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Diabetic Retinopathy and Growth Hormone
CORRESPONDENCE
VOL. 83, NO. 6
fluorescein solution was injected via the left or right antecubital vein and an E C G tracing was again obtained for 3 0 seconds. A third tracing was taken approximately five minutes after the injection was completed. None o f the patients had any electrocardiographic changes temporally related to the injection o f fluorescein dye with the exception o f minor tachy- or bradycardia during injection. Specifically, no arrhythmias, P R prolongations, Q R S widening, S T elevation or depression, or T-wave inversion were noted. O n e patient, a 62-year-old white woman with a history o f angina pectoris, was admitted to the coronary care unit with chest pain four hours after the fluorescein injection. Her E C G was completely unaffected by the fluorescein dye and was normal. W e c o n c l u d e from this study that there are no electrocardiographic changes during fluorescein angiography or immediately thereafter and, therefore, no electrocardiographic evidence of a cardiotoxic effect o f intravenously administered fluorescein dye. N O R M A N T. B Y E R S ,
M.D.
F R A N C I S G. L A P L A N A , M . D .
Washington,
D.C.
Diabetic Retinopathy and Growth Hormone Editor: As more knowledge is gleaned about the metabolic and hormonal relationships in diabetes, the pathogenesis o f the disease and its complications has grown more complex. Recently, many tests have been developed and many substances isolated that influence the hormonal agents which are believed to be involved in the pathogenesis o f this disease. I n particular, serendipitous clinical findings have led to many published reports on the relationships o f growth hormone and the pathogenesis o f diabetes and diabetic retinopathy.
929
T h e enormous number o f variables such as blood glucose, insulin, glucagon, growth hormone levels, patient age, disease duration, and the like, and in some cases their ongoing interrelationships during the time course of any o n e study, especially when altered b y various inhibitory or stimulatory tests, points out the extreme difficulty in controlling all factors except that factor o n e is studying in any experiment on the subject. I n the paper b y Peter M. Holland, Maurice B . Landers, Harold E . Lebovitz, and Myron L . Wolbarscht, "Levodopastimulated growth hormone secretion and diabetic retinopathy" (Am. J . Ophthalmol. 8 2 : 6 1 2 , 1976), the conclusion that there is no relationship between diabetic retinopathy and serum growth hormone can b e questioned for a n u m b e r o f reasons: Is the duration o f disease in the two groups comparable? T h e r e is no mention o f how the original diagnoses were made and h e n c e disease duration from case to case may not b e comparable, as well as the fact that the mean disease duration was 4 4 % longer in the group with retinopathy than in the group without retinopathy. Is the total growth hormone release controlled by relation to the b l o o d glucose levels of the subjects? T h e o n e control b l o o d glucose sample was drawn before levodopa was administered. As levodopa is known to cause elevation o f plasma glucose, this o n e control value may bear no relationship to patients' b l o o d levels after levodopa administration and, as a result, poststimulus glucose to growth hormone levels may have varied between the two groups. Are the two groups similar in their expected responses to levodopa? T h e authors mentioned that three patients in Group 1 and none in Group 2 had bouts o f ketoacidosis in the year before the study. In the study b y Hägen and associ-
930
AMERICAN JOURNAL O F OPHTHALMOLOGY
ates, arginine infusion had a heightened effect on growth hormone secretion in the ketosis-prone group; levodopa may have a similar variability in its effect. B e c a u s e o f the large number o f variables that must b e controlled in such a study before useful results can b e obtained, an agent that has a unique inhibitory effect on serum growth hormone (somatostatin has p o s s i b i l i t i e s ) must be introduced in prospective double-masked fashion with concurrent control o f as many extraneous factors as possible, such as tendency to ketosis or hypoglycemia, age, disease duration, blood glucose levels, exertion, insulin, and glucagon levels. T h e n the growth hormone levels should be compared to retrogression or decreased incidence of retinopathy. T h e difficulties in organizing such a study are obvious and delineate the problems involved in studying this most complex and interesting disease entity. 1
2
PETER BERKOWITZ,
Montreal,
J U N E , 1977
show no basis for making such relationships. W e determined the duration o f disease by using the data the physician used initially to diagnose diabetes. I f growth hormone was involved in the genesis o f proliferative retinopathy, and the group with proliferative diabetic retinopathy had diabetes for a longer duration, one might expect their growth hormone levels to be higher at the present time than the levels in the group without retinopathy. All patients in the group with retinopathy had what we interpreted to b e active growth o f new vessels. Boyd and coworkers have demonstrated that the growth hormone response to levodopa was not affected by subsequent oral or intravenous glucose administration. W e do not know about the effect o f ketosis on levodopa-stimulated growth hormone secretion. 1,2
P E T E R M . HOLLAND, M . D .
