Increased incidence of euthyroid and hyperthyroid goiters independently of thyrotropin in patients with acromegaly

The incidence of palpable goiters, the thyroid functional state and thyroid radioisotope uptake was analyzed retrospectively in 80 patients with acromegaly and 80 patients with prolactinomas. 71% of all patients with acromegaly had an enlargement of the thyroid (goiter); 49% of them had diffuse and 39% nodular goiters. The incidence of goiters in patients with prolactinomas from the same iodine deficient geographic region was only 35% (82% diffuse and 18% nodular). 17.5% of acromegalic patients underwent thyroid surgery before diagnosis of growth hormone excess. 17.5% of acromegalic patients with goiters had autonomous areas in their thyroids and 5% were clearly hyperthyroid. Goiters developed slightly more often in females (74%) than in males (67%). The mean preoperative growth hormone level was higher in acromegalic patients with goiter. The incidence of goiters was positively correlated with the documented time of elevated growth hormone concentration in serum. Two patients with exaggerated response of thyrotropin (TSH) (delta TSH greater than 20 mU/l) to the application of thyrotropin-releasing hormone (TRH) had no goiters. On the other hand most patients (61%) with goiters had a low TSH-response to TRH (delta TSH less than 10 mU/l) representing in part occult autonomy of thyroid function. No patient with prolactinoma has had previous thyroid surgery nor thyroid autonomy. One patient with prolactinoma suffered from Graves' disease and none of the acromegalic patients had this disease. We finally conclude that the elevation of growth hormone leads to increased incidence of euthyroid and hyperthyroid (autonomous) goiters independently of the influence of TSH.     

Oral thyrotropin-releasing hormone (TRH) test in acromegaly

The effects of 40 mg oral and 200 microgram intravenous TRH were studied in patients with active acromegaly. Administration of oral TRH to each of 14 acromegalics resulted in more pronounced TSH response in all patients and more pronounced response of triiodothyronine in most of them (delta max TSh after oral TRh 36.4 +/- 10.0 (SEM) mU/l vs. delta max TSH after i.v. TRH 7.7 +/- 1.5 mU/l, P less than 0.05; delta max T3 after oral TRH 0.88 +/- 0.24 nmol/vs. delta max T3 after i.v. TRH 0.23 +/- 0.06 nmol/l, P less than 0.05). Oral TRH elicited unimpaired TSH response even in those acromegalics where the TSH response to i.v. TRH was absent or blunted. In contrast to TSH stimulation, oral TRH did not elicit positive paradoxical growth hormone response in any of 8 patients with absent stimulation after i.v. TRH. In 7 growth hormone responders to TRH stimulation the oral TRH-induced growth hormone response was insignificantly lower than that after i.v. TRH (delta max GH after oral TRH 65.4 +/- 28.1 microgram/l vs. delta max GH after i.v. TRH 87.7 +/- 25.6 microgram/l, P greater than 0.05). In 7 acromegalics 200 microgram i.v. TRH represented a stronger stimulus for prolactin release than 40 mg oral TRH (delta max PRL after i.v. TRH 19.6 +/- 3.22 microgram/, delta max PRL after oral TRH 11.1 +/- 2.02 microgram/, P less than 0.05). Conclusion: In acromegalics 40 mg oral TRH stimulation is useful in the evaluation of the function of pituitary thyrotrophs because it shows more pronounced effect than 200 microgram TRH intravenously. No advantage of oral TRH stimulation was seen in the assessment of prolactin stimulation and paradoxical growth hormone responses.     

