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1.  Are Vasomotor Symptoms Associated with Alterations in Hemostatic and Inflammatory Markers? Findings from the Study of Women’s Health Across the Nation 
Menopause (New York, N.Y.)  2011;18(10):1044-1051.
Emerging research suggests links between menopausal hot flashes and cardiovascular risk. The mechanisms underlying these associations are unclear, due in part to the incomplete understanding of the physiology of hot flashes. We aimed to examine the longitudinal associations between hot flashes/night sweats and both inflammatory and hemostatic markers, controlling for cardiovascular risk factors and estradiol concentrations.
Participants in the Study of Women’s Health Across the Nation (SWAN) (N=3199), a longitudinal cohort study, were ages 42–52 years at cohort entry. Women completed interviews (hot flashes, night sweats: none, 1–5, 6 days in past 2 weeks), physical measures (blood pressure; height; weight), and a blood draw (C-reactive protein, high sensitivity; plasminogen activator inhibitor-1; Factor VIIc, tissue plasminogen activator antigen (tPA-ag); fibrinogen; glucose; serum estradiol) yearly for 8 years. Hot flashes/night sweats were examined in relation to each inflammatory/hemostatic marker in linear mixed models adjusting for demographic factors, cardiovascular risk factors, and medication use, and additionally serum estradiol.
Compared to experiencing no flashes, reporting hot flashes was associated with higher tPA-aglog (hot flashes 1–5 days: % change (95%CI): 3.88(2.22–5.58), p<0.0001; ≥6 days: % change (95%CI): 4.11(1.95–6.32), p<0.001) and higher Factor VIIclog (hot flashes ≥6 days: % change (95%CI): 2.13(0.80–3.47), p<0.01) in multivariable models. Findings persisted after adjusting for estradiol. Findings for night sweats were similar but attenuated with adjustment.
Frequent hot flashes were associated with higher Factor VIIc and tPA-ag. Hemostatic pathways may be relevant to understanding hot flashes physiology and links between hot flashes and cardiovascular risk.
PMCID: PMC3183159  PMID: 21926929
Menopause; vasomotor symptoms; hot flashes; inflammation; coagulation; hemostasis
2.  Hot flashes and cardiac vagal control during women’s daily lives 
Menopause (New York, N.y.)  2012;19(4):406-412.
The physiology of menopausal hot flashes is not well understood. The autonomic nervous system may play a role in hot flashes, but the current understanding is limited. We previously demonstrated in the laboratory that decreases in high frequency heart rate variability, an index of cardiac vagal control, occur during hot flashes relative to preceding and following periods. In the present study, we tested whether we would observe a similar phenomenon in the ambulatory setting. We additionally considered respiratory rate in these associations.
21 peri- and postmenopausal women ages 40–60 reporting daily hot flashes were monitored both for physiologic and reported hot flashes and heart rate variability over a 24-hour period as they went about their daily lives. Heart rate variability estimates were derived using the band-limited variance method. The interval during the hot flash was compared to two non-flash periods prior to and following the hot flash via mixed effects models.
Heart rate variability significantly decreased during hot flashes relative to periods preceding (b=0.31, SE=0.03 p<0.0001) and following (b=0.30, SE=0.03, p<0.0001) physiologic hot flashes (covariates: age, race, education, menopausal status, physical activity, body mass index, anxiety). Findings were comparable considering self-reported hot flashes. Findings persisted controlling for respiratory rate.
Significant decreases in cardiac vagal control occurred during hot flashes assessed during women’s daily lives. These findings extend our work in the laboratory to the ambulatory setting, further shedding light on the physiology of hot flashes and underscoring a potential role of parasympathetic function in hot flashes.
PMCID: PMC3292670  PMID: 22095062
hot flashes; hot flushes; vasomotor symptoms; heart rate variability; autonomic nervous system; menopause
3.  Hot Flashes and Carotid Intima Media Thickness among Midlife Women 
Menopause (New York, N.Y.)  2011;18(4):352-358.
Emerging evidence suggests associations between menopausal hot flashes and cardiovascular risk. Whether hot flashes are associated with intima media thickness (IMT) or IMT changes over time is unknown. We hypothesized that reported hot flashes would be associated with greater IMT cross-sectionally and with greater IMT progression over two years.
Participants were 432 women ages 45-58 at baseline participating in SWAN Heart, an ancillary study to the Study of Women's Health Across the Nation. Measures at the SWAN Heart baseline and follow-up visit two years later included a carotid artery ultrasound, reported hot flashes (past two weeks: none, 1-5, ≥6 days), and a blood sample for measurement of estradiol.
Women reporting hot flashes ≥6 days in the prior two weeks had significantly higher IMT than women without hot flashes at baseline (mean difference(SE), mm =0.02(0.01), p=0.03) and follow-up (mean difference(SE), mm =0.02(0.01), p=0.04) visits, controlling for demographic factors and cardiovascular risk factors. Reporting hot flashes at both study visits was associated with higher follow-up IMT relative to reporting hot flashes at neither visit (mean difference(SE), mm=0.03(0.01), p=0.03). Associations between hot flashes and IMT largely remained after adjusting for estradiol. An interaction between hot flashes and obesity status was observed (p=0.05) such that relations between hot flashes and IMT were observed principally among overweight/obese women. Hot flashes were not associated with IMT progression.
