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Insulin-induced growth hormone response in patients with uterus carcinoma. I. Endometrial carcinoma
Europ. J. Cancer Vol. 13, pp. 801-804. Pergamon Press 1977. Printed in Great Britain
Insulin-induced Growth Hormone Response in Patients with Uterus Carcinoma. I. Endomemal Carcinoma* S. MADAJEWICZ~, J. HARUPPA and J. KAMINSKA Departments of Gynecology and Nuclear Medicine, Institute of Oncology, Warsaw, Poland A b s t r a c t - - T h e insulin-induced GH responses were studied in 37 patients with endometrial carcinoma and 11 healthy obese women. Mean Gift concentrations were significantly lower in the cancer patients. Quarter of patients showed abnormally low pituitary GH release. The GH responses in obese patients with endometrial carcinoma were significantly lower than those in thin.
INTRODUCTION
"Desirable" body weight was obtained from the Tables of Metropolitan Life Insurance Company [6]. For a given height the mean of the range for "medium frame" was considered 100% and the criterion of obesity was an actual weight greater than 115%. Twenty-three patients with e.c. were obese. The results of insulin-induced G H responses in obese patients with e.c. were compared to those in h.o.w. Because of J. Roth report that there is no difference in G H responsiveness to stimulation tests between the obese and thin [7], we considered our group of h.o.w, as a control group to thin patients with e.c. as well. After overnight fasting, patients and control women each received intravenously 0.1 units of regular insulin/kg b.w. Blood samples for glucose and GH concentrations were obtained prior to and at the 30, 45, 60, 90, 120 and 180 rain after the insulin injection. All patients and controls experienced at least a 50% fall in serum glucose concentrations with concomitant symptoms of neuroglycopaemia. Serum GH concentrations were measured by means of CEA-IRE-Sorin kit, and plasma glucose levels by the method of Asatoor-King [8]. Student-t test was used for statistical analysis.
GROWTH hormone has been shown to result in tumor development in laboratory animals [1, 2]; and there has also been some evidence that tumors develop more frequently in patients with acromegaly [3]. Benjamin found in patients with endometrial cancer increased G H secretion after insulin administration as well as paradoxical rises in its concentration following a glucose load [4, 5]. This paper represents the studies on disturbances in hypothalamopituitary axis regulation which are conducted in patients with endometrial carcinoma.
MATERIAL AND M E T H O D S Thirty-seven patients with endometrial cancer (e.c.) and 11 healthy obese women (h.o.w.) were studied. All patients had histologically proven carcinoma and were in good general condition. Patients with clinical diabetes were excluded. In order to make our conclusions more precise, patients were divided due to stage of disease and weight. Out of patients with e.c 28 were in stage I and 9 in more advanced stages.
RESULTS Accepted 22 October 1976. *Supported in part by Polish Academy of Science grant 310/VI. ~'Present address: Department of Thoracic Surgery, Roswell Park Memorial Institute, Buffalo, NY 14203, U.S.A.
Serum GH concentrations after the insulin stimulation are shown in Table 1 and in Fig. 1. Mean serum G H level rose from 1.1 4- 0"26 ng/ml (mean 4- S.E.) to 14.4 4- 2-90 ng/ml in whole group of patients with e.c., and 801
802
S. Madajewicz, or. Haruppa and J. Kaminska Table I.
Mean serum growth hormone concentrationsfollowing the insulin stimulation
Time (min)
0
30
45
60
90
120
180
14.4 2"09 19.9 3.55 10.9 2.32
11"0 1.91 15.1 2.74 8.4 2.49
6.4 1.56 7.8 1.96 5.5 2.24
2"9 0"66 3.2 1.14 2.6 0.82
healthy obese women (h.o.w.) 9.5 21.0 32"4 3.48 4-95 5.33
29.1 6.51
14.2 3.80
5"9 1.45
ng/ml endometrial carcinoma (e.c.) Whole group (n = 37) Thin (n = 14) Obese (n = 23)
Mean _+ S.E. Mean + S.E. Mean _+ S.E.
1.1 0'26 1.2 0.35 1.0 0.37
Mean + S.E. p e.e./ h.o.w. p Thin/ Obese
0"9 0.34
(n = 11)
2.8 0.84 4.7 2.03 1.7 0.56
8"0 1"76 11.9 3.46 5.2 1.34
N.S.
