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Plasma catecholamine concentrations in hyperthyroidism and hypothyroidism
Plasma Catecholamine Concentrations in Hyperthyroidism and Hypothyroidism P. Coulombe, J. H. Dussault, and P. Walker Using a modification of the ftuorometric method of Anton and Sayre,’ we have measured the plasma epinsphrine (E) and norepinephrine (NE) concentrations in patients with thyroid dysfunction. There was no significant difference in plasma E in hyperthyroid or hypothyroid subjects, the values being similar to those observed in normal subiects. There was a striking relationship between age and plasma NE in the euthyroid individuals (r = 0.685, p < 0.001, n = 41). Observed plasma NE concentrations were similar in control subjects (21.05 + 1.6 ng/lOO ml; mean -fr SEM) and hyperthyroid patients (22.33 * 2.0 ng/lOO ml). However, plasma NE was
significantly increased in hypothyroidism (35.46 + 3.9 ng/lOO ml; p < 0.01) and remained statistically different when the age factor was excluded (31.31 * 2.67 ng/lOO ml; p < 0.025). There was no correlation between plasma NE and serum thyroxine ( T4), free thyroxine (FT,), or triiodothyronine (T,), in any of the three groups studied. These data indicate that hyperthyroidism is accompanied by normal plasma NE concentrations and that hypothyroidism is associated with significantly increased plasma NE concentrations, possibly in an attempt to compensate for the lack of thyroid hormones.
SIGNS AND SYMPTOMS encountered in hyperthyroidism suggest an overactivity of the sympathetic nervous system. Although the exact mechanism governing the interaction between catecholamines and thyroid hormones remains unclear, several hypotheses have been advanced. Increased catecholamine secretion by the adrenal medulla or sympathetic nerve endings, and the increased sensitivity of peripheral tissues to sympathetic nervous stimuli ’ found that levels of urinary norepinephare the most common. Bayliss et al. rine (NE) were low in some cases of hyperthyroidism and high in some cases of hypothyroidism-results which have been confirmed by Ghione and associates.2 Using a double-isotopic derivative technique, Christensen3 observed that plasma NE concentration was low in hyperthyroid patients and significantly increased in hypothyroidism, whereas plasma epinephrine (E) remained unchanged. Using a modification of the original fluorometric method of Anton and Sayre,4,5 we have measured the plasma catecholamine concentrations in patients with thyroid disorders and in normal subjects, with particular interest in the possibility of a relationship between NE and age, as originally suggested by Christensen.3
S
EVERAL
From the Service d’Endocrinologie et Metabolisme. Le Centre Hospital& de I’Ltniversite Lav,al. Quebec, Canada. Receivedforpublication October 13. 1975. Supported bv Quebec Medical Research Council Grant 720-050. Reprint requests should be addressed to J. H. Dussault. M.D., M.Sc., Laboratoire de Recherches en Endocrinologie et MPtabolisme. Le Centre Hospitalier de I’Universite Laval. 2705, boul. Laurier. Quebec GI V4G2, Canada. 5~1976 bv Grune & Stratton, Inc.
