DOC!",YVNT CONTROL DATA. R & DC~t'u~urC~ieti~.d~~nat ills bO~ 01 hmftrl ne mnfig nowiton omupt he entered when ahe ovder~i f;,Ar~t is .ei.I

OI GIN6 AT.Nr ACTIVIT' (Cohporate authý 0 1FOTSýUA JrLZ1'r

Departmnt of Mcdicine

"IKNDO(CRI1LOGY SY.MPOSIUM.Vol IT , • No 2 PR •hSE2NT CONCEPTS 13 l 2 KMIAL M EDICINE, February 1971*( Z . It ,, . . .-

• . O•.•C lP T• lL O "• .• •.'p, ot report and Incl.eivo • ,, )'

Syviposium (Medical), February 197l _

*- AUTHORIP-I (f'usef neme. middle Initial. l ast no)

Dellor, John J. Jr. (Guest Edit () 3 aontributors: Deller JJ J4 evin P , Eichnrr :i,FN Panagiotir Mol, (3oldsmith RS, B3i gl c ri .T

S t' .FOrNT DAT 7 A. TOTAL NO. tip Gt '7b. No. OF, PeFs

, February 1971 83 vo 105-1871 10500. tCON TR A C T 0 F Gil AN H M. to. ORIGINATOR'S REPOR~T N~lfBEC4I3

NI/A N/Ab. PR•OJECT NO.

"bb. OTHER REPORT NO(S) (Any othv, nmber. that • •ay be ssslý,-'.(h i s rep o o lt) /d. _ _ _ _ _ _ _ _ _ _ _ _ _ _

1I0. 0STIRIBUTION S'ATENIENT

Distribution of this document is ur•"Urited.

1'5 UOPLIMENTARy f(izN, 12. SPONSORING MILITARY ACTIVIIYEach LETTEAN G•ERAL HOS ITAL9symposium in sone specialty of medicine. IX= A GENERA HOSPITAL[~itriutifl omespciaty f m~c~ine {Pre~iio of' San Francisco, California 9't.29

There are 12 issues each year (per volume),

ý0. ; , S ,IA C T

.This issue of Present Concepts is .n attempt to solve some of the diagnosticdilems which the physician encounters when he considers clinically a patient -.;'oappears to have an endocrinopathyo. The authors have appz'oahced their subjects in apractical and up-to-date.fashion' (perhaps at times dispelling some of the old"standards" and introducing some of the newer concepts which have evolved from rc"-c.t

;retearch). 'The articles are titled as follows: -'fiagnosis of hypothalamic-pituitaorydysfunction0, '"valuation of secondary amenorrhea•, 'Acromegaly. Diagosis and treat-ment", -Diabetes insipidusg•, '.Pathophysiolog• of th thyroid gland'& "Hyperparatby-roidism", )Evaluation of adrenal dysfunctionl," cnd 5zineralocorticoid' hormones (M>ciiin hypertension'".

[06 ,4 21 1 Aiit m t-- A"oD 1Lc0 " TN' ,SSIFIED

UNCIASSfIEI).. LINK A LINK ELINK C

KYO119ROLE WT ROLIS WT ROLE WT

V }iYY.3{AAMM -Pituitary dysfunction

PITUIT¶ARY-hypothalaniic dysfunction

AI4MORREA,2 secondary

ACRO)M~ALY

'THYROID GIAND, pathopbysiology -

PARA.THrOIDISM., hyper-

HYPE A1AWT.Tf~I DISM

;.JRE71AL GLANDS, dysfunction

HORMONFS, MfINh'WICORTICOID (mui)

HYPETEUSION, Role off steroid hormones fromadrenal gland

H"YPERMINERALOCORTICCXDISM

PRESENT CONCEPTS IN iNTERNAL MEDICINE

GUEST EDITOR FOR FEBRUARY 1971

COL John J. Deller, Jr., MCii-�iEndocrinologist. andQief, Department of Medicine

ASSISTANT EDITORLottii. Applewhite, M.S.

EDITORIAL BOARD

COL. John J. Deller, Jr., MC Chief, Department of MedicineLTC Neil W, Culp, MC Assistant Chief, Department of

Medicine and Chief,Hematology

COL Ccorge B., Hamilton, MC Chief, GastroenterologyCOL Hugh S. Wiley, MC Chitf, DermatologyCO'L, Melvin D., Cheitlin, MC Chief, CardiolegyCOL Joseph L. McGerity, MC Chief, Allergy

.TC James L, Stewart, "r. MC Chief, PediatricsL, C Darrell S. Buchanan, MC Chief, NeurologyLi C Edward E. Mays, MC Chief, "'ulmonary ind Infectious

Diseases

LETTERMAN GENERAL HOSPIH A].

Presi ho of San týranciscc, California 94129

PRESF4T CONCEPTS IN INTERNAL MEDICINEVOLUME IV February 1971 NInt" 2

ENDOCRINOLOPYSYMPOSIUM

CONTENTS

Foreword ......................................... 1 05

AR TICL ES

DIAGNOSIS OF HYPOITHALAMIC-PITUITARY DYSFUNCTION ................ 107COL John J. Defier, Jr., MC

EVALUATION OF SECONDARY AMENORRHEA .................................. .. 119COL John J. Deller, Jr., MC

ACROMEGALY. Diagnasis and Teatment ........................................... 131Seymour R. Levin, M.D.

DIABETES INSIPIDUS ......................................... 137MAJ Harvey L. Eichner, MC

PATHOPHYSIOLOGY OF THE THYROID GLAND .................... 147MAJ N.M. Panagiotis, MC

HYPERPAKATHYROIDISM .......... ............ .............I........ 5Ralph S. Goldsmith, M.D

EV4,LUATION CF ADRENAL DYSFUNCTION ................... 171MAJ Harvey L. Fichner, MC

MINERALOCORTICOID HORMONES (MCH) IN HYPERTENSION ............... 179Edward G. Siglieri, M.D.

Department of Afedwine

1.1 7Ir RM I V GENI RAt. IOSI'I 'A 1

- t

g NEXT MONTII'S SYMPOSIUM

HEMATOLuCY

Articles

PLATELET FUNCTION

RED CELL G-6-PD DEFICIENCY

HYPOPLASTIC ANEMIA

HEMOPHILIA A

HEMOSTATIS AND INTRAVASCULAR COAGULATION

Prr,•, t ( '~ncept, Vorl iV A',) 2, Februar. 1 71

I!

FOREWORD

Often when an Endocrinopathy is considered clinically, one fiads himselfin a quandry as to how to expeditiously, economically, nd yet accuratelypursue the diagnosis - and perhnps also when to stop the pursuit!

This issue of Present Concepts is an attempt to solve some of these diag-nostic dilemmas. The authors have approached their subjects in a practi-cal and up-to-date fashion, perhaps at times dispelling some of the old"standards" and introducing' some of th: newer concepts which haveevolved from r :cent research.

Our own staff, Doctor Eichner, Doctor Panagiotis and I would like toexpress our appreciation to our three guest authors for their unique con-ti-ibutions which stem from a vast experience with their topics.

Doctor levin, one of Doctcr Feter Forsham's shining stars, has given us thebenefit of his studies on acromegaly and the most gratifying results beingobtained at the University of Califorr.ia's San Francisco Medical Centerwith cryohypophysectomy,

Doctor Goldsmith's reputation as an endocrinologist is enviable and hisstudies and publications: on the parathyroid gland are well-known to allstuders of metabolism, I'm ýiwavs eager to read his latest thoughts.

A long-tine friend and mucb-admired colleague (but late getting his manu-

script in - and that's why it appears last!) is Doctor Bighen. Ed's work in

the area of mineralocorticoid metabolism has been fascinat)ng and illuminatingHis paper for Present Concept~s is another gem.

As we go to press with this issue, I wonder what's left for me to tell myhouse staff - guess I can always talk about Diabetes

COL JOHN J DELLER, JR., MCGuest Editor

Preutni Concept Vo'l !I' No 2. +,bruarv 1O'71I

To le--m how to treat di~wase, one must Icamr how '-( djpow i•l The

diagnosis us the best trumnp -,n the ý.;heme of trc-ajrp,.j(..

Jean Martin aarcot

I

II

I

It'lt• "'"ent G)nu!ntl. ," • A> I. it•bnwnar :97Y;

S~107

DIAGNOSIS OF HYPOTHALAMIC-PITUITARY DYSFUN(,CTION

COL John J. Ddler, It., MC

In recent years, reseazc.h into the functional status ofSthe anterior pitxutary gland has centered stround studies

directed at defining the chemotransmitt-r mechaniems of thehypothalamus. It has been found that neurohormones -lib-erated from the region of the median eminence of the hypo-thalamis into the hypophyseal portal circulation regulatesecretion of the pituitary tropic hormones. /1-3/ Hypo-physiotropic factors affecting all the pituitary hormoneshave been described . /4/ Most of the known neurohormoneselaborated by the hypothalamus act as "releasing factors".There is evidence that ther" are both releasing and in-hibiting factors for growth hormone and melanocyte stimu-lating hormone, and an inhibit.ing facor for the releaseof prolactin. /2/ it may well be that all releasinp factorshave dual controls, which have not been defined. The focuson the hypothalamus and the discovery of these neurohormoneshas relegated the anterior pituitary gland to a position of-Pc.(ndary importance, removing it from its previously

esteemed position as the "master gland". It now appearsthat the anterior pituitary simply serves as a factory forproduction aud e'torage of hormones which can only be re-

leased upon signalling from higher brain cei ters. When con-sidering failure of the anterior pituitary gland, therefore,one imst also consider the potential of the basic disoaseprocess lying in the hypothalamus and, indeed, in a numberSof nyndromes this has proven to be the case.

Etiology

Classically, the etiology of anterior pituitary failurehas been considered in two general categories - non-neoplasticconditions and tumors. The classic prototype of the non-necplaýtic l.esions is Sheehan's syndrome - infarction of theanterior pituitary gland msbsequent to p-,stpartum heriorrhage.

-C vCf7 t ('U" I o I Ao, 2, !' bru1) 1 q 71

(

4 108

Diagnosis of Hypothalamic-Pituitary Dysfunction - Deller

A variety of other forms of vascular disease, however, havealso produced infarction of the anterior pituitary, namely,caaotid arteL7 occlusion, temporal arteritis and vascularca.plications associated with diabetes. Many cases are onrecord also of granulomatous disease of tihe anterior pitui-tary and hypothalamus which have led to pituitary insufficiency;in chiJ.drenHand-Schuller-Christian disease, hemn-rhromatosis,sarcoidosis, tuberculosis and non-tuberculous giant cell granu-lomas (a syndrcme often associated with multiglandular granu-l1a). /5/

A u=ber of tumors arising within the pituitary glandhave caused both syndromes of hypopituitarism and a varietyof syndromes of hyperpituitarism. Over 80 percent of suchtumors arise from chromophobe cells, somewhat less than 10

percent from acidophils and rarely from basophils. Tumorsarising outside the pituitary have occasionally destroyedthe gland by encroachment. The most coimmon of these havebeen craniopharyngicnas. Other tumors arising in the areaof the hypothalamus have led to syndromes reflected by partialpituitary insufficiency, probably by interfering with neuro-endocrine secretions from the hypothalamic nuclei.

Clinical Features

The pwrest form of anterior pituitary ingufficiency isthat which occurs following hypoph5 ectomy. Total hypophysec-tcomy results in signs of adrenal Jtsufficieicy within thefirst two weeks following surgery. V7ycthy:oidLsm occursSAithin eight weeks and subsequently there is gradual atrophyof the gonads and hypogonadism. total hypophysectomy alsoproduces "posterior pituitary" failuire with diabetes insipidus.However, the diabetes insipidus which develops in the faceof anterior pituitary failure is generally milder than whenthe anterior pituitary remains intact. (This is probablyattributable to decreased glomerular filtration rate and in-creased tubular reabsorption of water which occurs in patientswho are growth-hormone and cortisone depleted.) Although iT,is true that total hypophysectomy without replacement therapyis incompatable with life, most pathologic conditions whichcause aniterior pituitary insufficiency occur gradually, withsymptoms appearing subtly after the destruction of appro-ximately 75 rc-cent of the gland. It is ýnese cases which

Pre'sent ' ,n(. vP ets, I '4 No -2. 1- c'ru a r v 19 71

109

Diagnosis of Hypothalamic-Pituitary Dysfunction Deller

frequently present as diagnostic problems.

In the classic situation of anterior pituitary failureof gradual onset a chazar-oeriotic "dropout" of pituitairy func-tion occurs; first -4th gonadotropins followed by growthhormone, thyrotropic, and adrerocorticotropic hormones. Itis evident, however, that the clinical features of anteriorpituitary failure will iury with the age at onset, sex,suddenness of onset, basic etiology (whether there is a space-occupying lesion or only tropic hormone loss) and the siteI of the lesion, i.e., pituitary or hypothalamus. If anteriorpituitary failune occurs during childhood the major mani-festation will be failure to grow. (This subJict has beenI; covered in a previous issue of this Journal.)/6/ When thedisease occurs in a woman during tl-e childbearing years themost common presenting complaint is amenorrhea. This is thetopic of another paper in this symposium. (pp 119.1?9)Although Sheehan~s syndrome is not nearly as common a causeof anterior pituitary failure tcday as it once was, it isa drwAatic enough occurrence th'iat the symptoms of thispart icnlar form of anterior pituitAry failure should bebritfly reviewed.

Sheehan's Syndrome M71

Tht patlophysiology, of Sheehan's syndrome is based onthe fact that there is h~pertrophy of the anterior pituitarygland during pregnancy with an involution occurring post-partunm. If postpartum hemorrhage results in ischemic shock,the pituitary gland il subject to infarction. An early clueto the diagnosis of She-h~n's ,yadrome io rapi6 mainary in-volution and failur-- of lacta-tion Jn thE earlj postpartumperiod. This •s uizIly followed by otstheni,! wei&b, loss,failure of return oi menses, and progressive signs o' end-organ failure, if these patients go vunrecognized, they willdevelop palor, and iAke or, a Asxy myxedematous appearance.They gradually lose axillary and pubic hair and usuallydevelop a mild anemia. Fequently such patients are mis-taken as having anorexia nervosa. However, a careful his-ývz-r and physical emmination will differentlate this con-dition from that form of hypopituitarism in whic? patienttdo not develop the prof'ond wasting cf anorexia nerw.•o, !'•i le

patients with anorexia nervosa do not develop the opo-iapattern as describ-4 above,. The labor-atory evaluauion wil).

Diagnosis of Hypothalamic -Pituitary Dysfunction Deller

separate any clinically confusing problems.

Although Sheehan's syndrome serves as a prototype of anaccelerated form of total anterior pituitary failure it shouldbe emphasized that whenever a patient presents with any mani-festations of end-organ endocrine failure, either unihormonalor multihormonal, vne must consider that the basic pathologymay lie in the hypothalamus as well as in the pituitary,, /8/When the patient's disease is due to a tumor, in addition toendocrine deficiencies, the patient may present with headacheand a v-ariety of visual disturbances due to encroachment on theoptic chiasm and the cranial nerves controlli,.j extraocularmotion which cross above the diaphragma sellae. If the tumoris arising in the hypothalamus a number of functions may bedisturbed which frecrtently require careful clinical analysis:sleep-wakefulness, appetite-satiety, thirst, temperatureregulation, libido and various behavorial and motivationalterations. A carefully performed neuro-ophthalmologicexamination is critical in such cases. As a number of intra-sellar tumors produce excessive tropic hormones, patientbmay present with a combination of a syndrome cl pituitaryexcess such as acromegaly or Cushing's syndrome while atthe same time they have eviderce of insufficiency of otherpituitary functions. Thus, a wide spectrum of pituitarydysfunction may be seen with hypersecretion of c s hormoneand insufficiency of others. A rnumber of syndromes due to theloss of individual pituitary or hypothalamic functionshave been described. /9/

Laboratory Evaluation

A complete evaluation of the hypothalamic-pituitarysystem should include direct assay of hypothalamic re-leasing and inhibiting factors, pituitary tropic hormoaes,target gland functions, and in addition, studies to detectspace-ocuupying lesions. There are currently available bothindirect methods of evaluating hypothalamic function as wellas direct assays of some neurohoinones. At present, however,despite the concentrated research in this area, the directapproach to hypothalamic function in the clinical evaluationo4 hypothalamic-pituitary syndromes is not yet z:ractical.

Prewent Conm'pis V1o I ,' N 2, tI'hroari 1971

Diagnosis oj Hypothalamnic-Pitu;tary Dysfunction - Deller

It is worthwhile, however, even at this point in time toconsider those tests wich mlghtlpoint to the hypothalamus asthe primary site of a lesion. Krieger et al /10/ have recentlypublished a comparative study of endocrine tests of use inhypothalamic disease. These authors studied 14 subjects whopresented with neurologic symptoms (vivial disturbances or head-aches for the most part) and no clinical endocrine dysfunction,Discrete lesions were defined in 12 of thase subjects. Of thethree studies compared - circadian periodicity of plasma 11-OHCS levels, insulin-hypoglycemic stimulus for grow-th hormoneand 11-OHCS, and metapyrone responsiveness - abnormalities inthe circadian rhythm of plasma 11-OHCS were found to bethe earliest and most consistent endocrine alteration in thesepatients. Thus, in thoealuation of a patient with a suspectedhypothalamic syndrome such testing may be of value in placingthe lesion.

Another approach tc, "differential testing" of hypothalamic-pituitary function which may have practical clinical appli-cation is comparing plasma l1-OHCS responses to vasopressin andACTH infusions.

It should 'he -ecalled thdi, the "posterior hypophysis" isnot in itself an endocrine gland, but rather' it is merely theadotal end of the supraoptico-hypothalamic tract which syn-thesizes vasopressin at its hypothalamic end and dischargesit from the posterior lobe of the pituitary. Thus, vasopressinoriginating in the hypothalamus may be considered a "releasingfactor" for certain anterior pituitary hormones.

Both synthetic lysine vasopressin and natural aqueousvasopressin have been administered to determine ACTH (viacortisol assay) and human growth hormone (HGH) (via radio-immunoassay) re6ponses. /11,12/ A normal response is a riseof approximately 10 micrograms per 100 ml of plasma cortisoland generally at lon'st a doubling and usually a three or four-fo-Ld rise in human growth hormone follow4 ng ten pressor unitsof aqueous vasolressin given intramuscularly. The peak riseof plasma cortisol usually occurs within 30 minutes and thepeak rise of human growth hormone within 60 minutes. Failureto respond to this "releasing factor" would suggest pituitarygland failure (and not hypothalamic dysfunction).

