LACK OF EFFECT OF HYPOPHYSECTOMY UPON METASTATIC ADRENOCORTICAL CARCINOMA WITH CUSHING’S SYNDROME: A CASE REPORT*
ABBIE I. KNOWLTON, M.D., JAMES LAWRENCE POOL, M.D. AND JOSEPH W. JAILER, M.D.
The Departments of Medicine, Neurosurgery, and Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons, and the Presbyterian Hospital, New York, N.Y.
T HE consideration of hypophysectomy as a palliative measure in the therapy of malignancy was stimulated by the appearance in 1950 and 1951 of a series of papers from Evans’ laboratory showing that the injec- tion of pituitary growth hormone over prolonged periods approximately doubled the incidence of spontaneously appearing neoplasms in rats (1), whereas in hypophysectomized animals observed for a comparable period of time, with or without growth hormone injections (2), far fewer tumors developed than in control animals.
An interesting review of the literature by Archer (3) included 13 in- stances of hypopituitarism and coexisting neoplasms. Of these, 4 were cancers of the stomach, 3 of the bronchi, 2 of the uterine cervix, and 1 each of esophagus, colon, mediastinum and thyroid (sarcoma). Hence, in hu- mans, the existence of hypopituitarism does not preclude the appearance of cancer.
The effect of hypophysectomy, once a neoplasm is established, has not, to our knowledge, been investigated in animals. In humans, a report by Shimkin et al. (4) of hypophysectomy in a young man with metastatic malignant melanoma appeared last year. In the nine weeks which the patient survived postoperatively, clinical evidence of hypopituitarism supervened. At death the findings, apart from the evidences of neoplasm, included complete absence of hypophyseal tissue with the exception of one focal area containing about two dozen cells, and atrophy of the target endocrine organs. No significant effect of the operation upon the growth of the neoplasm could be demonstrated.
More recently Luft and Olivecrona (5, 6) have described the application
* Aided by grants from the Albert and Mary Lasker Foundation, the James Founda- tion Gift for Brain Surgery, and the American Cancer Society, as recommended by the Committee on Growth, National Research Council.
of this operation in 12 patients with malignancy. Of these, one with a chorionepithelioma and another with a breast neoplasm were strikingly improved. An additional patient has been reported by Perrault et al. (7).
The subject of the present case report was a young man with an evident metastatic adrenocortical carcinoma, presenting the clinical_picture of Cushing’s syndrome. Hypophysectomy was undertaken in this patient in the hope that 1) the growth of the neoplasm might, like that of normal adrenal tissue, in some measure be dependent upon the endogenous produc- tion of ACTH, and/or 2) the operation might serve nonspecifically to inhibit tumor growth. The results of the operation were clinically disap- pointing. Indeed, the paucity of demonstrable change in endocrine function was striking during the seven weeks of life following the operation. Since no remaining pituitary tissue could be demonstrated at autopsy these unusual findings were considered to be related to the persistence of hor- mone production by the autonomous malignant tissue, which in one sense maintained the patient’s life, while in another it hastened his demise.
C.R. (P.H. unit #072193), was a 26-year-old married man who was referred to Dr. Henry Aranow, Jr., and by him to the wards of the Columbia-Presbyterian Medical Cen- ter in November 1951, with a history of progressive weakness and a 29-pound weight gain over a period of four months. Hypertension had been noted by his family physician two and a half months after onset of symptoms. For this, the patient was given a 1,000-calorie salt-poor diet, during which treatment he lost 20 pounds in ten days. At the time of his hospitalization further questioning brought out the additional points that his weight gain had been limited to the head and trunk, and that there had been changes in his skin; his face had become ruddy and dry, and he had demonstrated a tendency to easy bruis- ability, with acneiform lesions. He admitted nocturia, averaging three times nightly, but he specifically denied having headaches, loss of libido or backache.
On physical examination he appeared a pleasant, intelligent young man of asthenic build, his height being 184 cm. and weight 67.7 Kg. In contrast to his over-all leanness, his face appeared rounded and chipmunk-like, with a ruddy complexion. Body hair was present in normal male distribution; however, dryness and thinness of the skin were evident. Careful search revealed three small purple striae, one inside the left thigh, and one above and posterior to each iliac crest. His blood pressure was 190/120, pulse 80, and temperature 99º F. per rectum. The rest of the findings on physical examination were within normal limits. Specifically his eyegrounds appeared normal. There was no evi- dence of cardiac enlargement or decompensation, i.e., no basal rales, peripheral conges- tion, hepatic enlargement or ankle edema.
