If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Reprint requests should be addressed to Robert R. Freedman, PhD, Department of Psychiatry and Behavioral Neurosciences and Department Obstetrics and Gynecology, Wayne State University School of Medicine, C. S. Mott Center, 275 East Hancock Street, Detroit, Michigan 48201.
Department of Psychiatry and Behavioral Neurosciences and Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
Hot flashes are the most common symptom of the climacteric and occur in about 75% of perimenopausal and postmenopausal women in Western societies. Although hot flashes accompany the withdrawal of estrogen at menopause, the decline in estrogen levels is not sufficient to explain their occurrence. Elevated sympathetic activation acting through central α2-adrenergic receptors contributes to the initiation of hot flashes, possibly by narrowing the thermoneutral zone in symptomatic women. Hot flashes are then triggered by small elevations in core body temperature acting within this narrowed zone. A relaxation-based method, paced respiration, has been shown in 3 controlled investigations to significantly reduce objectively measured hot flash occurrence by about 50% with no adverse effects. In 6 studies of physical exercise, however, investigators did not find positive effects on hot flashes, possibly because exercise raises core body temperature, thereby triggering hot flashes. Although many epidemiologic studies have found increased reports of sleep disturbance during the menopausal transition, recent laboratory investigations have not found this effect, nor have they found that hot flashes produce disturbed sleep. Therefore, sleep complaints in women at midlife should not routinely be attributed to hot flashes or to menopause.
The frequency of hot flashes can range from 5 per year to 50 per day, with great variations among individuals or even within an individual. They generally persist for 1 to 5 years, but in some women they can continue for as long as 44 years.
found that high body mass index (BMI) is directly related to hot flash frequency. This may be caused by the effect of increased insulation from body fat, resulting in elevated core body temperature (Tc), which triggers hot flashes.
Peripheral vasodilation, demonstrated by increased skin temperature and blood flow, occurs during hot flashes in all body areas that have been investigated (Figure 1). Skin temperature increases in the digits, cheek, forehead, upper arm, chest, abdomen, back, calf, and thigh.
measured the whole body sweat rate to be about 1.3 g/min in 1 subject. We simultaneously recorded measures of sweating and skin conductance from the sternum during 29 hot flashes in 14 women.
There was a close temporal correspondence between both measures that increased significantly. Measurable sweating occurred during 90% of the flashes.
Increased sternal skin conductance has proved to be the best objective marker of menopausal hot flashes to date. A 2-μS increase in conductance measured within 30 seconds corresponded with 95%,
The skin conductance measurement is particularly useful for the evaluation of treatment studies because it can be recorded outside the laboratory over prolonged intervals and does not require the patient’s intervention. Using the same recording methods with ambulatory monitors, investigators found an 86% agreement between the skin conductance criterion (2 μS/30 sec) and patient event marks.
Although hot flashes accompany the withdrawal of estrogen at menopause, the decline in estrogen levels is not sufficient to explain their occurrence. There is no correlation between hot flash occurrence and plasma,
However, later research showed that women with isolated gonadotropin deficiency had hot flashes but no LH pulses and women with hypothalamic amenorrhea had LH pulses but no hot flashes.
Thus, there is no consistent evidence of the involvement of an opiate system in hot flashes.
Norepinephrine (NE) plays a major role in thermoregulation acting, in part, through α2-adrenergic receptors. Plasma levels of 3-methoxy-4-hydroxyphenylglycol (MHPG), the main metabolite of NE, were found to be significantlyhigher in symptomatic than in asymptomatic postmenopausal women
Further study then showed that injection of yohimbine, an α2-adrenergic antagonist that raises levels of brain NE, provoked hot flashes in symptomatic women and that injection of clonidine ameliorated them.
Taken together, these data suggest that elevated sympathetic activation, acting through central α2-receptors, plays a role in the initiation of hot flashes. Because estrogens modulate these receptors,
Mechanisms of ovarian steroid regulation of norepinephrine receptor-mediated signal transduction in the hypothalamus implications for female reproductive physiology.
it is possible that menopausal estrogen withdrawal is involved in this mechanism.
Thermoregulation and hot flashes
In homeotherms, Tc is regulated between an upper threshold for sweating and a lower threshold for shivering. Between these thresholds is a neutral zone within which major thermoregulatory responses (sweating, shivering) do not occur.
Fine thermoregulatory adjustments within the neutral zone are effected by variations in peripheral blood flow. According to this theory, the heat dissipation responses of the hot flash (sweating, peripheral vasodilation) would be triggered if Tc were elevated such that the upper threshold was crossed. We showed that there is a circadian rhythm of hot flashes that is related to the circadian rhythm of Tc: hot flashes are more frequent when Tc is highest.