An ACTH infusion following this test Pnd producinga normal cortisol response would confirm that the lesion was

Prc'.enl ('Coicp~s. Vol IV N (, 2 IF hr drv- 194 71

112

Diagnosti of Hypothalamic.Piruiiar.v Dysfunction - Deller

pituitary rather than adrenal. This test can be accomplishedby obtaining plasma samples for 11-OHCS in the basal state and30 minutes after intramuscular injection of 25 units of ACTHor 0.25 mg of ccyntropin, a synthetic corticotropin. Thenormal response is at least a 10 microgram per 100 ml increasein 11-OHCS over the basal sample. /13/ A similar differentialtest for the hypothalamic-pituitary gonadal system usingclcmiphene citrate (Clcmid®) and gonadotropins is presentlyunder study by Paulsen at the University of Washington.These methods approach the ultimate use of specific hypo-thalamic-produced neurohormones In stimulation testing fordysfunction of the hpothalamic-pituitary system. With therapid progress in defining and synthetizing the specificneurohormones, /14/ th se indirect methods of assaying endo-crine function and ati empting to isolate the site of pathologywill be replaced by -",re specific tests in the near future.

Pituitary Function

The greatest advance to date in evaluating pituitaryfunction is the current availability of methodology for hor-iaonal analys-s on serum rather than u'ine. The use of bloodspecimens rather -',an 24-aour urine coliactions has at thesame time ohoz ...--d the "work-up", and improved the accuracyof diagnostic testing. Our current approach to the evalu-ation of suspected hypopituitarism, whether it be initiatedbecause of a suspected single hormonal deficiency (i.e.,growth retardation, infertility, amenorrhea), panhypopituitar-ism or a tumor, includes a survey of all endocrine functionsof ýhe )itui~ary gland. The usual procedure for evai,•tinrpituitary fiirntion consists of three phases: (1) pituitarynormonp asL •, (2) target gland function, and (3) search foran anatomically Jefinable lesion.

TABLE I lists the pituitary hormones and the basic approachto their study. Prescntly, there are no clinically availableassay procedures for melanocyte st½mulatinx horrone (MSH) orprolactin. Rarely decreased pigmentation may b3 noted inlMSH deficiency and galactorrhea may be present with pro-lactin inhibiting factor deficiency (the latter finding wouldsuggest a hyp-thalamic lesion).

Pr~wtu (': ~!'t.1I~ Ao 2 btw~uarv 1

"113

Diagnosvis of Hypothalamic-Pituitary Dysfunction - Deller

TABLE I

TESTS OF PITIJITARY FUNC, ION

PITUITARY DIRECT ASSAY TARGET GLAND (T)M 4ONHORMONE FUNCTION TEST STIMULATION

%EST

Melanocyte Not available Physical:. Nonestimulating Hypopigmentationhormone (MSH)

Prolactin Not available Physical: Galactt Thea None

Growth hormone (GH) Radioirnmunoassay Physical: Children, ina.din, hypo-growth delay g,

vasopressin

Adrenocorticotropic Radioimmunoassay Plasma, I I -OHCS, ACTtH orhormone (ACTH) urine 17-OHCS, 1l-KS cos.yiltropin

Thyroid Rachoimmunoassay T4, RAI TSHstimulatinghormone (TSH)

Follicle stimulating- Radioimmunoassay Female-. Medical D&C. Nonclutemnizing vaginal corn index.hormone (FSH-LH) urinary estrogens.

Male: Semen analysis.urinary testosterone

Growth hormone measurement by radioimmunoassay is cur-rently the most widely available direct assaey of a pituitaryhormone. The standard test employT tho use of insulin-hypo-glycemia (0.15 units regular crystaline insulin/kilogram bodyweight givP7 intravenously). A fall in blood glucose ofgreater th £ 50 percent of the baseline value should be fol-lowed by a rise in growth hormone by 60 minutes to at leasttwice the fasting value in normal individuals.

The vasouressin test for growth hormone stimulation hasalready been mentioned. Recently, measuring the growth hor-mcne level after the potent natural stimulus )f normal sleep

Pr(qse,ýt Conc'ept. VolI /V1 No 2,, 1,(hruart 1971

114

Diagnosis of Hyporhaiamic-Pituitar.v D.vsfuncuion - Deller

has bean reported to be perhaps the most sensitive "stiiu-lation test". /16/ This, however, is generally an ivpitac-tical procedure. Failure to appreci".te a peak growth hor-mone rise following natural sleep might, however, be indica-tive of a hypothalamic lesion (author's speculation)!

Immunoassay of ACTH is a difficult procedure and does nothave widespread availability. The most practical &•st, there-fore, is the measurement of plasma 11-OHCS (so-callea "PlasmaF"). The evaluation of the circadian periodicity of -heplasma 11-OHCS has already been muntioned an has its useful-ness as a parameter of measurement after ACTH or cosyntropinstimulation. Although this rapid plasma test may be discrim-inating between primary and secondary adrena' failure, ifthere is no response after a single test one musc revert toa three-day urinary ACTH stimulation procedure. In this in-stance, a baseline 24-hour urine is collected for 17-OHCS ard17-KS, then 25 -nits of ACTH or 0.25 mgm cosyntropin is admin-istered intPavenously in 1,000 cc saline over eight hours onthree successive days. Urine is collected on the second andthird day of the infusion. In pituitary insufficiency thereis a gradual steady rise in the daily excretion of thesesteroids while in Addison's disease there is no rise and oftenthere is a fall,

Direct assay of TSH is also not 6enerally available andone usually relies on serum thyroxin (14) testing, radio-iodine (RAI) uptake by the thyroid gland, or both studies.Abnormally low values on these tests call for the use of aTSH stimulation procedure. This test is best conducted byadministering 10 units of TSH intramuscularly daily for threedays aiid repeating the Ta4 szd RAI uptake on the third day.A normal end-organ response would be indicated by 1he T4'value falling within the normal range and the RAI uptakedoubling itself. Failure of such a response would indicateprimary hypothyroidism. The use of synthetic thyrotropin-releasi-ng factor in man has just recently been reported. /17/

The use of tests for the hypothalamic-pitu• ry-gonadalaxis (FFSH-LH) are outlined in a subsequent paper in thisissue. (pp /22123) The standar4 measurement of urinr rygonadotropins by bioassay is an insensitive index of pituitaryfunction. However, repeated determinations which fail tc,show a significant excretion of gonadotropins is indicative

"Wrescnt C(oncepts, V;l, , It' ,No , 2 Februari it) -1

Diagnosis of Hypothalamic.Pstuilary Dysfunction - Deiler

of hypothalamic or pituitary insufficiency. Recently radio-imunoassay procedures have been developed for both FSH andLH, but these methods are not yet generally available. /18/Thus, indirect methods are still ccmmonly employed, such as,when evaluating the female patient one usually uses the"medical D and C", vaginal cornification count or urinaryestrogen excretion; and when dealing with the male patient asemen amnlysis and urinary testosterone levels are used.

COMMENT

The search for an anatomically definable lesion in thepituitary-hypothalamic region falls in two disciplines: (1)neurophthalmology, and 2) neuroradiology. Although precisevisual field examinations are painstaking and time consumingand ara best done by an ophthalmologist, the great bulk ofsignificant field defects, particularly those arising aroundthe optic chiasm can be demonstrated by simple confrontationtechniques and should be part of the basic "work-up". A care-ful neurphthalmological evaluation may also detect other moresubtle defects than the classic bitemporal hemianopsia and canii•dicate extension of tumors beyond the chiasm.

Neuroradiology of the sella and suprasellar region playsthe f.inal role im localizing tumors of the pituitary andhypothabl•3s. The first step in this area is to obtain plainfilms and laminograms of the sella turcica. Arteriographyand pneumoencephalography provide additional and complementarydata and are important procedures in final localization oftumors, especially whenever a surgical approach is contemplated.More detailed and specific aspects of these studies are coveredin a recent excellent review in the Annals of Intcmal Medicine_/4/

Present Concepts. Vol IV 'Vo 2. Februar IV 71

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Diagnosis of Hypothalant -Pit utar' Dysfunction Deller

References

1. Reichlin S: Fsdicpo1 progress, neuroendocrinology.New ng : Med 26o:1182-1191, 1246-1250, 1296-1303, 1963

2. Guillemin R: Hpothalamic factors releasing pituitaryhormones. Rec DroIr Hormone Res 20:89-99,1964

3. Hariai GW, Reed M, Fawcett CP:. Hypothalamic releasingfactors and the control of anterior pituitary function.Brft f Bull 22:266-272, 19%

4. Houser G, Et al: UCLA Interdepartmental conference, Trendsin Clinical Neuroendocrinology. Ann Intern Med 73:783-807,1970

5. Williams RH: Textbook of Endocrinology, 4th ed. Phila-delphia: W. B. Saunders, TiW .. Chapter 2.

6. Deller JJ: Growth hormone in the evaluation of growthretardation. Present Concepts in Intern Med 2:18-26,(Jan) 1969

7. Sheehan HL, Stanfield JP: The pathogenesis of postpartumnecrosis of the anterior lobe of the pituitair gland.Acta Endocrinol 37:479-485, 1961

8. Baver HG: Endocrine and motabolic conditions related topathology in the hypothalamus: a rsview. J Nerv Ment Dis128:323-338, 1959

9. Brasel JA, Wright JC, Wilkins L, 6t al: An evaluation ofseventy-five patients with hypopituitarism beginning in.hildhood. Amer J Med 30:484-498, 1965

10. lKrieger DT, Gluck 3, Silverberg A, et al: Comparativestudy of eadocrine te3sts in hypothalamic disease:circadian periodicity of plasma 11-OHCS levels, plasma11-OHCS and growth bormone response to insulin hypoglycemiaand metaprone responsiveness. J Clin Endocr 28:1539-1598,1970

11. Landon J, James VKT, Stoker DJ: Plasma-cortisol responseto Lysine-vasopressin: comparison with other tests ofhuman pituitary-4tdenocortica] function. Lancet 2:1156-1159, 1965

12. Eddy RL, Aqueouo vitsopressin provocative test of anteriorpituitary functicoa. J Olin Endocr 281836-1839, 1968

13. Smilo RP, Forshxa PH.: Liagmnostic approach to hypofunction&nd hyperfl.notJo:. of the adrena L corter. Postgrad Med46:146-152, 1969

14. Schultz AV, ri~nbra A, Bowers CY, st a.i Pur'ificationof hypothalam'c, releaFing hormones of" hidn origin.J lin EnadooýZr 31:21-200, 1970

15. DUe-lr JJ, Boulis MW, Harriss 14E, et al: Growth hormoneresponse patterns to sex hormones e'mi'inistrUtion ir growth

r tardation. Emj J A 't5 917•) Y ,

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Diagnosis of Hypothalam ic-Pituiarmv Dysfunction - Deller

16. Mace JW, Gotlin RJ, Smssin JR, et al- Usefulness ofpart-sleep human growth hormone release as a test ofphysiologic growth hormone secretion. J Clin Endocr31:225-226, 1970

17. Hershman JM, Pittman JA Jr: Response to syntheticthyrotropin-releasing hormone in man. J Glin Endocr31:457-460, 1970

18. Odell WD, Ross GT, Rayford PL: Radioinuznoassay forhuman luteinizing hormone. Metabolism 15?287, 1966

Prewenl Concepts, Vol IV No 2, Februvrp 1971

- - -.. .. . . . ... .. -. -

118

After I thought I was beginning to understand the functioning of thepituitary gland I came across a summary of the work of Doctor Alvarez.Bvillawho found that the effects of hypophysectomy are almost entirely reversed byplacing SALIVARY GLAND grafts into the emptied sella of dogs! The dogsso grafted are reported to have normal thyroid, adrenal and gonadal function -they can even reproduce and apparently lack only the ability to grow in anormal fashion and to lactate!)

But don't be a skeptic - this makes sense (ha) when one considersthe report by Narasimban and Ganla from Poona, India. These authors re,moved the submandibular (salivary) glands from litermates of several differentSammal species up to monkeys and guess what they discovered? The animalswithout submandibular glands showed severe retardation in their growth'2

Who would have ever thought that the SALIVARY GLANDS were soommnpotent?

I ltospital Practice., Sept., 1968.2Ann. Fndo , Sent-Oct., 1968.

Present Cf'n,'epts, Vol IV' i'o 2. 1ebruary, 197,1

EVALUATION OF SECONDARY AMENORRHEA

COL John J. Deller, Jr., MC

Few events in the reproductive life of a woman givq9 rise,to more emotional reaction than a missed period. Thi: wventis even more upsetting when she also dis--vers hal.z on herchin. When these events occur in ary given woman a red flaggoes up - and it ia up to her doctor to reel it in. Thisdiscussion will be concerned with the practical approach tosecondary amenorrhea with or without associated hirsuiti=or virilism. Figure 1 depicts the "anatomy of arenorrhea".

-h L'AERL .I m.'Ie'n ii li,lt,ln .*fl

HYPOTHALAMUS

- ANERIOA PITUITARY

-; THVROID

ADRENALS

FI• I "he "anatom, ot amcnoirhea'

Ptre'Cu s ( t (?I(n CI i ep t F 2. 1 (/h 4 j / i~u '

12"•

Eraluation of Secondary A menorrhea Delier

Before imbarkiznv on an evaluation of the various patho-logic causes of s , )ndary amenorrxhea., one mast alwe.ys con-sider first the tui moat ccumkon physiologic causts -.pregnancy and the menopause. The first of tinsse is easilyscreened by the Gravidsx@ pregnancy tst; th? latter, how-ever, may be somewhat moe difficult to define outside theimeditte perimenopausal period.

The "psyche and the soma" in some rath,.r obscure waysalso frequently affect menstruation. A variety of psycho-genic mechanisms have been proposed for the amenorrhea whichis not infrequently seen in girls leavirg home to attendschool or in girls whose husbands leave them for militaryduty, or at anytime ihen a strong emotional attachment hasbeen broken. A more profound psychogenic am•enorrhea maytake the form of pseudocyesis, a rare condition seen in youngwomen disturbed over their inability to get pregnant. Inthese cases, there is probably a persistent hypothalamicstimulus which causes continuous release of lteinizinghormone (LH) which in tarn maintains tne onrpus luteum andpermits the development of the symptom complex of earlypregnancy. Those chronic medical conditions which can leadto amenorrhea are usually obvious after s careful history andphysical examination. There is generally evidence of mal-nutrition (e'.ther emaciation or gross obes-4 ty) or a chronicwasting illness such as tuberculosis, uad-stage renal orcardiac failure or cancer. The amenorrhea in these in-stances is merely one feature of a number of bodily dys-functions. After these considerations have been excluded,the bulk of the remaining amenorrheas must be explained onsome specific endocrinopathy. The approach to the patientwith a suspected endocrine amenorrhea, (with or withouthirsuitism or virilism) should be preceded by three things:(1) a damn thorough history; (2) a pregnancy test; and (3)accurate determination of the size and shape of the ovariesif you can't feel them (and you often can't because ofcomuonly associated obesity in many of these patients), dopelvic pneumography BEFORE surveyirng the entire endocrinesystem. You will be 'way ahead in the end - and your patientwill have a good bit more money left in her pocket.

P-rcs 'itn Co i. (ei) s,~ I I j I Ao 'bruur i

121

Evaluation of Secondary Armenorrhea Deller

TABLE I lists the galactorrhe&-amenorrhea syndromes whichhave been defined. The occurrence of amenorrhea and p rsistentlactation fol2owing pregnancy was first described by Chiari in1885 and later fully characterized by Fromnel in 1882. /1/More recently Ross and Nusynowitz /2/ in 1968 reviewed casesof postpartum amenorrhea and galactorrhea essociated with pri-maxy hypothyroidism and cured by thyroid administration.irgonez and Del Castillo /3/ characterized a nonpuerpual syn-drome of galactorrhea and amenorrhea in 1953. Forbes et al /4/described a similar set of patients in 1954, but half of theirshad pituitary tumors and they proposed that the others probablyalso had tumors. Witlin the past few yaars tUds combinationhas also been described in women having t~k! birth controlpills, 15/ There are logically two mecbanimas to explain suchsyndrom:j: (1) a pituitary tumor may be producing excessive

Srcla -1 (or growth hormone, i.e., galactorrhea may occur inacroamgaly) while at the sawe time impairing gonadotropinproduction, or (2) since the hypothalamic releasing factor forLH (LHF) and the inhibiting factor for prolactin (PIF) arefrequently located in the same area of the hypothalmus, alesion in tbat area could at the same time block LPF and PIF.If a pituitaty tumor cannot be defined, it is likely that whengala-torrhe is present the defect lies in the hypothalamus andthe lesion may be definable aw-comically or it may be a"functional" alteration.

TABLE i

AMENORRHEA/GALACTORRIH A SYNDROMFS

SYNDROME RELATIONSHIPS i)URAI ION

Chian (1885) - Frofnmel (1882) Postpartum Usualiy mempOrty

Ross-Nusynowitz (1968) Postpartum ',sl de- Responds tiý, thyroidg'-ýe hyput 1yroudism

Argon7-D:l Castillo (1953) ldiopat-!1i Usually permaleint

Forles-A- bnrght ý 1954) P10itugary tumor iJsudi, perninl(n rW

",t-Mll" (1966) Cra . Ust y o tm.

Prrý**! " ,tl ,'fw ,f •,. 1 (4 1 X| , ",' 2. / tl}'b uc:', • "

122

Evaluation of Secondary A m enorrh ca - Deller

PITUITARY AM 'NORRHIEA

Amenorrhea of pituitary origin mey be associated with pan-bypopituitarism, isolated deficits of FSH-LH, or syndromes ofpituitary excess, i.e,. Cushing's syndrome and acromegaly. /6/Thus, a general assessment of pituitary function (pp 112.iliin this sympocizm) is indicated. When menses cease due tcpituitary gland failure, one can assume there is a deficiencyin pituitery-gonodotropin secretion and this is termed "hypo-gonadotropie amenorrhea". To confirm this diagnosis one ofthe simplest tests to apply is the "medical D & C". This testsimply defines the adequacy of endogenous estrogen production -

An an estrogen deficient envirozent there can be no withdrawalbleeding after progesterone administration. This test can bedone by administering one injection of medroxyprogesteroneacetate intramuscularly (375 mg Delalutin 0 ) or giving itorally for five days (20 mg Provera@ daily). A positiveresponse - vaginal bleeding within a week following proges-terone administration - effectively rules out a hypotAalamic-pituitary deficiency as the cause of amenorrhea. This test,howmever, does not definitcy pinpoint the lesion regardless orthe response. Another simple test for "hypoestrogenism" isthe use of vaginal cytology or the cornefication index. /7/Again, this alone is not a discriminating test - that is,a deficiency index may be seen with primary ovarian failureas well as pituitary failure, but unen associated with absentgonadotropins and taken in the total context of the case itis further evidence of pituitary insuffic;iency.

The measurement of urinary gonadotropins is a highlyvariable and frequently unreliable index of hypothalamic-pituitary activity. However, when several determinationsare made and the gonadotropin levels are consistently lessthan five mouse-uterine units one can accept the results asbeing indicative of a def." iency of gonadotropin secretion.More recently radioirmmanAssay procedures for both FSH and LHhave become available and with more widespread usage willprovide the most sensitive index of hypothalamic-pitaita-ry-gonadotropin produetton. The absence of FSH by iumunoassaywould place the les. on in the pituitary or hypothalawas. Theatility of clomiphene citrate to produce a measurable risein FSH may further localize the lesion to the hypothalamus(author's sp-culation).

