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Sleep during development: sex and gender differences

Patricia Franco, Benjamin Putois, Aurore Guyon, Aude Raoux, Maria Papadopoulou,
Anne Guignard-Perret, Flora Bat-Pitault, Sarah Hartley, Sabine Plancoulaine

PII: S1087-0792(20)30019-8
DOI: https://doi.org/10.1016/j.smrv.2020.101276
Reference: YSMRV 101276

To appear in: Sleep Medicine Reviews

Received Date: 20 December 2018

Revised Date: 16 November 2019
Accepted Date: 23 January 2020

Please cite this article as: Franco P, Putois B, Guyon A, Raoux A, Papadopoulou M, Guignard-Perret A,
Bat-Pitault F, Hartley S, Plancoulaine S, Sleep during development: sex and gender differences, Sleep
Medicine Reviews, https://doi.org/10.1016/j.smrv.2020.101276.

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© 2020 Published by Elsevier Ltd.

 1

Sleep during development: sex and gender differences

Patricia Francoa,b*, Benjamin Putoisa,b, Aurore Guyona,b, Aude Raouxa,b, Maria

Papadopouloua, Anne Guignard-Perreta,b, Flora Bat-Pitaultc, Sarah Hartleyd, Sabine

Plancoulainee

Affiliations:

a
Sleep Pediatric Unit, Woman Mother Child Hospital, Civil Hospices of Lyon, Lyon1

University, F-69500, France; b Physiology of Brain Arousal System Research laboratory,

CRNL, INSERM-U1028, CNRS UMR5292, Lyon1 University, Lyon, F-69000, France; c

Child and Adolescent Psychopathology Unit, Salvator Hospital, Public Assistance-Marseille

Hospitals, Aix-Marseille II University, Marseille, F-13000, France; d AP-HP Raymond

Poincaré Hospital, Sleep Unit, Physiology Department, 92380 Garches, EA 4047 Versailles-

St Quentin en Yvelines University, France; e INSERM, UMR1153, Centre of Research in

Epidemiology and StatisticS (CRESS), Team on research on EARly Origins of Health

(EAROH), Villejuif, F-94807 France, Paris-Descartes University, France.

Corresponding author: Patricia Franco, MD, PhD

Pediatric Sleep Unit, Woman Mother Child Hospital

59, boulevard Pinel, 69500 Lyon, France

Tel: (+33)427-856-052, Fax: (+33)427-869-230

e-mail: Patricia.Franco@chu-lyon.fr

Running title: Sex differences in sleep development

Conflict of interest: none in relation with this article

Specific funding: none

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SUMMARY

Sleep occupies a substantial proportion of life. Sleep modifications parallel brain

development during childhood. Sex and gender differences have been reported in brain

development and many clinical and psychosocial conditions. This narrative review provides

insight into the differences between girls and boys in terms of brain maturation and plasticity

related to sleep and sleep characteristics (physiology, sleep duration) during development.

KEYWORDS

Sleep; sex-specific; gender; maturation; infant; children; adolescents.

 3

ABBREVIATIONS

CI: Confidence interval

DIMS: Difficulty in initiating and maintaining sleep

DIS: Difficulty initiating sleep

DMS: Difficulty maintaining sleep

DOES: Disorders of excessive somnolence

EEG: Electroencephalogram

EMA: Early morning awakening

FS: Fast spindles

HPA: Hypothalamic–pituitary–adrenal

IQ: Intelligence quotient

MRI: Magnetic resonance imaging

NREM: Non-rapid eye movement sleep

OR: Odds ratio

PSG: Polysomnography

REM: Rapid eye movement sleep

SDSC: Sleep disorder scale for children

SS: Slow spindles

SWA: Slow wave activity

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1. INTRODUCTION

Sleep structure and characteristics evolve considerably throughout birth, childhood,

adolescence, and adulthood. Sleep development parallels brain development and maturation

up to adulthood. However, sleep features are likely to be determined through an interaction

between genetic and environmental factors, although their respective contributions are

unknown. It is important to note here that the distinction between “sex” and “gender” is not

an easy one. Herein, “sex” will refer to the biological (genitalia and genetic) differences

between males and females and “gender” to the more complex concept of gender with

reference to social and cultural differences rather than biological ones.

