Clinicians can successfully assess menopausal women with sleep complaints by performing a thorough sleep history, determine whether they are experiencing hot flashes, and if there was an acute event that initiated insomnia.
By Rochelle Zak, MD
Menopause is a time of major change for women. In particular, there is an increase in insomnia, with estimates as high as 61%,1 almost double the 33% to 36% incidence that is seen with premenopausal women.2 Although these data suggest that subjectively women perceive their sleep as worse during menopause, a recent large population-based polysomnographic study showed that postmenopausal women had better sleep documented on full-night polysomnography than did premenopausal women, although they were less satisfied with their sleep. The improved sleep measures were longer total sleep times, increased amount of delta sleep, and less time awake in bed.3 One possible explanation given in the accompanying editorial is that these findings may reflect an increased drive to sleep from greater daytime fatigue from the lack of estrogen in the postmenopausal population4; however, one also wonders if these differences, while statistically significant, are not really physiologically significant (the increase in total sleep time is 13.4 minutes). Nonetheless, there is a significant population of menopausal women who note a change in their sleep that accompanies their hormonal changes. The literature primarily identifies four causes of poor sleep in menopausal women including hot flashes, affective disorders, insomnia of menopause, and sleep-disordered breathing (SDB).
Menopause is defined as 1 year after menstrual periods have stopped. Hormonal changes begin, however, before the final menses. During this time, there is a fall in estradiol and inhibin with a rise in follicle-stimulating hormone and a lesser rise in luteinizing hormone. Circulating estrogens shift from estradiol to estrone, predominantly produced by the extraglandular conversion of androstenedione, and there is only a minimal fall in testosterone production.5 During this time, hot flashes, depression, and anxiety occur.
Hot flashes are thought to be generated by the preoptic area of the anterior hypothalamus and are associated with an increase of brain norepinephrine metabolism. Hot flashes are generally described as warmth beginning around the face and spreading to the chest, often accompanied by skin redness, sweating, and palpitations. Other symptoms include nocturnal awakenings, nausea, dizziness, and headache.6 The awakenings generally precede the peripheral vasomotor manifestations.7 Hot flashes affect 75% to 85% of perimenopausal and postmenopausal women. Most women experience hot flashes for only 1 year but around 25% will experience them for 5 years,6 and a small minority may have them for the rest of their life.8 An elevation in core body temperature precedes the hot flashes,9 and the frequency of hot flashes can be affected by the ambient temperature prior to bedtime, being decreased in cooler temperatures and increased in warmer temperatures.10 Polysomnographically, hot flashes can appear as awakenings, generally accompanied by tachycardia and sometimes with sweat artifact.
The role of hot flashes in the insomnia of menopause is controversial. Some polysomnographic studies clearly showed an association of hot flashes with nocturnal awakenings7 and decreased sleep efficiency,10,11 while others found no correlation between the presence of hot flashes and polysomnographic measures of poor sleep.12 However, in this last study of menopausal symptoms and sleep quality, a high frequency of hot flashes was associated with impaired subjective sleep quality. Although there are studies that argue both for and against the role of hot flashes in the insomnia of menopause, some women who experience hot flashes will clearly tell you that they awaken during the night sweating. Others, who are not aware of their hot flashes occurring during the night, will mention that nocturnal awakenings decreased after treatment for hot flashes was instituted. Therefore, one should approach each patient individually and consider whether hot flashes are playing a role in insomnia.
