Sleep is an essential physiological process, especially for proper brain function through the formation of new pathways and processing information and cognition. Therefore, when sleep is insufficient, this can result in pathophysiologic conditions. Sleep deficiency is a risk factor for various conditions, including dementia, diabetes, and obesity. Recent studies have shown that there are differences in the prevalence of sleep disorders between genders. Insomnia, the most common type of sleep disorder, has been reported to have a higher incidence in females than in males. However, sex/gender differences in other sleep disorder subtypes are not thoroughly understood. Currently, increasing evidence suggests that gender issues should be considered important when prescribing medicine. Therefore, an investigation of the gender-dependent differences in sleep disorders is required. In this review, we first describe sex/gender differences not only in the prevalence of sleep disorders by category but in the efficacy of sleep medications. In addition, we summarize sex/gender differences in the impact of sleep disorders on incident dementia. This may help understand gender-dependent pathogenesis of sleep disorders and develop therapeutic strategies in men and women.
Sleep is an essential physiological phenomenon characterized by changes in various physiological functions, including brain activity, respiration, and heart rate. Sleep plays a vital role in the functioning of the brain by forming new pathways and processing information. Many studies have shown that enough sleep helps to improve memory and learning, increase attention and creativity, and assist decision making (Krueger
The amount of sleep a person needs varies, but adults need an average of seven hours and thirty minutes of sleep per day. Older people require more sleep. Sleep consists of two states that are known as rapid eye movement (REM) sleep and nonrapid eye movement (NREM) sleep. REM is good for memory retention. When in REM, the brain takes information from the short-term memory and transfers it to long-term memory. NREM includes all sleep stages other than REM and is also called atmospheric sleep. Unlike REM sleep, there is usually little or no eye movement. NREM sleep can be broken down into four stages: stage 1, stage 2, stage 3, and stage 4, and growth hormone production and cell recovery begin (Susic, 2007).
When sleep is insufficient, or sleep quality is poor, this can have various adverse effects on the musculoskeletal system, heart, lungs, and even emotions. This can harm a person’s health. Sleep disorders have a high prevalence, affecting 25 to 30% of the population. They are known to cause poor quality of life due not only to secondary physical illnesses but also from psychological stress caused by the sleep disorder (Kiley
Scientific studies have long focused on one gender, with the assumption that studies of one gender would lead to similar results. However, lots of conditions display sex/gender differences in terms of their prevalence and pathogenesis. The gender of patients has shown to affect the risk of getting particular conditions as well as the patient’s prognosis (Golden and Voskuhl, 2017).
Additionally, sex/gender differences in the pharmacokinetics of medicines can also affect the efficacy and side effects of certain drugs (Tannenbaum
The International Classification of Sleep Disorders identifies seven major categories of sleep disorders. These include insomnia, sleep-related breathing disorders, central disorders of hypersomnolence, circadian rhythm sleep-wake disorders, sleep-related movement disorders, and parasomnias. The sex/gender differences in the prevalence of sleep disorders have been summarize in Table 1.
Insomnia is defined as difficulty in starting sleep, maintaining sleep, and waking up early in the morning. Before diagnosing insomnia, sleep disorders that significantly disrupt daily functioning are important factors to consider. Primary insomnia is a symptom of sleep deprivation, not due to medical, mental or environmental causes. The main symptom is having trouble sleeping or not recovering from starting or maintaining sleep for more than a month (Hung
Regarding the sex/gender differences in the prevalence of insomnia, many studies have reported that insomnia occurs more frequently in women (Morphy
In contrast, Breslau
SBD is characterized by abnormal breathing during sleep. These disorders are classified as obstructive sleep apnea, central sleep apnea, sleep-related hypoventilation disorders, and sleep-related hypoxia disorders (Sateia, 2014). The prevalence of SBD has not been well studied in women, since age, body mass index, and menopause have a considerable impact on the outcomes.