Of course, the radiographic features of a lesion irthe pituitary region provides the best localizing evi(nce,but normal radiographs early in the course of n aeno:'rhea

Prescn; (,,cepit (,I o/ /V A 2. 1 chruarv I V" I

123

Evaluation of Secondary Amenorrhca - Deller

syndrome do not rule out hypothalamic or pituitary disease.

THE THYROID - Malfunction, a cause of amenorrhea

Secondary menorrhea may be seen in association with eitherthytoxicosie or hypothyroidin. In the case of thyrotoxi-cosis the diagnosis is usually evident. Hypothyroidism as thecause of amenorrhea, however, is often subtle. Even whenconsidered there may be caly border ine low thyroid functiontests. These should not be overlooked, because these may pro-vide the answer, and a trial of thyroid therapy is occasionallyrewarding in such cases.

ADRENAL, VIRILISM

Up to this point the causes of secondary amenorrhea havebeen unassociated with hfrsutism or virilism. When thesefeatures are part of the amenorrhea syndrome, one is mostlikely dealing with either adrenal or an ovarian dysfunctionand the adrenal cortex is by far the more frequent source oftrue virilism than the ovary. /9/ The adrenal virilisingsyndromes causing secondary amenorrhea may be conv. 'entlydiv.ded into three typed: (1) primary adrenal hb per-plasia (frequently called acquired adrenogenital eyndrome);(2) secondary adrenal hyperplasia; and (3) functional adrenaltumors (benign adenucas and carcinomas).

The wck of Eberlein and Bongiovanni /10/ has clarifiedthe basic pathojMo&tic mechanisms of RrAM adrenal hyper-plazia. The lack of one or more of the enzymes in the adrenalcortex (most cononly the C-21 hydroxylase) necessary forthe spithesis of hydrocortisone from pregnenolone resultsin a dtficient production of hydrocortisone and a subsequentincrea:ed production of ACV! '-y the pituitary which forcesthe adrenal to prduce increasing amounts of other pregneno-lone metabolitte - etiocholanolone, androstenedione andteatost-rono, When Buch a defect is only partial or minimal,It may not become evident until adult life and thus be thecause of variable degreea of oligomonorrhea, hirsutism and

Pa~i.z(7i;~~p~..~'I NUVo2, kcbruor 19 71

124

Eraluation of Secondary Amenorrhea - )eller

Secondary adrenal hyMerplasia is the result of a primaryoverproduction of ACTH which generally res-its in Cushing'ssyndrome. However, such patients are also subject to excessiveproducetion of "weak androgens", and menstrual alterations withminor virilim may be predominant clinical features.

_Adencs. of tý&a adrenal are also more cdmidnly consideredto be the cause of Dishing's syidrme rather than adrenalviriiki, yet if the adenoma is comprised primarily of cellsdestined to produce androgens (a "less sophisticated process")an adrenal virilizing syndrcoe may result.

The most severe forms of virilism ocar with functioningadrenagl malignancies. Adrenal carcinomas tend to occur inwomen over 40 ani they usually develop rapidly with full viril-ization appearing over a few months. Fortunately, however,such tumors are relatively uncommon because the mortality rateof those individuals who develop them approaches 75 percent. /9/

A complete schmea for evaluating patients with suspectedadrenal virilism is depicted in TABLE Mi. In primary adrenalhyperplasia, a typical "steroid profile" usually is found. Ifthese tests do not confirm primary hyperplasia, a suppressiontest is necessary to distinguish between secondary hyperplasiaand tumor. If the basal urinary 17-ketosteroid and/or 17-hydroxysteroid excretion is moderately elevated and cannot bedepressed significantly witl 2 mg Decadron@ given fcur timesdaily for three days, one is dealing with a "tumor". Thereis little point in attemptinL to further resolve whether thepathology in such a case is an adenoma or a carcinoma. Itshould be promptly located by radiographic 'echniques -

pyelography with tomography, retroperitonea. CO insufflation,renal arteriography or adrenal venography - whichever yourhospital is most caprble of doing and the patient should betreated -urgically.

!Prevnt Concepi•, Vol IV No 2, Februurt 1)71

IS1/25

fA'aluaiior of Secondary Ameno;.hea Deller

TABLE 11

SCHEMA FOR EVALUATING PATIENTS WITH SUSPECTED ADRENAL VIRIIISM

TEST PRIMARY SECONDARY BENIGN CARCINOMAADRENAL ADRENAL ADENOMA

HYPERPLASIA HYPERPLASIA

Plasma "cortisol" t tUrie 1'7OHC S t t t

Unie 17-KS t(mo&ot) t(modest) t(noderate) timarked)

"Pl'-anetriol t Normal Normal Variable

Te-tosterone Normal Ncrmal Variable

Suppression of + +I t-KS/17-OHaSwith corcisol (8 ing Deca/day) (8 mg Deca/day) (8 mg Deca/day)

X-ray diagnosis No tumor No tumor UJrtcral tumoi Unilateral tmmort+bilateral +bilateral nhay re4uir- usually can be'1argpmment enhurgment vascular con- demonstrated

contrait study by tomographytpituitaxyenlargement

I _ _ _ Il _ __J_ _ _ _ _ _ __I_ _ _ _ _ _ _

OVARIAN VIRILISM

Although the ovaries may be a ca'ne of virilism inassociatiou with amenorrhea, it is usually mild and limited

* to otesity and hirsuiti.m in the polycvsti: syndrome. T'umorsof the ovary, alt'nxgh potential causes of virilism are rarein their occurrence RM are f~equentiy unassoeiated with ex-cessive vndrogen prodxtction when they do occ'". As mentionedin the introduction, an accurate description of the ovaries --si'ýe, shape and synmetry - should be established at the out-set of any approach to the amenorrhea syndromes. Or approachto this is that if +, ccmpetent observers cannot Ratisfythemselves that th. ovaries and uterus are normal in size.shap'e and relationship to each other, then pelvic pneumographyis performed (or Peritonescopy if your favorite gynecologistprefers).

Presctit (,•ncep,s, V,, IV A'o 2, Ftbruarv 1971

VP

126

-valuation of Secondary Amenorrhea - Deller

The technique of pelvi mumogrrIAy is relatively simpleand uncoplicated. /11/ IL can be performed in the radiologyd,-artment and either ',O-, 'c -itrous oxide should be esed.A gas is instilled into tne peritoneal cavity under a gavityflow (water bottle displacement is the safest tthnique) viaa 20 gauge spinal needle inserted into the left periumbilicai.region. After approximately two liters have been so placedthe patient is tipped into a prone, 45 degree, head downposition (use shoulder bars) and a PA projection is takenthrough the pelvis. Additional views (lazeral and obliquescan be obtained but rarely add significant information). The%Ga%0!÷q to be expected from such a study are shown in "igure 2.

Why all this fuss about the pelvic pneumogram? - simplybecause it alone provides the most important diagnostic in-formation about the role of the ovaries in these patients.Bilrteral enlargement means polycys'ic disease and unilateralenlargement signals a tumor!

In our experience by faz the most common pathologic ovari-an cause of amenor.hea is the polycystic ovary syndrome. Thisoften becomes maniest in the teens or occasionally after asingle pregnancy vith the development c C menstrual irregu-larity progressing to amanorrhea and um ally associated withobesity and mild tc modest hirsuitism (but not always).Characteristically, 17-ketosteroid production is normal oiýat most "borderline high". Of course, the "adrenal steroids",17-OHCS and pregnantriol, are always normal. Testoster-one isfrequently elevated and an exaggerated response to stimu-lation with gonadotropin is the rule in cases of the chorionicpolycystic ovary syndrome. ,/2/

rhe rarer syr•-ome ef hypertbecosis can not be clinicallydifferentiated from polycystic disease although it apparentlyhas a more common association with hypertension and flucoseintolerance. The 3ndlcations for treatment of these two syn-dromes are the same.

There arc four tyz es of ovarian tumors which have thepotential of inducing virilization: (1) acrhenoblastomas(sertoli and Leydig cells), (2) hilus elel tumors (Leydigcells), (3) lipid ceil tumors (adrenal rests) and (4) goivdu-blastomas.

Preweii Concepts, V ' f IV No 2, i,(brv.arý, 11 71

Evaluation of Secondary Amenorrhea - Deller 127

4-~

A B

U DFie 2. Pe1hc piuernograrns Apelvic anatomy, B. noril -1 pn cullI ogranII, C & D poly-

cystic ovaries

Presen i Coticep:'%, L'o0 I V No 2, Fchruarv, 19 71

128

Evaluation of Secondary Am enorrhea - Delker

Even the most common of these, the arrhenoblastoma, israre .- only about 200 cases having been reported. Thesetumors occur bilaterally and may be malignant (20 per-Scit). "-td -tumor is prone to occur during the early re-

dUtve years and therefore, is the one of most concern1g th. differential diagnosis of amenorrhea during thisp•wiod. /9/ The majority of ovarian tumors can be pal-phsted and most of those that cannot can be discovered on

COMMENT

After all this discussion, I have left little to say inconclusion except that an accurate diagnosis of amenorrhea canbe a most gratifying experience. The therapy for the differ-ent etiologies of amenorrhea is often quite different andspecific. Although the evaluation can sometimes be quitesimple on other occasions it may require long and complicatedstudy. However, one happy mother makes it all worthwhile!

References

1. GREENBLATT, RB, CAR40NAN N, HAGLER W: Chiari-Fron•melsyndrome: A syndrome characterized by galactorrhea,amenorrhea, and pituitary dysfunction. Report of twocases. Obstet Gynec 7:165-170, 1956

2. ROSS F, NUSYNOWITZ ML: A syndrome of primary hypothyroid-ism, amenorrhea and galactorrhea. j 9= idogr 28:591-595, 1968

3. ARGONZ J, DEL CASTILLO F. A syndrtze characterized L.restrogenic insufficiency, galactorrhea, and decreasedurinary gonadotropin. J Clin Endocr 13:79-87, 1953

afPre,t, t Concep Is, V[0I f V No 2, Febru 7ry 1971

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Evaluation of Secondary Am enorrhlea - Deller

4. FOIDES AP, HERIOM4N PH, GRISWOLD GO, et al: Syndromecharacterized by galactorrhea, amenorrhea, and lowurinary F.S.H. Comparison with acromegaly and normal 1lactation. J Clin Endo-= 14:265-271, 1954

5. ROSEN SW, GAHRES EE: Nonpuerperal galactorrhea and thecontraceptive pill. Obstet Gynec 29:730-731, 1967

6. WnILLIAM RH: Teitbook of E, 4th ed,Philadelphia: W.B. Saunders, 1968. pp 55-66

7. TA-JUNG LIA, SU-OHIN LIN: The vaginal cytogram: Aguide to substitution therapy for states of ovariandeficiency. Z.A.M.A. 185:84.-849, 1963

8. GREENBLATT HB, PUEBLA RA, FAUCHER GL: Secornary amenorrhea&d ZM t 2:135-1,44, 1965

9. EMERSON K JR: Virilizing syndromes. HostitaJ Medicine6:93-110, 1970

10. EBELHEIN WR, BONGIOVANNI AM: Pathophysiology of con-genital adrenal hbvperplasia. Metabolism 9:326-340, 1960

11. SCHULZ E, ROSEN SW: Gynecography: Technique and inter-pretation. Amer J Ren- 86:866-878, 1961

12. DMIR JJ JR, WEGIENKA LC, CONTE NF, et al: Testosteronemetabolism in idiopathic hirsuitian. Ann W63:369-376, 1965

Present Concepts, Vol It' No 2, Pebruary, 1971

130

We now have quite effective means of treatin3 patients with ovulatoryfailure. Usually the main call for therapy is infertility. When such is the case,differentiating whether the functional lesion Is in the hypothalamus, the pitui.tawy or the ovary can direct the course of therapy. When there is evidence ofsignificant estrogenic deficiency and hypogonadotropism, Clomiphene citrate isunlikely to be effective. On the other hand, in such instances "FSH" may bequite effective, either alone or in combination with "LW". Patients with posi-tive estrogenic activity often respond well to Clomiphene citrate.i In thetreatment of the infertility of the Stein-Leventhal syndrome, these agentsshould be given an adequate trial before surgery is contemplated - but if theyfail, rest assured, Wedge Resection is still quite effective even though we stilldon't understand why.2

ULancet. 21 Dec 19682J Obstel Gynaec Brit Comm, Nov 1968

Present Concepts,, Vol IV No 2., February 1971

'3'

ACROMEGALYDiagnosis and Treatment

Seymour R. Levin, M.D.*

Acromegaly is a clinical condition resulting 7romautonomous secretion of growth hormone (GH) during adultlife.

Normally, GH has a relatively predictable diurnalpattern. Upon arising, the healthy subject has a fastingimmunoreactive GH level of less than 5 mug/mR Meals arefollowed by low values for the first two hours and then GHrises, somewhat, three to four hours after eating. Duringthe first hour or two of sleep, the growth hormone risesappreciably, reaching a peak during the first period of deepsleep. This is "slow wave sleep," after the rapid eye n.ove-ment (RW) phase.

Acromegalic patients, however, have higt, fasting Gffwhich respcnds incompletely or atypically to meals and havea high, ihconsistent nocturnal pattern. This secretion maycome from an adenoma (basophil or eosinophil) or a hyper-plastic pituitary gland.

Many stimuli of GH release have been studied; includingemotional and physical stress, hypoglycemia, amino acid in-fusion, and acute lowering of free fatty acids. Estrogenenhances these GH rises. On the other hand, some substanceslower GH. Prominent suppressants are rises in senrm glucoseand free fatty acids. Medroxyprogesterone, cortisol, andthorazine appear to blunt induced rises in serum GH.

Diurnal variation and responses to stimuli and suppres-sants appear to be mediated through a hypothalamic growthhormone releasing factor.

*Senior Research Fellow, Metabolic Research Unit, University of California, San Francidco MediualCenter

?resent Concepti, Vol IV No 2. February 1971

132

Acromegaly - Levin

Diagnosis

The diagnosis of acromegaly requires both clinical andlaboratory clues. High, relatively autonomous hypersecreticnof GH, as seen in acromegaly, forms the basis for vbEt we be-lieve is the best single test for the diagnosis, i.e. thenonsuppressibility of elevated fasting GI by .00 grams oforal glucose, one hour after ingestion. The inability ofglucose to suppress GE, coupled with the essential clinicalfeatures, makes the diagnosis.

CLINICAL ASPECTS

Symptoms

In our experience with over 70 acromegalic patients, wehave seen that they come to us w~th the disease detected atvarious stages. Early symptoms are non-spmcific and includeswesting, easy iatigability, and hand paresthesias. Later,headaches appear, and increasing foot, hand, and head sizeare noted. Loss of libido and menstrual disorders emerge.Late symptoms are cosmetic deformities and problems secondaryto diabetes, cardiovascular disease, pain in the joints, orimpingement on the optic chiasm with resultant bitemporalhemianopsia.

Signs

The best physical sign is the doughy feeling of the handduring the hand clasp. There is usually a warm sweat reflect-ing hypermetabolism. Acral enlargement is usually seen.Coarse facial features vary in degree. A characteristic voicedue to vocal cord thickening is present. We have seen skinpapillomas and acanthosis nigricans in some of our patients.Those with a carpal tunnel syndrome have a Tinel's sign (tapover extended volar wrist and paresthesias spread over the

palm).

Present Conaepts, Vol IV No 2, FebruarY 1971

133

Acromegaly - Levin

Laboratory Findings

Fasting GH in our laboratory is 5 mug/ml in normalsubjects. However, facters mentioned above can elevate thisfrsting level. We thus give 100 grams oral glucose and, innormal subjects, Gil falls usually to .mug/ml. Mean fast-ing GC in 50 of our acror.egalic patients was 52 mug/ml andshowed non-suppression or incomplete suppression afterglucose.

In addition to glucose non-suppressi'l1e elevations inGH, 50 percent of patients have glucose intolerance. Anadditional 10 percent have clinical dir~betes mellitus. Inmost cases, without clinical diabetes, serum insulin iselevated, reflecting the effect c2 Gi in impairing theaction of insulin. We serum phc~sphorus, fasting, iselevated or normal, but this chemical f"als to show normaldiurnal variation (normally lower at 7 A.M. than at 4 P.M.).Sevent7 percent of patients have hypcrcalcuria (history ofstonei in 10 percent). Adrenal and thyroid function areusually normal preoperatively.

Tests have confirmed tumors of other endocrine glands(predominantly thyroid and parathyroid) in some patients.

Radiograruic Signs

The best single radiologic sign is the presence ofthickened heel pads. Measuring the shortest distance betweenthe calcaneus aimd plantar skin surface, normal subjectsaverage 17.8 mm (range 13-21). Acromegalic individualsaverage 25 mm (range 17-34). Negroes have a higher meanvalue, and edema, habitual barefootedness, and myxedema mayalso thicken the heel pads. Pn enlarged sella wac seen inmost of our patients (98 percent) and usually is accompaniedby an elongated mandiblt and large frontal sinuses("diagnostic triad"). Radiologically detectible osteoporosiswas often seen in middle aged &nd older patients. Thesessmoid index is the product of the largest and smallestperpendicular diameters of the thumb sesamoid. Normal range-is from i-21 mm. Acromegalic subjects often hay- an indexof over 30 mm. Preparatory to most forms of treatmentpatients have pneumoencephalography and angiography toevaluate the direction of tumor growth.

Present Concepts, V[l IV No 2, f'ebuarY 1971

134

Acromegahy - Levin

Differential Diag" -- ;

Active a..- moiegaly must be distinguished from "inactive"acromegaly, myiedema (sometimes called "myxomegaly" becausethick lips, coarse skin, and deep voice in both conditionscan cause some confusion), pachydermoperiostitis (a conditionwith thick skin folds and lips, prominent brows), otherpituitary tumors, and constitutional cosmetic changes. Thesecan all be distinguished by their normal growth hormone, andcareful clinical differentiatioin.

The joint deformities of acromegaly may simulate rheuma-toid arthritis, since both mt, have enlarged proximal inter-phalangeal joint enlargement and pal.. But acromegalicpatients do not have morning stiffness characteristic ofrheumatoid arthritis. Pain in large joints with or withouteffusion may rimulate osteoarthritis, but in acromegaly. thejoint space appears large, due to cartilegenouz overgrowth.In o.zteosrthritis the joint space is oftcn small. It As ofinterest that several other conditions may sometimes haveglucose non-suppressible GH levels. These include severestarvation, some neoplasms, uremia, chronic liver alsease.Clinical evidence, in these cases, however, helps to rule outacromegaly.

TREATMENT

The rationale for treatment involves an attempt tc re-duce the progression of metatolic abnormalities and cardio-vascular iisease which shorten and disrupt the patient'slife. The idea method of treatment would reduce growthhormone ard relieve pressure on adjacent structures whilepreserving remaining pituitary function.

