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1.  The Relationship between Menopausal Symptoms and Heart Rate Variability in Middle Aged Women 
Korean Journal of Family Medicine  2011;32(5):299-305.
Background
The study of the correlation of menopausal symptoms with heart rate variability (HRV) has not been adequate. The aim of this study was to investigate the relationship between postmenopausal symptoms measured by the menopause rating scale (MRS) and HRV.
Methods
We assessed postmenopausal symptoms (using MRS) with age, BMI, educational status, occupation, marital status, alcohol and caffeine consumption, smoking history, exercise, duration of sleep and amenorrhea, degree of anxiety and depression, menarcheal age, and heart rate variability. For evaluation of HRV, the record of electrocardiogram for 5 minutes in the resting state was divided into temporal categories and frequency categories, and analyzed.
Results
No significant differences in age, BMI, duration of amenorrhea, heart rate, systolic blood pressure, diastolic blood pressure, fasting blood sugar, triglyceride, and high-density lipoprotein were observed between two groups, which were divided according to menopausal symptoms. Low frequency/high frequency (LF/HF) ratio was significantly higher in symptomatic women, compared with asymptomatic women (P < 0.05). No significant differences of HRV index by the severity of postmenopausal symptoms were observed. LF/HF ratio of HRV parameters showed a significant increase in moderate or severe degree of "hot flashes" and "sleep problem" score (P < 0.05). Anxiety scale in symptomatic women was significantly higher than in asymptomatic women (P < 0.05).
Conclusion
The above data suggest that postmenopausal symptoms are associated with altered autonomic control of heart rate. In particular, hot flashes and sleep problems in moderate or severe degree are related to increase of sympathetic nerve activity.
doi:10.4082/kjfm.2011.32.5.299
PMCID: PMC3383141  PMID: 22745867
Postmenopausal Symptoms; Menopause Rating Scale; Heart Rate Variability
2.  Mechanisms of cutaneous vasodilation during the postmenopausal hot flash 
Menopause (New York, N.Y.)  2011;18(4):359-365.
Objective
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.
Methods
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.
Results
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.
Conclusion
Elevations in skin blood flow during the postmenopausal hot flash are neurally mediated primarily through BTX sensitive nerves; presumably sympathetic cholinergic.
doi:10.1097/gme.0b013e3181f7a17a
PMCID: PMC3117955  PMID: 21107299
Skin Blood Flow; Sympathetic Cholinergic; Menopause
3.  Hot Flashes and Carotid Intima Media Thickness among Midlife Women 
Menopause (New York, N.Y.)  2011;18(4):352-358.
Objective
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1097/gme.0b013e3181fa27fd
PMCID: PMC3116932  PMID: 21242820
atherosclerosis; women; hot flashes; vasomotor symptoms; epidemiology; cardiovascular disease
4.  Life Course Trajectories of Systolic Blood Pressure Using Longitudinal Data from Eight UK Cohorts 
PLoS Medicine  2011;8(6):e1000440.
Analysis of eight population-based and occupational cohorts from the UK reveals the patterns of change of blood pressure in the population through the life course.
Background
Much of our understanding of the age-related progression of systolic blood pressure (SBP) comes from cross-sectional data, which do not directly capture within-individual change. We estimated life course trajectories of SBP using longitudinal data from seven population-based cohorts and one predominantly white collar occupational cohort, each from the United Kingdom and with data covering different but overlapping age periods.
Methods and Findings
Data are from 30,372 individuals and comprise 102,583 SBP observations spanning from age 7 to 80+y. Multilevel models were fitted to each cohort. Four life course phases were evident in both sexes: a rapid increase in SBP coinciding with peak adolescent growth, a more gentle increase in early adulthood, a midlife acceleration beginning in the fourth decade, and a period of deceleration in late adulthood where increases in SBP slowed and SBP eventually declined. These phases were still present, although at lower levels, after adjusting for increases in body mass index though adulthood. The deceleration and decline in old age was less evident after excluding individuals who had taken antihypertensive medication. Compared to the population-based cohorts, the occupational cohort had a lower mean SBP, a shallower annual increase in midlife, and a later midlife acceleration. The maximum sex difference was found at age 26 (+8.2 mm Hg higher in men, 95% CI: 6.7, 9.8); women then experienced steeper rises and caught up by the seventh decade.
Conclusions
Our investigation shows a general pattern of SBP progression from childhood in the UK, and suggests possible differences in this pattern during adulthood between a general population and an occupational population.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
About a third of US and UK adults have high blood pressure (hypertension). Although hypertension has no obvious symptoms, it can lead to life-threatening heart attacks, stroke, and other forms of cardiovascular disease (CVD). It is diagnosed by measuring blood pressure—the force that blood moving around the body exerts on the inside of large blood vessels. Blood pressure is highest when the heart is pumping out blood (systolic blood pressure [SBP]) and lowest when the heart is re-filling with blood (diastolic blood pressure [DBP]). Normal adult blood pressure is defined as an SBP of less than 130 millimeters of mercury (mm Hg) and a DBP of less than 85 mm Hg (a blood pressure of 130/85). A reading of more than 140/90 indicates hypertension. Many factors affect blood pressure, but overweight people and individuals who eat fatty or salty food are at high risk of developing hypertension. Moreover, blood pressure tends to increase with age. Mild hypertension can often be corrected by making lifestyle changes, but many people take antihypertensive drugs to reduce their blood pressure.
Why Was This Study Done?
Several trials have indicated that SBP is an important, modifiable risk factor for CVD. But, to determine the best way to prevent CVD, it is important to understand how SBP changes through life and how lifestyle factors affect this age-related progression. Textbook descriptions of age-related changes in SBP are based on studies that measured SBP at a single time point in groups (cohorts) of people of different ages. However, such “cross-sectional” studies do not capture within-individual changes in SBP and may be affected by environmental effects related to specific historical periods. The best way to measure age-related changes in SBP is through longitudinal studies in which SBP is repeatedly measured over many years in a single cohort. Such studies are underway, but it will be some decades before individuals in these studies reach old age. In this study, therefore, the researchers use data from multiple UK cohorts that had repeated SBP measurements taken over different but overlapping periods of life to investigate the life course trajectory of SBP.
