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Journal of the American Academy of Physician Assistants:
CME

Perimenopausal sleep disturbance: Beyond estrogen replacement

Quincy, Brenda PhD, MPH, PA‐C

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Author Information

Brenda Quincy is an associate professor and academic coordinator, Department of Physician Assistant Studies, Elon University, Elon, North Carolina.

No relationships to disclose.

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Abstract

LEARNING OBJECTIVES:

* Discuss the manifestations and impact of sleep disorders on perimenopausal women

* Describe a comprehensive evaluation of perimenopausal symptoms

* Identify limitations of hormone therapy for the management of perimenopausal sleep disorders

* Formulate a management plan for a patient with perimenopausal sleep disturbance

The inability to fall asleep and stay asleep can have neurobehavioral consequences that significantly impact a middle‐aged woman's ability to function and her quality of life.

Sleep disturbance is a common problem for women progressing through the menopausal transition. Although the specific purposes and processes of sleep may not be fully understood, sleep is generally agreed to be important to energy level, alertness, productivity, and overall sense of well‐being. According to the National Institutes of Health (NIH) State‐of‐the‐Science statement on sleep disturbance in menopausal women, disturbed sleep affects as many as 39% to 47% of women during the perimenopause and up to 60% of postmenopausal women.1 Sleep disturbance in perimenopausal and postmenopausal women has been found to occur less frequently than typical vasomotor symptoms but as commonly as vaginal dryness.2 Although not all studies report the same degree of impact, sleep quality does seem to worsen as women progress through the menopausal transition from late reproductive phase to postmenopause.3‐5

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MANIFESTATIONS OF DISORDERED SLEEP

The three most common patterns of sleep disturbance reported by patients include difficulty falling asleep, waking in the middle of the night, and awakenings in the early morning. The American Academy of Sleep Medicine (AASM) recommends that health care providers include an assessment of the restorative quality of sleep in their workup of insomnia. The presence of at least a mild degree of functional impairment is also an important component of the clinical diagnosis of insomnia. Complaints of sleep disturbance may be assessed either subjectively, through self‐reported rating scales addressing quality of sleep, timing of sleep, and daytime sleepiness, or objectively, with assessment tools like polysomnography (PSG). Insomnia and restless legs syndrome (RLS) are two types of sleep disturbance that generally are diagnosed and managed based on clinical presentation and response. PSG is indicated for sleep apnea and periodic limb movement disorder or for patients with insomnia when they do not respond to usual therapy or when they present with additional symptoms that suggest a different or additional sleep disorder.6

Research has demonstrated that several other history and physical examination findings often accompany problems with sleep in midlife women.7 Hot flushes, depressed mood, anxiety, and joint and back pain are associated with trouble falling asleep and with awakenings in the middle of the night or in the early morning. In addition, all three patterns of sleep disturbance were more common in women who had a history of sexual abuse, were experiencing increased stress in their lives, or considered themselves in poor health. Alcohol intake may decrease the time needed to fall asleep but does not improve nighttime or early morning awakenings.7 Poor‐quality sleep usually accompanies the common vasomotor symptoms of menopause.8 Additionally, for some women, financial difficulties in their lives increase the likelihood of experiencing difficulty sleeping.9 There have been conflicting reports in the literature about whether sleep quality in perimenopausal women varies according to race. According to Hall and colleagues, the sleep quality of black women was worse than that of white women, both by subjective report and objective measurement.9 In another study however, race was not an independent predictor of the quality of a woman's sleep.8

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IMPACT OF POOR SLEEP

Historically, most of the research on the effects of insufficient sleep has been focused on total sleep deprivation. However, women progressing through the menopausal transition are more likely to experience partial sleep deprivation that may occur in a variety of patterns: fragmentation of sleep (common with sleep apnea); elimination of certain physiologic stages of sleep (as may occur with certain medications); and shortened sleep duration, also referred to as sleep restriction.10 The most likely pattern to affect perimenopausal women is sleep restriction. In the sleep literature, when people who were restricted to 8 hours, 6 hours, or 4 hours of sleep per night were compared with people who did not sleep at all for 3 nights, those who were restricted to 4 hours or 6 hours of sleep experienced decreases in their performance of math tasks and tasks requiring psychomotor vigilance. Those who slept only 4 hours per night performed some tasks as poorly as those who had lost 2 full nights of sleep. Additionally, while the partially sleep‐deprived group had performance loss as significant as the total deprivation group, those who were only partially deprived reported much less change in their daytime sleepiness. This important finding suggests that while sleep restriction has significant neurobehavioral effects, people are largely unaware of the deficits—a potentially dangerous combination.11 The finding also underscores the importance of asking patients not only about whether they feel sleepy during the day but also about the number of hours of sleep they get on an average night.