The various means of treatment in use today are trans-phenoidal cryohypophysectomy, radiofrequency, yttriumimplantation, surgical hypophysectomy, alpha particleradiation, and conventional x-irradiation. Except for thelast modality, all have shown appreciable reduction in GHwithin a few aays to one year. Measured GH of patients afterconventional radiation has indicated that this treatment isrelatively ineffective. Recently, medroxyprgesterrne hr'been shown to reduce GH in acronegalV,. Its pertanence and

Piesent Cornepts, IFo1 I/V V'o 2 Febmuarv /1)7/

7135

Acrcomegaiy - Levin

its place in t.he.apy remain to be• fully evaluaten. At theUniversity oi -i,•fornia Medical L-nter we have treated 6¶cases of active acromegaly .vith cronhypophysect-Amy in thepast four years. We have observed the complications andresponse to tr•:atwent. Transient postoperative cor'pl'ca-tions included diabetes insipidus (16/65); extraocularmuscle weakness or viLlal field impairment, or both (10/65);hyponatremia (8/65). Thtse problems remitted in severaldays. Two patients have had diabetes insipidus for severs±months postoper&tively, which has responded to chlorpripamioe.Three patients developed curebrospinal fluid rhinorrhea, twoof whom contracted pneumoccccal meningitis, which respondeOto penicillin. Rhinorrhea remitted spontaneously. There havebven no deaths.

in the six-day postoperative periou there i! a decreasein hand volume and ring size. In the six-week to four-year!'cllowu~, grow',.h horrione was reduced to less than 10 mug/ml5r 51. of 65 p&tients. Six patients have required adrenalsteroid replacemenr. based on inadequate sterolc response totests with metyrepone and/or insulin hypoglycemia. Reductionin G3 has been accompanied by subjective impr-vemnent, reduc-tion -n serum insulin, and the presence of improved glucosetolerance.

R eferenr!-

1. Daughaday W-I: Growth hormone assay in Pcromepaly, qirAntism,dwarfism and hypooituitprism. Postgrnd Yed h5:PI4-0l, 969

2 Davidoff LM: Studies in acromegaly. E ndocrinolopvl0:453-h83, 19?6

a. Adams JE, Se!ymour RJ, Earl JM, et al; Trnnssnhenoid31cryohypoohysectomy in acromegaly. Clinical iand endocrlnolori-cal evqluation. J Neurosarg PP:iOO.-Oh, 196c

h. Wright A.-, Hill DM, Lowy C, et al: Mortalitv ir 'cromn aly.Ouart J Med 39:1-16, 1970

5. Glick SM, Roth J, Yalow RS, et alj RePu1l'ti-n of Prowthhormone secretion. Recent Proa Hormone P-s 1: ]- , 1065

6. Lgwrence AM, Yirsters L: Progestins in +h----J 'djci1 ,n,,,tyareentof active acromegaly., J (lin Endocr Th(':6b6-65 , 107)

Present (Concepts. Vol IV No 2. February 1V71

-I 1). • 1 3 6

A croe•~aiy - Levin

7. Sherrman S, Sooseng Y , Penjamin ), et n1: Effect of chlor-tromzine on ser'm grovth-hormone concentration in ran.Ne._.• J Med P84:72-75 (Jan 114) 1971

I

I

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DIABETES INSIPIDUS

MAJ Harvey L. Eichner, MC

Despite the presence of two hormones, antidiuretichormone (ADH) and oxytociti, in the posterior pituitarysecretion, disorders of the neurohypophysis alone haveno clinical significance. Lack of oxytocin causes noimpairment of parturition or breastfeeding, while ADHsecretion is not determined by the competence of theneurophyophysis. ADH, or arginine vasopressin in man, isformed in the supraoptic and paraventricular nuclei of thehypothalamus. Axons of the ganglion cells in these nucleiextend down the neurohypophysial tract into the posteriorpituitary; and secretory granules containing vasopressinare trdneported within the axons from the site of for-matron in the hypothalanub to the site of release in theposterior pituitary. Permanent diabetes insipidus (DI)results from destruction of the hypothalamic nuclei orihe axons above the median eminence but damage to theneurohypophysial tract below the median eminence or ab-lation of the posterior pituitary itself causes only tran-sient polyuria. Vasopressin may also be produced by non-endocrine tumors such as oat-cell carcinomas of the lung,which is among the causes of the syndrome of inappro-priate secretion of antidiuretic hormone. This discussionconcerns itself with defects in the secretion or action ofvasopressin rather than the posterior pituitary gland.

Regulation of Vasopressin Secretion

The two factors exerting primary effects on vasopressinsecretion are extracellular fluid volume and osmolality.Reduction in the bWood volume by as little as ten percentresults in an increase in vasopressin secretion. It isthought that the volume receptors are located in the leftatrium and aortic arch or carotid arteries. Somewherein the distribution of tle internal carotid arteries,probably in the anterior typothalamus, are the osmoreceptorsthat sense slight change. !- oxtracellular fluid osmnolality.\ .Sopressin is secreted in man when the plasma osm ,lality

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exceeds 290 mOsM per liter. Of the two, volume change appearsto be the more powerful stimulus. Increase in fluid volume ordecrease in omaolality inhibits vasopressin release. Otherstimuli of vasopressin secretion include pharmacologic agentssuch as nicotine, morphine, barbiturateri, ether and acetyl-choline, emotional factors such as pain, anger and fear andexercise or physical stress,,

Thirst is also regulated by osmotic changes and by volumechanges) with the volume changes taking precedence. The thirstcenter is located in close proximity to that. for antidiuresisin the hypothalamus and in the absence of normal vasopressinrelease, an intact thirst center will maintain osmolality byincreasing the desire for fluids. Even with a total absenceof ADH, plasm osmolality will remain in the normal rangeunless there is a lesion in the thirst center also or drink-

ing is prevented by unconsciousness.

Action of Vasopressin

Vasopressin acts on vascular smooth muscle to producevasoconstriction; decreases secretion of sweat; decreasessalivary, gastric, p~ucreatic, and biliary secretion; de-creases water and sodium reabsorption by intestinal mucosa;increases gastrointestinal motility and peristaltic activity,primarily of the large bowel; decreases coronary blood flowand cardiac output, probably as a result of its pressoreffects; and has some oxytocic activity. These extrarenaleffects, however, occur only when much larger doses thanthose required to produce antidiuresis are administered.

Th- major physiologic action of vasopressin is on thedistal portion of the nephron, primarily the collecting duct,to allow passage of water from the hypotonic urine into therenal medullary interstitial space which is hypertonic.Tubular permeability is alter3d to allow movement of waterby the formation of cyc'ic 3', 5' - adenosine monophosphate(cyclic-AMP) as a result of stimulation of adenyl cyclase byvasopressin. The renal effects of vasopressin can be mimickedby cyclic-AMP but the emct means by which cyclic-AMP increasein tubular cells affects cellular water permeability is notknown.

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Nhen ADH is deficient, diuresis of dilute urine resultsbut a significant increase in serum omiolality occurs onlyin the absence of an increased water-intake. A triphasicresponse has been note, to destruction of the hypothalamiccenter for antidiuresis or pituitary stalk section. Thiscousists of four -o five days of polyuria and polydipsiafollowed by about six days of intense antidiuresis due todegeneration of nerve tissues in the nemohypophysis car-rying vasopressin. This is then followed by permanentpolyuria and polydipsia. Diabetes insipidus is character-ized by the failure of the kidney to concentrate the urinedespite a decrease in extracellular fluid volume or in-crease in osmolality and the correction of this defect byexogenous vasopressin.

DIFFERENTIAL DIAGNOSIS

Polyuria may be the result of a pathologic defect invasopressin release, of the physiologic suppression of ADHcr of renal factors including unresponsiveness to vasopressinend increased solute load per nephron. TABLE I lists thesignificant causes of polyuria and major etiologic categories.wome types of polyuris are produced by more than one mechan-ion but only the rost important is listed. In psychogenicpolydipsia for example there is not -nly suppression of ADHby the excessive water intake but L..,-. renal -'nresponsive-ness due to reduced renpl medullary toni.Lty.

All of these disorders can be readily distinguished ina single outpatient visit with the exception of nephrogenicdiabetes insipidus, true diabetes insipidus and compulsivewater drinking. An adequate history, urinalysis, bloodurea nitrogen, glucose, potassium and calcium will for allpra.ctical 7'uzoses allow the physician to narrow thediagnostic possibilities to the three disorders.

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TABLE, i

CLASSIFICATION OF '.'( .URlA

Polywuria with dimi,Ashed vasopressin secretionInability tc secrete ADH - true diabetes insipiduw

"¶umo.sGranulomatous diseaseSurgery and traumaHereditaryIdiopathic

Physiologic suppression of ADHPsychogenic polydipsiaLesion of the thirst centerPharmacologic suppression with alcohol

Polyuria of renal originRenal unresponsiveness to vasopressin

Nephrogenic diabetes insipidusHc-.ditary anatomic defects -cystic disease of the kidney.medullary cystic disease

Inflammatory disease - glomer•lo-nephritis, pyelonephrutis

Toxic - hypercaicemia, copper Lnd: ry poisoning

Fanconi •vndrome,ypokalemlrMis%;.Psneous - irklecell diseat-,

cystim,.is, rct2J arterial diseaseIncreased solute output per nephron

(Osmotic diuresis)Chronic nephritisGlycosuriaMannitolSalt diuresis following relief of uripary

obstruction

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Nephrogeric Diabetes Insipidus

Nephrogenic diabetes lnsipidus is a hereditary disordermanifested by unresponsiveness of the distal ttibular cells tonormal endogenous vasopressin secretion. Half of the maleoffspring of heterozygous female carriers are affected butthe sons of affected males are not, while the female hetero-zygotes may have a partial defect; ail of this is in keep-ing with an X-linked mode of inheritance. It has beenpostulated that all cases in North America are descendants offemale Ulster Scottish settlers who arrived In Halifax, NovaScotia on the Flcpewell in 17610 The patients have polyuriaand polydipsia from infancy and, if unrecognized, developchronic dehydration and resultant mental deficiency. Al-though they are unresponsive to vasopressin, they willfreqpently have a reduction in polyuria on treatment withthiazide diuretics and a low-salt diet. The history isusually suggestive although hereditary pituitary diabetesinsipidus may be confused with the nephrogenic type.Patients with psychogenic polydipsia and even with truediabetes insipidus may be relatively unresponsive to vaso-pressin after prolonged high intake of water and medullarysolute washout but will respond after a period of reducedwater intake. Patients with nephrogenic diabetes insi-pidus have no increase in cyclic-3',5'-AMP in the urineafter vasopressin. Those who normally respond to ADH dohave this increase, and this difference may become a tech-nique for distinguishing between nephrogenic type true diabetas_nesipidus.

Differentiation between Diabetes Insipidus and Compulsive Water Dnnlang

Since there are methods of determining vasopressin inplasma by rat bioassay of antidiuretic activity and by radio-

im•unoassay, it should be relatively simple to diagnose dia-betes insipidus by confirmation of a lack of vasopressin aftera perioc of dehydration or saline infusion. Unfortunately,the current assay methods are not sensitive enough to givediagnostic assistance; therefore a number of indirect testsmust be used. The occurrence of poly,.ria and polydipsiafollowing head trauma or pituitary surgery, or in the presenceof a brain tumor or eosinophilic granuloma does not lead to

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much difficulty in diagnosis but a large percentage (30-45 per-cent) of cases are idiopathic.

Distinguishing the initial event - polyuria or polydipsiahas been considered an important diagnostic clue, but this canbe a challenge in a patient with no other evidence of organicillness. A preference for ice-water and abrupt onset of poly-uria followed by polydipsia in the patient with diabetes In-sipidus is a helpful clue (polydipsia which precedes polyuriais more gradual in onset and these patients usually have otherevidence of emotional disturbance, i.e., psychogenic polydipsia).These findings are not constant, however, and can only suggestthe diagnosis; neither is there anything characteristic onphysical examination. A comparison of serum and urine osmola-lity will i-ule out diabetes insi.pidus when the urine osmolalityis higher than that of the serum in the hydrated patient, but

* this will not differentiate most patients with psychogenic* I polydipsia as they also have low urine osmolality in the hy-

drated state. The serum osmolality tends to be lower thannormal in the compulsive water drinker and highe.: than normalin the diabetes insipidus patient but there is considerable over-lap.

Several tests have beer devised to confirm the diagnoeisof diabetes insipidus and each has its difficulties - bothin performing the test and in interpreting it. The salineinfusion test first described by Hickey and Hare, with subse-quent modifications, most notably those of Carter and Robbins,is essentially a stimulus to vasopressin release by increas-ing plasma osmolality with hypertonic saline. In the hydrate('normal subject or compulsive water drinker a 75 percent ae-crease in urine flow rate and a rise in urine osrolality isexpected. Variations in results may be due to previous degreeof hydration, individual sensitivity and the rate of infusion.The infusion may cause an osmoti.c diuresis with false positiveresults in psychogenic polydipsia or it may be inadequate tostimulate antidiuresis. There is also the danger :f producingcongestive heart failure due to salt and fluid overload. Forthese reasons, saline infusion tests are not the best means ofdiscriminating between psychogenic polydipsia and true diabetesinsipidus and should be reser-red for those few in whom thediagnosis is not clear after a water deprivation test.

The use of nicotine to stimu)ate vasopressin release hashad its advocates, but it is unreliable, is accompanied by

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unpleasant side-effects, and wAll not be considered further.

The water deprivation test, is preferred as the mostusefui diagnostic test for the diagnosis of diabetes insip-idus. Its stimulus is the most physiologic and, if properlydone, is safe and sensitive. The patient should be restrictedto a daily fluid intake below three liters for a week beforethe test, since prolonged polydipsia reduces renal responsive-ness to ADH. A method for performing the water deprivationtest is given in TABLE II. The patient with true diabetesinsipidus will remain in a negative water balance with lowurine osmolality and serum osmolality rising above 300 mOsM/kg. He may give evidence of clinical dehydration with tachy-cardia and hypotension and, if severe enough, the glomerularfiltration rate will fall. This may cause a rise in theurine osmolality above that of the plasma with a false nega-tive test result, but this may be prevented by discontinu-ing the test if blood press-re falls significantly or de-hydration reaches five percent of body weight. The patientwith psychogenic polydipsia may experience severe anxietywith water deprivation and may surreptitiously drinkwater despite instructions to the contrary. It is, there-fore, imperative that patients be constantly observed dur-ing dehydration. If prepared with partial water restric-tion, the compulsive water drinker will raise his urineosmolality to above 600 mOsMAg. This increase in urineosmolality may begin early in the test period and steadilyprogress. His urine volume will be reduced and the bodyweight and serum osmolality will usually stabilize. Thepatient with severe diabetes insipidus will not toleratedehydration for long and an adequate weight loss occursusually within four to eight hours, at which puint vaso-pressin injection will cause a 50 percent or greater in-crease in urine oamolality. Failure of urine osmolalityto rise above plasma osmolality on dehydration and failureof a further rise with vasopressin is diagnostic of nephro-genic diabetes insipidas. The psychogenic polydipsia patientmay take considerably longer for adequate dehydration andthat is why a standard length of time for the water depriv-ation test will not pick up some of these patients.

The greatest problem has arisen in making the diagnosisof partial vasopressin d,'ficiency. In this group is prob-ably the Lajority of diabetes insipidus patients. Theresponse to 14lydration in these patier.ts ranges from levelsindicative of Cevere diabetes insipidus to elevations in

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TABLE II

EVALUATION OF PATIENT SUSPECTED OF DIABETES INSIPIDUSMethod for Performing Water Deprivation Test

Initial workup - History, neurological examination, skull roentgenogram, visual fieldstudies, laboratory tests including plasma and urine osmolality, complete bleadc',ll count, urinalysis, fasting blood sugar, blood urea nitrogen, creatinisc. and,ithers

By these studies the diagnostic possibilities are narrowed down to true diabetesinsipidus. nephrogenic diabetes insipidus, and compulsive water drinking (in-cluding psychogenic polydipsia and the rare patient with a thirst center lesion)

Water Deprivation Test

-+ Restrict fluid intake to 3000 cc daily for one week, or 1500-2000 cc for threedays preceding the test (a small amount of vasopressin may be used).

Begin test in early morning. Have patient void and record weight: detei,mneurine and serum osmolality. (Other measurements of hydration and soluteconcentration, such as hematocrit, serum sodium, and urinary gravity aresuperfluous.)

SAfter starting test, allow patient to have no fluid intake (he may wet mouthwith no more than 30 cc of water per Pour or ice chips). Supervise himconstantly.

SDetermine urine output+ urine osmolality, and post-voiding weight every hour.Determine serum osmolalit) every two houis.

UNDPOINT OF TIST. When .... (a) serum osmolality exceeds urine osinolality:

(b) weight loss is greater than five percent of body weight, or (c) hypo.tension develops., whichever comes first.Urine osmolahitv failing to surpass plasma osmolahty is inlhcative of truediabetes insipidus or nephrogenic diabetes intipidus

If serum osmolahty does not exceed the urine osmolality.Inject 5 u aqueous vasopressm subcutaneously and measure urine outputand osmolahty for several hours.

Response to rasopressin is diagnostic of true diabetes instpidus and lacAof response is diagnostic of the nephrogenic type. If serum osinolalitYis exceeded bh urine osmolalitv, it usually indicates compulsive waterdrinking but a further elevat;on in urine osmolahty after exogenous vaso-pressin suggests partial diabetes insipidus

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Diabetes Insipidus - ELichner

urine osmolality undistinguishable from. normal. A furtherrise in 'rine osmolality with exogenous vasopressin on com-pletion of water deprivation has been proposed as a meansof diagnosing partial diabetes insipidus with high urineosmolality as opposed to psychogenic polydipsia. It hasbeen the practice in the past to push for a diagnosis inorder to prevent the compulsive water drinker from under-going a lifetime of painful injections. With the recentadvent of chlorpropamide (DiabineseG) therapy for partialvasopressin deficiency and lypressin (synthetic lysine-vasopresein) nasal spray, the treatment is not as difficultfor the patient and is certainly cheaper than psychotherapy.

SUGGESTED READING

Textbooks

Kleeman CR, Vorherr H: Water metvbolism and the neurohypo-physial ho-mones. IN Duncan's Diseases of Metabolism.

