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The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 1 110-116
Copyright © 2001 by The Endocrine Society

Original Studies

Impairment in Cognitive and Exercise Performance during Prolonged Antarctic Residence: Effect of Thyroxine Supplementation in the Polar Triiodothyronine Syndrome1

H. Lester Reed, Kathleen R. Reedy, Lawrence A. Palinkas, Nhan Van Do, Nancy S. Finney, H. Samuel Case, Homer J. LeMar, James Wright and John Thomas

Endocrine Service (H.L.R., N.V.D., N.S.F., H.J.L.), Departments of Medicine and Clinical Investigation (J.W.), Madigan Army Medical Center, Tacoma, Washington 98431; U.S. Food and Drug Administration (K.R.R.), Rockville, Maryland 20857; Department of Family and Preventive Medicine (L.A.P.), University of California at San Diego, La Jolla, California 92093; Department of Exercise Science and Physical Education (H.S.C.), Western Maryland College, Westminster, Maryland 21157; and Office of Naval Research (J.T.), Arlington, Virginia 22217

Address all correspondence and requests for reprints to: H. Lester Reed, Division of Medicine, Middlemore Hospital, Private Bag 93311, Otahuhu, Auckland 6, New Zealand. E-mail: lreed{at}middlemore.co.nz


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Humans who work in Antarctica display deficits in cognition, disturbances in mood, increased energy requirements, a decline of thyroid hormone products, and an increase of serum TSH. We compared measurements in 12 subjects, before deployment (baseline), with 11 monthly studies during Antarctic residence (AR). After 4 months of AR (period 1), half of the subjects (T4 group) received L-thyroxine [64 nmol·day-1 (0.05 mg·day-1)]; and the other half, a placebo (placebo group) for the next 7 months of AR (period 2). During period 1, there was a 12.3 ± 5.1% (P < 0.03) decline on the matching-to-sample (M-t-S) cognitive task and an increase in depressive symptoms, compared with baseline. During the intervention in period 2, M-t-S scores for the T4-treated group returned to baseline values; whereas the placebo group, in contrast, showed a reduced M-t-S score (11.2 ± 1.3%; P < 0.0003) and serum free T4 (5.9 ± 2.4%; P < 0.02), compared with baseline. The change in M-t-S score was correlated with the change in free T4 (P < 0.0003) during both periods, and increases in serum TSH preceded worsening scores in depression, tension, anger, lack of vigor, and total mood disturbance (P < 0.001) during period 2. Additionally, the submaximal work rate for a fixed O2 use decreased 22.5 ± 4.9% in period 1 and remained below baseline in period 2 (25.2 ± 2.3%; P < 0.005) for both groups. After 4 months of AR, the L-thyroxine supplement was associated with improved cognition, which seems related to circulating T4. Submaximal exercise performance decrements, observed during AR, were not changed with this L-thyroxine dose.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
HUMANS WHO LIVE at high latitudes are exposed to environmental extremes of photoperiod length, low temperatures, low relative humidity, seasonal changes in activity, increased electromagnetic radiation, and both social and geographic isolation. More than 280 million people live in circumpolar regions; however, very little is known about the cumulative effects of this environment on human physiology. Antarctica provides an ideal natural laboratory for the study of human responses to extended severe winter conditions (1). Some of these responses may be applicable to residents in more temperate climates.

Military and civilian members of the United States Antarctic Program, who live in a residence in Antarctica (AR) above the 70o S latitude, for extended periods of time, experience deficits in cognition and alterations in mood (2, 3). In 1989, the incidence of self-reported depression (62.1%), irritability (47.6%), and concentration or memory deficit (51.5%) was significant (P < 0.001) (4).

Antarctic residents have also developed a constellation of physiological and hormonal changes called the polar T3 syndrome (5, 6, 7). This syndrome is characterized by an elevation in TRH-stimulated TSH (6) and nonstimulated TSH (7, 8) in the absence of pituitary resistance to thyroid hormones (6). Additionally, a small decline in serum free T3 (FT3) and free T4 (FT4), a doubling in both T3 distribution volume and plasma appearance and clearance rate, as well as a small decrease in T4 distribution volume further help define this condition (8, 9). Physiologically, and presumably as part of hypothermic cold adaptation (10), this group of residents has a fall in body temperature (11) and an apparent 40% increase in daily energy requirements (6, 9).

