Opposite Effects of Dexamethasone on Serum Concentrations of 3,3'?5'-Triiodothyronine (Reverse T3) and 3,3',5-Triiodothyronine (T3) INDER J. CHOPRA, DONALD E. WILLIAMS, JACQUES ORGIAZZI, AND DAVID H. SOLOMON Department of Medicine, UCLA Center for the Health Sciences, Los Angeles, California because the dialyzable fractions of rT3 and T3 following steroid administration were not different from those before it. Serum T4 did not change appreciably in treated hypothyroid cases, but decreased in Graves' disease cases from a mean baseline value of 23.5 fig per 100 ml to 18.4 jug per 100 ml 3 days after beginning dexamethasone. In addition, 3 hyperthyroid cases were studied before, during, and after administration of dexamethasone, 2 mg every 6 h for 5 days. Serum rT3 increased again as noted above and the increase persisted until about 24 hours after the last dose of the steroid. Serum T3 decreased considerably and remained decreased as long as studied, at least 4 days after discontinuing the steroid. Serum T» decreased appreciably in 2 of the 3 cases studied. The data suggest that 1) conversion of T4 to T3 and to rT3 may occur via two distinct pathways in the metabolism of T4; 2) the changes in serum rT3 and T3 observed in our study may be due in part at least to a steroid-induced 'shift' in the metabolism of T4 whereby conversion of T4 to T3 is diminished and that to rT3 is enhanced; 3) in addition to the effect on peripheral metabolism of T4, steroids appear to reduce the circulating thyroid hormones in Graves' disease by another mechanism, probably by reduction in thyroid secretion. (J Clin Endocrinol Metab 41: 911, 1975)
ABSTRACT. Dexamethasone, 2 mg every 6 hours for 4 doses, was given to 4 hypothyroid patients receiving treatment with synthetic thyroxine (T4) and to 8 untreated hyperthyroid patients with Graves' disease, and serum concentrations of thyroid hormones were measured by radioimmunoassays. Serum concentration of 3,3',5'-triiodothyionine (reverse T3, rT;i) increased appreciably within 8 hours after the first dose of dexamethasone, was maximum at 24-32 hours after beginning dexamethasone, and remained elevated for about 24 hours after discontinuing the steroid. The mean baseline serum rT3 was 58 ng/per 100 ml in treated hypothyroid patients and 119 ng per 100 ml in patients with Graves' disease; the corresponding maximal postdexamethasone serum rT3 values were 87 and 170 ng per 100 ml, respectively. As serum rT3 increased, serum concentration of 3,3',5-triiodothyronine (T3) decreased. The decrease in serum T3 was significant at about 24 hours alter beginning dexamethasone and was maximal at about 30 hours in both groups of cases under study. The decrease in serum T3 persisted in treated hypothyroid cases for about 24-48 hours and in Graves' disease cases as long as studied, at least 5 days after discontinuing dexamethasone. The changes in serum rT3 and T3 could not be attributed to the effect of dexamethasone on serum protein binding of the iodothyronines
W
E HAVE reported recently that acute administration of a glucocorticosteroid, dexamethasone, is associated with a rapid and persistent decrease in serum concentration of 3,3',5-triiodothyronine (T3) in hyperthyroid or euthyroid patients with Graves' disease (1,2). Findings of a similar decrease in serum thyroglobulin and some, Supported in part by USPHS Grants AM-16155 and AM 17251, NIH Research Career Development Award I K04 AM-70,225 (Dr. Chopra), and UCLA Clinical Research Center Grant RR-865. Received April 29, 1975. Reprints: Dr. Inder J. Chopra, Department of Medicine, UCLA Center for the Health Sciences, Los Angeles, California 90024.
albeit less marked, decrease in thyroxine (T4) suggested that steroids may cause a decrease in thyroid secretion in Graves' disease (1). However, diminution in serum T3 has also been observed following administration of dexamethasone to normal subjects and to hypothyroid patients receiving treatment with synthetic T4; the decrease in serum T3 in these subjects, however, was not accompanied by appreciable decreases in serum T4 and thyroglobulin (1,3). These findings suggest that corticosteroids may effect a reduction in the peripheral conversion of T4 to T3 (3). Recent studies have also indicated that 3,3',5'triiodothyronine (reverse T3, rT3) is another 911
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JCE & M • 1975 \'ol 41 • No 5
CHOPRA, WILLIAMS, ORGIAZZI AND SOLOMON
912
product of peripheral metabolism of T4 (4). As against T3, which is biologically much more potent than T4 (5), rT3 has little calorigenic activity (6,7). Reverse T3 has actually been suggested to have antiT4 effects (8). Interestingly, in several situations, e.g. the newborn, systemic illnesses and malnutrition, where serum T3 and/or peripheral conversion of T4 to T3 have been shown to be decreased, serum rT3 and/or production of rT3 are increased (9-19). These studies raised a possibility that steroids may lower T3 by causing a shift in the metabolism of T4 whereby conversion of T4 to T3 may be impaired, while that to rT3 may be enhanced. The present paper describes the relative changes in serum concentrations of T3 and rT3 during and following administration of dexamethasone to treated hypothyroid as well as untreated hyperthyroid subjects; steroids
were noted to have opposite effects on serum rT3 and T3. The data suggest that steroids may indeed effect the change in metabolism of T4 mentioned above. Materials and Methods Patients. Eleven hyperthyroid patients (4 male and 7 female) with Graves' disease, and 4 hypothyroid women receiving treatment with 0.2-0.4 mg of synthetic T4 (Synthroid) were the subjects of study. The diagnosis of Graves' disease was based on typical clinical findings including diffuse goiter and supranormal values of serum T4, T3, and thyroid radioiodine uptake. Each of the treated hypothyroid patients had received T4 for 3 months or more. Studies with dexamethasone. Dexamethasone, 2 mg orally every 6 hours for 4 doses, was given to 8 hyperthyroid patients and 4 treated hypothyroid cases. In addition, dexamethasone was given orally to 3 hyperthyroid patients in
TABLE 1. Serum concentrations of rT3, T3> and T4 before, during, and after administration of Days of study
l*t Case
Age
no.
