Postmenopausal physiological changes.

The hallmark of menopause is the marked reduction of estradiol levels due to ovarian failure. This, among other factors result in hot flashes, the most common menopausal symptom. Hot flashes (HFs) can be measured objectively, both inside and outside the laboratory, using sternal skin conductance, an electrical measure of sweating. We have found that HFs are triggered by small elevations in core body temperature (T C ), acting within a greatly reduced thermoneutral zone. This reduction is caused by elevated central sympathetic activation, among other factors. There is a circadian rhythm of HFs peaking at 1825 h. Imaging studies have shown that hot flash activation begins in the brainstem, followed by the insula and by the prefrontal cortex. HFs in the first, but not the second half of the night can produce awakenings and arousals. This is because rapid eye movement (REM) sleep suppresses thermoregulatory effector responses, which include hot flashes.

Menopause and sleep.

CLINICAL SCENARIO: An obese, 50-year-old woman complains of hot flashes, poor sleep, snoring, and daytime sleepiness. She states that these problems have bothered her for about 4 years. Her partner recently complained about her snoring and restlessness, prompting this visit. She has become hypertensive. What should she do?

Temporal sequencing of brain activations during naturally occurring thermoregulatory events.

Thermoregulatory events are associated with activity in the constituents of the spinothalamic tract. Whereas studies have assessed activity within constituents of this pathway, in vivo functional magnetic resonance imaging (fMRI) studies have not determined if neuronal activity in the constituents of the tract is temporally ordered. Ordered activity would be expected in naturally occurring thermal events, such as menopausal hot flashes (HFs), which occur in physiological sequence. The origins of HFs may lie in brainstem structures where neuronal activity may occur earlier than in interoceptive centers, such as the insula and the prefrontal cortex. To study such time ordering, we conducted blood oxygen level-dependent-based fMRI in a group of postmenopausal women to measure neuronal activity in the brainstem, insula, and prefrontal cortex around the onset of an HF (detected using synchronously acquired skin conductance responses). Rise in brainstem activity occurred before the detectable onset of an HF. Activity in the insular and prefrontal trailed that in the brainstem, appearing following the onset of the HF. Additional activations associated with HF's were observed in the anterior cingulate cortex and the basal ganglia. Pre-HF brainstem responses may reflect the functional origins of internal thermoregulatory events. By comparison insular, prefrontal and striatal activity may be associated with the phenomenological correlates of HFs.

Menopausal hot flashes: mechanisms, endocrinology, treatment.

Hot flashes (HFs) are a rapid and exaggerated heat dissipation response, consisting of profuse sweating, peripheral vasodilation, and feelings of intense, internal heat. They are triggered by small elevations in core body temperature (Tc) acting within a greatly reduced thermoneutral zone, i.e., the Tc region between the upper (sweating) and lower (shivering) thresholds. This is due in part, but not entirely, to estrogen depletion at menopause. Elevated central sympathetic activation, mediated through α2-adrenergic receptors, is one factor responsible for narrowing of the thermoneutral zone. Procedures which reduce this activation, such as paced respiration and clonidine administration, ameliorate HFs as will peripheral cooling. HFs are responsible for some, but not all, of the sleep disturbance reported during menopause. Recent work calls into question the role of serotonin in HFs. This article is part of a Special Issue entitled 'Menopause'.

Escitalopram treatment of menopausal hot flashes.

OBJECTIVE: The aim of this study was to determine the effects of 10 and 20 mg/day of escitalopram on objectively recorded hot flashes and on the rectal temperature threshold for sweating. METHODS: Two studies were performed: 16 women received 10 mg/day and 26 women received 20 mg/day escitalopram for 8 weeks. They were randomly assigned in equal numbers to receive active drug or placebo in a double-blind fashion. Hot flash frequency was measured with an ambulatory recorder during the first 3 weeks and during the 8th week of the study. Rectal temperature threshold for sweating was measured during the 1st and 8th weeks of the study using published methods. RESULTS: In the first study, there were no significant effects whatsoever for any measure. In the second study, the escitalopram group showed an average decline in hot flash frequency of 14.4%, whereas the placebo group showed an average increase of 6.7% (P < 0.05). However, there were no significant effects across time for either group. There were no significant effects whatsoever for rectal temperature sweating thresholds. CONCLUSIONS: Escitalopram at 10 or 20 mg/day is not effective in the treatment of menopausal hot flashes.

Heart rate variability in menopausal hot flashes during sleep.

OBJECTIVE: The aim of this study was to determine if heart rate variability changes during hot flashes recorded during sleep. METHODS: This study was performed in a university medical center laboratory with 16 postmenopausal women demonstrating at least four hot flashes per night. Polysomnography, heart rate, and sternal skin conductance to indicate hot flashes were recorded in controlled, laboratory conditions. RESULTS: For the frequency bin of 0 to 0.15 Hz, spectral power was greater during waking compared with non-rapid eye movement sleep and less during stages 3 and 4 compared with stages 1 and 2. Power was greater during hot flashes compared with subsequent periods for all hot flashes. Power was greater during hot flashes compared with preceding and subsequent periods for those recorded during stage 1 sleep. For waking hot flashes, power in this band was higher before hot flashes than during or after them. CONCLUSIONS: These data are consistent with our theory of elevated sympathetic activation as a trigger for menopausal hot flashes and with previous work on heart rate variability during the stages of sleep.

