Circadian variation of thyrotropin in childhood

We evaluated the circadian variation of serum TSH in 96 normal children, aged 5-18 yr. Blood samples were obtained hourly for 24 h, and serum TSH was measured using an immunoradiometric assay with a sensitivity of 0.2 mU/L and an intraassay coefficient of variation of 4.9%. The nadir serum TSH value, defined by the three consecutive hourly TSH concentrations having the lowest mean, occurred between 1000 and 1900 h, while the peak TSH value, defined by the three consecutive hourly TSH concentrations having the greatest mean, occurred between 2100 and 0600 h. The mean nadir serum TSH was 1.6 +/- 0.1 mU/L, and the mean peak TSH was 3.7 +/- 0.2 mU/L. The mean nocturnal TSH surge (percent increase in TSH from nadir to peak) was 144% (95% confidence limits, 50-300%) and did not correlate with serum T4, free T4, or T3 concentrations. Seventy-six children were given TRH (7 micrograms/kg). The mean peak serum TSH after TRH was 16.0 +/- 1.1 mU/L (95% confidence limits, 9.0-42.0 mU/L), and it occurred by 30 min after TRH administration in 92% of the children. The absolute peak nocturnal serum TSH and peak post-TRH serum TSH values correlated significantly (r = 0.62; P less than 0.001), while age, gender, and pubertal status did not correlate with either the nocturnal TSH surge or the TSH response to TRH. We conclude that normal children have a circadian variation of serum TSH characterized by a nocturnal TSH surge, and that the peak of serum TSH, which occurs at night, correlates with the peak serum TSH level after TRH administration.     

Starvation induces a partial failure of triiodothyronie to inhibit the thyrotropin response to thyrotropin-releasing hormone

During starvation the response of TSH to TRH decreases in many subjects. This could be due to an increased sensitivity to TSH secretion to circulating thyroid hormones. To study this hypothesis, 13 subjects were starved twice for 2-day periods. After both starvation periods, a standard TRH test (200 micrograms TRH, iv) was performed; during 1 starvation period 15 micrograms T3 were injected iv 24 h before the TRH test. The TRH tests were also performed while on normal nourishment, once without pretreatment and once 24 h after the iv injection of 15 micrograms T3. The spontaneous decrease of the TSH response to TRH was seen in 10 of 13 subjects. In these 10 subjects it decreased from 18.0 +/- 1.9 to 9.7 +/- 1.2 microU/ml (mean +/- SEM; P < 0.001). The additional inhibition of the TRH test with T3 was small compared with the one observed under normal conditions. In starvation, T3 decreased the maximal TSH response from 9.7 +/- 1.2 to 8.4 +/- 1 microU/ml (P = NS), while during the control period the maximal TSH response fell from 18.0 +/- 1.9 to 11.4 +/- 1.3 microU/ml (P < 0.001). These data indicate a diminished effectiveness of T3 in inhibiting TSH secretion and are consistent with the hypothesis of a more generalized resistance of target organs to T3 during starvation in man.     

Physiological regulation of circadian and pulsatile thyrotropin secretion in normal man and woman

The circadian and pulsatile TSH secretion profiles were investigated in 5 females at the time of menstruation and 21 healthy males by sampling blood every 10 min for 24 h. Computer-assisted analysis, i.e. the Cluster and Desade programs, revealed means of 9.9 +/- 1.7 (Cluster) and 11.4 +/- 3.9 (Desade) pulses/24 h. More than 50% of the TSH pulses were detected between 2000-0400 h. Male and female subjects showed no significant difference in the basal mean and pulsatile secretion of TSH or in the TSH response to TRH (200 micrograms). Repetition of the TSH secretion analysis in 4 healthy subjects after 1, 2, and 6 months (2 subjects) revealed a significantly better cross-correlation within than between individuals (P less than 0.0001). We modulate the circadian TSH secretion pattern by acute sleep withdrawal or prolonged sleep after a night of sleep withdrawal in six healthy male volunteers. Sleep withdrawal augmented the nightly TSH secretion (mean serum TSH, 2.1 +/- 1.3 mU/L; mean TSH in sleep, 1.3 +/- 0.5 mU/L; P less than 0.05), whereas sleep after sleep withdrawal almost completely suppressed the circadian variation (mean TSH, 1.1 +/- 0.7 mU/L; P less than 0.01). This modulation is due to a significant decrease in pulse amplitude, but not to an alteration in the frequency or temporal distribution of TSH pulses.     

