The Effect of Somatostatin on TSH Levels in Patients with Primary Hypothyroidism C. LUCKE, B. HOFFKEN, AND A. VON ZUR MUHLEN Division of Clinical Endocrinology, Hannover, West Germany
Department
ABSTRACT. Somatostatin, a growth hormone inhibiting factor (GHIF), was infused into 8 patients with primary hypothyroidism at a dosage of 1000 fig for 105 min. GHIF caused a suppression of TSH
T
HE inhibitory effect of somatostatin, a growth hormone inhibiting factor (GHIF), on the secretion of growth hormone (GH), was first described by Brazeau et al. (1) and subsequently confirmed by several groups. This peptide prevents nocturnal sleep-induced GH secretion (2) as well as the response to a variety of stimuli (3-7). In acromegaly, a marked fall of GH levels is observed during the infusion of GHIF (6-9). Recent studies indicate that the suppressive effect is not limited to the secretion of GH. An inhibitory action on the output of other hormones, e.g. insulin (6,8,10-12), glucagon (6,12,13) and gastrin (14,15), is well established. Conflicting data exist concerning its action on prolactin (3,5,7,8,18). Several reports indicate a blunting effect of GHIF on TSH levels following TRH (7,16, 17), while no change could be observed on basal TSH levels during GHIF infusion (3,5). In the following we will report data on the effect of GHIF on TSH levels with primary hypothyroidism and elevated TSH levels. Material and Methods Studies were performed in 8 hypothyroid patients 48-69 years of age (57.1 ± 2.9, mean ± SE).
Received March 10, 1975. Reprints: Dr. C. Lucke, Division of Clinical Endocrinology, Department of Medicine, Medizinische Hochschule Hannover, West Germany. Supported by Deutsche Forschungsgemeinschaft Lu 183/2.
of Medicine,
Medizinische
Hochschule
levels from 42.6 to 76.9% of preinfusion levels with a mean nadir of 65.0 ± 4.0%;(mean ± SEM). (J Clin Endocrinol Metab 41: 1082, 1975)
They had T4 levels of less than .5 to 4.8 /xg/100 ml (normal 4.5-14 ^g/ml) and T3 levels of less than .2 to .9 ng/ml (normal .6-1.8 ng/ml). TSH levels were elevated in all patients (see below). At the time the studies were performed hypothyroidism had been recently discovered and no treatment had been instituted. None of the patients had a history of previous neck surgery or treatment with radioactive iodine for hyperthyroidism. Following cannulation of a vein, 125 /i,g linear GHIF* was injected as a bolus. Subsequently 875 jug of GHIF, dissolved in 50 ml of normal saline, was infused for 105 min using a Braun infusion pump. Blood was drawn every 15 min for 2 h and again 1 h later. Specimens were eentrifuged immediately and sera kept frozen at —20 C for later determination of TSH. No side effects from the infusion of GHIF were observed. T3 and T4 were determined by RIA (18) and TSH as previously described (19). Values were expressed in % of baseline values.
Results The infusion of GHIF resulted in a suppression of TSH levels in all instances. Individual nadir levels ranged from 42.6 to 76.9% of preinfusion values (65.0 ± 4.0%, mean ± SE). A significant drop was apparent after 15 min of infusion (Fig. 1). Nadir levels, seen at 90 and 105 min, however, were not significantly lower than levels at 60 and 75 min. Following termination of the infusion there was a rapid rise which reached preinfusion * Purchased from Serono Company, Freiburg, West Germany.
