8)'.€¦ · by means of techniques described in detail elsewhere (7), the distribution and...

THE EFFECT OF ESTROGENSUPONTHE PERIPHERAL METABOLISMOF THYROXINE* t

By J. THOMASDOWLING,1 NORBERTFREINKEL AND SIDNEY H. INGBAR

(From the Thorndike Memorial Laboratory, Second and Fourth (Harvard) Medical Services,Boston City Hospital; the Department of Medicine, Harvard Medical School, Boston,

Mass.; the Howard Hughes Medical Institute, the Department of Medicine,Veterans Administration Center, Los Angeles; and the Department of

Medicine, University of California Medical Center,Los Angeles, Calif.)

(Submitted for publication August 13, 1959; accepted March 25, 1960)

In plasma, thyroxine is avidly bound to specificproteins present in low concentration, particularlythe so-called thyroxine-binding globulin (TBG)and thyroxine-binding pre-albumin (TBPA)(1-4). Several observations indicate that suchprotein-hormone interactions are of physiologicalimportance. In vitro, the ability of cellular sys-tems to accumulate thyroxine from suspendingmedia is conditioned by the thyroxine-bindingpotency of the proteins within the media (5, 6).In addition, the volume of distribution and rate ofturnover of thyroxine in vivo resemble those ofcertain plasma proteins (7, 8)'. Finally, abnormalthyroxine-binding by TBG and TBPA has beenobserved in a variety of states in which the periph-eral metabolism of thyroid hormone is disturbed(9-12). It therefore seemed possible that inter-actions with plasma proteins might in part regu-late the peripheral utilization and degradation ofthyroxine.

An ideal test of this hypothesis would be pro-vided by studies of hormonal metabolism per-formed before and during the administration oflarge quantities of purified binding protein. How-ever, adequate quantities of these materials are notyet available. Therefore, it. has been necessaryto assess the effects of alterations in thyroxine-binding induced by pharmacological means. Large

* Presented in part at the Annual Meeting of theAmerican Goiter Association, San Francisco, Calif., June16, 1958.

t This investigation was supported in part by ResearchGrant no. A-267 from the National Institute of Arthritisand Metabolic Diseases, Bethesda, Md., and in part bythe Medical Research and Development Board, Office ofthe Surgeon General, Department of the Army, underContract no. DA-49-007-MD-412.

1:Work performed in part during tenure as a Fellowin Cancer Research of the American Cancer Society.

doses of estrogen have been shown to induce pro-nounced increases in the thyroxine-binding ac-tivity of TBG (13), with little or no change in thebinding activity of TBPA (14). The presentstudies concern the effects of estrogens and of theincrease in thyroxine-binding by TBGwhich theyinduce on the peripheral metabolism of thyroxinein patients with diverse states of thyroidal func-tion.

MATERIAL ANDMETHODS

By means of techniques described in detail elsewhere(7), the distribution and peripheral turnover of I`l-la-beled thyroxine1 have been assessed before and duringmaximum estrogen-induced increase in circulating TBG.Definitions of terms employed and their mode of calcu-lation are noted in the appendix. Patients studied in-cluded 8 women with treated myxedema, 3 with intactthyroidal function, and 4 with thyrotoxic Graves' dis-ease. In 10 of the eumetabolic patients, paired studieswere performed before and during the administration ofdiethylstilbestrol. Comparison of the effects of diethyl-stilbestrol and estradiol benzoate were made in 5 of thesepatients.

The sequence of the study periods, details of thyroidalreplacement therapy, and dosage and duration of estro-genic therapy in each subject are presented in Table I.Duration of estrogenic therapy ranged between 19 and54 days, and measurements of thyroxine turnover duringperiods of estrogenic therapy were performed during thelast 8 to 10 days of the treatment period. Subjects withintact thyroidal function, excepting V.D., were given 30mg of methimazole by mouth every 6 hours during eachstudy period in order to prevent thyroidal recycling ofI"1 liberated by peripheral deiodination of radioactivethyroxine. The serum protein-bound iodine (PBI)2 andthyroxine-binding activity of TBG were assessed at 3day intervals throughout control and treatment periods.

