Perimenopausal and Menopausal Sleep Disturbance
A distinct entity from insomnia
Happy New Year everyone, and what better way to start the year than with a commitment to better sleep! Sleep is the foundation of recovery from mental and physical activity, and helps keep our physiologic processes in balance for maintaining good health. But it is such a struggle for so many people - especially in midlife. Today we review of an excellent article published in the Journal Menopause that can help you on your way to better sleep! Enjoy! Dr. Carla
As a Menopause Specialist and a menopausal woman myself, I cannot think of anything more disruptive to the experience of life than poor sleep night after night after night. Even during my training as an OBGYN resident when we would work 36-hour shifts every third night, we at least knew that the shift would end and sleep was promised. In perimenopause and menopause (and postpartum, for that matter), you don’t know when (or if) the sleepless nights will end leading to exhaustion, depression, health issues, and overall poor quality of life.
Today’s post summarizes an excellent review published in the journal Menopause earlier this year. The authors discuss the latest knowledge surrounding sleep disturbance during perimenopause and menopause. I liked this review because it goes deeper than sleep hygiene and avoiding caffeine after 3pm. It discusses peri/menopausal sleep disturbance as a distinct entity from insomnia with respect to causes, physiology, and approach to intervention. As always, my editorial commentary will follow.
REVIEW -Sleep disturbance associated with the menopause
Maki PM, Panay N, and Simon JA.
Menopause: The Journal of The Menopause Society 2024 Vol. 31, No. 8, pp. 724-733 DOI: 10.1097/GME.0000000000002386
Sleep disturbance during perimenopause and menopause is a frequent and disruptive problem second only to vasomotor symptoms (VMS) (“hot flashes”) in prevalence that can lead to significant disruption of life activities impacting personal and social relationships, work, and health. It is characterized by frequent sleep interruptions, nighttime awakenings and/or greater wakefulness after sleep onset (WASO), poor quality, and insufficient restorative sleep.
When associated with the menopause transition, disruptive sleep patterns can occur in women without a prior history of sleep problems with 40- 69% of midlife women reporting sleep disturbance. However, the proportion of women meeting the criteria for an insomnia diagnosis is much lower (4% and 40%).
Impact of menopausal sleep disruption
Over time, sleep disruption can have a significant impact on physical and mental health and quality of life including:
Significant increases in the risk of unemployment
Loss of approximately $2 billion per year in productivity in the US.
Shift in nutrient utilization that promotes body fat gain, potential development of metabolic syndrome, and other related issues independent of changing estrogen levels during menopause.
Links with subclinical markers of cardiovascular disease risk independently of VMS
Association with deteriorating mental health, particularly with symptoms of depression and anxiety
Studies of cognitive performance across the menopause transition identified sleep disruption as the major predictor of declines in verbal learning and memory areas and when persistent can result in impaired mental acuity and forgetfulness.
Defining Sleep Problems
A frustrating tendency in the mainstream medical community is that if a patient shares a concern with their provider and it doesn’t fit into a nice neat little diagnostic box, she may very well go untreated or even misdiagnosed. As we mentioned previously, 40-69% of perimenopausal and menopausal women report sleep disturbance but only 4-40% meet the diagnostic criteria for insomnia. This discrepancy underscores the need for a comprehensive conversation with our patients to understand their experiences, challenges, and goals.
Understanding the types of sleep disorders people experience creates a starting point of consideration when a woman shares her struggles with sleep. Below are three sleep disorder diagnoses that the authors cite as increasing in frequency among perimenopausal/menopausal women:
Chronic Insomnia - The most severe form of sleep disturbance. It is defined by the DSM-V criteria as difficulty with initiating and maintaining sleep and/or early-morning awakening with the inability to return to sleep causing significant distress/impairment in daytime functioning 3 nights/week for at least 3 months.
Sleep-Disordered Breathing (SDB)
Obstructive sleep apnea (OSA) is a condition where the upper airway repeatedly narrows or closes disrupting airflow. Treatment includes measures that relieve the obstruction such as positive airway pressure devices or oral appliances.
Central sleep apnea (CSA) is a condition where breathing repeatedly stops and starts during sleep due to improper signaling by the brain to the muscles that control breathing. Treatment targets the underlying cause (Medical conditions, medications, neurological causes, and use of continuous positive airway pressure.
Restless Leg Syndrome (RLS) - A neurological disorder that causes discomfort in the lower extremities and the constant urge to move them. The cause is mostly unknown but is thought to be related to dopamine signaling in the brain. Treatments for RLS may include reducing aggravating factors, iron supplementation, or dopaminergic medications.
Sleep Disturbance Associated with Menopause
Studies of sleep disturbance in menopausal women identified increases in the number of night-time awakenings and the time spent awake after sleep onset (WASO). This varied from those with chronic insomnia in these studies in that total sleep time and hyperarousal seen in younger women were not observed.
Another difference between chronic insomnia and sleep disturbance associated with menopause is that a reduced ability to fall asleep (sleep-onset insomnia) is a less common complaint during the menopause transition where more nighttime awakenings are observed.
Lastly, menopausal sleep disturbance can be related to fluctuations in estradiol levels, hot flashes, and mood disorders whereas primary insomnia cannot be attributed to an underlying cause.
Physiology
The hallmark of the menopausal transition is the change in pattern and levels of estradiol production by the ovaries. These changes have a cascade of downstream physiological effects that frequently impact sleep:
Decline in nighttime melatonin levels resulting in disturbance of circadian mechanisms that can impact sleep
VMS (“hot flashes”) and changes in core body temperature follow a circadian pattern and can be more frequent at night.
