Sleep and Menopause Sara Nowakowski, MS, Charles J. Meliska, PhD, L. Fernando Martinez, BA, and Barbara L. Parry, MD
Corresponding author Sara Nowakowski, MS Department of Psychiatry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. E-mail:
[email protected] Current Neurology and Neuroscience Reports 2009, 9:165–172 Current Medicine Group LLC ISSN 1528-4042 Copyright © 2009 by Current Medicine Group LLC
Understanding sleep complaints of menopausal women is an emerging area of clinical and research interest. In this article, we summarize the most relevant and recent literature to provide an update on sleep in perimenopause and postmenopause. Our discussion includes the causes, clinical diagnosis, and treatment of sleep disorders in perimenopausal and postmenopausal women.
Introduction Menopause, defined as the cessation of menstruation for at least 1 year, is due to degeneration of ovaries and follicles and changing ovarian hormone levels. Decreased ovarian function precedes menopause in the climacteric or perimenopausal period along with menstrual cycle changes and vasomotor symptoms, typically beginning gradually, long before menses cease. The worldwide population of 470 million postmenopausal women is increasing—1.5 million women enter menopause yearly—and is expected to reach 1.2 billion by 2030 [1]. Complaints of sleep disturbance, usually in the form of intermittent awakenings, often accompany menopause. Large population-based studies suggest that 28% to 64% of perimenopausal or postmenopausal women report sleep disturbance [2,3]. Polysomnography (PSG) studies document reduced sleep effi ciency, with sleep initiation and maintenance diffi culties in postmenopausal versus premenopausal women [4,5]. Sleep disruption in menopause is exacerbated by obstructive sleep apnea (OSA), periodic limb movements of sleep (PLMS), and mood disorders (anxiety, major depression). This review summarizes current fi ndings and provides an update of the available literature on the causes, clinical diagnosis, and treatment of menopauserelated sleep disorders.
Subjective Sleep Disturbance Menopausal women historically have complained of sleep disturbance. Ballinger [6] surveyed 539 women 40 to 55 years old. Compared with their premenopausal, perimenopausal, and menopausal counterparts, postmenopausal women without menses for at least a year reported more difficulty falling and staying asleep. Groups did not differ, however, in early morning awakenings. Owens and Matthews [7] studied 521 healthy women 42 to 50 years old at varying levels of menopausal status. About 42% reported some type of sleep disturbance. Sleep difficulty was associated with increased psychological distress. Those with trouble falling asleep and those waking earlier had higher blood pressures or waist–hip ratios. After 3 years of follow-up, the transition from premenopause to postmenopause was associated with a significant increase in sleep disturbance in women not using hormone replacement therapy (HRT). The authors’ interpretation of these fi ndings was that amelioration of hot flashes with HRT did not prevent sleep disturbances. More recently, Park et al. [8] examined sleep, mood, melatonin, light, and wrist activity in 384 postmenopausal women. Self-reported sleep latency was positively correlated with insomnia, mood disturbance, hot flashes, hypertension, use of antihypertensive medication, and melatonin acrophase and offset and was negatively associated with global assessment of functioning, light exposure, and wrist activity. Subjective studies indicate that, compared with premenopausal or perimenopausal women, postmenopausal women tend to report higher incidences of sleep disturbance that may be associated with factors such as depressed mood, hot flash severity, and elevated measures of body mass index (BMI) and waist–hip ratio, which are predominant in this population.
Objective Sleep Disturbance Objective sleep is routinely measured using PSG or actigraphy, a system that detects movement and the absence of movement to infer sleep and wakefulness. Actigraphy has been validated in several categories, including insomnia [9], PLMS [10–12], and postmenopausal women [13]. PSG combines electroencephalography (EEG), electromyography, and electrooculography to score sleep stages.
