FREE THYROID HORMONE LEVELS AND TSH RESPONSE TO TRH IN PATIENTS WITH AUTONOMOUS THYROID ADENOMATA AND NORMAL T3 AND T4

Free thyroid hormone levels together with basal and TRH stimulated TSH levels, have been determined in 50 patients with autonomous thyroid adenomata, who had normal serum total T3 and T4 values. Similar measurements were made in 33 healthy subjects. FT3 and FT4 plasma levels were significantly higher (P less than 0.01 and P less than 0.05 respectively), and basal and TRH stimulated TSH were significantly lower (P less than 0.05 and P less than 0.001 respectively) in the patients than in the controls. The TSH response to TRH was decreased in spite of normal free thyroid hormones in 25 patients and in a further ten both the delta TSH after TRH and the free fractions were normal. Eighteen patients were studied over periods from 4 37 months by repeating thyroid hormone levels and TRH tests. In six of them a change of these parameters toward toxicity was observed. The data obtained in the longitudinal study indicate that the values of free thyroid hormones and the result of the TRH test obtained by a single determination may represent different steps in the evolution of autonomous thyroid adenomata rather than a distinct pathophysiological condition.     

Prolactin and TSH response to TRH and metoclopramide before and after l-thyroxine therapy in subclinical hypothyroidism

The effects of the dopamine (DA) receptor antagonist metoclopramide on the plasma thyroid stimulating hormone (TSH) and prolactin (PRL) levels were studied in 8 patients with subclinical hypothyroidism (defined as absence of clinical signs of hypothyroidism with normal thyroid hormone levels, normal or slightly increased basal plasma TSH levels and increased and long-lasting TSH response to TRH) before and after l-thyroxine replacement therapy. Metoclopramide induced a significant (p less than 0.01) TSH release in the subclinical hypothyroid patients. Two weeks after l-thyroxine replacement therapy (50 micrograms/day), the TSH response to metoclopramide was completely blunted in subclinical hypothyroidism. In these patients a significant (p less than 0.01) inhibition of TSH response to intravenous thyrotropin-releasing hormone (TRH) was also observed after treatment with thyroid hormone. In analogy to the TSH behavior, plasma PRL secretion in response to metoclopramide and TRH administration was significantly (p less than 0.05) inhibited in the subclinical hypothyroid patients after l-thyroxine replacement therapy.     

END-ORGAN RESPONSES TO THYROXINE THERAPY IN SUBCLINICAL HYPOTHYROIDISM

We studied variables known to change with thyroid hormone status in 18 patients with subclinical hypothyroidism before and during treatment with thyroxine in a dose sufficient to restore the plasma TSH response to TRH to normal. There was an associated increase in both plasma total T4 and free T4 within the normal range but plasma total T3 and free T3 were unchanged. As a result of thyroxine treatment there was a small but significant increase (P less than 0.05) in left ventricular ejection fraction (LVEF) with maximal exercise but no significant changes in LVEF at rest and moderate exercise, continuously monitored mean sleeping heart rate, day/night ratios of urinary sodium excretion, peripheral nerve conduction velocities, fasting serum triglycerides, total cholesterol (TC), high density lipoproteins (HDL) or TC/HDL ratios. On this evidence we do not consider that thyroxine replacement therapy is indicated in patients with subclinical hypothyroidism.     

Thyrotropin and prolactin secretory patterns during 24-hours infusion of thyrotropin-releasing hormone in calves.

