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Hypoglycemia and dwarfism associated with the isolated deficiency of growth hormone
Hypoglycemia and Dwarfism Associated with the Isolated Deficiency of Growth Hormone
By JOHN
F. WILBER AND WILLIAM D. ODELL
W e have studied a 7 year old dwarfed boy with a history of severe, recurrent hypoglycemic episodes since age 1 and retarded bone age. Hepatic, adrenal, and thyroid function were normal. He demonstrated fasting hypoglyeemla with blood sugars of 30-40 mg. per cent. H e was not sensitive to L-leueine but showed insulin sensitivity and hypoglycemie unresponsiveness. Glyeogenolysis in responSe to both epinephrine and glueagon was appropriate. Fasting plasma
growth hormone levels were less than 1 m~ G m . / m l . (normal 1-3), and no rise was seen after insulin-induced hypoglycemia, Similarly, these low growth hormone levels did not rise 3 - 6 hours after a glucose tolerance test. Treatment with human growth hormone reversed the alterations in carbohydrate metabolism. It is concluded that the patient suffered from an isolated growth hormone deficiency which resulted in dwarfism and alterations in carbohydrate metabolism.
T H A S B E E N S H O W N r e c e n t l y t h a t p l a s m a g r o w t h h o r m o n e levels increase during fasting and hypoglycemia and decrease after carbohydrate ingestion. 1 T h e i m p o r t a n c e of t h e s e c h a n g i n g g r o w t h h o r m o n e levels to c a r b o h y d r a t e m e t a b o l i s m is at p r e s e n t o n l y s p e c u l a t i v e . W e h a v e s t u d i e d a 7 y e a r o l d d w a r f e d b o y w i t h an i s o l a t e d d e f i c i e n c y cf g r o w t h h o r m o n e assoc i a t e d w i t h s e v e r e f a s t i n g h y p o g l y c e m i a . S t u d i e s of c a r b o h y d r a t e m e t a b o l i s m p r i o r to a n d d u r i n g h u m a n g r o w t h h o r m o n e t r e a t m e n t c o n s t i t u t e t h e b a s i s of this r e p o r t ,
I
CASE REPORT A 7 year old Puerto Rican boy (fig. 1) was referred to the National Cancer Institute in September, 1963, because of recurrent hypoglycemic episodes. He was the product of a full-term normal delivery and weighed 5 lbs. 6 oz. at bi'rth. Growth and development were normal until about 1 year of age, when during the early morning he experienced an episode of unconsciousness and generalized motor seizures. A blood sugar at this time was found to be 19 mg. per cent. Ten to 15 such morning hypoglycemic episodes occurred during the next 11~ years. Following a prolonged untreated episode lasting 6-12 hours at age 21/2, he experienced right-sided weakness and difficulty in speaking. After this he experienced more frequent seizures, often without hypoglycemia. In addition, mental development progressed slowly, and growth was observed to be severely retarded. After age 5 the frequency of hypoglyeemic episodes appeared to decrease. On physical examination he appeared to be a short, healthy, active child with mild right hemiparesis. Blood pressure was 100/70 ram. Hg.; pulse was 74/minute. His height of 92.0 cm. and weight of 13.1 Kg. were more than 3 standard deviations below the mean for his chronologic age of 7. Arm span and height were equal. The general physical examination was within normal limits with the exception of mild right-sided hemiparesis and a partial motor aphasia. The liver and spleen were not enlarged. Intellectual performanee was at a level of 3-4 years.
