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Lack of effect of thyroid hormones on the growth hormone response to thyrotropin-releasing hormone in acromegaly
Lack of Effect of Thyroid Hormones on the Growth Hormone Response to Thyrotropin-Releasing Hormone in Acromegaly Harold
E. Carlson,
James
R. Sowers,
Serum growth hormone (GH) responses to thyrotropin-releasing hormone (TRH) were evaluated in 14 patients with acromegaly following treatment with thyroid hormones. After an initial TRH test, seven patients received L-triiodothyronine, 100 fig daily for seven days; the GH response to TRH was not significantly altered by this treatment. Similar findings were noted in two acromegalic subjects who were tested with TRH before and after
and
Robert
W. Rand
longer periods of administration of l-thyroxine. Four of five additional subjects with acromegaly who had received replacement doses of thyroid hormones for an average of 6.6 yr demonstrated GH responses to TRH which were similar to those seen in subjects not receiving thyroid hormones. Acute or long-term administration of replacement doses of thyroid hormones seems to have minimal effect on the GH response to TRH in acromegaly.
P
ATIENTS WITH ACROMEGALY frequently demonstrate increments in serum growth hormone (GH) following administration of thyrotropinreleasing hormone (TRH), according to several recent reports.lm3 Although pretreatment with thyroid hormones will blunt or abolish the thyrotropin (TSH) and prolactin (PRL) responses to TRH in normal subjects,4aS the possible suppressive effect of thyroid hormones on the GH rise following TRH in acromegaly has not been systematically examined. MATERIALS
AND
METHODS
Fourteen patients with acromegaly participated in the study; all gave informed consent to the procedures performed. Seven acromegalic subjects known to demonstrate at least a 50% rise in GH following TRH (subjects l-7, designated group 1) underwent testing with TRH before and after receiving L-triiodothyronine (T3), 25 rg orally four times daily for 7 days. In group II, two subjects (numbers 8 and 9) were tested with TRH before and after receiving more prolonged treatment with L-thyroxine. Five additional subjects in group II (patients 10-14) were tested with TRH only once; they had received thyroid hormone therapy for extended periods of time. Table 1 gives details of the clinical status of both groups of patients. In all cases, TRH testing was performed after an overnight fast; medications other than thyroid hormones and replacement corticosteroids were omitted on the morning of the test. Following the insertion of an indwelling butterfly needle into an antecubital vein, blood samples were collected for hormonal assay before and over a 2-hr period following the intravenous injection of 500 rg of TRH (kindly provided by Abbott Laboratories, North Chicago, Ill.). Sixteen normal subjects studied in our laboratory showed no serum GH response to this dose of TRH. Serum GH was measured in a double-antibody radioimmunoassay using reagents provided by the National Pituitary Agency (NIAMDD); the sensitivity of this assay is about 0.3 ng/ml. and
