Sleep Disturbance in Perimenopausal Women
Article information
Abstract
Female sex hormones are involved in various physiological processes including sleep and the circadian cycle. During menopausal transition, various symptoms caused by hormonal changes can occur. Among various perimenopausal symptoms, sleep disturbance is one of the most common and important health issues. More than 40% of perimenopausal women report sleep problems, which not only lower quality of life but also pose substantial health risks including increased cardiovascular risk. Factors contributing to sleep disturbances during perimenopause include direct changes in sleep due to decline of female sex hormones and indirect changes resulting from perimenopausal symptoms. This article will address the influence of female sex hormones on sleep and circadian rhythm, sleep changes in perimenopausal women and their possible mechanisms, prevalent sleep disorders during perimenopause, and their treatments.
INTRODUCTION
Human sleep depends on the circadian cycle. The circadian cycle regulates the vital physiology and metabolic cycles in humans, with an approximate 24-hour periodicity [1]. The circadian cycle is driven by the suprachiasmatic nucleus (SCN), the brain’s central circadian clock, and is organized as a hierarchical multi-oscillator system that transmits signals to peripheral clocks distributed throughout the cerebral cortices and the body [2]. Another important substance mediating the circadian cycle is melatonin, a neurotransmitter secreted by the pineal gland in response to light level stimuli, providing feedback to the SCN [3]. Melatonin exerts beneficial effects on sleep through its synchronizing effects on circadian rhythms [4].
Sex hormones have a bidirectional relationship with the circadian cycle. It is known that the SCN is involved in the control of the hypothalamus, which secretes gonadotropin-releasing hormones [5], and melatonin has also been shown to influence sexual function and reproduction [6]. Changes in sex hormones also affect the circadian cycle. Paul et al. [7] reported that gonadal function has significant correlation to sex differences in the sleep-wake cycle in mice. Additionally, the fact that women have more estrogen and progesterone receptors in the SCN compared to men suggests an influence of female sex hormones on the circadian cycle [8,9]. There are also studies indicating that the effects of melatonin are modulated by gonadal steroids. Animal studies have reported that gonadal steroids might modulate melatonin receptor expression [10], and another study claimed that the degree to which melatonin affects body temperature regulation and gonadotrophin in premenopausal women depends on the menstrual cycle [11].
The most significant change in female hormones is menopause. Menopause is defined as the cessation of cyclic ovarian function. It is diagnosed after 12 months of amenorrhea resulting from the permanent cessation of ovarian function which typically occurs around the age of 51 [12]. The transitional phase leading to menopause is known as perimenopause, which can begin several years before the final menstrual period (mean age of 47 years) and is characterized by irregular menstrual cycles and fluctuations in hormone levels [13]. The pathophysiology of menopause involves a complex interplay of hormonal changes. At the beginning of perimenopause, declines in estrogen and progesterone levels occur due to dysregulated ovulation [12]. The reduction in estrogen levels disrupts the feedback mechanisms in the hypothalamus and pituitary gland, leading to increased levels of follicle-stimulating hormone (FSH). In the early phase of perimenopause, follicular phase estradiol and luteal phase progesterone levels are lower in premenopausal women, and FSH levels are elevated but variable because the majority of cycles are ovulatory [14,15]. The late menopausal transition is characterized by FSH levels ≥25 IU/L, which implies the cessation of follicular development and ovulation [16]. After menopause, FSH levels continue to rise over the first two years following the final menstrual period, after which they gradually stabilize [16].
Perimenopause is characterized by various symptoms that significantly impact a woman’s quality of life [17]. These symptoms are primarily due to hormonal fluctuations and can vary widely among individuals. Common symptoms related to perimenopause are as follows: sleep disturbance [18,19], vasomotor symptoms (hot flashes and night sweats) [18,20,21], psychiatric symptoms including depressed mood [22-24], sexual dysfunction [25,26], joint or muscle pain [21,27], and urogenital symptoms [28,29]. Among these, problems related to sleep are particularly significant. Many perimenopausal women report experiencing poor sleep quality, which significantly impacts their quality of life. In this paper, we will discuss sleep changes among perimenopausal women, prevalent sleep disorders in perimenopausal periods including insomnia and sleep-disordered breathing (SDB), and their treatments.
