Randomized Controlled Cross-over Study for Hot Flash Management: Efficacy Novel Wrist Cooling Device in Cancer Treatment-Induced and Menopausal Vasomotor Symptoms

Randomized Controlled Cross-over Study for Hot Flash Management: Efficacy Novel Wrist Cooling Device in Cancer Treatment-Induced and Menopausal Vasomotor Symptoms | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Randomized Controlled Cross-over Study for Hot Flash Management: Efficacy Novel Wrist Cooling Device in Cancer Treatment-Induced and Menopausal Vasomotor Symptoms Nazlı Uçar, Arash Shirvani, Michael F. Holick This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6173150/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Hot flashes significantly impact quality of life in cancer patients undergoing hormone deprivation therapy and postmenopausal women. Pharmaceutical interventions often carry substantial risks. This double-blind randomized crossover trial evaluated the efficacy of KÜLKUF, a wrist-mounted cooling device that rapidly delivers a 47°F cooling stimulus upon activation, in 27 participants (n = 10 breast cancer, n = 12 prostate cancer, n = 5 postmenopausal women) experiencing at least two moderate-to-severe hot flashes daily. Compared to baseline measurements, the active cooling intervention reduced severe hot flash episodes by 46% (p < 0.02) and total daily hot flashes by 18%. Subgroup analysis revealed consistent therapeutic effects across all participant categories, with severe hot flash reductions of 41% in breast cancer patients and 50% in both postmenopausal women and prostate cancer patients. Univariate analysis adjusted for age and underlying condition confirmed a significant reduction in hot flash severity (p < 0.01). The crossover design, which achieved perfect retention with no dropouts, allowed participants to serve as their own controls, enhancing statistical power despite the modest sample size. No adverse events or tolerability issues were reported throughout the study period. These findings suggest that targeted peripheral thermosensory input via wrist cooling represents a promising non-pharmaceutical approach for managing vasomotor symptoms across diverse patient populations. Health sciences/Endocrinology Health sciences/Health care Health sciences/Oncology Health sciences/Signs and symptoms Hot Flashes Breast Cancer Prostate Cancer Menopause KÜLKUF Wrist Cooling Device Figures Figure 1 Figure 2 Figure 3 Figure 4 One-Sentence Summary Targeted wrist cooling reduces severe hot flashes by 46% in cancer patients and postmenopausal women through rapid thermosensory modulation. Introduction Hot flashes — sudden, temporary sensations of body warmth, often accompanied by flushing and sweating is associated with sleep difficulty, cognitive dysfunction, severe fatigue, higher pain severity and decreased quality of life. 1 – 7 It has been estimated that hot flashes affect up to 80% of women going through the menopause transition, 80% of men with prostate cancer undergoing or after completion of androgen deprivation therapy and 50–80% of breast cancer patients who are being treated or were treated with hormone deprivation therapy. 1 – 7 Thus millions of men and women worldwide are plagued with this life-altering vasomotor symptom that can significantly impact their quality of life. While a range of treatments exist, most are tailored to menopause-related symptoms and may not be appropriate for breast and prostate cancer patients who were on or who have been treated with hormone deprivation therapy. 7 – 10 Current pharmaceutical options for managing hot flashes are limited by significant side effects. 7 – 11 Consequently, there is an increasing demand for non-pharmaceutical interventions to alleviate hot flash severity for all patients suffering from devastating hot flashes. Traditional remedies, such as yoga and acupuncture have demonstrated moderate efficacy. 12 , 13 It was observed that acupuncture improves menopausal hot flashes compared to no treatment however not compared with sham acupuncture. 13 A small pilot study with yoga intervention revealed 8 weeks of yoga intervention reduced hot flash frequency by 30%. 12 Although not fully understood, the likely mechanism for the induction of hot flashes is due to an alteration in the thermal regulatory center in the hypothalamus that is innervated by kisspeptin/neurokinin B/dynorphin (KNDy) neurons. These neurons are stimulated by the neuropeptide neurokinin B. This neuropeptide interacts with the neurokinin 3 receptors regulating body temperature by controlling vasomotor function. Lack of estrogen inhibits this process, thereby inducing vasodilation to increase heat dissipation that ultimately results in increased heat loss through the skin resulting in profuse sweating and can lead to chills. Fezolinetant which is a nonhormonal selective neurokinin 3 receptor antagonist, through its actions restores normal sensitivity of the thermoregulatory center. This medication has been approved for reducing the frequency and severity of hot flashes in menopausal women. 15 – 17 However, this medication like many other medications to treat hot flashes has significant side effects, and this medication also carries a black box warning. The wrist with its high neurological sensitivity has been a target for the development of devices to treat and/or improve such conditions as motion sickness, Parkinson’s disease, Tourette’s syndrome, and hand tremors. 19 – 21 The wrist has also been identified as an effective site for targeted cooling therapy. A study investigated the feasibility of a novel wearable thermal device for the management of bothersome hot flashes in patients with prostate cancer. This wrist cooling device provided an intermittent low intensity cooling that gave a perceived 5–9°F feeling of coolness for men with prostate cancer and was associated with improvement in sleep, quality of life, enjoyment of life and concentration. 22 We hypothesize that the use of a wrist cooling device that delivered almost instantly high intensity cooling at the onset of a hot flash could signal the hypothalamus that the body is experiencing intense cooling thereby shutting off the overheating signal mitigating the impending vasomotor response (hot flash). We further hypothesize that this device could be equally effective in reducing hot flash severity in menopausal women and breast and prostate cancer patients. KÜLKUF is a wrist wraparound device with a 3 x 3 cm porcelain plate that is placed on the wrist’s ventral surface. (Fig. 1 ) When activated the porcelain plate almost instantly attains a temperature of 47°F and a fan on the opposite side of the plate is turned on to remove the heat. We conducted a double-blinded, randomized controlled crossover pilot study approved by our Institutional Review Board to assess KÜLKUF’s impact on mitigating hot flash severity. Results Study population and baseline characteristics The study employed a rigorous randomized crossover design as depicted in the CONSORT flow diagram (Fig. 2 ). Of the 33 individuals assessed for eligibility, 6 were excluded (4 for not meeting inclusion criteria and 2 who declined participation), resulting in 27 participants who were randomized into the study. The final cohort comprised 10 breast cancer patients, 5 postmenopausal women, and 12 prostate cancer patients. The demographic analysis revealed a notable age difference between female and male participants, with women having a mean age of 48.7 ± 13.4 years, while men were considerably older with a mean age of 70.8 ± 7.3 years. This age discrepancy reflects the typical age of onset for the underlying conditions causing hot flashes in these populations. All participants experienced at least two moderate or severe hot flashes daily for a minimum of two months before enrollment, ensuring that the study population accurately represented individuals with established and persistent hot flash symptomatology. The prolonged baseline requirement helped distinguish participants with transient hot flashes from those with chronic symptoms requiring intervention. In the randomized crossover design, 15 participants were initially allocated to the KÜLKUF device group while 12 received the placebo device first. After a two-week period, participants crossed over to the alternative intervention for another two weeks. The placebo device was carefully designed to be identical in appearance to the active KÜLKUF device, featuring a functioning fan but lacking the critical wrist