Triiodothyronine and Thyroxine in Hyperthyroidism

COMPARISONOF THE ACUTECHANGESDURING

THERAPYWITH ANTITHYROID AGENTS

J. ABUID and P. R. LARSEN

From the Division of Endocrinology and Metabolism, Department of Medicine,University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261

A B S T R A C T In 66 untreated patients with hyper-thyroidism, serum triiodothyronine (Ts) and thyroxine(T4) concentrations were measured by immunoassay.The mean T3 level was 478±28 ng/100 ml (all valuesmean±SEM) and the T4 was 20.6±0.6 ilg/lOO ml. Theserum T4/Ts ratio by weight was 48±2 as opposed to avalue of 71±3 in euthyroid adults. There was a signifi-cant inverse correlation of the T4/Ts ratios with serumT3 (r 0.77; P

little metabolic effect unless it is deiodinated to T8 inthe peripheral tissues (1). Although thyrotoxicosis ismost commonly associated with increases in circulatinglevels of both To and Ts, review of the available studiesindicates that the concentration of the latter is generallyelevated to a greater extent than is To (2). The mecha-nism of this disproportionate increase in Ts and itsmetabolic implications are not clearly understood. Sinceserum Ts elevations appear to be consistently presentin hyperthyroid patients and since T3 may be the activeform of thyroid hormone, it was of interest to documentthe changes in its concentration during therapy withcommonly used antithyroid agents. In addition, the half-life of Ts is short so that inhibition of Ts productionshould be rapidly reflected in decreases in serum hor-mone concentrations. Preliminary studies from this lab-oratory have indicated that substantial changes in cir-culating Ts may occur within 24 h of initiation of therapy(3). The studies reported below were performed tocompare changes in Ts and To levels during the earlytime periods after starting treatment with propylthioura-cil (PTU) or methylmercaptoimidazole (MMI) aloneor in combination with iodide.

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METHODSThe patients employed in this study were clinically andchemically hyperthyroid. All were hospitalized at the Uni-versity of Pittsburgh Health Center Hospitals. In 66 pa-tients serum T3 and To concentrations were measured beforetreatment by radioimmunoassay techniques described previ-ously (4, 5). 28 patients with Graves' Disease were studiedduring therapy while inpatients either in the Clinical Re-search Unit or the medical wards of the Presbyterian-University Hospital or V. A. Hospital. These patients weregiven various drug regimens on a random basis. All drugswere administered orally every 6 or 8 h with one exceptionwhere NaI was administered intravenously. Collection ofblood samples was performed at two different times beforetherapy and every 12-24-h after initiation of therapy andfor 5 days in most cases. The samples were allowed toclot, and the serum was separated and frozen until as-sayed. Serial determinations of T3 and T4 were performedin duplicate, at two dilutions, in the same assay for eachpatient, and at least in two different assays. T4/Ts ratioswere calculated on a weight basis. The study groups wereas follows:

(a) PTU, MMI, or iodide alone. Nine patients werestudied during therapy with either PTU (three),MMI (three), or iodide alone (three). Mean dailydoses were 817 mg (range 750-900 mg) for PTU,80 mg (range 60-90) for MMI, and 15 gtt. ofsaturated solution of potassium iodide (SSKI) in thethree patients receiving iodide.

(b) PTU or MMI in combination with iodide. 19 pa-tients were studied in this group. 11 received PTU+ iodide and eight received MMI+ iodide. Meandaily doses were 827 mg (range 300-1,600 mg) forthe PTU group and 88 mg (range 75-120) for theMMI group. Iodides were usually given as SSKI, 5gtt. every 8 h.