SLEEP CHANGES IN PERIMENOPAUSAL WOMEN AND ITS POSSIBLE MECHANISM
A high proportion of perimenopausal women report subjective sleep difficulties. A previous study examining the sleep quality of 12,603 middle-aged women aged 40–55 found that self-reported sleep difficulties ranged from 40.5% to 43.8% in the perimenopause group, which is higher compared to 31.4% in premenopausal women [19]. A meta-analysis of 24 studies on sleep disturbance in menopausal women confirmed that the prevalence of sleep disturbance is higher in perimenopausal (odds ratio [OR] 1.60), postmenopausal (OR 1.67), and surgical postmenopausal women (OR 2.17) than in premenopausal women [30]. In the Study of Women’s Health Across the Nation (SWAN), which tracked 3,045 middle-aged women for eight years, 34.3% of perimenopausal women reported sleep discomfort which is higher compared to 28.0% of premenopausal women [31]. Sleep disturbances in menopausal women are primarily characterized by subjective sleep discomfort and poor sleep quality, while polysomnography studies show controversial results. Polysomnography performed in the SWAN study revealed no significant differences between the perimenopausal and premenopausal groups [32], and the study of Wisconsin cohort also found that there were no significant polysomnographic changes associated with the transition to menopause, except for an increase in obstructive apnea in menopausal women [33,34]. However, late-perimenopausal and postmenopausal women exhibited more high-frequency beta EEG activity, suggesting greater cortical hyperarousal during sleep than premenopausal and early-perimenopausal women [32].
Some of these sleep disturbances are attributed to the hormonal changes of perimenopause. While the data on the impact of menopause on the circadian cycle is limited, some previous studies suggest hormonal changes and alterations in the circadian cycle. Animal models also suggest that alterations in reproductive hormone secretion may affect circadian rhythmicity [35]. In addition, previous study found that melatonin secretion in menopausal women is lower compared to premenopausal women [36]. Another study examining the melatonin levels and circadian regulation of 21 premenopausal and postmenopausal women revealed an advanced circadian phase in postmenopausal women, characterized by more fragmented sleep or early morning awakenings [37]. Some authors propose that the complex interaction between melatonin and the gonadal hormonal milieu depends more on the effects of melatonin rather than on its own levels [38]. Moreover, changes in melatonin levels induce significant alterations in the biological function of almost every organ, with potential implications for sleep quality [39].
Hormonal changes can directly and indirectly affect sleep quality and sleep discomfort, in addition to their effects on the circadian cycle. Previous study examining estrogen levels and sleep quality in perimenopausal women has shown that lower estradiol and higher luteinizing hormone (LH) levels are associated with poor sleep quality [40]. Replacement of estrogen in perimenopausal women could improve sleep by increasing total sleep time, and decreasing sleep latency, the number of awakenings after sleep, and the number of cyclic spontaneous arousals [41]. Polysomnography study also have shown that estrogen replacement is associated with an increase in both slow-wave sleep and REM sleep [42,43]. This could be due to increased core temperatures following peripheral vasodilation caused by a decrease in estrogen level, resulting in hot flashes [44]. Hot flashes and core temperature contribute to sleep fragmentation and reduced sleep quality [45-47]. Progesterone is known to have a stimulating effect on γ-aminobutyric acid receptors, exerting a hypnotic and sedative effect [48]. In addition, proogesterone is a potent respiratory stimulant associated with a decrease in episodes of obstructive sleep apnea (OSA) [49]. During pregnancy, when progesterone levels are high, OSA occurs less frequently, and the lower incidence of OSA in premenopausal women compared to men is also thought to be attributed to this effect [50]. Perimenopausal psychiatric symptoms including depression or anxiety related to hormone change also influence sleep [51,52].
