Increased Growth Hormone Responses to Growth Hormone Releasing Hormone and Thyrotropin Releasing Hormone in Patients with Metastatic Testicular Cancer P. Pietschmann, R. Kuzmits and G. Schernthaner II. Medizinische Universitatsklinik, Wien, Austria
In 16 patients with metastatic testicular cancer and 10 age matched male control subjects growth hormone (GH) responses to growth hormone releasing hormone (GHRH; 1 ug/kg body weight iv.) and thyrotropin releasing hormone (TRH; 200 ug iv.) were measured. Basal GH levels and GH levels following stimulation with GHRH or TRH were significantly increased in cancer patients compared to control subjects. 9 patients with testicular cancer were studied both in the stage of metastatic disease and after they had reached a complete remission. In complete remission GH responses to GHRH tended to decrease but the differences did not reach statistical significance. Our data suggest an alteration of hypothalamic and/or pituitary regulation of GH secretion in patients with metastatic testicular cancer. Key words
Pat. Nr. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Histological classification
tumor stage
hCG* (mU/ml)
AFP** (ng/ml)
Seminoma MTT MTU MTI Seminoma MTI Seminoma MTU Seminoma MTI MTU Seminoma MTT MTU MTU MTI
IIC IV L3 IV L3 IVCL2 MB IV L2 IV L1 IV CL3 IV L2 III B IV CL3 II C IV CL3 II C IVCL3 IV L1
29/0 298.317/0 0/0 27/0 3/0 66/0 1/0 59 0/0 111 0 1 788569 0 183 47/0
2.2/5.9 94.7/13.2 1.2/5.4 130/2.6 3.1/3.3 5.1/8.8 6.8/7.9 900 3.11/5.1 5.9 75000 7.5 32.9 669 360 95/7.4
Growth Hormone - Growth Hormone Releasing Hormone - Thyrotropin Releasing Hormone Testicular Cancer - Metastatic Cancer
Introduction In some pathological conditions such as acromegaly (Irie and Tsushima 1972), type-I diabetes mellitus (Dasmahapatra, Urdanivia and Cohen 1981), renal insufficiency (Gonzales-Barcena, Kastin, Schalch, Torres-Zamora, Perez-Pasten, Katoand Schally 1973) or liver disease (Panerai, Salerno, Manneschi, Cocchi and Midler 1977) paradoxical GH responses to TRH which do not occur in normal subjects, have been observed. Kamijo, Saito, Yachi and Wada (1980) reported that 33 out of 50 cancer patients showed a paradoxical GH response to an iv. injection of 500 (ug thyrotropin releasing hormone (TRH). Pituitary GH secretion is dually regulated by GHRH and somatostatin. In 1982 growth hormone releasing hormone was isolated from two human pancreatic tumors that have caused acromegaly (Rivier, Spiess, Thorner and Vale
Horm. metabol. Res. 22 (1990) 109-113 © Georg Thieme Verlag Stuttgart • New York
1983; Guillemin, Brazeau, Bohlen, Esch, Ling and Wehrenberg 1982). It is now well established that synthetic GHRH is a specific stimulator of GH secretion in man (Rosenthal, Schirock, Kaplan, Guillemin and Grumbach 1983). As the paradoxical GH responses to TRH in cancer patients suggest a disturbed regulation of GH secretion, we studied GH responses to GHRH and TRH in patients with metastatic testicular cancer. Patients and Methods 16 non-obese patients with metastatic testicular cancer (mean age: 35 + 3 years) and 10 non-obese male control subjects (35 ± 5 years) were studied. All testicular cancer patients presented with metastatic disease and were referred to our department for further chemotherapy. Clinical data of the patients are summarized in Table 1. Histological evaluation was performed according to Pugh
Received: 9 Nov. 1988
Accepted: 30 June 1989 after revision
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Summary
Table 1 Clinical characteristics of patients with testicular cancer. In the patients which were studied before chemotherapy and in complete remission both the values before and after treatment are given. *normal range < 1 mU/ml; "normal range < 20 ng/ml.
Horm. metabol. Res. 22(1990)
P. Pietschmann, R. Kuzmits and G. Schernthaner
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110
Fig. 1 GH responses to GHRH (upper panel) and TRH (lower panel) in patients with metastatic testicular cancer ( • — • ) and in control subjects ( • — • ). * P < 0.05; * * P < 0.025; * * * P < 0.0125; * * * * P < 0.005.
Fig. 2 GH responses to GHRH (upper panel) and TRH (lower panel) in patients with testicular cancer in metastatic stage of the disease ( • • ) and in complete remission ( O O).