(yr)
Sex
1
50
F
rT3* T3*
T4f 2
54
F
rT3
T3 T4
Baseline — 15min.
(AM)
54 196 12.0
2
3
PM
AM
PM
AM
PM
61 220 13.7
61 193 12.3
100 170 11.5
106 155 11.0
75 178 13.5
66 148 11.1
49 230 18.0
53 200 14.6
62 230 15.3
74 185 14.0
74 175 14.0
76 185 13.2
71 215 12.7
0
3
23
F
rT3 T3
T4
74 250 12.8
66 220 10.7
93 213 10.8
103 210 12.5
108 158 9.8
88 220 10.1
61 193 12.0
4
46
F
rT3 T3 T4
43 98 11.2
50 88 10.5
42 110 10.0
58 85 11.2
60 88 14.0
66 78 12.4
50 85 13.0
rT3
55.0 ±6.70
57.5 ± 3.70
64.5 ± 10.6
83.7 ±10.8
186 ± 26.6
162 ±27.1
87.0 ±11.9 144 ±19.2
76.3 ±4.51 165 ±30.5
62.0 ±4.49 160 ±28.3
12.3
12.2 ±0.42
Mean ± SE
T3
193 ±33.7
T4
13.5 ±1.5
182 ± 31.7 12.4 ± 1.04
12.1 ±1.17
12.3 ±0.63
12.2 ±1.08
±0.77
* ng/100 ml. f fig/100 ml.
*t Dexamethasone was started after "0" blood sample on day 1.
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913
REVERSE T, AND T, AFTER DEXAMETHASONE a dose of 2 nig every 6 hours for 5 days (20 doses). Blood was obtained before and twice daily at about 9 AM and 5 PM during and for 4-6 days following the administration of dexamethasone.
values was taken to represent the baseline value. Serum T3 and T4 values of 6 hyperthyroid cases noted here have been reported earlier (1). These are included here for the purpose of a complete report in conjunction with newer data.
Hormonal studies. Serum rT3, T3, and T4 were measured by radioimmunoassays described pre- Free rTs and T3. To examine the changes in viously (4,20,21). Antiserum against rT3 was pro- serum protein binding of rT3 after administraduced by immunization of rabbits with D,L- tion of dexamethasone, we measured the dialyzrT3-human serum albumin conjugate (4). Recent able fractions of rT3 and T3 before and at 24 studies in our laboratory have revealed that to 30 hours after beginning dexamethasone when L-iT3 and D,L-rT3 react similarly with this anti- changes in serum total rT3 and T, were clearly sorum; their radioimmunoassay dose-response evident. The dialyzable rT3 and T3 were curves were essentially identical. The values measured using modifications of equilibrium at various time periods of study were compared dialysis methods described previously for T4 to the baseline value by Student's two-tailed and T 3 (22-25). In brief, the method consisted t test for paired data. The values in the blood of addition of predialyzed radioactive rT3 and/or samples obtained immediately prior to adminis- radioactive T3 to serum diluted 1:10 (23), dialysis tration of dexamethasone were used as the base- in plastic cells and precipitation of the dialysate line value in several cases. In other patients, with magnesium chloride (22). The dialyzable in whom an additional baseline sample was fraction determined by using diluted serum and obtained 15 min earlier, the mean of the two correcting for dilution was underestimated comdexamethasone (2 mg every 6 h for 4 doses) to hypothyroid patients receiving treatment with synthetic T4
AM
6
5
4 PM
AM
PM
AM
7 PM
AM
PM
— —
— —
53 225 16.1
49 260 16.1
— —
— —
—
61 185 12.1
72 185 —
60 260 14.0
68
58
58
225 —
250
250
15.8
15.3
70 190 12.7
66 175 12.7
49 215 14.6
52 215 14.6
49 240 16.1
54 230 17.0
63 228 10.9
59 230 11.1
76 288 10.1
81 283 13.5
65 283 11.6
248 —
52 78 13.5
52 93 12.4
88
12.4
52 88 10.5
49 110 13.0
54 110 13.5
54 130 13.0
61.5 ±3.71 170 ±32.2 12.3 ±0.55
65.7 ±3.75 171 ±28.5 12.1 ±0.49
59.3 ±6.05 213 ±44.2 12.8 ±1.00
63.2 ±7.01 203 ±41.1 12.9 ±1.22
55.2 ±3.89 212 ±34.1 14.5 ±1.5
55.3 ± 1.33 182 ±36.5 15.3 ± 1.01
53.5 ±0.50 178 ± 47.5 • 14.5' ±1.55
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CHOPRA, WILLIAMS, ORGIAZZI AND SOLOMON
914
pared with the results with undiluted serum (24). Therefore, a correction factor was determined for each iodothyronine by simultaneous measurements in whole and diluted pooled serum of hospitalized patients. The correction factor was 1.79 for rT3 and 1.37 for T3. These values were applied to diluted test specimens. Results
Effect of administration of dexamethasone for one day. Serum rT3, T3, and T4 values before, during, and following one day of administration of dexamethasone in four treated hypothyroid cases are described in Table 1. Change in serum rT3 and T3 at various times of study are presented in
JCE & M • 1975 Vol 41 • No 5
Fig. 1. Serum rT3 increased and serum T3 decreased significantly following administration of dexamethasone (Fig. 1). The mean pre-dexamethasone serum rT3 was 58 ng per 100 ml; it increased to a mean peak value of 87 ng per 100 ml on day 2 (PM) (Table 1). On the other hand, serum T3 decreased from the mean baseline value of 182 ng per 100 ml to a mean minimum of 144 ng per 100 ml on day 2 (PM). The increase in rT3 was statistically significant until day 3 (AM), whereas the decrease in serum T3 was statistically significant until day 4 (AM) (Fig. 1). Serum T4 did not change appreciably during or following administration of dexamethasone (Table 1).
