A number of compounds have the ability to inhibit thyroid hormone synthesis (Fig.5-3). Irrespective of their mechanism of action, they are collectively called goitrogens, because as a result of a decrease in serum thyroid hormone level. TSH secretion is enhanced, causing goiter formation. Some goitrogens occur naturally in food, and others are in drugs with goitrogenic side effects. The least toxic and those possessing the highest thyroid-inhibiting activity are used in the treatment of hyperthyroidism.
 |
| Figure 5-3. Structural formulas of some drugs that affect the thyroid. |
Dietary Goitrogens
The discovery of natural and synthetic substances that impair the synthesis of thyroid hormone are landmarks in the history of pharmacology.131 These substances are discussed in more detail in Chapter 20. Although iodide deficiency is, without doubt, the major cause of endemic goiter and cretinism throughout the world, dietary goitrogens may play a contributing role in some endemics, and may possibly be the dominant factor in certain areas. The dietary goitrogens fall into several categories, more than one of which may occur in the same food.
Certain foods contain cyanogenic glucosides,132 compounds that, upon hydrolysis by glucosidase, release free cyanide. These foods include almond seeds and such important dietary items as cassava, sorghum, maize, and millet. Cassava contains enough cyanogenic glucoside to be lethal if large quantities are consumed raw. Ordinarily, the root is extensively soaked, then dried and powdered. Most of the cyanide is lost in this process; that left in the root is liberated after ingestion and converted to SCN-. Chronic poisoning due to cassava is responsible for a tropical neuropathy in Nigeria133 and Tanzania, and is suspected of being a contributing cause of goiter in Central Africa.134,135
Other important classes of antithyroid compounds arise from hydrolysis of the thioglucosides.132,136,137 These compounds are metabolized in the body to goitrin or thiocyanates and isothiocyanates, and ultimately to other sulfur containing compounds, or are excreted as such. They are important in the goitrogenic activity of seeds of plants of the genus Brassica and the cruciferae, compositae, and unbelliferae. Among the plants containing these compounds are cabbage, kale, brussel sprouts, cauliflower, kohlrabi, turnip, rutabaga, mustard, and horseradish. Cattle may ingest these goitrogens and pass them to humans through milk, as observed in Australia,138 Finland,139,140 and England.141 . The isothiocynate, cheiroline, occurs in the leaves of choumoellier and may be related to a focal area of endemic goiter in Australia. The goitrogen is thought to be transmitted from forage to cows, to milk, and finally to children. Although there is considerable circumstantial evidence relating these compounds to endemic goiter, it has been difficult to prove their role with certainty.
Thiocyanate is a well-known inhibitor of iodide trapping when in high concentration in blood. The blood levels obtained by ingestion of dietary goitrogens are rarely of this degree. Inhibition of iodide trapping, and thyroid peroxidase activity, and augmentation of urinary iodide loss, as demonstrated by Delange and Ermans and co-workers, all my play a role in the goitrogenic activity.132,134,135 Thiocyanate may also reduce the iodine content of breast milk or animal milk and thus indirectly impact the thyroid function of young children in areas of marginal iodine sufficiency. 141a
Astwood et al. and Greer142,143 found that turnips contain progoitrin, which is a mustard oil thioglycoside. It undergoes rearrangement by enzymes in human enteric bacteria, or in the turnip, to be converted to goitrin, an active goitrogenic thioglycoside, L-5-vinyl-2-thio-oxazolidone.144,145 Goitrin inhibits oxidation of iodine and its binding to thyroid protein in the same way as do the thiocarbamides.
Several endemics of goiter have been attributed to dietary goitrogens, usually acting together with iodine deficiency. Goitrin is apparently present in cow's milk in Finland.146 In the Pedgregoso region of Chile, pine nuts of the tree Araucaria americana are made into a flour and consumed in large amounts, and may be related to endemic goiter.147,148 In the Cauca river valley of Colombia, sulfur-containing compounds found in the water supply, derived from sedimentary rocks containing a large amount of organic matter, are believed to be responsible for endemic goiter.149 At least, extracts from these waters are goitrogenic in rats. Pearl millet has been reportd to cause goiter development in goats. 149a
Other mechanisms may also contribute to dietary goitrogenicity. Thus, diets high in soybean components or other materials increasing fecal bulk may cause excess fecal loss of T4 and increase the need for this hormone.150-153 These diets are low in iodine content, and soybean has been thought but not proven to contain a goitrogen.
The goitrogens, by blocking hormone synthesis, deplete the thyroid of iodide; this reduction itself increases the sensitivity of the gland to TSH.154 This sensitivity, in turn, further promotes goitrogenicity.
According to their principal mode of action on thyroidal iodine metabolism, antithyroid drugs are divided into two categories: (1) the monovalent anions, which inhibit iodide transport into the thyroid gland, and (2) a large number of compounds that act through inhibition of thyroidal iodide binding and iodotyrosine coupling. The most important representatives of this latter category of compounds are the group of thionamides. The effect of the drugs in the first category is counteracted by exposure to excess iodine, whereas iodine has no, and at times even potentiates, the action of drugs in the second category. Other drugs inhibit thyroid hormone secretion or act through yet unknown mechanism. A list of these agents is provided in Table 5-1.
Monovalent Anions. Certain monovalent anions (SCN-, Cl04-, NO3-) inhibit transport of iodide into the thyroid gland and thereby depress iodide uptake and hormone formation.164-166 Thiocyanate stimulates efflux of iodide from the thyroid as well,167 and also inhibits iodide binding and probably coupling.168,169 A large number of complex anions, such as monofluorosulfonate, difluorophosphate, and fluoroborate,170 inhibit iodide transport. Of these, fluoroborate,171 like perchlorate,172 is concentrated by the thyroid gland. These ions have a molecular volume and charge similar to those of iodide, and may compete with iodide for transport.170,171 Perchlorate is sufficiently active to be useful clinically.173 Perchlorate and thiocyanate also displace T4 from thyroid hormone-binding serum proteins in vivo and in vitro and cause a transient elevation of free T4.174 In contrast to the pharmacologic effects of perchlorate, concerns have been raised about the potential health effects of environmental perchlorate exposure, especially in municipal water supplies. Several studies have been unable to detect an increase in hypothyroidism 174a, congenital hypothyroidism 174b, or thyroid cancer 174c in exposed populations.