1 Obtained from Abbott Laboratories, Oak Ridge,Tenn.

2 Determined by Bio-Science Laboratories, BeverlyHills, Calif.

1119

1120 DOWLING, FREINKEL AND INGBAR

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TABLE II

Effect of estrogens on the fecal excretion and degradation of thyroxine*

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%dose L/day LI'day ,ug l/day ;tg I/day1 27.5 38.9 0.24 0.29 0.64 0.45 22.4 29.3 58.7 46.12 37.4 40.6 0.36 0.29 0.60 0.42 20.5 27.2 34.2 39.73 29.8 28.7 0.26 0.21 0.60 0.52 12.8 15.8 39.7 30.24 42.0 29.5 0.47 0.24 0.65 0.58 24.0 16.6 33.1 39.95 23.2 16.2 0.23 0.14 0.78 0.75 15.7 11.7 51.9 60.48 21.6 9.6 0.30 0.11 1.08 1.07 12.5 6.3 45.3 59.8

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* For definition of terms, see Appendix.t Standard error of the mean differenice.

Studies of thyroxine turnover during the treatment pe-riod were begun when a new steady state had beenachieved, as indicated by constancy of values for TBGand PBI. Values for TBG presented in Table I repre-sent the range and mean of 4 to 5 measurements madeduring control or steady state treatment periods.

Additional studies were performed during periods inwhich the PBI and the binding activity of TBG werechanging after the initiation or withdrawal of estro-genic hormone. In Patient 6, the fractional rate ofperipheral turnover of thyroxine was observed duringa 24 day period beginning immediately after institutionof treatment with diethylstilbestrol. Patient 9 was stud-ied from the fifth through the eighteenth day followingcessation of therapy with diethylstilbestrol.

The 4 women with thyrotoxicosis were studied whilehospitalized on a metabolic ward. Diethylstilbestrol wasadministered only after constancy of basal oxygen con-sumption had been achieved. After attainment of maxi-mal augmentation in TBG during the administration ofestrogen, studies were again performed. Thereafter, alltherapy was discontinued until TBG levels, concentrationsof PBI and TBG, and basal oxygen consumption stabi-lized at values comparable to those found prior to estro-genic treatment. Thyroxine turnover studies were thenrepeated. At the termination of these tests, the patientswere given propylthiouracil in dosage and duration suffi-cient to induce clinical and laboratory evidences of eu-metabolism. Studies of peripheral turnover of thyroxinewere then repeated.

Estimates of the thyroxine-binding activity of TBGwere obtained by means of a technique, described in de-tail elsewhere (15), which has since been superseded inthe authors' laboratories (4). In brief, the method em-ployed consisted of conventional paper electrophoresis inveronal buffer, pH 8.6, of serum labeled with I"'-thyrox-ine and enriched to several standard concentrations withstable thyroxine. At each concentration, the percentagedistribution of added hormone between TBG and albu-

mni was assessed in both experimental sera and con-comitantly electrophoresed control sera. As indicatedin an earlier communication (15) alterations in the bind-ing activity of TBG are associated with qualitatively sim-ilar changes in the distribution of thyroxine between TBGand albumin at each of the concentrations of hormoneemployed. Therefore, only values obtained at a singleconcentrationi, 47.5 ,ug thyroxine per 100 ml, are pre-sented. This technique does not afford an estimate of theabsolute thyroxine-binding capacity of TBG. Neverthe-less, comparison of changes in TBG which occur duringpregnancy, assessed by this method (15) and by methodswhich permit estimation of binding maxima (16), indi-cate that the two techniiques provide qualitatively similarinformation.3

Statistical analyses were performed by the "paired t"test, as described by Snedecor (17). An earlier studysuggested that the presence of a functioning thyroidgland does not alter the kinetics of thyroxine turnoverperipherally, since values for normal subjects and pa-tients with treated myxedema were similar (7). There-fore, in the present studies, results related to the effectsof estrogen on the peripheral turnover of thyroxine in alleumetabolic normal anid athyrotic subjects were pooled.