DEXAMETHASONE 2 mg
I
* I I REVERSE T3
LJ ID
+ 80i
HYPOTHYROID PATIENTS ON F$ WITH T 4
+ 60-
GRAVES' DISEASE PATIENTS
+ 40-
FIG. 1. Changes in serum concentration of rT3 and T3 during and after administration of dexamethasone, 2 mg every 6 h for 4 doses. Data are expressed as percent change from baseline. Actual serum levels of rT3 and T3 are presented in Tables 1 and 2.
UJ X /
LJ (I) CD
O U_ LJ
I
-20-
-40' Significantly different from baseline pm 1
am
2
pm
am
pm 3
am
pm 4
pm
am pm
DAYS OF STUDY
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REVERSE T, AND T, AFTER DEXAMETHASONE The changes in serum rT3 and T3 noted above were not due to steroid-induced alterations in serum protein binding of these iodothyronines. Thus the mean (±SE) dialyzable fractions of rT3 and T3 were 0.31 ± 0.01 and 0.35 ± 0.04%, respectively, before steroid administration. The corresponding values 24-30 h after beginning steroid administration were 0.32 ± 0.01% for rT3 and 0.36 ± 0.03% for T3. Serum rT3, T3, and T4 in 8 hyperthyroid patients are described in Table 2; the changes in rT3 and T3 compared with the baseline are noted in Fig. 1. Serum rT3 increased from a mean pre-dexamethasone value of 119 ng per 100 ml to peak mean value of 170 ng per 100 ml on day 2 (AM). On the other hand, serum T3 decreased from a mean pre-dexamethasone value of 622 ng per 100 ml to a mean value of 362 ng per 100 ml on day 2 (PM) (Table 2). The increase in serum rT3 was statistically significant from day 1 (PM) to day 3 (AM). The decrease in serum T3 was statistically significant throughout 6 days of study. The mean peak increase in rT3 of 82.8% on day 2 (PM) in hyperthyroid cases was somewhat (but not significantly) higher than the corresponding peak value of 53% in treated hypothyroid cases. The duration of the increase in serum rT3 was similar in the two groups under study (Fig. 1). The mean maximal decrease in serum T3 of 37% on day 2 (PM) in hyperthyroid cases was not significantly different from the corresponding value of 21% in treated hypothyroid cases. However, the decrease in serum T3 at each time interval from day 2 (AM) through day 6 (PM) was significantly more pronounced in patients with Graves' disease than in treated hypothyroid subjects. Serum T4 also decreased significantly in Graves' disease cases following dexamethasone administration. The mean pre-dexamethasone value was 23.5 fxg per 100 ml; it decreased to 18.4 /xg per 100 ml on day 4 (AM) (P < 0.02).
915
Effect of administration of dexamethasone for five days. Thyroid hormone levels during these studies in three Graves' disease patients are described in Table 3 and the percent of change from baseline in rT3 and T3 are presented in Fig. 2. The increase in serum rT3 was observed within a few hours after administration of dexamethasone; it was nearly maximal, about 70-75% above the baseline value, by 24-48 hours after beginning dexamethasone. High levels were maintained until about 12 hours after the last dose of dexamethasone; thereafter serum rT3 was similar to the baseline value (Fig. 2). Serum protein binding of rT3 did not change appreciably during the study. The mean dialyzable fraction of serum rT3 before, at 48 h after beginning dexamethasone, on the last day of steroid administration, and at 3 or 4 days after withdrawal of the steroids was 0.37 ± 0.03, 0.37 ± 0.02, 0.36 ± 0.03, and 0.34 ± 0.02%, respectively. These values did not differ significantly from one another. Serum T3 decreased promptly after beginning dexamethasone; it remained significantly below the baseline value as long as studied until about 72 hours after the last dose of dexamethasone. Just as in the case of rT3, the serum protein binding of T3 did not change during these studies. The mean dialyzable fraction of T3 before, at 48 h after beginning dexamethasone, on the last day of steroid administration, and at 3 or 4 days after withdrawal of the steroids was 0.56 ± 0.07, 0.55 ± 0.07, 0.55 ± 0.66, and 0.53 ± 0.05%, respectively. Serum T4 decreased considerably in 2 out of 3 patients studied (cases 1 and 3, Table 3). The maximal decrease in case 1 was 23% on day 7 (AM); it was 39% in case 3 on day 6 (AM). Case 2 did not demonstrate a consistent change in serum T4. Discussion Recent studies indicate that, in addition to T3, rT3 is another significant product
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JCE & M • 1975 Vol 4i • No 5
CHOPRA, WILLIAMS, ORGIAZZI AND SOLOMON
916
of the peripheral metabolism of T4 (4). It has been estimated that normally only about 3% of serum rT3 originates from thyroidal secretion; the rest apparently derives from peripheral mono-deiodination of T4 (26). The present studies indicate that administration of steroids results in a prompt increase in serum rT3 persisting for about 24 hours after completion of a course of steroid (Figs. 1 and 2). As serum rT3
increased, serum concentration of T3 decreased. The changes in serum rT3 and T3 were not attributable to a change in the serum binding of this iodothyronine; the absence of an appreciable change in the free fraction or serum binding of T3 (and T4) has also been observed in other studies (1,27,28). These findings are also concordant with those of other studies indicating lack of an appreciable change in the kinetics
TABLE 2. Serum concentrations of rT3, T3, and T4 before, during, and after Days of study 1*t Case no.