M.D.
M A U R I C E B. LANDERS III, M . D .
Quebec
H. E. LEBOVITZ, M . D . MYRON WOLBARSHT, PH.D.
Durham,
REFERENCES 1. Hägen, J . C , Lawrence, A. M., and Kirstein, L.; Abnormal growth hormone (GH) secretion in ketosis prone diabetics. J . Lab. Clin. Med. 78:993, 1971. 2. Somatostatin and diabetes, editorial. Lancet 1:1323, 1975.
Reply Editor: W e appreciate Dr. Berkowitz's thoughtful letter, and are in full agreement regarding the problems o f controlling the multiple variables in the clinical study. T h e concluding paragraph o f our paper points out that "there does not appear to be any clear data for assuming a relationship between diabetic retinopathy and serum growth h o r m o n e . " W e are simply stating that our data and a review o f the data o f others which may or may not have purported to show such a relationship
North
Carolina
REFERENCES 1. Boyd, A. E . Ill, Lebovitz, H. E . , and Pfeiffer, J. B.: Stimulation of human growth-hormone secretion by L-dopa. N. Engl. J . Med. 283:1425, 1970. 2. Boyd, A. E . Ill, Lebovitz, H. E . , and Feldman, J. M.: Endocrine function and glucose metabolism in patients with Parkinson's disease and their alteration by L-dopa. J . Clin. Endocrinol. Metab. 33:829, 1971.
Peripapillary Changes in Glaucoma Editor: I read the interesting article, "Peripapillary changes in g l a u c o m a " (Am. J . Ophthalmol. 8 1 : 3 4 1 , 1 9 7 6 ) by J . T . Wilensky and Allan E . Kölker, and am pleased they found some evidence in support o f my c o n t e n t i o n that peripapillary changes may b e an early sign o f glauco1
VOL. 83, NO. 6
fluorescein solution was injected via the left or right antecubital vein and an E C G tracing was again obtained for 3 0 seconds. A third tracing was taken approximately five minutes after the injection was completed. None o f the patients had any electrocardiographic changes temporally related to the injection o f fluorescein dye with the exception o f minor tachy- or bradycardia during injection. Specifically, no arrhythmias, P R prolongations, Q R S widening, S T elevation or depression, or T-wave inversion were noted. O n e patient, a 62-year-old white woman with a history o f angina pectoris, was admitted to the coronary care unit with chest pain four hours after the fluorescein injection. Her E C G was completely unaffected by the fluorescein dye and was normal. W e c o n c l u d e from this study that there are no electrocardiographic changes during fluorescein angiography or immediately thereafter and, therefore, no electrocardiographic evidence of a cardiotoxic effect o f intravenously administered fluorescein dye. N O R M A N T. B Y E R S ,
M.D.
F R A N C I S G. L A P L A N A , M . D .
Washington,
D.C.
Diabetic Retinopathy and Growth Hormone Editor: As more knowledge is gleaned about the metabolic and hormonal relationships in diabetes, the pathogenesis o f the disease and its complications has grown more complex. Recently, many tests have been developed and many substances isolated that influence the hormonal agents which are believed to be involved in the pathogenesis o f this disease. I n particular, serendipitous clinical findings have led to many published reports on the relationships o f growth hormone and the pathogenesis o f diabetes and diabetic retinopathy.
