Abnormal TSH Response Research Articles

ANE syndrome caused by mutated RBM28 gene: a novel etiology of combined pituitary hormone deficiency

A homozygous loss-of-function mutation in the gene RBM28 was recently reported to underlie alopecia, neurological defects, and endocrinopathy (ANE) syndrome. The aim of the present study was to characterize the endocrine phenotype of ANE syndrome and to delineate its pathogenesis. Detailed neuroendocrine assessment was performed in five affected male siblings harboring the homozygous p.L351P mutation in RBM28. All five affected patients, aged 20-39 years, displayed absent puberty, hypogonadism, and variable degrees of short stature. Low IGF1 concentration and a lack of GH response to provocative tests in all siblings were consistent with GH deficiency. Low testosterone and gonadotropin levels with absence or low response to GnRH stimulation indicated hypogonadotropic hypogonadism. ACTH deficiency evolved over time, and glucocorticoid replacement therapy was initiated in four patients. Thyroid analysis showed variable abnormal TSH response to TRH stimulation, suggesting hypothalamic compensated hypothyroidism in four subjects and laboratory hypothyroidism (low free thyroxine) in one patient. Low prolactin levels were shown in one case. The endocrine defects characteristic of ANE syndrome are compatible with variable combined anterior pituitary hormone deficiency (CPHD), which evolves gradually over the years, indicating long-term hormonal monitoring. We propose that defects in the cellular Wnt/beta-catenin signaling pathway underlie this endocrinopathy. RBM28 gene defects should be added to the growing list of gene defects associated with syndromic CPHD.

A relação entre a função tireoidiana e a depressão: uma revisão

The role of the thyroid gland in primary depressive disorder is unclear. Although there is evidence that patients with subtle underlying defects in thyroid function may be more prone to developing depressive disease, the specific abnormality in thyroid function associated with depressive disorders remains poorly understood. In this review, we outline the major findings concerning depression and thyroid function, with particular attention on the relationship between thyroid function and cerebral monoamines. Literature searches were performed by Medline, with secondary-source follow-up. The documented hypothalamus-pituitary-thyroid (HPT) axis abnormalities in some depressed patients are: elevated T4 concentrations, abnormal TSH responses to TRH; presence of antithyroid antibodies and elevated CSF - TRH concentrations. The relation of these abnormalities of HPT function, the main monoamines and the diagnostic subtypes of patients with depression is complex and does not directly support a linear relationship. After many years of research, the precise relationship between the HPT axis and depressive disorders remains obscure, and the mechanism underlying the thyroid abnormalities in depressive patients remains indeterminate. Thus, considerable further investigation will be necessary to understand the role of the HPT axis in the pathogenesis and treatment of depressive disorders.

Three year follow-up of borderline congenital hypothyroidism

The purpose of this study was to determine whether children with borderline hypothyroidism in the neonatal period had persistent hypothyroidism after 3 years of levothyroxine replacement therapy. Fourteen term infants with slightly abnormal newborn screening results (thyroxine < 10th percentile, thyroid stimulating hormone [TSH] <40 μU/mL) were identified. The subsequent serum confirmatory TSH results of 12 subjects were modestly elevated (5.3 to 18.8 μU/mL, normal 0.6 to 4.6), whereas 2 subjects who had borderline confirmatory TSH (4.6 and 4.7 μU/mL) had abnormal TSH responses to thyrotropin releasing hormone testing. After 3 years of therapy, levothyroxine was discontinued in 13 patients, and repeat thyroid function tests were obtained 1 month later. Levothyroxine was not discontinued in one patient because he had an elevated random TSH (10 μU/mL) while receiving therapy. At 3 years of age, 13 patients had persistently abnormal thyroid function tests (TSH >4.6 μU/mL or a thyroid releasing hormone test result consistent with primary hypothyroidism), and levothyroxine was reinitiated. Only one patient had normal thyroid function studies. Although prospective studies are still lacking, we recommend levothyroxine replacement in newborns with borderline hypothyroidism.

Endocrine disorders in 66 suprasellar and pineal tumors of patients with prepubertal and pubertal ages.