(1976). The staging procedure was performed according to the Royal Marsden Staging Classification (Peckham 1981) including physical examination, chest x-ray, abdominal ultrasonic and computed tomography. All subjects gave their informed consent. After an overnight fast with subjects recumbent for at least 2 hours an iv. catheter was placed in a suitable vein. Blood specimens were obtained before (-30, 0 min) and after (15, 30,45,60 and 90 min) an iv. bolus injection of 1 ug/kg b. w. growth hormone releasing hormone 1-44 (GHRH 1-44, Bissendorf Peptides, Wedemark, Germany). After an interval of at least one day in all patients and control subjects TRH tests were performed with the same protocol as described above except that 200 u.g TRH (Hoechst, Germany) were injected iv. at time 0.
All patients received a sequential alternating chemotherapy consisting of vinblastine, bleomycin and cisdiamminedichloro-platinum (Einhorn and Donohue 1977) (2 cycles) and etoposide (100 mg/m 2 day 1-3), ifosfamide (1.5 g/m 2 day 1-3) and cisdiamminedichloroplatinum (20 mg/m day 1-5) (2 cycles). In 6 patients chemotherapy resulted in a complete remission, in 3 patients surgical excision of residual tumor was performed after the patients were tumor marker (alpha feto protein (AFP), B human chorionic gonadotropin (hCG)) negative following chemotherapy. Complete remission was assessed by negative tumor markers (AFP, hCG) and no evidence of any residual tumor after chemotherapy alone or after additional successfull surgical resection of residual tumor masses.
In 9 testicular cancer patients GHRH and TRH tests were performed both in the stage of metastatic disease before chemotherapy and after the patients had reached a complete remis-
GH was measured by radioimmunoassay (Tandem B HGH, Hybritech Liege, Belgium). Intraassay and interassay coefficient variation were 3.8 % and 5.2 % respectively (at 8.1 ng/ml and 7.8 ng/ml, respectively). The minimum detectable concentration was 0.2
Growth Hormone Responses in Cancer Patients
Horm. metabol. Res. 22 (1990)
ng/ml. In addition, prolactin and TSH levels following TRH administration and basal testosterone and estradiol levels were determined by radioimmunoassay (TSH by RIAa-gnost hTSH, Behring, Marburg, Germany; prolactin by Maiaclone, Serono, Milano, Italy; testosterone by Sorin Biomedia, Saluggia, Italy; estradiol by a radioimmunoassay of Diagnostic Products Corporation, LA, USA). AFP was determined by an enzymeimmunoassay (AFP-EIA Diagnostic Kit, Abbot Laboratories, North Chicago, USA), hCG was measured by radioimmunoassay (HCG-RIA, Serono, Milano, Italy).
parable in the state of metastatic disease and in complete remission (Fig. 2). Prolactin and TSH levels following TRH administration in patients with testicular cancer and control subjects and in patients with testicular cancer before chemotherapy and in complete remission were not statistically different (Fig. 3, Prolactin data not shown). Basal testosterone levels in patients with testicular cancer and control subjects were not statistically different (4.5 ± 0.7 vs. 4.7 ± 0.6 ng/ml).
All the data in the text, tables and thefiguresare preTwo testicular cancer patients with excessively sented as the mean ± SEM. Paired and unpaired Student's t-test and elevated hCG levels had markedly increased estradiol levels linear correlation coefficient were used for statistical analysis. (pt. no. 2: 907 pg/ml, pt. no. 13: 599 pg/ml). In the other patients serum estradiol levels were not statistically different Results from the control subjects (29.0 ± 6.3 vs. 23.5 ± 4.1 pg/ml). In Basal GH levels and GH responses to GHRH the cancer patients no significant correlation between serum in patients with metastatic testicular cancer were significantly estradiol level and AGH could be established (r = -0.02, increased when compared with matched controls (Fig. 1; N. S.). AGH = peak GH level - basal GH level: 13.9 ± 4.2 ng/ml vs Discussion 6.1 ± 1.1 ng/ml; P < 0.05). In patients with metastatic testicular cancer a significant increase of GH levels after TRH Our results demonstrate elevated basal GH stimulation was observed (basal GH levels: 1.7 ± 0.5 ng/ml levels and increased GH responses following GHRH and a vs. peak GH level 3.9 ± 1.0 ng/ml; P < 0.01) whereas in the control subjects basal GH levels (0.4 ± 0.1 ng/ml) and GH paradoxical GH response to TRH injection in patients with levels after TRH administration (peak GH level: 1.0 ± 0.6 metastatic testicular cancer. ng/ml) were not statistically different. GH levels after stimulaElevated levels of GH might be due, at least in tion with TRH were significantly increased in cancer patients when compared with control subjects (Fig. 1). GH responses part, to unspecific stress. However, as the GHRH and TRH to GHRH as well as the areas under the GH response-curves tests were performed with an interval of at least one week after (43.8 ± 11.9 ng/15 min • ml vs. 69.7 + 31.1 ng/15 min - ml) orchidectomy, unspecific stress in our cancer patients was untended to decrease in patients in complete remission com- likely greater than in the control subjects. In addition, as orpared to GH responses in the state of metastatic disease, how- chidectomy is a relatively small operation, postoperative alever, the differences did not reach statistical significance (Fig. terations do not seem to be responsible for the increased GH 2). GH responses following TRH administration were com- responses observed in our study.