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Each measure detects electrical currents radiated from the scalp, muscles, and eyes. PSG allows for objective measurement, excellent temporal resolution, and direct quantitative measures of brain and somatic activity during sleep. Systematic studies using objective sleep measures have produced mixed fi ndings. Some PSG studies contradict subjective sleep complaints during menopause. Shaver et al. [5] examined 82 women age 40 to 59 who classifi ed themselves as good or poor sleepers. Comparing sleep architecture and continuity using PSG, as well as psychological and somatic symptom distress, they found that self-classifi ed good and poor sleepers did not differ in any somnographic variables, but self-declared poor sleepers reported more psychological distress than good sleepers. Classifi ed by sleep effi ciency, good and poor sleepers did not differ in psychological distress, but poor sleepers had more wakefulness and stage 2 sleep and less rapid eye movement (REM) sleep than good sleepers. Using a home-based sleep monitoring device to examine sleep in 21 college students, Pace-Schott and colleagues [14] found that objective measures were correlated with subjective estimates of sleep latency, but poor sleepers were less accurate than good sleepers in estimating their sleep-onset latency. Ehlers and Kupfer [15], exploring power spectral analysis EEG sleep in men and women 20 to 40 years old, found men and women in their 20s to have similar slow-wave sleep percentages measured by EEG and power spectral analysis. They also found reduced slow-wave sleep, REM sleep time, REM activity, REM density, and REM intensity and increased stage 2 sleep in men but not women in their 30s. Thus, REM and slow-wave sleep decreased more rapidly in men than women from age 20 to 40. Jean-Louis et al. [16] obtained 24-hour PSG home recordings from 21 women 56 to 77 years old. Women slept an average of 439 minutes over 24 hours, with 10% of sleep time recorded out of bed. Older women had more afternoon–evening sleep, but some women even slept shortly after arising in the morning. In a large epidemiologic study of premenopausal, perimenopausal, and postmenopausal women, sleep was measured with subjective report and objective PSG measurement [17]. Menopausal status was moderately related to self-reported sleep dissatisfaction, but objective sleep quality was not worse in perimenopausal or postmenopausal women than in premenopausal women. In fact, postmenopausal woman had more deep sleep and significantly longer total sleep time. In 21 premenopausal (age 45–51), 29 postmenopausal (age 59–71), and 11 young (age 20–26) women, Kalleinen et al. [18••] recorded objective sleep quality with PSG as well as subjective sleep quality, sleepiness, and mood. Although insomnia complaints were more frequent in menopause, objective measures of total sleep time and sleep efficiency were similar in premenopause and postmenopause. Premenopausal and postmeno-
pausal women, however, had less total sleep time, sleep efficiency, and activity and duration of slow-wave sleep and more wake after sleep onset than younger women. Sleep complaints in menopause were independent of sleepiness, disturbed objective sleep quality, or mood. Thus, sleep problems may be due more to aging than to menopausal changes. Findings such as these suggest that, contrary to subjective reports, there may be few objective differences in sleep architecture between premenopausal and postmenopausal women. Although studies show that older women who report poor sleep throughout the night experience more awakenings and stage 2 sleep and less REM sleep than self-reported good sleepers, there is no conclusive association between menopausal status and objective measures of poor sleep. The apparent discrepancy between subjective complaints and objective fi ndings in menopausal women may arise from tendencies to exaggerate symptoms of sleep disruption or misperception of sleep state. Because a patient’s perception cannot be irrelevant or inconsequential, selfreport measures are useful in conjunction with objective measures. Ultimately, the issue is not which measure is best but which combination of approaches best allows us to appreciate both subjective and objective components of menopausal insomnia. Self-reports reflect patients’ experience of their sleep disorders and the effectiveness of treatments they receive. Actigraphy and PSG allow for greater confidence in the validity of subjective reports. Used in combination with subjective reports, actigraphy or PSG may provide the best means to identify and quantify sleep misperceptions.
Mechanisms Estrogen and progesterone Reduced estrogen and progesterone levels are associated with menopause symptoms such as hot fl ashes, irritability, depressed mood, fatigue, and insomnia. Exogenous estrogen reportedly decreases sleep latency and awakenings after sleep onset while increasing total sleep time, presumably due to decreases in hot fl ashes. Lower estrogen is associated with increased peripheral and central temperature, resulting in menopausal hot fl ashes. Murphy and Campbell [19] studied hormones and sleep quality in 10 postmenopausal women age 57 to 71 who were at least 5 years past menopause. Lower estradiol and higher luteinizing hormone (LH) levels were associated with poor sleep quality. Signifi cant elevations from basal LH levels (ie, LH pulses) occurred more frequently after sleep onset, and 30 of 32 LH pulses preceded long awakenings. Higher body core temperature before and during sleep was correlated with poorer sleep effi ciency and higher LH levels. Progesterone, acting as an anxiolytic through its actions on γ-aminobutyric acid receptors, exerts a hypnotic effect and is a potent respiratory stimulant
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associated with a decrease in OSA episodes. It has been proposed that lower levels of progesterone during menopause contribute to OSA [19].
