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Original Studies |
Departments of Radiology and Nuclear Medicine, Neuropathology (G.S.-D.) and Psychiatry (M.B.), Universitätsklinikum Benjamin Franklin, Free University of Berlin, and the Department of Medicine (K.-J.G.), Universitätsklinikum Rudolf Virchow, Humboldt University, 12200 Berlin, Germany
Address all correspondence and requests for reprints to: Dr. Andreas Baumgartner, Department of Radiological Diagnostics and Nuclear Medicine, Hindenburgdamm 30, 12200 Berlin, Germany.
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Abstract |
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Serum concentrations of 3,3'-T2 were measured in 4 groups of patients with nonthyroidal illnesses (NTI), i.e. brain injuries (n = 15), sepsis (n = 24), liver disease (n = 22), and brain tumors (n = 23). The mean serum concentration of 3,3'-T2 in 62 healthy controls was 46.6 ± 20.0 pmol/L. 3,3'-T2 levels declined significantly with increasing age. They were significantly lower in patients with brain injury (34.2 ± 19.4 pmol/L; P = 0.006), were at the upper limit of normal in patients with sepsis (57.0 ± 36.9 pmol/L; P = 0.06), and were elevated in patients with liver disease (72.6 ± 56.7 pmol/L; P = 0.04) and brain tumors (89.0 ± 40.9 pmol/L; P = 0.01). The serum levels of T3 were significantly lower than those in controls in all 4 patient groups. Serum concentrations of 3,3'-T2 were significantly enhanced in 9 patients with hyperthyroidism (85.4 ± 43.0 pmol/L; P = 0.01) and were reduced in 12 patients with hypothyroidism (14.9 ± 9.2 pmol/L; P = 0.001). In both normal brain tissue, obtained either intraoperatively or excised postmortem, and brain tumors, the concentrations of 3,3'-T2 ranged between 50–300 fmol/g. In healthy controls, 2 different forms of acute stress (sleep deprivation and delivering a lecture) significantly increased serum levels of T4 and T3, but did not affect those of 3,3'-T2 or 3,5-T2.
In conclusion, our results show that, contrary to expectation, a low T3 syndrome in NTI is not always associated with low serum concentrations of 3,3'-T2. The production of 3,3'-T2 in NTI seems to be regulated in a disease-specific manner, resulting in unchanged, reduced, or elevated hormone concentrations.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Patients with NTI may suffer from different forms of relatively severe stress, e.g. fear, fever, sleep disturbances, etc. We therefore investigated the effects of two acute stressors, i.e. sleep deprivation and delivering a lecture, on the serum concentrations of 3,3'-T2 and 3,5-T2 in healthy volunteers to study the reactivity of these hormones in response to external stimuli.
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Subjects and Methods |
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The patients and healthy controls were the same as those whose serum levels of 3,5-T2 had been previously reported (6).
The serum concentrations of 3,3'-T2 were measured in the following patients and control samples.
Patients with sepsis. Twenty-four patients admitted to the intensive care unit, either postoperatively or after trauma, and whose clinical course was complicated by sepsis were studied. Ten of these patients had peritonitis, and 14 had pneumonia. Ten were women, and 14 were men; their mean age was 56.2 ± 19.0 yr (range, 16–89 yr). The diagnosis of sepsis was established according to criteria previously published (14).
Patients with liver disease. The serum levels of the two iodothyronines were measured in 22 patients with severe liver disease before liver transplantation. Nine were women, and 13 men; their mean age was 50.4 ± 30.2 yr (range, 23–82 yr). The patients were suffering from various underlying liver diseases, such as chronic hepatitis, Morbus Wilson, hemochromatosis, and alcoholic cirrhosis.
