HYPOPITUITARISMBy A. A. G. LEWIS, B.Sc., M.D., M.R.C.P.

Physician to the Connaught Hospital and the Woodford Jubilee HospitalSaltwell Research Scholar, Royal College of Physicians (From the Professional Medical Unit, Middlesex Hospital)

IntroductionMany of the clinical features of hypopituitarism

were described by Simpson in I872 in his accountof the symptoms associated with post-partumsuperinvolution of the uterus. The syndrome re-sulting from the simultaneous failure of severalendocrine glands was described by Claude andGougerot in I907, but at this time the dominantrole of the adenohypophysis in the endocrinesystem was not appreciated. Douglas Robertson(Ig95b) has recently drawn attention to the paperby Glinski (1913) describing the association ofanterior pituitary necrosis with post-partumhaemorrhage. Simmonds published his account ofthe necropsy of a patient suffering from atrophy ofthe anterior lobe in I9I4. He did not at firstrealize the importance of the small size of thethyroid and adrenals, in fact he emphasized thattheir histology was normal. In subsequent papershe developed his conception of pituitary failure,though in the course of this he stressed undulycertain features of his cases such as cachexia andprogeria. It was particularly unfortunate that inthe title of two of his papers the word ' Kachexie 'should have appeared, for this became inseparablyassociated for many years afterwards with the syn-drome of panhypopituitarism.

In I942 Escamilla and Lisser published an ex-tensive review of the literature, collecting detailsof ioi cases of this condition. Their four criteriaof severe pituitary deficiency (loss of weight, lossof sexual function, asthenia and a B.M.R. below-zo per cent.) ensured that at least one ofSimmonds' original misconceptions would be per-petuated. Fraser and Smith in 1941 stated thatthe nutrition of these patients was usually good.This was further emphasized by Sheehan andSummers (I949) in their detailed description of thesyndrome resulting from seve*re longstandinghypopituitarism. This account was based on 95cases in which complete or nearly completedestruction -of the anterior lobe was found atnecropsy,' and is therefore the most authoritative

available. It confirms and extends the descriptionof the syndrome of panhypopituitarism arisingfrom post-partum necrosis of the anterior lobegiven by Sheehan in a series of papers. This par-ticular condition is now frequently referred to asSheehan's disease.

In recent years, as the recognition of theessential features of the complete syndrome be-came clearer, and as biochemical tests and hormoneassays for the investigation of suspected cases cameto be more widely used, more interest has beentaken in the less severe degrees of pituitary failure,and several papers have appeared describing suchcases (Cooke and Sheehan, 1950; Oelbaum,Ig952a). One result of this increased interest hasbeen a clearer understanding of the natural historyof the disease, many aspects of which have recentlybeen discussed by Hubble (I952).The Hormones of the Anterior PituitaryThe adenohypophysis produces at least six

hormones: Follicle-stimulating (FSH), luteinis-ing or interstitial-cell-stimulating (LH or ICSH),lactogenic or luteotropic, thyrotropic (TSH),adrenocorticotropic (ACTH) and growth hormone.There is increasing evidence that the adrenal

cortex secretes more than one hormone and thatSelye's original conception that the gland pro-duces both glucocorticoids and mineralocorticoidswas correct. Whether his hypothesis that the pro-duction of the latter is stimulated by a differentpituitary hormone from the former is also true isnot known, but it appears very improbable. It isstifl doubtful whether adrenal androgen productionis stimulated by ACTH or by LH.

Anterior pituitary extracts also inhibit theaction of hexokinase in catalyzing the transforma-tion of glucose to glucose-6-phosphate, an in-hibition'which is opposed by insulin. It has beenclaimed (Li, 1952) that growth hormone an-tagonizes the action of insulin and that this maypartly explain its diabetogenic activity in animals.Although this activity appears to be that of growth

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hormone itself, the latter always produces growthin young animals, not diabetes (Young, I952).The exact relationship between the growth hor-mone and the glycotropic action of the anteriorpituitary is therefore not clearly known, but thereis no doubt that the gland plays a direct part inthe regulation of the blood sugar by opposing theperipheral action of insulin.

