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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 4 1529-1533
Copyright © 2004 by The Endocrine Society

Special Feature

Elevation in Serum Thyroglobulin during Prolonged Antarctic Residence: Effect of Thyroxine Supplement in the Polar 3,5,3'-Triiodothyronine Syndrome

Nhan Van Do, Lizbeth Mino, George R. Merriam, Homer LeMar, H. Samuel Case, Lawrence A. Palinkas, Kathleen Reedy and H. Lester Reed

Internal Medicine Service, Madigan Army Medical Center (N.V.D., H.L.R.), Tacoma, Washington 98431; New Mexico Resonance (L.M.), Albuquerque, New Mexico 89111; Veterans Affairs Puget Sound Health Care System, Tacoma, Washington 98493, and Division of Metabolism, Endocrinology, and Nutrition, University of Washington (G.R.M.), Seattle, Washington 98195; Endocrine Service, William Beaumont Army Medical Center (H.L.), El Paso, Texas 79920; Department of Exercise Science and Physical Education, McDaniel College (H.S.C.), Westminster, Maryland 21157; Department of Family and Preventive Medicine, University of California (L.A.P.), San Diego, California 92093; U.S. Food and Drug Administration (K.R.), Rockville, Maryland 20857; and Multicare Medical Group (H.L.R.), Tacoma, Washington 98415

Address all correspondence and requests for reprints to: Dr. Nhan Van Do, Stanford Medical Informatics, Medical School Office Building, x-215, 251 Campus Drive, Stanford, California 94305-5479. E-mail: nhan.do{at}us.army.mil.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Extended Antarctic residence (AR) is associated with an increase in serum TSH, a decrease in free T4, and an increase in T3 production and clearance. It is not clear whether these adaptations reflect changes in clearance alone or whether intrinsic thyroidal synthetic activity also changes. Thyroglobulin (Tg) secretion is an independent marker of intrinsic thyroid activity whose kinetics are independent of those of T3 and T4. In this study we examined changes in Tg levels in healthy subjects before and during AR and their responses to thyroid supplementation to help determine whether alterations in thyroid activity, and not just kinetics of clearance, underlie the changes seen with the polar T3 syndrome. In cohort 1, we compared measurements of TSH and Tg in 12 subjects before deployment and monthly for 11 months during AR. In cohort 2, we compared the same measurements in 12 subjects monthly for 11 months of AR. Subjects were randomized to receive either placebo or levothyroxine in cohort 1 for 7 months and in cohort 2 for 11 months. Tg increased over baseline during the first 4 months of AR by 17.0 ± 4.6% and after 7 more months by 31.7 ± 4.3% over baseline in the placebo group of both cohorts (P < 0.0002). When L-T4 was taken, Tg returned to a value not different from baseline (4.5 ± 3.9%). The percent changes from baseline in serum TSH and Tg during AR were highly correlated (P < 0.00003) in the placebo group for both cohorts. The rise in Tg with TSH and the reduction in Tg with L-T4 provide evidence of target tissue response to TSH and further confirm the TSH rise as physiologically significant. The results also suggest that the adaptive changes in thyroid hormone economy with AR reflect TSH-dependent changes in thyroid synthetic activity, which may help explain a portion of the increases in T3 production found with AR.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
OVER THE PAST two decades, Antarctica has served as a natural laboratory to study physiological responses to severe winter conditions and habitation in circumpolar regions (1, 2, 3, 4, 5, 6, 7). Thyroid hormone has been a focus of our interest because it is partly responsible for the regulation of body temperature, energy expenditure, and cardiac and skeletal muscle functions, and its homeostasis is affected by temperature, photoperiod, and seasonal changes (8, 9, 10, 11). Thyroid hormone also affects mood and memory, disorders of which have been reported in inhabitants of Antarctica (12, 13, 14). In our earlier studies we found that inhabitants of this continent experience a constellation of physiological and thyroid hormonal changes known as the polar T3 syndrome (6). This syndrome is characterized by an increase in serum T3 production and clearance, a decrease in free T4 (FT4), and an increase in serum TSH.

After 6 months of Antarctic residence (AR) serum TSH has been shown to increase by approximately 30%. One surrogate marker of thyroid activity during AR that we evaluated was lipid metabolism (15). An earlier study by our group (15) demonstrated covariability between a rise in serum TSH and an increase in serum lipids during extended AR. Additionally, we recently reported (5) that the rise in serum TSH with AR is concurrent with a decline in cognition, which is reversed with T4 supplementation. This observation is in agreement with previous reports of mood and memory improvement with T4 administration in the setting of subclinical hypothyroidism (12). Some of these same subjects from our previous study (5) are included in this report with regard to newly observed changes in thyroglobulin (Tg).