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KEY POINTS

- Sleep disturbance is a common problem for women throughout the menopausal transition.

- Sleep disturbance may manifest as difficulty falling asleep or middle of the night or early morning awakenings.

- Sleep disturbance often occurs with hot flushes, aching, stiffness and pain in joints, depressed mood, and anxiety.

- Sleep restriction may cause neurobehavioral changes without the patient being aware of them.

- Perimenopausal sleep disturbance is often associated with other chronic illnesses.

- In addition to estrogen therapy, perimenopausal sleep disturbance may be treated with antidepressants, hypnotics, herbal remedies, or nonpharmacologic methods.

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OTHER COMORBID MENOPAUSAL SYMPTOMS

Disturbed sleep is only one of the challenges associated with menopause. The most commonly reported symptoms are the classic vasomotor hot flushes and aching, pain, and stiffness in joints. Many women also report symptoms of depression and anxiety12 decreased libido, and vaginal dryness.5 In a 2010 review of nearly 150 published studies regarding types of sleep disorders and various management strategies, a number of parameters associated with sleep disturbance were identified. They included behavioral factors, such as caffeine intake; stress and tension levels; vasomotor symptoms and hormone fluctuations; anxiety and depression; and primary sleep disorders, such as obstructive sleep apnea and RLS. Associations between any of these factors and sleep disturbance during the menopausal transition are not likely to surprise clinicians. However, there was also evidence for a relationship between sleep disturbance in perimenopausal and postmenopausal women and a number of medical problems. These included fibromyalgia and chronic pain, hypertension, cancer, thyroid dysfunction, gastroesophageal reflux, and obesity13 While the discovery of these associations does not prove that decreased sleep causes all these health problems, it does stress to health care providers the importance of being aware of the full gamut of potential health concerns (and how they inform management decisions) in the care of women during the menopausal transition.

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THERAPEUTIC OPTIONS

Hormonal therapy

Long‐term hormone therapy (HT) for chronic disease management and treatment of menopausal symptoms has been surrounded by controversy in the past decade. Nonetheless, hormonal therapy may remain an option for symptoms of sleep disturbance. A study of three different combinations of treatment options for sleep disturbance was conducted among perimenopausal and postmenopausal Japanese women. The first group received nutrition and health education; the second group received education plus conjugated estrogen; and the third group received education plus a benzodiazepine with hypnotic effects. Results showed that both the estrogen and the benzodiazepine decreased the severity of the sleep disturbance. The estrogen group also reported significant improvement in their vasomotor symptoms. Only the hypnotic group experienced improvement in the time required to fall asleep and in the restorative quality of sleep.14 Another small randomized controlled study of HT versus placebo in menopausal women found that taking estrogen resulted in significant improvement both in subjective ratings of sleep quality and in sleep efficiency (time asleep divided by total time in bed) as measured by PSG; the placebo group saw no improvement.15

Estrogen replacement may have beneficial effects on sleep for perimenopausal women, but the safety of longterm estrogen therapy remains a concern. In response to the concerns raised since the Women's Health Initiative (WHI) in 2001, the Cochrane Collaboration conducted a review of 23 randomized controlled trials that compared the effects of estrogen taken for at least 1 year (with or without a progestin) versus placebo. A total of 42,830 women were involved. The investigators found that after healthy women had used combined hormone therapy for 1 year, the risk of a cardiovascular event increased significantly, and after 3 years of continuous use, the risk of stroke was higher. In addition, there was an increased risk of venous thromboembolism (VTE), gallbladder disease, and breast cancer, and in older women, there was an increased risk of dementia. The increased risk of VTE, stroke, and gallbladder disease was also found in women who took long‐term estrogen alone.16 The position of the American Congress of Obstetricians and Gynecologists is that HT should be used to control menopausal symptoms (predominantly vasomotor complaints) at the lowest dose and for the shortest amount of time possible. HT is not recommended for prevention of heart disease.17

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Other pharmacologic options

Antidepressants and hypnotic agents are possible pharmacologic alternatives to estrogens in the treatment of sleep disorders in perimenopausal women. There is good evidence that the antidepressant escitalopram 10 to 20 mg/day improves the quality of sleep in otherwise healthy perimenopausal and postmenopausal women.18