cooling component. This design element was crucial for maintaining participant blinding and isolating the specific effect of localized cooling on hot flash symptoms. The study achieved excellent retention with no participants lost to follow-up in either arm, and all 27 participants completed both phases of the crossover design. This high completion rate strengthens the reliability of the study findings by minimizing attrition bias. Hot Flash Severity and Frequency The KÜLKUF cooling device demonstrated significant efficacy in reducing both the severity and frequency of hot flashes across the study population. When compared to baseline measurements, participants using the active cooling device experienced a substantial 46% reduction in severe hot flashes (p < 0.02), indicating both clinical and statistical significance. The intervention also showed broader benefits by reducing the total daily hot flash burden by 18% across all severity categories (Fig. 3 ). Statistical analysis employed appropriate methods for crossover design studies, including tests for period effects and carryover effects, with none detected. Within-subject comparisons provided moderate statistical power (65.3%) despite the small sample size (n = 27). The subgroup analysis revealed remarkably consistent therapeutic effects across different patient populations, suggesting that the mechanism of action is independent of the underlying cause of hot flashes. The reduction in severe hot flashes was particularly pronounced in postmenopausal women and prostate cancer patients, both groups showing a 50% decrease in severe episodes during active treatment. Breast cancer patients also derived substantial benefit with a 41% reduction in severe hot flashes while using the KÜLKUF device. To account for potential confounding variables, we conducted a univariate analysis with adjustments for both age and underlying condition. This more rigorous statistical approach further confirmed the significance of the findings, with the cooling device maintaining a statistically significant reduction in hot flash severity (p < 0.01) even after these adjustments. This suggests that the observed benefits are truly attributable to the intervention rather than demographic or disease-specific factors. The temporal analysis of treatment effects, visualized in the scatter plot (Fig. 4 ), demonstrated that the reduction in hot flash frequency was consistent throughout the active treatment period. The data points show a clear and persistent separation between the active treatment condition and both the baseline and placebo periods across all participant groups throughout the 14-day study period (Fig. 4 ). This consistency over time suggests that the therapeutic effect is stable and does not diminish with continued use, an important consideration for any intervention targeting chronic symptoms. Multiple regression modeling further demonstrated that the treatment effect remained significant (p < 0.05) after controlling for baseline hot flash frequency, age, and underlying condition. The effect size (Cohen's d) for reduction in severe hot flashes was calculated as 0.47, indicating a medium treatment effect. The placebo device produced minimal changes from baseline (approximately 5–7% reduction, p = 0.31), confirming that the observed benefits were specifically related to the cooling mechanism rather than psychological factors or the physical presence of a wrist device. The vertical axis measures the number of severe hot flash episodes experienced per day, while the horizontal axis represents the consecutive days of the study period. The data points for each day demonstrate a consistent pattern where the cooling device intervention produced a notable reduction in severe hot flash frequency compared to both the baseline and placebo conditions. The trend lines clearly indicate this treatment effect, with the red dashed line (cooling device) positioned consistently below both the black dashed line (baseline) and the green solid line (placebo) throughout the observation period. This visual representation confirms the statistical findings of significant hot flash reduction with the KÜLKUF device across all participant groups, providing a day-by-day visualization of the treatment's sustained effectiveness over the two-week intervention period. Safety and tolerability of the KÜLKUF Cooling Device The KÜLKUF wrist cooling device demonstrated an excellent safety and tolerability profile throughout the clinical evaluation period. No adverse events were reported by any of the participants during the active treatment, placebo, or follow-up phases of the study. The absence of side effects is particularly noteworthy given the varied participant population that included breast cancer patients, prostate cancer patients, and postmenopausal women. Several aspects of the device design likely contributed to this favorable safety profile. The controlled cooling temperature of 47°F (8°C) was carefully selected to provide therapeutic benefit without reaching temperatures that could potentially cause cold-induced tissue damage or discomfort. The ventral wrist placement area contains minimal subcutaneous fat and no major structures that would be vulnerable to cold injury at the operating temperatures used. Participants reported high compliance with the treatment protocol, suggesting that the device was comfortable enough for regular use. The wraparound design allowed for secure positioning without excessive pressure or restriction of movement. No skin irritation, discoloration, numbness, or paresthesia was observed at the application site during regular safety assessments. The device's rapid temperature regulation and integrated fan system prevented condensation buildup, which might otherwise have caused skin maceration with prolonged use. Additionally, the porcelain plate material proved non-allergenic across all participants, including those with sensitive skin or known contact allergies to other materials. Given these findings, the KÜLKUF cooling device appears to be a safe intervention that can be recommended for managing hot flashes without the concerns associated with pharmacological alternatives, which often carry risks of drug interactions or systemic side effects. The favorable safety profile supports its potential for long-term use in chronic hot flash management, though further studies with extended duration would be valuable to confirm sustained safety over longer periods. Discussion Our findings reveal a significant 46% reduction in severe hot flash severity with targeted wrist cooling, providing compelling evidence for the efficacy of non-pharmaceutical interventions in vasomotor symptom management. This reduction far exceeds the clinical significance threshold established in prior literature and represents a marked improvement in quality of life for our diverse patient population. The consistency of this effect across all three subgroups—breast cancer patients (41% reduction), postmenopausal women (50% reduction), and prostate cancer patients (50% reduction) suggests a common neurophysiological mechanism underlying hot flash generation and mitigation that transcends the varying etiologies. Comparing our results to established interventions, the 41–50% reduction in hot flash severity is comparable to the 49% reduction observed in breast cancer patients receiving acupuncture and exceeds the 34.2% reduction reported for postmenopausal women practicing yoga. 13 , 14 However, KÜLKUF offers several distinct advantages: immediacy of effect, patient autonomy, absence of specialized training requirements, and lack of travel burden. This combination of efficacy and accessibility positions KÜLKUF as a particularly promising intervention in the therapeutic landscape. The observed 18% reduction in total daily hot flash frequency, while not the primary focus of our intervention, warrants further investigation as it suggests potential neuroadaptive mechanisms. This unexpected finding may indicate that consistent peripheral thermosensory input could potentially recalibrate hypothalamic thermoregulatory set points over time, similar to the progressive adaptation seen in thermal exposure therapies. 