Sleep in the Menopause Transition
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1 Sleep in the Menopause Transition Hadine Joffe, MD, MSc Director, Women s Hormone & Aging Research Program Associate Professor, Harvard Medical School Vice Chair for Research & Director of Women s Mental Health Division, Department of Psychiatry, BWH Director, Psycho Oncology Research, DFCI
2 Symptoms Attributed to Menopause Transition Strong evidence 1. Vasomotor symptoms (hot flashes, night sweats) 2. Sleep disturbance 3. Depression 4. Vaginal dryness 5. Breast tenderness Weak evidence 1. Cognitive problems 2. Sexual dysfunction 3. Menorrhagia 4. Urinary incontinence 5. Back pain 6. Stiff or painful joints NIH State-of-the-Science Panel, Ann Intern Med 2005
3 Common Sources of Sleep Disturbance in Menopause Transition General Sleep disorders Mental health Hot flashes Stress Primary insomnia Depression estradiol FSH inhibin B progesterone testosterone Menopausespecific Agerelated Caffeine Obstructive sleep apnea Periodic limb movement disorder Restless legs syndrome Anxiety Health Chronic pain, fibromyalgia Obesity GERD HTN Thyroid disease Cancer Joffe H, Semin Reprod Med 2010; Freedman RR, Menopause 2007
4 1. Hot flash associated sleep interruption 2. Are there sleep changes independent of hot flashes? Hormone-related changes Overview Sleep apnea, restless legs syndrome, periodic limb movements 3. Treatment of sleep disturbance and insomnia associated with hot flashes and menopause
5 Overview Part 1 1. Hot flash associated sleep interruption 2. Are there sleep changes independent of hot flashes? Hormone-related changes Sleep apnea, restless legs syndrome, periodic limb movements 3. Treatment of sleep disturbance and insomnia associated with hot flashes and menopause
6 Impact of new-onset nighttime hot flashes on PSG sleep fragmentation in WASO (p=0.007) in awakenings (p=0.05) Change in PSG WASO per night (min) None Infrequent Frequent * Change in PSG # Awakenings per night None Infrequent Frequent Hot flash frequency group None (n=9) Infrequent (n=10) Frequent (n=10) 62% increase in WASO for every additional nighttime hot flash 3% increase in awakenings from baseline for every additional nighttime hot flash Results for objective nighttime hot flashes are consistent p=0.02 p = 0.03 PSG = polysomnography WASO = wake time after sleep onset (min) Joffe, Sleep 2013
7 Moving Away from a 1-to-1 Link Between Hot Flashes and Sleep Interruption 1. Pairing of hot flashes with wakefulness Approximately 2/3 of hot flashes linked with an awakening 1-3 # awakenings and sleep stage transitions exceeds number of hot flashes 1,2 Approximately ¼ of wake time attributed to hot flashes 3 2. Physiologic processes underlying the hot flash state rather than the hot flash event per se may be responsible in part for sleep fragmentation a. Preceding cortical activation 4 b. Autonomic system perturbation sympathetic 5 and/or parasympathetic 6,7 tone c. Preceding temperature rise 8 Uncoupling of individual hot flashes from individual awakenings X Move from thinking of physiologic changes around hot flash event to the hot flashes state CNS activity may drive hot flashes and sleep interruption in parallel rather than exclusively through a linear relationship 1 Bianchi, et al. J Clin Sleep Med 2016; 2 Joffe, Sleep 2013; 3 de Zambotti M, Fertil Steril 2014; 4 Freedman, Cereb Cortex 2013; 6 Freedman, Menopause 2011; 6 De Zambotti, Menopause 2013; 7 Thurston, Menopause 2010; 8 Carpenter, Menopause 2004
8 Overview Part 2 1. Hot flash associated sleep interruption 2. Are there sleep changes independent of hot flashes? Hormone-related changes Sleep apnea, restless legs syndrome, periodic limb movements 3. Treatment of sleep disturbance and insomnia associated with hot flashes and menopause