These findings provided some indication that women reporting hot flashes ≥6 days in the prior two weeks may have higher IMT than women without hot flashes, particularly for women who are overweight or obese. Further work should determine whether hot flashes mark adverse underlying vascular changes.
PMCID: PMC3116932  PMID: 21242820
atherosclerosis; women; hot flashes; vasomotor symptoms; epidemiology; cardiovascular disease
4.  Mechanisms of cutaneous vasodilation during the postmenopausal hot flash 
Menopause (New York, N.Y.)  2011;18(4):359-365.
Menopausal hot flashes can seriously disrupt the lives of symptomatic women. The physiological mechanisms of the hot flash efferent responses, particularly in the cutaneous circulation, are not completely understood. The aim of this study was to examine the mechanisms of increases in skin blood flow during the postmenopausal hot flash in symptomatic women.
Healthy postmenopausal women rested in a temperature controlled laboratory while responses prior to and during hot flashes were recorded for three unique protocols. Protocols 1 and 2: Women were locally pretreated with an intradermal injection of botulinum toxin A (BTX; blocks the release of neurotransmitters from sympathetic cholinergic nerves) in the forearm (protocol 1) and in the glabellar region (protocol 2). Protocol 3: Skin sympathetic nerve activity from the peroneal nerve was recorded, along with skin blood flow and sweating within the region innervated by that neural signal. Skin blood flow was indexed using laser-Doppler flowmetry at BTX-treated and adjacent untreated control sites. The onset of a hot flash was objectively identified as a transient and pronounced elevation of sternal sweat rate.
The elevation in forearm (protocol 1) and glabellar skin blood flow (protocol 2) during hot flashes were attenuated at BTX sites relative to adjacent untreated sites (P<0.05 for both protocols). In protocol 3, skin sympathetic nerve activity significantly increased during hot flashes and returned to pre-flash levels following the hot flashes.
Elevations in skin blood flow during the postmenopausal hot flash are neurally mediated primarily through BTX sensitive nerves; presumably sympathetic cholinergic.
PMCID: PMC3117955  PMID: 21107299
Skin Blood Flow; Sympathetic Cholinergic; Menopause
5.  The Effects of Valerian Root on Hot Flashes in Menopausal Women  
Hot flash is among the most common complaints of menopausal women, affecting their career, social activities and quality of life. This study aimed to investigate the effects of Valerian on hot flashes in menopausal women. In this double blind clinical trial, 68 menopausal women with the chief complaint of hot flash were enrolled using sampling at hand and were randomly divided into drug and placebo groups. The women in the drug group were prescribed 255 mg Valerian capsules 3 times a day for 8 weeks. The women in the placebo group were prescribed identical capsules filled with starch. Then, severity and frequency of hot flashes were measured and recorded through questionnaires and information forms in three levels (2 weeks before, four and eight weeks after the treatment). The Severity of hot flashes revealed a meaningful statistical difference pre- and post- Valerian treatment (p <0.001) while this difference was not meaningful in the placebo group. Further, the comparison of the two groups regarding the severity of hot flash after the treatment showed a meaningful statistical difference (p <0.001). Valerian has also led to a reduction of hot flash frequencies 4 and 8 weeks after the treatment (p <0.001) but this difference was not meaningful in drug like group. Valerian can be effective in treatment of menopausal hot flash and that it can be considered as a treatment of choice for reduction of hot flashes among the women who are reluctant to receive hormone therapy due to fear or any other reason.
PMCID: PMC3813196  PMID: 24250592
Valerian; Hot flash; Menopause; Herbal medicine
6.  Treatment of Menopausal Hot Flashes with 5-Hydroxytryptophan 
Maturitas  2009;65(4):383-385.
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 (SSRI’s), which increase the amount of serotonin in the synaptic gap, have shown some promise in the amelioration of hot flashes.
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.
No significant effects of 150 mg/day 5-HTP upon hot flash frequency were found. The 5-HTP group had 23.8 ± 5.7 (SD) hot flashes/24 hours prior to treatment and 18.5 ± 9.6 at the end of treatment. The placebo group had 18.5 ± 9.6 before treatment and 22.6 ± 12.4 at treatment completion.
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.
PMCID: PMC2834831  PMID: 20031347
Hot flash; Serotonin; 5-Hydroxytryptophan (5-HTP); Menopause
Menopause (New York, N.Y.)  2011;18(8):897-900.
To determine if heart rate variability changes during hot flashes recorded during sleep.
This study was performed in a university medical center laboratory with 16 menopausal 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.