Age (yr)
1
18
M
rT 3 * T3*
2
24
M
3
29
4
IodoBaseline Sex thyronine -15min.
(AM)
2 PM
3
AM
PM
AM
PM
0 110 675 23.3
130 700 23.3
200 440 24.5
180 475 26.0
130 420 18.5
130 450 20.0
rT 3 T3 T4
66 480 22.5
86 460 18.0
160 290 19.0
140 195 19.5
94 260 17.0
82 300 16.0
F
rT 3 T3 T4
96 500 30.0
125 500 33.0
180 450 32.0
220 350 30.0
200 390 30.0
—
33
M
rT 3 T3 T4
86 825 23.0
105 725 24.5
170 625 23.0
170 540 26.0
140 540 23.0
110 625 20.0
5
24
F
rT 3 T3 T4
190 1100 34.0
260 1150 35.0
330 575 31.0
260 390 30.0
190 550 28.0
150 550 29.0
6
. 50
M
rT 3 T3 T4
62 235 17.0
68 260 16.0
100 160 14.0
110 175 15.5
78 140 13.0
82 125 15.5
7
39
F
rT 3 T3 T4
40 285 18.8
35 285 18.5
46 310 17.0
60 225 17.9
66 245 19.0
33 225 13.0
35 210 16.3
8
28
F
rT 3 T3 T4
96 910 19.0
110 875 20.0
135 1000 20.0
160 700 17.0
175 525 20.0
130 700 18.0
120 625 20.0
rT3
94.4 ± 16.4
119 ±22.9
170 ±28.0
125 ± 19.7
T3
622 ± 106.5
638 ± 112.3 23.4 ±2.55
433 ±69.0
165 ±21.5 362 ±51.5 23.2 ± 1.93
101 ± 14.4 412 ±76.7 19.5 ± 1.75
T«t
Mean ± SE
T4
23.5 ±2.04
22.3 ±2.32
403 ±66.9 20.1 ±2.26
*ng/100ml. t /u.g/100 ml. •*t Dexamethasone was given on day 1 after obtaining baseline blood sample.
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REVERSE T, AND T, AFTER DEXAMETHASONE of the peripheral metabolism of T4 and T3 during acute administration of steroids (29-31). These considerations, together with the finding of a decrease in serum T3 and no change in serum T4 following steroid administration to hypothyroid cases receiving exogenous T4, suggest that steroids may reduce the production of T3 from T4. Our studies, indicating an increase in serum rT3 when T3 decreases, suggest that
917
during steroid administration, some of the T4 normally metabolized to T3 may be channeled to the production of rT3. This conclusion would be in error if steroids were merely to cause a diminution in the metabolic clearance rate of rT3. However, the lack of an effect of steroid treatment on the kinetics of other iodothyronines (T4 and T3) as well as on the serum binding of rT3 does not support this possibility,
administration of dexamethasone (2 mg every 6 h for 4 doses) to Graves' disease patients
AM
PM
AM
PM
AM
PM
AM
PM
66 360
72 310
62 350
68 290
64 400
74 300 —
— — —
— — —
— —
— —
—
— —
18.0
160 275 18.2
90
775 23.0
170 700 26.0
50 120 10.0
28 225 15.3
17.0
140 225 23.0
110 725 23.0
170 725 27.0
62 155 14.0
29 265 —
19.0
105 320 24.8
94 675 20.0
170 725 29.0
62 135 14.0
21 270 13.2
82
96
82
750
675
840
19.0
100 310 23.0
100
925
28.0
170 750 27.0
68 165 16.0
29 265 18.5
80 840
16.0
18.0
92.3 ±20.3
97.0
85.1 ± 17.5
89.3 ± 16.7
458 18.4 ± 1.95
±2.00
20.0
110
17.0
± 104.2
94 260
875
18.0
± 18.1 440 ' ±96.7 20.1
19.0
28.0
100 310 22.4
120 825 26.0
135
140
150
285 27.0
900
1000
68 215
68 185
33.0
12.5
16.0
21
29 19.0
92
92
875
840
19.0 82.0 ± 13.47
19.0
474
499
536
560
± 116.1
± 122.4
± 133.54
21.4 ± 1.77
—
—
—
— —
—
—
89.0 ± 13.77
± 101.5 19.4 ±2.19
33.0
250 17.5
20.4 ±2.04
1050
32.5
22.5 ±2.5
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9.18
CHOPRA, WILLIAMS, ORGIAZZI AND SOLOMON TABLE
JCK & M • 1975 Vol 41 • No 5
3. Serum concentrations of rT3, T3) and T4 before, during, and after 5 days of Days of study 2
1
Case
Age
(yr)
Sex
Irxiothyronine
Baseline - 1 5 min.