Metabolism, Vol. 25, No. 9 (September), 1976
973
974
COULOMBE,
MATERIALS
DUSSAULT,
AND WALKER
AND METHODS
This study includes 41 normal subjects, 21 untreated patients with hyperthyroidism, and 13 patients with untreated primary hypothyroidism. All subjects were selected on the basis of their clinical status, as confirmed by specific thyroid function tests, including serum thyroxine (T,). free thyroxine (FT4). and triiodothyronine (T3). All subjects had a diastolic blood pressure of less than 90 mm Hg, since hypertension is known to elevate the level of circulating catecholamines,6 and they were free of cardiac and renal disease and diabetes mellitus. None of the subjects was receiving any medication known to alter adrenergic activity. After 15 min in the supine position, blood was drawn into chilled heparinized (37 USP/tube) vacutainers containing 10 mg sodium metabisulfite* and immediately centrifuged at 4°C. 6000 rpm for 10 min. Plasma was immediately separated and stored at -2O”C, pending assay within 2 wk. Serum T, and T, were measured by specific radioimmunoassay.‘.’ while the FT, was measured by the dialysis method of Sterling and Brenner.’ Plasma catecholamines were measured by a modification of the fluorometric method of Anton and Sayre.4*5 Briefly, after extraction and isolation using chromatography on an activated alumina column, the catecholamines were transformed into trihydroxy-indol-fluorescent products and measured at two different wavelengths (410 fi and 518 p for E and 395 p and 500 p for NE). Increased sensitivity has been obtained by replacing the flat mirror in the spectrofluorometert by an ellipsoidal condensing system.$ This new system allowed us to measure plasma catecholamines in 8 ml of plasma, with a coefficient of variation of less than 129; for E and less than 840 for NE. Recovery experiments have been performed using standard solutions of NE and E in a ratio of 4:I. where the standards are treated as plasma specimens. Statistical analyses analysis
was computed
have
been performed
according
using
to the method
the two-tailed
Student’s
t test. and
regression
of least mean squares.
RESULTS
1 summarizes the results of recovery of NE and E in eight experiments, in which standard solutions were treated as plasma samples. Mean recovery for E was 84 & 2.78% (mean f SEM) and was 85 & 1.87: for NE. There was a significant linear relationship between plasma NE concentration and age in normal subjects, as depicted in Figure 1 (r = 0.685, p < 0.001, n = 41). No such relationship was observed for E. Table
Table 1. Standard Quantity
Recovery Using Ellipsoidal Quantity
Added
= norepinephrine;
Recovery
Found
(Oh) E
E
NE
E
4.0
1 .o
2.97
0.99
75
99
4.0
1 .o
3.63
0.85
90
85
4.0
1 .o
3.25
0.86
81.3
86
4.0
1 .o
3.55
0.89
89
89
4.0
1 .o
3.36
0.78
84
78
4.0
1 .o
3.53
0.77
88.4
77.5
4.0
1 .o
3.28
0.81
82
81
NE
NE
4.0
1 .o
3.53
0.75
88
75
4.0
1 .o
3.39
.83
85
84
-
7.0
.02
SEM NE
System
(w)
(w) Experiment
Condensing
E = plasma
epinephrine.
*Baker Co. iAminco Bowman Spectrofluorometer, $American Instrument Co.
American
Instrument
Co.
1.8
2.78
PLASMA
CATECHOLAMINE
975
CONCENTRATIONS
IO
20
30
50
40 AGE
Fig. 1. Correlation between plasma norepinephrine relation is highly significant at the 0.001 level.
60
70
, 80
(YEARS)
and age in 41 normal
subjects.
The cor-
Table 2 illustrates the thyroid hormone and plasma catecholamine concentrations in the three groups studied. Thyroid hormone concentrations were significantly increased in hyperthyroidism and decreased in hypothyroidism (p < 0.01). Serum E concentration was unaltered in the three groups. Serum NE was unchanged in the hyperthyroid group but was significantly increased in the hypothyroid patients (p < 0.01) when compared to the euthyroid control subjects. Due to the significant relationship between age and plasma NE concentration, we have corrected our values in order to eliminate the age factor (see Appendix). As expected, there was no significant difference demonstrable between the hyperthyroid and control groups (Table 2). since the mean ages of the two groups are similar. However, the corrected plasma NE concentration in the hypothyroid patients was still significantly increased (p < 0.023, indicating that hypothyroidism is associated with a true increase in plasma NE concentration. There was no correlation observed between plasma catecholamine and thyroid hormone concentrations. DISCUSSION
Many of the signs and symptoms of hyperthyroidism are similar to those produced by epinephrine, and several studies have been designed to study the interrelationship of catecholamines and thyroid hormones. Our data for epinephrine concentrations in hyperthyroidism and hypothyroidism are consistent with previous observations2*3 and are of the same order of magnitude as those found in normal subjects. Furthermore, there is good agreement between the values we have observed and those reported by Christensen,3 who employed a double-isotopic derivative technique. In addition, we have previously reported
976
COULOMBE,
DUSSAULT,
AND WALKER
PLASMA
CATECHOLAMINE
CONCENTRATIONS