The pituitary-thyroid axis in acromegaly

The pituitary-thyroid axis of 12 acromegalic patients was evaluated by measurement of the serum concentrations (total and free) of thyroxine (T4), triiodothyronine (T3) and reverse T3 (rT3) and thyrotropin (TSH), growth hormone (GH) and prolactin (PRL) before and after iv stimulation with thyrotropin releasing hormone (TRH). Using an ultrasensitive method of TSH measurement (IRMA) basal serum TSH levels of the patients (0.76, 0.07-1.90 mIU/l) were found slightly, but significantly (P less than 0.01), lower than in 40 healthy controls (1.40, 0.41-2.50 mIU/l). The total T4 levels (TT4) were also reduced (84, 69-106 nmol/l vs 100, 72-156 nmol/l, P less than 0.01) and significantly correlated (P less than 0.02, R = 0.69) to the TSH response to TRH, suggesting a slight central hypothyroidism. The acromegalics had, however, normal serum levels of TT3 (1.79, 1.23-2.52 nmol/l vs 1.74, 0.78-2.84 nmol/l, P greater than 0.10), but significantly decreased levels of TrT3 (0.173, 0.077-0.430 nmol/l vs 0.368, 0.154-0.584 nmol/l, P less than 0.01) compared to the controls. The serum concentration of the free iodothyronines (FT4, FT3, FrT3) showed similar differences between acromegalics and normal controls. All the acromegalics showed a rise of serum TSH, GH and PRL after TRH. Positive correlation (P less than 0.05, R = 0.59) was found between the TSH and GH responses, but not between these two parameters and the PRL response to TRH. These findings may be explained by the existence of a central suppression of the TSH and GH secretion in acromegalic subjects, possibly exerted by somatostatin. Euthyroidism might be maintained by an increased extrathyroidal conversion of T4 to T3.     

Clinical usefulness and limitations of serum thyrotropin measurement by 'ultrasensitive' methods. Comparisons of five kits

Five different ultrasensitive thyrotropin (TSH) assay kits (Boots-Celltech, Immunotech, ORIS-CIS, Travenol and Boehringer) have been used for TSH measurements in various conditions. All the kits were based on an immunometric method but differed with regard to components and procedure. The sensitivity appeared essentially the same for the five kits (0.10 microU/ml) as well as the intraassay precision (coefficient of variation less than 12%). In contrast, the interassay coefficients of variation in the low TSH range varied from 12.8 to 21.3%. Discrepancies from kit to kit were observed and accounted for by differences in the components and procedure of the kits. Basal serum TSH was determined in normal subjects (n = 261) and in patients with thyroid dysfunction (n = 392). No overlap was shown between normals and patients with overt hypothyroidism. In contrast, an overlap existed between normals and hyperthyroids for all the kits but one. Measurements in patients with nontoxic goiter showed that TSH may be undetectable in clinically euthyroid patients, whatever the kit used. After TRH stimulation, 95% of the 375 patients tested associated either an absence of response to TRH with undetectable basal TSH values, or a blunted response with low basal TSH levels or normal response with normal basal TSH concentrations. However, 9 patients with suppressed TSH showed a response to TRH and 7 patients with normal basal TSH levels presented an exaggerated response to TRH. Taken together, these results demonstrate that even though ultrasensitive measurements of TSH do not meet the expectation of completely discriminating euthyroid from hyperthyroid patients, ultrasensitive TSH assay kits represent a powerful tool in the diagnosis of thyroid dysfunction, which would eliminate, in most instances, the need for TRH test and diminish thyroid hormone assay requests.     

Significance of serum thyrotropin and plasma dopamine concentration in the regulation of thyroid function in elderly subjects

In our previous study, we observed a tendency towards an age-related increase in the serum thyrotropin (TSH) concentration. Regulatory mechanisms of TSH secretion in elderly subjects were studied. In 43 elderly subjects, serum TSH did not correlate significantly with serum T4, T3 free T4 or rT3. Further, those with increased TSH (greater than 5 mU/l, 9 subjects) did not overlap with those with low T3 (less than 0.92 nmol/1, 8 subjects). Increases in serum TSH were not associated with the presence of circulating anti-thyroid autoantibodies. A TRH test using a 500 micrograms single bolus injection was performed in 15 subjects. TSH response (basal: 1.92 +/- 1.42 (s.d.) mU/1, peak: 11.25 +/- 5.33 mU/1, sigma: 26.74 +/- 12.89 mU/1, respectively) did not differ significantly from that of younger subjects. T3 response after TRH varied greatly and a close correlation was observed between basal T3 and peak T3 (r = 0.86), and also between peak T3 and delta T3 (r = 0.81). A significant correlation was observed between sigma TSH and basal T3 (r = 0.60). Neither plasma cortisol, epinephrine nor norepinephrine concentrations showed any significant correlation with basal and TRH-stimulated TSH or T3 concentrations. However, the plasma dopamine concentration correlated significantly with sigma TSH (r = 0.60) and basal T3 (r = 0.52), respectively. In conclusion, the increase in serum TSH observed in elderly subjects was felt to represent a physiological adaptation to maintain serum T3. Low T3 subjects appear to have a disturbance in this mechanism, with decreased TSH and T3 response to TRH stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Euthyroid hypothyrotropinemia in children of short stature

