322

ANTITHYROID DRUGSBy JAMES CROOKS, M.B., M.R.C.P.(Lond. and Ed.), FR.F.P.S.G.

Senior Medical Registrar, University Department of Medicine, Gardiner Institute, Western Infirmary, Glasgow

Antithyroid drugs may be defined as chemicalagents which interfere with the synthesis, releaseor peripheral action of the thyroid hormone.A large number of chemically unrelated com-pounds are covered by this definition, but it isintended to deal only with those which have a placein the practical management of hyperthyroidism.Such drugs can be divided into three categories:

(I) Drugs preventing the synthesis of organiciodine from inorganic iodide.

(2) Drugs inhibiting the iodide trap of thethyroid.

(3) The iodide ion.Thiourea, the parent compound of most of the

antithyroid drugs of the first group which are usedtherapeutically, was shown to be goitrogenic byGriesbach et al. (i941) and Kennedy (1942).The latter also showed that a derivative of thioureawas responsible for the goitrogenic properties ofBrassica seeds. Astwood (I943) further confirmedthe antithyroid activity of thiourea and its de-rivatives and in I944 published the first clinicalreport on thiourea and thiouracil in the treatmentof hyperthyroidism. The toxic effects of thesedrugs soon diminished the initial enthusiasm forantithyroid drug therapy, but this was revived bythe introduction of 4-methyl thiouracil and6-N-propyl thiouracil, which because of theirgreater potency were effective in smaller doses andhad fewer side effects. Both drugs had extensiveclinical trials and are still widely used. Stanleyand Astwood (I949) then demonstrated thatI - methyl - 2 - mercaptoimidazole (methimazole,'Mercazole,'' Tapazole') had greater antithyroidactivity than any other known compound, whileBartels and Sjogren reported a successful clinicaltrial of the drug in 195I. Methimazole is widelyused in the United States, but in this country2 - carbethoxythio - I - methyl - glyoxaline (carbi-mazole, ' Neomercazole ') synthesized by Riming-ton and his associates (195I), is the more popularof the imidazole derivatives.The history of drugs inhibiting the iodide trap

of the thyroid began with the demonstration byMarine and his associates (1932) that acetonitrileand related compounds could produce thyroidhyperplasia and that the effect was antagonized byiodine., In I953, Wyngaarden et al., studied theantithyroid activity of various anions and con-

cluded that the perchlorate ion was the mostpotent inhibitor of the iodide-trapping mechanismof the thyroid. This was followed in 1954 bysuccessful clinical trials of potassium perchloratein hyperthyroidism (Godley and Stanbury, I954;Morgans and Trotter, I954).

Iodide is the oldest of the antithyroid drugs andwas the only one available for clinical use up to1943. Although it had been occasionally used inhyperthyroidism during the early part of the 2othcentury, its use only became popular followingPlummer's report of a successful clinical trial in1923.

Group I: Drugs Preventing the Iodination ofTyrosineThe antithyroid drugs to be discussed in this

group are methyl thiouracil, propyl thiouracil,methimazole and carbimazole.

Mechanism of ActionWhile the exact mechanism of action of these

drugs is controversial, there is general agreementthat they interfere with the iodination of thethyroid hormone precursors without affecting theability of the gland to concentrate the iodide ion.The three current hypotheses given to explain thisaction are:

(i) They may inhibit the enzyme systems whichoxidize ionic to elemental iodine.

(2) They may compete with iodide as a sub-strate for this oxidative enzyme.

(3) Elemental iodine may be reduced to theiodide ion depriving the thyroid cell of iodinenecessary for synthesis of the thyroid hormone.Whatever the exact machanism of action, the

level of circulating hormone falls, leading to in-creased production of thyrotropic hormone bythe pituitary with consequent thyroid hyperplasia.Structure-Activity RelationshipsThe antithyroid activity of these drugs has been

studied using radioiodine techniques (Stanley andAstwood, I947; Macgregor and Miller, 1953)and their potencies relative to thiouracil are shownin parentheses below:

Thiouracil (i), Methyl thiouracil (2), Propylthiouracil (0.75), Methimazole (Ioo), Carbimazole(10o).

