Climacteric

ISSN: 1369-7137 (Print) 1473-0804 (Online) Journal homepage: http://www.tandfonline.com/loi/icmt20

Randomized clinical trial of a handheld cooling ® device (Menopod ) for relief of menopausal vasomotor symptoms R. L. Reid, B. Magee, J. Trueman, P. M. Hahn & J. Pudwell To cite this article: R. L. Reid, B. Magee, J. Trueman, P. M. Hahn & J. Pudwell (2015) Randomized ®

clinical trial of a handheld cooling device (Menopod ) for relief of menopausal vasomotor symptoms, Climacteric, 18:5, 743-749, DOI: 10.3109/13697137.2015.1042856 To link to this article: http://dx.doi.org/10.3109/13697137.2015.1042856

Published online: 15 Sep 2015.

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Date: 06 November 2015, At: 11:59

CLIMACTERIC 2015;18:743–749

Randomized clinical trial of a handheld cooling device (Menopod®) for relief of menopausal vasomotor symptoms R. L. Reid*,†, B. Magee†, J. Trueman*,†, P. M. Hahn*,† and J. Pudwell† *Division of Reproductive Endocrinology and Infertility, and †Department of Obstetrics and Gynaecology, Queen’s University, Kingston, Ontario, Canada Key words: COOLING DEVICE, MENOPAUSE, HOT FLUSHES

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ABSTRACT Objective Anecdotal reports suggest that application of a cool device to the back of the neck at the onset of a hot flush can afford symptomatic relief. The effects of a novel handheld mechanical cooling device in a population of perimenopausal women with moderate-to-severe vasomotor symptoms were evaluated. Methods In this randomized, double-blind, sham-controlled pilot study, 40 perimenopausal women experiencing   7 moderate-to-severe hot flushes per day were recruited at a single university site. Women were randomized to the active (n  20) or sham (n  20) device, which was applied to the back of the neck with each hot flush over the 4-week treatment period. Hot flush scores were calculated based on frequency and severity of symptoms. The Carpenter Hot Flash Related Daily Interference Scale and Zung Anxiety Scale were used to evaluate impact on quality of life. At study end, participants completed an open-ended questionnaire to assess the degree of unblinding and overall subjective improvement in symptoms with use of the device. Results No statistically significant differences were observed between the effects of the active and sham device. However, thematic analysis of the open-ended questionnaire revealed that 12/17 women (70.6%) in the active group, compared to 4/18 (22.2%) women in the sham group felt the device provided some symptomatic relief. Conclusions Although the majority of women using the active device acknowledged that its cooling effect afforded a degree of symptomatic relief, the symptom scores chosen for this pilot study did not reflect a beneficial effect.

BACKGROUND Menopausal women now make up one of the largest demographics in developed countries. As the ‘baby boomers’ transition into menopause over the next decade, there will be unprecedented demand for effective therapies for menopausal vasomotor symptoms. Daytime hot flushes and night sweats with sleep disturbance affect 60–80% of women as they enter menopause1. Symptoms are often self-limited, lasting 3–7 years; however, for some, the symptoms persist for decades2. The hot flush is a physiological mechanism that rapidly dissipates heat in order to reduce the body’s core temperature to within the so-called thermoneutral zone. Research suggests

that, in menopause, the thermoneutral zone narrows, making perimenopausal women more prone to sudden diffuse vasodilation and perspiration when their core temperature rises even slightly3. The unpredictability of hot flushes, often associated with an abrupt red flush across the face and neck and profuse sweating, can make many women anxious. They may fear disruption at work or lack of control of these embarrassing and often disabling symptoms. Non-pharmacologic treatments for menopausal hot flushes include lifestyle and behavior modification, such as the use of fans, layered clothing, avoidance of known triggers like hot drinks and alcohol or a cool shower before bed. The

Correspondence: Professor R. L. Reid, Department of Obstetrics and Gynaecology, Victory 4, Kingston General Hospital, Kingston, Ontario, Canada, K7L2V7; E-mail: [email protected] ORIGINAL ARTICLE © 2015 International Menopause Society DOI: 10.3109/13697137.2015.1042856