Unique association of hypothyrotropinemia with euthyroidism was described in 2 children of short stature. Both had a history of intrauterine growth retardation (IUGR), but showed an appropriate growth rate after infancy (5 cm/y). Growth hormone secretion after provocation tests was normal, whereas TSH response to TRH was absent. With a highly sensitive TSH radioimmunoassay (RIA) and a specific RIA for TSH-alpha-subunit, both responded to a high dose of TRH stimulation. Serum thyroid hormones were within the normal range, while prolactin response to TRH was exaggerated. Exogenous thyroxine (T4) supplement in case 1 did not improve his growth rate, indicating absence of hypothyroidism. Case 2 was treated with stanozolol, which accelerated his growth velocity to 8 cm/y. During the treatment, serum T4 gradually decreased to 50% of the initial level, but blunted TSH response to TRH remained unchanged. These results indicate that their thyrotrophs are resistant to TRH stimulation and the pituitary setpoint of TSH release is unusually high. The exact mechanism involved in maintaining euthyroidism despite hypothyrotropinemia remains to be elucidated, but a common history of IUGR appears to play a role in producing this pituitary-thyroid state.     

Clinical importance of reversibility in primary goitrous hypothyroidism.

Twenty seven hypothyroid patients with a serum concentration of thyroid stimulating hormone (TSH) of over 40 mU/1 were followed up for three to 20 weeks without replacement therapy. The serum thyroid hormone concentrations increased with a dramatic decrease in serum TSH values in 14 patients (reversible group) but there was no significant change in the other 13 (irreversible group). Fourteen out of 19 patients with goitre but none of the eight patients without goitre belonged to the reversible group. All of the 11 patients with a high uptake of iodide by the thyroid, three of the six with a normal uptake, and none of the 10 with a low uptake belonged to the reversible group. These observations indicate that patients with goitrous hypothyroidism with a preserved thyroid uptake of iodide are likely to become euthyroid spontaneously without replacement therapy.     

Further Observations on the Effect of Synthetic Thyrotrophin-releasing Hormone in Man

Synthetic thyrotrophin-releasing hormone (TRH) given intravenously in doses of 50 μg or more causes a significant rise in serum thyroid-stimulating hormone (TSH) levels but has no effect on serum growth hormone, plasma luteinizing hormone, or plasma 11-hydroxycorticosteroids under carefully controlled basal conditions.The peak TSH response to intravenous TRH occurs at 20 minutes. The mild and transient side effects, which occur only after intravenous TRH, include nausea, a flushing sensation, a desire to micturate, a peculiar taste, and tightness in the chest. There is considerable variability in response to a given dose of TRH in the same subject on different occasions and in different subjects. Oral administration of TRH in doses of 1 mg and above causes a rise in serum TSH, maximal at two hours, a consistent response being obtained at doses of 20 mg and above. A rise in serum protein-bound iodine (P.B.I.) follows that of TSH, a consistent response being observed at 40-mg doses of TRH orally. Measurements of serum TSH after intravenous administration of TRH or of serum TSH or serum P.B.I. after oral TRH should prove useful tests of pituitary TSH reserve.     

A sensitive immunoradiometric assay for serum thyroid stimulating hormone: a replacement for the thyrotrophin releasing hormone test?

The value as a thyroid function test of a new, rapid, and highly sensitive immunoradiometric assay for thyroid stimulating hormone (TSH) was assessed in 188 consecutive new patients with suspected hyperthyroidism. The diagnosis was made on clinical grounds and on the basis of serum total triiodothyronine and thyroxine concentrations and the response of TSH to thyrotrophin releasing hormone (TRH) as measured by radioimmunoassay. In all except one patient the basal TSH concentration by immunoradiometric assay predicted the response of TSH by radioimmunoassay to TRH, an undetectable value being recorded in patients with a subnormal response and a measurable value in those with a normal test result. This clear relation was not observed for basal TSH concentrations as measured by radioimmunoassay. In a series of 39 hospital inpatients with acute or chronic non-thyroidal illness, of whom 11 had low concentrations of total thyroxine or triiodothyronine, or both, basal TSH concentrations were detectable by both radioimmunoassay and immunoradiometric assay in all cases and were associated with normal responses to TRH. The immunoradiometric assay for TSH, which is commercially available, may therefore obviate the need for the more time consuming TRH test and simplify the approach to thyroid function testing in patients with suspected hyperthyroidism.     