1082
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1083
GHIF AND TSH IN HYPOTHYROIDISM
10O
FIG. 1. Effect of GHIF on TSH levels in hypothyroid patients. Baseline (preinfusion) levels expressed as 100%. Bars represent
80
SEM. Somatostatin 8.3)jg/min
30
levels at the end of the study (180 min). Figure 2 shows the individual preinfusion and nadir values. Discussion While the suppressive effect of GHIF on GH, insulin and glucagon has been unanimously accepted, conflicting data exist on other hormones like prolactin (3,5,7,8,17) and TSH. In healthy volunteers several authors found TSH levels unaltered by the infusion of GHIF (3,5). Others, however, observed a blunting effect on TRH-induced TSH secretion (7,16,17). Our data for the first time demonstrate a suppressive effect on TSH levels not acutely raised by exogenous releasing hormone, but presumably elevated by endogenous hypersecretion of TRH. There is no apparent reason why basal TSH levels are not affected in healthy persons, but this may very well be due to the fact that these levels are low and frequently barely measurable by RIA and thus reductions in serum TSH levels are not easily detected in normal subjects. The suppressive effect is not a complete one and accounts only for about 35%. This is comparable to the partially suppressive effect observed following stimulation with TRH in normals (7,16). The physiologic importance of our data remains to be clarified. As GHIF seems to have no effect on TSH in healthy persons,
60
120
90
-n-
180 min
a physiologic role has to be established, as the effect is seen in unusual circumstances and with pharmacologic doses only. If it is true, however, as postulated by Abraham et al. (20), that an autoregulatory (feedback) mechanism exist for the secretion of GH, exogenous GH might induce considerable output of GHIF with subsequent blockade of GH and TSH secretion. Furthermore, the overlapping effect of GHIF and TSH might aquire considerable importance, whenever a long acting somatostatin might be available for treatment of acromegaly or
150
125-
FlG. 2. Individual preinfiision (left) and nadir levels of TSH during infusion of GHIF.
~ E
100
75
50
25
Nadir
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1084
LUCKE, HOFFKEN AND VON ZUR MUHLEN
possibly juvenile diabetes (13). Secondary hypothyroidism, as well as glucose intolerance from blunted insulin secretion, might very well follow treatment of this kind. Reversable secondary hypothyroidism during treatment with GH has been recently described in patients with GH deficiency, presumably due to endogenous hypersecretionofGHIF(21). References 1. Brazeau, P., W. Vale, R. Burgus, N. Ling, M. Butcher, J. Rivier, and R. Guillemin, Science 179: 77, 1973. 2. Parker, D. C , L. G. Rossman, T. M. Siler, J. Rivier, S. S. C. Yen, and R. Guillemin,/ Clin Endocrinol Metab 38: 496, 1974. 3. Copinschi, G., E. Virasoro, L. Vanhaelst, R. Leclercq,
4. 5. 6.
7.
8.
J. Golstein, and M. L'Hermite, Endocrinology 3: 441, 1974. Prange Hansen, A., H. 0rskov, K. Seyer-Hansen, and K. Lundbaek, Br MedJ 3: 523, 1973. Siler, T. M., G. van den Berg, and S. S. C. Yen, 7 Clin Endocrinol Metab 37: 632, 1973. Mortimer, C. H., D. Carr, T. Lind, S. R. Bloom, C. N. Mallinson, A. V. Serially, W. M. G. Tunbridge, L. Yeomans, D. H. Coy, A. Kastin, G. M. Besser, and R. Hall, Lancet I: 697, 1974. Hall, R., A. V. Serially, D. Evered, A. J. Kastin, C. H. Mortimer, W. M. G. Tunbridge, G. M. Besser, D. H. Coy, D. J. Goldie, A. S. McNeilly, C. Phenekos, and D. Weightman, Lancet II: 7829, 1973. Yen, S. S. C , T. M. Siler, and G. W. DeVane, N EnglJ Med 290: 935, 1974.