Plasma levels of thyrotropin (TSH), prolactin (Prl), growth hormone (GH), thyroxine (T4), and triiodothyronine (T3) were measured in response to continuous 24-h infusion of synthetic thyrotropin-releasing hormone (TRH) in normal and surgically thyroidectomized (THYX) calves in a series of 2 experiments. In the 1st experiment, the low dose of TRH (0.077 microgram/min) had no effect on any hormone levels measured. Plasma TSH concentration increased significantly (p less than 0.05) in response to TRH infusion (0.77 microgram/min) in both experiments, but plasma TSH levels plateaued and then declined in both cases despite continued TRH infusion and irrespective of the presence or absence of a thyroid gland. A similar pattern of secretion, though less markedly decreased over time, was observed for plasma Prl in both experiments. The higher dose (0.77 microgram/min) of TRH had no effect on plasma GH concentration in the 1st infusion, but did result in a significant (p less than 0.05) increase in overall mean concentration of GH in both normal and THYX calves in the 2nd experiment. Removal of the thyroid gland, thus removing the source of increasing T4 and T3 levels seen in normal calves infused with TRH, failed to alter the secretory patterns of TSH and Prl. These data suggest that feedback inhibition by increasing plasma thyroid hormone concentrations was not responsible for the failure of TSH and, to a lesser extent, Prl to maintain chronically elevated plasma levels in response to continuous 24-h TRH infusion. It is suggested that a depletion of pituitary TSH and Prl stores readily secretable in response to a constant dosage level of TRH may be responsible for the secretory patterns observed.     

The hypothalamic-pituitary-thyroid axis in type 1 diabetes: influence of diabetic metabolic control

The influence of diabetic metabolic control on indices of thyroid function was studied in 9 euthyroid, insulin-dependent (Type 1) diabetics. During chronic poor metabolic control (mean fasting blood glucose 13 mmol/l and HbA1 concentrations 14.7%) serum T3 concentrations were low (P less than 0.01) while serum T4 and basal TSH concentrations were normal. After 6-8 weeks of improved metabolic control, mean HbA1 concentrations had fallen to 10.7% (P less than 0.01) and serum T3 concentrations had increased into the normal range. Serum T4 and basal TSH concentrations were unchanged. The serum TSH response to iv TRH remained normal throughout the study. In Type 1 diabetics, with chronic poor metabolic control, the serum T4 concentration and the TSH response to TRH are therefore appropriate indicators of thyroid function.     

Effect of clomifene on thyroid function in normal men.

To study the effect on thyroid function 100 mg of clomifene citrate was given once a day to two groups of healthy male volunteers for 5 and 12 consecutive days, respectively. In both groups serum concentrations of TSH, thyroxine, triiodothyronine, T3 resin uptake test and thyroid hormone binding proteins were measured before, during and after oral administration of clomifene. The effect of clomifene treatment was evaluated in Group 1 by means of serum FSH and LH measurements. Further in Group 2 the serum TSH response to iv TRH (200 microgram) was also investigated. The mean per cent elevations in serum concentrations of FSH and LH were 145 and 200, respectively. In Group 1 a small but statistically significant decrease within reference limits in triiodothyronine (P less than 0.01) and free thyroxine index (P less than 0.02) was found on day 4 of clomifene. On day 5 a slight increase in TSH was observed (P less than 0.05). In Group 2 the response of TSH to TRH showed a non-significant increase after 5 days and a significant increase (P less than 0.01) after 12 days of clomifene. Eight days after discontinuation of the drug the response was restored to normal. No changes in the thyroid hormone binding proteins in serum could be demonstrated. Though the observed changes were slight, they indicate that clomifene exerts an influence directly on the thyroid function.     

Hypothalamic-pituitary-thyroidal function in eumenorrheic and amenorrheic athletes.