For the frequency bin of 0–0.15 Hz, spectral power was greater during waking compared to nonREM sleep and less during Stages 3, 4 compared to Stages 1 and 2. Power was greater during hot flashes compared to subsequent periods for all hot flashes. Power was greater during hot flashes compared to 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.
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.
PMCID: PMC3181047  PMID: 21522045
Hot flashes; heart rate variability; sleep; thermoregulation; sympathetic activation
8.  Management of menopause-associated vasomotor symptoms: Current treatment options, challenges and future directions 
Hot flashes are one of the most common and distressing symptoms associated with menopause, occurring in more than 75% of postmenopausal women. They are especially problematic in breast cancer patients since some breast cancer therapies can induce hot flashes. For mild hot flashes, it is proposed that behavioral modifications are the first step in management. Hormonal therapies, including estrogens and progestogens, are the most well known effective agents in relieving hot flashes; however, the safety of these agents is controversial. There is an increasing amount of literature on nonhormonal agents for the treatment of hot flashes. The most promising data regard newer antidepressant agents such as venlafaxine, which reduces hot flashes by about 60%. Gabapentin is another nonhormonal agent that is effective in reducing hot flashes. While many complimentary therapies, including phytoestrogens, black cohosh, and dehydroepiandrosterone, have been explored for the treatment of hot flashes; none can be recommended at this time. Furthermore, there is a lack of strong evidence to support exercise, yoga, or relaxation for the treatment of hot flashes. Paced respirations and hypnosis appear to be promising enough to warrant further investigation. Another promising nonpharmacological therapy, currently under investigation, involves a stellate ganglion block.
PMCID: PMC2971731  PMID: 21072305
vasomotor symptoms; hot flashes; menopause; therapy
9.  Effects of Licorice on Relief and Recurrence of Menopausal Hot Flashes 
Vasomotor hot flash is the most common and distressful complication of menopausal women. Its treatment is the most frequent clinical challenge. As a result, an effective and harmless therapy is needed. This double-blind controlled clinical trial was conducted to determine the effects of licorice roots on the relief and recurrence of hot flash in menopausal women referring to the healthcare centers affiliated to Shahid Beheshti Medical University in 2010.
Ninety menopausal women complaining of hot flash were selected by reviewing their records in healthcare centers and randomly divided into 2 licorices (3 capsules daily containing 330 mg licorice abstract) and placebo (3 capsules daily containing 330 mg starch) groups over the 8 weeks of intervention and 4 weeks of follow-up. Two weeks prior to the intervention, the severity as well as frequency of hot flashes and the foods taken were asked and documented with questionnaires and data sheets. Data within and between the groups were analyzed by ANOVA with repeated measurements and t-test respectively.
Means of age and body mass index (BMI) of the subjects in licorice and placebo groups were 53 ± 3.2, 52.69 ± 2.8, 24.71 ± 3.2 and 23.61 ± 3.3, respectively. The groups were similar in terms of intervening variables. The frequency of hot flash decreased significantly in the experimental (than the placebo group) and this lasted for 2 weeks after the administration of the capsules. The severity of hot flash decreased in the licorice group as well. This decrease was also seen in the placebo group in the first week of the intervention. Decreased hot flash in the placebo group was only significant after the 1st week of intervention compared to the previous period. Recurrence of frequency and severity of hot flashes occurred 2 weeks after the termination of therapy.
The significant decrease in the placebo group after the 1st week of the intervention may be attributed to the psychological effects of placebo. Licorice roots decreased the frequency and severity of hot flashes. The administration of this harmless, inexpensive herb well accepted by the menopausal women together with the appropriate and continuous physical activities and consumption of dairy products are recommended for relieving this complication.
PMCID: PMC3832176  PMID: 24250477
Menopause; Menopausal women; Vasomotor hot flash; Post menopausal hot flash; Herbal medicine; Licorice
10.  Brain blood flow and cardiovascular responses to hot flashes in postmenopausal women 
Menopause (New York, N.Y.)  2013;20(3):10.1097/GME.0b013e31826e45f0.
This study tested two related hypotheses: 1) that brain blood flow is reduced during the postmenopausal hot flash; and, 2) the magnitude of this reduction in brain blood flow is greater during hot flashes where blood pressure is reduced.
Eleven healthy, normotensive, postmenopausal women rested in a temperature-controlled laboratory (~25°C) for approximately 120 minutes while waiting for a hot flash to occur. The onset of a hot flash was objectively identified by an abrupt increase in sternal sweat rate (capacitance hygrometry). Middle cerebral artery blood velocity (MCAv, transcranial Doppler) and mean arterial pressure (Finometer®) were measured continuously. Each hot flash was divided into 8 equal segments and the segment with the largest reduction in MCAv and mean arterial pressure identified for each hot flash.
Twenty-five hot flashes occurred during the experimental sessions (lasting 6.2 ± 2.8 min, 3 ± 1 hot flashes per participant). Seventy-six percent of hot flashes were accompanied by a clear reduction (greater than 5%) in brain blood flow. For all hot flashes, the average maximum decrease in MCAv was 12 ± 9% (7 ± 6 cm.s−1). This value did not correlate with corresponding changes in mean arterial pressure (R=0.36).