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Indications for UseIn recent years the indications for the use of these

drugs in hyperthyroidism have become moreclearly defined. Most authorities agree thatyoung adults with small or moderately enlarged,diffuse goitres should be given a prolonged trialof antithyroid drugs. When the disease occursduring pregnancy or puberty this form of therapyallows more flexible control of thyroid functionduring a period when the metabolic demands onthe thyroid are varying. Before partial thyroidec-tomy is carried out toxicity should be controlledby treatment with one of these drugs. In somethyrocardiac subjects where rapid control oftoxicity is required a short course of one of thedrugs of this group can begin ten days afterradioiodine therapy. Finally, in patients wherethe diagnosis of thyrotoxicosis remains in doubtafter full investigation, the patient's reponse toantithyroid drug therapy should be observed.

DosageA large number of dosage schemes have been

used. For example, Iversen (195I) gave 750 mg.methyl thiouracil daily for one to three months.reducing the amount until a dose of 125 mg. wasgiven daily on alternate days. On the other handHimsworth (1948), in an attempt to avoid myxo-edema, used an initial daily dose of 200 mg.methyl thiouracil with maintenance doses of 25to 0oo mg. The scheme of dosage for methylthiouracil used in this department, 600 mg. dailyfor two weeks, then 300 mg. daily until the patientis euthyroid, followed by a maintenance dose of50 to Ioo mg. daily, has been found to be entirelysatisfactory.

In the case of propyl thiouracil approximatelythe same dosage scheme may be used as for methylthiouracil, though many workers have tended touse slightly lower doses.The variation in schemes of dosage has persisted

with the newer drugs of this group, methimazoleand carbimazole. For both substances initialdoses of 20 to 40 mg. daily followed by main-tenance doses of 5 to I5 mg. daily usually producesatisfactory results, though in some cases a largerinitial dose is necessary.

In arriving at the optimum dose, a balance hasto be struck between the rate of control of symp-toms and the incidence of toxic effects, the higherthe dose the more rapid being the rate of controland the higher the incidence of toxic effects.

Response to Treatment(i) Rate of Control. The therapeutic response

to treatment as measured by the disappearanceof the symptoms and most of the signs of hyper-thyroidism is uniformly satisfactory, and the

majority of cases treated with methyl thiouracil inthis department become euthyroid in four to tenweeks. The rate of control of the disease wouldappear to be related to the dose of each drug andnot to the drug itself, for example, 30 mg. ofmethimazole daily appears to control hyper-thyrodism more rapidly than 300 mg. methylthiouracil daily, but no more rapidly than 600 mg.methyl thiouracil daily. Other factors can in-fluence the rate of control, for example, patientswith nodular glands tend to respond slowly,though ultimate control is satisfactory. In casesresponding unexpectedly slowly or incompletelythe cause is usually found to be one of thefollowing:

(i) Failure of the patient to take the prescribedtablets or to space the doses properly.

(ii) A course of iodine has preceded theantithyroid drug.

(iii) A larger dose of the drug is required.(iv) The diagnosis of hyperthyroidism is wrong.(2) Changes in Clinical Features. The most

persistant symptom is heat intolerance, while thelast physical sign to disappear, excluding thegoitre and the eye signs, is the tachycardia. Whenauricular fibrillation is present before treatmentreversion to sinus rhythm is obtained in aboutone-third of cases within four months, but someof those continue to have paroxysms of fibrillationalthough euthyroid. Failure and partial success insuch cases is doubtless due to coincident coronaryartery disease. Weight increase tends to lagbehind the disappearance of most of the otherfeatures. The goitre in most cases is unchangedat first, but occasionally may increase slightly.The bruit too persists. During maintenancetherapy the gland size usually remains unchanged.However, in some cases it diminishes markedlyand this is associated with a greater possibility ofpermanent remission. In this department regularexophthalmometry readings have shown, in 15per cent. of subjects, a significant increase inexophthalmos, which tends to regress whentreatment is stopped. This compares favourablywith the 75 per cent. increase after partial thyroid-ectomy reported by Soley (1942).