Sex and gender differences have been established for many clinical conditions such as

cardiovascular or autoimmune diseases, in endocrinology, neurology, and psychiatry[1] as

well as in different psychosocial conditions[1, 2]. However, few studies have been conducted

on the impact of sex differences on sleep maturation. Since sex differences have been

reported in brain structural volume from infancy to late adulthood[3, 4] this could argue in

favor of sex differences according to age in sleep development and characteristics.

This article aims to provide a narrative review of the differences between girls and boys in

brain maturation and plasticity related to sleep and sleep characteristics (sleep physiology

sleep architecture and duration) during development.

2. BRAIN MATURATION, PLASTICITY, SLEEP, AND COGNITION

Sex influences over brain maturation begins early in life. In a recent study, Makki et al.[5]

scanned 21 newborn aged 39 days (11 boys), during natural sleep, using diffusion tensor

imaging. The authors found that compared to boys, the inter-hemispheric fibers were more

developed in girls and that this could result from a larger axonal diameter, highly packed

fibers, or better-developed myelin sheath. This anatomical difference may in turn explain
 5

Thordstein et al.’s findings that demonstrated lower infra slow EEG activity during sleep and

increased EEG frequencies during wakefulness in full term girls, suggesting an earlier

maturation of cortical functions in girls compared to boys[6].

This earlier maturation may influence sleep: in a large study on 97 preterm infants (51 girls),

videotaped during 4-hour interfeeding intervals at 31 to 39 weeks postmenstrual, boys showed

less active sleep, were more drowsy, and showed less defined and more diffuse states during

wakefulness compared to girls[7]. Recently, Bach et al. showed that in healthy preterm

neonates (21 boys and 17 girls, 34 weeks of gestational age, studied at 37±2 weeks post-

conceptional age) boys slept less, presented more wakefulness after sleep onset, had more

active sleep and less quiet sleep than girls[8]. However, in preterm babies and neonates, the

existence of sex-related differences in sleep is still controversial [9-11].

The electroencephalogram (EEG) records the brain's spontaneous electrical activity over a

period of time and EEG power reflects the sum of inhibitory and excitatory postsynaptic

potentials in thousands of neural columns sampled by an individual electrode. Sleep slow

wave activity (SWA; EEG delta power between 0.75 and 4.5 Hz), reflecting sleep depth, has

an inverted U-shape with age. It increases in the first years of life, reaches its maximum

shortly before puberty, and declines throughout adolescence [3, 4, 12-14]. Recently, it has

been suggested that the topographic distribution of SWA during non-rapid eye movement

(NREM) sleep parallels cortical maturation from childhood through adolescence [15]. Indeed,

the age of fastest NREM delta decline has a similar distribution to that of maturational

cortical thinning measured by structural magnetic resonance imaging (MRI) [16], indicating

that SWA may be a marker of brain maturation. Ringli et al. showed, in 22 age-matched

children and adolescents (50% boys, mean age 13.4 years, range: 8.7–19.4 years), that girls

had higher slow wave sleep percentage and SWA power than boys[17]. Indeed, SWA during

the first 60 min of NREM sleep was higher in girls over bilateral cortical areas related to

language functions, while in boys SWA was increased over the right prefrontal cortex, a
 6

region also involved in spatial abilities. Gray matter thickness, based on magnetic resonance

image estimation, revealed that girls showed larger cortical thickness in the language related

clusters, while no significant difference was found in the frontal cluster. The authors

concluded that cortical areas governing functions in which one sex outperforms the other

exhibit increased sleep SWA and thus may indicate a maturation of sex-specific brain

function and higher cortical plasticity during development. Another characteristic EEG

feature of the NREM sleeping brain are slow (SSs, 11–13 Hz) and fast (FSs, 13–16 Hz)

spindles. These are also spatially dominant, in the frontal and centro-parietal cortex for the