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Fig. 3 TSH levels following TRH administration in patients with metastatic testicular cancer ( • — • ) and in control subjects ( O — O ) (left panel) and in patients with testicular cancer in the metastatic stage of the disease ( • — # ) and in complete remission ( O — O ) (right panel).
Serum testosterone and estradiol levels have been implicated in the regulation of G H secretion (Evans, Krieg, Limber, Kaiser and Thorner 1985; Link, Blizzard, Evans, Kaiser, Parker and Rogol 1986; Lang, Schemthaner, Pietschmann, Kurzand Stephenson 1987). However, the data of our study do not provide evidence that in testicular cancer patients and control subjects the different G H responses might be caused by different serum levels of testosterone or estradiol. Thus the presence of metastatic disease seems to be the factor predominantly responsible for the increased G H responses to G H R H and TRH in testicular cancer patients. Our results confirm the observation of Kamijo et al. (1980) that in tumor patients similarly as in patients with acromegaly (Irie and Tsushima 1972) and in type-I diabetes mellitus (Dasmahapatra, Urdanivia and Cohen 1981; Schemthaner, Spona, Ludwig and Bieglmayer 1978) paradoxical G H responses to TRH occur. The cause of paradoxical G H responses to TRH has not been clearly determined, alterations in the pituitary receptors mediating G H secretion have been suggested in acromegaly (he Dafniet, Gamier, Bression, Brandi, Racadot and Peillon 1985). In type-I diabetes mellitus, G H responses to TRH (Chiodera, Coiro, Speroni, Capretti, Muzzetto, Volpiand Butturini 1984) as well as to G H R H can be blunted by cholinergic receptor blockade, whereas in acromegaly both G H levels following TRH and G H R H cannot be suppressed by pretreatment with atropine (Pietschmann, Luger and Schemthanerl9S5; Pietschmann, Schemthaner and Luger 1986). These data suggest that the mechanisms underlying paradoxical TRH induced G H secretions are heterogenous. The increased GH responses to G H R H in patients with metastatic testicular cancer suggest an alteration of hypothalamic a n d / o r pituitary function in this disorder. Pituitary GH secretion is dually regulated by the hypothalamic peptides growth hormone releasing hormone and somatostatin (Schaff-Blass, Burstein and Rosenfield 1984). It might be speculated that the increased G H levels after G H R H and the paradoxical responses to TRH observed in cancer patients might be due to a decreased secretion of (hypothalamic) somatostatin; however, the similar TSH responses to TRH in the patients and the controls do not support the hypothesis of a decreased somatostatin secretion in patients with testicular cancer. In testicular cancer patients who were studied both before chemotherapy and in complete remission, G H responses to G H R H tended to decrease, but the differences did not reach statistical significance. Our data suggest that increased GH responsiveness to G H R H in testicular cancer patients might normalize in complete remission, but possibly the interval between the completion of chemotherapy and the G H R H tests might have been too short to demonstrate complete normalization of G H secretion. Emerman, Leahy, Gout and Bruckovsky (1985) reported elevated basal GH levels in breast cancer patients; Kamijo et al. (1980) found paradoxical G H responses to TRH in cancer patients with various types of primary tumors. These data in the literature indicate that abnormalities in G H secre-