It is not clear whether the adaptations of the polar T3 syndrome reflect changes in intrinsic thyroidal synthetic activity or changes in clearance rate alone. The objective of this study was to determine whether this rise in TSH is related to increased thyroid activities using TSH-dependent Tg as a marker. A rise in Tg would reflect a biologically significant change in TSH. The study compared changes in serum Tg with those in serum TSH during Antarctic residence to determine whether T4- and TSH-dependent Tg are affected by living in Antarctica.

We chose Tg as a marker for several reasons, including sensitivity, suppressibility, and seasonal variability (16, 17, 18, 19). Tg, a precursor of T3 and T4, is produced only by benign or malignant thyroid tissues, as shown by the study by Fugazzola et al. (20) using sensitive Tg assays and mRNA. Stimulated Tg, even in small amounts, can be assumed to come from the thyroid (20), and as Tg values are affected by small changes in thyroid volume, it is a sensitive indicator of thyroidal activity (20, 21, 22).

Under normal physiological conditions, TSH is the most important regulator of Tg synthesis and secretion (18). Torres et al. (22) showed that TSH stimulation in small amounts by both natural and recombinant TSH can rapidly increase the Tg level. When TSH is suppressed with exogenous T4, the Tg level is also suppressed quickly and reproducibly, as demonstrated by Wang et al. (23). Seasonal changes in serum Tg have been reported in northern countries (16). Our own prior study (5) demonstrated seasonal variabilities in TSH (5) when subjects had a sufficient dietary intake of at least 150 µg/d (5).

Other conditions that can cause abnormal serum Tg levels include abnormal clearance from renal failure; abnormal release from toxic nodules or thyroiditis; abnormal leakage from needle aspiration or thyroid surgery; abnormal stimulation by substances with TSH-like bioreactivity, such as thyroid-stimulating immunoglobulin from Graves’ disease; and chronic stimulation from iodine deficiency, goitrogens, or TSH-producing pituitary adenoma (16, 17). Tg levels, however, are not affected by age, sex, or body weight (16), and if the factors that may affect Tg are excluded, as in this study, then Tg can be used as a reliable marker of thyroidal activity.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subject characteristics: cohort 1 (1996–1997)

Other aspects of studies conducted in this cohort, particularly the effects of T4 supplementation on cognition and exercise capacity, have been previously reported (5).

Twelve euthyroid subjects (11 men and one woman) from the winter-over personnel at McMurdo Station, Antarctica, participated in this study. Recruitment of participants and initiation of study protocol occurred at Port Hueneme, CA, before the arrival of the subjects in Antarctica. Cohort 1 had all baseline measurements performed in California before leaving for Antarctica. There were 15 subjects who originally enrolled in the study. Exclusion criteria were thyroid disease; psychiatric illnesses; pregnancy; significant cardiac, renal, hepatic, or pulmonary disease; alcohol or drug dependency; and medications known to affect thyroid function. All subjects in both cohorts gave written consent. The protocol was approved by the institutional review board at Madigan Army Medical Center. The characteristics of the subjects are presented in Table 1Go.


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  		TABLE 1. Subject demographics with metabolic measures

 
Subject characteristics: cohort 2 (1997–1998)

Twelve euthyroid subjects (13 men and four women) from the winter-over personnel at McMurdo Station, Antarctica, participated in this study. Exclusion criteria were the same as for cohort 1. Seventeen subjects were initially enrolled. Recruitment of participants and initiation of the study protocol occurred within 1 month of the arrival of the subjects at McMurdo. In contrast to cohort 1, cohort 2 had baseline measurements performed in Antarctica. The characteristics of the subjects are presented in Table 1Go.

The subjects had various job positions at McMurdo. The minimum daily outdoor or environmental exposure was 30 min/d. When outdoors, each subject wore standard-issue polar cold weather clothing that commonly left hands and face exposed. Testing conditions were maintained at a mean indoor temperature of 24 C. Relative humidity during the metabolic studies was 39%.

Study protocol: cohort 1 (1996–1997)

After baseline measurements, subjects were stratified according to gender and body mass index, then randomly assigned to either the placebo group (PG) or the T4-treated group (T4G). From September to January (period 1), all subjects from both groups consumed each day a placebo capsule containing one pharmaceutical-grade opaque white no. 2 size gelatin capsule containing rice grains. From February to August (period 2), in a double-blinded protocol, subjects assigned to T4G were given dosages of L-T4 (50 µg levoxyl; USP, NDS 0689-1118-10, Daniels Pharmaceuticals, St. Petersburg, FL) in the same gelatin capsule with the same rice filler, and subjects assigned to the PG continued to consume one placebo capsule per day. In both study protocols monthly pill counts were performed to ensure compliance. This element of compliance was over 90% as we have previously reported (5).

