Gender differences in obstructive sleep apnoea, insomnia and restless legs syndrome in adults – What do we know? A clinical update

Accepted Manuscript Gender differences in obstructive sleep apnoea, insomnia and restless legs syndrome in adults - what do we know? A clinical update Jenny Theorell-Haglöw, Ph.D., Christopher B. Miller, Ph.D., Delwyn J. Bartlett, Ph.D., Brendon J. Yee, Ph.D., Hannah D. Openshaw, B.Sc., Ronald R. Grunstein, Ph.D. PII:

S1087-0792(17)30061-8

DOI:

10.1016/j.smrv.2017.03.003

Reference:

YSMRV 1024

To appear in:

Sleep Medicine Reviews

Received Date: 3 October 2016 Revised Date:

20 March 2017

Accepted Date: 20 March 2017

Please cite this article as: Theorell-Haglöw J, Miller CB, Bartlett DJ, Yee BJ, Openshaw HD, Grunstein RR, Gender differences in obstructive sleep apnoea, insomnia and restless legs syndrome in adults what do we know? A clinical update, Sleep Medicine Reviews (2017), doi: 10.1016/j.smrv.2017.03.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT TITLE: Gender differences in obstructive sleep apnoea, insomnia and restless legs

RUNNING HEAD: Gender differences in common sleep disorders

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syndrome in adults - what do we know? A clinical update.

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Jenny Theorell-Haglöw1,2*, Ph.D., Christopher B Miller1, Ph.D., Delwyn J Bartlett, Ph.D., Brendon J Yee1, Ph.D., Hannah D Openshaw1, B.Sc., Ronald R Grunstein1, Ph.D. CIRUS, Centre for Sleep and Chronobiology, Woolcock Institute of Medical Research,

University of Sydney, Australia 2

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Department of Medical Sciences, Respiratory, Allergy and Sleep Research, Uppsala

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University, Sweden

Work performed at: The Woolcock Institute of Medical Research

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* Corresponding author:

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Jenny Theorell-Haglöw

Department of Medical Sciences, Respiratory, Allergy and Sleep Research, Uppsala University, Sweden

[email protected]; [email protected] Telephone: +46 18 6110242 Fax: +46 18 6110228

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ACCEPTED MANUSCRIPT Word count: 6,247

ACKNOWLEDGEMENTS

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The authors have no conflicts of interest.

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ACCEPTED MANUSCRIPT SUMMARY Research in sleep medicine over the last decades has involved a broad variety of sleep disorders in both men and women. Gender differences have been identified in sleep physiology as well as in the three most common sleep disorders: obstructive sleep

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apnoea (OSA), insomnia and restless legs syndrome (RLS). However, research on gender differences in sleep medicine appears limited. This clinical review aims to give an

updated overview of gender differences, in relation to prevalence, clinical presentation,

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treatment and quality of life in OSA, insomnia and RLS. Future research directions in the

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adult population will also be discussed.

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KEYWORDS

ALFF BMI

apnoea-hypopnea-index

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AHI

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GLOSSARY OF TERMS

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Gender, sleep apnoea, insomnia, restless legs, review, clinical

amplitude of lower frequency fluctuation

body mass index

CBT-I

cognitive behavioural treatment for insomnia

CPAP

continuous positive airway pressure

EEG

electroencephalogram

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Epworth Sleepiness Scale

FSH

follicle-stimulating hormone

HRT

hormone replacement therapy

LH

luteinizing hormone

MAD

mandibular advancement devices

OA

oral appliances

OC

oral contraceptives

ODI

oxygen desaturation index

OSA

obstructive sleep apnoea

PSG

polysomnography

NREM

non-rapid eye movement

RERA

respiratory effort related arousal

REM

rapid eye movement

RLS

restless legs syndrome

TST UARS

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SWS

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ESS

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ACCEPTED MANUSCRIPT

slow wave sleep total sleep time

upper airway resistance syndrome

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ACCEPTED MANUSCRIPT INTRODUCTION General sleep physiology changes both with age and gender(1-3). Although changes in objective sleep seem to be generally the same for both sexes women seem to have longer total sleep time (TST) and sleep latency but also less slow wave sleep (SWS) compared

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with men of same age(3). In addition, observational studies on general sleep physiology in adult populations have found gender differences with women showing better

objective sleep quality with shorter sleep onset latency, better sleep efficiency and

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longer TST than men using home actigraphy(4) or in-lab polysomnography (PSG)(1). In addition, indicators of objective good sleep (TST, sleep efficiency and arousals) seem to

subjective sleep complaints(5).

