Peripheral Thermoregulatory Modulation for Hot Flash Management: Efficacy of Novel Wrist Cooling Device in Cancer Treatment-Induced and Menopausal Vasomotor Symptoms.

This prospective, 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 protocol was 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 (April 29, 2021). Trial Registration number is NCT04865432 . Informed consent was obtained from all participants before enrollment. Interested individuals contacted the study team by email or social media. They were assessed in person, by telephone, or by zoom to determine eligibility. Inclusion criteria required participants to be at least 21 years of age with a history of at least experiencing 2 moderate or severe hot flashes for the past 2 months. Exclusion criteria included cooling sensitivity disorder (e.g., Raynaud’s phenomena), lack of cooling sensation at the wrist, or current use of pharmaceutical or device-based treatments for hot flashes. 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 2 boxes labeled 1 and 2 and 3 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. This cooling temperature (47.2 °F/8.3 °C) was chosen based on prior pilot testing and physiological considerations. Cooling below this threshold can paradoxically induce compensatory heat production through vasoconstriction and shivering. It was concluded that 47-50 °F produced the greatest symptom relief with optimal comfort and safety. 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 min 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 s. 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. 33 At the end of 2 weeks the participant in person or by Zoom was informed to open box number 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 min when it automatically shuts off. They were instructed to record the use of the device and the type of hot flash/VMS they experienced during the day and night 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/VMS and now included a separate section specifically labeled as the device use. At the end of week 4 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 number 2 and use the device and record the use of the device and the type of hot flash/VMS they experienced in the days and nights 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. 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. All statistical analyses were performed using SPSS version 28. The crossover design was analyzed using appropriate paired statistical methods, with each participant serving as their own control to maximize statistical power and minimize between-subject variability. Descriptive statistics were calculated for all baseline demographic and clinical variables. Continuous variables are presented as mean ± standard deviation, while categorical variables are presented as frequencies and percentages. Age differences between male and female participants were assessed using independent samples t -tests. The primary outcome (reduction in severe hot flash episodes) was analyzed using paired t -tests comparing the active KÜLKUF treatment period to baseline measurements. Secondary outcomes included changes in total daily hot flash/VMS frequency and moderate hot flash/VMS episodes, analyzed using the same paired approach. Prior to analysis, we tested for period effects (systematic differences between treatment periods) and carryover effects (residual effects from the first treatment period affecting the second period) using appropriate crossover methodology. Period effects were assessed by comparing outcomes between weeks 3-4 versus weeks 5-6 across all participants. Carryover effects were evaluated by comparing the sum of both treatment periods between participants who received active treatment first versus those who received placebo first. No significant period or carryover effects were detected ( P > 0.10 for all comparisons). Subgroup analyses were performed for each participant category (breast cancer patients, prostate cancer patients, and postmenopausal women) using paired t -tests within each group. Given the pilot nature of this study, formal power calculations indicated 65.3% power to detect the observed effect size for the primary outcome (α = 0.05). Subgroup analyses should be interpreted with particular caution due to limited statistical power: the postmenopausal cohort ( n = 5) provided only 51.2% power to detect large effects, while other subgroups similarly lacked adequate power for definitive conclusions. To control for potential confounding variables, we performed multivariable analysis using generalized linear mixed models with random intercepts for participants to account for the repeated measures design. Fixed effects included treatment condition (active vs placebo), age (continuous), and underlying condition (breast cancer, prostate cancer, or postmenopausal status). The model used a Poisson distribution with log link function for count data (hot flash frequency) and normal distribution for severity scores. Additionally, univariate regression analysis was conducted with hot flash severity as the dependent variable and treatment condition as the primary predictor, adjusting for age and underlying condition as covariates. Cohen's d was calculated for the primary outcome to quantify the magnitude of treatment effect, using the formula for paired samples: d = (mean difference)/(standard deviation of differences). Effect sizes were interpreted as small (d = 0.2), medium (d = 0.5), or large (d = 0.8) according to established conventions. Complete case analysis was performed as no participants were lost to follow-up. For any missing diary entries (individual days), we conducted sensitivity analyses using multiple imputation methods to ensure robustness of findings. The placebo device response was analyzed using paired t -tests comparing placebo treatment periods to baseline measurements. This analysis helped distinguish specific cooling effects from nonspecific device effects. To assess consistency of treatment effects over time, we analyzed daily hot flash frequencies throughout each treatment period using repeated measures analysis, with treatment day as a within-subject factor. Statistical significance was set at α = 0.05 for all analyses. Given the pilot nature of this study and the limited number of planned comparisons, no formal correction for multiple testing was applied, though results should be interpreted with appropriate caution. Device usage compliance was analyzed descriptively, calculating the percentage of hot flash episodes during which participants used the assigned device. Safety outcomes were assessed through descriptive analysis of reported adverse events and participant interviews.