P. Pietschmann, R. Kuzmits and G. Schemthaner tion as demonstrated in our study may not be confined to patients with metastatic testicular cancer but also might be found in other types of malignant disease. In conclusion, our findings of an increased G H responsiveness to G H R H and paradoxical G H responses to TRH in patients with metastatic testicular cancer provide evidence of an altered pituitary and/or hypothalamic regulation of G H secretion in this disorder. References Chiodera, P., V. Coiro, G. Speroni, L. Capretti, P. Muzzetto, R. Volpi, U. Butturini: The growth hormone response to thyrotropin-releasing hormone in insulin-dependent diabetics involves a cholinergic mechanism. J. Clin. Endocrinol. Metab. 59:794-797 (1984) Dasmahapatra, A., E. Urdanivia, M. P. Cohen:Growth hormone response to thyrotropin-releasing hormone in diabetes. J. Clin. Endocrinol. Metab. 52:859-862 (1981) Einhom, L. H., J. P. Donohue: Cisdiamminedichloroplatinum, vinblastine and bleomycin chemotherapy in disseminated testicular cancer. Ann. Int. Med. 87:293-298 (1977) Emerman, J. T., M. Leahy, P. W. Gout, N. Bruckovsky: Elevated growth hormone levels in sera from breast cancer patients. Horm. Metabol. Res. 17:421-424(1985) Evans, W. S., R. J. Krieg, E. R. Limber, D. L Kaiser, M. O. Thorner: Effects of in vivo gonadal hormone environment on in vitro hGRF40-stimulated GH release. Am. J. Physiol. 249: E276-E280 (1985) Gonzales-Barcena, D., A. J. Kastin, D. S. Schalch, M. Torres-Zamora, E. Perez-Pasten, A. Kato, A. V. Schally: Responses to thyrotropinreleasing hormone in patients with renal failure and after infusion in normal men. J. Clin. Endocrinol, metab. 36:117-120 (1973) Guillemin, R., P. Brazeau, P. E. Bohlen, F. Esch, N. Ling, W. Wehrenberg: Growth hormone releasing factor from a human pancreatic tumor that caused acromegaly. Science 218: 585-587 (1982) Irie, M., T. J. Tsushima: Increase of serum growth hormone concentration following thyrotropin-releasing hormone injection in patients with acromegaly or gigantism. J. Clin. Endocrinol. Metab. 35:97-100(1972) Kamijo, K., A. Saito, A. Yachi, T. Wada:Growth hormone response to thyrotropin-releasing hormone in cancer patients. Endocrinol. Japon.27:451-455 (1980) Lang, I., G. Schemthaner, P. Pietschmann, R. Kurz, J. M. Stephenson: Effect of sex and age on growth hormone response to growth hormone-releasing hormone in healthy individuals. J. Clin. Endocrinol. Metab., September 1987 (1987) Le Dafniet, M., P. Gamier, D. Pression, A. M. Brandi, J. Racadot, F. Peillon: Correlative studies between the presence of thyrotropinreleasing hormone (TRH) receptors and the in vitro stimulation of growth-hormone (GH) secretion in human GH-secretion adenomas. Horm. Metab. Res. 17:476-479(1985) Link, K., R. M. Blizzard, W. S. Evans, D. L. Kaiser, M. W. Parker, A. D. Rogol: The effect of androgens on the pulsatile release and the twenty-four-hour mean concentration of growth hormone in peripubertal males. J. Clin. Endocrinol. Metab. 62:159-164 (1986) Panerai, A. E., F. Salerno, M. Manneschi, D. Cocchi, E. E. Mtiller: Growth hormone and prolactin responses to thyrotropin releasing hormone in patients with severe liver disease. J. Clin. Endocrinol. Metab. 45:134-140(1977) Peckham, M. /.'Investigation and staging: General aspects and staging classification. In: The management of testicular tumours (Ed. Peckham M.J.) London: Edward Arnold, pp. 89-95 (1981) Pietschmann, P., A. Luger, G. Schemthaner: Failure of cholinergic muscarinic blockade on hpGRF 1-44 and TRH-induced growth hormone response in acromegaly. Acta Endocrinol. 109: (Suppl. 270) 125, Abstr. (1985) Pietschmann, P., G. Schemthaner, A. Luger: Effect of cholinergic muscarinic receptor blockade on human pancreatic growth hormone releasing hormone 1-44 induced growth hormone secretion in
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acromegaly and type-I diabetes metlitus. J. Clin. Endocrinol. Requests for reprints should be addressed to: Metab. 63:389-393 (1986) Pugh, R. C.B.:Testiculartumors-thepanel classification. In: Pugh R. Dr. P. Pietschmann C. B., ed., Pathology of the testis. London: Blackwell Scientific Department of Medicine II Publications 144-146(1976) University of Vienna Rivier, J., J. Spiess, M. Thorner, W. Vale Characterisation of a growthGarnisongasse 13 hormone releasing factor from a human pancreatic tumor. Nature A-1090 Vienna (Austria) 300:276-278(1983) Rosenthal, S. M., E. A. Schirock, S. L. Kaplan, R. Guillemin, M. M. Grumbach: Synthetic human pancreas growth hormone-releasing factor (hpGRFl-44-NH2) stimulates growth hormone secretion in normal men. J. Clin, endocrinol. Metab. 57:677-679 (1983) Schaff-Blass, E., S. Burstein, R. L. Rosenfield: Advances in diagnosis and treatment of short stature, with special reference to the role of growth hormone. J. Paediatr. 104:801-813 (1984) Schemthaner, G., J. Spona, H. Ludwig, C. Bieglmayer: Pituitary functions in type-I diabetes: abnormal growth hormone response to thyrotropin releasing hormone. Diabetologia 14: 268 Abstr. (1978)
