Pharmacokinetics of 3,5,3'-triiodothyroacetic acid and its effects on serum TSH levels

1989 ◽  
Vol 121 (5) ◽  
pp. 651-658 ◽  
Author(s):  
C. Menegay ◽  
C. Juge ◽  
A. G. Burger
Keyword(s):  
Time Course ◽  
Kinetic Studies ◽  
Volume Of Distribution ◽  
Potency Ratio ◽  
Control Serum ◽  
Tsh Secretion ◽  
Dose Response Effect ◽  
Acid Administration ◽  
Serum Tsh ◽  
Tsh Levels

Abstract. 3,5,3'-triiodothyroacetic acid is an effective inhibitor of TSH secretion in central hyperthyroidism. Serum 3,5,3'-triiodothyroacetic acid was measured with an RIA preceded by immunoprecipitation. An anti-3,5,3'-triiodothyroacetic acid antibody was obtained in rabbits, using 3,5,3'-triiodothyroacetic acid coupled to hemocyanin and diazotized benzidine as antigen (crossreactivity with T4, T3, tetraiodothyroacetic acid was 0.2, 1.1, and 5%, respectively). Endogenous 3,5,3'-triiodothyroacetic acid levels could not be detected in 14 euthyroid, 10 hypothyroid and 10 hyperthyroid sera (detection limit 0.055 nmol/l). Kinetic studies were performed in 6 healthy male subjects who received an oral and an iv dose of 1050 μg of 3,5,3'-triiodothyroacetic acid. The serum measurements were analysed according to a non-compartmental method. The half-life of 3,5,3'-triiodothyroacetic acid was 6 h 22 min ± 29 min, the volume of distribution was 114 ± 9 1/70 kg, and the plasma clearance rate was 298 ± 14 1 · (70 kg)−1 · day−1. Highest 3,5,3'-triiodothyroacetic acid levels were measured after 40 min (for T3 2–3 h) and its absorption was 67±6%. The nadir of the mean TSH levels was 0.72 ± 0.09 mU/l 6 h after 3,5,3'-triiodothyroacetic acid administration. However, the time course of serum TSH response did not differ from that obtained after administration of 37.5 μg T3. The dose-response effect for TSH was studied using oral doses of 350, 700, 1400 and 2800 μg 3,5,3'-triiodothyroacetic acid. TSH was measured 9 h after 3,5,3'-triiodothyroacetic acid administration at 17.00 h, and compared with control serum TSH levels obtained at 08.00 h (1.53 ± 0.11) and at 17.00 h the day before the test (1.87 ± 0.11). They were 1.05 ± 0.15 (N = 9, mean ± sem), 0.83 ± 0.08 (N = 24), 0.66 ± 0.06 (N = 24), and 0.43 ± 0.02 mU/l (N = 6), respectively. In conclusion, TSH inhibition by 3,5,3'-triiodothyroacetic acid is similar to T3, with a potency ratio of 1 to 18.

scholarly journals Inhibition of pituitary type 2 deiodinase by reverse triiodothyronine does not alter thyroxine-induced inhibition of thyrotropin secretion in hypothyroid rats

2005 ◽  
Vol 153 (3) ◽  
pp. 429-434 ◽  
Author(s):  
P Cettour-Rose ◽  
T J Visser ◽  
A G Burger ◽  
F Rohner-Jeanrenaud
Keyword(s):  
Specific Inhibitor ◽  
Adult Rats ◽  
Reverse T3 ◽  
Brown Adipose ◽  
Tsh Secretion ◽  
Serum T3 ◽  
Serum T4 ◽  
Serum Tsh ◽  
Tsh Levels