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 small subgroup sizes, particularly the postmenopausal cohort ( n = 5), limit the generalizability of subgroup findings and require cautious interpretation. Fig. 2 CONSORT 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 2-week treatment period. Following baseline hot flash frequency and severity recording, participants crossed over to the alternate intervention for a second 2-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. CONSORT 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 2-week treatment period. Following baseline hot flash frequency and severity recording, participants crossed over to the alternate intervention for a second 2-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. 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 2 moderate or severe hot flashes daily for a minimum of 2 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 2-week period, participants crossed over to the alternative intervention for another 2 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. The KÜLKUF cooling device demonstrated significant efficacy in reducing both the severity and frequency of hot flashes/VMS across the study population. When compared to baseline measurements, participants using the active cooling device experienced a substantial 46% (95% CI: 18% to 74%, P < 0.02) reduction in severe hot flashes, indicating both clinical and statistical significance. The intervention also showed broader benefits by reducing the total daily hot flash burden by 18% (95% CI: 2% to 34%) across all severity categories ( Fig. 3 ). Fig. 3 Impact 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 < 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. Impact 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 < 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. 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/VMS. The reduction in severe hot flashes/VMS 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 conditions. 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. Fig. 4 Consistent 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 3 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). 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 2-week intervention period. Consistent 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 3 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). 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 2-week intervention period. Multiple regression modeling further demonstrated that the treatment effect remained significant ( P < 0.05) after controlling for baseline hot flash/VMS frequency, age, and underlying condition. The effect size (Cohen's d) for reduction in severe hot flashes was calculated as 0.47, indicating a clinically meaningful improvement. To contextualize this finding, participants experiencing an average of 4-5 severe hot flashes/VMS daily at baseline saw this reduced to approximately 2-3 severe episodes daily during active treatment. This translates to 1-2 fewer severe hot flashes/VMSs per day, potentially improving sleep quality, reducing disruption to daily activities, and decreasing the psychological distress associated with unpredictable hot flash/hot flush/night sweats/VMS. The placebo device produced minimal changes from baseline (approximately 5% to 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 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 nonallergenic 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.

These preliminary findings suggest that the wrist cooling device may offer a safe and effective non-pharmacologic treatment for reducing hot flash/hot flush/night sweats/VMS 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, adequately powered, multi-center trials with objective outcome measures are needed to confirm these preliminary results and assess long-term efficacy and safety. Future studies should also address the methodological limitations identified in this pilot work, including the challenge of maintaining participant blinding and the reliance on subjective outcome measures.