The treatment of hot flashes has, until recently, generally been with hormone replacement therapy (HRT)—either estrogen or estrogen with a progestin. The results of the Women’s Health Initiative,13 showing some untoward health effects of HRT, have raised concerns about the safety of HRT, although these results apply to the hormonal preparations used (oral conjugated equine estrogen and oral medroxyprogesterone) and it may be that the newer preparations available (transdermal estradiol and pure oral progesterone) are safer. Nonetheless, HRT use for hot flashes was the mainstay of treatment and, therefore, should be briefly discussed. The literature on the efficacy of HRT in treating hot flashes in sleep is difficult to interpret. First, some polysomnogram-based studies used objective ways to measure hot flashes and others used subject questionnaires without objectively measuring hot flash frequency. In addition, some used oral conjugated estrogen, others used transdermal estradiol, and others a combination of an estrogen and a progestin for different amounts of time (it can take a few months to see the effects of HRT). Finally, some were placebo-controlled and others were not. Therefore, although one can find studies that show that HRT can be effective in treating hot flashes7,14-16 and others that do not,17,18 it is unclear which are correct. In any case, one should take the same approach to an individual patient as mentioned above and evaluate whether HRT is appropriate and see if it is effective. Alternative treatments for hot flashes have included clonidine, neurontin, and selective serotonin reuptake inhibitor (SSRI) medications.
As with any patient who presents with difficulty initiating and maintaining sleep or unrefreshing sleep, practitioners should consider the possibility of mood disorders. It is unclear if the hormonal changes of menopause, per se, can account for depression and anxiety in this population8 or if the depression and anxiety that can be seen associated with menopause represent a response to life circumstances19 or relate to the presence of hot flashes.5,20 Of interest, there was a study in which women were treated with HRT for hot flashes and did not have improvement in sleep quality despite a decrease in hot flashes until psychotherapy was added, suggesting a role of depression in their insomnia.21 Addressing psychiatric causes of insomnia and providing appropriate treatment are important in this population.
In an excellent review article of this topic,20 the authors suggest that as with any instance of insomnia, there can be a precipitating factor, subsequent to which the insomnia then becomes self-perpetuating—what they term a primary insomnia of menopause. This type of insomnia may be induced by hot flashes but then continues as the patient develops anxiety toward trying to sleep or elements of inadequate sleep hygiene. Thus, this type of insomnia would best be treated with the behavioral techniques that are a mainstay of our profession: cognitive behavioral therapy, sleep restriction, education about the principles of good sleep hygiene, and relaxation techniques.
The final proposed mechanism for poor sleep in postmenopausal women is SDB. Recent data conclude that menopause is an independent risk factor for SDB. After controlling for age, body mass index (BMI), and several lifestyle factors,22 postmenopausal women were 2.6 times more likely than premenopausal women to have an apnea-hypopnea index (AHI) greater than 5, and 3.5 times more likely to have an AHI greater than 15. A large polysomnography-based study estimated the prevalence of SDB (defined as an AHI greater than or equal to 15 per hour of sleep) as 3.9% in postmenopausal women, statistically greater than the 0.6% found in pre-menopausal women.23
Female Morning Exercisers Get Better Night’s Rest
It may come as no surprise that a recent study found that stretching and exercise may improve sleep quality in overweight, postmenopausal women. But the researchers also concluded that it matters when those woman hit the gym.
Morning exercisers who worked out at a moderate intensity for at least a half hour each morning, 7 days per week, experienced fewer problems falling asleep than those who exercised less. Conversely, women who performed evening exercises experienced little or no improvement in sleep onset or quality.
One possible explanation, the researchers note, is that morning versus evening exercise may differentially modulate circadian rhythms that affect sleep quality. More research is needed to confirm this theory, say the researchers.
The study was conducted at Seattle’s Fred Hutchinson Cancer Research Center and appears in the November issue of the journal Sleep.
Proposed mechanisms for SDB in postmenopausal women include a change in the distribution of body fat24 and a decrease in progesterone.25 With menopause, there is an increase in the waist:hip circumference ratio, which may explain the increased prevalence of SDB in menopausal women as they lose the hourglass shape and begin to resemble a man’s more linear shape. The Wisconsin Sleep Cohort data showed that, after controlling for either the waist:hip circumference ratio or neck girth, men were no longer at an increased risk of having an AHI greater than 5.24 Since women increase their abdominal fat with menopause,5 it seems possible that this fat redistribution alone may play a role in the development of SDB.