Thionamides. The thionamide and thiourylene drugs do not prevent transport of iodide into the thyroid gland, but rather impair covalent binding of iodide to TG.175-177 They may be competitive substrates for thyroid iodide peroxidase, preventing the peroxidation of iodide by this enzyme. In small doses, the thiocarbamides inhibit formation of iodothyronines from iodotyrosyl precursors. When slightly larger amounts are present, iodination of MIT and tyrosine is prevented.177,178 Minute amounts (10-8 M) have, paradoxically, a stimulatory effect on iodination in thyroid slices.179
The basic structure necessary for the antithyroid action of these drugs is
N
|
S
|
-N=C-X-
where X may be C, N, or O180,181 (Fig. 5-3). The thiocarbamides are metabolized in the thyroid gland by transsulfuration.182 The enzyme responsible may also be involved in the iodide peroxidase enzyme system.183 Glands under TSH stimulation metabolize the antithyroid drugs at an accelerated rate, as has been shown for thiourea.184
Iodide is released more rapidly from a gland blocked by PTU than from one blocked by perchlorate.165,185 This action occurs presumably because PTU prevents the utilization of all iodide available to the gland (transported from the blood or formed in the gland by deiodination of iodotyrosines), whereas potassium perchlorate prevents uptake of iodide but does not inhibit reutilization of iodide derived from within the gland. T4 disappears from the PTU-blocked rat thyroid at a faster rate than do iodotyrosines.185
In addition to the effects on the thyroid gland, PTU (and, to a much lesser extent, methimazole) partially inhibits the peripheral deiodination of T4186-191 and its hormonal action.188,192-194 PTU acts directly on body tissues to inhibit the normal formation of T3 from T4.191,195 Coincidentally, fecal excretion of T4 increases.186 In order to inhibit goiter induced by antithyroid drugs in rats, one must maintain the T4 concentration in blood at a higher level that is normal for the species.188,192 Presumably, inhibition of T4 monodeiodination by the antithyroid drug leads to a buildup of T4 in blood and diminishes the availability of T3 in the tissues.191 Higher doses of T4 or higher blood levels may be sufficient to push the reaction toward T3 and allow formation of quantities sufficient to prevent goiter.
Metabolism of the antithyroid drugs has been observed after administration of 35S-labeled drugs. Methimazole is rapidly absorbed from the gastrointestinal tract in humans. It reaches a peak plasma level about an hour after administration, and then declines gradually to near zero levels at 24 hours. These drugs are accumulated and degraded in the thyroid, since they are substrates of the peroxidase.196,197 Carbimazole is accumulated as its metabolic product, methimazole. The concentration ratio between thyroid and plasma for unmetabolized methimazole in rats may approach 25, eight hours after administration of the drug. The metabolic products derived from the drug are excreted in the urine, largely during the first day.
A number of other drugs, including the aminoheterocyclic compounds and substituted phenols, act as goitrogens principally by impairing TG iodination (Fig. 5-3). They are in general far less potent in their goitrogenic effect than the thionamides. None are used therapeutically as antithyroid drugs; rather, goitrogenesis is an undesirable side effect of their use. Some the compounds have multiple effects and thus influence thyroid physiology at various levels. These compounds are individually discussed in greater detail. A comprehensive list is provided in Table 5-1.
Sulfonamides. Sulfonamides, particularly those containing an aminobenzene grouping, have antithyroid activity. Acetazoleamide (Diamox), the diuretic agent, has a strong effect on animals and humans.198,199 Its action, prevention of intrathyroidal iodide binding, is not related to carbonic anhydrase inhibition. Sulfadiazine and sulfisoxazole have a similar action, probably through a synergistic effect on iodide.89
Sulfonylureas. Sulfonylureas, derivatives of sulfonamides and used as hypoglycemic-antidiabetic agents, also inhibit the synthesis of thyroid hormone. They include carbutamide, tolbutamide, methahexamide, and possibly chlorpropamide, but not the phenylethyl biguanide (Fig. 5-3). They impair thyroidal RAIU and cause goiter in the rat.200,201 Carbutamide is much more potent than tolbutamide. Carbutamide, 2 g/day (but not 1 g/day), may reduce the thyroidal RAIU in humans to 20% of control values, but the uptake gradually rises as treatment is continued and is normal after 20 weeks. From 1 to 2 g tolbutamide per day does not affect RAIU in humans.202 Thus, in the usual dose range, tolbutamide will not depress thyroid function.
Chlorpropamide in large doses (3-7 g) depresses the RAIU in humans; the common therapeutic doses (up to 1 g daily) usually have no effect on serum T4.203 A mild antithyroid action is often reflected in a rise in RAIU, which may be found after the agents are withdrawn.
These drugs inhibit hormone synthesis by inhibition of iodide binding. In most instances, the pituitary compensates for the effect and maintains a euthyroid state by increased synthesis of TSH. Nevertheless, hypothyroidism is said to be more common in diabetic patients on sulfonylureas than in patients treated by other means.204
Sulfonylureas also block binding of T4 to the carrier proteins in serum and thus depress the T4 concentrations.205 This effect is most pronounced after intravenous administration.