The consequences of hot flashes/hot flushes//night sweats/VMS experienced by perimenopausal and postmenopausal women, aging men and breast and prostate cancer patients cannot be overstated. These overwhelming devastating symptoms not only have a significant impact on the quality-of-life, affect decision-making for life preserving hormone deprivation therapy for breast cancer and prostate cancer patients but also have significant economic and societal consequences. When just considering the consequences of VMS suffered by postmenopausal women it was reported in a study of 252 273, women (mean age 56 years), who did not receive medical therapy for VMS that they had 1.5 million more outpatient health care visits, 82% more all-cause outpatient visits and a 121% more VMS-related outpatient visits. This translated to a 57% decrease in work productivity due to loss of days with an estimated incremental direct cost totaling $339,599,458 and indirect work productivity loss cost of $27,668,410. 34 , 35 The KÜLKUF wrist cooling device achieved a clinically meaningful 46% reduction in severe hot flashes, demonstrating significant efficacy as a nonpharmaceutical intervention. This effect size exceeds established clinical significance thresholds and was consistent across diverse populations: breast cancer patients (41%), postmenopausal women (50%), and prostate cancer patients (50%). The uniform response across different etiologies suggests a common neurophysiological pathway that can be effectively targeted through peripheral cooling. 27 , 36 , 37 , 38 , 39 , 40 KÜLKUF offers several distinct advantages compared to other nonpharmaceutical interventions including yoga and acupuncture which on review were not recognized as being effective nor recommended by The North American Menopause Society. 17 Whereas hormone replacement therapy can take several days to several weeks for some women to achieve its maximum benefit in controlling VMS, 7 KÜLKUF can induce almost immediately an effect that can be initiated every time the patient is beginning to experience the initiation of a hot flash/hot flush/night sweats/VMS, 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/VMS 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 KNDy neuron set points over time, similar to the progressive adaptation seen in thermal exposure therapies. 26 , 38 , 39 , 40 We hypothesize that the mechanism may involve thermosensory signaling through cold receptors at the wrist. The ventral wrist surface contains transient receptor potential melastatin 8 cold-sensitive ion channels that may transmit signals to the hypothalamus, the specific central mechanisms requires further investigation. 37 , 39 This rapid peripheral cooling input may interrupt the NKB-mediated signaling cascade and thermal sensory input by sympathetic cholinergic neurons, nitric oxide and an unknown neurotransmitter that trigger vasodilation and sweating during hot flashes/VMS. 36 , 38 , 40 Targeting the KNDy network through a more direct neurosensory input by the rapid cooling of the peripheral thermosensory neurons has an additional advantage. Thermosensory signaling is not subjected to poor drug brain bioavailability, drug metabolism nor drug-drug interactions that can be associated with pharmaceuticals. These and other factors including drug toxicity often limit pharmaceutical clinical utility that can lead to clinical failures as was observed with fezolinetant. We hypothesize that the rapid, almost instantaneous cooling sensation (47 °F) potentially creates a powerful competing neural signal that overrides the aberrant hypothalamic response, effectively "resetting" the thermoregulatory system before the full vasomotor cascade develops. 27 , 36 , 37 , 38 , 39 , 40 The absence of reported adverse effects throughout this short-term study period further underscores KÜLKUF's safety profile, contrasting sharply with pharmaceutical interventions like fezolinetant, which carries an FDA boxed warning related to hepatic toxicity. 41 These preliminary safety and efficacy findings suggest KÜLKUF warrants further investigation as a potential intervention 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% to 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 and peripheral thermoregulatory dysfunction suggests a more dynamic and modifiable relationship between peripheral thermoreceptors and central thermoregulatory centers than previously appreciated. 21 , 27 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 noninvasive neuromodulation approaches in managing complex autonomic symptoms.

Several important limitations warrant careful consideration when interpreting these findings. First, this pilot study was significantly underpowered with only 65.3% power to detect the observed effect size for the primary outcome, leaving a 34.7% probability of Type II error. Subgroup analyses were particularly underpowered, with the postmenopausal cohort ( n = 5) providing only 51.2% power to detect even large effects, while other subgroups similarly lacked adequate statistical power for definitive conclusions. Second, maintaining true double-blinding proved impossible due to the perceptible cooling sensation of the active device. Despite using identical-appearing control devices, participants could distinguish between active and placebo treatments, potentially introducing expectation bias. This unintentional unblinding is particularly concerning given our reliance on subjective, self-reported outcome measures. Third, while standardized diaries represent the current gold standard for hot flash assessment, they remain susceptible to recall bias despite our prospective design. The absence of objective physiological measures (such as skin conductance or core temperature monitoring) limits our ability to confirm subjective reports. Fourth, the brief study duration (2 weeks per treatment phase) was insufficient to assess long-term efficacy, potential adaptation effects, or optimal timing strategies. The sustainability of the benefits observed and any potential diminishing effects over time remain unknown. Finally, participants were recruited through social media and clinical trial websites, which may have introduced selection bias toward individuals particularly motivated to find nonpharmaceutical solutions, potentially limiting generalizability to broader patient populations. To partially mitigate this concern, future studies should consider incorporating objective physiological measures (such as skin conductance or core temperature monitoring) alongside subjective reports and potentially employing alternative control conditions that provide different but equally noticeable sensations. 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.