<0.01
<0.01
<0.001
<0.001
<0.05
<0.05
N.S.
<0.001
<0.001
<0.001
<0.001
<0.01
N.S.
mg ¢iOOm[
160150140130
9575- \
• ~t
65- ~
120
~
55-
/
345 /
I10 I00 90 SO 7O 60 50 40
f~
ng Inl
2O I0
304560
o
~o
eo
go
o
3~
6b
9b
do
I':o
M I N UTES
Fig. 2. Multiplicity of maximum GH increments plotted against time in patients with endometrial carcinoma.
3()
6()
9()
Ii0
llJO MINUTES
Fig. 1. Mean serum GH and glucose concentrationfoUowlng the insulin stimulation in patients with endometrial carcinoma ( - - - - ) a n d in control group ( ).
from 0.9 _+ 0-34 ng/ml to 32"4 _+ 5"33 ng/ml in the controls. M e a n G H concentrations following the insulin stimulation were significantly lower in patients with e.c. than in the
controls. Nine patients (25% of total) showed less than 5 ng/ml increment of GH concentration; these patients were obese. W h e n responses to insulin stimulation were expressed as m a x i m u m multiplicity over the basal value of GH, 8 patients showed values below 10. Nine patients showed rise in G H concentrations at the 90th min; 5 of them were obese. Five patients showed rise in G H concentrations only after 120 min, and 3 did not any; all of them but one were obese (Fig. 2). Seventeen patients had the peak responses at or after the 90th rain while only 3 out of 11 h.o.w, showed the peak at the 90th min and 2 had the value of multiplicity of increment less than 10 (Fig. 3).
Insulin-Induced Growth Hormone Response in Patients with Uterus Carcinoma
803
The G H responses to hypoglycemia were significantly lower in obese patients than in the thin (Table 1 and Fig. 4). We did not find any influence of stage of disease on the results.
14
DISCUSSION
30 45 60
0
30
60
90
MINUTES
Fig. 3.
Multiplicity of maximum GH increments plotted against time in control group,
rag/7100 ml 85 75 65 55 45 35 25-
ng/ml
18 .~
I
"t
J
':1
I, \\\
I
J.l:
30
60
,T
-k
',
90
120
M a n y authors have been unable to document any significant difference in G H release in men which could be related to age or sex [9, 10]. Johansen has given evidence that there is a decrease in the metabolic clearance rate of G H in diabetics, rather than increase in secretion [11]. Obesity decreases G H responsiveness to stimulation tests [12]; but some reports notify that there is no difference between the obese and thin [7]. We have found that survival rate after the cobalt-therapy was higher in obese patients with e.c. than in the thin ones. Does this fact depend upon the different hormonal environment ? We found serum G H concentrations after insulin injection significantly lower in patients with e.c. than in h.o.w. ; this observation is in variance to that of Benjamin [4]. Eight out of 37 patients with e.c. reached a peak of G H response at the 120th min or later, and 5 of them had abnormally low G H responses (less than 5 ng/ml). It means that 13°/o of patients had G H deficiency and other 9% showed delayed pituitary release. All of them but one were obese. It might be useful to measure not only serum G H concentrations but also the amount or capacity of tissue receptors for this hormone. It is conceivable that despite of normal G H level the capacity of G H receptors may be increased as in some cases of breast cancer [ 13]. At the present time the role played by G H in endometrial carcinoma remains unclear.
180
MINUTES
Fig. 4. Mean serum GH and glucose concentrationfollowing the insulin stimulation in thin (. . . . ) and obese ( ) patients with endometrial carcinoma.
Acknowledgements--The authors wish to thank Prof. L. Tarlowska, M.D. and Dr. J. Szymendera for their encouragement and helpful discussion. We are also grateful to Dr. J. Nauman for his cooperation and providing the control group.
REFERENCES 1. 2. 3. 4. 5.