The impact of chronic high volume athletic training on thyroid hormone economy has not been defined. We investigated the status of the hypothalamic-pituitary-thyroid axis (H-P-T) in women athletes with regular menstrual cycles (CA) and with amenorrhea (AA). Their data were compared with each other and with those derived from cyclic sedentary women (CS) matched for a variety of confounding factors including the intensity of exercise, caloric intake, and body weight. Alterations of the H-P-T axis were observed in women athletes compared to CS. While serum levels of T4, T3, free T4, free T3 and rT3 were substantially reduced (P less than 0.01) in AA, only serum T4 levels were significantly decreased in CA. Further, remarkable differences were found between CA and AA in that serum levels of free T4 (P less than 0.01), free T3 (P less than 0.01), and rT3 (P less than 0.05) were significantly lower in AA than in CA. Thyroid binding globulin and sex-hormone binding globulin concentrations were within their normal ranges for all groups of subjects. Both 24-h mean TSH levels and the circadian rhythm of TSH secretion were also comparable. However, the TSH response to TRH stimulation was blunted (P less than 0.01) in AA when compared to CA, but not to CS. Whereas the underlying mechanism(s) to account for the "global" reduction of circulating thyroid hormone in the face of normal TSH levels in AA is presently unknown, these observations provide information of clinical significance: 1) chronic high volume athletic training in women athletes with menstrual cyclicity is accompanied by an isolated T4 reduction; 2) an impaired H-P-T axis occurs selectively in athletic women in whom chronic high volume athletic training is associated with compromised hypothalamic-pituitary-ovarian function and amenorrhea.     

Subtle primary hypothyroidism in patients treated for acute lymphoblastic leukemia

We evaluated serum thyroid hormone and thyroid antibody levels, the serum TSH response to TRH, and the circadian pattern of serum TSH in 10 children and adolescents after radiation therapy for acute lymphoblastic leukemia. Four patients had received central nervous system preventive cranial irradiation and intrathecal chemotherapy, and the remaining 6 patients were treated with craniospinal irradiation for central nervous system relapse. Serum total T4 and T3 concentrations were within the normal range and thyroid antibodies were negative in all patients. Four patients who had received craniospinal irradiation had low free T4 levels. Prior to TRH administration, the overall mean serum TSH concentration was 5.4 +/- 1.3 mU/l, and the mean peak response to TRH was 33 +/- 6.5 mU/l. Both were significantly increased when compared to the levels observed in our control population (p less than 0.05 and less than 0.025, respectively). The overall mean nadir diurnal TSH was 3.6 +/- 0.8 mU/l, and the mean peak nocturnal TSH was 6.9 +/- 1.3 mU/l, both significantly elevated when compared to normal children (p less than 0.025). The mean nocturnal TSH surge, however, was not significantly different from normal. Four of 6 children treated with craniospinal irradiation, and one of four children treated with cranial irradiation had increased basal and peak serum TSH concentrations in response to TRH. One of the patients treated with cranial irradiation had an abnormal nocturnal TSH surge. We conclude that subtle primary hypothyroidism is relatively common in patients with acute lymphoblastic leukemia, particularly in those who have been treated with craniospinal irradiation.     

ALTERATIONS IN THYROID HORMONE METABOLISM DURING CHEMOTHERAPY IN PATIENTS WITH TESTICULAR CARCINOMA

In a prospective study, the effects of chemotherapy on thyroid function in patients with non-seminoma testicular carcinoma were evaluated. Thirty-one patients were studied; in sixteen immunoassayable HCG was present, but altered thyroid function could not be established. In fifteen patients an exaggerated TSH response to TRH was observed. In these patients, although T3 and T4N values were normal, basal TSH levels were higher compared to patients with a normal TSH response, probably due to preceding lymphangiography.During chemotherapy, T4N, T3 and rT3 levels rose significantly, but basal TSH levels and the TSH response to TRH decreased. In contrast, the prolactin responses to TRH increased. The observed changes in thyroid function during chemotherapy appear to result from delayed thyroid hormone clearance, probably caused by an effect of chemotherapy on deiodinating enzyme activity. This would result, in an increase in T4N and rT3 levels and a fall in TSH levels and in the TSH response to TRH. Furthermore, after therapy the raised T4N and lowered TSH levels remained, whilst the FT3 level did not change either during or after therapy, suggesting an unaltered hypothalamic/pituitary axis.     

