Medical Faculty University of Geneva Geneva, CH 1211 Switzerland
Address all correspondence and requests for reprints to: Professor Albert G. Burger, M.D., 9D, plateau de Frontenex, CH-1223 Cologny (Ge), Switzerland. E-mail: agburger{at}bluewin.ch.
The environmental factors and endocrine disruptors affecting thyroid hormones and the hypothalamic-pituitary-thyroid axis have not been studied extensively, possibly because of difficulties in recognizing minor disturbances of thyroid function. In terms of the physiological adaptations of thyroid function to seasonal changes, our knowledge is also rather poor because most of the studies were done before the availability of third generation serum TSH measurements. In these early studies, only TRH tests could give us an idea of the fine-tuning of TSH secretion. The measurement of the free T4 and T3 concentrations is also delicate, and it is likely that the modern one- or two-step techniques used in autoanalyzers are not as reliable as measuring these hormones by ultrafiltration or by dialysis (1). Unfortunately, the latter techniques are rarely used.
Before discussing the results obtained in the Antarctic, reported in this issue of JCEM (2), the data from Belgium, which has a moderate climate, are briefly reviewed (3). Circulating concentrations of TSH, in addition to a distinct circadian rhythm, also demonstrate circannual variations, low in spring and summer and highest in the autumn. Differences are quite small, ranging from a low of 1.48 mU/liter to a high of 1.85 mU/liter, about a 25% difference. This is mirrored by circulating T3 concentrations, but with even smaller differences. No seasonal differences have been found in T4 concentrations. These albeit small changes are supportive of earlier data using TRH stimulation testing. The obvious question is whether these variations in TSH and T3 are an expression of an internal clock or are secondary to environmental effects, and/or even something else.
Other factors need to be considered before climate change can be held responsible for these changes. Iodine intake in Belgium is in the lower end of the recommended range. Yet, the same small circannual changes in TSH are also seen in hypothyroid and T4-substituted subjects, demonstrating that the changes are independent of the iodine supply (4). The importance of the rare earth element selenium on thyroid metabolism has been revealed recently with the discovery that the three important peripheral monodeiodinases are selenoproteins (5). Selenium deficiency induces a characteristic thyroid hormone profile, including high TSH, high T4, and low T3. Although the selenium supply is marginal in Western Europe, it is unlikely that selenium deficiency can increase serum TSH alone without the concomitant presence of iodine deficiency as well. Also, the low ratio of T3 to T4 with a high TSH is not the hallmark of circannual changes in thyroid function (6).
It is likely that seasonal changes in thyroid hormone metabolism reflect some adaptive internal mechanism, and studies under extreme climatic conditions might help to elucidate this mechanism (7). Much has been learned about the physiological adaptations to extreme climatic conditions using animal models, for instance, hibernators (woodchuck or marmot), estivators (bears), and homeotherms (rat). Circannual changes in thyroid function and/or metabolism have been reported in many of these models. The discovery of increased thermogenesis in "brown fat" in small rodents exposed to the cold has markedly increased interest in this field. Brown fat is brown because it contains adipocytes packed with mitochondria containing uncoupling protein-1, which is driven by a unique ß-adrenoceptor that resists down-regulation during chronic sympathetic stimulation, the ß-3 adrenoceptor (8, 9). This system of nonshivering thermogenesis allows for continued heat production during cold exposure and is responsible for the ability of small rodents to maintain homeothermy. Thyroid hormones play an important role in this thermogenic mechanism in brown fat. The conversion of T4 to T3 by the tissue-specific type-2 monodeiodinase is essential for the local sympathetic stimulation (10). This unique system of nonshivering thermogenesis becomes less important as the size of homeotherms increases. For instance, brown fat is a source of heat in human newborns and small infants but not later in life. There have been some reports claiming that such a mechanism can be reactivated in severely or chronically cold-challenged adults, but this postulate is not generally accepted (11, 12).
In addition, true hibernators have adapted marked seasonal changes in the circulating concentrations of thyroid hormones and their binding proteins (13). Bears are not true hibernators and apparently show little evidence for adaptive mechanisms other than to lower their body temperatures while sleeping. Many questions remain concerning the thyroidal adaptations to extreme climatic conditions, including at the level of the hypothalamic-pituitary axis, within the thyroid gland, in the levels of transport proteins, in changes in peripheral thyroid hormone metabolism and cellular thyroid receptor expression or function.