Tumor oncotypes, initial symptoms and endocrine disturbances before and/or 1 month after surgery were studied in 66 patients with prepubertal and pubertal ages having suprasellar or pineal intracranial tumors. Neoplasms found in patients of prepubertal age were: 15 craniopharyngiomas (CRA), 24 neuroepithelial-cell-derived tumors (NEC), 5 germ cell tumors (GERM) and 4 other lesions (OTHER). In patients of pubertal age, there were 7 CRA, 7 pituitary tumors (PIT), 2 NEC, 1 GERM and 1 OTHER. Approximately 90% of patients had visual abnormalities as one of the initial signs and symptoms, while 59% had increased intracranial pressure. Short stature was observed in only 10% of patients. Before surgery, somatotropic function was found to be deficient (by 2 pharmacological tests) in 90-100% of patients with CRA, PIT or GERM and in 40% of patients with NEC. Overt hypothyroidism was found in 5-25% of CRA, NEC or GERM but in 40% of PIT. Abnormal TSH responses to TRH were observed in 64% of CRA and in 29% of NEC. Low basal serum cortisol was found in 21 or 6% of patients with CRA or NEC, but in 100 or 60% of patients with PIT or GERM, respectively. Diabetes insipidus was diagnosed in 13.6% of all patients. Surgery produced few additional disturbances in endocrine function, except for the incidence of diabetes insipidus which was doubled. Gonadotropic deficiency was found in most patients of pubertal age with CRA and PIT. They were readily differentiated by the high prolactin or growth hormone (GH) levels of the latter.(ABSTRACT TRUNCATED AT 250 WORDS)

The growth hormone, prolactin and TSH response to TRH and L‐dopa in patients with hyperprolactinaemia and a normal‐sized sella turcica may denote a pituitary adenoma

Forty-one patients with hyperprolactinaemia and suspected prolactinomas were studied. Growth hormone (GH) and thyrotropin (TSH) secretory patterns after thyrotropin releasing hormone (TRH) were affected in the majority of patients. The disturbances were observed regardless of tumour size as indicated by the radiological sella size. In patients with hyperprolactinaemia and normal-sized sella turcica, an abnormal GH and TSH response to TRH can be helpful in the diagnosis of a microadenoma. The hyperprolactinaemia per se and its effect on dopaminergic hypothalamic neurones may be the cause of the GH and TSH response. By contrast, many patients with macroprolactinomas showed insufficient GH secretory capacity.

Iodine-Induced Hypothyroidism in Euthyroid Subjects with a Previous Episode of Subacute Thyroiditis*

The effects of the administration of pharmacological quantities of iodide on thyroid function in 18 euthyroid patients with a previous history of painful subacute thyroiditis (SAT) were evaluated, and the results compared to those of iodide administration to 12 euthyroid patients with a previous history of thyroid surgery (TX) for benign nodular thyroid disease. After baseline thyroid function tests, saturated solution of potassium iodide (SSKI; 10 drops; 300 mg iodide) was administered daily for 120 days, and serum T4, T3, and TSH concentrations were assessed 15, 30, 60, 90, 120 days and 2-4 months after SSKI was discontinued. Iodide perchlorate discharge tests were carried out before SSKI administration, and TRH tests were performed on the last day of iodide administration. Two SAT subjects developed clinical evidence of hypothyroidism with markedly elevated serum TSH concentrations, and SSKI was discontinued on days 60 and 90, respectively. Thirteen of 18 SAT patients had at least 1 abnormal thyroid function test (iodide perchlorate discharge test, elevated serum TSH concentration, and abnormal TSH response to TRH) compared to 2 of 12 TX patients. These findings strongly suggest that euthyroid subjects with a previous history of SAT are prone to develop iodide-induced hypothyroidism, suggesting that subtle abnormalities in the thyroid organification of iodide and subsequent thyroid hormone synthesis persist years after the episode of SAT.

