J. Endocrinol. Invest. 15: 167-171,1992
Plasma growth hormone (GH) responses to corticotropinreleasing hormone in patients with acromegaly -The effect of dexamethasone pretreatment and the comparison with GH responses to thyrotropin-releasing hormone, gonadotropinreleasing hormone and GH-releasing hormone A. Utsumi, K. Hanew, A. Sugawara, Y. Shimizu, O. Murakami, H. Ikeda, and K. Yoshinaga Second Department of Internal Medicine and Department of Neurosurgery (HI), Tohoku University, Sendai, Japan ABSTRACT. It has been reported that paradoxical GH responses to corticotropin-releasing hormone (CRH) occur in only few patients with acromegaly. However, we have observed such responses in 7 of 14 active acromegalic patients. Therefore, we have studied the GH responses to thyrotropin-releasing hormone (TRH) (500 I1g, iv), gonadotropin-releasing hormone (LHRH) (100 I1g, iv) and GH-releasing hormone (GHRH) (100 I1g, iv) in these patients to examine the relationships between the GH responses to CRH and the responses to these hypothalamic hormones. Further, these patients received human CRH (1-41) NH2 (100 I1g, iv) with or without dexamethasone (Dex) pretreatment (1 mg/100 ml saline, iv, from -30 to + 30 min) to study the mechanism of CRH-induced GH secretion, and a perifusion experiment was performed using adenoma tissue obtained at surgery from one patient (1 0-7M CRH and TRH were added) to elucidate whether CRH acts directly at the pituitary level. Aberrant GH responses induced by CRH were found in 7 of 14 (50%) acromegalic patients (TRH re-
sponders: 10/13,77%; LHRH responders: 2/9,22%; GHRH responders: 10/12,83%). In these patients, percent GH increment induced by CRH ranged from 81 to 144% (Mean ± SE, 118 ± 8%), and the GH peak (19 ± 3 min) appeared as early as after TRH (23 ± 4 min, N = 10). Plasma GH responses to CRH were not affected by Dex pretreatment in 4 acromegalic patients (AUC of GH responses: before, 3730 ± 1339; after Dex, 3867 ± 1616 I1g/L min), whereas plasma ACTH responses of 7 patients including CRH nonresponders were significantly suppressed (AUC of ACTH responses: before, 181 ± 1827; after Dex, 1090 ± 384 I1g/L-min) (p = 0.0156). In the perifusion experiment,CRH also stimulated GH release as well as TRH. These results indicate that: i) Paradoxical GH responses to CRH in acromegalic patients are not so rare, suggesting multiple abnormalities of the cell membrane of the tumor somatotrophs; ii) The relationship between CRH and glucocorticoids as is present in normal corticotrophs is lacking in GH adenoma cells.
INTRODUCTION
doxical GH responses to corticotropin-releasing hormone (CRH) have been described only in 3 out of 25 (11 %) of these patients (3-6). We have, however, observed such responses in 7 of 14 (50%) patients with active acromegaly. Therefore, we administered TRH, LHRH and growth hormone-releasing hormone (GHRH) to these patients to investigate the relationships between the GH responses to CRH and the responses to the other hypothalamic hormones. In addition, we have studied whether CRH-responsive somatotroph tumors have some similarities with normal corticotrophs in terms of responsiveness to an exogenous glucocorticoid (dexamethasone). Furthermore, we performed a perifusion experiment using adenoma tissues obtained
It is well known that paradoxical GH responses to thyrotropin-releasing hormone (TRH) and gonadotropin-releasing hormone (LHRH) are observed in a significant proportion of patients with acromegaly (1, 2). In contrast, in literature para-
1This work was supported in part by a grant from the Intractable Disease Division, Public Health Bureau, Ministry of Health and Welfare, Japan.
Key-words: CRH, dexamethasone, GH, ACTH, acromegaly. Correspondence: Dr. A. Utsumi, Tohoku University School of Medicine, The Second Department of Internal Medicine 1-1 Seiryocho. Sendai 980 - Japan. Received January 14, 1991; accepted October 31. 1991.
167
A. Utsumi, K Hanew, A. Sugawara, et al.
at surgery from one patient to elucidate whether CRH acts on the tumorous somatotroph directly or not.
combined administrations of CRH plus TRH, CRH plus GHRH and TRH plus GHRH. Blood sarTlples for hormone assays were collected via an indwelling iv cannula at -30,0 min before and 15,30,45,60,90, 120 min after the administration of each agent.