Thyrotropin-secreting pituitary adenoma: a case report.

We report a 44-year-old male with a thyrotropin (TSH)-secreting pituitary adenoma. Based serum free triiodothyronine (FT3, 12.1 pmol/l) and free thyroxine (FT4, 28 pmol/l) were increased with normal basal TSH (3.1 mU/l). There was impaired TSH response to thyrotropin releasing hormone (TRH) test. Serum TSH was suppressed to 59% of the basal level after oral administration of 1.4 mg 3,3'-5-triiodothyroacetic acid (triac), whereas no suppression was observed after 75 micrograms daily administration of triiodothyronine (T3). Serum concentrations of alpha-subunit of TSH (TSH-alpha) and TSH-alpha/TSH molar ratio were high, being 1.95 micrograms/l, and 4.4, respectively. Pituitary CT and MRI scan showed the presence of a macroadenoma in the anterior lobe of the pituitary gland. Histopathology of the excised pituitary confirmed the diagnosis of a TSH-producing adenoma. A positive correlation between TSH and FT3 (r = 0.66, P less than 0.01) or FT4 (r = 0.54, P less than 0.01) was observed in serial sera obtained before and after operation.     

The thyroid reserve in children with chronic lymphocytic thyroiditis revealed by the thyrotropin-releasing hormone and thyroid-stimulating hormone tests

Serum thyroid hormone and TSH concentrations were measured before and after the administration of TRH (10 micrograms/kg body weight) and bovine TSH (10 IU) in 14 children with chronic lymphocytic thyroiditis. The TRH test showed that the responsiveness of TSH was positively correlated with the basal TSH (P less than 0.001) and inversely with the increase in serum thyroid hormones, for delta T3 (P less than 0.05) and for delta T4 (P less than 0.001). Overall, the patients had significantly lower mean values for basal T4, but not for T3. The TSH test revealed that the delta T3 was positively correlated with delta T4 (P less than 0.05). delta T3 after TSH administration was positively correlated with it after TRH (P less than 0.05). The patients were divided into three groups on the basis of their peak TSH values after TRH administration. In Group 1 (peak value below 40 microU/ml; N = 5); T3 increased significantly after TRH and TSH administrations (P less than 0.05 and P less than 0.025, respectively). In addition, delta T4 was significant after TSH administration. In Group 2 (peak TSH above 40 and less than 100 microU/ml; N = 6); only delta T3 after TRH was significant (P less than 0.05). In Group 3 (peak TSH above 100 microU/ml; N = 3); the response of thyroid hormones was blunted. Thus, the thyroid hormone responses to endogenous TSH coincided with that to exogenous TSH, and the exaggerated TSH response to TRH indicates decreased thyroid reserve.     

Cyclosporine A inhibits the secretion of certain anterior pituitary hormones in patients with nephrotic syndrome.

To clarify the effects of cyclosporine A (CsA) on the secretion of serum thyrotropin (TSH), prolactin (PRL), luteinizing hormone (LH) and follicular stimulating hormone (FSH), we performed TRH and LH-RH testing in 4 patients with the nephrotic syndrome before and after the administration of CsA, 6 mg/kg/day for 4 to 12 weeks. Prior to CsA all patients responded normally to TRH with respect to TSH and PRL secretion. Two patients showed normal response of LH and FSH to LH-RH stimulation while the response in 2 other patients, who were both menopausal, was exaggerated. By the third or fourth week of CsA administration the basal and peak TSH and PRL values declined significantly in all patients in response to TRH stimulation while those of LH and FSH showed only a modest decrease in response to LH-RH stimulation. Two to 4 weeks after the cessation of CsA the response of TSH, PRL and FSH returned to the pretreatment level. These observations suggest that: 1) CsA exerts an inhibitory effect on the secretion of at least TSH and PRL in humans, and 2) the effect of CsA on the pituitary may be partially reversible after the cessation of the therapy.     