JCE & M • 1975 Vol -1 ] • No (i
9. Besser, G. M., C. H. Mortimer, D. Carr, A. V. Schally, D. H. Coy, D. Evered, A. J. Kastin, W. M. G. Tunbridge, M. O. Thorner, and R. Hall, Br MedJ 1: 352, 1974. 10. DeVane, G. W., T. M. Siler, and S. S. C. Yen J Clin Endocrinol Metab 38: 913, 1974. 11. Alberti, K. G. M. M., S. E. Christensen, J. Iversen, K. Seyer-Hansen, N. J. Christensen, A. Prange Hansen, K. Lundbaek, and H. 0rskov, Lancet II: 1299, 1973. 12. Koerker, D. J., VV. Ruch, E. Chideckel, J. Palmer, C. J. Goodner, J. Ensinck, and C. C. Gale, Science 184: 482, 1974. 13. Gerich, J. E., M. Lorenzi, V. Schneider, J. H. Karam, J. Rivier, R. Gullemin, and P. H. Forsham.iV Engl J Med 291: 544, 1974. 14. Bloom, S. R., C. H. Mortimer, M. O. Thorner, G. M. Besser, R. Hall, A. Gomez-Pan, V. M. Roy, R. C. G. Russel, D. H. Coy, A. J. Kastin, and A. V. Schally, Lancet II: 1106, 1974.
15. Arnold, R., J. Kobberling, N. S. Track, and
W. Creutzfeldt, Ada Endocrinol (Kbh) Suppl. 193: 75, 1975. 16. Siler, T. M., S. S. C. Yen, W. Vale, and R. Guillemin, J Clin Endocrinol Metab 38: 742, 1974. 17. Vale, W., C. Rivier, P. Brazeau, and R. Guillemin, Endocrinology 95: 96P 1974. 18. Hehmiann, R., and C. Schneider, Radiologe 14: 156, 1974. 19. von zur Miihlen, A., and D. Emrich, Z. Klin Chem Klin Biochem 8: 257, 1971. 20. Abrams, R. L., M. M. Grumbach, and S. L. Kaplan, J Clin Invest 50: 940, 1971. 21. Lippe, B. M., A. J. van Herle, S. G. LaFranchi, R. P. Uller, N. Lavin, and S. A. Kaplan, J Clin Endocrinol Metab 40: 612, 1975.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 13 November 2015. at 09:31 For personal use only. No other uses without permission. . All rights reserved.
Department
ABSTRACT. Somatostatin, a growth hormone inhibiting factor (GHIF), was infused into 8 patients with primary hypothyroidism at a dosage of 1000 fig for 105 min. GHIF caused a suppression of TSH
T
HE inhibitory effect of somatostatin, a growth hormone inhibiting factor (GHIF), on the secretion of growth hormone (GH), was first described by Brazeau et al. (1) and subsequently confirmed by several groups. This peptide prevents nocturnal sleep-induced GH secretion (2) as well as the response to a variety of stimuli (3-7). In acromegaly, a marked fall of GH levels is observed during the infusion of GHIF (6-9). Recent studies indicate that the suppressive effect is not limited to the secretion of GH. An inhibitory action on the output of other hormones, e.g. insulin (6,8,10-12), glucagon (6,12,13) and gastrin (14,15), is well established. Conflicting data exist concerning its action on prolactin (3,5,7,8,18). Several reports indicate a blunting effect of GHIF on TSH levels following TRH (7,16, 17), while no change could be observed on basal TSH levels during GHIF infusion (3,5). In the following we will report data on the effect of GHIF on TSH levels with primary hypothyroidism and elevated TSH levels. Material and Methods Studies were performed in 8 hypothyroid patients 48-69 years of age (57.1 ± 2.9, mean ± SE).