INSOMNIA
Insomnia is the most common sleep disorder among women, and its prevalence worsens in menopausal women. In a study of 6,079 mid-life women, the prevalence of insomnia during perimenopause screened by a Pittsburgh Sleep Quality Index (PSQI) score of 5 or higher was approximately 41.7% [53]. According to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria of chronic insomnia, 26% of 982 perimenopausal women qualified for a diagnosis of insomnia lasting six months or more with difficulty maintaining sleep being the most common symptom [46]. Polysomnography findings also revealed poorer sleep efficiency, more wakefulness after sleep onset, and shorter total sleep time among perimenopausal women with the insomnia diagnosis [54].
This problem related to maintaining sleep in perimenopausal women is mainly related to hot flashes, one of the vasomotor symptoms in perimenopause. Hot flash is defined as an exaggerated heat dissipation response resulting in widespread cutaneous vasodilation and upper body sweating [55]. It lasts approximately 3–10 minutes and may be accompanied by sensations of heat, sweating, flushing, chills, anxiety, and shivering [56]. Hot flash emerges as estrogen levels decrease, but its mechanism is more complex than just estrogen withdrawal [57]. It is assumed that the involvement of central noradrenergic activity, serotonergic mechanisms, and LH secretion are correlated with hot flashes [44,58,59]. Previous studies have found that hot flash is strongly associated with a diagnosis of insomnia and that there is a correlation between an increased risk of chronic insomnia symptoms and the severity of hot flashes [46,60]. It is also found that the presence of hot flashes and the number of awakenings per hour of sleep measured by polysomnography are significantly correlated with each other [54].
Psychiatric symptoms are also known to affect perimenopausal insomnia. It has been established through previous studies that psychiatric symptoms, including depression and anxiety, are prevalent in menopausal women [61,62]. Depression and sleep are believed to have a bidirectional relationship in perimenopausal women, as well as in general population [51,63]. The correlation between depressive symptoms and vasomotor symptoms is also suggested to contribute to insomnia in perimenopausal women. Previous research has found that perimenopausal women with vasomotor symptoms are 4.39 times more likely to have depression, regardless of prior depression history [64].
Hormone replacement therapy might be effective for treating insomnia in perimenopausal women when vasomotor symptoms including hot flashes are present [14,50,65]. Hormone replacement therapies targeting insomnia symptoms in perimenopausal women recommend the application of low-dose estrogen or progesterone, which are known to improve subjective sleep quality and sleep continuity [50,65]. However, the results of previous studies are somewhat controversial. According to a review paper published in 2014, hormone replacement therapy showed significant sleep improvement effects in more than ten studies, including randomized controlled trial (RCT), while more than five studies reported no sleep improvement effects [65]. This review suggests using hormone replacement therapy to manage insomnia in perimenopausal women but recommends selecting based on dosing and formulation heterogeneity in previous studies and considering the risk/benefit of hormone replacement therapy itself. The Women’s Health Initiative showed that hormone replacement therapy decreased perimenopausal symptoms and the risk of osteoporotic fractures but found no long-term cardiovascular benefit and confirmed prior studies showing an increased risk of breast cancer [66,67]. Therefore, it is not recommended as a first-line treatment for insomnia in perimenopausal women without prominent vasomotor symptoms [50]. Additionally, the North American Menopause Society advises using hormone replacement therapy for no more than five years and at the lowest effective dose possible to minimize possible side effects [68].
Antidepressants, including fluoxetine, paroxetine, and venlafaxine, are known to help alleviate hot flashes [65,69,70], but they are not recommended for improving sleep [71]. Antidepressants are recommended to be used for perimenopausal insomnia only when accompanied by depressive symptoms. Studies have reported that escitalopram significantly improved sleep in perimenopausal women with depressive symptoms, and there are also findings of significant effects with mirtazapine and controlled-release melatonin [72,73]. Gabapentin is also known to help improve insomnia symptoms accompanied by hot flashes [74,75]. Among dietary supplements for perimenopausal women, soy isoflavones have shown significant effects in reducing hot flashes and improving sleep symptoms in RCTs [76,77]. Sedative hypnotics can be used for acute, short-term treatment as in general insomnia. Since the most prevalent sleep complaints in perimenopausal women involves difficulty in sleep maintenance, eszopiclone could be the choice of drug. Previous studies have also shown that eszopiclone improves sleep quality and vasomotor symptoms [78,79].