Initially laboratory studies revealed the following: hemoglobin 15.0 Gm., erythrocyte count 5.6 million per cu. mm .; white blood cell count 11,000 per cu. mm .; polymorpho- nuclear leucocytes 82 per cent; lymphocytes 16 per cent, monocytes 2 per cent. The quantitative eosinophil count was 25 per cu. mm., and the erythrocyte sedimentation rate was 7 mm. in one hour. Urinalysis: specific gravity 1.023; no albumin or glucose; microscopic, unremarkable. The Mazzini test for syphilis gave negative results. The con- centration of blood sugar, fasting, was 103 mg. per 100 cc. After an oral dose of 100 Gm. of glucose the blood sugar level rose at one-half hour to 204, at one hour to 303, and at
two hours to 339, with a final value at three hours of 213 mg. per 100 cc. Serum sodium concentration was recorded as 139.1 and 144.1 mEq., potassium as 2.6 and 2.8 mEq., carbon dioxide 35.8 and 37.3 m Eq. and chlorides 96.1 and 98.7 mEq. per liter; urea nitro- gen 11 mg., calcium 9.9 mg., phosphorus, 2.7 mg., and alkaline phosphatase 3.5 Bodansky units per 100 cc. The initial value for urinary 17-ketosteroid excretion was 35.5 mg. (nor- mal, 8-20) in twenty-four hours, and for “corticoids” as determined by the formaldehy- dogenic method, 2.8 (normal, 0.5-1.5) mg. in twenty-four hours.
An electrocardiogram and an electroencephalogram showed nothing abnormal. A benzodioxane test gave no evidence that the hypertension was due to excess amounts of circulating epinephrine or norepinephrine.
X-ray examination of the skull showed no abnormality of the sella turcica and no de- mineralization, nor was there any evident demineralization of the thoracic spine. The initial x-ray films of the chest showed no cardiac enlargement and normal lung fields. By intravenous pyelography, there was a suggestion of an irregularity of the left renal pelvis. The introduction of air retroperitoneally outlined a mass above the left kidney, which was even more clearly delineated by an aortogram.
Course: After preoperative preparation with 100 mg. of cortisone acetate (given in- tramuscularly at twelve-hourly intervals beginning thirty-six hours before the procedure) and 5 mg. of desoxycorticosterone acetate (given the morning of operation), Dr. George Cahill removed the left adrenal and tumor on December 11, 1951. The tumor weighed 407 Gm. and Dr. M. M. Melicow reported that histologically it appeared malignant. Nests of cells were noted extending out beyond the tumor capsule. A surprising finding was the histologic pattern of the adjacent “normal” adrenal tissue; instead of the antic- ipated atrophy, this tissue appeared hyperplastic with a preponderance of “foam cells.”
The postoperative period was essentially uneventful and at the time of discharge on December 27, 1951, fifteen days after operation, the patient was feeling well and was receiving no medication. Although the persistence of significant hypertension raised the question of possible metastases, comfort was derived from the normal serum electrolyte values at the time of discharge (sodium 141.2, potassium 3.5, carbon dioxide 30.0 and chloride 100.0 mEq. per liter), along with a fall in the urinary 17-ketosteroid excretion to 14.5 mg. per twenty-four hours.
At home during the ensuing weeks his symptoms recurred and, in addition, he had pain in the mid-thoracic spine. When seen in clinic at the end of a month’s time, his blood pressure was recorded as 170/120. Plethora persisted and new developments were tender- ness over the seventh thoracic vertebra and hepatomegaly to the extent of two finger- breadths. These were considered indicative of metastases and the patient was readmitted to the hospital.
