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chronological age

FIGURE 9 Effects of thyroid therapy on growth and development of a child with no functional thyroid tissue. Daily treatment with thyroid began at 4.5 years of age (vertical arrow). Bone age rapidly returned toward normal, and the rate of growth (height age) paralleled the normal curve. Mental development, however, remained infantile. (From Wilkins L. The diagnosis and treatment of endocrine disorders in childhood and adolescence, Springfield, IL: Charles C Thomas, 1965.)

chronological age

FIGURE 9 Effects of thyroid therapy on growth and development of a child with no functional thyroid tissue. Daily treatment with thyroid began at 4.5 years of age (vertical arrow). Bone age rapidly returned toward normal, and the rate of growth (height age) paralleled the normal curve. Mental development, however, remained infantile. (From Wilkins L. The diagnosis and treatment of endocrine disorders in childhood and adolescence, Springfield, IL: Charles C Thomas, 1965.)

Metabolism Oxidative Metabolism and Thermogenesis

More than a century has passed since it was recognized that the thyroid gland exerts profound effects on oxidative metabolism in humans. The so-called basal metabolic rate (BMR), which is a measure of oxygen consumption under defined resting conditions, is highly sensitive to thyroid status. A decrease in oxygen consumption results from a deficiency of thyroid hormones, and excessive thyroid hormone increases BMR. Oxygen consumption in all tissues except brain, testis, and spleen is sensitive to the thyroid status and increases in response to thyroid hormone (Fig. 10). Even though the dose of thyroid hormone given to hypothyr-oid animals in the experiment shown in Fig. 10 was large, there was a delay of many hours before effects were observable. In fact, the rate of oxygen consumption in the whole animal did not reach its maximum until 4 days after a single dose of hormone. The underlying mechanisms for increased oxygen consumption are not well understood.

Oxygen consumption ultimately reflects activity of mitochondria and is coupled with formation of high-energy bonds in ATP. Physiologically, oxygen consumption is proportional to energy utilization. Thus if consumption of oxygen increase, there must be increased utilization of energy or the efficiency of coupling ATP production with oxygen consumption must be altered. T3 appears to accelerate ATP-depen-dent processes, including activity of the sodium potassium ATPase that maintains ionic integrity of all cells and to decrease efficiency of oxygen utilization. In normal individuals activity of the sodium potassium ATPase is thought to account for about 20% of the resting oxygen consumption. Activity of this enzyme is decreased in hypothyroid individuals, and its synthesis is accelerated by thyroid hormone. A variety of other metabolic reactions are also accelerated by T3, and the accompanying increased turnover of ATP contributes to the increase in oxygen consumption.

ATP synthesis is limited by availability of ADP in the mitochondria. ADP is regenerated from breakdown of ATP at various extramitochondrial sites and must be returned to the interior of the mitochondria. Transport of ADP across the inner mitochondrial membrane and phosphorylation to ATP are driven by the proton gradient created by the electron transport system, which thus couples ATP synthesis with oxygen consumption. Leakage of protons across the inner mitochondrial membrane ''uncouples'' oxygen consumption from ATP production by dissipating the gradient. As a result, electron transport to oxygen proceeds at a rate that is unlimited by availability of ADP, and the energy derived is dissipated as heat rather than as formation of high-energy phosphate bonds. Leakage of protons into the mitochondria depends on the presence of special uncoupling proteins (UCP) in the inner mitochondrial membrane. To date three proteins thought to have uncoupling activity have been identified in mitochon-drial membranes of various tissues. All three appear to be up-regulated by T3. Although the physiologic importance of UCP-1 seems firmly established (see later discussion), the physiologic roles of UCP-2 and UCP-3 remain controversial.

Thyroid Hormone and Temperature Regulation

Splitting of ATP not only energizes cellular processes but also results in heat production. Thyroid hormones are said to be calorigenic because they promote heat production. It is therefore not surprising that one of the classical signs of hypothyroidism is decreased tolerance to cold, whereas excessive heat production and sweating are seen in hyperthyroidism. Effects of thyroid hormone on oxidative metabolism are seen only in animals

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