RESULTS0o- 0 0 Serum Ts, T4, and T4/T, ratios in untreated thyro-to 0 toxicosis. The mean Ts and To concentrations in the0r \serum of 66 untreated hyperthyroid patients were 4784

| 28 ng/100 ml and 20.6±0.6 ug/100 ml.V In virtually all° 200 400 600 800 1,000 ZOO 4o00 patients the circulating levels of these two hormones are

T3 (ng/IOOml) increased, but greater increases in Ts were apparent in0 0 most. As a result, in all but two of the subjects studied

I0_r, 0.213 the T4/Ta ratio in serum is lower than the mean valueo N.S.

o 0 0 0 of 71±3 which we have observed in euthyroid subjects0o _ (2). The mean T4/T8 ratio in the hyperthyroid subjects0oL &o' 0 was 48±2. When the T4/Ts ratios are plotted againstc ).° 00 oo0 the concentrations of either T8 or T. in the same speci-0 08008 000 0 ment, there is a significant inverse correlation between0o - o° 0 0 the Ti/T8 ratios and the concentration of Ts (Fig. 1).!0 o8 In contrast, there is no significant correlation between10 T4/Ts ratios and T4. These findings indicate that in-o A I , creases in circulating Ts in hyperthyroidism are not ac-10 I5 20 25 30 35 40 companied by proportionately large increases in serum

T4 (49/100 ml) To.URE 1 Correlation between serum T4/Ts ratios (by Acute changes in serum Ts, T4, and T4/T: ratios inght) and the concentration of Ta and T4 in the serum hyperthyroid patients treated with iodide, MMI, or PTU6 untreated hyperthyroid subjects. Ts and T4 were mea-d in the same sample, 'All values are given as mean+SEM unless indicated.

202 1. Abuid and P. R. Larsen

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FIGURE 2 Serum T3, T4, and T4/T3 ratios in hyperthyroid subjects treated with iodide, MMI,or PTU alone. Numbers in parentheses are the daily dosages. Iodide was given as SSKI5 gtt. q. 8 h in the three subjects shown.

alone. In Fig. 2 are shown results of preliminary stud-ies performed to explore the quantitative changes in Tsand T4 in patients receiving these agents. With iodidetherapy, there is an acute decrease in circulating Ts to50% of the initial level by day 4. To values are also sig-nificantly lower on day 4, but the decrease is only to70% of control levels. The mean T4/Ts ratio at 4 dayswas 58 compared to 42 initially. The more rapid decreasein serum Ts than in serum T4 was anticipated followinginhibition of thyroidal secretion since the half-life of Tsis considerably shorter than T4. Therefore, the increasein the T4/Ti is consistent with an acute inhibition ofthyroidal secretion which has been previously demon-strated to occur during iodide administration to hyper-thyroid subjects (6, 7). The failure of serum Ts to fallto normal levels is presumably a reflection of both in-complete inhibition of thyroidal release as well as per-sistence of Ts production from T4 in the periphery.

With MMI therapy the pattern of changes varies. Inone patient there is an acute decrease in serum Ts toabout 55% of the initial level by day 3 and an associateddecrease in serum T. of less magnitude. In the other twopatients, a slight decrease in T3 levels to about 70% of

the initial level was seen in one, no change in Ts in theother, and neither showed significant changes in T4.The heterogeneity of the response pattern of these pa-tients to MMI is not surprising since this drug inhibitssynthesis of thyroid hormones but has no effect on therelease of previously formed hormonal stores. Sincethese may vary quantitatively in different individualswith hyperthyroidism, early changes in serum Ts andT4 concentrations during treatment with MMI would beexpected to vary accordingly.

During treatment with PTU the decreases in serumTa concentrations were more uniform. Mean serum Tsconcentrations decreased significantly to 50% of the ini-tial level on day 3. The decreases in serum T3 occurredin the absence of significant decreases in serum T4 andare reflected in marked acute increases in the T4/Tsratios. The uniformity of the response to PTU and themagnitude of the decrease in serum Ts concentrationssuggested an effect different from that of MMI.