From the Medical and Research Services, Veterans Administration Wadsworth Hospital Center, and the Departments of Medicine and Surgery, UCLA School of Medicine, Los Angeles, Cali’ Receivedforpublication August 13, 1976. Supported by Veterans Administration research funds. Reprint requests should be addressed to Dr. Harold E. Carlson, Endocrinology Section, VA Wadsworth Hospital Center, Wilshire and Sawtelle Blvds. Los Angeles, Calif: 90073. Q 1977 by Grune & Stratton, Inc. Metabolism, Vol. 26, No. 7 (July), 15’77
801
41.M
65. M
50, F
5
6
7
i
External
48.M
4
Mean
None
60,M
3
and
SEM for group
irradiation
irradiation
External
irradiation
external
Surgery
irradiation
External
NOW
23.M
2
NOW
Acromegaly
Treatment for
43,M
Age. Sex
1
Group I
Number
Patient
I
Thyroid
9.8
10.0
13.0
6.7 f 2.1 0.1 f 0.08
134*9 328 zt 44
5.9 f 0.9
7.2 + 0.8
8.5 iz 1.4
9.5
8.7
0
13.0 0.5
6.1
1.6
4.8
6.2
7.5
10.0
9.3
11.5
4.5
7.4
(w/ml)
zIPRL
16.4
0
7.0 * 0.9
473
0 3.6
None
5.7
152
0 3.8
T3*
T3*
7.6
5.0
None
130 495
6.4
None
303
92
4.0
334
3.0
160
206
8.0
9.9
1.7
0.3
112
218
9.4
3.0
T3*
T3’
None
f3*
None
T3*
None
f3*
5.1
0
3.1
149
6.1
W/ml)
ATSH
5.5
146 268
7.0
T3 (Wdl)
Basal
T3’
T4 @g/dl)
None
Therapy
Hormone
49*
24
57zt 32 15+4
1
8
188
246
13
19
19
21
54
42
53
16~4
5
5
15
20
9
8
10
9
12
18
34
45
14 33
18 22
-
(w/ml)
AGH
20
in Acromegalic SubjectsPretreatedWith Thyroid Hormones
B.XOl
ResponsestolRH
Daily
fable I. Hormone
2,177 rt 1,131
2,805 i 1,891
2
10,920 8,545 289
532
820 816
994
3,255
2,790
1,318
2,242
768
1,585
(ng minjml)
ARCI
GH Response
g
F
z! u
9 Lz Y
g .=
: A
53, M
49, M
47, F
43, F
40, F
59, M
9
10
11
12
13
14
surgery
surgery
NolIe
irradiation
external
Surgery and
irradiation
external
Surgery and
NolIe
irradiation
external
Surgery and
0.2mg
x 4yr
x 6yr
240mg
Thyroid,
120mg
Thyroid,
x 8yr
x 15yr
0.15 mg x 2 mo
210mg
Thyroid,
90mg
Thyroid,
T4,
x 3mo
0.15 mg x 2 mo
NOW
T4,
*Dosage 25 pg L-T, orally four times daily for 7 days.
33, M
8
Group II
9.2
10.0
9.2
11.0
184
293
166
203
294
0
0
0.2
0
0
0
166
9.0
9.6
148
0
0.5
14.0
167
90
10.8
13.7
5.8
9.3
0.8
14.5
6.3
3.9
6.2
9.9
5.8
0.1
2
1
30
17
58
78
91
9
4
1
5
770
12
72
66
130
9
7
3.5
55
26,618
573
1.905
2,788
6,640
715
580
CARLSON,
804
SOWERS,
AND RAND
Fig. 1.
Mean f SEM serum GH reTRH (500 c(g i.v. at time 0) in sewn patients with ocromegoly
sponses
TIME
the interassay
coefficient
immunoassay
procedure
radioimmunoassays Sinha
et al.,”
of variation of
reported
utilizing
,MIN”TES)
Pekary
samples from a single patient TRH
is S”/,,. Serum et al.,6
supplied
while
TSH
was measured T4
serum
Serum PRL
and
T,
was measured
by the National
according were
t test for paired data.
administration
Integrated
were calculated
to the method
Agency
growth
using previously
to the radio-
assessed in specifc
according
Pituitary
were run in the same assay for each hormone.
sons were made using Student’s for the 2 hr following
7 days.
previously.7
reagents
to
(NIAMDD).
Statistical
hormone
of All
compari-
response areas
described methods.’