A . A . KONEFF, H. D. MOON and M. E. SIMPSON,Neoplasm in rats treated with pituitary growth hormone--IV. Pituitary gland. Cancer Res. 11~ 113 (1951). H . D . MOON,M. E. SIMPSONand C. H. LI, Neoplasm in rats treated with pituitary growth hormone--V. Absence of neoplasm in hypophysectomized rats. Cancer Res. 119 535 (1951). W. H. DAUOHADAY, The adenohypophysis. In Textbook of Endocrinology. (Edited by R. H. Williams) p. 27. W. B. Saunders, Philadelphia (1968). F. BENJAMIN,Growth hormone response to insulin hypoglycemia in endometrial carcinoma. Obstet. Gynecol. 439 257 (1974). F. BENJAMIN, D. J. CASPER and L. SHERMAN,Growth hormone secretion in patients with endometrial carcinoma. New Engl. J. Med. 2819 1448 (1969).
804
S. Madajewicz, d. Haruppa and J. Kaminska 6. 7. 8. 9. 10. I 1. 12. 13.
C . M . M~cBRYDE, The diagnosis of obesity. Med. Clin. N. Amer. 48, !307 (1964). J. ROTH, S. M. GLICK, R. S. YALOW and S. A. BERSON, Secretion of human growth hormone: physiologic and experimental modification. Metabolism 12, 577 (1963). E.J. KINO, Micro-Analysis in medical biochemistry. (Edited by I. D. P. Wootton) 3rd Edn. J. and A. Churchill, London (1956). R . J . DUDL,J. W. ENSlNCK,H. E. PALMERand R. H. WILLIAMS,Effect of age on growth hormone secretion in man. J. din. Endocr. 37, 11 (1973). J. MERIMEE,J. A. BURGESSand D. RABINOWlTZ,Preliminary communication: sex-determined variation in serum insulin and growth hormone response to amono acid stimulation, or. din. Endocr. 26, 791 (1966). K. JOHANSEN,J. S. SOELDNERand R. E. GLEASON, Insulin, growth hormone and glucagon in prediabetes mellitus--a review. Metabolism 23, 1185 (1974). P . M . CROCKFORD and P. A. SALMON, Hormones and obesity: changes in insulin and growth hormone secretion following surgically induced weight loss. Canad. med. Ass. or. 103, 147 (1970). I. de SOUZA and L. MOROAN, Growth-hormone dependence among human breast cancers. Lancet il, 182 (1974).
Insulin-induced Growth Hormone Response in Patients with Uterus Carcinoma. I. Endomemal Carcinoma* S. MADAJEWICZ~, J. HARUPPA and J. KAMINSKA Departments of Gynecology and Nuclear Medicine, Institute of Oncology, Warsaw, Poland A b s t r a c t - - T h e insulin-induced GH responses were studied in 37 patients with endometrial carcinoma and 11 healthy obese women. Mean Gift concentrations were significantly lower in the cancer patients. Quarter of patients showed abnormally low pituitary GH release. The GH responses in obese patients with endometrial carcinoma were significantly lower than those in thin.
INTRODUCTION
"Desirable" body weight was obtained from the Tables of Metropolitan Life Insurance Company [6]. For a given height the mean of the range for "medium frame" was considered 100% and the criterion of obesity was an actual weight greater than 115%. Twenty-three patients with e.c. were obese. The results of insulin-induced G H responses in obese patients with e.c. were compared to those in h.o.w. Because of J. Roth report that there is no difference in G H responsiveness to stimulation tests between the obese and thin [7], we considered our group of h.o.w, as a control group to thin patients with e.c. as well. After overnight fasting, patients and control women each received intravenously 0.1 units of regular insulin/kg b.w. Blood samples for glucose and GH concentrations were obtained prior to and at the 30, 45, 60, 90, 120 and 180 rain after the insulin injection. All patients and controls experienced at least a 50% fall in serum glucose concentrations with concomitant symptoms of neuroglycopaemia. Serum GH concentrations were measured by means of CEA-IRE-Sorin kit, and plasma glucose levels by the method of Asatoor-King [8]. Student-t test was used for statistical analysis.
GROWTH hormone has been shown to result in tumor development in laboratory animals [1, 2]; and there has also been some evidence that tumors develop more frequently in patients with acromegaly [3]. Benjamin found in patients with endometrial cancer increased G H secretion after insulin administration as well as paradoxical rises in its concentration following a glucose load [4, 5]. This paper represents the studies on disturbances in hypothalamopituitary axis regulation which are conducted in patients with endometrial carcinoma.