A group of investigators report in this issue (2) new observations in response to these questions. They report evidence for physiological adaptations in thyroid functions, as well as to environmental temperature, photoperiod, gravity, and possible changes in time zone. Many of these observations were carried out during expeditions to the base of McMurdo in the Antarctic (77 degrees, 51 South, and 166 degrees, 37 East). The volunteers were mostly men (80%) with average age of 33.1 yr. They arrived at the site in early austral summer and stayed through the winter. The minimum average outdoor exposure was 0.5 h/d with face and hands mostly exposed. Food intake was increased 40%, and depression and cognitive dysfunction were frequent problems (14). In 1986, the authors reported that the integrated TSH response to TRH in the austral winter increased by 50% compared with that in a moderate climate (15). In later studies, circannual rhythms in unstimulated TSH levels were more pronounced and slightly shifted compared with those in moderate climate. The TSH levels were high on arrival in November and decreased in March, increasing again in the austral winter months (16). The question is whether these changes are purely central (hypothalamic-pituitary), a reflection of changes in peripheral thyroid metabolism, or a combination of the two?
They found a 42% increase in the circulating levels of thyroglobulin during the 42-wk stay in the Antarctic, suggesting for the first time that there was increased thyroidal secretion. The change in thyroglobulin concentrations could also be explained by hemorrhage or cyst formation and leakage of the protein, or even chronic dehydration. Against this, however, were the longitudinal changes and individual change in TSH levels and the observation that treatment with 50 µg of T4 reduced circulating thyroglobulin levels, both indicating that the changes in thyroglobulin were due to thyroidal secretion.
If increased secretion was the only change in thyroid homeostasis, one would expect an increase in serum T4 and T3 concentration. This is not the case, although the results of serum T4 and T3 measurements during the different expeditions were not strictly identical; one can say that serum T4 and free T4 did not change significantly and if anything, they had a tendency to decrease in austral winter months. Contrary to changes in serum binding proteins in small hibernating rodents, serum TBG concentrations remained unchanged (17). Serum total and free T3 levels decreased slightly but significantly. These minimal changes are misleading because detailed kinetic studies showed marked changes for this hormone and gave rise to the term "polar T3 syndrome." The authors demonstrated by two independent methods that the volume of distribution, its metabolism, and its production were significantly increased (18, 19). Kinetic studies estimated an increase of 140% of T3 production. They also gave increasing doses of T3 orally and observed after cold exposure a greater decline of serum T3 levels 24 h after the last dose. This also indicated that in the Antarctic, T3 metabolism is increased.
At first glance, such changes can only be due to thyroid hormone metabolism, yet the increase in thyroglobulin levels in the article in this issue (2) clearly indicates a participation of thyroidal secretion. An increase in thyroidal secretion is not incompatible with a role for monodeiodination because human thyroid contains deiodinase type 1 and type 2, the latter being stimulated by TSH, and could therefore contribute to an increased thyroidal secretion of T3 (5, 20).
What could be the triggering mechanism? In these subjects, food intake is greatly increased without a proportionate change in body weight. In a moderate climate, increased food intake has been shown to increase T3 production (21). However, under those conditions of controlled dietary increases alone, serum T3 is also increased, but not so in the Antarctic where more complex changes have to occur. Sympathetic tone is known to be increased by cold exposure (22, 23). In humans, the contribution of muscle may account for 40% of thermogenesis (24, 25). Human muscle is also rich in uncoupling protein-3, which could contribute to heat dissipation (26, 27, 28). This protein is induced not only by free fatty acids but also by T3 (29, 30, 31). In the Antarctic, during standardized submaximal exercise testing, the subjects showed a 2225% decrease in work efficiency; in other words, for the same amount of exercise, they used more oxygen (16). Could this be related to the higher T3 production rate? Exercise efficiency is not altered in mild hyperthyroidism (32). This 22% decrease of work efficiency can therefore not be an expression of straightforward tissue hyperthyroidism. Further work will be needed on that subject.
The effect of thyroid hormones on depression, cognition, and memory solicits controversial opinions because some authors report beneficial effects of thyroid hormone treatment, more specifically treatment with T4 and T3, in depression and manic diseases. Others consider this simply the result of fortuitous association. An advantage of the polar T3 syndrome is that depression and cognitive dysfunctions associated with extreme exposures can be studied prospectively. The authors have provided good evidence that thyroid hormone treatment can prevent or alleviate the depressive symptoms and the decline in cognition that accompanies extended residence in Antarctica (16). This observation is particularly interesting because recently an article has described positive mood changes with a combined treatment of T4 and T3 (33). More recent articles have not been able to confirm these findings, but they were done in completely different settings, the first one in Lithuania, the other in Australia and North America (34, 35). It is certainly possible, however, that further studies of the adaptations of thyroid function in extreme climatic conditions, such as in the Antarctic, may uncover and elucidate new central nervous system effects of thyroid hormones.
Received February 19, 2004.
Accepted February 19, 2004.
References
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