What Did the Researchers Do and Find?
The researchers used statistical models to analyze data from longitudinal studies of SBP in seven population-based cohorts (the participants were randomly chosen from the general population) and in one occupational cohort (civil servants). SBP measurements were available for 30,372 individuals with ages spanning from seven years to more than 80 years. The researchers' analysis revealed four phases of SBP change in both sexes: a rapid increase in SBP during adolescent growth, a gentler increase in early adulthood, a midlife acceleration beginning in the fourth decade of life, and a period in late adulthood when SBP increases slowed and then reversed. This last phase was less marked when people taking antihypertensive drugs were excluded from the analysis. After adjusting for increases in body mass index (a measure of body fat) during adulthood, the magnitude of the SBP age-related changes was similar but the average SBP at each age was lower. Compared to the population-based cohorts, the occupational cohort had a lower average SBP, a shallower annual increase in SBP, and a later midlife acceleration, possibly because of socially determined modifiable SBP-related factors such as diet and lifestyle. Finally, although women had lower SBPs in early adulthood than men, they experienced steeper midlife SBP rises (probably because of a menopause-related effect on salt sensitivity) so that by the seventh decade of life, men and women had similar average SBPs.
What Do These Findings Mean?
These findings describe the general pattern of age-related progression of SBP from early childhood in the UK. The findings may not be generalizable because other populations may be exposed to different distributions of modifiable factors. In addition, their accuracy may be affected by differences between cohorts in how SBP was measured. Nevertheless, these findings—in particular, the slower midlife increase in SBP in the occupational cohort than in the population-based cohorts—suggest that the key determinants of age-related increases in blood pressure are modifiable and could be targeted for CVD prevention. Further research is now needed to identify exactly which factors affect the life course trajectory of SBP and to discover when these factors have their greatest influence on SBP.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000440.
The US National Heart Lung and Blood Institute has patient information about high blood pressure (in English and Spanish)
The American Heart Association provides information on high blood pressure and on cardiovascular diseases (in several languages)
The UK National Health Service Choices Web site also provides detailed information for patients about hypertension and about cardiovascular disease
MedlinePlus provides links to further information about high blood pressure, heart disease, and stroke (in English and Spanish)
doi:10.1371/journal.pmed.1000440
PMCID: PMC3114857  PMID: 21695075
5.  Cutaneous and hemodynamic responses during hot flashes in symptomatic postmenopausal women 
Menopause (New York, N.Y.)  2008;15(2):290-295.
Objective
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.
Design
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).
Results
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).
Conclusions
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.
doi:10.1097/gme.0b013e3180ca7cfa
PMCID: PMC2840382  PMID: 17700502
Skin blood flow; Blood pressure; Hot flash
6.  The Effect of Folic Acid on Menopausal Hot Flashes: A Randomized Clinical Trial 
Journal of Caring Sciences  2013;2(2):131-140.
Introduction: The use of alternative therapies for the treatment of menopausal hot flashes has increased due to the serious risk of hormone therapy. Most alternative therapies have not been accepted by women. Therefore, conducting a study to find effective treatment, which has a low rate of complications and is more acceptable, is necessary. The aim of this study was to assess the effects of folic acid on menopausal hot flashes. Methods: In the present study 70 menopausal women were placed into two groups of 35 with random allocation, and were treated with folic acid 1 mg tablets and placebo tablets once a day during four weeks. Information was gathered by questionnaire, interviews, and hot flash diary during five stages. Comparisons of within-group Results were performed by ANOVA and between-group results were performed using ANCOVA. Data were analyzed by SPSS for Windows. Results: There was a significant difference between mean severity, duration, and frequency of hot flashes before and after treatment within both groups. In comparing the results between the groups, mean hot flash severity in second, third, and fourth weeks were significantly different. The mean hot flash frequency was significantly different in third and fourth weeks, and the mean hot flash duration was significantly different in the fourth week. Conclusion: The results of the present study indicated that folic acid was effective in reducing the severity, duration, and frequency of hot flashes during menopause. Therefore, it can be recommended as an affordable and accessible method for treating menopausal hot flash for women.
doi:10.5681/jcs.2013.016
PMCID: PMC4161099  PMID: 25276719
Menopause; Hot flash; Folic acid
7.  Risk Stratification by Self-Measured Home Blood Pressure across Categories of Conventional Blood Pressure: A Participant-Level Meta-Analysis 
PLoS Medicine  2014;11(1):e1001591.
Jan Staessen and colleagues compare the risk of cardiovascular, cardiac, or cerebrovascular events in patients with elevated office blood pressure vs. self-measured home blood pressure.
Please see later in the article for the Editors' Summary
Background
The Global Burden of Diseases Study 2010 reported that hypertension is worldwide the leading risk factor for cardiovascular disease, causing 9.4 million deaths annually. We examined to what extent self-measurement of home blood pressure (HBP) refines risk stratification across increasing categories of conventional blood pressure (CBP).
Methods and Findings
This meta-analysis included 5,008 individuals randomly recruited from five populations (56.6% women; mean age, 57.1 y). All were not treated with antihypertensive drugs. In multivariable analyses, hazard ratios (HRs) associated with 10-mm Hg increases in systolic HBP were computed across CBP categories, using the following systolic/diastolic CBP thresholds (in mm Hg): optimal, <120/<80; normal, 120–129/80–84; high-normal, 130–139/85–89; mild hypertension, 140–159/90–99; and severe hypertension, ≥160/≥100.
Over 8.3 y, 522 participants died, and 414, 225, and 194 had cardiovascular, cardiac, and cerebrovascular events, respectively. In participants with optimal or normal CBP, HRs for a composite cardiovascular end point associated with a 10-mm Hg higher systolic HBP were 1.28 (1.01–1.62) and 1.22 (1.00–1.49), respectively. At high-normal CBP and in mild hypertension, the HRs were 1.24 (1.03–1.49) and 1.20 (1.06–1.37), respectively, for all cardiovascular events and 1.33 (1.07–1.65) and 1.30 (1.09–1.56), respectively, for stroke. In severe hypertension, the HRs were not significant (p≥0.20). Among people with optimal, normal, and high-normal CBP, 67 (5.0%), 187 (18.4%), and 315 (30.3%), respectively, had masked hypertension (HBP≥130 mm Hg systolic or ≥85 mm Hg diastolic). Compared to true optimal CBP, masked hypertension was associated with a 2.3-fold (1.5–3.5) higher cardiovascular risk. A limitation was few data from low- and middle-income countries.
