cated thyroid to the 4 schizophrenic patients are

SERUM IODINE OF EUTHYROID SUBJECTS TREATED WITHDESICCATED THYROID 1, 2

BY DOUGLAS S. RIGGS, EVELYN B. MAN, AND ALEXANDER W. WINKLER

(From the Laboratory of the Fairfield State Hospital, Newtowm, Connecticut, and the Departmentsof Psychiatry and Internal Medicine, Yale University, School of Medicine,

and the New Haven Hospital and Dispensary, New Haven)

(Received for publication March 19, 1945)

The changes in serum iodine and basal meta-bolic rate which occur when myxedematous pa-tients are treated with desiccated thyroid havebeen reported in the preceding paper (1). Manyeuthyroid subjects differ from myxedematous pa-tients in their ability to tolerate comparativelylarge amounts of dried thyroid without manifest-ing significant signs or symptoms of hypermetabo-lism (2). In the present paper, the influence ofthyroid feeding on serum iodine as well as onbasal metabolism of euthyroid subjects is de-scribed, and the mechanism of euthyroid toleranceto large doses of desiccated thyroid is discussed.

MATERIALS AND METHODS

Data from 2 groups of patients are presented.The first group consisted of 4 female schizophrenic

patients in the Fairfield State Hospital, who were chosenfor their willingness to cooperate in an extended experi-mental study. None of the 4 showed any evidence ofthyroid dysfunction, and all were in reasonably goodphysical condition. The medical and psychiatric statusof each patient is summarized at the end of the paper.The basal metabolic rate of each patient was deter-

mined once a week. Duplicate 8-minute tests were per-formed using the Sanborn Motor-Grafic metabolism appa-ratus. Patients were required to rest in bed for 1½hours before the test. The lower of the 2 rates deter-mined during each test period was used rather than theaverage of both readings. Basal metabolic rates of pa-tients Pa., Ve., and Vi. were usually quite satisfactorilymeasured, those of Wi. less accurately. Body weight,pulse rate, oral temperature, and blood pressure weremeasured under basal conditions. Concentrations of pre-cipitable iodine and of filtrable iodine in serum fromvenous blood were determined each week by methodspreviously described (3, 4). If the serum could not beprecipitated at once it was placed in a securely-stoppered

1This investigation was aided by a grant from theFluid Research Funds of the Yale University School ofMedicine.

2 preliminary report of this work has appeared in theProceedings of the American Society for Clinical Investi-gation in the Journal of Clinical Investigation, 1944, 23,931.

50 ml. Erlenmeyer flask and stored in a quick-freezingchamber. When frozen sera were analyzed, great carewas exercised to agitate the thawed serum thoroughlybefore taking duplicates for analysis, because during freez-ing the serum proteins are concentrated at the bottom ofthe flask. The accuracy of serum iodine determinationwas about ± 0.5 gamma per cent. Serum total proteinswere determined each week-by the falling drop method ofBarbour and Hamilton (5). Serum total cholesterol andserum titrated fatty acids were determined at monthlyintervals by methods previously described (6, 7). Com-plete blood counts were done every 2 or 3 weeks through-out the course of the investigation. The first 5 weeks ofthe study of each patient constituted a control period.U.S.P. desiccated thyroid * was then given daily in pow-dered form as a suspension in a small amount of waterunder the close supervision of a graduate nurse or of anexperienced head attendant. The dose was increased step-wise at 4-week intervals from 3 to 6, 10, 15, and finallyto 20 or 25 grains per day. The highest dose was main-tained for 6 to 8 weeks, and then abruptly discontinued.Thereafter the patients were followed until no furthersignificant changes in serum iodine or basal metabolicrate were observed. Minor individual variations fromthe program outlined above appear in Figure 1.The second group consisted of 9 ambulatory patients

followed for considerable periods of time in the metabolismclinic of the New Haven Hospital. The clinical statusof each of these patients is described in the legend ofFigure 2. Determinations of basal metabolic rate andserum total iodine were made at approximately monthlyintervals. Barring unusual iodine intake, serum totaliodine does not differ significantly from serum precipitableiodine. The dose of thyroid and the duration of treat-ment of each patient are indicated in Figure 2. Data con-cerning the metabolic response of 3 of these subjects tovarious doses of thyroid have already been published (2).

