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.     

Graves' ophthalmopathy and subclinical hypothyroidism: diagnostic value of the thyrotropin releasing hormone test.

Five patients with Graves'' ophthalmopathy and no previously documented clinical or laboratory evidence of hyperthyroidism were studied. Their serum levels of thyroxine and triiodothyronine (T3) and their T3 uptake were normal. Although the baseline serum level of thyrotropin (TSH) was normal in two patients, it was increased on the other three, and when TSH releasing hormone (TRH) was administered the T3 response was impaired in three patients and the TSH response was exaggerated in all five. These findings facilitated the diagnosis of subclinical hypothyroidism and distinguished the patients from those with Graves'' ophthalmopathy and normal thyroid function or subclinical hyperthyroidism. Thyroid antibodies were detected in the serum of four of the five patients, suggesting the coexistence of chronic autoimmune thyroiditis; this disorder could account in part for the subclinical hypothyroidism, which was even present in the two patients in whom thyroid-stimulating immunoglobulin was found in the serum. These observations indicate the value of a TRH stimulation test in detecting subclinical hypothyroidism in patients with Graves'' ophthalmopathy who appear from clinical and routine laboratory studies to have normal thyroid function but could have normal function or subclinical hyperthyroidism.     

High incidence of chronic lymphocytic thyroiditis in apparently healthy school children: epidemiological and clinical study.

An epidemiological survey on the incidence of juvenile chronic lymphocytic thyroiditis was performed in 10,220 apparently healthy school children in Ishikawa district, Japan. The subject of present study included 6,244 school children (2,831 boys and 3,413 girls, ages 6-18 yrs.) in Kanazawa City and 3,976 children (2,055 boys and 1,921 girls, ages 6-18 yrs.) in Wajima City. The first group was selected as a representative of urban area and the second group as that of seaside area. Children who have goiter or firm thyroid were selected for testing antithyroglobulin and anti-microsomal antibodies in sera. Final diagnosis of chronic lymphocytic thyroiditis was made on histological specimen obtained by needle biopsy on the antibody positive subjects. The overall incidence of chronic lymphocytic thyroiditis in these children was 3.0 per 1,000, whereas the incidence in adolescent girls was as high as 8.2 per 1,000. There was a considerable sex difference in the prevalence, the ratio of female to male was 6.5:1, and the incidence increased with age. The incidence in seaside area was 5.3 per 1,000 that was significantly higher than in urban area, 1.4 per 1,000 (p less than 0.005). Histologically, 26 of 30 cases (87%) were classified as focal thyroiditis and 4 cases (13%) were diffuse thyroiditis. Serum T4-I and T3 values within normal range in all patients, but resting TSH was elevated in 1 of 23 cases and TSH response to TRH was exaggerated in 3 of 23 cases. Impaired organification of iodide was observed in 6 of 32 cases by iodide-perchlorate discharge test. The present study demonstrates that juvenile chronic lymphocytic thyroiditis is highly prevalent among apparently healthy school children and early recognition of the disease with preventive care for hypothyroidism in future should be stressed.     

A case with isolated ACTH deficiency accompanying chronic thyroiditis

An unusual case of isolated ACTH deficiency with coexisting chronic thyroiditis in a 53-year-old man is reported. The patient was admitted with a 2-year history of generalized fatigue, a 13-kg weight loss, muscular weakness, and frequent hypotensive and hypoglycemic attacks. On admission serum thyroxine and triiodothyronine were significantly elevated. Basal TSH concentration was not detected and TSH showed no response to TRH, but one month after replacement therapy with hydrocortisone it was shown that serum T3, T4 and TSH response were all within normal limits. Thyroid antibodies were positive and biopsy of the thyroid gland showed chronic thyroiditis. Arginine and 1-Dopa provoked a subnormal rise in GH with a maximum of 5.6 ng/ml and 5.0, respectively. One month after treatment with hydrocortisone, GH response to 1-Dopa and arginine increased to the normal range. Prolactin response to TRH was normal and FSH response to LHRH was also normal. LH showed an exaggerated response to LHRH, although a normal response was revealed after treatment with hydrocortisone. We also presented a summary of 44 Japanese cases, 23 males (mean age; 46 yrs old) and 21 females (mean age; 48 yrs old), with isolated ACTH deficiency.     