Received 09-03-2015 Revised 15-04-2015 Accepted 15-04-2015

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Menopod® for hot flushes cornerstone of pharmacologic therapy is estrogen replacement. However, entrenched beliefs about the possible adverse consequences of hormone replacement therapy have made many women fearful of this approach4. Cooling devices have been used with great success in other genres. Workers exposed to high temperatures (e.g. firefighters, hazardous material responders) rely on active body cooling devices, but generally these involve large over-clothing apparel5. A cooling neck collar has been shown to increase the time to volitional exhaustion on a treadmill by dampening the perceived level of thermal strain6. Similarly, periodic extraction of heat from glabrous skin of the palms can enhance resistive exercise training7. Anecdotes suggest that application of any cold object, even a canned drink from the refrigerator, to the back of the neck at the onset of a hot flush may afford symptomatic relief as needed. The impracticality of constantly running to the fridge led to the development of a portable and discrete cooling device (Menopod®, from Alexander Medical) that, with the click of a button, can rapidly and repeatedly lower the temperature of the wide metal plates on its surface to 5°C. This pilot study is the first to report on the effectiveness of a compact cooling device for relief of menopausal vasomotor symptoms.

METHODS Design This was a double-blind, randomized pilot study to compare the effects of an active and a sham portable handheld cooling device (Menopod®) for relief from menopausal vasomotor symptoms (Figure 1). This Queen’s University Research Ethics Board (REB)approved clinical trial was conducted through the Clinical Investigation Unit at Kingston General Hospital between October 2013 and June 2014 (ClinicalTrials.gov Identifier: NCT01281332). Advertisements in a local newspaper were used to identify potential candidates. Candidates were screened

Figure 1

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The Menopod® handheld cooling device

Reid et al. by telephone interview and then interviewed in person to assess physical health and suitability for enrolment. Eligible women were between 40 and 65 years of age, in good health, and peri- or postmenopausal as defined by a follicle stimulating hormone (FSH) level of  30 IU/l and amenorrhea for a minimum of 6 consecutive months. Eligible women reported a minimum of seven moderate-to-severe hot flushes per day without the use of any concomitant therapies in the 8 weeks prior to or during the study period. These therapies included estrogens, progestins, selective serotonin reuptake inhibitors or serotonin and norepinephrine reuptake inhibitors, gabapentin, clonidine, belladonna-ergotamine-phenobarbital, and any complementary/alternative medicines such as Dong Quai, black cohosh, evening primrose oil, soy protein diets and multibotanicals. Exclusion criteria included Class II obesity (body mass index  35 kg/m2), alcohol or drug abuse, serious medical conditions (coronary artery disease, stroke, cancer, chronic renal or hepatic disease, depression and other psychiatric disease, diabetes), or the perception that their lifestyle or job would preclude them from using the mechanical device during hot flushes as required. A computer-generated randomization sequence was used to assign 40 women to receive either an active (n  20) device (vibration followed by rapid cooling of copper plates for 1 min, followed by a second vibration) or a sham (n  20) device (vibrations 1 minute apart but no cooling effect). The randomization sequence was concealed from all participants except the study nurse who dispensed the randomly assigned device and demonstrated its use. We used authorized deception to minimize the possibility of unblinding8. Study participants were advised that deception was being used in this research to maximize the possibility of attaining valid results. They were told that the REB approved the use of deception after considering all potential benefits and risks. The consent form listed a number of possible mechanisms of action that the device may employ, including radiofrequency, magnetic field, vibration and cooling effect. They were told that they would be informed about the true mechanism of action at the study conclusion and that any woman assigned a sham device would be given an active device in exchange. Sloan and colleagues previously demonstrated that a sample size of ‘25–30 patients will provide a reasonably close estimate to final results for pilot studies’ evaluating new treatments for vasomotor symptoms9. A sample size of 40 women for this pilot study was selected based on funding limitations, recognizing that there is a paucity of prior studies on vasomotor symptoms while using the cooling device to provide insight into the anticipated magnitude of change and variability in measurements. After providing informed consent, participants completed baseline surveys (the Hot Flash Related Daily Interference Scale (HFRDIS)10 and the Zung Self-Rating Anxiety Scale11) and had a single serum FSH determination to confirm menopausal status. To evaluate frequency and severity of vasomotor symptoms, and to confirm inclusion criteria, women were provided a structured diary in which to record number, severity and duration of hot flushes over a 24-h period.