Previous studies have indicated that PTU inhibitsperipheral deiodination of To in hyperthyroid subjects(8, 9). Since this effect of PTU is associated with in-hibition of Ts production in animals, it seemed possible

TX and T4. Acute Changes with Therapy 203

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FIGURE 3 Serum T3 and T4 in hyperthyroid subjects treatedwith PTU or MMI in combination with iodide. Values arethe mean±SEM of 11 subjects for PTU+ iodide andeight subjects for MMI+ iodide. The line joining the T4values was determined by least squares analysis of theregression curve.

that a similar mechanism could account for the acutedecreases in serum T3 seen in these patients (10).Therefore, we examined this possibility under conditionswhere the qualitative and quantitative contributions ofsecretion of preformed hormones was minimized by theconcomitant administration of iodide. MMI, which hasnot been shown to have a peripheral effect in man, pro-vided a control for the antithyroid effect of PTU (11,12).

Acute changes in serum Ti and T4 in hyperthyroidpatients treated with PTUor MMI combined with iodide.The effect of treatment of hyperthyroid patients withthe combination of PTU or MMI with iodide is shownin Fig. 3, and the individual data are presented in TableI. Mean initial serum Ts and To concentrations weresimilar in both groups. Statistically significant differencesin serum Ts concentrations were observed on days 1 and

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2, with greater decreases in serum Ts obtained withPTU+ iodide. In this group, mean initial Ta was 586ng/100 ml and fell to 326 in the first 24 h of treatment(P

TABLE I

T3 and T4 during Treatment of Hyperthyroidism with PTUor MMI in Combination with Iodide

T3 T4

Day of therapy Day of therapy DailySubj ect 0 1 2 3 4 5 0 1 2 3 4 5 dose

ng/1OO ml g/I100 ml mg*

PTU + Iodide

F. B. 935 635 239 256 216 254 25.6 24.4 23.1 21.7 19.6 20.2 750WV. K. 913 294 268 255 275 40.0 29.6 29.7 29.8 25.9 - 1,600C. H. 700 512 - 266 24.3 24.3 - - 15.6 750B. R. 659 211 194 - 158 24.6 21.8 19.2 - 18.2 1,200M. F. 584 309 237 215 27.2 24.1 24.5 21.4 - 900K. P. 570 326 255 238 20.4 21.0 18.0 18.0 - 450E. J. 529 415 382 370 331 313 24.9 27.6 27.9 25.2 24.6 22.9 450E. C. 495 271 236 261 245 263 24.1 21.8 20.8 21.0 20.2 19.6 750C. O. 414 260 243 198 194 190 15.2 11.9 11.7 11.2 10.4 9.6 300T. K. 353 164 163 114 149 18.6 16.5 17.1 16.6 16.9 16.4 1,200M. B. 326 236 203 130 166 18.3 17.7 - 18.5 18.9 15.6 750

Mean 586 326 248 231 221 214 23.9 21.9 21.3 20.4 19.0 17.5 827SEM 61 41 21 20 21 19 2.0 1.5 1.9 1.8 1.7 1.6 115

MMI + Iodide

M. P. 965 839 586 586 410 373 31.7 30.6 24.5 22.9 19.7 20.3 75E. H. 923 653 575 463 - 31.1 34.1 27.8 26.5 - 90W. K. 829 885 849 - 694 679 28.2 - 27.5 28.3 28.2 120B. B. 778 600 432 343 230 368 20.0 21.1 19.3 18.9 16.4 19.8 90M. C. 490 394 309 237 252 282 20.2 17.3 17.9 18.6 16.9 15.8 90J. M. 451 585 336 313 334 236 14.1 19.8 14.5 11.6 14.7 10.0 90C. G. 413 310 311 243 244 209 18.2 15.7 15.9 14.1 13.5 12.3 75S. P. 314 278 207 218 206 198 12.6 11.3 9.6 9.0 9.6 9.1 75

Mean 645 568 452 344 339 335 22.0 21.4 19.6 18.7 17.0 14.6 88SEM 90 81 73 51 65 63 2.6 3.1 2.3 2.5 2.2 2.0 5

Pt NS

group could not be explained on the basis of higher ini-tial serum Ts concentrations in the patients receivinglarger doses of this drug since the initial T3 values inthe groups receiving different doses of PTU were es-sentially the same. Specifically, the mean initial T3 con-centrations were 504+47, 614+132, and 627±115 inpatients receiving daily doses of 300-450 mg (three),750 mg (four), and 900-1,600 mg (four), respectively(Table I).

