INTRODUCTION

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IT IS WELL KNOWN THAT AUTONOMIC THERMOREGULATION and thermal comfort in response to cold stimuli differ even among healthy individuals (10, 24, 28, 29, 34). In Japan, we often encounter women complaining of persistent and intolerable coldness in their bodies and/or fingertips and toes even in a heated room (20-23°C) in winter. Those women also suffer from coldness even in summer in an air-conditioned room (23-26°C), where most people feel thermally comfortable (2). This unusual feeling of coldness in women is commonly called hi-e-sho in Japanese (18, 23), meaning "cold syndrome." However, the mechanism for cold syndrome remains unknown, and there is no medical definition for it. Our primary question is whether the women complaining of the unusual coldness really feel colder than normal women in the same environment due to some specific mechanisms.

Several factors possibly involved in cold syndrome were proposed. They are briefly summarized as follows (18, 23): 1) gender (more than 30% of women in all age groups suffer from cold syndrome, however, the syndrome is rare in men) and 2) body composition (both thin and obese women tend to have the syndrome). These factors are known to influence thermoregulation and/or thermal sensitivity in a cold environment (24, 28, 29). Moreover, it has already been suggested that body core and/or skin temperatures are basic determinants for thermal comfort of cold (5, 9, 10, 12, 13, 16). Thus we assume that differences in body temperature per se and/or thermal sensitivity to cold are fundamental mechanisms in those suffering from the unusual coldness. In this study, we assessed the differences between young nonobese Japanese women with and without the feeling of unusual coldness during a mild-cold exposure. We tested two hypotheses: 1) whether body core and/or skin temperatures decrease more in women who suffer from unusual coldness than those who do not and/or 2) whether women who suffer from unusual coldness feel discomfort from the cold more than those who do not for any given reduction in those temperatures.

	METHODS

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Twelve Japanese female subjects participated in the present study. They gave informed consent for the experimental protocol, which was approved by the Human Investigation Committee of Osaka University Faculty of Medicine. We selected young (19-26 yr of age) women whose body weight and height were close to the average for Japanese young women (51 kg and 159 cm, respectively) to exclude any possible direct effects of age (10) and body composition (29) on body temperature and thermal comfort. In addition, because there is no medical definition of cold syndrome, we chose the subjects based on the 10-question interview shown in Table 1, which contained typical complaints of those suffering from unusual coldness. Subjects were those who answered yes more than seven times in the interview [n = 6, cold-sensitive group (C)] and those who answered yes less than three times in the interview [n = 6, normal group (N)]. Those who answered yes three to seven times were excluded from this study. Selected subjects proved to be healthy by medical examination and had regular menstruation cycles. Subjects in the present study were selected from 66 applicants. One person conducted this selection. The subjects for both groups grew up and currently live in a similar climatic environment. Their physical characteristics are shown in Table 2. All values were similar between the two groups.

Two different experimental sessions were conducted for each subject: 1) an exposure of 23.5°C (cold session) and 2) a time-control session at the ambient temperature of 29.5°C (control session). The order of the two sessions was randomly chosen with a 2-day interval. The temperatures were chosen, based on the comfort chart of Fanger (7), in which the ambient temperature of 29.5°C is within the neutral range of thermal comfort and that of 23.5°C induces a mild cold feeling in naked individuals. Before this experiment, we also verified similar findings in Japanese women, wearing similar clothes, who suffer from unusual coldness and those who do not [i.e., 1) they felt neither cold or cool nor hot or warm at 29.5°C, and 2) the temperature of 23.5°C was not too cold to induce shivering or sudden reduction in body temperature]. All experiments were conducted during the early follicular phase, determined by the day of menstruation cycle, and in summer in Japan (from July to September) to avoid seasonal acclimation to a cold environment. Subjects fasted from 8:00 PM on the day before the experiment. They came to the laboratory at 8:00 AM on the experimental day. Dressed in sleeveless shirts and short pants, they entered the environmental chamber maintained at 29.5°C with a relative humidity of 50%. Subjects rested in a sitting position for 1.5 h while all measuring devices were applied. A Teflon catheter (20 gauge) was placed in a left forearm vein for blood sampling. Subjects rested for another 40 min to obtain baseline data in both sessions. Then, in the cold session, room temperature was decreased to 23.5°C within 40 min and kept at this level for another 80 min. In the control session, the chamber temperature was kept at 29.5°C for the entire period.