Objectives: Intrapituitary triiodothyronine (T3) production plays a pivotal role in the control of TSH secretion. Its production is increased in the presence of decreased serum thyroxine (T4) concentrations and the enzyme responsible, deiodinase type 2 (D2), is highest in hypothyroidism. In order to document the role of this enzyme in adult rats we developed an experimental model that inhibited this enzyme using the specific inhibitor, reverse T3 (rT3). Methods: Hypothyroidism was induced with propylthiouracil (PTU; 0.025 g/l in drinking water) which in addition blocked deiodinase type 1 (D1) activity, responsible for the rapid clearance of rT3 in vivo. During the last 7 days of the experiment, the hypothyroid rats were injected (s.c.) for 4 days with 0.4 or 0.8 nmol T4 per 100 g body weight (bw) per day. For the last 3 days, the same amount of T4 was infused via s.c. minipumps. In additional groups, 25 nmol rT3/100 g bw per day were added to the 3-day infusion of T4. Results: Infusion of 0.4 nmol T4/100 g bw per day did not affect the high serum TSH levels, 0.8 nmol T4/100 g bw per day decreased them to 57% of the hypothyroid values. The infusions of rT3 inhibited D2 activity in all organs where it was measured: the pituitary, brain cortex and brown adipose tissue (BAT). In the pituitary, the activity was 27%, to less than 15% of the activity in hypothyroidism. Despite that, serum TSH levels did not increase, serum T4 concentrations did not change and the changes in serum T3 were minimal. Conclusions: We conclude that in partly hypothyroid rats, a 3-day inhibition of D2 activity, without concomitant change in serum T4 and minimal changes in serum T3 levels, is not able to upregulate TSH secretion and we postulate that this may be a reflection of absent or only minimal changes in circulating T3 concentrations.

RESPONSE OF NORMAL, HYPOTHYROID AND HYPOTHALAMO-PITUITARY INSUFFICIENT CHILDREN TO SYNTHETIC THYROTROPHIN-RELEASING HORMONE

1971 ◽  
Vol 51 (3) ◽  
pp. 483-488 ◽  
Author(s):  
G. MILHAUD ◽  
P. RIVAILLE ◽  
M. S. MOUKHTAR ◽  
E. BINET ◽  
J. C. JOB
Keyword(s):  
Time Course ◽  
Solid Phase ◽  
Thyroid Stimulating Hormone ◽  
Normal Children ◽  
Thyrotrophin Releasing Hormone ◽  
Releasing Hormone ◽  
Tsh Secretion ◽  
Course Changes ◽  
Serum Tsh ◽  
Tsh Deficiency

SUMMARY Thyrotrophin-releasing hormone (TRH) was synthesized by the solid phase technique, administered to 13 children, and the time-course changes in the serum level of thyroid-stimulating hormone (TSH) assessed. In eight normal children, peak levels of TSH occurred 20 min after the injection, and circulating TSH remained significantly raised for 60 min. In three hypothyroid children, the increase in serum TSH was much greater than in normal children, suggesting the existence of large pituitary TSH stores. In two hypopituitary children with TSH deficiency, TSH reserves seemed normal. One of these patients had a craniopharyngioma; after operation, the increase in serum TSH was reduced. These results show that assay of serum TSH after administration of synthetic TRH provides a test which distinguishes pituitary from hypothalamic defects affecting TSH secretion.

Rapid adaptations of serum thyrotrophin, triiodothyronine and reverse triiodothyronine levels to short-term starvation and refeeding

1984 ◽  
Vol 105 (2) ◽  
pp. 194-199 ◽  
Author(s):  
Jean-Noel Hugues ◽  
Albert G. Burger ◽  
A. Eugene Pekary ◽  
Jerome M. Hershman
Keyword(s):  
Serum Cortisol ◽  
Starvation Period ◽  
Short Term ◽  
Mean Values ◽  
Fed State ◽  
Tsh Secretion ◽  
The Mean ◽  
Serum Tsh ◽  
Tsh Levels

Abstract. Nutrition influences thyroid function at the level of TSH secretion, at the level of monodeiodination, and possibly elsewhere. In order to study the effect of starvation on TSH secretion, 8 healthy male volunteers fasted for 30 h and were then refed with 800 kcal. Refeeding was performed at 19.00 h and blood was sampled at 20 min intervals until midnight. Control experiments were performed in the same subjects both when they were normally fed and when the starvation period was prolonged a further 5 h until midnight. Starvation decreased serum TSH levels to below 1 mU/l, and without refeeding the nocturnal peak of the TSH nycthemeral rhythm was abolished. With refeeding serum TSH tended to increase towards midnight and was significantly higher than during starvation. However, the serum TSH levels remained significantly below those at the same time of the day in the absence of a preceding starvation period. Serum T3 levels were significantly lower than in the fed state. The mean values were 1.84 ± 0.03 vs 2.30 ± 0.06 nmol/l (120 ±2 vs 150 ± 4 ng/100 ml, mean ± sem P < 0.01). Refeeding did not result in a measurable change in serum T3 concentration (1.80 ± 0.05 nmol/l; 120 ± 3 ng/100 ml, mean ± sem, n.s.). The contrary was true for rT3 levels which increased in starvation and tended to fall with refeeding, but this decrease was not significant. As glucocorticoids have been implicated in the control of monodeiodination and TSH secretion, serum cortisol levels were also measured. They did not differ during the 3 experimental periods. The results show that short-term starvation and refeeding may be a valuable tool for studying in vivo control of TSH secretion. The results show that short-term starvation and refeeding may be a valuable tool for studying in vivo control of TSH secretion.