These findings demonstrate that hot flashes are often accompanied by clear reductions in brain blood flow that do not correspond with acute reductions in mean arterial blood pressure.
PMCID: PMC3566296  PMID: 23435027
Menopause; hot flash; brain blood flow
Maturitas  2009;65(1):69.
Recent epidemiological studies suggest that hot flashes may have a detrimental impact on the cardiovascular system. The purpose of this study was to examine the associations between hot flashes and blood pressure among women aged 45 to 54 years who had never used hormone therapy.
Study Design
Data were analyzed from 603 women who participated in the Midlife Health Study, a cross-sectional study conducted in the Baltimore Metropolitan region.
Main Outcome Measures
All participants came to the clinic where systolic and diastolic blood pressure was measured, height and weight were assessed, and a questionnaire was administered that ascertained detailed data on history of hot flashes and participant demographics and health habits.
The data showed that 56.9% of the participants reported ever experiencing hot flashes. In the age-adjusted analyses, both systolic and diastolic blood pressures were significantly and positively associated with hot flashes. However, the estimates were markedly attenuated and not statistically significant after adjustment for age, race, smoking status, current alcohol use, body mass index, and use of an anti-hypertensive agent or a cholesterol-lowering medication. Similar results were observed for moderate or severe hot flashes, hot flashes experienced for one or more years, and hot flashes experienced within the previous 30 days.
These findings indicate that hot flashes are not significantly associated with blood pressure during midlife.
PMCID: PMC2815260  PMID: 19945805
Blood pressure; cardiovascular disease risk; hot flashes; midlife; menopause
Menopause (New York, N.Y.)  2009;16(4):728-734.
Evaluate associations between hot flashes and depressed mood in the menopausal transition and associations of these symptoms with reproductive hormone changes.
10-year follow-up in a population-based cohort of the women who had no experience of hot flashes or depressed mood at baseline.
The incidence of hot flashes significantly increased compared to the incidence of depressed mood in the 10-year follow-up (P<0.001). Sixty-seven percent of the women reported hot flashes, 50% reported depressed mood, and 41% reported both symptoms during the study interval. Reporting both hot flashes and depressed mood was greater than expected if the processes operated independently (P<0.001). Of the women who experienced both symptoms, depressed mood was more likely to precede hot flashes (RR=2.1, 95% CI: 1.5, 2.9). Within-woman increases in FSH levels were associated with the onset of depressed mood in unadjusted analysis (P=0.05). Increased FSH levels, decreased Inhibin b levels and the variability of estradiol were significantly associated with hot flashes. FSH and Inhibin b remained significantly associated with hot flashes in the final multivariable models (P<0.001).
Both hot flashes and depressive symptoms occur early in the menopausal transition in women with no previous experience of these symptoms. Depressive symptoms are more likely to precede hot flashes in women who report both symptoms. The findings support the concept that the changing hormonal milieu of the menopausal transition is one of multiple factors associated with the onset of symptoms.
PMCID: PMC2860597  PMID: 19188849
13.  Cutaneous and hemodynamic responses during hot flashes in symptomatic postmenopausal women 
Menopause (New York, N.Y.)  2008;15(2):290-295.
The aim of this study was to test the hypothesis that the postmenopausal hot flash is accompanied by rapid decreases in arterial blood pressure and increases in cutaneous vascular conductance (CVC), as evaluated by continuous measurements of these variables in symptomatic women.
Twelve healthy, normotensive, postmenopausal women rested in a temperature-controlled laboratory (26°C) for approximately 90 minutes. The onset of a hot flash was objectively identified as a transient and pronounced elevation of sternal sweat rate (capacitance hygrometry).
Twenty-three hot flashes were recorded during the experimental sessions (3.4 ± 1.4 min; range, 1.3–6.5 min). Mean arterial blood pressure decreased 13 ± 2 mm Hg during 11 hot flashes in five participants. Data from these participants, categorized as responders, were analyzed separately from data for those participants whose blood pressure did not change during their hot flashes (n = 7, 12 hot flashes). Heart rate (obtained from an electrocardiogram) significantly increased during the hot flashes, but there was no difference between the responder and nonresponder groups (9 ± 2 vs 10 ± 1 beats/min, respectively; P > 0.05). The increase in CVC was not different between groups at either the forearm (15% ± 3% vs 12% ± 3% maximal CVC, P > 0.05) or sternum (24% ± 5% vs 21% 3% maximal CVC, P > 0.05).
These data demonstrate that in a subset of participants, the hot flash is accompanied by a significant reduction in blood pressure, but there is no difference in CVC between these women and women with no drop in blood pressure.
PMCID: PMC2840382  PMID: 17700502
Skin blood flow; Blood pressure; Hot flash
14.  History of hot flashes and aortic calcification among postmenopausal women 
Menopause (New York, N.Y.)  2010;17(2):256-261.
