Cushing’s Syndrome with Hypoglycemia Caused by Adrenocortical Carcinoma
MICHAEL J. EYMONTT, GRANT GWINUP, FRED A. KRUGER, DONALD E. MAYNARD, AND GEORGE J. HAMWI
Division of Endocrinology and Metabolism, Department of Medicine, and Clinical Research Center, University Hospitals, Ohio State University, 410 West Tenth Avenue, Columbus, Ohio 43201
ABSTRACT. The thirteenth case of hypo- glycemia associated with an adrenocortical carcinoma is reported. Preoperative levels of plasma insulin-like activity were normal by the rat epididymal fat-pad assay. Urinary 17- ketosteroids and 17-hydroxycorticoids, as well as plasma and urinary cortisol, were markedly elevated. The 17-ketosteroid frac- tionation showed markedly increased dehydro- epiandrosterone, androsterone and etiochol- anolone. Leucine, tolbutamide and manga- nese failed to produce hypoglycemia. At operation a 1450-g adrenocortical tumor was
found. Arterial-venous blood glucose differen- tial across the tumor was small. It is suggested that greatly increased secretion of anabolic steroids may channel amino acids into protein synthesis, thus making amino acids unavail- able for gluconeogenesis. It is postulated that in adrenal abnormalities associated with steroid hypersecretion either hypo- or hyper- glycemia may be produced, depending upon the relative proportions of catabolic and anabolic compounds secreted. (J Clin Endocr 25: 46, 1965)
T THE ASSOCIATION of hypogly- cemia with nonpancreatic tumors has been reported in over 60 instances (1). In the majority of cases the tumor has been a large fibrosarcoma. The first instance in which hypoglycemia was associated with an adrenocortical car- cinoma was reported by Anderson in 1930 (2). Until now there have been 12 similar cases reported (3-10). The pur- pose of this paper is to present the thirteenth such case with the results of special studies performed to characterize the hypoglycemia and to suggest a mechanism by which the hypoglycemia may be produced by steroids elaborated from the adrenocortical tumor.
Case Report
A 19-yr-old white married female1 had been well until 7 months before admission,
Received June 11, 1964; accepted August 24, 1964.
This study was supported in part by USPHS Clinical Research Center Grant FR-34, USPHS Training Grant T1 AM-5118, USPHS Research Grant AM-04052 and The Endocrine Research Fund of Ohio State University.
1 Referred to us through the courtesy of
when she noted the onset of facial hirsutism. Since that time her weight had gradually in- creased from 103 to 115 pounds. An acnei- form eruption had appeared on the face and over the back. She noted rounding of the face and some swelling of the feet. Her men- ses had become irregular during the 3 months preceding admission. For approximately 4 months before admission she had noted re- current episodes of profound weakness, trembling, double vision and hunger. These characteristically occurred in the morning before breakfast or at other times following strenuous activity. She had learned that these symptoms could be relieved promptly by taking carbohydrates in any form. The past history and system review were remark- ably negative.
Examination showed a well-developed, round-faced, alert young female with dark hair on the upper lip and chin and yellow downy hair over the sides of the face. The pulse was 80/min and the blood pressure was 142/94 mm Hg. The skin was oily, and there was an acneiform eruption on the face and upper back. Increased hair growth was noted on the forearms and legs, and escutcheon was
Major Fred W. TenEyck, MCUSAF, and Lt. Col. M. I. Freedman, MCUSAF, of the Wright- Patterson Air Force Base Hospital, Dayton, Ohio.
of the male type. There was a firm, non- tender, rounded mass which extended ap- proximately 6 cm below the left costal mar- gin and which moved with respiration. The liver was not enlarged. There were no striae or ecchymoses. The clitoris was questionably enlarged, but the pelvic examination was otherwise negative. The rest of the physical examination was within normal limits.