In the course of the latter study, the majority of hot flashes were found to be preceded by small but statistically significant elevations in Tc as measured by an ingested telemetry pill. This finding was replicated in 2 further studies.
suggesting that the upper threshold is lowered in symptomatic women. We therefore measured the sweating and shivering thresholds and calculated the width of the thermoneutral zone in symptomatic and asymptomatic postmenopausal women.
We assessed the sweating threshold by raising Tc using peripheral heating and bicycle exercise, and found that the thermoneutral zone was 0.0°C in the symptomatic women and 0.4°C in the asymptomatic women, mainly owing to a lowering of the sweating threshold in the former group. The Tc sweating thresholds were the same for heating and for exercise, and they were accompanied by objective and subjective hot flashes in every case. Sweat rates in the symptomatic women were twice those of the asymptomatic women (P <0.05). No hot flashes occurred in the asymptomatic women. Thus, we believe that hot flashes are triggered by Tc elevations acting within a greatly reduced thermoneutral zone in symptomatic postmenopausal women (Figure 2). A hot flash, consisting of sweating and peripheral vasodilation, is triggered when Tc reaches the upper threshold. Tc then declines and, when the lower threshold is crossed, shivering occurs. In a subsequent study, we found that the Tc elevations also occur in asymptomatic women.
Therefore, the critical factor in the etiology of hot flashes is the narrowing of the thermoneutral zone.
Figure 2Small core body temperature (Tc) elevations acting within a reduced thermoneutral zone trigger hot flashes (HFs) in symptomatic postmenopausal women. The thermoneutral zone is narrowed in symptomatic women (with HF) compared with asymptomatic women (non-HF). Elevated brain norepinephrine (NE) in animals reduces this zone. Yohimbine (YOH) elevates brain NE and should reduce the zone. Conversely, clonidine should widen it. 5-HT = serotonin; MHPG = 3-methoxy-4-hydroxyphenylglycol (the primary NE metabolite); SSRI = serotonin-selective reuptake inhibitor.
Conversely, clonidine reduces NE release, raises the sweating threshold, and lowers the shivering threshold. Thus, we suggest that elevated brain level of NE is likely to narrow the thermoregulatory interthreshold zone in symptomatic postmenopausal women (Figure 2).
Behavioral treatment for hot flashes
Because elevated sympathetic activation has been implicated in the genesis of hot flashes, relaxation-based procedures have been used to treat them. In the first investigation,
postmenopausal women with frequent hot flashes were randomly assigned to receive 6 weekly sessions of progressive muscle relaxation and slow, deep breathing (paced respiration) or α-wave electroencephalographic (EEG) biofeedback (placebo control procedure). The relaxation procedure significantly reduced both objective symptoms recorded in the laboratory and diary-recorded hot flash frequency by about 50% compared with the control procedure. A second study was performed in which a group of subjects received slow deep breathing alone, a second group received muscle relaxation exercises alone, and a third group received α-wave EEG biofeedback.
Treatment outcome was assessed by ambulatory monitoring of sternal skin conductance responses, which were used to define hot flashes. Only the paced respiration group showed a significant decline (50%) in hot flash frequency. There were no significant changes shown in the 2 other groups. To determine whether reduced sympathetic activation was the mechanism by which paced respiration ameliorates hot flashes,
we therefore measured plasma MHPG, epinephrine, NE, cortisol, and platelet α2-receptors during paced respiration and α-wave EEG biofeedback in 24 symptomatic women. Treatment outcome was again assessed by ambulatory monitoring of sternal skin conductance. The paced respiration group showed a significant decline in hot flash frequency (again about 50%) compared with no change in the control group. However, there was no significant change in any biochemical measure for either group. Thus, the mechanism through which paced respiration reduces hot flash frequency remains to be determined. The last controlled study
randomly assigned symptomatic postmenopausal women to receive relaxation response training (paced respiration plus mental focusing), a reading control group, or no treatment. The relaxation response group showed a significant decline in hot flash intensity but not frequency. There was no significant change in the other groups. Thus, we conclude that paced respiration training produces a significant decline in hot flash frequency and, perhaps, intensity. There is no known harmful effect.
Physical exercise also has been used as a potential treatment for hot flashes. There have been 3 randomized clinical trials and 3 other studies. The largest randomized clinical trial (N = 173)
compared a moderate-intensity exercise intervention with a stretching control group over 1 year. Exercise significantly increased the severity of hot flashes with no change in their occurrence. A Japanese study
compared 20 women in a 12-week education and exercise program with 15 no-treatment controls. There were no significant effects on hot flashes. A Swedish study
compared 15 women in a 3 times weekly exercise program with 15 women receiving oral estradiol. There was no change in hot flash frequency in the exercise group, but a 90% decrease in hot flashes was observed in the estradiol group.