, Bondy PK (e(A Philadelphia: WB Saunders, 1969 p0 1103-11h9Leaf A, Coggins CH: The neurohypophysis. IN Textbook ofEndocrilo. Williams RH (ed). Philadelphia: WB Saunders,

Pertin rt ArticlesBarlow ED, DeWardener HE: Corpulsive water drinking.Ciuart J Med 281:235-258, 1)59

Bode HH, Crawt.ord JD: Nephrogenic dibhetps lnsioidus l-iNorth Anaerica. The Hopewell hypothesis. New Ir J Med2,0:7?5)0754ýh, 196)

Brown WE Jr, Rynearson EH: A orocedure for the diLgnosis ofdiabetes insipidus. Proc Staff Meet. MaLo Cinic. 19:67-68,

Cartoer AC, Robbins J: The use of hy-ocrtonic al.ie ii ej,in the difrerentinl dtapriosis of di' hetes insiuidus andpsychogenic polydipsia. J Clin Endocrinol 7:753-766, 1 907

DeWardener HE: Polyuria. J Chron Dio 11:1'))-212, 1960Dies F, Ran:ol S Rivera A: Differe:itid'- di.-nozis bet*.'eendiabetes insipicus and compulsive Tolydi*r-uL. Ann Intern ?M½'!Ps:!0o-7np, 1961

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146 ~Diabetes Insipidus - Eirkner

dui~.-i eneud V: l!br-ione's ýf the narvali-1i jo-t.:<ru,:-Iand and th~eir nitura!ily viccurririg anplh)i-nez 4) ;

Rtv Har, ih K: The renal excretirin or' chI 'ri. 4r torndin i~e i-nuipidnur. J Cl1in Invest Z3):7'Y0-77E', 1 ),

Mliler M~, DalakoF T, MosJes AM, 4'e1ern!-n ii, "r3tefet.iv 11:f

Re(-rM' 'gt~i-n of Pa;-tial detectc in -niidi-ro~tic hor'ev':,-en re ti -)n. t:±in Intern Med 73-721-729, 1?7'i

J"AM4A 20~3:8)2-103, i'ý68Mozes AM, Street~en WPl: Dlifferentiation of piAyuric !%vtes

by mneasure-nent of responses tc changes in plis~ia osmý'la~lit~yInd'iced by hypertonic saline infusions. A-nor J Med 1.42:369-377),1967

Price JDE, Lauener N: Serum~ and urin~e -,s-io1:;lit!ies in thodifferential diagynosis of po1.yiric states. J Clin E.ndc-rirol26:14~3-1011 i?66- - _ ___

rhom~s WO. Jr: Diabetes Insiniduas. J Clin Endocrinoil

Cuttle --': Diabetes insipidus. A-ner Heart J 49: 577-ý'91, 1-65Utiger RD: Disorders of ADH secretion. Med CIIi N A--,er

of antidiuretic hormione. Amer J Mcd ~:5-i1 ~Mlilttple aut~hor-3hip. Symposium on antidi'iretic hormione.

Amer J Med Miy 1967. Entire i~z91e.

Present Concepts., Vol IV No 2, Februari' 1971

147

PATHOPHYSIOLOGY OF THE THYROID GLAND

MAJ N.M. Panagiotis, MC

Over a century has passed since Graves' recorded the his-tory of a young girl with exophthalmos and hyperthyroidism.Since that time this small gland has been the focus of investi-gation by a parade of distinguished physicians and scientists.Consequently more is known about the physiology of thyroidgland than any other endocrine gland. It is the purpose ofthis review to try to provide some of thi.s information in amanner which helps the clinician evaluate patients with thy-roid disorders. We will deal primarily with extremes offunction -- hyperthyroidis and hypothyroidism. An attempthas been mado to review briefly the pathophysiology of thesedisorders, provide meaningful information to help in thediagnosis, and review some principles of therapy.

Embryology and Phylogeny

In Its embryogenesis, in certain aspects of its function,and in its phylogenetic development, the thyroid gland revealsits primitive relation to the gastrointestinal tract. Thehuman thyroid anlage is first recognized at about one monthafter conception when the embryo is approximately 3.5 to 4.0DR in length. Normally the thyroglossal duct dissolves :ndfragments about the second month after conception. Fvidencesuggests that fetal thyrotropin (i.e., thyroid stimulatinghormone, TSH) influences the rate of anatomical maturationof the thyroid. later in fetal life the thyroid is definite-ly responsive to TSH because fetal goiter occurs when themother is given a goitrogen, although maternal TSH does notcross the placental barrier. Functional differentiation ofthe gland occurs concomitantly with anatomical developmentand its chronology follows the sequence through which thethyroid hormones are normally synthesized in the mature gland.

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Pathophys;ology of the Thyroid Widand - Panagiotis

Anatomy

The thyroid is normally one of the largest endocrineorgans. It weighs approximately 20 grams in North Americanadults. The normal thyroid gland is comprised of two lobesJoined by an isthmus. The right lobe of the thyroid is nor-really more vascular than the left, is often the larger of thetwo, and tends to enlarge more in disorders associated withdiffuse increase in slse.

Major Aspects of Normal Thyroid Hormone Economy

Formation of normal quantities of thyroid hormone ultimately depends upon the availability of adequate quantitiesof exogenous iodine. The sources of iodine are dietary andperipheral deiodination of thyroid hormones; and the avenuesof iodide removal are via the thyroid and kidney. The appor-tionment of iodide between the thyroid and kidney is a functionof their individual accumUlative capacities for this anion.Such activity can eminentl.v be expressed by the conventionalclearance concept which reiates the amount a',umulated perunit ti•e to the plasma c icentration. Since, under mostcircumstances, renal clearance of iodide is constant, homeo-static adjustment to maintAin normal iodide accumulation aremrdlated by changes in thyroid clearance sites.

IntrathyroidaJ iodine metabolism is a comple, of stepsleading to the end- product which is production of thyroid hor-mones, thyronine (T4 ) and triodothyronine (T3 ). These six

steps include: active iodide trunsport; organic-bindingwhich yields monolodothyrosine (MIT)and diiodotyrosine (DIT)in thyroglobulin; coupling which yields thyronines, mainlyt.,rxine (T4 ) and 3,5,3 trilodothyronine (T3) in thyroglob- .ulin; storage wnich is a unique feature of thyroid gland;proteolysis which allows the release of MIT, DIT, T4 and T3from peptide bonds; and delodination of MIT and DIT which Isthe process of partial re-utilization and partial loss ofresulting iodide.

The nature, physical state and tarnover of thyroid hor-mones in the blood, includes the components of venous effluent

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Pathophysiology ol the Thyroid Gland. Panagious

from thyroid T4 , T3 , iodine and binding of hormonal product,i.e., thyroxine bindin globulins (TBG); and thyroxine bind-ing pre-albumin (TBPA) and albumin. The nature of the inter-action is a reversible binding of equilibrium of the type T4

plus TG O T 1-TBG coqlex. The intensity of the interactionreveals that f4 binds firmly with 99.95 percent bound and 0.05percent free. Tr'iiodotbyronine (T3 ) is not bound by TEPA,and binds weakly to TUG.

A mass of evidence, which will not be reviewed in thispaper indicates that only the free hormone is available totissues and is metabolioally active and susceptible to degre-dation, while the bound hormone acts as a metabolically inertreservoir. Additional evidence indicates that homeostaticmchanims, when wrmally operative, are sensitive to a normalconcentration of free hormone in the blood and seek to defendit, even though the total and protein-bound hormone may berequired to change when achieving this end.

In the case of T4 , an asount equal to %hat contained in

about one liter of plasea is cleared by peripheral tissueseach day. In the case of T3 , the clearance rate is aboutseven liters per day. Therefore, even if the hormones weresecreted in equal amounts, the concentration of T4 in theplama would be •a~ times greater than the concentrationof T3 . Actually, less T3 than T4 is secreted and so the ratioof T4pT 3 in the plam. exceeds 7:1. Because of its rar4 .dturnover, physiologic replacement doses of T3 , or even dosessufficient to produce thyrotoxicosis, do not materiallycontribute to the easureable concentration of thyroid hor-mono in the blood.

The peripheral degradation and metabolism of thyroidhorzmo is primrily delodination r ill 1tissues. In theliver, biliary excretion occurs la % vcuaa :#i suas glucurnide as vell as sulfate esters.

The homeostatic regulation of thyroid function normallyadjusts to meet the needs of peripheral tissues. The feed-back regulation of TSH secretion is affected by free T4 and

free T3 . These hormones probably effect the hypothalamicTSH releasing factor (T;W); there is also a direct inhibitionof TSH production. An autoregulation exists within the thy-roid itself. There is an inverse relation which existsbetween (a) the glandular content of organic iodine and (b)the activity or hormone-forming processes and their respon-aiveness to TSH.

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Ammsient of Thyroid Hormone Economy

Virtually every aspect of thyroid hormone economy issusoeptible to investigation, although some do not lendthemelves well to study in a clinical setting. For clin-ical use, procedures fall into four major categories. A.Tests of thyroid function per M; B. Tests related to theoncentration and transport of hormones in the blood; 0.Tests Uhich assess the metabolic impact of thyroid hormonesin tissues; and D. Tests which assess the integrity ofbamostatio mecham s.

TESTS OF THYROID FUNKTION, . se1311 labels endogenous non-radioaotive iodide 1271 in

the extraollular fluid (EGF). The fraction of a dose of

LI which is accumulated in the thyroid therefore indicatesthe proportion of endogenous iodode within the EuF whichenters the thyroid. It doe. not neasure the absolute amountof iodine which enters the gland. In a steady state,, per-cntage uptake approximates the percent of the iodine intake

which is aocumulated within the thyroid. The percentage up-take in any ocndition is a function of the relative magnitudesof the thyroid and renal clearance rates. Factors which in-fluenos the 1311 uptake are, In general, (1) exogenous thy-roid hormone which usually suppresses the uptake; (2) factorswhich affect glandular hormone content, including the anti-thyroid drugs; (3) and normality of intrathyroidal iodinemetabolim.

MWASUREMENT OF HORMONE CONCENTRATION

Tests which measure directly the low concentrations of

intact thyroid hormones in the blood are generally availabla.Sensitive methods are also acailable to measuxe the iodin#,which the thyroid hormones contain. These inciude proteinbound iodine, butanol-extractable iodine, total iodine, andtotal T4.

Protein-bound iodine P)usu y is a measure ofiodine in T4 bound ra er firmly to surface of aprotein molecula, but is not an integral part ofthe molecule itself. Normally, PBI is 4-8 ug/lO0 ml.

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PathophYsiology of the Thyroid Gland - Panagiotis

.Butanol-extractable iodine (BEI) is in the bloodwhen acid butanol splits T4 and T3 from bindingproteins; then these, with iodide, are extractedfrom serum into butanol. Iodide is removed frombutanol by an alkaline wash, leaving T4 and T3

in butanol. Normally, BEI is no more than 0.6peroent lower than PBI.

Total Iodine is the measurement of all forms ofiodine - Tj, T3 iodide, exogenous iodinatedcompounds, abnormal endogenou- products. Normally,it is no more than 1.0 ug/lO0 ml greater than PBI.

LTotal TA is now measured by a binding displacementmethd frot described by W,•phy-Pattaee It has

the advantage of eliminating exogenous 13lI contam-ination. Its disadvantage is that it is a difficult

test to perform and expensive. However, this is thethyroid test of choice. Range is 1-2 ug/l00 ml lowerthan the PBI. A column method is also available, butdoes not exclude contaminants as well as Murphy-Pattee.

AJSSF SfENT OF HORMONE-BINDING INTERACTIONS

Electropheretic analysis of individual binding proteinsassesLes the endogenous distribution and the binding capaci-(TBG, 18-25 ug T4 /100 ml serum; TBPA, approximately 200 ugT4~/100 m.1 serum).

The measu,"ment of free T4 is indirect and performed onan experimental basis. It is normally 0.05 percent of thetotal T4 . There is a formula to assess the absolute concen-tration of free T4 (assume PBI is composed only of T4 iodine).

PBI/0.66 = concentration of T4concentration of T4 3 % free - concentration of free T4 .(Normally 2.5 mug/l00 ml serum)

Another indirect assessment of thyroid function is theT4 index. This is based on total T4, and the in vitro uptakesof 1311 labeled T3 . (T4 x T3 uptake = T4 index). The index

is increased in hyperthyroidism and decreased in hypothyroidism.

The percent of a hormone in the blood which is unboundvarles directly with the concentratinn of the hormone and in-versely with both the concentration of the individual bind-ing proteins and their spe 'ific affinities for the hormone in

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question. The concentration of free T4, rather than the pro-portion of free T4, is closely related to the metabolic state.However, the proportion of free T4 may be a helpful diagnosticindex. TABLE I.

FACTORS WHICH ALTER THE CONCENTRATION OF HORMONE IN THE BLOOD

Sinoe the removal of thyroid hormones from the bloodoontorms 4D a first ozder reaction (constant percent per unittime), c' inges in hormone secretion will result in comparablechanges in circulating hormone concentration. Cionsequencesof increased secretion will result in (1) increased hormonein blood with no appreciable change in TBG; (2) increase inPBI; (3) increased peroentage of free T4 (increased frac-tional T4 turnover); (4) increased absolute T (increasedtotal T4 turnover and thyrotoxicosis); and (5) increased in3itr uptake of T4 and T3 . Consequences of decreased secre-tion are the converse of (1) through (5).

In these situations, homeostatic mechanisms are inop-erative, usually because of underlying thyroid disease. Theconcentration of free hormone is not defended and hyperthy-roidiam or hypothyroidism ensues.

When there is primary alteration in binding proteins,there is no malfunction of homeostatic mechanisus, merely achange in the activity (presumably in the concentration) ofone of the binding proteins. Therefore, a normal concentra-tion of free T4 and a normal metabolic state can be defended.

Primary changes in hormone binding appear to influenceto concentration of hormone in the blood and the kinetics ofits turnover, but do not basically alter the metabolic statusof the patient, ý3linically they have significance becausethey affect laboratory tests commonly used in the diagnosisof thyroid disease.

The factors which produce alterations in binding proteinsare (1) increased TBG -- pregnancy, estrogen administration,contraceptive steroids ("the pill"), estrogen-producing tumors,hydatid moles, acute hepatitis, acute porphyria, familial ilio-pathic syndrome; (2) decreased TBG --- androgen administration,anabolic steroids, D.ilanti*)and derivatives, familial idiopathicsyndrome, nephrosis; (3) increased TBPA --- none are known; and(4) decreased TBPA - salicylates and congeners, se-ere nonspecific illness (malignancy, infection, surgery, etc).

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TABLE Z

USUAL RESULTS OF COMMONLY EMPLOYED LABORATORY TESTS -

IN VARIOUS THYROID CONDITIONS

""I %FREE T4 or T3 TSHUPTAKE T 4 TONI BEJ IN VITRO T3 BMR SUPPRESSION STIMULATION

Iodine Defic:ency NJ N.4 N. N,, NJ N ...Iodine Exces

(eumetabolic)Iodide 4 N t N N N ....

Ogiic dyes 4 N f t N N ... cc.Iodide Myxedema 4 4 t 4 4 4 No response

Biosynthetic Defects Vaiklble Nj N, t, 4 N, 4 N.4 N.4

Thyrotoxicosis FactitiaT4 o, Desiccated

thyroid 4 " t t t ... 1 ,.PBIvariable

T3 4 4 4 4 4 t t13i• PBIFunctioning Adenoma

Non-toxic NJ, N N.t N N N AbnormalToxic t t t t t t Abnormal

Toxic MultinodulaA

Goiter tN t t t t t Abnormal

Diffuse Toxic Goite

Active t t t t t t Abnormal ...Latent N, t N N N N N Abnormal ...

Inactive N N N N N N N

Active Ophthal-mopathy(non.toxic) N, t N N N N N Abnormal

Myxedema

Primary 4 , , 4 4 1 ... No responsePituitary 4 4 4 4 4 .. t 3 , 1,PBI

Hashimoto's Disease variable

Eumetabolic Nj N N,t N N N N

Hypometabolic ' ,N , 4,N 4 4 4 N No response

Decreased Thyroid

Resew N, NJ. N, 4- N,4 N W, N. response

Subacute Thyroiditis I• ",t t ,N Nt N, N, ... Variable

N VTE- Where more thaas one result is iridica, sd, the first is the more common,Ellipsis (... ) denotes tet a oot indicated for diagnostic puiposc,,

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There are also non-hormonal factors which influence themasureents of hormone concentration and it is important todifferentiate between (a) protein-bound iodine in which theiodine is part of a molecule (such as T4 or iodinated dyes)which is bound t_. the surface of a protein molecule and (b)the variety of iodine-containing proteins (iodoproteins) inwhich the iodine is part of an iodinated amino acid which,in turn, in an integral part of the amide skeletion of theprotein itself. The factors which increase apparent hormonecontent are (1) endogenous iodoproteins -- thyroglobulin andalbumin-like iodoproteins, which are secreted by thyroid, butare hormonally inactive. These are found in Hashimoto's dis-ease and in some cases of non-toxic goiter; measured in PBI,but not in BI; (2) pharmacological doses of iodine resultin increased total iodine, increased PBI (iodoprotein formed),and have no effect on seru= thyroxine or on T4 by binding dis-placement wthod when carefully administered; (3) organiciodinated rlyes, such as those used for contrast media, whichbind to plamna proteins (are extracted into butanol and notre-extracted into alkaline wash) and therefore increase totaliodine, PBI and BEI but not total thyroxine; and (4) iodinecontaining medications which generally act like inorganiciodide.

Mercurial diuretic complex with iodino and interferes withthe measurement and decreases the apparent hormone content.The factors indicated in this section do i•ot interfere withthe interaction between the thyroid hormones and their bindingproteins, b( cause even those which are bound to protein, suchas x-ray contrast media, are bound to albumin, rather thanTBG and TBPA. Therefore. they do not interfere with testswhich assess theae interactions, i.e., percent free T4 , invitro uptake tests, or total T4 measured by Murphy-Patteemethod or theoretically by column.

TESTS WHICH ASSESS THE METABOLIC IMPACT OF fHYRO , ORMONFS IN TISSUES

The basal metabolic rate (C4R), whlc- sures the rest-ing energy requirer -'t, varies directly wi e quantity ofthyroid hormone available to "Issues, and iF so influencedby other hormones (epinephrine, glucocorticoids, growth hor-mone). Normally the BMR ranges from -10 to dO0 Dercent.

There are sources of pcspible error. An inoryase in the

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ENR is caused by the patient's smoking, e•,ing, anxiety,fever, dyspnea, or shivering. There is a4 so an i::rease inthe 3HR if he has heart failure, pheochromocytoir, a perfo-rated ear drum or an acromegalic terdency; or there may bean outward leak In the apparatus. There is a decrease inthe EM if the patient is starved, has a thiamine deficiency,Addison's disease, or nephrosis; or there may be an inwardleak in apparatus, i.e. poor soda lime. Serum cholesterolis increased in hypothyroidism and tends to be decreased inhyperthyroidism, bat this is not pathogomonic. Normally,it ranges between 120-250 mg/100 ml.

TESTS WHICH ASSESS THE INTEGRITY OF HOMEOSTATIC MECHANISMS

Suppression TestsThe suppression test is a method of evaluating the integ-

rity of the hypothalamic pituitary thyroid axis. Exogenousthyroid hormone normally suppresses secretion o" TSH and leadsto a decrease in thyroid 1311 uptake. Usually T3 is used (75ug for 2-3 weeks), however, T4 can also be used. The latterthe advantage that the drug is given in one dose and evalua-tion of radioactive iodine uptake is performed in seven days.When TSH secretion is inhibited, secretion of T4 by the thy-roid is slowed and T4 concentration in the blood declines.This parameter is lost with the use of the 24 suppressiontest. Since T3 does not contribute materially to the FBI,the FBI decreases. Either the FBI or 1311 uptake responsecan be used as an index of thyroid suppression with the useof T3 . A normal suppressive response is reflected in a de-crease of TMWuptake to less than 10 percent or less thanhalf of control value, and a decrease of FBI or T4 into sub-normal range. An abnormal response signifies breakdown ofhomeostasis possibly caused by autonomy of thyroid function,absolute or relative autonomy of suorathyroidal regulation,or presence of an ectopic thyroid stimuaator. It is almostuniversally accepted that a patient with a normal suppressionresponse cannot be thyrotoxic. However, in some circumstances(i.e., Graves' disease and hyperfunctioning adenoma) an ab-no-m.al suppression response may be present without thyro-toxicosis. The test is most useful in diagnosing borderlinehyperthyroidism and in evaluating therapy.