Hemoglobin was 13.5 g/100 ml, hematocrit was 41 %, and wbc was 10,500/ mm3 with total neutrophils 76%, lymphocytes 23%, and eosinophils 1%. Urinalysis was negative. Serum sodium was 154 mEq/l, potassium 3.6 mEq/1, chloride 117 mEq/1, and CO2 27 mEq/l. Albumin was 3.6 g/100 ml and globulin 2.1 g/100 ml. Serum calcium, phos- phorus and alkaline phosphatase were nor- mal. Following an overnight fast, the patient awakened in a confused state, and the blood glucose was 27 mg/100 ml. Repeated fasting blood sugars ranged between 20 and 40 mg/100 ml. Urinary and plasma steroids were greatly increased (Table 1).
X-ray studies of the skull, chest and upper gastro-intestinal tract were normal. The excretory urogram confirmed the presence of a large mass in the left upper abdomen with marked downward displacement of the left kidney and kinking of the left ureter. The electrocardiogram was normal.
During the period of study the patient re- ceived a regular diet with a special midnight feeding. She experienced several episodes of blurred vision and cloudy sensorium when breakfast was delayed so that special studies could be done. These episodes were relieved by the ingestion of carbohydrates.
At operation, there was a large tumor fill- ing the left upper quadrant. It was necessary to remove the spleen and part of the tail of the pancreas so that the tumor itself could be
resected. The tumor was brownish yellow and weighed 1450 g (Fig. 1). The right adrenal gland was judged to be atrophic. There was no evidence of metastasis, and no other ab- normalities were found on exploration of the abdomen and pelvis. A liver biopsy was taken.
A microscopic examination of the tumor revealed it to be an adrenocortical carcinoma with invasion of the capsule (Fig. 2). The spleen showed extramedullary hematopoie- sis. The pancreatic tissue was normal. The liver tissue showed no metastatic foci.
No hypoglycemic manifestations occurred postoperatively, and the fasting blood glu- cose ranged between 63 and 84 mg/100 ml. Serum sodium was 142 mEq/l, potassium 4.2 mEq/1, chlorides 99 mEq/l, and CO2 28 mEq/1. Three months following operation the Cushingoid features had almost com- pletely disappeared and the urinary steroids were normal.
| Preoperative range | Postoperative range | |
|---|---|---|
| Urine (24-hr) | ||
| 17-Ketosteroids | 85.8-236.0 mg | 1.1-6.8 mg |
| 17-Hydroxycorticoids | 35.7- 48.9 mg | 1.1-6.1 mg |
| Cortisol | 2199 µg | 10.0 µg |
| Aldosterone | 50 µg | 6.5 µg |
| Plasma Cortisol | ||
| 8 AM | 27.1 µg/100 ml | 12.6 ug/100 ml |
| Noon | 27.2 ug/100 ml | |
| 8 PM | 29.0 µg/100 ml |
Special Studies and Methods
Effects of agents known to produce hypo- glycemia under certain conditions were evaluated in the following manner: an aque- ous suspension containing L-leucine, 150 mg/kg of body weight, was administered orally in the fasting state. Blood sugars were obtained at 15, 30, 60, 90 and 120 min. Sodium tolbutamide, 1 g in distilled water, was injected intravenously over a 2-min period. Blood sugars were obtained at 15, 30, 60, 90, 120, 150 and 180 min. Manganese chloride, 10 mg, was administered orally, and blood sugars were obtained at 30, 60, 90, 120, 150 and 180 min. At the time of operation, blood was obtained from an artery going to the tumor and from a vein coming from the tumor for glucose analysis.
Fasting serum was assayed for insulin-like activity using a modification of the rat epi- didymal fat-pad technique as described by Power et al. (11). A portion of the adrenocor- tical tumor was quick-frozen and later sub- jected to acid-alcohol extraction and assayed for insulin-like activity using the fat-pad technique.2
? Kindly performed by Dr. Lawrence Power, University of Michigan, Metabolic Research Laboratory.