PanhypopituitarismPathology. In a large number of cases destruc-

tion of the anterior lobe follows a severe post-partum circulatory collapse. Sheehan and Mur-doch (I938) thought that the blood flow to theanterior lobe was reduced at delivery,.and thatcirculatory collapse would then favour thrombosisin the small vessels, with infarction and necrosis ofmuch of the secretory tissue. They found a re-lationship between the degree of collapse and thefrequency of necrosis in a series of cases; necrosisoccurred in seven of the eight with the most severedegree of collapse. Both collapse and necrosiswere found to be more frequent in multiparae.The necrosis may be very extensive, only smallislets of healthy tissue remaining.

In other cases there may be scarring, fibrosis orcystic degeneration of the anterior lobe for whichno definite cause can be found. Occasionally ahead injury appears to have been responsible.Sometimes evidence is found of previous destruc-tive lesions due to tuberculosis, gummatousnecrosis, or other granulomata. Syphilis of thepituitary is a rare condition; the subject has re-cently been reviewed by Oelbaum (I952b).Bleisch and Robbins (1952) collected accounts of50 cases with granulomata involving the anteriorlobe, and added four of their own. In many ofthese cases there was other evidence of syphilis,tuberculosis or sarcoidosis. Occasionally traumaappeared to have been the cause, and the pos-sibility of primary specific pituitary degenerationcould not always be excluded. In some cases thesella turcica seems to be empty at post-mortemexamination (' empty sella '). This appearance isprobably produced by healing and extremescarring of a granulomatous condition.

Other causes of hypopituitarism include sur-gical hypophysectomy and cysts and tumours,either in the sella or in its neighbourhood.

In 76 of the 95 cases collected by Sheehan andSummers, all the other endocrine glands werecertainly or probably atrophied. Only in six ofthe 95 had at least one endocrine gland beendefinitely normal (endocrine atrophy was presentin only half the cases of moderate pituitarydamage). The adrenal glands were small; onlythe medulla and the zona fasciculata of the cortexremained. The thyroid was small and atrophic;

in i5 cases it was only represented by densefibrous tissue. The female genitalia and ovarieswere atrophic, the endometrium being merely alayer of cubical epithelium. No developingfollicles or corpora lutea were seen in the ovaries.In males the testes were atrophic and the prostateand penis small. In spite of the fact that theweights of the patients were within the normalrange, most of the viscera were small.

Clinical FeaturesIn severe longstanding hypopituitarism all the

features described by Sheehan and Summers(I949) are usually present. The most character-istic picture is seen in women who have recoveredfrom post-partum haemorrhage complicated bypituitary necrosis. There is usually a history ofvery severe collapse following delivery or manualremoval of the placenta, which required the trans-fusion of several pints of blood. Lactation wasnever established and menstruation and libidonever returned. Afterwards the patient becamedull and apathetic, mentally slow and sensitive tocold, with no interest in running the home, oftenretiring to bed or sitting in front of the fire forlong periods of the day. Occasionally a psychosishas been suspected. The appearance and speechare characteristic, the patient having a forlorn,round-shouldered attitude and describing hersymptoms in a dreary voice. The face is pale andflabby, sometimes with a slight yellow tint fromcarotinaemia. The mucosae are pale and theeyebrows thin. The body hair has disappearedapart from some remaining on the labia majora.The skin is thin and dry, and depigmentation,which gives it a wax-like appearance, is wide-spread. Even the areolae are pale. Erythema abigne frequently occurs on the shins, but the areasare not pigmented. There is no tanning after ex-posure to sunlight. Pain in the knees and stiffnessare common, and with the apathy and physicalweakness may cause the patient to lie in bed almostas if suffering from a spastic paraplegia. Nocturiais the rule, and the patient may notice that she doesnot pass large volumes of urine after drinkingduring the day. Atrophy of the vagina may lead tosevere dyspareunia. Sterility is almost invariable.There is an anaemia, often normochromic. Bloodpressure may be normal or low. X-ray of thechest does not reveal the large heart of myxoedema,but the E.C.G. may show low voltage curves,sometimes with changes due to hyperkalaemia.