(AM)
no. 1
20
F
rTa*
T4t
82 625 13.6
Ts T4
66 310 14.0
2
3
29
50
F
3
PM
AM
PM
AM
PM
84 580 15.0
94 560 14.0
135 410 13.0
150 345 14.0
180 375 13.6
135 395 14.0
76 305 13.2
82 310 15.0
90 215 13.2
90 215 15.0
86 225 14.0
86 215 15.0
0
M
rTa T:, T4
115 462 16.0
180 330 16.0
260 230 18.0
240 230 15.0
220 182 12.0
220 218 10.6
Mean
rT3
98 ± 11.9
119 ±30.9
162 ±50.9
160 ±43.6
162 ± 39.7
140 ± 33.0
T3
442 ± 74.3
400 + 80.2
285 ± 62.65
263 ± 41.1
261 ±58.5
276 ±59.5
± SE
T
ABSTRACT. Dexamethasone, 2 mg every 6 hours for 4 doses, was given to 4 hypothyroid patients receiving treatment with synthetic thyroxine (T4) and to 8 untreated hyperthyroid patients with Graves' disease, and serum concentrations of thyroid hormones were measured by radioimmunoassays. Serum concentration of 3,3',5'-triiodothyionine (reverse T3, rT;i) increased appreciably within 8 hours after the first dose of dexamethasone, was maximum at 24-32 hours after beginning dexamethasone, and remained elevated for about 24 hours after discontinuing the steroid. The mean baseline serum rT3 was 58 ng/per 100 ml in treated hypothyroid patients and 119 ng per 100 ml in patients with Graves' disease; the corresponding maximal postdexamethasone serum rT3 values were 87 and 170 ng per 100 ml, respectively. As serum rT3 increased, serum concentration of 3,3',5-triiodothyronine (T3) decreased. The decrease in serum T3 was significant at about 24 hours alter beginning dexamethasone and was maximal at about 30 hours in both groups of cases under study. The decrease in serum T3 persisted in treated hypothyroid cases for about 24-48 hours and in Graves' disease cases as long as studied, at least 5 days after discontinuing dexamethasone. The changes in serum rT3 and T3 could not be attributed to the effect of dexamethasone on serum protein binding of the iodothyronines
W
E HAVE reported recently that acute administration of a glucocorticosteroid, dexamethasone, is associated with a rapid and persistent decrease in serum concentration of 3,3',5-triiodothyronine (T3) in hyperthyroid or euthyroid patients with Graves' disease (1,2). Findings of a similar decrease in serum thyroglobulin and some, Supported in part by USPHS Grants AM-16155 and AM 17251, NIH Research Career Development Award I K04 AM-70,225 (Dr. Chopra), and UCLA Clinical Research Center Grant RR-865. Received April 29, 1975. Reprints: Dr. Inder J. Chopra, Department of Medicine, UCLA Center for the Health Sciences, Los Angeles, California 90024.
albeit less marked, decrease in thyroxine (T4) suggested that steroids may cause a decrease in thyroid secretion in Graves' disease (1). However, diminution in serum T3 has also been observed following administration of dexamethasone to normal subjects and to hypothyroid patients receiving treatment with synthetic T4; the decrease in serum T3 in these subjects, however, was not accompanied by appreciable decreases in serum T4 and thyroglobulin (1,3). These findings suggest that corticosteroids may effect a reduction in the peripheral conversion of T4 to T3 (3). Recent studies have also indicated that 3,3',5'triiodothyronine (reverse T3, rT3) is another 911
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JCE & M • 1975 \'ol 41 • No 5
CHOPRA, WILLIAMS, ORGIAZZI AND SOLOMON
912
product of peripheral metabolism of T4 (4). As against T3, which is biologically much more potent than T4 (5), rT3 has little calorigenic activity (6,7). Reverse T3 has actually been suggested to have antiT4 effects (8). Interestingly, in several situations, e.g. the newborn, systemic illnesses and malnutrition, where serum T3 and/or peripheral conversion of T4 to T3 have been shown to be decreased, serum rT3 and/or production of rT3 are increased (9-19). These studies raised a possibility that steroids may lower T3 by causing a shift in the metabolism of T4 whereby conversion of T4 to T3 may be impaired, while that to rT3 may be enhanced. The present paper describes the relative changes in serum concentrations of T3 and rT3 during and following administration of dexamethasone to treated hypothyroid as well as untreated hyperthyroid subjects; steroids
were noted to have opposite effects on serum rT3 and T3. The data suggest that steroids may indeed effect the change in metabolism of T4 mentioned above. Materials and Methods Patients. Eleven hyperthyroid patients (4 male and 7 female) with Graves' disease, and 4 hypothyroid women receiving treatment with 0.2-0.4 mg of synthetic T4 (Synthroid) were the subjects of study. The diagnosis of Graves' disease was based on typical clinical findings including diffuse goiter and supranormal values of serum T4, T3, and thyroid radioiodine uptake. Each of the treated hypothyroid patients had received T4 for 3 months or more. Studies with dexamethasone. Dexamethasone, 2 mg orally every 6 hours for 4 doses, was given to 8 hyperthyroid patients and 4 treated hypothyroid cases. In addition, dexamethasone was given orally to 3 hyperthyroid patients in
TABLE 1. Serum concentrations of rT3, T3> and T4 before, during, and after administration of Days of study
l*t Case
Age
no.
(yr)
Sex
1
50
F
rT3* T3*
T4f 2
54
F
rT3
T3 T4
Baseline — 15min.