977
that epinephrine secretion rate and metabolic clearance rate are unaltered in lo Therefore, it would suggest that in hyperstates of thyroid dysfunction. thyroidism and hypothyroidism, adrenal function is little disturbed. Unlike epinephrine, the bulk ‘of norepinephrine found in the circulation is derived from sympathetic nerve terminal. Previous reports3.” have suggested that plasma NE concentrations are decreased in hyperthyroidism. We, on the other hand, have found no significant differences in plasma NE concentrations between hyperthyroid and euthyroid subjects. It is unlikely that this discrepancy reflects methodological differences, since the sensitivity of our assay was 0.25 ng/ml, and recovery of NE standards treated as plasma samples are similar to those previously reported.3 However, it is possible that this discrepancy may be accounted for on the basis of the striking relationship that we have noted between plasma NE concentration and age (r = 0.685. n = 41, p < 0.001: Fig. 1). Since our hyperthyroid group was of the same mean age as the control subjects, there is very little change in the plasma NE concentrations when corrected for the age factor. The hyperthyroid subjects reported by Christensen3 were significantly younger than the control subjects and therefore, the decreased serum NE concentrations observed in hyperthyroidism in that study may be more apparent than real. Furthermore, should plasma NE and thyroid hormone concentrations be inversely related,” one would expect to observe some correlation between these two parameters. We have been unable to document this correlation in agreement with previous studies.-’ These data allow us to formulate an alternative hypothesis for the interaction of catecholamines and thyroid hormones. In euthyroid subjects, both are important for calorigenesis, and both appear to act independently at the myocardial level to stimulate myocardial contractility. Although previous studies have suggested an increased sensitivity to catecholamine stimulation in hyperthyroidism,12 more recent reports have failed to confirm this possibility.‘3.‘4 These observations have been extended by experimental work in rats, where the activity of tyrosine hydroxylase, the rate-limiting enzyme in catecholamine synthesis, has been shown to be unchanged in the midbrain of hyperthyroid rats.” Furthermore, tissue NE concentration, synthesis, and -‘H-NE efflux are unchanged in hyperthyroid ratsI Such observations are consistent with our data, indicating normal plasma NE concentrations in hyperthyroidism, and suggest a synergistic effect of thyroid hormones and catecholamines, whereby the hyperdynamic circulation observed in hyperthyroidism could be explained by a direct effect of thyroid hormones on the myocardium, acting via activation of the membrane-bound adenyl cyclase systemI or by occupying specific nuclear receptor sites,‘” m addition to the presence of normal myocardial catecholamine concentrations.‘6 However, in hypothyroidism, plasma NE is significantly increased,2.3vi’ even after correction for the age factor, suggesting that in this state adrenergic activity is augmented in an effort to compensate for the lack of thyroid hormones. In support of this possibility are the observations that midbrain tyrosine hydroxylase activity and tissue NE concentrations and rate of 3HpNE efflux are significantly increased in hypothyroid rats.‘j.16
978
COULOMBE,
DUSSAULT,
AND WALKER
Why plasma NE concentration and age should be so closely interrelated is not readily apparent, although it is interesting to note that with advancing age, serum T, declines significantly. I9 The absence of a negative correlation between plasma NE and thyroid hormone concentrations in hypothyroidism is not surprising, since serum T, is not a good indicator of hypothyroidism, and since measurements of thyroid hormone concentrations, particularly T,, are frequently at, or near, the limit of sensitivity of conventional radioimmunoassay techniques. Our failure to document such a correlation in the normal subjects may be related to the population or to an insufficient number of subjects studied, since we, too, have noted a significant negative correlation between age and serum T,.* Furthermore, these significant correlations may merely reflect the aging process itself and do not necessarily reflect a causal effect of T, on plasma NE in normal individuals. In hypothyroidism, on the other hand, marked diminution in thyroid function with consequent perturbations in calorigenesis, thermogenesis, and cardiac contractility would evoke a compensatory adrenergic response. That no such correlation is seen in hyperthyroidism supports this possibility and suggests that thyroid hormoneecatecholamine interaction is relatively weaker than previously believed. Clearly, more work is necessary to further elucidate the complex interrelationship between catecholamines and thyroid hormones. ACKNOWLEDGMENT We wish to express their expert expertise
technical
our appreciation assistance,
in the preparation
to Mme. Christiane
and to Mile.
