J Clin Endocrinol Metab 42: 193, 1976 EFFECTS OF ALCOHOL ON GROWTH HORMONE SECRETION IN ACROMEGALY G. TAMBURRANO, S. TAMBURRANO, S. GAMBARDELLA, and D. ANDREANI Cattedra di Medicina Costituzionale ed Endocrinologia, Universita di Roma, Italy ABSTRACT. In 3 normal subjects and in 4 acromegalic patients pretreatment with an alcohol infusion for 4 hours at a constant rate reduced the GH response to Arginine, when comparison was made with pretreatment with saline. The reduction in acromegalics was more marked and sustained than in normals. Thought it is likely that the effect of alcohol is exerted on hypothalamic centers, a direct influence on the pituitary cannot be excluded.
Recent investigations carried out by our group(i) have shown that alcohol exerts a remarkable influence upon insulin, glucagon,cortisol and growth hormone in normal subjects after 12 as well as after 36 hours of fasting. In these investigations it was observed that ethanol reduces the response of GH to Arginine after both periods of fasting. Furthermore in a chronic alcoholic suffering from severe hypoglycemia,a lack of GH response to various stimuli was found(i);after 9 months of abstinence this patient no longer presented hypoglycemia and GH levels were satisfactory. Arky and Freinkel(2),Bagdade et al. (3,4),Merry and Marks(5,6),Freinkel et al.(7),Pek et al.(8).Turner et al.(9), Kalkhoff and Kim(io) reported on the secretion of insulin,glucagon,cortisol and GH in normal subjects,in patients suffering from obesity, insuloma and diabetes and in alcoholics,but to our knowledge no data are available in patients suffering from pituitary tumors. In order to establish the relationships between alcohol and GH secretion we have studied the effect of an acute administration of alcohol on the GH response to Arginine in 4 acromegalics and 3 normal subjects.
MATERIALS AND METHODS After a 12 hours fasting period 3 normal alcohol-naive volunteers and 4 non treated acromegalics were subjected to a 4 hours intravenous infusion of saline followed by and infusion o£ Arginine (30g in 400 ml of saline for 30 minutes).After one week and following an identical period of fasting a 15 % alcohol solution in saline was injected for 4 hours(310 mg/min)and again the Arginine test was performed. Blood samples for BG and GH were collected at the required intervals through a plastic catheter introduced Into the antecubital vein of the opposite arm. BG and GH were determined according to the methods currently employed in our laboratory and described in previous papers (11). RESULTS In normal subjects BG and GH levels observed during the alcohol infusion were similar to those observed during saline(tab.1).However, during the Arginine test which followed BG values were slightly lower after alcohol than after saline,though differences were not statistically significant; also GH levels were lower than normal and after 20 as well as 30 minutes from the start of the Ar-
193
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4) S.A.
3) P.A.
2) C.E.
ACROMEGALICS 1) P.A.
+ SEM.
3) A.D.
2) G.S.
NORMAL SUBJECTS 1) G.M.
4) S.A.
3) P.A.
2) C.E.
ACROMEGALIC3 1) P.A.
-
-
-
S A S A S A S A
A
S
S A S A S A
S A S A S A S A
A
S
16 24 7.7 10 46 45 46 67
.8b .5 .6 .6 .8 5.7 .7 .06 2.2 1.71
79 88 88 90 154 168 77 56
81 10 83 7
89 98
- S - A
3) A.D.
MEAN + SEM.