TSH secretion in Cushing's syndrome: relation to glucocorticoid excess, diabetes, goitre, and the 'sick euthyroid syndrome'

Thyrotrophin (TSH) secretion was studied in 63 patients with Cushing's syndrome (53 patients with pituitary dependent Cushing's disease, eight with adrenocortical tumours, and two with the ectopic ACTH syndrome). Prior to treatment, TSH response to 200 micrograms of TRH intravenously was significantly decreased compared to controls; TSH response was 'flat' (increment less than 2 mU/l) in 34 patients (54%). Patients with a flat response to TRH had significantly higher morning and midnight cortisol levels than patients with a TSH response of 2 mU/l and more; this was not due to differences in serum thyroid hormone levels. Basal TSH, TSH increment after TRH, and stimulated TSH value, but not serum triiodothyronine, were correlated with cortisol measurements (0800 h serum cortisol, midnight cortisol, and urinary free corticoid excretion). After exclusion of 40 patients with additional disease (severe systemic disease, diabetes mellitus, or goitre), cortisol-TSH correlations were even more pronounced (r = -0.73 for midnight cortisol and stimulated TSH levels), while in the patients with additional complications, these correlations were slight or absent. Successful treatment in 20 patients was associated with a rise in thyroid hormone levels and the TSH response to TRH. These results indicate that (1) the corticoid excess but not serum T3 is the principal factor regulating TSH secretion in Cushing's syndrome, (2) a totally flat response to TRH is rare, and (3) TSH suppression and lower than normal serum thyroid hormone levels are reversible after treatment. Since factors like severe systemic disease, diabetes mellitus and goitre also affect TSH secretion, they tend to obscure the statistically significant correlations between cortisol excess and TSH secretion.     

Thyroid function in adults with Down's syndrome.

The thyroid status of 82 institutionalized adults with Down's syndrome has been assessed. Compared to age and sex matched control subjects, these patients had significantly lower mean total serum thyroxine (T4) and triiodothyronine (T3) concentrations (T4; 69.1+/-22.2 nmol/1; (mean+/-SD) vs. 100.1+/-19.1, P less than 0.001; T13; 1.61+/-0.47 nmol/1 vs. 1.76+/-0.34, P less than 0.025), lower free thyroxine index (FTI), (FTI; 66.1+/-22.4 vs. 95.1+/-20.2, P less than 0.001), and higher basal serum thyrotrophin (TSH) concentrations (TSH; 7.6+/-10.7 mU/1 vs. 3.8+/-1.5, P less than 0.001). These changes were not related to age or sex. Abnormalities in one or more test of thyroid function were demonstrated in at least 38 (46%) of the 82 patients. Two main patterns of abnormality were defined: 1) subnormal T4, FTI and elevated basal TSH levels (primary hypothyroidism) in 13 (16%). All seven of the 13 patients in whom TRH tests were performed showed the expected exaggerated TSH response, and seven out of the 13 patients (54%) had positive thyroid antibodies, 2) Subnormal T4, subnormal or low normal FTI, and basal TSH levels within the normal range in 18 (22%). The mean basal TSH concentration was, however, significantly higher than in patients with normal T4 and FTI levels, suggesting a minor degree of thyroid failure. Only two of the 18 patients (11%) had positive thyroid antibodies. Of the 17 patients in the group tested, 13 showed a normal TSH response to TRH, three an exagerrated response (all females), and one had an impaired response. Other patterns of abnormal thyroid function were observed occasionally: one female patient had biochemical T3 toxicosis; another had the biochemical pattern of subclinical hypothyroidism, four patients with normal basal T4, FTI and TSH levels showed an exaggerated TSH response to TRH and one patient had an impaired response. These data indicate that htyroid dysfunction, in particular hypothyroidism, is common in adults with Down's syndrome, though specific tests are usually required to make the diagnosis. The general reduction in thyroid function in Down's syndrome may be due to impaired development of the thyroid gland. However, frank chemical hypothyroidism may occur only when thyroiditis is superimposed on preexisting diminished thyroid reserve.     

