Etiology of goiter in man

ETIOLOGY

OF GOITER

IN MAN*

NEW CONCEPTS

CORNELIUSB. DECOURCY, M.D.

AND

JOSEPH L. DECOURCY,

M.D.

Cincinnati, Ohio

T

HE establishment of the existence and powerful operation of whoIe systems of goitrogens wouId alone seem to necessitate a drastic revision of the famiIiar concepts concerning the etioIogy of goiter in man. But aIso the newer biochemica1 and pharmacoIogica1 knowledge comprehends such nove1 factors as biologic or metabolic competition between structuraIIy incIuding structura1 reIated compounds, anaIogues antagonistic to thyroxine. In accordance with cIear scientific Iogic, the possibIy basic causative action of a variety of chemical influences hitherto unknown or neglected must be taken into consideration in work upon the probIem of goiter etiology. The purpose of this paper is to indicate the possibilities that must be accounted for by adequate researches rather than to specuIate upon presumable probabilities. Justification for such a discussion of possibiIities is found in the fact that the probIem of goiter causation has not previousIy been considered in the Iight of the newer and apparentIy revoIutionary findings in regard to goitrogens and metaboIic competition between simiIar and, in certain instances, dissimirar moIecuIes, especiaIIy thyroxine and related compounds. GOITROGENS The existence of goitrogens was suspected for centuries. InnumerabIe earIy writers suggested that some chemicai cause of goiter, especiaIIy endemic goiter, wouId be discovered in drinking water or certain articIes of diet. In many goiter regions the comparativeIy high concentrations of caIcium in the water have repeatedIy attracted attention to this element as a possibIe etioiogic factor. Excess of pork or * From the Department

of Surgery,

fat was long suspected, as by St. Lager (I 867). Indeed it was shown by Marine and Lenhart (1910) that thyroid hyperpIasia may be induced in dogs and brook trout by the feeding of pig’s Iiver. McCarrison (1920) reported that fat-feeding had a similar effect in pigeons; MeIIanby and MeIIanby (1921) aIso brought about thyroid hyperpIasia in dogs by the same means. Bircher (191 I) stated that he was able to induce the appearance of Iarge goiters in white rats by giving them water from a region in which goiter was endemic; further, these animals showed great enlargement of the heart with hypertrophy of the Ieft ventricIe. HeIIwig (1944) expressed the belief that a high caIcium intake may indeed be the cause not onIy of goiter but of “ goiter heart ” ; and his experimental findings on white rats fed a high-caIcium diet were simiIar to those reported by Bircher to foIIow administration of “goiter-causing” water. No confirmation of such work has been forthcoming. Other Iines of investigation have been vastIy more profitabIe and the results are now indisputabIe. Numerous goitrogens have been shown to be present in common foods of animaIs and man, and systems of compounds having goitrogenic activity have been found among famiIiar or newIy synthesized drugs. In 1928 Chesney, CIawson and Webster noted that a coIony of rabbits were rapidIy becoming goiterous; it was soon estabIished that the etiologic factor was present in cabbage. The thyroid glands were extremeIy hyperpIastic but the animaIs had low metaboIic rates. Iodine administration was found to prevent the development of but when iodine was “ cab5age goiter,” DeCourcy

661

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Ohio.