94 75
61 76
.0
- S - A
- S - A
TIME
18 21 5.6 8 40 26 41.4 40.5
.5 .4 .6 .3 .6 1.6 .6 .03 .7 .41
85 83 90 88 151 175 76 53
48 15.5 35 26
7
16 16 7.2
.6 .4 .6 .3 .6 .6 .6 .00 .4 .08
84 82 92 86 144 169 75 62
77 6 76 9
85 93
90 94 81 9 79 8
81 73
65 62
V
19 13 8.2 8 31 16. 3 22. 5 18
.06 .4 .06
.5 .7
.6 .5 .6 .3 .8
87 78 91 80 144 164 77 60
7
79 6 73
89 88
81 68
69 64
20 12 7.7 6 37 15.6 13 16
.7 .4 .5 .5 2.4 .2 1.2 .60 .3 .08
84 76 88 78 136 162 72 56
75 7 70 7
87 84
76 64
64 64
83 76 82 65 115 128 68 62
18 12 7.2 4 26 14 19 6.3
.15
•6
1.5 .9 2.2 .5 1.0 .4 1.5 . .34
18 10 7.1 33 19 8.5 11.9 6.1
5.8 .3 .5 .4 2.4 1.68 .4 .12
.7
1.0
GROWTH HORMONE
83 76 86 72 . 130 142 66 57
71 6 69 9
84 87
90 87 72 10 71 8
68 60
62 )60
240
72 61
56 66
SALINE OR ALCOHOL 60 90 1-20 180
90 75
63 67
30
BLOOD GLUCOSE INF.
94 118 114 117 142 164 96 76
83 3 77 12
97 100
84 69
77 62
-270
21 9 5 2 32 105 8.8 6
19 10 8 3 30 12 12 8
7.4 1.9 1.0 3.9 8.3 7.1 .6 .5 5.0 10.8 4.2 .5 •5.0 *8.4 1.18 1.84 *2.8 *.7 1.18 .15
*p o
I—I
c z
a o o s
CD
RAPID COMMUNICATIONS ginine infusion differences appeared to be statistically significant ( p * 0.05)(Tab.i). In the acromegalic patients blood glucose was usually lower during alcohol infusion,but higher during the Arginine test when compared with the values recorded during saline(Tab.1). In this respect the behavior of BG was strikingly different from normal. GH levels were lower both during alcohol infusion and during the Argi nine test. Comparing the differences in percent changes of GH levels, statistical significance was observed during alcohol and afterwards during the Arginine test (Fig. I ) . DISCUSSION The reduction in GH levels observed during the Arginine test after alcohol infusion in acromegalics shows that alcohol affects GH secretion not only in normals,as previously demonstrated(i). It is likely that ethanol acts depressing hypothalamic stimulatory centers,as research by Merry and Marks(5,6)also seems to indicate, but a direct effect on the pituitary cannot be excluded; in this respect the reduction in GH levels during alcohol infusion and before Arginine must be taken into consideration.However, as acromegalic patients show a wide range of response to drugs affecting hypothalamic and pituitary function,the response to alcohol must be studied in those patients in whom hypothalamic control is completely, abolished. Theoretically it may also be assumed that alcohol stimulates the secretion of somatostatin,bu to our knowledge no data are available so far. VZhatever the mechanism may be, it seems important to outline that a substance such as alcohol may reduce the abnormal secretion by a tumor. During alcohol infusion in acromegalics reduction of blood glucose has also been observed, whereas
195
following Arginine BG was higher than after saline, however, no definite conclusion on this phenomenon can be drawn because of the insufficient number of patients and controls. Reduction of GH secretion following alcohol may explain the observation of hypoglycemia observed by Walsh et al. (12) in 2 diabetics. It is possible that chronic intoxication by alcohol gives rise to a persistent GH defect which may be reverted by alcohol withdrawal; but further research is necessary to lend support to this hypothesis. REFERENCES 1. Andreani, D., G. Tamburrano, S-. Tamburrano, S. Gambardella. Hormonal changes in alcoholihypoglycemia. Diabetologia, 10:357, 1974. 2. Arky, R.A., N. Freinkel. The response of plasma human growth hormone to insulin and ethanol-induced hypoglycemia in two patients with "isolated adrenocorticotropic defect". Metabolism, 13:547,1964. 3. Bagdade, J.D., E.L. Bierman, and D. Porte. Counter-regulation of basal insulin secretion during alcohol hypoglycemia in diabetic and normal subjects. Diabetes, 21:65,1972. 4. Bagdade, J.D., D. Gate, and D. Porte. Hormone fuel interrelationship during alcohol hypoglycemia in man. Proc. Soc.Exp. Biol. Med., 141:540,1972. 5. Merry,J., and V. Marks. Plasma hydrocortisone response to ethanol in chronic alcoholics. Lancet,1:921,1969. 6. Merry, J., and V. Marks. The effect of alcohol,barbiturate, and diarepen on hypothalamic-pituitary-adrenal function in chronic alcoholics. Lancet,3: 990,1972.