Decreased growth hormone (GH) response to oral clonidine in endemic cretinism: effect of L-T3 therapy

As GH secretion is dependent upon thyroid hormone availability, the GH responses to clonidine (150 micrograms/m2) and the TSH and PRL response to TRH were studied in eight endemic (EC) cretins (3 hypothyroid, 5 with a low thyroid reserve) before and after 4 days of 100 micrograms of L-T3. Five normal controls (N) were also treated in similar conditions. Both groups presented a marked increase in serum T3 after therapy (N = 515 +/- 89 ng/dl; EC = 647 +/- 149 ng/dl) followed by a decrease in basal and peak TSH response to TRH. However, in the EC patients an increase in serum T4 levels and in basal PRL and peak PRL response to TRH after L-T3 therapy was observed. One hypothyroid EC had a markedly elevated PRL peak response to TRH (330 ng/dl). There were no significant changes in basal or peak GH values to treatment with L-T3 in normal subjects. In the EC group the mean basal plasma GH (2.3 +/- 1.9 ng/ml) significantly rose to 8.8 +/- 3.2 ng/ml and the mean peak response to clonidine (12.7 +/- 7.7 ng/ml) increased to 36.9 +/- 3.1 ng/ml after L-T3. Plasma SM-C levels significantly increased in N from 1.79 +/- 0.50 U/ml to 2.42 +/- 0.40 U/ml after L-T3 (p less than 0.01) and this latter value was significantly higher (p less than 0.05) than mean Sm-C levels attained after L-T3 in the EC group (respectively: 1.14 +/- 0.59 and 1.78 +/- 0.68 U/ml). These data indicate that in EC the impaired GH response to a central nervous system mediated stimulus, the relatively low plasma Sm-C concentrations, and the presence of clinical or subclinical hypothyroidism may contribute to the severity of growth retardation present in this syndrome.     

Fasting decreases thyrotropin responsiveness to thyrotropin-releasing hormone: a potential cause of misinterpretation of thyroid function tests in the critically ill

We have previously reported that caloric deprivation inhibits peripheral T4 metabolism and blunts the TSH response to TRH in euthyroid obese subjects. To determine whether these phenomena also occur in hypothyroid subjects, T4, T3, rT3, and the TSH response to TRH were measured initially and after a 60-h fast in seven hypothyroid patients. Short term fasting caused a 29% decrement in the maximum serum TSH increment and a 32% decrement in the integrated TSH response to TRH (P less than 0.01). In two subjects with mild hypothyroidism, basal TSH as well as the TSH response to TRH were reduced to levels within the normal range. Specifically, basal TSH values decreased from 7.6 to 3.5 microU/ml and from 11 to 4.1 microU/ml. In the seven subjects, mean serum T3 decreased significantly from 88 to 60 ng/dl, (P less than 0.05) and rT3, initially undetectable in six of seven subjects, rose to detectable or low normal values in four of seven subjects, serum T4 remained at 2.7 micrograms/dl during both study periods. We conclude that 1) fasting induces changes in both peripheral thyroid hormone metabolism and the hypothalamic-pituitary axis in hypothyroid individuals which are qualitatively similar to those that occur in euthyroid subjects; and 2) in certain hypothyroid subjects, fasting alone can decrease basal TSH values to within the normal range. If these data can be extrapolated to critically ill subjects whose caloric intake may be diminished, they suggest that basal TSH concentrations in moderately and severely hypothyroid critically ill subjects will accurately reflect the biochemically hypothyroid state. However, mild degrees of hypothyroidism in critically ill subjects might be overlooked due to the lowering effect of fasting or poor caloric intake alone on basal TSH concentrations.     