Menopausal hot flashes are considered largely a quality of life issue. However, emerging research also links hot flashes to cardiovascular risk. In some investigations, this risk is particularly apparent among women using hormone therapy. The study aim is to ask whether a longer history of reported hot flashes over the study period was associated with greater aortic and coronary artery calcification. Interactions with hormone therapy use are examined in an exploratory fashion.
Participants included 302 women participating in the Healthy Women Study, a longitudinal study of cardiovascular risk during the peri- and post-menopause initiated in 1983. Hot flashes (any/none) were assessed when women were 1, 2, 5, and 8 years postmenopausal. Electron beam tomography measures of coronary artery calcification and aortic calcification were completed in 1997–2004. Associations between the number of visits reporting hot flashes, divided by the number of visits attended and aortic or coronary artery calcification (transformed) were examined in linear regression models. Interactions by hormone therapy use were evaluated.
Among women using hormone therapy, a longer history of reporting hot flashes was associated with increased aortic calcification, controlling for traditional cardiovascular risk factors (b=2.87, SE=1.21, p<0.05). There were no significant associations between history of hot flashes and coronary artery calcification.
Among postmenopausal women using hormone therapy, a longer history of reporting hot flashes measured prospectively was associated with increased aortic calcification, controlling for traditional cardiovascular risk factors. Hot flashes may signal adverse cardiovascular changes among certain postmenopausal women.
PMCID: PMC2837097  PMID: 20042895
hot flashes; hot flushes; aortic calcification; coronary calcification; hormone therapy; atherosclerosis
15.  The Effect of Dietary Intake on Hot Flashes in Menopausal Women 
To describe the relation between dietary intake and menopausal hot flashes.
Two studies are reported: a controlled, repeated-measures study and a descriptive study.
The controlled study was conducted in a general clinical research center of a large Midwestern university. The descriptive study was conducted in a metropolitan community in the Southwest.
Ten healthy symptomatic postmenopausal women participated in the controlled study and 21 symptomatic women completed the observational study.
The controlled study included a 30-hour intensive blood sampling protocol of two sequential experimental phases with an observational phase between them. In the observational phase, each participant served protocol-specific meals and snacks at predetermined times.
Main Outcome Measure
Skin conductance monitoring provided continual assessment while blood glucose levels were analyzed every 30 minutes in the controlled study.
Eating provided a hot flash-free period that averaged 90 minutes in both studies. Also, hot flash frequency increased as time between meals increased.
Our evidence indicates that hot flash frequency is suppressed after eating, while hot flashes are experienced when blood glucose falls between meals. Nursing interventions aimed at maintaining stability in blood glucose level may be effective in reducing menopausal hot flashes.
PMCID: PMC2765999  PMID: 17489931
Hot Flashes; Women’s Health; Nutrition; Menopause
16.  Mindfulness Training for Coping with Hot Flashes: Results of a Randomized Trial 
Menopause (New York, N.Y.)  2011;18(6):611-620.
Study the effect of participation in a mindfulness training program (Mindfulness Based Stress Reduction) on degree of bother from hot flashes and night sweats.
Randomized trial of 110 late perimenopausal and early post-menopausal women experiencing average of ≥5 moderate or severe hot flashes (including night sweats)/day. A wait list control was used, with three-month post-intervention follow-up. Main outcome was degree of bother from hot flashes and night sweats in previous 24 hours. Secondary measures: hot flash intensity, quality of life, insomnia, anxiety, perceived stress.
Baseline average hot flash frequency was 7.87 (SD 3.44) and 2.81 night sweats (SD 1.76)/day. Mean bothersomeness score was 3.18 (SD 0.55) (‘moderately bothered/extremely bothered’). All analyses were intent to treat, and controlled for baseline values. Within-woman changes in bother from hot flashes differed significantly by treatment arm (week × treatment arm interaction P=0.042). At completion of intervention, bother in the MBSR arm decreased on average by 14.77% versus 6.79% for WLC. At 20 weeks total reduction in bother for MBSR was 21.62% and 10.50% for WLC. Baseline-adjusted changes in hot flash intensity did not differ between treatment arms (week × treatment arm interaction P=0.692). The MBSR arm made clinically significant improvements in quality of life (P=0.022), subjective sleep quality (p=0.009), anxiety (P=0.005), and perceived stress (P=0.001). Improvements were maintained 3 months post-intervention.
Our data suggest that MBSR may be a clinically significant resource in reducing the degree of bother and distress women experience from hot flashes and night sweats.