There has been a great deal of controversy andmisunderstanding about the weight of thesepatients ever since Simmonds emphasized the oc-currence of cachexia. Many of them look thin andill, but they are not cachectic or emaciated in the

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strict sense. Sheehan and Summers stressed thatthe body weight was not usually abnormal.Other authors consider that a moderate lossof weight is common. In reviewing the de-tails of 35 cases of post-partum necrosis Farquhar-son (I950) found that only seven weighed less thanIoo lb., five being described as' thin or emaciated.'He also stated: ' It would appear that completedestruction of the gland is followed at once by lossof weight and other symptoms of the disease.' Itseems probable that the apathy and loss of interestand of appetite found in the severe cases may leadto considerable weight loss at various times in thecourse of the illness. The case described byAitken and Russell (i934), in which the pituitarywas destroyed by haemorrhage into a chromo-phobe adenoma, lost 35 lb. in as many weeks afterthe haemorrhage, while the case of Farquharsonand Graham (193I), with post-partum necrosis,gained 20 lb. when her appetite improved for someyears before death. A complication such astuberculosis, which is not uncommon, may alsoreduce the weight.While post-partum necrosis of the gland is the

commonest cause of pituitary failure in women, inmen the syndrome results from fibrosis, granulomaor tumour. The onset is gradual, usually withloss of libido and of potentia. The externalgenitalia and prostate become small and the voicemay become high-pitched. The patient rarelyhas to shave.A number of these patients become comatose,

often with little warning. In many cases this isdue to hypoglycaemia, which may occur even aftercomparatively short periods of fasting or after theadministration of insulin given to stimulate theappetite or as a diagnostic measure. Other casesare liable to crises similar to those of Addison'sdisease with diarrhoea, vomiting and collapse.Occasionally coma is associated with disturbancesof body temperature, either with fever and tachy-cardia at the onset of an infection, to which thepatient may readily succumb, or, rarely, withsevere hypothermia. Sheehan and Summers(1952) have described one case in which the tem-perature had to be measured with a bacterio-logical thermometer, being as low as 87° F. Thepatient was pulseless and the heart beat slow andalmost imperceptible. She was revived by im-mersion in a warm bath.

Laboratory Investigations(I) Urinary 17-ketosteroids. Fraser and Smith

(I941) found an excretion of less than 0.5 mg./24 hr.in nine of ten cases, the normal range in women fortheir laboratory being 5 to I5 mg./24 hr. Venningand Browne (I949) and Escamilla (I949) reported,somewhat higher values, but in every case they

were below the normal range, being relativelylower in males.

(2) Insulin tolerance test. Details of this test aregiven by Fraser and Smith (I94I). An attempt ismade to assess two variables-the sensitiv'ity toinsulin and the response to the hypoglycaemiawhich insulin produces. All cases should be on ahigh carbohydrate diet for four days previously.After withdrawing blood for fasting blood sugarestimation, insulin is injected intravenously toreduce the blood sugar level by at least 45 per cent.Normally this may be achieved by a dose of o.Iunits/kg.,'but in suspected panhypopituitarism notmore than one-third of this dose should be given asthere may be great sensitivity to insulin. It isbest to talk to the patient as clouding of conscious-ness may be the first indication of dangerously lowblood sugar levels, in which case the test should beterminated with a glucose drink. Blood is takenfor glucose estimations at 20, 30, 45, 6o and- I20minutes after the injection. . Normally when theblood sugar level has been halved the response israpid and the normal level is regained within twohours. There may be considerable delay inmyxoedema and in Addison's disease, but insevere hypopituitarism the response may be almostabsent, and this feature, together with the greatsensitivity to insulin, is characteristic.The test should not be performed if the fasting

blood sugar is much below normal as it may be incases of hyperpituitarism.

(3) Conadotropins. The urinary excretion ofFSH is greatly reduced (Klinefelter, Albright andGriswold, '943; Escamilla, 1949). The test isbased on the original method of Zondek (I930),depending on the enlargement of the uterus ofimmature mice by extracts of tne urine injectedafter serial dilution. Extracts can be preparedeither by alcohol precipitation or by ultra-centrifugation.

(4) Robinson-Power-Kepler test. This empiricaltest depends upon the summation of the anomaliesof renal function found in adrenal deficiency.These are: (a) Lowered renal blood flowand glomerular filtration rate with consequentlowered urea clearance and raised blood urea. Inpanhypopituitarism this is partly due to the de-ficiency of growth hormone which is probablyresponsible for the microsplanchnia. The averageweight of the two kidneys in Sheehan and Sum-mers's cases was i70 g. (normal 300 g.); (b)failure of water diuresis in response to a waterload, with nocturia. The cause of this is uncertain,but appears to be due to loss of tubular selectivity,the patient being unable to pass large volumes ofdilute urine, or small volumes of very concentratedurine, in response to the appropriate stimuli.Severe cases pass small volumes of urine with a

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chloride concentration similar to that of the plasma,irrespective of hydration, or dehydration, duringthe day (Chalmers and Lewis, i95I). At nightlarge volumes of less concentrated urine may bepassed (Robertson, I95Ia).