From the Endocrinology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. Received for publication Nov, 6, I964. 590 METABOLISM, VOL. 14, No. 5 (MAy), 1965
HYPOGLYCEMIA AND DWARFISM
591
Fig. 1 . - - P a t i e n t in September, 1963. Laboratory data included a hemoglobin of 12.4 rag./100 ml. and a white blood count of 6,100/ram 3 with a normal differential, count. The urine had a specific gravity of 1.018 and a pH of 6.0. There was no albulninuria, glycosuria, or sediment abnormalities. Blood urea nitrogen was 10 nag. per cent; serum sodium 138 mEq./L., potassium 4.3, chloride 100, and carbon dioxide combining power 25. The sermn alkaline phosphate was 17 King-Armstrong units, total protein 7.2 Gin. per cent, glutamic oxalacetic transaminase 28 units, glutamic pyruvic transaminase 27 units, total bi]irubin 0.1 mg. per cent. X-rays of the sella turcica were normal. Bone age was 3% years, more than 2 standard deviations below the mean for the patient's chronologic age. An electroencephalogram showed diffuse widespread irregular slow wave frequencies over both hemispheres. Bilaterally synchronous epileptiform discharges were occasionally seen, SPECIAL LABORATORY STUDIES A d r e n a l c o r t i c a l f u n c t i o n was assessed in several ways. F o l l o w i n g a w a t e r load of 20 cc./Kg, b o d y w e i g h t orally, t h e p a t i e n t excreted 63 p e r c e n t i n 5 hours ( n o r m a l m o r e t h a n 55 p e r c e n t ) . T w e n t y - f o u r h o u r u r i n a r y 17-hydroxysteroid excretion was 2.1 rag. ( n o r m a l for this size a n d a g e ) . P l a s m a PorterSilber c h r o m o g e n s w e r e n o r m a l (11 ~g. p e r c e n t ) at 8:00 a.m. w h e n t h e b l o o d
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WILBER A N D O D E L L
sugar was normal. One hundred twenty-five rag. of Metopirone were given orally every 4 hours for 24 hours. Plasma Porter-Silber chromogens rose appropriately to 49 t~g. per cent, and urinary 17-hydroxysteroids .rose to 5.1 rag. The protein bound iodine was 5.1 t~g. per cent; the 24 hour radioiodine uptake by the thyroid was 26 per cent. On 7 occasions 24-hour urinary gonadotropin excretion was determined. Gonadotropic activity was detected on 4 occasions and was not detected on 3 others.* Twenty-four hour urinary vanillinmandelic acid excretion was 1.2 mg., within the range of normal. Carbohydrate metabolism was studied to determine the cause of the hypoglycemia. Blood glucose was measured by Autoanalyzer-Technicon method, which measures total reducing substances (normal range 70-120 mg. per cent).2 On 5 occasions the patient was fasted 24 hours a n d the mean blood sugar was 34 mg. per cent. On 7'occasions blood sugar was measured before break.fast after 12 hours fasting. These values ranged from 30 to 81 mg. per cent with a mean of 61 rag. per cent (table 1). Epinephrine and glucagon tolerance tests (fig. 2) revealed that the patient's blood sugar rose in response to these glycogenolytic agents. Insulin sensitivity was demonstrated by administering 0.08 units/Kg, body weight of crystalline insulin (1/3 the usual dose), ~ subcutaneously after a 6-hour fast (fig. 2). This produced a greater than 50 per cent reduction in the blood sugar at 30, 60, and 120 minutes, demonstrating both insulin sensitivity a n d hypoglycemic unresponsiveness# Possible leucine sensitivity was investigated by administering 2 Gin. of L-leucine orally on 2 occasions. No fall in blood sugars was noted over a 3-hour period in either instance. On 2 occasions insulin levels were determined by radioimmunoassay5 after a 24-hour fast when blood sugar values were low. No insulin was detectable on either of these occasions. On 2 other occasions insulin levels were measured after an overnight fast, and these levels were 5.6 and 4.7 ~ units/ml. (normal 0-56 for adults). Serum growth hormone levels were measured by radioimmunoassay in 2 laboratories by the method of Glick et al. 6 Two determinations were made after a 24-hour fast when hypoglycemia was present. The growth hormone levels were 0.1 and 0.2 m~gm./ml. (normal in adultsl and children over 2 years after a 12-ho,ur fast 1-3 m~gm./ml.). Growth hormone levels were also determined during a glucose tolerance test (1:5 Gin. glueose/Kg, body weight). All growth hormone values were less than 1 m~gm./ml., showing the absence of the expected normal rise at 4 to 6 hours despite hypoglycemia at 3 and 4 hours (fig. 3). A single intramuscular injection of 5 mg. of human *On one occasion greater than 50 and less than 20'0 mouse uterine units were detected. On 3 occasions greater than 10 and less than 50 units were detected. In this laboratory normal adult males excrete less than 200 units and occasionally no gonadotropin is detected in single samples. Prepubertal children often excrete gonadotropic hormone activity in these ranges. While the term "isolated" growth hormone deficiency depends on gonadotropin secretion being normal, this cannot be assessed in any other way prior to puberty, Gonadotropins are present in this-boy's urine, and we assume puberty will ultimately occur.
HYPOGLYCEMIA
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growth hormone was given 4 hours prior to a repetition of the glucose tolerance test, shown by the upper curve in figure 3. The marked elevation in serum free fatty acids resulting from the 5 mg. growth hormone dose is shown in figure 4. Subsequently, growth hormone* was given over a 2-month period at a dose of 2.5 mg. intramuscularly 3 times weekly. During the 6-month period prior to growth hormone treatment, there was no linear growth. During the 2-month period of growth hormone treatment height increased 4.5 cm., and a positive nitrogen balance 50 per cent above control values occurred during the first 5-day period of treatment. Serum alkaline phosphatase rose from 17 to 38 K.-A. units. A glucose tolerance test performed after 2 months of growth hormone treatment was within normal limits. The response to fasting was studied during continued growth hormone treatment, and these results are summarized in table 1. It should be noted that fasting hypoglycemia was generally absent when growth hormone was given 2-4 hours prior to determination. However, fasting hypoglycemia was not prevented when growth hormone was given 24 hours prior to glucose measurement. *A mixture of Raben and Wilhelmi Human Growth Hormone was used in these studies.
