Menopausal hot flashes pose risks beyond discomfort

Nearly all women experience menopause symptoms to some degree, but for some women, symptoms can be so severe that they interfere with quality of life and potentially have long-term health effects.

Hot flashes, the hallmark symptom of menopause, have been implicated in night sweats, sleep disturbances, cognitive and mood disorders and even risk for cardiovascular disease, among other conditions.

“Initially felt to be just a nuisance, vasomotor symptoms are now linked to CV ... and cognitive risks,” JoAnn V. Pinkerton, MD, NCMP, executive director of The North American Menopause Society, told Endocrine Today. “Women with frequent vasomotor symptoms have a greater than twofold increased odds of developing coronary heart disease over 14 years, with more subclinical CVD and more aortic calcifications and intima-media thickness.”

Which women will experience hot flashes in menopause, and to what extent, cannot be predicted, but there do seem to be ethnic variations in symptoms, which may be related to variations in diet, environment, lifestyle, cultural beliefs and genetics, according to Pinkerton.

“In the Study of Women’s Health Across the Nation (SWAN), Caucasian women had more muscle aches, difficulty with sleep and irritability,” Pinkerton said. “African American women were more likely to experience both hot flashes and night sweats, which lasted longer and were more intense, but [these women] were more positive about menopause. Chinese and Japanese women were less likely to have night sweats and hot flashes but [had] less enthusiasm about menopause.”

In this issue, Endocrine Today talked with the experts about menopause symptoms, their risk factors and the most effective treatments.

Frequent hot flashes

Vasomotor symptoms are likely the symptom most people think of when they consider menopause. Anywhere from 40% to 85% of women will have vasomotor symptoms at some point during the menopause transition, said Pinkerton, who is also a professor of obstetrics and gynecology and the division director for Midlife Health at the University of Virginia Health System. Recent research is revealing that hot flashes can start earlier and persist longer than popularly believed.

“In SWAN, hot flashes continued for 4.5 years after the last period,” Pinkerton said. “Reports have shown hot flashes on average to last 7 years, but they may last longer — 10 years, 20 years or longer.”

In one study of SWAN participants, published in JAMA Internal Medicine, Nancy E. Avis, PhD, of the department of social sciences and health policy at Wake Forest School of Medicine, in Winston-Salem, North Carolina, and colleagues analyzed data from 1,449 women aged 42 to 52 years to determine duration of menopausal vasomotor symptoms. They found that frequent hot flashes that began during premenopause or perimenopause tended to persist the longest, with a median duration of more than 11.8 years — 9.4 years after the final menstrual period.

Similarly, severity of vasomotor symptoms varies from woman to woman. In a 2013 study published in Menopause, Jennifer Whiteley, EdD, senior director at Pfizer, and colleagues reviewed data from the 2010 U.S. National Health and Wellness Study on 3,267 women aged 40 to 75 years (mean age, 58 years) who reported no menstrual bleeding or spotting for at least 1 year. Of the cohort, 53% reported experiencing no vasomotor symptoms, 28% reported mild symptoms, 14% reported moderate symptoms and 4% reported severe vasomotor symptoms. The women with moderate to severe symptoms had significantly lower health status scores and reported more physician visits for menopause symptoms compared with women who reported no vasomotor symptoms. Women with moderate to severe symptoms who were employed also reported more work presenteeism and impairment in activities of daily living compared with women reporting mild symptoms.

Although there is no way to predict the onset of hot flashes, there are some loose associations between symptom prevalence and demographic factors, according to Pinkerton. For example, in the study by Avis and colleagues, prevalence was higher among black women, those with less education, lower income and mood disorders, and among cigarette smokers.

Vasomotor symptoms are also more prevalent among women with obesity, according to Mary Ann Lumsden, BSc(Hons), MBBS, MRCOG, MD, FRCOG, president of the International Menopause Society and professor of obstetrics and gynecology at the University of Glasgow, Scotland. “The reason they’re more likely is because fat acts as an insulator — it’s like having a coat on all the time — so, it tends to make flushing and sweating worse,” she told Endocrine Today.

Researchers have yet to discover why certain women have more severe symptoms or have symptoms for an extended duration. “It appears to be based on how women are wired in their brain,” Holly L. Thacker, MD, director of the Center for Specialized Women’s Health and executive director of Speaking of Women’s Health at the Cleveland Clinic, told Endocrine Today. “Some people are wired to flash and others are not. Not every woman’s brain perceives fluctuations in hormone levels in absolute values.”

Changes in circulating blood flow and a decrease in core body temperature can trigger a hot flash episode, according to Pinkerton.