Hot flashes Hot flashes affect about 35 million women in the United States [20]. A hot flash is defined as a sudden heat dissipation response consisting of widespread cutaneous vasodilatation, profuse sweating, modest tachycardia, increased metabolic rate, and feelings of “a rush of intense heat” [21]. Though typically lasting 3 to 5 minutes, they can exceed 20 minutes [22]. Risk factors predisposing to hot flashes include smoking, reduced physical activity, and high BMI [23]. Both scientific and anecdotal explanations implicate hot flashes in menopausal sleep disruption [2,24,25]. For example, estrogen therapy reduces hot flashes and sleep disturbance. Erlik and colleagues [25] found that waking episodes associated with hot flashes lasted twice as long as those not accompanied by hot flashes. Contrary to the belief that hot flashes cause sleep disturbance, Shaver et al. [26] found that perimenopausal and postmenopausal women with hot flashes tended to have lower sleep efficiencies and longer REM latencies than women without them, but most wake episodes preceded rather than followed hot flashes. Woodward and Freeman [27] performed 24-hour ambulatory recordings of hot flashes and sleep in 12 postmenopausal women with and seven without hot flashes. Hot flashes were associated with increased stage 4 sleep and a shortened fi rst REM period. Hot flashes in the 2 hours before sleep onset were positively correlated with the amount of slow-wave sleep. The authors concluded that central thermoregulatory mechanisms underlying hot flashes might affect hypnogenic pathways inducing sleep and heat loss in the absence of a thermal load. Some sleep problems are independent of hot flashes [7,28–30]. Freedman and Roehrs [31] compared postmenopausal women with and without hot flashes and found no differences in sleep measured by PSG; when hot flashes did occur, they tended to follow rather than precede arousals and awakenings. Freedman and Roehrs [32••] also found that hot flashes were associated with more arousals in the fi rst rather than the second half of the night, suggesting that hot flashes disrupt sleep because the thermoregulatory effects of REM sleep suppress hot flashes associated with arousals and awakenings. Hot flashes may accompany rather than cause awakenings. Woods and colleagues [33] examined menopausal symptoms and endocrine levels during the menopausal transition in a longitudinal study of 41 women. Hot flash severity was positively correlated with follicle-stimulating hormone (FSH) and negatively correlated with estrogen, and hot flash severity and depressed mood were associated with sleep disruption. Freeman et al. [34•] confirmed these findings in a 9-year longitudinal study showing that the prevalence of hot flashes, physical symptoms, and depressed mood increased during the menopausal transi-
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tion, and estrogen and FSH fluctuations were associated with these symptoms. Another study of participants in the Seattle Midlife Women’s Health Study showed that reduced estrone levels were associated with hot flash severity [35]. Huang and colleagues [36] studied 3167 older, postmenopausal women with osteoporosis, of whom 375 (11.8%) reported bothersome hot flashes at baseline. Symptoms were most common in women who were less educated, more recently menopausal, had previously used estrogen or had undergone hysterectomy, and had higher BMI, higher FSH levels, lower high-density lipoprotein levels, vaginal dryness, and trouble sleeping. Notably, estradiol level was not a significant predictor of symptoms. In summary, the etiology and physiological causes of hot flashes remain largely unknown, but the initial trigger is thought to be caused by an imbalance of hormones and reduced estrogen, resulting in an increased blood flow in the hypothalamus, where temperature is regulated. Consequently, a hot flash occurs where blood vessels dilate, heart rate increases, and sweat glands open.