Danielle
Jacques
Gutrard
and Mme.
for her patience
Lise Garceau and
for
secretarial
of this manuscript.
REFERENCES 1. Bayliss RIS, Edwards OM: Urinary excretion of free catecholamines in Graves’ disease. J Endocrinol 49: 167, 1971 2. Ghione S, Pellegrini M, Capri A, Valori C. Donato L: Plasma and urinary catecholamine levels and thyroid activity in relation to cardio-
cholamines
vascular changes in hyper and hypothyroidism. Horm Metab Res 6:93, 1974 3. Christensen NJ: Plasma noradrenaline and adrenaline in patients with thyrotoxicosis and myxoedema. Clin Sci Mol Med 45: 163, 1973 4. Anton AH, Sayre DF: A study of the factors affecting the aluminum oxide trihydroxyindole procedure tbr the analysis of catecholamines. J Pharmacol 138:360, 1962 5. Genest J. Simard S. Rosenthal J, Boucher R: Norepinephfine and renin content in arterial tissue from different vascular beds. Can J Physiol Pharmacol47:87. 1969 6. Simard SJ: Valeur diagnostique des cate-
8. Chbpra IJ, Ho RS, Lam RW: An improved radioimmunoassay of triiodothyronine in serum: its application to clinical and physiological studies. J Lab Clin Med 80:729, 1972 9. Sterling K. Brenner. MA: Free thyroxine in untreated serum: simplified measurement with the aid of magnesium precipitation. J Clin Invest 45: 153, 1966 10. Coulombe P, Dussault JH, Letarte J, Simard SJ: Catecholamine metabolism in thyroid diseases: I. Epinephrine secretion rate in hypothyroidism and hyperthyroidism. J Clin Endocrinol Metab 42: 125, 1976 Il. Stoffer SS, Jiang N, Gorman CA, Pikler
*Unpublished
data.
plasmatiques
dans le test au gluca-
gon pour le phtochromocytome. Union Med Can 103:460, 1974 7. Chopra IJ: A rapid radioimmunoassay for measurement of thyroxine in unextracted serum. J Clin Endocrinol Metab 34:938, 1972
PLASMA
CATECHOLAMINE
979
CONCENTRATIONS
GM: Plasma catecholamines in hypothyroidism and hyperthyroidism. J Clin Endocrinol Metab 36:587. 1973 12. Schneckloth RE, Kurland GS. Freedburg AS: Effect of variation in thyroid function on the pressor response to norepinephrine in man. Metabolism 2:546. 1953 13. Spitzer JJ, Gold M. Miller AN, and Scott JC: Metabolic effects of norepinephrine on the heart in relation to the functional status of the thyroid. Metabolism 17:740, 1968 14. Levey GS: Catecholamine sensitivity, thyroid hormone and the heart: a reevaluation. Amer J Med 50:413, 1971 15. Emlen W. Segal DS, Mandel AJ: Thyroid state: effects on pre- and postsynaptic central noradrenergic mechanisms. Science 175:79, 1972
16. Tu T, Nash CW: The influence of prolonged hyper and hypothyroid states on the noradrenaline content of rat tissues and the accumulation and efflux rates of tritiated noradrenaline. Can J Physiol Pharmacol 53:74, 1975 17. Levey GS, Epstein SE: Activation of cardiac adenyl cyclase by thyroid hormone. Biochem Biophys Res Commun 33:990, 1968 18. Oppenheimer JH, Schwartz HL, Surks Ml: Tissue differences in the concentration of triiodothyronine in pituitary, heart, brain and testis. Endocrinology 94:897, 1974 19. Rubinstein HA. Butler VP, Werner SC: Progressive decrease in serum triiodothyronine aging: radioconcentrations with human immunoassay following extraction of serum, J Clin Endocrinol Metab 37:247, 1973
APPENDIX
According
to Fig. 1, the regression
line is
Y = 0.685 + 0.609x. The corrected
NE concentration NE,
can therefore = NE,
where NE, = NE, = CY= x = X=
corrected NE concentration: observed NE concentration; slope of the regression line: mean age for the group: age of the patient.