Standard oral glucose tolerance tests were done pre- and postoperatively using 100 g of glucose. A dexamethasone suppression test was done using 2 mg of dexamethasone (9a- fluoro-118,17,21-trihydroxy-16a-methyl-41,4- pregnadiene-3,20-dione) every 6 hr for 5 days while urine was collected for steroid analysis. Plasma cortisol was done by the method of Mattingly (2). The 17-ketosteroids and 17- hydroxycorticoids were measured by the methods of Klendshoj et al. (3) and of Porter and Silber (4), respectively. The 17-keto- steroids were fractionated as trimethylsilyl ethers by gas-liquid chromatography on a 5% XE-60 column following solvolysis by the method of Jacobsohn and Lieberman (5). Urinary aldosterone was measured by the method of Nowaczynski et al. (6). Blood sugars were done on the Autoanalyzer, using a modification of the method of Hoffman (7).
Results
The results of the administration of L-leucine, sodium tolbutamide and man- ganese chloride are depicted graphically in Fig. 3. The slope of the blood glucose curve following administration of these compounds did not differ from a control
BLOOD GLUCOSE (mg/100 ml)
60
CONTROL (fasting)
50
TOLBUTAMIDE
40
L-LEUCINE
30
MANGANESE
20
10
0
1/4 1/2
1
2
3
HOURS
curve except for an increase in blood glucose when the tolbutamide was given. Fasting serum contained 180 uU/ml of insulin-like activity (normal: 60-250 „U/ml) and the tumor 350 uU/g, this value being within the normal range for muscle, liver and kidney tissue (11, 18).
The blood glucose of arterial blood supplying the tumor was 191 mg/100 ml and that of the venous blood draining the tumor was 188 mg/100 ml. The glucose tolerance test performed prior to surgery (Fig. 4) showed fasting hypo- glycemia with an increase to 194 mg/100 ml at two hours and a return to hypo- glycemic levels at four and five hours. After operation, the blood glucose curve was normal for the first three hours but developed an unusual compensatory rise at four and five hours.
The urinary and plasma steroids pre- and postoperatively are shown in Table 1. The urinary cortisol was markedly elevated preoperatively, but aldosterone was only minimally increased. Before operation, plasma cortisol was increased and showed no diurnal variation. Frac- tionation of the 17-ketosteroids showed a urinary excretion of androsterone 16% (normal: 38-50%), etiocholanolone 41%
(normal: 30-47%), and 36-hydroxy-45- androsten-17-one 43% (normal: 16- 20%).
Five days of dexamethasone suppres- sion (Table 2) produced no significant decrease in the urinary steroids.
Discussion
Various hypotheses have been pro- posed to explain the mechanism of the production of hypoglycemia associated with nonpancreatic tumors. The hypoth- esis that has received the most atten- tion is the possibility that such tumors may manufacture insulin or insulin-like materials. To date six reports suggest that insulin-like activity has been found in increased amounts in the tumor or serum of patients with nonislet cell tumors associated with hypoglycemia (19-24).
In a case of adrenocortical carcinoma associated with hypoglycemia reported by Williams et al., plasma insulin-like activity was measured by the rat dia- phragm and was found to be normal (10). In diabetic patients increased insulin-like activity may be demonstrated by the epididymal fat assay, but it may be nor- mal by the rat diaphragm assay. Since
180
160
BLOOD GLUCOSE (mg/100 ml)
140
120
100
FIG. 4. Pre- and post- operative oral glucose tolerance tests.
80
60
PREOPERATIVE
40
POSTOPERATIVE
20
0
1/2
1
2
3
4
5
HOURS
failure to demonstrate increased insulin- like activity by the fat-pad assay would be better evidence for its absence, we chose to use this method rather than the rat diaphragm and we feel, therefore, that the normal results are more signifi- cant.
Although Oleesky et al. have reported probable leucine sensitivity in a patient with fibrosarcoma and hypoglycemia (25), no other such cases have been recorded. In our patient hypoglycemia was not produced by leucine.