SSs and FSs, respectively [18, 19]. Studies on sleep spindle modifications with age have

shown controversial results. Scholle et al. reported global U-shaped modifications for spindle

length and density between three months and 16 years of age, with a nadir around two years

and a plateau from five to 16 years[20]. Shinomiya et al. reported a decrease in the power of

SSs until the age of 13 years, but little change in the power of FSs between four and 24

years[21]. Individual profiles in sleep EEG spindles reflect the microstructural properties of

white matter tracts with high numbers of spindles being related to high axial diffusivity in

white matter structures[22]. Spindles have been shown to constitute a physiological index of

overall mental efficiency or intelligence[23]: SSs were shown to correlate with visual

perceptual learning[24], and FSs with more complex abilities and processes, such as fluid

intelligence (fluid-IQ)[25], visuo-spatial memory[26], learning ability[27] and word-location

associations[28]. In a recent study, including 24 healthy adolescents (12 males) with an age

range of 15–22 years (mean: 18 years), Bodizs et al. reported that FSs density was increased

during adolescent development and that fluid IQ correlated with FSs density and amplitude

but only in girls and especially in the fronto-central regions[29]. The girl-specificity of the

FS-IQ relationship reported here in adolescents is reminiscent of earlier reports in adults

suggesting that anatomical measures of white matter structures are markers of cognitive

ability in women, but not in men [30, 31].

 7

To conclude, the anatomical differences between girls and boys, the relationships

between slow waves and cortical function, white matter structure and sleep spindling

together with the link between FSs and IQ in females, but not in males serve as indirect

evidence for a sex-modulated association between cortical maturation and function. We

note that these differences seem to appear early in life.

3. SLEEP DURATION AND QUALITY

In a large UK population-based cohort study on 11,500 children (50% boys) followed from

birth to 11 years-old with repeated sleep measures based on parent-reported questionnaires,

Blair et al. found that girls consistently slept five to ten minutes longer than boys from six to

115 months[32]. This was related to later wake times in girls rather than to earlier bedtime

and remained significant despite the slightly longer daytime sleep duration in boys[32].

Similar results have been observed for night sleep duration in early infancy (14–27

months)[33], preschoolers[34] and school aged children[35-38]. Leger et al., in a French

cross-national study on 9,251 children aged 11 to 15 years-old, 50.7% of which were boys,

showed that during non-week days, the total sleep duration was longer in girls than in boys

(10h12 min vs 9h50 min)[39]. No differences however, were found during weekdays. The

girls also presented more problems initiating sleep than boys (e.g. 18.3% vs 14.8% at 11y and

25.5% vs 15.9% at 15y). Sleep debt, as defined by a difference between week- and non-week-

days’ sleep duration of more than 2 hours, was found to be more frequent in girls than in boys

(31.9% vs 22.1%). These studies, based on questionnaires, were confirmed by objective data

using actigraphy-based sleep features from a Finnish longitudinal study including 188

children, 52.6% of which were girls, at ages 8 and 12 years [40]. Overall, older age was

correlated with shorter sleep duration, especially on weekdays, and later bedtimes on both

weekdays and weekends when controlling for sex, or both sex and pubertal status. Girls of

age 8 years old slept significantly longer on both weekdays and weekends, and had less
 8

fragmented sleep than boys of the same age. By the age of 12, longer sleep duration was

observed in girls only on weekends. Girls had also lower sleep latency and better sleep quality

with higher sleep efficiency and lower sleep fragmentation than boys, at that age.