Conclusions
HBP substantially refines risk stratification at CBP levels assumed to carry no or only mildly increased risk, in particular in the presence of masked hypertension. Randomized trials could help determine the best use of CBP vs. HBP in guiding BP management. Our study identified a novel indication for HBP, which, in view of its low cost and the increased availability of electronic communication, might be globally applicable, even in remote areas or in low-resource settings.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Globally, hypertension (high blood pressure) is the leading risk factor for cardiovascular disease and is responsible for 9.4 million deaths annually from heart attacks, stroke, and other cardiovascular diseases. Hypertension, which rarely has any symptoms, is diagnosed by measuring blood pressure, the force that blood circulating in the body exerts on the inside of large blood vessels. Blood pressure is highest when the heart is pumping out blood (systolic blood pressure) and lowest when the heart is refilling (diastolic blood pressure). European guidelines define optimal blood pressure as a systolic blood pressure of less than 120 millimeters of mercury (mm Hg) and a diastolic blood pressure of less than 80 mm Hg (a blood pressure of less than 120/80 mm Hg). Normal blood pressure, high-normal blood pressure, and mild hypertension are defined as blood pressures in the ranges 120–129/80–84 mm Hg, 130–139/85–89 mm Hg, and 140–159/90–99 mm Hg, respectively. A blood pressure of more than 160 mm Hg systolic or 100 mm Hg diastolic indicates severe hypertension. Many factors affect blood pressure; overweight people and individuals who eat salty or fatty food are at high risk of developing hypertension. Lifestyle changes and/or antihypertensive drugs can be used to control hypertension.
Why Was This Study Done?
The current guidelines for the diagnosis and management of hypertension recommend risk stratification based on conventionally measured blood pressure (CBP, the average of two consecutive measurements made at a clinic). However, self-measured home blood pressure (HBP) more accurately predicts outcomes because multiple HBP readings are taken and because HBP measurement avoids the “white-coat effect”—some individuals have a raised blood pressure in a clinical setting but not at home. Could risk stratification across increasing categories of CBP be refined through the use of self-measured HBP, particularly at CBP levels assumed to be associated with no or only mildly increased risk? Here, the researchers undertake a participant-level meta-analysis (a study that uses statistical approaches to pool results from individual participants in several independent studies) to answer this question.
What Did the Researchers Do and Find?
The researchers included 5,008 individuals recruited from five populations and enrolled in the International Database of Home Blood Pressure in Relation to Cardiovascular Outcome (IDHOCO) in their meta-analysis. CBP readings were available for all the participants, who measured their HBP using an oscillometric device (an electronic device for measuring blood pressure). The researchers used information on fatal and nonfatal cardiovascular, cardiac, and cerebrovascular (stroke) events to calculate the hazard ratios (HRs, indicators of increased risk) associated with a 10-mm Hg increase in systolic HBP across standard CBP categories. In participants with optimal CBP, an increase in systolic HBP of 10-mm Hg increased the risk of any cardiovascular event by nearly 30% (an HR of 1.28). Similar HRs were associated with a 10-mm Hg increase in systolic HBP for all cardiovascular events among people with normal and high-normal CBP and with mild hypertension, but for people with severe hypertension, systolic HBP did not significantly add to the prediction of any end point. Among people with optimal, normal, and high-normal CBP, 5%, 18.4%, and 30.4%, respectively, had a HBP of 130/85 or higher (“masked hypertension,” a higher blood pressure in daily life than in a clinical setting). Finally, compared to individuals with optimal CBP without masked hypertension, individuals with masked hypertension had more than double the risk of cardiovascular disease.
What Do These Findings Mean?
These findings indicate that HBP measurements, particularly in individuals with masked hypertension, refine risk stratification at CBP levels assumed to be associated with no or mildly elevated risk of cardiovascular disease. That is, HBP measurements can improve the prediction of cardiovascular complications or death among individuals with optimal, normal, and high-normal CBP but not among individuals with severe hypertension. Clinical trials are needed to test whether the identification and treatment of masked hypertension leads to a reduction of cardiovascular complications and is cost-effective compared to the current standard of care, which does not include HBP measurements and does not treat people with normal or high-normal CBP. Until then, these findings provide support for including HBP monitoring in primary prevention strategies for cardiovascular disease among individuals at risk for masked hypertension (for example, people with diabetes), and for carrying out HBP monitoring in people with a normal CBP but unexplained signs of hypertensive target organ damage.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001591.
This study is further discussed in a PLOS Medicine Perspective by Mark Caulfield
The US National Heart, Lung, and Blood Institute has patient information about high blood pressure (in English and Spanish) and a guide to lowering high blood pressure that includes personal stories
The American Heart Association provides information on high blood pressure and on cardiovascular diseases (in several languages); it also provides personal stories about dealing with high blood pressure
The UK National Health Service Choices website provides detailed information for patients about hypertension (including a personal story) and about cardiovascular disease
The World Health Organization provides information on cardiovascular disease and controlling blood pressure; its A Global Brief on Hypertension was published on World Health Day 2013
The UK charity Blood Pressure UK provides information about white-coat hypertension and about home blood pressure monitoring
MedlinePlus provides links to further information about high blood pressure, heart disease, and stroke (in English and Spanish)
doi:10.1371/journal.pmed.1001591
PMCID: PMC3897370  PMID: 24465187
8.  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.
Objective
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1097/gme.0b013e31821f5d39
PMCID: PMC3183159  PMID: 21926929
Menopause; vasomotor symptoms; hot flashes; inflammation; coagulation; hemostasis
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.  HOT FLASHES AND BLOOD PRESSURE IN MIDLIFE WOMEN 
Maturitas  2009;65(1):69.