In 16 patients with metastatic testicular cancer and 10 age matched male control subjects growth hormone (GH) responses to growth hormone releasing hormone (GHRH; 1 ug/kg body weight iv.) and thyrotropin releasing hormone (TRH; 200 ug iv.) were measured. Basal GH levels and GH levels following stimulation with GHRH or TRH were significantly increased in cancer patients compared to control subjects. 9 patients with testicular cancer were studied both in the stage of metastatic disease and after they had reached a complete remission. In complete remission GH responses to GHRH tended to decrease but the differences did not reach statistical significance. Our data suggest an alteration of hypothalamic and/or pituitary regulation of GH secretion in patients with metastatic testicular cancer. Key words
Pat. Nr. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Histological classification
tumor stage
hCG* (mU/ml)
AFP** (ng/ml)
Seminoma MTT MTU MTI Seminoma MTI Seminoma MTU Seminoma MTI MTU Seminoma MTT MTU MTU MTI
IIC IV L3 IV L3 IVCL2 MB IV L2 IV L1 IV CL3 IV L2 III B IV CL3 II C IV CL3 II C IVCL3 IV L1
29/0 298.317/0 0/0 27/0 3/0 66/0 1/0 59 0/0 111 0 1 788569 0 183 47/0
2.2/5.9 94.7/13.2 1.2/5.4 130/2.6 3.1/3.3 5.1/8.8 6.8/7.9 900 3.11/5.1 5.9 75000 7.5 32.9 669 360 95/7.4
Growth Hormone - Growth Hormone Releasing Hormone - Thyrotropin Releasing Hormone Testicular Cancer - Metastatic Cancer
Introduction In some pathological conditions such as acromegaly (Irie and Tsushima 1972), type-I diabetes mellitus (Dasmahapatra, Urdanivia and Cohen 1981), renal insufficiency (Gonzales-Barcena, Kastin, Schalch, Torres-Zamora, Perez-Pasten, Katoand Schally 1973) or liver disease (Panerai, Salerno, Manneschi, Cocchi and Midler 1977) paradoxical GH responses to TRH which do not occur in normal subjects, have been observed. Kamijo, Saito, Yachi and Wada (1980) reported that 33 out of 50 cancer patients showed a paradoxical GH response to an iv. injection of 500 (ug thyrotropin releasing hormone (TRH). Pituitary GH secretion is dually regulated by GHRH and somatostatin. In 1982 growth hormone releasing hormone was isolated from two human pancreatic tumors that have caused acromegaly (Rivier, Spiess, Thorner and Vale
Horm. metabol. Res. 22 (1990) 109-113 © Georg Thieme Verlag Stuttgart • New York
1983; Guillemin, Brazeau, Bohlen, Esch, Ling and Wehrenberg 1982). It is now well established that synthetic GHRH is a specific stimulator of GH secretion in man (Rosenthal, Schirock, Kaplan, Guillemin and Grumbach 1983). As the paradoxical GH responses to TRH in cancer patients suggest a disturbed regulation of GH secretion, we studied GH responses to GHRH and TRH in patients with metastatic testicular cancer. Patients and Methods 16 non-obese patients with metastatic testicular cancer (mean age: 35 + 3 years) and 10 non-obese male control subjects (35 ± 5 years) were studied. All testicular cancer patients presented with metastatic disease and were referred to our department for further chemotherapy. Clinical data of the patients are summarized in Table 1. Histological evaluation was performed according to Pugh
Received: 9 Nov. 1988
Accepted: 30 June 1989 after revision
Downloaded by: Universite Laval. Copyrighted material.
Summary
Table 1 Clinical characteristics of patients with testicular cancer. In the patients which were studied before chemotherapy and in complete remission both the values before and after treatment are given. *normal range < 1 mU/ml; "normal range < 20 ng/ml.