Rectal temperature (T_re) was measured with a thermister probe (NEC Sanei) placed 12 cm from the anal sphincter. Skin temperatures at eight sites (forehead, chest, back, abdomen, upper arm, forearm, thigh, and calf) were measured with copper-constantan thermocouples. Temperatures were recorded every 10 s and averaged over 10 min. Mean temperatures for the eight skin sites (T_sk) were calculated on the basis of the regional area (17). In addition, temperature at the ventral surface of the left first fingertip (T_fin) was also measured as an index temperature of the extremities. The accuracy for all the measurements was ±0.1°C. Heart rates (HR) and blood pressure were measured every 10 min (CH-611C, Citizen). Mean arterial pressure (MAP) was calculated as (systolic arterial pressure + 2 × diastolic arterial pressure)/3. Laser-Doppler flow (LDF) on the right forearm was measured by laser Doppler flowmetry (ALF 21, Advance) as an index of skin blood flow and averaged every 10 min. Cutaneous vascular conductance (CVC) was calculated as LDF/MAP. Changes in LDF and CVC were expressed as percent changes from the averaged values during the last 20 min of each baseline period (100% LDF and CVC). Metabolic rate was assessed by indirect calorimetry to evaluate heat production process; expiratory gas of a subject was collected through a face mask (Hans Rudolph, Kansas City, MO), then oxygen and carbon dioxide concentrations and flow rate of the expiratory gas were analyzed every 30 s (AE280s, Minato Medical Science). Metabolic rate was calculated by the values for nonprotein respiration quotient and oxygen consumption rate, and expressed as kilocalories per body surface area (m²) per hour.

Subjects were asked to report thermal comfort for the body and extremities (fingertips and toes) separately every 10 min by marking on a 15-cm line rating scale, which was labeled "cold" 2.5 cm from the left end and "not at all" 2.5 cm from the right end (22). We instructed the subjects to mark on the scale how strong they felt cold discomfort, thus cold meant that they felt severe discomfort due to the cold environment or due to cold extremities. In addition, subjects were allowed to mark the comfort beyond the cold or not-at-all point if necessary. Then the length from the point of not at all to the marked point was measured as the rating score of thermal comfort (shown as a negative value if subjects marked their comfort beyond the not-at-all point).

A 10-ml blood sample was taken at 40, 90, and 160 min after the onset of the baseline period for each session. The blood was divided into plain and EDTA-containing tubes and then centrifuged to serum and plasma. The samples were stored at 80°C until assay. Plasma concentrations of norepinephrine and epinephrine were measured by high-pressure liquid chromatography (model HLC-725CA, Toso). Intra-assay coefficients of variation were 0.7 and 2.4% at 174 and 380 pg/ml standards for norepinephrine and 2.5 and 2.7% at 28 and 246 pg/ml standards for epinephrine, respectively. Serum total thyroxine (T₄) level was determined by enzyme immunoassay (ICN, Orangeburg, NY), and the intra-assay coefficients of variation were 2.0 and 2.5% for 2.0 and 25 µl/dl standards, respectively. Serum cortisol concentration was determined by radioimmunoassay, and the intra-assay coefficients of variation were 4.2 and 2.9% for 3.0 and 25.0 µl/dl standards, respectively.

The differences in physical characteristics between the two groups were compared by t-test. Differences in the measurement values between the C and N groups or the cold and control sessions were assessed by ANOVA with repeated measures. A significant difference of means between the two groups or sessions at a specific time point was subsequently identified by the Newman-Keuls procedure. Regression analysis was conducted by the standard least-square method. Statistical differences in slopes or intercepts for the regression lines between the C and N groups were assessed by t-test. All values are presented as means ± SE, and a null hypothesis was rejected at the level of P < 0.05.