Studies during this second admission revealed the development of marked abnor- malities in serum electrolyte concentration (sodium 153.6, potassium 1.9, carbon dioxide 41.8 and chlorides 94.7 mEq. per liter), the appearance of frank diabetes (fasting blood sugar levels, as high as 222 mg. per 100 cc., and a daily insulin requirement of 20 to 35 units to control partially the heavy glycosuria), and a return to a markedly increased 24-hour urinary excretion of 17-ketosteroids (51.6, 40.8, 39.3 and 53.1 mg.). Apart from this physiologic evidence of excessive and abnormal adrenal function, there were con- firmatory findings of metastatic disease, which included x-ray shadows suggestive of pulmonary metastases and of an osseous lesion in T7, and a bromsulphalein retention of 20 per cent thirty minutes after the injection of the dye. The neutral extract of a 24-hour urine specimen was chromatographed according to the Devis (8) modification of the Dingemanse method. The eluates showing the highest concentration of Zimmermann
chromogen were analyzed by infrared spectrophotometry through the courtesy of Dr. Seymour Lieberman (Fig. 1). Dehydroisoandrosterone was found in no higher concen- tration than in the urine of the normal male, the values for which are included in the figure for comparison. This steroid is often found in high concentrations in certain adrenal tumors. Androsterone and etiocholanolone were present in higher concentration in this patient than in a normal man. More significant, however, was the finding of appreciable
100
90
80
C.R. -
Normal Ở —
70
MG “17-KS”
60
50
I
I
-
-
-
40
.30
20
10
0
5
10
15
20
25
30
35
40
45
ELUATE NUMBER
quantities of 11-keto-etiocholanolone, as contrasted with the excretion in the normal male. This steroid is a known degradation product of cortisone or 17-hydroxycorticoster- one.
The patient was given 100 milligrams of cortisone over a four-day period, to deter- mine whether the resulting suppression of pituitary function with reduction in endoge- nous ACTH excretion would influence the adrenal steroid output of the metastases, i.e., whether the tumor remained to any extent under pituitary influence. The third and fourth day of cortisone injections his 24-hour urinary excretion of 17-ketosteroids was 56.1 and 63.0 mg., respectively, indicating no downward trend in steroid output. In this he differed from patients in whom Cushing’s syndrome is associated with adrenal hyperplasia (9).
Radiation of the pituitary was contemplated, although the foregoing results augured poorly for the likelihood of its being beneficial, However, before such therapy could be instituted, an acute organic psychosis developed, with associated schizophreniform features which necessitated his being admitted to the New York Psychiatric Institute.
While there, on an unrestricted carbohydrate intake, a dose of standard insulin up to 80 units per day was required partially to control his glycosuria.
At this time hypophysectomy was suggested as an admittedly desperate thera- peutic approach. Accordingly, on February 28, 1952, Dr. J. L. Pool performed a com- plete hypophysectomy through a right frontal craniotomy.
Sections of the excised anterior pituitary showed “Crooke’s” changes in the basophils. The operation lasted four hours, and from a neurologic point of view the patient’s course was eminently satisfactory both during and throughout the postoperative period. Di- lantin and phenobarbital were given postoperatively and penicillin prophylactically. To protect against possible hypoglycemia after hypophysectomy the patient was given cortisone preoperatively and this was continued for three days postoperatively, in di- minishing dosage. Subsequently, in view of persistent heavy glycosuria, it was omitted; for the remaining six and one-half weeks of his life no adrenal substitution therapy was given.
Immediately after operation insulin was administered with some trepidation but it soon became apparent that sensitivity to this hormone had not been markedly altered, and 10 to 20 units of insulin were required daily until the day of his death. Eighteen blood sugar determinations were made during the seven-week period following hy- pophysectomy, during which the fasting values varied from 177 to 444 mg. per 100 cc. Throughout the period, intermittent glycosuria persisted.
Despite the fact that no adrenal substitution therapy was employed after the third postoperative day, serum sodium values did not fall below normal, and twenty-four hours prior to death a value of 135.3 mEq. per liter was obtained (Table 1). The serum potassium concentration rose from the strikingly low preoperative levels and terminally was 4.7 mEq. per liter.
Throughout the post-hypophysectomy period the excretion of 17-ketosteroids con- tinued to be strikingly elevated. A single determination of urinary “corticoids” made four weeks after hypophysectomy was 8.4 mg. in twenty-four hours, a markedly ele- vated value.
Postoperatively the urine volume rose to 4,300 cc. in the first twenty-four hours; and when heavy glycosuria was not present, the specific gravity was extremely low. Posterior pituitary extract was given in doses of 5 units, and the urine volume diminished some- what although, because of incontinence, accurate measurements could not be obtained. It was found expedient, both from the point of view of the patient’s comfort and as a practical help in nursing care, to continue posterior pituitary extract, which was given twice daily. During this regimen, urinary output ranged as high as 3,700 cc. in the ab- sence of heavy glycosuria.