Objectives
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.
Results
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.
Conclusions
These findings indicate that hot flashes are not significantly associated with blood pressure during midlife.
doi:10.1016/j.maturitas.2009.10.013
PMCID: PMC2815260  PMID: 19945805
Blood pressure; cardiovascular disease risk; hot flashes; midlife; menopause
11.  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
12.  HEART RATE VARIABILITY IN MENOPAUSAL HOT FLASHES DURING SLEEP 
Menopause (New York, N.Y.)  2011;18(8):897-900.
Objective
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 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.
Results
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.
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.
doi:10.1097/gme.0b013e31820ac941
PMCID: PMC3181047  PMID: 21522045
Hot flashes; heart rate variability; sleep; thermoregulation; sympathetic activation
13.  The Effect of Dietary Intake on Hot Flashes in Menopausal Women 
Objectives
To describe the relation between dietary intake and menopausal hot flashes.
Design
Two studies are reported: a controlled, repeated-measures study and a descriptive study.
Setting
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.
Participants
Ten healthy symptomatic postmenopausal women participated in the controlled study and 21 symptomatic women completed the observational study.
Interventions
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.
Results
Eating provided a hot flash-free period that averaged 90 minutes in both studies. Also, hot flash frequency increased as time between meals increased.
Conclusions
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.
doi:10.1111/j.1552-6909.2007.00142.x
PMCID: PMC2765999  PMID: 17489931
Hot Flashes; Women’s Health; Nutrition; Menopause
14.  Efficacy and Safety of Remifemin on Peri-Menopausal Symptoms Induced by Post-Operative GnRH-a Therapy for Endometriosis: A Randomized Study versus Tibolone 
Background
The aim of this study was to investigate clinical efficacy and safety of Remifemin on peri-menopausal symptoms in endometriosis patients with a post-operative GnRH-a therapy.
Material/Methods
We treated 116 women who had endometriosis with either Remifemin (n=56) 20 mg bid po or Tibolone (n=60) 2.5 mg qd po for 12 weeks after GnRH-a injection. The efficacy was evaluated by Kupperman menopausal index (KMI), and hot flash/sweating scores. The safety parameters such as liver and renal functions, lipid profile, endometrial thickness, and serum sex hormone level, as well as the incidence of adverse events were recorded.
Results
(1) After GnRH-a therapy, KMI and hot flash/sweating scores in both groups increased significantly (P<0.05) but we found no significant difference for KMI (2.87±1.40 for Remifemin and 2.70±1.26 for Tibolone) and hot flash/sweating scores (0.94±1.72 for Remifemin and 1.06±1.78 for Tibolone) between the 2 groups (P>0.05). (2) No statistical change was observed in liver or renal functions and lipid profile in both groups before and after the treatment (P>0.05). The post-therapeutic serum FSH, LH, and E2 level and endometrial thickness decreased remarkably in both groups (P<0.05). E2 level in the Remifemin group was obviously lower than that in the Tibolone group (P<0.05), and FSH and LH levels were strongly higher (P<0.05). No significant difference in thickness were found in either group (P>0.05). The Remifemin group had far fewer adverse events than the Tibolone group (P<0. 05).
Conclusions
Compared with Tibolone, Remifemin had a similar clinical efficacy and was safer for the peri-menopausal symptoms induced by GnRH-a in endometriosis patients.
doi:10.12659/MSM.891353
PMCID: PMC4211309  PMID: 25321621
Drug Therapy; Endometriosis; Treatment Outcome
15.  Are hot tubs safe for people with treated hypertension? 
Background
People with hypertension are commonly warned to check with a physician before using a hot tub, but there is little literature on which to base this advice. We compared symptoms, heart rate, and systolic and diastolic blood pressure in response to 10 minutes of hot-tub immersion in a group of patients with treated hypertension and in a control group normotensive subjects.
Methods
We recruited 21 patients (18 men and 3 women aged 43–76 years) with stable, treated hypertension and 23 control subjects (14 men and 9 women aged 19–83 years) without hypertension. They were studied, in mid-afternoon, at a public facility. Systolic and diastolic blood pressure and heart rate were measured at baseline, during immersion in a hot tub at 40°C and for 10 minutes after immersion. We asked each subject to report any symptoms.
Results
None of the subjects reported dizziness, chest pain or palpitations. During immersion, systolic blood pressure fell in both groups, from a mean (and standard deviation [SD]) of 144 (17) mm Hg to 122 (18) mm Hg in the hypertensive group (p < 0.05) and from 130 (14) mm Hg to 110 (17) mm Hg in the control group (p < 0.05). It returned toward baseline within 10 minutes after the subjects left the hot tub. Diastolic blood pressure also fell, whereas heart rate was increased in both groups. The hypertensive group showed a slightly lower maximal increase in heart rate than the normotensive group (5 [SD 5] v. 13 [SD 10] beats/minute, p < 0.05).
Interpretation
Immersion in a hot tub for 10 minutes lowers blood pressure in subjects with treated hypertension, but no more than in normotensive control subjects. Spending 10 minutes in a hot tub should be safe for most treated hypertensive patients.
PMCID: PMC280579  PMID: 14662661
16.  Alcohol Intake and Blood Pressure: A Systematic Review Implementing a Mendelian Randomization Approach 
PLoS Medicine  2008;5(3):e52.
Background
Alcohol has been reported to be a common and modifiable risk factor for hypertension. However, observational studies are subject to confounding by other behavioural and sociodemographic factors, while clinical trials are difficult to implement and have limited follow-up time. Mendelian randomization can provide robust evidence on the nature of this association by use of a common polymorphism in aldehyde dehydrogenase 2 (ALDH2) as a surrogate for measuring alcohol consumption. ALDH2 encodes a major enzyme involved in alcohol metabolism. Individuals homozygous for the null variant (*2*2) experience adverse symptoms when drinking alcohol and consequently drink considerably less alcohol than wild-type homozygotes (*1*1) or heterozygotes. We hypothesise that this polymorphism may influence the risk of hypertension by affecting alcohol drinking behaviour.