(AM)
54 196 12.0
2
3
PM
AM
PM
AM
PM
61 220 13.7
61 193 12.3
100 170 11.5
106 155 11.0
75 178 13.5
66 148 11.1
49 230 18.0
53 200 14.6
62 230 15.3
74 185 14.0
74 175 14.0
76 185 13.2
71 215 12.7
0
3
23
F
rT3 T3
T4
74 250 12.8
66 220 10.7
93 213 10.8
103 210 12.5
108 158 9.8
88 220 10.1
61 193 12.0
4
46
F
rT3 T3 T4
43 98 11.2
50 88 10.5
42 110 10.0
58 85 11.2
60 88 14.0
66 78 12.4
50 85 13.0
rT3
55.0 ±6.70
57.5 ± 3.70
64.5 ± 10.6
83.7 ±10.8
186 ± 26.6
162 ±27.1
87.0 ±11.9 144 ±19.2
76.3 ±4.51 165 ±30.5
62.0 ±4.49 160 ±28.3
12.3
12.2 ±0.42
Mean ± SE
T3
193 ±33.7
T4
13.5 ±1.5
182 ± 31.7 12.4 ± 1.04
12.1 ±1.17
12.3 ±0.63
12.2 ±1.08
±0.77
* ng/100 ml. f fig/100 ml.
*t Dexamethasone was started after "0" blood sample on day 1.
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913
REVERSE T, AND T, AFTER DEXAMETHASONE a dose of 2 nig every 6 hours for 5 days (20 doses). Blood was obtained before and twice daily at about 9 AM and 5 PM during and for 4-6 days following the administration of dexamethasone.
values was taken to represent the baseline value. Serum T3 and T4 values of 6 hyperthyroid cases noted here have been reported earlier (1). These are included here for the purpose of a complete report in conjunction with newer data.
Hormonal studies. Serum rT3, T3, and T4 were measured by radioimmunoassays described pre- Free rTs and T3. To examine the changes in viously (4,20,21). Antiserum against rT3 was pro- serum protein binding of rT3 after administraduced by immunization of rabbits with D,L- tion of dexamethasone, we measured the dialyzrT3-human serum albumin conjugate (4). Recent able fractions of rT3 and T3 before and at 24 studies in our laboratory have revealed that to 30 hours after beginning dexamethasone when L-iT3 and D,L-rT3 react similarly with this anti- changes in serum total rT3 and T, were clearly sorum; their radioimmunoassay dose-response evident. The dialyzable rT3 and T3 were curves were essentially identical. The values measured using modifications of equilibrium at various time periods of study were compared dialysis methods described previously for T4 to the baseline value by Student's two-tailed and T 3 (22-25). In brief, the method consisted t test for paired data. The values in the blood of addition of predialyzed radioactive rT3 and/or samples obtained immediately prior to adminis- radioactive T3 to serum diluted 1:10 (23), dialysis tration of dexamethasone were used as the base- in plastic cells and precipitation of the dialysate line value in several cases. In other patients, with magnesium chloride (22). The dialyzable in whom an additional baseline sample was fraction determined by using diluted serum and obtained 15 min earlier, the mean of the two correcting for dilution was underestimated comdexamethasone (2 mg every 6 h for 4 doses) to hypothyroid patients receiving treatment with synthetic T4
AM
6
5
4 PM
AM
PM
AM
7 PM
AM
PM
— —
— —
53 225 16.1
49 260 16.1
— —
— —
—
61 185 12.1
72 185 —
60 260 14.0
68
58
58
225 —
250
250
15.8
15.3
70 190 12.7
66 175 12.7
49 215 14.6
52 215 14.6
49 240 16.1
54 230 17.0
63 228 10.9
59 230 11.1
76 288 10.1
81 283 13.5
65 283 11.6
248 —
52 78 13.5
52 93 12.4
88
12.4
52 88 10.5
49 110 13.0
54 110 13.5
54 130 13.0
61.5 ±3.71 170 ±32.2 12.3 ±0.55
65.7 ±3.75 171 ±28.5 12.1 ±0.49
59.3 ±6.05 213 ±44.2 12.8 ±1.00
63.2 ±7.01 203 ±41.1 12.9 ±1.22
55.2 ±3.89 212 ±34.1 14.5 ±1.5
55.3 ± 1.33 182 ±36.5 15.3 ± 1.01
53.5 ±0.50 178 ± 47.5 • 14.5' ±1.55
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CHOPRA, WILLIAMS, ORGIAZZI AND SOLOMON
914
pared with the results with undiluted serum (24). Therefore, a correction factor was determined for each iodothyronine by simultaneous measurements in whole and diluted pooled serum of hospitalized patients. The correction factor was 1.79 for rT3 and 1.37 for T3. These values were applied to diluted test specimens. Results
Effect of administration of dexamethasone for one day. Serum rT3, T3, and T4 values before, during, and following one day of administration of dexamethasone in four treated hypothyroid cases are described in Table 1. Change in serum rT3 and T3 at various times of study are presented in
JCE & M • 1975 Vol 41 • No 5
Fig. 1. Serum rT3 increased and serum T3 decreased significantly following administration of dexamethasone (Fig. 1). The mean pre-dexamethasone serum rT3 was 58 ng per 100 ml; it increased to a mean peak value of 87 ng per 100 ml on day 2 (PM) (Table 1). On the other hand, serum T3 decreased from the mean baseline value of 182 ng per 100 ml to a mean minimum of 144 ng per 100 ml on day 2 (PM). The increase in rT3 was statistically significant until day 3 (AM), whereas the decrease in serum T3 was statistically significant until day 4 (AM) (Fig. 1). Serum T4 did not change appreciably during or following administration of dexamethasone (Table 1).