be written
+ a(X - x)
as
significantly increased in hypothyroidism (35.46 + 3.9 ng/lOO ml; p < 0.01) and remained statistically different when the age factor was excluded (31.31 * 2.67 ng/lOO ml; p < 0.025). There was no correlation between plasma NE and serum thyroxine ( T4), free thyroxine (FT,), or triiodothyronine (T,), in any of the three groups studied. These data indicate that hyperthyroidism is accompanied by normal plasma NE concentrations and that hypothyroidism is associated with significantly increased plasma NE concentrations, possibly in an attempt to compensate for the lack of thyroid hormones.
SIGNS AND SYMPTOMS encountered in hyperthyroidism suggest an overactivity of the sympathetic nervous system. Although the exact mechanism governing the interaction between catecholamines and thyroid hormones remains unclear, several hypotheses have been advanced. Increased catecholamine secretion by the adrenal medulla or sympathetic nerve endings, and the increased sensitivity of peripheral tissues to sympathetic nervous stimuli ’ found that levels of urinary norepinephare the most common. Bayliss et al. rine (NE) were low in some cases of hyperthyroidism and high in some cases of hypothyroidism-results which have been confirmed by Ghione and associates.2 Using a double-isotopic derivative technique, Christensen3 observed that plasma NE concentration was low in hyperthyroid patients and significantly increased in hypothyroidism, whereas plasma epinephrine (E) remained unchanged. Using a modification of the original fluorometric method of Anton and Sayre,4,5 we have measured the plasma catecholamine concentrations in patients with thyroid disorders and in normal subjects, with particular interest in the possibility of a relationship between NE and age, as originally suggested by Christensen.3
S
EVERAL
From the Service d’Endocrinologie et Metabolisme. Le Centre Hospital& de I’Ltniversite Lav,al. Quebec, Canada. Receivedforpublication October 13. 1975. Supported bv Quebec Medical Research Council Grant 720-050. Reprint requests should be addressed to J. H. Dussault. M.D., M.Sc., Laboratoire de Recherches en Endocrinologie et MPtabolisme. Le Centre Hospitalier de I’Universite Laval. 2705, boul. Laurier. Quebec GI V4G2, Canada. 5~1976 bv Grune & Stratton, Inc.
Metabolism, Vol. 25, No. 9 (September), 1976
973
974
COULOMBE,
MATERIALS
DUSSAULT,
AND WALKER
AND METHODS
This study includes 41 normal subjects, 21 untreated patients with hyperthyroidism, and 13 patients with untreated primary hypothyroidism. All subjects were selected on the basis of their clinical status, as confirmed by specific thyroid function tests, including serum thyroxine (T,). free thyroxine (FT4). and triiodothyronine (T3). All subjects had a diastolic blood pressure of less than 90 mm Hg, since hypertension is known to elevate the level of circulating catecholamines,6 and they were free of cardiac and renal disease and diabetes mellitus. None of the subjects was receiving any medication known to alter adrenergic activity. After 15 min in the supine position, blood was drawn into chilled heparinized (37 USP/tube) vacutainers containing 10 mg sodium metabisulfite* and immediately centrifuged at 4°C. 6000 rpm for 10 min. Plasma was immediately separated and stored at -2O”C, pending assay within 2 wk. Serum T, and T, were measured by specific radioimmunoassay.‘.’ while the FT, was measured by the dialysis method of Sterling and Brenner.’ Plasma catecholamines were measured by a modification of the fluorometric method of Anton and Sayre.4*5 Briefly, after extraction and isolation using chromatography on an activated alumina column, the catecholamines were transformed into trihydroxy-indol-fluorescent products and measured at two different wavelengths (410 fi and 518 p for E and 395 p and 500 p for NE). Increased sensitivity has been obtained by replacing the flat mirror in the spectrofluorometert by an ellipsoidal condensing system.$ This new system allowed us to measure plasma catecholamines in 8 ml of plasma, with a coefficient of variation of less than 129; for E and less than 840 for NE. Recovery experiments have been performed using standard solutions of NE and E in a ratio of 4:I. where the standards are treated as plasma specimens. Statistical analyses analysis
was computed
have
been performed
according
using
to the method
the two-tailed
Student’s
t test. and
regression
of least mean squares.