RESULTS

A. Fairfield State Hospital Patients

The changes in basal metabolic rate, serum pre-cipitable iodine and other significant variables be-fore, during, and after administration of desic-cated thyroid to the 4 schizophrenic patients aredepicted in Figure 1. In general the signs and

* Parke-Davis Brand.722

SERUM IODINE OF EUTHYROID SUBJECTS ON DESICCATED THYROID

Basal

Metabolic

Rate

0-_-0

ThyroidDose

Grainsper Day

Basal

Metabolic

Rate

9-o o

Thyroid00"

Grainsper Day

Serum14

Iodine12

%

10Precipitable

a

6

4Filtrable

2 O-O-

16Serum

14lodine

12r%

10Precipitabe

8-

6Filtrable

40-0-o

4 8 .12 16 20 24 28 32 36 40 44 48 4 8 12 16 20 24 Weeks

FIG. 1. THE EFFECT OF LARGE DoSES OF DESICCATED THYROID ON SERUM IODINE, BASAL METABOLIC RATE,AND OTHER VIABLES IN THE EUTHYROID SCHIZOPHRENIC PATIENTS

The significant changes depicted in these graphs are discussed in the text. Each point represents a

different determination. The basal metabolic rate of Wi. on the twenty-eighth week (denoted by "T" inthe graph) is probably too high since the patient had an oral temperature of 100.10 F. when the ratewas determined. The question mark on the graph of thyroid dose for Pa. indicated that for a 2-weekperiod the dose of thyroid was indeterminate, but probably small.

