Act& ledica Seandinavicn. Vol. CXLV, fnsc. V, 1963.

From University Hospital Rikshospitalet, Department of Internal Medicine, Oslo, Norway. (Physician in chief Prof. P. A. Owren, M. D.)

Diabetes and Hypopituitarism. A Case of Diabetes with Postpartum Necrosis of the Anterior Lobe of

the Pituitary Ctlnnd Followed by Improvement of the Diabetes. BY

HAAKON STORM MATHISEN,

(Submitted for publioation November 19, 1962.)

Glinski (1912) and Simmonds (1914) discovered that a destructive lesion of the anterior lobe of the hypophysis may be associated with a characteristic deficiency syndrome. The clinical significance of postpartum hemorrhage as a cause of pituitary necrosis was first clarified by Sheehan (1937). It is a well- established fact (Houssay, 1930) that pancreatectomy in hypophysectomized dogs is followed by mild diabetic symptoms only, the hyperglycaemia and glycosuria being much less severe than in non-hypophysectomized animals. Clinical experience along these lines is scarce. Lyall & Innes (1935) described a case of diabetes with a pituitary tumour causing improvement of the diabetic symptoms. According to Israel & Conston (1952) only seven cases in all have been reported of pituitary hypofunction in true diabetics.

The following is a record of a patient with diabetes, who developed hypo- pituitarism after delivery in 1945; she has been controlled regularly during the past thirteen years:

The patient is a farmer’s wife, aged 30. Her family history presented no important features. Fourteen years old she had alopecia after scarlet fever, and about the same time her diabetes was discovered.

Seventeen years old she was admitted into the University Hospital of Oslo suffering from diabetic coma. Her requirement of insulin was found to be 80 I. U. when on a diet with 150 g of carbohydrates. During the following years she was hospitalized several times, often due to diabetic coma. In 1943 her requirement of insulin was about 116 I. U. on an average diet with 125 g of Carbohydrates. In 1946 the patient became preg- nant, and her insulin requirement decreased slightly during pregnanoy. The delivery was complicated with fever and hemorrhage, and since then her requirement of insulin

DIABETES A S D IIYI’OI’ITUITARISM.

insulin I.U. 120 ~ Rcquircmcnt of I nsulin

40

20

Pregnant

1 .- B - Y

i

32 7

Fig. 1.

further decreased to about 35 I. U. She had no lactation. Her child, however, developed normally. During the following years she had repeated attacks of hypoglycemia, and the daily

dose of insulin, therefore, had to be reduced gradually down to 8 I. U.

Fig. 2. 14-yeere-old. before disoovery of diebetee.

338 HAAKON STORM MATELSEN.

Fig. 3. On admission 1951.

Menstruation became irregular and scarce with long periods of amenorrhoea. She has not since been ptegnant.

In October 1951 the patient was admitted into the University Hospital because of menorrhagia of several months' duration.

Physical examination. Complete loss of hair was found, not only of the head, but also of eyebrows, axillae and pubes. The skin, especially of the face, was dry and atrophic. Her voice was rough and hoarse. She had severe constipation.

Diabetic cataract of the left eye had been operated on in 1946, and she had now cataract of the right eye. In the Gynaecological Department i t was found that this young woman had developed ))senile)) oolpitis and had a rather atrophic uterus.

Cardiovascular system. The basal blood pressure was 901'70 mm Hg. Radiographically the heart and the aortic shadows were normal. The electrocardiogram showed no abnormalities.

Radiography. The pituitary fossa was rather small, but normal in shape. There was no radiographic evidence of lesion in the skull.

Neurological examination disclosed signs of diabetic polyneuritis. EEG normal.

DIABETES AND HYPOPITUITARISM. 329

Laboratory Examination.

Hematology. Blood count showed Hb 74 % (11.4 g per 100 ml), red cells 3,740,000 per cmm, colour index 0.09, white cells 9,000 per ccm, neutrophils 57 %, lyphocytes 33 %, monocytes 7 yo, eosinophils 2 %, basophila 1 yo. The erythrooyte sedimentation rate (E. 5. R.) was increased to 65 mm in one hour (Westergren).