Received March 10, 1975. Reprints: Dr. C. Lucke, Division of Clinical Endocrinology, Department of Medicine, Medizinische Hochschule Hannover, West Germany. Supported by Deutsche Forschungsgemeinschaft Lu 183/2.
of Medicine,
Medizinische
Hochschule
levels from 42.6 to 76.9% of preinfusion levels with a mean nadir of 65.0 ± 4.0%;(mean ± SEM). (J Clin Endocrinol Metab 41: 1082, 1975)
They had T4 levels of less than .5 to 4.8 /xg/100 ml (normal 4.5-14 ^g/ml) and T3 levels of less than .2 to .9 ng/ml (normal .6-1.8 ng/ml). TSH levels were elevated in all patients (see below). At the time the studies were performed hypothyroidism had been recently discovered and no treatment had been instituted. None of the patients had a history of previous neck surgery or treatment with radioactive iodine for hyperthyroidism. Following cannulation of a vein, 125 /i,g linear GHIF* was injected as a bolus. Subsequently 875 jug of GHIF, dissolved in 50 ml of normal saline, was infused for 105 min using a Braun infusion pump. Blood was drawn every 15 min for 2 h and again 1 h later. Specimens were eentrifuged immediately and sera kept frozen at —20 C for later determination of TSH. No side effects from the infusion of GHIF were observed. T3 and T4 were determined by RIA (18) and TSH as previously described (19). Values were expressed in % of baseline values.
Results The infusion of GHIF resulted in a suppression of TSH levels in all instances. Individual nadir levels ranged from 42.6 to 76.9% of preinfusion values (65.0 ± 4.0%, mean ± SE). A significant drop was apparent after 15 min of infusion (Fig. 1). Nadir levels, seen at 90 and 105 min, however, were not significantly lower than levels at 60 and 75 min. Following termination of the infusion there was a rapid rise which reached preinfusion * Purchased from Serono Company, Freiburg, West Germany.
1082
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1083
GHIF AND TSH IN HYPOTHYROIDISM
10O
FIG. 1. Effect of GHIF on TSH levels in hypothyroid patients. Baseline (preinfusion) levels expressed as 100%. Bars represent
80
SEM. Somatostatin 8.3)jg/min
30
levels at the end of the study (180 min). Figure 2 shows the individual preinfusion and nadir values. Discussion While the suppressive effect of GHIF on GH, insulin and glucagon has been unanimously accepted, conflicting data exist on other hormones like prolactin (3,5,7,8,17) and TSH. In healthy volunteers several authors found TSH levels unaltered by the infusion of GHIF (3,5). Others, however, observed a blunting effect on TRH-induced TSH secretion (7,16,17). Our data for the first time demonstrate a suppressive effect on TSH levels not acutely raised by exogenous releasing hormone, but presumably elevated by endogenous hypersecretion of TRH. There is no apparent reason why basal TSH levels are not affected in healthy persons, but this may very well be due to the fact that these levels are low and frequently barely measurable by RIA and thus reductions in serum TSH levels are not easily detected in normal subjects. The suppressive effect is not a complete one and accounts only for about 35%. This is comparable to the partially suppressive effect observed following stimulation with TRH in normals (7,16). The physiologic importance of our data remains to be clarified. As GHIF seems to have no effect on TSH in healthy persons,
60
120
90
-n-
180 min
a physiologic role has to be established, as the effect is seen in unusual circumstances and with pharmacologic doses only. If it is true, however, as postulated by Abraham et al. (20), that an autoregulatory (feedback) mechanism exist for the secretion of GH, exogenous GH might induce considerable output of GHIF with subsequent blockade of GH and TSH secretion. Furthermore, the overlapping effect of GHIF and TSH might aquire considerable importance, whenever a long acting somatostatin might be available for treatment of acromegaly or
150
125-
FlG. 2. Individual preinfiision (left) and nadir levels of TSH during infusion of GHIF.
~ E
100
75
50
25
Nadir
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 13 November 2015. at 09:31 For personal use only. No other uses without permission. . All rights reserved.
