven
tilat
ion
in th
e aff
ecte
d fe
mal
es
The
impr
ovem
ent w
as m
aint
aine
d 3
wee
ks a
fter
trea
tmen
t �
HRT
and
CPA
P w
ere
equa
lly e
ffici
ent i
n de
crea
sing
AH
I (-4
.4 ±
8.5
vs
-7.2
± 4
.4; p
= N
S). C
PAP
was
mor
e eff
ectiv
e to
redu
ce re
spira
tory
eff
orts
(-21
.1 ±
20.
5 vs
-0.8
± 1
3.9;
p =
0.0
06),
whe
reas
HRT
sig
nific
antly
re
duce
d en
d-tid
al p
ress
ure
of C
O2 c
ompa
red
with
CPA
P (-
0.8
± 0.
4 vs
-0
.5 ±
0.6
; p =
0.0
37)
[75]
AH
I: A
pnea
–hyp
opne
a in
dex;
CPA
P: C
ontin
uous
pos
itive
airw
ay p
ress
ure;
HRT
: Hor
mon
e-re
pla
cem
ent t
hera
py; M
AD
: Man
dibu
lar a
dvan
cem
ent d
evic
e; N
S: N
onsi
gnifi
cant
; OR:
Odd
s ra
tio; O
SA: O
bstr
uctiv
e sl
eep
apne
a;
RDI:
Resp
irato
ry d
istu
rban
ce in
dex;
RR:
Rel
ativ
e ris
k.
Clin. Pract. (2012) 9(5)574 future science group
Review | Campos-Rodríguez, Martínez-García & Montserrat
although patients are advised to avoid them, sev-eral studies have failed to clearly demonstrate any increase in the AHI with these medications [56].
� Mandibular advancement devicesMandibular advancement devices (MADs) are oral appliances attached to the dental arches to protrude the mandible mechanically and reposi-tion the lower jaw forward and downward dur-ing sleep. They aim to improve the patency of the upper airway during sleep by increasing its dimensions and reducing its collapsibility [57]. This treatment is an alternative to CPAP ther-apy, and is recommended for the treatment of patients with mild-to-moderate OSA, or those who do not tolerate CPAP. These devices have been consistently shown to improve the number of respiratory events, daytime sleepiness, snor-ing and sleep fragmentation compared with pla-cebo, although they are less useful than CPAP in achieving normalization of the AHI and other OSA-related outcomes [58,59].
Only one study has analyzed potential gen-der differences in treatment outcomes with this therapy (Table 2). In this large prospective study comprising 490 men and 120 women with OSA (AHI ≥10) treated with MAD, women were 2.4-times more likely (95% CI: 1.19–4.87; p = 0.01) to achieve treatment success (defined as an AHI <10 in both the supine and lateral positions) than men [60]. Mild OSA was the best predictor of treatment success in women with MAD (OR: 12.1; 95% CI: 1.51–97.8). The authors justified the higher success rate of MAD in women with the finding that women enlarge their pharynx more during mandibular advancement than men [61]. In this study, no gender differences in the tolerability of the device were found. Other stud-ies have not found any differences in gender with respect to adherence or side effects [62].
The findings of the aforementioned study await confirmation, as other studies addressing the role of MAD in OSA have not analyzed its effects on men and women separately.
� SurgeryA variety of surgeries have been used to treat OSA, including uvulopalatopharyn-goplasty (UPPP), laser-assisted uvuloplasty (LAUP), nasal septoplasty, oromaxillofacial surgery, radiofrequency volumetric tissue reduc-tion and tracheostomy. Surgery is most effective in patients with extremely large tonsils, nasal
polyps or other obstructive anatomic lesions, as well as in patients with mild OSA. However, surgical treatment is not a first-line treatment for this sleep disorder in adults [63]. In a Cochrane review of seven randomized controlled trials, the results of surgery were inconsistent, and signifi-cant improvement in polysomnography occurred in only three trials, while health-related quality of life improved in only four trials [64]. The com-ments on the clinical significance of both of these findings were limited, and the review concluded that surgery failed to have any impact on symp-toms (except in two trials) and that no significant overall benefit was found. Furthermore, even in those studies that achieved an improvement in quality of life immediately after surgery, this was rarely sustained for more than 12–24 months [64]. In another meta-ana lysis evaluating 18 sur-gical studies, the success rate (as measured by the number of patients achieving a post-surgery AHI ≤5) was 13% for Phase I procedures, including UPPP, and 43% for Phase II procedures, includ-ing osteotomies [65]. Finally, a systematic review of randomized controlled trials and observational studies reported persistent side effects after UPPP in approximately half of the patients, especially in the form of difficulty in swallowing, globus sensation and voice changes [66]. None of these studies analyzed a possible gender effect in any of the final outcomes assessed, such as AHI, quality of life and snoring, so it is unknown if surgical techniques are equally effective to improve OSA parameters in men and women.