Patients with head and/or brain injury. Fifteen patients admitted to an intensive care unit with a diagnosis of closed head injury were also studied. Six of these patients were women, and 9 were men; their mean age was 36.2 ± 33.8 yr (range, 28–44 yr). Blood samples were drawn from all patients during the first 2 days after the injury, when the subjects were still in an unconscious state. The critically ill patients admitted to the intensive care unit were treated with appropriate antibiotics and various drugs given to stabilize vital functions. When necessary, in patients with sepsis and head injuries hemodynamic stabilization was achieved by controlled volume load, dobutamine, and, where required, norepinephrine. Four patients with sepsis were also given dopamine. None of these patients was receiving glucocorticoids. Patients with known thyroid disorders or thyroid hormone supplementation were not included in the study. All patients received 30–35 cal/kg BW daily either enterally or parenterally (70% in carbohydrate form and 30% in lipid form). Amino acids (1.5 g/kg BW) were also given.
Patients with brain tumors. Twenty-three patients hospitalized for brain surgery in the Department of Neurosurgery were also investigated. Twelve were women, and 11 were men; their mean age was 50.1 ± 12.5 yr (range, 22–70 yr). Six of these patients had a glioblastoma, 5 had meningioma, 4 had astrocytoma, and 5 were scheduled for removal of brain metastases, their primary tumors being at a different site. The general condition of all of these patients was relatively good. None of them was suffering from a severe concomitant disease. Blood samples were drawn immediately before the operation, i.e. during full anesthesia. The anesthetics propofol and fentanyl and a muscle relaxant were employed.
Patients with thyroid disorders. Nine patients with hyperthyroidism (6 women and 3 men; mean age of 36.3 ± 4.5 yr; range, 28–44 yr) and 12 patients with hypothyroidism (8 women and 4 men; mean age of 46.7 ± 5.6 yr; range, 37–59 yr) were also studied before treatment for the underlying thyroid disorder was instituted.
Healthy controls. Sixty-two healthy subjects were studied for comparison. Thirty-two of them were women, and 30 were men; their mean age was 47.3 ± 18 yr (range, 22–89 yr). As an age dependence of 3,3'-T2 levels has been reported in previous studies (8, 15), we took care to include large enough percentages of all relevant age groups in the control group. Ten subjects were between 20–30 yr of age, 10 were between 30–40 yr, 9 were between 40–50 yr, 11 were between 50–60 yr, 9 were between 60–70 yr, 9 were between 70–80 yr, and 4 were over 80 yr. The subjects below 60 yr of age were employees of various departments of the Klinikum Benjamin Franklin who were personally known to the authors. Controls older than 60 yr were healthy retired volunteers who occasionally work for a drug research institute and whose good and stable state of health had been documented in the records of this institute for a period of several years. None of the controls had any apparent clinical illness at the time of the investigation or any history or current signs of thyroid disorder, or was currently taking thyroid hormones or any other medication known to affect serum concentrations of thyroid hormones, such as oral contraceptives or ß-adrenergic blockers (16, 17).
All blood samples from the patients and healthy controls were always drawn in the morning between 0700–1000 h. As blood samples were drawn from all patients routinely for diagnostic purposes, this opportunity was used to obtain 5 mL additional blood to determine thyroid hormone levels for research purposes.
Samples of normal human tissue were collected by the Department of Neurosurgery and Neuropathology of the Klinikum Benjamin Franklin, respectively. They had been excised during neurosurgical operations (n = 5) for therapeutic purposes or at autopsy (n = 5) for histopathological investigation. Samples from various regions of the brain (cortex, hippocampus, pons, and cerebellum) were obtained from donors at autopsy, which was performed between 24–96 h after death. Between death and autopsy, the bodies were stored at 4–6 C. Four of the donors were male, and one was female; their mean age was 58.4 ± 12.5 yr (range, 36–70 yr). They had died of different disorders not primarily affecting the brain, such as lymphoma, myocardial infarction, diabetes mellitus, primary pulmonary hypertension, and dilated cardiomyopathy. The effects of storage temperature and the time interval between death and autopsy on thyroid hormone concentrations were investigated in the striata of male Sprague-Dawley rats (n = 12). After decapitation, the brain regions of the controls (n = 4) were immediately frozen on dry ice and stored at -70 C until assay. The tissue from the two additional groups (each n = 4) was kept at room temperature for 4 h. Thereafter, it was stored at 4 C for 24 and 96 h, respectively, before freezing. This design was chosen to simulate postmortem events in humans.