DISCUSSIONThe significant inverse correlation of T4/T3 ratios withserum Ts concentrations in untreated hyperthyroidismindicates that greater increases in circulating T3 relativeto T4 are consistently observed in this condition. Thisrelative excess of T8 could be due either to relativelysmaller increases in the metabolic clearance of T3 thanin the metabolic clearance of T4 or to a disproportionateincrease in the production rate of this hormone. Studiesby Nicoloff, Low, Dussault, and Fisher in hyperthyroidsubjects suggest that the former possibility is unlikelysince parallel increases in the disappearance rates ofboth labeled Ts and T4 were observed in this condition(13). The study further estimated that there was a 7-foldincrease in the daily production of Ts whereas productionof T4 was increased only 3.5-fold. The relative overpro-duction of T3 in turn could be a result of either increasedthyroidal Ts secretion or increased quantities of Ts aris-ing from peripheral deiodination of T4 or both. Reviewof recent studies by several laboratories suggests thatthis latter pathway is the major source of circulating T3in euthyroid subjects (2). If one assumes that the frac-tion of T4 which is converted to Ts per day remains con-stant in hyperthyroidism, then rough estimates of therelative contribution of the two pathways to the periph-eral T3 pool can be made. While the precise proportionof the peripheral T3 pool deriving from T4 is a matter ofdebate, a recent review of the literature suggests that aminimum of about two-thirds comes from this source(2). This would amount to about 80 ng/100 ml of thenormal serum T3 concentration of about 120 ng/100 ml.If peripheral T3 production were increased 3.5-fold as istotal T4 production in hyperthyroidism (i.e., if the frac-tional T4 to Ts conversion remains constant) an increaseto a serum T8 concentration of 280 ng/100 ml would beanticipated. This amounts to 46% (280/610) of themean serum Ts level in 19 patients examined in detailin this study. These approximations would indicate thatthe thyroid and the periphery contribute about equallyto the Ts pool in hyperthyroidism and that the acute in-hibition of either pathway would cause similar initialdecreases in serum Ts concentrations.

The observation that iodide alone caused a rapid fallin circulating T3 is evidence substantiating the acute in-

hibition of thyroid hormone secretion produced by thisagent in hyperthyroid subjects. The acute inhibition ofrelease of 'I from prelabeled glands was first demon-strated by Goldsmith and Eisele (14) using epithyroidcounting techniques and more recently verified in studiesby Wartofsky, Ransil, and Ingbar by analysis of thechanges in stable and labeled serum T4 concentrationsduring iodide administration (7). The latter reported amean decrease of 74% in To secretion rate. Since thehalf-life of Ts is short relative to To, changes in theconcentration of this hormone are more abrupt thanchanges in the latter. Since some decreases in T4 werepresent during iodide therapy, peripheral T3 productionwas presumably decreased as well and contributed tothe overall changes observed. The effect of an agent suchas MMI on T3 levels is more difficult to analyze. It isapparent that despite the presence of effective inhibitionof T4 and Ts synthesis, release of these hormones willcontinue until the preformed stores are depleted. Theduration of continued T3 and T4 secretion will be afunction of the amount of colloid and the thyroidal re-lease rate in each individual. Thus, a heterogeneous re-sponse might be expected in any group of hyperthyroidpatients. This was observed in the three patients re-ceiving MMI (Fig. 2). A similar type of responsewould be anticipated in patients treated with PTU if itsonly mechanism of action was to inhibit thyroidal hor-mone production. However, in our preliminary studies,the decreases in serum T3 during therapy with PTUalone appeared to be both more acute and more con-sistent than those seen with MMI. This effect was dif-ferent from that obtained with iodide alone in that si-multaneous decreases in T4 concentration were minimal.Consequently, the increases in T#/Ta ratios were greaterwith PTU than with either MMI or iodide. The con-sistency of the response pattern during PTU therapyargued against the chance occurrence of low intrathy-roidal pools of Ts relative to To in the patients treatedwith this drug. Alternatively, it suggested that perhapsthe acute decrease in serum Ts in the absence of sig-nificant changes in serum T4 could result from inhibitionof peripheral T3 production from T4.