� Transnasal insufflationThe transnasal insufflation of warm and humidi-fied air at a flow rate of 20 l/min through an open nasal cannula system has been shown to achieve a therapeutic reduction of the sleep-disordered event rate in approximately 25–33% of the patients investigated in two studies [67,68]. The relief of upper airway obstruction was most likely due to small but consistent increases in pharyngeal pressure on transnasal insufflation, which decreased the severity of inspiratory flow limitation. Although this is still an experimen-tal therapy, recent data have shown that the response rate was increased in patients who pre-dominantly had REM-related events [68]. Since REM-related OSA is particularly common in women, they may obtain greater benefits from this new therapy. Future studies should confirm these preliminary results.
575future science group www.futuremedicine.com
Gender differences in treatment recommendations for sleep apnea | Review
� Hormone-replacement therapy Postmenopausal women have been reported to be 3.5–4-times more likely to have OSA com-pared with premenopausal women, suggesting that female sexual hormones may protect against the development of OSA [17,18,69]. Female sex hor-mones may be implicated in the pathogenesis of OSA in different ways: they may improve upper airway dilatory muscle function and thereby sta-bilize the upper airway, they may alter the sta-bility of the respiratory controller and they may have an impact on body fat distribution.
Two large studies suggest a role for hormone-replacement therapy (HRT) in the treatment of OSA in postmenopausal women (Table 2). Bixler and colleagues found that the risk of having OSA in those postmenopausal women treated with HRT was similar to that of premenopausal women (OR: 0.9; 95% CI: 0.1–5.8), whereas postmenopausal women without HRT showed a higher prevalence of this sleep disorder (OR: 4.3; 95% CI: 1.1–17.3) [17]. Concurrent with these data, the Sleep Heart Health Study cohort exam-ined the relationship between HRT and OSA in 2852 women aged 50 years or older and found that the prevalence of OSA was significantly lower in those women undergoing HRT, even after adjustment for confounders (OR: 0.55; 95% CI: 0.41–0.75) [70]. Other studies that have ana-lyzed this issue have yielded conflicting results, but the main concern is the small number of women enrolled. A study of six postmenopausal women with mild-to-moderate OSA has shown that estrogen monotherapy reduced the AHI from a mean of 22.7 to 12.2 event/h, and no additional benefit was seen with the addition of progesterone [71]. Pickett and colleagues studied nine postmenopausal women after 1 week of treatment with placebo or combined progestin and estrogen [72]. HRT reduced the AHI from 15 ± 4 to 3 ± 1 events/h, on average. Cistulli and colleagues investigated the effect of estrogen alone or in combination with progesterone on 15 postmenopausal women with OSA [73]. After a mean of 50 days of treatment, the AHI did not significantly change (43 ± 9 vs 40 ± 10; p = NS) and there was no difference in response between the estrogen-only group and the estrogen plus progesterone group. Similarly, another study in 21 postmenopausal women could not show any beneficial effect of medroxyprogesterone 30 mg for 1 month in sleep-disordered breathing [74]. Medroxyprogesterone at a dose of 60 mg daily
for 14 days has been shown to improve ventila-tion and end-tidal pressure of carbon dioxide in a sample of ten women with predominantly partial upper airway obstruction during sleep, although CPAP was more efficient than hormones in decreasing respiratory efforts [75].