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AND ODELL
Table 1.--Effects of Growth Hormone on Fasting Blood Glucose After Growth Hormone Treatment
Blood Glucose i n rag. p e r cent a f t e r 12-hr. f a s t Blood glucose a f t e r 24-hr. f a s t
Before G r o w t h H o r m o n e
2-4 Hrs. a f t e r G I t
24 Hrs. a f t e r G H
Mean--61 81,80,76,57,55,45,30
Mean--74 86,81,76,71,70,67,65
Mean--55 78,59,57,47,47,42
Mean--34 44,34,32,31,30
Mean--68 77,68,65,60
Not measured
DISCUSSION This patient suffered fi'om severe fasting hypoglycemia, and therefore known causes were searched for systematically. Glycogen storage diseases were excluded by the absence of hepatomegaly, normal liver function, and appropriate responses to epinephrine and glucagon. Adrenalcortical and thyroid insui~eiency were excluded by normal tests of adrenal and thyroid function. Hypersecretion o.f insulin appeared unlikely because of the long untreated course without progression of the disease, the low insulin levels when hypoglycemia was present, and by the marked sensitivity to insulin. Leucine sensitivity was absent. The fact that this patient exhibited dwarfism with normal body proportions and a markedly retarded bone age suggested that dwarfism was secondary to growth hormone insufficiency. This was supported by the demonstration of abnormally low serum growth hormone levels by radioimmunoassay. The presence of both fasting hypoglycemia and isolated growth hormone deficiency in this patient raised the intriguing possibility that they might be related. Furthermore, the elegant demonstration by Roth et al. 1 of the rapid fluctuations in growth hormone levels on fasting, hypoglycemia, or carbohydrate loading suggested that growth hormone might be important in the hour-to-hour maintenance of euglycemia in man. Treatment of our patient with growth hormone produced a dramatic aIteration in carbohydrate metabolism. A single injection of growth hormone (5 rag.) prevented fasting hypoglycemia and resulted in a diabetic-type glucose tolerance curve. This response is in contrast to the response of normal children and adults receiving growth hormone, who very rarely exhibit changes in carbohydrate tolerance despite a decrease in insulin sensitivity.7 Moreover, Crigler has reported a patient with so-called "idiopathic hypoglycemia of infancy" in whom treatment with human growth hormone failed to alter the hypoglycemia.8 It should be mentioned, however, that hypoglycemias of certain other etiologies have been treated successfully with growth hormone2 Therefore, we cannot exclude fully the possibility that growth hormone insufficiency and hypoglycemia are not causally related in this patient but represent 2 independent defects. Hypoglycemia was prevented after a 12-hour fast only when growth hormone was administered during the fasting peried. This phenomenon is interesting in light of the kinetics of growth hormone studied with intravenous and intramuscular injection of unlabeled human growth hormone and growth hormone labeled with IlS~.1~ The maximum serum levels of growth hormone
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Serum growth hormone levels were measured at the untreated times. after intramuscular injection occurred at 2-8 hours and rapidly declined after that time. Although serum levels of growth hormone do not necessarily refleet activity at sites of action, these pharmacologic data fit well with our observations. In view of these observations, it seems apparent that the usual growth hormone dosage schedules used in treatment of hypopitnitary dwarfs would not be likely to correct abnormalities of carbohydrate metabolism. The mechanism by which growth hormone prevents hypoglycemia in our patient is not presently understood. However, when patients with hypoglycemia from other causes have been treated with growth hormone, no changes in insulin secretion and insulin kinetics have been s h o w n . ~,11 For more detailed accounts of the known effects of growth hormone on carbohydrate metabolism, the reader is referred to recent reviews on this subject, 9,12 Studies of carbohydrate metabolism in patients with hypopituitarism are not common, and the incidence of hypoglycemia is not generally known. However, recently Brazel, Wilkins and Blizzard have examined fasting blood sugars in 41 patients with idiopathic hypopituitarism and found 12 (27 per cent) to have values less than 50 mg. per cent. 13 Thirty per cent had sensitivity to insulin. In addition, the patient described herein is probably not the first to be reported with this syndrome. Nadler, Neuman and Gershberg recently have described a 1 year old boy with growth retardation, leucine sensitivity, fasting hypoglycemia, arid low blood sulfate factor levels in the presence of normal