MATERIALS AND METHODS In vivo studies Fourteen patients with active acromegaly, 9 men and 5 women, aged 28 to 73 yr, were studied. Eleven of 14 patients were untreated, and the other two had previously received unsuccessful transsphenoidal adenomectomy and the remaining one had received pituitary irradiation. Informed consent was obtained from all patients. Clinical and laboratory data in the patients are given in Table 1. All tests were started between 08:00-09:00 h after an overnight fast. Synthetic human CRH( 1-41) NH2 100 I-1g (Protein Research Foundation, Osaka) was injected iv as a bolus injection at 09:00 h. GHRH (100 f..lg, iv; Sumitomo, Osaka), TRH (500 f..lg, iv; Tanabe, Osaka) and LHRH (100 f..lg, iv; Oaiichi, Tokyo) were administered to the majority of patients according to the methods previously reported (7, 8). Seven patients (#1,4, 5, 6, 8, 12, 14) also received CRH after pretreatment with 1 mg dexamethasone (Oex) (dissolved in 100 ml 0.9% saline, iv from -30 to 30 min). Further, three patients responsive to CRH, TRH and GHRH received
In vitro study A perifusion experiment with adenoma tissue obtained at surgery from patient #6 was performed as follows. The adenoma tissues were dissected into 1 mm fragments in diameter and transferred to a 1 ml chamber packed with Sephadex G-100, and perifused with Krebs-Ringer-Bicarbonate-Glucose (KRBG) solution saturated with 95%0 2 and 5% CO 2, To these tissues TRH (1 0-7M/5ml), CRH (1 0-7M/5ml) and KCI (50mM/5ml) were administered and eluates were collected by an automatic fraction collector, at the rate of 0.44 ml/tube/ min. KCI trial was carried out in order to confirm that the cells were still biologically active.
Measurements and Statistical Analysis Samples were kept frozen at -20 C until assayed. Plasma GH, IGF-I, PRL and ACTH were measured in duplicate using commercial RIA kits (GH: Oainabot, Tokyo; IGF-I: Nichols Institute, San Juan Capistrano, CA) or immunoradiometric assay kits (pRL: Oaiichi, Tokyo; ACTH: Japan OPC, Tokyo). The intra- and interassay coefficients of variation were 4.1 % and 4.7% for GH, 3.2% and 5.0% for PRL, both 8% for IGF-I, 3.8% and 4.2% for ACTH, respectively. The normal range of GH,PRL and IGF-I in our Institution is below 5 f..lg/L, 1.5 to 15.0 f..lg/L, and 0.7 to 2 ng/L,respectively.The sensitivities of the GH, PRL, IGF-I and ACTH assays were 0.2 f..lg/L, 0.3 f..lg/L, 0.1 U/L and 5.0 ng/L, respectively. Randomization test was used for statistical evaluation of the effect of Oex and for the evaluation of maximum GH increment to each secretagogue. Chi-square test was used for comparison of the frequency of GH responders to various secretagogues. All values were expressed as the mean ± SE.
Table 1 - Clinical and laboratory data in 14 patients with
acromegaly. Patient
Sex
Age (yr)
GH (1l9/L)
PRL (llg/ml)
IGF-I (U/ml)
Previous therapy
18 25
2 1 4 14
4.4 4.0 3.7 3.1
(- )
(- )
(- )
CRH responders
1 2 3 4
F
46 37 33 61
5
M
36
5
1
4.2
6
M
41
47
5
4.0
8
5
4.0 8.6
7
F
M M
M
58
50 18
(- ) (- )
(- ) Radiation
1
CRH nonresponders F
70
16
27
9
F
52
83
6
4.0
(- )
10 11 12
M
28
63
7
3.1
Surgery 2
F
45 84
13 14
M
37
2.7 3.5 2.7
Surgery2
M
60
9 56 39 14
(- )
M
73 40
2.4
(- )
8
8 5
RESULTS Plasma GH responses to CRH and other hypothalamic hormones Plasma GH responses were defined as positive when the increment exceeded 50% from the basal level since physiological GH fluctuation within 3h were below 30% (7). Responses of plasma GH to CRH and other hypothalamic hormones or agents are summarized in Table 2. A significant rise in plasma GH was observed in 7 of 14 patients (50%) after CRH admin-
(- )
(- )
'Linear X-ray irradiation, 2transsphenoidal adenomectomy. The normal ranges in our Institution are as follows: GH, < 5 llg/L; PRL, 1.5-15119/L; IGF-I, O.7-2U/ml
168
GH responses to CRH in acromegaly
In three patients (#2,4,6) responsive to CRH,TRH and GHRH, the combined administration of CRH and GHRH brought about further GH increases (% increment: CRH, GHRH, CRH+GHRH, #2, 131, 358, 1319%, #4, 125,88, 1022%). Similarly, the combination of TRH and GHRH exerted synergistic effect on GH secretion (% increment: TRH, GHRH, TRH+GHRH, #2, 258, 358, 1464%; #4, 112, 88, 687%, #6, 134, 92, 525%). But the combination of CRH and TRH did not give additive effect on GH response compared to single administration of these agents (% increment: CRH, TRH, CRH + TRH, #4, 125, 112, 122%; #6,106, 134,80%).