Attempts to evaluate thyroid function were of necessity limited. The patient’s emo- tional lability made it difficult to measure his basal metabolic rate. However, in the fourth week after hypophysectomy a fairly satisfactory pair of tracings averaged -1 per cent. Serum cholesterol concentration (on two occasions in the third and fourth post- operative week) was low, perhaps related to his widespread malignant disease. His mental abnormalities precluded the cooperation necessary to obtain an estimation of radioactive iodine uptake.
The patient continued to deteriorate slowly following the hypophysectomy, although his appetite remained good. His mental abnormalities fluctuated from day to day but the basic aberration remained unchanged. Ascites developed, and the hypertension de- creased gradually postoperatively and in the week prior to death ranged from 140/86 to 130/84. In the seventh postoperative week frank pulmonary edema occurred; in spite of
| Three wks. preop. | Imme- diately preop. Feb. 27 | Postoperative week | |||||||
|---|---|---|---|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | 6 | 7 | |||
| Mar. 5 | Mar. 12 | Mar. 21 | Mar. 25 | Apr. 1 | Apr. 7 | Apr. 15 (day before death) | |||
| Weight, Kg. | 60.5 | 59.85 | 57.78 | 59.0 | 60.0 | 58.19 | |||
| Blood pressure | 180/120 | 180/120 | 152/94 | 148/86 | 140/88 | 140/100 | 150/90 | ||
| Cortisone acetate, daily dose (mg.) | 75-25 | 0 | 0 | 0 | 0 | 0 | 0 | ||
| Insulin, daily dose (units) | 0 | 45* | 24* | 20* | 0 | 15t | 20+ | 10} | |
| Glycosuria (max.) | +++ | ++++ | ++++ | ++++ | ++++ | +++ | ++++ | 0 | |
| Fasting blood sugar (mg./100 cc.) | 222 | 308₫ | 384 | 213 | 179 | 213 | 204 | 225 | 211± |
| Urine specific gravity, (max.) § | 1.010 | 1.004 | 1.015 | 1.012 | 1.015 | ||||
| Post. pituitary hormone, daily dose (units) | 5 | 5 | 10 | 10 | 10 | 10 | 0 | ||
| Serum sodium | 153.4 | 137.0 | 137.2 | 143.0 | 144.1 | 140.9 | 144.2 | 138.3 | 135.3 |
| potassium | 2.3 | 2.9 | 3.8 | 2.7 | 2.8 | 3.5 | 3.5 | 2.9 | 4.7 |
| (mEq./L.) CO2 | 39.3 | 29.5 | 38.2 | 33.8 | 33.9 | ||||
| chlorides | 98.0 | 96.2 | 97.4 | 94.8 | 100.3 | ||||
| Urinary 17-ketosteroids (mg./ 24 hrs.) | 63.0 | 41.6 | 45.1 | 44.0 | |||||
| Urinary corticosteroids (mg./24 hrs.) | 8.4 | ||||||||
| Basal metabolic rate (%) | -1 | ||||||||
| Serum cholesterol (mg./100 cc.) | 117 | 138 | |||||||
| Blood vol. (cc.) | 4,450 | 4,760 | |||||||
| Plasma vol. (cc.) | 3,000 | 2,950 | |||||||
| Hematocrit (%) | 32.6 | 38.5 | 38.1 | ||||||
* Standard insulin.
t NPH insulin.
# Not fasting.
§ Maximal gravity recorded when urine contained no more than ”+” glucose and when eight hours or more had elpased since an injec- tion of posterior pituitary hormone.
A. I. KNOWLTON, J. L. POOL AND J. W. JAILER
February, 1954 HYPOPHYSECTOMY IN METASTATIC ADRENAL CA. 211
treatment with the usual measures, this edema persisted and led to his death twenty- four hours later.
Autopsy findings revealed 2,500 cc. of bloody ascitic fluid and great clusters of grape- like tumor nodules which hung from the peritoneal surfaces. The heart weighed 350 Gm. and the aorta was surprisingly free of atheromata. The lungs were edematous. A few subpleural nodules were present in both lower lobes. The liver weighed 4,440 Gm., and on cross-section there were myriads of tumor nodules of all sizes up to 8 centimeters in diameter. The pancreatic tissues appeared normal. The right kidney weighed 175 Gm .; the left, though not weighed, appeared to be about the same size.