596
WZLSEXaAND ODELL 3.0
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adrenal and thyroid function. 11 The hypoglycemia was corrected b y treatment with growth hormone. The etiology of the isolated deficiency of growth h o r m o n e is unknown. Isolated deficiencies of A C T H have been reported previously and postulated to be caused by specific hypothalamic disturbances. 14,1~ In animals, isolated disturbances of A C T H and T S H secretion have been p r o d u c e d b y destruction of specific areas of the hypothalamus, a~,l~ Moreover, certain data suggest that growth hormone also m a y be controlled b y central nervous influences, 1r-19 so that one could speculate that the isolated deficiency of growth h o r m o n e is caused b y specific hypothalamic disturbances. ACKNOWLEDGMENTS
We are indebted to Dr. Ann Lawrence of the University of Chicago and Mrs. Rosalyn Yalow and Solomon Berson of the Bronx Veterans Administration Hospital for their immunoassays of serum insulin, to Drs. Seymour Glick of the Bronx Veterans Administration Hospital and Robert Utiger of Washington University for their performance of growth hormone immunoassays, and to Jacqueline Van De Kamp of the National Instittttes of Health for the free fatty acid determinations. We are also grateful to Dr. Jesse Ro~ of the National Institute of Arthritis and Metabolic Diseases for his numerous helpful suggestions. REFERENCES 1. Roth, J., Glick, S. M., Yalow, R.S., 988, 1963. and Berson, S. A.: Hypoglycemia: A 2. Hoffman, W. S.: A rapid photoelectric potent stimulus to secretion of method for the determination of glui growth hormone. Science 140:987cose in blood and urine. J. Biol,
597
HYPOGLYCEMIA AND DWARFISM
Chem. 120:51-55, 1937. 3. Silver, H. K., Kempe, H. C., and Bruyn, H. B.: Handbook of Pediatrics. Lange Medical Publications, 1957, p. 23. 4. Fraser, R., Albright, F., and Smith, P. H.: The value of the glucose tolerance test, the insulin tolerance test, and the glucose-insulin tolerance test in the diagnosis of endocrinological disorders of carbohydrate metabolism. J. Clin. Endocrinol. & Metab. 1:297306, 1941. 5. Yalow, R. S., and Berson, S. A.: Immunoassay of endogenous plasma insulin in man. J. Clin. Invest. 39: 1157-1175, 1960. 6. Glick, S. M., Roth, j., Yalow, R. S., and Berson, S. A.: Immunoassay of human growth hormone in plasma. Nature 199:784-787, 1963. 7. Raben, M. S.: Growth hormone. New Eng. J. Med. 266:31-35, 82-86, 1962. 8. Crig|er, J. F., Knapp, J. A.., and Chagnon, J.: Observations on metabolic effects of glucagon and growth hormone (human and beef) in an infant with idiopathic hypoglycemia and hyperinsulinism. J. Dis. Child. 96:432, 1958. 9. Mahon, W. A., Mitchell, M. L., Steinke, J., and Raben, M. S.: Effect of human growth hormone on hypoglycemic states. New Eng. J. Med. 267:11791183, 1962. 10. Parker, M. L., Utiger, R. D., and Daughaday, W. H.: Studies on human growth hormone. II. The physiological disposition and metabolic fate of human growth hormone in man. J. Clin. Invest. 41:262-268, 1962.
11. Nadlcr, H. L., Neumann, L. L., and Gershberg, H.: Hypoglycemia, growth retardation, and probable isolated growth hormone deficiency in a 1year-old child. J. Pediat. 63:977-983, 1963. 12. Finkel, M. J.: Human growth hormone. Am. J. Med. 32:588-598, 1962. 13. Brazel, J. A., Wright, J. C,, Wilkins, L., and Blizzard, R. M.: An evaluation of 75 patients with hypopituitarism beginning in childhood. In preparation. 14. Odell, W. D., Green, G. M., and Williams, R. H.: Hypoadrenotropism: The isolated deficiency of adrenotropic hormone. J. Clin. Endocrinol. & Metab. 20:1017-1028, 1960. 15. Greer, M. A., and Erwin, H. L.: Evidence of separate hypothalamic centers controlling corticotropin and thyrotropin secretion by the pituitary. Endocrinology 58:665-670, 1956. 16. Porter, J. C.: Secretion of corticosterone in rats with anterior hypothalamic lesions. Am. J. Physiol. 204:715-718, 1963. 17. Hertz, R.: Growth in the hypophysectomized rat sustained by pituitary grafts. Endocrinology 65:926-931, 1959. 18. Reichlin, S.: Growth and the hypothalamus. Endocrinology 67:760-773, 1960. 19. Abrams, R. L., Parker, M., Santander, 15, l~eiclalin, S., and Daughaday, W. H.: Hypothalamic regulation of growth hormone secretion. Abstracts of the Fifty-sixth Annual Meeting of Am. Soc. Clin. Investigation, p. 19, 1964.
1ohn F. Wilber, M.D., Clinical Associate, Endocrinology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Md. William D. OdeU, M.D., Senior Investigator and Attending Physician, Endocrinology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Md.