RESULTS Group I. In this group of subjects, the maximum increment in TSH in response to TRH (ATSH) was virtually abolished by 1 wk pretreatment with T,, lOOpg/day, while the PRL response (APRL) was slightly but not significantly blunted (Table 1). Mean basal serum GH, however, was unaltered. as were the maximum incremental rise in GH(AGH) and the integrated GH response area (Fig. 1, Table 1). The GH response to TRH was nearly abolished by T, pretreatment in only one subject (number 7). Mean serum T, in group I was slightly lower, while mean serum T, was elevated following the hormone treatment, as expected. Group II. In the two subjects who were tested before and after thyroxine therapy (patients 8 and 9), the GH increment after TRH was minimally altered by the hormone treatment, while the TSH response to TRH was severely reduced (Table 1). In patients 10-14, in whom only one TRH test was performed, GH rises were noted to be similar to those seen in patients not receiving any thyroid hormone, in four of five cases (patients IO-13), while TSH responses were minimal or absent (Table 1). PRL responses in group II were variable. DISCUSSION
In previous studies, the effects of thyroid hormone treatment on the GH response to TRH in acromegaly have been noted only in isolated cases;2,9,‘0 in these instances, no effect was seen. The current, more extensive studies support that view. Neither short-term treatment with TSH-suppressive doses on T3 nor long-term therapy with thyroxine or dessicated thyroid appeared to have any significant effect on the rise in GH seen after TRH in most cases of acromegaly. Although one of five acromegalics who received only a single posttreatment
THYROID
HORMONES
805
IN ACROMEGALY
TRH test failed to show a GH increment (patient 14), it is our experience, as well as that of others, that 107$40% of patients with acromegaly will not of demonstrate a GH response to TRH. ‘J,~,‘OThe lack of significant suppression the PRL response to TRH, which we observed following T, treatment for 1 wk, is not surprising, since longer periods of thyroid hormone administration appear to be necessary for PRL suppression.4xs Thus the neoplastic somatotrophs in acromegaly seem to lack the feedback regulatory system seen in normal thyrotrophs and lactotrophs, in which thyroid hormones exert a suppressive effect on TRH-induced pituitary hormone release;4*s whether this is a concomitant of neoplasia is not yet known. In a practical sense, insofar as the GH response to TRH may be useful in the diagnosis of acromegaly,3,‘0 the present findings indicate that since valid results may be obtained in nearly all subjects receiving full replacement doses of thyroid hormones, such therapy need not be discontinued for testing purposes. ACKNOWLEDGMENT Theauthors wish to thank Jacqueline Briggs, Jung Park, Nancy Meyer, and Alan Reed for skilled technical assistance in the performance of the radioimmunoassays and Anna Lisa Hernandez for typing the manuscript. We are also grateful to the nurses of the Special Diagnostic and Treatment Unit of Wadsworth VA Hospital for assistance with the TRH tests.
REFERENCES 1. lrie M, Tsushima T: 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 2. Faglia G, Beck-Peccoz P, Ferrari C, et al: Plasma growth hormone response to thyrotropin-releasing hormone in patients with active acromegaly. J Clin Endocrinol Metab 36:12591262, 1973 3. Samaan NA, Leavens ME, Jesse RH Jr: Serum growth hormone and prolactin responses to thyrotropin-releasing hormone in patients with acromegaly before and after surgery. J Clin Endocrinol Metab 38:957-963, 1974. 4. Refetoff S, Fang VS. Rapoport B, et al: Interrelationships in the regulation of TSH and prolactin secretion in man: Effects of L-DOPA, TRH, and thyroid hormones in various combinations. J Clin Endocrinol Metab 38:450-457, 1974 5. Yamaji T: Modulation of prolactin re-
lease by altered levels of thyroid hormones. Metabolism 23:745-75 I, 1974 6. Pekary AE, Hershman JM, Parlow AF: A sensitive and precise radioimmunoassay for human thyroid stimulating hormone. J Clin Endocrinol Metab 41:676-684, 1975 7. Sowers JR, Hershman JM, Pekary AE, et al: Effect of N”“‘-methyl-thyrotropin releasing hormone on the human pituitarythyroid axis. J Clin Endocrinol Metab 43:741748, 1976 8. Sinha YN, Selby FW, Lewis UJ, et al: A homologous radioimmunoassay for human prolactin. J Clin Endocrinol Metab 36:509-516, 1973 9. Gomez-Pan A, Tunbridge WMG, Duns A, et al: Hypothalamic hormone interaction in acromegaly. Clin Endocrinol4:455-460, 1975 IO. Tolis G, Kovacs L, Friesen H, et al: Dynamic evaluation of growth hormone (GH) and prolactin (HPRL) secretion in active acromegaly with high and low GH output. Acta Endocrinol 78:251-257, 1975
E. Carlson,
James
R. Sowers,
Serum growth hormone (GH) responses to thyrotropin-releasing hormone (TRH) were evaluated in 14 patients with acromegaly following treatment with thyroid hormones. After an initial TRH test, seven patients received L-triiodothyronine, 100 fig daily for seven days; the GH response to TRH was not significantly altered by this treatment. Similar findings were noted in two acromegalic subjects who were tested with TRH before and after
and
Robert
W. Rand
longer periods of administration of l-thyroxine. Four of five additional subjects with acromegaly who had received replacement doses of thyroid hormones for an average of 6.6 yr demonstrated GH responses to TRH which were similar to those seen in subjects not receiving thyroid hormones. Acute or long-term administration of replacement doses of thyroid hormones seems to have minimal effect on the GH response to TRH in acromegaly.