Horm. metabol. Res. 22(1990)
P. Pietschmann, R. Kuzmits and G. Schernthaner
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110
Fig. 1 GH responses to GHRH (upper panel) and TRH (lower panel) in patients with metastatic testicular cancer ( • — • ) and in control subjects ( • — • ). * P < 0.05; * * P < 0.025; * * * P < 0.0125; * * * * P < 0.005.
Fig. 2 GH responses to GHRH (upper panel) and TRH (lower panel) in patients with testicular cancer in metastatic stage of the disease ( • • ) and in complete remission ( O O).
(1976). The staging procedure was performed according to the Royal Marsden Staging Classification (Peckham 1981) including physical examination, chest x-ray, abdominal ultrasonic and computed tomography. All subjects gave their informed consent. After an overnight fast with subjects recumbent for at least 2 hours an iv. catheter was placed in a suitable vein. Blood specimens were obtained before (-30, 0 min) and after (15, 30,45,60 and 90 min) an iv. bolus injection of 1 ug/kg b. w. growth hormone releasing hormone 1-44 (GHRH 1-44, Bissendorf Peptides, Wedemark, Germany). After an interval of at least one day in all patients and control subjects TRH tests were performed with the same protocol as described above except that 200 u.g TRH (Hoechst, Germany) were injected iv. at time 0.
All patients received a sequential alternating chemotherapy consisting of vinblastine, bleomycin and cisdiamminedichloro-platinum (Einhorn and Donohue 1977) (2 cycles) and etoposide (100 mg/m 2 day 1-3), ifosfamide (1.5 g/m 2 day 1-3) and cisdiamminedichloroplatinum (20 mg/m day 1-5) (2 cycles). In 6 patients chemotherapy resulted in a complete remission, in 3 patients surgical excision of residual tumor was performed after the patients were tumor marker (alpha feto protein (AFP), B human chorionic gonadotropin (hCG)) negative following chemotherapy. Complete remission was assessed by negative tumor markers (AFP, hCG) and no evidence of any residual tumor after chemotherapy alone or after additional successfull surgical resection of residual tumor masses.
In 9 testicular cancer patients GHRH and TRH tests were performed both in the stage of metastatic disease before chemotherapy and after the patients had reached a complete remis-
GH was measured by radioimmunoassay (Tandem B HGH, Hybritech Liege, Belgium). Intraassay and interassay coefficient variation were 3.8 % and 5.2 % respectively (at 8.1 ng/ml and 7.8 ng/ml, respectively). The minimum detectable concentration was 0.2
Growth Hormone Responses in Cancer Patients
Horm. metabol. Res. 22 (1990)
ng/ml. In addition, prolactin and TSH levels following TRH administration and basal testosterone and estradiol levels were determined by radioimmunoassay (TSH by RIAa-gnost hTSH, Behring, Marburg, Germany; prolactin by Maiaclone, Serono, Milano, Italy; testosterone by Sorin Biomedia, Saluggia, Italy; estradiol by a radioimmunoassay of Diagnostic Products Corporation, LA, USA). AFP was determined by an enzymeimmunoassay (AFP-EIA Diagnostic Kit, Abbot Laboratories, North Chicago, USA), hCG was measured by radioimmunoassay (HCG-RIA, Serono, Milano, Italy).
parable in the state of metastatic disease and in complete remission (Fig. 2). Prolactin and TSH levels following TRH administration in patients with testicular cancer and control subjects and in patients with testicular cancer before chemotherapy and in complete remission were not statistically different (Fig. 3, Prolactin data not shown). Basal testosterone levels in patients with testicular cancer and control subjects were not statistically different (4.5 ± 0.7 vs. 4.7 ± 0.6 ng/ml).