The role of hormonal therapy has also been assessed in men. 1 week of medroxiprogesterone 150 mg was not effective in decreasing the AHI, apnea duration or mean fall in oxygen saturation in ten men with severe OSA [76].
Although HRT was initially advocated as a possible alternative therapy for postmenopausal women with OSA, the inconsistent evidence and the increased risks of breast cancer, stroke and heart disease associated with this therapy clearly outweighs its potential benefits and it is there-fore not recommended as a first-line treatment in women with OSA.
Conclusion & future perspectiveDespite the great differences in prevalence, pathogenesis, clinical complaints and severity of OSA between men and women, few studies have addressed potential gender differences in treatment recommendation for this sleep disor-der. To date, the evidence for therapeutic benefit with several types of treatment has been assessed in predominantly male populations and studies have not been designed to separately analyze their effects in each gender, so it is not known whether the beneficial effects reported with these therapies can be extended to women. This lack of reliable information also precludes the development of specific protocols tailored to the characteristics of this population, leading physicians to treat women following male criteria. Only very recent studies have found that CPAP treatment may improve quality of life and reverse cardiovascular mortality associated with OSA in women. However, further research is needed to confirm these data and fully understand the role of CPAP treatment in women with this sleep disorder. Other issues related to this treatment remain unclear; for instance, whether the pressure requirements are different in the two genders, or whether gender itself is a predictive factor for compliance with the device. Additional studies are also needed to clarify the impact of other non-CPAP therapies (such as weight loss, intraoral devices, surgery and hypoglossal stimula-tion) in women with OSA. Although investigation of the potential effect of HRT on OSA severity has yielded conflicting results, the increased health
Clin. Pract. (2012) 9(5)576 future science group
Review | Campos-Rodríguez, Martínez-García & Montserrat
risk associated with this therapy advise against any extension of its use as a major line of treatment for postmenopausal women with sleep apnea.
In conclusion, although recent studies suggest that CPAP treatment may be effective in overcom-ing a wide range of adverse consequences of OSA in women, there is still a long way to go. High-quality trials involving large samples of women are needed to assess the clinical effectiveness of different treatment options in this population.
Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a finan-cial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert t estimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
References Papers of special note have been highlighted as:� of interest�� of considerable interest
1 Young T, Palta M, Dempsey J et al. The occurrence of sleep-disordered breathing among middle-age adults. N. Engl. J. Med. 328, 1230–1235 (1993).
2 Duran J, Esnaola S, Rubio R, Iztueta A. Obstructive sleep apnea–hypopnea and related clinical features in a population-based sample of subjects aged 30 to 70 yr. Am. J. Respir. Crit. Care Med. 163, 685–689 (2001).
3 O’Connor C, Thornley KS, Hanly PJ. Gender differences in the polysomnographic features of obstructive sleep apnea. Am. J. Respir. Crit. Care Med. 161, 1465–1472 (2000).
4 Redline S, Kump K, Tishler PV, Browner I, Ferrette V. Gender differences in sleep disordered breathing in a community-based sample. Am. J. Respir. Crit. Care Med. 149, 722–726 (1994).
5 Gottlieb DJ, Whitney CW, Bonekat WH et al. Relation of sleepiness to respiratory disturbance index: the Sleep Heart Health Study. Am. J. Respir. Crit. Care Med. 159, 502–507 (1999).
6 Baldwin CM, Kapur VK, Holberg CJ, Rosen C, Nieto FJ. Associations between gender and measures of daytime somnolence in the Sleep Heart Health Study. Sleep 27, 305–311 (2004).
7 de Silva S, Abeyratne UR, Hukins C. Impact of gender on snore-based obstructive sleep apnea screening. Physiol. Meas. 33, 687–601 (2012).
8 Sforza E, Chouchou F, Collet P, Pichot V, Barthelemy JC, Roche F. Sex differences in obstructive sleep apnoea in an elderly French population. Eur. Respir. J. 37, 1137–1143 (2011).
9 Quintana-Gallego E, Carmona-Bernal C, Capote F et al. Gender differences in obstructive sleep apnea syndrome: a clinical study of 1166 patients. Respir. Med. 98, 984–989 (2004).