P
ATIENTS WITH ACROMEGALY frequently demonstrate increments in serum growth hormone (GH) following administration of thyrotropinreleasing hormone (TRH), according to several recent reports.lm3 Although pretreatment with thyroid hormones will blunt or abolish the thyrotropin (TSH) and prolactin (PRL) responses to TRH in normal subjects,4aS the possible suppressive effect of thyroid hormones on the GH rise following TRH in acromegaly has not been systematically examined. MATERIALS
AND
METHODS
Fourteen patients with acromegaly participated in the study; all gave informed consent to the procedures performed. Seven acromegalic subjects known to demonstrate at least a 50% rise in GH following TRH (subjects l-7, designated group 1) underwent testing with TRH before and after receiving L-triiodothyronine (T3), 25 rg orally four times daily for 7 days. In group II, two subjects (numbers 8 and 9) were tested with TRH before and after receiving more prolonged treatment with L-thyroxine. Five additional subjects in group II (patients 10-14) were tested with TRH only once; they had received thyroid hormone therapy for extended periods of time. Table 1 gives details of the clinical status of both groups of patients. In all cases, TRH testing was performed after an overnight fast; medications other than thyroid hormones and replacement corticosteroids were omitted on the morning of the test. Following the insertion of an indwelling butterfly needle into an antecubital vein, blood samples were collected for hormonal assay before and over a 2-hr period following the intravenous injection of 500 rg of TRH (kindly provided by Abbott Laboratories, North Chicago, Ill.). Sixteen normal subjects studied in our laboratory showed no serum GH response to this dose of TRH. Serum GH was measured in a double-antibody radioimmunoassay using reagents provided by the National Pituitary Agency (NIAMDD); the sensitivity of this assay is about 0.3 ng/ml. and
From the Medical and Research Services, Veterans Administration Wadsworth Hospital Center, and the Departments of Medicine and Surgery, UCLA School of Medicine, Los Angeles, Cali’ Receivedforpublication August 13, 1976. Supported by Veterans Administration research funds. Reprint requests should be addressed to Dr. Harold E. Carlson, Endocrinology Section, VA Wadsworth Hospital Center, Wilshire and Sawtelle Blvds. Los Angeles, Calif: 90073. Q 1977 by Grune & Stratton, Inc. Metabolism, Vol. 26, No. 7 (July), 15’77