“Initially, the vessels dilate, and then they constrict,” Pinkerton said. “The hot flashes are more likely to occur with a decline in estrogen, and they’re felt to be caused by changes in the temperature regulation part of the brain, in the internal thermostat. ... Neurobiology includes transmitters in the brain, such as norepinephrine and serotonin with increasing evidence that hypothalamic kisspeptin/neurokinin B/dynorphin neurons are involved in thermoregulation and temperature dysregulation,” Pinkerton said.

“We found that [in] women who flush, the skin blood vessels are very reactive,” Lumsden said, referring to a study she conducted with colleagues examining the physiology of hot flashes. “We think that is simply a heat-loss mechanism because there is a lot of evidence that women who flush are also at increased CVD risk.”

Effect on CV health

“The menopause transition is often the time of accelerating CV risk,” Rebecca Clark Thurston, PhD, professor of psychiatry, clinical and translational science, epidemiology and psychology at University of Pittsburgh, told Endocrine Today.

Frequent, severe and bothersome hot flashes may be a marker for subclinical CVD beyond traditional CVD risk factors or endogenous estradiol levels, according to Thurston.

Thurston and colleagues analyzed SWAN data on 492 women aged 45 to 58 years without CVD and with an intact uterus and at least one ovary. They found that women who reported any vasomotor symptoms in the prior 2 weeks had significantly poorer vascular endothelial function and greater aortic calcification vs. women reporting no vasomotor symptoms, even in models adjusted for CVD risk factors and estradiol levels. Women with vasomotor symptoms at least 6 days in the prior 2 weeks also had increased carotid intima media thickening, controlling for CVD risk factors and estradiol.

Yet, Thurston said, measures of vasomotor symptoms in SWAN were purely subjective, relying on participants’ memories during a 2-week period. “So, rough measures,” she said.

In a second study, Thurston and colleagues assigned 295 nonsmoking women aged 40 to 60 years to use a physiologic monitor and record their symptoms in an ambulatory digital journal. They again found that among women with daily vasomotor symptoms, more frequent vasomotor symptoms were associated with higher rates of subclinical CVD, including higher carotid intima media thickness and plaque. These associations were unaccounted for by CVD risk factors or hormone levels.

“The reason we used subclinical CVD measures is very few women have clinical CVD at midlife,” Thurston said.

Increased intima-media thickening also was observed in women who do not get enough sleep — less than 5 hours of objectively measured sleep per night, according to Thurston. This appears to be independent of menopause symptoms and CV risk factors.

Thurston noted that these findings are based on observational data; currently, there is no evidence of causality. She and colleagues examined potential mechanisms, such as psychological stress, depression, anxiety and blood pressure.

“We just couldn’t explain it,” Thurston said. In the next phase of their research, Thurston and colleagues aim to study the influence of the hypothalamic-pituitary-adrenal axis in this area.

Cognitive symptoms, sleep disruption

Vasomotor symptoms can lead to “brain fog” for some women during menopause. Cognitive symptoms, such as problems with word finding, are not uncommon, according to Thacker.

“It does seem like estrogen helps support verbal fluency and some domains of memory,” Thacker said. “We know that women with premature or early menopause who are untreated have a higher rate of dementia and neurocognitive decline and Parkinson’s disease.

“Blood flow studies in the brain show massive shifts in blood flow in women who are flashing,” Thacker said. “Having hot flashes is potentially not good for brain blood flow and brain function, especially if there’s sleep disturbance.”

Many women experience sleep disturbances during the menopause transition. The most frequent problem is an insomnia-type pattern, which in menopause means difficulty staying asleep, according to Hadine Joffe, MD, MSc, associate professor of psychiatry, Harvard Medical School.

Up to 50% of menopausal women report some level of sleeping difficulty, according to Joffe. An additional 25% to 30% of women report insomnia, defined as 3 months of persistent trouble falling or staying asleep that affects daytime well-being or functioning.

Vasomotor symptoms are the primary culprit for sleep issues, according to Joffe. “People wake up with a hot flash, and then may or may not have trouble falling back to sleep and then feel unrefreshed and may have poor daytime function, with fatigue,” Joffe told Endocrine Today.

Besides affecting daytime cognitive function and alertness level, this type of insomnia influences a woman’s “sense of pleasure and well-being and enjoyment in relationships and daytime connections,” she said.

“Both sleep disruption and nighttime hot flashes, but not daytime hot flashes, independently contribute to mood disturbance in women whose estrogen levels have fallen during menopause,” Joffe said.