Treatment of menopausal hot flashes with 5-hydroxytryptophan.

OBJECTIVE: Much recent research has focused on nonhormonal treatments for menopausal hot flashes. The purpose of the present study was to determine the effects of 5-hydroxytroptophan (5-HTP), the immediate precursor of serotonin, upon menopausal hot flashes. Selective, serotonergic, reuptake inhibitors (SSRIs), which increase the amount of serotonin in the synaptic gap, have shown some promise in the amelioration of hot flashes. METHODS: We administered 5-HTP or placebo, in double-blind fashion, to 24 postmenopausal women reporting frequent hot flashes. Treatment outcome was measured using a miniature, electronic, hot flash recorder. RESULTS: No significant effects of 150 mg/day 5-HTP upon hot flash frequency were found. The 5-HTP group had 23.8 + or - 5.7 (SD) hot flashes/24 h prior to treatment and 18.5 + or - 9.6 at the end of treatment. The placebo group had 18.5 + or - 9.6 before treatment and 22.6 + or - 12.4 at treatment completion. CONCLUSIONS: At the dose given, 5-HTP does not significantly ameliorate frequency of menopausal hot flashes, as measured objectively with an electronic recorder. Given the small size, this study must be considered preliminary in nature.

Sleep disturbance in menopause.

OBJECTIVE: To determine the sources of sleep complaints in peri- and postmenopausal women reporting disturbed sleep. DESIGN: A total of 102 women, ages 44 to 56 years, who reported disturbed sleep were recruited through newspaper advertisements. They were assessed with the Pittsburgh Sleep Quality Index and the Hamilton Anxiety and Depression Rating Scales. Complete polysomnography was performed in a controlled laboratory setting. Results were analyzed by multiple regression. RESULTS: Fifty-three percent of the women had apnea, restless legs, or both. The best predictors of objective sleep quality (laboratory sleep efficiency) were apneas, periodic limb movements, and arousals (R=0.44, P<0.0001). The best predictors of subjective sleep quality (Pittsburgh Sleep Quality Index global score) were the Hamilton anxiety score and the number of hot flashes in the first half of the night (R=0.19, P<0.001). CONCLUSIONS: Primary sleep disorders (apnea and restless legs syndrome) are common in this population. Amelioration of hot flashes may reduce some complaints of poor sleep but will not necessarily alleviate underlying primary sleep disorders. Because these can result in significant morbidity and mortality, they require careful attention in peri- and postmenopausal women.

Miniature hygrometric hot flash recorder.

OBJECTIVE: To design and test a miniature ambulatory hot flash recorder that uses neither electrodes nor gel. DESIGN: In the first study, putative hot flashes recorded by using a relative humidity sensor were compared with patient event marks. In the second study, relative humidity recorded by using a complete prototype recorder was compared with sternal skin conductance recordings made on a Biolog recorder, as well as with event marks. SETTING: University medical center. PATIENT(S): Ten healthy postmenopausal women reporting frequent hot flashes and using no medication. INTERVENTION(S): Body heating in laboratory. MAIN OUTCOME MEASURE(S): Positive predictive value (PPV), sensitivity, specificity. RESULT(S): In both laboratory studies, the PPV, sensitivity, and specificity among all three measures (relative humidity, skin conductance level, event) were 100%. In the field, a relative humidity increase of 3% per minute compared with skin conductance level-detected hot flashes yielded a PPV of 95.6%, a specificity of 95.2%, and a sensitivity of 90.9%. CONCLUSION(S): This device should be useful as an endpoint in clinical trials of treatments for hot flashes.

Effects of REM sleep and ambient temperature on hot flash-induced sleep disturbance.

OBJECTIVE: To determine whether hot flashes produce sleep disturbance in postmenopausal women. DESIGN: This study was performed in a university medical center laboratory with 18 postmenopausal women with hot flashes, six with no hot flashes, and 12 cycling women, all healthy and medication free. Polysomnography, skin and rectal temperatures, and skin conductance to detect hot flashes were recorded for four nights. Nights 2, 3, and 4 were run at 30 degrees C, 23 degrees C, and 18 degrees C in randomized order. RESULTS: During the first half of the night, the women with hot flashes had significantly more arousals and awakenings than the other two groups and the 18 degrees C ambient temperature significantly reduced the number of hot flashes, from 2.2 +/- 0.4 to 1.5 +/- 0.4. These effects did not occur in the second half of the night. In the first half of the night, most hot flashes preceded arousals and awakenings. In the second half, this pattern was reversed. CONCLUSIONS: In the second half of the night, rapid eye movement sleep suppresses hot flashes and associated arousals and awakenings. This may explain previous discrepancies between self-reported and laboratory-reported data in postmenopausal women with hot flashes.