PMCID: PMC3123409  PMID: 21372745
Mindfulness; menopause; hot flashes; sleep; quality of life; perceived stress
17.  Acupuncture as Treatment of Hot Flashes and the Possible Role of Calcitonin Gene-Related Peptide 
The mechanisms behind hot flashes in menopausal women are not fully understood. The flashes in women are probably preceded by and actually initiated by a sudden downward shift in the set point for the core body temperature in the thermoregulatory center that is affected by sex steroids, β-endorphins, and other central neurotransmitters. Treatments that influence these factors may be expected to reduce hot flashes. Since therapy with sex steroids for hot flashes has appeared to cause a number of side effects and risks and women with hot flashes and breast cancer as well as men with prostate cancer and hot flashes are prevented from sex steroid therapy there is a great need for alternative therapies. Acupuncture affecting the opioid system has been suggested as an alternative treatment option for hot flashes in menopausal women and castrated men. The heat loss during hot flashes may be mediated by the potent vasodilator and sweat gland activator calcitonin gene-related peptide (CGRP) the concentration of which increases in plasma during flashes in menopausal women and, according to one study, in castrated men with flushes. There is also evidence for connections between the opioid system and the release of CGRP. In this paper we discuss acupuncture as a treatment alternative for hot flashes and the role of CGRP in this context.
PMCID: PMC3205728  PMID: 22110545
18.  Are hot flashes associated with sleep disturbance during midlife? 
Maturitas  2011;71(1):34-38.
Sleep disturbance and hot flashes are common during menopause, but their association is not well understood. We sought to understand the associations among sleep disturbance and the frequency, bothersomeness, and interference of hot flashes in mid-life women.
Study Design
STRIDE is a study of women ages 40–65 years at varied menopausal stages. We examined the cross-sectional associations of sleep disturbance with the frequency and bothersomeness of hot flashes, and interference of hot flashes with work, social, and leisure activities during the 2nd year of STRIDE.
Main Outcome Measure
Self-reported sleep disturbance
Of the 623 women with complete data, 370 (59%) reported having hot flashes. Bivariate analyses showed that reporting hot flashes with bother, but not hot flashes alone, was associated with sleep disturbance (odds ratio [OR] [95% confidence interval (CI)]: 2.8[2.0–4.0] and 1.3[0.7–2.5], respectively). In multivariable models, women reporting bothersome hot flashes were more likely to report sleep disturbance (OR [95% CI]: 2.1 [1.4–3.2]) compared to women who reported no hot flashes. When the perceived interference of hot flashes with work, social activities, and leisure activities were included in the model, the relationships between bothersome hot flashes and sleep disturbance disappeared.
Hot flashes are not associated with sleep disturbance, unless they are bothersome. Mid-life patients should routinely be queried about the bothersomeness of their hot flashes.
PMCID: PMC3253872  PMID: 22051577
Menopause; hot flashes; sleep disturbance
19.  Childhood abuse or neglect is associated with increased vasomotor symptom reporting among midlife women 
Menopause (New York, N.Y.)  2008;15(1):16-22.
This study tested the hypothesis that women exposed to childhood abuse or neglect would have an increased likelihood of reporting hot flashes and night sweats during the menopausal transition.
This hypothesis was evaluated in 332 white and African American women participating in the Study of Women’s Health Across the Nation Mental Health Study, a prospective investigation of women transitioning through menopause. Childhood abuse and neglect were measured once with the Child Trauma Questionnaire. Vasomotor symptoms (any/none hot flashes, night sweats) were reported annually over 8 years. Associations between maltreatment and vasomotor symptoms were estimated with generalized estimating equations.
Childhood abuse or neglect was associated with increased reporting of hot flashes (odds ratio = 1.73, 95% CI: 1.23–2.43) and night sweats (odds ratio = 1.75, 95% CI: 1.26–2.43) in age-adjusted models. Results persisted in multivariable models and across several types of abuse and neglect.
The experience of childhood abuse and neglect is associated with increased vasomotor symptom reporting in adulthood. The sequelae of childhood abuse and neglect may persist well into adulthood to influence the occurrence of vasomotor symptoms at midlife.
PMCID: PMC2957816  PMID: 18257140
Menopause; Vasomotor symptoms; Hot flashes; Child abuse; Neglect; Maltreatment
20.  Objective hot flashes are negatively related to verbal memory performance in midlife women 
Menopause (New York, N.Y.)  2008;15(5):848-856.
To test the hypothesis that hot flashes specifically relate to verbal memory performance by examining the relationship between objective hot flashes and cognitive test performance in women with moderate to severe vasomotor symptoms.
In an observational study, 29 midlife women (mean age, 53 y) with moderate to severe hot flashes provided measures of objective hot flashes with an ambulatory hot flash monitor, subjective hot flashes with a diary and questionnaire, and objective measures of verbal memory and other cognitive functions with standardized neuropsychological tests.
The mean number of objective hot flashes was 19.5 per day (range, 6 to 35), including 15.3 (range, 6 to 35) during waking hours and 4.2 (range, 0 to 9) during sleep. The mean sensitivity (ie, subjective detection of objectively measured hot flashes) was 60%. Regression analyses revealed that total number of objective hot flashes, sleep duration, and verbal knowledge were significant predictors of delayed verbal memory. Verbal fluency correlated positively with objective daytime hot flashes. Hot flashes did not predict performance on any of the other secondary cognitive measures (ie, attention, working memory, visual memory), although poor sleep predicted worse performance on several outcome measures.