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given after the goiter had developed, a severe thyrotoxicosis resulted promptly. These findings were confirmed by Marine, Baumann, Spence and Cipra (1929, 1932) who determined aIso that the Ieaves of contained some many brassica pIants goitrogen. Suk (193 I ) reported the endemic occurrence of Iarge goiters in a community in Carpathian Ruthenia where the principa1 dietary item was cabbage. Because of the reported isoration of certain nitriIe compounds from the Ieaves of severa brassicae (cabbage, BrusseIs sprouts, cauIiffower), the action of a number of cyanide compounds on the thyroid gIands of Iaboratory animaIs was investigated by Marine and his associates (1932, Ig34), Spence (1932, 1934) and others. It was observed that methy cyanide and certain other nitriIes produced marked thyroid hyperpIasia with Iow metaboIic rates and exophthaImos. SharpIess et a1. (1939) recorded the production of goiter in rats by feeding raw or treated soy bean Aour; such goitrogenic action was prevented by administration of iodine. In 1941 Kennedy and Purves found that rape seed and the seed of other brassicae can be used to produce goiters in rats. Mackenzie, Mackenzie and McCoIIum, aIso in 1941, found that when suIfaguanidine was fed to rats for short periods of time, there resuIted a marked enIargement and hyperpIasia of the thyroid gIand, an effect that was not inhibited by iodine. Richter and CIisby (1941, 1942) noted that phenyIthiourea was goitrogenic, and, at abdut the same time, Kenhedy, Purves and Griesbach described in greater detai1 the goitrogenic action of rape seed, Kennedy later (1942) attributing this action to aIIy1 thiourea, presumabIy a constituent of rape seed, The concepts that goiter resuIting from the action of suIfonamides and thiourea is compensatory and that the primary effect of such substances is inhibition of synthesis of thyroid hormone were set forth by the researches of the Mackenzies (1943) and Astwood and his associates

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(1943). Astwood and others foIIowed up the suggestion that compounds reIated to the sulfonamides and thiourea might be valuable therapeutic agents. ?‘he chemical nature of the compounds which inhibit the function of the thyroid gIand was discussed by Astwood (1943) who at that time remarked that the compounds tested couId be divided into three cIasses: thiourea derivatives, those containing an aminobenzene grouping and the thiocyanates. The thioureas as a group are the most active goitrogens, thiouraci1 showing the highest activity. The aminobenzene derivatives include the common suIfonamide drugs, of which suIfadiazine is the most active. Iodine administration prevents the goitrogenic action of the thiocyanates but not that of the other two cIasses. The differentiation of the antithyroid action of thiouraci1, thiourea and paraaminobenzoic acid from suIfonamides by iodine administration has very recentIy been described in detai1 by C. G. Mackenzie (1947). Mackenzie observed that smaI1 amounts of iodine inhibit the goitrogenie action of thiouraci1 by 50 to IOO per cent in rats, depending upon the IeveI of the goitrogen empIoyed. Higher IeveIs of iodide do not increase this inhibition but suppress thyroid hyperpIasia. When a low IeveI of sulfaguanidine is administered, the goitrogenic effect is augmented by a high IeveI of iodide; but this augmentation, or synergistic action, is not noted with either Iow IeveIs of iodine or a high IeveI of suIfaguanidine. NevertheIess, according to Mackenzie, iodide seems to increase the degree of thyroid hyperpIasia under a11 the conditions studied. Further, parabaminobenzoic acid resembles thiouraci1 rather than suIfaguanidine insofar as both its goitrogenic and hyperpIastic actions are inhibited by iodide. Mackenzie concIuded that thiouraci1, thiourea and para-aminobenzoic acid differ from the suIfonamides in the primary biochemica1 reactions responsibIe for their effects on the thyroid gIand. Thus it is apparent that considerabIe modification of

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DeCourcy-Etiology

earlier views concerning the reIation of iodine intake to goitrogenic action is necessary. Depending upon the iodine level and upon the goitrogen, the goitrogenic action is either intensified or inhibited. Other fundamenta1 differences between goitrogens have been brought to light. Rawson, Tannheimer and Peacock (1944) employed a radioactive isotope to demonstrate that the thiocyanate goiter readily takes up iodine whereas the enIarged gIands resuhing from thiouracil administration do not. Species difference is still another highly important factor. When administered to chicks, aminobenzene derivatives show no goitrogenic effect (Mackenzie and Mackenzie, rg43), whereas in this species thiourea derivatives have high goitrogenic activity (Astwood et al., 1944; Mixner et aI., 1944.) It is we11 estabIished that administration of desiccated thyroid or thyroxine inhibits the action of goitrogens in general (Webster and Chesney, 1928; Marine et al,, 1932; Astwood, 1943; SaIter et aI., 1943). Griesbath, Kennedy and Purves (rgq.1) showed that the pituitaries of animaIs having goiters produced by a brassica seed diet present histoIogic changes similar to those observed in the pituitaries of thyroidectomized animals. These investigators reported aIso that hypophysectomy prevents the deveIopment of goiters in animaIs which later receive goitrogens. Hence there arose the concept that the action of the various drugs which produce goiter is by means of an inhibition of, or interference with, the manufacture of the norma thyroid hormone (Rawson, Hertz and Means, 1943; Franklin and Chaikoff, 1943; Salter et aI., 1943). The resuIting increase in activity of the thyrotropic hormone of the pituitary induces hyperpIasia of the thyroid cells, thyroid hormone production being at the same time decreased rather than increased. These investigations eventuaIIy Ied to the introduction of goitrogens into therapy of hyperthyroidism (Astwood, 1943; Himsworth, 1943; Williams and BisseII, 1943).