Another proposed mechanism is the change in hormones. A large cross-sectional polysomnographic study26 compared postmenopausal women with pre-menopausal women but controlled for BMI and neck circumference. The authors found an increase in the prevalence and severity of SDB in postmenopausal versus premenopausal women, implicating hormonal changes as the cause of this increase. Although these authors did not speculate on the exact hormonal mechanism, many have suggested that progesterone loss may be playing a role. Progesterone is a known respiratory stimulant in awake women27; however, progesterone treatment of men with sleep apnea has shown limited effect28,29 and not much more effectiveness in women.30
The next issue is the effectiveness of hormone therapy in treating SDB. The literature on women is difficult to analyze since each study used different hormonal regimens and often presented different parameters (some used indices and others total numbers of respiratory events) with different definitions of hypopnea.
Although there is a suggestion that the increase in SDB is a function of hormone changes, attempts to treat SDB with hormones have not proved successful. Two studies have evaluated the effect of HRT on women with moderate to severe SDB. One prospective but not placebo-controlled study looking at subjects with moderate SDB treated with HRT found a statistically significant effect with HRT but not resolution of the SDB. There was a fall in mean AHI from 34 to 25 with estrogen use alone and from 30 to 17.6 when estrogen was combined with progesterone.31 A second study similarly looked at subjects before and after HRT with a baseline average AHI of 43 but found a fall in AHI to only 40, with different subjects on different hormonal regimens.32 Moderate to severe SDB is generally best treated with nasal continuous positive airway pressure (NCPAP), which should be considered for this population as well.
Patients with mild SDB do not always tolerate NCPAP and having an alternative treatment would be helpful. A recent pilot study using the newer, more physiologic forms of HRT in a population of postmenopausal women with mild to low-moderate SDB found an effect with estrogen but, again, it did not normalize the AHI.33 The average AHI at baseline was 22.7, which fell to 12.2 with transdermal estradiol. The surprise, however, was that the addition of oral pure progesterone, the hormone whose lack is presumed to be the cause of the problem, actually resulted in an increase in AHI to 16.2, no longer statistically different from baseline. Possible explanations for this surprising finding include the small sample size of six women and the short exposure to HRT.
In contrast, the large cross-sectional studies that compare postmenopausal women on and off HRT find an ameliorative effect of HRT on SDB. A large polysomnographic study of a general population of women23 found that for postmenopausal women taking HRT (either oral estrogen or oral estrogen and a progestin), the prevalence of sleep apnea (1.1%) was not statistically different from the premenopausal group (0.6%). The postmenopausal group without HRT had a prevalence (5.5%) that was similar to that of men determined from a prior study (7.2%). The results of the Sleep Heart Health Study also showed a protective effect of HRT.34 Women who used either estrogen or estrogen and progesterone had half the prevalence of SDB as postmenopausal women who did not use HRT. Thus, epidemiological data suggest a therapeutic effect of HRT.
One can see that although the literature does not prove that HRT can be used as definitive treatment for SDB in postmenopausal women, there is a suggestion that the newer, more physiologic hormone preparations may be effective in mild SDB.
Given the above, what is the best approach to women going through menopause with sleep complaints? As always, the first step is to perform a thorough sleep history, looking for symptoms suggestive of intrinsic sleep disorders, such as SDB (snoring or gasping at night) or restless legs syndrome (an indescribable feeling in the limbs and urge to move them at night), and treat them as usual with the question about whether HRT has a role in treating mild SDB. One should also assess whether the patient is experiencing hot flashes—even if she is unaware of them occurring at night—and treat these appropriately. Mood disorders should also be addressed. Finally, one should look for an acute event that initiated insomnia, such as hot flashes or a personal trauma, that has since resolved but resulted in an irregular sleep-wake schedule or elements of inadequate sleep hygiene, which should then be duly treated. Finally, a recent study looking at the efficacy of stretching versus exercise in reducing symptoms of insomnia in a group of postmenopausal women not using HRT found that stretching and morning exercise could be helpful while evening exercise was detrimental35 (see sidebar).
Rochelle Zak, MD, is clinical instructor of Neurology in Psychiatry at the Sleep-Wake Disorders Center of New York-Presbyterian Hospital, White Plains, NY.
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