(3) Assessment of Response. The only satis-factory method of ascertaining response totreatment is by clinical assessment, changes inobjective signs being particularly valuable. Thebasal metabolic rate, using Robertson and Reid'sstandards, usually falls within the normal rangeone to three weeks before the patient is clinicallyeuthyroid. The serum cholesterol tends to riserapidly after two to three weeks of treatment, butis not of value in deciding when the patient iseuthyroid.

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Duration of Treatment, Remissions and RelapsesThose authorities who advocate long periods of

continuous antithyroid drug therapy have theore-tical support for their view in that these drugs areunlikely to shorten the course of the disease andthat when prolonged remissions are obtained thedisease has spontaneously run its course. Iversen(I95I) for example, believes that treatment shouldbe carried on for six months or longer, whileDunlop and Rolland (I950) found a relapse rate of69 per cent. after treatment of under one year,compared with 33 per cent. over one year. Onthe other hand, Bartels (I950) and Goodwin et al.(1954) maintain that the duration of treatmentbears no relation to the length of the subsequentperiod of remission. Eight of twenty patientstreated here with methyl thiouracil and kept on amaintenance dose for three months only, relapsedwithin six months. Higher relapse rates havebeen found in cases with post-operative recur-rences and nodular goitres (McCullagh et al.,195 ) and one of the reasons for the great variationof results obtained by different workers is likelyto be found in the type of cases treated.On the basis of the available evidence it would

appear that at least a year's continuous therapywith an antithyroid drug is desirable except inpatients with mild thyrotoxicosis and small diffusegoitre, who might be given shorter courses,particularly if there is a diminution in the size-ofthe goitre during treatment.

Pre-operative TreatmentIt is generally agreed that antithyroid drugs of

this group should be used to prepare a thyrotoxicpatient for partial thyroidectomy. Some autho-rities, however, believe that such pre-operativepreparation is not always necessary and wouldconfine it to severe cases (McCullagh andSurridge, 1948; Pemberton et al., 1949). How-ever, there has been a definite decrease inoperative mortality since the use of these drugspre-operatively became general. In the two weekspreceding operation iodine in the form of potas-sium iodide 30 mg. daily should be substitutedin order to diminish the vascularity of the gland.Treatment During Pregnancy

Goitre and hypothyroidism have been reportedto occur in the infants of mothers receiving anti-thyroid drug therapy (Eaton, 1945; Ball andMorrison, 1948), but this is an uncommon event.Astwood (I951) points out that if the dose of theantithyroid drug has been adjusted to ensure anormal output of hormone by the maternal thyroidit is unlikely that the function of the foetal glandwould be significantly depressed. He reported22 completed pregnancies in I9 patients, the 22

living children showing no evidence of thyroiddisturbances. In most instances where a goitrehas been reported in an infant there is evidence ofoverdosage and it is the practice in this departmentto under-treat pregnant subjects since pregnancyitself is a hypermetabolic state. In three casestreated in this way during the past year, none ofthe children had a goitre. The infants in suchcases should not be breast fed in order to avoid thetransmission of the antithyroid drug in the milk.The importance of the flexible control of thyro-

toxicosis in pregnancy made possible by the use ofantithyroid drugs is underlined by the highincidence of miscarriages and stillbirths inuntreated cases.

Complications of TreatmentThe first two drugs used, thiourea and thiouracil,

were extremely toxic and no drug of this group hasproved to be totally free from side-effects. Themore recently introduced compounds are, however,relatively safe therapeutic agents.There is a group of toxic effects which are very

uncommon and which include nausea, vomiting,diarrhoea, jaundice and headache. Only themajor toxic effects will be considered in detail andthey can be conveniently divided into sensitivityreactions and depression of bone marrow elements.

