Q&A: Brain receptors may present therapeutic target for sleep disturbances in menopause
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Key takeaways:
- Up to 69% of midlife women report sleep disturbances.
- Estrogen effectively treats hot flashes, but not sleep disturbance in menopause.
- Sleep disturbances in menopause impact hot flashes, mood, pain and brain fog.
Currently, cognitive behavioral therapy for insomnia is the gold standard treatment for sleep disturbances associated with menopause, and research is underway to better target neurons responsible for sleep disturbances.
“Sleep disturbance is an unmet need for midlife women,” Pauline M. Maki, PhD, professor of psychiatry, psychology and obstetrics and gynecology, director of the Women’s Mental Health Research Program and senior director of research in the Center for Research on Women and Gender at the University of Illinois, told Healio. “While there’s recognition of hot flashes being a key symptom of menopause, there’s less understanding and awareness of how sleep problems increase during the menopause transition, how prevalent they are and what characterizes menopause-related sleep disturbance and distinguishes it from other types of sleep disturbance.”
Maki and colleagues conducted a narrative review, published in Menopause, searching PubMed for systematic reviews, meta-analyses, reviews, society guidelines and original research on sleep disturbances associated with menopause. The authors categorized and explained the development of sleep disturbances associated with menopause and concluded more research is needed to understand their etiology and categorize the neuronal circuits involved to create more targeted therapies.
Healio spoke with Maki about the review as well as how common sleep disturbances associated with menopause are, current available treatments and how sleep disturbances impact women’s health and overall well-being.
Healio: How do menopausal women present with sleep disturbances?
Maki: Up to 69% of midlife women report sleep problems. The typical aspects of sleep that are affected in menopause are not difficulty falling asleep or difficulty waking up, but difficulty maintaining sleep once you’ve fallen asleep. We measure this scientifically as wake after sleep onset. It’s these awakenings during the course of sleep that really characterize menopause-related sleep disturbance. Other aspects of sleep can be disturbed, but that is the more prominent feature of menopause-related sleep disturbance.
Healio: Why are sleep disturbances so common in menopause? Is it just due to hot flashes or something more?
Maki: We think that it’s something more, though clearly, hot flashes do play a role. How do we know that? There are beautiful studies of women who are wearing ambulatory sensors, that sense when they’re having a hot flash and when they’re awakening, and what they find is that 75% of the time that a woman has a hot flash, she wakes up. It’s clearly the case that there are periods of wakefulness that surround the time in which a woman has a hot flash. And we know that women experience hot flashes on average for 7.4 years and, if they’re Black, it’s 10 years. Many women experience these symptoms night after night, and many women’s menopause symptoms go untreated.
So, sometimes treating the hot flashes can improve sleep in women. It’s important to also recognize that most periods of wakefulness are not associated with a hot flash. So, if you tallied up the number of minutes that a woman is awake at midlife during the night, most of those periods of wakefulness occur outside of a hot flash. There’s something else going on that might explain that, and to be honest with you, we do not fully understand the factors that contribute to that type of wakefulness in women.
If sleep disturbance at menopause was due mostly to hot flashes, then treating hot flashes with estrogen should improve sleep quite a bit because estrogen is the gold standard treatment for hot flashes. But that’s not the case. The randomized trial data do not show a clear benefit of estrogen on sleep, even though it’s really effective in treating hot flashes. It doesn’t seem to be just the estrogen, and it doesn’t seem to be just the hot flashes, so there might be something else going on. That’s where this theoretical idea is emerging that a type of neuron that plays a critical role in hot flashes, called a KNDY (“candy”) neuron and the receptors on those KNDy neurons, may also play an important role in sleep disturbance related to menopause.
Healio: How do sleep disturbances impact quality of life for midlife women?
Maki: One thing that’s important to recognize is that not all women have these sleep disturbances. My menopause isn’t your menopause. Some women are very fortunate, and they go through menopause without experiencing bothersome symptoms. For the other women, sleep disturbances impact work-related quality of life, relationships, overall quality of life, and chronic sleep disturbance is associated with lower mood. You don’t have to be a neuroscientist to know that when you’re chronically sleep deprived, you can be a bit punchier, and you don’t handle your stressors as well. For many women, poor sleep goes on for years and, generally, the sleep disturbances continue after the perimenopause. We’re looking oftentimes at chronic sleep deprivation in women.
Healio: Are sleep disturbances related to other symptoms of menopause? If so, how?
Maki: Sleep disturbance is strongly associated with depressive symptoms. There are studies that follow day-to-day associations to ask the question: Is it that the hot flashes caused the mood problems or the do the mood problems cause the hot flashes, that kind of temporal association, and it does appear that our hot flashes on Monday predict our mood on Tuesday.
The relationship among these menopause symptoms is very complex. Sleep is linked to depressive symptoms, and in part, that association is due to hot flashes. When we stay awake instead of sleeping, our moods the next day are lower. In addition, fatigue, which is a commonly reported symptom among women, is strongly associated with sleep disturbance. Women report higher levels of pain in menopause, and women’s pain can lead to sleep disturbances, especially the common complaint of pain in the neck area and upper shoulders. So, if you’re having that pain, you might be tossing and turning at night.
There’s a rather complicated association between waking up during the nighttime and mood disturbance. Women have a propensity to ruminate, meaning that we often think about personal problems and worry about them. When we wake up at night, rather than immediately going back to sleep, we often ruminate and that can lead to more time spent awake. You have to train yourself to let your mind shut down once you’ve woken up.