Other sleep disorders OSA results from complete or partial obstruction of the airway, causing an awakening. Physical signs of OSA include loud snoring, daytime sleepiness, a sensation of shortness or gasping for breath, witnessed apnea episodes, dry mouth, and morning headaches. Risk factors for OSA include excessive weight and aging. Epidemiologic studies reveal a high prevalence of undiagnosed OSA and have consistently shown that even mild sleep apnea is associated with significant morbidity. Undiagnosed OSA is independently associated with increased hypertension, cardiovascular disease, stroke, daytime sleepiness, motor vehicle accidents, and diminished quality of life. Evidence suggests that sleep apnea risk increases in perimenopausal and postmenopausal women [37]. In an epidemiologic study based on 3233 women in California, Ohayon [2] found that along with poor health and chronic pain, sleep apnea is associated with chronic insomnia. Decreases in levels of progesterone, a known respiratory stimulant, have also been implicated. Although more common in men, OSA increases with age in women [38]. Using hospital records and results of sleep studies of 601 patients of a university hospital pulmonary clinic, Anttalainen et al. [37] found that although premenopausal and postmenopausal women present with similar signs and symptoms when referred to sleep studies, the prevalence of sleep disordered breathing tended to be higher in postmenopausal than premenopausal women (86.2% vs 79.4%, respectively) and more severe (68.1% vs 35.8%, respectively). Resta and colleagues [39] studied 133 women with BMI ≥ 30 and found that 44% had a respiratory disturbance index (RDI) ≥ 10. Neck circumference, BMI, and age were the strongest predictors of RDI value. OSA occurred more than twice as often in postmenopausal than premenopausal women and more often in women with a larger neck circumference and higher waist–hip circumference ratio [39].
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PLMS occurs in 5% of healthy 30- to 50-year-olds, but the prevalence rises to 40% of the population over the age of 65 [40,41]. Patients with restless legs syndrome (RLS) or PLMS report strange sensations in their legs that disrupt sleep or cause them to jump and to move around to relieve discomfort, disrupting sleep and causing daytime sleepiness. Using PSG, Hachul de Campos et al. [4] found that 7.8% of postmenopausal women who complained of insomnia had periodic leg movements. Freedman and Roehrs [28] recorded sleep via PSG in 102 women (age 44–56) who reported sleep disturbance and found that 53% had apnea, RLS, or both disorders. In summary, sleep apnea and PLMS appear to increase with age. Menopausal women appear to be particularly vulnerable to OSA due to decreased progesterone and increased BMI and neck circumference. Clinicians should note increased risk of basic sleep disorders when assessing sleep disorders in menopausal women.
Mood change Women are at a higher risk than men for developing clinical depression [42] and are particularly vulnerable during times of reproductive hormonal change [43]. Several studies identify the menopausal transition as a time of increased risk for the onset of depression [44]. In a longitudinal study, 231 women 35 to 47 years old with no current or prior history of depression were followed for 8 years. During the menopausal transition, women were 2.5 times more likely to be diagnosed with depression relative to the period when they reported regular menstrual cycles [44]. Women reporting chronic insomnia have a higher risk of developing depression, and menopausal depressed women report more frequent and longer awakenings than healthy menopausal women [45]. Baker and colleagues [24] found sleep disruption and mood alterations were significantly greater in perimenopausal than premenopausal women 40 to 55 years old. Actigraphic data showed perimenopausal women experienced longer and more frequent arousals resulting in significantly less sleep. Sleep and mood changes were significantly related in the perimenopausal but not the premenopausal group. The authors suggested that perimenopausal mood changes are mediated by sleep disruption. In contrast, Clark et al. [46] found no relationship between sleep disturbance and menopausal status or symptoms or anxiety and depression scores in a survey of 23 women 40 to 55 years old. Hollander and colleagues [47] studied sleep and mood in 218 African American and 218 white women 35 to 49 years old. About 17% of them reported poor sleep. Significant independent associations with poor sleep included a greater incidence of hot flashes, higher anxiety and depression levels, lower estradiol levels in women 45 to 49 years old, and greater caffeine consumption. As part of the Women’s Health Initiative, Wallace-Guy et al. [48] found that in 154 postmenopausal women (mean age, 66.7), the overall amount of light exposure throughout 24 hours was negatively correlated with sleep latency, wake within sleep, and depressed mood.
In summary, studies examining the relationship of sleep and mood disorders in menopausal women are inconsistent. The complex relationship between sleep and depression appears bidirectional. Although the interaction between sleep and mood remains unclear, women are particularly vulnerable to both disrupted sleep and depressed mood during the menopausal transition.