723

724 DOUGLAS S. RIGGS, EVELYN B. MAN, AND ALEXANDER W. WINKLER

BMR04 r

44,1 S%ni 16186

I 1

Thyr-oid-l0 ul

daily

JulVY,1942 July 1943 July 1944

16849

Dec.1942 Juneo 1943

A1348 1

-0-

940 1941 Jul y 943 July 1944

July 1942 July 1943 July1944

20842 JR

~~~~~~~~~~~~~~~~I

Apr. 1943 Apr.1944 July 1943 Jan. 1944

J ulIy 1942.Jan. 1943, July1942 July I,

FIG. 2. BASAL METABOLIC RATE AND SERUM IODINE IN VARIOUS NONMYXEDEMATOUS SUBJECTS RECEIVING THY-ROID MEDICATION AT VARIOUS LEVELS OF DOSAGE FOR EXTENDED PERIODS OF TIME

In general, metabolic rate and serum iodine are well correlated with one another but poorly correlated with thelevel of thyroid dosage. The differences in response to thyroid among various subjects should be noted.The reactions to thyroid medication of the basal metabolism alone of the 3 subjects on the extreme left (16186,

A13481, and A44014) have been described elsewhere and their case histories summarized there (2).J. R. and B. B. were normal subjects who had been receiving thyroid for some time prior to this study solely

because of initially low basal metabolic rates. Case 16849 and D. L. were normal subjects with an initial slightdepression of metabolism who were deliberately placed on increasing doses of thyroid. Case 20842 underwent a

subtotal thyroidectomy in 1942 which was followed by hypoparathyroidism and a low basal metabolic rate. Atthe time of the first observation by us (April, 1943), she had been on 3 grains of thyroid daily for some time, andwas very nervous. Thyroid medication was first reduced to 1 grain a day and then omitted altogether. No clini-cal signs of thyroid deficiency ever developed. She was treated throughout with calcium and Hytakerol. CaseB32017 represents a somewhat similar case followed from time of operation. Thyroid medication was given soon

after operation because of definite symptoms of hypothyroidism. The dose was gradually raised to 5 grains daily,then stopped altogether. No symptoms of hypothyroidism developed, although both iodine and metabolism dropped.

symptoms of the patients during the period ofexcessive thyroid medication were those of a mildto moderate degree of hyperthyroidism, withoutexophthalmos or palpable enlargement of the thy-roid gland.With thyroid medication, the metabolic rates

rose somewhat, but were not consistently main-tained above + 15 per cent until the dose was in-creased to 10 grains per day or more. With fur-ther increase in dosage, metabolic rates frequentlyrose above + 30 per cent, but never exceeded+ 50 per cent. With discontinuance of thyroid

treatment the metabolic rates fell rapidly at first.Subsequently, however, the fall was much lessrapid, so that the decrease in basal metabolic rateapproximated the logarithmic decay curve notedby previous observers (8, 9).The serum precipitable iodine values for the 4

patients during the initial 5-week control periodwere well within normal limits. The serum iodinetended to rise following thyroid administration.As with the basal metabolic rate, however, franklyabnormal levels (above 8.0 gamma per cent) were

not consistently maintained until a dose of 10

0+1

5-o1Ij 30f5

DL

Fob. 1943 Aug

1943 July 1944


grains per day was reached. Further increases inthyroid dose occasioned further increases in serum

precipitable iodine (10). When thyroid treat-ment was discontinued the serum precipitableiodine fell so abruptly that within a single weeknormal or subnormal values were attained. Bythe end of the third or fourth week without thy-roid, distinctly low values, comparable to thoseobserved in untreated myxedema, were found.Thereafter the serum precipitable iodine again in-creased until normal levels were attained by thefifth week after cessation of medication.The mean of 20 control determinations of serum

filtrable iodine on the group of schizophrenic pa-tients was 0.4 gamma per cent. The tendency ofthe serum filtrable iodine to rise when large dosesof desiccated thyroid were administered is de-picted in Figure 3. With cessation of treatment,the serum filtrable iodine rapidly reverted to a

normal low level.

23D

o~~~~~~~~~W

2I1.0 ,.

c*

a

3 6 10 1/5 20 25 2-5 9-15Thyrord Dose Grains per Day W"kls ofter Thlyroid

was stopped

FIG. 3. THE EFFECT OF LARGE DOSES OF DEsiccATEDTHYROID ON SERUM FiLTRA.BLE IODINE IN THE EUTHY-ROID SCHIZOPHRENIC PATIENTSEach point represents the average of all determinations

for a given patient on a given dose of thyroid. The largerthe dose, the higher in general is the filtrable iodine ofserum. After 2 to 5 weeks concentrations of filtrableiodine had returned to normal.

From initial normal values the serum choles-terol of Vi.., Ve., and Wi. fell during thyroid treat-ment. Pa. also had extremely low serum choles-terol values during treatment but unfortunately

a cholesterol determination was not obtained dur-ing the control period. The greatest decreasewas occasioned by the change from 0 to 3 grainsper day, larger doses having comparatively muchless effect. When thyroid administration wasdiscontinued, the serum cholesterol concentrationreturned to normal.Serum total protein decreased in response to

the administration of thyroid. When thyroidtreatment was stopped the serum protein tendedto rise slowly toward the original level.The influence of thyroid feeding on body weight