23 , 24 The KNDy neuronal complex in the hypothalamus likely mediates this effect, as these neurons integrate multiple sensory inputs, including peripheral temperature signals, to regulate vasomotor tone. 17 The neurophysiological mechanism underlying KÜLKUF's efficacy likely involves rapid thermosensory signaling through high-density cold receptors concentrated at the wrist. The ventral wrist surface contains abundant transient receptor potential melastatin 8 (TRPM8) cold-sensitive ion channels that transmit rapid afferent signals to the hypothalamus via the spinothalamic tract. 25 This rapid peripheral cooling input may interrupt the neurokinin B-mediated signaling cascade that triggers vasodilation and sweating during hot flashes. 26 The instantaneous cooling sensation (47°F) potentially creates a powerful competing signal that overrides the aberrant hypothalamic response, effectively "resetting" the thermoregulatory system before the full vasomotor cascade develops. 27 The absence of reported adverse effects throughout the study period further underscores KÜLKUF's safety profile, contrasting sharply with pharmaceutical interventions like fezolinetant, which carries an FDA boxed warning. 28 This favorable safety profile, combined with the consistent efficacy across participant subgroups, positions KÜLKUF as a viable first-line intervention for hot flash management in diverse patient populations, particularly those for whom hormone replacement therapy is contraindicated. It is worth noting that while our protocol was double-blinded, participants inevitably became aware of which device provided cooling sensation. However, several factors mitigate potential placebo effects. First, the crossover design allowed for within-subject comparison, controlling for individual response variability. Second, the quantitative nature of hot flash frequency provides an objective measure less susceptible to expectation bias. Third, the magnitude of effect (46% reduction) substantially exceeds typical placebo responses in hot flash interventions, which typically range from 15–25%. Finally, the consistency of effect across subgroups with differing baseline expectations suggests a genuine physiological rather than psychological mechanism. Our findings have broader implications for understanding thermoregulatory homeostasis. The efficacy of peripheral cooling in mitigating central thermoregulatory dysfunction suggests a more dynamic and modifiable relationship between peripheral thermoreceptors and central thermoregulatory centers than previously appreciated. 23 This relationship may extend to other conditions involving thermoregulatory dysfunction, such as sleep disturbances, autonomic disorders, medication-induced hyperthermia and life-threatening fevers. From a translational perspective, KÜLKUF offers a rare example of successful bench-to-bedside application of basic thermoregulatory neuroscience. By potentially targeting specific neural pathways with precisely timed intervention, we demonstrate the potential for non-invasive neuromodulation approaches in managing complex autonomic symptoms. This paradigm could inform future developments in wearable therapeutics for various neurological and autonomic conditions. While our findings demonstrate promising reductions in hot flash severity, several critical limitations stemming from the pilot study design warrant cautious interpretation. The total sample size (n = 27) provided 65.3% power to detect the observed 46% reduction in severe hot flashes (α = 0.05, effect size d = 0.477), leaving a 34.7% probability of Type II error for this primary outcome1. Subgroup analyses are particularly underpowered, the postmenopausal cohort (n = 5) had only 51.2% power to detect even large effects (d = 1.12), while prostate cancer patients (n = 12) reached just 58.9% power for their 50% reduction. Furthermore, while standardized diaries represent the current gold standard for hot flash assessment, they remain susceptible to recall bias despite our prospective design. Additionally, the study duration was insufficient to assess long-term efficacy, adaptation effects, or potential changes in intervention timing strategies that might optimize outcomes. Future research directions should include larger-scale validation studies with extended follow-up periods, incorporation of objective physiological measurements such as sternal skin conductance and core temperature monitoring, and investigation of potential dose-response relationships between cooling intensity, duration, and symptom relief. Neuroimaging studies examining hypothalamic activity before and after intervention could further elucidate the central mechanisms underlying KÜLKUF's efficacy. Conclusion These preliminary findings suggest that the wrist cooling device may offer a safe and effective non-pharmacologic treatment for reducing hot flash frequency and severity in cancer patients and postmenopausal women. While this pilot study provides encouraging results, it is important to acknowledge its limitations, including the relatively small sample size. Furthermore, the assessment of hot flash frequency and severity relied on self-reported data obtained from standardized diaries, which are subject to recall bias, although we used a prospective design to minimize this effect. Although the cooling device's mechanism is thought to involve signaling the hypothalamus via rapid wrist cooling, further investigation is warranted to fully elucidate the underlying physiological pathways. Larger, multi-center trials are needed to confirm these results and assess long-term efficacy and safety. Materials and Methods Study design and participants This perspective double-blinded randomized controlled crossover pilot study was conducted in the United States between January 2024 and January 2025. Participants were recruited by social media and from the ClinicalTrials.gov information website. The study was conducted either in person or remotely by video Zoom. The study protocol was reviewed and approved by Boston University Medical Center’s Institutional Review Board (H-43277). All methods were performed in accordance with the relevant guidelines and regulations. This study followed the CONSORT 2010 guidelines. This study is registered at ClinicalTrials.gov (29/04/2021). Trial Registration number is NCT04865432. Informed consent was obtained from all participants before enrolling in the study. Interested individuals contacted us through email and social media. They were assessed in person or by telephone or video zoom for prescreening to determine if they met the inclusion and exclusion criteria approved for the study. To be eligible, participants had to be at least 21 years of age with a history of at least experiencing two moderate or severe hot flashes for the past 2 months. The participants were excluded if they had a cooling sensitivity disorder like Raynaud’s phenomena, if they were unable to experience cooling sensitivity on their wrist, or if they took any pharmaceutical or used a device to control their hot flashes. Intervention Participants were provided with a consent form and were either consented in person or remotely by Zoom video. After obtaining informed consent, the participant was provided with two boxes labeled 1 and 2 and three diaries. The boxes were randomly labeled using a computer-generated randomization (1:1) chart. The study personnel and study participants were blinded to the box allocation. One of the boxes contained the KÜLKUF device which when the square button on the device was depressed, it was turned on resulting in the porcelain plate almost instantly attaining a temperature of 47°F and a fan turned on the opposite side to release heat. The control device in the other box was identical in appearance to the KÜLKUF device with the exception that when the device was turned on only the fan was turned on. When turned on the device stayed on for 5 minutes and then automatically shut off. The participants had the option of turning the device off if it was uncomfortable by pressing the square switch for 2 seconds. The participant, either in person or by video Zoom was instructed for the first 2 weeks to record their number and type of hot flashes in a standardized diary to document their baseline activity. 