The circulating thyroid hormone values observed with AR suggest, at least in part, a cerebral and pituitary hypothyroxinemia, which seems associated with cognitive and mood symptoms consistent with this hypothesis. Hypothyroidism is known to be associated with cognitive deficits, mood alterations (12, 13), and changes in visual evoked potentials (14). Cognition and mood are also affected in subclinical hypothyroidism, where serum TSH is minimally elevated and the peripheral products are normal (15). A recent report suggests that memory may be affected in some individuals, even when the serum TSH is in the upper half of the normal range (16). Administration of T4 improves mood and cognitive performance in individuals with subclinical hypothyroidism (15).

We consequently hypothesized that normalizing these circulating thyroid hormone parameters with T4 supplementation may improve cognitive performance and mood state (15). In this paper, we report the effects of T4 [64 nmol·day-1 (0.05 mg·day-1)]) and placebo, during AR, on cognition, mood, resting and exercise O2 use, and serum thyroid hormones.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects

Twelve (11 male and 1 female) healthy euthyroid subjects, all members of the annual military party that wintered over at McMurdo Sound, Antarctica, participated in this study. The protocol was approved by the Madigan Army Medical Center Institutional Review Board, and all subjects gave written informed consent. Subjects were similar to one another with regard to age, body mass index (BMI), body surface area (BSA), exercise capacity, and resting O2 consumption [resting metabolic rate (RMR)] at the beginning of the protocol (Table 1Go). Our original study group included 14 subjects, 1 of whom had subclinical hypothyroidism and another of whom was noncompliant with the protocol, causing both to be excluded from further study. No subject had a history of depressive or thyroid disease, and all were screened by a military physical and psychological assessment. Available diet contained a minimum of 1,182 nmol/day (150 µg) iodine (7, 9), and no chronic medications were taken. These subjects were studied in September, 1996, while in Port Hueneme, CA (34° 09' N; 119° 12' W) before departing for Antarctica (baseline), then again between 10 and 18 days after arrival at McMurdo Sound, Antarctica (77° 51' S, 166° 37' E), in October, 1996, and monthly thereafter through August, 1997. The environmental conditions of temperature and photoperiod during the study are shown in Fig. 1Go, with period 1 lasting the first 4 months of AR and ending with near-total sunlight, and period 2 extending from February to August during the austral autumn and winter.


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  		Table 1. Subject demographics with metabolic measures

 


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  		Figure 1. The protocol design indicated for the two groups shows that both groups consumed a placebo (hatched bar) for the first 4 months (period 1) of the study. During period 2, the T4G (black bar) received 64 nmol·day-1 (0.05 mg·day-1) T4, and the PG (hatched bar) continued the placebo . The arrow indicates arrival in McMurdo, and the mean temperature (solid line) and photoperiod (dashed line) are indicated.

 
During outdoor activity, each subject wore standard polar cold-weather clothing, with which the face and hands are commonly exposed. The minimum outside exposure was approximately 0.5 h·day-1 (6, 9), indoor fluorescent lighting of normal intensity was used, and all subjects maintained routine 8-h·day-1 sleep cycles. Indoor living compartment temperature was between 18 and 25 C, although there is a substantial vertical thermal gradient in Antarctica (17). The laboratory air temperature was between 22.6 and 23.7 C, and relative humidity was between 63.7 and 81.5% during blood sampling and metabolic testing.

Study protocol

After baseline measurements, the subjects were rank-ordered, then randomly assigned to either a placebo group (PG) or T4-administration group (T4G). Both groups consumed (daily) a pharmaceutical-grade, opaque, white, gelatin capsule beginning in September, 1996, and ending after the last measurement in August, 1997. Placebo capsules were consumed by both groups for the first 4 months of AR (period 1) in a single-blind fashion (Fig. 1Go). After 4 months (period 2), in a double-blind protocol, the placebo capsules were replaced with capsules containing 64 nmol (0.05 mg) L-thyroxine (Levoxyl; Daniels Pharmaceuticals, Inc., St. Petersburg, FL) for the T4G, while the PG continued with placebo. Therefore, the mean dose of 32.3 ± 0.5 nmol·m-2·day-1 (25.1 ± 0.4 µg·m-2·day-1) represented an attempt to normalize the 65-nmol·m-2 T4 deficit previously suggested to be present during period 2 (9). This conversion occurred in the month of February and preceded the March testing period by a mean of 26.5 days. Pill counts were maintained during the monthly capsule distribution, and a representative rate of medication compliance of 92.5% was noted in March.