929
T h e enormous number o f variables such as blood glucose, insulin, glucagon, growth hormone levels, patient age, disease duration, and the like, and in some cases their ongoing interrelationships during the time course of any o n e study, especially when altered b y various inhibitory or stimulatory tests, points out the extreme difficulty in controlling all factors except that factor o n e is studying in any experiment on the subject. I n the paper b y Peter M. Holland, Maurice B . Landers, Harold E . Lebovitz, and Myron L . Wolbarscht, "Levodopastimulated growth hormone secretion and diabetic retinopathy" (Am. J . Ophthalmol. 8 2 : 6 1 2 , 1976), the conclusion that there is no relationship between diabetic retinopathy and serum growth hormone can b e questioned for a n u m b e r o f reasons: Is the duration o f disease in the two groups comparable? T h e r e is no mention o f how the original diagnoses were made and h e n c e disease duration from case to case may not b e comparable, as well as the fact that the mean disease duration was 4 4 % longer in the group with retinopathy than in the group without retinopathy. Is the total growth hormone release controlled by relation to the b l o o d glucose levels of the subjects? T h e o n e control b l o o d glucose sample was drawn before levodopa was administered. As levodopa is known to cause elevation o f plasma glucose, this o n e control value may bear no relationship to patients' b l o o d levels after levodopa administration and, as a result, poststimulus glucose to growth hormone levels may have varied between the two groups. Are the two groups similar in their expected responses to levodopa? T h e authors mentioned that three patients in Group 1 and none in Group 2 had bouts o f ketoacidosis in the year before the study. In the study b y Hägen and associ-
930
AMERICAN JOURNAL O F OPHTHALMOLOGY
ates, arginine infusion had a heightened effect on growth hormone secretion in the ketosis-prone group; levodopa may have a similar variability in its effect. B e c a u s e o f the large number o f variables that must b e controlled in such a study before useful results can b e obtained, an agent that has a unique inhibitory effect on serum growth hormone (somatostatin has p o s s i b i l i t i e s ) must be introduced in prospective double-masked fashion with concurrent control o f as many extraneous factors as possible, such as tendency to ketosis or hypoglycemia, age, disease duration, blood glucose levels, exertion, insulin, and glucagon levels. T h e n the growth hormone levels should be compared to retrogression or decreased incidence of retinopathy. T h e difficulties in organizing such a study are obvious and delineate the problems involved in studying this most complex and interesting disease entity. 1
2
PETER BERKOWITZ,
Montreal,
J U N E , 1977
show no basis for making such relationships. W e determined the duration o f disease by using the data the physician used initially to diagnose diabetes. I f growth hormone was involved in the genesis o f proliferative retinopathy, and the group with proliferative diabetic retinopathy had diabetes for a longer duration, one might expect their growth hormone levels to be higher at the present time than the levels in the group without retinopathy. All patients in the group with retinopathy had what we interpreted to b e active growth o f new vessels. Boyd and coworkers have demonstrated that the growth hormone response to levodopa was not affected by subsequent oral or intravenous glucose administration. W e do not know about the effect o f ketosis on levodopa-stimulated growth hormone secretion. 1,2
P E T E R M . HOLLAND, M . D .
M.D.
M A U R I C E B. LANDERS III, M . D .
Quebec
H. E. LEBOVITZ, M . D . MYRON WOLBARSHT, PH.D.
Durham,
REFERENCES 1. Hägen, J . C , Lawrence, A. M., and Kirstein, L.; Abnormal growth hormone (GH) secretion in ketosis prone diabetics. J . Lab. Clin. Med. 78:993, 1971. 2. Somatostatin and diabetes, editorial. Lancet 1:1323, 1975.
Reply Editor: W e appreciate Dr. Berkowitz's thoughtful letter, and are in full agreement regarding the problems o f controlling the multiple variables in the clinical study. T h e concluding paragraph o f our paper points out that "there does not appear to be any clear data for assuming a relationship between diabetic retinopathy and serum growth h o r m o n e . " W e are simply stating that our data and a review o f the data o f others which may or may not have purported to show such a relationship
North
Carolina
REFERENCES 1. Boyd, A. E . Ill, Lebovitz, H. E . , and Pfeiffer, J. B.: Stimulation of human growth-hormone secretion by L-dopa. N. Engl. J . Med. 283:1425, 1970. 2. Boyd, A. E . Ill, Lebovitz, H. E . , and Feldman, J. M.: Endocrine function and glucose metabolism in patients with Parkinson's disease and their alteration by L-dopa. J . Clin. Endocrinol. Metab. 33:829, 1971.
Peripapillary Changes in Glaucoma Editor: I read the interesting article, "Peripapillary changes in g l a u c o m a " (Am. J . Ophthalmol. 8 1 : 3 4 1 , 1 9 7 6 ) by J . T . Wilensky and Allan E . Kölker, and am pleased they found some evidence in support o f my c o n t e n t i o n that peripapillary changes may b e an early sign o f glauco1