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decrease faster across age in men than in women, whereas the opposite is seen for

Disorders such as anxiety and depression have an impact on sleep and are more

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common in women(2, 6) which could be argued to contribute to gender differences in general sleep. However, hormonal changes after puberty has been suggested as a factor contributing to gender differences in sleep seen in the adult population(2, 7). Across

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male adulthood, sex steroid levels show a slow linear decline with age(8, 9) and studies

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on sleep restriction in young men show that sleep disturbances appear to induce hormone changes with reduced levels of circulating testosterone(10). Contrary to this, throughout female adulthood sex steroid levels are characterized by the monthly cycles of menses and in addition, the reproductive milestones of menarche, pregnancy, breastfeeding, and menopause which impact sex steroid exposure(11). Differences in objective sleep and subjective symptoms across the menstrual cycle found the luteal phase is associated with longer sleep latency, lower sleep efficiency, less percentage SWS, more awakenings and arousals and poorer subjective sleep quality(12-14) compared with the 5

ACCEPTED MANUSCRIPT follicular phase. Most knowledge in hormonal effects on sleep comes from studies in animal models(12) and have shown that female sex hormones impact on sleep, with peaks in oestradiol and progesterone being associated with increased number of awakenings and more time spent awake(15). Therefore it is possible that gender

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differences developing after puberty are likely, at least in part, to relate to hormonal differences rather than just higher rates of disorders such as anxiety and depression

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previously noted in women(2, 6).

Over the last three decades, research in sleep medicine has covered several sleep

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disorders; the most common being obstructive sleep apnoea (OSA), insomnia and restless legs syndrome (RLS). Studies in adults have included both men and women; however, the focus on gender differences in sleep medicine and their clinical impact in common sleep disorders are relatively unexplored, although some clinically focused

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reviews have covered this area, the most recent one published in 2006(2). Therefore, the aim of this review was to give an updated clinical overview of gender differences in the three most common sleep disorders, OSA, insomnia and RLS, in the adult population,

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with focus on prevalence, clinical presentation, treatment and impact on quality of life.

GENDER DIFFERENCES IN COMMON SLEEP DISORDERS Obstructive sleep apnoea OSA is the most common form of sleep apnoea, characterized by recurrent episodes of breathing cessation due to complete or partial obstruction of the upper airway and associated with oxygen desaturations and/or sleep fragmentation.

Prevalence 6

ACCEPTED MANUSCRIPT OSA is highly prevalent(16-18) in both population-based studies and clinical cohorts. In the landmark study of the Wisconsin Sleep Cohort (352 men and 250 women, 30-60 years) 24% of the men and 9% of the women were found to have OSA (apnoeahypopnea-index; AHI≥5) whereas 4% of the men and 2% of the women had OSA

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syndrome defined as AHI≥5 plus excessive daytime sleepiness(19). Since then several population-based studies have added to this OSA prevalence. In a recent review on the epidemiology of sleep apnoea Franklin et al. present an overview of the 9 population-

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based studies performed by 2013(17). Together the studies show a prevalence of OSA defined at an AHI ≥5 to have a mean of 22% (range, 9-37%) in men and 17% (range, 4-

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50%) in women(17). Since this review, other publications(16, 18) can be added suggesting a mean prevalence of 27.3% (range, 9-86.0%) for OSA in men and 22.5% (range, 3.7-63.7%) in women. The prevalence of the OSA syndrome occurred in 6% (range, 3-18%) of men and in 4% (range, 1-17%) of women when adding the numbers

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from the newer studies(16, 18) to the review by Franklin et.al(17). Therefore, there is consistent evidence that OSA is more common in men than women in the general population with a male-to-female ratio of approximately 1.5:1. Prevalence data for the

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OSA syndrome is presented in Figure 1.

OSA increases throughout life in both sexes(20) whereas it appears that the OSA syndrome decreases in the elderly in both sexes(21). This may relate to a reduction in sleepiness in the elderly or perhaps a survivor effect where OSA impacts on mortality in middle aged(22). It has also been proposed that there may be cardioprotective effects of chronic intermittent hypoxia and that apnoeas during sleep may activate adaptive pathways in the elderly(23).

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ACCEPTED MANUSCRIPT Gender differences in upper airway anatomy and function exist with women having a more stable upper airway thereby being less susceptible to OSA(23-27). In addition, men and women differ in ventilatory response to chemical stimuli with men more susceptible to the influence of chemical stimuli than women(28, 29). Furthermore,

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increased abdominal and neck fat is more common in men and associated with OSA(30). These are all factors that could influence the gender difference in OSA prevalence.

Although, hormonal effects could play an important role in the pathogenesis of OSA, as

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the prevalence seems to be higher in post- versus pre-menopausal women(31, 32), the pathophysiological roles of hormones are still unclear. The gender differences in

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prevalence also remains in the elderly(18, 33) showing that factors other than hormones play a role.

Clinical presentation

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Polysomnographic features

Several studies have shown women to have lower AHI, more partial obstruction and shorter events compared with men(30, 34). O’Connor and co-workers showed in one of

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the largest studies of polysomnographic features of OSAS(35) that although severity of

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sleep apnoea was similar in women and men during rapid eye movement (REM) sleep, women had less severe OSA during NREM sleep, thereby having a larger proportion of their respiratory events during REM sleep compared with men, and also a higher prevalence of REM related sleep apnoea events(35). Men on the other hand, had OSA event more frequently in the supine position. The results were not dependent on age or weight and there was also no evidence of an influence of medications, such as antidepressants(35). Women also seem to have more respiratory effort related arousal (RERA) events and upper airway resistance syndrome (UARS)(30). Later studies have 8

ACCEPTED MANUSCRIPT shown similar results (20, 34-36) however, the clinical relevance of these results are still unclear and this may also indicate that women do not have less sleep disordered breathing but do not fit exactly with current scoring criteria and therefore could be

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undertreated.