TSH and prolactin secretions in Hashimoto's thyroiditis following withdrawal of thyroid hormone therapy

Changes in the pituitary-thyroid axis in patients with Hashimoto's thyroiditis following withdrawal of thyroid suppressive therapy were analyzed. The group of patients with thyroid adenoma served as control (group I). Patients with Hashimoto's thyroiditis were divided into 2 groups on the basis of serum TSH levels 8 weeks after discontinuing the exogenous thyroid hormone (group II, less than 10 microunits/ml; group III, more than 10 microunits/ml). During treatment with L-T4(200 micrograms/day) or L-T3(50 micrograms/day), there was no significant difference in serum T4-I and T3 levels among the three groups. Following L-T4 withdrawal, basal serum TSH levels were higher at 2 to 8 weeks in groups II and III than in group I. Serum TSH response to TRH was greater at 4 to 8 weeks in groups II and III than in group I. Following L-T3 withdrawal, basal serum TSH levels were higher at 1 and 2 weeks in group II than in group I, while those of group III were consistently higher during the study. Higher TSH responses to TRH were observed at 1 to 8 weeks in groups II and III. Neither basal nor TRH-induced prolactin (PRL) secretion differed significantly among the three groups. We have demonstrated that pituitary TSH secretion in patients with Hashimoto's thyroiditis is affected more by withdrawal of thyroid hormone therapy than in patients with thyroid adenoma. In addition, the present findings suggest a difference between the sensitivity of thyrotrophs and lactotrophs in Hashimoto's thyroiditis after prolonged thyroid therapy is discontinued.     

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.     

Effect of triiodothyronine administration on the plasma TSH and prolactin responses to TRH in patients with hypothalamic-pituitary insufficiency.

A study was carried out in 10 patients with multiple pituitary hormone deficiencies to determine the response of thyroid-stimulating hormone (TSH) and prolactin (PRL) to thyrotropin-releasing hormone (TRH) and their suppressibility by treatment with triiodothyronine (T3) given at a dose of 60 microgram/day for 1 week. In 3 patients the basal tsh values were normal and in 7 patients, 2 of whom had not received regular thyroid replacement therapy, they were elevated. The response of TSH to TRH was normal in 6 patients and exaggerated in 4 (of these, 1 patient had not received previous substitution therapy and 2 had received only irregular treatment). The basal and stimulated levels of TSH were markedly suppressed by the treatment with T3. The basal PRL levels were normal in 7 and slightly elevated in 3 patients. The response of PRL to TRH stimulation was exaggerated in 2, normal in 6 and absent in 2 patients. The basal PRL levels were not suppressible by T3 treatment but in 4 patients this treatment reduced the PRL response to TRH stimulation. From these findings the following conclusions are drawn: (1) T3 suppresses TSH at the pituitary level, and (2) the hyperreactivity of TSH to TRH and the low set point of suppressibility are probably due to a lack of TRH in the type of patients studied.     

Effect of lithium on hypothalamic-pituitary-thyroid function in patients with affective disorders.

Hypothalamic-pituitary-thyroid (H.P.T.) function was assessed in 17 patients on maintenance doses of lithium carbonate for a mean period of 21 months (range 1-67 months) and by serial studies on four patients from the start of lithium treatment for a maximum of six months. An exaggerated thyrotrophin (TSH) response to intravenous thyrotrophin-releasing hormone (TRH) occurred in 14 of the 17 patients on maintenance treatment, though basal TSH levels were raised in only three. Two of the three patients were clinically and biochemically hypothyroid and showed a delayed recovery of normal H.P.T. function after lithium was stopped. There were no significant differences in thyroid hormone or basal TSH levels between the euthyroid lithium-treated.     