In this test a water load of 20 ml./kg. is given tothe fasting patient in the morning, after the nighturine specimen has been collected. Furtherspecimens are collected at hourly intervals. Inthe patient with adrenal deficiency none of thesespecimens will be larger than that collected over-night because of the nocturia and failure of diuresisin this condition, but this anomaly is not diag-nostic. In the second part of the test the followingindex is derived:

Vol. of largest day urine Plasma chloride Urinary ureax X

Vol. of night urine Urinary chloride Blood urea

In adrenal deficiency the factors of the numeratortend to be lower than in normals, while those of thedenominator are greater, so that the figure de-rived is a low one. Robertson, Power and Kepler(I94I) found that the factor was below 25 inadrenal deficiency and above 30 in normals,though occasionally cases with cachexia or withhepatic or renal failure gave anomalous results.

(5) B.M.R. This is abnormally low, usuallybelow -30. The serum cholesterol may beraised, but is not usually in the range found inprimary myxoedema.

(6) Plasma electrolytes. The sodium and chlor-ide levels may be low and that of potassium high,but the figures are often normal.

(7) Response to the injection of ACTH. It maytake several injections of the hormone to elicit afull adrenal response, which may tnerefore be lessat first than that found in normals but greater thanthat in Addison's disease. It has been suggested(McIntosh et al., 1950) that this incomplete re-sponse may be valuable in diagnosis and that aclear distinction can be made between the rises in17-ketosteroid excretion in patients with hypo-pituitarism and in normals after ACTH. However,this perhaps overestimates the significance ofminor variations in the results of a complicatedchemical analysis.

Incomplete LesionsDetailed study of the patients suffering from

post-partum necrosis of the anterior lobe has ledto an appreciation of the true nature of the syn-drome of hypopituitarism. Where haemorrhageand collapse in the p erperium have been followedby the appearance of less complete degrees of de-ficiency the definite time of onset fixed by theclinical history has enabled the evolution of thedisease to be followed from the beginning. Several

cases have been recorded where quite a small sur-viving remnant of the gland has been found post-mortem and has evidently prevented the occurrenceof any of the symptoms of the syndrome. This isanalogous to the finding that only a small part ofthe secreting tissue of the neurohypophysis mayprevent the occurrence of diabetes insipidus. Insome cases the complete syndrome of panhypo-pituitarism may only develop after many years.Hubble (i952) describes a case in -which the pubichair disappeared and amenorrhoea developed aftera post-partum haemorrhage, but adrenal andthyroid failure were delayed for 25 years. Thisemphasizes the importance of Sheehan and Sum-mers's description of the complete syndrome, forthey were careful to base this only on the study oflongstanding severe cases.

In many other cases the pituitary failure maynever be more than partial. Sheehan and Mur-doch (1938) reviewed the histories of I28 womenwho had suffered from post-partum haemorrhageand collapse between 1930 and i936. Absence ofany mammary reaction was the commonest sign ofpituitary failure and occurred in 44 cases. Threeof these were in the group with the least degreeof collapse and had no other symptoms. Men-struation was absent or infrequent in 32 cases,while body hair was lost in only i . Failure oflactation and of sexual function are therefore thecommonest symptoms, but the second of these isnot invariable. Several cases have been reportedin which extensive destruction of the gland hasbeen found post-mortem, but menstruation andeven pregnancy had occurred after the onset ofthe disease. Bishop and de Mowbray (I95i) havedescribed a patient who developed symptoms ofhypopituitarism with almost complete amenor-rhoea after a pregnancy at the age of 22. Shetwice became pregnant subsequently, going toterm on the second occasion and improving con-siderably during this time, but relapsing after theconfinement.Oelbaum (1952a) emphasizes the variability of

endocrine dysfunction in post-partum hypo-pituitarism. One case showed. only a deficiency ofgonadotropin excretion; amenorrhoea was com-plete, but thyroid and adrenocortical function wereconsidered to be normal. The urinary I7ketosteroid excretion was 7.0 mg./24 hr., and theinsulin tolerance test normal. Another case hada normal gonadotropin excretion but was found tohave an infantile uterus at a subsequent laparo-tomy. Cooke and Sheehan tI950) stress thatpatients may suffer from genital superinvolution,deficiency of thyroid or adrenal cortical functionor hypoglycaemia or from any combination ofthese, and believe that the irregularities depeid onthe amount of the pituitary destroyed and the

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time which has elapsed since destruction. One oftheir cases menstruated for six years before thefull syndrome developed. Another developedamenorrhoea and genital atrophy after her onlypregnancy but breast-fed the baby for three months.