Deficient pulsatile thyrotropin secretion in the low-thyroid-hormone state of severe non-thyroidal illness

1994 ◽  
Vol 130 (2) ◽  
pp. 132-136 ◽  
Author(s):  
Nicola Custro ◽  
Vincenza Scafidi ◽  
Salvatore Gallo ◽  
Alberto Notarbartolo
Keyword(s):  
Thyroid Hormone ◽  
Healthy Subjects ◽  
Normal Subjects ◽  
Healthy Individuals ◽  
Circadian Variations ◽  
Tsh Secretion ◽  
Thyroid Hormone Levels ◽  
Rhythmic Change ◽  
Serum Tsh ◽  
Tsh Levels

Custro N, Scafidi V, Gallo S, Notarbartolo A. Deficient pulsatile thyrotropin secretion in the low-thyroid-hormone state of severe non-thyroidal illness. Eur J Endocrinol 1994;130:132–6. ISSN 0804–4643. Twenty-four-hour thyrotropin (TSH) profiles in eight severely ill patients were compared with those of six healthy subjects. The profiles were assessed using the cosinor method to evaluate circadian variations and using the Pulsar algorithm to analyze episodic secretion. In the normal subjects, the typical periodicity of TSH secretion showed a mean level in the rhythm (mesor) of 2.03 mU/l, The amplitude (half the extent of rhythmic change in the cycle) was 0.58 mU/l; the acrophase (the delay from midnight (0 degrees) of the highest level in the rhythm) was −9.9 degrees. In contrast, severely ill patients showed only slight and anticipated elevations of serum TSH levels (mesor 0.93 mU/l, amplitude 0.22 mU/l, acrophase +82.4 degrees). Moreover, whereas the episodic TSH secretion in healthy individuals consisted of 5–8 pulses/24 h, mainly clustered around midnight, only one pulse of reduced amplitude was detected in two of the eight severely ill patients and no pulses in the other six. Since earlier studies have indicated that the loss of TSH pulsatility is associated with the relative insensitivity of the thyrotrophs to low thyroid hormone levels and our analytical procedures have demonstrated that 24 h pulsatile pattern of TSH closely overlapped with baseline TSH secretion, it seems reasonable to assume that low-thyroid-hormone state, deficient pulsatile TSH secretion and altered nyctohemeral TSH periodicity do not coincide by chance, but that there is a causal relationship between such abnormalities in severely ill patients. Nicola Custro, Cattedra di Patologia Medica, Via del Vespro, n.141, 90127 Palermo, Italy

NEUROTRANSMITTER CONTROL OF THYROTROPHIN SECRETION IN HYPOTHYROID RATS

1978 ◽  
Vol 89 (1) ◽  
pp. 100-107 ◽  
Author(s):  
P. T. Männistö ◽  
T. Ranta
Keyword(s):  
Dopaminergic System ◽  
Tap Water ◽  
Male Rats ◽  
Noradrenergic System ◽  
High Dose ◽  
Tsh Secretion ◽  
Pre Treatment ◽  
Open Question ◽  
Serum Tsh ◽  
Tsh Levels

ABSTRACT The effect of drugs modifying dopaminergic, noradrenergic and serotonergic systems on the serum TSH levels was studied in the male rats made hypothyroid by giving 10 mg/l of propylthiouracil in tap water for 4 days. Apomorphine (2.5 mg/kg, given once −30 min before sacrifice; or four times −120, 90, 60 and 30 min before sacrifice), bromocryptine (10 and 20 mg/kg, 2 h before sacrifice) and piribedil (50 and 100 mg/kg, 4 h) decreased the serum TSH concentrations. The effect of a single dose of apomorphine (2.5 mg/kg, 30 min before sacrifice) was partially reversed by a pimozide pre-treatment (2.5 mg/kg, 2 h). Clonidine (1 mg/kg but not 0.01 or 0.1 mg/kg, 2 h before sacrifice) further elevated the high TSH levels whereas α-methyl-p-tyrosine (300 mg/kg, 2 h), phenoxybenzamine (50 mg/kg, 2 h) and diethyldithiocarbamate (300 mg/kg, 2 h) significantly decreased TSH secretion. The effect of clonidine (1 mg/kg, 2 h) was partially antagonized by phenoxybenzamine (20 mg/kg, 2 h). A high dose of 5-HTP (300 mg/kg, 2 h) increased serum TSH concentrations whereas p-chlorophenylalanine (100 mg/kg, 2 h) decreased it. When both drugs were given together, the serum TSH levels did not change. L-tryptophan (100–300 mg/kg, 2 h) uniformly decreased the serum TSH concentrations in all experiments. It is concluded that in the hypothyroid rats, the secretion of TSH is inhibited by dopaminergic system, and stimulated by noradrenergic system. The effect of 5-HT pathways remained an open question.