Five samples of healthy tempo-cortical lobe tissue were obtained during temporal lobe resection in patients with temporal lobe epilepsy. Pieces of tumor tissue were obtained during surgery from the patients from whom serum samples had been collected (see above). Tissues obtained at operation were immediately frozen in liquid nitrogen and stored at -70 C until assay.
An night of sleep deprivation was performed in six healthy male subjects, all of whom were physicians working at the Klinikum Benjamin Franklin. Their mean age was 32 ± 3 yr (range, 27–37 yr). An indwelling catheter was inserted in the cubital vein in all subjects at 2000 h. Blood was drawn at 20-min intervals between 2200–0600 h. During this period the subjects were not permitted to sleep. They spent the night together watching television, reading, or playing games. All of them also spent 3 control nights of sleep in a sleep laboratory. The first 2 nights served for adaptation, and on the third night an iv catheter attached to a tube passed through a hole in the wall into the next room was placed in the forearm. Each volunteer retired to bed at 2100 h, and the lights were switched off at 2200 h. Blood samples were drawn every 20 min between 2200–0600 h. Electroencephalogram recordings were performed during the same period.
In the second stress experiment, blood samples were drawn from 10 physicians before and after delivering a lecture at a clinical conference. This type of stress has previously been shown to induce pronounced increases in serum cortisol (18). The conference took place between 1500–1700 h. Thus, four blood samples were collected: one at 1500 h and one at 1700 h on the day of the conference and two additional samples at 1500 and 1700 h, respectively, on a control day not less than 1 week later.
Hormone determinations
Reagents. Tetraiodothyroacetic acid (Tetrac),
triiodothyroacetic acid (Triac), diiodothyroacetic acid (Diac),
T4, T3, rT3,
3,5-diiodo-L-thyronine (3,5-T2),
3,3'-diiodo-L-thyronine (3,3'-T2),
3',5'-diiodo-L-thyronine (3',5'-T2), and
thyronine of highest available purity as well as 3,3'-T2
conjugate to BSA for antibody production were purchased from Henning
Berlin (Berlin, Germany).
Mercury-[(O-carboxyphenyl)thio]ethyl sodium salt
(merthiolate), L-cysteine, and BSA were purchased from
Sigma Chemical Co. (St. Louis, MO). The tracer
3-bromo-[5-125I]thyronine
(3-Br-[5-125I]T1) was provided by R. Thoma,
Formula GmbH (Berlin, Germany). Phosphate buffer (0.04 mol/L; pH 8.0)
containing 243 mg/L merthiolate and 2 g/L BSA served as the
experimental buffer. The iodoamino acids were dissolved in 0.1 mol/L
sodium hydroxide and diluted to final assay concentrations using this
buffer. Either the 3-Br-[5-125I]T1 tracer or
the 3,3'-T2 tracer was dissolved in experimental buffer
containing 100 mg/L L-cysteine. The stop solution formed by
the experimental buffer, 30% (wt/vol) polyethylene glycol and 1.3
mg/mL bovine 
-globulin was pipetted (1 mL/tube) to precipitate the
antibody-bound radioactivity in either the 3,3'-T2 or the
3,5-T2 RIA.