Serology. The Wassermann reaction in serum was negative. Thyroid Gland. The basal metabolic rate (B. M. R.) was -47 (standards of Aub-Dubois),

serum cholesterol level 262 mg per 100 ml, suggesting that thia was not a case of primary myxoedema, and that the fall in basal metabolism was due to secondary dysfunction of the thyroid gland.

Adrenal Gland and Kidney. The total base was 141 mEq per litre, the serum potassium 23.4 mg, the non-protein nitrogen 69 mg, per 100 ml, and the serum chlorides 101 mEq/l. The urinary excretion of chlorides was 102 mEq/l and of urea 1,710 mg/100 ml. There was proteinuria, and the urea clearance gave a mean of 32 per cent. The Robinson- Kepler-Power water test was found positive with retention of water after intake of 20 ml per kilo of bodyweight. The Addison index was low, viz. 6. 17-ketosteroids in the urine were decreased to 0.8 and 0 mg per 24 hours.

Carbohydrate metabolism. A high sensitivity to insulin was demonstrated, the blood sugar decreasing from 0.500 to 0 .060 % after 12 I. U. of insulin (protamhe). An insulin test with 8 I. U. insulin intramuscularly resulted in decrease of blood sugar from 0 .420 to 0.147 % in three hours. 0.1 I. U. of insulin intravenously per kilo of bodyweight gave decrease in blood sugar from 0.370 to 0.170 % in one hour. Without insulin treatment the patient developed ketonuria and blood sugar about 0.600 yo.

Dingnosis.

The clinical picture resembled that of myxoedema, though the skin, especially of the face, was found to be thinner and more atrophic than usual in this disease. In addition were found clinical and laboratory signs of adrenal cortical insuf- ficiency without changes in pigmentation. There were also abnormalities of the menstrual cycle and of the secondary sex characteristics with loss of axillary and pubic hair, indicating a disturbance of the gonadal function. The clinical picture therefore, was characteristic of pluriglandular deficiency syndrome of the type seen in hypopituitarism.

Treatment. The patient was treated with thyroxin in small doses only because of the

well-known sensitivity to thyroxin observed in patients suffering from hypo- pituitarism. A daily amount of 0.2 to 0.3 mg l-thyroxin-sodium for seventeen days did not influence the requirement of insulin, but increased the B. M. R. from -47 % t o -35 %.

During the following seventeen days the thyroxin treatment was combined with corticotropin (ACTH) prepared from whale hypophysis (manufactured by Nyegaard & Co., Oslo). The usual decrease of eosinophilio cells in the blood was found during corticotropin treatment, indicating normal response of the supra- r end glands. Apparently corticotropin is predominantly a ,glyco-corticotropic

330 HAAKON STORM MATHISEN.

hormone)) (Selye, 1951). In doses of 15-20 mg daily this type of corticotropin reduced the sensitivity to insulin, and the daily requirement increased from 8 to 40 I. U. A total of 225 mg corticotropin was given in the course of seventeen days without untoward reaction. The antagonism between insulin and adrenal cortical hormone is pointed out by Thorn (1949), who studied the metabolic changes in a diabetic with Addison’s disease. According to Selye (1951) pure, synthetic gluco-corticoids (e. g. cortisone) act essentially as ACTH.

As recommended by Summers & Sheehan (1951) the treatment was continued with cortisone, 50 mg daily, combined with 1-thyroxin-sodium 0.8 mg daily as before. This small amount of cortisone had no influence on the requirement of insulin. During this treatment the clinical condition improved, the patient felt well, the voice and the skin became normal, and the blood pressure increased to normal values. The patient was discharged after forty-two days’ treatment, the B. M. R. then being -32 per cent.

