Menopausal hot flushes and night sweats: where are we now?

OBJECTIVE: An overview of the current knowledge on the etiology and treatment of vasomotor symptoms in postmenopausal women. MATERIALS AND METHODS: Acknowledged experts in the field contributed a brief assessment of their areas of interest which were combined and edited into the final manuscript. RESULTS: Women around the world experience vasomotor symptoms as they enter and complete the menopause transition. Vasomotor symptoms, specifically hot flushes, are caused by a narrowing of the thermoneutral zone in the brain. This effect, although related to estrogen withdrawal, is most likely related to changes in central nervous system neurotransmitters. Peripheral vascular reactivity is also altered in symptomatic women. Estrogen replacement therapy is the most effective treatment for hot flushes. Of the other interventions investigated, selective serotonin and selective norepinephrine reuptake inhibitors and gabapentin show efficacy greater than placebo. Objective monitoring of hot flushes indicates a robust improvement with hormone replacement therapy but little to no change with placebo. These data suggest that the subjective assessment of responses to therapy for vasomotor symptom results in inaccurate data. Hot flushes have recently been associated with increased cardiovascular risks and a lower incidence of breast cancer, but these data require confirmation. CONCLUSIONS: Vasomotor symptoms are experienced by women of all ethnic groups. They are caused by changes in the central nervous system associated with estrogen withdrawal and are best treated with estrogen replacement therapy. Objective monitoring of hot flushes indicates that placebo has little to no effect on their improvement. Subjective assessments of hot flushes in clinical trials may be inaccurate based on objective measurement of the frequency of hot flushes. Based on preliminary reports, women experiencing hot flushes have an increased risk of cardiovascular disease and a reduced incidence of breast cancer.

Cooling-induced contraction and protein tyrosine kinase activity of isolated arterioles in secondary Raynaud's phenomenon.

OBJECTIVE: To investigate the response of skin arterioles from control subjects and patients with scleroderma and Raynaud's phenomenon (RP/SSc) to cooling and modulators of protein tyrosine kinase (PTK) activity. METHODS: We used the microvessel perfusion technique to characterize the response of isolated dermal arterioles (100-200 microm, outside diameter) from normal (n = 17) and RP/SSc (n = 17) subjects to cooling from 37 degrees to 31 degrees C. Fluorescent immunohistochemistry was used to measure tyrosine phosphorylation. RESULTS: Arterioles from control subjects exhibited dilation in response to cooling from 37 to 31 degrees C whereas those from RP/SSc subjects contracted (+4.3 +/- 1.7 vs -16.7 +/- 3.1%, P < 0.05, n = 6). In the presence of the protein tyrosine phosphatase inhibitor sodium orthovanadate (SOV, 10 microM), the response of arterioles from control subjects did not change; however, arterioles from RP/SSC subjects exhibited a significantly greater contraction (-72.6 +/- 19.7%; P < 0.05, n = 6). Tyrosine phosphorylation of arterioles at 37 degrees C from control and RP/SSc subjects was similar. In response to cooling to 31 degrees C, however, arterioles from RP/SSc subjects exhibited a significantly greater increase in tyrosine phosphorylation compared with those from control subjects (43 +/- 7.0% vs 10 +/- 3.8%; P < 0.01). SOV increased tyrosine phosphorylation in arterioles from both groups (73 +/- 11.6% vs 42 +/- 5.6%; P < 0.05, n = 5). Arterioles from RP/SSC subjects precontracted with norepinephrine exhibited greatly attenuated relaxation to acetylcholine compared with those from control subjects. CONCLUSION: The results of this study support the view that the hallmark of Raynaud's phenomenon associated with scleroderma, cooling-induced vasospasm, appears to be mediated by an increase in PTK activity possibly exacerbated by impaired endothelium-dependent vasodilation.

Effect of temperature and modulators of protein tyrosine kinase activity on the reactivity of isolated venules in secondary Raynaud's phenomenon.