10 Shepertycky MR, Banno K, Kryger MH.
Differences between men and women in the clinical presentation of patients diagnosed with obstructive sleep apnea syndrome. Sleep 28, 309–314 (2005).
11 Ye L, Pien GW, Ratcliffe SJ, Weaver TE. Gender differences in obstructive sleep apnea and treatment response to continuous positive airway pressure. J. Clin. Sleep Med. 5, 512–518 (2009).
�� Shows that women with obstructive sleep apnea (OSA) had greater impairment in daytime functioning and symptoms than men, and that continuous positive airway pressure treatment can be equally effective in improving functional status and relieving symptoms in both genders.
12 Simpson L, Mukherjee S, Cooper MN et al. Sex differences in the association of regional fat distribution with the severity of obstructive sleep apnea. Sleep 33, 467–474 (2010).
13 Pillar G, Malhotra A, Fogel R, Beauregard J, Schnall R, White DP. Airway mechanics and ventilation in response to resistive loading during sleep: influence of gender. Am. J. Respir. Crit. Care Med. 162, 1627–1632 (2000).
14 Sforza E, Petiau C, Weiss T, Thibault A, Krieger J. Pharyngeal critical pressure in patients with obstructive sleep apnea syndrome. Clinical implications. Am. J. Respir. Crit. Care Med. 159, 149–157 (1999).
15 Rowley JA, Zhou X, Vergine I, Shkoukani MA, Badr MS. Influence of gender on upper airway mechanics: upper airway resistance and Pcrit. J. Appl. Physiol. 91, 2248–2254 (2001).
16 Rowley JA, Sanders CS, Zahn BR, Badr MS. Gender differences in upper airway compliance during NREM sleep: role of neck circumference. J. Appl. Physiol. 92, 2535–2541 (2002).
17 Bixler EO, Vgontzas AN, Lin HM et al. Prevalence of sleep disordered breathing in women: effects of gender. Am. J. Respir. Crit. Care Med. 163, 608–613 (2001).
18 Young T, Finn L, Austin D, Peterson A. Menopausal status and sleep-disordered breathing in the Wisconsin Sleep Cohort Study. Am. J. Respir. Crit. Care Med. 167, 1181–1185 (2003).
19 Greenberg-Dotan S, Reuveni H, Simon-Tuval T, Oksenberg A, Tarasiuk A. Gender differences in morbidity and health care utilization among adult obstructive sleep apnea patients. Sleep 30, 1173–1180 (2007).
20 Tarasiuk A, Greenberg-Dotan S, Brin YS, Simon T, Tal A, Reuveni H. Determinants affecting health-care utilization in obstructive sleep apnea syndrome patients. Chest 128, 1310–1314 (2005).
21 Hedner J, Bengtsson-Bostrom K, Peker Y, Grote L, Rastam L, Lindblad U. Hypertension prevalence in obstructive sleep apnoea and sex: a population-based case–control study. Eur. Respir. J 27, 564–570 (2006).
22 Punjabi NM, Caffo BS, Goodwin JL et al. Sleep-disordered breathing and mortality: a prospective cohort study. PLoS Med 6(8), e1000132 (2009).
23 Redline S, Yenokyan G, Gottlieb DJ et al. Obstructive sleep apnea-hypopnea and incident stroke. The Sleep Heart Health Study. Am. J. Respir. Crit. Care Med. 182, 269–277 (2010).
24 Gottlieb DJ, Yenokyan G, Newman AB et al. Prospective study of obstructive sleep apnea and incident coronary heart disease and heart failure. The Sleep Heart Health Study. Circulation 122, 352–360 (2010).
25 Montserrat JM, Ferrer M, Hernandez L et al. Effectiveness of CPAP treatment in daytime function in sleep apnea syndrome. A randomized controlled study with an optimized placebo. Am. J. Respir. Crit. Care Med. 164, 608–613 (2001).