By JOHN
F. WILBER AND WILLIAM D. ODELL
W e have studied a 7 year old dwarfed boy with a history of severe, recurrent hypoglycemic episodes since age 1 and retarded bone age. Hepatic, adrenal, and thyroid function were normal. He demonstrated fasting hypoglyeemla with blood sugars of 30-40 mg. per cent. H e was not sensitive to L-leueine but showed insulin sensitivity and hypoglycemie unresponsiveness. Glyeogenolysis in responSe to both epinephrine and glueagon was appropriate. Fasting plasma
growth hormone levels were less than 1 m~ G m . / m l . (normal 1-3), and no rise was seen after insulin-induced hypoglycemia, Similarly, these low growth hormone levels did not rise 3 - 6 hours after a glucose tolerance test. Treatment with human growth hormone reversed the alterations in carbohydrate metabolism. It is concluded that the patient suffered from an isolated growth hormone deficiency which resulted in dwarfism and alterations in carbohydrate metabolism.
T H A S B E E N S H O W N r e c e n t l y t h a t p l a s m a g r o w t h h o r m o n e levels increase during fasting and hypoglycemia and decrease after carbohydrate ingestion. 1 T h e i m p o r t a n c e of t h e s e c h a n g i n g g r o w t h h o r m o n e levels to c a r b o h y d r a t e m e t a b o l i s m is at p r e s e n t o n l y s p e c u l a t i v e . W e h a v e s t u d i e d a 7 y e a r o l d d w a r f e d b o y w i t h an i s o l a t e d d e f i c i e n c y cf g r o w t h h o r m o n e assoc i a t e d w i t h s e v e r e f a s t i n g h y p o g l y c e m i a . S t u d i e s of c a r b o h y d r a t e m e t a b o l i s m p r i o r to a n d d u r i n g h u m a n g r o w t h h o r m o n e t r e a t m e n t c o n s t i t u t e t h e b a s i s of this r e p o r t ,
I
CASE REPORT A 7 year old Puerto Rican boy (fig. 1) was referred to the National Cancer Institute in September, 1963, because of recurrent hypoglycemic episodes. He was the product of a full-term normal delivery and weighed 5 lbs. 6 oz. at bi'rth. Growth and development were normal until about 1 year of age, when during the early morning he experienced an episode of unconsciousness and generalized motor seizures. A blood sugar at this time was found to be 19 mg. per cent. Ten to 15 such morning hypoglycemic episodes occurred during the next 11~ years. Following a prolonged untreated episode lasting 6-12 hours at age 21/2, he experienced right-sided weakness and difficulty in speaking. After this he experienced more frequent seizures, often without hypoglycemia. In addition, mental development progressed slowly, and growth was observed to be severely retarded. After age 5 the frequency of hypoglyeemic episodes appeared to decrease. On physical examination he appeared to be a short, healthy, active child with mild right hemiparesis. Blood pressure was 100/70 ram. Hg.; pulse was 74/minute. His height of 92.0 cm. and weight of 13.1 Kg. were more than 3 standard deviations below the mean for his chronologic age of 7. Arm span and height were equal. The general physical examination was within normal limits with the exception of mild right-sided hemiparesis and a partial motor aphasia. The liver and spleen were not enlarged. Intellectual performanee was at a level of 3-4 years.
From the Endocrinology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. Received for publication Nov, 6, I964. 590 METABOLISM, VOL. 14, No. 5 (MAy), 1965
HYPOGLYCEMIA AND DWARFISM
591
Fig. 1 . - - P a t i e n t in September, 1963. Laboratory data included a hemoglobin of 12.4 rag./100 ml. and a white blood count of 6,100/ram 3 with a normal differential, count. The urine had a specific gravity of 1.018 and a pH of 6.0. There was no albulninuria, glycosuria, or sediment abnormalities. Blood urea nitrogen was 10 nag. per cent; serum sodium 138 mEq./L., potassium 4.3, chloride 100, and carbon dioxide combining power 25. The sermn alkaline phosphate was 17 King-Armstrong units, total protein 7.2 Gin. per cent, glutamic oxalacetic transaminase 28 units, glutamic pyruvic transaminase 27 units, total bi]irubin 0.1 mg. per cent. X-rays of the sella turcica were normal. Bone age was 3% years, more than 2 standard deviations below the mean for the patient's chronologic age. An electroencephalogram showed diffuse widespread irregular slow wave frequencies over both hemispheres. Bilaterally synchronous epileptiform discharges were occasionally seen, SPECIAL LABORATORY STUDIES A d r e n a l c o r t i c a l f u n c t i o n was assessed in several ways. F o l l o w i n g a w a t e r load of 20 cc./Kg, b o d y w e i g h t orally, t h e p a t i e n t excreted 63 p e r c e n t i n 5 hours ( n o r m a l m o r e t h a n 55 p e r c e n t ) . T w e n t y - f o u r h o u r u r i n a r y 17-hydroxysteroid excretion was 2.1 rag. ( n o r m a l for this size a n d a g e ) . P l a s m a PorterSilber c h r o m o g e n s w e r e n o r m a l (11 ~g. p e r c e n t ) at 8:00 a.m. w h e n t h e b l o o d