Paschkis and Cantarow (I95 ) reported one casewith normal 17-ketosteroid excretion but hypo-glycaemia unresponsiveness, and four with theconverse. These results favour the hypothesis thatadrenal androgen production is controlled by thesecretion of LH rather than the suggestion, madeby the authors, that the adrenal functions may beindividually suppressed.

In 1940 Means, Hertz and Lerman describedthe syndrome of' pituitary myxoedema.' This isessentially a condition of hypopituitarism in whichthe predominant features are those of thyroiddeficiency. Unless carefully sought, signs of de-ficiency of other pituitary hormones may not befound and the case may be mistaken for one ofprimary myxoedema. It must be borne in mindthat while hypopituitarism frequently occurswithout much loss of weight, any such loss in thecourse of the disease is strongly against the diag-nosis of primary myxoedema. It is important torecognize such cases because they may react in ananomalous manner to thyroid. Occasionally smalldoses may precipitate an adrenal crisis, presum-ably by suddenly increasing the demand foradrenal hormones. On the other hand some casesare resistant to thyroid and show little improve-ment with doses effective in primary myxoedema.Chromophobe adenomata frequently cause pro-

gressive hypopituitarism. Here again in the greatmajority of cases sexual failure occurs first.Amenorrhoea occurs in women, without meno-pausal symptoms, and in men there is loss oflibido and potentia. Dott, Bailey and Cushing(I925) emphasized the importance of these symp-toms early in the course of pituitary destruction bychromophobe tumours. In many cases there islittle evidence of other deficiencies for many years,and it is possible for enlargement of the sella andoptic atrophy to occur with normal pituitaryfunction.

Pituitary DwarfismIn this condition, hypopituitarism in childhood

manifests itself mainly in failure of growth. Thechild is small but normally proportioned. Usuallysexual maturation never occurs so that a very slowrate of growth may be maintained for many years.The signs of thyroid and adrenal deficiency are notusually evident. Sometimes the cause is apituitary tumour such as a craniopharyngioma. Inother cases there appears to be an isolated de-ficiency of growth hormone production. Hewer(I944) reported the necropsy of a female dwarf who

had had one child. Of 2,000 cells in the anteriorpituitary only o.z per cent. were eosinophils.

Occasionally cases occur with isolated de-ficiencies of gonadotropic or of thyrotropic hor-mones (Hubble, 1952).Hypopituitarism Secondary to Nutritionaland Psychogenic Factors

In a recent stimulating review of the course ofanterior hypopituitarism Hubble (I952) has dis-cussed the failure of sexual function and growththat may occur in such conditions as anorexianervosa and coeliac disease. While amenorrhoeain anorexia nervosa is frequently psychogenic,there is reason to believe that in some cases it isdue to the malnutrition. It is known that in ratsa deficient diet may depress sexual function beforerestricting growth. Banks, Lloyd and Scowen(I952) reported that severe diet restriction in twowomen after the menopause reduced the excretionof FSH to zero in a few weeks. There is usuallyno other evidence of pituitary deficiency inanorexia nervosa, though the B.M.R. is usuallylow. Thorn et al. (I950) observed a low 17-ketosteroid excretion and considered that this wasevidence of impaired adrenal function, but otherlaboratory investigations such as the insulintolerance test and the Robinson-Power-Keplertest are normal.

Dwarfism is usual when coeliac disease per-sists into adult life, in fact, if skeletal develop-ment is retarded by more than a few years itusually persists, at least partially, even when thenutritional deficiencies are completely corrected.One of Hubble's cases was still growing in histhirties, so that production of sex hormones (whichultimately limit growth by causing fusion of theepiphyses) was evidently more depressed than thatof growth hormone.