801
41.M
65. M
50, F
5
6
7
i
External
48.M
4
Mean
None
60,M
3
and
SEM for group
irradiation
irradiation
External
irradiation
external
Surgery
irradiation
External
NOW
23.M
2
NOW
Acromegaly
Treatment for
43,M
Age. Sex
1
Group I
Number
Patient
I
Thyroid
9.8
10.0
13.0
6.7 f 2.1 0.1 f 0.08
134*9 328 zt 44
5.9 f 0.9
7.2 + 0.8
8.5 iz 1.4
9.5
8.7
0
13.0 0.5
6.1
1.6
4.8
6.2
7.5
10.0
9.3
11.5
4.5
7.4
(w/ml)
zIPRL
16.4
0
7.0 * 0.9
473
0 3.6
None
5.7
152
0 3.8
T3*
T3*
7.6
5.0
None
130 495
6.4
None
303
92
4.0
334
3.0
160
206
8.0
9.9
1.7
0.3
112
218
9.4
3.0
T3*
T3’
None
f3*
None
T3*
None
f3*
5.1
0
3.1
149
6.1
W/ml)
ATSH
5.5
146 268
7.0
T3 (Wdl)
Basal
T3’
T4 @g/dl)
None
Therapy
Hormone
49*
24
57zt 32 15+4
1
8
188
246
13
19
19
21
54
42
53
16~4
5
5
15
20
9
8
10
9
12
18
34
45
14 33
18 22
-
(w/ml)
AGH
20
in Acromegalic SubjectsPretreatedWith Thyroid Hormones
B.XOl
ResponsestolRH
Daily
fable I. Hormone
2,177 rt 1,131
2,805 i 1,891
2
10,920 8,545 289
532
820 816
994
3,255
2,790
1,318
2,242
768
1,585
(ng minjml)
ARCI
GH Response
g
F
z! u
9 Lz Y
g .=
: A
53, M
49, M
47, F
43, F
40, F
59, M
9
10
11
12
13
14
surgery
surgery
NolIe
irradiation
external
Surgery and
irradiation
external
Surgery and
NolIe
irradiation
external
Surgery and
0.2mg
x 4yr
x 6yr
240mg
Thyroid,
120mg
Thyroid,
x 8yr
x 15yr
0.15 mg x 2 mo
210mg
Thyroid,
90mg
Thyroid,
T4,
x 3mo
0.15 mg x 2 mo
NOW
T4,
*Dosage 25 pg L-T, orally four times daily for 7 days.
33, M
8
Group II
9.2
10.0
9.2
11.0
184
293
166
203
294
0
0
0.2
0
0
0
166
9.0
9.6
148
0
0.5
14.0
167
90
10.8
13.7
5.8
9.3
0.8
14.5
6.3
3.9
6.2
9.9
5.8
0.1
2
1
30
17
58
78
91
9
4
1
5
770
12
72
66
130
9
7
3.5
55
26,618
573
1.905
2,788
6,640
715
580
CARLSON,
804
SOWERS,
AND RAND
Fig. 1.
Mean f SEM serum GH reTRH (500 c(g i.v. at time 0) in sewn patients with ocromegoly
sponses
TIME
the interassay
coefficient
immunoassay
procedure
radioimmunoassays Sinha
et al.,”
of variation of
reported
utilizing
,MIN”TES)
Pekary
samples from a single patient TRH
is S”/,,. Serum et al.,6
supplied
while
TSH
was measured T4
serum
Serum PRL
and
T,
was measured
by the National
according were
t test for paired data.
administration
Integrated
were calculated
to the method
Agency
growth
using previously
to the radio-
assessed in specifc
according
Pituitary
were run in the same assay for each hormone.
sons were made using Student’s for the 2 hr following
7 days.
previously.7
reagents
to
(NIAMDD).
Statistical
hormone
of All
compari-
response areas
described methods.’