MATERIAL AND M E T H O D S Thirty-seven patients with endometrial cancer (e.c.) and 11 healthy obese women (h.o.w.) were studied. All patients had histologically proven carcinoma and were in good general condition. Patients with clinical diabetes were excluded. In order to make our conclusions more precise, patients were divided due to stage of disease and weight. Out of patients with e.c 28 were in stage I and 9 in more advanced stages.
RESULTS Accepted 22 October 1976. *Supported in part by Polish Academy of Science grant 310/VI. ~'Present address: Department of Thoracic Surgery, Roswell Park Memorial Institute, Buffalo, NY 14203, U.S.A.
Serum GH concentrations after the insulin stimulation are shown in Table 1 and in Fig. 1. Mean serum G H level rose from 1.1 4- 0"26 ng/ml (mean 4- S.E.) to 14.4 4- 2-90 ng/ml in whole group of patients with e.c., and 801
802
S. Madajewicz, or. Haruppa and J. Kaminska Table I.
Mean serum growth hormone concentrationsfollowing the insulin stimulation
Time (min)
0
30
45
60
90
120
180
14.4 2"09 19.9 3.55 10.9 2.32
11"0 1.91 15.1 2.74 8.4 2.49
6.4 1.56 7.8 1.96 5.5 2.24
2"9 0"66 3.2 1.14 2.6 0.82
healthy obese women (h.o.w.) 9.5 21.0 32"4 3.48 4-95 5.33
29.1 6.51
14.2 3.80
5"9 1.45
ng/ml endometrial carcinoma (e.c.) Whole group (n = 37) Thin (n = 14) Obese (n = 23)
Mean _+ S.E. Mean + S.E. Mean _+ S.E.
1.1 0'26 1.2 0.35 1.0 0.37
Mean + S.E. p e.e./ h.o.w. p Thin/ Obese
0"9 0.34
(n = 11)
2.8 0.84 4.7 2.03 1.7 0.56
8"0 1"76 11.9 3.46 5.2 1.34
N.S.
<0.01
<0.01
<0.001
<0.001
<0.05
<0.05
N.S.
<0.001
<0.001
<0.001
<0.001
<0.01
N.S.
mg ¢iOOm[
160150140130
9575- \
• ~t
65- ~
120
~
55-
/
345 /
I10 I00 90 SO 7O 60 50 40
f~
ng Inl
2O I0
304560
o
~o
eo
go
o
3~
6b
9b
do
I':o
M I N UTES
Fig. 2. Multiplicity of maximum GH increments plotted against time in patients with endometrial carcinoma.
3()
6()
9()
Ii0
llJO MINUTES
Fig. 1. Mean serum GH and glucose concentrationfoUowlng the insulin stimulation in patients with endometrial carcinoma ( - - - - ) a n d in control group ( ).
from 0.9 _+ 0-34 ng/ml to 32"4 _+ 5"33 ng/ml in the controls. M e a n G H concentrations following the insulin stimulation were significantly lower in patients with e.c. than in the
controls. Nine patients (25% of total) showed less than 5 ng/ml increment of GH concentration; these patients were obese. W h e n responses to insulin stimulation were expressed as m a x i m u m multiplicity over the basal value of GH, 8 patients showed values below 10. Nine patients showed rise in G H concentrations at the 90th min; 5 of them were obese. Five patients showed rise in G H concentrations only after 120 min, and 3 did not any; all of them but one were obese (Fig. 2). Seventeen patients had the peak responses at or after the 90th rain while only 3 out of 11 h.o.w, showed the peak at the 90th min and 2 had the value of multiplicity of increment less than 10 (Fig. 3).
Insulin-Induced Growth Hormone Response in Patients with Uterus Carcinoma
803
The G H responses to hypoglycemia were significantly lower in obese patients than in the thin (Table 1 and Fig. 4). We did not find any influence of stage of disease on the results.
14
DISCUSSION
30 45 60
0
30
60
90
MINUTES
Fig. 3.