Obstructive sleep apnea is defined as at least five apnea low respiration indices per hour and is prevalent in 24% of American adult men and 9% of women (Young
The main symptom of hypersomnolence is characterized by excessive daytime sleepiness (EDS) despite regular day and nighttime sleep timings (Khan and Trotti, 2015). This affects between 4% to 6% of the population (Dauvilliers and Buguet, 2005). Such sleepiness can be caused by medical conditions, sleep disorders, illegal and prescribed substances, work, and family needs (including shift work), and insufficient time asleep (Khan and Trotti, 2015). This review focuses on the main symptoms of hypersomnolence.
More than a tenth of the Australian adult population has EDS, 10.4% for men, and 13.6% for women. The prevalence of EDS increases with age, affecting about one-third of people over 80 years old (Hayley
The circadian rhythm is often called the human internal clock and is about 24 h. The migration phase interacts with homeostatic sleep that drives to create waking hours during the day and lasting sleep at night. When this cycle is broken, sleep for 24 h is fragmented and scattered, which leads to sleep problems (Romeijn
The prevalence of DSPD is about 1.1–4.5% in adolescents and 0.48–1.5% in adults. Sex/gender differences in the prevalence of DSPD have not been reported in adults, but it is more common in adolescent boys (4.5%) than girls of a similar age (2.7%) (Singer
Female workers may tend to sleep less than men and become sleepy at work, but the evidence of this is weak. As a potential risk factor for the development of jet lag disorder, gender has not been thoroughly studied, and no definitive conclusions have been drawn. Many studies have included only male subjects, and only one case analyzes gender as a risk factor. Using multiple regression analysis, males were found to be less fatigued after a long flight of more than 10 h. As such, there is not enough data to conclude gender as a risk factor for jet lag disorder (Sack
Parasomnia is a sleep disorder associated with abnormal movements, behaviors, emotions, perceptions, and dreams that occur between sleep stages or when waking up. Parasomnia is a combination of dissociated sleep states that are partially awakened during the transition between awakening, NREM sleep, and REM sleep (Fleetham and Fleming, 2014). These include sleepwalking, drooling, night terrors, nightmares, diggers, and REM sleep behavior disorders. Each disease varies in its frequency and can occur every night or only a few times a year (Kazaglis and Bornemann, 2016). REM sleep behavior disorder (RBD) is the clinically most relevant REM parasomnia (Howell, 2012).
A review of 115 patients with polysomnogram-identified RBD at the Academic Sleep Center found a 2:1 ratio of males (65%) to females (35%) (Ju
Sleep-related movement disorders are abnormal movements that occur during sleep or when falling asleep. Sleep-related movement disorders include Restless Leg Syndrome (RLS; Willis-Ekbom Disease), periodic limb movement disorders, rhythmic movement disorders, sleep-related bruxism, and sleep-related leg cramps (Silber, 2013). In the case of RLS, repeated limb movements occur during sleep, but waking paresthesia is the most common symptom (Sateia, 2014). RLS is a common cause of sleep initiation and maintenance failures, affecting about 8–10% of the population (Howell, 2012).