Polychlorinated Biphenyls Animal studiehave suggested that polchlorinated bihenyls (PCBs) may reduce thyroid hormone levels by decreasing synthesis, increasing biliary excretion of conjugated metabolites and displacing T4 from binding proteins. 205a A review of studies in humans, did not find significant or consistent changes. 205a
General Mechanisms of Action
A large number of substances may affect thyroid gland function and thyroid hormone metabolism and action. The list continues to grow with the introduction of new diagnostic agents, drugs, and food additives. Drugs affect the transport, metabolism, action and excretion of T4 and its derivatives as well as regulation at all levels of the hypothalamic-pituitary-thyroid axis. Some drugs may induce hypothyroidism or thyrotoxicosis, and if autoimmune mechanisms are involved, the thyroid dysfunction may not resolve with discontinuance of the drug. Some compounds may not have any direct effect on thyroid hormone economy or regulation, but have clinical relevance by interfering in specific diagnostic assays.
Compounds are discussed and listed below based on their major mechanisms of action. Many drugs have more than one mechanism of action and the explanation for observed abnormalities is not always known. Results of experiments conducted in animals or in vitro are not always applicable to human pathophysiology. Compounds which alter thyroid hormone secretion are generally goitrogens or anti-thyroid drugs and were discussed in the preceeding section. Selected compounds with significant effects on the thyroid, wide-spread use or that are of particular interest in understanding the mechanism of drug effects are described in greater detail.
Some hormones and drugs may affect thyroid hormone transport in blood by altering the concentration of the binding proteins in serum. Thyroid hormone transport may also be affected by substances that compete with the binding of thyroid hormone to its carrier proteins (Table 5-2). TBG synthesis is increased by estrogens220-223 and decreased by androgens and anabolic steroids.223,224 Estrogen’s effect to increase TBG is blunted or reversed by tamoxifen and raloxifene.224a The most extensively studied compounds that interfere competitively with thyroid hormone binding to the carrier proteins in serum are salicylates, diphenylhydantoin, and heparin.212,225-231,231a,b A clinically significant effect of furosemide211 may only be seen with very high doses and with accumulation with renal failure.
In general, the effect of increased hormone binding is an increase in the serum concentration of total (bound) T4 and of reduced binding is a decrease in the total (bound) T4, with T3 effected to a lesser extent. There is no significant effect on the absolute concentration of the metabolically active fractions of FT4 and FT3, or usually their free indices (FT4I and FT3I). In the steady state, the quantity of thyroid hormone reaching peripheral tissues and the pathways and amount of hormone degradation remain unaltered. However, before this steady state is reached, an acute perturbation in the equilibrium between free and bound hormone brings about transient changes in thyroid hormone secretion and degradation. The hypothalamic-pituitary-thyroid axis participates in the reestablishment of the new steady state. For example, as illustrated in Figure 5-4, an abrupt increase in the concentration of TBG shifts the equilibrium between total and bound hormone, causing a decrease in the concentration of free hormone. The consequences are fourfold. First, there is a shift in the exchangeable hormone from tissues to blood. Second, a decreased hormone content in tissues diminishes its absolute degradation rate. Third, a decline in hormone concentration in tissues activates the hypothalamic-pituitary axis, causing an increase in TSH secretion. Fourth, the latter acts on the thyroid gland to step up its hormonal secretion and reestablish an appropriate thyroid hormone/TBG ratio. Thus, a normal thyroid hormone concentration in serum and tissues and hormonal production and disposal rates are reestablished. TSH concentration returns to normal, and a new steady state is maintained at the expense of an increased intravascular pool and a decreased fractional turnover rate and total distribution space of thyroid hormone.232,233 The reverse sequence of events accompanies an acute decrease in TBG concentration or binding (Fig. 5-4).
 |
| Figure 5a-4. Graphic representation of the sequence of events after an acute change in serum TBG concentration in a subject with normally controlled thyroid hormone secretion and metabolism. The communicating vessel principle is used for analogy. The width of the two large vessels represents available T4-binding capacity in serum (TBG) and in peripheral cells (TISSUE), which are partially saturated by T4 (gray areas). The fluid represents thyroid hormone (T4 in this example, although an analogous diagram can be drawn for T3). The height of fluid in the small central vessels represents free T4 concentration in equilibrium with bound T4 in each of the large vessels. FT4 is proportional to the level of saturation of the binding sites in serum (TBG) and in cells (TISSUE). Thyroidal secretion (supply) of hormone is represented by the input of fluid through the faucet, and hormone metabolism (disposal) by the overspill of the tissue reservoir. For further details see text. (From S. Refetoff and J.T. Nicoloff in Endocrinology L DeGroot (ed), W.B. Saunders, Co., Philadelphia, 1985, p 564, with permission of the publisher) |
Agents that may alter the extrathyroidal metabolism of thyroid hormone are listed in Table 5-3. Several drugs with wide use in clinical practice inhibit the conversion of T4 to T3 in peripheral tissues. Glucocorticoids,239,240 amiodarone,241,242 and propranolol243-245 are a few examples. As expected, their most profound effect on thyroid function is a decrease in the serum concentration of T3,239,241,243 usually with a concomitant increase in the rT3 level.239,241 An increase in the serum T4 concentration has also been observed on occasion.241,245 The serum TSH concentration may also occasionally rise,241 provided the drug does not have a direct inhibitory effect on the hypothalamic-pituitary axis.246 In the absence of inherent abnormalities in thyroid hormone secretion or in its regulation, TSH levels should return to normal and hypothyroidism should not ensue from the chronic administration of compounds the only effect of which is to interfere partially with T4 monodeiodination.