29 At the end of 2 weeks the participant in person or by Zoom was informed to open box #1 and remove the device and attached the device to the wrist with the porcelain square on the ventral side of the wrist. They were instructed that as soon as they felt an impending hot flash they should turn on the device as soon as possible and keep the device active for up to 5 minutes when it automatically shuts off. They were instructed to record the use of the device and the type of hot flash they experienced after using the device in a second diary for weeks 3 and 4 which was identical to the first diary documenting the number and type of hot flashes and now included a separate section specifically labeled as the device use. At the end of week four the participant was asked in person or by Zoom to take a piece of tape in the box, place the device that they had used for the past 2 weeks in the box and then tape it shut. This prevented unwanted access to the device that may have given them some relief from their hot flashes. The participants were then instructed to open box #2 and use the device and record the use of the device and the type of hot flash they experience during weeks 5 and 6 of the study. At the end of the study the participant was asked either in person or by Zoom if they experienced any significant side effects during the trial, and whether they felt that one device was more effective in improving their quality of life. Outcomes and assessments Randomization was performed using a computer-generated sequence to ensure allocation concealment. The primary outcome was the reduction in severe hot flash severity compared to baseline as measured by participant diaries. Secondary outcomes included changes in total daily hot flash frequency and participant-reported quality of life. Declarations Funding: Institutional recourses. Conflict of Interest: None of the authors have any conflicts of interest for this study. Data availability: The raw data will be available upon request from Dr. Michael F. Holick nine months after this manuscript is published. Author Contribution MFH, NU, AS wrote the main manuscript. MFH, NU, AS prepared figures 1-5. 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Available at: https://www.fda.gov/safety/medical-product-safety-information/fda-adds-warning-about-rare-occurrence-serious-liver-injury-use-veozah-fezolinetant-hot-flashes-due Guttuso, T. Jr., DiGrazio, W. J. & Reddy, S. Y. Review of hot flash diaries. Maturitas 71 , 213–216 (2012). Additional Declarations No competing interests reported. Supplementary Files TheSupplementaryInformationfile.pdf CONSORT2010Checklist.doc AdjustedCONSORT2010FlowDiagramMS.pdf Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6173150","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":450053168,"identity":"3c812eb9-46a7-4d4f-861e-ebe9bdfd2a31","order_by":0,"name":"Nazlı Uçar","email":"","orcid":"","institution":"Boston University, Chobanian \u0026 Avedisian School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Nazlı","middleName":"","lastName":"Uçar","suffix":""},{"id":450053169,"identity":"5c126d6d-4f69-4e9e-9c17-a2e53bb641d6","order_by":1,"name":"Arash Shirvani","email":"","orcid":"","institution":"Boston University, Chobanian \u0026 Avedisian School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Arash","middleName":"","lastName":"Shirvani","suffix":""},{"id":450053170,"identity":"dfe734aa-f0e3-4c1c-8842-08a77a08257b","order_by":2,"name":"Michael F. Holick","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAArUlEQVRIiWNgGAWjYDAC5jMMDA8MGAz4JUA8NmK0sOUwMCQAtUjOIE0LA4OBwQ1itei28R58kFBgZ2x8u8eA4UPZYcJazI7xJRskGCSbmd05Y8A44xwxWu73mEkkGBywMbuRY8DM20aULTwQLcYzgFr+kqLFzEACqIWRSC3GIL8YS9w5VnCw51w6UVoMH3z4Y2fYP7t544MfZdaEtaCAAySqHwWjYBSMglGACwAA4Bk4PpCqLbEAAAAASUVORK5CYII=","orcid":"","institution":"Boston University, Chobanian \u0026 Avedisian School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Michael","middleName":"F.","lastName":"Holick","suffix":""}],"badges":[],"createdAt":"2025-03-06 19:38:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6173150/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6173150/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":82150794,"identity":"15eff8b9-a6cf-4d10-ae1b-f4db9a118264","added_by":"auto","created_at":"2025-05-07 07:18:10","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":108361,"visible":true,"origin":"","legend":"\u003cp\u003eKÜLKUF: Advanced Wrist Cooling Device. The image features three views of the KÜLKUF wrist cooling device. The left image (A) shows the front view with its distinctive mesh design and small rectangular accent. The middle image (B) displays the back view, featuring the 3×3 cm porcelain cooling plate that makes direct contact with the skin. The right image (C) demonstrates how the device is worn on the wrist, with the cooling plate positioned against the ventral (inner) surface of the wrist. When activated, the KÜLKUF rapidly cools its porcelain plate to approximately 47°F (8°C). The device incorporates a small fan on the opposite side of the cooling plate that helps dissipate heat, enhancing the cooling efficiency. The wraparound design ensures secure placement while allowing for comfortable movement during use.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6173150/v1/a7b3d876178967fc6a512248.jpeg"},{"id":82150797,"identity":"c2998e0e-0c15-44bf-b9e0-8cec9392b6f4","added_by":"auto","created_at":"2025-05-07 07:18:10","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":412518,"visible":true,"origin":"","legend":"\u003cp\u003eCONSORT Flow Diagram of Participant Enrollment and Study Design for the KÜLKUF Device Clinical Trial. This diagram illustrates the flow of participants through each stage of the randomized crossover clinical trial evaluating the KÜLKUF cooling wrist device for hot flash management. From the 33 individuals initially assessed for eligibility, 6 were excluded (4 not meeting inclusion criteria, 2 declining participation), resulting in 27 participants who were randomized to receive either the KÜLKUF device (n=12) or placebo device (n=15) during the first two-week treatment period. Following baseline hot flash frequency and severity recording, participants crossed over to the alternate intervention for a second two-week period. The study achieved perfect retention with no participants lost to follow-up in either treatment sequence, and all 27 participants were included in the final analysis. This crossover design allowed participants to serve as their own controls, enhancing statistical power and minimizing the impact of individual variability on the assessment of treatment efficacy.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-6173150/v1/3d1f79f83aa37fdccb916a5e.png"},{"id":82150800,"identity":"a3fc297c-9c32-48a6-a5c3-750a807e829a","added_by":"auto","created_at":"2025-05-07 07:18:10","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":118734,"visible":true,"origin":"","legend":"\u003cp\u003eImpact of KÜLKUF Cooling Device on Hot Flash Reduction Across Severity Levels. This bar graph illustrates the efficacy of the KÜLKUF wrist cooling device in reducing hot flashes compared to baseline and placebo conditions. The data shows that the KÜLKUF device significantly reduced severe hot flashes by 46% (p\u0026lt;0.02) and total daily hot flashes by 18% relative to baseline measurements. The graph categorizes hot flash episodes by severity (mild, moderate, and severe) with color-coded bars representing baseline (red), placebo (yellow), and active cooling device (blue) conditions. Green arrows with percentages indicate the magnitude of reduction between baseline and the cooling device intervention.\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6173150/v1/a8d4e6695e27fb5804b1f5c5.jpg"},{"id":82153543,"identity":"0b8467fe-dc6c-4370-96a8-f4b7d4a6f801","added_by":"auto","created_at":"2025-05-07 07:26:10","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":160797,"visible":true,"origin":"","legend":"\u003cp\u003eConsistent Reduction in Severe Hot Flash Frequency with KÜLKUF Cooling Device During 14-Day Treatment Period. This scatter plot illustrates the daily frequency of severe hot flashes over a 14-day observation period comparing three intervention conditions: baseline (no device, black circles with black dashed trend line), active cooling device (KÜLKUF, pink diamonds with red dashed trend line), and placebo (green asterisks with solid green trend line).\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6173150/v1/3088a6b6285cd75f4cbe29ec.jpg"},{"id":87547624,"identity":"7dc8c6c8-53e5-42d3-865d-3dd9b53ab9d4","added_by":"auto","created_at":"2025-07-25 05:32:44","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1222204,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6173150/v1/e6985a51-0fb8-42c2-a56b-c6dfb053fa77.pdf"},{"id":82153541,"identity":"e9019cfb-3c59-47ec-a415-b7df112bc35e","added_by":"auto","created_at":"2025-05-07 07:26:10","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":40443,"visible":true,"origin":"","legend":"","description":"","filename":"TheSupplementaryInformationfile.