RESULTS

Data obtained in individual patients are pre-sented in Tables I and II. Mean values and sta-tistical intercomparisons are summarized in TablesII and III.

3Neither estimates of the thyroxine-binding activityof TBG, as herein obtained, nor of its absolute bindingcapacity afford information concerning the absolute quan-tity of protein present. Presumably, alterations in bind-ing activity may reflect changes in either the concentra-tion of TBG or its bindinig stoichiometry.


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Eumetabolic subjects. Previously described ef-fects of large doses of estrogen on PBI (13, 18)and on the binding activity of TBG (13) wereconfirmed in the present study. Increases inPBI during estrogenic therapy occurred not onlyin patients with intact thyroidal function, but alsoin patients with treated myxedema. For the en-tire group, mean values of the PBI increased from5.8 to 7.6 jig per 100 ml. For the patients withtreated myxedema alone, PBI increased signifi-cantly (p < 0.001) from a mean of 5.5 to 7.1 4gper 100 ml. Concomitantly, in sera enriched withstable thyroxine at a concentration of 47.5 ug per100 ml, the proportion of radioactive thyroxinebound to TBG increased from a mean of 54.4to 79.5 per cent.

In ten paired observations, diethylstilbestrolincreased the mean thyroxine distribution space(TDS) from 8.8 to 9.3 L, a change of borderlinestatistical significance. Mean thyroxine half-time(Ti) also increased from 6.6 to 8.9 days, whilethe fractional rate of turnover of hormone (k)correspondingly decreased from 10.7 to 7.9 percent per day. Despite the increase in TDS, meandaily thyroxine clearance (C) decreased from

0.94 to 0.73 L per day. The product of dailyhormonal clearance rate (C) and hormonal con-centration (PBI) represents the quantity of hor-monal iodine removed from the peripheral thy-roxine space daily (D). As a result of reciprocalchanges in its constituent functions, D remainedunchanged during estrogenic therapy in the groupas a whole. Small, random differences betweencontrol and treatment values of D, noted in indi-vidual patients, were probably the result of errorsintrinsic to the technique of measurement. Fol-lowing equilibration of PBI and TBG, basal oxy-gen consumption during estrogenic treatment didnot differ from control values.

As a result of increases in both TDS and PBI,the mean quantity of exchangeable (extrathy-roidal) hormonal iodine (ETT) increased sig-nificantly from 506 to 699 ug during administra-tion of estrogen. Derived values for the fractionof total hormonal disposal accounted for by fecalexcretion (Fmax) did not change significantly forthe group as a whole.

In the five patients who received both types ofestrogen, significant differences in the effects of

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diethylstilbestrol and estradiol benzoate could notbe discerned.

Studies performed in Patient 6 throughout the24 day period following initiation of estrogenictherapy, and in Patient 9 following cessation oftreatment, are depicted in Figures 1 and 2. InPatient 6 the control rate of peripheral turnoverof thyroxine was 10.2 per cent per day and wasfollowed in successive weeks by rates estimatedto be 7.9, 6.6, and 7.3 per cent per day. Increasesin thyroxine-binding by TBG were detected onthe fourth day of administration of diethylstil-bestrol, and reached a maximum after 14 days.In Patient 9, following a pretreatment rate of 10.7per cent per day, the fractional rate of turnoverof thyroxine decreased to 6.6 per cent per dayduring continued estrogenic therapy. After ces-sation of treatment, increased thyroxine-bindingby TBG persisted for a time and turnover rateremained retarded at 7.3 per cent per day, al-though withdrawal vaginal bleeding had occurred.