The effect of selective noradrenergic denervation on thyrotropin secretion in the rat

The effect of DSP4 [N-(2-chloroethyl)-N-ethyl-2 bromobenzylamine], a neurotoxin which selectively lesions noradrenergic projections from the locus coeruleus, on thyrotropin (TSH) secretion was investigated in the rat. DSP4 treatment (60 mg/kg injected i.p. 10 days prior to experimentation) significantly decreased the noradrenaline (NA) content of the hippocampus, frontal cortex and hypothalamus of the rat brain. DSP4 treatment did not affect the clonidine (250 micrograms/kg, i.p ) or TSH-releasing-hormone (TRH 5 micrograms/kg i.v.) induced stimulation or the isoproterenol induced inhibition of TSH secretion in the rat. These results suggest that the noradrenergic projection from the locus coeruleus to the hypothalamus does not play a significant role in the regulation of TSH secretion. Furthermore, the noradrenergic deficiency did not give rise to the development of the abnormal TSH response to TRH administration which is frequently observed in depression.

Impact of improved tsh assays on definitions of abnormal TSH response to TRH

Impact of improved tsh assays on definitions of abnormal TSH response to TRH

Abnormal Thyroid Function In Hyperemesis Gravidarum

Thyroid function was evaluated in 41 consecutive women with hyperemesis gravidarum (HG). In 11, increased free thyroxin concentrations (FT4) were measured. After one week of conservative therapy, 4 patients with persistent emesis were treated with antithyroid agents. Three of these 4 displayed other signs of hyperthyroidism. Emesis resolved in the other 7 patients within a week of conservative therapy. FT4 levels also returned to normal in these 7 patients within several weeks. Thyrotropin-releasing hormone (TRH) was administered to 10 of the 11 patients. Abnormal TSH responses, suggesting varying degrees of autonomous thyroid function were noted in all 4 patients treated with antithyroid drugs and in 3 of the untreated patients. Underlying clinical signs and symptoms of hyperthyroidism should be sought in patients with HG. In the presence of persistent emesis, despite conservative therapy of at least one week's duration and the presence of abnormal thyroid function studies, the use of antithyroid agents should be considered.

Serum thyrotropin (TSH) responses to thyrotropin-releasing hormone (TRH) in patients with anorexia nervosa and bulimia: Influence of changes in body weight and eating disorders

Serum thyrotropin (TSH) responses to thyrotropin-releasing hormone (TRH) were studied in 47 women with anorexia nervosa (AN) (group I) and in 11 bulimic patients of normal weight (group II). In group I, TSH responses were low in nine patients, delayed in 32 and normal in six. Patients with a normal TSH response had a lesser degree of anorexia than those with a delayed TSH response. Bulimia and vomiting were more frequently observed in the low response group. The maximum increase in TSH concentrations following TRH administration in the group I patients with vomiting (4.0 ± 0.90 μU/ml, mean ± S.E.) was significantly lower than that in the group I patients without vomiting or in normal controls (11.2 ± 0.82 μU/ml and 11.1 ± 2.34 μU/ml, respectively). Twenty-five patients with abnormal TSH responses in group I were retested after weight gain. Initially, TSH responses were low in six and delayed in 19. Following weight recovery, responses continued to be abnormal in five of the six and in eight of the 19, respectively. The symptoms of eating disorders continued in all patients with abnormal TSH responses even after weight recovery, whereas patients with normal responses after weight gain recovered from all symptoms. Of 11 patients in group II, six had abnormal TSH responses to TRH; the responses were delayed in four and low in two. Patients with normal responses had a lesser degree of eating disorder, compared with abnormal responders. These observations suggest that abnormal TSH responses in patients with AN were not necessarily due to weight loss alone; rather, they may be related to the eating disorder itself.

Normal thyrotrophin response to intravenous thyrotrophin releasing hormone administration: the best index of optimal L-thyroxine therapy in primary hypothyroidism.