Differential DiagnosisAnorexia nervosa. This is the condition which is

most frequently mistaken for Simmonds' disease,and there is no doubt that descriptions of the latterin the past have been vitiated by reports of casesin which these two conditions have been confused.The patient with anorexia nervosa in an advancedstage is emaciated, but in spite of this her mentaland physical activity is often quite remarkable,whereas in panhypopituitarism the patient is dull,apathetic and inert even when the weight is normal.In anorexia nervosa amenorrhoea occurs early butbody hair is not lost. Apart from a low B.M.R.the other laboratory investigations are generallynormal.

Addison's disease. Body hair is often absent andthe urinary excretion of I7-ketosteroids is low inwomen with Addison's disease, presumably be-

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cause of the failure of production of adrenalandrogens, but in hypopituitarism the character-istic pigmentation of Addison's disease is notseen and low blood pressure with low serum levelsof sodium and chloride and high potassium occurmuch less often. As Thorn et al. (Ix949) havepointed out, the adrenal deficiency of hypo-pituitarism appears to lead predominantly, tohypoglycaemia rather than to hypochloraemia. Inthe insulin tolerance test the patient with Ad-dison's disease may be less rather than moresensitive to insulin than normal (possibly becauseof increased glycotropic activity of the anteriorpituitary), though there is hypoglycaemia un-responsiveness (Fraser, Albright and Smith,I94').Myxoedema. The importance of distinguish-

ing between primary myxoedema and so-calledpituitary myxoedema has been emphasized above.While the latter type rarely occurs without sexualfailure, as Hubble has stressed, reports in theliterature of cases in yvhich menstruation and preg-nancy have occurred in undoubted hypopituitarism.do not make even this distinction completely re-liable. In primary myxoedema urinary I7-ketosteroid excretion may be very low and theblood sugar may n6t return to normal in the in-sulin tolerance test. A distinction between thesetwo conditions may therefore be very difficult tomake. A detailed inquiry into the sexual function,menstrual rhythm and obstetric history, carefulexamination of the fundi and of the visual fields,radiological examination of the pituitary fossa andinvestigation of adrenal function may therefore benecessary in a doubtful case. The difficulty ofmaking this distinction again emphasizes the im-portance of starting thyroid therapy with smalldoses of the hormone and the dangers of givingthyroid indiscriminately to any patient.

Primary ovarian insufficiency (Albright, Smithand Fraser, 1942). This is sometimes mistakenfor hypopituitarism. There may be other stigmatasuch as webbing of the neck, coarctation of theaorta or cubitus valgus. Body hair is scanty butnot absent, and the breasts are small. Sexualfunctions have never matured and the body pro-portions are eunuchoid, the span being greater thanthe height. These patients are not dwarfs but areusually moderately stunted, the height often beingabout 4 ft. 8 in. Assay of the urinary FSH ex-cretion clinches the diagnosis for it is high in thiscondition.

Other mistaken diagnoses, commonly made onaccount of the appearance, are those of anaemia ornephritis, the latter particularly when nocturia is aprominent symptom. 'Post-partum debility,'neurosis and various psychoses may also bediagnosed.

TreatmentSheehan and Murdoch (I938) reported a case

in which improvement occurred during pregnancyfollowing previous post-partum necrosis, and itwas thought that some hyperplasia of the remnantof the anterior lobe had occurred. The case ofBishop and de Mowbray improved in pregnancybut relapsed later. The patients reported byJakob (1923) and Farquharson, Belt and Duff(I938) became worse after pregnancy. It appears,therefore, that the chances of any real improve-ment occurring as the result of pregnancy, even in.the unlikely event of conception taking place afterpost-partum necrosis, are extremely small.

Pituitary failure is not an indication for surgeryin cases with cysts or tumours in the neighbour-hood of the sella; in the great majority of casessurgery is undertaken to save the sight. Opera-tion may, in fact, abolish what little endocrinefunction remains, with a fatal outcome (Grant,1948). Caughey, James and Macleod (I952) re-ported four cases in which prolonged stupor de-veloped after operations on pituitary tumours.Recovery occurred in two on treatment withcortisone.