OBJECTIVE: To investigate the response of skin venules from healthy controls and scleroderma patients with Raynaud's phenomenon (RP/SSc) to cooling and to modulators of protein tyrosine kinase (PTK) activity at normal and reduced temperature. METHODS: We used the microvessel perfusion technique to characterize the response of isolated dermal venules (200-400 microm outside diameter) from normal (n = 10) and RP/SSc (n = 8) subjects to cooling and to contractile agents at 37 and 31 degrees C. RESULTS. The response to clonidine at 37 degrees C was less in venules from patients with RP/SSc compared to controls; the contraction to serotonin was greater in venules from RP/SSc patients versus controls; at 31 degrees C, venules from RP/SSc patients contracted to both clonidine and serotonin to a greater extent versus controls; and contraction to these agonists was reversed by cumulative addition of genistein (1-100 microM). Venules from controls and patients with RP/SSc exhibited slight vasodilation to cooling from 37 to 31 degrees C. In the presence of the protein tyrosine phosphatase inhibitor sodium orthovanadate (10 microM), venules from controls now exhibited a small contraction (-5.1 +/- 3.2%) and venules from RP/SSC subjects a significantly greater contraction (-38.7 +/- 9.0%; p < 0.05). CONCLUSION: Our study supports the view that RP/SSc is the result of defects in the peripheral vasculature.

Physiology of hot flashes.

Hot flashes are the most common symptom of the climacteric, although prevalence estimates are lower in some rural and non-Western areas. The symptoms are characteristic of a heat-dissipation response and consist of sweating on the face, neck, and chest, as well as peripheral vasodilation. Although hot flashes clearly accompany the estrogen withdrawal at menopause, estrogen alone is not responsible since levels do not differ between symptomatic and asymptomatic women. Until recently it was thought that hot flashes were triggered by a sudden, downward resetting of the hypothalamic setpoint, since there was no evidence of increased core body temperature. Evidence obtained using a rapidly responding ingested telemetry pill indicates that the thermoneutral zone, within which sweating, peripheral vasodilation, and shivering do not occur, is virtually nonexistent in symptomatic women but normal (about 0.4 degrees C) in asymptomatic women. The results suggest that small temperature elevations preceding hot flashes acting within a reduced thermoneutral zone constitute the triggering mechanism. Central sympathetic activation is also elevated in symptomatic women which, in animal studies, reduces the thermoneutral zone. Clonidine reduces central sympathetic activation, widens the thermoneutral zone, and ameliorates hot flashes. Estrogen virtually eliminates hot flashes but its mechanism of action is not known.

Circadian rhythm of objectively recorded hot flashes in postmenopausal breast cancer survivors.

OBJECTIVE: Similar to the circadian rhythm of core body temperature, hot flashes have been found to exhibit a circadian rhythm in healthy, naturally postmenopausal women, with a peak in frequency at 18:25 h. However, to date, no studies have evaluated whether this same pattern is found among breast cancer survivors reporting hot flashes. DESIGN: Daily hot flash frequencies were measured among 21 postmenopausal breast cancer survivors using validated 24-h sternal skin conductance monitoring. RESULTS: Hot flashes were noted in all women, ranging in frequency from 1 to 30 per 24-h period. A majority of the sample (86%) experienced > or = 1 nighttime hot flash, with 48% exhibiting > or = 3 but < or = 7 nighttime hot flashes. For the total sample, a modest circadian rhythm was noted with a peak in hot flash frequency occurring at 16:10 h. However, significant variability was observed across individual women, and, as a whole, breast cancer survivors demonstrated distorted to obliterated rhythms. CONCLUSIONS: Data suggest that hot flashes in postmenopausal breast cancer survivors do not follow the same circadian pattern as previously seen in healthy, naturally postmenopausal women. Findings have implications for (1) understanding the potential for sleep disturbances and fatigue in breast cancer survivors experiencing hot flashes, and (2) future research examining circadian rhythms of core body temperature and hot flashes in breast cancer survivors.

Abnormal responses to endothelial agonists in Raynaud's phenomenon and scleroderma.

OBJECTIVE: To further specify the site of vascular dysfunction in patients with Raynaud's phenomenon (RP) and scleroderma. METHODS: Ten patients with RP and scleroderma and 11 healthy control subjects received brachial artery infusions of sodium nitroprusside, an endothelium independent vasodilator, bradykinin, and substance P while bilateral finger blood flow was measured with venous occlusion plethysmography. RESULTS: Both groups showed vasodilation to sodium nitroprusside. However, in response to the endothelium dependent compounds bradykinin and substance P, the controls showed vasodilation, whereas the patients showed vasoconstriction. CONCLUSION: The vascular defect in RP and scleroderma does not lie at the site of the muscarinic receptor, but possibly in a distal signaling mechanism.

The Raynaud's Treatment Study: biofeedback protocols and acquisition of temperature biofeedback skills.