Eighty percent of menopausal/perimenopausal women experience vasomotor symptoms. When moderate to severe, women are 3 times more likely to experience awakenings from sleep. Interestingly, when VMS are objectively measured using instrumentation such as polysomnography, the results suggest that sleep can be disturbed even when VMS occur when women are unaware of them.
Mood disorders such as anxiety and depression increase in perimenopausal and menopausal women. Those with a history of clinical anxiety or depression earlier in life are at particularly high risk. Sleep and mood have been found to have a bi-directional relationship where mood disturbance can disrupt sleep and disrupted sleep and can cause exacerbation of mood symptoms. Likewise, effective treatment of mood symptoms can improve sleep and improved sleep can result in better mood.
The hormonal fluctuations associated with the menopause transition may cause sleep disturbance independently of other menopause symptoms due to a direct effect on the hypothalamic sleep center. Several studies have demonstrated that increased follicle-stimulating hormone (FSH) and decreasing estradiol levels are associated with difficulty staying and falling asleep.
The positive effects of progesterone on sleep have been well-documented over the years. Further, estrogen administration can increase REM sleep and decrease sleep latency according to one study cited by the authors.
The common thread that ties many of these physiological elements together lies in the hypothalamus of the brain, which plays a central role in the control of body temperature, circadian rhythms, reproductive hormonal regulation, and mood, along with many other physiologic functions that keep the body in balance.
Within the hypothalamus are specialized nerve cells called KNDy neurons that play a role in temperature regulation and modulation of the reproductive hormones via Gonadotropin-releasing (GnRH) hormone. When estrogen declines, these nerve cells become hyperactive which is believed to be involved in the physiology behind temperature dysregulation and hot flashes. KNDy neurons also play a role in the stress response system and mood, co-localizing with corticotropin-releasing hormone (CRH), serotonin, and dopamine.
Recent studies of a new class of medications called NK1 and NK3 receptor antagonists have demonstrated effectiveness in improving sleep and mood symptoms in menopausal women. Fezolinitent is an NK3 receptor antagonist that was FDA-approved in May 2023 for the treatment of hot flashes.
Treatment of Sleep Disturbance Associated with Menopause
The authors review the current treatments for sleep disturbance associated with menopause and their limitations.
Identifying and treating medical causes of sleep disturbance and counseling on good sleep hygiene are recommended as initial approaches to address sleep disturbance, however these measures are frequently unsuccessful
Hormone therapy can be effective if sleep disturbance is related to hot flashes. However, in the absence of hot flashes, the effectiveness is uncertain. Oral micronized progesterone has been suggested to improve sleep, as well as decrease hot flash frequency.
Anti-depressant medications such as selective serotonin reuptake inhibitors (SSRIs), most notably, Paroxetine, have sedative effects and may benefit women with sleep disturbance associated with hot flashes and depression. However, some SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs) may actually worsen sleep disturbance in individuals with mood conditions.
Sedative-hypnotic medications such as benzodiazepines (ex - Diazepam (Valium), Xanax (Alprazolam) and non-benzodiazepines (Zolpidem (Ambien) can be effective for sleep disturbance in the short term, however, they are generally not recommended in postmenopausal women due to an increased risk of falls, bone fracture, and osteoporosis in this population. Further, use of these medications for more than 4 weeks can lead to the development of tolerance, addiction, dependence, and withdrawal symptoms
Cognitive Behavioral Therapy for insomnia (CBT-i) is the recommended first-line approach for insomnia disorder in peri/menopausal women, however, accessibility to trained providers is a challenge, and the treatment is time-intensive.
Supplements - Dietary supplements such as probiotics, omega-3, and herbal medicines (eg, isoflavones, pollen extracts, red clover) are used to manage menopausal symptoms including sleep disturbance. However, studies of their efficacy are conflicting and often of poor quality. Melatonin is frequently used to induce drowsiness and may be effective in reducing sleep disturbance among postmenopausal women, but results from clinical studies are mixed. Melatonin is only available over-the-counter in the United States.
NK-1 and NK-3 receptor antagonists modulate hypothalamic KNDy neuronal activity and have shown promising efficacy in addressing hot flashes and sleep disturbances in multiple studies.
In My Humble Opinion….
Although the authors paint a bleak picture of effective treatment options for managing sleep disruption during menopause, the silver lining lies in the knowledge that has been gained in understanding this problem:
1 - Sleep disruption in perimenopause and menopause is a distinct problem that is different from chronic insomnia, sleep-disordered breathing, and restless leg syndrome. Recognizing this distinction helps to focus efforts on the root cause of the sleep disturbance.
2 - There is a clearer understanding of the interplay between hot flashes, mood, sleep, and the changing hormonal paradigm of the menopause transition. Understanding how these factors interact in each individual helps target symptoms more effectively.
3 - The key discovery of the role of KNDy neurons and the development of neurokinin-3 (NK3) receptor antagonists have given us another FDA-approved pharmacologic tool for managing the symptoms that can result in sleep disturbance associated with menopause.
4 -Advances in wearable technology have given us a powerful tool to collect sleep data in the comfort of our own homes and even track associations with sleep patterns. The more information we have about our own sleep patterns, the better we can identify the factors that impact sleep for an individual and target interventions accordingly.
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