Normalization of basal thyrotrophin (TSH) level is used as the endpoint in L-thyroxine (L-T4) therapy of primary hypothyroidism. However, several reports have questioned the reliability of this index because of seasonal variation of TSH. Therefore, we studied 85 consecutive patients with primary hypothyroidism over a period of 3.5 y. In these patients, TSH response (delta TSH) to intravenous thyrotrophin releasing hormone (TRH) administration was examined when basal TSH was normalized with L-T4 therapy. Eight patients showed a blunted response (delta TSH less than 5 microU), whereas 27 patients demonstrated an exaggerated response (delta TSH greater than 25 microU). Thus, 42% of patients were apparently on inappropriate L-T4 dosage. These abnormal TSH responses normalized on adjusting the L-T4 dosage alone; prolonged therapy with the same dose failed to normalize TSH responses. Minor seasonal variations of basal TSH were observed in 30% of patients. However, TSH response to TRH remained normal. Hence, no adjustment of L-thyroxine dose was required. This study, therefore, demonstrates that normalization of TSH response to TRH administration rather than basal TSH may be the best index of adequate L-thyroxine therapy in primary hypothyroidism.

Masked Thyroid Dysfunction in Elderly Patients With Atrial Fibrillation

To the Editor. —We read with interest the article by Cobler et al 1 in the SeptemberArchives. We recently studied masked thyroid dysfunction in 72 elderly patients with atrial fibrillation (40 men, 32 women; mean age, 75.6 years). Patients with mitral stenosis and apparent thyroid disease were excluded from our study. Thyroid dysfunction was diagnosed by determinations of triiodothyronine (T 3 ) and thyroxine (T 4 ) radioimmunoassay levels, T 3 resin ratio, thyrotropin (thyroidstimulating hormone [TSH]) level, and TSH response to 250 μg of intravenous thyrotropin-releasing hormone (TRH). If hyperthyroidism was suspected, an iodine 123 uptake test or a thyrotropin-binding-inhibitory immunoglobulin assay or both were carried out. A TRH stimulation test was also performed in 30 age-matched controls without atrial fibrillation. None of the controls had an abnormal TRH-stimulated TSH response. In patients with atrial fibrillation, hyperthyroidism was found in five cases (6.9%), while hypothyroidism was found in six cases

926 LONG TERM ENDOCRINE SEQUELAE IN MEDULLOBLASTOMA PATIENTS

Over 50% of pts. with medulloblastoma who receive conventional therapy with craniospinal irradiation will be alive and free of disease five yrs. from diagnosis. Endocrine evaluation was performed in 22 pts. aged 2½-23½ yrs. at time of diagnosis, status post treatment for medulloblastoma. Evaluations were performed 2 mos. to 6 3/4 yrs. after diagnosis. The pts. received either 12 mos. of chemotherapy and/or radiation therapy. The mean radiation dose to the neuraxis and hypothalamus was 3600 rads. Three pts. had completed their growth prior to onset of disease. Post-treatment, decreased growth rates were observed in 13 pts. Only 3 of 10 pts. tested had deficient GH response to stimulation. Elevated TSH levels were noted in 15 pts. with abnormal TSH responses to TRH in 13 of 13 tested. Compensated thyroidal hypothyroidismwas observed in 13 pts., 1 patient each had thyroidal hypothyroidism, or hypothalamic hypothyroidism. We conclude that an abnormal growth rate associated with a normal GH response to standard stimuli, postulated to be caused by growth hormone neurosecretory dysfunction, and compensated hypothyroidism are frequent complications of therapy for medulloblastoma. Further, standard provocative tests of GH reserve are inadequate to define neurosecretory growth dysfunction; a trial of GH treatment may be indicated in children with poor growth rates. In addition, treatment with thyroid hormone of patients with compensated hypothyroidism should be considered. These therapies may allow achievement of normal growth and development and thus, decrease survivor's morbidity.

Gonadotropin, prolactin and TSH secretion in patients with myasthenia gravis

Hypothalamic pituitary function was studied in 13 patients with myasthenia gravis. Gonadotropin, TSH, and prolactin dynamics were investigated using conventional provocative stimuli. No consistent abnormality was found in either gonadotropin or prolactin release. Abnormal TSH responses to TRH administration was present in six of the 13 patients in association with normal free thyroxine indices and the absence of antithyroid antibodies. This latter observation is relevant when the association of myasthenia gravis with hyperthyroidism, thyroiditis and hypothyroidism is considered.