Effects of three-day oral cholecystography on serum iodothyronines and TSH concentrations: comparison of the effects among some cholecystographic agents and the effects of iopanoic acid on the pituitary-thyroid axis

The effects of repeated doses of oral cholecystographic agents on serum thyroxine (T4), 3,3',5-triiodothyronine (T3), 3,3',5'-triiodothyronine (rT3) and thyrotrophin (TSH) concentrations were studied in 37 euthyroid male subjects. Iobenzamic acid, tyropanoic acid, iopanoic acid, and ipodate sodium, in a dosage of 3 g for 3 days, respectively, induced a significant decrease in serum T3 and an increase in rT3 within 24 h after the initial dose, followed by an increase in TSH and a slight increase in T4. The extent of the changes in rT3 varied between the agents, ipodate causing the greatest change, but without any relation to the changes in T3 or T4. Responses of serum T4, T3, rT3 and TSH concentrations to exogenous thyrotrophin-releasing hormone (TRH) and bovine TSH were also studied before and after 3-day doses of iopanoic acid. In 11 subjects given iopanoic acid, the response to TSH to TRH (500 micrograms, iv) was increased but the T3 response was unchanged. A dose of TSH (10 U.S.P. units, im) caused a significant increase in serum T3 and a decrease in TSH concentrations in 5 subjects both before and after cholecystography. It is thus suggested that in euthyroid subjects given multiple doses of oral cholecystographic agents, (1) the primary and consistent events are the reciprocal changes of serum T3 and RT3, although the extent of the changes is not coordinately reciprocal; (2) the responsiveness of the pituitary thyrotrophs and thyroid to TRH is preserved; and (3) the high basal and TRH-induced TSH in the serum may be ascribed to the decrease in the serum T3 concentration.     

A new case of familial partial generalized resistance to thyroid hormones: study of 3,5,3'-triiodothyronine (T3) binding to lymphocyte and skin fibroblast nuclei and in vivo conversion of thyroxine to T3

A clinically euthyroid 30-yr-old man with high serum levels of both total (T4, 14.5 micrograms/dl; T3, 272 ng/dl) and free (FT4, 33 pg/ml; FT3, 9.7 pg/ml) thyroid hormones and inappropriately normal TSH levels, both basally and after TRH stimulation, is described. Peripheral indices of thyroid hormone action and the patient's clinical status were not modified by the prolonged administration of supraphysiological doses of both T4 (up to 900 micrograms/day) and T3 (up to 80 micrograms/day), which decreased but did not completely abolish the TSH response to TRH. However, the TSH response to TRH was normally blunted by dexamethasone administration, which also reduced serum T4 and T3 levels to normal. T3 binding to nuclei of mononuclear leukocytes and cultured skin fibroblasts was normal. The overall pattern demonstrates that the patient was affected by partial peripheral resistance to thyroid hormone action. Study of the patient's family revealed the same hormone pattern in the patient's father, suggesting an autosomal dominant mode of inheritance. An in vivo study performed after the iv injection of tracer doses of [125I]T4 and [131I]T3, demonstrated increased production rates (PR) of both T4 [PR, 113.0 micrograms/day X m2; normal subjects, 55.4 +/- 12.3 (mean +/- SD); n = 13] and T3 (PR, 41.1 micrograms/day X m2; normal subjects, 16.3 +/- 2.7). In vivo conversion of T4 to T3 was also evaluated in the patient; a nearly normal T4 to T3 conversion factor was found (0.3108 vs. 0.2576 +/- 0.0422 in normal subjects). In four hyperthyroid patients, the T4 to T3 conversion factors were similar (0.2932 +/- 0.0600), while the PRs of T4 and T3 were increased (PR of T4, 308.6 +/- 85.6; PR of T3, 110.3 +/- 35.0 micrograms/day X m2) compared to those in the normal subjects.     