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6173150/v1/cf3e230d6075ec99b9e76b8c.pdf"},{"id":82150803,"identity":"1f0cd802-6333-464c-8873-67fed05716a0","added_by":"auto","created_at":"2025-05-07 07:18:10","extension":"doc","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":225792,"visible":true,"origin":"","legend":"","description":"","filename":"CONSORT2010Checklist.doc","url":"https://assets-eu.researchsquare.com/files/rs-6173150/v1/0bb9ccf9fbedd9d683eda725.doc"},{"id":82154762,"identity":"8bcacd10-75ed-43e8-93bc-2e2bc9491ab9","added_by":"auto","created_at":"2025-05-07 07:34:10","extension":"pdf","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":49113,"visible":true,"origin":"","legend":"","description":"","filename":"AdjustedCONSORT2010FlowDiagramMS.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6173150/v1/5b5242ab63a1d7f1e7e7013b.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Randomized Controlled Cross-over Study for Hot Flash Management: Efficacy Novel Wrist Cooling Device in Cancer Treatment-Induced and Menopausal Vasomotor Symptoms","fulltext":[{"header":"One-Sentence Summary","content":"\u003cp\u003eTargeted wrist cooling reduces severe hot flashes by 46% in cancer patients and postmenopausal women through rapid thermosensory modulation.\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eHot flashes \u0026mdash; sudden, temporary sensations of body warmth, often accompanied by flushing and sweating is associated with sleep difficulty, cognitive dysfunction, severe fatigue, higher pain severity and decreased quality of life.\u003csup\u003e\u003cspan additionalcitationids=\"CR2 CR3 CR4 CR5 CR6\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e It has been estimated that hot flashes affect up to 80% of women going through the menopause transition, 80% of men with prostate cancer undergoing or after completion of androgen deprivation therapy and 50\u0026ndash;80% of breast cancer patients who are being treated or were treated with hormone deprivation therapy.\u003csup\u003e\u003cspan additionalcitationids=\"CR2 CR3 CR4 CR5 CR6\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e Thus millions of men and women worldwide are plagued with this life-altering vasomotor symptom that can significantly impact their quality of life. While a range of treatments exist, most are tailored to menopause-related symptoms and may not be appropriate for breast and prostate cancer patients who were on or who have been treated with hormone deprivation therapy.\u003csup\u003e\u003cspan additionalcitationids=\"CR8 CR9\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e Current pharmaceutical options for managing hot flashes are limited by significant side effects.\u003csup\u003e\u003cspan additionalcitationids=\"CR8 CR9 CR10\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e Consequently, there is an increasing demand for non-pharmaceutical interventions to alleviate hot flash severity for all patients suffering from devastating hot flashes.\u003c/p\u003e \u003cp\u003eTraditional remedies, such as yoga and acupuncture have demonstrated moderate efficacy.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e It was observed that acupuncture improves menopausal hot flashes compared to no treatment however not compared with sham acupuncture.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e A small pilot study with yoga intervention revealed 8 weeks of yoga intervention reduced hot flash frequency by 30%.\u003csup\u003e12\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eAlthough not fully understood, the likely mechanism for the induction of hot flashes is due to an alteration in the thermal regulatory center in the hypothalamus that is innervated by kisspeptin/neurokinin B/dynorphin (KNDy) neurons. These neurons are stimulated by the neuropeptide neurokinin B. This neuropeptide interacts with the neurokinin 3 receptors regulating body temperature by controlling vasomotor function. Lack of estrogen inhibits this process, thereby inducing vasodilation to increase heat dissipation that ultimately results in increased heat loss through the skin resulting in profuse sweating and can lead to chills. Fezolinetant which is a nonhormonal selective neurokinin 3 receptor antagonist, through its actions restores normal sensitivity of the thermoregulatory center. This medication has been approved for reducing the frequency and severity of hot flashes in menopausal women.\u003csup\u003e\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e However, this medication like many other medications to treat hot flashes has significant side effects, and this medication also carries a black box warning.\u003c/p\u003e \u003cp\u003eThe wrist with its high neurological sensitivity has been a target for the development of devices to treat and/or improve such conditions as motion sickness, Parkinson\u0026rsquo;s disease, Tourette\u0026rsquo;s syndrome, and hand tremors.\u003csup\u003e\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e The wrist has also been identified as an effective site for targeted cooling therapy. A study investigated the feasibility of a novel wearable thermal device for the management of bothersome hot flashes in patients with prostate cancer. This wrist cooling device provided an intermittent low intensity cooling that gave a perceived 5\u0026ndash;9\u0026deg;F feeling of coolness for men with prostate cancer and was associated with improvement in sleep, quality of life, enjoyment of life and concentration.\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eWe hypothesize that the use of a wrist cooling device that delivered almost instantly high intensity cooling at the onset of a hot flash could signal the hypothalamus that the body is experiencing intense cooling thereby shutting off the overheating signal mitigating the impending vasomotor response (hot flash). We further hypothesize that this device could be equally effective in reducing hot flash severity in menopausal women and breast and prostate cancer patients. K\u0026Uuml;LKUF is a wrist wraparound device with a 3 x 3 cm porcelain plate that is placed on the wrist\u0026rsquo;s ventral surface. (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) When activated the porcelain plate almost instantly attains a temperature of 47\u0026deg;F and a fan on the opposite side of the plate is turned on to remove the heat. We conducted a double-blinded, randomized controlled crossover pilot study approved by our Institutional Review Board to assess K\u0026Uuml;LKUF\u0026rsquo;s impact on mitigating hot flash severity.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy population and baseline characteristics\u003c/h2\u003e \u003cp\u003eThe study employed a rigorous randomized crossover design as depicted in the CONSORT flow diagram (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Of the 33 individuals assessed for eligibility, 6 were excluded (4 for not meeting inclusion criteria and 2 who declined participation), resulting in 27 participants who were randomized into the study. The final cohort comprised 10 breast cancer patients, 5 postmenopausal women, and 12 prostate cancer patients.\u003c/p\u003e \u003cp\u003eThe demographic analysis revealed a notable age difference between female and male participants, with women having a mean age of 48.7\u0026thinsp;\u0026plusmn;\u0026thinsp;13.4 years, while men were considerably older with a mean age of 70.8\u0026thinsp;\u0026plusmn;\u0026thinsp;7.3 years. This age discrepancy reflects the typical age of onset for the underlying conditions causing hot flashes in these populations.\u003c/p\u003e \u003cp\u003eAll participants experienced at least two moderate or severe hot flashes daily for a minimum of two months before enrollment, ensuring that the study population accurately represented individuals with established and persistent hot flash symptomatology. The prolonged baseline requirement helped distinguish participants with transient hot flashes from those with chronic symptoms requiring intervention.\u003c/p\u003e \u003cp\u003eIn the randomized crossover design, 15 participants were initially allocated to the K\u0026Uuml;LKUF device group while 12 received the placebo device first. After a two-week period, participants crossed over to the alternative intervention for another two weeks. The placebo device was carefully designed to be identical in appearance to the active K\u0026Uuml;LKUF device, featuring a functioning fan but lacking the critical wrist cooling component. This design element was crucial for maintaining participant blinding and isolating the specific effect of localized cooling on hot flash symptoms.