Cortical activation during menopausal hot flashes.

OBJECTIVE: To determine regions of brain activation associated with menopausal hot flashes and sweating. DESIGN: Controlled laboratory study. SETTING: University medical center. PATIENT(S): Symptomatic postmenopausal women and asymptomatic eumenorrheic women. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Brain activation measured by functional magnetic resonance imaging. RESULT(S): Significant (P<.001) areas of activation during hot flashes in symptomatic women included the insula and anterior cingulate cortex. Sweating in the eumenorrheic women was associated (P<.001) with activity in the anterior cingulate and superior frontal gyrus. CONCLUSION(S): Activation of the insular cortex is associated with the "rush of heat" described during menopausal hot flashes. Thermoregulation in humans appears to be represented in a distributed cortico-subcortical network rather than in a single localized structure.

Thermoregulatory effects of 3,4-methylenedioxymethamphetamine (MDMA) in humans.

RATIONALE: Although 3,4-methylenedioxymethamphetamine (MDMA; Ecstasy) has been reported to cause fatal hyperthermia, few studies of the effects of MDMA on core body temperature in humans have been conducted demonstrating increased body temperature. In rats, MDMA causes hyperthermia at warm ambient temperatures but hypothermia at cold ones. OBJECTIVES: In this study, the physiological and subjective effects of MDMA in humans were determined at cold (18 degrees C) and warm (30 degrees C) ambient temperatures in a temperature and humidity-controlled laboratory. METHODS: Ten healthy volunteers who were recreational users of MDMA were recruited. Four laboratory sessions were conducted in a 2x2 design [i.e., two sessions at 30 degrees C and two at 18 degrees C, two during MDMA (2 mg/kg, p.o.) and two during placebo, in double-blind fashion]. Core body temperature (ingested radiotelemetry pill), skin temperature (four weighted sites), heart rate, blood pressure, metabolic rate (indirect calorimetry), shivering (electromyogram levels), and sweat rate (capacitance hygrometry) were measured as well as subjective effects for several time periods following capsule ingestion. RESULTS: MDMA produced significant elevations in core body temperature and metabolic rate in both warm and cold conditions. MDMA also produced significant elevations in blood pressure and heart rate and significantly increased several ratings of subjective effects similar to those previously reported. There were no differences related to ambient temperature for any of the subjective effects, except that ratings of cold and warm were appropriate to the ambient temperature and were not influenced by MDMA. CONCLUSIONS: Unlike findings in rats, MDMA increased core body temperature regardless of ambient temperature in humans. These increases appeared related to increases in metabolic rate, which were substantial. These findings warrant further investigations on the role of MDMA and other stimulants in altering metabolism and thermogenesis.

Pathophysiology and treatment of menopausal hot flashes.

Hot flashes are the most common symptom of menopause. Although the appearance of hot flashes coincides with estrogen withdrawal, this does not entirely explain the phenomenon because estrogen levels do not differ between symptomatic and asymptomatic women. Luteinizing throughout? hormone pulses do not produce hot flashes nor do changes in endogenous opiates. Recent studies suggest that hot flashes are triggered by small elevations in core body temperature (T(c)) acting within a reduced thermoneutral zone in symptomatic postmenopausal women. This narrowing may be due to elevated central noradrenergic activation, a contention supported by observations that clonidine and some relaxation procedures ameliorate hot flashes. Because hot flashes are triggered by T(c) elevations, procedures to reduce T(c), such as lowering ambient temperature, are beneficial. Estrogen ameliorates hot flashes by increasing the T(c) sweating threshold, although the underlying mechanism is not known. Recent studies of hot flashes during sleep call into question their role in producing sleep disturbance.

Effects of symptomatic status and the menstrual cycle on hot flash-related thermoregulatory parameters.

OBJECTIVE: To compare core body temperature variation, sweating thresholds, and sweat rate in symptomatic and asymptomatic postmenopausal women and in eumenorrheic women in the follicular and luteal phases. DESIGN: Twelve symptomatic and 10 asymptomatic postmenopausal women and 12 eumenorrheic women were recorded in a temperature- and humidity-controlled laboratory during thermoneutral and warm conditions. Core body temperature variation was measured with an ingested radiotelemetry pill, basal body temperature with a rectal thermistor, skin temperature with four skin surface thermistors, and sweat rate with a capacitance hygrometer. RESULTS: Symptomatic women had significantly lower sweating thresholds and higher maximum sweat rates compared with all other women. These results could not be explained by differences in estrogen, progesterone, or body mass index. CONCLUSIONS: Postmenopausal women with hot flashes are uniquely characterized by low sweating thresholds and high sweat rates, relative to asymptomatic and eumenorrheic women.

Hot flashes: behavioral treatments, mechanisms, and relation to sleep.

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 alpha(2)-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.