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WILBER A N D O D E L L
sugar was normal. One hundred twenty-five rag. of Metopirone were given orally every 4 hours for 24 hours. Plasma Porter-Silber chromogens rose appropriately to 49 t~g. per cent, and urinary 17-hydroxysteroids .rose to 5.1 rag. The protein bound iodine was 5.1 t~g. per cent; the 24 hour radioiodine uptake by the thyroid was 26 per cent. On 7 occasions 24-hour urinary gonadotropin excretion was determined. Gonadotropic activity was detected on 4 occasions and was not detected on 3 others.* Twenty-four hour urinary vanillinmandelic acid excretion was 1.2 mg., within the range of normal. Carbohydrate metabolism was studied to determine the cause of the hypoglycemia. Blood glucose was measured by Autoanalyzer-Technicon method, which measures total reducing substances (normal range 70-120 mg. per cent).2 On 5 occasions the patient was fasted 24 hours a n d the mean blood sugar was 34 mg. per cent. On 7'occasions blood sugar was measured before break.fast after 12 hours fasting. These values ranged from 30 to 81 mg. per cent with a mean of 61 rag. per cent (table 1). Epinephrine and glucagon tolerance tests (fig. 2) revealed that the patient's blood sugar rose in response to these glycogenolytic agents. Insulin sensitivity was demonstrated by administering 0.08 units/Kg, body weight of crystalline insulin (1/3 the usual dose), ~ subcutaneously after a 6-hour fast (fig. 2). This produced a greater than 50 per cent reduction in the blood sugar at 30, 60, and 120 minutes, demonstrating both insulin sensitivity a n d hypoglycemic unresponsiveness# Possible leucine sensitivity was investigated by administering 2 Gin. of L-leucine orally on 2 occasions. No fall in blood sugars was noted over a 3-hour period in either instance. On 2 occasions insulin levels were determined by radioimmunoassay5 after a 24-hour fast when blood sugar values were low. No insulin was detectable on either of these occasions. On 2 other occasions insulin levels were measured after an overnight fast, and these levels were 5.6 and 4.7 ~ units/ml. (normal 0-56 for adults). Serum growth hormone levels were measured by radioimmunoassay in 2 laboratories by the method of Glick et al. 6 Two determinations were made after a 24-hour fast when hypoglycemia was present. The growth hormone levels were 0.1 and 0.2 m~gm./ml. (normal in adultsl and children over 2 years after a 12-ho,ur fast 1-3 m~gm./ml.). Growth hormone levels were also determined during a glucose tolerance test (1:5 Gin. glueose/Kg, body weight). All growth hormone values were less than 1 m~gm./ml., showing the absence of the expected normal rise at 4 to 6 hours despite hypoglycemia at 3 and 4 hours (fig. 3). A single intramuscular injection of 5 mg. of human *On one occasion greater than 50 and less than 20'0 mouse uterine units were detected. On 3 occasions greater than 10 and less than 50 units were detected. In this laboratory normal adult males excrete less than 200 units and occasionally no gonadotropin is detected in single samples. Prepubertal children often excrete gonadotropic hormone activity in these ranges. While the term "isolated" growth hormone deficiency depends on gonadotropin secretion being normal, this cannot be assessed in any other way prior to puberty, Gonadotropins are present in this-boy's urine, and we assume puberty will ultimately occur.
HYPOGLYCEMIA
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TIME Fig. 2.--Results of glueagon, epinephrine and were given at time zero.
insulin toleranee
tests. The drugs
growth hormone was given 4 hours prior to a repetition of the glucose tolerance test, shown by the upper curve in figure 3. The marked elevation in serum free fatty acids resulting from the 5 mg. growth hormone dose is shown in figure 4. Subsequently, growth hormone* was given over a 2-month period at a dose of 2.5 mg. intramuscularly 3 times weekly. During the 6-month period prior to growth hormone treatment, there was no linear growth. During the 2-month period of growth hormone treatment height increased 4.5 cm., and a positive nitrogen balance 50 per cent above control values occurred during the first 5-day period of treatment. Serum alkaline phosphatase rose from 17 to 38 K.-A. units. A glucose tolerance test performed after 2 months of growth hormone treatment was within normal limits. The response to fasting was studied during continued growth hormone treatment, and these results are summarized in table 1. It should be noted that fasting hypoglycemia was generally absent when growth hormone was given 2-4 hours prior to determination. However, fasting hypoglycemia was not prevented when growth hormone was given 24 hours prior to glucose measurement. *A mixture of Raben and Wilhelmi Human Growth Hormone was used in these studies.