A large (N = 1,323), population-based, retrospective study in Linkoping, Sweden,
at a health maintenance organization in California also found no effect of exercise on hot flashes. A retrospective, population-based study in Lund, Sweden (N = 6,917),
Menopause-related symptoms what are the background factors? A prospective population-based cohort study of Swedish women (The Women’s Health in Lund Area Study).
found that vigorous exercise (>3 hr/wk) was associated with significant reductions in hot flash frequency and intensity in a small number of women (4%), but this was confounded by other factors.
Taken together, the above studies do not demonstrate significant, positive effects of physical exercise on menopausal hot flashes. Our finding that exercise triggers hot flashes in the laboratory may, in part, explain these results.
It is generally believed that hot flashes produce arousals and awakenings from sleep, leading to fatigue and, possibly, impaired performance. However, this notion is challenged by 2 recent laboratory investigations.
symptomatic and asymptomatic postmenopausal women and premenopausal women of similar ages were recorded under controlled laboratory conditions. They were screened to eliminate those (1) with any drug use; (2) with any sleep, physical, or mental disorder; or (3) with a BMI >30. There were no group differences on any sleep stage measure, on sleep or fatigue questionnaires, or on any performance test. When hot flashes occurred (mean ± SD, 5.2 ± 2.9 per night), they tended to follow, rather than precede, arousals and awakenings. These data provide no evidence that hot flashes produce sleep disturbance in symptomatic postmenopausal women.
Table 1Do hot flashes and sleep disturbance occur with menopause?
We replicated these findings in a more recent investigation. A total of 18 symptomatic and 6 asymptomatic postmenopausal women and 12 women with eumenorrhea of similar ages were recorded on warm (30°C ambient), neutral (23°C), and cold (18°C) nights. There was no significant effect of room temperature for any group on any physiologic sleep measure. All subjects expected worse sleep on the warm versus the cold night (P <0.01), but only the symptomatic women reported lighter and less refreshing sleep on the warm versus the cold night (P <0.005). These results demonstrate that reports of worse sleep in symptomatic women at warm ambient temperatures are due to expectancies rather than to physiologic effects.
These findings are strongly supported by those of a large recent epidemiologic investigation.
The Wisconsin Sleep Cohort Study measured sleep quality by complete laboratory polysomnography and by self-reports in a probability sample of 589 premenopausal, perimenopausal, and postmenopausal women. Sleep quality was not worse in perimenopausal or postmenopausal women or in symptomatic compared with asymptomatic women on any measure. Taken together, these studies suggest that sleep complaints in women at midlife should not routinely be attributed to hot flashes or to menopause. Rather, the underlying disorder (e.g., sleep apnea) should be ascertained, and appropriate treatment should be based on these findings.
Summary
Hot flashes are triggered by small elevations in Tc acting within a reduced thermoneutral zone in symptomatic postmenopausal women. This reduction is probably caused by estrogen withdrawal and elevated central sympathetic activation, among other factors. Relaxation-based procedures incorporating paced respiration are safe and effective in ameliorating hot flashes. Physical exercise, however, is not efficacious in the treatment of hot flashes. Although most epidemiologic studies report increased sleep disturbance at menopause, this is not supported by laboratory physiologic studies, nor has the role of hot flashes in producing sleep disturbances been proved.
References
Avis N.E.
Crawford S.L.
McKinlay S.M.
Psychosocial, behavioral, and health factors related to menopause symptomatology.
The opinions offered at the National Institutes of Health (NIH) State-of-the Science Conference on Management of Menopause-Related Symptoms and published herein are not necessarily those of the National Institute on Aging (NIA) and the Office of Medical Applications of Research (OMAR) or any of the cosponsoring institutes, offices, or centers of the NIH. Although the NIA and OMAR organized this meeting, this article is not intended as a statement of Federal guidelines or policy.
Publication of the online supplement was made possible by funding from the NIA and the National Center for Complementary and Alternative Medicine of the NIH, US Department of Health & Human Services.
Research conducted by Dr. Freedman was supported by MERIT Award No. R37-AG05233 and by Grant No. MH-63089 from the National Institutes of Health.
Study of Women’s Health Across the Nation (SWAN).
00904-6&id=gr1.gif){kind=link}
00904-6&id=gr2.gif){kind=link}