In the great majority of cases the only possibletreatment is some form of hormonal replacementtherapy. A course of ACTH (25 mg. intra-muscularly, six-hourly for a few days) brings abouta dramatic improvement in those cases with symp-toms of adrenal deficiency. Increased appetite,activity and libido, and euphoria and gain ofweight occur, and this improvement may last forweeks after the end of the course (Rolland andMatthews, 1952; Summers and Sheehan, I951;Hart, 195I). A normal diuretic response to watermay be obtained (Chalmers and Lewis, I95i), andthe nocturia may lessen. Hypoglycaemia may beprevented. Cortisone (25 mg. a day by mouth)brings about a similar improvement and is the bestmaintenance therapy. Either ACTH or cortisoneshould be given whenever surgery becomes neces-sary. Treatment of the adrenal deficiency withDOCA and extra salt give much less dramaticresults than in cases of Addison's disease, thoughit may be beneficial.

Thyroid should only be given with extremecaution, starting with ~ gr. daily while the patientis under observation. The simultaneous ad-ministration of ACTH, DOCA or extra saltreduce the risk of precipitating an adrenal crisis.In some cases the dose of thyroid can be greatlyincreased and the effects may be striking, par-ticularly on the lethargy and the mental changes.

Injections of growth hormone are ineffective inpituitary dwarfism. Growth may be stimulatedby androgen therapy but will cease when this

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brings about fusion of the epiphyses; 5oo-I0oooi.u. of chorionic gonadotropin twice a week.maystimulate growth and sexual function in thesecases.

Adult females with hypogonadism can be givenoestrogens with benefit.

In all cases testosterone therapy is beneficial,often strikingly so. In addition to stimulating asense of wellbeing and libido, it brings about in-creased protein anabolism with a positive nitrogenbalance and weight gain in both sexes. Musculardevelopment and vigour increase and, in males,the penis enlarges and erections become frequent.It is claimed that spermatogenesis may be stimu-lated (Hurxthal, Bruns and Musulin, I949).Body hair is increased. These actions have beendiscussed by Oelbaum (I952b). Methyl testo-sterone can be given sublingually, testosterone pro-pionate can be given by injection or, most con-veniently, 200 mg. of testosterone can be im-planted.

Crisis and coma call for immediate and vigoroustreatment. As hypoglycaemia is the commonestsingle cause large quantities of glucose must begiven by mouth or intravenously. ACTH andcortisone can be given simultaneously but theireffect will not be felt for some hours, so thatdiarrhoea and vomiting call for intravenous saline

and cortical extract (preferably lipo-adrenalcortex if this is available, as this contains moreglucocorticoid fraction). DOCA (5 or Io mg.)should be injected intramuscularly at the sametime, and as infection is so frequently the cause ofthe collapse, a large intramuscular dose of peni-cillin or intravenous aureomycin should begiven.The treatment of pituitary coma has recently

been fully discussed by Sheehan and Summers(1952). They observed no improvement followingintravenous cortisone, saline or DOCA. Theyemphasized the importance of recognizing hypo-thermic coma. This occurred in one of theirpatients in spite of previous injections of DOCA,recovery occurred after immersion in a warm bath.One of the dangers of hypopituitarism lies in

the fact that the patient may be so apathetic thatshe fails to realize when her condition has de-teriorated and a doctor may not be called until acrisis or coma has developed. Death may followwith appalling suddenness in. such cases in spiteof all efforts on the part of the physician. Theprognosis in any severe case of hypopituitarism istherefore always grave and never exactly pre-dictable. The patient must be kept under regularobservation and must be told to report at once ifany infection develops.

BIBLIOGRAPHYAITKEN, R. S., and RUSSELL, DOROTHY (I934), Lancet, ii,

802.ALBRIGHT, F., SMITH, P. H., and FRASER, R. W. (1942),

Amer. _7. med. Sci., 204, 625.BANKS, P. J., LLOYD, H. M., and SCOWEN, E. F. (1952),

' Ciba Foundation Colloquia on Endocrinology,' Vol. 4, p. 289.London, J. & A. Churchill.

BISHOP, P. M. F., and DE MOWBRAY, R. R. (I95x), Proc. R.Soc. Med., 44, I63.

BLEISCH, V. R., and ROBBINS, S. L. (1952), Arch. intern. Med.,89, 877.

CAUGHEY, J. E., JAMES, A., and MACLEOD, E. K. (1952),Brit. med. 7., 1, I2i6.

CHALMERS, T. M., and LEWIS, A. A. G. (I95i), Lancet, ii,I I 58.

CLAUDE, H., and GOUGEROT, H. (1907), C. r. soc. Biol., 63,785.