of Goiter GOITER

PRODUCTION

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IN MAN BY GOITROGENS

Hundreds of compounds have been tested and found goitrogenic and toxic in when administered to varying degrees animals. Many have been and are being used extensively (if not indiscriminately) in the treatment of thyrotoxicosis and even non-toxic adenomatous goiter. It is obvious, therefore, that many different agents not only may cause goiter in man but are actuahy being therapeuticahy employed as a result of their recognized goitrogenic action. Goitrogenesis as an undesirable sideeffect of a number of chemotherapeutic agents has also become a familiar manifestation. Goiters deveIop in a certain smaI1 percentage of hypertensive patients who are being treated with thiocyanate (Barker et al., 1941; FahIung, 1942; Kobacker, 1942; FouIger and Rose, 1943; Rawson et aI., 1943). The observations of Rawson and associates are typical. Goiters appeared in two patients who were receiving potassium thiocyanate for treatment of hypertension. Decreased thyroid function was indicated by cIinica1 symptoms of hypothyroidism, Iow basa1 metabolic rates and plasma protein iodine levels usually observed in myxedema. An extreme hyperpIasia of the thyroid gIand was demonstrated in biopsy materia1 removed from one patient. In one case there was exophthaImos with Iid lag. In both cases the goiters and clinica signs of hypothyroidism disappeared when thyroid was administered in conjunction with thiocyanate. A number of cases of goiter associated with sulfonamide therapy have been recorded, and reIated compounds have also been shown to be goitrogenic. In fact, goitrogenesis must now be recognized as an occupationa hazard. PerrauIt and Bovet (1946) stated that in 1913 Jeantet of Lyons, France, observed unusua1 goiters in workmen empIoyed in the extraction of aminothiazoIe which is used in the preparation of sulfathiazole. PerrauIt and Bovet were suffrcientIy impressed by the goitrogenic

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activity and Iack of toxicity of aminothiazole to try it in therapy of hyperthyroidism. The resuIts in a Iarge group of patients convinced these workers that the goitrogen is more effective and much Iess toxic than thiouraci1. Rawson, Hertz and Means (1943) have remarked that the action of goitrogens must be regarded as a probIem of practica1 importance in view of “the advocated use of soy beans in the modern diet, the IiberaI prescribing of the suIfonamides in ,cIinicaI medicine and widespread use of thiocyanate in treating hypertension.” Recent research suggests additiona possibiIities that have practica1 aspects. The very number of different substances aIready shown to be goitrogenic is remarkabIe and may not have received the attention it wouId seem to deserve. The extreme lability of the thyroid gIand, Iong recognized as the most IabiIe organ in the human body, is thus once again made manifest. Hundreds of substances have been proved goitrogenic when ingested in food or water. Many of these substances may be regarded as drugs from one point of view, but from another they are food factors, some indisas in the instance of parapensabIe, aminobenzoic acid. Many common foods contain goitrogenic substances; this fact is now beyond question. ObviousIy, the ancient speculation that goitrogens wouId be found in foods has been transmuted into estabIished fact. The fact is highIy suggestive of possibiIities, many of which wouId seem to be eminentIy worthy of practica1 consideration. The number of classes of goitrogens is being steadiIy augmented. A striking addition to the Iist of known goitrogens is seIenium. In 1946 Seifter and associates reported that the thyroid gIands of white rats show increase in size, hyperpIasia and Ioss of coIIoid after ten days on a diet containing 0.05 to 0.1 per cent of an organic seIenium compound (bis-4-ace-taminophenyI-seIenium). After 105 days on a diet containing the seIenium compound at the Iower IeveI, the animaIs deveIop muItipIe adenomas of the thyroid gIand.