Each month for the subsequent 12 months participants reported to the medical facility at McMurdo to provide blood for TSH, FT4, and free T3 (FT3) determinations and also for measurements of resting metabolic rate and submaximal oxygen consumption.

Study protocol: cohort 2 (1997–1998)

The study design in this protocol was a randomized, double-blind, and placebo-controlled trial. After baseline measurements, subjects were stratified according to gender and body mass index and then were randomly assigned to either a PG or the T4G. Placebo and L-T4 administration began immediately after randomization. Each month for the subsequent 12 months, participants reported to the medical facility at McMurdo to provide blood for TSH, FT4, and FT3 determinations and for measurements of resting metabolic rate and cycle ergometry. For this cohort, period 1 is defined as October to January, and period 2 is February to August.

These two cohorts were combined to increase the number of subjects and the power of the study. The subjects were comparable with regard to demographic data and environmental exposure. The protocols differed only in that T4 treatment was given in both periods 1 and 2 for cohort 2, whereas the treatment group in cohort 1 received T4 only during period 2.

Biochemical measurement

Blood for thyroid hormone analysis was collected after a 12-h fast at baseline in September for cohort 1 and in October for cohort 2, and then monthly. Blood was allowed to clot at room temperature and was separated for storage at –70 C. At the end of the study the frozen samples were transported from Antarctica at –70 C to Tacoma, WA, for analysis. Samples were stored at –70 C until being assayed in duplicate in batches. TSH was measured by a commercial kit (Diagnostic Systems Laboratories, Inc., Webster, TX). FT4 and FT3 were also measured by commercial kits (AxSYM, Abbott Laboratories, Chicago, IL) Tg was measured using chemiluminescence kits from Nichols Institute Diagnostics (San Juan Capistrano, CA; product 604240). The reference ranges for these assays and conversion factors for Systeme International (SI) units are: for Tg (nanograms per milliliter), to covert to SI units multiply conventional units by 1.0 to equal micrograms/liter (reference values, 3–42 ng/ml); for TSH (microunits per milliliter), to convert to SI units multiply by 1.0 to equal milliunits per liter (reference range, 0.5–5.0 mU/liter); for serum FT4 (nanograms per deciliter), to covert to SI units multiply conventional units by 12.87 to equal picomoles per liter (reference values, 0.17–1.85 ng/dl); for serum FT3 (picograms per milliliter), to covert to SI units multiply conventional units by 1.536 to equal picomoles per liter (reference values, 1.45–3.48 pg/ml). Analysis was carried out using ANOVA, linear regression, and occasional isolatedt testing. Unless otherwise stated, significance was determined at the P < 0.05 level, and ±SEM values are listed.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The mean baseline serum Tg for all subjects was 17.06 ± 3.48 ng/ml. Tg increased with AR to 25.7 ± 3.6% over the baseline (P < 0.0001) in the combined PGs of both cohorts. The increase in Tg was 17.0 ± 4.6% over baseline in period 1 and 31.7 ± 4.3% over baseline in period 2 in the PG of both cohorts (P < 0.0002). The increase between periods 1 and 2 was significant in this paired group. When T4 was determined during period 2, Tg returned to a value not different from baseline (4.5 ± 3.9%) in this group. When the subjects in the T4G of cohort 1 who received placebo during period 1 were added to the placebo groups to expand the analysis, the change in Tg from baseline (24.0 ± 3.5% over baseline) was similar to those in both cohort PGs (25.7 ± 3.6%), as listed above (Table 2Go). Additionally, when all subjects taking L-T4 were pooled over both periods, the Tg value was not different from baseline (–0.06 ± 2.71%; Table 2Go).


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  		TABLE 2. Baseline and mean change in Tg, TSH, T4, and T3 from baseline during AR

 
The mean baseline serum TSH was 1.99 ± 0.16 µU/ml. During AR, serum TSH for all placebo subjects in both cohorts increased 42.6 ± 8.30% above the baseline (Table 2Go); with T4 it declined to –12.4 ± 5.2% below baseline in the T4G for both cohorts, indicating a difference from baseline and between PG and T4G. The relationship between TSH and Tg in cohort 1 is shown in Fig. 1Go. The percent changes from baseline in serum TSH and Tg during AR were highly correlated (r = 0.441; P < 0.00003) in the PGs for both cohorts, but this relationship was weaker in the T4G for both cohorts (r = 0.226; P < 0.050). The percent changes in FT4 and FT3 were not correlated with the percent change in Tg in the PG of both cohorts. However, the percent changes in FT4 (P < 0.01) and FT3 (P < 0.05) were negatively correlated with the percent change in Tg in the treatment groups of both cohorts.