26 Henke KG, Grady JJ, Kuna ST. Effect of nasal continuous positive airway pressure on neuropsychological function in sleep
577future science group www.futuremedicine.com
Gender differences in treatment recommendations for sleep apnea | Review
apnea–hypopnea syndrome. A randomized, placebo-controlled trial. Am. J. Respir. Crit. Care Med. 163, 911–917 (2001).
27 Jenkinson C, Davies RJO, Mullins R, Stradling JR. Comparison of therapeutic and subtherapeutic nasal CPAP for obstructive sleep apnea: a randomized, prospective, parallel trial. Lancet 353, 2100–2105 (1999).
28 Monasterio C, Vidal S, Duran J et al. Effectiveness of continuous positive airway pressure in mild sleep apnea–hypopnea syndrome. Am. J. Respir. Crit. Care Med. 164, 939–943 (2001).
29 Banno K, Manfreda J, Walld R, Delaive K, Kryger MH. Healthcare utilization in women with obstructive sleep apnea syndrome 2 years after diagnosis and treatment. Sleep 29, 1307–1311 (2006).
� Showed that the healthcare costs and number of ambulatory visits in women with OSA significantly dropped in the 2 years after the diagnosis and treatment of the sleep disorder.
30 Marin JM, Carrizo SJ, Vicente E, Agusti AG. Long-term cardiovascular outcomes in men with obstructive sleep apnea–hypopnea with or without treatment with continuous positive airway pressure: an observational study. Lancet 365, 1046–1053 (2005).
31 Parra O, Sanchez-Armengol A, Bonnin M et al. Early treatment of obstructive apnoea and stroke outcome: a randomised controlled trial. Eur. Respir. J. 37, 1128–1136 (2011).
32 Campos-Rodriguez F, Peña-Griñan N, Reyes-Nuñez N et al. Mortality in obstructive sleep apnea-hypopnea patients treated with positive airway pressure. Chest 128, 624–633 (2005).
33 Marti S, Sampol G, Muñoz X et al. Mortality in severe sleep apnoea/hypopnoea syndrome patients: impact of treatment. Eur. Respir. J. 20, 1511–1518 (2002).
34 Doherty LS, Kiely JL, Swan V, McNicholas WT. Long-term effects of nasal continuous syndrome cardiovascular outcomes in sleep apnea positive airway pressure therapy on cardiovascular outcomes in sleep apnea syndrome. Chest 127, 2076–2084 (2005).
35 Martinez-Garcia MA, Soler-Cataluña JJ, Ejarque-Martinez L et al. CPAP treatment reduces mortality in ischemic stroke patients with obstructive sleep apnea. Am. J. Respir. Crit. Care Med. 180, 36–41 (2009).
36 Kufoy E, Palma JA, Lopez J et al. Changes in the heart rate variability in patients with obstructive sleep apnea and its response to acute CPAP treatment. PLoS ONE 7(3), e33769 (2012).
37 Morrish E, Shneerson JM, Smith IE. Why does gender influence survival in obstructive sleep apnoea? Respir. Med. 102, 1231–1236 (2008).
38 Campos-Rodríguez F, Martínez-García MA, de la Cruz-Morón I, Almeida-González C, Catalán-Serra P, Montserrat JM. Cardiovascular mortality in women with obstructive sleep apnea with and without continuous positive airway pressure treatment: a cohort study. Ann. Intern. Med. 156, 115–122 (2012).
�� Found that in women, untreated severe OSA was associated with a 3.5-times greater cardiovascular mortality risk, compared with a non-OSA control group. It also reported that adequate continuous positive airway pressure treatment may reduce this excess of mortality.
39 Jayaraman G, Majid H, Surani S, Kao C, Subramanian S. Influence of gender on continuous positive airway pressure requirements in patients with obstructive sleep apnea syndrome. Sleep. Breath. 15, 781–784 (2011).
40 Sin DD, Mayers I, Man GCW, Pawluk L. Long-term compliance rates to continuous positive airway pressure in obstructive sleep apnea. A population-based study. Chest 121, 430–435 (2002).
41 Pelletier-Fleury N, Rakotonanahary D, Fleury B. The age and other factors in the evaluation of compliance with nasal continuous positive airway pressure for obstructive sleep apnea syndrome. A Cox’s proportional hazard analysis. Sleep Med. 2, 225–232 (2001).