Methods and Findings
We carried out fixed effect meta-analyses of the ALDH2 genotype with blood pressure (five studies, n = 7,658) and hypertension (three studies, n = 4,219) using studies identified via systematic review. In males, we obtained an overall odds ratio of 2.42 (95% confidence interval [CI] 1.66–3.55, p = 4.8 × 10−6) for hypertension comparing *1*1 with *2*2 homozygotes and an odds ratio of 1.72 (95% CI 1.17–2.52, p = 0.006) comparing heterozygotes (surrogate for moderate drinkers) with *2*2 homozygotes. Systolic blood pressure was 7.44 mmHg (95% CI 5.39–9.49, p = 1.1 × 10−12) greater among *1*1 than among *2*2 homozygotes, and 4.24 mmHg (95% CI 2.18–6.31, p = 0.00005) greater among heterozygotes than among *2*2 homozygotes.
Conclusions
These findings support the hypothesis that alcohol intake has a marked effect on blood pressure and the risk of hypertension.
Using a mendelian randomization approach Sarah Lewis and colleagues find strong support for the hypothesis that alcohol intake has a marked effect on blood pressure and the risk of hypertension.
Editors' Summary
Background.
High blood pressure (hypertension) is a common medical condition that affects nearly a third of US and UK adults. Hypertension has no symptoms but can lead to heart attacks or strokes. It is diagnosed by measuring blood pressure—the force that blood moving around the body exerts on the inside of large blood vessels. Blood pressure is highest when the heart is pumping out blood (systolic pressure) and lowest when it is filling up with blood (diastolic pressure). Normal blood pressure is defined as a systolic pressure of less than 130 millimeters of mercury (mmHg) and a diastolic pressure of less than 85 mmHg (a blood pressure of 130/85). A reading of more than 140/90 indicates hypertension. Many factors affect blood pressure, but overweight people and individuals who eat too much salty or fatty foods are at high risk of developing hypertension. Mild hypertension can often be corrected by lifestyle changes, but many people also take antihypertensive drugs to reduce their blood pressure.
Why Was This Study Done?
Another modifiable lifestyle factor thought to affect blood pressure is alcohol intake. Observational studies that ask people about their drinking habits and measure their blood pressure suggest that alcohol intake correlates with blood pressure, but they cannot prove a causal link because of “confounding”—other risk factors associated with alcohol drinking, such as diet, might also affect the study participant's blood pressures. A trial that randomly assigns people to different alcohol intakes could provide this proof of causality, but such a trial is impractical. In this study, therefore, the researchers have used “Mendelian randomization” to investigate whether alcohol intake affects blood pressure. An inactive variant of aldehyde dehydrogenase 2 (ALDH2; the enzyme that removes alcohol from the body) has been identified. People who inherit the variant form of this gene from both parents have an ALDH2 *2*2 genotype (genetic makeup) and become flushed and nauseated after drinking. Consequently, they drink less than people with a *1*2 genotype and much less than those with a *1*1 genotype. Because inheritance of these genetic variants does not affect lifestyle factors other than alcohol intake, an association between ALDH2 genotypes and blood pressure would indicate that alcohol intake has an effect on blood pressure without any confounding.
What Did the Researchers Do and Find?
The researchers identified ten published studies (mainly done in Japan where the ALDH2 gene variant is common) on associations between ALDH2 genotype and blood pressure or hypertension using a detailed search protocol (a “systematic review”). A meta-analysis (a statistical method for combining the results of independent studies) of the studies that had investigated the association between ALDH2 genotype and hypertension showed that men with the *1*1 genotype (highest alcohol intake) and those with the *1*2 genotype (intermediate alcohol intake) were 2.42 and 1.72 times more likely, respectively, to have hypertension than those with the *2*2 genotype (lowest alcohol intake). There was no association between ALDH2 genotype and hypertension among the women in these studies because they drank very little. Systolic and diastolic blood pressures showed a similar relationship to ALDH2 genotype in a second meta-analysis of relevant studies. Finally, the researchers estimated that for men the lifetime effect of drinking 1 g of alcohol a day (one unit of alcohol contains 8 g of alcohol in the UK and 14 g in the US; recommended daily limits in these countries are 3–4 and 1–2 units, respectively) would be an increase in systolic blood pressure of 0.24 mmHg.
What Do These Findings Mean?
These findings support the suggestion that alcohol has a marked effect on blood pressure and hypertension. Consequently, some cases of hypertension could be prevented by encouraging people to reduce their daily alcohol intake. Although the Mendelian randomization approach avoids most of the confounding intrinsic to observational studies, it is possible that a gene near ALDH2 that has no effect on alcohol intake affects blood pressure, since genes are often inherited in blocks. Alternatively, ALDH2 could affect blood pressure independent of alcohol intake. The possibility that ALDH2 could effect blood pressure independently of alcohol is intake made unlikely by the fact that no effect of genotype on blood pressure is seen among women who drink very little. Additional large-scale studies are needed to address these possibilities, to confirm the current finding in more people, and to improve the estimates of the effect that alcohol intake has on blood pressure.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050052.
The MedlinePlus encyclopedia has a page on hypertension (in English and Spanish)
The American Heart Association provides information for patients and health professionals about hypertension
The UK Blood Pressure Association provides information for patients and health professionals on all aspects of hypertension, including information about alcohol affects blood pressure
The Explore@Bristol science center (a UK charity) provides an alcohol unit calculator and information on the effects of alcohol
The International Center for Alcohol Policies provides drinking guidelines for countries around the world
doi:10.1371/journal.pmed.0050052
PMCID: PMC2265305  PMID: 18318597
17.  Brain blood flow and cardiovascular responses to hot flashes in postmenopausal women 
Menopause (New York, N.Y.)  2013;20(3):10.1097/GME.0b013e31826e45f0.
Objective
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.
Methods
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.
Results
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).
Conclusion
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.
doi:10.1097/GME.0b013e31826e45f0
PMCID: PMC3566296  PMID: 23435027
Menopause; hot flash; brain blood flow
18.  Prospective Evaluation of Hot Flashes during Pregnancy and Postpartum 
Fertility and sterility  2013;100(6):1667-1672.