Hot flashes which are sudden, temporary intense sensations of body warmth, often accompanied by flushing and sweating during the day and night (night sweats) are referred to as vasomotor symptoms (VMS). 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 VMS predominantly occur around the head, chest, and upper back and are associated with sleep disturbances, cognitive dysfunction, severe fatigue, increased pain severity, and decreased quality of life. 1 , 2 , 3 , 4 , 5 , 6 , 7 , 10 It has been estimated within the next 25 years 1 billion women worldwide will be older than 50 years and therefore likely begin to experience menopause. Approximately 80% of postmenopausal women will experience these life altering VMS. 11 These symptoms can occur up to 12 months before menopause and continue for a median of 7.4 years. One third of the women can continue to have moderate-to-severe VMS for more than 10 years. 11 The most effective and standard of care therapeutic intervention to mitigate VMS is hormone replacement therapy. However, many women cannot or prefer not to take advantage of this effective therapy. Premenopausal and postmenopausal women who are eligible for hormone replacement therapy often decline its use (54% in the USA, 56% in Europe, and 79% in Japan) 12 for a variety of reasons including publicity and fear related to increased risk for breast cancer and cardiovascular disease including increased risk for thromboembolism and stroke. 7 , 12 , 13 , 14 Furthermore, hormone replacement therapy is contraindicated about 10% of women. 12 Men experience VMS during normal aging as a result of decreased circulating concentrations of testosterone. It has been estimated from a Swedish survey that 31% of noncastrated aging men experience VMS and 50% found that these affected their quality of life. 15 Eighty percent of men with prostate cancer undergoing androgen deprivation therapy (ADT) have been reported to experience VMS. These symptoms may continue even after stopping ADT. Due to the mental distress and life altering symptoms associated with VMS result in some prostate cancer patients discontinuing ADT. 5 , 15 Similarly 50% to 80% of breast cancer patients receiving hormone deprivation therapy experience the unpleasant experiences of VMS which are often more severe than menopausal women experience due to the complete absence of estrogen while on hormone deprivation therapy. 7 , 10 , 11 These life altering symptoms can also lead to the decision to discontinue hormone deprivation therapy, potentially increasing risk for recurrence and mortality. 1 , 2 , 3 , 4 , 16 Therefore, a wide variety of interventions have been investigated as alternative nonhormonal therapies for relief of these devastating symptoms. 11 Current evidence-based treatments include lifestyle modifications (weight loss), behavioral interventions (cognitive-behavioral therapy, clinical hypnosis), procedural approaches (stellate ganglion block), and pharmaceutical agents such as selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, gabapentin, and oxybutynin, as recommended by The North American Menopause Society. However, other commonly used interventions, including supplements, herbal remedies, cooling techniques, trigger avoidance, exercise, yoga, and acupuncture, lack sufficient evidence-based support according to The North American Menopause Society's 2023 position statement. 17 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 , 18 , 19 , 20 , 21 , 22 Serelys Homme therapy was found to be effective on the incidence and severity of VMS in prostate cancer patients receiving ADT and radiation. 23 Most nonhormonal pharmaceutical options for managing hot flashes including selective serotonin-uptake inhibitors are limited by significant side effects. 7 , 17 , 18 , 19 , 20 , 21 , 22 This creates an urgent need for safe, effective, nonpharmaceutical interventions suitable for diverse patient populations experiencing debilitating VMS. Hot flashes result from abrupt estradiol decline in menopausal women and cancer patients undergoing hormone deprivation therapy. This hormonal withdrawal feedback alters hypothalamic thermoregulation through Kisspeptin/Neurokinin B/Dynorphin (KNDy) neurons in the arcuate nucleus. Reduced estradiol increases kisspeptin expression by KNDy neurons, activating the hypothalamic-pituitary-gonadal axis and increasing gonadotropin-releasing hormone and luteinizing hormone production. Simultaneously, KNDy neurons release neurokinin B [NKB]), which interacts with neurokinin 3 receptors (NK3R), activating the thermal regulatory center. This signaling pathway is the defense mechanism to prevent body overheating by causing vasoconstriction of visceral organs and triggering heat dissipation, by augmenting cutaneous blood flow, inducing cutaneous vasodilation, and causing evaporative cooling by sweating which are characteristic of hot flashes/hot flushes/night sweats/VMS. 8 , 21 The discovery linking the genetic variation in TACR3 gene that encodes for the NK3R with variability in experience of hot flashes reported among women provided the rationale for developing interventions to blockade the NKB signaling pathway including oral NK3R antagonists. 