Many studies have reported a higher prevalence of RLS in women than in men (Lopes Da Silva and Storm Van Leeuwen, 1977; Kushida
Sex/gender-related differences at genetic and molecular levels also affect the differences in the degree of drug response (Wang and Huang, 2007). Although sex disparities in the incidence and mortality of disease have been observed for a variety of conditions, chemotherapy has been conducted independently of sex (Keitt
BZD, also known as “benzo,” are a type of psychoactive drug whose core chemical structure is the fusion of benzene rings and diazepine rings. Benzodiazepines enhance the effect of the neurotransmitter gamma-aminobutyric acid (GABA) on the GABA receptors, resulting in sedation, hypnosis (sleep induction), anxiety relief (antianxiety), anticonvulsants, and muscle relaxation. High doses of many short-acting benzodiazepines can also cause pre and post-mortem memory loss and dissociation. This property makes benzodiazepines useful for treating insomnia, anxiety, agitation, seizures, alcohol withdrawal, muscle spasms, and medication before medical or dental procedures (Chen
Triazolam among BZDs displays a gender difference when treating sleep disorders. Triazolam is a triazolobenzodiazepine with hypnotic properties for use in insomnia associated with acute or chronic insomnia, inpatient situational insomnia, and other disease states (Pakes
On the other hand, among men, AUC increases with age, and clearance decreases. However, sex/gender differences in triazolam kinematics were not apparent (Greenblatt
Zolpidem, and non-BZD, such as zopiclone and zaleplon, exhibit a hypnotic effect similar to BZDs with good safety profiles. Non-BZDs generally cause less disruption of normal sleep structures than BZDs. In particular, psychomotor and memory disorders can react better to non-BZDs compared to long-lasting BZDs. For the long-term treatment of insomnia, which is not usually recommended, zolpidem and zopiclone are good options because they do not develop resistance quickly and are less likely to be abused (Wagner and Wagner, 2000). Some side effects include anaphylaxis, behavioral changes, withdrawal, and central nervous system (CNS) depression (Bjurstrom and Irwin, 2019; Kim
Zopyclones are cyclopyrrolones that are believed to act on the GABAA receptor complex at sites that are not chemically related to BZDs and are distinct but closely related to the BZD binding site (Wadworth and McTavish, 1993). Unlike zolpidem, the residual effect of zopiclone in CRSD patients was not significantly different among genders (Leufkens and Vermeeren, 2014).
Suvorexant (MK-4305, Merck), an orexin receptor antagonist, was recently approved by the FDA for the treatment of sleep onset and sleep maintenance insomnia (Lee-Iannotti and Parish, 2016). This medication promotes the natural transition from wakefulness to sleep by inhibiting orexin neurons that promote wakefulness. Suvorexant improves sleep initiation and sleep retention and is well tolerated with fewer side effects (Bennett
CNS stimulants are used for narcolepsy, excessive deficiency disorder, or excessive drowsiness include methyl phenadate, atomoxetine, modafinil, armodafinil, and amphetamine. Stimulants that are no longer used for medical conditions include cocaine, ecstasy, and methylenedioxymethamphetamine (MDMA) (George, 2000).
Modafinil is a waking drug that is prescribed to patients with narcolepsy, but it is increasingly being used by healthy individuals, to increase attention spans, and relieve fatigue. The main pharmacokinetic parameters of modafinil acid are higher in women than in men, regardless of their half-life, when compared in patients with CDH and CRSD (Guo
CNS depressants are effective in treating various conditions by slowing brain activity. These drugs affect neurotransmitter GABA, causing side effects such as drowsiness, relaxation, and reduced inhibition (Cordovilla-Guardia
Sodium oxybate is a prescription drug used to treat two symptoms of narcolepsy: sudden muscle weakness and EDS (Morgenthaler
There was no significant difference (
Melatonin receptor agonists are analogs of melatonin that bind to and activate melatonin receptors. Agents of melatonin receptors have a number of therapeutic uses, including the treatment of sleep disorders and depression (Silvia
Lameltheon is a selective melatonin receptor (MT1 and MT2) agonist approved by the US Food and Drug Administration for the treatment of insomnia, characterized by the difficulty of starting sleep (Erman
Activation of dopamine agonist receptor is associated with the regulation of several neurobiological processes such as cognition, learning, and memory, motivation, pleasure, and sleep (Moreira
Pramipexole, ropinirole (recommended strength: standard), and dopa decarboxylase inhibitors are recommended for the treatment of patients with RLS. Given the potential for side effects, including heart valve damage, patients with RLS can be treated with cabergoline only if other recommended drugs do not work (Aurora
Dopamine agonists and carbidopa/levodopa have become desirable treatments for both RLS and periodic limb movements in sleep. For once-a-day treatment with carbidopa/levodopa, problems associated with increased morning dose recoil of leg movements have been reported to occur in about one-quarter of patients (Allen and Earley, 1996).