Assessment and Intervention Nonpharmacologic approaches A sleep history should include simple screening questions such as, “Are you bothered by sleeping problems? Are you fatigued or sleepy during the day? Do you have trouble falling or staying asleep? Are you snoring? Do you experience sensations in your legs when in bed?” Inquiry about medical, psychiatric, and social history and other menopausal complaints (hot flashes, night sweats, incontinence, diminished libido, vaginal dryness, fatigue, depressed mood) is useful [49,50]. The Epworth Sleepiness Scale [51] may help determine the level of sleepiness that may be associated with basic sleep disorders. Tests of estrogen and progesterone for menopausal sleep disturbances have produced mixed fi ndings, with most showing little efficacy [45]. Hormonal fluctuation and vasomotor symptoms, such as night sweats, may precipitate sleep disturbance, but physiological arousals and behavioral conditioning appear to perpetuate insomnia [52]. Behavioral conditioning often occurs during transient periods of induced insomnia that does not resolve after causative factors are eliminated. Thus, cognitive behavioral therapy for insomnia (CBT-I) that includes challenging irrational or distorted beliefs about sleep, education on proper sleep hygiene, relaxation techniques (breathing exercises, relaxation, biofeedback), sleep restriction, and stimulus control therapy may benefit these patients and should be considered a fi rst line of treatment. CBT-I has been shown to be more efficacious than zopiclone for short- and long-term management of adult insomnia [53]. Furthermore, CBT may provide education and coping skills for climacteric symptoms. In an open-trial, pilot study of CBT for the treatment of climacteric symptoms, Alder et al. [54] found significant improvements in anxiety, depression, partnership relations, sexuality, hot flashes, and cardiac complaints from before to after intervention in 30 menopausal women.
Antidepressants Using antidepressants to treat sleep disruption in the absence of depression is not recommended. Some antidepressants and mood stabilizers (eg, venlafaxine, gabapentin) may ameliorate mood and vasomotor symptoms but may aggravate insomnia. Escitalopram (a selective serotonin reuptake inhibitor [SSRI]) was more effective than estrogen and progestogen therapy in improving depressive symptoms in perimenopausal and postmenopausal women and had a positive impact
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on other menopause-related symptoms [55]. Although studies show that SSRIs are ineffective in treating vasomotor symptoms [56], serotonin-norepinephrine reuptake inhibitors such as duloxetine appear to signifi cantly improve menopausal sleep, mood, and vasomotor and physical symptoms [57].
Benzodiazepine and nonbenzodiazepine hypnotics A short-acting nonbenzodiazepine hypnotic may be warranted for short-term use for acute, initial insomnia. However, tolerance, withdrawal, dependence, and exacerbation of depression may occur when hypnotics are used longer than 2 weeks, and discontinuation of treatment may elicit rebound insomnia. Although the long-term effects of hypnotics are unknown, increased mortality has been linked with hypnotic use [58]. Zaleplon and zolpidem are more effective in treating problems initiating sleep but less effective with problems maintaining sleep. Soares et al. [59] enrolled 410 perimenopausal or early postmenopausal women with insomnia (age 40–60) in a double-blind, placebo-controlled study and found that eszopiclone (3 mg) significantly improved mood, quality of life, and menopause-related symptoms. These newer-generation nonbenzodiazepines have less tolerance, withdrawal, and dependence liability than traditional benzodiazepines, thereby reducing abuse potential, but still have habit-forming properties, and long-term use remains undesirable.
Hormone therapy The efficacy of HRT for sleep and mood disturbances remains unclear, with some studies fi nding positive results and others fi nding no benefit. The marked subjective improvement in sleep with HRT [60] is contrasted with a lack of consistent sleep improvement when assessed with PSG [61]. Estrogen is the drug of choice when treating hot flashes, but its efficacy in treating sleep disturbances is unclear. In a thorough review of the literature, Parry et al. [45] noted that, compared with placebo, treatment with estrone reduces frequency and duration of nighttime wakefulness, increases amount of REM sleep, decreases hot flash frequency, and improves mood. Treatment with conjugated estrogen appears to reduce sleep latency, increase REM minutes and percentage, and improve vasomotor symptoms and objective/subjective sleep efficiency and sleep quality. Similarly, the transdermal estradiol is associated with increased sleep quality, reduced sleep latency and number of awakenings, and improvement in somatic, mood, and vasomotor symptoms. Nevertheless, recent work by Kalleinen and colleagues [62] on 17 premenopausal (age 45–51) and 18 postmenopausal (age 58–70) women who slept in a laboratory for two nights before and after 6 months of estrogen-progestin treatment (EPT) disputes this trend. Compared with placebo, premenopausal women receiving EPT had more awakenings from stage 1 sleep, and postmenopausal women with EPT had a greater total number of
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awakenings and decreased slow-wave activity. Although the limited fi ndings were mostly unfavorable to EPT, one cannot conclude that EPT deteriorates sleep more than placebo. Further, although this study showed that neither middle-aged cycling premenopausal women nor older postmenopausal women benefit from EPT in terms of sleep quality, treatment with progesterone alone has shown significant reductions in time spent intermittently awake and a significant increase in REM sleep in the fi rst third of the night in postmenopausal women [63].