And sleep is tied to brain fog. Chronic sleep deprivation is certainly associated with poor concentration and memory. There’s a relationship between loss of sleep and eating behaviors. Researchers have compared eating patterns and food cravings between healthy adults who were forced to stay awake in the laboratory and healthy adults with good sleep the night before. Those who were sleep deprived will crave the less healthy foods, and they will have a higher level of desire for those foods. So, sleep can affect a variety of different systems in the body and sleep has associations with a number of different menopausal symptoms.
Healio: How are sleep disturbances associated with menopause treated?
Maki: The gold standard treatment for sleep disturbance is a behavioral therapy. It’s not a drug. It’s a behavioral therapy called cognitive behavioral therapy for insomnia (CBTI), and it helps us develop a sleep habit. Sleep is something we can train our bodies to do, and CBTI trains us in how to teach our bodies how to fall asleep, and what to do when we wake up so that those wake episodes are as short as possible. CBTI is the No.1 rated approach for treating sleep disturbance.
Women can get CBTI and there are self-help manuals and apps for that. Then, occasionally, depending on where a woman lives, she can get a provider to train her with CBTI. Randomized trial data for this is very good. It takes discipline. I don’t know about you, but sometimes I want to have a glass of wine at night and sometimes I don’t want to go to bed at the same time every night. There are aspects of CBTI that require us to change our habits, but for women who are able to do it, it’s highly effective. It’s one of the best evidence-based approaches for sleep, and the benefit is that, unlike the Z-drugs, like the benzos, they don’t have any addictive properties and you don’t have to worry about the side effects or the carryover effects or any concern that you’re driving might be affected. And the Z-drugs don’t restore real sleep.
I’d be remiss if I didn’t mention this other approach that that people sometimes use for sleep in midlife women, which is to take a progesterone pill at night. Progesterone acts on the same area of the brain in the same neurons as Z-drugs, and menopause care practitioners oftentimes will prescribe women to take their progesterone at night to help them to sleep.
Among women with bothersome hot flashes, it’s important to treat their hot flashes too, because 75% of awakenings are associated with hot flashes. For that, we have hormone therapy as the gold standard. We also now have the new nonhormonal neurokinin-3 antagonists recently FDA approved. Those are another option. Those neurokinin-3 antagonists, which have no estrogen effect, also seem to improve sleep, suggesting there might be something about the targets in the brain that those treatments affect, that might help to improve sleep, and that’s one of the future directions.
Healio: What other research is required for sleep disturbances associated with menopause?
Maki: Due to an amazing researcher from the University of Arizona, Naomi Rance, MD, PhD, led this important area of research, we now know why women have hot flashes. We didn’t know before why 80% of women experience it, and we didn’t understand the biological basis of it.
Now we know that hot flashes arise from a change in the function of neurons in an area of the brain called the hypothalamus. The hypothalamus is the area of the brain that takes care of basic bodily processes like sleep, hunger, body temperature regulation, etc. In the hypothalamus, there’s a special set of neurons, KNDy neurons. This name comes from the types of receptors found on those neurons — kisspeptin, neurokinin and dynorphin. These neurons also have receptors for estrogen.
To regulate our body temperature, estrogen acts to put the brakes on KNDy neurons and stops them from firing a signal that says, “sweat.” When estrogen is lost at menopause, the estrogen brakes are no longer turned on, so the KNDy neurons send a signal to “sweat.” That results in a hot flash. But there’s another way to tell those neurons not to sweat, and that is by acting on the neurokinin receptor, specifically by blocking the actions of neurokinin-b on a special type of neurokinin receptor, the neurokinin-3 receptor. Whereas estrogen signal to KNDy neurons is, “don’t sweat” the neurokinin-b signal is “go ahead and sweat.” So, another way to prevent the hot flash is to stop that neurokinin-b “go sweat” signal.
That’s how this new nonhormonal medication works to treat hot flashes — it blocks the neurokinin receptor and stops the “sweat” signal. The fancy name for the new nonhormonal medication is “neurokinin-3 receptor antagonist,” which just means that the drug blocks the neurokinin-3 receptor. If the receptor is blocked by the medication, neurokinin-b can’t act on that receptor and can’t send a “sweat” signal. The new medication doesn’t involve estrogen at all. Medications that are effective in treating hot flashes can work on either estrogen or neurokinin receptors.
Now what does this have to do with sleep? There seems to be some benefit for sleep if you block that neurokinin-3 receptor, and there seems possibly to be even more benefit if you also block that neurokinin-1 receptor on that same neuron.
There are two nonhormonal interventions for hot flashes that have been shown to be effective. One is FDA approved, and that is Veozah and that acts on neurokinin-3 and that’s fezolinetant (Astellas). There’s another drug that has been shown in phase 2 trials, OASIS 1 and 2, and that’s elinzanetant (Bayer) that effects neurokinin-1 and neurokinin-3. Both of those drugs seem to improve sleep, but perhaps the one that also antagonizes neurokinin-1 might do it a little more reliably. Neurokinin-1 receptors may also play a role in hot flashes. Researchers are looking at whether we could treat menopause-related sleep problems by targeting neurokinin receptors on the KNDy neuron, that same neuron that triggers the hot flashes. And we want to know what role neurokinin-1 and -3 receptors play in sleep disturbance, as well as the role of KNDy neurons in sleep more generally.
Healio: Is there anything else you’d like to add?
Maki: I would caution women against using alcohol to relax before bedtime. Women deal with a lot at midlife, they’re sleep deprived and maybe their levels of stress are high because menopause can also change how the brain responds to stress. It turns out that although alcohol makes us feel tired at first, it actually leads to sleep disturbance. The other thing that can be really helpful is to engage in aerobic exercise during the day. The more exercise you engage in, the better your sleep, so that can also provide some benefits.
For more information:
Pauline M. Maki, PhD, can be reached at pmaki1@uic.edu.