The whole region of the left adrenal was filled with large masses of white and reddish tumor, packed together like fieldstones in a wall. No adrenal tissue was unequivocally identified on the left. The right adrenal was entirely free of tumor, and was reduced in size (weight, 3.5 Gm.). On section the cortex was obviously thinner than usual, and bright orange in color; the medulla appeared normal.
The prostate was small, measuring perhaps 2 cm. in diameter. The testes were small and soft. The thyroid weighed 15 Gm. and was slightly nodular. Three parathyroids were found; they were of normal size and appearance. No osteoporosis was grossly de- tectable.
The brain, apart from the evidence of the operative procedures, was grossly normal. The pituitary fossa appeared empty.
Microscopic examination: The skin showed atrophy of the dermis and epidermis. The heart and aorta were essentially normal. In the lungs the presence of pulmonary conges- tion was confirmed; some areas showed pneumonia and foci of carcinoma. The liver, in addition to multiple areas of tumor invasion, showed a number of foci of necrosis, mostly central. Most of the tumor cells on section resembled cortical cells depleted of lipid, al- though there were undifferentiated variants.
The right adrenal gave the impression of a miniature but perfect gland, except for the marked vacuolization of nearly all cells of the cortex. The medulla was not remarkable. The prostate showed some piling up of epithelium in the glandular lumina. In the testes, basement membranes were thickened and, although there was some cell division among spermatocytes, no spermatozoa were seen. The thyroid contained follicles of medium size, composed of low cuboidal cells with abundant colloid. In the pancreas, islets of Langer- hans seemed unusually abundant. The parathyroids were not remarkable. Brain: In sections of the floor of the sella turcica no pituitary tissue was found. The leptomeninges about the tuber cinereum and infundibulum contained some red blood cells, lymphocytes and small numbers of large mononuclear cells. There were numerous small recent hemor- rhages in the tuber cinereum, and the adjacent floor of the third ventricle showed a fresh proliferation of ependymal granulations. The supraoptic nucleus on one side showed a decrease in the total number of its nerve cells and an associated astrocytosis. The same nucleus on the other side was disrupted by a series of small recent hemorrhages, and was rather edematous, as was the adjacent superficial aspect of the dorsal portion of the optic tract. There was shrinkage of many of the nerve cells in the corpora mammillaria. The paraventricular nuclei bilaterally showed no unusual change.
DISCUSSION
Hypophysectomy was advocated in this patient, with the hope that the neoplastic tissue would prove to have that dependency upon an endogenous supply of ACTH which characterizes the normal adrenal cortex. Were this
the case, regression of the tumor could be anticipated following surgical removal of the pituitary. This hope was not substantiated postoperatively, and the patient’s downhill course appeared unaffected by the procedure. The alternate possibility that tumor growth might be depressed non- specifically by the induction of a hypopituitary state remained unexplored, since the continued production of steroids by the metastatic cells prevented the establishment of panhypopituitarism.
An astonishing feature of this patient’s course was the sustained ability of the highly malignant tissue to elaborate a variegated steroid pattern. Since autopsy indicated that the pituitary had been satisfactorily ex- tirpated and the one remaining adrenal was atrophic, as was to be expected from the deprivation of all ACTH, it is evident that the source of the adrenal steroids was the metastatic tumor tissue.
Perhaps the most striking evidence of steroid activity was the fact that hypophysectomy had no significant effect upon the diabetes. Heavy glycosuria persisted, insulin requirements were essentially unchanged, each of the eighteen blood sugar determinations made postoperatively showed significantly elevated values, and no definitive insulin shocks were en- countered. This condition obtained, although no adrenal substitution therapy was given for the last six weeks of life. It should be mentioned that the first hypophysectomy involving a normal pituitary, reported by Chabanier et al. in 1936 (10), was undertaken in a young boy with severe diabetes. Postoperatively his daily insulin requirement fell from about 140 units to only 80 units. However, unlike the patient in the present report, no autopsy was performed; hence, the completeness of the hypophysec- tomy was not established. Certainly since the classic studies of Houssay, the ameliorating effect of hypophysectomy on pre-existing diabetes has been well recognized, and it is well known that recurrent hypoglycemia may present a difficult problem in the management of hypopituitary pa- tients. In view of this, the physiologic activity of this patient’s neo- plastically produced “steroids” is the more impressive.