Synthesis of 3,3'-T2 tracer. Labeled
3,3'-T2 of maximum specific radioactivity was obtained
by radioiodination of 3-iodo-L-thyronine with chloramine-T
(19). 3-Iodo-L-thyronine was dissolved in 0.01 mol/L sodium
hydroxide, chloramine-T (Merck, Darmstadt, Germany), and sodium
disulfite in 0.1 mol/L phosphate buffer, pH 7.0. For labeling, 10-µL
volumes of the following reagents were pipetted into a Microflex vial
(Radiochemical Center, Amersham, Aylesbury, UK) containing 40 µL 0.5
mol/L phosphate buffer (pH 7.5), 37 megabecquerels (1 mCi)
125I (
0.5 nmol iodine; Radiochemical Center, Amersham),
2 nmol 3-iodo-L-thyronine, and 0.2 µmol chloramine-T.
After an incubation period of 30 s, 1.5 µmol sodium disulfite
were added. The reaction mixture was injected onto the high performance
liquid chromatography (HPLC) column. HPLC separation of
3,3'-T2 was carried out using a 5-µm Eurospher
100-C18, 4 x 250-mm column (Knauer, Berlin, Germany).
The column was equilibrated with a gradient of 100% methanol and 0.02
mol/L ammonium acetate buffer, pH 4.0 (volumes, 55 and 45 mL), at a
flow rate of 1 mL/min. After running the gradient, the column was
washed with 100% methanol at a flow rate of 1 mL/min for 30 min to
remove contaminants that elute from the column. 3'-T1 and
3,3'-T2 eluted from the column after 9 and 22 min,
respectively. The fraction eluting from the HPLC column corresponding
to the 3,3'-[125I]T2 peak was collected and
eluted with 100% methanol containing 0.25% concentrated ammonia. This
solution was stored at -20 C. The radiochemical purity was tested by
thin layer chromatography (silica gel 60 F254 plates, Merck) in ethyl
acetate-methanol-3 mol/L ammonia (volumes, 50, 20, and 10 mL). The Rf
values were 0.15 and 0.30 for 3,3'-T2 and
3'-T1, respectively.
Preparation of 3,3'-T2-binding antiserum. Antiserum to 3,3'-T2 was produced in three rabbits immunized by serial injections of a conjugate of 3,3'-T2 to BSA in complete Freund’s adjuvant as described previously (20). All immunized rabbits produced antisera satisfactory for RIA of 3,3'-T2. The antiserum selected for experiments was obtained after three injections of the immunogen, 8 weeks after starting immunization. It was used in a final dilution of 1:150,000, which bound about 40% of tracer in an incubation volume of 250 µL.
Preparation of test samples. For the serum
3,3'-T2 or 3,5-T2 measurements, serum was
extracted with 2 vol dehydrated alcohol, evaporated to dryness, and
taken up in the experimental buffer. The tissue concentrations of
3,3'-T2 were determined after extraction of the tissue
samples, as previously described (21) with some modifications. In
brief, tissue samples were homogenized using a solution containing
methanol (100%) and 1 mmol/L 6-n-propyl-2-thiouracil (PTU),
extracted twice in the homogenization solution, and purified through
Bio-Rad AG 1 x 2 resin columns (Bio-Rad Laboratories, Richmond,
CA). The iodothyronines were eluted with 70% acetic acid, evaporated
to dryness for approximately 2 h at room temperature by using a
speed vacuum pump (Virtis Co., New York, NY) incorporating a
refrigerating system (-20 C), and taken up into the experimental
buffer. Both 3,3'-T2 and 3,5-T2 appeared to be
relatively stable during evaporation of the serum/tissue extracts (the
recoveries of known concentrations of 3,3'-T2 and
3,5-T2 were 96 ± 5.6% and 93 ± 4.7%,
respectively). Extracts from either 200 µL original serum or
approximately 100 mg tissue were processed individually and assayed
together within the same run. Each sample was determined in triplicate.