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Menopod® for hot flushes Participants were instructed to activate and apply the Menopod® to the back of their neck at the onset of every hot flush or night sweat throughout the 4-week study. All vasomotor events were treated the same in the analysis regardless of whether they occurred during the day or overnight. A 4-week study period was selected because, unlike hormonal interventions that may take time to reach a steady state, we anticipated that any benefit of the cooling device would be readily apparent within 4 weeks of use. The Menopod® is 12  7 cm (weight 380 g) handheld miniature refrigeration unit operating on the principle of the Peltier Thermoelectric Cooler. When activated, it effectively lowers skin temperature to 5°C in 15 s. The 1-min cooling effect is preceded and followed by a brief vibration to alert the wearer to the onset and cessation of action. The device can be reactivated eight to ten times before the 3.7-volt battery must be recharged. The unit is fluid-resistant to prevent fluid ingress and the low voltage prevents any risk of electric shock. The sham device was identical in size, weight, and appearance to the Menopod®. The sham device also alerted the wearer to the onset and cessation of action through vibration; however, no cooling effect was delivered.

Rating scales Hot flush diary A daily hot flush diary was used to record the time of onset, the duration in minutes, and the severity of symptoms for all hot flushes and night sweats on the last day of each treatment week (24 h). Severity was rated from 1 to 4 correlating with mild, moderate, severe or very severe symptoms. Written descriptions of each level of severity were provided in order to standardize scores. Women used their wrist watch to time the onset and resolution of each hot flush in minutes over this 24-h period.

Reid et al. In addition, the Zung Self-Rating Anxiety Scale was completed at baseline and at the end of each treatment week to determine whether women perceived less stress (were more ‘in control’) when in possession of the device. Each question on this validated 20-item questionnaire is scored on a Likert-type scale of 1 to 4. One reflects a response of ‘none or a little of the time’ and 4 reflects a response of ‘most or all of the time’. The raw total score was converted to an Anxiety Index score, which is used to clinically interpret a person’s level of anxiety, ranging from normal to extreme11. In a final questionnaire at the end of the study, all participants were asked whether they thought they had received an active or sham device to determine the rate of unblinding. In this questionnaire, open-ended questions were used to assess reasons why they believed they had received the active or sham device, reasons why they felt the device was or was not helpful, and ways in which the device may be improved. A thematic analysis of these responses was conducted.

Data analysis The two primary outcome parameters were the average hot flush score, and the average duration (min) of hot flush episodes over the course of one 24-h day9. These outcomes were recorded by participants in a diary, designed by our research team, on five separate days throughout the course of the study, once during the evaluation phase and once per week at the end of each 1-week treatment period. The two primary summary measures were the change from baseline to week 4 for the average hot flush score and for the average hot flush duration (min). The delta (Δ) value, average change for active device minus the average change for sham device, was calculated. The summary measures were compared using the Mann–Whitney test (GraphPad InStat version 3.06). A significance level of 0.05 was used for all tests. The same analysis was performed for the secondary outcomes of quality of life and anxiety.

Hot flush score The hot flush score was calculated as the product of the number and severity (rated 1–4) of each vasomotor symptom over a 24-h period9.

Quality of life and Anxiety scales At baseline and once-weekly thereafter, participants completed the HFRDIS10. This validated, 10-item scale assesses the impact of hot flushes on nine daily activities that are known to be specifically influenced by hot flushes (e.g. work, leisure, sleep, sexuality, etc.). The tenth item addressed overall quality of life in the preceding week. Participants are asked to what degree hot flushes interfere with each daily activity, with 0 reflecting no interference and 10 reflecting complete interference. Higher total scores indicate greater interference and diminished quality of life.