Table 2 - Plasma GH responses to (% of basal value) the releasing hormone in CRH-responsive and CRH non-responsive acromegalic patients. Patient
CRH (100 ~g iv)
TRH (500 ~g iv)
LHRH (100 ~g iv)
GHRH (100 ~g iv)
197
229
CRH responders 1
144
61
2
131
358
3
126
129
4
125
112
22
88
5
116
489
882
506
6
106
134
92
7
81
29
262
176
CRH test with or without Oex pretreatment Figure 1 demonstrates that Dex pretreatment had no significant effect on CRH induced peak GH level or on peak appearing time in 4 CRH responders. Also, areas under the response curve (AUC), calculated by trapezoidal integration of GH responses to CRH, in 4 CRH responders were not different without (3730 ± 1339) or with Dex pretreatment (3967 ± 1616 ~g/L min) (p = NS). Including these 4 patients, the reproducibility of GH responses to CRH were confirmed in every patient examined. However, ACTH responses to CRH in seven cases including 3 CRH nonresponders were significantly suppressed by Dex pretreatment (AUC: without Dex, 1811 ± 827; with Dex 1090 ± 384 (ng/L min, p = 0.0156) (Table 3). GH release pattern in perifusion experiment using adenoma tissues from one patient (#6) In the perifusion experiment, an almost similar GH release pattern was observed after the administra-
CRH nonresponders 8
39
9
28
1,312 27
8
10
23
48
8
49
11
16
3,032
0
68
12
15
535
0
21
13
5
1,114
33
98
14
2
12
77
112
istration. GH peaks appeared at 15 min in 5 of these 7 CRH responders and at 30 min in the other 2 patients after the administration (mean ± SE: 19 ± 3 min). Percent GH increment induced by CRH ranged from 81 % to 144% (118 ± 8%). Plasma GH responses to TRH were examined in 7 CRH responders and 6 CRH nonresponders. TRH responders were found in 6 of 7 CRH responders (86%) and 4 of 6 CRH nonresponders (67%) (p = NS). Percent GH increments induced by TRH ranged from 61 % to 489% (185 ± 34%) in the CRH responders and from 535% to 3032% (+ 1498 ± 269%) in the CRH nonresponders (p < 0.01 vs CRH responders). Plasma GH responses to LHRH were also examined in 3 CRH responders and 6 CRH nonresponders. Only 2 patients had an increase in plasma GH levels after LHRH injection and both of them were CRH responders (patient #2: 197%, patient #5: 882%). Six CRH responders and 6 CRH nonresponders received administration of GHRH. All CRH responders (100%) and 4 of 6 CRH nonresponders (67%) responded to GHRH (p = NS). Percent GH increments induced by GHRH tended to be larger in CRH responders than in CRH nonresponders although the difference was not statistically significant (CRH responders: +88 to 506%,225 ± 35% vs CRH nonresponders: +68 to 112%, 93+7% P = NS).
Table 3 - Plasma ACTH responses to CRH with or without pretreatment of dexamethasone in 7 patients with acromegaly (AUC, ng/L min). Patient
Dex (-)
Dex (+)
CRH responders 714
600
4
661
600
5
2,838
1,303
6
700
614
600
600
CRH nonresponders 8 12
739
14
6,423
600 3,31
'The difference is statistically significant (p = 0.0156) in randomization test for two paired samples.