DEXAMETHASONE 2 mg
I
* I I REVERSE T3
LJ ID
+ 80i
HYPOTHYROID PATIENTS ON F$ WITH T 4
+ 60-
GRAVES' DISEASE PATIENTS
+ 40-
FIG. 1. Changes in serum concentration of rT3 and T3 during and after administration of dexamethasone, 2 mg every 6 h for 4 doses. Data are expressed as percent change from baseline. Actual serum levels of rT3 and T3 are presented in Tables 1 and 2.
UJ X /
LJ (I) CD
O U_ LJ
I
-20-
-40' Significantly different from baseline pm 1
am
2
pm
am
pm 3
am
pm 4
pm
am pm
DAYS OF STUDY
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REVERSE T, AND T, AFTER DEXAMETHASONE The changes in serum rT3 and T3 noted above were not due to steroid-induced alterations in serum protein binding of these iodothyronines. Thus the mean (±SE) dialyzable fractions of rT3 and T3 were 0.31 ± 0.01 and 0.35 ± 0.04%, respectively, before steroid administration. The corresponding values 24-30 h after beginning steroid administration were 0.32 ± 0.01% for rT3 and 0.36 ± 0.03% for T3. Serum rT3, T3, and T4 in 8 hyperthyroid patients are described in Table 2; the changes in rT3 and T3 compared with the baseline are noted in Fig. 1. Serum rT3 increased from a mean pre-dexamethasone value of 119 ng per 100 ml to peak mean value of 170 ng per 100 ml on day 2 (AM). On the other hand, serum T3 decreased from a mean pre-dexamethasone value of 622 ng per 100 ml to a mean value of 362 ng per 100 ml on day 2 (PM) (Table 2). The increase in serum rT3 was statistically significant from day 1 (PM) to day 3 (AM). The decrease in serum T3 was statistically significant throughout 6 days of study. The mean peak increase in rT3 of 82.8% on day 2 (PM) in hyperthyroid cases was somewhat (but not significantly) higher than the corresponding peak value of 53% in treated hypothyroid cases. The duration of the increase in serum rT3 was similar in the two groups under study (Fig. 1). The mean maximal decrease in serum T3 of 37% on day 2 (PM) in hyperthyroid cases was not significantly different from the corresponding value of 21% in treated hypothyroid cases. However, the decrease in serum T3 at each time interval from day 2 (AM) through day 6 (PM) was significantly more pronounced in patients with Graves' disease than in treated hypothyroid subjects. Serum T4 also decreased significantly in Graves' disease cases following dexamethasone administration. The mean pre-dexamethasone value was 23.5 fxg per 100 ml; it decreased to 18.4 /xg per 100 ml on day 4 (AM) (P < 0.02).
915
Effect of administration of dexamethasone for five days. Thyroid hormone levels during these studies in three Graves' disease patients are described in Table 3 and the percent of change from baseline in rT3 and T3 are presented in Fig. 2. The increase in serum rT3 was observed within a few hours after administration of dexamethasone; it was nearly maximal, about 70-75% above the baseline value, by 24-48 hours after beginning dexamethasone. High levels were maintained until about 12 hours after the last dose of dexamethasone; thereafter serum rT3 was similar to the baseline value (Fig. 2). Serum protein binding of rT3 did not change appreciably during the study. The mean dialyzable fraction of serum rT3 before, at 48 h after beginning dexamethasone, on the last day of steroid administration, and at 3 or 4 days after withdrawal of the steroids was 0.37 ± 0.03, 0.37 ± 0.02, 0.36 ± 0.03, and 0.34 ± 0.02%, respectively. These values did not differ significantly from one another. Serum T3 decreased promptly after beginning dexamethasone; it remained significantly below the baseline value as long as studied until about 72 hours after the last dose of dexamethasone. Just as in the case of rT3, the serum protein binding of T3 did not change during these studies. The mean dialyzable fraction of T3 before, at 48 h after beginning dexamethasone, on the last day of steroid administration, and at 3 or 4 days after withdrawal of the steroids was 0.56 ± 0.07, 0.55 ± 0.07, 0.55 ± 0.66, and 0.53 ± 0.05%, respectively. Serum T4 decreased considerably in 2 out of 3 patients studied (cases 1 and 3, Table 3). The maximal decrease in case 1 was 23% on day 7 (AM); it was 39% in case 3 on day 6 (AM). Case 2 did not demonstrate a consistent change in serum T4. Discussion Recent studies indicate that, in addition to T3, rT3 is another significant product
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JCE & M • 1975 Vol 4i • No 5
CHOPRA, WILLIAMS, ORGIAZZI AND SOLOMON
916
of the peripheral metabolism of T4 (4). It has been estimated that normally only about 3% of serum rT3 originates from thyroidal secretion; the rest apparently derives from peripheral mono-deiodination of T4 (26). The present studies indicate that administration of steroids results in a prompt increase in serum rT3 persisting for about 24 hours after completion of a course of steroid (Figs. 1 and 2). As serum rT3
increased, serum concentration of T3 decreased. The changes in serum rT3 and T3 were not attributable to a change in the serum binding of this iodothyronine; the absence of an appreciable change in the free fraction or serum binding of T3 (and T4) has also been observed in other studies (1,27,28). These findings are also concordant with those of other studies indicating lack of an appreciable change in the kinetics
TABLE 2. Serum concentrations of rT3, T3, and T4 before, during, and after Days of study 1*t Case no.