Biochemical measurements

Blood for thyroid hormone analysis was collected just before the metabolic measures at baseline and then monthly after arrival in Antarctica (Fig. 1Go). Sampling was completed between 0530–1100 h, just before metabolic testing and after a 12-h fast. Blood was allowed to clot at room temperature, then was separated and stored at -70 C. From Antarctica, all samples were transported in October, 1997, at -70 C, to Tacoma, WA, where they remained at this temperature until they were coassayed, in duplicate, using a batch method for subject and assay. FT4 and FT3 were analyzed using commercially available kits (AxSYM; Abbott Laboratories, Abbot Park, IL) with an intraassay coefficient of variance (CV) of 6% and 7%, respectively, and an assay detection limit of 5.15 pmol/L (0.4 ng/dL) and 1.69 pmol/L (1.1 pg/mL), respectively. TSH was measured by a commercial kit (Diagnostic Systems Laboratories, Inc., Webster, TX) with an intraassay CV of 4% and effective lower detection limit of 0.03 mU/L. The reference ranges and conversion to SI units used for these assays are: FT4, 2.19–23.81 pmol/L (ng/dL x 12.87 = pmol/L); FT3, 2.22–5.35 pmol/L (pg/mL x 1.536 = pmol/L); and TSH, 0.5–5.1 mU/L.

Cognitive testing

After orientation and training, subjects achieved a mean proficiency of 74% accuracy with the matching-to-sample task (M-t-S) (18, 19, 20, 21). In this task, a grid pattern of red and green squares is presented on a computer screen and, after a delay, the grid is replaced with 2 similar patterns, 1 of which is the original. This test of attention, spatial and short-term memory, and pattern recognition uses 20 trials and has been reported to show 10% differences in similar paired groups (20). Subjects used individual identical computers, located in quiet areas, to carry out this monthly testing. Our within-subject CV for this test was 10.5% during repeated testing at baseline.

Each month, subjects also completed the profile of mood states and the Center for Epidemiological Studies depression (CES-D) scale (22, 23). The profile of mood states is a 65-item, self-report mood questionnaire that obtains data on 6 factors: tension-anxiety, depression-dejection, anger-hostility, vigor-activity, fatigue-inertia, and confusion-bewilderment. A total mood disturbance score was calculated by summing the scores of the individual factors after weighting the vigor-activity score negatively, thereby providing a global estimate of affective state. This test of mood has been used in previous polar studies in Antarctica (23) and to test changes in mood with therapy of hypothyroidism (12). The CES-D scale (22) was used to measure depressive symptoms, where respondents described their mood, over the preceding week, by rating each of the 20 items, on a scale from 0–3.

Metabolic measurements and exercise protocols

While subjects were dressed in shorts, socks, and an undershirt, body weight and a tympanic temperature (Tty) (Model HH-300, Exergen Corp., Watertown, MA) were measured. Our one female subject also had urine measured for pregnancy determination. The subjects then rested for 20 min, in the supine position, covered with a light blanket. Subsequently, standard O2 utilization measures were obtained for 10 min (SensorMedics Metabolic Cart, Model 2900z; SensorMedics Corp., Yorba Linda, CA) (24, 25). The two identical metabolic carts were calibrated using barometric pressure and temperature corrections with standard concentrations of O2 and CO2 and were reassessed before each new subject. The O2 and CO2 analyzers have an accuracy of 0.03% and 0.05%, respectively, and the ventilation volume is accurate to ±3%.