169
A. Utsumi, K. Hanew, A. Sugawara, et al.
TRH
32l 100..1
l
0.8
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I
1 50mM I
r
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Plasma growth hormone (GH) responses to corticotropinreleasing hormone in patients with acromegaly -The effect of dexamethasone pretreatment and the comparison with GH responses to thyrotropin-releasing hormone, gonadotropinreleasing hormone and GH-releasing hormone A. Utsumi, K. Hanew, A. Sugawara, Y. Shimizu, O. Murakami, H. Ikeda, and K. Yoshinaga Second Department of Internal Medicine and Department of Neurosurgery (HI), Tohoku University, Sendai, Japan ABSTRACT. It has been reported that paradoxical GH responses to corticotropin-releasing hormone (CRH) occur in only few patients with acromegaly. However, we have observed such responses in 7 of 14 active acromegalic patients. Therefore, we have studied the GH responses to thyrotropin-releasing hormone (TRH) (500 I1g, iv), gonadotropin-releasing hormone (LHRH) (100 I1g, iv) and GH-releasing hormone (GHRH) (100 I1g, iv) in these patients to examine the relationships between the GH responses to CRH and the responses to these hypothalamic hormones. Further, these patients received human CRH (1-41) NH2 (100 I1g, iv) with or without dexamethasone (Dex) pretreatment (1 mg/100 ml saline, iv, from -30 to + 30 min) to study the mechanism of CRH-induced GH secretion, and a perifusion experiment was performed using adenoma tissue obtained at surgery from one patient (1 0-7M CRH and TRH were added) to elucidate whether CRH acts directly at the pituitary level. Aberrant GH responses induced by CRH were found in 7 of 14 (50%) acromegalic patients (TRH re-
sponders: 10/13,77%; LHRH responders: 2/9,22%; GHRH responders: 10/12,83%). In these patients, percent GH increment induced by CRH ranged from 81 to 144% (Mean ± SE, 118 ± 8%), and the GH peak (19 ± 3 min) appeared as early as after TRH (23 ± 4 min, N = 10). Plasma GH responses to CRH were not affected by Dex pretreatment in 4 acromegalic patients (AUC of GH responses: before, 3730 ± 1339; after Dex, 3867 ± 1616 I1g/L min), whereas plasma ACTH responses of 7 patients including CRH nonresponders were significantly suppressed (AUC of ACTH responses: before, 181 ± 1827; after Dex, 1090 ± 384 I1g/L-min) (p = 0.0156). In the perifusion experiment,CRH also stimulated GH release as well as TRH. These results indicate that: i) Paradoxical GH responses to CRH in acromegalic patients are not so rare, suggesting multiple abnormalities of the cell membrane of the tumor somatotrophs; ii) The relationship between CRH and glucocorticoids as is present in normal corticotrophs is lacking in GH adenoma cells.
INTRODUCTION
doxical GH responses to corticotropin-releasing hormone (CRH) have been described only in 3 out of 25 (11 %) of these patients (3-6). We have, however, observed such responses in 7 of 14 (50%) patients with active acromegaly. Therefore, we administered TRH, LHRH and growth hormone-releasing hormone (GHRH) to these patients to investigate the relationships between the GH responses to CRH and the responses to the other hypothalamic hormones. In addition, we have studied whether CRH-responsive somatotroph tumors have some similarities with normal corticotrophs in terms of responsiveness to an exogenous glucocorticoid (dexamethasone). Furthermore, we performed a perifusion experiment using adenoma tissues obtained
It is well known that paradoxical GH responses to thyrotropin-releasing hormone (TRH) and gonadotropin-releasing hormone (LHRH) are observed in a significant proportion of patients with acromegaly (1, 2). In contrast, in literature para-
1This work was supported in part by a grant from the Intractable Disease Division, Public Health Bureau, Ministry of Health and Welfare, Japan.
Key-words: CRH, dexamethasone, GH, ACTH, acromegaly. Correspondence: Dr. A. Utsumi, Tohoku University School of Medicine, The Second Department of Internal Medicine 1-1 Seiryocho. Sendai 980 - Japan. Received January 14, 1991; accepted October 31. 1991.
167
A. Utsumi, K Hanew, A. Sugawara, et al.
at surgery from one patient to elucidate whether CRH acts on the tumorous somatotroph directly or not.
combined administrations of CRH plus TRH, CRH plus GHRH and TRH plus GHRH. Blood sarTlples for hormone assays were collected via an indwelling iv cannula at -30,0 min before and 15,30,45,60,90, 120 min after the administration of each agent.