in this group of patients was remarkably variable.Wi. lost weight during the whole period of medi-cation but had already been losing weight duringthe control period. Vi. maintained weight on 3and 6 grains daily but lost weight on larger doses.Pa. and Ve. showed no striking weight changesduring the entire period of thyroid treatment.With discontinuance of thyroid medication thebody weight tended to rise. The increase wasmost striking in Ve. who gained 25 pounds in 6weeks, attaining a level considerably above herinitial weight. None of the patients would admitany change in appetite during or following theperiod of thyroid feeding.

The changes in heart rate roughly paralleled thechanges in basal metabolic rate. On the average a changeof 10 per cent in the metabolic rate was associated witha change of 5 beats per minute in the heart rate. Duringthe period of thyroid feeding the pulse pressures of all 4patients rose considerably. For patients Ve. and Vi., therise was due to a simultaneous increase in systolic anddecrease in diastolic pressures. For patient Pa., thepulse pressure rise was due almost entirely to a markedincrease in systolic pressure, the diastolic pressure show-ing no significant trend. The reverse was true for pa-tient Wi. In general there was a fairly high degree ofcorrelation between the pulse pressure and pulse rate.Such minor fluctuations in body temperature as occurredduring the study appeared to be due to random variationand could not be correlated with basal metabolic rate ordose of thyroid. The average oral temperature underbasal conditions for all readings on all patients was veryclose to 98.00 F. Of 139 temperature readings only 8fell outside the range of 97.0° F. to 99.00 F. The eryth-rocyte count and hemoglobin of Pa. and Ve. showed nosignificant variations during the course of the study. Theother 2 patients developed a slight anemia during the pe-riod of thyroid feeding. Wi.'s hemoglobin dropped froman average of 11.6 grams per 100 ml. on 0 to 6 grains ofthyroid per day, to an average of 10.4 grams per 100 ml.on 15 to 20 grains of thyroid per day. The corresponding

725

DOUGLAS S. RIGGS, EVELYN B. MAN, AND ALEXANDER W. WINKLER

change for Vi. was from 12.9 grams per 100 ml. to 11.6grams per 100 ml. The red cell count fell commensu-rately. Although the total leucocyte count of Wi. under-went considerable fluctuation during the experimentalperiod, no definite trend was evident. For the other 3patients a distinct drop in the total leukocyte count duringthyroid medication occurred. The lowest total whitecounts for Ve., Pa., and Vi. were 3,300, 4,300 and 4,700cells per cubic millimeter, respectively. This fall in totalwhite count was due almost entirely to a decrease in theabsolute number of neutrophils. Although there was arelative lymphocytosis, the absolute number of lympho-cytes was remarkably constant. After thyroid was stoppedthe hemogram tended to return to normal.

B. New Haven Hospital Patients

Figure 2 illustrates the effects of smaller dosesand smaller increments of dosage continued overlonger periods of time than those used in theschizophrenic patients of Figure 1. Changes ofserum iodine and of basal metabolism in 9 non-myxedematous patients on various levels of thy-roid medication are charted. In general the re-sults were quite similar to those shown in Figure1. Basal metabolism followed serum iodine, whileboth were poorly correlated with the dose of thy-roid in most subjects. Different subjects ex-hibited tolerance in varying degrees; 16186 failedto respond to 3 grains, but responded to 5 grainsdaily; A13481 tolerated 8 grains daily withoutsignificant change; 16849 tolerated only 2 grainsdaily and exhibited a distinct response to 3 grains.B32017 responded to 2 grains shortly after opera-tion, while still partially hypothyroid; later 3grains daily were tolerated but a sustained re-sponse followed a daily dosage of 5 grains. Fallof serum iodine to subnormal levels upon abruptcessation of medication, followed by spontaneousrecovery, is well illustrated in case 16186 (1942and 1943). Under comparable circumstancesserum iodine also fell and recovered less dra-matically in case A13481, and fell in case A44014.

DISCUSSION

Except for exophthalmos and goiter, most fea-tures of naturally occurring Graves' disease werereproduced by the oral administration of driedthyroid in large doses. Basal metabolism andserum precipitable iodine were elevated, whileserum cholesterol was depressed. The' responsesof body weight, heart rate, and blood pressure were

similar to those of spontaneous hyperthyroidism.The changes in total leukocyte count and in therelative proportion of lymphocytes in Graves' dis--ease were reproduced by thyroid medication.

The effect on the basal metabolism of doses ofthyroid below 6 or 8 grains per day was exceed-ingly capricious. For instance, the metabolic rateof Vi. (Figure 1) rose markedly on 3 grains ofthyroid daily but failed to change significantlywhen the dose was doubled. The rate of A13481was unaltered by a gradual increase of thyroid to8 grains daily, while 16849 responded to an incre-ment of dose as small as 1 grain daily. With in-crease of dosage above 10 grains daily the meta-bolic rate always rose somewhat above normal,but the relationship between dose and responsewas unpredictable and highly irregular. Theseobservations confirm the experience of previousworkers (2, 11, 12).