594
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Table 1.--Effects of Growth Hormone on Fasting Blood Glucose After Growth Hormone Treatment
Blood Glucose i n rag. p e r cent a f t e r 12-hr. f a s t Blood glucose a f t e r 24-hr. f a s t
Before G r o w t h H o r m o n e
2-4 Hrs. a f t e r G I t
24 Hrs. a f t e r G H
Mean--61 81,80,76,57,55,45,30
Mean--74 86,81,76,71,70,67,65
Mean--55 78,59,57,47,47,42
Mean--34 44,34,32,31,30
Mean--68 77,68,65,60
Not measured
DISCUSSION This patient suffered fi'om severe fasting hypoglycemia, and therefore known causes were searched for systematically. Glycogen storage diseases were excluded by the absence of hepatomegaly, normal liver function, and appropriate responses to epinephrine and glucagon. Adrenalcortical and thyroid insui~eiency were excluded by normal tests of adrenal and thyroid function. Hypersecretion o.f insulin appeared unlikely because of the long untreated course without progression of the disease, the low insulin levels when hypoglycemia was present, and by the marked sensitivity to insulin. Leucine sensitivity was absent. The fact that this patient exhibited dwarfism with normal body proportions and a markedly retarded bone age suggested that dwarfism was secondary to growth hormone insufficiency. This was supported by the demonstration of abnormally low serum growth hormone levels by radioimmunoassay. The presence of both fasting hypoglycemia and isolated growth hormone deficiency in this patient raised the intriguing possibility that they might be related. Furthermore, the elegant demonstration by Roth et al. 1 of the rapid fluctuations in growth hormone levels on fasting, hypoglycemia, or carbohydrate loading suggested that growth hormone might be important in the hour-to-hour maintenance of euglycemia in man. Treatment of our patient with growth hormone produced a dramatic aIteration in carbohydrate metabolism. A single injection of growth hormone (5 rag.) prevented fasting hypoglycemia and resulted in a diabetic-type glucose tolerance curve. This response is in contrast to the response of normal children and adults receiving growth hormone, who very rarely exhibit changes in carbohydrate tolerance despite a decrease in insulin sensitivity.7 Moreover, Crigler has reported a patient with so-called "idiopathic hypoglycemia of infancy" in whom treatment with human growth hormone failed to alter the hypoglycemia.8 It should be mentioned, however, that hypoglycemias of certain other etiologies have been treated successfully with growth hormone2 Therefore, we cannot exclude fully the possibility that growth hormone insufficiency and hypoglycemia are not causally related in this patient but represent 2 independent defects. Hypoglycemia was prevented after a 12-hour fast only when growth hormone was administered during the fasting peried. This phenomenon is interesting in light of the kinetics of growth hormone studied with intravenous and intramuscular injection of unlabeled human growth hormone and growth hormone labeled with IlS~.1~ The maximum serum levels of growth hormone
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Serum growth hormone levels were measured at the untreated times. after intramuscular injection occurred at 2-8 hours and rapidly declined after that time. Although serum levels of growth hormone do not necessarily refleet activity at sites of action, these pharmacologic data fit well with our observations. In view of these observations, it seems apparent that the usual growth hormone dosage schedules used in treatment of hypopitnitary dwarfs would not be likely to correct abnormalities of carbohydrate metabolism. The mechanism by which growth hormone prevents hypoglycemia in our patient is not presently understood. However, when patients with hypoglycemia from other causes have been treated with growth hormone, no changes in insulin secretion and insulin kinetics have been s h o w n . ~,11 For more detailed accounts of the known effects of growth hormone on carbohydrate metabolism, the reader is referred to recent reviews on this subject, 9,12 Studies of carbohydrate metabolism in patients with hypopituitarism are not common, and the incidence of hypoglycemia is not generally known. However, recently Brazel, Wilkins and Blizzard have examined fasting blood sugars in 41 patients with idiopathic hypopituitarism and found 12 (27 per cent) to have values less than 50 mg. per cent. 13 Thirty per cent had sensitivity to insulin. In addition, the patient described herein is probably not the first to be reported with this syndrome. Nadler, Neuman and Gershberg recently have described a 1 year old boy with growth retardation, leucine sensitivity, fasting hypoglycemia, arid low blood sulfate factor levels in the presence of normal