Treatment of other sleep disorders Various methods are used to alleviate snoring, OSA, and sleep disordered breathing. Much like insomnia, rigorous evaluation and a detailed history are necessary to diagnose sleep-related breathing disorders. Continuous positive airway pressure (CPAP) and auto-CPAP are efficacious and are the treatment of choice for OSA [64]. Based on assertions that higher premenopausal estrogen and progesterone levels might account for the lower incidence of breathing-related sleep disorders in premenopausal women, a number of studies have tested whether administration of estrogen and progesterone might decrease sleep apnea and hypopnea in menopausal women and found inconsistent results. Pickett et al. [65] found that the combination of estrogen and progestins significantly decreased the number and duration of apnea/hypopnea episodes, whereas Saaresranta et al. [66] observed that estrogen use and especially a high serum estradiol concentration predicted higher mean overnight arterial oxyhemoglobin saturation, suggesting that estrogen therapy may have favorable respiratory effects. Other studies show no significant improvements in the number of episodes of sleep apnea in postmenopausal women treated with estrogen and/or medroxyprogesterone [67,68]. Further research on pharmacologic suppression of estrogen and progesterone in healthy young women has demonstrated that, although participants subjectively noticed some increased snoring, there was no change in PSG-measured arousal index and no evidence of sleep fragmentation to suggest the presence of increased upper airway resistance during sleep [69]. Thus, while hormonal changes that occur during the menopausal transition may increase the risk of apena, apnea/hypopnea appears to be only slightly improved by exogenous administration of hormone therapy. Dopamine agonists such as pramipexole or ropinirole hydrochloride have been approved by the US Food and Drug Administration for treating RLS and been shown to be effective in reducing symptoms [70]. Research on the treatment of RLS and PLMS in menopausal women is lacking; there are a few studies of the effects of HRT on PLMS. In one case study, transdermal estradiol was given twice a week to a symptomatic postmenopausal patient with a high PLMS index who complained of insomnia and leg pain. The patient experienced a significant decrease in PSG-measured PLMS as well as an increase in REM and slow-wave
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sleep (stages 3 and 4), with a reported overall improvement of symptoms [71]. A randomized controlled study showed that estrogen replacement improved subjective sleep quality regardless of periodic limb movements or related arousals. However, movement intensity, duration, and intervals did not change with estrogen therapy [72].
Conclusions Insomnia, anxiety, and depression are closely interrelated and are more prevalent in women than in men. Improving sleep hygiene should be considered a first approach to treatment. CBT alone or with pharmacologic interventions relieves mood and sleep disorders in some women. Patients suffering from sleep disturbance and psychological disturbance should be referred to a mental health professional. Antidepressants such as SSRIs appear to be effective in treating insomnia in menopausal women, presumably by relieving underlying depression. A short-acting nonbenzodiazepine hypnotic like zolpidem and zaleplon may be used in the short term (< 2 weeks) for acute insomnia. HRT may be effective for some women, particularly those with vasomotor symptoms. When considering treatment with HRT, menopausal women should discuss the benefits and risks with their physicians. Estrogen and progestins should be used at the lowest doses for the shortest duration needed to achieve treatment goals. Treatment for these basic sleep disorders is best administered by a board-certified physician, CBT therapist, or sleep specialist. If patients report symptoms consistent with OSA, RLS, PLMS, or other sleep disorders, a referral to a sleep specialist is recommended.
Disclosures No potential confl icts of interest relevant to this article were reported.
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