Other mechanisms by which some compounds affect the extrathyroidal metabolism of thyroid hormone are acceleration of the overall rates of deiodinative and nondeiodinative routes of hormone disposal. Examples of drugs acting principally through the former mechanism are diphenylhydantoin and phenobarbital,247-249 and via the latter, colestipol237, ferrous sulfate238a, aluminum hydroxide238b and sucralfate238c. Patients receiving these drugs should increase the secretion of hormone from the thyroid gland in order to compensate for the enhanced hormonal loss through degradation or fecal excretion. Thyroid hormone concentration in blood should remain unaltered. However, hypothyroid patients receiving such drugs may require higher doses of exogenous hormone to maintain a eumetabolic state (Chapter 9). In patients on thyroid hormone therapy who are also taking drugs which bind thyroid hormone in the gastrointestinal tract, the administration of the two drugs at different times will markedly reduce or eliminate the effect on thyroid hormone absorption.
Acute increases in serum T4 and FT4 concentration after the injection of insulin or during halothane anesthesia have been attributed to an enhanced release of T4 normally stored in the liver.250,251
The last two decades have seen a prodigious growth in the list of substances that can be shown to act on the hypothalamic-pituitary axis (Table 5-4). Although many of these compounds are used frequently, only a few have significant effects on thyroid function via this central mechanism. Furthermore, patients receiving these drugs rarely have any abnormality of serum TSH although the response of TSH to the administration of TRH may be altered. An effect of these drugs may be seen in patients with untreated or partially treated primary hypothyroidism. In patients with an elevated basal level of serum TSH, addition of these drugs may produce a further increase or a significant diminution.
Although the following paragraphs discuss the general mechanisms of action for these compounds, specific mechanisms are not always known. A major problem in interpretation is the variability of experimental designs. These variables include doses, routes of administration, duration and time of treatment, drug combinations, age and sex of subjects, hormonal status at the time of testing, and time of blood sampling. Furthermore, observed responses may be effected by the method of data analysis. For example, results of TSH responses to TRH have been expressed in terms of changes in the absolute value, increments or decrements from the basal level, and percent of the basal value at either the peak and nadir of the response or the integrated area over the duration of the response.
The most potent suppressors of pituitary TSH secretion are thyroid hormone and its analogs. They act on the pituitary gland by blocking TSH secretion through the mechanisms discussed in Chapter 4. Some TSH-inhibiting agents listed in Table 5-4, such as, fenclofenac and salicylates, may act solely by increasing the free thyroid hormone level through interference with its binding to serum proteins. Other agents appear to have a direct inhibitory effect on the pituitary and possibly on the hypothalamus. The most notable is dopamine and its agonists. They have been shown to suppress the basal TSH levels in euthyroid persons284,285 and in patients with primary hypothyroidism.267,284-286 More uniformly, they suppress the TSH response to the administration of TRH.268,285,287,288 In contrast, most dopamine antagonists increase TSH secretion.150-155 Increases in the basal TSH and in its response to TRH have been observed in euthyroid persons,252,255 as well as in patients with primary hypothyroidism250-256 who have been given these drugs. A notable exception to this rule, which casts some doubt on the assumed mechanism of action of dopamine antagonists, is neuroleptic dopamine blocker, pimozide, which has been reported to reduce the elevated serum TSH level in patients with primary hypothyroidism.289
Iodine and some iodide-containing organic compounds cause a rapid increase in the basal and TRH-stimulated levels of serum TSH. This effect is undoubtedly due to a decrease in the serum thyroid hormone concentration either by inhibition of hormone synthesis and secretion by the thyroid gland81,82 or by a selective decrease in the concentration of T3.290 The latter effect is mediated through the inhibition of T3 generation from T4. A more selective, intrapituitary inhibition of T4 to T3 conversion appears to be responsible for the TSH-stimulating effect of the radiographic contrast agent iopanoic acid58 and amiodarone. Iodine does not stimulate TSH secretion in patients in whom it has produced hyperthyroidism. 94 A decrease in the free thyroid hormone concentration in serum, albeit minimal in magnitude, may also be responsible for the increase in TSH levels observed during treatment with clomifene.260
It has been postulated that some agents may act by modifying the effect of TSH on its target tissue. For example, theophylline may potentiate the action of TSH through its inhibitory effect on phosphodiesterase, which may lead to an increase in the intracellular concentration of cAMP.291 In fact, the presence of the pituitary is required to demonstrate that methylxanthines augment the goitrogenic effect of a low-iodine diet in the rat.292 One of the postulated effects of diethyl ether anesthesia in the rat is inhibition of the action of TSH on the thyroid gland,293 although it has also been reported to induce a transient redistribution of T4 between serum and tissues.294
A handful of drugs seem to act by blocking some of the peripheral tissue effects of thyroid hormone. Others appear to mimic one or several manifestations of the thyroid hormone effect on tissues. Guanethidine releases catecholamines from tissues.295 It has a beneficial effect in thyrotoxicosis, including a decrease in BMR, pulse rate, and tremulousness.296,297 This agent has little effect on the thyroid gland, but depresses manifestations of thyrotoxicosis that are mediated by sympathetic pathways. The sympatholytic agents phentolamine and dibenzyline have been reported both to depress and to stimulate thyroid function in animals. Their action is not clear, and it is of muinimal clinical significance.298-300 Among several a-adrenergic blocking agents tested, only phentolamine showed an inhibitory effect on the TSH response to TRH.271
Theoretically, thyroid hormone effects could be blocked by drugs which interfere with the tissue uptake of thyroid hormone or binding to its receptors. Inhibition of both cellular uptake and nuclear receptor binding has been demonstrated in vitro for amiodarone in hepatocytes and cultured pituitary cells. Inhibition of cellular thyroid hormone uptake has also been reported for calcium channel blockers and benzodiazapines. Furosemide and non-steroidal anti-inflammatory drugs reduce T3 binfding to cytosolic receptors. There is, however, no clear evidence that any of these drugs have a clinically significant effect on thyoid hormone action.