For non-pharmacological treatments, cognitive behavioral therapy for insomnia (CBT-I), an effective first-line treatment for chronic insomnia, can be used for perimenopausal insomnia. A study involving 106 perimenopausal women who received telephone-administered CBT-I found that CBT-I improved sleep quality regardless of the improvement in perimenopausal symptoms including hot flashes, and the treatment effect persisted for up to six months [80]. Additionally, previous studies have shown that exercise can significantly improve sleep quality. Kline et al. [81] have found a correlation between indicators such as sleep quality, PSQI, sleep efficiency, and high-intensity physical activity in a study conducted with 339 perimenopausal women. Another study, which compared low-intensity stretching and high-intensity physical activity among 173 participants, found significant improvements in sleep quality in both groups and a correlation between increased physical activity and sleep improvement [82].
SLEEP-DISORDERED BREATHING
SBD, particularly OSA, shows a gender difference in prevalence, with rates of 22% in men and 17% in women [83]. The prevalence of OSA tends to increase with age in both men and women, but there is a significant difference before and after menopause in women. Premenopausal women have about one-third the prevalence of OSA compared to men, and there is approximately a threefold difference in OSA prevalence between premenopausal and postmenopausal women [34,84,85]. It has also been found that about 20% of women with OSA develop the condition during perimenopause [86].
The reasons for the differences in OSA prevalence before and after menopause are not clearly understood but may relate to the effects of sex hormones, blood concentration of leptin, and weight gain after perimenopause [50]. Among the hormonal changes around menopause, progesterone is thought to have the most significant impact on SDB in women. Since progestogens are potent respiratory stimulants, it has been speculated that they protect women from SDB until menopause [87]. It is also suggested that the protective role of progesterone may be due to its effect on the upper-airway dilator muscles. A previous study found that the activity of upper-airway dilator muscles was greater during the luteal phase, when progesterone levels are high; less in postmenopausal women; and increased with hormone replacement therapy [88]. Hormone replacement therapy is associated with a lower prevalence of SDB, which also suggests the influence of sex hormones on the development of OSA [34,89]. Leptin, a hunger-suppressing adipokine, also stimulates breathing, and it is noted that women have a higher average blood concentration of leptin than men [90]. A previous study found that higher leptin levels were associated with a better upper airway neuromuscular response in women [91]. After menopause, blood concentration of leptin decreases in women [92]. This loss of leptin, which could cause the development of abdominal obesity, insulin resistance, and leptin resistance, might partially explain the association between menopause and OSA [50]. In addition, body weight gain after menopause might lead to a higher BMI, larger neck circumference, and higher waist-hip ratio, which could affect the prevalence of OSA [93]. Weight gain after menopause could also lead to a change in body habitus, with an accumulation of adipose tissue in the upper part of the body as well as a shift toward visceral adipose deposition, which is also a critical risk factor for OSA [34,94].
OSA is one of the major risk factors for cardiovascular disease, including hypertension, heart failure, atrial fibrillation, coronary artery disease, and stroke in the general population [95-99]. Especially in women, OSA is related to an increased risk of heart failure after adjustment for previous myocardial infarction, menopausal status, age, waist circumference, alcohol or tobacco use, and hormone replacement therapy [100]. Given the health risks associated with untreated SDB, women suspected of having the disorder should be formally evaluated and treated. However, OSA tends to be underdiagnosed in women. Among the general population with symptoms of SDB, women are significantly less likely to be diagnosed compared to men (25% vs. 14%, p<0.001), and they are also less likely to receive any treatment (17% vs. 11%, p=0.05) [101]. Considering that progression through menopausal stages is associated with SDB severity, with a 4% higher apnea-hypopnea index for every additional year since entering the menopausal transition, it is crucial to properly screen and treat OSA in perimenopausal women [102].
The gold standard treatment for OSA is continuous positive airway pressure (CPAP) [64]. Although there is evidence of a correlation between hormonal changes in menopausal women and the development and the less prevalence of OSA in groups undergoing hormone replacement therapy [34,89], studies on the actual effects of hormone replacement therapy on perimenopausal women with OSA have shown conflicting results [103]. Several studies on the therapeutic effect of exogenous hormone administration among postmenopausal women with sleep apnea showed no significant improvement in the number of apneas [103-105]. Therefore, hormone replacement therapy is not primarily recommended for the treatment of OSA in menopausal women considering the risks of hormone therapy [106].