The Raynaud's Treatment Study (RTS) compared temperature biofeedback training and a behavioral control procedure (frontalis EMG biofeedback) with nifedipine-XL and a medication placebo for treatment of primary Raynaud's phenomenon (RP) in a large (N = 313) multicenter trial. The present study describes the RTS biofeedback protocols and presents data on the acquisition of digital skin temperature and frontalis EMG responses in the RTS. The findings point to substantial problems with acquisition of physiological self-regulation skills in the RTS. Only 34.6% of the Temperature Biofeedback group (N = 81) and 55.4% of the EMG Biofeedback group (N = 74) successfully learned the desired physiological response. In contrast, 67.4% of a Normal Temperature Biofeedback group (N = 46) learned hand warming. Multivariate analysis found that coping strategies, anxiety, gender, and clinic site predicted acquisition of hand-warming skills whereas variables related to RP disease severity did not. Physiological data showed vasoconstriction in response to the onset of biofeedback and also found that performance in the initial sessions was critical for successful acquisition. These findings indicate that attention to the emotional and cognitive aspects of biofeedback training, and a degree of success in the initial biofeedback sessions, are important for acquisition.

Clonidine raises the sweating threshold in symptomatic but not in asymptomatic postmenopausal women.

OBJECTIVE: To determine the effects of clonidine, which reduces central sympathetic activation, on the sweating threshold in postmenopausal women with and without hot flashes. DESIGN: Laboratory physiologic study. SETTING: University medical center. PATIENT(S): 12 healthy postmenopausal women reporting frequent hot flashes and 7 reporting none. INTERVENTION(S): In two separate sessions, participants received a blind intravenous injection of clonidine HCl (2 microg/kg of body weight) or placebo, followed by body heating. MAIN OUTCOME MEASURE(S): Core body temperature, mean skin temperature, sweat rate, sternal skin conductance level, and blood pressure. RESULT(S): Symptomatic women had significantly lower core body temperature sweating thresholds than asymptomatic women after receiving placebo. Clonidine significantly increased this threshold in symptomatic women but lowered it in asymptomatic women. CONCLUSION(S): These results support the hypothesis that elevated brain norepinephrine levels reduce the sweating threshold in symptomatic women, thereby contributing to the initiation of menopausal hot flashes.

Effects of menstrual cycle and race on peripheral vascular alpha-adrenergic responsiveness.

Gender differences in the incidence of many cardiovascular diseases may be due to the effects of sex hormones. Both alpha(1)- and alpha(2)-adrenergic receptors produce vasoconstriction in peripheral blood vessels and have demonstrated gender effects in previous studies. In addition, race has been shown to influence the effects of some alpha-adrenergic stimuli. We therefore sought to determine the effects of the menstrual cycle and race on peripheral blood flow responses to the intra-arterial infusion of phenylephrine (alpha(1)-agonist) and clonidine (alpha(2)-agonist). Ten white and 8 black women were studied during the early luteal phase and the follicular phase; these phases were verified in each woman through measurements of plasma estradiol and progesterone. Plasma norepinephrine was measured with HPLC. During phenylephrine infusion, there was significantly greater vasoconstriction in the luteal phase versus the follicular phase (P<0.05). There were no differences (P>0.8) between white and black women. During clonidine infusion, white women showed significantly more vasoconstriction in the follicular phase than during the luteal phase (P<0.006). For black women, the responses for both phases did not differ (P>0.9). Blood pressures were significantly higher in the black women (diastolic P<0.005, systolic P<0.05). The luteal-phase elevation of alpha(1)-adrenergic responses may be due to elevated levels of estradiol, progesterone, or both. The lack of luteal-phase reduction in alpha(2)-adrenergic vasoconstriction in black women may contribute to their increased pressor responses to adrenergic stimuli.

Endothelial and adrenergic dysfunction in Raynaud's phenomenon and scleroderma.

OBJECTIVE: To investigate the involvement of endothelial and adrenergic mechanisms in patients with Raynaud's phenomenon (RP) and scleroderma. METHODS: Ten patients with RP and scleroderma and 10 healthy volunteer controls were studied. Intraarterial methacholine, sodium nitroprusside, and clonidine were administered while bilateral finger blood flow was measured with venous occlusion plethysmography. RESULTS: Compared to the controls, the patients showed diminished responses to methacholine, an endothelium dependent vasodilator, and to clonidine, an alpha2-adrenergic agonist. However, both groups showed similar responses to sodium nitroprusside, an endothelium independent vasodilator. CONCLUSION: The findings were consistent with previous histological evidence of endothelial damage in scleroderma blood vessels. Failure to release nitric oxide from vascular endothelium may play a role in RP in patients with scleroderma.