The evidence that PTU inhibits deiodination of To inthe experimental animal has been extensively reviewedby Morreale de Escobar and Escobar del Rey (15). Re-cent studies by Oppenheimer, Schwartz, and Surks havefurther documented that PTU administration to ratsresults in a decrease in the generation of labeled Ts fromlabeled T4 (10). Other studies have reported evidenceof inhibition of T4 deiodination in hyperthyroid subjects(8, 16). More recently, Nicoloff reported that PTUcaused an acute inhibition of T. deiodination in euthyroidsubjects (12). This effect was not shared by eitherMMIor iodide.

206 J. Abuid and P. R. Larsen

To our knowledge, there are no previous studies ofthe effect of PTU-induced inhibition of T4 deiodinationon peripheral Ts production in either hyperthyroid oreuthyroid subjects. It was apparent from the preliminarystudies that the comparison of the effects of MMI andPTU on peripheral Ts production in hyperthyroidismwould be complicated by the previously discussed dif-ferences in thyroidal stores in different individuals. Toovercome this problem, PTU and MMI were combinedwith iodide. Under these circumstances, the release ofboth thyroid hormones would be expected to be decreasedto approximately 25% of the initial rate. Acute changesin circulating T3 would, then, better reflect primary ef-fects on peripheral T8 production. The gradual decreasein circulating T3 observed in the patients receiving MMI+ iodide did not appear substantially different from theeffects of iodide alone in the preliminary studies. Theserum Ts concentration appeared to plateau at about 340ng/100 ml or 53% of the control level at about 3 days,consistent with the approximations outlined previously.The abrupt decrease of the serum T3 to 56% of controlon day 1 and to 42% of control on day 2 in the PTUgroup indicates that both pathways for T3 productionare inhibited. The decreasing T4 levels in both groupswas presumably a result of the iodide therapy. Whilethere was no significant difference in the serum T4 valuesbetween the two groups, this disappearance slope ap-peared shallower in the PTU-treated group as wouldbe anticipated if T4 deiodination were inhibited. Whilecirculating T, might then tend to be higher in this group,it was primarily the significant decreases in circulatingT3 which resulted in the marked elevations in the serumT4/T8 ratio. Since the drugs were given in roughly theaccepted potency ratio, namely, 10: 1 for PTU versusMMI, it is probable that the inhibition of thyroid hor-mone synthesis induced by these agents was also equiva-lent. Because of the substantial acute inhibition of thy-roidal release rate produced by iodide, small differencesin the inhibition of thyroid hormone synthesis in thetwo groups would play little role in the observedresponses.

However, the concomitant administration of iodideand antithyroid drugs requires one further comment.If inhibition of thyroid hormone formation were incom-plete with these amounts of PTU and MMI, then theadditional amounts of iodide could lead to the synthesisof greater amounts of hormones than would be formedin the presence of the antithyroid drugs alone. SincePTU is perhaps less than 10% as potent as MMI byweight (17), one could speculate that the T4/Ts ratioof newly synthesized hormones in PTU-treated patientswould be greater than in MMI-treated patients, sincegreater restriction of iodine organification could resultfrom the more efficient blockade by the latter drug.