In pharmacology, bioavailability is a subcategory of absorption and part of the dosage of unmodified drugs that reaches the systemic circulation, one of the main pharmacokinetic properties of the drug. By definition, the bioavailability is 100% when the drug is administered intravenously. However, if the drug is administered via other routes (for example, orally), bioavailability can generally decrease or vary (due to incomplete absorption and primary metabolism). Bioavailability is one of the essential tools in pharmacokinetics because it must be taken into account when calculating doses for unused routes of administration (Heaney, 2001). Women with PD have greater levodopa bioavailability than men. Sex-related differences in drug disposition may, although statistically significant, be slightly related to drug prescription. Movement disorders were seen in 38 of 33 patients (33%). However, no gender difference was observed in those with dyskinesia (Martinelli
Sleep disturbance has been widely reported to be causatively related to various conditions, including cardiovascular disease, diabetes, and neurological disorders. Although the relationship between sleep disorders and the prevalence of neurogenic diseases has been widely reported, most studies have focused on sleep apnea, and relatively few studies have investigated the relationship between insomnia and neurological disorders (Gu
A recent study from Taiwan’s National Health Institute has reported that patients with primary insomnia showed a 2.14- fold (95% confidence interval, 2.01–2.29) increase in dementia risk than those without insomnia. In their study, younger patients under the age of 40 with primary insomnia had a higher incidence of dementia than older patients. Consistently, other recent studies also demonstrated that sleep disturbances could enhance the risk of developing dementia, and insomnia may increase the risk of AD (Shi
Taken together, these findings elucidate the influence of sleep disturbances on the incidence of dementia both in younger adults and older adults. However, the mechanism underlying the association between primary insomnia and dementia is unclear, and the information about the subtype or level of insomnia necessary to induce dementia is not clear. Therefore, further research in this area is needed to validate these findings.
SBD, a disorder characterized by recurrent arousals from sleep and intermittent hypoxemia, is common among older adults and affects up to 60% of older adults (Yaffe
One prospective cohort study that used overnight polysomnography confirmed that women aged 65 years or older with SBD had a higher risk of developing cognitive impairment and dementia as compared with women without SBD (Yaffe
A study (Chang
In addition to insomnia, EDS is one of the most frequently reported sleep disruptions in older adults (Foley
EDS is one of the well-known nonmotor symptoms of Parkinson’s disease (PD), affecting up to 50% of patients with PD (Hobson
During waking, there has been known to be rhythms in synaptic plasticity (Chaudhury
From these reports, it is suggested that circadian activity rhythms may be biomarkers for advanced aging and dementia even though further study is need to understand the mechanism for this link.
RBD has been reported to be a preclinical symptom of asynucleinopathies, such as dementia with Lewy bodies (DLB) and PD (Schenck
Based on a prospective study of a population-based sample, shorter REM sleep percentage and longer latency to REM sleep were shown to be independently associated with a higher risk of incident dementia (Pase
Individuals suffering from RBD tend to be male with symptoms starting in later middle age. Idiopathic RBD is a robust prodromal marker of synuclein–dependent neurodegenerative disorder, such as DLB and PD. Pathologic studies have demonstrated that patients with RBD have a more diffuse and severe deposition of synuclein (Postuma
SRMD is considered to be a class of sleep disorders, which is characterized by simple, stereotyped repetitive movements during sleep. Patients with SRMD are reported to experience fragmented sleep, disturbance of sleep initiation, and excessive daytime sleepiness, resulting in decreased quality of life (Pigeon and Yurcheshen, 2009). Among SRMD, periodic limb movement disorder and restless legs syndrome are the most common sleep complaints, which involve nocturnal involuntary limb movements. The prevalence of periodic limb movement disorder and RLS has been reported to affect 3 to 10% of the general population, increasing with age (Ohayon and Roth, 2002). Both conditions have been reported to be associated with several physical disorders and mental abnormalities. They have been linked to poorer quality of life through fatigue, compromised work performance, and impaired social and family life (Earley and Silber, 2010). It has been suggested that SRMD is a common complication and comorbidity of neurodegenerative disorders such as PD. However, the relationship of SRMD, such as periodic limb movement disorder and RLS with cognitive impairments like dementia, remains unclear. Researches investigating the relationship between sleep disorders and cognitive illness have predominantly focused on sleep behavior disorders and degenerative dementia. A recent longitudinal study using data from the National Health Insurance Research Database showed that individuals with SRMD had 3.952 times (95% CI=1.124–4.767) higher risk of developing all-cause dementia as compared with individuals without SRMD (Lin