42 Woehrle H, Graml A, Weinreich G. Age and gender-dependent adherence with continuous positive airway pressure therapy. Sleep Med. 12, 1034–1036 (2011).
43 Anttalainen U, Saaresranta T, Kalleinen N, Aittokallio J, Vahlberg T, Polo O. CPAP adherence and partial upper airway obstruction during sleep. Sleep. Breath. 11, 171–176 (2007).
44 Budhiraja R, Parthasarathy S, Drake CL. Early CPAP use identifies subsequent adherence to CPAP therapy. Sleep 30, 320–324 (2007).
45 Conwell W, Patel B, Doeing D et al. Prevalence, clinical features, and CPAP adherence in REM-related sleep-disordered breathing: a cross-sectional analysis of a large clinical population. Sleep. Breath. 16, 519–526 (2012).
46 Peppard PE, Young T, Palta M, Dempsey J, Skatrud J. Longitudinal Study of Moderate Weight Change and Sleep-Disordered
Breathing. JAMA 284, 3015–3021 (2000).
47 Tuomilehto HPI, Seppa JM, Partinen MM et al. Lifestyle intervention with weight reduction. first-line treatment in mild obstructive sleep apnea. Am. J. Respir. Crit. Care Med. 179, 320–327 (2009).
48 Newman AB, Foster G, Givelber R, Nieto FJ, Redline S, Young T. Progression and regression of sleep-disordered breathing with changes in weight. Arch. Intern. Med. 165, 2408–2413 (2005).
� Shows that weight loss is less effective in women than in men to reduce the apnea–hypopnea index.
49 Young T, Shahar E, Nieto FJ et al. Predictors of sleep-disordered breathing in community-dwelling adults: the Sleep Heart Health Study. Arch. Intern. Med. 162, 893–900 (2002).
50 Jordan AS, Wellman A, Edwards JK et al. Respiratory control stability and upper airway collapsibility in men and women with obstructive sleep apnea. J. Appl. Physiol. 99, 2020–2027 (2005).
51 Greenburg DL, Lettieri CJ, Eliasson AH. Effects of surgical weight loss on measures of obstructive sleep apnea: a meta-analysis. Am. J. Med. 122, 535–542 (2009).
52 Guimaraes KC, Drager LF, Genta PR et al. Effects of oropharyngeal exercises on patients with moderate obstructive sleep apnea syndrome. Am. J. Respir. Crit. Care Med. 179, 962–966 (2009).
53 Schwartz AR, Barnes M, Hillman D et al. Acute upper airway responses to hypoglossal nerve stimulation during sleep in obstructive sleep apnea. Am. J. Respir. Crit. Care Med. 185, 420–426 (2012).
54 Wetter DW, Young TB, Bidwell TR, Badr MS, Palta M. Smoking as a risk factor for sleep-disordered breathing. Arch. Intern. Med. 154, 2219–2224 (1994).
55 Scrima L, Broudy M, Nay KN et al. Increased severity of obstructive sleep apnea after bedtime alcohol ingestion: diagnostic potential and proposed mechanism of action. Sleep 5, 318–328 (1982).
56 Camacho ME, Morin CM. The effect of temazepam on respiration in elderly insomniacs with mild sleep apnea. Sleep 18, 644–645 (1995).
57 Ng AT, Gotsopoulos H, Qian J et al. Effect of oral appliance therapy on upper airway collapsibility in obstructive sleep apnea. Am. J. Respir. Crit. Care Med. 168, 238–241 (2003).
58 Barnes M, McEvoy RD, Banks S et al. Efficacy of positive airway pressure and oral appliance in mild to moderate obstructive
Clin. Pract. (2012) 9(5)578 future science group
Review | Campos-Rodríguez, Martínez-García & Montserrat
sleep apnea. Am. J. Respir. Crit. Care Med. 170, 656–664 (2004).
59 Gagnadoux F, Fleury B, Vielle B et al. Titrated mandibular advancement versus positive airway pressure for sleep apnoea. Eur. Respir. J. 34, 914–920 (2009).