Effect of non aromatizable androgens on LHRH and TRH responses in primary testicular failure

We have assessed the gonadotropin, TSH and PRL responses to the non aromatizable androgens, mesterolone and fluoxymestrone, in 27 patients with primary testicular failure. All patients were given a bolus of LHRH (100 micrograms) and TRH (200 micrograms) at zero time. Nine subjects received a further bolus of TRH at 30 mins. The latter were then given mesterolone 150 mg daily for 6 weeks. The remaining subjects received fluoxymesterone 5 mg daily for 4 weeks and 10 mg daily for 2 weeks. On the last day of the androgen administration, the subjects were re-challenged with LHRH and TRH according to the identical protocol. When compared to controls, the patients had normal circulating levels of testosterone, estradiol, PRL and thyroid hormones. However, basal LH, FSH and TSH levels, as well as gonadotropin responses to LHRH and TSH and PRL responses to TRH, were increased. Mesterolone administration produced no changes in steroids, thyroid hormones, gonadotropins nor PRL. There was, however, a reduction in the integrated and incremental TSH secretion after TRH. Fluoxymesterone administration was accompanied by a reduction in thyroid binding globulin (with associated decreases in T3 and increases in T3 resin uptake). The free T4 index was unaltered, which implies that thyroid function was unchanged. In addition, during fluoxymesterone administration, there was a reduction in testosterone, gonadotropins and LH response to LHRH. Basal TSH did not vary, but there was a reduction in the peak and integrated TSH response to TRH. PRL levels were unaltered during fluoxymesterone treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

The hypothalamic-pituitary axis in diabetes mellitus

The hormonal response to LHRH and TRH was evaluated in three groups of male diaetics. Five patients were receiving therapy with the hypoglycemic agent glibenclamide, five were on NPH insulin and five were on dietary therapy alone. When compared to controls, the latter two groups had intact gonadotropin responses to LHRH. Despite normal basal gonadotropin levels, however, the group receiving glibenclamide therapy showed significantly exaggerated LH and FSH responses to LHRH. Both basal PRL and TSH levels, as well as the responses to TRH were normal in all three groups. These results indicate that LH, FSH, TSH and PRL secretion is intact in uncomplicated diabetes mellitus. The exaggerated LH and FSH responses to LHRH in the glibenclamide treated subjects are probably related to primary gonadal involvement; alternatively, there may be augmented pituitary gonadotropin secretion in this group.     

Relationship of iodide-induced increase in TSH response to TRH to changes in serum thyroid hormones.

Large doses of iodide (500 mg three times a day) administered to normal men for 10--12 days caused a rise in basal serum TSH and a concomitant rise in the peak TSH response to TRH. The basal and peak levels of TSH were highly correlated (p less than 0.001). However, the iodide-induced rise in the peak TSH after TRH was poorly correlated with concomitant changes in serum thyroid hormones. Serum T3 wa not lower after iodide and, while serum T4 was somewhat lower, the fall in serum T4 was unexpectedly inversely rather than directly correlated with the rise in the peak TSH response to TRH. Thus, increased TSH secretion after iodide need not always be directly correlated with decreased concentrations of circulating thyroid hormones even when large doses of iodide are used. Clinically, a patient taking iodide may have an increased TSH response in a TRH stimulation test even though there is little or no change in the serum level of T3 or T4.     

Thyrotropin-releasing hormone stimulation test in patients with pituitary pathology

OBJECTIVES: To evaluate the value of the thyrotropin-releasing hormone (TRH) stimulation test in the diagnostic work-up of the thyroid function in patients with pituitary pathology. METHODS: To compare the thyrotropin (TSH) response and the absolute and fold changes after TRH administration in 35 patients with pituitary pathology and 26 normal subjects. RESULTS: Nine of the patients and 2 of the normal subjects had a pathological response. No difference in the thyrotropic response to TRH was found either for the actual values, or for the absolute or fold changes of TSH between the groups. CONCLUSION: The role of the TRH test in the evaluation of thyroid function in patients with pituitary pathology is modest. The best variables for evaluation of the presence of central hypothyroidism are still a free thyroxine estimate combined with an inappropriately low TSH.     

Assessment of the relationship between serum thyroid hormone levels and peripheral metabolism in patients with anorexia nervosa