Pulsatile secretion of thyrotropin during fasting: a decrease of thyrotropin pulse amplitude

The effect of fasting on circadian and pulsatile TSH secretion was investigated in eight healthy subjects (four men and four women in the follicular phase). Each subject was studied twice, once during 24 h with normal food intake and once during the last 24 h of a 60-h fast. Blood was sampled every 10 min during 24 h for measurement of TSH by a sensitive immunoradiometric assay. Fasting induced a decrease in plasma T3 [1.73 +/- 0.06 vs. 1.36 +/- 0.04 nmol/L; P less than 0.01 (mean +/- SE), control period vs. fasting] and thyroglobulin (52 +/- 8 vs. 35 +/- 7 pmol/L; P less than 0.001) and an increase in plasma rT3 (0.30 +/- 0.06 vs. 0.44 +/- 0.09 nmol/L; P less than 0.02). Plasma T4, thyroid hormone binding index, and free T4 were not statistically different in both periods. The mean plasma 24-h TSH concentration was lower during fasting than in the control period (2.0 +/- 0.3 vs. 1.0 +/- 0.2 mU/L; P less than 0.005). This was associated with a decrease in mean TSH pulse amplitude during fasting (Desade program: 0.6 +/- 0.1 vs. 0.3 +/- 0.1 mU/L; P less than 0.01; Cluster program: 0.5 +/- 0.1 vs. 0.2 +/- 0.1 mU/L; P less than 0.05), whereas TSH pulse frequency during fasting was unchanged (Desade program: 8.4 +/- 0.9 vs. 9.8 +/- 0.8 pulses/24 h; Cluster program: 9.5 +/- 0.5 vs. 7.9 +/- 0.9 pulses/24 h). There was a highly significant correlation between the mean 24-h TSH concentration and the mean TSH pulse amplitude during both the control period and fasting. Although the decrease in TSH concentration during fasting was evident over 24 h, fasting especially decreased the absolute (1.3 +/- 0.3 vs. 0.4 +/- 0.1 mU/L, P less than 0.02) and the relative (101 +/- 18% vs. 40 +/- 14%; P less than 0.02) nocturnal TSH surge (mean TSH 0000-0400 h vs. mean TSH 1500-1900 h). The decreased nocturnal TSH surge during fasting was associated with a significantly decreased TSH pulse amplitude, but with an unaltered number of TSH pulses between 2000-0400 h. In conclusion, fasting decreases 24-h TSH secretion and the nocturnal TSH surge in the absence of a change in plasma T4 concentration. This is associated with a decreased TSH pulse amplitude, whereas TSH pulse frequency remains unchanged.     

Different prolactin, thyrotropin, and thyroxine responses after prolonged intermittent or continuous infusions of thyrotropin-releasing hormone in rhesus monkeys

Serum PRL, TSH, and T4 secretion during prolonged continuous or intermittent iv infusions of TRH were studied in 14 adult ovariectomized rhesus monkeys (Macaca mulatta). For 9 days, TRH was administered intermittently at 0.33 or 3.3 micrograms/min for 6 of every 60 min and continuously at 0.33 micrograms/min. With both modes, the PRL levels and responsiveness to TRH simulation peaked on day 1 and then fell to levels that were still higher than the preinfusion values; levels for the intermittently treated group on days 3-9 were 2- to 4-fold above prestimulation levels and significantly (P less than 0.01) higher than levels for the continuously treated group. Elevated basal levels and PRL responses to TRH pulses were similar during the 0.33 and 3.3 micrograms/min pulses of the 9-day treatment period. For both TRH modes, TSH levels were elevated significantly (P less than 0.001) on day 1 [this increase was higher with continuous infusion (P less than 0.001)] and then fell to preinfusion levels by day 3. Serum T4 also increased during both continuous and intermittent TRH stimulations. However, serum T4 levels were significantly lower (P less than 0.01) after intermittent TRH (both 0.33 and 3.3 micrograms/min) than after continuous (0.33 micrograms) TRH (8 +/- 1.1 and 10 +/- 1.8 micrograms T4/dl vs. 18 +/- 3.1 micrograms, respectively). These PRL and T4 responses were replicated when the mode of administering 0.33 micrograms/min TRH was reversed after 9 days. An iv bolus of TRH (20 micrograms) after 9 days of continuous or intermittent TRH infusion caused significant release of PRL and TSH, an indication that neither mode of administration resulted in pituitary depletion of releasable hormone. We have concluded that intermittent TRH is more effective in elevating serum PRL, and continuous TRH is more effective in raising TSH and T4 levels. Thus, the manner of TRH secretion by the hypothalamus may determine its relative physiological importance in the stimulation of lactotropes and thyrotropes.     