1084
LUCKE, HOFFKEN AND VON ZUR MUHLEN
possibly juvenile diabetes (13). Secondary hypothyroidism, as well as glucose intolerance from blunted insulin secretion, might very well follow treatment of this kind. Reversable secondary hypothyroidism during treatment with GH has been recently described in patients with GH deficiency, presumably due to endogenous hypersecretionofGHIF(21). References 1. Brazeau, P., W. Vale, R. Burgus, N. Ling, M. Butcher, J. Rivier, and R. Guillemin, Science 179: 77, 1973. 2. Parker, D. C , L. G. Rossman, T. M. Siler, J. Rivier, S. S. C. Yen, and R. Guillemin,/ Clin Endocrinol Metab 38: 496, 1974. 3. Copinschi, G., E. Virasoro, L. Vanhaelst, R. Leclercq,
4. 5. 6.
7.
8.
J. Golstein, and M. L'Hermite, Endocrinology 3: 441, 1974. Prange Hansen, A., H. 0rskov, K. Seyer-Hansen, and K. Lundbaek, Br MedJ 3: 523, 1973. Siler, T. M., G. van den Berg, and S. S. C. Yen, 7 Clin Endocrinol Metab 37: 632, 1973. Mortimer, C. H., D. Carr, T. Lind, S. R. Bloom, C. N. Mallinson, A. V. Serially, W. M. G. Tunbridge, L. Yeomans, D. H. Coy, A. Kastin, G. M. Besser, and R. Hall, Lancet I: 697, 1974. Hall, R., A. V. Serially, D. Evered, A. J. Kastin, C. H. Mortimer, W. M. G. Tunbridge, G. M. Besser, D. H. Coy, D. J. Goldie, A. S. McNeilly, C. Phenekos, and D. Weightman, Lancet II: 7829, 1973. Yen, S. S. C , T. M. Siler, and G. W. DeVane, N EnglJ Med 290: 935, 1974.
JCE & M • 1975 Vol -1 ] • No (i
9. Besser, G. M., C. H. Mortimer, D. Carr, A. V. Schally, D. H. Coy, D. Evered, A. J. Kastin, W. M. G. Tunbridge, M. O. Thorner, and R. Hall, Br MedJ 1: 352, 1974. 10. DeVane, G. W., T. M. Siler, and S. S. C. Yen J Clin Endocrinol Metab 38: 913, 1974. 11. Alberti, K. G. M. M., S. E. Christensen, J. Iversen, K. Seyer-Hansen, N. J. Christensen, A. Prange Hansen, K. Lundbaek, and H. 0rskov, Lancet II: 1299, 1973. 12. Koerker, D. J., VV. Ruch, E. Chideckel, J. Palmer, C. J. Goodner, J. Ensinck, and C. C. Gale, Science 184: 482, 1974. 13. Gerich, J. E., M. Lorenzi, V. Schneider, J. H. Karam, J. Rivier, R. Gullemin, and P. H. Forsham.iV Engl J Med 291: 544, 1974. 14. Bloom, S. R., C. H. Mortimer, M. O. Thorner, G. M. Besser, R. Hall, A. Gomez-Pan, V. M. Roy, R. C. G. Russel, D. H. Coy, A. J. Kastin, and A. V. Schally, Lancet II: 1106, 1974.
15. Arnold, R., J. Kobberling, N. S. Track, and
W. Creutzfeldt, Ada Endocrinol (Kbh) Suppl. 193: 75, 1975. 16. Siler, T. M., S. S. C. Yen, W. Vale, and R. Guillemin, J Clin Endocrinol Metab 38: 742, 1974. 17. Vale, W., C. Rivier, P. Brazeau, and R. Guillemin, Endocrinology 95: 96P 1974. 18. Hehmiann, R., and C. Schneider, Radiologe 14: 156, 1974. 19. von zur Miihlen, A., and D. Emrich, Z. Klin Chem Klin Biochem 8: 257, 1971. 20. Abrams, R. L., M. M. Grumbach, and S. L. Kaplan, J Clin Invest 50: 940, 1971. 21. Lippe, B. M., A. J. van Herle, S. G. LaFranchi, R. P. Uller, N. Lavin, and S. A. Kaplan, J Clin Endocrinol Metab 40: 612, 1975.
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