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of Goiter

As is we11 known, seIenium occurs in toxic concentrations in the soi1, water and vegetation of areas in at Ieast thirteen States. More than IOO,OOOacres of seIeniferous farmIand have been taken out of cuItivation in recent years. Nevertheless, many areas whose soi and water contain seIenium (at a comparativeIy Iow and presumabIy non-toxic IeveI) stiI1 are under cuItivation. The significance of the Iow content of seIenium in wheat grown in such seIeniferous soi remains to be determined. The significance of goitrogenic agents in cabbage, cauIiffower, other edibIe brassica pIants, and in soy beans is apparentIy greater, and is generaIIy beIieved, perhaps correctIy, to have no reIationship to endemic goiter. PossibiIities can be eIiminated onIy by research. Investigations upon the effects of goitrogens ingested by man must henceforth be guided by the knowIedge that species differences are at times marked. Another compIicating factor is the possibIe synergism between two or more different goitrogens received at the same time and between iodine (at a certain IeveI) and one or more goitrogens (Mackenzie, 1947). Moreover, now that the existence of many antithyroid substances has been estabIished, the possibiIity is suggested that there may be groups of substances whose primary “tarthe thyroid get organ ” is the pituitary, gIand being secondariIy affected. Synergism between antipituitary and antithyroid substances-in varying combinations and concentrations-must be placed on the Iist of possibiIities. STRUCTURAL

ANALOGUES

ANTAGONISTIC

TO

THYROXINE

The discovery of bioIogic and metaboIic competition between structuraIIy reIated compounds has incited extensive biochemica1 researches whose findings aIready constitute a great new division of physioIogic chemistry (WooIIey, 1947). Within the past few years there have been found in nature or synthesized in the Iaboratory compounds which are structuraIIy simiIar

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to, but bioIogica1ly antagonistic to metaboIicaI1y important substances. These agents compete with hormones, vitamins or other metabohtes and manifest their effects by the production of signs of deficiency of the metabolite to which the “ bio-antagonist ” is reIated in specific structura1 ways. For instance, in the testing of the presumed vitamin-like activity of substances structuraI1y reIated to thiamine, it was found that instead of exhibiting thiamine-like effects certain structura1 anaIogues of thiamine induce signs of vitamin B1 deficiency when the Iaboratory animal receives the “ bio-antagonist ” and thiamine (at a lever otherwise high enough to prevent the appearance of signs of deficiency). Because many “ bio-antagonists” of metaboIicaIIy important substances have been found to produce signs of deficiency of the anaIogous metabohte, WooIIey proposed that a new series of pharmacoIogic agents might be produced by aItering the structures of hormones or vitamins in definite ways. According to WooIIey: “It was considered possibIe that such inhibitory structural anaIogues couId be found against certain hormones which, as a resuIt of overproduction, or diminished rate of destruction in the body, are the causative agents of disease. The excess hormone might be CounterbaIanced by administration of the structurally reIated antagonist.” WooIIey ( 1946) has been abIe to synthesize several new ethers of N-acetyldiiodotyrosine (structura1 anaIogue of thyroxine) that have been found to counteract the pharmacoIogic effects of thyroxine in experimenta1 animaIs, Investigators interested in the etioIogy of goiter must now consider the fact of the existence of structura1 anaIogues of thyroxine that counteract the effects of the hormone. Such anaIogues, “ bio-antagonists,” may exist in foods or may be produced normaIIy or pathoIogicaIIy in the body. Because thyroxine inhibits the action of many if not a11 goitrogens, a priori it wouId seem that the administration of goitrogen in conjunction with a bio-antagonist of

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thyroxine wouId be expected to enhance markedIy the action of the goitrogen. (It is to be noted that certain of the bioantagonists of thyroxine which were synthesized by WooIIey have at once a strong antagonistic action (antithyroxine properites) and a weak thyrosine-Iike activity. The antithyroxine substance when administered aIone shows weak thyroxinelike activity; administered in conjunction with thyroxine, the bio-antagonist signally diminished the effects of the metaboIite. Goitrogens do not show thyroxine-Iike activity). The existence of antihormones has long been postuIated. Antithyroxine bio-antagonists are antihormones. IODINE