These subjective and objective data confirmed that girls sleep longer with less sleep

fragmentation compared to boys from infancy to adolescence. With the curtailment of

sleep during adolescence, the girls need to catch up more sleep during the weekend than

boys. As these changes are present from infancy, it is likely that a biological cause

underpins sex differences in sleep duration and quality.

4. SLEEP PHYSIOLOGY

The delayed timing of sleep in adolescence is usually attributed to external influences, such as

academic obligations, light exposure via the use of electronic devices and social

opportunities[41]. However, the mechanism underlying adolescent changes in sleep patterns

is thought to derive from two primary endogenous components: the circadian system and the

homeostatic drive. The homeostatic drive for sleep, or sleep pressure, increases with the

duration of waking and dissipates during sleep[42]. According to this model, human

adolescents develop a resistance to sleep pressure that allows them to stay up later. At the

same time, their circadian phase becomes relatively delayed, which provides them with a

drive to stay awake later in the evening and sleep later in the morning[43].

4.1. Homeostatic drive

Cortical synaptic density, cortical metabolic rate, and SWA amplitude (i.e. delta power)

decline in a parallel fashion by about 50% between the ages 10 and 20 years [44]. Synaptic

pruning in adolescence may be the final ontogenetic manifestation of the mechanism of

overproduction and subsequent pruning of neural elements used repeatedly during earlier

development of the nervous system. It may represent a sacrifice of the relative plasticity of the
 9

child’s brain (e.g., ability to recover function after lesions) for increased speed and efficiency

of information processing. As shown previously, steep decline in delta power across

adolescence is a marker of late brain maturation driven by cortical synaptic pruning[13].

Campbell et al. found a robust relationship between this maturational change in sleep

electrophysiology and pubertal development. They demonstrated that adolescent girls have a

1.2 year earlier onset in the decline of delta power than adolescent boys[45], significantly

related to puberty maturation driven mainly by the hypothalamic-pituitary-adrenal (HPA) axis

and production of adrenal androgens.

4.2. Circadian Clock

Children present early chronotypes that progressively delay during development, reaching a

maximum ‘lateness’ around the age of 20 years. After 20, this phenomenon is reversed and

chronotypes progressively advance with increasing age. Boys typically present later

chronotypes than girls. This sex difference reverses around the age of 50 years, which

coincides with the average age of menopause[46]. In adolescence and adulthood, external

influences, including evening screen exposure and social opportunities, are often considered

responsible for the delayed timing of sleep [47]. Current evidence demonstrates, however,

that social factors cannot completely account for the adolescent delayed sleep onset typical of

an evening chronotype. The developmental timing of the adolescent transition into a more

evening chronotype suggests a physiological cause. Girls begin to show a delay in sleep

timing one year earlier than boys[45], paralleling both the electrophysiology changes

described previously, and a younger pubertal onset . Moreover, different studies indicated that

the delayed timing of sleep during human adolescence probably represents a developmental

change common across mammalian species[48]. In all species studied, circadian phase delay

appears to begin around the onset of puberty; we note however, that in humans, the peak

phase of delay occurs either during or following the final stages of gonadal development. All
 10

these studies, showing a significant sex difference in the changes of chronotype with age,

indicate — directly or indirectly — the involvement of endocrine factors [49, 50].

Altogether, these results strongly suggest sex differences in sleep physiology which are

influenced by pubertal maturation, explaining the earlier onset of decreased slow wave

sleep and circadian delay observed in adolescent girls.

5. SEX DIFFERENCES AND SEX STEROIDS

In animal models, oestradiol in female rodents acts to consolidate and enhance sleep-wake

activity at the appropriate time of day [51, 52]. No effect was seen in males [53]. Testosterone

has no effect in both male and female animals. Oestradiol may influence sleep wake states by

acting on neurons of the ventro-lateral preoptic area, an established sleep-promoting nucleus

but also on wake-promoting hypocretin system of the hypothalamus [54, 55]. Studies have

also suggested that the activity of suprachiasmatic nucleus, the master pacemaker for

circadian clock, could also be influenced by sex steroids [56]. Indeed, women have a shorter

circadian period than men [57] which could lead to a desynchrony between circadian timing

and sleep behavior. This suggests than women could sleep at later circadian times leading to

less restorative sleep.