RESULTS Group I. In this group of subjects, the maximum increment in TSH in response to TRH (ATSH) was virtually abolished by 1 wk pretreatment with T,, lOOpg/day, while the PRL response (APRL) was slightly but not significantly blunted (Table 1). Mean basal serum GH, however, was unaltered. as were the maximum incremental rise in GH(AGH) and the integrated GH response area (Fig. 1, Table 1). The GH response to TRH was nearly abolished by T, pretreatment in only one subject (number 7). Mean serum T, in group I was slightly lower, while mean serum T, was elevated following the hormone treatment, as expected. Group II. In the two subjects who were tested before and after thyroxine therapy (patients 8 and 9), the GH increment after TRH was minimally altered by the hormone treatment, while the TSH response to TRH was severely reduced (Table 1). In patients 10-14, in whom only one TRH test was performed, GH rises were noted to be similar to those seen in patients not receiving any thyroid hormone, in four of five cases (patients IO-13), while TSH responses were minimal or absent (Table 1). PRL responses in group II were variable. DISCUSSION
In previous studies, the effects of thyroid hormone treatment on the GH response to TRH in acromegaly have been noted only in isolated cases;2,9,‘0 in these instances, no effect was seen. The current, more extensive studies support that view. Neither short-term treatment with TSH-suppressive doses on T3 nor long-term therapy with thyroxine or dessicated thyroid appeared to have any significant effect on the rise in GH seen after TRH in most cases of acromegaly. Although one of five acromegalics who received only a single posttreatment
THYROID
HORMONES
805
IN ACROMEGALY
TRH test failed to show a GH increment (patient 14), it is our experience, as well as that of others, that 107$40% of patients with acromegaly will not of demonstrate a GH response to TRH. ‘J,~,‘OThe lack of significant suppression the PRL response to TRH, which we observed following T, treatment for 1 wk, is not surprising, since longer periods of thyroid hormone administration appear to be necessary for PRL suppression.4xs Thus the neoplastic somatotrophs in acromegaly seem to lack the feedback regulatory system seen in normal thyrotrophs and lactotrophs, in which thyroid hormones exert a suppressive effect on TRH-induced pituitary hormone release;4*s whether this is a concomitant of neoplasia is not yet known. In a practical sense, insofar as the GH response to TRH may be useful in the diagnosis of acromegaly,3,‘0 the present findings indicate that since valid results may be obtained in nearly all subjects receiving full replacement doses of thyroid hormones, such therapy need not be discontinued for testing purposes. ACKNOWLEDGMENT Theauthors wish to thank Jacqueline Briggs, Jung Park, Nancy Meyer, and Alan Reed for skilled technical assistance in the performance of the radioimmunoassays and Anna Lisa Hernandez for typing the manuscript. We are also grateful to the nurses of the Special Diagnostic and Treatment Unit of Wadsworth VA Hospital for assistance with the TRH tests.
REFERENCES 1. lrie M, Tsushima T: 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 2. Faglia G, Beck-Peccoz P, Ferrari C, et al: Plasma growth hormone response to thyrotropin-releasing hormone in patients with active acromegaly. J Clin Endocrinol Metab 36:12591262, 1973 3. Samaan NA, Leavens ME, Jesse RH Jr: Serum growth hormone and prolactin responses to thyrotropin-releasing hormone in patients with acromegaly before and after surgery. J Clin Endocrinol Metab 38:957-963, 1974. 4. Refetoff S, Fang VS. Rapoport B, et al: Interrelationships in the regulation of TSH and prolactin secretion in man: Effects of L-DOPA, TRH, and thyroid hormones in various combinations. J Clin Endocrinol Metab 38:450-457, 1974 5. Yamaji T: Modulation of prolactin re-
lease by altered levels of thyroid hormones. Metabolism 23:745-75 I, 1974 6. Pekary AE, Hershman JM, Parlow AF: A sensitive and precise radioimmunoassay for human thyroid stimulating hormone. J Clin Endocrinol Metab 41:676-684, 1975 7. Sowers JR, Hershman JM, Pekary AE, et al: Effect of N”“‘-methyl-thyrotropin releasing hormone on the human pituitarythyroid axis. J Clin Endocrinol Metab 43:741748, 1976 8. Sinha YN, Selby FW, Lewis UJ, et al: A homologous radioimmunoassay for human prolactin. J Clin Endocrinol Metab 36:509-516, 1973 9. Gomez-Pan A, Tunbridge WMG, Duns A, et al: Hypothalamic hormone interaction in acromegaly. Clin Endocrinol4:455-460, 1975 IO. Tolis G, Kovacs L, Friesen H, et al: Dynamic evaluation of growth hormone (GH) and prolactin (HPRL) secretion in active acromegaly with high and low GH output. Acta Endocrinol 78:251-257, 1975