Administration of diethylstilbestrol to thewomen with Graves' disease was also accompaniedby slowing of the fractional rate of peripheralturnover of thyroxine (Table I). In all four pa-

tients, this rate was as slow or slower than thatsubsequently observed after antithyroid treatment.In Patients 12 and 13, estrogenic therapy was ac-companied by amelioration of symptoms of thyro-toxicosis and by reduction of basal metabolic ratesto normal. In these patients, in contradistinctionto the two patients who experienced no sympto-matic benefit, PBI was unchanged or decreasedduring estrogenic therapy as compared to controlperiods. Correspondingly, calculated values fordaily hormonal disposal (D) in these two womenwere markedly reduced, approaching values ob-tained after treatment with antithyroid drugs.

DISCUSSION

In agreement with the recently published find-ings of Engbring and Engstrom (19), the presentstudies seem clearly to indicate that the prolongedadministration of either natural or synthetic es-trogenic hormones is associated with pronouncedchanges in the peripheral metabolism of thyroxine.These include a decrease in the fractional rate ofturnover of thyroxine and hence in the rate ofclearance of the hormone from its peripheral dis-

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tribution space. Concomitantly, both the concen-tration and total quantity of hormone within thespace increase, so that the absolute rate of hor-monal disposal remains unchanged. These stud-ies, however, were undertaken to assess the ki-netic effects of an increase in the thyroxine-bind-ing activity of TBG. Estrogens were merelyemployed as a means of altering TBG. Thus, itis critical to distinguish between changes in thekinetics of thyroxine metabolism which resultedfrom alterations in TBG and those which mighthave arisen from a direct effect of estrogens onthe cellular degradation or disposal of the hor-mone.

Certain data suggest that estrogens may directlyinfluence cellular oxidative metabolism and itsresponse to thyroid hormone. While estrogensgenerally stimulate genital structures, several es-trogens have been found to depress oxygen con-sumption of homogenates of rat brain (20) andliver (21), and of fresh rat liver mitochondria in-cubated with Krebs' cycle intermediates and di-phosphopyridine nucleotide (22). Animals treatedwith estrogen have been reported to be unusuallyresistant to large doses of thyroid hormone (23-26). and diethylstilbestrol has been shown tohasten the return of oxygen consumption to nor-mal following cessation of thyroid feeding in rats(27). However, it is not known whether sucheffects on oxidative metabolism might result fromor lead to changes in the intracellular metabolismof thyroxine. More direct efforts to evaluate thisquestion have led to contradictory conclusions,since estrogens have had variable effects on thedegradation of thyroxine by cellular preparations,in zvitro (28, 29). Finally, in vzivo, estrone doesnot affect the disappearance of thyroxine from theplasma of rats or rabbits (30, 31).

Thus, it is possible that the slowing of thyroxineturnover induced by estrogens during the presentstudies may have resulted either from a direct ef-fect of these hormones on the cellular degradationof thyroxine or from an effect on cellular oxida-tive metabolism reflected secondarily in delayedthyroxine turnover. However, there is no sub-stantial evidence to suggest that this was the case.On the other hand, there is considerable evidenceto indicate that the slowing of thyroxine turnoverherein produced resulted from an increase in thebinding activity of TBG. In vitro, the static dis-

tribution of thyroxine between cellular and extra-cellular binding proteins is conditioned by theirrelative abundance and binding avidity (5, 6,32). An increase in the binding activity of pro-teins in the suspending medium favors retentionof thyroxine in the extracellular phase. If, asseems likely, similar relationships pertain in vivo,then increases in TBG should decrease the pro-portion of peripheral hormone within cellularconfines. Since the degradation of thyroxine isan intracellular event, this should, in turn, di-minish the fractional rate of turnover of hormonewithin the thyroxine space as a whole (12, 33).

In the present experiments, studies in Patient6 illustrate the rapidity with which slowing ofthyroxine turnover may follow the exhibition ofdiethylstilbestrol. This rapid change might sug-gest a direct cellular effect of the estrogen were itnot that circulating TBG increased with equalrapidity. In Patient 9, retarded turnover of thy-roxine and augmentation of TBG persisted aftercessation of estrogenic therapy. Although with-drawal vaginal bleeding had occurred in this in-terval. it remains possible that diminishing butphysiologically significant stores of estrogen per-sisted during that time.