EFFECT OF FENOLDOPAM, A DOPAMINE D-1 RECEPTOR AGONIST, ON PITUITARY, GONADAL AND THYROID HORMONE SECRETION

The influence of fenoldopam, a dopamine (DA) D-1 receptor agonist, on basal and GnRH/TRH stimulated PRL, GH, LH, TSH, testosterone and thyroid hormone secretion was studied in nine normal men. All men received 4-h infusions of either 0.9% saline or fenoldopam at an infusion rate of 0.5 microgram/kg min, 12-16 ml/h, adjusted according to weight. After 3 h of infusion, 50 micrograms GnRH and 100 micrograms TRH was given i.v. Blood samples were collected every 15 min from 1 h before to 1 h after the infusion for a total of 6 h for measurements of PRL, LH, FSH, GH, TSH, testosterone, T4 and T3. The median PRL concentration increased significantly (P less than 0.01) to 128%, range 87-287, of preinfusion levels, compared to the decline during control infusion (85%, 78-114). Basal TSH levels declined significantly to 71% (60-91) during fenoldopam compared with 82% (65-115) during control infusion (P less than 0.05). Basal LH, FSH, GH and thyroid hormones were similar during fenoldopam and control infusions (P greater than 0.05). The LH response to GnRH/TRH was significantly (P less than 0.02) increased by fenoldopam infusion. Basal and stimulated testosterone concentration was lower during fenoldopam (P less than 0.01) infusion compared with control. Other hormones were similar after GnRH/TRH stimulation during fenoldopam and saline infusions. These results suggest that DA D-1 receptors are involved in the modulation of pituitary hormone secretion. We suggest that the effect of fenoldopam on PRL and TSH is mainly at the hypothalamic level. Regarding the effect on LH concentrations, an additional direct effect of fenoldopam on testosterone regulation can not be excluded.     

Thyroid hormone turnover in patients with small cell carcinoma of the lung

Patients with small cell carcinoma of the lung often present with symptoms suggestive of hyperthyroidism i.e. weight loss without anorexia. Consequently [125I]T4 and [131I]T3 turnover was studied using simultaneously iv bolus injection and noncompartmental analysis in 6 patients with untreated small cell carcinoma of the lung and 14 normal subjects of comparable ages. Both T4 and T3 production rates were enhanced, T4 production being in median 135 nmol.day-1.70 kg-1 (range 111-200) in patients with small cell carcinoma of the lung vs 98 nmol.day-1.70 kg-1 (range 69-134) in controls (P less than 0.01), and T3 production being 46 nmol.day-1.70 kg-1 (range 33-65) vs 31 nmol.day-1.70 kg-1 (range 24-45) (P less than 0.01). The mean transit time was shortened for both T4 and T3, T4 mean transit time being 5.9 days (3.9-8.0 days) vs 8.3 days (6.1-11.2 days) in controls (P less than 0.01), and T3 mean transit time being 0.74 days (0.36-0.98 days) vs 1.03 days (0.81-1.45 days) in controls (P less than 0.01). Serum total and free T4 and T3 levels were unchanged. Basal serum TSH levels and the TSH response to iv TRH were also normal. Thyroid-stimulating immunoglobulins were only present in the serum in 1 of 6 patients. Thus, thyroid hormone production seemed under pituitary regulation. The peripheral effect of thyroid hormones was evaluated measuring serum sex hormone binding globulin levels, which were increased to in median 270% (77-310%) (P less than 0.01) of that in controls, suggesting some degree of hyperthyroidism in liver tissue.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pituitary-thyroid function in chronic renal failure assessed by a highly sensitive thyrotropin assay

Pituitary-thyroid function was assessed in 40 patients with chronic renal failure undergoing regular maintenance hemodialysis and in 35 normal subjects. Serum thyroid hormone levels were significantly lower in the dialysis patients than in the normal subjects (P less than 0.001) and were in the hypothyroid range in a high proportion of dialysis patients (total T3, 25%; free T3, 45%; total T4, 55%; free T4, 45%; and free T4 index, 38%). The reduced free thyroid hormone levels could not be explained by currently recognized assay artefacts. Serum TSH levels were higher than in the normal subjects (P less than 0.01), but still within the normal range for most (35 of 40) dialysis patients and did not correlate significantly with total or free thyroid hormone concentrations in either group. These results suggest some impairment in the thyroidal response to TSH and impaired pituitary response to low serum thyroid hormone levels, the latter implying resetting of the normal feedback mechanism such that diminished thyroid hormone production evokes a smaller than normal increase in TSH secretion. This diminished thyrotroph sensitivity to reduced serum thyroid hormone levels may be beneficial in severe nonthyroidal illness.     