DEFICIENCY

AND

ENDEMIC

GOITER

In 1916 Marine and KimbalI (1917) instituted the prevention of endemic goiter in man by iodine prophyIaxis on a large scale through the pubIic schooIs of Akron, Ohio. By 1920 it had been demonstrated convincingly that the incidence of endemic goiter in adoIescent girIs couId be reduced to a very Iow figure by keeping the thyroid saturated with iodine (Marine and KimbaI1, 1920). This briIIiant and convincing demonstration of the definite relation between iodine deficiency and endemic goiter resuIted, as is we11 known, in the aImost universa1 adoption of iodine prophylaxis as a public heaIth measure in goiter regions. The successes have been impressive. For instance, in 1924 a survey showed that the incidence of goiter in certain goiter sections of Michigan was 38.6 per cent. Iodine prophyIaxis (by *iodized saIt) reduced the incidence to 8.2 per cent. In CIeveIand the incidence of goiter among schoo1 chiIdren was found to be 31 per cent in 1924; iodine prophyIaxis brought the incidence down to 18.5 per cent in 1937; the incidence among non-users of iodized saIt was 30.7 per cent in 1937, among users of iodized saIt, 7.7 per cent (KimbaII, 1939). Because of negIect of this definitely indispensabIe pubIic hearth measure, goiter has been on the increase in a number of goiter sections (KimbaIl, 1946).

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Because of such great successes resuhing from the large scaIe use of iodine prophylaxis in endemic goiter regions, many authors have promuIgated the concIusion that iodine deficiency is the cause of a11 cases of endemic or simpIe goiter. NevertheIess, there are many facts which such a conclusion does not take into account. Iodine prophyIaxis is effective in most but not a11 cases. KimbaII (1939, 1946) stated that in certain sections of Michigan the incidence of goiter “among those using iodized saIt reguIarIy ” was 2.88 per cent in 1936, tweIve years after the institution of iodine prophyIaxis in these sections. In CIeveIand in 1937 the incidence of goiter among schoo1 chiIdren who were users of iodized saIt (presumabIy since earIy infancy) was 7.7 per cent. It is a fact that iodine administered at a comparativeIy high IeveI does not completely soIve the problem of endemic goiter; chiIdren presumabIy “saturated” with iodine-certainIy receiving iodine at a higher IeveI than the average individua1 in many regions where goiter does not occur-nevertheIess show a strikingIy high incidence of goiter. In a recent editoria1 on progress and future in the treatment of goiter, CoIe (1944) stated: “It must be emphasized that restoration of the proper iodine intake aIone cannot be expected to eIiminate goiter because goiter of a11 types stiI1 exists aIong the seaboard where iodine intake (particuIarIy in drinking water) is presumabIy adequate. Moreover, the added intake of iodine in iodized saIt in these communities during the past few years has not resuIted in any decrease in goiter. As a matter of fact, in some communities (for example, New OrIeans) the incidence of goiter appears to be on the increase.” The incidence of goiter in parishes (the counties of other states) in the southern part of Louisiana, where iodine intake appears to be we11 above the average for the country at Iarge, has impressed a number of authors. Mahorner (1944) has remarked

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in a recent paper: “Goiter is not uncommon among peoples inhabiting the banks of certain bayous. These rivers, often very were originaIIy estuaries of the deep, Mississippi River. The surrounding Iands are Aat and Iow and frequentIy marshy and were formed by aIIuvia1 deposits of the Mississippi River. The diet of the peopIe inhabiting this area consists presumably of much sea foods, and the iodine content of their vegetables is reIativeIy high. The peopIe themseIves aIong these bayous recognize that noduIar goiters are common. The explanation as to why the people in this Iow ffat area shouId have more goiters than those in the rest of Louisiana is not available. AI1 the soil of this area was brought down the river possibIy from the upper Mississippi and the Ohio Rivers, which drain goiter belts. A positive goitrogenie factor thus may have been transported.” There are additiona evidences that deficiency of iodine cannot account for all cases of simpIe goiter. Sporadic goiter occurs in regions where the iodine intake is high. “ Epidemics” of goiter have been known to occur, as remarked many years ago by Hirsh (I 883) ; these must have been evanescent exacerbations of genera1 conditions among a popuIation already affected by deficiency of iodine, but the iodine dehciency does not expIain the sudden increase in incidence of endemic goiter. And now, of course, the production of goiters deliberately (in therapy of hyperthyroidism by administration of goitrogens) and inadvertently (by thiocyanates, suIfonamides and related compounds) has become a familiar demonstration of goitrogenesis without iodine deficiency. ETIOLOGY