In a study of 28 premenopausal women without sleep disorders or hot flashes assigned to the gonadotropin-releasing hormone agonist leuprolide to rapidly induce menopause, Joffe and colleagues correlated subjectively recorded hot flash and sleep diaries with physiologically monitored vasomotor symptoms and depressive symptoms. They found that increases in light sleep, awakenings, non-REM arousals, subjective sleep quality and reduced perceived sleep efficiency all predicted worsening depressive symptoms. The number of self-reported nighttime hot flashes — but not objectively measured nighttime or self-reported daytime hot flashes — was also associated with worsening depressive symptoms.

Furthermore, the risk for sleep apnea, which results in sleep disruptions and profound daytime sleepiness, increases during menopause. “[Sleep apnea is] common during menopause,” Joffe said. “It is not as common in women in general, but [in] menopause or early postmenopause, it appears there’s a risk for it.”

Restless leg syndrome, which leads to difficulty falling asleep, is another menopause-related sleep issue. About 80% of women with restless leg syndrome will also have periodic leg movement during sleep, which can impair daytime wakefulness, according to Joffe. This condition is more common in women than men, has a genetic component and increases with age. “So, part of the challenge with all this is you’re trying to distinguish any age-related factors from truly hormone- and menopause-related factors,” Joffe said.

Some evidence indicates that decreasing estradiol and increasing follicle-stimulating hormone levels are linked to menopause-related sleep problems. “Whether they’re directly causing it ... we’re far from understanding that as a specific causal pathway,” Joffe said. “It may be more a marker of the brain’s sensitivity to some of these changes.”

Normal phase of life

There is no way to prevent menopause or its symptoms. “We don’t have any way to preserve ovaries or doing ovary transplants at this point in time,” Thacker said. “If women live long enough, they’re going to become menopausal, which is a normal phase of life. It may or may not be an endocrinopathy.”

However, the menopause transition can be managed. First, women with existing health conditions can mitigate symptoms with good disease control. “Women with undiagnosed or inadequately treated diabetes or thyroid may have worsening hot flashes,” Pinkerton said.

There are multiple treatment options available. For the typical woman who reaches natural menopause and is symptomatic, hormone therapy remains the first-line treatment, virtually eliminating vasomotor symptoms in nearly 80% of women, according to Lumsden.

HT is also the most effective treatment for the potential consequences of menopause-related vasomotor symptoms, such as poor sleep quality, irritability, cognitive issues and subsequent reduced quality of life, Pinkerton said.

Pinkerton has conducted research on a novel tissue selective estrogen complex that contains the selective estrogen receptor modulator bazedoxifene plus a conjugated estrogen (Duavee, Pfizer) for reducing vasomotor symptoms while also preventing bone loss. This combination has been shown to protect the uterus without the need for progesterone, and 2-year data indicated neutral effects to the breast.

Although compounded bioidentical hormones are available, these formulations are unregulated, which gives some practitioners pause about prescribing them. “Compounded bioidentical hormones have not been tested for efficacy or safety,” Pinkerton said. “FDA-approved HT is preferred unless there is a specific medical indication, allergy or unavailability.”

Phase 3 data on an oral combination estradiol/progesterone pill will be presented at the Endocrine Society annual meeting in April, according to Pinkerton.

Nonhormonal treatment options

Nonhormonal treatment options are also available. Low-dose antidepressants, both selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors, as well as gabapentin and the clonidine patch can reduce vasomotor symptoms by 50% to 60%, according to Pinkerton.

Only one antidepressant, low-dose paroxetine (Brisdelle, Sebela Pharmaceuticals), has received FDA approval for this indication, according to Thacker.

Lumsden has researched the use of another antidepressant, venlafaxine, to reduce vasomotor symptoms. “At low doses, they can decrease flushing,” Lumsden said. “Nowhere near as effectively as HT in the main, but they can be useful in women, for example, who have breast cancer ... who don’t want to take HT.”

Research on complementary and alternative therapies, such as black cohosh and phytoestrogens, has shown that many are no better than placebo.

“But placebo works in upward of 30% of women and will make their symptoms better,” Lumsden said. “I’m supportive of anything that works as long as people take them sensibly and recognize that they’re not totally without their side effects. One or two of them react with drugs, and some are estrogenic. One needs to be a little bit cautious.”

One phytoestrogen has had promising early results in Japan. “There is a phytoestrogen that is in development in Japan called equol [(Equelle, Otsuka Pharmaceutical Co.)], which appears to work more effectively for hot flashes than placebo, but that’s not available in this country yet,” Pinkerton said.

Stellate ganglion blocking may be a treatment option for vasomotor symptoms, especially for patients with breast cancer. “It is effective, but it is a procedure that has to be done with great care because they’re blocking your stellate ganglion up near your carotid artery,” Pinkerton said.