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TSH Tests

The TSH test methods and normal responses are highlyvaried, but their potential of assessing the ability of thy-roid to increase its level of function makes their use sig-nificant. When the 1311 uptake reflects an expected increase,it indicates ability of the thyroid to increase new hormonesynthesis. Uptake may be absent when the gland is rich inorganic iodine, for example, when plasma iodide concentrationis high. When the PBI reflects an expected increase, it in-dicates ability of the thyroid to enhance release of pre-formedhormone. FBI may be low when glandular hormone stores are low,for example after absence of T.3H s÷t.4"* 1 +inn.

These tests are clinically useful to differentiate theprimary form pituitary myxedema, to evaluate function capacityof thyroid during thyroid hormone therapy, and to diarvnosedecreased thyroid rv.rve.

PATHOPHYSIOLOGY OF MAJOR THYROID DISEASES

Non-toxic Goiter; Sunple Goiter; Colloid Goiter

Goiter is not a single disease, but a group of diseasesof diverse etiologies manifesting themselves via a final com-mon pathophysiologic and pathological pathway. There are twobasic pathogenetic prerequisites: (1) a thyroid gland whichis, anatomically, intrinsically normal at the onset, (2)superimposition of any of a variety of factors which impairthe capacity of the gland to synthesize adequate quantitiesof active hormone. Compensatory TSH response leads to goiterformation and stimulation of those processes in hormone bio-

syLthesis which are uniinvolved in the basic disturbance.Usually, this compensatory response makes possible secretionof adequate amounts of hormone, so that the patient is euthy-roid, but goitrous (non-toxic goiter). In some instances,when the impairment of synthesis is severe, the compensatoryresponse is inadequate and the patient is hypotnyrold (goi-trous hypothyroidism). Thus the metabolic state of the patientwith these disorders may range from severe hypothyroidism tonormal. The cau&es are both extrinsic and intzinsic.

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The extrinsic factors are dier habits permitting io-dine deficiency (and resulting in classical endemic goiter,but rarely causing hypothyroidism, except for endemic cretin-im,, the precise pathogenesis of which is not understood),a-d dietary goitrogens (comuing from plants of the Brassicaseries, cabbage, turnips, mustard and others, or beingtransmitted through animal vectors, suorh as milk from animalsgiven goitrogenic feed); and pharmacolorical agents, includ-I "Z comon antithyroids. para-amino-salicylate, :.esorcinol,phanylbutazone, ccbalt (possibly most goitrogenic in children),and iodide. In a =all proportion of peculiarly susceptibleindividuals, iodide in large doses acts as a goitrogen, pro-ducing a sustained blockade of organic binding (iodide goiteror iodide myxedema). The precise pathogenesis is not under-stood, but this zesponse to iodide is especially prone tooccur in the fetuses of mothers given iodide during pregnancy.The major action of the other goitrogens cited above is alsoto block organic-binding and coupling.

The intrinsic factors include a numtar of biochemicaldisorders involving discrete steps in hormone synthesis,storage, §r release. The biochemical lesion is usually inbornand familial. When severe, it is usually manifest in child-hood as gcitrous hypothyroidiem. When less severe, it is man-ifest as non-toxic goiter, often not discovered or prominentuntil times of "thyroid stress" during adolescence, pregnancy,or menopause.

In these disorders, laboratory findings are exceedinglyvariable in view of the diverse etiologic factors and varyingseverity of the physiological lesions. Some of the most char-acteristic results are listed in TABLE I. Treatment is thyroidhormone to block the stimulus (TSH). If this is not successfulor if there is mechanical obstruction of the underlying anatom-ical structures then ablative therapy is recommended.

Msorders Associated vAt4 Thyroi ltoxicosj,

Thyrotoxicosis is a syndrome, not a disease, and is pro-duced by an oversupply of thyroid hormone to the tissues.These include thyivtoxicosis facticia - i.e., an over-ingestionof thyroid hormone, and struma ovarii. The latter is rare.In addition, one may have a p*tient with hyperfunctioning ade-ncoa ("hot nodule"). This is a benign adenoma which does not

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require TSH stimulation. Hormone secreted by adenoma suppres-see TSR, so the remainder of gland is hypoactive and atrophic.The 1311 uptake is increased in the adenoma and the uptake insurrounding tissue stimulated by TSH. Not all adenomas ofthis type produce thyrotoxicosis. Some secrete quantities ofhormone approximately equivalent to normal output ("warm nod-ule"). The laboratory data are reviewed in TABLE I. Themost important group of disorders in thyrotoxicosis are thoseof Graves' disease or diffuse toxic goiter ---- a diseaseclinically characterized by goiter, thyrotoxicosis, and ex-ophthalmos. However, the thyroid amn ophthalmic manifesta-tions may antecede one another by years or may never co-existin the same patient. Another feature of the disease is atendency toward cy.c'Lcity, either the thyroid or ophthali±'cmanifestations, or both, undergoing periods of activity orinactivity for reasons which are not known. An 5ntrinsicfeature of the disease is a breakdown of homeostatic regula-tion of thyroid function, as evidenced by an abnormal sup-pressive response to exogenous hormone. The disease may bestaged in three phases -- (a) active, characterized bythyrotoxicosis, active ophthalmopathy, or both, and an ab-normal suppression test; (b) latent, characterized by nothyrotoxicosis or active ophthalmopathy and an abnormal sup-pression test; or (c) inactive, characterized by no thyro-toxicosis or active ophthalmopathy and a normal suppressionteat.

The pathogenesis of Graves' disease remains unsolved.In the last decade a great deal of attention has been directed

F to thyroid abnormalities in particular the long-acting thyroidstimulating hormone tLATS). Accumulating evidence indicatesthat LATS is a gamma blobulin, that it is synthesized inJlymphoid tissue and that it interacts with thyroid microsomes.Lately its role as the cause of Graves' disease has come underattack and at present time the subject is controversial.

ainical Phcture

The clinical findings of Graves' disease are listed inTABLE II. It is important to note that the diagnosis isdoubtful without finding tncreased thyroid tissue.

Of interest, but rare is thyrotoxicosis resulting fromincreased production of T3 by the thb'roid instead of' T4 . lewmethods are presently being describe& including a T, radio-immunoassay which will allow the clinician to make this diagnosis.

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Therefore, if one presents with clinical picture of thyrotox-icosis and total T4 is normal or low, T3 toxicosis should besuspected.

Treatment

The types of therapy fall into two major categories:(1) blockade of hormone formation which includes (a) inhi-bition of iodide transport - thiocyanate and perchlorate;(b) inhibition of coupling and organic binding - thionamedes;(z) inhibition of hormone release - iodide; (d) inhibitionof peripheral effect - reserpine, guanethedine; and (2)ablation of thyroid tissue with radioactive iodine, subtotalthyroidectozy, or both.

Qiemothempy,

Of the drugs used in the blockade of hormone production,propylthiouracil and tapazole are used most often. Althoughthe dose of propylthiouracil varies with the patient, in gen-eral, dcsage will start at no less than 300 mg per day. Dosesas high as 1200 mg have been used. Since tapazole is 20 to30 times more potent than propylthiouracil, the dose is ac-cordingly smaller. The drugs are effective within two veeksand within six weeks patients are usially eumetabolic. *Re-actions to the drugs are numeroaa, of which agranulecytosisis the most serious. The long term therapeutic resulta havebeen unimpressive, with less than 50 praent of patalents re-maining euthyroid after 12 to i8 =ontha, of treatent, Thereis no intrinsic damage to the thyroid gland, and lating inyx-edema does not occur, w•hivh are adnntages; but ther*e arealso disadvantages - long period of t"eai nt and highrecurrene- rate when treatment is discontinued.

Swrgery

Subtota! tbMoidecv, ozy is P defindtive ablative proce:durewhich effectively removei hyperthyzoidiw,. The ýrurgical com-plications are well kmo-an. Urfortunately, the reduction inhypothyroidism is not significantly lees with surgery than.-ith radioiodine therapy.

Radii ýtheyqz~v

Si•iotherapy offers the advantA:es o" being economicaland :efinitlve. Ths dcoe uge is variable; but, in g-neral,

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is in the range of 140-160 uc/gm of tissue. The incidence ofleukemia and carcinoma of the thyroid is no greater when thesepatients are compared to the population as a whole. The com-plication of hypothyroidism is common in patients with thyro-toxicosis and in some series of treat sd patients has beenreported to be ab high as 70 percent of the group.

COMMENT

on the Cho,.: of Therapy

In patients not likely to be parents, the treatment ofchoice is radiolodine. The question of treatment remainsopen in the case of young adults. Since our experience intreating these patients with radiciodine is limited and ourknowledge of genetic damage sparse, it is generally acceptedpractice to treat them with surgery or antithyroid drugs.However, some communities are now using radioidine in thisgroup routinely, and are willing to handle the hypothyroidismwith replacement medications. Surgery is of course the treat-ment of choice in obstructive complications, but this shouldbe recommended only after thorough evaluation.

Disorders Associated with Insufficient Hormone Production

The syndrome which results from an inadequate supply ofthyroid hormone to the tissue is designated as hypothyroidismor myxedema, although the latter term usually connotes aseverer disorder. The clinical symptoms associated with myx-edema are noted in TABLE III. Hypothyroidism can be brokendown into two major classes: goitrous hypothyroidism and nongoitrous hypothyroidism. The former includes the severe var-iant of non-toxic goiter and Hashimoto's disease. The latterincludes the athyrotic patient (i.e., one who has an inadequatefunctioning thyroid mass). This group is comprised of patientssuffering from primary myxedema, postoperative mjxedema, andpost 1311 myxedema. In athyroitic varieties, the secrotionof TSH is increased. The laboratory findings are summarizedin TABIZ 1. In pituitar-j myxedema, the thyroid is basicallynormal but TSH is decreased. In differentiating between thetwo, TSH stimulation best :s useful. Hashimoto's thyroiditisdisease is the culprit 1.,1ich led to the current vogue of in-terest in immunological disorders. A variety of antithyroidantibodies is found in the sera of patients with Hashinoto'sdiseas3 but the role of these antibodies in the pathogenesis

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TABLE 11

INCIDENCE OF SYMPTOMS AND SIGNSOBSERVED IN 247 PATIENTS WITH THYROTOXICOSIS*

SYMVPOM PERCENT SYMPlTOM PERCENT

Nervousness 99 Increased appetite 65Increased sweating 91 Eye complaints 54Hypersensitvity to heat 89 Swelling of lep 35Palpkitation 89 HypetdefecationFatigue 88 (without dianhe) 33Weight loss 85 Diarrhea 23Tachycudm 82 Anorexia 9Dyspnea 75 Constipation 4

-Weakness 70 Weight pin 2

SIGN PERCENT SIGN PERCENT

Tachycardlat 100 Eye signs 71Goite4r 100 Atrial fibrillation 10Skin changes 97 Splenomeply 10Tremor 97 Gynecomastia !0Bruit over thyroid 77 Liver pahws 8

• Ingbar SH. Used with pennissfon.In other studies thyrotoxic patients with normal pulse rate have been observed.According to Williams. R.H. J Chn Endocrinol 6:l, 1946

TABLE III

SYMPTOMATOLOGY OF MYEDEMA*(77 Cases - 64 Women, 13 Men)

PERCENT PERCENTSYMPTOMS OF CASES SYMPTOM OF CASES

Wealkne s 99 Constipation 61Dry skin 97 Gain in weight 59Coarse skin 97 Loss of hair 57Lethargy 91 Pall'r of lips 57Slow speech 91 Dy 1j ea 55Edema of eyelds 90 Peripheral edema 55Sensation of cold 89 Hoarseness or aphonia 52Decreased sweating 89 Anorexia 45Cold skin 83 Nervousness 35Thick tongue 82 r.lenorhagia 32Edema of face 79 Palpitation 31Coarseness of hair 76 Deafness 30Pallor of tkin 67 Precordial pain 25Memory impairment 66

•lngbar SH Used with permnusron.

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of the disease is unclear. The functional abnormalities con-sist of mild defect of organic binding, and release of ab-normal iodoprotein. The course may be broken into two phases.In the early phase function of thyroid is increased --- ithas an increased tlI uptake and a higher PBI rate; however,the BRI or T4 and metabolic state is normal. Occasionally,the clinical and laboratory picture of thyrotoxicosis isseen in patients whose thyroid glands appear to demonstrateHashimoto's disease, both clinically and histologically.Here, the thyrotozicosis may disappear or be followed by hypo-thyroidism even in absence of treatment.

Subacute Thyroidltis

This disease, also termed giant-col!-thyroiditid, pseudo-tuberculous thyroiditis, or deQuervain's thyroiditis, is aself-limited and often a massively inflammatory disorder ofthe thyroid. The onset may be gradual or abrupt, but thespontaneous course is usually prolongid.

The functional abnormalities reveal a loss of biosyntheticfunction with 1311 uptake almost invariably kubnormai. Thereis a disruption of storage function with a release of preformediodoproteins and peptides which yields a high PBI. Occasion-ally active hormones are release, the BEI is high and thepatient transiently thyrotoLic. A markedly elevated erythro-cytic sedimentation rate is characteristib.

Treatment of Hypothyroidism

The result of treatment of hypothyroidism in the adultis generally one of the most gratifying to the physician be-cause of the ease and completeness with which the disease re-sponds to the administration of thyroid hormone. Treatmentis carried out with one of two general types of preparation:either synthetic hormone or thyroprotein dervied from animalthyroid glands. In the former category, both sodium thyroxine(levothyroxine) and sodium triiodothyronine (lLothyronine)have been employed. In the second category, desiccated thy-roid extract, USP, is most commonly used. The approximateequivalence of biological potency is 2 ! thyroid

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extract one grain (60 ag), levothyroxine (T4 ) 100 ug andliothyronine (T3 ) 25 ug. Recently a umiber of preparationshave been prepared compounding T4 plus T3 (T7 , if you please).These offer no particular advantages except the restorationof a normal PBI.

When first diagnosed, hypothyroidism usually has beenlong-standing and seldom requires prompt reversal. 3onsequent-ly, according to a consensus of authorities in the field, res-toration of a normal metabolic state should be undert+Akenslowly. It should be kept in mind that the untreated hypothy-roid patient is inordinately sensitive to smanl doses of thy-roid hormone. The initial daily dose therefore should notexceed 30 ag of tkyroid abstract or 50 ug of levothyroxine.,Xre should be taken in the hypothyroid patient with heartdisease and in the patient with long standing hypothyroidism,because over enthusiastic treatment may precipitate heartfailure or myocardial infarction or may provide relativeadrenocortical insufficiency in the latter. In these casesan initial daily dose of 8 or 15 mg of thyroid extract isrecommended. Thereafter the dose is increased 15 to 30 mgdaily until a maintenance dose and eumecabolic effect is a-chieved within three weekn. This usually requires 120 to 180mg of thyroid daily.

The interval between initiation of treatment and appear-ance of first evidence of improvement depends upon the sizeof dose employed. An early clinical response is a diuresis,followed by increase in pulse and blood pressure, increasedappetitie and decrease in constipation. Psychomotor activityincreases and delay of deep tendon reflex abates. Hoarsenessabates slowly and changes in the integument may reqllire monthsto disappear.

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REFERENCES

Textbooks

Ingbar SH, Woebor KA: Thyroid. IN Textbook of Endocrinolo•y, 4th ed.W4illiams iH (ed). Philadelphia: W.B. Saunders Company, 1968

Pitt-Rivers R, Trotter WR (eds): The Thyroid. London, Butterworths,1964

Other

Braverman LE, Ingbar SH: The metabolism of thyroid hormones as relatedto protein-oinding. J Chron Die 14:484-494, 1961

Ingbar SH: Physiological consideration in the treatment of diffusetoxic goiter. Arch Intern Med 107:932-951, 1961

Smart GA, Owen SC: Thyroiditis and hypothyrDidism. J Chron Dis14:537-543, 1961

Ingbar SH, Frienkel N: Hypothlyroidism Disease. Chicago: 7ae YearBook Publishers, September 1958

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HYPERPARATHYROIDISM

Ralph S. Codsmith, M.D.*

Ryperparathyroidism is, perhaps, a unique disease -it his long been convidered interesting, and even ex-citing, despite its being thought to be relatively un-comnon. This seems all the more unusual in view of ourlack of knowledge of the natural history of the disease,a fact directly attributable to the simultaneous publica-tion of the description of the disease and the method ofcuring it (surgical extirpation). /1/ Increasingly,evidence is accumulating that Aither the disease is notnearly so rare as we once thought or we are smack in themiddle of an epidemic. Although we do not perform analysesfor serum calcium routinely in our own institution, in 1969we recognized 165 patients with primary hyperparathyroidism.Indeed, our incidence (based on the total number of serumcalcium determinations not number of patients) was onediagnosis of hyperparathyroidism for every 250 serumcalciums! It has been reported previously /2/ that onein 800 patients coming through the door of a clinic inBliffton, Indiana, had this disease, diagnosed solely one basis of routine measurement of serum calcium. Our owndata are incomplete in this regard, but it is clear froma small survey which we performed on a series of patientsundergoing routine health eaminations that the incidenceof this disease may be even higher than one in 800.

The foregoing is intended to make the additional pointthat a good serum calcium determination is an important main-stay in recognition of at least the majority of these patients,irrespective of whether or not one requires the presence ofhypercalcemia to make the diagnosis. As reported previouslyfrom this institution, even before the advent of superioranalytical techniques such as atomic absorption spectrometry,a careful laboratory can have a narrow normr-1 range of serum

*Director, Clihncal Study lnit. Mayo Clinic, Rochester, Minnesota

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calcium. /3/ Without going into great detail about thesedata, it suffices to emphasize that we consider a serum cal-cium of 10.2 mg/100 cc as representing hypercalcemia (thisvaries a little with age and sex). Furthermore, this degreeof hypercalcemia may be enough to warrant parathyroidectomy.

A few words are warranted about our indications forsurgery, because we are following a protocol which is de-signed to teach us something of the natural history of thedisease, untreated and treated. Therefore, with the excep-tion of several specific indications for surgery, we areoperating on only half of the patients, but following aJ 1 ofthem closely. Our specific indications for surgery are:

(1) serum calcium in excess of 11 mg/100 cc

(2) roentgenographic osteitis fibrosa

(3) active nephrolithiasis (passage of gravel, growthor increase in number of stones during previous sixmonths

(4) impaired renal function

(5) associated, otherwise unexplained problems (recurrentpancreatitis, intractable peptic ulcer symptoms, ex-cessive gastric acid, psychogenic difficulties

(6) inability to "live with the diagnosis".