COOKE, R. T., and SHEEHAN, H. L. (I95O), Brit. med. 7., i, 928.DOTT, N. M., BAILEY, P., and CUSHING, H. (1925), Brit..7.

Surg., 13, 314-ESCAMILLA, R. F. (I949), Ann. intern. Med., 30, 249.ESCAMILLA, R. F., and LISSER, H. (1942), J. clin. Endocrinol.,

2, 65.FARQUHARSON, R. F. (I950), ' Simmonds' Disease.' Spring-

field, C. C. Thomas.FARQUHARSON, R. F., and GRAHAM, D. (193I), Tr. Ass.

Amer. Phys., 46, I50.FARQUHARSON, R. F., BELT, T. H., and DUFF, G. L. (1938),

Tr. Amer. Clin. and Climatol. A., 54, io6.FRASER, R. W., and SMITH, P. H. (194I), Quart. .7. Med., Io,

297.FRASER, R. W., ALBRIGHT, F., and SMITH, P. H. (I941),

.. clin. Endocrinol., I, 297.GLINSKI, L. K. (1913), Przegl. Lek., 4, I3.GRANT, F. (1948), . Amer. med. Ass., 136, 668.HART, F. D. (I95i), Brit. med. J., ii, 795.HEWER, T. F. (I944), J. Endocrinol., 3, 397.HUBBLE, D. (1952), Lancet, i, 1123.HURXTHAL, L. M., BRUNS, H. J., and MUSULIN, N. (I949),

.7 clin. Endocrinol., 9, 1245.JAKOB, A. (1923-4), Virchowv's Arch., 246-7, ISI.

KLINEFELTER, H. F., ALBRIGHT, F., and GRISWOLD,G. C. (I943), J. clin. Endocrinol., 3, 529.

LI, C. H. (1952), ' Ciba Foundation Colloquia on Endocrinology',Vol. 4, p. 260. London, J. & A. Churchill.

McINTQSH, H. W., McALPINE, H. T., SINGER, B., andHOFFMAN, M. M. (1950), 'Proceedings of the First ACTHConference,' p. 20. London, J. & A. Churchill.

MEANS, J. H., HERTZ, S., and LERMAN, J. (1940), Tr. Ass.Amer. Phys., 55, 32.

OELBAUM, M. H. (1952a), Brit. med. J., ii, I o.OELBAUM, M. H. (I952b), Quart. J. Med., 21, 249.PASCHKIS, K. E., and CANTAROW, A. (I95I), Ann. intern.

Med., 34, 669.ROBERTSON, J. D. (I95Ia), Lancet, ii, 282.ROBERTSON, J. D. (I5sib), Brit. med. J., i, 921.ROBINSON, F. J., POWVER, M. H., and KEPLER, A. J. (194I),

Proc. Mayo Clin., I6, 577.ROLLAND, C. F., and MATTHEWS, J. D. (1952), Brit. med. J.,

i, 1220.

SHEEHAN, H. L., and MURDOCH, R. (I938), J. Obst. Gynaec.Brit. Emp., 45, 456.

SHEEHAN, H. L., and SUMMERS, V. K. (1949), Quart. J. Med.,18, 3I9.

SHEEHAN, H. L.; and SUMMERS, V. K. (1952), Brit. med. J.,i, 1214.

SIMMONDS, M. (I914), Dtsch. Med. Wschr., 40, 322.SIMPSON, J. Y. (I872), ' Clinical Lectures on Diseases of Women.'

Edinburgh (quoted by Sheehan and Murdoch).SUMMERS, V. K., and SHEEHAN, H. L. (i95I), Brit. nred. J.,

ii, 564.THORN, G. W., FORSHAM, P. H., FRAWLEY, T. F., HILL,

S. R., ROCHE, M., STAEHELIN- D., and WILSON, D. L.(I950), New Engl. J. Med., 242, 783.

THORN, G. W., FORSHAM, P. H., PRUNTY, F. T. G.,BERGNER, G.&E., and HILLS, H. E. (1949), Ann. N.Y.Acad. Sci., 50, 646.

VENNING, E. H., and BROWNE, J. S. L. (I947), J. clin. Endo-crinol., 7, 74.

YOUNG, F. G. (1952), 'Ciba Foundation Colloquia on Endo-crinology,' Vol. 4, p. 255. London, J. & A. Churchill.

ZONDEK, B. (1930), Klin. Wschr., 9I, 1207.

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