The results were corrected on the basis of individual recovery data
obtained after the addition of tracer (1000 cpm/tube) during the
initial extraction process. This amount of tracer did not affect the
RIA measurements. The extraction procedure yielded mean recoveries of
82.1 ± 3.4% (range, 73.6–88.1%) and 85.3 ± 3.8% (range,
77.2–94.1%) for 3,5-T2 and 3,3'-T2,
respectively.
RIA procedure for 3,3'-T2. The RIA
of 3,3'-T2 in serum and extracted tissue was carried
out in 10 x 55-mm plastic tubes, adding various reagents as
follows: 1) experimental buffer to give a final volume of 250
µL/tube, 2) 50 µL 3,3'-T2 standard at concentrations
ranging from 0.49–60 fmol/tube (for the serum measurements, standards
were diluted in experimental buffer containing the same volume of
ethanol-extracted hormone-free serum as the unknown samples), and 3)
100 µL tracer solution containing around 6000 cpm
3,3'-T2. After 24-h incubation at room temperature, the
antibody-bound iodothyronine portion was precipitated by adding 1 mL
polyethylene glycol stop solution, prepared by adding to the
experimental buffer 30% (wt/vol) polyethylene glycol and 2.3 mg/L
bovine -globulin, and centrifuged. The supernatant was discarded,
and precipitated bound radioactivity was counted. The RIA procedure for
3,5-T2 was performed as previously described (6). To ensure
that thawing the serum samples twice had no effect on the serum
concentrations of 3,3'-T2, three different samples of serum
from healthy controls were thawed and refrozen five times. The
concentrations of 3,3'-T2 were measured each time after
thawing. The results showed that repeated thawing had no effect on the
serum hormone concentrations.
In all patients the serum concentrations of T4, free T4, T3, rT3, and TSH were measured as previously described (6, 22, 23). For each assay, hormone determinations were performed on the serum samples drawn from the patient groups together with those from some of the healthy controls.
Data analysis. The data are presented as the mean ± SD, and P < 0.05 was considered significant. The mean ± 2 SD were regarded as within the normal range. Linear regression analysis was conducted to evaluate the effects of age and sex on 3,3'-T2 concentrations in the healthy subjects. Comparison of hormone concentrations of the patients and controls was performed using the Mann-Whitney U test. For comparison of hormone concentrations in the two stress experiments, we applied the Wilcoxon rank test.
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Results |
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Figure 1
represents the standard
curve showing the displacement of the 3,3'-T2 tracer from
the specific antibody to 3,3'-T2 effected by increasing
concentrations of nonradioactive 3,3'-T2. The statistics
reveal significant inhibition of
3,3'-[125I]-T2 binding after the addition of
3,3'-T2 concentrations as low as 0.3 fmol/tube. This
sensitivity threshold allowed detection of 1.8 fmol/g and 1.5 pmol/L
3,3'-T2 in the tissue and serum, respectively.
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The inter- and intraassay coefficients of variation (CVs) for tissue samples were determined in more than five tests. The intraassay CVs ranged between 6.8–7.2, and the interassay CVs ranged between 7.4–8.6. The measurements were performed using two different samples, both of which caused 50% inhibition of 3,3'-T2 antibody binding.
Table 1 shows the proportions of various
iodothyronines and iodotyrosines, tested in four or five different
concentrations, that bound to the specific antibody to
3,3'-T2. Cross-reaction of the antibody to
3,3'-T2 with the majority of the compounds tested was
minimal. In particular, only 0.04% of the Triac reacted with the
3,3'-T2 antibody.
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shows the effects of
several drugs used for the treatment of intensive care patients on the
binding of 3,3'-[125I]T2 to its specific
antibody. Two of the 12 drugs tested showed no detectable effects. The
highest cross-reactivity was measured for fentanyl (2 x
10-5). The cross-reactivities of all other drugs were
between 1–5 orders of magnitude lower.