Among the multiple effects the ß-adrenergic blocker, propranolol, has on thyroid hormone economy, it appears to reduce the peripheral tissue responses to thyroid hormone (see also Chapters 3 and 11). Dinitrophenol enhances oxygen consumption by a direct effect on tissues and thus mimics one of the actions of thyroid hormone.301
Estrogens. Hyperestrogenism, either endogenous (caused by pregnancy, hydatidiform moles, or estrogen-producing tumors) or exogenous (due to the administration of estrogens), is accompanied by an increase in TBG and a decrease in TTR concentrations in serum.220-222 Estrogens are the most common cause of TBG elevation, and this effect can be produced even after their topical application. The magnitude of TBG increase is in part dose related and occurs in women as well as in men. While tamoxifen blocks the estrogen induced increase of TBG224a, tamoxifen alone in post-menopausal women increases TBG and T4 and 3 levels.301a . The selective estrogen receptor modulator (SERM) raloxifene, increases TBG, produces small increase in T4 and insignificant changes in free T4. 301b,301c Estrogen increases the complexity of oligosaccharide side chains and, as a consequence, the number of sialic acids in the TBG molecule which in turn prolongs its survival in serum.302 The concentrations of other serum proteins, including several that bind hormones, such as cortisol-binding globulin and sex-hormone binding globulin, are also increased.303
The consequences of increased TBG concentration in serum are higher serum levels of T4, T3 and rT3 and, to a lesser extent, other metabolites of T4 deiodination. The fractional turnover rate of T4 is depressed principally due to an increase in the intravascular T4 pool. On the other hand, the FT4 and FT3 concentrations and the absolute amount of hormone degraded each day remain normal.232,233 Transient changes in these parameters during the early changes in TBG concentration can be anticipated as described above. Some of the effects of pregnancy on thyroid function are also mediated by an estrogen-induced increase in the serum TBG concentration. The effects on thyroidal and renal iodide clearance and BMR are mediated by different mechanisms (see Chapter 3).
The effect of estrogen, if any, on the control of TSH secretion is controversial. Contradictory results suggesting a stimulatory304 and an inhibitory305,306 effect have been obtained by different investigators and both stimulation and inhibition has been shown in a single study depending on the dosage utilized.306a In a study of the effects of Tamoxifen, TSH was elevated at 3 months but not at 6 months.306b Although women show a greater TSH responsiveness to TRH than men,306-308 administration of pharmacologic doses of estrogens does not appear to have a significantly enhancing effect.309,310
The effects of estrogens in the rat are not identical to those observed in humans. Estrogens do not induce changes in the concentration of serum T4-binding proteins in the rat.22 Thus, investigations carried out in this species are not always representative in interpreting the effects of estrogens observed in humans
Androgens. Androgens decrease the concentration of TBG in serum and thereby reduce the level of T4 and T3.223,311 The TTR concentration, however, is increased.223 As with estrogens, the concentration of free hormone remains unaffected, and the degradation rate of T4 is normal at the expense of an accelerated turnover rate.223 TSH levels are normal.305 Anabolic steroids with weaker androgenic action have the same effect, although similar changes observed during danazol therapy have been attributed to its androgen-like properties.224
Salicylates. Acetylsalycilic acid has been identified as the most commonly administered medication which may cause significant alterations in measured parameters of thyroid function.224b,224c Salicylate and its noncalorigenic congeners (Fig. 5-3) compete for thyroid hormone-binding sites on serum TTR and TBG.225-228 As a result, the serum concentrations of T4 and T3 decline and their free fractions increase.228 The turnover rate of T4 is accelerated, but degradation rates remain normal.225,226 Salicylate and its noncalorigenic congeners also suppress the thyroidal RAIU but do not retard iodine release from the thyroid gland.312 The impaired respone to TRH313 and the hypermetabolic effect314 of salicylates have been attributed to the increase in the FT4 and FT3 fractions. If this were correct, hormonal release from the serum-binding proteins should produce only a temporary suppression of the thyroidal RAIU and transient hypermetabolism, but both effects are observed during chronic administration of salicylates.225,226 In addition, this mechanism of action does not explain the lack of calorigenic effect of some salicylate congeners despite their ability to also displace thyroid hormone from its serum-binding proteins.
In vitro studies have demonstrated an inhibitory effect of salicylate on the outer ring monodeiodination of both T4 and rT3,315 but lack of typical changes in serum iodothyronine levels suggests that this action is less important in vivo.