Sensitivity ReactionsA skin rash is the most common manifestation

and is usually urticarial although a variety of othertypes of rashes do occur. Another commonsensitivity reaction is drug fever. Much lesscommonly lymph and salivary gland enlargement,arthralgia and conjunctivitis have been reported.These reactions tend to occur between the tenthand eighteenth days of treatment or within thefirst 14 days after treatment has been resumed.The reactions usually last two to three days and theskin rashes generally respond to treatment with anantihistaminic drug such as promethazine hydro-chloride. The less severe reactions of this type donot require the cessation of therapy, but since theincidence of subsequent bone-marrow depressionis increased in such cases, it is probably advisableto change to an alternative therapeutic agent, suchas potassium perchlorate. There would seem tobe little to choose between methyl thiouracil,prophyl thiouracil and methimazole with respectto the incidence of those reactions but withcarbimazole the incidence would appear to be less(Burrell et al., I956).Agranulocytosis

This is the only potentially lethal complicationof treatment with this group of drugs. Theagranulocytosis may be of two types, the com-

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moner being impairment of white cell maturationat the pre-myelocyte or myelocyte level and, sincethe availability of penicillin, carrying a goodprognosis. The other, and graver type where thematuration defect is at myeloblast level, can bedifferentiated by a marrow biopsy which shouldalways be carried out in cases suspected ofagranulocytosis. There seems to be little doubtthat thiouracil produced this complication moreoften than any of the others and Moore (1946)found an incidence of 2 per cent. in 9,281 cases.

Reviewing the results of other workers usingmethyl thiouracil, Barfred (I947) found that 9of 604 cases developed agranulocytosis, anincidence of 1.49 per cent. Bartels (1948)reporting 486 cases treated with propyl thiouracilfound two cases of agranulocytosis (0.4 per cent.),but the initial dosage used for propyl thiouracilhad a less potent antithyroid action than methylthiouracil and it is likely that the toxicity of thetwo drugs are comparable. Using methimazole,Bartels and Sjogren (195i) had one case of severegranulocytopenia in Ioo treated cases, andDoniach (I953) using carbimazole in 120 patientsfound no toxic effects and attributed this to a moregradual release by hydrolysis of the active ' thiol 'group which it has in common with methimazole.In this last series it is of interest that three patientswho had had toxic effects with methyl thiouracilhad no complications on carbimazole. Burrellet al. (1956) concluded that carbimazole was theleast toxic of this group of drugs in a survey of1,046 patients and a review of the literature, buteight cases of agranulocytosis have already beenreported in the United States and this countryduring the use of this drug.

In the practical management of the patient mostauthorities now agree that there is little yalue incarrying out serial white blood counts at weeklyor longer intervals because agranulocytosis canoccur so rapidly. Close, but not obsessive watchshould be kept over the patient under treatment,especially during the first eight weeks, when theincidence of toxic effects is highest.Group II: Drugs Inhibiting the Iodide Trapof the ThyroidThe anions which possess a significant goitro-

genic, action are, in order of decreasing activity,perchlorate, thiocyanate and nitrate. Thiocyanateand nitrate have no therapeutic importance asantithyroid drugs because of their toxicity.Potassium perchlorate has, however, been usedsuccessfully in the treatment of thyrotoxicosis andmuch of the description which follows is based onpersonal experience in over 50 cases treated duringthe past i8 months.

Mechanism of ActionThe goitrogenic action of these anions can be

overcome by the administration of iodide and thissuggests they interfere with the uptake of inorganiciodide by the thyroid (Franklin et al., I944;Wyngaarden et al., 1953). Furthermore, in-organic iodide already trapped by the thyroid isdischarged by the administration of the anions.The exact mechanism by which the anions act isunknown, but presumably if the circulating bloodiodide level is high enough, the block can beovercome.