Multiplicity of maximum GH increments plotted against time in control group,
rag/7100 ml 85 75 65 55 45 35 25-
ng/ml
18 .~
I
"t
J
':1
I, \\\
I
J.l:
30
60
,T
-k
',
90
120
M a n y authors have been unable to document any significant difference in G H release in men which could be related to age or sex [9, 10]. Johansen has given evidence that there is a decrease in the metabolic clearance rate of G H in diabetics, rather than increase in secretion [11]. Obesity decreases G H responsiveness to stimulation tests [12]; but some reports notify that there is no difference between the obese and thin [7]. We have found that survival rate after the cobalt-therapy was higher in obese patients with e.c. than in the thin ones. Does this fact depend upon the different hormonal environment ? We found serum G H concentrations after insulin injection significantly lower in patients with e.c. than in h.o.w. ; this observation is in variance to that of Benjamin [4]. Eight out of 37 patients with e.c. reached a peak of G H response at the 120th min or later, and 5 of them had abnormally low G H responses (less than 5 ng/ml). It means that 13°/o of patients had G H deficiency and other 9% showed delayed pituitary release. All of them but one were obese. It might be useful to measure not only serum G H concentrations but also the amount or capacity of tissue receptors for this hormone. It is conceivable that despite of normal G H level the capacity of G H receptors may be increased as in some cases of breast cancer [ 13]. At the present time the role played by G H in endometrial carcinoma remains unclear.
180
MINUTES
Fig. 4. Mean serum GH and glucose concentrationfollowing the insulin stimulation in thin (. . . . ) and obese ( ) patients with endometrial carcinoma.
Acknowledgements--The authors wish to thank Prof. L. Tarlowska, M.D. and Dr. J. Szymendera for their encouragement and helpful discussion. We are also grateful to Dr. J. Nauman for his cooperation and providing the control group.
REFERENCES 1. 2. 3. 4. 5.
A . A . KONEFF, H. D. MOON and M. E. SIMPSON,Neoplasm in rats treated with pituitary growth hormone--IV. Pituitary gland. Cancer Res. 11~ 113 (1951). H . D . MOON,M. E. SIMPSONand C. H. LI, Neoplasm in rats treated with pituitary growth hormone--V. Absence of neoplasm in hypophysectomized rats. Cancer Res. 119 535 (1951). W. H. DAUOHADAY, The adenohypophysis. In Textbook of Endocrinology. (Edited by R. H. Williams) p. 27. W. B. Saunders, Philadelphia (1968). F. BENJAMIN,Growth hormone response to insulin hypoglycemia in endometrial carcinoma. Obstet. Gynecol. 439 257 (1974). F. BENJAMIN, D. J. CASPER and L. SHERMAN,Growth hormone secretion in patients with endometrial carcinoma. New Engl. J. Med. 2819 1448 (1969).
804
S. Madajewicz, d. Haruppa and J. Kaminska 6. 7. 8. 9. 10. I 1. 12. 13.
C . M . M~cBRYDE, The diagnosis of obesity. Med. Clin. N. Amer. 48, !307 (1964). J. ROTH, S. M. GLICK, R. S. YALOW and S. A. BERSON, Secretion of human growth hormone: physiologic and experimental modification. Metabolism 12, 577 (1963). E.J. KINO, Micro-Analysis in medical biochemistry. (Edited by I. D. P. Wootton) 3rd Edn. J. and A. Churchill, London (1956). R . J . DUDL,J. W. ENSlNCK,H. E. PALMERand R. H. WILLIAMS,Effect of age on growth hormone secretion in man. J. din. Endocr. 37, 11 (1973). J. MERIMEE,J. A. BURGESSand D. RABINOWlTZ,Preliminary communication: sex-determined variation in serum insulin and growth hormone response to amono acid stimulation, or. din. Endocr. 26, 791 (1966). K. JOHANSEN,J. S. SOELDNERand R. E. GLEASON, Insulin, growth hormone and glucagon in prediabetes mellitus--a review. Metabolism 23, 1185 (1974). P . M . CROCKFORD and P. A. SALMON, Hormones and obesity: changes in insulin and growth hormone secretion following surgically induced weight loss. Canad. med. Ass. or. 103, 147 (1970). I. de SOUZA and L. MOROAN, Growth-hormone dependence among human breast cancers. Lancet il, 182 (1974).