Preserved thyroidal secretion of thyroxione in acromegalic patients with suppressed hypophyseal secretion of thyrotrophin

OBJECTIVE--We have assessed the mechanisms which maintain euthyroidism in acromegalic patients despite the suppression of thyrotrophin (TSH) secretion. MATERIALS--Fourteen untreated patients with acromegaly were analysed. Ten patients were also studied after pituitary surgery. METHODS--Thyroid hormones, growth hormone (GH), insulin-like growth factor-I (IGF-I) and thyroidal uptake of radioactive iodine, thyrotrophin releasing hormone (TRH) test and basal metabolic rate (BMR) were measured before and after pituitary surgery. RESULTS--Nine patients had palpable goitres. The TSH response to TRH stimulation was suppressed in eight patients, who maintained normal serum levels of total T3, T4 and free T4. The patients with normal TSH response had lower levels of free and total T4 than controls. The response of TSH to TRH correlated inversely with the serum level of total and free T4, and also with the plasma level of IGF-I (r = -0.74, P less than 0.05, n = 9). After pituitary surgery, the serum levels of total and free T4 were elevated for at least up to 6 months, with a decrease in the T3/T4 ratio and the BMR. CONCLUSION--GH may have a direct stimulatory action on the thyroid secretion of T4 possibly via increased IGF-I, despite suppressed TSH secretion. The post-operative elevation of serum T4 suggests the persistent secretion of T4 from the thyroid gland, in spite of instantaneous normalization of the accelerated conversion of T4 to T3, even after reduction of excess GH secretion.     

Serum thyrotropin and prolactin in the syndrome of generalized resistance to thyroid hormone: responses to thyrotropin-releasing hormone stimulation and short term triiodothyronine suppression

Serum TSH and PRL levels and their response to TRH were measured in 11 patients with generalized resistance to thyroid hormone (GRTH), 6 euthyroid subjects, and 6 patients with primary hypothyroidism. TSH and PRL levels and their response to TRH were also measured after the consecutive administration of 50, 100, and 200 micrograms T3 daily, each for a period of 3 days. Using a sensitive TSH assay, all GRTH patients had TSH values that were elevated or within the normal range. On the basis of a normal or elevated TSH level, GRTH patients were classified as GRTH-N1 TSH (5 patients) or GRTH-Hi TSH (6 patients), respectively. Only GRTH patients with previous thyroid ablative therapy had basal TSH values greater than 20 mU/L. TSH responses, in terms of percent increment above baseline, were appropriate for the basal TSH level in all subjects. No GRTH patient had an elevated basal PRL level. PRL responses to TRH were significantly increased only in the hypothyroid controls compared to values in all other groups. On 50 micrograms T3, 7 of 12 (58%) nonresistant (euthyroid and hypothyroid) and 1 of 11 (9%) resistant subjects had a greater than 75% suppression of the TSH response to TRH. On the same T3 dose, 2 of 12 (17%) nonresistant and 4 of 11 (36%) resistant subjects had a greater than 50% suppression of the PRL response to TRH. On 200 micrograms T3, all subjects, except for 1 with GRTH, had a greater than 75% suppression of the TSH response to TRH. On the same T3 dose, while 11 of 12 (92%) nonresistant subjects had a greater than 50% reduction of the PRL response to TRH, only 3 of 10 (30%) resistant patients showed this degree of suppression (P less than 0.005). Without previous ablative therapy, serum TSH in patients with GRTH is usually normal or mildly elevated. The TSH response to TRH is proportional to the basal TSH level and is suppressed by exogenous T3. However, on 200 micrograms T3 basal TSH was not detectable (less than 0.1 mU/L) in all euthyroid subjects, but it was measurable in three of four GRTH patients with normal TSH levels before T3 treatment. PRL levels in GRTH are normal even when TSH is elevated. The PRL response to TRH is not increased in GRTH. In all subjects, exogenous T3 suppresses the PRL response to TRH to a lesser degree than the TSH response, but this difference is much greater in patients with GRTH.     