Hypothalamic regulation of pulsatile thyrotopin secretion.

To determine the mechanism underlying pulsatile TSH secretion, 24-h serum TSH levels were measured in three groups of five healthy volunteers by sampling blood every 10 min. The influence of an 8-h infusion of dopamine (200 mg), somatostatin (500 micrograms), or nifedipine (5 mg) on the pulsatile release of TSH was tested using a cross-over design. The amount of TSH released per pulse was significantly lowered by these drugs, resulting in significantly decreased mean basal TSH serum levels. However, pulses of TSH were still detectable at all times. The TSH response to TRH (200 micrograms) tested in separate experiments was significantly lowered after 3 h of nifedipine infusion compared to the saline control value. Nifedipine treatment did not alter basal, pulsatile, or TRH-stimulated PRL secretion. The persistence of TSH pulses under dopamine and somatostatin treatment and the blunted TSH responses to nifedipine infusion support the hypothesis that pulsatile TSH secretion is under the control of hypothalamic TRH. The 24-h TSH secretion pattern achieved under stimulation with exogenous TRH in two patients with hypothalamic destruction through surgical removal of a craniopharyngioma provided further circumstantial evidence for this assumption. No TSH pulses and low basal TSH secretion were observed under basal conditions (1700-2400 h), whereas subsequent repetitive TRH challenge (25 micrograms/2 h to 50 micrograms/1 h) led to a pulsatile release of TSH with fusion of TSH pulses, resulting in a TSH secretion pattern strikingly similar to the circadian variation. These data suggest that pulsatile and circadian TSH secretions are predominantly controlled by TRH.     

Thyroglobulin release after graded endogenous thyrotropin stimulation in man: lack of correlation with thyroid hormone response

The serum thyroglobulin (Tg), T3, and T4 responses to graded endogenous TSH stimulation were examined in 30 normal subjects for up to 96 h after TRH administration. Increasing TSH rises were elicited by TRH administration as follows: 1) 500 micrograms iv as a single bolus in 10 subjects [mean peak serum TSH, 14.3 +/- 1.8 (SE) microU/ml]; 2) 1000 micrograms infused iv in 2 h in 10 subjects (mean peak TSH, 25.5 +/- 2.6 microU/ml); 3) 40 mg orally in 10 subjects (mean peak TSH, 27.5 +/- 3.0 microU/ml, with a delayed and more prolonged rise). Nine subjects received saline and were used as controls. A significant serum T3 and T4 rise followed the TSH increase in all subjects, and the mean peak value was always reached 4 h after TRH. In contrast, a significant serum Tg increase occurred only in 3, 6, and 9 subjects after 500 micrograms, 1000 micrograms, and 40 mg TRH, respectively. In addition, the time of the Tg peak and its duration was extremely variable but it was always delayed in respect to serum T3 and T4 peaks, occurring 6 to 72 h after TRH administration. No correlation was found between serum Tg and T3 or T4 increases after TRH in any of the three groups. These studies indicate that a significant Tg release in man usually occurs only after intense and prolonged TSH stimulation of the thyroid. In addition, the Tg increase is delayed in respect to the thyroid hormone increase and it is not correlated with them.     