There is also support for a combination therapy comprising the antidepressant mirtazapine and the complementary agent melatonin. A series of cases in the literature reported on perimenopausal women who were started on mirtazapine 15 mg/day. Once their sleep symptoms were under control, prolonged‐release melatonin 2 mg was added, and over several weeks, the mirtazapine was tapered off. The women experienced improvement in their sleep that began on the mirtazapine and was maintained even after the mirtazapine was discontinued and they were taking melatonin alone. The advantage of this particular regimen was the shift in side‐effect profile. During the mirtazapine‐alone period, the women experienced the customary increase in body mass index (BMI), but they lost some of the weight after the transition to melatonin, netting a mean increase of 1 kg of body weight. The combined regimen of mirtazapine with the addition of melatonin and tapering of mirtazapine produced great benefits in sleep quality while tempering the unwanted effect of weight gain.19

The hypnotic agent eszopiclone has also been studied for the treatment of sleep disturbance in perimenopausal and postmenopausal women. At 3 mg/day, eszopiclone significantly improved insomnia symptoms. Of the 50 subjects who completed both the placebo and treatment arms, three withdrew for side effects of dizziness, jitteriness, or palpitations. Although eszopiclone has no effect on the vasomotor symptoms of menopause, it did alleviate symptoms of anxiety and depression and improve overall quality of life.20

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Complementary and alternative therapies

In addition to melatonin, two other complementary medicine options for the treatment of menopausal symptoms include isoflavones and valerian. Isoflavones are plant‐derived compounds that have been investigated for benefits in a number of different health issues. In the case of sleep disturbance, treatment with isoflavones 80 mg/day for 4 months in postmenopausal women resulted in significant improvement in PSG‐measured sleep efficiency and fewer episodes of insomnia, as well as reduced severity and frequency of hot flushes, compared with placebo.21 Valerian is another plant‐derived compound that has been studied for its effects on insomnia in postmenopausal women. In a randomized trial, valerian extract 530 mg twice daily resulted in significantly greater improvement in subjective sleep quality than placebo. However, only about one‐third of those in the valerian group (compared with 4% of those taking placebo) experienced an improvement in sleep.22

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Nonpharmacologic options

Therapeutic massage and yoga are two of the nonpharmacologic options studied for their effects on sleep disturbance in women during the menopausal transition. When twice‐weekly therapeutic massage was compared with passive movement or no intervention at all over a 4‐month period, massage was shown to significantly decrease the severity of insomnia (as rated by the patients themselves), as well as to improve symptoms of depression and overall quality of life. Passive movement also helped insomnia, but neither intervention resulted in a significant change in PSG measurements.23 Similarly, yoga was shown to have significantly greater effects on subjective measures of sleep than passive stretching, but again, there were no significant changes in PSG measurements.24

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CONCLUSION

For many women in midlife, sleep disturbance is a significant problem that often worsens and is accompanied by other symptoms throughout the menopausal transition. Sleep disturbance can be easily assessed in the primary care office using a simple tool like the Insomnia Severity Index (Table 1). PAs should take a holistic approach that includes assessment of the many common symptoms that affect women in this phase of their life (eg, hot flushes, night sweats, changes in mood, joint aches and stiffness, vaginal dryness) in addition to the sleep disturbance. These symptoms should be considered in addition to other comorbid disease and personal preferences in developing individualized management plans.

Table 1
Table 1
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Treatment options are numerous (Table 2). Hormone replacement therapy may be an option for women who are perimenopausal or in very early postmenopause and have substantial vasomotor complaints as well. Hormone therapy should be low‐dose and short‐term, with careful patient education and monitoring for adverse effects. Antidepressants may be a viable option for women who have mood disturbances accompanying their insomnia. A combined program of melatonin and an antidepressant, with eventual tapering of the antidepressant, may be a good choice for the woman with minimal mood symptoms and great concern about weight gain. Valerian and isoflavones are options for women with contraindications for hormone therapy or for those who prefer not to take a pharmaceutical agent. Nonpharmacologic therapies, such as massage and/or yoga, may be effective for some women and certainly are potentially very useful as adjunctive measures. Overall, sleep disturbance is an important concern to women in midlife when they present to their primary care provider. Including questions on quality of sleep, exploring associated menopausal symptoms and comorbid diseases, and partnering with patients to develop a management plan tailored to their individual situation is critical to effective care. JAAPA

Table 2
Table 2
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REFERENCES

1. National Institutes of Health State-of-the Science Panel. National Institutes of Health State-ofthe-Science conference statement: management of menopause-related symptoms. Ann Intern Med. 2005;142(12 pt 1):1003-1013.

2. Dennerstein L, Lehert P, Guthrie JR, Burger HG. Modeling women's health during the menopausal transition: a longitudinal analysis. Menopause. 2007;14(1):53-62.

3. Kravitz HM, Zhao X, Bromberger JT, et al. Sleep disturbance during the menopausal transition in a multi-ethnic community sample of women. Sleep. 2008;31(7):979-990.