Feasibility and psychometrics of an ambulatory hot flash monitoring device.

OBJECTIVE: To assess the feasibility and psychometric properties of a lightweight, automated, ambulatory sternal skin conductance monitor to measure frequency of hot flashes (HFs) among breast cancer survivors (BCSs). DESIGN: A total of 19 postmenopausal BCSs and 5 premenopausal healthy comparison women participated by wearing the monitor for 24 h during their normal daily activities, including sleep. HFs were assessed using subjective (diaries, event markers) and objective (skin conductance) methods. RESULTS: Problems with subjective reporting of HFs were reported by 35% of BCSs. Technological problems and discomfort related to wearing the monitor were minimal. A total of 243 HFs were recorded using the skin conductance monitor by 17 BCSs and 5 premenopausal women (BCS group M = 13.4; range, 1-30). Subjective reporting of HFs was associated with a 31-33% false-positive rate. Skin conductance monitoring during waking hours was associated with a 30% false-negative rate. CONCLUSIONS: The monitor is a feasible method for objectively assessing HFs in BCSs. Data support continued use of sternal skin conductance as an objective measure of HF frequency. This technology should prove useful as an objective measure of HFs in future intervention research aimed at alleviating the symptom and improving quality of life among BCSs.

Acute effect of nitric oxide on Raynaud's phenomenon in scleroderma.

Intra-arterial infusions of L-arginine and sodium nitroprusside significantly decreased the occurrence of laboratory-induced Raynaud's phenomenon in scleroderma patients. Raising the concentration of nitric oxide may be of therapeutic value in this population.

A thermal vascular test for distinguishing between patients with Raynaud's phenomenon and healthy controls. Raynaud's Treatment Study Investigators.

This study tested the reliability and validity of a diagnostic thermal vascular test (TVT) for patients with Raynaud's Phenomenon (RP). The TVT examined digital blood pressure responses to combined cooling and occlusion and was developed as part of the Raynaud's Treatment Study, a multicenter clinical trial comparing the efficacy of biofeedback and pharmacological treatment. A computerized system permitted efficient, accurate, and uniform testing at different geographical sites. A comparison of 199 patients with RP and 52 healthy controls is reported. The TVT showed a sensitivity of 79% and a specificity of 88%. Test-retest reliability was acceptable (r = .80). Addition of a psychological challenge failed to improve the discrimination between patients with RP and controls. The TVT separated patients with RP and controls as well as or better than existing tests and did so with enhanced ease of operation.

Reduced thermoregulatory null zone in postmenopausal women with hot flashes.

OBJECTIVE: Most menopausal hot flashes are preceded by small elevations in core body temperature. If the thermoneutral zone between the thresholds for sweating and shivering is reduced in women with symptoms, the triggering mechanism for hot flashes could be explained. STUDY DESIGN: We studied 12 postmenopausal women with symptoms and 8 without symptoms. We measured body temperatures with a rectal probe, an ingested telemetry pill, and a weighted average of rectal and skin temperatures. Each woman underwent 3 experimental sessions: determination of the sweating threshold by body heating, determination of the shivering threshold by body cooling, and replication of the sweating threshold with exercise. RESULTS: The women with symptoms had significantly smaller interthreshold zones than did the symptom-free women for all 3 measures of body temperature: rectal temperature, 0.0 degrees C +/- 0.06 degrees C versus 0.4 degrees C +/- 0.18 degrees C (P <.005); telemetry pill temperature, 0.0 degrees C +/- 0.11 degrees C versus 0.4 degrees C +/- 0.18 degrees C (P <.005); and mean body temperature, 0.8 degrees C +/- 0.09 degrees C versus 1.5 degrees C +/- 0.20 degrees C (P <. 0006). Sweat rates were significantly higher among the women with symptoms (0.06 +/- 0.002 mg. cm(-2). min(-1)) than among the women without symptoms (0.03 +/- 0.001 mg. cm(-2). min(-1), P <.05). Sweating thresholds during exercise did not significantly differ from those during body heating. During exercise all the women with symptoms and none of the women without symptoms had hot flashes. CONCLUSIONS: Menopausal hot flashes in women with symptoms may be triggered by small elevations in body temperature acting within a reduced thermoneutral zone.

Behavioral and pharmacologic interventions: the Raynaud's Treatment Study.

