gender differences in treatment recommendations …...gender differences in treatment...

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


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.


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.



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,



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


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.


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

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-wee

k w

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s, s

ix o

f the

se

wom

en w

ere

also

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unde

r CPA

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eatm

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�14

day

s of

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impr

oved

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in th

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mal

es

The

impr

ovem

ent w

as m

aint

aine

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ks a

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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

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with

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P (-

0.8

± 0.

4 vs

-0

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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;

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: 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

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istu

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RR:

Rel

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k.



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.



� 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



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

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gender differences in treatment recommendations …...gender differences in treatment...

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