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RAPID COMMUNICATIONS
196
7. Freinlcel, N.,D.L. Singer, R.A. Arky, S.J. Bleicher, J.B. Anderson, and C. K. Silbert. Alcohol hypoglycemia.I. Carbohydrate metabolism of patient with clinical alcohol hypoglycemia and the experimental reproduction of the syndrome v/ith pure ethanol. J.. Clin. Invest.,42:1112, 1963. 8. Pek, S., C.Floyd,S.S. Fajans, R.F. Knopf, P.N. Weisman, and J.W. Conn. Augmentation by ethanol of arginine induced increases in plasma glucagon in men. Program 53rd Meeting Endocr. Soc.,S.Francisco,June 1951, pag.56.
JCE & M • 1976 Vol 42 • No 1
1.0. Kalkhoff ,R.K. , H.J.Kim. Metabolic responses to fasting and ethanol infusion in obese,diabetic subjects. Relationship to insulin deficiency. Diabetes,22:372,1973. 11. Andreani,D.,F. Fallucca, G. Tamburrano, M. Javicoli,and G. Menzin ger. Insulin, glucagon and grov/th hormone in primary adul mixoedema. Diabetologia, 10:7,1974. 12. Walsh, C.H., and D.J. O'Sullivan. Effect of moderate alcohol intake on control of diabetes. Diabetes, 23:440,1974.
9. Turner, R.C., N.W.Oakley, J.D.N. Nabarro. Changes in plasma insulin during ethanol induced hypoglycemia. Metaboli sm,22:111,197 3. A LC O H O L S A L I N E
basal-level
200
ACROMEGALICS (4)
Z
o or O 1
100 O cr
O
•
60 P < 0.05 P < 0.01
120 ••• ••••
180 P < 0.005 P < 0.0025
240
270
300
330 360 minutes
GH levels in 4 a c r o m e g a l i c s during alcohol infusion followed by arginine infusion.
Fig. 1.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 18 November 2015. at 13:30 For personal use only. No other uses without permission. . All rights reserved.
Recent investigations carried out by our group(i) have shown that alcohol exerts a remarkable influence upon insulin, glucagon,cortisol and growth hormone in normal subjects after 12 as well as after 36 hours of fasting. In these investigations it was observed that ethanol reduces the response of GH to Arginine after both periods of fasting. Furthermore in a chronic alcoholic suffering from severe hypoglycemia,a lack of GH response to various stimuli was found(i);after 9 months of abstinence this patient no longer presented hypoglycemia and GH levels were satisfactory. Arky and Freinkel(2),Bagdade et al. (3,4),Merry and Marks(5,6),Freinkel et al.(7),Pek et al.(8).Turner et al.(9), Kalkhoff and Kim(io) reported on the secretion of insulin,glucagon,cortisol and GH in normal subjects,in patients suffering from obesity, insuloma and diabetes and in alcoholics,but to our knowledge no data are available in patients suffering from pituitary tumors. In order to establish the relationships between alcohol and GH secretion we have studied the effect of an acute administration of alcohol on the GH response to Arginine in 4 acromegalics and 3 normal subjects.
MATERIALS AND METHODS After a 12 hours fasting period 3 normal alcohol-naive volunteers and 4 non treated acromegalics were subjected to a 4 hours intravenous infusion of saline followed by and infusion o£ Arginine (30g in 400 ml of saline for 30 minutes).After one week and following an identical period of fasting a 15 % alcohol solution in saline was injected for 4 hours(310 mg/min)and again the Arginine test was performed. Blood samples for BG and GH were collected at the required intervals through a plastic catheter introduced Into the antecubital vein of the opposite arm. BG and GH were determined according to the methods currently employed in our laboratory and described in previous papers (11). RESULTS In normal subjects BG and GH levels observed during the alcohol infusion were similar to those observed during saline(tab.1).However, during the Arginine test which followed BG values were slightly lower after alcohol than after saline,though differences were not statistically significant; also GH levels were lower than normal and after 20 as well as 30 minutes from the start of the Ar-
193
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 18 November 2015. at 13:30 For personal use only. No other uses without permission. . All rights reserved.