Radioimmunoassay of Human Serum Thyrotrophin

The double antibody radioimmunoassay of serum thyroid-stimulating hormone (TSH) allows measurement of circulating levels of the hormone in most normal subjects. The serum TSH level in normal subjects is 1·6 ± 0·8μU/ml. Patients with non-toxic goitre and acromegaly have normal TSH levels. Values are always raised in hypothyroid patients (with primary thyroid disease) and are significantly lowered in those with hyperthyroidism. Of the many stimuli used in an attempt to raise TSH levels in normal adult subjects only three—synthetic thyrotrophin-releasing hormone, ethinyloestradiol, and carbimazole plus iodides—have been effective. The major clinical application of the TSH immunoassay lies in the diagnosis of minor degrees of hypothyroidism. An impaired response of serum TSH to synthetic thyrotrophin-releasing hormone should also help in the diagnosis of hypopituitarism affecting TSH production.     

Further studies on delineating thyroid-stimulating hormone (TSH) reference range

The aim of the study was to evaluate thyroid-stimulating hormone (TSH) concentration in a reference group and to compare it with the TSH in subjects with high probability of thyroid dysfunction. The study population consisted of 852 subjects. The reference group consisting of 316 subjects was obtained by the exclusion of the subjects having thyroid disease, taking thyroid influencing drugs, having increased thyroid peroxidase (TPO) antibodies, or having abnormal thyroid ultrasound. 42 high probability of thyroid dysfunction subjects were defined by the association of increased TPO antibody concentration, changed echogenicity, and changed echosonographic structure of thyroid parenchyma. In the reference group TSH reference range was 0.45?mU/l (95% CI 0.39-0.56?mU/l) to 3.43?mU/l (95% CI 3.10-4.22?mU/l). To distinguish reference and high probability of thyroid dysfunction group a TSH threshold was calculated. At a threshold value of 3.09?mU/l (95% CI 2.93-3.38?mU/l), specificity was 95% and sensitivity 38.1%. Using 2 different approaches to find upper limit of the TSH reference range we obtained similar results. Using reference group only a value of 3.43?mU/l was obtained. Using both reference group and subjects with the high probability of thyroid dysfunction we obtained 95% CI for the upper reference limit between 2.93 and 3.38?mU/l. Based on these premises, it could be argued that conservative estimate of the TSH upper reference range should be 3.4?mU/l for both sexes.     

Cardiopulmonary bypass: a low T4 and T3 syndrome with blunted thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH)

Thyroid hormone serum concentrations, the thyrotropin (TSH) and prolactin (PRL) response to thyrotropin-releasing hormone (TRH) were evaluated in patients undergoing cardiopulmonary bypass (CPB) conducted in hypothermia. During CPB a marked decrease of thyroxine (T4) and triiodothyronine (T3) concentration with a concomitant increase of reverse T3 (rT3) were observed similarly to other clinical states associated with the 'low T3 syndrome'. Furthermore, in the present study elevated FT4 and FT3 concentrations were observed. In a group of patients, TRH administered during CPB at 26 degrees C elicited a markedly blunted TSH response. In these patients, PRL concentration was elevated but did not significantly increase after TRH. The increased concentrations of FT4 and FT3 were probably due to the large doses of heparin administered to these patients. Thus, the blunted response of TSH to TRH might be the consequence of the elevation of FT4 and FT3 in serum, however, other factors might play a role since also the PRL response to TRH was blocked.     

Ophthalmic Graves's disease: natural history and detailed thyroid function studies.

Of 27 patients with ophthalmic Graves''s disease (OGD) who had been clinically euthyroid three years previously, one became clinically hyperthyroid and seven overtly hypothyroid. Improvement in eye signs was associated with a return to normal of thyroidal suppression by triiodothyronine (T3) and of the response of thyroid-stimulating hormone (TSH) to thyrotrophin-releasing hormone (TRH). Of a further 30 patients with OGD who had not been studied previously, three were overtly hypothyroid. Of the combined series, 46 patients were euthyroid, 18 (40%) of whom had an impaired or absent TSH response to TRH, and 3(6-7%) an exaggerated response. Eleven out of 37 patients (29-7%) had abnormal results in the T3 suppression test. There was a significant correlation between thyroidal suppression by T3 and the TSH response to TRH. Total serum concentrations of both T3 and thyroxine (T4) were closely correlated with T3 suppressibility and TRH responsiveness. Free T4 and T3 (fT3) concentrations were normal in all but three patients, in whom raised fT3 was accompanied by abnormal TSH responses and thyroidal suppression. The presence of normal free thyroid hormone concentrations in patients with impaired or absent TSH responses to TRH is interesting and challenges the concept that free thyroid hormones are the major controlling factors in the feedback control of TSH.     