It has been observed that basal and/or TRH-stimulated serum TSH levels occasionally conflict with the actual values of circulating thyroid hormones in patients with anorexia nervosa. In the present study sixteen female patients with anorexia nervosa during self-induced starvation displayed clinical findings suggesting hypothyroidism, e.g., cold intolerance, constipation, bradycardia, hypothermia and hypercholesterolemia in association with decreased serum total T3 (62.8 +/- 5.2 ng/dl) and T4 (6.6 +/- 0.3 micrograms/dl). Markedly decreased T3 correlated positively with average heart rate (r = 0.5655, P less than 0.025) and negatively with total cholesterol (r = -0.7413, P less than 0.005). This result may suggest that peripheral metabolic state of the underweight anorexics depends considerably upon the serum T3 concentration. Despite decreased total thyroid hormones, free T4 assayed by radioimmunoassay was normal in all five cases examined (1.4 +/- 0.2 ng/dl) and the free T4 index in fifteen cases was normal except in one case. Basal TSH was not increased and TSH response to exogenous TRH was not exaggerated in any. These results may be compatible with a theory that free T4 has a dominant influence on pituitary TSH secretion. Furthermore, glucocorticoids may also have some influence on depressed TSH response, because an inverse correlation between increased plasma cortisol and the sum of net TSH increase after TRH was observed in twelve cases examined. In conclusion, it is suggested that normal sensitivity of peripheral tissues and pituitary thyrotroph to different circulating thyroid hormones is maintained in anorexia nervosa patients even during severe self-induced starvation, and that the metabolic state in these patients is considerably under the influence of circulating T3.     

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.     

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.     

A case of Graves' disease with false hyperthyrotropinemia who developed silent thyroiditis.

We encountered a patient who developed silent thyroiditis during the course of Graves' disease. The diagnosis of silent thyroiditis was made on the basis of a low thyroidal 131I uptake, no response to the thyrotropin releasing hormone (TRH) test, and subsequent hypothyroidism despite the presence of high titers of thyrotropin (TSH) receptor antibody (TRAb) and thyroid stimulating antibody (TSAb). The patient, in addition, had a discrepancy between serum TSH and thyroid hormone values. This was due to the presence of interfering substances that react to mouse IgG in the sera since serum TSH levels were decreased in a dose dependent manner by the addition of increasing amounts of mouse IgG to the sera. It should therefore be noted that silent thyroiditis can develop in patients with Graves' disease. Furthermore, clinicians should be aware that two-site immunoassay kits that use mouse monoclonal antibodies are subject to interference by some substances, possibly antibodies which react to mouse IgG.     

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.     

Maturation of the pituitary-thyroid axis during the perinatal period.

To clarify the maturation process of the pituitary-thyroid axis during the perinatal period, thyrotropin (TSH) response to thyrotropin releasing hormone (TRH) and serum thyroid hormone levels were examined in 26 healthy infants of 30 to 40 weeks gestation. A TRH stimulation test was performed on 10 to 20 postnatal days. Basal concentrations of serum thyroxine (T4), free thyroxine (free T4) and triiodothyronine (T3) were positively correlated to gestational age and birth weight (p less than 0.001-0.01). Seven infants of 30 to 35 gestational weeks demonstrated an exaggerated TSH response to TRH (49.7 +/- 6.7 microU/ml versus 22.1 +/- 4.8 microU/ml, p less than 0.001), which was gradually reduced with gestational age and normalized after 37 weeks gestation. A similar decrease in TSH responsiveness to TRH was also observed longitudinally in all of 5 high responders repeatedly examined. There was a negative correlation between basal or peak TSH concentrations and postconceptional age in high responders (r = -0.59 p less than 0.05, r = -0.66 p less than 0.01), whereas in the normal responders TSH response, remained at a constant level during 31 to 43 postconceptional weeks. On the other hand, there was no correlation between basal or peak TSH levels and serum thyroid hormones. These results indicate that (1) maturation of the pituitary-thyroid axis is intrinsically controlled by gestational age rather than by serum thyroid hormone levels, (2) hypersecretion of TSH in preterm infants induces a progressive increase in serum thyroid hormones, and (3) although there is individual variation in the maturation process, the feedback regulation of the pituitary-thyroid axis matures by approximately the 37th gestational week.     

Transient hypothyroidism associated with increased anti-microsomal antibodies.

An unusual case of transient hypothyroidism during the course of chronic thyroiditis was reported. A 25 years old female noticed the remarkable enlargement of thyroid gland 3 months after paturition and was developed to be hypothyroidism with decreased blood thyroid hormone and increased serum TSH. The patient recovered to be euthyroid spontaneously in association with the decrement of goiter size. Anti-thyroid microsomal antibody increased concomitantly with hypothyroid period and decreased parallel with the recovery of thyroid function. The ratio of TSH potency estimated by bioassay to that by immunoassay changed during the course. Possible etiologic factors of this transient changes were discussed.