After measurement of the resting O2 uptake, the subjects began the submaximal testing with the cycle ergometer (Monark model 818E; Monark, Vansbro, Sweden). Each subject pedaled at 50 rpm for 3 min at stair-step work rates of 0, 25, 50, and 75 W. Data were collected from the steady-state final 2 min of each work rate, hereafter referred to in watts (24). During all submaximal tests, peak values of O2 consumption (O2) were below 50% maximum O2 use (O2max) (26). Submaximal studies were carried out at baseline and then twice at each monthly period, always following the RMR measure, and separated by a 20-min rest period. O2max was measured at baseline and at the end of period 2 using standard criteria (27).

Calculations from O2max and exercise performance. Each submaximal test was used to fit a linear regression model of O2 vs. work rate in watts (P < 0.01) (26); and from that an intercept, the regressed RMR (RMRr), and slope ({Delta}O2/{Delta}Watt) were derived. A standardized work rate (WRs) was calculated using a midrange O2 of 400 mL·min-1·m-2 for each individual (26). Because of the submaximal nature of the work rate and an unchanged respiratory exchange ratio between the resting RMR (0.814 ± 0.027) and the completion of the submaximal period (0.844 ± 0.022), we report only the O2, as is customary (24).

Analysis

The data were subjected to an ANOVA for within-period, between-period, and group differences. If differences within a period existed, then individual step-wise repeated model fitting or iterative regression analyses were carried out to determine the structure of the change (Systat; Systat Inc., Evanston, IL), and the parameters were compared in a paired fashion when appropriate (28). Relationships between serum measures and cognitive function were carried out with linear regression, ANOVA, and analysis for covariance. Unless otherwise stated, significance was determined at the P < 0.05 level, and ± SEM are listed.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Physiological parameters of subjects (Table 1Go)

Tty declined from baseline by 0.87 ± 0.10 C for the pooled value representing all of period 1 and by 1.21 ± 0.10 C for the pooled value representing all of period 2 (P < 0.0001). No group difference was noted. O2max, the time to reach O2max, the maximum work achieved with O2max, resting heart rate, and body weight, BMI, and BSA were not different between groups, nor was there a significant change in these measures over the study.

Thyroid hormone measurements (Table 2Go and Fig. 2Go)

Serum FT4 in the PG declined from baseline (13.6 ± 0.3 pmol/L) over the entire study, by a mean of 4.72 ± 1.89% (P < 0.017) and, specifically, by 5.93 ± 2.37% as a pooled measure for all of period 2. FT4 in the T4G was not different from the PG in baseline or in period 1. However, in period 2, the pooled monthly value increased 8.10 ± 2.63% over baseline (P < 0.03), and this change was different from the PG (P < 0.006) represented by the final measurement in period 2, of 14.3 ± 0.6 pmol/L, compared with 12.9 ± 0.3 pmol/L for the PG.


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  		Table 2. Thyroid hormone and mood scores with group comparisons

 


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  		Figure 2. The six PG subjects were used to determine a 12-month change in serum TSH over the study (P < 0.001). The mean (solid line) and ±SEM (···) of the individually fitted sine function parameters are shown (P < 0.01).

 
Serum FT3 declined slightly from baseline by a mean 3.67 ± 1.30% in both groups (P < 0.04) over the entire study. The pooled values for period 2 showed no group difference and are represented by the final monthly measurement in period 2, of 3.82 ± 0.17 pmol/L for the PG and 3.61 ± 0.23 pmol/L for the T4G.

Serum TSH in the PG showed an effect of time (P < 0.001), over the 12-month study, with a sine distribution, where the mean amplitude and period are shown in Fig. 2Go [1.14·sine (0.812·months in Antarctica), (P < 0.01)]. The model predicted a period of 7.74 months, with peak values (46.1 ± 6.8%) in November and (46.0 ± 6.7%) in July above the mesor. The minimum was predicted during March as 46.1 ± 6.8% below the mesor (Fig. 3Go). Serum TSH was not different between the PG and the T4G in baseline or over period 1. However, the pooled period 2 mean serum TSH in the T4G was reduced to1.64 ± 0.33 mU/L or 24.1 ± 0.2% below the mesor for the PG (P < 0.00001) and, although somewhat lower, was not different than baseline. The same PG seasonal pattern for TSH was not observed for the T4G.