In contrast to the poor correlation betweenthyroid dose and metabolic rate was the excellentcorrelation under most circumstances betweenserum precipitable iodine and metabolic rate. Astable serum iodine was regularly associated withfailure of response of basal metabolism to thyroidmedication (Figure 2). Whenever the metabolicrate increased significantly, there was a parallelincrease in serum iodine. Each point in Figure 4represents 1 pair of values of those 2 variablesderived from the 4 experiments of Figure 1. Val-ues after discontinuance of thyroid medicationhave been excluded. The distribution is curvi-linear. Assuming the relationship to be logarith-mic, as indicated by the solid lines in the graph,the coefficients of correlation between the basalmetabolic rate and the logarithm of the serumprecipitable iodine were + 0.93, + 0.92, + 0.88,and + 0.81 for Pa., Ve., Vi., and Wi., respec-tively. This high degree of correlation indicatesa close functional relationship, but by no meansproves that the relationship is actually a logar-ithmic one. Indeed, if the same logarithmic rela-tionship is assumed to extend'below the normalrange into the zone of values associated with hypo-thyroidism, the theoretical curve fails utterly tocoincide with the observed values.With increasing thyroid dosage, there was al-

most no lag of the rise in the basal metabolismbehind that of the serum iodine. This is shown in

726


0-20 0 V@. 0 PM* 0

a:.

.30 00 0~~~0

.20 0Fo 0 0

+200 1° W.

.10 0 00

00 0 00

-to 00-20 8 0 wi.

6 8 10 12 14 16 6 8 10 12 14 16Serum PrecIpitable Iodine r

FIG. 4. CORRELATION BETWEEN SERUM PRECIPITABLEIODINE BASAL METABoLIc RATE IN FouR EUTHYROIDSCHIZOPHRENIC PATIENTS

The points represent individual determinations of serumprecipitable iodine and corresponding values of basal meta-bolic rate. Values determined after thyroid was dis-continued are omitted for reasons discussed in the text.The solid lines are the regression curves obtained whenbasal metabolic rate is assumed to be a function of thelogarithm of the serum precipitable iodine.

Figure 5, in which changes in serum iodine andin metabolic rate of the 4 schizophrenic patientsfollowing an increase in thyroid dose have beenplotted against time. The curves represent meanvalues for all doses. On the average, the serumiodine had almost attained its maximum level 1week following a change in dose, while the basalmetabolic rate required 2 weeks to reach its maxi-mum level. This difference is of doubtfulsignificance.

This apparent parallelism in Figure 5 may con-ceal a true lag in metabolic response behind in-crease in serum iodine concentration, since dosagewas being progressively increased. With cessationof thyroid dosage, certainly, serum iodine fellmuch more abruptly than did the basal metabolicrate. In fact all correlation between the 2 vari-

ables was lost during the few weeks just afterabrupt withdrawal of medication. Had thesepoints been included in Figure 4, the correlationbetween serum iodine and basal metabolic ratewould have been considerably less exact.Whereas the serum precipitable iodine of Wi. andVe. fell to a low point 3 weeks following with-drawal of thyroid, the basal metabolic rates didnot reach their lowest post medication values for9 to 15 weeks (Figure 1). The serum iodine ofVi. dropped to a definitely subnormal value bythe first week after interruption of medication,while the simultaneous basal metabolic rate wasstill + 15 per cent (Figure 1). Decline of theserum iodine without comparable fall of the basalmetabolic rate following sudden interruption ofthyroid medication also appeared in cases 16186,A13481, and A44014 (Figure 2). A similar lagof the metabolic response behind the serum iodine

e

ol

.1aC6

ar

4

at

0

2

I

: K

.

0a

S

U..5

Weeks after o chonge in dose of thyroid

FIG. 5. PARALLELISM BTEWEEN THE RATE OF CHANGEOF SERUM PRECIPITABLE IODINE AND OF BASAL METABOLICRATE AFTER AN INCREASE IN THYROID DOSE

With increasing thyroid dosage there is almost no lagin the rise in the basal metabolism behind that of theserum iodine. This contrasts with the marked lag ofbasal metabolism behind serum iodine with abrupt dis-continuance of thyroid medication (Figures 1 and 2).The increase in serum precipitable iodine or in basal

metabolic rate occasioned by an increase in the dose ofthyroid has been plotted against the time elapsed sincethe change in dose. The origin corresponds to the lastvalue obtained while the previous dose was being adminis-tered. The points represent average values for increasingthyroid dosage in all 4 schizophrenic patients and for allincrements of dose.

727


concentration has been observed following thy-roidectomy (patient B32017, and Figure 2 of thepreceding paper) and following discontinuance ofthyroid medication in patients with myxedema(1).Presumably the lag of metabolic response be-

hind serum iodine means that the thyroid hor-mone tends to disappear from the serum beforeit disappears from the tissues. The subnormalvalues of the serum iodine developing immediatelyafter discontinuance of thyroid medication sug-gest not only inhibition by the medication ofnormal activity of the thyroid gland, but also adistinct delay in resuming its usual full activity.Persistence of an excessive rate of destruction ofthyroid hormone may be a contributory factor.