Symptoms of OSAS

The male-to-female referral ratio in clinical populations is reportedly higher than the

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male-to-female ratio in population-based studies(37, 38) and several reasons could be responsible for the shown gender discrepancy between clinic and community

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populations. One reason could be that women are less likely to seek help for OSA symptoms compared with men. However, women with OSA are shown to have a high health care consumption(39) and have significantly more frequent physician visits and hospitalizations prior OSAS diagnosis than men(40). Thus, this rather suggest that

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medical care providers fail to suspect or to diagnose OSA in female patients(34). Some studies argue that women do not show the OSA classic symptomatology (i.e. less likely to have an Epworth Sleepiness Scale (ESS) score of >10 although feeling sleepy at similar

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rates(41)), fewer complaints of snoring and apnoeic episodes but more complaints of

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insomnia, RLS, depression, nightmares, palpitations, and hallucinations(42), and are thereby being under-diagnosed(43). Data from the Wisconsin Sleep Cohort show that men and women with AHI>20/h are diagnosed with with OSAS to the same extent however, fewer women than men are diagnosed if having an AHI of 5-20/h(44) and previous publications have argued that this may be due to gender differences in symptoms at lower AHI, particularly regarding excessive daytime sleepiness, habitual snoring, and witnessed apnoeas(34). In addition, community sample data as well as data from relatively large clinical cohorts have shown women to more often report insomnia, 9

ACCEPTED MANUSCRIPT difficulties falling asleep, and awakening with leg cramps than men(41) or have a diagnosis of insomnia or depression at the time of OSA diagnosis(42, 45), thereby stating that women are more likely to suffer from “atypical” symptoms. Greenberg-Dotan and co-workers also show that women had more treatment with antipsychotics, anxiolytics,

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and/or antidepressants and they suggest that women with OSA more often suffer from insomnia, anxiety, and depression(39). However, as insomnia, anxiety and depression are all more common in women in the general population(46) one would expect to find

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more women than men with these symptoms. In addition, a recent study in a large

cohort of insomnia patients found that similar to gender differences reported in general

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population studies, men had a greater OSA prevalence than women(47). Also, it was recently shown that the prevalence of major depression in OSA is 6% in a general OSA patient sample there is no difference in the prevalence between sexes(48). Similarly, gender differences in excessive daytime sleepiness in OSAS, with sleepiness being more

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pronounced in female patients have been shown(42) however, because of the strong relationship between excessive daytime sleepiness and complaints of fatigue, depression and/or insomnia, these symptoms are also more commonly reported by

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women(34). Nonetheless it is also possible that long-term effects of disruption of REM

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sleep shown in women, may contribute to explain why women are symptomatic at lower apnoea-hypopnea-index compared with men(34).

Contrary to studies showing gender differences in symptoms, there are several clinical studies showing no gender differences in symptomatology after matching or adjusting for factors such as age, AHI, body mass index (BMI) and ESS(45, 49, 50) although some of them(44) may have been underpowered to detect a gender-specific difference in these symptoms due to low numbers of women with AHI >15 /h being included. 10

ACCEPTED MANUSCRIPT Nonetheless, women seem to present less frequently with a primary complaint of witnessed apnoeas(45) whereas men tend to have sleeping partners who were more concerned about witnessed apnoeic events(38). This is consistent with women more often coming alone to clinical interviews(51) and overweight women who snore are 7

events may be under-reported or under-observed in women.

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times more likely to be divorced compared with matched men(52). Snoring and apnoeic

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Finally, there is the possibility of OSA not presenting differently by gender but

differently by individual. Supporting this theory is data from a recent large clinical

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cohort study(53) where cluster analysis showed three distinct clusters of OSA patients: the ‘‘disturbed sleep group’’, the ‘‘minimally symptomatic group’’, and the ‘‘excessive daytime sleepiness group’’. In the study, there were no differences in terms of gender, BMI, AHI, and hypoxia variables between clusters. The authors conclude that because of

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these different patterns of clinical presentation there is need for offering more personalized therapies in the future(53). Regardless of whether women present with so called “atypical symptoms” or not it is clear that women have symptoms relating to OSA

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and that they do seek medical help for these symptoms. It is up to the medical

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professionals to assess this further and think of potential differential diagnosis.

Treatment

OSA treatment is generally focused in three main areas: continuous positive airway pressure (CPAP), oral appliances (OA)/mandibular advancement devices (MAD) and weight loss, with CPAP being the cornerstone of treatment.

CPAP 11

ACCEPTED MANUSCRIPT CPAP has proven effective in several studies and treating OSA has shown to reduce morbidity(54, 55) as well as morbidity(56, 57). In addition, in patient cohorts long-term follow-up of CPAP treatment show reduction of sleep maintenance insomnia in both sexes, whereas symptoms of sleep onset insomnia and early morning awakening

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insomnia seem to persist regardless of CPAP treatment(58). Although improvement in clinical outcomes such as apnoea symptoms, neurobehavioral performance, mood state and functional status does not vary by gender(59), Mermigkis et al.(60) have

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demonstrated in a large patient cohort, that CPAP therapy seems to reverse elevated markers of systemic inflammation faster in men than women which may indicate gender

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differences in CPAP effects on cardiovascular risk factors. However, future studies on the role of gender for outcome response to CPAP treatment needs to be conducted.