RESULTS
1 summarizes the results of recovery of NE and E in eight experiments, in which standard solutions were treated as plasma samples. Mean recovery for E was 84 & 2.78% (mean f SEM) and was 85 & 1.87: for NE. There was a significant linear relationship between plasma NE concentration and age in normal subjects, as depicted in Figure 1 (r = 0.685, p < 0.001, n = 41). No such relationship was observed for E. Table
Table 1. Standard Quantity
Recovery Using Ellipsoidal Quantity
Added
= norepinephrine;
Recovery
Found
(Oh) E
E
NE
E
4.0
1 .o
2.97
0.99
75
99
4.0
1 .o
3.63
0.85
90
85
4.0
1 .o
3.25
0.86
81.3
86
4.0
1 .o
3.55
0.89
89
89
4.0
1 .o
3.36
0.78
84
78
4.0
1 .o
3.53
0.77
88.4
77.5
4.0
1 .o
3.28
0.81
82
81
NE
NE
4.0
1 .o
3.53
0.75
88
75
4.0
1 .o
3.39
.83
85
84
-
7.0
.02
SEM NE
System
(w)
(w) Experiment
Condensing
E = plasma
epinephrine.
*Baker Co. iAminco Bowman Spectrofluorometer, $American Instrument Co.
American
Instrument
Co.
1.8
2.78
PLASMA
CATECHOLAMINE
975
CONCENTRATIONS
IO
20
30
50
40 AGE
Fig. 1. Correlation between plasma norepinephrine relation is highly significant at the 0.001 level.
60
70
, 80
(YEARS)
and age in 41 normal
subjects.
The cor-
Table 2 illustrates the thyroid hormone and plasma catecholamine concentrations in the three groups studied. Thyroid hormone concentrations were significantly increased in hyperthyroidism and decreased in hypothyroidism (p < 0.01). Serum E concentration was unaltered in the three groups. Serum NE was unchanged in the hyperthyroid group but was significantly increased in the hypothyroid patients (p < 0.01) when compared to the euthyroid control subjects. Due to the significant relationship between age and plasma NE concentration, we have corrected our values in order to eliminate the age factor (see Appendix). As expected, there was no significant difference demonstrable between the hyperthyroid and control groups (Table 2). since the mean ages of the two groups are similar. However, the corrected plasma NE concentration in the hypothyroid patients was still significantly increased (p < 0.023, indicating that hypothyroidism is associated with a true increase in plasma NE concentration. There was no correlation observed between plasma catecholamine and thyroid hormone concentrations. DISCUSSION
Many of the signs and symptoms of hyperthyroidism are similar to those produced by epinephrine, and several studies have been designed to study the interrelationship of catecholamines and thyroid hormones. Our data for epinephrine concentrations in hyperthyroidism and hypothyroidism are consistent with previous observations2*3 and are of the same order of magnitude as those found in normal subjects. Furthermore, there is good agreement between the values we have observed and those reported by Christensen,3 who employed a double-isotopic derivative technique. In addition, we have previously reported
976
COULOMBE,
DUSSAULT,
AND WALKER
PLASMA
CATECHOLAMINE
CONCENTRATIONS
977
that epinephrine secretion rate and metabolic clearance rate are unaltered in lo Therefore, it would suggest that in hyperstates of thyroid dysfunction. thyroidism and hypothyroidism, adrenal function is little disturbed. Unlike epinephrine, the bulk ‘of norepinephrine found in the circulation is derived from sympathetic nerve terminal. Previous reports3.” have suggested that plasma NE concentrations are decreased in hyperthyroidism. We, on the other hand, have found no significant differences in plasma NE concentrations between hyperthyroid and euthyroid subjects. It is unlikely that this discrepancy reflects methodological differences, since the sensitivity of our assay was 0.25 ng/ml, and recovery of NE standards treated as plasma samples are similar to those previously reported.3 However, it is possible that this discrepancy may be accounted for on the basis of the striking relationship that we have noted between plasma NE concentration and age (r = 0.685. n = 41, p < 0.001: Fig. 1). Since our hyperthyroid group was of the same mean age as the control subjects, there is very little change in the plasma NE concentrations when corrected for the age factor. The hyperthyroid subjects reported by Christensen3 were significantly younger than the control subjects and therefore, the decreased serum NE concentrations observed in hyperthyroidism in that study may be more apparent than real. Furthermore, should plasma NE and thyroid hormone concentrations be inversely related,” one would expect to observe some correlation between these two parameters. We have been unable to document this correlation in agreement with previous studies.