\u003c/p\u003e \u003cp\u003eThe study achieved excellent retention with no participants lost to follow-up in either arm, and all 27 participants completed both phases of the crossover design. This high completion rate strengthens the reliability of the study findings by minimizing attrition bias.\u003c/p\u003e \u003cp\u003e\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eHot Flash Severity and Frequency\u003c/h3\u003e\n\u003cp\u003eThe K\u0026Uuml;LKUF cooling device demonstrated significant efficacy in reducing both the severity and frequency of hot flashes across the study population. When compared to baseline measurements, participants using the active cooling device experienced a substantial 46% reduction in severe hot flashes (p\u0026thinsp;\u0026lt;\u0026thinsp;0.02), indicating both clinical and statistical significance. The intervention also showed broader benefits by reducing the total daily hot flash burden by 18% across all severity categories (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eStatistical analysis employed appropriate methods for crossover design studies, including tests for period effects and carryover effects, with none detected. Within-subject comparisons provided moderate statistical power (65.3%) despite the small sample size (n\u0026thinsp;=\u0026thinsp;27).\u003c/p\u003e \u003cp\u003eThe subgroup analysis revealed remarkably consistent therapeutic effects across different patient populations, suggesting that the mechanism of action is independent of the underlying cause of hot flashes. The reduction in severe hot flashes was particularly pronounced in postmenopausal women and prostate cancer patients, both groups showing a 50% decrease in severe episodes during active treatment. Breast cancer patients also derived substantial benefit with a 41% reduction in severe hot flashes while using the K\u0026Uuml;LKUF device.\u003c/p\u003e \u003cp\u003eTo account for potential confounding variables, we conducted a univariate analysis with adjustments for both age and underlying condition. This more rigorous statistical approach further confirmed the significance of the findings, with the cooling device maintaining a statistically significant reduction in hot flash severity (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) even after these adjustments. This suggests that the observed benefits are truly attributable to the intervention rather than demographic or disease-specific factors.\u003c/p\u003e \u003cp\u003eThe temporal analysis of treatment effects, visualized in the scatter plot (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e), demonstrated that the reduction in hot flash frequency was consistent throughout the active treatment period. The data points show a clear and persistent separation between the active treatment condition and both the baseline and placebo periods across all participant groups throughout the 14-day study period (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). This consistency over time suggests that the therapeutic effect is stable and does not diminish with continued use, an important consideration for any intervention targeting chronic symptoms.\u003c/p\u003e \u003cp\u003eMultiple regression modeling further demonstrated that the treatment effect remained significant (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) after controlling for baseline hot flash frequency, age, and underlying condition. The effect size (Cohen's d) for reduction in severe hot flashes was calculated as 0.47, indicating a medium treatment effect.\u003c/p\u003e \u003cp\u003eThe placebo device produced minimal changes from baseline (approximately 5\u0026ndash;7% reduction, p\u0026thinsp;=\u0026thinsp;0.31), confirming that the observed benefits were specifically related to the cooling mechanism rather than psychological factors or the physical presence of a wrist device.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe vertical axis measures the number of severe hot flash episodes experienced per day, while the horizontal axis represents the consecutive days of the study period. The data points for each day demonstrate a consistent pattern where the cooling device intervention produced a notable reduction in severe hot flash frequency compared to both the baseline and placebo conditions.\u003c/p\u003e \u003cp\u003eThe trend lines clearly indicate this treatment effect, with the red dashed line (cooling device) positioned consistently below both the black dashed line (baseline) and the green solid line (placebo) throughout the observation period. This visual representation confirms the statistical findings of significant hot flash reduction with the K\u0026Uuml;LKUF device across all participant groups, providing a day-by-day visualization of the treatment's sustained effectiveness over the two-week intervention period.\u003c/p\u003e\n\u003ch3\u003eSafety and tolerability of the KÜLKUF Cooling Device\u003c/h3\u003e\n\u003cp\u003eThe K\u0026Uuml;LKUF wrist cooling device demonstrated an excellent safety and tolerability profile throughout the clinical evaluation period. No adverse events were reported by any of the participants during the active treatment, placebo, or follow-up phases of the study. The absence of side effects is particularly noteworthy given the varied participant population that included breast cancer patients, prostate cancer patients, and postmenopausal women.\u003c/p\u003e \u003cp\u003eSeveral aspects of the device design likely contributed to this favorable safety profile. The controlled cooling temperature of 47\u0026deg;F (8\u0026deg;C) was carefully selected to provide therapeutic benefit without reaching temperatures that could potentially cause cold-induced tissue damage or discomfort. The ventral wrist placement area contains minimal subcutaneous fat and no major structures that would be vulnerable to cold injury at the operating temperatures used.\u003c/p\u003e \u003cp\u003eParticipants reported high compliance with the treatment protocol, suggesting that the device was comfortable enough for regular use. The wraparound design allowed for secure positioning without excessive pressure or restriction of movement. No skin irritation, discoloration, numbness, or paresthesia was observed at the application site during regular safety assessments.\u003c/p\u003e \u003cp\u003eThe device's rapid temperature regulation and integrated fan system prevented condensation buildup, which might otherwise have caused skin maceration with prolonged use. Additionally, the porcelain plate material proved non-allergenic across all participants, including those with sensitive skin or known contact allergies to other materials.\u003c/p\u003e \u003cp\u003eGiven these findings, the K\u0026Uuml;LKUF cooling device appears to be a safe intervention that can be recommended for managing hot flashes without the concerns associated with pharmacological alternatives, which often carry risks of drug interactions or systemic side effects. The favorable safety profile supports its potential for long-term use in chronic hot flash management, though further studies with extended duration would be valuable to confirm sustained safety over longer periods.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur findings reveal a significant 46% reduction in severe hot flash severity with targeted wrist cooling, providing compelling evidence for the efficacy of non-pharmaceutical interventions in vasomotor symptom management. This reduction far exceeds the clinical significance threshold established in prior literature and represents a marked improvement in quality of life for our diverse patient population. The consistency of this effect across all three subgroups\u0026mdash;breast cancer patients (41% reduction), postmenopausal women (50% reduction), and prostate cancer patients (50% reduction) suggests a common neurophysiological mechanism underlying hot flash generation and mitigation that transcends the varying etiologies. Comparing our results to established interventions, the 41\u0026ndash;50% reduction in hot flash severity is comparable to the 49% reduction observed in breast cancer patients receiving acupuncture and exceeds the 34.2% reduction reported for postmenopausal women practicing yoga.