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Studies have shown gender differences in the level of CPAP pressure required to treat OSA with both a cross-sectional Japanese case-control study and a retrospective US study showing that female patients require significantly lower levels of CPAP than male

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patients matched for BMI(61) or after correction for the severity of OSA(62). These observations are in line with evidence of a lower pharyngeal critical closing pressure in

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women(23). A specific CPAP treatment algorithm for women has been recently tested(63), showing significant treatment effectiveness but the difference was small and the clinical relevance at this point is certainly questionable(63).

Although CPAP is highly efficacious when used, adherence is a significant problem(64). Factors such as use of oro-nasal mask, low effective pressure and side-effects have, in a prospective cohort study, all been associated with poor adherence also after adjusting for potential confounders including gender but also depression(65), indicating that 12

ACCEPTED MANUSCRIPT gender may be of less importance for poor adherence. Furthermore, sleep onset insomnia and early morning awakening insomnia also negatively affect adherence(58). There are conflicting evidence as to whether there are gender-related differences in CPAP usage with a Canadian long-term population-based study showing higher CPAP

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usage in female OSAS patients(66) whereas a more recent study in German patients showed slightly higher CPAP usage in m(67). However, there seems to be a paucity of

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Non-CPAP therapies for OSAS

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studies on the role of gender on CPAP acceptance and adherence.

Oral appliances and weight loss are the most common treatment alternatives to CPAP. Oral appliances are devices that reposition the lower jaw and soft tissue structures of the mouth to increase upper airway size during sleep, and are a primary treatment

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option for adults with mild to moderate OSA and for those who cannot tolerate CPAP. A review by Lin et al. state that oral appliances have been shown to be less effective in reducing the AHI(28) with a rate of treatment success (AHI<10) collectively from results

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of randomized, crossover, placebo-controlled studies of approximately 50%(68)

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although a later randomized controlled trial did not CPAP to be inferior to MAD(69). However, to our knowledge there are to date no systematic studies or meta-analysis of gender differences in regards to the efficacy of non-CPAP therapies for OSAS. To date there is also only one study performed in a clinical cohort that has examined sex differences in OA treatment response(70). In this patient cohort women were more than twice as likely to experience treatment success compared with men possibly due to women enlarging their pharynx more than men during OA treatment despite having a more narrow pharynx than men(70). Having mild OSA was predictive of treatment

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ACCEPTED MANUSCRIPT success in both sexes, however having OSA predominantly in supine position predicted treatment success only in men whereas in the patients with non-supine OSA women showed better treatment success(70).

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As excess weight is a strong determinant of OSA risk(71), lifestyle interventions focusing on weight loss are commonly recommended in all management of OSA(72). Weight loss has been associated with a smaller AHI reduction in women compared with men(73).

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Nonetheless, the randomized trial “Sleep AHEAD” has shown that intensive lifestyle interventions are more effective at reducing AHI in women compared with men at both

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short term (1 year)(74) and long-term (4 years) despite weight gain between follow-up visits(75). However, no studies have specifically examined the efficacy, predictors, or outcomes associated with weight loss therapies focusing on gender differences.

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Finally, while some earlier experimental studies found HRT to reduce OSA severity in postmenopausal women(76), more recent placebo-controlled, randomized, doubleblind, parallel-group studies have failed to show such an effect(77). Given the

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inconsistent findings of HRT on treatment efficacy, HRT is not recommended specifically

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for treating OSA in postmenopausal women(78).

Impact on quality of life

OSA has a known impact on quality of life and functional status (a component of quality of life that describes the burden of living with a disease), even in patients with mild OSA(79). In addition, depression, poor sleep quality, daytime sleepiness, minimum oxygen saturation level, BMI and age are all related to physical as well as mental quality of life in OSA patients, with depression being the strongest predictor(80). However, 14

ACCEPTED MANUSCRIPT objective measures such as AHI or oxygen desaturation index (ODI) does not seem correlated with quality of life in OSA(80). On the other hand, gender differences in quality of life and functional status of OSA patients have not been well investigated. A large case-control study in OSA patients reported that compared with men with similar

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OSA severity, women reported lower perceived health status and poorer functional

status and it was further hypothesized that the lower functional status in women could partly explain their higher health care consumption(39). In addition, in a multi-centred

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international study of CPAP treatment women report lower functional status, especially in activity levels and general productivity despite similar age, degree of obesity, and OSA

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severity(59). Recent data from the the Sleep Heart Health Study show that the impact of OSA on quality of life is different for men and women showing larger effects in women, largely explained by presence of daytime sleepiness(81) Nonetheless, it is still unknown whether menopausal or hormonal status and also presence of psychological symptoms

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in women contribute to this difference. In addition, as different instruments may assess different aspects of quality of life and correlations among quality of life instruments are not high(81) there is a pressing need for a reliable measures of quality of life for patients

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with OSA and studies assessing gender difference in quality of life and also address

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factors such as menopausal status and concurrent medical and psychological conditions. Finally, with a better understanding of the impact of OSA on quality of life and functional status in both sexes we can help develop appropriate additions to traditional treatments for OSA.