	RESULTS

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Baseline T_re ranged from 36.2 to 37.2°C and from 36.2 to 37.6°C in both sessions in the C and N groups, respectively (Fig. 1B). There was no difference in T_re between the two groups in each session or between the cold and control sessions in each group. T_re remained unchanged during the 160-min measurement except for in the control session in the C group, which increased (P < 0.05) from the baseline value at 140-160 min. Baseline values for T_sk and T_fin were similar between the C and N groups (Fig. 1, C and D). Both T_sk and T_fin in the cold session in both groups were lower (P < 0.05) than those in the control session at 50-160 min and 70-160 min, respectively. T_sk in the cold session decreased with the reduction in ambient temperature without any difference between the two groups, reaching 31.1 ± 0.1 and 31.1 ± 0.2°C at the end in the C and N groups, respectively. In contrast, T_fin in the C group decreased more (P < 0.05) than in the N group at 120-160 min, reaching 23.6 ± 0.2 and 25.6 ± 0.5°C in T_fin at the end in the C and N group, respectively. Differences in baseline T_re, T_sk, and T_fin between the control and cold sessions in each subject were ~0.3°C in T_re and ~0.2°C in T_sk and T_fin.

View larger version (27K): [in this window] [in a new window]   Fig. 1.   Ambient temperature (Ta; A), rectal temperature (Tre; B), mean skin temperature (Tsk; C) from 8 sites, and fingertip temperature (Tfin; D) during the cold and control sessions in the cold sensitive (C) and normal (N) groups. Values are means ± SE (n = 6). *Significantly different between the C and N groups in each session (P < 0.05). Significantly different between the cold and control sessions within a group (P < 0.05).

HR remained unchanged in the control sessions in both groups. However, HR in the C group gradually decreased (P < 0.05) from baseline in the cold session and from baseline in the control session (Fig. 2A). MAP remained unchanged for all sessions (Fig. 2B) in both groups. The percentages of both LDF and CVC in the cold session were lower (P < 0.05) than those in the control session at 70-110 min and 80-160 min in the C and N groups, respectively (Fig. 2, C and D).

View larger version (32K): [in this window] [in a new window]   Fig. 2.   Heart rates (HR; A), mean arterial pressure (MAP; B), and percentage changes in laser-Doppler flow of the skin (%LDF; C) and cutaneous vascular conductance (%CVC; D) during the cold and control sessions in the C and N groups. One hundred percent of LDF and CVC denote the averaged levels at 20-40 min during baseline. Values are means ± SE (n = 6). Significantly different between the cold and control sessions within a group (P < 0.05).

Figure 3 illustrates the metabolic rate estimated by indirect calorimetry. The metabolic rate in the C group was higher (P < 0.05) than in the N group both in the cold and control sessions. There was no significant difference in the metabolic rate between the cold and control sessions in each group.

View larger version (31K): [in this window] [in a new window]   Fig. 3.   Metabolic rate estimated by indirect calorimetry during the cold and control sessions in the C and N groups. Values are means ± SE (n = 6). *Significantly different between the C and N groups in each session (P < 0.05).

Figure 4 shows plasma norepinephrine (Fig. 4A), epinephrine (Fig. 4B), serum T₄ (Fig. 4C), and cortisol levels (Fig. 4D) in all experimental sessions. Those baseline values were similar in all experimental sessions except for a lower (P < 0.05) T₄ level in the C group than in the N group (5.9 ± 0.4 and 8.8 ± 0.7 µg/dl in the C and N groups, respectively). Plasma norepinephrine level in both groups was greater (P < 0.05) during the cold session compared with the control session (at 90 min only in the C group and 160 min in both groups) without any significant difference between the two groups. However, neither cortisol nor T₄ levels were different between the cold and control sessions in each group.

View larger version (23K): [in this window] [in a new window]   Fig. 4.   Plasma norepinephrine (NE; A) and epinephrine (Epi; B) levels and serum total thyroxine (T4; C) and cortisol (D) at 40, 90, and 160 min during the cold and control sessions in the C and N groups. Values are means ± SE (n = 6). *Significantly different between the C and N groups in each session (P < 0.05). Significantly different between the cold and control sessions within a group (P < 0.05).

The rating score of thermal comfort for the body was greater in the C group than in the N group at 50-160 min in the cold session (Fig. 5A). The score for the extremities was also greater in the C group than in the N group at 90-160 min in the cold session (Fig. 5B). The scores for both body and extremities in the cold session were greater than in the control session at 50-160 min in the C group and 80-160 min in the N group. There were no significant differences in the scores between the C and N groups in the control session. In addition, the scores did not change throughout the control session in each group.