Basal oxygen uptake: a new technique for an old test

To assess the metabolic effects of T4 and T3, we measured serum total T4 (TT4), free T4 (FT4), total T3 (TT3), TSH, and basal oxygen uptake (VO2) in eight normal subjects in the basal state and after treatment with L-T3 (T3) and sodium ipodate for 2 weeks. T3 treatment resulted in a rise of serum TT3 from a baseline of 137 +/- 16 (+/- SE) to a peak of 239 +/- 15 ng/dl. Serum TT4 declined from 8.14 +/- 0.56 to 6.08 +/- 0.43 micrograms/dl, FT4 from 1.59 +/- 0.13 to 1.03 +/- 0.05 ng/dl, and TSH from 1.74 +/- 0.24 to 0.56 +/- 0.16 microU/ml. Basal VO2 increased from 2.66 +/- 0.11 to 3.15 +/- 0.09 ml/kg X min. Ipodate, on the other hand, led to a lower serum TT3 concentration (102 +/- 21 ng/dl), higher serum TT4 and FT4 (9.59 +/- 0.5 micrograms/dl and 1.91 +/- 0.13 ng/dl, respectively), and elevated TSH (3.64 +/- 0.14 microU/ml). Basal VO2 was reduced to 2.44 +/- 0.06 ml/kg X min. Linear regression analysis revealed an excellent positive correlation between serum TT3 and basal VO2 (n = 25; r = 0.747; P less than 0.001) and a significant negative correlation between serum TT3 and TSH (n = 26; r = -0.526; P less than 0.01). Serum TT4 and FT4 correlated negatively with VO2 and positively with serum TSH. The higher T4 level during ipodate treatment was associated with lower VO2 and higher TSH, and vice versa when T4 was suppressed while receiving T3. When ipodate was given concomitantly with T3 to five subjects, only the effects of T3, characterized by increased VO2 and decreased TSH, were evident. These data indicate that both basal VO2 and serum TSH are sensitive indices of thyroid hormone activities. The latter gives only the directional change (hyper- or hypothyroidism), while the former more accurately quantitates the magnitude of the derangement. Moreover, it appears that in man, T3, and not T4, is the primary hormone that regulates thermogenesis and TSH secretion.     

Differing thyrotropin responses to increased serum triiodothyronine concentrations produced by overfeeding and by triiodothyronine administration

The effects of overfeeding and triiodothyronine (T3) administration on basal serum thyrotropin (TRH) concentrations and the TSH response to thyrotropin-releasing hormone (TRH) was studied in normal subjects. Eight normal volunteers were fed their usual diet plus 2,000 kcal carbohydrate daily for 7 days. Their mean serum T3 concentrations increased from 102 +/- 6 (SEM) ng/dl to 126 +/- 10 ng/dl; there were no changes in serum thyroxine (T4) and basal serum TSh concentrations or the TSh response to TRH. Five of these subjects were fed their usual diet plus 10 micrograms T3 for 3 days and 20 micrograms T3 for 4 days divided doses. Their mean serum T3 concentrations increased from 104 +/- 6 ng/dl to 140 +/- 8 ng/dl. Mean serum T4 and basal serum TSH concentrations declined and serum TSH responses to TRH were significantly reduced. In both instances serum T3 concentrations remained within the normal range. These results indicate that increases in serum T3 concentrations of similar magnitude induced by augmented extrathyroidal T3 production and T3 administration have different effects on thyrotroph function.     

Reduced thyroid function after thyrotropin stimulation.

The course of serum T4 and T3 return to baseline after TSH stimulation was studied in two groups at six normal subjects over 28 days after im bovine TSH (b TSH; 0.15 U/kg). In the first group of six subjects, serum bTSH rose from undetectable levels to a mean peak of 5.6 +/- 0.5 ng/ml (mean +/- SE) at 2 h, and fell below detectable levels by 24 h with a t1/2 of 7 +/- 1 h. T4 rose to a peak 59 +/- 10% above basal levels within 24 h, returned to basal levels on day 7, then dropped below basal levels on days 9-24, with a nadir of -16 +/- 4% on day 14. Free T4 paralleled T4 levels. T3 rose to a peak 104 +/- 28% above basal at 24 h, then fell faster than T4, reaching basal levels by day 4. During the period of low T4, T3 was at or below basal levels. Human TSH (h TSH) concentration dropped when T4 and T3 rose, but did not rise above basal levels when T4 and T3 fell below basal levels. Neither a T3 elevation nor an increased percentage of free T4 was present during the time of reduced T4 levels. The same pattern of thyroidal response was seen in the second group of six subjects. In this second group, hTSH response to repeated TRH challenge was studied. During the period of reduced T4 and T3, hTSH response to TRH was diminished. On day 28, T4, T3, hTSH, and hTSH response to TRH returned to basal levels. We conclude that the brief elevation of T4 and T3 after bTSH stimulation exerts a suppressive effect on the pituitary which extends beyond the period of elevated thyroid hormone levels, and that delay in pituitary recovery is the mechanism of the decreased thyroid function after acute bTSH stimulation.     