Insomnia

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ACCEPTED MANUSCRIPT Clinical insomnia is a heterogeneous disorder that is characterized as a complaint of dissatisfaction with sleep quantity or quality and is associated with one (or more) of the following symptoms including: difficulty initiating or maintaining sleep (frequent awakenings or problems returning to sleep) or early-morning awakening with an

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inability to return to sleep (82). The disturbance must also significantly impact daytime functioning and occur three nights per week for at least three months to be considered

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chronic (82).

Prevalence

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Insomnia is a highly prevalent condition in the general population, with estimations of prevalence ranging from 10% to 40% depending on whether it is viewed as a symptom (30% prevalence) or a specific disorder (5-10% prevalence) (83-85). Overall, clinical insomnia appears prevalent in about 10% of the population worldwide(85, 86). These

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wide estimations are due to differences in the definition of insomnia (for an overview please see(83, 84)). Consistent changes to both the Diagnostic and Statistical Manual of Mental Disorders (DSM-5)(82) and the International Classification of Sleep Disorders

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(ICSD-3)(87) now consider insomnia as a specific disorder which may help limit the

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variable range in the future. Female sex is a risk factor for insomnia(46, 88, 89) and gender differences are thought to begin in adolescence with the onset of menstruation(90). From the HUNT-2 population cohort study from Norway, 13.5% of patients reported insomnia symptoms and the prevalence was found to interact with age and gender. The prevalence in older women (aged 80-89 years) was 32% compared to 20% for older men(91). Previous research has established that women are about 1.25 times more like to suffer from insomnia than men (46, 85, 92-95). However, there is a

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ACCEPTED MANUSCRIPT paucity of studies exploring why women appear to be more vulnerable to insomnia compared with men. Figure 1 shows prevalence (with range) by gender, for insomnia.

Clinical presentation

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Insomnia presents often as a longstanding distressing difficulty with sleep quality or quantity despite adequate sleep opportunity. Insomnia has previously been classified according to a number of subtypes including: psychophysiological (specific trigger often

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accompanied by hyperarousal / hypervigilance; stress response); idiopathic (extending from childhood with cause unknown); sleep state misperception insomnia (discrepancy

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between subjective reports and objective measures of sleep duration)(96). These however have now been collapsed into a single diagnosis due to a lack of clinical utility(87, 97).

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Women present more frequently to health care providers with insomnia than men(98) and the proportion of female patients with insomnia presenting to family physicians in Australia has remained steady at about 60% from 2000-15(99). Elderly women are also

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more likely to suffer from chronic insomnia than men, possibly representing the fact

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that women tend to live longer, but there are also changes across all ages(100). Longitudinal and meta-analytic studies have demonstrated an interaction between age and gender as women are more likely to develop insomnia in middle age (mid 30’s - mid 50’s) than men, and this has been shown to persist into older age (mid 50’s - mid 70’s) (46, 100). Attending family physician consultations is more common for women (101). This is most likely reflecting how women were the predominant child carers which required frequent visits for both the health of the child and mother. Other factors include difficulties with menopause and menstrual cycle and health checks with 17

ACCEPTED MANUSCRIPT pregnancy (102-104). In a large epidemiological study of insomnia symptoms from Quebec, Canada, women reported insomnia symptoms more frequently to their family physician compared with men who were more likely to visit a specialist(105). Women may therefore find it more normal to present and discuss other difficulties including

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insomnia compared with men. Until there is a comprehensive evaluation of the different presenting styles of men and women to primary care settings we will not be able to understand key components to why women are more likely than men to present

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clinically for insomnia.

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Although physiological factors can potentially and negatively impact on sleep they are unlikely to explain all aspects of gender in insomnia. Insomnia is also common in patients with breast cancer and is influenced by associated diagnostic anxiety and depression, fatigue, and treatment-related sleep disruption(106). The transition to

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menopause plus the development of other co-morbid conditions may precipitate and even trigger the onset of insomnia at this stage of life however other underlying gender

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Treatment

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vulnerabilities are less clear (100).

Pharmacotherapy and cognitive behavioural treatment (CBT-I) are the two main evidence-based treatment modalities for chronic insomnia. In primary care settings, hypnotics are predominately used to manage insomnia and although effective initially they lack long-term efficacy(107, 108).

Hypnotics may act differently in women than men due to different pharmacokinetics with implications for next day functioning including poorer driving performance(109). 18

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cases by 50% (Zolpidem and Eszopiclone)(110-112).

CBT-I is considered the first-line treatment for insomnia and consists of a

multicomponent psychological intervention delivered by a psychologist either

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individually, in small groups, or through automated web-based programs(108, 113). In the short-term (2-4 weeks) it is as effective as hypnotics but has lasting effects over time

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and is considered a better safety option compared to hypnotics (114). Gender does not appear to mediate CBT-I outcomes(105, 115). However, in all of these studies there were more women enrolled than men. Previously this finding was perceived as

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reflecting prevalence rates but may also be an example of gender acceptability to CBT-I.