The Raynaud's Treatment Study (RTS) exemplified clinical trials with treatments that differ qualitatively both in their modes and in their methods of delivery. The RTS compared finger-temperature biofeedback to slow-release nifedipine, a calcium channel blocker, in patients with primary Raynaud's disease. Factors influencing the study design were the nature of the interventions and control measures of the protocol, the possibility of perceived differences by the patients between the treatments once the final protocol was developed, and concern on the part of the investigators over the fact that the primary endpoint was self-reported. This paper presents the final statistical model: a double parallel design with both a placebo group and a nonspecific behavioral control group.

Effect of modulators of protein tyrosine kinase activity on gender-related differences in vascular reactivity at reduced temperature.

We used the isolated-muscle-bath technique to examine the effect of protein tyrosine kinase (PTK) and protein tyrosine phosphatase (PTP) inhibitors on the response of rings of tail artery from male and female rats to cooling and reduced temperature in the absence and presence of two PTK-dependent (clonidine and serotonin) and one PTK-independent (phenylephrine, PE) agonists. At 37 degrees C, reactivity to clonidine, serotonin, and PE was the same in tail artery from female and male rats. At 25 degrees C, reactivity to clonidine and serotonin, but not PE, was greater in tail artery from female rats compared with those from male rats. Sodium orthovanadate (SOV) eliminated the gender-related difference in the contractile effect of clonidine and serotonin at 25 degrees C. The sensitivity to relaxation by genistein was considerably greater for clonidine and serotonin at both temperatures as compared with PE. At 25 degrees C the sensitivity to genistein was greater for the clonidine and serotonin-contracted rings from female rats. In the presence of SOV, temperature reduction led to contraction of rat-tail artery. This effect was greater in rings from female rats. Our results strongly implicate differences in the activity of the PTK transduction pathway as the cause of the observed gender-related differences in agonist-mediated contraction at 25 degrees C and in cold-induced vasoconstriction.

Biochemical, metabolic, and vascular mechanisms in menopausal hot flashes.

OBJECTIVE: To determine if increases in core body temperature preceding most hot flashes are caused by increased metabolic rate, peripheral vasoconstriction, or central noradrenergic activation. DESIGN: Laboratory physiological study. SETTING: University medical center. PATIENT(S): Fourteen healthy, postmenopausal women reporting frequent hot flashes. INTERVENTION(S): Data were recorded for 3 hours in a temperature- and humidity-controlled room. MAIN OUTCOME MEASURE(S): Core body temperature, mean skin temperature, respiratory exchange ratio, sternal skin conductance, plasma 3-methoxy-4-hydroxyphenylglycol, and vanillylmandelic acid. RESULT(S): Twenty-nine physiologically defined hot flashes were recorded. Increases in core body temperature, measured with an ingested radiotelemetry capsule, preceded 76% of the flashes. Increased metabolic rate began after increased core temperature. Peripheral vasoconstriction did not occur. Plasma levels of 3-methoxy-4-hydroxyphenylglycol, a metabolite of brain norepinephrine, increased significantly, whereas vanillylmandelic acid, a peripheral metabolite, did not. CONCLUSION(S): Core body temperature elevations preceding menopausal hot flashes are not driven by peripheral vasoconstriction or increased metabolic rate, but probably by a central noradrenergic mechanism.

Differences in alpha2-adrenoceptor modulation of calcium channels in vascular smooth muscle cells of male and female rats.

Effects of the alpha2-adrenergic agonist clonidine on current through Ca2+ channels was recorded from vascular smooth muscle cells isolated from tail arteries and aortae of male and female rats. The average Ba2+ current in control was not significantly different between males and females; however, clonidine (1 microM) enhanced Ba2+ current through Ca2+ channels in cells from females, but not from males. The greater sensitivity of vascular smooth muscle cells to clonidine may underlie different contractile responses to alpha2-adrenergic agonists between males and females.

Familial aggregation of primary Raynaud's disease.

OBJECTIVE: To determine the occurrence of familial aggregation of primary Raynaud's disease. METHODS: Twenty-three patients with primary Raynaud's disease and their first-degree relatives were assessed by questionnaire and, when possible, by physical examination. The same procedures were performed on the patients' spouses and the spouses' first-degree relatives, who served as the control group. RESULTS: The prevalence of Raynaud's disease was significantly higher in the families of the probands than in the control families when assessed by questionnaire (26.1% versus 5.5%; P < 10(-5)), and by physical examination (11.2% versus 2.8%; P = 0.015). CONCLUSION: These findings demonstrate that there is significant familial aggregation of primary Raynaud's disease.