Objective
To determine the prevalence, course, and risk factors for hot flashes during pregnancy and postpartum.
Study Design
Women (N=429) were assessed prospectively during pregnancy (weeks 20, 30, 36) and up to a year after delivery (weeks 2, 12, 26, 52). A clinical interview, physical measurements, and questionnaires were administered at each visit.
Results
Thirty-five percent of women reported hot flashes during pregnancy and 29% reported hot flashes after delivery. In multivariable binomial mixed effects models, women who were younger (per year: OR(95%CI): 0.94(0.88–0.99)), had a higher pre-pregnancy body mass index (BMI; per unit increase: OR(95%CI): 1.05(1.01–1.10)), and had less than a college education (OR(95%CI): 2.58(1.19–5.60); vs. college) were more likely to report hot flashes during pregnancy. Higher depressive symptoms were associated with hot flashes during pregnancy (per unit increase: OR(95%CI): 1.08(1.04–1.13)) and after birth (OR(95%CI): 1.19(1.14–1.25), multivariable models).
Conclusion
Hot flashes, typically considered a menopausal symptom, were reported by over a third of women during pregnancy and/or postpartum. Predictors of hot flashes during this reproductive transition, including depressive symptoms, low education, and higher BMI are similar to those experienced during menopause. Future work should investigate the role of hormonal and affective factors in hot flashes during pregnancy and postpartum.
doi:10.1016/j.fertnstert.2013.08.020
PMCID: PMC4167790  PMID: 24035604
Hot flashes; pregnancy; postpartum; night sweats; vasomotor symptoms
19.  STUDIES ON EXPERIMENTAL HYPERTENSION  
Constriction of the aorta just above the origin of both main renal arteries invariably resulted in elevation of the carotid systolic and carotid mean pressure. The hypertension was not immediate, but developed in about the same time as after constriction of the main renal arteries (3). Constriction of the aorta just below the origin of both main renal arteries had no significant effect on the carotid systolic or carotid mean pressure. Since these results were first reported (1), Rytand (88, 89) has shown by an indirect method, namely, the demonstration of the development of cardiac hypertrophy, that hypertension in the upper part of the body can be produced in the rat by constriction of the aorta just above the origin of both main renal arteries. The immediate effect of constriction of the aorta either below or above the main renal arteries is a fall of blood pressure (femoral mean pressure) below the site of the clamp, the extent of the fall being directly dependent upon the degree of constriction of the aorta. Of particular interest is the eventual elevation of the femoral mean pressure above the normal in some animals with the aorta constricted or even occluded above the origin of the main renal arteries. This was most pronounced and persistent in those animals in which, in addition, the aorta below the origin of the renal arteries, and, in some animals, the main renal arteries, also were constricted. The most important factors which determined this elevation of blood pressure in the lower part of the body were probably increased flow of blood into the vascular bed below the clamp and peripheral vasoconstriction of renal and humoral origin, as in the case of the hypertension produced by constriction of the main renal arteries alone (2–86). Although elevation of the carotid systolic or carotid mean pressure occurred invariably within 24 to 48 hours after the constriction of the aorta above the site of origin of both main renal arteries, yet there was a tendency, after a variable period, for the elevated blood pressure to become lower or even to drop to the original level. Increased constriction, and finally occlusion of the aorta, above the origin of the main renal arteries, and even constriction or occlusion of the aorta below the renal arteries, in addition, failed to induce hypertension that persisted for a long time at a high level. In order to produce this effect, it was necessary to constrict the main renal arteries as well. The possible explanation of the failure of the hypertension to persist for a long time after constriction of the aorta alone, is that the initial ischemia of the kidneys disappeared due to the improvement of the blood flow through the kidneys as a result of (a) the increase of the natural accessory circulation to the kidneys; (b) the increased blood pressure above the site of the clamp and consequent increased flow of blood into the part of the aorta below the clamp; (c) increased pressure below the site of the clamp due, in great part, to peripheral vasoconstriction, and in part to the increased inflow of blood into the lower part of the body through the aorta and collateral channels. For the dog, this method is not necessary for the production of persistent hypertension. Constriction of the main renal arteries is easily performed and is effective for the production of generalized hypertension (2–11). However, constriction of the aorta in addition to constriction of the renal arteries results in greatly elevated persistent hypertension. Constriction of the aorta alone above the origin of the main renal arteries would be useful in the dog only for the production of relatively short periods of hypertension in the upper part of the body. For small animals it may be a more effective and useful method. In the dog, the only technical difficulty encountered was the erosion of the wall of the aorta by the clamp. This may not occur in small animals. In previous studies (2–11) that have dealt with the constriction of the main renal arteries, this accident rarely occurred. When the constriction of the aorta above the origin of the main renal arteries was of moderate degree, or was gradually made very great, the resultant hypertension was not accompanied by impairment of renal excretory function, as determined by urea clearance or by the quantity of urea, creatinine or non-protein nitrogen in the blood, the benign phase of hypertension (3). When the constriction of the aorta was suddenly made very great, impairment of the renal excretory function usually followed, and the animal developed fatal convulsive uremia and characteristic vascular lesions, the malignant phase of hypertension (9). These facts, are all indicative of the renal origin of the hypertension which results from the constriction of the aorta just above the origin of both main renal arteries. Hypertension did not persist for a sufficiently long time to permit any conclusive comparison between the effect of the high and low pressures on the structure of the vascular system, above and below the site of the clamp, respectively. During the period of survival of these animals, no significant differences were observed between the appearance of the vascular system of the upper part of the body and that of the lower part of the body, and significant cardiac hypertrophy did not develop. In the aorta and large arteries, intimal arteriosclerosis was not observed. In the aorta of one old animal several small plaques of calcification were found in the media, but these were present in the portion of the aorta below, as well as above the clamp, and they were no larger or more abundant than were observed in some old dogs with normal blood pressure. Dogs 3–50 and 3–83, that are still alive, with very high blood pressure above the site of the aortic clamps, and relatively low pressure (though greater than normal) below the site of the aortic clamps, will be valuable for the determination of possible differences between the effects of the two levels of blood pressure in the large and small blood vessels. In these dogs also, it will be possible to determine the effect of the persistently high blood pressure on the myocardium. The possible application of the results of this study to the problem of the pathogenesis of human eclampsia is mentioned here for consideration. Since this condition occurs in pregnancy only at a time when the uterus is greatly enlarged, it is at least possible that the mass may press on the aorta or both main renal arteries sufficiently to produce renal ischemia. The suddenness with which the uremic convulsive phase of eclampsia develops is in keeping with this idea. In the dog, an aggravating effect of pregnancy on an already established hypertension has not been noted. As a matter of fact, most of the hypertensive dogs that have become pregnant, have shown a slight or moderate fall, rather than an increased rise of pressure. Since the dog stands with the body in a horizontal position, and does not lie on its back, pressure of the pregnant uterus on the aorta and blood vessels is less than in human beings who stand erect and frequently lie on their backs. The soundness of this suggestion could be tested by placing pregnant women, in the early stage of eclampsia, in a position which could relieve possible pressure on the aorta and main renal arteries. A possible explanation of the fall of pressure in the pregnant hypertensive dogs is the compensatory effect of the normal kidneys of the pups, as in the case of an animal with one main renal artery constricted and the other kidney normal. As has been shown (3, 31, 72), the presence of one normal kidney in an animal hypertensive due to constriction of the other main renal artery, results, after a variable period, in a return of the blood pressure to normal. How the normal kidney acts to produce this effect is not known.