Decreased thyroidal response to thyrotropin in type II diabetes mellitus

The responses to TRH and bovine TSH (bTSH) were compared in 19 men with uncontrolled type II diabetes mellitus and eight healthy control subjects. Baseline serum TSH, T3 and T4 were similar in both groups and the rise of serum TSH, T3 and T4 following the intravenous (IV) administration of TRH (500 micrograms) was not significantly different. Diabetic subjects showed a blunted response to the subcutaneous (sc) administration of bTSH (5 U) when their maximal serum T3 and T4 values were compared with controls (T4, 9.4 +/- 0.3 v 12.3 +/- 1.1 micrograms/dL, P less than .005; T3, 185 +/- 9 v 233 +/- 17 ng/dL, P less than .025; diabetic v control). When the response to bTSH was examined in seven patients after 4 to 5 days of strict glycemic control, the maximal T3 response was found to increase in six, and the maximal T4 response in five. These data show that the thyroidal secretory response to large doses of TSH is decreased in uncontrolled diabetes mellitus and that strict glycemic control frequently improves the response.     

Thyrotropin suppression by 3,5-dimethyl-3'-isopropyl-L-thyronine in man.

The thyromimetic activity of 3,5-dimethyl-3'-isopropyl-L-thyronine (DIMIT), a nonhalogenated thyroid analog, was studied in adult men using suppression of TRH-induced TSH release to assess this activity. In nine men, aged 30-58 yr, the TSH increment after 500 microgram TRH iv was compared to the TSH response to TRH 24 h after oral administration of 1 mg DIMIT. Eight euthyroid subjects had normal baseline TSH levels of 1.5 +/- 0.2 (SE) microunit/ml that fell significantly to 0.7 +/- 0.2 microunit/ml 24 h after DIMIT (P less than 0.005). Their TSH increments after TRH fell from 15.3 +/- 2.8 to 6.7 +/- 1.6 microunit/ml 24 h after DIMIT (P less than 0.001). One subject with probable Hashimoto's thyroditis had an elevated TSH of 18 microunit/ml, with an exaggerated TSH response to TRH of 72 microunit/ml. His basal TSH fell to 7.6 and his TSH increment fell to 14.3 microunit/ml 24 h after DIMIT. The suppression of TSH was relatively prolonged. In four subjects, the TSH response to TRH was still blunted from 5-12 days after DIMIT. In one subject, the TSH increment returned to normal 15 days after DIMIT. DIMIT had no significant effect on PRL secretion. There was no evidence of toxicity in patients receiving DIMIT. DIMIT has effective thyromimetic activity in man, as shown by its significant and prolonged suppression of TSH secretion.     

Effects of repetitive administration of thyrotropin-releasing hormone at short intervals in acromegaly

We investigated the pattern of GH secretion in response to repetitive TRH administration in patients with active acromegaly and in normal subjects. Nine acromegalic patients and 10 normal subjects received three doses of 200 micrograms of TRH iv at 90-min intervals. There was a marked serum GH rise in acromegalic patients after each TRH dose (net incremental area under the curve [nAUC]: first dose = 4448 +/- 1635 micrograms.min.l-1; second dose = 3647 +/- 1645 micrograms.min.l-1; third dose = 4497 +/- 2416 micrograms.min.l-1; NS), though individual GH responses were very variable. In normal subjects TRH did not elicit GH secretion even after repeated stimulation. Each TRH administration stimulated PRL release in acromegalic patients, though the nAUC of PRL was significantly higher after the first (1260 +/- 249 micrograms.min.l-1) than after the second and the third TRH administration (478 +/- 195 and 615 +/- 117 micrograms.min.l-1, respectively; P less than 0.01). In normal subjects too, PRL secretion was lower after repeated stimulation (first dose = 1712 +/- 438 micrograms.min.l-1; second dose = 797 +/- 177 micrograms.min.l-1; third dose = 903 +/- 229 micrograms.min.l-1 P less than 0.01), though different kinetics of PRL secretion were evident, when compared with acromegalic patients. TSH secretion, assessed in only 4 patients, was stimulated after each TRH dose, though a minimal but significant reduction of nAUC of TSH after repeated TRH challenge occurred. Both T3 and T4 increased steadily in the 4 patients. The same pattern of TSH, T3, and T4 secretion occurred in normal subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