All the data in the text, tables and thefiguresare preTwo testicular cancer patients with excessively sented as the mean ± SEM. Paired and unpaired Student's t-test and elevated hCG levels had markedly increased estradiol levels linear correlation coefficient were used for statistical analysis. (pt. no. 2: 907 pg/ml, pt. no. 13: 599 pg/ml). In the other patients serum estradiol levels were not statistically different Results from the control subjects (29.0 ± 6.3 vs. 23.5 ± 4.1 pg/ml). In Basal GH levels and GH responses to GHRH the cancer patients no significant correlation between serum in patients with metastatic testicular cancer were significantly estradiol level and AGH could be established (r = -0.02, increased when compared with matched controls (Fig. 1; N. S.). AGH = peak GH level - basal GH level: 13.9 ± 4.2 ng/ml vs Discussion 6.1 ± 1.1 ng/ml; P < 0.05). In patients with metastatic testicular cancer a significant increase of GH levels after TRH Our results demonstrate elevated basal GH stimulation was observed (basal GH levels: 1.7 ± 0.5 ng/ml levels and increased GH responses following GHRH and a vs. peak GH level 3.9 ± 1.0 ng/ml; P < 0.01) whereas in the control subjects basal GH levels (0.4 ± 0.1 ng/ml) and GH paradoxical GH response to TRH injection in patients with levels after TRH administration (peak GH level: 1.0 ± 0.6 metastatic testicular cancer. ng/ml) were not statistically different. GH levels after stimulaElevated levels of GH might be due, at least in tion with TRH were significantly increased in cancer patients when compared with control subjects (Fig. 1). GH responses part, to unspecific stress. However, as the GHRH and TRH to GHRH as well as the areas under the GH response-curves tests were performed with an interval of at least one week after (43.8 ± 11.9 ng/15 min • ml vs. 69.7 + 31.1 ng/15 min - ml) orchidectomy, unspecific stress in our cancer patients was untended to decrease in patients in complete remission com- likely greater than in the control subjects. In addition, as orpared to GH responses in the state of metastatic disease, how- chidectomy is a relatively small operation, postoperative alever, the differences did not reach statistical significance (Fig. terations do not seem to be responsible for the increased GH 2). GH responses following TRH administration were com- responses observed in our study.
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Fig. 3 TSH levels following TRH administration in patients with metastatic testicular cancer ( • — • ) and in control subjects ( O — O ) (left panel) and in patients with testicular cancer in the metastatic stage of the disease ( • — # ) and in complete remission ( O — O ) (right panel).
Serum testosterone and estradiol levels have been implicated in the regulation of G H secretion (Evans, Krieg, Limber, Kaiser and Thorner 1985; Link, Blizzard, Evans, Kaiser, Parker and Rogol 1986; Lang, Schemthaner, Pietschmann, Kurzand Stephenson 1987). However, the data of our study do not provide evidence that in testicular cancer patients and control subjects the different G H responses might be caused by different serum levels of testosterone or estradiol. Thus the presence of metastatic disease seems to be the factor predominantly responsible for the increased G H responses to G H R H and TRH in testicular cancer patients. Our results confirm the observation of Kamijo et al. (1980) that in tumor patients similarly as in patients with acromegaly (Irie and Tsushima 1972) and in type-I diabetes mellitus (Dasmahapatra, Urdanivia and Cohen 1981; Schemthaner, Spona, Ludwig and Bieglmayer 1978) paradoxical G H responses to TRH occur. The cause of paradoxical G H responses to TRH has not been clearly determined, alterations in the pituitary receptors mediating G H secretion have been suggested in acromegaly (he Dafniet, Gamier, Bression, Brandi, Racadot and Peillon 1985). In type-I diabetes mellitus, G H responses to TRH (Chiodera, Coiro, Speroni, Capretti, Muzzetto, Volpiand Butturini 1984) as well as to G H R H can be blunted by cholinergic receptor blockade, whereas in acromegaly both G H levels following TRH and G H R H cannot be suppressed by pretreatment with atropine (Pietschmann, Luger and Schemthanerl9S5; Pietschmann, Schemthaner and Luger 1986). These data suggest that the mechanisms underlying paradoxical TRH induced G H secretions are heterogenous. The increased GH responses to G H R H in patients with metastatic testicular cancer suggest an alteration of hypothalamic a n d / o r pituitary function in this disorder. Pituitary GH secretion is dually regulated by the hypothalamic peptides growth hormone releasing hormone and somatostatin (Schaff-Blass, Burstein and Rosenfield 1984). It might be speculated that the increased G H levels after G H R H and the paradoxical responses to TRH observed in cancer patients might be due to a decreased secretion of (hypothalamic) somatostatin; however, the