Cold hypersensitivity in the hands and feet (CHHF) is a physical condition in which there is a sensation of noxious cold in an individual’s extremities even under conditions that would not typically evoke such a sensation. Although the precise mechanism of CHHF remains unknown, it has been linked to a heritable phenotype [1] and hypersensitive vasoconstrictor response of the terminal vessels. 
Theoretically, hypersensitive vasoconstriction of the terminal vessels of the internal iliac artery, namely, the penile artery, negatively affects erectile function. CHHF, caused by contraction of blood vessels in the extremities due to psychological stress, neurovascular disease, or medical factors [2], can increase the risk of developing erectile dysfunction (ED). Conversely, CHHF has also been reported to be associated with lower rates of metabolic and cardiovascular diseases including hypertension (HTN), diabetes mellitus (DM), impaired fasting glucose, dyslipidemia, stroke, fatty liver, and angina pectoris [3], which are known risk factors of ED. 
As the potential effects of CHHF on ED are contradictory, there is a need to clarify the relationship between these two pathologies. This study examined the relationship between ED and CHHF in a large cohort of young Taiwanese men. We believe that the findings of the present study will expand our understanding of the pathophysiology of ED, especially in young men.

Sexually active Taiwanese men aged 20–40 were recruited via an online questionnaire comprising general demographic information, comorbidities, subjective thermal sensations of their hands and feet in the past 6 months, and their erectile function using the International Index of Erectile Function-5 (IIEF-5). 
Those who responded "cold" to both hands and feet were defined to have CHHF, while those who answered "warm" or "intermediate" to both hands or feet were classed as the non-CHHF group. Those who answered "I don't know" or "cold" to only one of these two questions were excluded from the present study [3]. Participants who reported cold sensation of hands and feet were classified to have CHHF; those with IIEF-5 score ≤ 21 were considered to have ED. 
Pearson’s chi-square test or Student's t-test were used to compare differences between participants with and without CHHF. Univariate and multivariate logistic regression analyses were performed to investigate predictors of ED in young Taiwanese men.

Among 2,199 participants, 1,191 (54.2%) and 613 (27.9%) were classified as having ED and CHHF, respectively. Men with CHHF were significantly younger, with lower body mass index and total IIEF-5 scores (p <0.001). Participants with CHHF had lower prevalence of diabetes mellitus but higher prevalence of ED, psychiatric disorders (PD), and insomnia (Table 1). In the univariate analysis (Table 2), age ≥30 years, obesity (BMI ≥30 kg/m2), PD, insomnia, lack of regular exercising habits (especially no regular aerobic exercise), and CHHF were significantly correlated with ED. After adjusting for age, obesity, smoking history, comorbidities, and exercise habits, CHHF remained an independent predictor of ED among young Taiwanese men (odds ratio [OR] 1.404, 95% confidence interval [CI] 1.156 – 1.704; p = 0.001).

The prevalence of CHHF in men has been reported to be approximately 10.4–44.3%, which is comparable to the 27.9% incidence found in our study. In the present study, CHHF was found to be associated with increased prevalence of ED (59.5%) among young Taiwanese men. Among all participants in the present study, 54.2% were found to have ED, which was substantially higher than that reported previously. Surveys that rely on volunteers inevitably contain selection bias. We speculate that Internet users with ED likely look up information associated with ED and are therefore more likely complete the online questionnaire in the present study.
The mean age and BMI were lower in the CHHF group, which is consistent with earlier study [3]. CHHF is known to be associated with a lower waist circumference and waist-to-hip ratio in men. The increased layer of fat insulation in obese men could reduce core-to-skin heat loss, which could prevent them from developing CHHF. 
Participants with CHHF had significantly higher incidence of smoking history. Cigarette smoke contains nicotine, carbon monoxide, and oxidants that can damage the endothelium, and thus impair endothelial vasodilation. Increased sympathetic activation due to cigarette smoke may also be a potential contributing factor for CHHF. 
Participants with CHHF had a significantly lower incidence of DM, similar to the findings by Bae et al.[3] Cold stress has been reported to induce adiponectin secretion in the white adipose tissue, leading to diet-induced thermogenesis through elevated glucose utilization, thereby reducing the prevalence of hyperglycemia among men with CHHF. We also found no differences in the incidence of HTN and dyslipidemia between the two groups. However, other studies have indicated that people with CHHF have a lower prevalence of HTN, dyslipidemia, and risk of metabolic syndrome [3]. This may be because those studies predominantly involved women, whereas, we recruited only young men. 
The participants with CHHF had significantly higher rates of PD and insomnia than those without CHHF. We speculated that patients with PD would have a higher sympathetic tone, resulting in vasoconstriction of the terminal vessels of the hands and feet. Those with CHHF would also have difficulty falling asleep because of the uncomfortable coldness of their hands and feet when lying in bed. It has been reported that the degree of peripheral blood vessel dilatation of the hands and feet is a good physiological predictor of rapid onset of sleep.
CHHF can be regarded as dormant Raynaud's phenomenon (RP) without changes in the color of the terminal extremities [1]. RP is associated with reduced skin blood flow, which is exacerbated by cold temperatures or emotional stress. Increased sympathetic receptor activation in blood vessels, endothelial dysfunction, increased concentration of endothelin-1 (ET-1), and various anomalies in the central thermoregulatory system have been hypothesized to be potential contributors to the development of primary RP. Symptoms of RP are similar to those of primary vascular dysregulation (PVD). Vascular dysregulation refers to the regulation of blood flow which is not adapted to the needs of the respective tissues. Vasospasm can cause a reduction in body temperature anywhere on the surface of the body, not only on the hands, feet, or nose, but also at the scrotum. The sensation of cold extremities, a leading symptom of PVD, is supported by finger skin temperature measurements before. A likely basis for PVD is endothelial dysfunction, which results in an imbalance in endothelium-derived vasoregulatory factors with high ET-1 and low nitric oxide (NO) plasma levels. In addition to vascular endotheliopathy, the autonomic nervous system is also compromised. This affects young men in particular, and testosterone has been proposed to play a role. The pathophysiology of ED is similar to that of PVD. We hypothesized that high ET-1 and low NO plasma levels, which signify autonomic dysregulation and endothelial dysfunction, would be a common pathophysiology of CHHF and ED in young men.

Our study indicates that CHHF is a common condition among young Taiwanese men, accounting for 27.9% of study participants. After adjusting for predisposing factor, CHHF remained a significant predictor of ED among youth. Autonomic dysregulation and subclinical endothelial dysfunction may be common pathophysiology of CHHF and ED.

Hur, Y. M. et al. Feeling of cold hands and feet is a highly heritable phenotype. Twin Res Hum Genet 15, 166-169 (2012). https://doi.org:10.1375/twin.15.2.166
Bae, K. H. et al. The definition and diagnosis of cold hypersensitivity in the hands and feet: finding from the experts survey. Integr. Med. Res. 7, 61-67 (2018). https://doi.org:10.1016/j.imr.2017.11.001.
Bae, K. H. et al. The association between cold hypersensitivity in the hands and feet and chronic disease: results of a multicentre study. BMC Complement. Altern. Med. 18, 40 (2018). https://doi.org:10.1186/s12906-018-2082-3.

Continence 12S (2024) 101541
DOI: 10.1016/j.cont.2024.101541