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4) S.A.
3) P.A.
2) C.E.
ACROMEGALICS 1) P.A.
+ SEM.
3) A.D.
2) G.S.
NORMAL SUBJECTS 1) G.M.
4) S.A.
3) P.A.
2) C.E.
ACROMEGALIC3 1) P.A.
-
-
-
S A S A S A S A
A
S
S A S A S A
S A S A S A S A
A
S
16 24 7.7 10 46 45 46 67
.8b .5 .6 .6 .8 5.7 .7 .06 2.2 1.71
79 88 88 90 154 168 77 56
81 10 83 7
89 98
- S - A
3) A.D.
MEAN + SEM.
94 75
61 76
.0
- S - A
- S - A
TIME
18 21 5.6 8 40 26 41.4 40.5
.5 .4 .6 .3 .6 1.6 .6 .03 .7 .41
85 83 90 88 151 175 76 53
48 15.5 35 26
7
16 16 7.2
.6 .4 .6 .3 .6 .6 .6 .00 .4 .08
84 82 92 86 144 169 75 62
77 6 76 9
85 93
90 94 81 9 79 8
81 73
65 62
V
19 13 8.2 8 31 16. 3 22. 5 18
.06 .4 .06
.5 .7
.6 .5 .6 .3 .8
87 78 91 80 144 164 77 60
7
79 6 73
89 88
81 68
69 64
20 12 7.7 6 37 15.6 13 16
.7 .4 .5 .5 2.4 .2 1.2 .60 .3 .08
84 76 88 78 136 162 72 56
75 7 70 7
87 84
76 64
64 64
83 76 82 65 115 128 68 62
18 12 7.2 4 26 14 19 6.3
.15
•6
1.5 .9 2.2 .5 1.0 .4 1.5 . .34
18 10 7.1 33 19 8.5 11.9 6.1
5.8 .3 .5 .4 2.4 1.68 .4 .12
.7
1.0
GROWTH HORMONE
83 76 86 72 . 130 142 66 57
71 6 69 9
84 87
90 87 72 10 71 8
68 60
62 )60
240
72 61
56 66
SALINE OR ALCOHOL 60 90 1-20 180
90 75
63 67
30
BLOOD GLUCOSE INF.
94 118 114 117 142 164 96 76
83 3 77 12
97 100
84 69
77 62
-270
21 9 5 2 32 105 8.8 6
19 10 8 3 30 12 12 8
7.4 1.9 1.0 3.9 8.3 7.1 .6 .5 5.0 10.8 4.2 .5 •5.0 *8.4 1.18 1.84 *2.8 *.7 1.18 .15
*p o
I—I
c z
a o o s
CD
RAPID COMMUNICATIONS ginine infusion differences appeared to be statistically significant ( p * 0.05)(Tab.i). In the acromegalic patients blood glucose was usually lower during alcohol infusion,but higher during the Arginine test when compared with the values recorded during saline(Tab.1). In this respect the behavior of BG was strikingly different from normal. GH levels were lower both during alcohol infusion and during the Argi nine test. Comparing the differences in percent changes of GH levels, statistical significance was observed during alcohol and afterwards during the Arginine test (Fig. I ) . DISCUSSION The reduction in GH levels observed during the Arginine test after alcohol infusion in acromegalics shows that alcohol affects GH secretion not only in normals,as previously demonstrated(i). It is likely that ethanol acts depressing hypothalamic stimulatory centers,as research by Merry and Marks(5,6)also seems to indicate, but a direct effect on the pituitary cannot be excluded; in this respect the reduction in GH levels during alcohol infusion and before Arginine must be taken into consideration.However, as acromegalic patients show a wide range of response to drugs affecting hypothalamic and pituitary function,the response to alcohol must be studied in those patients in whom hypothalamic control is completely, abolished. Theoretically it may also be assumed that alcohol stimulates the secretion of somatostatin,bu to our knowledge no data are available so far. VZhatever the mechanism may be, it seems important to outline that a substance such as alcohol may reduce the abnormal secretion by a tumor. During alcohol infusion in acromegalics reduction of blood glucose has also been observed, whereas