Age (yr)
1
18
M
rT 3 * T3*
2
24
M
3
29
4
IodoBaseline Sex thyronine -15min.
(AM)
2 PM
3
AM
PM
AM
PM
0 110 675 23.3
130 700 23.3
200 440 24.5
180 475 26.0
130 420 18.5
130 450 20.0
rT 3 T3 T4
66 480 22.5
86 460 18.0
160 290 19.0
140 195 19.5
94 260 17.0
82 300 16.0
F
rT 3 T3 T4
96 500 30.0
125 500 33.0
180 450 32.0
220 350 30.0
200 390 30.0
—
33
M
rT 3 T3 T4
86 825 23.0
105 725 24.5
170 625 23.0
170 540 26.0
140 540 23.0
110 625 20.0
5
24
F
rT 3 T3 T4
190 1100 34.0
260 1150 35.0
330 575 31.0
260 390 30.0
190 550 28.0
150 550 29.0
6
. 50
M
rT 3 T3 T4
62 235 17.0
68 260 16.0
100 160 14.0
110 175 15.5
78 140 13.0
82 125 15.5
7
39
F
rT 3 T3 T4
40 285 18.8
35 285 18.5
46 310 17.0
60 225 17.9
66 245 19.0
33 225 13.0
35 210 16.3
8
28
F
rT 3 T3 T4
96 910 19.0
110 875 20.0
135 1000 20.0
160 700 17.0
175 525 20.0
130 700 18.0
120 625 20.0
rT3
94.4 ± 16.4
119 ±22.9
170 ±28.0
125 ± 19.7
T3
622 ± 106.5
638 ± 112.3 23.4 ±2.55
433 ±69.0
165 ±21.5 362 ±51.5 23.2 ± 1.93
101 ± 14.4 412 ±76.7 19.5 ± 1.75
T«t
Mean ± SE
T4
23.5 ±2.04
22.3 ±2.32
403 ±66.9 20.1 ±2.26
*ng/100ml. t /u.g/100 ml. •*t Dexamethasone was given on day 1 after obtaining baseline blood sample.
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REVERSE T, AND T, AFTER DEXAMETHASONE of the peripheral metabolism of T4 and T3 during acute administration of steroids (29-31). These considerations, together with the finding of a decrease in serum T3 and no change in serum T4 following steroid administration to hypothyroid cases receiving exogenous T4, suggest that steroids may reduce the production of T3 from T4. Our studies, indicating an increase in serum rT3 when T3 decreases, suggest that
917
during steroid administration, some of the T4 normally metabolized to T3 may be channeled to the production of rT3. This conclusion would be in error if steroids were merely to cause a diminution in the metabolic clearance rate of rT3. However, the lack of an effect of steroid treatment on the kinetics of other iodothyronines (T4 and T3) as well as on the serum binding of rT3 does not support this possibility,
administration of dexamethasone (2 mg every 6 h for 4 doses) to Graves' disease patients
AM
PM
AM
PM
AM
PM
AM
PM
66 360
72 310
62 350
68 290
64 400
74 300 —
— — —
— — —
— —
— —
—
— —
18.0
160 275 18.2
90
775 23.0
170 700 26.0
50 120 10.0
28 225 15.3
17.0
140 225 23.0
110 725 23.0
170 725 27.0
62 155 14.0
29 265 —
19.0
105 320 24.8
94 675 20.0
170 725 29.0
62 135 14.0
21 270 13.2
82
96
82
750
675
840
19.0
100 310 23.0
100
925
28.0
170 750 27.0
68 165 16.0
29 265 18.5
80 840
16.0
18.0
92.3 ±20.3
97.0
85.1 ± 17.5
89.3 ± 16.7
458 18.4 ± 1.95
±2.00
20.0
110
17.0
± 104.2
94 260
875
18.0
± 18.1 440 ' ±96.7 20.1
19.0
28.0
100 310 22.4
120 825 26.0
135
140
150
285 27.0
900
1000
68 215
68 185
33.0
12.5
16.0
21
29 19.0
92
92
875
840
19.0 82.0 ± 13.47
19.0
474
499
536
560
± 116.1
± 122.4
± 133.54
21.4 ± 1.77
—
—
—
— —
—
—
89.0 ± 13.77
± 101.5 19.4 ±2.19
33.0
250 17.5
20.4 ±2.04
1050
32.5
22.5 ±2.5
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9.18
CHOPRA, WILLIAMS, ORGIAZZI AND SOLOMON TABLE
JCK & M • 1975 Vol 41 • No 5
3. Serum concentrations of rT3, T3) and T4 before, during, and after 5 days of Days of study 2
1
Case
Age
(yr)
Sex
Irxiothyronine
Baseline - 1 5 min.
(AM)
no. 1
20
F
rTa*
T4t
82 625 13.6
Ts T4
66 310 14.0
2
3
29
50
F
3
PM
AM
PM
AM
PM
84 580 15.0
94 560 14.0
135 410 13.0
150 345 14.0
180 375 13.6
135 395 14.0
76 305 13.2
82 310 15.0
90 215 13.2
90 215 15.0
86 225 14.0
86 215 15.0
0
M
rTa T:, T4
115 462 16.0
180 330 16.0
260 230 18.0
240 230 15.0
220 182 12.0
220 218 10.6
Mean
rT3
98 ± 11.9
119 ±30.9
162 ±50.9
160 ±43.6
162 ± 39.7
140 ± 33.0
T3
442 ± 74.3
400 + 80.2
285 ± 62.65
263 ± 41.1
261 ±58.5
276 ±59.5
± SE
T