Acetylsalicylic acid mimics some actions of thyroid hormone, but does not reverse classic manifestations of hypothyroidism. While salicylate administration may lower serum cholesterol levels,316 it does not provide a therapeutic effect in myxedema, or lower TSH levels.317 Administration of 8 g aspirin daily raises the BMR to normal in myxedema, accelerates the circulation, and increases sweating, but it has no effect on the skin change, the electrocardiogram, or the mental state.316
Because of some analogies between the effects of salicylates and nitrophenol, uncoupling of oxidative phosphorylation has been suggested as one of its possible mechanisms of action. If this were the case, direct chemical action does not appear to be involved since analogs of salicylate that do not uncouple oxidative phosphorylation in vitro are active in vivo.318
p-Aminosalicylic acid and p-aminobenzoic acid are closely related chemically to salicylate. They inhibit iodide binding in the thyroid gland and are goitrogenic.319,320 These agents also displace thyroid hormone from its serum protein-binding sites.321 Abnormalities of thyroid function tests have been also reported in patients treated with salsalate.322
Heparin. Patients receiving heparin chronically may have increased FT4 and FT3.230,231 Reciprocal changes in serum TSH have been reported.231 While it had been suggested that heparin might interact with the T4-binding proteins to alter the steric configuration of the binding sites and reduce the affinity of the proteins for T4 and T3210, it is now thought that heparin acts via the activation of lipoprotein lipase to increase free fatty acid levels which may displace T4 from binding proteins. This effect is most likely to be significant when the levels of albumin are low and triglycerides are high such as during hyperalimentation with lipid solutions. Even low doses of heparin may be sufficient to cause artifactual, in vitro, increase in T4 especially when measured by equilibrium dialysis.231a Although initially reported with crude heparin preparations, this heparin effect has also been noted with enoxaparin. 231b
Glucocorticoids. Physiologic amounts, as well as pharmacologic doses of glucocorticoids influence thyroid function. Their effects are variable and multiple, depending on the dose and on the endocrine status of the individual. The type of glucocorticoid and the route of administration may also influence the magnitude of the effect.323 Known effects include (1) decrease in the serum concentration of TBG and increase in that of TTR;324,325 (2) inhibition of the outer ring deiodination of T4 and probably rT3;239,240 (3) suppression of TSH secretion;246,326,327 (4) a possible disease in hepatic binding of T4; and (5) increase in renal clearance of iodide.328,329
The decrease in the serum concentration of TBG caused by the administration of pharmacologic doses of glucocorticoids results in a decrease in the serum total T4 concentration and an increase in its free fraction and the resin uptake test result. The absolute concentration of FT4 and FT4I remain normal. The more profound decrease in the concentration of serum T3 compared to T4 associated with the administration of pharmacologic doses of glucocorticoids cannot be solely ascribed to their effect on serum TBG. It is due to the decreased conversion of T4 to T3 in peripheral tissues. Thus, glucocorticoids reduce the serum T3/T4 ratio and increase that of rT3/T4 in hypothyroid patients receiving replacement doses of thyroid hormone.239 This steroid effect is rapid and may be seen within 24 hours.239,240 In rats, dexamethasone has been shown to decrease T4 to T3 conversion in liver homogenates. 329a
Earlier observations of cortisone-induced depression of uptake and clearance of iodide by the thyroid328,329 now are understood to be the result of steroid suppression of TSH secretion. Pharmacologic doses of glucocorticoids suppress the basal TSH level in euthyroid subjects and in patients with primary hypothyroidism, and decrease their TSH response to TRH.246,326,327,329b The latter effect is less marked in the presence of hypothyroidism.327 Administration of as little as 34 mg. of hydrocortisone over 24 hours can be shown to reduce the pulse amplitude and mean TSH release the nocturnal rise of TSH and the T3 and TSH response to TRH.329b Administration of the glucocorticoid antagonist, mifepristone, produces an increase in TSH that remains within the normal range accompanied by a transient decrease in total but not free T4.329c Normal adrenocortical secretion appears to have a suppressive influence on pituitary TSH secretion because patients with primary adrenal insufficiency have a significant elevation of TSH.330 In cultures from rat pituitary tumors, hydrocortisone increased the number of TRH receptors 331 Dexamethasone has also been shown to increase the transcription, translation and processing of TRH precursors. 331a,b The mechanism of glucocorticoid action on the hypothalamic-pituitary axis is covered in Chapter 4.
No single change in thyroid function can be ascribed to a specific mode of action of glucocorticoids. For example, a diminished thyroidal RAIU may be due to the combined effects of TSH suppression and increased renal clearance of iodide. Similarly, a low serum TT4 level is the result of suppressed thyroidal secretion due to diminished TSH stimulation as well as the decreased serum level of TBG. One of the common problems in clinical practical is to separate the effect of glucocorticoid action on pituitary function from that of other agents and those caused by acute and chronic illness. This situation arises often since steroids are commonly used in a variety of autoimmune and allergic disorders as well as in the treatment of septic shock. The diagnosis of coexisting true hypothyroidism is difficult, if not impossible. Due to the suppressive effects of glucocorticoids on the hypothalamic-pituitary axis, the low levels of serum T4 and T3 may not be accompanied by an increase in the serum TSH concentration, which would otherwise be diagnostic of primary hypothyroidism. In such circumstances, a depressed rather than an elevated serum rT3 level may be helpful in the detection of coexistent primary thyroid failure.
Pharmacologic doses of glucocorticoids induce a prompt decline in serum T4 and T3 concentrations in thyrotoxic patients with Graves' disease.239 Amelioration of the symptoms and signs in such patients may also be accompanied by a decrease in the elevated thyroidal RAIU and a diminution of the TSH receptor antibody titer.325,332 This effect of glucocorticoids may be due in part to its immunosuppressive action since it has been shown that administration of dexamethasone to hypothyroid patients with Hashimoto's thyroiditis causes an increase in the serum concentration of both T4 and T3.333
Iodinated Contrast Agents. The principal effect of some iodine-containing radiologic contrast media is inhibition of T4 to T3 conversion by inhibiting both Type I and Type II 5’-deiodinase. In fact, they may be the most potent of all agents known to interfere with this step of iodothyronine metabolism. A triiodo-and a monoamino-benzene ring with a proprionic acid chain appear to be required because iodinated contrast agents without this chemical structure have little or no effect.334 Several of these agents, namely, ipodate (Oragrafin) and iopanoic acid (Telepaque), are used for oral cholecystography.