Additional evidence that estrogenic effects onthe fractional turnover of thyroxine result fromaltered hormonal binding has recently been ob-tained in two patients whose sera demonstratedspontaneous abnormalities in the thyroxine-bind-ing capacity of TBG. The first patient. recentlyreported by Beierwaltes and Robbins (34), dis-played an apparently idiopathic increase in TBG,associated with abnormalities in the turnover ofthyroxine remarkably similar to those induced byestrogens in the present studies. The plasma ofthe second patient was virtually devoid of TBG.Administration of estrogen induced edema andgynecomastia, but the binding capacity of TBGwas not increased and the kinetics of thyroxinemetabolism were unaltered (14).

From the foregoing observations in isolated cel-lular systems and in patients, it would appear thatthe effects of estrogenic hormones on the kineticsof thyroxine metabolism are indeed the result ofconcomitantly induced changes in the binding ac-tivity of TBG. Rate limitations imposed by TBGon the removal of thyroxine from its peripheraldistribution compartment might be exerted

126


through effects on either the excretory or thedegradative disposal of hormone, or both. Sinceurinary losses of intact thyroxine contribute butvery slightly to the total disposal of the hormone(35, 36), decreased urinary excretion of iodinecould not have accounted for the slowing of frac-tional turnover rates induced by estrogens. Incontrast, fecal excretion of iodinated organiccompounds contributes significantly to total hor-mone turnover (7, 37). Accordingly, estimatesof the fraction of hormone removed from the thy-roxine space by fecal excretion before and duringestrogenic therapy were made in seven patients.Variable, seemingly random alterations in cal-culated values for the fractional removal of hor-mone by the fecal route (Fmax) occurred. Suchvariations may have been attributable to inaccura-cies in the estimation of Fm.,x. Nevertheless, frac-tional fecal excretion of thyroxine appeared to de-crease during estrogenic therapy in five out ofseven patients. For the group as a whole, how-ever, changes in Fmax were not statistically sig-nificant. Values for the rate of fecal clearanceof hormone, calculated as the product of the hor-monal clearance rate and the fecal fraction, weredecreased in six of seven patients, and for thegroup as a whole the decrease was significant atthe 5 per cent level. Nonexcretory, presumablydegradative clearances, calculated as the differencebetween total and fecal clearance rates were di-minished during estrogenic therapy in all patients.For the group as a whole, this change was highlysignificant (p < 0.01). It would thus appear thatboth the degradative metabolism and the fecalexcretion of thyroxine are limited by the associa-tion between thyroxine and TBG. This conclu-sion is consonant with the observations of Ras-mussen (38) and of Myant (39), which indicatethat the fecal or biliary elimination of thyroxineis increased when hormonal binding sites in theplasma are more nearly saturated than normal.

The present studies can be divided into threeperiods: 1) a control period in which PBI andTBG were constant; 2) a period of two to fourweeks beginning shortly after the administrationof estrogen, in which PBI and TBGwere rising ;4

4 In an earlier study from this laboratory (13), a con-sistent increase in PBI was not found during estrogenictherapy in patients with treated myxedema. However,the present studies should afford a more reliable index

and 3) a period in which PBI and TBG, thoughincreased, were again constant, despite continuedadministration of estrogen. In patients withtreated myxedema, hormonal supplies were con-stant throughout the period of observation. Con-stancy of PBI's during the control period wouldindicate that influx and removal of hormone wereequal. Since this was also true during the finalperiod, hormonal disposal must then have returnedto control levels. This was confirmed, within thelimits of experimental error, by kinetic studieswith labeled thyroxine. These further indicatedthat the quantity of hormone removed by bothfecal and degradative routes had returned to nor-mal by that time.