Possible mechanisms of euthyroid tolerance tothyroid medication. In discussing possible rea-sons for the relative insensitivity of euthyroidsubjects to desiccated thyroid, a group of workers(2) suggested that "the non-myxedematous sub-ject possesses the ability, wanting in patients withmyxedema, to inactivate thyroid substance andintravenous thyroxine." Perhaps it would havebeen more conservative to have suggested merelythat this ability to inactivate thyroid hormone isvery much greater in euthyroid subjects than inthose with myxedema. The data of the presentpaper provide further support for this hypothesis,in that they disprove the existence of any de-creased sensitivity of the tissues of the euthyroidsubject to the thyroid hormone. The metabolicrate rises at least as much, for a given rise inserum iodine, in euthyroid as in myxedematoussubjects (Figure 6). Of course a much largerdose of thyroid is required to produce a grossrise of serum iodine in the euthyroid subjects.The rise in the metabolic rate to supranormallevels in euthyroid subjects, induced by hugedoses of desiccated thyroid was associated with arise in serum iodine of about the same degree asthat found in spontaneous hyperthyroidism ofcomparable severity. Whenever the metabolicrate was unaffected by thyroid medication, theserum iodine was also unchanged. It has beenpointed out before (2) that impaired absorptionof thyroid substance from the gastrointestinaltract by euthyroid subjects is an unsatisfactoryexplanation of their greater tolerance, since they

are also comparatively insensitive to thyroxineadministered parenterally. Also difficulty in ab-sorption is never seen either in spontaneous orinduced myxedema, so that it is highly improbablethat euthyroid subjects without intestinal defectsare peculiar in their absorption of thyroid hor-mone. Some storage of the hormone in the thy-

0

0 25.0.020

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* 150S

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Myxedemo

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.S. H.

6

/6/ 2.0// // '.5

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1/' 1

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/If -- 4 Euthyroids - F

1 2 3 4 5Average Increase in Serum Iodine r %

FIG. 6. RELATIONSHIP BETWEEN THE INCREASE OFSERUM PRECIPITABLE IODINE AND OF BASAL METABOLICRATE OF MYXEDEMATOUS PATIENTS AND OF EUTHYROIDSUBJECTS GIVEN DESICCATED THYROID

The increase in basal metabolic rate above the averagepremedication level is plotted against the correspondingincrease in serum precipitable iodine at various levels ofthyroid dosage. The dose in grains per day is indicatedby the figures on the curves. The curve for the patientswith myxedema was calculated from data reported in thepreceding paper (1). Data from the 2 groups of euthy-roid subjects reported here are plotted separately, theNew Haven- Hospital patients being indicated by shortdashes, the Fairfield State Hospital patients by longdashes. Each point is the average for all patients in agiven group on a given dose of thyroid.Note that the basal metabolic rate rises at least as

much per unit increase in serum iodine in the euthyroidsubjects as in those with myxedema, but that a muchlarger dose of thyroid is required.

5

L.

5

v

.728

4C

3C


roid gland as colloid is possible, but does not ex-

plain the indefinite persistence of tolerance. En-largement of the thyroid gland was never notedeven after weeks of administration of huge dosesof thyroid substance to the schizophrenic subjects,although the gland would have had to increase byseveral hundred grams had even half the adminis-tered hormone been stored. Extensive temporarystorage in the thyroid gland or elsewhere is alsoimprobable because a low serum iodine developsduring the period following cessation of medica-tion, and because subsequently there is never evi-dence of excessive release of stored hormone.

Inhibition of hormone production by the thy-roid gland apparently did occur, but this factoronly partially explains euthyroid tolerance to thy-roid medication. There is good experimental evi-dence that the administration of thyroid hormoneto intact animals depresses the normal activity ofthe thyroid gland (13, 14). In the present studyof human subjects, the fall in serum iodine to very

low levels when thyroid medication was abruptlywithdrawn probably resulted from inhibition ofnormal production of hormone by the thyroidgland during the previous period of thyroid medi-cation. Normal production of the hormone is,however, equivalent to not more than 3 grains ofdesiccated thyroid per day (1), so that completecessation of endogenous production of hormonewould account only for tolerance to this smalldaily dose. Were this the only mechanism con-

cerned with the maintenance of tolerance, serum

iodine and basal metabolism of all euthyroid sub-jects should respond to as much as 5 or 6 grainsof thyroid daily. In point of fact, however, some

normal subjects can tolerate as much as 8 grainsdaily without any significant alteration in serum

iodine or metabolic rate (Figure 2).A logical explanation of tolerance to amounts

of desiccated thyroid in excess of 3 grains per

day is that the normal thyroid gland can inactivatethe exogenous hormone. This it might do by de-grading active hormonal iodine to inorganiciodine, by a reversal of the reactions which, tindernormal circumstances, lead to the formation ofhormone from inorganic iodine. The significantrise in the inorganic filtrable fraction of the serum

iodine during massive thyroid feeding (Figures 1

and 3) would lend support to this hypothesis. It

is not certain that all the inactivation takes placein the thyroid gland. Any large measure of in-activation anywhere else, however, would implya fundamental difference between the tissues ofeuthyroids and the tissues of myxedematous pa-tients with respect to their ability to dispose ofthyroid hormone, since the only known differencebetween adequately-treated myxedematous pa-tients and euthyroid subjects is the presence offunctional thyroid tissue in the latter.