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RESULTS Forty women were randomized to receive either an active (n  20) or sham (n  20) device (Figure 2). Complete records for primary outcomes were available for 19 women in each group (one woman on review did not meet inclusion criteria and one had missing data). Demographic variables showed that the groups were well matched through randomization (Table 1). The mean age was 54 years and the mean body mass index was comparable at 25 kg/m2 for the two groups. Information regarding menopausal status and symptoms is outlined in Table 2. Most women had recently experienced natural menopause with the mean FSH level around 90 IU/l. The majority of the women reported a constellation of hot flushes, night sweats, and sleep disturbance.

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Menopod® for hot flushes

Figure 2

Reid et al.

Flow chart for Menopod® study

Results for the primary outcome measures are shown in Table 3. The hot flush score decreased by 9.0 points (standard deviation, SD  12.8) for women with the active device between the pre-treatment assessment and week 4, while women using the sham device showed a decrease of 3.8 points (SD  10.9). There was wide variability in individual hot flush scores and the difference was not statistically significant (Δ 5.2; p  0.191). The duration of hot flushes comparing pre-treatment to week 4 increased by 0.2 min (SD  2.4 min) in the active group and decreased by 0.8 min (SD  1.5 min) in the sham group (Δ 1; not significant, p  0.523). Results for the secondary outcomes are shown in Table 4. The overall quality of life score decreased by 0.5 points (SD  2.7) in the active device group and by 0.9 points (SD  1.8) in the sham device group. This comparison showed no significant difference (Δ 0.4; p  0.838). The HFRDIS showed a reduction of 5.9 points (SD  15.6) in women using

the active device and 9.0 points (SD  11.9) in those assigned to sham devices (Δ 3.1; p  0.804). One woman failed to provide evaluable data for the Zung Anxiety scale so calculations are based on 19 participants using the active device and 18 participants using the sham device. It is important to note, however, that the majority of women, 12 (63.2%) in the active group and 15 (83.3%) in the sham group, had baseline anxiety scores in the normal range (p  0.313). Of those with scores outside of the normal range, only one woman in the active device group had marked-to-severe anxiety, while all others had minimal-to-moderate anxiety. With this caveat, the Anxiety Index score increased by 0.4 points (SD  7.0) in the active device group and decreased by 1.5 points (SD  8.1) in the sham device group. This comparison showed no significant difference (Δ 1.9; p  0.395). While significant differences were not observed for the primary or secondary outcomes, themes found in the open-

Table 1 Demographic comparison of active and sham device groups. Data are given as mean   standard deviation (range) or n (%) Demographic Age (years) Body mass index (kg/m2) Current smokers Current alcohol consumers

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Active device group (n  19) 53.8   4.3 25.0   2.2 2 12

(47–63) (21.6–29.6) (10.5%) (63.2%)

Sham device group (n  19) 54.9   3.2 25.5   2.3 2 15

(50–61) (20.5–29.0) (10.5%) (78.9%)

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Menopod® for hot flushes

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Table 2 Menopausal status and symptom comparison of active and sham device groups. Data are given as mean   standard deviation (range) or n (%) Demographic

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FSH (IU/l) Menopause status Natural Surgical: TAHBSO Current menopausal symptoms Hot flushes Night sweats Sleep disturbance Vaginal dryness Mood disturbance Anxiety Headaches FSH, follicle stimulating salpingoophorectomy

hormone;

Active device group (n  19)

Sham device group (n  19)

84.3   38.5 (44.0–185.5)

95.4   26.2 (61.0–144.0)

18 (94.7%) 1 (5.3%)

18 (94.7%) 1 (5.3%)

19 18 17 8 3 6 12

19 19 18 6 8 4 15

TAHSBO,

ended questions from the end-of-study questionnaire provided valuable information about the device (n  17 for the active device group and n  18 for the sham device group). Overall, 12 women (70.6%) in the active group, compared to four women (22.2%) in the sham group, felt the device provided some symptomatic relief. Many women using the active device commented that it had a salutary effect, nine women (52.9%) commented that they liked the cold sensation and that it afforded a sense of relief from the hot flush, and five women (29.4%) said it diminished the severity of their symptoms. With regards to the device itself, ten women (58.8%) felt it was too large, seven women (41.2%) felt it could be more discrete and four women (23.5%) felt that the battery life was too short. Of the participants, 12 of 17 (70.6%) with an active device and 13 of 18 (72.2%) with a sham device correctly identified which device they had received, indicating a high rate of unblinding.