AUGMENTATION OF PITUITARY THYROTROPHIN RESPONSE TO THYROTROPHIN RELEASING HORMONE DURING SUBPHYSIOLOGICAL TRI-IODOTHYROININE THERAPY IN HYPOTHYROIDISM

Five hypothyroid patients are reported with increased pituitary TSH response to TRH during administration of T3. In one patient treated with intravenous T3, 50 micrograms daily for 10 days, the peak serum TSH and total pituitary TSH reserve after TRH increased coincident with increases in serum T3 and T4 levels and a decrease in the basal TSH concentration. In four patients treated with oral T3, the peak serum TSH and total pituitary TSH reserve after TRH increased during administration of subphysiological doses of T3. Peak serum T3 levels occurred 4 h after ingestion and increased progressively with increasing T3 doses. Serum TSH levels decreased modestly with the nadir at 4 h after T3 ingestion and then returned to basal levels at 24 h. Augmentation of TSH responses to TRH occurred simultaneously with decreases in serum cholesterol, as well as increases in the pituitary prolactin response to TRH, and increase in the GH and cortisol response to insulin induced hypoglycaemia where these responses could be studied. These data demonstrated a positive effect of subphysiological T3 therapy in these hypothyroid patients on the TSH response to TRH as well as increases in the responses of other pituitary hormones to stimulation.     

The influence of long-term low dose thyrotropin-releasing hormone infusions on serum thyrotropin and prolactin concentrations in man

The purpose of the present study was to evaluate in man the relative thyrotroph and lactotroph response to a 48-h low dose constant TRH infusion. Before, during, and after the 75 ng/min TRH constant infusion, serum samples were obtained every 4 h in six euthyroid ambulating male subjects for measurements of TSH, PRL, T4, and T3. The TSH response, employing a specific and sensitive human TSH RIA, demonstrated a significant rise from the mean basal pre-TRH value of 2.35 +/- 0.64 microU/ml (+/- SEM) to 3.68 +/- 0.80 (P < 0.005) during the TRH infusion; this value fell below the basal level to 1.79 +/- 0.47 (P < 0.05) post infusion. Serum T4 values were increased above basal both during (P < 0.025) and after (P < 0.025) TRH infusion, whereas serum T3 values were not significantly changed throughout the entire study period. The daily TSH nocturnal surge was augmented in both absolute and relative terms during the first 24 h or the TRH infusion, unchanged during the second 24 h of infusion, and inhibited during the first postinfusion day. Other than a minimal increase in serum PRL during the first few hours of the infusion, no significant alteration in the mean basal concentration or circadian pattern of PRL secretion was evident during or after the low dose TRH infusion. These findings would indicate that 1) near-physiological stimulation of the pituitary with TRH produces a greater stimulation of TSH release than of PRL release and 2) the factor or factors producing the circadian TSH surge may not be mediated through fluctuations in endogenous TRH.     

Different rates of thyrotropin suppression after total body scan in patients with thyroid cancer: effect of an optimal saturation regimen with thyroxine or triiodothyronine

The rate of TSH suppression in patients with differentiated thyroid cancer, when therapy is re-started after total body scan, was investigated adopting an optimal saturation regimen, either with T4 or with T3. The first group of 6 patients received T4 as follows: from day 1 to 7 = 22, 11, 6, 4, 3.5, 3.2, 3.2 micrograms/day/kg body weight (b w) and continued with 3.2; the second group of 8 patients received T3 as follows: 2.4, 1.8, 1.4, 1.2, 1.1, 1.1 micrograms/day/kg BW and continued with 1.1. At time 0, TSH levels were high in all patients (range 80-180 microU/ml); T3 and T4 levels were below the limit of detectability. After the beginning of the therapy, the decrease of TSH levels and the inhibition of TSH response to TRH occurred faster in patients taking T3 than in patients taking T4. In the former, at day 7, mean basal TSH level was 1.9 +/- 0.5 microU/ml and 30 min after 200 micrograms TRH iv mean TSH level was 9.9 +/- 4.4 microU/ml; at day 10 they were 1.4 +/- 0.5 and 2.7 +/- 0.8 microU/ml respectively. In the latter, at day 7, mean basal TSH level was 4.6 +/- 3.9 microU/ml and 30 min after TRH mean TSH level was 42.2 +/- 34.2 microU/ml. Only at day 20 they were 0.8 +/- 0.2 and 1.2 +/- 0.9 microU/ml respectively. In patients taking T3 by saturation regimen, serum levels of T3 rose rapidly to supranormal values (at day 3, mean serum T3 level was 297 +/- 62 ng/100 ml), reached a peak at day 5 (340 +/- 62 ng/100 ml) and decreased thereafter, always remaining however above normal limits.(ABSTRACT TRUNCATED AT 250 WORDS)     