Another evidence of the physiologic activity of steroids elaborated by the metastatic tumor was the maintenance of serum electrolyte levels in the absence of added salt, or steroid replacement therapy. The abnormal- ities associated with excessive cortisone were intermittently present post- operatively-the carbon dioxide content of the blood was consistently elevated and the potassium and chloride levels were frequently reduced below normal. The sodium concentration fluctuated, but was for the most part normal.
A feature of hypophysectomy which has recently been investigated ex- perimentally in Evans’ laboratory by Garcia et al. (11) and by Van Dyke et al. (12) is the reduced blood and red cell volume. These workers have
shown that whereas this abnormality is not corrected in rats by the ad- ministration of growth hormone, it is corrected by the administration of ACTH with the resulting normal amounts of circulating cortical hormones. In the present patient it was of interest to note that no change in blood volume (Table 1) could be demonstrated between the first and fifth weeks after hypophysectomy.
Corroborating these physiologic evidences of hormone secretion were the studies on urinary excretion of steroid metabolites. On the basis of the chromatographic studies it is possible to say that although quantitatively in great excess, the pattern of steroid secretion in this patient conformed to that seen in normal subjects, except that there was a higher percentage of 11-keto-etiocholanolone (Fig. 1).
Following the operation there was a significant reduction in blood pres- sure, not to normal values but certainly to a more normal range than had existed previously. How much this should be ascribed to the hypophysec- tomy is problematical. Certainly all other evidences of hyperadrenalism persisted and yet it seems unlikely that the reduction could have been the result of the inanition associated with malignancy, since the patient held his weight and continued to eat well. One last but particularly tragic aspect of the persistent hyperadrenalism was the continued psychotic condition.
Little comment can be made upon the function of the posterior pituitary, because of the paucity of data. Immediately after hypophysectomy the patient’s fluid turnover was markedly abnormal; undoubtedly part of this was due to heavy glycosuria, but when glycosuria was intermittently absent the patient continued to excrete large volumes of urine of low specific gravity. He was treated for this condition with posterior pituitary extract, until his death. In the latter weeks, a rise in urinary specific gravity to as high as 1.015 suggested some amelioration of the diabetes insipidus.
Even less can be said regarding thyroid function. The normal basal metabolic rate obtained in the fifth week after hypophysectomy is out of line with the gross anatomic evidence of atrophy of this gland at autopsy. However, the patient was paranoid and in a borderline state of cardiac failure; these factors may have prevented his achieving a basal state.
SUMMARY
This report describes a 26-year-old man with metastatic adrenocortical carcinoma, accompanied by typical Cushing’s syndrome. No significant change in the clinical picture occurred after complete removal of the pituitary, with the exception of the appearance of a state resembling mild
diabetes insipidus. No steroid replacement therapy was given subsequent to the first week after hypophysectomy. Nevertheless, the severe diabetes mellitus, normal serum electrolyte values or values suggesting hypo- chloremic alkalosis, markedly elevated urinary excretion of 17-ketosteroids and corticoids, and the pre-existing psychosis all persisted essentially un- changed.
Death occurred seven weeks after extirpation of the pituitary. An autopsy confirmed the completeness of the hypophysectomy and demon- strated moderate atrophy of the target endocrine glands-thyroid, testes and remaining adrenal. Metastatic malignant tissue was widespread.
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10. CHABANIER, H .; PUECH, P .; LOBO-ONELL, C., and LELU, E .: Hypophyse et diabète à propos de l’ablation d’une hypophyse normale dans un cas de diabète grave, Presse Med. 44: 986, 1936.
11. GARCIA, J. F .; VAN DYKE, D. C .; HUFF, R. L .; ELMINGER, P. J., and ODA, J. M .: Increase in circulating red cell volume of normal and hypophysectomized rats after treatment with ACTH, Proc. Soc. Exper. Biol. & Med. 76: 707, 1951.
12. VAN DYKE, D. C .; SIMPSON, M. E .; GARCIA, J. F., and EVANS, H. M .: Inability of growth hormone to prevent the anemia which follows hypophysectomy, Proc. Soc. Exper. Biol. & Med. 81: 574, 1953.