RESTLESS LEGS SYNDROME AND PERIODIC LIMB MOVEMENT
Restless legs syndrome (RLS) and periodic limb movements (PLMs) are conditions that frequently occur during perimenopause, but their relationship with menopause is not clearly established. According to a survey study conducted with 3,501 middle-aged women, RLS showed a significant correlation with vasomotor symptoms but not with menopausal status or hormone replacement therapy [107]. The appearance of these two conditions during perimenopause may be due to their increased prevalence with age, suggesting that the overlap in timing could be coincidental [108]. Additionally, since these two are common sleep disorders, they might have been co-diagnosed alongside other sleep disorders that occur during menopause when women seek medical attention for sleep [50].
Dopamine agonists including pramipexole or ropinirole hydrochloride have been approved by the US Food and Drug Administration for treating RLS, and have been shown to be effective in reducing their symptoms [109]. However, they do not directly improve sleep, and long-term use is limited by augmentation. Alpha-2-delta ligand drugs such as gabapentin, enacarbil, and pregabalin could be another treatment option. These drugs are known to increase slow wave sleep and improve pain while having less impact on leg movements than dopamine agonists [110]. Although hormone replacement therapy has not been extensively studied in the field, it is assumed to be not particularly helpful for perimenopausal women with RLS and PLMs. An RCT conducted on perimenopausal women with RLS found that while estrogen therapy helped improve sleep quality, it did not alleviate RLS and PLMs symptoms [111]. Additionally, cyclic hormone replacement therapy has been reported to potentially worsen symptoms [50].
SUMMARY
As women transition through menopause, sleep difficulties become increasingly prevalent, significantly impacting their quality of life and daily functioning. Hormonal changes during perimenopause may lead to alterations in the circadian cycle, poor sleep quality, and an increased risk for SDB. In addition, vasomotor symptom during perimenopause is also responsible for frequent awakening and poor sleep maintenance. The complex interplay of direct and indirect influences on sleep during this period necessitates a comprehensive understanding and tailored approach to treatment.
Insomnia is prominent sleep problem in perimenopausal women. Vasomotor symptom, especially hot flash is a distinct and common contributor to perimenopausal insomnia, often disrupting sleep and contributing to prolonged wakefulness during the night. While hot flash is a significant factor, perimenopausal insomnia may also arise from hormonal fluctuations, mood disorders, and life stressors. Hormone replacement therapy for the perimenopausal insomnia with hot flash could be beneficial, but health professionals should consider the potential risks of hormone replacement therapy against its benefits. Antidepressants could also be used, particularly for those experiencing concurrent mood disturbances. Gabapentin and soy isoflavones are known to be effective in reducing insomnia symptoms related to hot flashes. Short-term use of sedative-hypnotics may also provide relief. As non-pharmacological treatment, CBT-I and exercise are found to be beneficial.
DB including OSA, which is often underestimated in women, requires increased vigilance during perimenopausal period. There is more than a threefold risk of developing OSA after postmenopause compared to premenopausal women. The development of OSA in perimenopause might be attributed to changes in sex hormones, decrease in leptin levels, weight gain, and alterations in fat disposition. Physicians must be proactive in evaluating and treating OSA in perimenopausal women, recognizing its cardiovascular implications. CPAP therapy should be considered for OSA in the population, and hormone replacement therapy is not a treatment of choice. RLS and PLMs are not directly related to perimenopause, but they also frequently occur during this period. Proper pharmacological management could be helpful in reducing symptoms.
Changes in sleep are an integral aspect of the quality of life for menopausal women. Addressing sleep disturbances in perimenopausal women demands thorough medical concern, proper diagnosis, and personalized medical treatments. By adopting a holistic approach to sleep disturbance related to perimenopause, healthcare providers can better support women through this transitional phase, fostering better sleep and overall well-being.
Notes
The author has no potential conflicts of interest to disclose.
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