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Serum concentrations of 3,3'-T2 in patients and controls
The mean serum concentration of 3,3'-T2 for the group of healthy controls (n = 62) was 46.6 ± 20.0 pmol/L. Linear regression analysis conducted to investigate the effects of age and gender on the variable "hormone" revealed a significant age effect (t = -3.661; P = 0.006). Thus, the 3,3'-T2 concentrations declined significantly with increasing age. No effect of sex was noted (t = 0.715; P = 0.48). The four groups of patients with NTI differed considerably with respect to age (see Materials and Methods). We, therefore, established a specific age- and sex-matched control group for each patient group.
Figure 2 shows the full results for the
serum concentrations of 3,3'-T2 in the controls and
different patient groups. The serum levels of 3,3'-T2 were
significantly enhanced in patients with hyperthyroidism
(P = 0.01) and were subnormal in those with
hypothyroidism (P = 0.001). In the group of patients
with NTI, serum levels of 3,3'-T2 were lower than those in
the controls in patients with brain injury (P = 0.006),
were normal in patients with sepsis (P = 0.06), and
were elevated in patients with liver disease (P = 0.04)
and brain tumors (P = 0.01). The normal range of
3,3'-T2 was defined as the mean ± 2 SD.
Although the serum levels of 3,3'-T2 in the patients with
brain injury were significantly reduced, the values of all but 2
patients were still within the normal range. In contrast, 9 of the 24
patients with sepsis had 3,3'-T2 concentrations above the
normal range, although their mean levels of 3,3'-T2 did not
differ significantly from those measured in the corresponding control
group. Six of the 22 patients with liver disease and 12 of the 23
patients with brain tumors had elevated serum levels of
3,3'-T2.
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The results of the stress experiments are presented in Tables 3 and 4.
For the sleep deprivation experiment we calculated the mean values for
each hormone measured in all blood samples between midnight and
0600 h and compared these values with those obtained during the
night of sleep, using the Wilcoxon rank test. From Table 3 it can be
seen that sleep deprivation induced a highly significant increase in
the serum concentrations of T4, T3, and TSH,
but remained without effect on those of 3,5-T2 and
3,3'-T2.
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shows that delivering a lecture induced significant
increases in the serum levels of T4 (at 1500 h) and
T3 (at both 1500 and 1700 h). However, no significant
effects were observed on 3,5-T2 or 3,3'-T2. The
increases in TSH concentrations at 1500 h on the day of the
lecture failed to reach statistical significance (P =
0.1; Table 4). However, TSH levels were significantly higher at
1500 h, before the lecture, than after it, at 1700 h
(P = 0.01). No such difference occurred on the control
day. The concentrations of cortisol were also measured to better
evaluate the severity of the stress effects. They were significantly
elevated at both measuring times (Table 4). Tissue concentrations of 3,3'-T2 in patients and controls
Concentrations of 3,3'-T2 in tissue from
different parts of the brain obtained from five donors at autopsy and
in samples obtained from the temporal and occipital cortex during
neurosurgery are shown in Fig. 3A.
3,3'-T2 was detectable in all tissue samples; the
concentrations ranged between 50–300 fmol/g. The concentrations of
3,3'-T2 in different brain tumors are shown in Fig. 3B.
They ranged between 15–350 fmol/g. The highest concentrations were
found in glioblastomas (281 ± 61 fmol/g), and the lowest in
astrocytomas (20 ± 6 fmol/g). The tissue levels of
T4, T3 and 3,5-T2 in these samples
have been reported previously (6). The results of the experiments
conducted to evaluate the effects of postmortem delay on iodothyronine
concentrations are presented in Fig. 4.
This figure shows that storing the brain samples at 4 C for 24 h
led to a fall in tissue concentrations of hormones of between 11–27%
(T4, -11%; T3, -16%; 3,3'-T2,
-27%; 3,5-T2, -15%). The respective decreases after a
storage period of 96 h at 4 C before freezing induced a 43%
reduction in T4 levels, a 28% fall in T3
concentrations, a 50% fall in 3,3'-T2, and a 29% fall in
3,5-T2. These data imply that the 3,3'-T2
levels measured in the different regions of the adult human brain at
autopsy and presented in Fig. 3 are probably 30–50% too low. This is
consistent with the fact that the concentrations of 3,3'-T2
measured in the tissue samples obtained intraoperatively (Cx in Fig. 3a) were indeed approximately 30% higher than those determined in
tissue obtained postmortem.