PMCID: PMC2133753  PMID: 19870869
20.  TEMPORAL ASSOCIATIONS OF HOT FLASHES AND DEPRESSION IN THE TRANSITION TO MENOPAUSE 
Menopause (New York, N.Y.)  2009;16(4):728-734.
Objective
Evaluate associations between hot flashes and depressed mood in the menopausal transition and associations of these symptoms with reproductive hormone changes.
Design
10-year follow-up in a population-based cohort of the women who had no experience of hot flashes or depressed mood at baseline.
Results
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).
Conclusions
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.
doi:10.1097/gme.0b013e3181967e16
PMCID: PMC2860597  PMID: 19188849
21.  Objective hot flashes are negatively related to verbal memory performance in midlife women 
Menopause (New York, N.Y.)  2008;15(5):848-856.
Objective
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.
Design
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.
Results
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.
Conclusions
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.
doi:10.1097/gme.0b013e31816d815e
PMCID: PMC2756983  PMID: 18562950
Cognition; Memory; Menopause; Hot flashes; Hormones; Vasomotor; Monitoring; Ambulatory
22.  Metabolic syndrome in premenopausal and postmenopausal women with type 2 diabetes: loss of protective effects of premenopausal status 
Background
Diabetes is probably responsible for worsening of metabolic syndrome (MetS)components. The aim of the present study was to compare the components of MetS between premenopausal and postmenopausal women with type 2 diabetes (T2DM).
Method
In this cross sectional study, we studied 639 women with T2DM that were divided in pre-menopausal (n = 221) and post-menopausal (n = 418) group. They were selected from participants of a diabetes clinic and assessed for MetS and its components. All MetS components were evaluated to follow age and duration of diabetes adjusted according to the ATP III criteria.
Results
The mean ages of pre-menopausal and post-menopausal were 43.33 ± 0.47 and 60.35 ± 0.38 years, respectively. MetS was defined for 88.3% of total subjects (87.5% and 87.7% in pre-menopausal and post-menopausal women with T2DM respectively). Systolic blood pressure (SBP) and waist circumference (WC) were significantly higher in post-menopausal women with T2DM in comparison with pre-menopausal ones. There were no significant differences in triglyceride (T.G) level, diastolic blood pressure (DBP) and high density lipoprotein cholesterol (HDL-C) between the two groups. Myocardial infarction (MI) occurred in 1% total subjects (1.3% and 1.8%) in pre-menopausal and post-menopausal women with T2DM, respectively (p = 0.21).
Conclusion
Worsening of MetS and its components except for SBP and waist circumference has been shown in pre-menopausal women with T2DM similar to post-menopausal ones. The observed differences may be explained by increasing age. With respect to increasing of myocardial infarction in premenopausal subjects, we suggest that diabetes can abolish the protective effects of premenopausal status for MetS and MI.
doi:10.1186/s40200-014-0102-5
PMCID: PMC4264312  PMID: 25506584
Metabolic syndrome; Menopause; Women; Cardiovascular disease
23.  Hypnosis for hot flashes among postmenopausal women study: A study protocol of an ongoing randomized clinical trial 
Background
Hot flashes are a highly prevalent problem associated with menopause and breast cancer treatments. The recent findings from the Women's Health Initiative have important implications for the significance of a non-hormonal, mind-body intervention for hot flashes in breast cancer survivors. Women who take hormone therapy long-term may have a 1.2 to 2.0 fold increased risk of developing breast cancer. In addition, it is now known that hormone therapy with estrogen and progestin is associated with increased risk of cardiovascular disease and stroke. Currently there are limited options to hormone replacement therapy as non-hormonal pharmacological agents are associated with only modest activity and many adverse side effects. Because of this there is a need for more alternative, non-hormonal therapies. Hypnosis is a mind-body intervention that has been shown to reduce self-reported hot flashes by up to 68% among breast cancer survivors, however, the use of hypnosis for hot flashes among post-menopausal women has not been adequately explored and the efficacy of hypnosis in reducing physiologically measured hot flashes has not yet been determined.
Methods/design
A sample of 180 post-menopausal women will be randomly assigned to either a 5-session Hypnosis Intervention or 5-session structured-attention control with 12 week follow-up. The present study will compare hypnosis to a structured-attention control in reducing hot flashes (perceived and physiologically monitored) in post-menopausal women in a randomized clinical trial. Outcomes will be hot flashes (self-report daily diaries; physiological monitoring; Hot Flash Related Daily Interference Scale), anxiety (State-Trait Anxiety Inventory; Hospital Anxiety and Depression Scale (HADS); anxiety visual analog scale (VAS rating); depression (Center for Epidemiologic Studies Depression Scale), sexual functioning (Sexual Activity Questionnaire), sleep quality (Pittsburgh Sleep Quality Index) and cortisol.