In a small preliminary study, insomnia comorbid with pain appears to result in some gender treatment differences(116). Men displayed significant positive reductions in

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sleep disturbances along with reduced pain related anxiety and catastrophizing. Women

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showed improved sleep latency with reductions in general fatigue and depression(116). In a review paper, it was hypothesized that gender determined the differences in the perception and the experience of pain(117). In a laboratory study, men tended to exhibit a higher pain threshold compared with women(118) whereas women appear to catastrophize more, potentially increasing pain sensitivity. Coping styles are also different. Men tend to use active coping styles, using their own resources whereas women tend to rely on social support (119). Therefore, psychological factors and

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ACCEPTED MANUSCRIPT cognition, may explain some of the gender differences between men and women in comorbid conditions with insomnia.

Impact on quality of life

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Insomnia is considered a 24-hour disorder due to known impairments of sleep and also daytime performance relating to fatigue, concentration, memory, work, academic or social functioning(82). A perceived and noticeable amount of daytime impairment will

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drive the patient to seek help for their insomnia symptoms(120). In a long term 11 year prospective study, there was a strong bi-directional relationship between untreated

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insomnia and untreated depression(91). Sleep-disturbance is often a prodromal symptom of depression or a recurring bout of depression and must be taken into consideration in a clinical setting(121). There is a need to treat both mood and sleep disturbance equally(122, 123). However increased depressive symptoms such as very

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low mood in the morning impacts on what the individual can undertake in relation to a consistent rise time, morning bright light and exercise which are key components of CBT-I. Whether these comorbid-symptoms of insomnia are more prevalent in one

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gender remains to be determined. Evaluation of coping styles between genders may

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reveal why women are more likely to present and seek treatment. In a community sample with a one year follow-up, anxiety (OR=4.27) and depression (OR=2.28) at baseline were related to new insomnia cases at follow-up(124). Gender differences were not apparent in this prospective study(124). Perceived daytime disturbance and potential subsequent effects to quality of life appear to drive women to seek treatment at family physician consultations (105). Further evaluation of treatment seeking behaviours across genders is warranted. Interestingly enough, the impact of healthrelated quality of life appears dependent on physical, social and emotional 20

ACCEPTED MANUSCRIPT functioning(125) but gender is not an identifiable component of this. There appears a paucity of studies exploring gender differences re quality of life in insomnia.

Restless Legs Syndrome

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Restless Legs Syndrome (RLS) is a common, but underdiagnosed neurological

sensorimotor disorder characterised by an urge to move the legs, usually accompanied or caused by uncomfortable and unpleasant sensations with symptoms increasing

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during periods of rest or inactivity(126). Symptoms are modulated by circadian rhythm, being worse in the evening and/or night(127) and therefore having a profound effect on

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sleep onset and return to sleep, and an increasing risk of developing anxiety and depression(128). RLS can be classified as either primary or secondary (related to or

Prevalence

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caused by another condition).

RLS is prevalent in the general population and in a review of 47 large population-based studies Ohayon et al. showed that a prevalence of RLS has been assess using different

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methods thereby giving a range from 1.9 to 15% in the general population(129, 130)

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with epidemiological studies identifying a significant adult female gender bias in the prevalence of RLS, which is not seen in children or teenagers. Factors such as a patients self-reporting their symptoms, the lack of uniform diagnostic criteria, various study designs, or different methods of data collection have all been argued to contribute to this variance(131) Yeh et al. showed in a review of large epidemiologic studies that there were gender differences in the rate of RLS in the general population with a prevalence of 5.0% (range 2-9.4%) in men and 8.8 (range 2.3-15.4%) in women(131). Since the review by Yeh et al. other studies showing prevalence for both men and women (132, 21

ACCEPTED MANUSCRIPT 133)can be added suggesting a mean prevalence of 4.6% (range 2-9.4%) in men and 8.6 (range 2.3-15.4%) in women. The onset of this disorder appears to begin in young adulthood, with the male-to-female ratio being approximately 1:1.5 in the general adult population, increasing in middle age and the elderly to 1:2(134) and from the review by

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Yeh et al. together with later studies the male-to-female ratio is approximately 1:2(131). Possible explanations for this gender bias including pregnancy, sex hormones and iron status which will be explored further in the following section. Figure 1 shows prevalence

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Clinical presentation

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(with range) by gender, for RLS.

As shown RLS is more common in women and several possible explanations for this are possible, the most common being pregnancy, sex hormones and iron status which will be explored further in this section. Studies on gender differences in clinical presentation

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are sparse however, in a group of 158 men and women Bentley et al. showed gender differences in sleep-related symptoms such as involuntary movements when awake, sleep onset difficulties or frequent awakenings at night, with women more often

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presenting the combination of all these symptoms. There was no difference for men and

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women in duration of RLS, incidence of family history, number of affected days per week, or severity of daytime sleepiness(135). In a review by Yeh et al. it was reasoned that due to gender differences in self-perception of suffering from illness symptoms, women report symptoms at a lower severity level compared with men(131). However, Yeh et al. further state that more studies are needed to consider the sexual difference in terms of perception of pain to see whether gender differences are a true demographic phenomenon(131).