Potassium Perchlorate in the Treatment ofThyrotoxicosisThe therapeutic value of perchlorate as an

antithyroid drug has not been fully evaluated.Weight for weight it is a less potent agent thanmethyl thiouracil and using a dose of 200 mg.three times daily the rate of control is morevariable than with methyl thiouracil, the euthyroidstate being achieved in from 7 to 20 weeks. Somepatients prove resistant to the drug, but in all butone of 52 cases adequate control was finallyachieved. It is possible that larger doses shouldbe used and our present dosage scheme is 200 mg.five times daily. Patients are advised to avoideating fish, taking cough mixtures and othermedicines containing iodine, and to use uniodisedsalt. The clinical response to treatment, apartfrom the rate of control, is similar to that producedby methyl thiouracil.As might be expected from the relatively simple

perchlorate molecule, the drug is the least toxicof the antithyroid drugs with therapeutic appli-cations. Of the 52 cases only one complained ofdyspepsia while taking the drug and this disap-peared although therapy was continued. Godleyand Stanbury (1954) reported one case of dyspepsiaand one case in whom a duodenal ulcer perforated,in a series of 24 patients treated with perchlorate.Morgans and Trotter (I954) treated I08 cases withthis drug and the only side effects observed weregastro-intestinal symptoms in two patients, oneof whom had a diaphragmatic hernia and the othera peptic ulcer. There is no evidence that perch-lorate causes hypersensitivity reactions, or has anydepressant effect on the bone marrow. It is,therefore, a valuable alternative in cases who havehad toxic effects caused by the drugs of Group I.

Potassium perchlorate is probably unsuitablefor the treatment of patients preceding partialthyroidectomy since Godley and Stanbury (I954)found that the glands were more vascular thanwould be expected with thiourea derivatives andiodide. The effect of perchlorate in the pregnantthyrotoxic subject has not so far been reported, but

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in one case treated here, the infant showed nothyroid abnormality at birth.

Group III: The Iodide IonIt is intended to discuss iodothiouracil along

with the iodide ion, as they behave similarly.Mechanism of ActionThe iodide ion when given in therapeutic doses

results in involution of the gland and an increase incolloid storage even in the presence of a goitrogen.It also leads to a reduction in the release of thyroidhormone (Ansell and Miller, I952). However,suppression of thyroxine synthesis and releasewould appear to be evanescent (Wolff et al., 1949).It is not clear whether iodide acts directly on thethyroid or by the inhibition of the pituitarysecretion of thyrotropic hormone.

Iodide and Iodothiouracil in the Treatment ofThyrotoxicosisThe symptomatic response of thyrotoxicosis to

the administration of iodide as potassium iodideor Lugol's iodine, is rapid and has been used asa therapeutic test. The maximum effect isobtained in o1 to 15 days but following this escapefrom control is common and there may even be anexacerbation of symptoms. It is mainly used inthe preparation of patients for partial thyroid-ectomy and it should be given for two weeksbefore operation either with or following one of thedrugs of Group I. When rapid control of toxicityis required after radioiodine therapy a course ofiodide lasting three weeks can be started ten daysafter the radioiodine has been given.

Opinions are divided concerning the place of5-iodo-2-thiouracil (iodothiouracil) in therapy,but Williams et al. (I949) came to the conclusionthat the response to this drug was more like thatobserved with iodide than with thiouracil. Therecommended initial dose of I50 mg. daily onlycontains 75 mg. of thiouracil. It is favoured bysome surgeons for pre-operative preparation, butlike iodide, has no place in the long-term treatmentof hyperthyroidism.Drugs having an Antithyroid Action as a Side-effectA number of drugs with therapeutic applications

in other fields have also an antithyroid action.Important examples of such goitrogens are para-aminosalicylic acid (Macgregor and Somner,1954), resorcinol (Bull and Fraser, 1951), andcobalt (Kriss et al., I955).The Advantages and Disadvantages of AntithyroidDrugsThe most important advantage possessed by