-’ These data allow us to formulate an alternative hypothesis for the interaction of catecholamines and thyroid hormones. In euthyroid subjects, both are important for calorigenesis, and both appear to act independently at the myocardial level to stimulate myocardial contractility. Although previous studies have suggested an increased sensitivity to catecholamine stimulation in hyperthyroidism,12 more recent reports have failed to confirm this possibility.‘3.‘4 These observations have been extended by experimental work in rats, where the activity of tyrosine hydroxylase, the rate-limiting enzyme in catecholamine synthesis, has been shown to be unchanged in the midbrain of hyperthyroid rats.” Furthermore, tissue NE concentration, synthesis, and -‘H-NE efflux are unchanged in hyperthyroid ratsI Such observations are consistent with our data, indicating normal plasma NE concentrations in hyperthyroidism, and suggest a synergistic effect of thyroid hormones and catecholamines, whereby the hyperdynamic circulation observed in hyperthyroidism could be explained by a direct effect of thyroid hormones on the myocardium, acting via activation of the membrane-bound adenyl cyclase systemI or by occupying specific nuclear receptor sites,‘” m addition to the presence of normal myocardial catecholamine concentrations.‘6 However, in hypothyroidism, plasma NE is significantly increased,2.3vi’ even after correction for the age factor, suggesting that in this state adrenergic activity is augmented in an effort to compensate for the lack of thyroid hormones. In support of this possibility are the observations that midbrain tyrosine hydroxylase activity and tissue NE concentrations and rate of 3HpNE efflux are significantly increased in hypothyroid rats.‘j.16
978
COULOMBE,
DUSSAULT,
AND WALKER
Why plasma NE concentration and age should be so closely interrelated is not readily apparent, although it is interesting to note that with advancing age, serum T, declines significantly. I9 The absence of a negative correlation between plasma NE and thyroid hormone concentrations in hypothyroidism is not surprising, since serum T, is not a good indicator of hypothyroidism, and since measurements of thyroid hormone concentrations, particularly T,, are frequently at, or near, the limit of sensitivity of conventional radioimmunoassay techniques. Our failure to document such a correlation in the normal subjects may be related to the population or to an insufficient number of subjects studied, since we, too, have noted a significant negative correlation between age and serum T,.* Furthermore, these significant correlations may merely reflect the aging process itself and do not necessarily reflect a causal effect of T, on plasma NE in normal individuals. In hypothyroidism, on the other hand, marked diminution in thyroid function with consequent perturbations in calorigenesis, thermogenesis, and cardiac contractility would evoke a compensatory adrenergic response. That no such correlation is seen in hyperthyroidism supports this possibility and suggests that thyroid hormoneecatecholamine interaction is relatively weaker than previously believed. Clearly, more work is necessary to further elucidate the complex interrelationship between catecholamines and thyroid hormones. ACKNOWLEDGMENT We wish to express their expert expertise
technical
our appreciation assistance,
in the preparation
to Mme. Christiane
and to Mile.