There is suggestive evidence that tolerance todesiccated thyroid may require considerable timefor full development. Many euthyroid patientsexperience a sharp rise in metabolic rate for afew weeks subsequent to an increase in thyroiddose, but if the dose is maintained for a longerperiod of time the metabolic rate tends to driftdownward towards its original level (2). Anylatency in the development of tolerance in the vari-ous patients described in this paper would be par-tially masked by the gradual step-wise manner inwhich the dose was increased. Three of the 4schizophrenic patients, while on the highest doseof thyroid for 6 to 8 weeks, showed no clear-cutevidence of a decreasing response. However, for2 of the patients there was some suggestion of apartial loss of tolerance during a lapse in thyroidtreatment. Pa. had been started on 15 grains ofthyroid per day, but after 1 week at this level thedosage was markedly reduced. Due to a confu-sion in orders, during the next 2 weeks she re-ceived irregularly an unknown, but probably smallamount of thyroid. With resumption of a regulardose of 15 grains per day, both serum precipitableiodine and basal metabolic rate rose to levels muchhigher than would have been expected from thispatient's previous responses. Similarly, when pa-tient Wi. was replaced on a dose of 20 grains perday after a lapse of 22 weeks, the serum iodineand metabolic rate both rose to a higher pointthan during the previous weeks on the same dose.These observations indicate the need for furtherinvestigation of the time necessary for the devel-opment of tolerance.The tolerance of non-myxedematous patients

to thyroid medication probably accounts for theapparent impunity with which large doses of driedthyroid may be administered under many circum-stances. Whether permanent ill effects may re-

729


sult from long continued administration of thyroidsubstance to euthyroid subjects is not known.Our experiments have demonstrated only func-tional depression of the thyroid gland, while thy-roid is being given and for a brief period after itswithdrawal. This fact alone, however, suggeststhat long continuance of thyroid medication maynot be wholly benign. On a priori grounds, cau-tion is certainly indicated, especially in the con-tinuous administration of thyroid to adolescentsand to patients recovering from subtotal thyroid-ectomy.

SUMMARY AND CONCLUSIONS

1. Many euthyroid subjects are able to tolerateconsiderable amounts of desiccated thyroid with-out significant alteration in either serum precipi-table iodine or basal metabolic rate.

2. The administration of larger quantities ofdried thyroid to euthyroid subjects produces ab-normal elevation of both serum iodine and basalmetabolic rate and elicits most of the signs andsymptoms of spontaneous hyperthyrodism, butthe dose of thyroid required is usually muchgreater than is needed to produce an equivalentdegree of hyperthyroidism in myxedematouspatients.

3. When the administration of desiccated thy-roid to euthyroid subjects is abruptly discontinued,the serum precipitable iodine frequently falls toabnormally low levels, probably indicating tempo-rary inhibition of hormone production by the nor-mal thyroid gland during, and for a brief periodfollowing, thyroid feeding.

4. Rapid and transient changes in serum pre-cipitable iodine may occur without comparablefluctuations in basal metabolic rate. When altera-tions in the level of serum precipitable iodine areslower and more sustained, the lag in metabolicresponse is not as evident, and there is a highdegree of correlation between the 2 variables.

5. The tissues of euthyroid subjects are at leastas sensitive to thyroid hormone as are those ofmyxedematous subjects.

6. Degradation of active hormonal iodine toinorganic iodine by the normal thyroid gland issuggested as the most likely explanation of thetolerance of euthyroid subjects to amounts ofdesiccated thyroid in excess of 3 grains per day.

PROTOCOLS

Ve. was a 33-year-old white female with schizophrenia,paranoid type, of at least 2 years' duration. Althoughcorrectly oriented and in good contact with her surround-ings, she believed herself persecuted by creatures halfman and half beast. She was highly co-operative. Hermental symptoms were uninfluenced by thyroid medica-tion. She was tall and thin without significant physicalabnormalities except for vasomotor instability character-ized by marked flushing of the skin of face, neck, andarms. Blood pressure was 100/60. On 6 grains of thy-roid daily the vasomotor instability increased, and thepatient fainted on 2 occasions. There was a slight tremorof the extended fingers. When larger amounts of thy-roid were administered, the tremor became more pro-nounced and the vasomotor instability was further accen-tuated. The skin was warm and moist. The patientcomplained of fatigue and a "'draggy" feeling. Whenthyroid was discontinued the tremor disappeared, the skinbecame drier, and the vasomotor instability decreased.Coincident with a marked gain in body weight, the patientbecame somewhat lethargic, but she never developed anysigns or symptoms of myxedema.

Vi. was a 23-year-old white female with a 3-year his-tory of schizophrenia, hebephrenic type. Before thyroidwas administered she was extremely lethargic, withdrawn,and almost mute. She was hallucinated and grinned in-appropriately. She was usually quite cooperative. Dur-ing treatment with desiccated thyroid, the patient becamemore talkative and much less lethargic, assisting withward work and taking long outdoor walks. With cessa-tion of thyroid medication she reverted to her previousmute and disinterested condition. While this improvementin energy output may have been related to the inducedhyperthyroidism, it should be noted that the patient hadpreviously experienced similar, but apparently spontane-ous, remissions. On physical examination prior to thy-roid administration the patient was well developed andslightly obese with acne of the face and hirsutism of theface, back, and extremities. Blood pressure was 114/65.In response to thyroid, she developed tachycardia and amoist, warm skin with increased perspiration, but therewas no definite tremor of the outstretched fingers. On25 grains of thyroid daily, she complained of fatigue, andslight dyspnea on exertion. Observations during the post-medication period were interrupted when the patient wastransferred to another hospital 5 weeks after thyroidfeeding was stopped.