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  		FIG. 1. Changes in TSH and Tg over time. The time sequences of both the percent change in Tg from baseline and the absolute value of TSH over 11 months of AR are shown for cohort 1. The serum Tg and TSH levels (TG-LT4 and TSH-LT4) of the treatment group that received 50 µg/d L-T4 starting in February, 1997, and the serum Tg and TSH levels (TG Placebo, TSH-Placebo) in the PG for cohort 1 are shown.

 
The baseline values for FT4 (1.38 ± 0.05 ng/dl) and FT3 (2.31 ± 0.07 pg/ml) are listed in Table 2Go for all subjects in both cohorts. In the PG of both cohorts during all of AR, FT4 declined by 1.41 ± 1.71% (P = NS), and FT3 was unchanged in these combined cohorts. With T4 administration, FT4 increased 8.99 ± 1.96% over baseline (P < 0.05), and FT3 declined by 4.98 ± 1.87% (P < 0.05).

Subjects excluded after the original 15 enrolled in cohort 1 included one for subclinical hypothyroidism and two others because of noncompliance with the study protocol. In cohort 2, 17 subjects were enrolled, and one was excluded because of clinical hyperthyroidism, three because of noncompliance with the study protocol, and one because of illness that necessitated evacuation from the station.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The results of this study indicate that the polar T3 syndrome reflects changes in intrinsic thyroid activity, as indicated by an elevation in Tg that is reversed by thyroid hormone supplementation. This observation extends our understanding of dynamic thyroid hormone economy beyond changes in thyroid hormone clearance kinetics.

Our prior study of Antarctic residents showed an increase in TSH up to 30% over a course of 10–11 months of AR (15). When a standard amount of TRH was given with graded and increasing does of oral T3 suppression, there was a 50% increase in the TSH response to TRH after 42 wk of AR at all levels of T3 administration (3). The percent TSH suppression by each T3 dose, however, was similar to baseline. Small decreases in total T3 and FT3 serum concentrations were observed compared with baseline values (3, 4). This observation suggests that changes in TSH responsiveness and circulating T3 levels are due to peripheral T3 metabolism and not to changes in pituitary sensitivity (3). Kinetic studies show a doubling of T3 production rate, clearance rate, and volume of distribution, which may be linked to the increase in serum TSH through changes in either circulating or tissue-specific T4 concentrations (6, 10).

This study shows that serum Tg increases with AR and is T4 dependent. The increase correlated with changes in TSH and was abolished by L-T4 supplementation. The results of this study and the prior observation of the covariability between lipid metabolism and thyroid hormone changes during AR suggest that the adaptive changes in thyroid hormone economy with AR reflect changes in thyroid synthetic activity and not in clearance rate alone, which may help explain the increases in T3 production (15). The approximately 5% decline in serum FT3 with T4 supplementation during AR further supports the role of glandular or T4-sensitive type II deiodinase enzymatic contribution to circulating FT3 that may be extenuated with AR. The Tg rise provides evidence of target tissue response to TSH. These alterations in thyroid gland activity could contribute to the biochemical, physiological, and cognitive changes that we and others have described in association with the polar T3 syndrome.


   Acknowledgments
 
We thank Monica Kletke for skilled conduct of the Tg assays, Jim Wright for laboratory assistance, and the winter-over members of the 1996–1997 and 1997–1998 crews at McMurdo for their participation in the study.


   Footnotes
 
This work was supported in part by National Science Foundation Grant OPP-9418466.

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, the National Science Foundation, or the U.S. Food and Drug Administration.

Results from this work were presented in part at the 83rd Annual Meeting of The Endocrine Society, Denver, CO, June 20–23, 2001.

Abbreviations: AR, Antarctic residence; FT3, free T3; FT4, free T4; PG, placebo group; T4G, T4-treated group; Tg, thyroglobulin.

Received October 15, 2003.

Accepted January 11, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Weller G, Bently CR, Elliot DH, Lanzerotti LJ, Webber P 1987 Laboratory Antarctica: research contributions to global problems. Science 238:1361–1368[Abstract/Free Full Text]
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  6. Reed HL, Silverman ED, Shakir KM Dons R, Burman KD, O’Brian JT 1990 Changes in serum triiodothyronine (T3) kinetics after prolonged Antarctic residence: the polar T3 syndrome. J Clin Endocrinol Metab 70:965–974[Abstract]
  7. Sawhney RC, Malhotra AS, Nair CS, Bajaj AC, Rajan KC, Pal K, Prasad R, Basu M 1995 Thyroid function during a prolonged stay in Antarctica. Eur J Appl Physiol 72:127–133[CrossRef]
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