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e However, K\u0026Uuml;LKUF offers several distinct advantages: immediacy of effect, patient autonomy, absence of specialized training requirements, and lack of travel burden. This combination of efficacy and accessibility positions K\u0026Uuml;LKUF as a particularly promising intervention in the therapeutic landscape. The observed 18% reduction in total daily hot flash frequency, while not the primary focus of our intervention, warrants further investigation as it suggests potential neuroadaptive mechanisms. This unexpected finding may indicate that consistent peripheral thermosensory input could potentially recalibrate hypothalamic thermoregulatory set points over time, similar to the progressive adaptation seen in thermal exposure therapies.\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e,\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e The KNDy neuronal complex in the hypothalamus likely mediates this effect, as these neurons integrate multiple sensory inputs, including peripheral temperature signals, to regulate vasomotor tone.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe neurophysiological mechanism underlying K\u0026Uuml;LKUF's efficacy likely involves rapid thermosensory signaling through high-density cold receptors concentrated at the wrist. The ventral wrist surface contains abundant transient receptor potential melastatin 8 (TRPM8) cold-sensitive ion channels that transmit rapid afferent signals to the hypothalamus via the spinothalamic tract.\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e This rapid peripheral cooling input may interrupt the neurokinin B-mediated signaling cascade that triggers vasodilation and sweating during hot flashes.\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e The instantaneous cooling sensation (47\u0026deg;F) potentially creates a powerful competing signal that overrides the aberrant hypothalamic response, effectively \"resetting\" the thermoregulatory system before the full vasomotor cascade develops.\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe absence of reported adverse effects throughout the study period further underscores K\u0026Uuml;LKUF's safety profile, contrasting sharply with pharmaceutical interventions like fezolinetant, which carries an FDA boxed warning.\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e This favorable safety profile, combined with the consistent efficacy across participant subgroups, positions K\u0026Uuml;LKUF as a viable first-line intervention for hot flash management in diverse patient populations, particularly those for whom hormone replacement therapy is contraindicated.\u003c/p\u003e \u003cp\u003eIt is worth noting that while our protocol was double-blinded, participants inevitably became aware of which device provided cooling sensation. However, several factors mitigate potential placebo effects. First, the crossover design allowed for within-subject comparison, controlling for individual response variability. Second, the quantitative nature of hot flash frequency provides an objective measure less susceptible to expectation bias. Third, the magnitude of effect (46% reduction) substantially exceeds typical placebo responses in hot flash interventions, which typically range from 15\u0026ndash;25%. Finally, the consistency of effect across subgroups with differing baseline expectations suggests a genuine physiological rather than psychological mechanism.\u003c/p\u003e \u003cp\u003eOur findings have broader implications for understanding thermoregulatory homeostasis. The efficacy of peripheral cooling in mitigating central thermoregulatory dysfunction suggests a more dynamic and modifiable relationship between peripheral thermoreceptors and central thermoregulatory centers than previously appreciated.\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e This relationship may extend to other conditions involving thermoregulatory dysfunction, such as sleep disturbances, autonomic disorders, medication-induced hyperthermia and life-threatening fevers.\u003c/p\u003e \u003cp\u003eFrom a translational perspective, K\u0026Uuml;LKUF offers a rare example of successful bench-to-bedside application of basic thermoregulatory neuroscience. By potentially targeting specific neural pathways with precisely timed intervention, we demonstrate the potential for non-invasive neuromodulation approaches in managing complex autonomic symptoms. This paradigm could inform future developments in wearable therapeutics for various neurological and autonomic conditions.\u003c/p\u003e \u003cp\u003eWhile our findings demonstrate promising reductions in hot flash severity, several critical limitations stemming from the pilot study design warrant cautious interpretation. The total sample size (n\u0026thinsp;=\u0026thinsp;27) provided 65.3% power to detect the observed 46% reduction in severe hot flashes (α\u0026thinsp;=\u0026thinsp;0.05, effect size d\u0026thinsp;=\u0026thinsp;0.477), leaving a 34.7% probability of Type II error for this primary outcome1. Subgroup analyses are particularly underpowered, the postmenopausal cohort (n\u0026thinsp;=\u0026thinsp;5) had only 51.2% power to detect even large effects (d\u0026thinsp;=\u0026thinsp;1.12), while prostate cancer patients (n\u0026thinsp;=\u0026thinsp;12) reached just 58.9% power for their 50% reduction. Furthermore, while standardized diaries represent the current gold standard for hot flash assessment, they remain susceptible to recall bias despite our prospective design. Additionally, the study duration was insufficient to assess long-term efficacy, adaptation effects, or potential changes in intervention timing strategies that might optimize outcomes.\u003c/p\u003e \u003cp\u003eFuture research directions should include larger-scale validation studies with extended follow-up periods, incorporation of objective physiological measurements such as sternal skin conductance and core temperature monitoring, and investigation of potential dose-response relationships between cooling intensity, duration, and symptom relief. Neuroimaging studies examining hypothalamic activity before and after intervention could further elucidate the central mechanisms underlying K\u0026Uuml;LKUF's efficacy.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThese preliminary findings suggest that the wrist cooling device may offer a safe and effective non-pharmacologic treatment for reducing hot flash frequency and severity in cancer patients and postmenopausal women. While this pilot study provides encouraging results, it is important to acknowledge its limitations, including the relatively small sample size. Furthermore, the assessment of hot flash frequency and severity relied on self-reported data obtained from standardized diaries, which are subject to recall bias, although we used a prospective design to minimize this effect. Although the cooling device's mechanism is thought to involve signaling the hypothalamus via rapid wrist cooling, further investigation is warranted to fully elucidate the underlying physiological pathways. Larger, multi-center trials are needed to confirm these results and assess long-term efficacy and safety.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and participants\u003c/h2\u003e \u003cp\u003eThis perspective double-blinded randomized controlled crossover pilot study was conducted in the United States between January 2024 and January 2025. Participants were recruited by social media and from the ClinicalTrials.gov information website. The study was conducted either in person or remotely by video Zoom. The study protocol was reviewed and approved by Boston University Medical Center\u0026rsquo;s Institutional Review Board (H-43277). All methods were performed in accordance with the relevant guidelines and regulations. This study followed the CONSORT 2010 guidelines. This study is registered at ClinicalTrials.gov (29/04/2021). Trial Registration number is NCT04865432. Informed consent was obtained from all participants before enrolling in the study.\u003c/p\u003e \u003cp\u003eInterested individuals contacted us through email and social media. They were assessed in person or by telephone or video zoom for prescreening to determine if they met the inclusion and exclusion criteria approved for the study. To be eligible, participants had to be at least 21 years of age with a history of at least experiencing two moderate or severe hot flashes for the past 2 months. The participants were excluded if they had a cooling sensitivity disorder like Raynaud\u0026rsquo;s phenomena, if they were unable to experience cooling sensitivity on their wrist, or if they took any pharmaceutical or used a device to control their hot flashes.