Monitoring treatment of congenital hypothyroidism by highly sensitive immunoradiometric assay for thyroid stimulating hormone

To assess the clinical value of a sensitive immunoradiometric assay for TSH (IRMA-TSH), serum IRMA-TSH levels were compared with those of a radioimmunoassay (RIA-TSH) in twenty-eight patients with congenital hypothyroidism. Among 144 samples taken from them, 44 samples showed undetectable RIA-TSH, while only 10 samples were undetectable by IRMA-TSH. In two patients prospectively followed, RIA-TSH levels were undetectable when serum T3 and T4 were normal. IRMA-TSH levels, however, were detectable when serum T4 levels were elevated or normal. The basal RIA- and IRMA-TSH levels in 4 groups (22 patients) were compared and classified according to the TSH response to TRH. The RIA-TSH levels were undetectable in any in group 1 (n = 7; absent response) or group 2 (n = 5; low response). At the same time, IRMA-TSH levels were undetectable in only three patients in group 1. In group 3 (n = 16; normal response), RIA-TSH levels were undetectable in three, whereas IRMA-TSH levels were detectable in all. The IRMA- and RIA-TSH levels rose in all in group 4 (n = 15; exaggerated response). These results suggest that the serum basal IRMA-TSH levels indicate the responsiveness of TSH to TRH more accurately than basal serum RIA-TSH levels. Therefore, it was concluded that IRMA-TSH may obviate the need for a TRH test and simplify the evaluation of adequate dosage in patients with congenital hypothyroidism during thyroxine treatment.     

Influence of synthetic thyrotropin-releasing hormone tartrate monohydrate on plasma gonadotropin concentration of normal males.

Synthetic thyrotropin-releasing hormone (TRH) tartrate monohydrate was administered by rapid intravenous injection to nine normal males. Plasma thyroid-stimulating hormone (TSH), luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were measured before and at selected periods after TRH injection. The mean plasma TSH value immediately prior to TRH injection was 3.5 muU/ml and the level 15 min after injection was 14.8 muU/ml. The mean plasma LH value immediately prior to TRH injection was 8.0 mIU/ml and the level 15 min after injection was 15.0 mIU/ml. The latter elevation was statistically significant (p less than 0.01), although it was just above the upper normal range. The mean plasma FSH value immediately prior to TRH injecion was 7.7 mIU/ml, and a significant difference was not observed after TRH administration. These results revealed that synthetic TRH tartrate monohydrate influenced the release of LH from the anterior pituitary.     

Nuclear thyroid hormone receptor binding in human mononuclear blood cells after goitre resection

Nuclear thyroxine and triiodothyronine receptor-binding in human mononuclear blood cells were examined in 14 euthyroid persons prior to and 1, 6, 24 and 53 weeks after goitre resection. One week after resection decreased serum T3 from 1.47 nmol/l to 1.14 nmol/l (P less than 0.05), FT4I from 103 a. u. to 94 a. u. and SHBG from 80 nmol/l to 69 nmol/l (P less than 0.05) followed after 6 weeks by a rise in serum TSH from 1.2 mU/l to 11.0 mU/l (P less than 0.05) suggesting an initial slight hypothyroidism. Nuclear receptor-binding of T4 and T3 increased within one week and eventually decreased to preresectional values. We conclude that the expected alteration of the metabolic state caused by resection of the gland is opposed by increased nuclear binding of T4 and T3.     

Variation of the thyrotropin-releasing-hormone (TRH) stimulated thyrotropin (TSH) response in comparison with the tyhroid-gland-suppression test and the triiodothyronine (T3) and thyroxine (T4) blood levels in the so-called euthyroid endocrine ophthalmopathy]

21 patients with active signs of euthyroid Graves' disease were given 400 mug thyrotropin-releasing hormone (TRH) i.v. All subjects with unresponsiveness to TRH had a nonsuppressible thyroidal 131I-uptake. On the basis of serum total T3 14 patients were hyperthyroid, 2 more had an elevated value of free T3. 4 patients with normal total T3 and nonsuppressible 131I-uptake were unresponsive to TRH, in 2 of them the free T3 fraction was elevated, however. 4 subjects with nonsuppressible 131I-uptake had a TRH stimulated TSH response. 2 of these subjects had hyperthyroid values of free and total T3 in serum and responded to TRH with an exaggerate TSH increment. The variations of TRH responsiveness may demonstrate a different threshold of the pituitary and the peripheral T3 receptors.