596
WZLSEXaAND ODELL 3.0
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adrenal and thyroid function. 11 The hypoglycemia was corrected b y treatment with growth hormone. The etiology of the isolated deficiency of growth h o r m o n e is unknown. Isolated deficiencies of A C T H have been reported previously and postulated to be caused by specific hypothalamic disturbances. 14,1~ In animals, isolated disturbances of A C T H and T S H secretion have been p r o d u c e d b y destruction of specific areas of the hypothalamus, a~,l~ Moreover, certain data suggest that growth hormone also m a y be controlled b y central nervous influences, 1r-19 so that one could speculate that the isolated deficiency of growth h o r m o n e is caused b y specific hypothalamic disturbances. ACKNOWLEDGMENTS
We are indebted to Dr. Ann Lawrence of the University of Chicago and Mrs. Rosalyn Yalow and Solomon Berson of the Bronx Veterans Administration Hospital for their immunoassays of serum insulin, to Drs. Seymour Glick of the Bronx Veterans Administration Hospital and Robert Utiger of Washington University for their performance of growth hormone immunoassays, and to Jacqueline Van De Kamp of the National Instittttes of Health for the free fatty acid determinations. We are also grateful to Dr. Jesse Ro~ of the National Institute of Arthritis and Metabolic Diseases for his numerous helpful suggestions. REFERENCES 1. Roth, J., Glick, S. M., Yalow, R.S., 988, 1963. and Berson, S. A.: Hypoglycemia: A 2. Hoffman, W. S.: A rapid photoelectric potent stimulus to secretion of method for the determination of glui growth hormone. Science 140:987cose in blood and urine. J. Biol,
597
HYPOGLYCEMIA AND DWARFISM
Chem. 120:51-55, 1937. 3. Silver, H. K., Kempe, H. C., and Bruyn, H. B.: Handbook of Pediatrics. Lange Medical Publications, 1957, p. 23. 4. Fraser, R., Albright, F., and Smith, P. H.: The value of the glucose tolerance test, the insulin tolerance test, and the glucose-insulin tolerance test in the diagnosis of endocrinological disorders of carbohydrate metabolism. J. Clin. Endocrinol. & Metab. 1:297306, 1941. 5. Yalow, R. S., and Berson, S. A.: Immunoassay of endogenous plasma insulin in man. J. Clin. Invest. 39: 1157-1175, 1960. 6. Glick, S. M., Roth, j., Yalow, R. S., and Berson, S. A.: Immunoassay of human growth hormone in plasma. Nature 199:784-787, 1963. 7. Raben, M. S.: Growth hormone. New Eng. J. Med. 266:31-35, 82-86, 1962. 8. Crig|er, J. F., Knapp, J. A.., and Chagnon, J.: Observations on metabolic effects of glucagon and growth hormone (human and beef) in an infant with idiopathic hypoglycemia and hyperinsulinism. J. Dis. Child. 96:432, 1958. 9. Mahon, W. A., Mitchell, M. L., Steinke, J., and Raben, M. S.: Effect of human growth hormone on hypoglycemic states. New Eng. J. Med. 267:11791183, 1962. 10. Parker, M. L., Utiger, R. D., and Daughaday, W. H.: Studies on human growth hormone. II. The physiological disposition and metabolic fate of human growth hormone in man. J. Clin. Invest. 41:262-268, 1962.
11. Nadlcr, H. L., Neumann, L. L., and Gershberg, H.: Hypoglycemia, growth retardation, and probable isolated growth hormone deficiency in a 1year-old child. J. Pediat. 63:977-983, 1963. 12. Finkel, M. J.: Human growth hormone. Am. J. Med. 32:588-598, 1962. 13. Brazel, J. A., Wright, J. C,, Wilkins, L., and Blizzard, R. M.: An evaluation of 75 patients with hypopituitarism beginning in childhood. In preparation. 14. Odell, W. D., Green, G. M., and Williams, R. H.: Hypoadrenotropism: The isolated deficiency of adrenotropic hormone. J. Clin. Endocrinol. & Metab. 20:1017-1028, 1960. 15. Greer, M. A., and Erwin, H. L.: Evidence of separate hypothalamic centers controlling corticotropin and thyrotropin secretion by the pituitary. Endocrinology 58:665-670, 1956. 16. Porter, J. C.: Secretion of corticosterone in rats with anterior hypothalamic lesions. Am. J. Physiol. 204:715-718, 1963. 17. Hertz, R.: Growth in the hypophysectomized rat sustained by pituitary grafts. Endocrinology 65:926-931, 1959. 18. Reichlin, S.: Growth and the hypothalamus. Endocrinology 67:760-773, 1960. 19. Abrams, R. L., Parker, M., Santander, 15, l~eiclalin, S., and Daughaday, W. H.: Hypothalamic regulation of growth hormone secretion. Abstracts of the Fifty-sixth Annual Meeting of Am. Soc. Clin. Investigation, p. 19, 1964.
1ohn F. Wilber, M.D., Clinical Associate, Endocrinology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Md. William D. OdeU, M.D., Senior Investigator and Attending Physician, Endocrinology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Md.