similar TSH responses to TRH in the patients and the controls do not support the hypothesis of a decreased somatostatin secretion in patients with testicular cancer. In testicular cancer patients who were studied both before chemotherapy and in complete remission, G H responses to G H R H tended to decrease, but the differences did not reach statistical significance. Our data suggest that increased GH responsiveness to G H R H in testicular cancer patients might normalize in complete remission, but possibly the interval between the completion of chemotherapy and the G H R H tests might have been too short to demonstrate complete normalization of G H secretion. Emerman, Leahy, Gout and Bruckovsky (1985) reported elevated basal GH levels in breast cancer patients; Kamijo et al. (1980) found paradoxical G H responses to TRH in cancer patients with various types of primary tumors. These data in the literature indicate that abnormalities in G H secre-
P. Pietschmann, R. Kuzmits and G. Schemthaner tion as demonstrated in our study may not be confined to patients with metastatic testicular cancer but also might be found in other types of malignant disease. In conclusion, our findings of an increased G H responsiveness to G H R H and paradoxical G H responses to TRH in patients with metastatic testicular cancer provide evidence of an altered pituitary and/or hypothalamic regulation of G H secretion in this disorder. References Chiodera, P., V. Coiro, G. Speroni, L. Capretti, P. Muzzetto, R. Volpi, U. Butturini: The growth hormone response to thyrotropin-releasing hormone in insulin-dependent diabetics involves a cholinergic mechanism. J. Clin. Endocrinol. Metab. 59:794-797 (1984) Dasmahapatra, A., E. Urdanivia, M. P. Cohen:Growth hormone response to thyrotropin-releasing hormone in diabetes. J. Clin. Endocrinol. Metab. 52:859-862 (1981) Einhom, L. H., J. P. Donohue: Cisdiamminedichloroplatinum, vinblastine and bleomycin chemotherapy in disseminated testicular cancer. Ann. Int. Med. 87:293-298 (1977) Emerman, J. T., M. Leahy, P. W. Gout, N. Bruckovsky: Elevated growth hormone levels in sera from breast cancer patients. Horm. Metabol. Res. 17:421-424(1985) Evans, W. S., R. J. Krieg, E. R. Limber, D. L Kaiser, M. O. Thorner: Effects of in vivo gonadal hormone environment on in vitro hGRF40-stimulated GH release. Am. J. Physiol. 249: E276-E280 (1985) Gonzales-Barcena, D., A. J. Kastin, D. S. Schalch, M. Torres-Zamora, E. Perez-Pasten, A. Kato, A. V. Schally: Responses to thyrotropinreleasing hormone in patients with renal failure and after infusion in normal men. J. Clin. Endocrinol, metab. 36:117-120 (1973) Guillemin, R., P. Brazeau, P. E. Bohlen, F. Esch, N. Ling, W. Wehrenberg: Growth hormone releasing factor from a human pancreatic tumor that caused acromegaly. Science 218: 585-587 (1982) Irie, M., T. J. Tsushima: Increase of serum growth hormone concentration following thyrotropin-releasing hormone injection in patients with acromegaly or gigantism. J. Clin. Endocrinol. Metab. 35:97-100(1972) Kamijo, K., A. Saito, A. Yachi, T. Wada:Growth hormone response to thyrotropin-releasing hormone in cancer patients. Endocrinol. Japon.27:451-455 (1980) Lang, I., G. Schemthaner, P. Pietschmann, R. Kurz, J. M. Stephenson: Effect of sex and age on growth hormone response to growth hormone-releasing hormone in healthy individuals. J. Clin. Endocrinol. Metab., September 1987 (1987) Le Dafniet, M., P. Gamier, D. Pression, A. M. Brandi, J. Racadot, F. Peillon: Correlative studies between the presence of thyrotropinreleasing hormone (TRH) receptors and the in vitro stimulation of growth-hormone (GH) secretion in human GH-secretion adenomas. Horm. Metab. Res. 17:476-479(1985) Link, K., R. M. Blizzard, W. S. Evans, D. L. Kaiser, M. W. Parker, A. D. Rogol: The effect of androgens on the pulsatile release and the twenty-four-hour mean concentration of growth hormone in peripubertal males. J. Clin. Endocrinol. Metab. 62:159-164 (1986) Panerai, A. E., F. Salerno, M. Manneschi, D. Cocchi, E. E. Mtiller: Growth hormone and prolactin responses to thyrotropin releasing hormone in patients with severe liver disease. J. Clin. Endocrinol. Metab. 45:134-140(1977) Peckham, M. /.'Investigation and staging: General aspects and staging classification. In: The management of testicular tumours (Ed. Peckham M.J.) London: Edward Arnold, pp. 89-95 (1981) Pietschmann, P., A. Luger, G. Schemthaner: Failure of cholinergic muscarinic blockade on hpGRF 1-44 and TRH-induced growth hormone response in acromegaly. Acta Endocrinol. 109: (Suppl. 270) 125, Abstr. (1985) Pietschmann, P., G. Schemthaner, A. Luger: Effect of cholinergic muscarinic receptor blockade on human pancreatic growth hormone releasing hormone 1-44 induced growth hormone secretion in
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Growth Hormone Responses in Cancer Patients
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