22

ACCEPTED MANUSCRIPT Pregnancy Around 20% of women will develop restless legs symptoms during pregnancy, albeit transitory and usually resolving at the end of the pregnancy(134) and is therefore a form of secondary RLS. What causes RLS to develop in pregnancy is currently unknown,

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however hormonal changes, lower iron levels and genetic predisposition are likely(129). Just having been pregnant doubles a woman’s risk of developing RLS in later life(126). A long-term follow-up study showed the incidence of chronic idiopathic RLS was 4-fold

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increased in women who had transient RLS during pregnancy than those he did not have RLS(136). A German population-based study found nulliparous women had a similar

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prevalence level as men. The study also found that risk increases with more children(137). Most women who experience RLS during pregnancy have a positive family history of the condition, suggesting a genetic link. Further support for this premise is that not all pregnant women develop RLS, suggesting pregnancy acts as a risk

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factor in those who have a genetic predisposition(136). As in women without RLS before pregnancy women with RLS have an increased prevalence of symptoms during pregnancy and in addition, moderate to severe pre-pregnancy RLS increase risk of both

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EP

antenatal and postnatal depression(138).

Hormonal influences

In women of child bearing age and older, hormones fluctuate on a weekly and monthly basis in relation to the menstrual cycle, pregnancy and menopause. This constantly fluctuating hormonal status in women but not men, suggests a cause for the gender differences seen in RLS prevalence. However, current evidence for the role of hormones is inconsistent and inconclusive and if hormonal changes are involved, then the expression and perception of symptoms would be expected to change accordingly with 23

ACCEPTED MANUSCRIPT the cycles, but this remains unsubstantiated(139). The development of RLS symptoms in many women during pregnancy again suggests a hormonal influence, with substantial increases in oestrogens, progesterone and prolactin(134). As not all pregnant women develop the condition, hormones cannot be the sole cause, however their role may be

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linked with their interactions with neurotransmitters such as dopamine(140).

Furthermore, in older women, HRT during menopause does not completely reverse the age-related changes in sleep seen in women and does not lead to an increase in

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prevalence of RLS(141). Adding to this dilemma the prevalence of RLS in trans-sexual patients undergoing hormonal therapies (either with testosterone or oestrogen

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treatments) were no different although the study was underpowered(142).

Iron status

Evidence for the effect of iron on the development of RLS is not clear-cut. After this

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point, serum ferritin levels in men increase greatly to around 250-200mg/l between the ages of 30-50, while women increase only very slightly between ages 15-49 years, to averages of around 35-40mg/l(141). These age related difference are often attributed

EP

to the gender differences in RLS, but do not occur until after the age of 30, which is 15

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years after the gender differences in serum ferritin develop(141). Gender differences in serum ferritin do not appear to increase the risk of RLS unless there is an additional stress, such as pregnancy, to the iron stores(141). Although low serum ferritin before, or in the early stages of pregnancy have been argued as a predictor of RLS developing during pregnancy(141), this cannot be considered the only factor involved as RLS symptoms quickly disappear after birth, while iron levels will take longer to restore(140). In addition, it has recently been reported in a local population study of repeat blood donors in Belgium(143) that many RLS sufferers have normal level of 24

ACCEPTED MANUSCRIPT serum ferritin and peripheral iron stores(141, 144). Low serum folate was shown to be associated with RLS in pregnant women however this finding was not replicated in a larger latter study(145). Nonetheless, conditions in which iron status is deficient (such as pregnancy, end-stage renal disease) have been shown to increase the risk of RLS, and

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in most cases, treatment of the deficiency reduces severity(129).

Other factors associated with the development of RLS may be related to low brain iron

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status in cerebrospinal fluid measurement and have indicated that low brain iron status may influence the development of RLS(134, 141). Reduced iron levels have been

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identified in the substantia nigra, and in the putamen, caudate and thalamus(144). As many studies suggest RLS patients do not have abnormal iron status, the pathophysiology of RLS may involve regional brain iron deficiency which requires

Treatment

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further exploration(144).

The current standard treatment of RLS is pharmacologic, most commonly with

EP

dopaminergic drugs, along with other non-dopaminergic agents also used(146). While

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randomized clinical trials have demonstrated their effectiveness, relief of symptoms is often incomplete particularly in the setting of neuropsychiatric comorbidity(147). These drugs are susceptible to loss of efficacy over time(148) and also augmentation(149) and therefore do not generally provide an effective long term treatment.

For women who suffer RLS during pregnancy, the first method of treatment usually involves behavioural, non-pharmacological methods such as reassurance, avoidance of exacerbating factors such as iron deficiency, moderate exercise, dietary changes, 25

ACCEPTED MANUSCRIPT stretching and massaging of the legs, showering on the backs of calf muscles particularly at night, and the use of compression devices(150).