these drugs in the treatment of thyrotoxicosis, is

the flexibility of control of thyroid function whichcan be achieved by careful prescribing. This is ofparticular value in those states where the metabolicdemands on the thyroid are fluctuating, forexample, in pregnancy and at puberty. Thisroom for therapeutic manoeuvre is also of value incases with marked exophthalmos where exacerba-tion following surgery may be feared and wherethe indications for radioiodine therapy may not befulfilled. .The absence of the risk of permanentmyxoedema is another advantage not shared bysurgery and radioiodine therapy. That this formof treatment can be given without admission tohospital may be of considerable economic ad-vantage to the patient and its general availabilityis of special value in areas where there is noskilled thyroid surgeon or centre equipped tocarry out radioiodine therapy.The main disadvantage of these drugs is the long

duration of therapy. Adequate and safe controlcan, however, be achieved by clinical assessmentalone, fairly frequently in the first two months,and at much longer intervals subsequently.However, even if this is done and the incon-venience of long term therapy minimised, thepersonality of some patients makes them unsuitablefor this form of treatment. With the introductionof carbimazole and perchlorate, the hazards oftherapy are comparable to that of the best surgeryand certainly less than that of inferior surgery.The overall relapse rate of 50 per cent. even afterlong term therapy with antithyroid drugs has beena great disappointment, especially since thepossibility of permanent remission cannot bepredicted before treatment is begun.

In conclusion, the effective use of antithyroid-drugs demands the selection of suitable patients,careful clinical assessment of progress and ad-justment of dosage, and above all, patience.Acknowledgement

I wish to thank Professor E. J. Wayne forhelpful criticism and advice regarding thepreparation of this paper.

BIBLIOGRAPHYANSELL, G., and MILLER, H. (1952), Lancet, ii, 5.ASTWOOD, E. B. (1943), J. Pharmacol., 78, 79.ASTWOOD, E. B. (I944), J. clin. Endocr., 4, 229.ASTWOOD, E. B. (I95I), Ibid., II, 1045.BALL, K. P., and MORRISON, B. (1948), Proc. roy. Soc. Med.,

41, I95.BARFRED, A. (1947), Amer. J. med. Sci., 214, 349.BARTELS, E. C. (1950), 'Progress in Clinical Endocrinology,'

p. 87, Heinemann, London.BARTELS, E. C. (1948), J din. Endocr., 8, 766.BARTELS, E. C., and SJOGREN, R. W. (I95I), Ibid., II, 1057,BULL, G. M., and FRASER, R. (I95I), Lancet, i, 851.BURRELL, C. D., FRASER, R., and DONIACH, D. (1956),

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that liver changes usually accompanied the con-dition (Cooke and Luxton, 1955) and a largerconfirmatory series appeared from the ClevelandClinic (Skillern, I956) last year. The raised yglobulin levels, their delayed return to normalafter thyroidectomy and the infiltration of thethyroid with lymphocytes, plasma cells and lym-phoid tissue prompted Roitt et al. (1956) to lookfor an immune response. They have reported aprecipitin reaction of serum with extract of humanthyroid gland and they postulate that it parallelsthe destruction of the patient's own thyroid, andespecially the colloid, by an auto-antibody.

It might well be expected that in subacutethyroiditis a similar positive flocculation test wouldbe obtained and W. R. Trotter and D. Doniach in-form me that they have obtained a positive reactionin the serum of two patients with this disease.For those who are interested in recent advances

in problems of immunology and thyroid diseasethere is an excellent leading article in the Lancet,May 25, 1957, Vol. I, p. 1075, which reviews thewhole subject up to the present time. This hasnow become one of the rapidly expanding frontiersof thyroid investigation.AcknowledgmentWe are indebted to the publishers of British

Surgical Progress 1955 for the blocks which appearin this article.