9 Is there a menopausal sleep disorder? Hormonal factors 1. Menopause stage associations 2. Link with reproductive hormone changes 3. Is there a mediating role of co-occurring hot flashes? Primary sleep disorders 1. Obstructive sleep apnea (OSA) 2. Restless legs syndrome (RLS) and periodic limb movement disorder (PLMD)
10 Summary of evidence for menopausal sleep disorder independent of hot flashes Hormonal factors Evidence for a menopausal sleep disorder Independent of hot flashes Related to menopause stage or to biomarkers of reduced ovarian reserve Related to changing reproductive hormone dynamics of menopause transition Primary sleep disorders Sleep apnea risk increases 2 3 fold Related to low estradiol and low progesterone PLMD associated with reduced sleep efficiency Kravitz & Joffe, Obgyn Clin N America 2011; Young, Am J Respir Crit Care Med 2003; Netzer, Sleep Breath 2003; Galvan, Menopause 2016; Freedman & Roehrs, Menopause 2007
11 Overview Part 3 1. Hot flash associated sleep interruption 2. Are there sleep changes independent of hot flashes? Hormone-related changes Sleep apnea, restless legs syndrome, periodic limb movements 3. Treatment of sleep disturbance and insomnia associated with hot flashes and menopause
12 Co-occurring Causes of Sleep Disturbance Spielman s 3P model : predisposing, precipitating, and perpetuating factors 1 Hot flashes Stress Depression Sleep apnea Primary insomnia RLS/ PLMD RLS = restless legs syndrome PLMD = period limb movement disorder 1 Spielman, Clin Psychol Rev 1986
13 Behavioral Treatment of Hot Flash-associated Sleep Disturbance CBTi for insomnia symptoms 1 6-session telephone CBT-insomnia vs. menopause education control 106 peri/postmenopause with ISI 12 and hot flashes CBTi more effective at 8 weeks and effect sustained at 24 weeks (p<0.01) Small benefits in less symptomatic patients 1. CBT for menopause 2 2. Exercise 3 Control 3. Melatonin 4 4. Acupuncture 5 CBT-i ISI = insomnia severity index CBT = cognitive behavioral therapy 1 McCurry & MsFLASH, JAMA Int Med 2016; 2 Chilcot, Maturitas 2014; 3 Sternfeld & MsFLASH, Menopause 2014; 4 Chen, Br Ca Res Treat 2015; 5 Bokmand, Breast 2013
14 Pharmacologic Approaches to Treating Hot Flash-associated Sleep Disturbance Clinical trials supporting efficacy 1. Hormone therapy Including estrogen + SERM combination 2. SSRI/SNRI 3. Gabapentin 4. GABA-A receptor non-benzodiazepines 1 Ensrud, Menopause 2012; 2 Pinkerton, NAMS 2013; 3 Newton, NAMS 2013; 4 Yurcheshen, et al. J Women s Health 2009; 5 Joffe, Semin Reprod Med 2010; 6 Pinkerton, Menopause 2013; 7 Joffe, Am J OBGYN 2010; 8 Dorsey, Clin Ther 2004; 9 Ensrud, Sleep 2015
15 Summary of Pharmacological Approaches to Treating Sleep Disturbance in Women with Hot Flashes Target both Target hot flashes Hot flashes Sleep quality Target sleep disturbance SSRI/SNRI escitalopram 1, paroxetine mesylate 2, venlafaxine 3 Gabapentin 4 Hormone therapy 3,5 Bazedoxifene/CEE 6 Hypnotics 7,8,9 CBTi 10 1 Ensrud, Menopause 2012; 2 Pinkerton, Menopause 2015; 3 Ensrud, Sleep 2015; 4 Yurcheshen, J Wom Health 2009; 5 Joffe, Semin Reprod Med 2010; 6 Pinkerton, Menopause 2014; 7 Joffe, Am J OBGYN 2010; 8 Dorsey, Clin Ther 2004; 9 Soares, Obstet Gynecol 2006; 10 McCurry &MsFLASH, JAMA Int Med 2016
16 Conclusions 1. Sleep disturbance characterized primarily by sleep interruption is common during the menopause transition. 2. Hot flashes contribute importantly but not exclusively to sleep interruption in midlife women. 3. Links between hot flashes and awakenings suggest that it is not a 1-to-1 relationship. 4. Factors contributing to sleep disruption independent of hot flashes: Changing reproductive hormone dynamics of menopause transition (but not progressive reproductive aging) Obstructive sleep apnea, RLS/PLMD 5. Treatment of menopause-associated sleep disturbance can involve primary therapy for hot flashes and/or primary behavioral and pharmacologic therapies for insomnia.
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