It should be noted that if sex differences in sleep depend largely on sexual hormones, these

changes do not begin at puberty. Biological sex and sex steroids influence brain development

as early as the fetal stage[58]. During gestation, sexual differentiation of the brain occurs

during a sensitive developmental window, when exposure to sex steroids results in the

masculinization and defeminization of neural substrates. In adulthood, the production and

release of sex steroids activates these differentiated neural circuits resulting in appropriate sex

behaviors. This brain differentiation during fetal life can explain sex differences in brain

organization and function present in infancy. Modification of neural substrates mediating

sleep by sex hormones in utero may result in a greater plasticity and responsiveness to sex
 11

steroids in women than men, and lead to the observed sex differences in sleep. However

changes in ovarian steroid secretion in women linked to puberty, the menstrual cycle,

pregnancy, and the menopausal transition coincide with sleep complaints [59, 60].

These results suggest that the action of oestradiol on neural substrates differentiated

during fetal life determine sex differences in sleep.

6. CLINICAL CONSEQUENCES

Recently, we evaluated the prevalence of sleep disorders in a sample of 381 French children

aged 4 to 16 years old [61]. In this study, we used an adapted version of the Sleep disorder

scale for children (SDSC) originally edited by Bruni et al.[62]. A total of 17.3% of school-

aged children aged between 4 and 16 years old presented with a pathological total score: 8.1%

scored pathologically on the “Difficulty in initiating and maintaining sleep (DIMS) score”,

4% on the “Sleep breathing disorders (SBD) score” and 2% on the “Disorders of excessive

somnolence (DOES) score”. In this study, we found a sex-ratio inversion with age on sleep

disorder prevalence. Between the ages of 4 and 8 years old, boys are 2.5 times more at risk of

having a significant pathological SDSC score than girls (27.8 % vs 10.9 %), and yet the

opposite is observed between the ages of 12 and 16 when girls are 2.5 times more at risk of

having a pathological total score than boys (24.7% vs 10%). More precisely, boys have more

NREM parasomnias than girls (8% vs 1%) between 4 and 8 years old, in accordance with the

study by Petit et al.[63]. Between 12 and 16 years old, girls are 3.3 times more at risk of

having a pathological score for insomnia than boys (9,4% vs 2.9%). Indeed, several studies

have reported an increased prevalence of insomnia symptoms with age [59, 64]. In a

longitudinal study including 7,507 children and adolescents (48.5% girls) aged between 6 and

17 years [59], insomnia symptoms increased from 3.4% to 12.2% in girls (3.6-fold) and from

4.3% to 9.1% in boys (2.1-fold). This was related to puberty maturation as defined using the

Tanner staging. The Tanner scale, a well-known technique used to define pubertal stage, is
 12

based on physical measurements of development based on external primary and secondary

sex characteristics (from Tanner 1: pre-pubertal to Tanner 5: mature adolescent)[65].

Insomnia symptoms were defined as difficulty initiating sleep (DIS), difficulty maintaining

sleep (DMS), and/or early morning awakening (EMA) ≥ 3 times/week in the past month.