21 , 22 , 24 , 25 Furthermore these new insights for the role of NK3R in the hypothalamic-pituitary-gonadal axis, for thermoregulation and the potential for variability in the responsiveness of the NK3R to various control signals can also help explain the basis for individual variability in vasomotor responses. 21 , 24 , 25 , 26 These recent revelations for the NKB/NK3R signaling as a mediator for hot flashes has led to the development of several NK3R antagonists, dynorphin analogs and kappa opioid receptor agonist that modulate KNDy neuron activity that have the potential to alleviate hot flashes. 7 , 8 , 9 , 20 , 21 , 24 , 25 , 26 Fezolinetant, a NK3R antagonist was found to restore the estrogen-induced disruption in KNDy neuronal activity. Clinical trials in menopausal women demonstrated that fezolinetant significantly reduced frequency and severity of hot flashes. 11 , 24 , 26 The most common adverse effects of this medication include headache, gastrointestinal disturbances including abdominal pain and diarrhea, insomnia, back pain, and elevated hepatic transaminase levels. The FDA in 2024 issued a warning regarding the rare occurrence of serious liver injury associated with taking this medication. Another promising medication, elinzanetant, which acts as a dual antagonist of the neurokinin-1 and NK3Rs has been found to significantly reduce VMS. 21 The targeting of neurokinin receptors with antagonists are now being considered for the treatment of polycystic ovary syndrome, uterine fibroids, and endometriosis. 25 Another promising avenue of investigation for controlling hot flashes relates to controlling neurosensory signaling that thermoregulate responses to heat and cooling, by warm-sensitive and cool sensitive neurons in the skin, spinal cord, muscles, and abdominal area that are linked to the hypothalamus. In response to cooling, thermoregulation is achieved by controlling blood flow to the skin mediated by the release of norepinephrine into arterioles in the peripheral vascular system, causing vasoconstriction thereby potentially counteracting cholinergic neurons and acetylcholine’s vasodilatory and sweating effect in the skin. 27 Vigorous exercise can increase core temperature resulting in increased cutaneous blood flow, vasodilation, and sweating. Various cooling modalities including cold water immersion, ice slurry ingestion, cooling garments, ice packs including rapid thermal exchange device have been used to help reduce exercise-induced core temperature increases. 28 Unpublished studies by Dhama Innovations Pvt Ltd found that 47-50 °C showed most relief from hot flashes whereas below 47 °C the body responded by increasing body temperature. 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. 29 , 30 , 31 The wrist has also been identified as an effective site for targeted cooling therapy. Peeke et al 32 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 at 89 °F 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. However, the use of the device was not associated with a statistically significant decrease in the number and severity of hot flashes. 32 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, through the cooling neuron signaling pathway, that the body is experiencing intense cooling thereby shutting off the overheating signals for initiating and controlling vasodilation and sweating thereby 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 breast cancer and prostate cancer patients. KÜLKUF is a wrist wraparound device with a 3 × 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. Fig. 1 KÜLKUF: Advanced wrist cooling device. The image features 3 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. KÜLKUF: Advanced wrist cooling device. The image features 3 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.

The authors have no conflicts of interest to disclose.