The comparative effect of T4 and T3 on the TSH response to TRH in young adult men.

The effect of graded increments of chronically administered oral T4 or T3 on the TSH response to TRH was studied in normal young adult men. The TSH response was assessed in the baseline state and after each increment of each hormone (two weeks at each dose level) using both 30 mug and 500 mug doses of TRH. Each thyroid hormone caused a dose-related decrease in the TSH response to TRH; thus the TSH response could be used as a bioassay for the biologic activity of the thyroid hormones in man. The dose of thyroid hormone that caused a 50% suppression of the TSH response, or the SD50, was not different with either 30 mug or 500 mug of TRH indicating that thyroid hormone suppression of the TSH response is not more easily detected with a small dose of TRH. The mean SD50 for T4 was 115 mug/day, for T3 stopped 2 h before testing the mean SD50 was 29 mug/day, and for T3 stopped 24 h before testing it was 45 mug/day. Using the average SD50 for the two T3 regimens (37 mug/day), the calculated relative potency indicates that oral T3 is 3.3 times as potent as oral T4, a value in reasonable agreement with the value previously estimated with a calorigenic end-point. The mean dose of T4 needed to decrease the TSH response to TRH to below the normal range (max delta TSH of 2 muU/ml) was 150 mug/day; this value is probably more appropriate than the SD50 in the treatment of patients with primary hypothyroidism or goiter and was about the same (160 mug/day) using a peak TSH after TRH of 3 muU/ml as an end-point. Estimation of the SD50 in each subject showed a 2- to 3-fold range with all regimens of thyroid hormones; similarly there was a 2-fold in the dose of T4 needed to suppress the TSH response to TRH to below the normal range. Further, the difference in the mean SD50 for the two T3 regimens indicates that a single daily dose of oral T3 does not exert a constant biologic effect throughout the day. Thus, because of individual variation and, in the case of T3, because of changing activity during the day a given dose of thyroid hormone may have a widely varying biologic effect. There was also a 3-fold range in the relative potency of T3 to T4 in the four subjects treated with both hormones. This suggests that the therapeutic administration of a fixed ratio fo T3 to T4 may have a variable effect from patient to patient. Finally, the serum T4 rose while the serum T3 did not at a dose of T4 that abolished the TSH response to TRH, indicating that circulating T4 is a determinant of TSH secretion in normal man.     

EVIDENCE FOR THYROIDAL SECRETION OF 3,3'',5''-TRIIODOTHYRONINE IN MAN AND ITS CONTROL BY TSH

Thyroidal secretion of 3,3',5'-triiodothyronine (reverse T3, rT3) and its control by TSH was assessed by measuring (1) arterio-venous hormone gradients in patients undergoing surgery, (2) changes of hormone concentrations after induction of anaesthesia, and (3) changes induced by TRH administration. In ten patients in whom thyroid activity was under TSH control (parathyroidectomy and non-toxic goitre) increased thyroid vein/carotid artery ratios (TV/CA) for rT3 (mean TV/CA ratio 2.53) were found when compared to six patients with non-toxic goitre on suppressive doses of T4 (mean TV/CA ratio, 1.27) (P less than 0.05). The mean calculated operative secretion rate of rT3 was 12.5 microgram/day but only 2.4 microgram/day in patients receiving T4. In thirteen patients undergoing elective surgery induction of anaesthesia significantly increased rT3 levels. In nine euthyroid adults intravenous TRH (200 microgram) increased peripheral venous rT3 levels between 3 h (P less than 0.005) and 8 h (P less than 0.05) after the injection. It is concluded that significant amounts of rT3 are secreted by the thyroid gland at operation and this is, in part, under TSH control.