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  		Figure 3. The mean changes, compared with baseline, for the paired M-t-S raw test score percent-correct (±SEM) are shown with respect to duration of Antarctic Residence. The whole study group (n = 12) is compared in the first and last month of period 1 (P < 0.02) (•; solid line). Changes in performance are represented midway through period 2 for both the T4G ({blacksquare}; dashed line), who were administered 64 nmol·day-1 (0.05 mg·day-1) T4 (P = not significant) during all of period 2 and the PG (•; solid line) (P < 0.0003).

 
Cognitive and mood assessment (Table 2Go and Fig. 3Go)

Cognitive assessment. M-t-S scores, which were similar between groups at baseline (PG, 76.8 ± 2.4%; T4G, 71.0 ± 2.2%), with a mean score for the whole study group of 73.9 ± 2.2% correct, remained unchanged from baseline for the first 3 months of period 1 (PG, 73.6 ± 3.1%; T4G, 72.4 ± 2.8%). By the final month of period 1 (January), the M-t-S score decreased to 64.4 ± 3.3% (P < 0.03) (PG, 60.7 ± 2.3%; T4G, 68.2 ± 6.4%) or 12.3 ± 5.1% below baseline measures. In contrast, during period 2, the T4G increased their score to 73.6 ± 5.0% or +4.0 ± 6.7% (not significant) above baseline, while the PG remained 11.2 ± 1.3% below baseline (P < 0.0003) with a mean score of 68.3 ± 3.0%.

Correlation of cognitive and thyroid hormone assessment. The percent change from baseline in individual subjects’ M-t-S scores was related to the % change in serum FT4 from baseline, by both the end of period 1 (January) (P < 0.04) and throughout all of period 2 (P < 0.01). Over the entire study, between January (period 1) and through period 2, for each 1.0% change in FT4, there was a 1.13 ± 0.26% change in the M-t-S score (P < 0.0003). This regression has an intercept of -5.5 ± 2.6% change in M-t-S score, with no change in FT4.

Mood assessment. Self-reported symptoms of depression, as measured by the CES-D scale, increased from baseline during period 1 in both groups (P < 0.05) (Table 2Go). Depressive symptoms remained higher, compared with baseline, throughout period 2 in both groups, but the difference did not reach significance (P = 0.07). The T4G reported less fatigue-inertia (P < 0.01) and confusion-bewilderment (P < 0.05), during period 2, than the PG.

Correlation of mood and thyroid hormone assessment. In both groups, increases in serum TSH, during period 2, preceded high scores for depression-dejection, tension-anxiety, anger-hostility, lack of vigor-activity, and total mood disturbance (P < 0.001). Declines in serum FT3, during period 2, preceded high scores for worsening fatigue-inertia and confusion- bewilderment in both groups (P < 0.05).

Metabolic and exercise assessment (Table 1Go)

The RMR increased from baseline in both groups by 11.0 ± 3.6% for the pooled value of all of period 1 (P < 0.05) and by 19.3 ± 4.7% for the pooled value in period 2 (P < 0.005). The individual group values, pooled for all of period 2, increased over baseline by 19.8 ± 2.8% (PG) and 18.9 ± 9.0% (T4G), but they did not differ from one another. Representative values for the final month of each period are listed in Table 1Go. There was no within-period change.

The WRs decreased from baseline (18.2 ± 0.9 W) over the study (P < 0.0001), to a mean for all of period 1 of 13.3 ± 0.4 W or a 22.5 ± 4.9% decline. For all of period 2, the mean of 13.6 ± 0.4 W represented a 25.2 ± 2.3% decrease from baseline. No difference was found between the groups or within a period.

The RMRr increased over the study (P < 0.02). From baseline (231 ± 8 mL·min-1·m-2), it increased for all subjects by 16.5 ± 3.2% as a pooled value for all of period 1 (P < 0.01), and the pooled value for period 2 remained elevated above baseline by 15.8 ± 3.1% (P < 0.04). The pooled value in period 2 for each group (PG, 264 ± 6 mL·min-1·m-2; T4G, 262 ± 7 mL·min-1·m-2) remained above baseline, without a difference between groups. There was no within-period change detected.