Danielle
Jacques
Gutrard
and Mme.
for her patience
Lise Garceau and
for
secretarial
of this manuscript.
REFERENCES 1. Bayliss RIS, Edwards OM: Urinary excretion of free catecholamines in Graves’ disease. J Endocrinol 49: 167, 1971 2. Ghione S, Pellegrini M, Capri A, Valori C. Donato L: Plasma and urinary catecholamine levels and thyroid activity in relation to cardio-
cholamines
vascular changes in hyper and hypothyroidism. Horm Metab Res 6:93, 1974 3. Christensen NJ: Plasma noradrenaline and adrenaline in patients with thyrotoxicosis and myxoedema. Clin Sci Mol Med 45: 163, 1973 4. Anton AH, Sayre DF: A study of the factors affecting the aluminum oxide trihydroxyindole procedure tbr the analysis of catecholamines. J Pharmacol 138:360, 1962 5. Genest J. Simard S. Rosenthal J, Boucher R: Norepinephfine and renin content in arterial tissue from different vascular beds. Can J Physiol Pharmacol47:87. 1969 6. Simard SJ: Valeur diagnostique des cate-
8. Chbpra IJ, Ho RS, Lam RW: An improved radioimmunoassay of triiodothyronine in serum: its application to clinical and physiological studies. J Lab Clin Med 80:729, 1972 9. Sterling K. Brenner. MA: Free thyroxine in untreated serum: simplified measurement with the aid of magnesium precipitation. J Clin Invest 45: 153, 1966 10. Coulombe P, Dussault JH, Letarte J, Simard SJ: Catecholamine metabolism in thyroid diseases: I. Epinephrine secretion rate in hypothyroidism and hyperthyroidism. J Clin Endocrinol Metab 42: 125, 1976 Il. Stoffer SS, Jiang N, Gorman CA, Pikler
*Unpublished
data.
plasmatiques
dans le test au gluca-
gon pour le phtochromocytome. Union Med Can 103:460, 1974 7. Chopra IJ: A rapid radioimmunoassay for measurement of thyroxine in unextracted serum. J Clin Endocrinol Metab 34:938, 1972
PLASMA
CATECHOLAMINE
979
CONCENTRATIONS
GM: Plasma catecholamines in hypothyroidism and hyperthyroidism. J Clin Endocrinol Metab 36:587. 1973 12. Schneckloth RE, Kurland GS. Freedburg AS: Effect of variation in thyroid function on the pressor response to norepinephrine in man. Metabolism 2:546. 1953 13. Spitzer JJ, Gold M. Miller AN, and Scott JC: Metabolic effects of norepinephrine on the heart in relation to the functional status of the thyroid. Metabolism 17:740, 1968 14. Levey GS: Catecholamine sensitivity, thyroid hormone and the heart: a reevaluation. Amer J Med 50:413, 1971 15. Emlen W. Segal DS, Mandel AJ: Thyroid state: effects on pre- and postsynaptic central noradrenergic mechanisms. Science 175:79, 1972
16. Tu T, Nash CW: The influence of prolonged hyper and hypothyroid states on the noradrenaline content of rat tissues and the accumulation and efflux rates of tritiated noradrenaline. Can J Physiol Pharmacol 53:74, 1975 17. Levey GS, Epstein SE: Activation of cardiac adenyl cyclase by thyroid hormone. Biochem Biophys Res Commun 33:990, 1968 18. Oppenheimer JH, Schwartz HL, Surks Ml: Tissue differences in the concentration of triiodothyronine in pituitary, heart, brain and testis. Endocrinology 94:897, 1974 19. Rubinstein HA. Butler VP, Werner SC: Progressive decrease in serum triiodothyronine aging: radioconcentrations with human immunoassay following extraction of serum, J Clin Endocrinol Metab 37:247, 1973
APPENDIX
According
to Fig. 1, the regression
line is
Y = 0.685 + 0.609x. The corrected
NE concentration NE,
can therefore = NE,
where NE, = NE, = CY= x = X=
corrected NE concentration: observed NE concentration; slope of the regression line: mean age for the group: age of the patient.
be written
+ a(X - x)
as