Discussion
This study will be the first full scale test of hypnosis for hot flashes; one of the first studies to examine both perceived impact and physiologically measured impact of a mind-body intervention for hot flashes using state-of-the-art 24 hour ambulatory physiological monitoring; the first study to examine the effect of hypnosis for hot flashes on cortisol; and the first investigation of the role of cognitive expectancies in treatment of hot flashes in comparison to a Structured-Attention Control.
Trial Registration
This clinical trial has been registered with ClinicalTrials.gov, a service of the U.S. National Institutes of Health, ClinicalTrials.gov Identifier: NCT01293695.
doi:10.1186/1472-6882-11-92
PMCID: PMC3200173  PMID: 21989181
24.  Efficacy of a Non-Hormonal Treatment, BRN-01, on Menopausal Hot Flashes 
Drugs in R&d  2012;12(3):107-119.
Background
Homeopathic medicines have a place among the non-hormonal therapies for the treatment of hot flashes during the menopause.
Objective
The objective of this study was to evaluate the efficacy of the non-hormonal treatment BRN-01 in reducing hot flashes in menopausal women.
Study Design
This was a multicenter, randomized, double-blind, placebo-controlled study carried out between June 2010 and July 2011.
Setting
The study was conducted in 35 active centers in France (gynecologists in private practice).
Patients
One hundred and eight menopausal women, ≥50 years of age, were enrolled in the study. The eligibility criteria included menopause for <24 months and ≥5 hot flashes per day with a significant negative effect on the women’s professional and/or personal life.
Intervention
Treatment was either BRN-01 tablets, a registered homeopathic medicine containing Actaea racemosa (4 centesimal dilutions [4CH]), Arnica montana (4CH), Glonoinum (4CH), Lachesis mutus (5CH), and Sanguinaria canadensis (4CH), or identical placebo tablets, prepared by Laboratoires Boiron according to European Pharmacopoeia standards. Oral treatment (2 to 4 tablets per day) was started on day 3 after study enrollment and was continued for 12 weeks.
Main Outcome Measure
The main outcome measure was the hot flash score (HFS) compared before, during, and after treatment. Secondary outcome criteria were the quality of life (QoL) [measured using the Hot Flash Related Daily Interference Scale (HFRDIS)], severity of symptoms (measured using the Menopause Rating Scale), evolution of the mean dosage, and compliance. All adverse events (AEs) were recorded.
Results
One hundred and one women were included in the final analysis (intent-to-treat population: BRN-01, n = 50; placebo, n = 51). The global HFS over the 12 weeks, assessed as the area under the curve (AUC) adjusted for baseline values, was significantly lower in the BRN-01 group than in the placebo group (mean ± SD 88.2 ± 6.5 versus 107.2 ± 6.4; p = 0.0411). BRN-01 was well tolerated; the frequency of AEs was similar in the two treatment groups, and no serious AEs were attributable to BRN-01.
Conclusion
BRN-01 seemed to have a significant effect on the HFS, compared with placebo. According to the results of this clinical trial, BRN-01 may be considered a new therapeutic option with a safe profile for hot flashes in menopausal women who do not want or are not able to take hormone replacement therapy or other recognized treatments for this indication.
Trial registration number (EudraCT): 2009-016959–21.
doi:10.2165/11640240-000000000-00000
PMCID: PMC3585763  PMID: 22852580
25.  Efficacy of a Non-Hormonal Treatment, BRN-01, on Menopausal Hot Flashes 
Drugs in R&D  2012;12(3):107-119.
Background
Homeopathic medicines have a place among the non-hormonal therapies for the treatment of hot flashes during the menopause.
Objective
The objective of this study was to evaluate the efficacy of the non-hormonal treatment BRN-01 in reducing hot flashes in menopausal women.
Study Design
This was a multicenter, randomized, double-blind, placebo-controlled study carried out between June 2010 and July 2011.
Setting
The study was conducted in 35 active centers in France (gynecologists in private practice).
Patients
One hundred and eight menopausal women, ≥50 years of age, were enrolled in the study. The eligibility criteria included menopause for <24 months and ≥5 hot flashes per day with a significant negative effect on the women’s professional and/or personal life.
Intervention
Treatment was either BRN-01 tablets, a registered homeopathic medicine containing Actaea racemosa (4 centesimal dilutions [4CH]), Arnica montana (4CH), Glonoinum (4CH), Lachesis mutus (5CH), and Sanguinaria canadensis (4CH), or identical placebo tablets, prepared by Laboratoires Boiron according to European Pharmacopoeia standards. Oral treatment (2 to 4 tablets per day) was started on day 3 after study enrollment and was continued for 12 weeks.
Main Outcome Measure
The main outcome measure was the hot flash score (HFS) compared before, during, and after treatment. Secondary outcome criteria were the quality of life (QoL) [measured using the Hot Flash Related Daily Interference Scale (HFRDIS)], severity of symptoms (measured using the Menopause Rating Scale), evolution of the mean dosage, and compliance. All adverse events (AEs) were recorded.
Results
One hundred and one women were included in the final analysis (intent-to-treat population: BRN-01, n = 50; placebo, n = 51). The global HFS over the 12 weeks, assessed as the area under the curve (AUC) adjusted for baseline values, was significantly lower in the BRN-01 group than in the placebo group (mean ± SD 88.2 ± 6.5 versus 107.2 ± 6.4; p = 0.0411). BRN-01 was well tolerated; the frequency of AEs was similar in the two treatment groups, and no serious AEs were attributable to BRN-01.
Conclusion
BRN-01 seemed to have a significant effect on the HFS, compared with placebo. According to the results of this clinical trial, BRN-01 may be considered a new therapeutic option with a safe profile for hot flashes in menopausal women who do not want or are not able to take hormone replacement therapy or other recognized treatments for this indication.
Trial registration number (EudraCT): 2009-016959–21.
doi:10.2165/11640240-000000000-00000
PMCID: PMC3585763  PMID: 22852580

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