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eIntervention\u003c/h3\u003e\n\u003cp\u003eParticipants were provided with a consent form and were either consented in person or remotely by Zoom video. After obtaining informed consent, the participant was provided with two boxes labeled 1 and 2 and three diaries. The boxes were randomly labeled using a computer-generated randomization (1:1) chart. The study personnel and study participants were blinded to the box allocation. One of the boxes contained the K\u0026Uuml;LKUF device which when the square button on the device was depressed, it was turned on resulting in the porcelain plate almost instantly attaining a temperature of 47\u0026deg;F and a fan turned on the opposite side to release heat. The control device in the other box was identical in appearance to the K\u0026Uuml;LKUF device with the exception that when the device was turned on only the fan was turned on. When turned on the device stayed on for 5 minutes and then automatically shut off. The participants had the option of turning the device off if it was uncomfortable by pressing the square switch for 2 seconds. The participant, either in person or by video Zoom was instructed for the first 2 weeks to record their number and type of hot flashes in a standardized diary to document their baseline activity.\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003eAt the end of 2 weeks the participant in person or by Zoom was informed to open box #1 and remove the device and attached the device to the wrist with the porcelain square on the ventral side of the wrist. They were instructed that as soon as they felt an impending hot flash they should turn on the device as soon as possible and keep the device active for up to 5 minutes when it automatically shuts off. They were instructed to record the use of the device and the type of hot flash they experienced after using the device in a second diary for weeks 3 and 4 which was identical to the first diary documenting the number and type of hot flashes and now included a separate section specifically labeled as the device use. At the end of week four the participant was asked in person or by Zoom to take a piece of tape in the box, place the device that they had used for the past 2 weeks in the box and then tape it shut. This prevented unwanted access to the device that may have given them some relief from their hot flashes. The participants were then instructed to open box #2 and use the device and record the use of the device and the type of hot flash they experience during weeks 5 and 6 of the study. At the end of the study the participant was asked either in person or by Zoom if they experienced any significant side effects during the trial, and whether they felt that one device was more effective in improving their quality of life.\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eOutcomes and assessments\u003c/h2\u003e \u003cp\u003eRandomization was performed using a computer-generated sequence to ensure allocation concealment. The primary outcome was the reduction in severe hot flash severity compared to baseline as measured by participant diaries. Secondary outcomes included changes in total daily hot flash frequency and participant-reported quality of life.\u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003eFunding: Institutional recourses.\u003c/p\u003e\n\u003cp\u003eConflict of Interest: None of the authors have any conflicts of interest for this study.\u003c/p\u003e\n\u003cp\u003eData availability: The raw data will be available upon request from Dr. Michael F. Holick nine months after this manuscript is published.\u003c/p\u003e\n\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\n\u003cp\u003eMFH, NU, AS wrote the main manuscript. MFH, NU, AS prepared figures 1-5. All authors reviewed and confirmed the final version of manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eChang, H. Y. et al. 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Rep.\u003c/em\u003e \u003cb\u003e5\u003c/b\u003e, 8466 (2015).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSantoro, N., Epperson, C. N. \u0026amp; Mathews, S. B. Menopausal symptoms and their management. \u003cem\u003eEndocrinol. Metab. Clin. North. Am.\u003c/em\u003e \u003cb\u003e44\u003c/b\u003e, 497\u0026ndash;515 (2015).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eU.S. Food and Drug Administration. FDA adds warning about rare occurrence of serious liver injury with use of Veozah (fezolinetant) for hot flashes due to menopause. \u003cem\u003eDrug Safety Communication\u003c/em\u003e (2025). Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.fda.gov/safety/medical-product-safety-information/fda-adds-warning-about-rare-occurrence-serious-liver-injury-use-veozah-fezolinetant-hot-flashes-due\u003c/span\u003e\u003cspan address=\"https://www.fda.gov/safety/medical-product-safety-information/fda-adds-warning-about-rare-occurrence-serious-liver-injury-use-veozah-fezolinetant-hot-flashes-due\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuttuso, T. Jr., DiGrazio, W. J. \u0026amp; Reddy, S. Y. Review of hot flash diaries. \u003cem\u003eMaturitas\u003c/em\u003e \u003cb\u003e71\u003c/b\u003e, 213\u0026ndash;216 (2012).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Hot Flashes, Breast Cancer, Prostate Cancer, Menopause, KÜLKUF, Wrist Cooling Device","lastPublishedDoi":"10.21203/rs.3.rs-6173150/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6173150/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eHot flashes significantly impact quality of life in cancer patients undergoing hormone deprivation therapy and postmenopausal women. Pharmaceutical interventions often carry substantial risks. This double-blind randomized crossover trial evaluated the efficacy of K\u0026Uuml;LKUF, a wrist-mounted cooling device that rapidly delivers a 47\u0026deg;F cooling stimulus upon activation, in 27 participants (n\u0026thinsp;=\u0026thinsp;10 breast cancer, n\u0026thinsp;=\u0026thinsp;12 prostate cancer, n\u0026thinsp;=\u0026thinsp;5 postmenopausal women) experiencing at least two moderate-to-severe hot flashes daily. Compared to baseline measurements, the active cooling intervention reduced severe hot flash episodes by 46% (p\u0026thinsp;\u0026lt;\u0026thinsp;0.02) and total daily hot flashes by 18%. Subgroup analysis revealed consistent therapeutic effects across all participant categories, with severe hot flash reductions of 41% in breast cancer patients and 50% in both postmenopausal women and prostate cancer patients. Univariate analysis adjusted for age and underlying condition confirmed a significant reduction in hot flash severity (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). The crossover design, which achieved perfect retention with no dropouts, allowed participants to serve as their own controls, enhancing statistical power despite the modest sample size. No adverse events or tolerability issues were reported throughout the study period. These findings suggest that targeted peripheral thermosensory input via wrist cooling represents a promising non-pharmaceutical approach for managing vasomotor symptoms across diverse patient populations.\u003c/p\u003e","manuscriptTitle":"Randomized Controlled Cross-over Study for Hot Flash Management: Efficacy Novel Wrist Cooling Device in Cancer Treatment-Induced and Menopausal Vasomotor Symptoms","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-07 07:18:05","doi":"10.21203/rs.3.rs-6173150/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d06d283f-7163-415c-9e3d-843cfef9453d","owner":[],"postedDate":"May 7th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":47891206,"name":"Health sciences/Endocrinology"},{"id":47891207,"name":"Health sciences/Health care"},{"id":47891208,"name":"Health sciences/Oncology"},{"id":47891209,"name":"Health sciences/Signs and symptoms"}],"tags":[],"updatedAt":"2025-07-25T05:24:28+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-07 07:18:05","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6173150","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6173150","identity":"rs-6173150","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}