BIBLIOGRAPHYCLARK, D. E., and NELSEN, T. S. (I953), Jour. Amer. med. Ass.,

COOKE,R. T., and WILDER, E. (I954), Lancet i, 984.COOKE, R. T., and LUXTON, R. W. (955), Ibd., i, 968.CRILE, G., Jr. (I948), Ann. Surg., 127, 640.CRILE G., Jr., and FISHER, E. R. (I953), Cancer, 6, 57. -

CRILE, G., Jr., and HAZARD, J. B. (i95I), J. clin. Endocr.,1, 1123.

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44 538FRASER R., and HARRISON, R.J. (I952), Lancet, i, 382.HAMLIN, E., Jr., and VICKERY, A L. (956), New Eng. J.

Med., 24, 742.HAZARD, J. B. (955) Amer. .. din. Path., 25, 399.HEPTINSTALL, R. I., and EASTCOTT, H. H. G. (i953).

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Ann. intern. Med., 39, I29.KING, B. T., and ROSELLINI, L. J. (x94s), J. Amer. med. Ass.,

12, , 267.LASSER, R. P. (93), Ibid., 152, 133.LINDSAY, S., DAILEY, M. E., FRIEDLANDER, J., YEE, G.,

and SOLEY, M. H. (1952) .. din. Endocr., 12, 1578; alsoTrans. Amer. Ass. Goiter (1952), pp. 384-411.

LINDSAY, S., and DAILEY, M. E. (I954), Surg. Gynec. Obstet.,98, 197

PERLOFF,W. H. (x9S6), . clin. Endocr., x6, 542.ROBBINS J., RALL, J. E., TRUNNELL, J. B., and RAWSON,

R.W. (i95x) Ibid.,Ix,txo6.ROITT, I. M., bONIACH, D., CAMPBELL, P. N., and HUD-

SON, R.V. (I956) Lancet, ii, 820.SKILLERN, P. G., ChILE, G., McCULLAGH, P., HAZARD,

J. B., LEWIS, L. A., and BROWN, H. (i956), J. din. Endoer.,T

6, 35.TAYLOR, S. (t955), 'Brit. Surg. Progress,' pp. 148-x60, London.

RUTHIN CASTLE, NORTH WALESA Clinic for the diagnosis and treatment of Internal Diseases (except Mental or Infectious Diseases). The

Clinic is provided with a staff of doctors, technicians and nurses.The surroundings are beautiful. The climate is mild. There is central heating throughout. The annual

rainfall is 30.5 inches, that is, less than the average for England.The Fees are inclusive and vary according to the room occupied.

For particulars apply to THE SECRETARY. Ruthin Castle, North Wales.Telegrams: Caetle. Ruthi. Telpomes: Ruchi 66

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McCULLAGH, E. P., and SURRIDGE, W. T. (x948), J. cin.Endocr., 8, o05I.

MACGREGOR, A. G., and MILLER, H. (I953), Lancet, i, 88r.MACGREGOR, A. G., and SOMNER, A. R. (1954) Ibid., ii, 93x.PEMBERTON, J. J., HAINES, S. F., and KEATING, F. R.

(1949), J. din. Endocr., 9, I232.PLUMMER, H. S. (1923), 7. Amer. med. Ass., 80, x955.SOLEY, M. H. (1942), Arch. intern. Med., 70, 2o6.STANLEY, M. M., and ASTWOOD, E. B. (x947), Endocrinology,

41 66.STANLEY, M. M., and ASTWOOD, E. B. (I949), Ibid., 44, 588.WILLIAMS, R. H., TOWERY, B. T., ROGERS W. F., TAG-

NON, R., and JAFFE, H. (1949), . clin. Endo., 9, 80.WOLFF J., CHAIKOFF, I. L., GOLDBERG, R. C., and

MEER, J. R. (949), Endocrinology, 4, 504.04.WYNGAARDEN, J. B., WRIGHT, B. M., and WAYS, P. (s952),

Ibid., 50, 537.

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