Erratum to “Time course observation of thyroid proliferative lesions and serum TSH levels in rats treated with thiourea after DHPN initiation”

1995 ◽  
Vol 88 (1) ◽  
pp. 123
Author(s):  
Takeo Shimo ◽  
Kunitoshi Mitsumori ◽  
Hiroshi Onodera ◽  
Kazuo Yasuhara ◽  
Masakazu Takahashi ◽  
...  
Keyword(s):  
Time Course ◽  
Serum Tsh ◽  
Tsh Levels

AUGMENTED SECRETION OF TSH IN RESPONSE TO TRH AFTER PRE-TREATMENT WITH DEXAMETHASONE FOR SIX DAYS IN RATS

1976 ◽  
Vol 82 (3) ◽  
pp. 710-714
Author(s):  
Tapio Ranta
Keyword(s):  
Acth Secretion ◽  
Short Term ◽  
Trh Stimulation ◽  
Tsh Secretion ◽  
Pre Treatment ◽  
Dose Levels ◽  
Serum Tsh ◽  
Tsh Levels ◽  
Stimulation Of ◽  
Intact Rats

ABSTRACT Serum TSH and corticosterone concentrations were measured in rats given TRH or exposed to short-term cold, as well as in intact rats, after pretreatment with dexamethasone for six days at two different dose levels (25 and 250 μg/100 g body weight). Both doses increased the secretion of TSH in response to TRH whereas cold-induced TSH secretion was not modified by pre-treatment with dexamethasone. In intact rats serum TSH levels did not differ significantly from controls. In all experiments the steroid blocked ACTH secretion. It was also found that administration of TRH produced a rise in serum corticosterone concentrations. Our results support the view that dexamethasone given for six days facilitates TRH stimulation of the pituitary whilst simultaneously inhibiting the secretion of TRH in response to cold.

DUAL ACTION OF ADRENERGIC SYSTEM ON THE REGULATION OF THYROTROPHIN SECRETION IN THE MALE RAT

1979 ◽  
Vol 90 (2) ◽  
pp. 249-258 ◽  
Author(s):  
Pekka Männistö ◽  
Tapio Ranta ◽  
Jouko Tuomisto
Keyword(s):  
Cold Exposure ◽  
Male Rats ◽  
Male Rat ◽  
Adrenergic System ◽  
Inhibitory Function ◽  
Adrenergic Activity ◽  
Tsh Secretion ◽  
Dual Action ◽  
Serum Tsh ◽  
Tsh Levels

ABSTRACT The effect of graded doses of drugs modifying adrenergic activity on basal and cold-stimulated TSH secretion was studied in male rats, ±-Methyl-p-tyrosine (±MPT) (16 h before 30 min cold-exposure), phenoxybenzamine (1 h), Ca-fusarate (1 h) and diethyldithiocarbamate (DDC) (1 and 18 h) dose-dependently depressed the cold-stimulated TSH secretion. The effect of reserpine (24 h) was not significant. Clonidine (1 h), dihydroxyphenylserine (DOPS) (1 h), noradrenaline (NA) (1 h), and l-Dopa (1 h) were also effective in decreasing serum TSH levels, but dopamine (DA) (ad 2 mg/kg, 1 h) had no effect. Basal TSH levels were also decreased by various doses of clonidine, DOPS and NA, given ip 1 h before sacrifice. Clonidine (1 mg/kg), NA (1 mg/kg), DA (2 mg/kg), ±MPT (300 mg/kg), phenoxybenzamine (2 or 20 mg/kg), Ca-fusarate (50 mg/kg) or l-Dopa (200 mg/kg) did not modify the TRH-induced TSH response. These results cannot be explained by assuming only a stimulatory function for the adrenergic system on the secretion of TSH in the rat. The site of the possible inhibitory function of noradrenaline in the control of TSH cannot be deduced from these results, but various possibilities are discussed.

