Environment and thyroid function.

The environmental factors and endocrine disruptors affecting thyroid hormones and the hypothalamic-pituitarythyroid 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 oneor 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 -adrenoceptor that resists down-regulation during chronic sympathetic stimulation, the -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 0021-972X/04/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 89(4):1526–1528 Printed in U.S.A. Copyright © 2004 by The Endocrine Society doi: 10.1210/jc.2004-0332