A decrease in the rate of deiodination of the outer ring of thyronines causes a profound decrease in the serum T3 concentration and an increase in the rT3 and T4 levels.334,335 The serum T4 concentration may reach values well within the thyrotoxic range.334 These changes are accompanied by an increase in serum TSH secretion.290 The latter is particularly notable, if not characteristic of these agents, probably because of their potent inhibitory effect on T3 generation in pituitary tissue.58 These agents have been used to study the regulation of thyroid hormone action via the process of iodothyronine deiodination.58,336 Changes persist for at least two to four weeks after their administration.334
Iodocontrast agents also decrease the hepatic uptake of T4337 and inhibit T3 binding to its nuclear receptors.338 These effects reduce both symptoms and thyroid hormone levels even when thyrotoxicosis occurs in settings where ongoing synthesis would be minimal such as thyrotoxicosis secondary to thyroid hormone ingestion338a , or sub-clinical hypothyroidism. 338b The antithyroidal effect of the iodine present in these agents is believed to be responsible for the falling T4 level and some of the amelioration of the symptoms and signs of thyrotoxicosis when they are administered to patients with Graves' disease338,338c,338d ,
Amiodarone. Most changes in thyroid function observed during the administration of this drug are similar to those seen with iodine-containing contrast agents. They include a marked decrease in serum T3, an increase in rT3, and a more modest elevation in the T4 concentration.241,339 Basal and TRH-stimulated TSH levels are increased. The principal mechanism of action is believed to be inhibition of both Type I and Type II 5’-deiodinase resulting in a marked reduction of T3 generation from T4. Amiodarone may reduce the entry of thyroid hormone into tissues339a, may reduce the binding of thyroid hormones to the receptor339b and may antagonize the effects of thyroid hormone at the cellular level.339c,339d The drug is used as an antianginal and antiarrhythmic agent and the bradycardia that almost invariably occurs when the drug is used in high doses, may suggest the presence of hypothyroidism.340
Amiodarone contains 37% iodine by weight. The major effects on thyroid function appear to be the result of its structural resemblance to thyroid hormone rather than its iodine content. In contrast to the typical alterations of thyroid hormone function, the more uncommon occurrence of frank hypothyroidism or thyrotoxicosis are products of the excess iodine released from the drug. The overall incidence of amiodarone induced thyroid disease is higher in areas of mild iodine deficiency340 as is the relative incidence of the thyrotoxic as compared to the hypothyroid form. 340 The iodine dependence of both of these diseases is confirmed by the improvement of both with the use of perchlorate to discharge iodine from the thyroid gland. 340a A second form of thyrotoxicosis which is a destructive thyroiditis does not respond to anti-thyroid drugs or perchlorate but is responsive to steroid therapy. 340a
Measurement of serum TSH, remains the most useful test in the differential diagnosis of hypothyroidism or thyrotoxicosis in amiodarone treated patients but the mild TSH elevation seen in euthyroid patients may make the diagnosis of mild to moderate hypothyroidism more difficult. If hypothyroidism is suspected, it is appropriate to obtain a measurement of the serum rT3 concentration. The absence of an elevated serum rT3 level in a patient receiving amiodarone suggests the patient is hypothyroid.
Diphenylhydantoin (Dilantin). Diphenylhydantoin (DPH) (Fig. 5-3) competes with thyroid hormone binding to TBG.228,229 This effect of DPH and diazepam, a related compound, has been exploited to study the conformational requirements for the interaction of thyroid hormone with its serum carrier protein229,341 It appears that the angle formed between the two phenyls and the hydantoin group of DPH is nearly identical to that formed between the two phenyls linked by an ether bond in T4.229 Although the affinity of DPH for TBG is far below that of T4, when used in therapeutic doses the serum concentration achieved is high enough to cause a significant occupancy of the hormone-binding sites on TBG. This effect of DPH is only partly responsible for the decrease in the total concentration of T4 and T3 in serum.
DPH accelerates the conjugation and clearance of T4 and T3 by the liver and probably enhances the conversion of T4 to T3.247,342 The net result is a decrease in the serum concentration of T4 and rT3 and, less consistently, that of T3343,344,344a,344b because the enhanced degradation of T3 is compensated for by an increase in its generation from T4. Yet, basal TSH- and TRH-stimulated values remain within the normal range343,344,344a,344b or slightly elevated.235,345 Calculated indices of FT4 are usually reduced, but the FT4 measured by dialysis is normal.247,343
Both DPH and diazepam are commonly used in clinical practice, the former most commonly as an anticonvulsant and the latter as an anxiolytic. Reduced serum levels of thyroid hormone in patients having therapeutic blood levels of DPH should not be viewed as indicative of thyroid dysfunction unless the TSH level is elevated. Treatment with T4 in such patients with a low T4 and normal TSH did not alter parameters of cardiac function or symptoms which might have been considered indicative of hypothyroidism.344b DPH therapy may increase the required dose of thyroid hormone replacement in athyreotic individuals.346 .
Phenobarbital. Chronic administration of phenobarbital to animals induces increased binding of thyroid hormone to liver microsomes and increased deiodinating activity.248,249,347,347a Phenobarbital administration reduces the biologic effectiveness of the hormone by diverting it to microsomal degradative pathways. In humans, phenobarbital augments fecal T4 clearance by nearly 100%,348 but serum T4 and FT4 levels remain near normal because of compensatory increases in T4 secretion. It is not apparent that barbiturates have an important effect on thyroid mediated metabolic action in normal humans, but it may potentate the effects of dilantin or carbamazapine. 348a The augmented hepatic removal of T4 induced by phenobarbital lower the absolute T3 disposal by nearly 25%, increase T4 clearance, and lower T4 and FT4I in patients with Graves' disease but does not produce a clinical response.348
Propranolol. Propranolol, a ß-adrenergic blocker, is commonly used as an adjunct in the treatment of thyrotoxicosis Propranolol is usually used in the treatment of cardiac arrhythmias, angina and hypertension. Information regarding its effects on thyroid hormone action, and application in the symptomatic treatment of thyrotoxicosis is found in Chapters 3 and 11, respectively.
Propranolol does not affect the secretion or overall turnover rate of T4, nor TSH release or its regulatory mechanisms.349,350 A small to moderate lowering effect on serum T3 has been reported in euthyroid subjects as well as in patients with hyperthyroidism or with myxedema under L-T4 replacement therapy.243,245,351,352 Reciprocal increases in serum rT3 and 3',5'-T2 levels have also been reported.352 Such data, combined with the finding by some investigators of minimal increases in serum T4245 levels, suggest a mild blocking effect of this drug on the 5'-deiodination of iodothyronines. This effect does not appear to be related to the ß-adrenergic-blocking action of propranolol, since other ß-blocking agents do not share the deiodinase-blocking property and yet are effective in treating symptomatic thyrotoxicosis.353,354 The beneficial effects include the reduction of tachycardia, anxiety, and tremor 355-357 although the metabolic effects of thyrotoxicosis remain unaffected.