Research into the mechanism of BZDs and the risk of dementia is ongoing. Well known mechanisms are the dynamic balance of the cholinergic and glutamate systems in the CNS, and the inhibitory action of GABA signaling through the GA-BAA receptor (Rissman
Another mechanism is the downregulation of GABA receptors after prolonged BZD exposure, which induces cognitive impairment (Shimohama
In a preliminary PAQUID (Personnes Agees Quid) study, 253 cases of dementia were identified after 15 years in 1063 men and women (average 78.2 years) who had no dementia and had not started BZDs until at least the third year of followup. That is, new use of BZD is associated with an increased risk of dementia, but no significant association was found between taking BZDs and gender (
A 10-year follow-up in the VISAT (Vieillissement, Santé, Travail) cohort study found that the long-term consumption of BZDs negatively affected cognitive abilities. Male cognitive abilities were not affected but affected female’s long-term memory (Boeuf-Cazou
From several studies on the use of non-BZD and sex/gender differences in the risk of developing dementia, no significant differences were found between non-BZD use and dementia risk. Zolpidem, a non-BZD hypnotic, is often used for short-term treatment of insomnia (Cheng
Zolpidem exposure, dementia effects, and sex/gender differences were studied in a retrospective cohort study using data from the National Health Insurance Research Database from 2001 to 2011. This study showed that psychoactive drug use was significantly and independently associated with cognitive function in older people. The use of high cumulative doses of zolpidem increased the risk of AD in older adults living in Taiwan, but there were no significant differences between men and women (male HR: 1.32, 95% CI=0.56–3.09, female HR: 1.38, 95% CI=0.80–2.38) (Cheng
The drugs used in several studies mainly included BZDs and zolpidem, but there was a limitation in that no evaluation of the sex/gender differences between individual drugs. Six of the seven papers that studied sex/gender differences relating to dementia risk between BZD and non-BZDs had insignificant results. Only one paper showed significant results in the sex/gender differences between hypnotics and the risk of developing dementia. Therefore, future studies on the use of BZD and non-BZDs should take into account individual drug studies on sex/gender differences in the risk of developing dementia. This is due to differences in the cognitive and metabolic capacity of men and women.
As describe in this review, the prevalence/incidence of sleep disorders and the efficacy of therapeutics of sleep disorders are significantly different by sex/gender. Sleep medications may only work for one gender or may have different benefits for men and women. There are very few drugs with a prescription difference between men and women even in the guidelines for drugs prescribed for sleep disorders. Sex plays a crucial role in improving individual pharmacogenomics and in developing personalized therapeutic medicines. Pharmacogenomic differences between the sexes might play a significant role in chemotherapy in the future. Further studies are needed to provide greater insight into sex differences in sleep disorders and their therapeutics.
As further describe in this review, the impact of sleep disorders on incident dementia was likely to be different by sex/gender, even though sex differences are not fully elucidated by each type of diseases. In fact, both male and female patients were included in many studies, however, most studies did not consider sex/gender issue separately. Because life span of women is longer than men in most countries, the impact of the risk factors on dementia may be more meaningful in women. In the context, sleep medications may have different impact in view of efficacy or side effect between men and women. Future studies of new therapeutics for sleep disorders should take into account intentional stratification by sex/gender, and appropriate sample sizes are needed to individually test the efficacy of treatment in men and women. In addition, further research is needed to understand the sex/gender specific effects of sleep disorders as a risk factor for the development of dementia and to investigate the underlying mechanisms of gender/gender differences.
This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2018R1D1A1B07048729); the Support Program for Women in Science, Engineering and Technology through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (2019H1C3A1032224); the Commercialization Promotion Agency for R&D Outcomes (COMPA) funded by the Ministry of Science and ICT (2018K000277); the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health & Welfare (HI18C0920), Republic of Korea.