The second period may be considered a phaseduring which the peripheral metabolism of hor-mone was re-adjusting to the effects of estrogenictherapy. During this time, hormonal removalmust have declined below control values, sinceboth the concentration and total content of hor-mone within the thyroxine space were increasing.Presumably, this reflected a sparing of hormoneby both fecal and degradative mechanisms. If so,then the quantity of hormone available to intra-cellular degradative sites must have declined be-low control values. The magnitude of this tissuedeficit of hormone at any moment in time cannotbe assessed. However, for the entire period ofapproximately one month's duration, a mean posi-tive balance of 193 ug of hormonal iodine per pa-tient was obtained. If fractional removal of hor-mone declined abruptly after initiation of estro-genic therapy while the increase in PBI occurredmore slowly, then the daily deficit of hormonewithin the tissues would have been relativelylarge during early portions of the period andwould have become progressively smaller as re-equilibration was approached. If, however, frac-tional turnover of hormone declined slowly andPBI increased pari passu, then there would have

of estrogenic effects in that a larger number of patientswas studied and PBI's were determined more frequently.In addition, it can be demonstrated mathematically thatwhen hormonal supplies are constant and fractional turn-over of hormone declines, the magnitude of the resultingincrease in PBI is proportional to the control PBI value(40). Accordingly, patients in the present study weremaintained on somewhat larger doses of thyroid hor-mone in order to insure the establishment of controlPBI's well within the normal range.

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occurred only a slight daily deficit in hormonal de-livery of relatively uniform magnitude throughoutthe period. Since TBG increased progressivelythroughout this phase, the latter possibility seemsthe more likely.

While, in patients with treated myxedema, thepostulated sequence of events is relatively simple,in patients with functioning thyroid glands it ispotentially more complex. Here, it might be an-ticipated that the reduction in hormonal flux tothe tissues would result in enhanced secretion ofthyrotropin. since hypophyseal homeostatic mecha-nisms seem directed toward maintaining constantsupplies of thyroid hormone to peripheral tissues(41). Consequent stimulation of the synthesisand release of thyroid hormone would serve todiminish the deficit in peripheral hormonal sup-plies and to hasten return to a steady state.However, it is questionable whether such an in-crease in thyroidal function actually occurs. Di-ethylstilbestrol has been found to increase the rateof release of thyroidal 131 of euthyroid patientsundergoing hypophyseal suppression by triiodo-thyronine (42). On the other hand, evidence ofhypophyseal activation has not been obtained.since repeated efforts to demonstrate an increasein the thyroidal uptake of iodine during therapywith diethylstilbestrol have failed (18. 43). Itmay be that the deficit in peripheral hormonalsupplies induced by the administration of estro-gens is never sufficiently great to activate secre-tion of TSH. Alternatively, previous stu(lies mayhave been performed during the final phase of theresponse to estrogens, when a new steady statehad been achieved.

Findings in patients with thyrotoxicosis wereof interest in several respects. Previously re-ported abnormalities in the kinetics of thyroxinemetabolism were confirmed. Thus, three of fourpatients displayed accelerated fractional rates ofthyroxine turnover both prior to treatment (7,37, 44) and following restoration of a eumetabolicstate by propylthiouracil (45). During adminis-tration of diethylstilbestrol, increased binding ac-tivity of TBG occurred in all patients. Concom-itantly, fractional rates of turnover became atleast as slow as those found subsequently duringantithyroid therapy. In Patients 14 and 15, theremaining findings were similar to those seen ineumetabolic subjects, in that PBI's increased, hor-

monal clearance rates declined, daily hormonaldisposal remained essentially unaltered, and meta-bolic status was unchanged.