Without these indications, patients are randomly assigned tosurgery or follow-up appointments.

To date, the 'mtreated group ]h•R yielded some surprisingdata; namely, that more than ten j. eent of them have progressedinto the "surgery mrw" category by virtue of :raving developedone or more of the indications for surgery. It appears- there-fore, that hyperparathyroidism may not be the benign diseasewe once thought it might be. The big questions, of course, are(1) how manw patients will ultimately develop problems callingfor surgery and (2) do psa.thyroidectomized patient-, fare bett(rin the long run than do untreated patients? We have no answerto the first question, but we are reasonably certain that theanswer to the second is "yes", with the exception of patientswith familial hyperparathyroidism or multiple adenomas. These

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latter groups are unique and present formndable, unresolvedproblems into which I carnnot delve further at this point.

To return to diagnosis, let me begin by saying that, inthe majority of patients, the diagnosis is clearly evident.In some, however, other causes for hypercalcemia must be soughtactively before resorting to the knife. Since we always per-form a nusiber of tests in addiition to serum calciuz in suspects,we have a moderate amount of information at hand to assist inthe diagnosis. Features which suggest further studies to Tookfor other causes of hypercalcemia are listed in TABLE I.

TABLE I

FEATURES OF HYPERCALCEMAIAFeatures which suggest further studies are necessary to find the causes of hypercalcemia

Features which exclude the diagnosis of hyperparatIhyroidism*

High norma' serum phosphorus

Urinary excretion of calcium in excess of 400 mg/day

Absence of roentgenoraphic osteitis fibrosa in the presence ofsevere hypercafcemia

Elevated alkaline phosphtase in the absence of osteitis fibrosa

Abnormal plasma protein electrophoresis

Elcvated erythrocyte sedimentation rate

Unusaal roentgenogranhic sppearance of bones

Weight lor,

Clinical deterioration

Serum parathyroid not in keeping with serum calcium

*The last feature (Serum parothroid not in keeping with serum calcium) is a possible exception

I must emphasize, however, that none of these features (withthe exception of the last one - (serum PTI not in keeping withseprm calcium) axcludes the diagnosis of hyperparaThyroidism,We do not ordinarily perform calcium infusions or phosphorusdeprivation tests because of the amount of time required, thelarge number of ?atieats, and the availability if PTI!

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Hyperparathyroidism . Goldsmith

measurement. Prior to having the latter available, I haveused both of the other tests extensively and have foundthem to be helpful.

The recent develpment of a sensitive and specificradioinmunoassay for serum parathyroid hormone (iPTH) has madelife much simpler in many ways for those who see large numbersof patients. The particular assay which we u3e has just beenreported by Arnaud and associates /4/ in the January 1971 issueof the Journal of Clinical Investigation. Without going in-to detail about the method, there are several points to men-tion specifically. First, normal subjects show a negativecorrelation between serum calcium and iPTH concentrations, sothat serum calcium must be taken into consideration when eval-uating iPTH. In other words, a value for iPTH which is normalfor a calcium of 9.1 mg/t00 cc may be distinctly elevated fora calcium of 10 mg/J00 cc. In contrast, patients w.th hyper-parathyroidism show a positive correlation between thesevariables. As a result, a two-point discriminant functionhas been derived to distinguish normal from hyperfunction.Secondaly, impaired renal function causes iPTH to begin increas-ing early. Interpretation of iPTH im the presence of azotemiais therefore fraught with hazard. Response to calcium infusionmay not resolve the difference between primary and secondarydisease, as we shall report shortly. Thirdly, in contrastto Reiss' assay, our assay usually distinguishes between thePTH from parathyroid glands and that from malignant tumors(of other than parathyroid origin). The practical consequenceof the latter observation is that iPTH in patients with canceris abnormally low (or undetectable) for the height of the serum cal-cium and generally permits identification of the3e patients.

It is not possible to describe all of the facets ofhyperparathyroidism which were brought out at the First Keat-ing Aemorial Sumposiirn, but I recommend it to you for a com-prehensive view of the current state of knowledge. It willappear in the May 1971 issue of the American Journal ofMedicine.

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Hyperparaihyroidism Goldsmith

References

1. Mancl F: Therapeutiseher Versuch Dei Ostitis Fibross Generalis*taMittels Exstirpation Cines Epithelkonerchen Tumors. Flin Wschr(Wein) 38:1343, 1925

2. Boonstra and Jackson, cited by Goldsmith RS, in mnnuscrirt.3. Keating FR Jr, Jones JD, Elveback ID, etal: Relation of age Pn6

sex to distribution of values in bealtby adult of serum calcium,inorganic phosDhorus, magnesium, alkaline Dhosphatsse, totalprotein, albumin and blood urea. J Lab Clin Med 1969

4. Arnaud CD, Hang S Tsao, Littledike T: Radioimmunoessay of hoganparathyroid hormone in serum. J Clin Invest 50:21-34 (Jan) 1971

Special ReferencesGoldsmith RS: Hyperparathyroidism, New Eng J Mecd 21:367-374, lo~SGoldsmith RF; Lboratory diagnosis of hyperoarathyroidism. Intern

Med Dig 2:13-19,1967

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170

Diseases of the parathyroid gland, a new classification based onetiologic and physioloeic considerations*

Hormonal deficiency or hypoperathyroidisinHypoparathyroidisen from absence or damage of parathyroid glands(primary hypoparathyroidism)

Following therapy of thyroid diseasePost-thyroidectomny, permanent or transientPost-radliolociine, permanent or transient

Cause unknown or idiopathic hypop~rathyroidismEarly onset

Sex linkedNon-sex linked with congenital aplasia of 3rd and 4th pharyngsAl pouches [DiGeorgesyndrome]

Late otisetFamilial

With Addison's disease and/or moniliasis [HAM syndrome)Without Addison's disease and/or monfliasisWith pernicious anemia

Hypoparathyroidism from suppression of parathyroid activity by hypercalcemia(secondary hypoparathyroidism)

Post-resection of parathyroid ade'.omaNeonatal from maternal hvperparathyroidismPhysiolor',c ftcori hypercalcemia of non-parathyroid origin

Hormonal unresponsiveness due to partial or tot.-l lack of parathyroidhormone-sensitive adenyl cyclase in renal tissue(pseudohypoparathyroidism' ,

FamilialWith brachydactyly and/or subcutaneous bone formationWithout brach-vdactyly or subcutaneoout bone formation

Swoadc

With brachydlactyly and/or subcutaneous bon'- formationWitnout brachydactyly or subcutaneous bone formationWith osteitis fibrosa cystica [pseudohypohyperparkithyroidismI

Related -ýriditionsIdiopathic brachydactyly. sporadic or f~imilial (pseudopseudohypo.parathyroidismIOsteorna cutisBasal cell nevus svndromeSteatarrhea

Continued on page 187

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171

EVALUATION OF ADRENAL DYSFUNCTION

MAJ Harvey L. Eichner, MC

-Hpofunction of the Adrenal Cortex

Decreased production of hormones from the adrenal cortexmay be the result of trophic hormone deficiency, congenitaldefects in corticosteroid synthesis or acquired damage to theadrenal gland. The latter, Addison's disease, is rost commonlyan auto-i=mrjne disorder associated with lymphocytic infiltrationof the adre-.aal c-rtex and circulating antiadrenal antibodies.Granuloma', ,'s diseases are next in frequency, particularlytubercu.l-sis which was once the leading cause of adrenal in-sufficihnc.;. Adrenal destruction may also occur in malignancyand amylcv,.osis; may be caused by infection, trauma, or abdominalsurgery; or may be the result of hemorrhage with necrosis.

Defects in cortisol formation mayoccur as the result ofa decrease in the activity of enzymes necessary for steroidbiosynthesis. Deficiencies of 21-hydroxylase, 11B-hydroxylase,17-hydroxylase and 3B-h*droxysteroid dehydrogenase have beenshown to occur as well as other rare forms not as well charac-terized. As a result of the lack of cortisol, adrenocortico-trophic hormone produ-tion is increased, the adrenals becomehyperplastic and there are excessive amounts of precursorsthat accumulate immediately behind the block in synthesis.Depending or the site of the defect, lack of secondary sexualcharacteristics, virilization, hypertension or hypotension

with salt loss or combinations may occur. This group of diseasesis referred to as congenital adrenal hyperplasia and they arediagnosed by the pattern of those steroids deficient and thoseelevated and by the response to glueocorticoid replacementwhich will suppress ACTH and Lhus suppress the elevated steroids.

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Evaluation of Adrenal Dysfunction - Eichner

Hypopituitarism as a cause of adrenal insufficiency iseasy to distinguish from Addison's disease. Frequently thecause of the pituitary lesion is obvious (as in head trauma)hypophysectomy or after prolonged steroid therapy. In diseasesaffecting the pituitary, ACTH is usually one of the last hormonesto be lost and therefore other features of hypopituitarism suchas hypothyroidism and gonadotrophin deficiency will be present.Patients with secondary adrenal insufficiency are generally palerather than pigmented (due to lack of ACTH, rather than excess)and are not usually severely lacking in mineralocorticoidhormone secretion since aldosterone is influenced by the renin-angiotensin system and serum potassium and to a lesser degreeinfluenced by ACTH. Except in the case of surgical ablationof the pituitary there is not a total lack of ACTH and mostpatients with hypopituitarism will not manifest frank adrenalinsufficiency except during stress. Defects in secretion ofthe hypothalamic hormone, corticotrophin releasing iLactor (CRF),may be responsible for same cases of secondary adrenal insuf-ficiency but without a means to measure COF this can only besuspected.

The clinical picture of adrenocortical insufficiency itselfconsists of nonspecific symptoms but if there is an intactpituitary and hyperpigmentation occurs, the diagnosis is morereadily made. Fatiguing easily and weakness ranging from mildto complete prostration; anorexia, nausea, vomiting and diarrhea;dehydration, hypovolemia, small heart size and hypotension;nervousness, emotional instability, dizziness and syncope; andhypoglycemia are common findings. Hyperpyrexia may be seen inacute cases and lymphoid hyperplasia and muscle cramps in somechronic cases. Evaluation of the increased melanin pigmentationmay be difficult as it is identical to natural pigmentationbut the changt, in pigmentation is more important than the amountor location. Because -f the insidious onset in most cases,these symptoms are frequently not noticed until an intercurrentinfection or surgical procedure results in acute collapse whichmay be fatal if not rapidly treated. Peripheral blood eosino-philia, lymphocytosis and decreased serum sodium to potas3iumratio may also be found.

The diagnosis of adrenal insufficiency can only be ýcn-firmed by laboratory tests which measure adrenal steroid output,

adrenal reserve and, directly or indirectly, ACTH production.Numerou prccedures have been devised for assaying adrevalsteroids but the most widely used teat is one for steroids with

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Evaluation of Adrenal Dysfunction E~hn*r

bydro~rl groups at carbon 17 and 21 and a ketone at carbon 20which give a specific color reaction with phenylhydrazine, thePorter-Silber roaction. Porter-Silber chromogens or 17-hydroxycor-ticosteroids (17-OHCS) are rmainly cortisol and when performedon plasma this procedure is a highly specific screening testfor adrenal insufficiency. if tests for urinary or plasmacortisol are abnormally low under basal conditions, functionaladrenal reserve must be tested with corticotrophin stimulation,because cortisol measurements may be diminished in patientswith severe wasting diseases, liver disease, myxedema, andin patients taking certain medications, such as diphenylhydantoin.The most expeditious stimulation test is the assay of plasma17-lWdroxycorticosteroids (sometimes incorrectly referred toas plasma "cortisol") in the basal state and 30 minutes after25 units of ACTH (or equivalent in synthetic corticotropiLin)intramuscularly. The second 3ample should be at least10 mg/100 ml greater than the first. For a more reliable testthe assay of 24-hour urine specimens (collected daily) for17-OHCS should be performed. At the start of the second day,an intravenous corticotropin infusion should be begun in oneliter of saline with 25 units of ACTH and given over eighthours. If hypopituitarism is suspected this may be continuedfor two or three conse'-utive days. In Addison's disease,there -wrill be a failure of the urinary 17-OHCS to approachnormal levels, even after the third day, while in ACTH de-ficiency there is a stepwise increase in 17-OHCS output. Thenormal range is about 3-12 mg/24 hours rising to 15-45 mg/24hours after a single eight-hour infusion.

If there is no response to corticotropin, even after threedays, the diagnosis of Addison's disease is confirmed and thereis no reason to measure pituitary reserve. If hypopituitarismis suspected and ACTH stimulation gives either a normal or asluggish response, pituitary reserve may be tested. The slowestand safest method is the 11B-hydroxylase inhibition methodusing metyrapone and measuring the ACTH-induced rise in urinary17-OHCS caused by blocking cortisol production. The standardprocedure, although modifications are rampant, is to collecturines for four days, two as controls, one during and one afterthe oral administration of 750 mg inetyrapone every four hoursfor 21+ hours and assay them for 17-OHCS. Normal individualsincrease their urinary 17-OHCS two to four times and this isg-eatest in the 24-hour period following treatment. Vasopressinor insulin-induc-d hypoglycemia are more rapid methods fc.

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Ev-aluation of A dre wi Dysfuhcdion - Ercln~r

dete-rmining pit-iA ry reserve causing sec-rtion of vortieo-tropin releasing factor from the hypothalamus. Both plasma.7-011CS aad growth hormone may be measured and this is aprocedure which can be completed in about 90 minutes anddoes not require hospitalization, Mirect measurement ofplasma ACTH by radioimmunoassay is available at some centersbut is not yet in wide enough use to make it a standard test.

Other diagnostic procedures are used to determine the:.tiology of Addison's disease and the extent of adrenalfailure. Assays for aldosterone may be performed and2-deoxyglucose infusion (as a test of adrenal medullaryfunction) may also help to distinguish between tubercularand "auto-immune" Addison's disease (adrenal medulla ismore likely to be normal in the "auto-immune" type). Ofcourse the usual diagnostic aids in the granulomatous diseasessuch as delayed cutaneous hypersensitivity may be helpful andtests for antiadrenal antibodies are also available.

Hyperfunction of the Adrenai '7Iand

While ie suspicion of acL'enal insufficiency is usuallylate in coming forth, confirming the diagnosis is a simplematter. In Cushing's syndrome, however, the disease issuspected far more often than 1t occurs and confirming thediagnosis is sometimes difficult. The clinical findings ofCushing's syndrome depend on the relative amounts of gluco-corticoids, mineralocorticoids *, and androgens secreted, andinclude mental changes, muscle wasting, thinning of the skin,red cheeks, purple striae over the abdomen, thighs and upperarms, truncal obesity with buffalo hump and supraclavicularfat pads, moon facies, easy bruisability, poor wound healing,osteoporosis, diabetes, hypertension, polyuria, deepening ofthe voice, hirsutism and baldness, acne, clitoral enlargementani amenorrhea in the female, and impotence in the male. Sinceobesity, hirsutism, osteoporosis, hypertension, diabetes andstriae are extremely common in the population and combinationsof these findings are not infrequently seen, there are manymore negative workups for Cushing's syndrome than positive.

Excess inm eralncorticoid secretion ;s dhiussed by Doctor Bigheri in this issue(pp 1 79-186)

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Eralua:t)n of Adrenal Dysfunction - Eichner

"Gushing's syndrome may be caused by exogenous steroidadmnstration, primary adrenal disease or increased adre-nalstiwdlation. Adenomas are the most common adrenal leuionsproducing excessive steroids but adrenal carcinomas mayalso be secretory, although they tend to be associated moreoften with androgen excess. Adrenal tumors are more commonin wonen and may be associated with other endocrine tumors,Nodular adrenal byperplasia, to be distinguished from diffuse

erp>asia, may be responsible for Cushing's syndrome, and,like the other adrenal lesions it is accompanied by low plasmaAOTh. and. non-sppressibility by dexamethasone. Corticotropin

over-production may be from the pituitary or various carcinomL3moft com1only of the lur,. Whilp pituitary tumors may produceACTLH, most of the matient- with diffuse adrenal byperplasiawho have increaseed corticotropin production have no demonstrablepituitary leson~. It is post-lated that in some of these peoplethe regulatory ý-echmnism for ACTH release is set too high,so that plexma cortiaol does not exert a negative feedbackeffect at the usual levels.

In a pat!?nt who is suspected of having Cushing's syndrome,laboratory studlea must first establish the diagnosis ofadrenocortical hypersecretion, and then the cause of theproblen. The most widely used screening test is also subt, 'to the greatest error, namely urinary Porter-Silber chromog6is.A single plasma "cortisol" (plasma 17-OHCS) will sometimes behigh enough to confirm the diagnosis but more helpful is aloss of diurnal variation in plasma 17-OHCS when the lateevening level is found to be as high or higher than the morningvalue. Other findings in laboratory studies include erythro-cytosis, neutrophilia, lymphopenia and eosinopenia of the peri-pheral blood, hyperglycemia or glucose intolerance, and hyper-calciuria. Measurement of urinary free cortisol has beenrecommended as a reliable means of distinguishing Cushing'ssyndrome from other causes of eleVLted cortisol excretion suchas obesity, thyrotoxicosis, emotional disorders, surgery andacromegaly. This value will be greater than 200 ug/21+ hrursin Cushing' s syndrome and usually below 125 ug/24 hours inother states. The free cortiso3 test is not available in allcenters, however, so the overnight dexnmethasone suppressiontest is usually used to confirm the presence of Cushing'ssyndrome. One milligram of dexamethasone is given at 11:00 PMalong with a sedative to insure rest; a plasma 17-OHCSdetermination is obtained the next morning. Normal personswill usually suppress their plasma 17-OHCS below 5 ug/100 mlwhile levels above 12 ug/100 ml are evidence for the diagnosisof Cushing's syndrome. The dexamethasone suppression testusing urinary 17-OHCS measurements (the small dosý dexamethasone

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Evaluation of A drenal Dysfunction - Eichner

suppression test of Liddle) requires two days to complete and

is subject to greater error than the overnight suppressiontest, and also offers no advantage in sensitivity.

Once a diagnosis of Cushing's syndrome has been made,the specific site of the lesion responsible must b, Identified.Primary adrenocortical lesions are associated with low plasmaACTH; ectopic corticotropin producing tumors are associatedwith elevated ACTH levels; while plasma ACTH may be normalor elevated in Cushing's syndromto of pituitary origin. TheACTH assay is therefore valuable although not all assays arereliable. The large dose dexamethasone suppression test ofLiddle, using 2.0 mg every six hours for two days can be usedto rule out inappropriate pituitary ACTH secretion (the othercauses of Cushing's syndrome are not suppressed by this dose.Also in diffuse adrenal hyperplasia the glands are usuallystill responsive to exogenous ACTH or to metyrapone-inducedendogenous ACTH increases and these tests may be used. Appropri-ate radiological studies to rule out a pituitary tumor, locatea potential extra-pituitary s':'•urce of ACTH production and

-identify a primary adren&L lesion are important adjuncts tothe function tests. The more sophisticated vascular contraststudies of the adrenal gland (renal arteriograms or adrenalrenograms) have been extremely usefu.A in localizing an adrenaltumor.

