Effects of the Environment, Chemicals and Drugs on Thyroid Function.
This chapter considers the effects of various environmental factors, drugs and chemicals, and nonthyroidal diseases on thyroid function. In animals, cold exposure causes a prompt increase in TSH secretion, which gives rise to thyroid hormone release and leads to thyroid gland hyperplasia. Part of this effect is due to an apparent increase in the need for thyroid hormone by peripheral tissues and to an excessive rate of hormone degradation and excretion. In humans, hypothermia causes a dramatic TSH secretion in the newborn, but this response is lost after the first few years of life. Exposure to heat has an opposite effect, although of lesser magnitude. A small seasonal variation in serum thyroid hormone levels that follow this general pattern has been reported. Simulated altitude and anoxia depress thyroid hormone formation in rats, but in humans serum T4 and T3 concentrations, T4 degradation, and oxygen consumption are at least temporarily augmented by high altitude. Starvation has a profound effect on thyroid function, causing a decrease in serum T3 concentration and a reciprocal increase in rT3 level. These changes are due to a selective inhibition of the 5′-monodeiodination of iodothyronines by peripheral tissues. Reduction in carbohydrate intake rather than total calorie deprivation appears to be the determinant factor. These alterations in thyroid function are believed to reduce the catabolic activity of the organism and thus to conserve energy in the face of decreased calorie intake. Chronic malnutrition is accompanied by similar changes. Overfeeding has opposite although transient effects. Physical and emotional stresses can have variable and opposite effects. Increased thyroid hormone secretion and serum levels have been observed in stressed animals and in acute psychiatric patients on admission. The physical stress of surgery causes a prompt decrease in the serum T3 concentration, probably as a consequence of decreased T3 neogenesis. This effect of surgery cannot be fully explained on the basis of increased adrenocortical activity or calorie deprivation. Many minerals alter the synthesis of thyroid hormone, mainly through their interference with iodide concentration and binding by the thyroid gland. The action of iodine is only briefly covered here since it is discussed in Chapters 2 and 13. Calcium, nitrate, bromine, rubidium, and fluorine are allegedly goitrogenic. Lithium carbonate, used in the usual doses for the treatment of affective disorders, can produce goiter in susceptible persons. It inhibits iodide binding and hormonal release from the thyroid gland, probably through a synergistic action with iodide. Numerous dietary goitrogens, including cyanogenic glucosides, thioglucosides, thiocyanate, and goitrin, are present in a wide variety of foods, and are believed to contribute to the occurrence of endemic goiter in some areas of the world. Monovalent anions such as thiocyanate and perchlorate inhibit iodide transport into the thyroid and cause goiter. Thionamide drugs such as PTU and the related compound, methimazole, inhibit thyroid peroxidase and thus prevent thyroid hormone synthesis. In addition, PTU but not methimazole inhibits the conversion of T4 to T3 in peripheral tissues. Under appropriate circumstances, sulfonamides, sulfonylureas, salicylamides, resorsinol, amphenone, aminoglutethamide, antipyrine, aminotriazole, amphenidone, 2,3-dimercaptopropanolol, and phenylbutazone have antithyroid action. A growing list of drugs and diagnostic agents have been found to affect thyroid economy by modulating the regulation of the hypothalamic-pituitary-thyroid axis, as well as by interfering with thyroid hormone transport, metabolism, excretion, and action. Some drugs, such as salicylates, diphenylhydantoin, and glucocorticoids, act at several levels. Several compounds, most notably estrogens, diphenylhydantoin, diazepam, heparin, halophenate, fenclofenac, and some biologically inactive thyroid hormone analogs compete with binding of thyroid hormone to its carrier proteins in serum. The only consequence of drugs affecting hormone transport is a decrease or increase in the concentration of total but not free hormone in serum. Glucocorticoids, drugs such as propranolol, and amiodarone and some iodinated contrast media inhibit the extrathyroidal generation of T3. The result is a decrease in serum T3 and an increase in rT3 concentrations, with a slight increase or no change in T4 values. Thyroid hormone disposal is accelerated by diphenylhydantoin and phenobarbital, which increase several of the pathways of hormone degradation, and by hypolipemic resins, which increase the fecal loss of hormone. Homeostasis is usually maintained by a compensatory increase in thyroid hormone secretion. Some drugs act through inhibition or stimulation of TSH secretion. Most notable of the former effect are dopamine agonists such as L-dopa and bromocryptine, as well as some -adrenergic blockers, glucocorticoids, acetylsalicylic acid, and opiates. A variety of dopamine antagonists as well as cimetidine, clomifene, and spirolactone appear to increase TSH secretion. These compounds seem to interfere with the normal dopaminergic suppression of the hypothalamic-pituitary axis. Observed changes in TSH secretion are not associated with significant metabolic alterations. Some of the drugs have an apparent effect on TSH secretion through changes induced at the levels of the free and active forms of the thyroid hormone. A handful of drugs appear to block or antagonize the action of thyroid hormone on tissues. These drugs include guanethidine, propranolol, and dinitrophenol. Some drugs may induce autoimmune thyroid disease. Notably among these are lithium, interferon and interleukin. The clinician should be thoroughly familiar with the effects of drugs, nonthyroidal illnesses, and other extraneous factors on thyroid function. These factors should all be taken into account in the differential diagnosis of primary thyroid disease.