View larger version (29K): [in this window] [in a new window]   Fig. 5.   Scores of thermal comfort of cold for body (A) and extremities (B) during the cold and control sessions in the C and N groups. Score 10 indicates cold and the score 0 indicates not cold at all. Values are means ± SE (n = 6). *Significantly different between the C and N groups in each session (P < 0.05). Significantly different between the cold and control sessions within a group (P < 0.05).

Figure 6 shows the relationships between T_sk and the rating score of thermal comfort for the body (Fig. 6A) and between T_fin and the rating score of thermal comfort for the extremities (Fig. 6B) at 30-130 min in the cold session (while both T_sk and T_fin gradually decreased). The relationships were linear (P < 0.05) both in the C and N groups. The slope and intercept of the regression line for T_sk and the rating score for the body were greater (P < 0.05) in the C group than in the N group. However, there were no differences in the regression slope and intercept for T_fin, and the rating score for the extremities between the C and N groups.

View larger version (26K): [in this window] [in a new window]   Fig. 6.   Relationships between Tsk and thermal comfort for the body (A) and Tfin and thermal comfort of cold for the extremities (B) at 30-130 min in the cold session. Values are means ± SE (n = 6).

	DISCUSSION

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In the present study, we assessed changes in body core and skin temperatures, and thermal comfort during a mild-cold exposure in young Japanese women complaining of unusual coldness in their daily lives. Those women reported stronger thermal sensitivity of the body and extremities to cold than normal women.

Thermal comfort for the body. The rating score of thermal comfort for the body was greater in the C group than in the N group in the cold session (Fig. 5A). It is well known that the body core and/or skin temperatures are prime inputs both for thermal comfort for the body and autonomic thermoregulatory responses (5, 9, 10, 12, 13, 16, 25, 26, 33), and several attempts have been made to determine the relative contribution of core and skin temperatures (5, 9, 12, 13, 16). Chatonnet and Cabanac (5) suggested that thermal comfort during a cold exposure was primarily derived from skin temperature in humans. Frank et al. (9) demonstrated that core and skin temperatures contributed equally to thermal comfort in humans. T_re, the index of core temperature, was not changed in the cold session in the C and N groups (Fig. 1B). Therefore, a reduction in T_sk was the prime stimulus affecting thermal comfort for the body in the present experimental conditions (Fig. 1C). However, there was no difference in T_sk between the C and N groups during the cold session. These results show that a greater decrease in body temperature was not the mechanism for the stronger cold discomfort for the body in the C group.

Thermal comfort for the extremities. A reduction in T_fin in the cold session was greater in the C group than in the N group (Fig. 1D). In contrast, there was no statistical difference in the regression slope for T_fin and the rating score of thermal comfort for the extremities between the two groups. The factors generating thermal comfort for the extremities remain unclear, and the temperature of the extremities was measured only at the tip of the first finger. However, an augmented reduction in the extremity temperature could have primarily attributed to the greater cold discomfort of the extremities in the C group (Fig. 5B).

Metabolic rate, skin blood flow, and body temperature. Metabolic rate, assessed to evaluate autonomic heat-production process, was lower in the C group than in the N group (Fig. 3). Despite the difference in metabolic rate, there were no statistical differences in T_re. However, T_re in the control session gradually increased (~0.2°C) in the C group, which may suggest the baseline T_re in the C group was rather reduced and restored to the desired level at the end. The exposure of 23.5°C did not increase metabolic heat production in both groups. Because the body composition, one of the heat-insulation mechanisms, was similar among the subjects in this study (Table 2), the reduction in skin blood flow could have kept T_re unchanged by attenuating heat dissipation through the skin.

Perspectives. Despite the findings of this study, all factors decreasing body temperature and increasing thermal sensitivity to cold are still likely mechanisms for cold syndrome in general. Thus cold syndrome may just indicate problems in thermoregulation and/or thermal perception in women. However, there is no specific factor to explain the high rate of cold syndrome in Japanese women (although an epidemiological survey has not been done so far). Our findings may be associated with a specific mechanism for cold syndrome.