Highly symptomatic women underreport the number of objective hot flashes that they experience by 43%. Verbal memory performance relates significantly to the objective number of hot flashes women experience but not to the number of hot flashes that they report. These findings suggest that physiological factors related to hot flashes, rather than psychological factors, predict poorer verbal memory function.
PMCID: PMC2756983  PMID: 18562950
Cognition; Memory; Menopause; Hot flashes; Hormones; Vasomotor; Monitoring; Ambulatory
21.  Differential Association of Modifiable Health Behaviors with Hot Flashes in Perimenopausal and Postmenopausal Women 
To determine the association of modifiable factors, such as smoking, body mass index, and alcohol use, with hot flashes, and to ascertain whether the association with hot flashes varies by menopausal stage.
A written survey completed by perimenopausal and postmenopausal women enrolling in a randomized, controlled trial of a menopause risk management program in 1999. Survey items included questions on demographics, health status, and health behaviors.
A Massachusetts-based health maintenance organization.
Female members, age 40 to 65, excluding women with chronic conditions precluding study participation, were randomly selected from an automated medical record system.
The majority of the 287 postmenopausal and 468 perimenopausal women participating in the study were white, college educated, and nonsmoking. Approximately 30% of both groups reported experiencing hot flashes. Separate multivariable logistic regression models were developed for perimenopausal and postmenopausal women to identify correlates of reporting any versus no hot flashes. After controlling for age, race, oral contraceptive use, hormone replacement therapy use, and depression, correlates of hot flashes in perimenopausal women were body mass index ≥25 kg/m2 (odds ration [OR], 2.00; 95% confidence interval [CI], 1.28 to 3.12) and alcohol use of 1 to 5 drinks per week (OR, 0.52; 95% CI, 0.31 to 0.86). The only significant correlate of hot flashes in the postmenopausal population was high dietary fat intake (OR, 0.35; 95% CI, 0.15 to 0.81).
Although study respondents were from similiar sociodemographic groups and received their health care in the same health maintenance organization, modifiable factors associated with hot flashes were different for perimenopausal and postmenopausal women.
PMCID: PMC1492484  PMID: 15209587
menopause; hot flash; BMI; alcohol; smoking; diet
22.  Daidzein-rich isoflavone aglycones are potentially effective in reducing hot flashes in menopausal women 
Menopause (New York, N.Y.)  2008;15(1):125-132.
The aim of this study was to determine the effect of DRIs on hot flash symptoms in menopausal women.
This was a randomized, double-blind, placebo-controlled trial of menopausal women, aged 38 to 60 years, who experienced 4 to 14 hot flashes per day. After a 1-week run-in period, a total of 190 menopausal women were randomized to receive a placebo or 40 or 60 mg/day of a DRI for 12 weeks. The primary outcome was the mean changes from baseline to week 12 in the frequency of hot flashes recorded in the participant diary. The secondary outcomes included changes in quality of life and hormonal profiles.
A total of 147 women (77%) completed the study. It was found that 40 and 60 mg of DRI improved hot flash frequency and severity equally. At 8 weeks hot flash frequency was reduced by 43% in the 40-mg DRI group and by 41% in the 60-mg DRI group, compared with 32% in the placebo group (P = not significant vs placebo). The corresponding numbers for 12 weeks were 52%, 51%, and 39%, respectively (P = 0.07 and 0.09 vs placebo). When comparing the two treatment groups with the placebo group, there were significant reductions in mean daily hot flash frequency. The supplement (either 40 or 60 mg) reduced hot flash frequency by 43% at 8 weeks (P = 0.1) and 52% at 12 weeks (P = 0.048) but did not cause any significant changes in endogenous sex hormones or thyroid hormones. Menopausal quality of life improved in all three groups, although there were no statistically significant differences between groups.
DRI supplementation may be an effective and acceptable alternative to hormone treatment for menopausal hot flashes.
PMCID: PMC3207039  PMID: 18257146
Hot flashes; Menopausal symptoms; Soybean germ; Isoflavones; Aglycones; Menopause
23.  Cortisol Levels during the Menopausal Transition and Early Postmenopause: Observations from the Seattle Midlife Women’s Health Study 
Menopause (New York, N.Y.)  2009;16(4):708-718.
Cortisol levels rise among some women during the late stage of the menopausal transition, but we know little about changes in cortisol levels in relation to menopause-related factors (menopausal transition (MT) stage, urinary estrone glucuronide, testosterone, FSH), stress-related factors (epinephrine, norepinephrine, perceived stress), symptoms (hot flashes, mood, memory and sleep), social factors (income adequacy, role burden, social support, employment, parenting, and history of sexual abuse) and health-related factors (depressed mood, perceived health, physical appraisal, BMI, and smoking). Aims were to examine the influence of menopause-related factors, stress-related factors, symptoms, social, and health-related factors on cortisol levels during the menopausal transition.