Present lio, ''epts. Vol IV No 2. Iebruarv 1971

Eraluation of A drenal Dysfunction - Eichner

SUGGESTED READINGReviewsBondy PK: The idmenal cortex in Duncan's Diseases ofMetaboli.M. Bundy -X! (ed). Philadelphia: W.B. Saunders,1969 pp 827-885

Catt LI: ABC of endocrinology: The adrenal cortex.Lancet 1:1275-1283, 1970

Eisenstein AB (ed): The Adrenal ortex. Boston: Little,Brown and Co., 1967

Forshab PH: The adrenal cortex in Textbook of Endocrinolopa.Williams RH (ed). Philadelphia: W.B. Saunders, 19 6P nn 2517-70

Pertinent Essay and Other Articles

Addison J: On the Constituti.onal and Local Effects of Diseasesof the Suprarenal Capsules. London: D. Highly, 1855

Blizzard RM, Kyle M: Studies of the adrenal antigens andantibodies in Addison's disease. J Clin Invest 42:1653-1660

Bongiovanni AM, Root AW: The adrenogenital syndrome. NewEn !L Med 268:1283-1289, 1342-1351, 1962

Cushing H: The basophil adenomas of the pituitary body andtheir clinical manifestations (pituitary basophilism). BullJohn Hopkins Hosn 50:137, 1932

Dunlop D: Eighty-six cases of Addison's disease. Brit Med J2:887-891, 1963

Eik-Nes K, Oandberg AA, Nelson DH, Tyler FH, Samuels LT:Changes in plasma levels of 17-hydroxycorticosteroids duringthe intravenous administration of ACTH I. A test of adreno-cortical capacity in the human. .' 21in Invest 33:1502-1508,1954

Jenkins D, Forsham PH, Laidlaw JC, Reddy WJ, Thorn GW: Useof ACTH in the diagnosis of adrenal cortical insufficiency.Amer J Med 18:3-14, 1955

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Evalualion of Adrenal Dysfunction - Vichner

Liddle GW, Estek HL., Kendall JW, Williams WC, Townes AW:Clinical application of a nevi test of pituitary reserve., Clin Endocrinol 19:875-894, 1959

Liddle GW: Tests of pituitary-adrmnal suppressibility in thediagnosis of Cushing's syndrome. J Clin Endccrinol 10:1539-1560,1960

Liddle GW, Island DP, Meador CK: Normal and abnormal corticotropinsecretion in man. Rec Pogr Horm Res 18:125-153, 1962

Liddle GW, Givens JR, Nicholson WE, Island DP: The ectopic ACTHsyndrome. Cancer Res 25:1057-1061, 1965

Lipsett MB, Pearson OH: Pathophysiology and treatment ofadrenal crisis. New Rn& J Med 254:511-514, 1956

Maynard DE, Folk RL, Riley JR, Wieland RG, Gwinup G, Hamwi GJ:A ra-pid test for adreno 6ortical insufficiency. Ann Intern Med64:552-556, 1966

Nichols T, Nugent CA, Tyler FH: Steroid laboratory tests inthe diagnosis of Cushing's 8yndrome. Amer J Med 45:116-128, 1968

Pavlatos FC, Smilo RP, Forsham PH: A rapid screening test forCushing's syndrome. JAMA 193:720-723, 1966

Ross EJ, Marshall-Jones P, Friedman M: Cushing's syndrome:Diagnostic criteria. uart J_ I d- 35:149-192, 1966

Tluci JR, Jagger PI, Lauler DP, Thorn GW: Rapid dexamethasonesuppression test for Cushing's syndrome. JAMA 199:379-382, 1967

Wegienka LC, Grasso GG, Forsham PH: Estimation of adrenomedullaryreserve by infusion of 2-deoxy-D-glucose. J Clin Endocrinol26:37, 1966

Weiss ER, Royyis GG, Nelson DH, Bethune JE: Evaluation ofstimulation and suppression tests in the etiological diagnosisof Cushing's syndrome. Ann Intern Med 71:941-949, 1968

Wkepper KD, Wegienka LC, Fudenberg HH: Immuinologic aspectsof adrenocortica! insufficiency. Amer J lied 46:206-216, 196)

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1 79

MINERALOCORTICOID HORMONES (MCH) IN HYPERTENSION

Edward G, Biglieri, M.D.*

The zdrenal gland secretes three steroid hormones whosemajor action is the regulation of electrolyte compositionin the body. Aldosterone, the most potent, deoxycorticosteror.e(DOC) and corticosterone (B) are secreted in smail quantities(a mean secretory rate of 114 ug 150 ug and 2.5 mg, respec-tively). Chronic overproduction of these oteroids will leadeventually to hypertension and potassium depletion. Thisresult is clearly expressed by an aldosterone-producingadenoma (APA). These MCHs demonstrate a unique duality ofregulation - aldosterone by the state of activation of therenin-angiotensin system (RAS) and DOC and B by adrenocor-ticotropin. The measurementq of" the indiridual hormones"-d thp plasna renin activity (PRA) or plasma renin concen-tration (PRC) will provide meaningful inf'ormation for thediagnosis of a hypermineralocorticoid state.

ALDOSTERONE EXCESS STATES

Clinical History

There are no clinical stigmata of aldosterone excessas one might expect with cortisol; headaches, however, arevery common in primary aldosteronis and are almost immedi-ately relieved postoperatively. Most of the symptoms,tiredness, weakness, polyuria, nocturia, are related topotassi= depletion. Demonstration of transient hypertensionduring a pregnancy is an important point in ,ne history, andis invariably present in APA patients. This also seemscoon in patients with insipient renovascular hypertensivedisorders. Numbness and -ingling are frequently associatedwith the alkalosis. It is important to note whetherpatients have been taking any kinds of steroids, diuretics,licorice and most important, oral contraceptives. It is

"-wsoItc Professor of Medicine. University of (aliforita School of Medcine. San I ranvisco

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Mineralocorticoid Hormones in Hypertension - Biglieri

normokalemic patient when 2.0 grams of sodium chloride areadministered with each meal for four days; sodium, potas-sium, chlorine, carbon dioxide, and hematocrit are thenmeasured. Usually an electrocardiograih is taken at thistime since potassium depletion is intensified by this man-euver and hypokalemia is observed in the patient with pri-mary aldosteronism. If either unprovoked hypokalemia orprovoked hypokalemia has been demonecrated on more than oneoccasion, the measurement of aldosterone is indicated.Patients on diuretic therapy do cause problems, and a usefulrapid screen to determine whether this is a cause of thehypokalemia is to measure the excretion of potassium immed-iately after discontinuing diuretic therapy. Frequentlyin this instance the urinary potassium ranges between 20-30mEq/24 hours, which indicates intense potassium conserva-tion. The finding cf greater than 50 mEq of potassium/24hours with hypokalemia is again presumptive evidence ofaldosterone excess.

Aldosterone Measurement

Outpatient aldosterone measurements are fraught withdifficulty. Aldosterone determinations were performed onspecimens from 192 outpatients who did not have an APA.This represents a highly selected group in that (1) thespecimens accepted were patients who demonstrated recentonset of hypertension; (2) at one time or another had hada borderline or low serum potassium, or (3) were young in-dividuals or patients with apparent abrupt onset of hyper-tension. Elevated values were found in 70 (36 percent).

The abnormal elevations not :.j to an APA were suallydue to four major factors. (i) failure to observe the re-quirement of an increased salt intake; (2) the variationsin day-to-day aldosterone production (aldosterone is quitesensitive to stress, trauma and ACTH discharge and the out-patient hypertensive patient is subject to these pressures);(3) influence of drug therapy -- usually the volume deple-tion associated with recent use of diuretics. (We routinelymeasure urint.ry sodium, and if it is less than 50 mEq/24hours, the assessment of aldosterone is not performed);and (4) estrogen therapy which usually elevates aidosteroneproduction.

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Mincralocorticoid Hormone: in Hypertension - Bighieri

Attempts to try to control this great va'-iaoility ofSthie outpatient measu-ement of aldosterone is accomplishedin several ways. Ingestion o7 a large quantity of salt hasproven to be useful at times, but is poorly tolerated by thepatients. Oar approach is to use 9-a--fluoro-hydrocortisone(Florlzaf@), 100 ug four times in one 24-hour period. Thisis continued for three days. The aldosterone is ccllectedon the third day. The patient is a2 so 'istructed to havea liberal salt intake. This is a form of an outpatient DOCAsuppression test. Sec -ndary hyperaldosteronism will supress

-. into the normal range. If, however, the level of aldosteronein such a specimen is elevated, we feel that the patientshould be hospitalized for more definitive testing such asthe ad stration of large amounts of WCO1 and the measure-ment of plasma renin activity.

11lGH LrVFLS 01 ALDOSTERONK IN 4YP-RT'ENSIVF PATIi-NTS

Elevated aldosterone production in the hypokalemic hyper-tensive patient is further p.-esumptive evidence for an APAbut other possibilities must be considered. Secondary hyper-aldosteronisu in hypertensive patients is usually easilyidentified by either history or physical e)mination. Thisgroup includes malignant hypertension, renovascular hyper-tension, essential hypertension on estrogen therapy (birthcontrol agents), and essential hypertensive patients recentlystarted o-a diuretic agerts,

Two additional measurements are most helpful in thedistincticn between primary and _icFdary hyperal 1-s teronism(1) the measArement of PRA or eRC aejd (2) tne a.dosteronejevel after the qdninistratimn of 10 mg of DOCA intramuscular-ly every 12 hours for three days. Primary adrenal oversecre-tion of aldosterone reyalts in hypertension and hypervolemiawhich suppresses reniL production as measurod by PRC and PRA.In secoidary hyperaldosteronism, PRA or PRC are elevated dueto probable intrarenal neplrcsclerosis and vasospasm inmalignant hypertension; decreased renal arterial pressurc inren- v.ascular hypertension, increase in renin aubs~rate andactivity, but not concentration in esorogen-treated patients,and reduced circulating blood volume after diui-etic treatment.

7'iie adijnistr,--•xt , t' DOCA, ho described, helps estab-"_sh aut-Lomy ano a Iu ,CKoIn•', RAS. The alrehly high levels

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Minerahpcortiwoid Hormones in Hypertension - Biglieri

of aldosterone in patients with an APA are never reducedinto the normal range by DOCA. However, suppression of theelevated levels into the normal range occurs after DOCA insecondary hyperaldosteronimn.

There are at least three primary adrenal -°uses of thesyndrome of primary aldosteronism: aldosterone-producingadenomas (APA); idiopathic hyperaldosteronism (IHA) (pseudo-primary aldosteroni~m or nodular hyperplasia); and gluco-corticoid remediable hypersIr]asteronism. Treatment with1.0 mg of dexamethasone for one week will cov.rect the hyper-tension and ho monal abnormalities in the latter group.This observation makes a strong point for the existance ofstill another aldosterone-stimulating agent. Glucocorticoidremediable hypertension is a rare occurrence.

The distinction between an APA and IHA is difficult.Patients with IHA are more than likely male, whose meanserum potassium concentration is subnormal, but not as lowas patients with APA; and have aldosterone production ratesthat are not as elevated as seen in APA. PRA levels aremore reduced in APA than in IHA. The distinction betweenthe two is jignificant because the removai _f -odular hyper-plastic glands usually does not :fect cure or ameliorationof the hypertension although the potassium depletion andits effects are corrected. The overnight recumbent PRCon a normal salt intake, at this time, seems to be the mostuseful discriminant bE tween A0 A and IHA. The levels areusually less than 1.0 ng/ml in APA and between 1-3 ng/ml inIHA (normal 3-9). Care must be exercised in the interpre-tation of the measurement of PRA after salt depletion, oftenaided by a diuretic and after 4 hours in the upright posture.S,'A are still responsive to this stimulus if it has suffi-cient magnitude. Tn both APA and IHA, PRA levels usuallyare still subnormal after these maneuvers. Adrenal veno-graphy and bilateral adxenal vein catheterization for aldo-sterone concentrations may be helpful, but are still onlyconsistently and successfully performed in specialized units.

NORMA" ALDOSTERONE L'VELV IN HYPIFRIFNSION

The hypertensive patient whose activity and salt intakeare well-controlled rarelj has increased aldosterone pro-duction. At the present time the most important observationis the renin values - ip to one-third ,L'c patients with

Pr crI-Jra

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Mineralocorticoid Hormones in Flypertension - Bigheri

essential h;-,ertension have subnormal values. The cause isnot known, but some may harbor a subclinical APA.

In '.he APA patieuts whose potassium depletion is profoundthe adreiail production of aldosterone may reach the normalrange. Potassium cepletion effects great increases in aldos-terone lev3ls.

REDUCED ALDOSTERONE LEVELS IN HYPERTENSION

The observation of a subnormal aldosterone level in ahypokalemic, hypertensive patient should immediately suggestthe possibility of the over-production of another mineral-ocorticoid hormone, especially if PRA is also reduced.Further evidence can be obtained by the administration ofspironolactoi•e. Correction of the hypokalemia and bloodpressure could be further evidence that DOC secretion is in-creased-and if not DOC, possibly an unrecognized MCH. Inadults, these findings would be sepn in patients with the17-hydroxylation syndrome. These patients are usuallyhypogonadal females with primary amenorrhea. Aldosteroneand 17-hydroxy steroids are low, but excessive amounts ofcorticosterone and deoxycorticosterone are secreted.

COMMENT

This is the approach to the investigation of a hyper-tensive patient for a hypeiminers ocorticoid state in theClinical Study Center. All hypei rensive patients shouldhave several serum pornassium concentrations measured aftersalt loading. Only after the repeated demonstration ofhypokalemia should the scheme outlined in this discussionhe followed. PRA as a screening test is not to be con-doned because of the great variability of levels in hyper-tensive subjects.

A "decision diagram" is presented in TPXbLE I.

I L ( , a , ept~ ' i l \ o 2 / cb ri a i

185

Mineralocorticoid Hormones in Hypertension - Biglieri

TABLE I

DECISION DIAGRAMApproach to the Investigation of a Hypertensive Patient for a Hyperminerah -)rtcoid State

ADRENAL CAUSES PRA DOCA

Primary(1) APA 4 --

(2) IHA I -•

Hypertension ELEVATED (3) Glucocorticoid rcsponsive 4

4 Second2ryHypokalemia (1) Malignant hypertension t 4

(2) Kenovascular nypertension t 44(3) Estrogens and essential 1 4

hypertension

Aldosterone I evel m** (4) Diuretics and hypertension t 4

-NOPMAL (I) Essential hypertension N or 4(2) APA with serum K -

depletion

REDUCED Other mineralocorticoid hormones(Correction of hypokalemia wouldsuggest another MCH)

(1) 17-hydroxylation deficiency 4 -

(DOC excess)(2) 1 1-hydroxylation deficiency -

(aldosterone N or 4)(3) Primary DOC lesion 4 -

Legen d"- urhjngeJSrý duced

t in,reasedN ,l44rmalPRA plasma renin activity)O( A chngc in aldosterone production

after DOCA adminitration

' cepts. I olt! t'. N ," February 19,71

; 86

Mincralocorticoid Hormones in Hypertension Biglieri

Rcferences

1. Conn, JW: Primary aldosteroniem: A new clinical syndrome.J Lab Clin Med 45: 661-664, 1955

2 Biglieri, EG, Slaton, PE, Schambelan, M and Kronfield,SJ: Hypermineralocorticoidism. Amer J Med 45: 170-175,1968

3. Biglieri, EG, Herron, MA, Brust, N: The 17-hydroxy-lation deficiency in man. J C Invest 45z 1946-1954,1966

4. Conn, JW, Rovner, °R, dohen, EL et al: Preoperativediagnosis of primary aldosteronisn. Arch Intern Med 123:113-123, 1969

5. Jose, A, Kaplan, IN: Plasma renin activity in the diag-nosis of primary aldosteronism. Arch Intern Med 123:141-146, 1969

6. Woods, JW, Liddle, GW, Stant EGJr, et al: Effect ofan adrenal inhibitor in hypertensive patients with sup-pressed renin. Arch Intern Med 123: 366-370, 1969

7. Jose, A, Tront, RC, Kaplan, NM: Suppressec plasmarenin activity in essential hypertension. AM Intern d72: 9-16, 1970

8. Baer, L, et al: Pseudo-primary aldosteronism. An entitydistinct from true primary -Idosteronism. Circ Res 27Suppl 1:203+, 1970

9. Salti, IS, Stiefel, M., Ruse, JL, et al: Nontumorousprimary aldosteronism. I. Type relieved by glucocorti-coid (glucocorticoid remediablo aldosteronia-). CanadMed Ass J 101: 1-10, 1969

10. Conn, JW, Cohen, EL, Rovner, DR, et al: Normokalemic pri-mary aldosteronism. J A M A 193: 200-206, 1965

11. Biglieri, EG. Slaton, PE, Kronfield, SJ, Schambelan, M:Diagnosis of an aldosteroiic--producing adenoma in primaryaldosteronism. J A M A 201: 510-514, 1967

12. Gunnels, JC, McCuffin, WL, Jr, Robinson, RR, et al:Hypertension, adrenal abnormalities, and alterations inplasma renin activity. Ann Intern Med 73: 901-911, 197k"

t 'rcs (,a, co ~/

/S 7

Continued from page 170

Hormonal excess or hyperparathyroidismHyperparathyroidism from tumor of parathyroid glands (primary hyperparathyroidism)

Beni~gn chiief cell adenoma, singla or multipleSporadicFamilialWith tumors of the' pituitary and pancreas [multiple endocri.ie neop asia Type I INith medullary car. inoma of the thyroid and pheochromocytomna [,nultipieendocrine neoplasia Type 2',Due to chronic hypc'-alcernia [tertiary hyperperathyroidism]

Functioning parathyroid carcinomnaFunctioning benign cystsFunctionling lipoadenomna

Hyperparathyroldism from hyperplasia of parathyroid glandsChief cell hyperplasia

Neonatal, sporadic or familialAdult [Cope syndrome]

Wasserhelle cell hyperplasiaHypcrparathyroldlsm from chronic stimulation of parathyroids by hypocalcemla

(secondary hyperparat~iyroidism)Inrtrauteri ne from maternal hypopearthyroidismChronic azotemia with or without renal osteodystrophySteetorrhea with or without osteomnaleciaHo monal unresponsiveness

Hyperparathyroidism from anomalous secretion of parathyroid hormone by a non-endocrine tumor [pseudohyperparathyroidism I

Renal cell carciiomaOat ce1I carcinoma of lungOther malignancies (specify)

Nonfunctioninci tumors of the parathyjroid glandsCarcinomaBenign cyst

Lipoadenoma

'This new classification of parathvroid disease has br-en proposed oy Docior Dd,.od Bronsky of the~

Un~versity of Illinois For further explaiialion arid refe~rences, read his article in Thekk~ Jo~~ofClrct Enbrnlg n nb/sm eptember 1970, pp 271 276

J J. D