The {Delta}O2/{Delta}Watt increased from baseline (9.17 ± 0.34 mL·min-1·watt-1) to 9.91 ± 0.22 mL·min-1·watt-1 for a pooled value for all of period 1, and it remained elevated at 10.14 ± 0.19 mL·min-1·watt-1 for the pooled value of period 2 (P < 0.04). This change represents a 9.2 ± 3.8% increase in period 1 and a 12.0 ± 4.1% increase in period 2, over baseline. No group difference over the study and no change within a period were detected.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
A T4 supplement of 64 nmol (0.05 mg) per day will improve both cognition and some self-reported mood scores during extended residence in Antarctica. Reductions in serum FT4 are correlated with poor responses on cognitive tests, and an elevated serum TSH precedes declines in mood. This supplement does not change the reduced submaximal exercise performance, body temperature, FT3, or elevated RMR observed during the same period.

Cognition and mood

A seasonal component for affective illness has been described; and, although the specific mechanisms are unknown, thyroid hormones have been suggested as a contributor (29, 30). Human cognitive performance declines under conditions of experimental cold air exposure and during military operations in cold geographical locations (18, 19, 20, 21). A 29% decline in the M-t-S score is noted while humans are exposed to cold air at 4 C (20). Tyrosine administered before the cold exposure reverses this cognitive defect which has been termed: cold induced amnesia (20). Living in heated housing conditions does not correct thyroid hormone changes observed during residence in cold environments (5, 8, 21).

Cognition and mood with T4 intervention. The relationship between the change in serum FT4 and the change in cognition is present both in period 1 and period 2, supporting the early association between these two variables within 4 months of AR. Changes in FT4 can account for approximately 56% of the decline in cognition in Antarctica, whereas other hormonal, environmental, and psychological features are also possible contributors. A fall in body temperature, as we report, is a hallmark of human hypothermic cold adaptation (10, 31). The effect of a 1.0-C reduction in Tty on mood and cognition during AR is unknown, although it may depress both. Based on the lack of a difference in RMR, RMRr, WRs, or pulse rate between groups, and the absence of a statistical decline in TSH below baseline for the T4G, it is unlikely that the treatment group was overreplaced with T4 in period 2. Additionally, it would be unusual for overreplacement to improve cognition in this protocol (32).

The specific role of T3 in the genesis of hypothyroid- associated psychological decrements was recently reported by Bunevièius, et al. (12). Our study does not address this issue directly, except that FT3, which is slightly decreased in both groups, over the study, is associated with more fatigue, confusion, and depression (CESD) independent of T4 administration. Although not significant, the serum FT3 tended to be 5.5% lower in the T4-treated group, compared with placebo, by the last month of the study. The reduced FT3, which may be statistically significant with an increased study population, suggests a thyroidal contribution to FT3. The doubling of T3 clearance, with cold exposure that is independent of TSH and T4 (33, 34), may help explain why compensation could be marginal. Because only 56% of the changes in cognition are related to changes in FT4, it is possible that declines in central nervous system (CNS) T3 may contribute to some of the remaining cognitive decrement during AR (12).

The majority of CNS T3 is generated locally by type-II deiodinase (5'DI-II). A tissue-specific increase in 5'DI-II activity during cold exposure, as described for rodent brown adipose tissue, could occur in human brain during AR and mild reductions in body temperature. Therefore, the serum TSH would be maintained at suboptimal levels in the setting of small decreases in serum FT4, as we observe. In this cold exposure model, we speculate that selective brain tissues with previously low local T3 contributions by 5'DI-II or Type-I deiodinase, such as the hypothalamus, may become increasingly dependent on circulating T4. With T4 administration, a specific CNS carrier protein, transthyretin (TTR), which carries T4 preferentially to T3, could ensure a homogeneous distribution of T4 to these CNS sites (35). Binding to TTR with its low-affinity sites would be augmented with increased serum FT4, and disassociation from TTR to brain tissue could be facilitated because of the relative reduction of T4 in the CNS.