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5. Freeman EW, Sammel MD, Lin H, et al. Symptoms associated with menopausal transition and reproductive hormones in midlife women. Obstet Gynecol. 2007;110(2 pt 1):230-240.

6. Schutte-Rodin S, Broch L, Buysse D, et al. Clinical guideline for the evaluation and management of chronic insomnia in adults. J Clin Sleep Med. 2008;4(5):487-504.

7. Woods NF, Mitchell ES. Sleep symptoms during the menopausal transition and early postmenopause: observations from the Seattle Midlife Women's Health Study. Sleep. 2010;33(4):539-549.

8. Pien GW, Sammel MD, Freeman EW, et al. Predictors of sleep quality in women in the menopausal transition. Sleep. 2008;31(7):991-999.

9. Hall MH, Matthews KA, Kravitz HM, et al. Race and financial strain are independent correlates of sleep in midlife women: the SWAN sleep study. Sleep. 2009;32(1)73-82.

10. Banks S, Dinges DF. Behavioral and physiological consequences of sleep restriction. J Clin Sleep Med. 2007;3(5):519-528.

11. Van Dongen HP, Maislin G, Mullington JM, Dinges DF. The cumulative cost of additional wakefulness: dose-response effects on neurobehavioral functions and sleep physiology from chronic sleep restriction and total sleep deprivation. Sleep. 2003;26(2):117-126.

12. Terauchi M, Hiramitsu S, Akiyoshi M, et al. Associations between anxiety, depression and insomnia in peri- and post-menopausal women. Maturitas. 2012;72(1):61-65.

13. Joffe H, Massler A, Sharkey KM. Evaluation and management of sleep disturbance during the menopause transition. Semin ReprodMed. 2010;28(5):404-421.

14. Terauchi M, Obayashi S, Akiyoshi M, et al. Effects of oral estrogen and hypnotics on Japanese periand postmenopausal women with sleep disturbance. J Obstet Gynaecol Res. 2011;37(7):741-749.

15. Silva BH, Martinez D, Wender MC. A randomized, controlled pilot trial of hormone therapy for menopausal insomnia. Arch Womens Ment Health. 2011;14(6):505-508.

16. Marjoribanks J, Farquhar C, Roberts H, Lethaby A. Long term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev. 2012 Jul 11;7:CD004143.

17. American College of Obstetricians and Gynecologists. Hormone therapy and heart disease. ACOG Committee Opinion No. 420. Obstet Gynecol. 2008;112(5):1189-1192.

18. Ensrud KE, Joffe H, Guthrie KA, et al. Effect of escitalopram on insomnia symptoms and subjective sleep quality in healthy perimenopausal and postmenopausal women with hot flashes: a randomized trial. Menopause. 2012;19(8):848-855.

19. Dolev Z. Case series of perimenopausal women with insomnia treated with mirtazapine followed by prolonged-release melatonin add-on and monotherapy. Arch Womens Ment Health. 2011;14(3):269-273.

20. Joffe H, Petrillo L, Viguera A, et al. Eszopiclone improves insomnia and depressive and anxious symptoms in perimenopausal and postmenopausal women with hot flashes: a randomized, double-blinded, placebo-controlled crossover trial. Am J Obstet Gynecol. 2010;202(2):171.e1-171.e11.

21. Hachul H, Brandão LC, D'Almeida V, et al. Isoflavones decrease insomnia in postmenopause. Menopause. 2011;18(2):178-184.

22. Taavoni S, Ekbatani N, Kashaniyan M, Haghani H. Effect of valerian on sleep quality in postmenopausal women: a randomized placebo-controlled clinical trial. Menopause. 2011;18(9):951-955.

23. Oliveira DS, Hachul H, Goto V, et al. Effect of therapeutic massage on insomnia and climacteric symptoms in postmenopausal women. Climacteric. 2012;15(1):21-29.

24. Afonso RF, Hachul H, Kozasa EH, et al. Yoga decreases insomnia in postmenopausal women: a randomized clinical trial. Menopause. 2012;19(2):186-193.

25. Morin CM, Belleville G, Bélanger L, Ivers H. The Insomnia Severity Index: psychometric indicators to detect insomnia cases and evaluate treatment response. Sleep. 2011;34(5):601-608.

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Section Description

EARN CATEGORY I CME CREDIT by reading this article and the article beginning on page 26 and successfully completing the posttest on page 55. Successful completion is defined as a cumulative score of at least 70% correct. This material has been reviewed and is approved for 1 hour of clinical Category I (Preapproved) CME credit by the AAPA. The term of approval is for 1 year from the publication date of January 2013.

© 2013 Lippincott Williams & Wilkins, Inc.

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