Reserpine. Reserpine formerly had wide use as an antihypertensive agent but has been replaced by more effective agents. Reserpine alters the manifestations of thyrotoxicosis by reducing anxiety, tachycardia, and tremulousness.358 This effect may arise from depression of autonomic centers or possibly from depletion of catecholamines in the peripheral tissues.359 Reserpine may depress the formation of iodotyrosines in thyroid tissue in vitro, but this action does not seem to be important clinically. Reserpine does not alter the results of thyroid function tests other than the BMR.358
Nitrophenols. 2,4-Dinitrophenol (Fig. 5-3) elevates the BMR, lowers the serum concentration of T4, accelerates the peripheral metabolism of T4, and depresses the thyroidal RAIU and secretion.275,360,361 The action is probably complex. The drug stimulates the metabolism by uncoupling oxidative phosphorylation in mitochondria.362 T4 in vitro also uncouples oxidative phosphorylation. Part of the effect of dinitrophenol may be to mimic the action of thyroid hormone on hypothalamic or pituitary receptor control centers; this effect would account for the diminished thyroid activity. Dinitrophenol also displaces thyroid hormone from T4-binding serum proteins.227 This action could lower the total hormone concentration in serum but should have no persistent effect on thyroid function. Dinitrophenol increases biliary and fecal excretion of T4, and this action largely accounts for the rapid removal of hormone from the circulation.363 Deiodination of T4 is also increased.364 Both of these effects may be related to displacement of hormone from TTR or to changes in metabolism of hormone in the liver.
2,4-Dinitrophenol does not share some of the most important properties of T4. It cannot initiate metamorphosis of tadpoles365 or provide a substitute for hormonal therapy in myxedema.
Dopaminergic Agents. It is generally accepted that endogenous brain dopamine plays a physiologic role in regulating TSH secretion via an effect on the hypothalamic-hypophyseal axis.252,366,367 Dopamine exerts a suppressive effect on TSH secretion and can be regarded as antagonistic to the stimulatory action of TRH at the pituitary level.284,287,367 Much of the information regarding the role of dopamine on the control of TSH secretion in humans has been derived from observations made during the administration of agents with dopamine-agonistic and -antagonistic activity (see Table 5-4 and Chapter 4).
Dopamine infusion is commonly used in the care of acutely ill hypotensive patients. It lowers the basal serum TSH level in both euthyroid and hypothyroid patients and blunts its response to the administration of TRH.252,284,287,368,368a
L-dopa, the precursor of dopamine, used in the treatment of Parkinson's disease and as a test agent in the diagnosis of pituitary diseases, also suppresses the basal and the TRH-stimulated serum TSH level in euthyroid subjects as well as in patients with primary hypothyroidism285,288,368b (Fig. 5-5). Metoclopropamide, a dopamine antagonist used as a diagnostic agent and in the treatment of motility disorders, increased TSH secretion. 368c
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| Figure 5-5. Effect of L-dopa on serum TSH in patients with hypothyroidism of long duration (chronic hypothyroidism), hypothyroidism of short duration (not receiving thyroid hormone for three to four weeks), and in euthyroidism. Mean ± SEM levels for TSH are expressed as a percentage of the mean basal TSH value and as the absolute increments or decrements from the mean basal TSH value. Results were analyzed by the Student t test and the statistical significance is indicated. (From S. Refetoff et al., J. Clin. Endocrinol. Metab., 38: 450, 1974, with permission of the publisher) |
A similar effect has been observed during the administration of 2-brom-a-ergocryptine (bromocryptine), a dopamine agonist used in the treatment of some pituitary tumors and to suppress lactation during the puerperal period. Although the agent has been shown definitely to diminish the high serum TSH levels in patients with primary hypothyroidism,286 a significant inhibitory effect on TRH-induced TSH secretion has not been clearly demonstrated,369,370
The exact mechanism whereby dopaminergic drugs inhibit pituitary TSH secretion remains unknown, although a direct interaction with pituitary receptors has been suggested.371 While some authors have cautioned that prolonged infusion of dopamine may induce secondary hypothyroidism and worsen the prognosis of severely ill patients,372 there is no evidence that chronic treatment with dopaminergic drugs induces hypothyroidism in less critically ill patients.288 These drugs have been used with variable success in the treatment of some rare pituitary-induced thyrotoxicoses.373,374 When measurements of the basal or stimulated serum TSH levels are used in the differential diagnosis of primary and secondary hypothyroidism, the concomitant use of drugs with dopamine-agonistic or -antagonistic activity should be taken into account in the interpretation of results.
Interferon and Interleukin These cytokines have been associated with the development of both hypothyroidism and thyrotoxicosis. 375-379 The overall rate of thyroid dysfunction induced by these agents is about 6%.379a They are used in the treatment of infectious diseases such as hepatitis, as well as malignancies including melanoma and renal cell carcinoma . Acute administration has been used as a model of illness as the effects are similar; interferon-a leads to a decrease in T3 an increase in rT3 and a fall In TSH. 380 In a group of euthyroid HIV infected patients, however, short term administration of interleukin-2 was observed to lead to an increase in TSH, T3, T4 and free T4. 381
Cytokine induced thyroid disease appears to be immune mediated. The incidence is much greater in females and in patients with positive anti-peroxidase and anti-TPO antibodies prior to the initiation of therapy. 375-377 During therapy, patients who were antibody positive may have a rise in titer, while antibody positivity may develop in previously negative patients.375 In patients treated with interferon, the incidence of thyroid disease is much higher in those with Hepatitis C than those with Hepatitis B.375 The thyrotoxicosis often occurs as a manifestation of a destructive thyroiditis.376,377 In many patients, the thyroid disease resolves within several months after stopping the cytokine therapy. 375,377
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 a-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.