OF

THYROTOXICOSIS

In experimenta animaIs severe thyrotoxicosis can be induced by (I) rendering the anima1 goiterous through the action of any one of variety of goitrogens and (2) administering iodine. Simiiar factors may be operative under natural conditions.

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This possibility shouId interest the “unitarians” especially, i.e., those who have long maintained that simple goiter, exophthaImic goiter and toxic adenoma have the same underlying pathoIogy. UntiI more has been determined concerning the action of goitrogens under natural conditions, discussion wouId be mere specuIation. In the meantime, we may wonder about apparent relevancy of the fact that iodine administration occasionaIIy causes exacerbation of Graves’ disease and may even, as many have asserted, precipitate Graves’ disease if reIativeIy high dosages are given to patients with simpIe goiter. Warington (1933), for instance, has pointed out: “Graves’ disease was not at that time recognized, but the description by Gairdner ( 1824) of the condition of goitrous patients after overvigorous treatment with iodine [eaves no doubt that the syndrome of Graves’ disease had been elicited or at least precipitated in them by the use of this drug.” ADENOMATOUS

COITEK

Gorbman (1946) has shown that prolonged feeding of a goitrogen (thiourea) to mice causes the deveIopment of adenomatous goiters. PresumabIy these “non-toxic adenomatous ” goiters couId readiIy be transformed into “ toxic adenomatous ” goiters by administration of iodine aIthough Gorbman has not mentioned the possibiIity. It is to be noted, however, that the goitrogen was fed at an extremeIy high leve1: thiourea constituted 2 per cent of the diet of the animaIs. (No approximation to such a IeveI is ever attempted in therapy with antithyroid substances.) METASTASES

OF

THYROID

TISSUE

Gorbman ( I 946)) after proIonged feeding of thiourea to mice, detected thyroid ceIIs in veins of the thyroid gIand, these ceIIs evidentIy having become detached from the highIy activated epitheIium. This finding led him to examine the Iungs wherein he was abIe to demonstrate histoIogicaIIy the

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presence of smaI1 isIands of thyroid-like ceIIs showing high mitotic activlity. (Resumption of the normal diet was followed by invoIution of the activated epithelium.) The significance of these observations in reIation to the possible natura1 action of goitrogens during a period of years cannot now be surmised. The possibIe co-action of a carcinogenic influence would be another consideration. TOXIC

AND

NON-TOXIC

ADENOMATOUS

GOITER

The demonstration of the existence of structural anaIogues antagonistic to thyroxine, i.e., “bio-antagonists” of thyroxine, suggests the possibiIity that the presence of some such antihormone may explain certain differences between toxic and nontoxic goiter. If the bio-antagonist were present in non-toxic adenomatous goiter, presumabIy at Ieast some of the effects of thyroid hormone would be counteracted. Disappearance of the biological competitor wouId, perhaps, explain the development of toxicity in a previously non-toxic case. A comphcating factor wouId be fluctuating iodine intake. “CARDIOTOXIC”

GOITER

As earIy as 1887 Schranz remarked the occurrence of cardiac abnormaIities in patients with goiter, especiaIIy adenomatous goiter, but without other symptoms or signs of a toxic condition. Among the many authors who have expressed a conviction that there is such an entity as “cardiotoxic” goiter are HertzIer (1936), Schmidt and HertzIer (1942), Rasmussen ( 1941) and Meyer and Ferguson (1942). Of course, as is we11 known, congestive heart faiIure may resuIt from thyrotoxicosis alone (Rose, I 946). PIummer (192 I) suggested that the thyroid gIand in certain thyrotoxic patients secretes an abnorma1 thyrogIobuIin-Iike substance. Rose (1946) remarked: “This suggestion may have been too readiIy abandoned.” Many authors have theorized that the heart may be directIy affected by a specific “cardiotoxic” agent elaborated by