Tolbutamide caused hypoglycemia in the majority of the islet-cell adenomas in which it has been tried. There is no re- port of a case in which tolbutamide has produced hypoglycemia in a nonislet cell tumor. In our case the administration of tolbutamide had no effect. In this con- nection, we disagree with the assumption of Boshell et al. that the increased in-
sulin-like activity that was measured when tolbutamide was administered to a patient with fibrosarcoma can be re- garded as evidence that the tumor secreted insulin (24). It is known that when tolbutamide is given to normal sub- jects increased insulin-like activity can also be measured. The secondary rise of blood glucose, which occurred when our patient received tolbutamide, remains unexplained.
Rubenstein et al. reported a young diabetic in whom manganese produced hypoglycemia (26). We administered manganese to our patient, but no effect could be demonstrated on the blood glucose.
The glucose level in the blood coming from the tumor was not appreciably lower than that in the blood going to the tumor. Utilization of glucose by the tumor would therefore seem an unlikely
| Date | 17-KS mg/day | 17-OH mg/day | Creatinine mg/day | |
|---|---|---|---|---|
| Base line | 8/1-2 | 131 | 48.3 | 1145 |
| 8/2-3 | 85.8 | 40.7 | 1160 | |
| Dexamethasone | 8/3-4 | 157 | 41.9 | 1513 |
| 2 mg every 6 hr | 8/4-5 | 128 | 34.3 | 1066 |
| 8/5-6 | 148 | 36.1 | 1103 | |
| 8/6-7 | 139 | 29.3 | 1111 | |
| 8/7-8 | 81.2 | 27.3 | 832 |
cause of the hypoglycemia. Another pos- siblity for the cause of hypoglycemia in nonislet cell malignancies would be hepatic metastases extensive enough to impair glucogenesis. In our patient the liver was normal on exploration and biopsy.
As we were unable to find evidence to support any of the various mechanisms which might be proposed to explain the hypoglycemia which occurs with adreno- cortical carcinomas, our attention was directed to recent reports concerning the effects of anabolic or androgenic steroids on carbohydrate metabolism. The ex- cessive secretion of such steroids may offer the most plausible explanation for the hypoglycemia in the patient that we have studied and in other similar cases reported in the literature.
It has been known for some time that under certain circumstances testosterone can cause a lowering in the fasting blood sugar level (27), and it has recently been demonstrated that methandienone (41- dehydro-17a-methyltestosterone), an anabolic steroid of low androgenicity, can supress the fasting blood sugar in normal subjects (28).
In support of the thesis that hypogly- cemia may be produced by the elabora- tion of such steroids by adrenal tumors is the finding of markedly elevated 17- ketosteroids whenever they have been measured in such cases (3-10). Dohan et al. (30) postulated that the hypogly-
cemia might be due to a defect of 11 beta-hydroxylation in the tumorous tis- sue and subsequent deficiency of cortisol which would, by virtue of the absence of its known stimulation of protein catabo- lism and gluconeogenesis, lead to hypo- glycemia. Such a hypothesis would ap- pear untenable because increased cortisol secretion has subsequently been demon- strated in other similar cases (10) and because of the demonstration of in- creased levels of cortisol in the plasma and urine of our case.
Another explanation is that the greatly increased secretion of anabolic steroids (as reflected by the markedly elevated excretion of androsterone, etio- cholanolone and 36-hydroxy-45-andro- sten-17-one in our patient) channels amino acids into protein synthesis and makes them unavailable for gluconeo- genesis. The suggestion that a similar situation may exist in other adrenal ab- normalities is supported by the finding of a fasting hypoglycemia in occasional cases of Cushing’s syndrome when ana- bolic steroids predominate, and more frequently in the adrenogenital syn- drome (31). In the latter, the hypogly- cemia is more often attributed to the concomitant cortisol deficiency. Never- theless, one might speculate that in abnormalities associated with excessive secretion of adrenal steroids either hyper- or hypoglycemia may occur, depending upon the relative amounts of the cata-
bolic steroids produced. Cases similar to the one presented would illustrate the end of a spectrum associated with a marked preponderance of steroids with anabolic properties.
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