There are currently few studies examining effects of standard dopaminergic treatments

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during pregnancy (after the first trimester) for it to be considered a safe option, but if there is a high severity of RLS, drug therapy may be used(150). Low dose opioids are considered relatively safe for use during pregnancy while there is inconclusive evidence

SC

on the safety of benzodiazepines and anticonvulsants(151). Due to possible links with low ferritin levels, iron supplementation may be prescribed, and is considered

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safe(152). In a long term study of pramipixole no gender differences have been found in treatment response rates, augmentation or tolerance(153). Limited treatment options exist for pregnant women with both RLS and depression. It is still unclear if RLS

Impact on quality of life

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treatment will have an impact on depressive symptoms(138).

Studies investigating gender differences in health related quality of life have reported

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worse results for women in general, yet there is disagreement around the reasons for

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these results(141). When assessing quality of life in RLS it is shown that RLS does have a negative impact on quality of life in both men and women and that RLS affects both physical and mental aspects of health related quality of life, however no differences between men and women have been established(141). Therefore, more studies are needed to investigate whether there is a gender difference and how it may impact on the different genders.

LIMITATIONS 26

ACCEPTED MANUSCRIPT This was a non-systematic clinical review covering the three most common sleep disorders. We chose to focus on prevalence, clinical presentation, treatment and impact on quality of life for each disorder as these are all clinically important areas. Due to the non-systematic approach, there is a risk of not including every pertinent gender study

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over all three sleep disorders. However, the search of the literature was made in

PubMed, selected journals, and reference lists of located manuscripts where the search criteria were adult male and female participants, publication date preferably after 2006

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(when the latest clinical review was published), and data on prevalence, clinical

presentation, treatment or quality of life. The literature search showed that studies

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aimed at specifically studying gender differences are sparse and the review therefore presents an overview of what we know on the three most common sleep disorders from studies in men, women and groups including both sexes. Another limitation is that we did not include other sleep disorders and therefore future research now needs to

CONCLUSION

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evaluate gender differences in specific sleep disorders with systematic reviews.

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This was a clinically aimed review using a careful selection of included references. We

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showed that there are also gender differences in the three most common sleep disorders, all of which impact sleep and also daytime function. While there are differences between men and women in hormonal status as well as in body composition, which may contribute to gender differences in diagnosis, clinical presentation and possibly treatment effect it is not likely that these are the only factors responsible for gender differences in sleep disorders and therefore further research is warranted. In addition, future research needs to evaluate gender differences in specific sleep disorders with a systematic approach. 27

ACCEPTED MANUSCRIPT Practice points •

OSA is more common in men than women in the general population with a maleto-female ratio of approximately 1.5:1. The male-to-female referral ratio in clinical populations is reportedly higher than the male-to-female ratio in

•

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population-based studies.

Previous studies collectively show that gender differences in characteristics of OSAS are seen in age (female patients are older (frequently post-menopausal)),

SC

have higher BMI, lower AHI, more REM-related OSAS and may require lower CPAP pressure. Some studies also argue that women with OSA show atypical

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OSAS symptoms although there are also studies not showing this difference but rather different cluster of patients and arguing that there is need for more personalized therapies in the future. •

Insomnia is both more severe and more prevalent in women however, why

unclear.

Hypnotics may act differently in women than men due to different

EP

•

TE D

women appear to be more vulnerable to insomnia compared with men is still

pharmacokinetics with implications for next day functioning. The effectiveness of

•

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CBT-I is not known to be mediated by sex. RLS onset begins in young adulthood with a clear predominance in women and increasing in middle age and the elderly. Pregnancy related RLS is a risk factor for future development of idiopathic RLS. Possible explanations for this gender difference include pregnancy, sex hormones and iron status.

28

ACCEPTED MANUSCRIPT Research agenda Future research on gender differences in sleep medicine should be focused at: •

The role of hormones and other factors that could explain gender differences in common sleep disorders needs further investigation. Most research in OSA is still focused on men yet there are gender differences, at

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•

least in the prevalence of OSA. Further investigation is needed to discern whether there are true gender differences in clinical presentation or if these differences

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are on an individual level. Research in middle aged women seems especially

important as this group experience the greatest increase in OSA prevalence and

•

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therefore may benefit the most from early detection and intervention. In insomnia, a crucial question is why women (especially in middle-late age) are more likely to suffer from chronic insomnia than men and several theories have been proposed including biological factors such as the menopause transition and

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development of other co-morbid conditions. These hypotheses require further evaluation in relation to treatment seeking behaviours which appear mediated by

•

EP

gender, perception of insomnia severity and quality of life. The factors behind the higher prevalence of RLS in women are complex and yet

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not fully understood. Further research in this area is required to determine causes and potential treatments based on gender.

•

Future research should explore the possibility to tailor treatment for common sleep disorders by gender.

•

Future research needs to evaluate gender differences in specific sleep disorders using a systematic approach.

29

ACCEPTED MANUSCRIPT FIGURE LEGEND Figure 1. Prevalence and range for obstructive sleep apnoea (OSA), insomnia, and restless legs syndrome (RLS), by gender. Male-to-female ratio (M/F ratio) is also

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presented for each sleep disorder. Data adapted from (16-18, 46, 131-133)

30

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