Arginine stimulates growth hormone secretion by suppressing endogenous somatostatin secretion

To determine how arginine (Arg) stimulates GH secretion, we investigated its interaction with GHRH in vivo and in vitro. Six normal men were studied on four occasions: 1) Arg-TRH, 30 g arginine were administered in 500 mL saline in 30 min, followed by an injection of 200 micrograms TRH; 2) GHRH-Arg-TRH, 100 micrograms GHRH-(1-44) were given iv as a bolus immediately before the Arg infusion, followed by 200 micrograms TRH, iv; 3) GHRH test, 100 micrograms GHRH were given as an iv bolus; and 4) TRH test, 200 micrograms TRH were given iv as a bolus dose. Blood samples were collected at 15-min intervals for 30 min before and 120 min after the start of each infusion. Anterior pituitary cells from rats were coincubated with Arg (3, 6, 15, 30, and 60 mg/mL) and GHRH (0.05, 1, 5, and 10 nmol/L) for a period of 3 h. Rat GH was measured in the medium. After Arg-TRH the mean serum GH concentration increased significantly from 0.6 to 23.3 +/- 7.3 (+/- SE) micrograms/L at 60 min. TRH increased serum TSH and PRL significantly (maximum TSH, 11.1 +/- 1.8 mU/L; maximum PRL, 74.6 +/- 8.4 micrograms/L). After GHRH-Arg-TRH, the maximal serum GH level was significantly higher (72.7 +/- 13.4 micrograms/L) than that after Arg-TRH alone, whereas serum TSH and PRL increased to comparable levels (TSH, 10.2 +/- 3.0 mU/L; PRL, 64.4 +/- 13.6 micrograms/L). GHRH alone increased serum GH to 44.9 +/- 9.8 micrograms/L, significantly less than when GHRH, Arg, and TRH were given. TRH alone increased serum TSH to 6.6 +/- 0.6 mU/L, significantly less than the TSH response to Arg-TRH. The PRL increase after TRH only also was lower (47.2 +/- 6.8 micrograms/L) than the PRL response after Arg-TRH. In vitro Arg had no effect on basal and GHRH-stimulated GH secretion. Our results indicate that Arg administered with GHRH led to higher serum GH levels than did a maximally stimulatory dose of GHRH or Arg alone. The serum TSH response to Arg-TRH also was greater than that to TRH alone. We conclude that the stimulatory effects of Arg are mediated by suppression of endogenous somatostatin secretion.     

TRH test as an index of suppression compared with the thyroid radioiodine uptake in euthyroid goitrous patients treated with thyroxine.

To determine an index of adequate suppression of pituitary TSH secretion in euthyroid goitrous patients treated with sodium levothyroxine (T4), TSH responses to 500 micrograms TRH given iv were compared with thyroid 24-h radioiodine uptakes during therapy with T4 in 12 euthyroid goitrous patients. The patients received sequentially 100, 150, 200, 250, and 300 micrograms T4 with the doses increased at 4-6 week intervals. The mean dose of T4 that reduced the peak TSH response to TSH to the lower limit of normal (TSH = 5 microU/ml) was 130 micrograms; the mean T4 dose that suppressed the TSH response to one-half the lower limit of normal (TSH = 2.5 microU/ml) was 165 micrograms. The mean T4 dose that nearly obliterated the TSH response was 200 micrograms; this degree of suppression occurred with doses of 100-300 micrograms T4 in individual patients. Suppression of thyroid uptake correlated closely with suppression of the TSH response to TRH. The goiter diminished in size significantly in 6 of the 12 patients during the 6 months of observation adn did not enlarge in any patient. The data indicate that suppression of the TSH response to TRH is a convenient technique to assess the adequacy of suppressive therapy of goiter.