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Discussion |
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Whereas reduced serum levels of 3,3'-T2 may simply result from a decrease in the availability of T3, the mechanisms leading to a rise in 3,3'-T2 production are presently unclear. 3,3'-T2 may be produced from T3 by inner ring deiodination or from rT3 by outer ring deiodination. The activity of type I 5'-deiodinase is said to be inhibited in NTI (1, 2, 3), which should result in lower, rather than higher, production of 3,3'-T2 from both rT3 and T3. However, an enhanced availability of rT3 as substrate could nevertheless contribute to an increase in the production of 3,3'-T2. To our knowledge there is as yet no experimental evidence of inhibition of the outer ring type II 5'-deiodinase (2, 3). Furthermore, inner ring deiodination of T3 may be catalyzed by different enzymes, e.g. type I 5'-deiodinase and type III 5-deiodinase, whose characteristics seem to vary from tissue to tissue (24). As far as we are aware, nothing definitive is known about the activities of these enzymes in the tissues of patients with NTI. The possibility that the specific inner ring deiodinase enzyme in diseased tissue is enhanced can therefore not be excluded at this point. Moreover, deiodination of T3 is facilitated by sulfation (25). Serum concentrations of T3 sulfate are indeed enhanced in patients with NTI (4, 5). On the other hand, desulfation may occur in human and rat tissues (26). Hypothetically, the elevated levels of 3,3'-T2 may derive from T3 sulfate via deiodination and desulfation. Finally, the possibility that specific changes in the metabolism or clearance rate of 3,3'-T2 in different NTIs may contribute to the changes in its serum concentrations cannot currently be excluded.
Another question that remains unanswered at present is whether the changes in the concentrations of 3,3'-T2 have some physiological significance. Several researchers have now reported various effects of 3,5-T2 on cellular respiration and other parameters (27, 28, 29, 30, 31, 32, 33), but in most cases rather high doses of hormone were needed to achieve this effect. A few studies have also reported effects of 3,3'-T2 on rat liver cytochrome oxidate activity and respiratory rate (29, 30). However, possible metabolic effects of 3,3'-T2 remain to be confirmed by in vivo experiments, and it is thus not yet possible to draw any conclusions regarding the physiological significance of the altered 3,3'-T2 concentrations in NTI.
NTIs are associated with different forms of stress, such as pain or fear. To evaluate whether stress effects are involved in the changes in diiodothyronines in NTI, we measured 3,5-T2 and 3,3'-T2 after two different forms of acute stress. Both during sleep deprivation and while delivering a lecture, the serum concentrations of T3 and T4 rose, but those of 3,5-T2 and 3,3'-T2 remained unchanged. Rises in the serum levels of T3 and T4 and also of TSH during sleep deprivation have frequently been reported (34, 35). Although TSH concentrations on the stress day were not significantly elevated as compared with those on the control day, the fact that the TSH levels were significantly higher before the lecture than they were afterward militates in favor of an involvement of TSH in the rises in serum concentrations of T4 and T3 during this kind of stress. As these increases in T3 and T4 occur in parallel, they are most likely due to enhanced secretion from the thyroid gland. Our results, therefore, suggest that 3,5-T2 and 3,3'-T2 are not directly secreted by the thyroid after the experience of an acute stressful stimulus and are not sensitive to acute psychological stress of up to 6-h duration.
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Footnotes |
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Received September 24, 1997.
Revised February 25, 1998.
Revised May 12, 1998.
Accepted May 20, 1998.
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