INFLUENCE OF PROPYLTHIOURACIL AND THYROXINE ON SYNTHESIS AND SECRETION OF THYROID STIMULATING HORMONE IN THE HYPOTHYROID RAT

1964 ◽  
Vol 46 (1) ◽  
pp. 111-123 ◽  
Author(s):  
John L. Bakke ◽  
Nancy Lawrence
Keyword(s):  
Control Level ◽  
Thyroid Stimulating Hormone ◽  
Synthesis Rate ◽  
Initial Size ◽  
Parallel Increase ◽  
Tsh Secretion ◽  
One Year ◽  
Serum Tsh ◽  
Tsh Levels ◽  
Stimulation Of

ABSTRACT Propylthiouracil (PTU) administration to rats produced a progressive and parallel increase in the serum TSH concentration and the thyroid weight over a one year period, but the pituitary TSH content followed a biphasic curve declining markedly for 4 weeks, returning to the control level in 10 weeks and then continuing to rise until a level 5 times the control was achieved after 32 weeks. Either physiologic replacement doses or toxic doses of thyroxine (DL-T4) caused depression of serum TSH levels, significant as early as one hour after administration, followed by an increased pituitary TSH content to as much as 8 times the starting level after 10-60 hours. Thus, T4 did not appear to directly inhibit TSH synthesis during this interval. The reaction appeared to be independent of the duration of prior PTU administration or the initial size and TSH potency of the pituitary gland or the dose of T4 between 2.5 μg/100 g in one day and 40 μg/100 g daily for 4 days. PTU was not essential to this reaction because it also occurred in radiothyroidectomized rats which never received PTU. This rise in pituitary TSH during the period when TSH secretion was suppressed indicated a net pituitary TSH synthesis of as much as 61 mU/h. These values were compatible with those obtained by indirect calculations and consistent with the temporary persistence of the pre-existing TSH synthesis rate although the possibility of the stimulation of TSH synthesis by the T4 was not excluded.

A STUDY OF THE MECHANISMS INVOLVED IN THE PRODUCTION OF IODINE-DEFICIENCY GOITER

1965 ◽  
Vol 49 (4) ◽  
pp. 610-628 ◽  
Author(s):  
Hugo Studer ◽  
Monte A. Greer
Keyword(s):  
Iodine Deficiency ◽  
Elevated Serum ◽  
Extensive Study ◽  
The Body ◽  
Total Evidence ◽  
High Iodine ◽  
Tsh Secretion ◽  
Serum Tsh ◽  
Tsh Levels ◽  
Made In

ABSTRACT An extensive study of the temporal sequence of changes in thyroid function after initiation of a low iodine regimen has been made in rats. Variables measured include: thyroid weight, 131I uptake, monoiodotyrosine/diiodotyrosine (MIT/DIT) and triiodothyronine/thyroxine (T3/T4) ratios, iodide clearance, and 127I content. Also measured were protein-bound iodine (PBI), inorganic iodide and thyrotrophin (TSH) levels in the serum. Significant thyroid hypertrophy was produced during the first week and before there was a fall in serum PBI. Temporally related to the appearance of goiter were a rise in 131I uptake, MIT/DIT ratio and iodide clearance and a fall in thyroidal 127I concentration. In contrast, a fall in total thyroidal 127I appeared later and was closely correlated with a decline in serum PBI concentration and a rise in the thyroidal T3/T4 ratio. Manipulations such as hypophysectomy, injections of iodide, thyroxine or TSH, and refeeding a high iodine diet gave results consistent with the view that changes produced by iodine deficiency involve both autonomous and TSH-dependent thyroidal mechanisms. Although elevated serum TSH levels could not be demonstrated until after the first week of the iodine-deficient regimen, the total evidence of these studies permits the conclusion that increased TSH secretion is the most important factor in producing the thyroidal response to iodine deficiency. It is shown that homeostatic mechanisms allow maintenance of a normal level of circulating thyroid hormone in an iodine-deficient state until the body iodine pool becomes too severely depleted to supply adequate iodide substrate to the thyroid. The changes observed closely resemble those found in human iodine-deficient goiters. Although the large goiters produced after several weeks of an iodine-deficient regimen were hyperplastic, they could readily be converted to typical colloid goiters by feeding a high iodine diet for a few days.

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