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a goiter, whether or not the basa1 metabohc rate is eIevated. The discovery of thyroxine anaIogues antagonistic to thyroid hormone indicates stiI1 another possibihty : Certain bio-antagonists may be modulators of the effects of thyroid hormone rather than direct antagonists. In fact, WooIIey (1946) presented no evidence to show that all effects of thyroxine are directIy counteracted by the antagonistic anaIogues tested. A moduIator of thyroid hormone activity wouId, presumabIy, counteract or compIeteIy ne&traIize certain effects of the metaboIite whereas other effects might even be augmented by a partia1 synergism. It is even conceivabIe that the physioIogic effects of a metaboIite might be given a new pitch or “keynote” so as to have the tota inff uence of the metaboIite exerted in a new, single direction toward some target organ such as the heart. It has not yet been demonstrated that any bio-antagonist is not a moduIator rather than a direct antagonist. It is to be noted that however great the quantity of bio-antagonist present in the body, the metaboIite is stiI1 present, capabIe of pIaying new r6Ies if not the oId. SUMMARY

AND

CONCLUSIONS

I. The demonstration of the existence of powerfu1 goitrogens, many of which occur naturaIIy, wouId seem to open the way to new concepts in the investigation of the causative factors in simple or endemic goiter. 2. Iodine deficiency is the outstandingIy important causative factor in the development of simpIe goiter, but other factors are important aIs0. 3. It is possibIe that goitrogens in drinking water, common foods or both are invoIved in the etioIogy of simpIe goiter. 4. New etioIogic concepts concerning goiter are aIso suggested by the demonstration of the existence of structura1 anaIogues of thyroxine that counteract or moduIate the effects of thyroid hormone. 5. Goitrogens and perhaps aIso bioantagonists of thvroxine mav.J be~~ invoIved c_J o-

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in the causation not onIy of simple goiter but aIso of exophthaImic goiter, toxic adenoma and non-toxic adenoma. 6. U.nder certain conditions proIonged ingestion of goitrogens may eventuaIIy cause the production of metastasizing tumors of the thyroid gIand. 7. “Cardiotoxic” goiter may exist as an entity caused by the action of a moduIator of thyroid hormone activity. REFERENCES

r. ASTWOOD, E. B. The chemica1 nature of compounds which inhibit the function of the thyroid gIand. J. Pbarmacol. Ed Exper. Tberap., 78: 79, 1943. 2. ASTWOOD, E. B. Chemotherapy in hyperthyroidism. Surnerv, _ “. 16: 679. 1944. 3. ASTWOOD, E. B., BIS&L; A-. and HUGHES, A. M. Inhibition of the endocrine function of the chick thyroid. Federation Proc., 3: 2, 1944. 4. ASTWOOD, E. B., SULLIVAN, J., BISSELL, A. and TYSLOWITZ, R. Action of certain sulfonamides and of thiourea on the function of the thvroid gIand. Endocrinology, 32: 210, 1943. 5. BARKER, M. H., LINDBERG,H. A. and WALD, M. H. Further experiences with thiocyanates. J. A. M. A., 117: 1591, 1941. 6. BIRCHER, E. Weitere HistoIogishe Befunde bei durch Wasser erzeugten Rattenstrumen und Kropfherzen. Deutscbe Ztscbr. f. Cbir., I 12: 368, 1911. 7. BIRCHER, E. Beitrage zur Kropffrage. II. Die toxische Struma (Kroofherz und Jodbasedow). Beitr. z. k&n. Cbir:, 14;: 580, 1927. 8. CHESNEY, A. M., CLAWSON, T. A. and WEBSTER, B. Endemic goiter in rabbits. I. Incidence and characteristics. Bull. Jobns Hopkins Hosp., 43: 261, 1928. g. COLE, W. H. Progress and future in the treatment of goiter. Surgerv, _ -. 16: 81 I. 1944. IO. FAHGND, G. T. R. PainfuI emargement of the

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