MATERIALS AND METHODS In vivo studies Fourteen patients with active acromegaly, 9 men and 5 women, aged 28 to 73 yr, were studied. Eleven of 14 patients were untreated, and the other two had previously received unsuccessful transsphenoidal adenomectomy and the remaining one had received pituitary irradiation. Informed consent was obtained from all patients. Clinical and laboratory data in the patients are given in Table 1. All tests were started between 08:00-09:00 h after an overnight fast. Synthetic human CRH( 1-41) NH2 100 I-1g (Protein Research Foundation, Osaka) was injected iv as a bolus injection at 09:00 h. GHRH (100 f..lg, iv; Sumitomo, Osaka), TRH (500 f..lg, iv; Tanabe, Osaka) and LHRH (100 f..lg, iv; Oaiichi, Tokyo) were administered to the majority of patients according to the methods previously reported (7, 8). Seven patients (#1,4, 5, 6, 8, 12, 14) also received CRH after pretreatment with 1 mg dexamethasone (Oex) (dissolved in 100 ml 0.9% saline, iv from -30 to 30 min). Further, three patients responsive to CRH, TRH and GHRH received
In vitro study A perifusion experiment with adenoma tissue obtained at surgery from patient #6 was performed as follows. The adenoma tissues were dissected into 1 mm fragments in diameter and transferred to a 1 ml chamber packed with Sephadex G-100, and perifused with Krebs-Ringer-Bicarbonate-Glucose (KRBG) solution saturated with 95%0 2 and 5% CO 2, To these tissues TRH (1 0-7M/5ml), CRH (1 0-7M/5ml) and KCI (50mM/5ml) were administered and eluates were collected by an automatic fraction collector, at the rate of 0.44 ml/tube/ min. KCI trial was carried out in order to confirm that the cells were still biologically active.
Measurements and Statistical Analysis Samples were kept frozen at -20 C until assayed. Plasma GH, IGF-I, PRL and ACTH were measured in duplicate using commercial RIA kits (GH: Oainabot, Tokyo; IGF-I: Nichols Institute, San Juan Capistrano, CA) or immunoradiometric assay kits (pRL: Oaiichi, Tokyo; ACTH: Japan OPC, Tokyo). The intra- and interassay coefficients of variation were 4.1 % and 4.7% for GH, 3.2% and 5.0% for PRL, both 8% for IGF-I, 3.8% and 4.2% for ACTH, respectively. The normal range of GH,PRL and IGF-I in our Institution is below 5 f..lg/L, 1.5 to 15.0 f..lg/L, and 0.7 to 2 ng/L,respectively.The sensitivities of the GH, PRL, IGF-I and ACTH assays were 0.2 f..lg/L, 0.3 f..lg/L, 0.1 U/L and 5.0 ng/L, respectively. Randomization test was used for statistical evaluation of the effect of Oex and for the evaluation of maximum GH increment to each secretagogue. Chi-square test was used for comparison of the frequency of GH responders to various secretagogues. All values were expressed as the mean ± SE.
Table 1 - Clinical and laboratory data in 14 patients with
acromegaly. Patient
Sex
Age (yr)
GH (1l9/L)
PRL (llg/ml)
IGF-I (U/ml)
Previous therapy
18 25
2 1 4 14
4.4 4.0 3.7 3.1
(- )
(- )
(- )
CRH responders
1 2 3 4
F
46 37 33 61
5
M
36
5
1
4.2
6
M
41
47
5
4.0
8
5
4.0 8.6
7
F
M M
M
58
50 18
(- ) (- )
(- ) Radiation
1
CRH nonresponders F
70
16
27
9
F
52
83
6
4.0
(- )
10 11 12
M
28
63
7
3.1
Surgery 2
F
45 84
13 14
M
37
2.7 3.5 2.7
Surgery2
M
60
9 56 39 14
(- )
M
73 40
2.4
(- )
8
8 5
RESULTS Plasma GH responses to CRH and other hypothalamic hormones Plasma GH responses were defined as positive when the increment exceeded 50% from the basal level since physiological GH fluctuation within 3h were below 30% (7). Responses of plasma GH to CRH and other hypothalamic hormones or agents are summarized in Table 2. A significant rise in plasma GH was observed in 7 of 14 patients (50%) after CRH admin-
(- )
(- )
'Linear X-ray irradiation, 2transsphenoidal adenomectomy. The normal ranges in our Institution are as follows: GH, < 5 llg/L; PRL, 1.5-15119/L; IGF-I, O.7-2U/ml
168
GH responses to CRH in acromegaly
In three patients (#2,4,6) responsive to CRH,TRH and GHRH, the combined administration of CRH and GHRH brought about further GH increases (% increment: CRH, GHRH, CRH+GHRH, #2, 131, 358, 1319%, #4, 125,88, 1022%). Similarly, the combination of TRH and GHRH exerted synergistic effect on GH secretion (% increment: TRH, GHRH, TRH+GHRH, #2, 258, 358, 1464%; #4, 112, 88, 687%, #6, 134, 92, 525%). But the combination of CRH and TRH did not give additive effect on GH response compared to single administration of these agents (% increment: CRH, TRH, CRH + TRH, #4, 125, 112, 122%; #6,106, 134,80%).