The situation might be analogous to studies in ratswhere iodine deficiency results in a decrease in the T4/Taratio of synthesized hormones (18). However, absoluteT3 production during the apparent plateau period (days3-5) appears to be about 50% greater during MMItherapy than during treatment with PTU. It thus seemsdifficult to explain the higher total T3 production ratein MMI-treated patients as due to a greater absoluterate of thyroidal Ts secretion resulting from more com-plete inhibition of organification. It is perhaps morelikely, at least acutely, that the high iodide levels, in ad-dition to inhibiting hormone release, also caused intra-cellular iodide concentrations sufficiently elevated tocause further inhibition of the organification process inboth groups through the Wolff-Chaikoff effect (19).The similarity of the pattern of response in the PTU-treated patients, whether or not added iodide was given,would add support to these theoretical arguments.

The previous studies in animals and man, as well asthe present results, point to inhibition of T4 deiodinationas the best explanation for the acute decreases in circu-lating Ti resulting from PTU therapy. Further supportfor this interpretation is found in the dose-response re-lationships between the "plateau" T4/Ts ratio (or theTs decrement on day 1) and the dose of PTU adminis-tered (Fig. 5). A similar dose-response relationshipover a range of 100-1,000 mg was demonstrated forPTU inhibition of To deiodination in euthyroid subjectsby Nicoloff (12). Previous investigations suggest thatthe maximum inhibition of T4 deiodination by PTU inthe rat is approximately 50% (15). If there is a simi-lar limit in man, a plateau in this curve should eventuallyoccur which was not evident in our studies nor in theabove mentioned studies in euthyroid subjects (12).

Certain clinical implications of this study deserve fur-ther comment. If T3 is the active form of thyroid hor-mone and serum concentrations are an accurate reflectionof the availability of this hormone to the cells, then theacute response of patients to treatment with PTU +iodide is clearly superior to the results with MMI +iodide. Whether the chemical improvements will beparalleled by more rapid clinical improvement is cur-rently under investigation. Unfortunately, the presentseries of patients was not objectively evaluated from aclinical standpoint. However, these results are sufficientlyimpressive to make PTU (as opposed to MMI) in com-bination with iodide, our drug-of-choice in the treatmentof patients with thyroid storm. In patients with lesssevere manifestations of thyrotoxicosis, the potentialbenefits of more rapid decreases in T3 levels with PTU+ iodide (or MMI+ iodide) must be weighed againstthe risks of giving two drugs simultaneously. The periph-eral effects of PTU might also be therapeutically ad-vantageous in the treatment of exogenous thyroxine in-

Ts and T4. Acute Changes with Therapy 207

toxication or in postsurgical or '3.I therapy-induced thy-roid storm where minimal effects of any agents on thy-roid hormone release are anticipated. In addition, thepresent studies are acute and may, therefore, have limitedapplicability to the effects of chronic PTU or MMItherapy on circulating Ts and T4 concentrations.

ACKNOWLEDGMENTSThe authors would like to express their appreciation toMs. Darina Sipula for her careful technical assistance andto Ms. Barbara Brenneman for her secretarial expertise.

This work was supported by Grant AM 14283 fromNIAMDD, Grant 0-20 from the Health Research andServices Foundation of Pittsburgh, and General ClinicalResearch Center Grant FR 56 from the National Institutesof Health.

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15. Morreale de Escobar, G., and F. Escobar del Rey.1967. Extrathyroidal effect of some antithyroid drugsand their metabolic consequences. Recent Prop. Horm.Res. 23: 87-137.

16. Furth, E. D., K. Rives, and D. V. Becker. 1966. Non-thyroidal action of propylthiouracil in euthyroid, hypo-thyroid and hyperthyroid man. J. Clin. Endocrinol.Metab. 26: 239-246.

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208 J. Abuid and P. R. Larsen