There was a sex-Tanner stage interaction with a female emergence of insomnia complaints at

Tanner stage 4 even after controlling for age, family income, and school start time. Similar

sex-Tanner stage interactions were found in DIS, DMS, and the Insomnia severity index total

score but not EMA. Insomnia symptoms were strongly associated with behavioral problems,

poor mental health and poor general health in both sexes. Boys with insomnia reported more

maladaptive lifestyles (smoking, alcohol, and energy drinks) whereas girls with insomnia

were more susceptible to emotional and relationship difficulties. The authors concluded that

pubertal maturation was associated with a progressive increase in the prevalence of insomnia

symptoms with the emergence of female preponderance in both prevalence and severity of

insomnia symptoms in late puberty. The mechanisms underlying the role of puberty in

leading to sex differences in insomnia symptoms are unclear. Several explanations may be

possible. First, gender differences in social expectations and effects of stress cannot be ruled

out. Indeed, it has been shown that adolescent girls experience more stressors than

adolescent boys[66, 67] and girls demonstrate more stress reactivity and depressive symptoms

than boys for equivalent levels of stress [68]. As stressful life events are a major risk factor of

insomnia symptoms in adolescents [69], higher levels of stress and more emotional reactivity

to stressors in adolescent girls may account for observed sex differences in insomnia

symptoms. Second, puberty-related sex differences in stress hormones might be another

contributing factor. Previous studies found that sex differences in HPA axis activity become

more pronounced with pubertal maturation [70, 71]. Given the links between insomnia and

increased HPA axis activity upon awakening in middle-aged adults and adolescents in late

puberty [72], the changes of HPA axis activity across different stages of puberty may be a key
 13

mechanism underlying the puberty-related onset of female insomnia preponderance. Third,

the fluctuation of ovarian hormones across menstrual cycle in girls during late puberty/post-

puberty may also account for sex differences in insomnia symptoms[45].

The findings of Calhoun et al. seem to confirm this model: in a cross-sectional study of 700

children aged 5 to 12 years (54% girls) a global prevalence of insomnia symptoms of 19.3%

was found with a significant interaction between sex and age [64]. Girls aged 11–12 years

showed a significantly higher prevalence of insomnia symptoms (30.6%) compared to girls

aged 5–7 (20.8%) or 8–10 years (16.3%), whereas the prevalence of insomnia symptoms in

boys was similar across all age groups (i.e., 5–7 (21.9%), 8–10 (17.3%), 11–12 years

(16.7%)). Controlling for anxiety and depression did not impact these results. Importantly,

significant sleep disturbances were observed objectively via polysomnography (PSG) in girls

aged 11–12 with insomnia symptoms compared to girls of the same age without insomnia

symptoms. In contrast, no PSG differences were observed in boys with or without insomnia

symptoms.

These data suggest that insomnia symptoms emerge during adolescence, especially in

girls aged 11-12 years, and are associated with objective sleep disturbances that may be

related to the hormonal changes associated with the onset of puberty. However, if the

biological effect is likely involved, the gender differences in stress exposure and

reactivity cannot be ruled out.

7. CONCLUSION

Sex differences in sleep appear in infancy and persist into childhood and adult life mediated

by oestradiol which plays a role in cortical maturation and function as early as fetal life. Girls

sleep longer with less sleep fragmentation compared to boys and these sex differences are

influenced by pubertal maturation, with an earlier onset of decreased slow wave sleep and
 14

circadian delay observed in adolescent girls. These underlying differences may be

exacerbated at puberty and lead to objective sleep disturbances which contribute to the higher

prevalence of insomnia symptoms in young adolescent girls

Practice Points
Sex differences exist:
1. in sleep micro- and macro-structures from foetus to adulthood: girls sleep longer and have
better sleep quality than boys
2. due to sex and steroid influence during brain maturation
2. in subjective insomnia complaints after puberty probably due to different reactions to
stress alongside the effects of steroid secretion on sexually differentiated brains
3. due to the influence of steroids, especially oestradiol, on the major sleep-wake brain
systems

Research Agenda
Further sleep studies are needed and should systematically consider sex differences
1. in conjunction with hormonal development (e.g. sexual hormones and stress hormones)
2. in the familial context notably taking into account parenting
3. in physiology and normative markers of sleep quality
4. in appropriate therapies for sleep disturbances
 15

ACKNOWLEDGEMENTS

We would like to thank Dr Véréna Landel for help in English revision of the manuscript.
 16

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