The effect of lifestyle changes, such as exercise and nutrition, on symptoms is questionable. “The evidence with exercise and flushing is contradictory,” Lumsden said. “My feeling is if you feel better in yourself, you eat well, take some exercise, then you’re likely to cope with any symptoms better.”

Managing sleep disturbances

There are ways to manage the sleep disturbances that occur during menopause. Women should practice good “sleep hygiene,” which are practices designed to help improve nighttime sleep quality. Sleep hygiene includes some predictable advice: Avoid caffeine at night and maintain a consistent sleep schedule, Joffe said.

For menopausal women, the suggestions include covering any clocks in the bedroom. “People wake up and the first thing they do is check the clock,” Joffe said. “As soon as you know what time it is, the brain is more alert, you’re more awake, you’re more annoyed. One of the most important things is to break the cycle between waking up and knowing what time it is.”

Another important strategy is to get out of bed for a short time when unable to sleep, Joffe said. “Go someplace ... [with] low lighting, no screens, nothing too engaging of the brain,” she said. The key is to identify some mental distraction that stops the bed-no sleep-frustration association, spend about 10 minutes engaged in that activity and then return to bed.

“Women reporting nighttime hot flashes and sleep disruption should be screened for mood disturbance,” Joffe said. “Treatment of mood disturbance in this population should include therapies that improve sleep interruption as well as nighttime hot flashes.”

Cognitive behavioral therapy for insomnia (CBTI) is another treatment for vasomotor-related insomnia. “That’s very effective,” Joffe said. CBTI is a structured, targeted sleep management program that occurs over multiple sessions. In the program, patients will use things like sleep hygiene methods, a sleep diary and counseling to help them overcome their insomnia.

The problem with CBTI is that there are few trained providers, according to Joffe. To address this issue, CBTI has gone digital with online resources and apps.

Future interventions

Investigators continue to search for new ways to manage menopause symptoms. One approach is a novel group of drugs that affect the release of pituitary hormones, according to Lumsden. “These are hormones that control the menstrual cycle,” Lumsden said. The kisspeptin neurokinin system influences the release of these hormones, and early data suggest that blocking this system can decrease vasomotor symptoms.

Thacker said she hopes to see some research on using stem cells to regenerate ovarian tissue for women younger than 40 years. Although HT will mitigate some of the symptoms, psychosexual problems and osteoporosis, it will not address all the neurologic decline associated with premature menopause, which affects about 1% of women.

With future research, Thurston said she hopes to tease out the mechanisms of vasomotor symptoms and how they relate to vascular health. She would like to see more behavioral health interventions that will help improve women’s quality of life and reduce their disease risks. – by Colleen Owens

• References:
• Avis NE, et al. JAMA Intern Med. 2015;doi:10.1001/jamainternmed.2014.8063.
• Joffe H, et al. J Clin Endocrinol Metab. 2016;doi:10.1210/jc.2016-2348.
• Thurston RC, et al. Circulation. 2008;doi:10.1161/CIRCULATIONAHA.108.776823.
• Thurston RC, et al. Stroke. 2016;10.1161/STROKEAHA.116.014674.
• Whiteley J. Menopause. 2013;doi:10.1097/gme.0b013e31827d38a5.

• For more information:
• Hadine Joffe, MD, MSc, can be reached at the Harvard Medical School, Brigham and Women’s Hospital, Thorn 1111, Boston, MA 02115; email: hjoffe@partners.org.
• Mary Ann Lumsden, BSc(Hons), MBBS, MRCOG, MD, FRCOG, can be reached at the University of Glasgow, Reproductive & Maternal Medicine, 2nd Floor, New Lister Building, Glasgow Royal Infirmary, 10-16 Alexandra Parade, Glasgow G31 2ER; email: maryann.lumsden@glasgow.ac.uk.
• JoAnn Pinkerton, MD, NCMP, can be reached at the University of Virginia Health System, 2955 Ivy Road, #104, Charlottesville, VA 22903; email: pinkerton@menopause.org.
• Holly L. Thacker, MD, can be reached at the Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195; email: thackeh@ccf.org.
• Rebecca C. Thurston, PhD, can be reached at the University of Pittsburgh, Women’s Behavioral Health Laboratory, 201 N. Craig St., Room 206, Pittsburgh, PA 15213; email: thurstonrc@upmc.edu.

Disclosure: Joffe reports receiving research grants from NIH and Merck and consultant fees from Merck, Mitsubishi Tanabe, NeRRe and SAGE. Thurston reports receiving NIH research grants. Lumsden, Joffe, Pinkerton and Thacker report no relevant financial disclosures.

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