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.

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.

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.

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.

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.

Core body temperature variation in symptomatic and asymptomatic postmenopausal women: brief report.

OBJECTIVE: To determine if core body temperature (T) fluctuations occur in asymptomatic as well as symptomatic postmenopausal women. DESIGN: Tc was recorded with an ingested radiotelemetry pill in symptomatic postmenopausal women who had a hot flash in the laboratory, in symptomatic women who did not have a hot flash in the laboratory, and in asymptomatic postmenopausal women. RESULTS: There were no significant differences in mean Tc or Tc variation, as measured by the standard deviation, among the three groups. CONCLUSION: Tc fluctuations are not unique to symptomatic postmenopausal women.

Hot flashes, core body temperature, and metabolic parameters in breast cancer survivors.

OBJECTIVE: To examine core body temperature, energy expenditure, and respiratory quotient among breast cancer survivors experiencing hot flashes and compare these data to published studies from healthy women. DESIGN: In an observational study, nine breast cancer survivors with daily hot flashes who met specified criteria spent 24 hours in a temperature- and humidity-controlled whole-room indirect calorimeter (ie, metabolic room). Demographic and disease/treatment information were obtained and the following were measured: hot flashes via sternal skin conductance monitoring (sampled every second); core body temperature via an ingested radiotelemetry pill (sampled every 10 seconds); and energy expenditure and respiratory quotient via a whole-room indirect calorimeter (calculated every minute). RESULTS: Circadian analysis of core temperature indicated wide variability with disrupted circadian rhythm noted in all women. Core temperature began to rise 20 minutes pre-flash to 7 minutes pre-flash (0.09 degrees C increase). Increases in energy expenditure and respiratory quotient increased with each hot flash. CONCLUSIONS: Findings are comparable to published data from healthy women and warrant replication in larger, more diverse samples of women treated for breast cancer.

Measurement of hot flashes by sternal skin conductance and subjective hot flash report in Puebla, Mexico.

OBJECTIVE: To measure hot flashes by sternal skin conductance in an urban Mexican population and to determine variables associated with hot flash reporting and measurement. DESIGN: From June 1999 to August 2000, 67 perimenopausal women aged 40 to 65 years participated in interviews, anthropometric measures, and a 2-h recording of sternal skin conductance. Changes in sweating were used to demonstrate the presence/absence of a hot flash. During the test, women were asked to report if they experienced a hot flash. RESULTS: During the study period, 10 women reported and demonstrated every hot flash, 24 women never reported or demonstrated a hot flash, 7 demonstrated hot flashes but did not report any of them, 7 reported hot flashes but did not demonstrate any of them, and 19 showed a mixture of responses. Women who demonstrated hot flashes by sternal skin conductance were measured in a warmer room, had more years of education, consumed more eggs as a child, recalled a heavier weight at age 18, and had a lower body mass index at interview compared with women who did not demonstrate hot flashes by sternal skin conductance. Women who subjectively reported hot flashes were measured in a warmer room, were more likely to be postmenopausal, reported more frequent consumption of coffee, and spent fewer months breast-feeding their last child compared with women who did not report the experience of hot flashes during the testing period. CONCLUSION: Room temperature explained part of the variation between women who did and did not demonstrate hot flashes via sternal skin conductance, between women who did and did not report the experience of hot flashes, and between women who did and did not demonstrate concordance in objective and subjective measures. In addition to room temperature, coffee intake, months spent breast-feeding the last child, and recalled weight at age 18 were important variables predicting hot flash experience.

Lack of sleep disturbance from menopausal hot flashes.

OBJECTIVE: To determine whether hot flashes produce disordered sleep in symptomatic postmenopausal women. DESIGN: Controlled laboratory study. SETTING: Healthy volunteers in a university medical center. PATIENT(S): Symptomatic and asymptomatic postmenopausal women and premenopausal women, all of similar ages (46-51 years). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Sleep electroencephalogram recordings, sternal skin conductance to record hot flashes, multiple sleep latency test to assess sleepiness, simple and divided attention performance tests, sleep and fatigue questionnaires. RESULT(S): Nineteen women were not selected for the following reasons: seven failed the drug screen, two had sleep apnea and periodic limb movements, one had periodic limb movements alone, two had body mass index (BMI) >30, one had hypertension, and six asymptomatic women had hot flashes in the laboratory. There were no significant group differences on any sleep stage measure. For example, for cycling vs. symptomatic vs. asymptomatic women: total sleep time, 6.9 +/- 0.7, 7.0 +/- 0.4, 7.0 +/- 0.4 hours; percentage stage 1 (light) sleep, 9.3% +/- 4.2%, 10.4% +/- 2.5%, 10.5% +/- 3.9%; number of brief arousals, 89.6 +/- 30.1, 111.9 +/- 45.8, 99.4 +/- 22.2; number of awakenings, 4.8 +/- 3.3, 6.7 +/- 2.1, 6.9 +/- 3.5. An average of 5.2 +/- 2.9 (+/-SD, range 1-18) hot flashes/night occurred in the symptomatic women. Of arousals occurring within 2 minutes of a hot flash, 46.7% occurred before, 46.7% occurred after, and 5.6% occurred simultaneously. Of awakenings occurring within 2 minutes of a hot flash, 55.2% occurred before, 40.0% after, and 5% simultaneously. There were no significant group differences on the multiple sleep latency test or any performance test or questionnaire measure. CONCLUSION(S): These data provide no evidence that hot flashes produce sleep disturbance in symptomatic postmenopausal women. Previous reports of increased sleep disturbance at menopause may be due to disorders that were screened out, such as sleep apnea and drug use.

Estrogen raises the sweating threshold in postmenopausal women with hot flashes.

OBJECTIVE: To determine if estrogen ameliorates hot flashes by raising the core body temperature sweating threshold, by reducing core body temperature fluctuations, and/or by reducing sympathetic activation (as measured by plasma 3-methoxy-4-hydroxyphenylglycol). DESIGN: Laboratory physiological study. SETTING: University medical center. PATIENT(S): Twenty-four healthy postmenopausal women reporting frequent hot flashes. INTERVENTION(S): Participants were randomly assigned, in double-blind fashion, to receive 1 mg/d 17beta-estradiol orally or placebo for 90 days. MAIN OUTCOME MEASURE(S): Core body temperature, core body temperature fluctuations, mean skin temperature, sternal sweat rate, laboratory hot flash counts (sternal skin conductance), plasma 3-methoxy-4-hydroxyphenylglycol. RESULT(S): The E(2) group had significant increases in plasma E(2) (8 +/- 2 vs. 132 +/- 22 pg/mL) and core body temperature sweating threshold (37.98 +/- 0.09 vs. 38.14 +/- 0.09 degrees C) and decreases in plasma FSH (58.8 +/- 8.9 vs. 40.1 +/- 7.6 mIU/mL) and hot flashes (1.4 +/- 0.5 vs. 0.6 +/- 0.6). These changes did not occur in the placebo group. There were no significant changes in any other measure. CONCLUSION(S): E(2) ameliorates hot flashes by raising the core body temperature sweating threshold, but does not affect core temperature fluctuations or plasma 3-methoxy-4-hydroxyphenylglycol.

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'.

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?

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.

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.

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.

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.