A subset of Seattle Midlife Women’s Health Study participants who provided data during the late reproductive, early and late MT stages or early postmenopause (PM) and who were not using hormone therapy or corticosteroids (N=132 women, up to 5218 observations) including menstrual calendars for staging the MT, annual health reports, health diaries, and overnight urine specimens (assayed for cortisol, catecholamines, estrone glucuronide and FSH) between 1990 and 2005 were included. Perceived stress, symptoms, and health behaviors were assessed in a health diary. Health-related and social factors were assessed in an annual health update. Multilevel modeling was used to test effects of menopause- related and other factors on overnight cortisol levels.
When tested with age as a measure of time, menopause-related covariates, including estrone glucuronide (E1G), FSH, and testosterone were associated with significant increases in overnight cortisol levels (p<.0001). Likewise, epinephrine and norepinephrine were each associated significantly with overnight cortisol levels (p<.0001). In multivariate analyses, E1G, FSH, and testosterone constituted the best set of predictors.
Overnight cortisol levels during the MT were associated with E1G, testosterone, and FSH levels. In addition, they were significantly and positively associated with epinephrine and norepinephrine. MT stage, symptoms, and social, stress-related, and health-related factors had little relationship to overnight cortisol levels when other biological indicators were considered.
PMCID: PMC2749064  PMID: 19322116
24.  The Association between Soy Nut Consumption and Decreased Menopausal Symptoms 
Journal of women's health (2002)  2007;16(3):361-369.
Epidemiological studies suggest a low incidence of hot flashes in populations that consume dietary soy. The present study examined the effect of soy nuts on hot flashes and menopausal symptoms.
Sixty healthy postmenopausal women were randomized in a crossover design to a therapeutic lifestyle changes (TLC) diet alone and a TLC diet of similar energy, fat, and protein content in which one-half cup soy nuts divided into three or four portions spaced throughout the day (containing 25 g soy protein and 101 mg aglycone isoflavones) replaced 25 g of nonsoy protein. During each 8-week diet period, subjects recorded the number of hot flashes and amount of exercise daily. At the end of each 8-week diet period, subjects filled out the menopausal symptom quality of life questionnaire.
Compared to the TLC diet alone, the TLC diet plus soy nuts was associated with a 45% decrease in hot flashes (7.5 ± 3.6 vs. 4.1 ± 2.6 hot flashes day, respectively, p < 0.001) in women with >4.5 hot flashes/day at baseline and 41% in those with ≤4.5 hot flashes/day (2.2 ± 1.2 vs. 1.3 ± 1.1, respectively, p < 0.001). Soy nut intake was also associated with significant improvement in scores on the menopausal symptom quality of life questionnaire: 19% decrease in vasomotor score (p = 0.004), 12.9% reduction in psychosocial score (p = 0.01), 9.7% decrease in physical score (p = 0.045), and a trend toward improvement in the sexual score, with a 17.7% reduction in symptoms (p = 0.129). The amount of exercise had no effect on hot flash reduction.
Substituting soy nuts for nonsoy protein in a TLC diet and consumed three or four times throughout the day is associated with a decrease in hot flashes and improvement in menopausal symptoms.
PMCID: PMC3229924  PMID: 17439381
25.  Peripheral blood flow in menopausal women who have hot flushes and in those who do not. 
BMJ : British Medical Journal  1989;298(6686):1488-1490.
OBJECTIVE--To compare blood pressure, heart rate, and peripheral vascular responsiveness in menopausal women who have hot flushes and in those who do not, and to assess the effect on these variables of treating women who have hot flushes with oestriol, a natural oestrogen, given vaginally. DESIGN--An open, non-randomised cohort study of flushing and non-flushing menopausal women. A before and after investigation of the effects of vaginal oestriol treatment on the circulation. SETTING--Referral based endocrinology clinic. PATIENTS--88 Consecutive menopausal women, 63 complaining of frequent hot flushes and 25 who had not flushed for at least a year. INTERVENTION--Treatment with vaginal oestriol 0.5 mg at night for six weeks in 18 of the women who had hot flushes. MEASUREMENTS AND MAIN RESULTS--Peripheral blood flow was measured by venous occlusion plethysmography at rest and in response to stressful mental arithmetic and anoxic forearm exercises. Blood flow in the forearm and its variability were significantly higher in flushing than in non-flushing women (4.1 (SD 1.7) and 3.1 (0.9) ml/100 ml tissue/min and 17% and 13% respectively). Blood pressure, heart rate, and blood flow in the hand were, however, similar in the two groups. No difference was found in the peripheral incremental response to either stress or anoxic exercise. Vaginal oestriol significantly lowered forearm blood flow from 4.4 (1.5) to 3.3 (1.1) ml/100 ml tissue/min but dilator responsiveness was unaffected. CONCLUSIONS--The peripheral circulation is different in menopausal women who have hot flushes compared with those who do not, with selective vasodilatation in the forearm. The lowered blood flow in the forearm after vaginal oestriol in flushing women may be relevant to the alleviation of vasomotor symptoms induced by oestrogen treatment.
PMCID: PMC1836700  PMID: 2503082

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