(100.0%) (94.7%) (89.5%) (42.1%) (15.8%) (31.6%) (63.2%) total

abdominal

hysterectomy

(100.0%) (100.0%) (94.7%) (31.6%) (42.1%) (21.1%) (78.9%)

and

bilateral

alleviate their hot flushes, such as running outdoors into the cold, lying on a cold tile floor, or even removing clothing. Reports also suggest that cold items, like a canned drink from the refrigerator, placed on the skin at the nape of the neck can reduce the intense sensation of heat that characterizes the typical hot flush. Though the internet offers for sale a range of cooling devices said to relieve hot flushes (e.g. cold packs that can be inserted into a brazier or a pillow case), we found no scientific reports evaluating such a method as a treatment for hot flushes. The Menopod®, a small portable handheld cooling unit has recently been developed as a cooling aid. This pilot study examined the effects of the Menopod® on hot flush severity and duration in a group of peri- and postmenopausal women with moderate-to-severe hot flushes. We reasoned that, if the device afforded immediate relief and restored a sense of confidence and control over the hot flushes, we might also observe reduced anxiety and improved quality of life. To optimize the quality of our data, we used a blinding technique called authorized or informed deception so that women would not immediately know if they were randomized to an active or sham device. Despite this, there was a high level of unblinding, as evidenced by the fact that, at

DISCUSSION Anecdotally, menopausal women plagued by severe vasomotor symptoms have been known to go to great lengths to

Table 3 Primary outcomes: hot flush score and duration compared between the active device group and the sham device group. Data are given as mean  standard deviation  Group Active device (n  19) Outcome for hot flush Score Duration (min)

Sham device (n  19)

Comparison

Base

Week 4

Change*

Base

Week 4

Change*

Delta†

p Value‡

28.6   10.2 4.3   2.0

19.6   15.3 4.5   4.0

9.0   12.8 0.2   2.4

25.7   8.5 5.1   2.7

21.9   14.7 4.3   2.4

3.8   10.9 0.8   1.5

5.2 1.0

0.191 0.523

*, Change  individual score at week 4 – individual score at base; †, Delta  mean change for active device – mean change for sham device; ‡, for Mann–Whitney test

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Menopod® for hot flushes

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Table 4 Secondary outcomes: comparison of active and sham device groups for quality of life (QOL) measured using the Hot Flash Related Daily Interference Scale (HFRDIS) (higher scores reflect lower quality of life) and anxiety scores using the Zung Self-Rating Anxiety Scale. Data are given as mean  standard deviation



Group Active device (n  19) Outcome Overall QOL score Total HFRDIS score Anxiety Index score

Base

Week 4

Sham device (n  19) Change*

4.9  4.5  0.5   3.2  3.3  2.7 46.2  24.8 40.3  25.1  5.9     15.6 Active device (n  19) 40.5  40.9  0.4   11.8  11.8  7.0

Base 3.4   2.7 39.9   15.8

Week 4

Comparison Change*

2.5  0.9   2.1  1.8 30.9  19.3  9.0    11.9 Sham device (n  18) 37.7  36.2  1.5   7.8  6.3  8.1

Delta†

p Value‡

0.4 3.1

0.838 0.804

1.9

0.395

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*, Change  individual score at week 4 – individual score at base; †, Delta  mean change for active device – mean change for sham device; ‡, for Mann–Whitney test