60 Marklund M, Stenlund H, Franklin KA. Mandibular advancement devices in 630 men and women with obstructive sleep apnea and snoring: tolerability and predictors of treatment success. Chest 125, 1270–1278 (2004).
� Mandibular advancement devices were shown to be more useful in women than in men in reducing OSA severity. In women, mild OSA predicted treatment success, whereas complaints of nasal obstruction were associated with therapy failure.
61 Battagel JM, Johal A, L’Estrange PR et al. Changes in airway and hyoid position in response to mandibular protrusion in subjects with obstructive sleep apnoea (OSA). Eur. J. Orthod. 21, 363–376 (1999).
62 McGown AD, Makker HK, Battagel JM, L’Estrange PR, Grant HR, Spiro SG. Long-term use of mandibular advancement splints for snoring and obstructive sleep apnoea: a questionnaire survey. Eur. Respir. J. 17, 462–466 (2001).
63 Elshaug AG, Moss JR, Hiller JE, Maddern GJ. Upper airway surgery should not be first line treatment for obstructive sleep apnoea in adults. BMJ 336, 44–45 (2008).
64 Sundaram S, Bridgman SA, Lim J, Lasserson TJ. Surgery for obstructive sleep apnoea. Cochrane Database Syst. Rev. 4, CD001004 (2005).
65 Elshaug AG, Moss JR, Southcott A, Hiller JE. Redefining success in airway surgery for obstructive sleep apnea: a meta-analysis and synthesis of the evidence. Sleep 30, 461–467 (2007).
66 Franklin KA, Anttila H, Axelsson S et al. Effects and side-effects of surgery for snoring and obstructive sleep apnea. A systematic review. Sleep 32, 27–36(2009).
67 McGinley BM, Patil SP, Kirkness JP, Smith PL, Schwartz AR, Schneider H. A nasal cannula can be used to treat obstructive sleep apnea. Am. J. Respir. Crit. Care Med. 176, 194–200 (2007).
68 Conwell W, Patel B, Doeing D et al. Prevalence, clinical features and CPAP adherence in REM-related sleep-disordered breathing: a cross-sectional analysis of a large clinical population. Sleep. Breath. 16, 519–526 (2012).
69 Dancey DR, Hanly PJ, Soong C, Lee B, Hoffstein V. Impact of menopause on the prevalence and severity of sleep apnea. Chest 120, 151–155 (2001).
70 Shahar E, Redline S, Young T et al. Hormone replacement therapy and sleep-disordered breathing. Am. J. Respir. Crit. Care Med. 167, 1186–1192 (2003).
� In this large study, the prevalence of OSA in women who used hormone-replacement therapy was approximately half the prevalence of nonusers. Hormone treatment was identified as an independent predictor associated with a lower prevalence of OSA.
71 Manber R, Kuo TF, Cataldo N, Colrain IM. The effects of hormone replacement therapy on sleep-disordered breathing in postmenopausal women: a pilot study. Sleep 2, 163–168 (2003).
72 Pickett CK, Regensteiner JG, Woodard WD et al. Progestin and estrogen reduce sleep-disordered breathing in postmenopausal women. J. Appl. Physiol. 66, 1656–1661 (1989).
73 Cistulli PA, Barnes DJ, Grunstein RR, Sullivan CE. Effect of short term hormone replacement in the treatment of obstructive sleep apnoea in postmenopausal women. Thorax 49, 699–702 (1994).
74 Block AJ, Wynne JW, boysen PG, Lindsey S, Martin C, Cantor B. Menopause, medroxyprogestrone, and breathing during sleep. Am. J. Med. 70, 506–510 (1981).
75 Saaresranta T, Polo-Kantola P, Rauhala E, Polo O. Medroxyprogesterone in postmenopausal females with partial upper airway obstruction during sleep. Eur. Respir. J. 18, 989–995 (2001).
76 Cook WR, Benich JJ, Wooten SA. Indices of severity of obstructive sleep apnea syndrome do not change during medroxyprogesterone acetate therapy. Chest 96, 262–266 (1989).