195
following Arginine BG was higher than after saline, however, no definite conclusion on this phenomenon can be drawn because of the insufficient number of patients and controls. Reduction of GH secretion following alcohol may explain the observation of hypoglycemia observed by Walsh et al. (12) in 2 diabetics. It is possible that chronic intoxication by alcohol gives rise to a persistent GH defect which may be reverted by alcohol withdrawal; but further research is necessary to lend support to this hypothesis. REFERENCES 1. Andreani, D., G. Tamburrano, S-. Tamburrano, S. Gambardella. Hormonal changes in alcoholihypoglycemia. Diabetologia, 10:357, 1974. 2. Arky, R.A., N. Freinkel. The response of plasma human growth hormone to insulin and ethanol-induced hypoglycemia in two patients with "isolated adrenocorticotropic defect". Metabolism, 13:547,1964. 3. Bagdade, J.D., E.L. Bierman, and D. Porte. Counter-regulation of basal insulin secretion during alcohol hypoglycemia in diabetic and normal subjects. Diabetes, 21:65,1972. 4. Bagdade, J.D., D. Gate, and D. Porte. Hormone fuel interrelationship during alcohol hypoglycemia in man. Proc. Soc.Exp. Biol. Med., 141:540,1972. 5. Merry,J., and V. Marks. Plasma hydrocortisone response to ethanol in chronic alcoholics. Lancet,1:921,1969. 6. Merry, J., and V. Marks. The effect of alcohol,barbiturate, and diarepen on hypothalamic-pituitary-adrenal function in chronic alcoholics. Lancet,3: 990,1972.
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RAPID COMMUNICATIONS
196
7. Freinlcel, N.,D.L. Singer, R.A. Arky, S.J. Bleicher, J.B. Anderson, and C. K. Silbert. Alcohol hypoglycemia.I. Carbohydrate metabolism of patient with clinical alcohol hypoglycemia and the experimental reproduction of the syndrome v/ith pure ethanol. J.. Clin. Invest.,42:1112, 1963. 8. Pek, S., C.Floyd,S.S. Fajans, R.F. Knopf, P.N. Weisman, and J.W. Conn. Augmentation by ethanol of arginine induced increases in plasma glucagon in men. Program 53rd Meeting Endocr. Soc.,S.Francisco,June 1951, pag.56.
JCE & M • 1976 Vol 42 • No 1
1.0. Kalkhoff ,R.K. , H.J.Kim. Metabolic responses to fasting and ethanol infusion in obese,diabetic subjects. Relationship to insulin deficiency. Diabetes,22:372,1973. 11. Andreani,D.,F. Fallucca, G. Tamburrano, M. Javicoli,and G. Menzin ger. Insulin, glucagon and grov/th hormone in primary adul mixoedema. Diabetologia, 10:7,1974. 12. Walsh, C.H., and D.J. O'Sullivan. Effect of moderate alcohol intake on control of diabetes. Diabetes, 23:440,1974.
9. Turner, R.C., N.W.Oakley, J.D.N. Nabarro. Changes in plasma insulin during ethanol induced hypoglycemia. Metaboli sm,22:111,197 3. A LC O H O L S A L I N E
basal-level
200
ACROMEGALICS (4)
Z
o or O 1
100 O cr
O
•
60 P < 0.05 P < 0.01
120 ••• ••••
180 P < 0.005 P < 0.0025
240
270
300
330 360 minutes
GH levels in 4 a c r o m e g a l i c s during alcohol infusion followed by arginine infusion.
Fig. 1.
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