During three weeks a t home the treatment was continued with 50 mg cortisone perorally, 0.2 mg 1-thyroxin-sodium, 0.6 mg stilboestrol and 12 I. U. insulin daily. The patient developed severe headache, however, increased blood pres- sure and oedema, and the cortisone treatment consequently had to be discon- tinued. A new period of cortisone treatment with only 25 mg daily perorally, also produced oedema and had to be discontinued after twenty-four days. Later she has been treated with methyl-testosterone sublingually, 10-20 mg daily, and thyroxin as mentioned. The B. M. R. has increased to -16 per cent, the patient is feeling quite well, and is working on the farm.

Discussion. The clinical symptoms and the laboratory findings indicated polyglandular

insufficiency with decrease of the thyroid, suprarenal and gonadial function, characteristic of hypopituitarism. The pituitary lesion had occurred after severe postpartum haemorrhage and infection (1946), which according to Sheehan is the most common cause of hypopituitarism.

A most interesting fact is the steadily declining requirement of insulin from 115 I. U. to 8 or 10 I. U. daily during the years 1945-1951. Her diabetes be- came very sensitive to insulin as shown by the blood sugar rapidly falling from a fasting level of about 0.600 per cent to hypoglycemic values after a few units of insulin. An insulin test with 6 I. U. intramuscularly brought the blood sugar down from 0.420 to 0.147 per cent in one hour. The development of hypo- pituitarism, therefore, resulted in a complete change in her diabetes. Until 1945 she had been hospitalized several tines due to dangerous coma. Since then she has repeatedly had attacks of hypoglycemia, in spite of steadi,y reducing the dosage of insulin.

Treatment with corticotropin, 15-20 mg daily for a short period, was fol- lowed by an increase in the requirement of insulin. A single dose of 5 mg corti- cotropin also developed an increase in blood sugar to about 0.500 per cent in a few hours. 5 mg cortico-depot (Nyco) gave a similar increase in blood sugar,

DIABETES AND HYPOPITUITARIBM. 331

which lasted for about three days. This increase in blood sugar mag depend upon admixture of growth hormone and not on the ACTH per Be. This assumption finds support in the fact that a daily dose of 25-50 mg cortisone (cortone NMerck,) was not followed by any increase in blood sugar. Cortone, however, produced arterial hypertension, headache and oedema, and treatment had t o be discon- tinued, therefore. Thyroxin treatment increased the B. M. R. from -47 t o -16 per cent without changing the sensitivity to insulin.

Summary. A case of diabetes is described in a woman aged 30, in whom marked improve-

ment in the diabetic condition associated with insulin sensitivity simultaneously with symptoms of postpartum necrosis of the anterior lobe of the pituitary gland. The clinical situation is considered to be analogous to tha t of an ex- perimental animal, in which both the pancreas and the pituitary gland are destroyed. The treatment is discussed.

References.

Glinski, L. K. (1912): Przegl. lekarski 4: 13, ref. (1913), Deutsch. med. Wochenschr., 39, 473; and Robertson, J. D. (1951), Br. med. J. 1: 921. - Howsay, B. A. & Biasotti, A. (1930): Rev. SOC. argent. biol., 6: 251; abstracted (1930) in Compt. rend. SOC. biol., 105: 121. - Israel, S. L. & Conston, A. S. (1952): J. A. M. A., 148: 189. - Lyall, A. & Innes, J. A. (1935): Lancet, 1: 318. - Selye, H. (1951): Proc. Second. A. C. T. H. Conf. Vol. I, Blakiston Cp. N. York. - Sheehan, H. L. (1937): J. Path. & Bact., 45: 189. - Simmonds, M. (1914): Virchows Arch. f. Path. Anat., 217: 226. - Summers, V. K. & Sheehan. H. L. (1951): Brit. med. J., 2: 564. - Thorn, G. W. (1949): The diagno- sis and treatment of adrenal insufficiency, C. C. Thomas Co., Oxford. - Thorn, G. W. & Clinton, M. jr. (1943): J. Clin. Endocrinol. 3: 335.

23-430613. Acta med. Scandinau. Vol . CXLP.