the end of the study, approximately 70% of the women in each arm correctly identified whether they had an active or sham device. No significant differences were observed between the active and sham devices in either the primary (hot flush score and duration) or secondary (anxiety and quality of life) outcome variables. While initially surprising, we believe the apparent lack of effect can be explained by several factors. First, intermittent application of a cooling device to attenuate the hot flush was never intended to alter the frequency of hot flushes. We had anticipated that it would only modify the duration and possibly the perception of intensity (but not the frequency component) of the hot flush score. Upon review of the end-of-study questionnaire, it became apparent that some women expected that the use of the device would completely prevent hot flushes and were understandably disappointed when symptoms continued. Second, the capacity to tolerate a hot flush can vary dramatically from one woman to another12. Some have speculated that women who are more fearful of hormone therapy may ‘tolerate’ even rather severe symptoms13. Not only does the severity of hot flushes show marked day-to-day and even hourto-hour variations but also their reliable assessment is prone to large inter- and intra-individual fluctuations13. ‘A reliable assessment of hot flush severity score requires a great deal of discipline to avoid underreporting during daytime when focused attention is required for the work at hand. Accurate recording of hot flushes at night is even more challenging. Both over- reporting and underreporting of symptoms occur frequently’14,15. As a result, self-reporting of hot flushes, as performed in this study, led to wide individual variations in the HFRDIS and quality of life. To accurately parse out precise details about hot flush severity for individual women, some authors have suggested that hot flushes should be assessed prospectively with interview tools to maximize objectivity9. The scales employed in this trial may not have been sensitive enough to detect small but potentially clinically significant benefits of the cooling device. For

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example, changes in duration may have been better assessed in the magnitude of seconds, rather than minutes. A post-hoc sample size determination based on the observed variation in the hot flush score (SD  12.7) suggests that a much larger study would be required to detect a 5-point difference in mean change in score between the active and sham devices. We calculate, based on an α value of 0.05 and power of 80%, that we would need 102 participants per group. The numbers in this small pilot study were clearly insufficient to address this issue. Higher levels of anxiety have been found in women with more severe hot flushes12. In this study, all but one woman reported anxiety levels in the minimal-to-moderate or normal range as per the Zung Anxiety Scale at baseline. Therefore, any improvements would be small, difficult to measure even if the device allowed women to feel ‘more in control’, and, arguably, not clinically relevant. The small number of women in this pilot study and the wide variation in hot flush severity coupled with self-report scales that may have lacked the ability to standardize symptom reporting among participants could explain the lack of statistical difference between the active and sham devices. Numerous participants reported that the Menopod® cooling device afforded a welcome reduction in the immediate severity of their hot flushes. For women who choose not to use pharmacological therapies approved for relief from menopausal vasomotor symptoms, such a device may afford a practical alternative. The benefits are more likely to be appreciated when counselling emphasizes that such a device is meant to attenuate, but not eliminate hot flushes, thus establishing realistic therapeutic expectations. Conflict of interest The authors report no confl ict of interest. The authors alone are responsible for the content and writing of this paper. Source of funding Supported by a research grant from Alexander Medical Inc.

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9. Sloan J, Loprinzini C, Novotny P, Barton D, Lavasseur B, Windschitl H. Methodological lessons learned from hot flash studies. J Clin Oncol 2001;19:4280–90 10. Carpenter JS. The Hot Flash Related Daily Interference Scale: A tool for assessing the impact of hot flashes on quality of life following breast cancer. J Pain Symptom Manage 2001;22:979–89 11. Zung WWK. A rating instrument for anxiety disorders. Psychosomatics 1971;12:371–9 12. Freeman EW, Sammel MD, Lin H, Gracia CR, Kapoor S, Ferdousi T. The role of anxiety and hormonal changes in menopausal hot flashes. Menopause 2005;12:258–66 13. Savolainen-Peltonen H, Hautamaki H, Tuomikoski P, Ylikorkala O, Mikkola TS. Health related quality of life in women with or without hot flashes: a randomized placebo-controlled trial with hormone therapy. Menopause 2013;21:732–9 14. Van der Zanden M, Van Gastel P, Bancsi L, de Boer H. Miniature hygrometric hot flush recorder as an objective indicator of hot flashes: a validation study. Menopause 2014; 22:207–11 15. Mann E, Hunter MS. Concordance between self reported and sternal skin conductance measures of hot flushes in symptomatic perimenopausal and postmenopausal women: a systematic review. Menopause 2011;18:709–22

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Randomized clinical trial of a handheld cooling device (Menopod®) for relief of menopausal vasomotor symptoms.

Anecdotal reports suggest that application of a cool device to the back of the neck at the onset of a hot flush can afford symptomatic relief. The eff...
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