In Patients 12 and 13, strikingly different find-ings obtained. Here, despite marked decreases inhormonal clearance rates, PBI's failed to increase.This could have occurred only if the flux of hor-mone from the thyroid gland to the periphery haddeclined during administration of estrogen. Fromthe data of other workers (46), it would appearthat estrogens may slow the rate of release ofglandular iodine in some patients with thyrotoxi-cosis. Because of the decreased hormonal clear-ance rates and the unchanged PBI's, daily hor-monal disposal in these patients decreased tovalues approaching those found during antithyroidtherapy. At the same time, there occurred amarked amelioration of the signs and symptoms ofthyrotoxicosis and reduction in basal metabolicrate. This favorable response was reminiscent ofthe occasional amelioration of thyrotoxicosis byestrogens reported by earlier workers (47). Fromthe present data, it is evident that the symptomaticremission of thyrotoxicity, which estrogens mayoccasionally induce, results from thyroidal andperipheral effects reflected in decreased hormonaldisposal. rather than from direct anti-oxidativeeffects within the tissues. However, those fac-tors which account for the variability in the thy-roidal response to estrogens, as seen in this andearlier studies, remiiain an intriguing enigma.

SUA MARY

The effects of diethylstilbestrol and of estradiolbenzoate upon the kinetics of thyroxine metabo-lism have been assessed in patients with intactthyroidal function. treated myxedema, or Graves'disease.

In all subjects, estrogen induced an increase inthe binding avidity of the thyroxine-binding glob-ulin (TBG), which was accompanied by markedretardation of the fractional rate of peripheralturnover of I"31-labeled thyroxine. In eumetabolicsubjects, concentration of protein-bound iodine(PBI) increased sufficiently to restore the dailydisposal of hormonal iodine to normal values.

Two of four thyrotoxic patients failed to dem-onstrate expected increases in the concentration ofPBI, and exhibited amelioration of symptoms andof hypermetabolism dcuring administration of es-

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trogen. During this period, daily hormonal dis-posal rates approached values found subsequentlyduring restoration of eumetabolism by propyl-thiouracil.

These observations are consistent with the hy-pothesis that thyroxine-binding by TBG exerts a

rate-limiting effect upon the peripheral metabo-lism of this hormone.

APPENDIX

In the foregoing manuscript, the following terms havebeen employed. These were described in detail in an

earlier communication (7).TDS, thyroxine distribution space; the virtual volume

of body fluids through which exchangeable thyroxinewould be distributed were it present throughout at thesame concentration at which it exists in the plasma.

PBI, concentration of hormonal iodine in the plasma,and, by definition, the geometrical mean concentrationof hormonal iodine in the TDS; assumed to representsolely iodine in thyroxine.

ETT, extrathyroidal thyroxine; the total quantity ofthyroxine within the TDS, in terms of its content ofiodine.

k, Fractional rate of turnover of thyroxine; the pro-portion of ETT removed from the TDS per unit time.

TA, thyroxine half-time; the time required for half ofthe ETT to be removed from the TDS.

C, thyroxine clearance rate; the volume of plasmawhich contains an amount of thyroxine equal to thatremoved from the TDS per unit time. Defined as "vol-ume turnover, V" in an earlier communication (7).

D, hormonal disposal rate; the quantity of hormoneremoved from the TDS per unit time, in terms of itscontent of iodine.

Fmax, the proportion of D accounted for by fecal ex-

cretion of hormone; fecal clearance, the volume of plasmawhich contains a quantity of hormone equal to that lostin the feces per unit time; degradative clearance, the vol-ume of plasma which contains a quantity of hormoneequal to that removed by nonexcretory pathways perunit time; fecal excretion, the quantity of hormone ex-

creted in the feces per unit time; degradative rate, thequantity of hormone removed by nonexcretory pathwaysper unit time.

ETT=PBIXTDS. C=TDSxk. D=CXPBI= ETT X k. T1 = 0.693/k. Fecal clearance = C X Fmax.Degradative clearance = C - fecal clearance. Fecal ex-

cretion = fecal clearance X PBI = D X Fmax. Degrada-tive rate = degradative clearance X PBI = D - fecal ex-

cretion.

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8)'.€¦ · by means of techniques described in detail elsewhere (7), the distribution and...

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