Table 2 - Plasma GH responses to (% of basal value) the releasing hormone in CRH-responsive and CRH non-responsive acromegalic patients. Patient
CRH (100 ~g iv)
TRH (500 ~g iv)
LHRH (100 ~g iv)
GHRH (100 ~g iv)
197
229
CRH responders 1
144
61
2
131
358
3
126
129
4
125
112
22
88
5
116
489
882
506
6
106
134
92
7
81
29
262
176
CRH test with or without Oex pretreatment Figure 1 demonstrates that Dex pretreatment had no significant effect on CRH induced peak GH level or on peak appearing time in 4 CRH responders. Also, areas under the response curve (AUC), calculated by trapezoidal integration of GH responses to CRH, in 4 CRH responders were not different without (3730 ± 1339) or with Dex pretreatment (3967 ± 1616 ~g/L min) (p = NS). Including these 4 patients, the reproducibility of GH responses to CRH were confirmed in every patient examined. However, ACTH responses to CRH in seven cases including 3 CRH nonresponders were significantly suppressed by Dex pretreatment (AUC: without Dex, 1811 ± 827; with Dex 1090 ± 384 (ng/L min, p = 0.0156) (Table 3). GH release pattern in perifusion experiment using adenoma tissues from one patient (#6) In the perifusion experiment, an almost similar GH release pattern was observed after the administra-
CRH nonresponders 8
39
9
28
1,312 27
8
10
23
48
8
49
11
16
3,032
0
68
12
15
535
0
21
13
5
1,114
33
98
14
2
12
77
112
istration. GH peaks appeared at 15 min in 5 of these 7 CRH responders and at 30 min in the other 2 patients after the administration (mean ± SE: 19 ± 3 min). Percent GH increment induced by CRH ranged from 81 % to 144% (118 ± 8%). Plasma GH responses to TRH were examined in 7 CRH responders and 6 CRH nonresponders. TRH responders were found in 6 of 7 CRH responders (86%) and 4 of 6 CRH nonresponders (67%) (p = NS). Percent GH increments induced by TRH ranged from 61 % to 489% (185 ± 34%) in the CRH responders and from 535% to 3032% (+ 1498 ± 269%) in the CRH nonresponders (p < 0.01 vs CRH responders). Plasma GH responses to LHRH were also examined in 3 CRH responders and 6 CRH nonresponders. Only 2 patients had an increase in plasma GH levels after LHRH injection and both of them were CRH responders (patient #2: 197%, patient #5: 882%). Six CRH responders and 6 CRH nonresponders received administration of GHRH. All CRH responders (100%) and 4 of 6 CRH nonresponders (67%) responded to GHRH (p = NS). Percent GH increments induced by GHRH tended to be larger in CRH responders than in CRH nonresponders although the difference was not statistically significant (CRH responders: +88 to 506%,225 ± 35% vs CRH nonresponders: +68 to 112%, 93+7% P = NS).
Table 3 - Plasma ACTH responses to CRH with or without pretreatment of dexamethasone in 7 patients with acromegaly (AUC, ng/L min). Patient
Dex (-)
Dex (+)
CRH responders 714
600
4
661
600
5
2,838
1,303
6
700
614
600
600
CRH nonresponders 8 12
739
14
6,423
600 3,31
'The difference is statistically significant (p = 0.0156) in randomization test for two paired samples.
169
A. Utsumi, K. Hanew, A. Sugawara, et al.
TRH
32l 100..1
l
0.8
CRH 11O-'M
~
KCl
I
1 50mM I
r
T
0.7 ::; co co
)
06
~
"'
-"
E
'0 50
J: (,!)
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03
C1