Wi. was a 54-year-old white female who had been hos-pitalized for 14 years because of schizophrenia, paranoidtype, characterized by fixed delusions of grandeur. Al-though much deteriorated mentally, she was cooperativeenough to serve as a subject in the present study. Herpsychosis was unaffected by thyroid medication. Theonly abnormality found on physical examination prior tothe administration of desiccated thyroid was slight nar-rowing, irregularity, and increased tortuosity of the retinalarteries. Blood pressure was 120/75. An x-ray of thechest was negative. On 6 grains of thyroid daily, the pa-

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tient felt somewhat weak, and on 1 occasion had a faint-ing spell, with marked pallor of the face, and imperceptiblepulse, but without loss of consciousness. On largeramounts of thyroid, a slight tremor of the extended fin-gers was noted, and on a few occasions there was transi-ent ankle edema. After 7 weeks on 20 grains of thyroiddaily the patient developed a fever of 1020 F. The totalleukocyte count was 11,200 with 73 per cent neutrophils.The pulse was 130 per minute. Except for a red andswollen but non-tender area at the base of 1 finger nail,there was no evidence of infection. Thyroid was dis-continued. Despite the administration of sulfadiazine, thetemperature continued to be somewhat elevated during thenext 4 days. A chest x-ray showed left ventricular hyper-trophy, but was negative for peripheral lung pathology.The only subjective complaint was stiffness and sorenessof the shoulders, which persisted for some time after thefever had subsided. Although the cause of the hyper-pyrexia was not clear, it was probably not due to thethyroid medication, since the same dose was later resumedfor 2 weeks without untoward consequences.

Pa. was a 23-year-old white female who developedsymptoms of schizophrenia, type undetermined, 3 yearsprior to admission. She was lethargic with brief periodsof manic excitement, and claimed that she was infested by"bristle beetles." She was well oriented and quite co-operative, but resented hospitalization and made severalattempts to escape. While thyroid was being adminis-tered, her comments and thinking appeared more co-herent; this was thought to be only a temporary im-provement unrelated to the thyroid medication. Physi-cally she was well developed but thin and pale. Bloodpressure was 100/60. Even on 15 grains of thyroid daily,tachycardia was the only physical sign of hyperthyroid-ism. Unfortunately the patient escaped from the hos-pital before the experimental program was completed.

BIBLIOGRAPHY

1. Winkler, A. W., Riggs, D. S., and Man, E. B., Serumiodine in hypothyroidism before and during thyroidtherapy. J. Clin. Invest., 1945, 24, 732.

2. Winkler, A. W., Lavietes, P. H., Robbins, C. L., andMan., E. B., Tolerance to oral thyroid and reaction

to intravenous thyroxine in subjects without myx-edema. J. Clin. Invest., 1943, 22, 535.

3. Riggs, D. S., and Man, E. B., A permanganate acidashing micromethod for iodine determinations. I.Values in blood of normal subjects. J. Biol. Chem.,1940, 134, 193.

4. Man, E. B., Smirnow, A. E., Gildea, E. F., andPeters, J. P., Serum iodine fractions in hyperthy-roidism. J. Clin. Invest., 1942, 21, 773.

5. Barbour, H. G., and Hamilton, W. F., The fallingdrop method for determining specific gravity. J.A. M. A., 1927, 88, 91.

6. Man, E. B., and Peters, J. P., Gravimetric determina-tion of serum cholesterol adapted to the Man andGildea fatty acid method with a note on the estima-tion of lipoid phosphorus. J. Biol. Chem., 1933,101, 685.

7. Bogdanovitch, S. B., and Man, E. B., The effects ofcastration, theelin, testosterone, and antuitrin-S onthe lipoids of blood, liver, and muscle of guineapigs. Am. J. Physiol., 1938, 122, 73.

8. Means, J. H., and Lerman, J., The curves of thy-roxine decay in myxedema and of iodine responsein thyrotoxicosis: their similarity and its possiblesignificance. Ann. Int. Med., 1938, 12, 811.

9. Boothby, W. M., and Baldes, E. J., Some quantitativerelationships of thyroxine calculated from its calori-genic action. J. Pharmacol. and Exper. Therap.,1925, 25, 139.

10. Farquharson, R. F., and Squires, A. H., Inhibitionof secretion of thyroid gland by continued ingestionof thyroid substance. Tr. A. Am. Physicians, 1941,56, 87.

11. Kunde, M. M., Studies on metabolism. VI. Experi-mental hyperthyroidism. Am. J Physiol., 1927, 82,195.

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13. Balasco, I. J., and Murlin, J. R. The effect of thy-roxin and thyrotropic hormone on basal metabolismand thyroid tissue respiration of rats at variousages. Endocrinology, 1941, 28, 145.

14. Cameron, A. T., and Sedziak, F. A., The effect ofthyroid feeding on growth and organ hypertrophyin adult white rats. Am. J. Physiol., 1921, S8, 7.

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cated thyroid to the 4 schizophrenic patients are

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