Serum TSH

A semiannual pattern of serum TSH is noted in Belgium, where differences of 29% occur between a bimodal peak in December and July and a trough in May (36). Although our findings agree with this report, the photoperiod in Antarctica is opposite; therefore, either the outdoor temperature exposure or the rate of change of photoperiod may play a significant role in this observation (30). Sawhney, et al. (37) report peaks of serum TSH between 3–4 months and again after 11–12 months of AR. Our subjects arrived in October and displayed the peaks after 1–3 and 9–11 months of AR.

This seasonal TSH pattern, which is common to both hemispheres, suggests the possibility of reductions during the rapid change in photoperiod near an equinox in March and September (Figs. 1Go and 2Go) or stimulation with 1–3 months of winter weather conditions. Factors such as body temperature, photoperiod, circulating FT4, dietary iodine, decreased androgen status (38), or cytokine alterations (38) may facilitate chronic TSH stimulation or a phase shift in the circadian pattern while in Antarctica. These possibilities could contribute to the augmented peaks of our seasonal curve, compared with those observed in Belgium (36). It is unlikely that the changes in thyroid hormones that we report are attributable to depression alone (13). Because this seasonal curve was not observed with the T4G, who had a 24% reduction in TSH and an 11% increase in FT4 in period 2, compared with the PG, we would suggest that reduced circulating FT4 could contribute significantly to its development.

Metabolic measures

Increased energy requirements associated with AR and other polar sites (37, 38, 39) have been inferred from dietary records (5, 9, 39). Without a change in resting heart rate and O2max, we would favor (as suggested by some, for hyperthyroidism) a skeletal muscle or peripheral vascular tone etiology to account for increased O2 use with AR (27, 40).

The direction and magnitude of the metabolic changes we see are in agreement with observations during hyperthyroidism (24, 25, 27). However, because an 8–15% increase in resting energy expenditure observed during thyroid overreplacement should be detectable in our study, it is unlikely that our T4 treatment group received excessive replacement when measured by either metabolic parameters or serum TSH (27, 41). Our study is limited by a small subject population, which is typical for this unique environment, and small group differences may have been obscured by the large between-period increases of 11–19% for metabolic measures with AR.

The increased T3 in skeletal muscles or other metabolically active tissues (9) may be dependent on a tissue-specific thyroid receptor or uptake increase associated with cold sensitive T3 tissue binding (8) and increased T3 clearance. Thus, skeletal muscle could extract T3 from the serum preferentially and show little metabolic effect on T4 therapy, as long as the serum FT3 concentrations remain similar between the treatment and placebo groups. Tissue-specific uptake (42), action (43, 44), and receptor isoform distribution (45) are well known.

We conclude that T4 supplementation can improve declines in cognition and mood, but it does not normalize exercise performance, body temperature, or serum FT3 observed during AR. Both the metabolic and cognitive features of this syndrome may well exist at other high-latitude extremes where screening for mood and thyroid disorders would be prudent. Further study is needed to determine the relevance of this work to lower latitude, temperate climate winters.


   Acknowledgments
 
This study could not have been completed without the dedicated support of the subjects from the Naval Support Force Antarctica, Dr. Mark Staudacher, and the helpful suggestions of Dr. K. M. M. Shakir during protocol development and manuscript review. The study group appreciates review of this manuscript by Drs. T. Dillard and F. Flynn and the editorial assistance of Ms. Christine Reed. We are also grateful for the support from the Antarctic Support Associates; in particular, Ms. Roberta Score, Mr. Russel Bixby, and Mr. Robert Robbins.


   Footnotes
 
1 Presented in part at the 80th Annual Meeting of The Endocrine Society, New Orleans, Louisiana, June 24–27, 1998, and the 71st Annual Meeting of The American Thyroid Association, Portland, Oregon, September 16–20, 1998. This work is supported in part by National Science Foundation Grant OPP-9418466 and Madigan Army Medical Center Department of Clinical Investigation Grant 96083. The opinions expressed herein are those of the authors and are not to be construed as reflecting the views of the Department of the Army, the Department of Defense, National Science Foundation, or U.S. Food and Drug Administration. Back

Received February 1, 2000.

Revised May 31, 2000.

Revised September 11, 2000.

Accepted September 19, 2000.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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