PROLACTIN AND TSH RESPONSES TO THE IN 146 HYPOPITUITARY DWARFS

Prolactin (PRL) and TSH were measured from 0 to 90-120 minutes after TRH 0.2 mg IV in 146 hypopituitary dwarfs : 76 with cranial radiotherapy and/or hypothalamic lesions (groupe A) and 70 without grossly detectable lesion (group B) including 14 after breech presentation and 19 isolated GH deficiency. Abnormal PRL responses, either delayed or outside the normal range, were found in 71 patients, 45 from group A (59 %) and 26 from group B (37 %). Abnormal TSH responses, delayed or outside the normal range, or in the normal range with low plasma T4, were found in 90 patients : 50 from group A (66 %) of which 26 had low T4 and 40 from group B (57 %) of which 19 had low T4. One of the responses at least was abnormal in 113 (77 %): 63 from group A (83 %) and 50 from group B (71 %), only 49 patients showing abnormal responses of both hormones. In group B, 19 patients with otherwise isolated GH deficiency and normal T4 had an abnormal response of one or two hormones. It may be concluded that 1/considering both TSH and PRL responses, TRH test is abnormal in most hypopituitary dwarfs including otherwise isolated GH deficient subjects. 2/ While the percentage of normal TSH response seems identical in the different etiological types an abnormal PRL response is more frequent in lesional hypopituitarism.

THYROID FUNCTION AND THYROID REGULATION IN EUTHYROID MEN WITH CHRONIC LIVER DISEASE: EVIDENCE OF MULTIPLE ABNORMALITIES

SUMMARYTotal and free serum thyroxine (T4) and triiodothyronine (T3), basal serum thyrotrophin (TSH) and the serum TSH response to a standard intravenous dose of thyrotrophin releasing hormone (TRH) have been measured in fifteen men with liver cirrhosis and in eight alcoholic men with fatty liver change. All the patients studied were clinically euthyroid. In cirrhotics, total T4 and free T4 (FT4) concentrations were normal as were free T3 (FT3) concentrations but total T3 concentrations were significantly reduced and basal TSH concentrations were significantly higher than normal. Alcoholics with fatty liver change had normal basal TSH concentrations and normal total and free thyroid hormone concentrations apart from reduced FT4. Correlation of thyroid function tests with liver function (serum albumin concentration) showed significant positive correlations for serum albumin with both total T3 and FT3 and significant negative correlations with both FT4 and basal TSH. Nine of fifteen cirrhotics had an abnormal serum TSH response to TRH, the commonest abnormal pattern being a delayed response (seven patients). Three of eight alcoholics with fatty liver change also had an abnormal TSH response to TRH. These findings not only show complex disturbances in hypothalamic‐pituitary‐thyroid relationships in chronic liver disease but also provide indirect evidence of reduced extra‐thyroidal conversion of T4 to T3.

Function of Hypothalamo-Pituitary Thyroid Axis in Depressed Patients

Nineteen out of 51 depressed patients showed abnormal TSH response to TRH in terms of exaggerated, diminished and delayed responses. The basal value of T3 and its response to TRH were significantly lower in patients with delayed or diminished response than in the normal subjects. These results indicate that the dysfunction of the hypothalamo-pituitary thyroid axis plays an important role in the pathogenesis of depression.

Abnormal TSH, PRL and GH response to TSH releasing factor in chronic renal failure.

TSH, PRL and GH response to TSH releasing factor as well as basal T4 and T3 were evaluated in a group of patients with chronic renal failure undergoing chronic hemodialysis. Serum T4 and T3 were lower than normal. Basal TSH was normal as compared to control, but did not rise after TRF stimulation. Larger dosages of TRF did not correct this abnormal response. Basal PRL was higher than control and remained at the same level during the test. GH was stimulated by the TRF with a peak occurring 20 min after injection. This abnormal secretion was not blunted by T3 administration. TRF half-life measured in 3 patients was 4 min. These data indicate that 1) there is an abnormal response to TRF in chronic renal failure which does not seem to be due to an altered sensitivity to, or metabolism of TRF; and 2) there is an abnormal TSH secretion which may be responsible for the low T4 and T3 measured in these patients.

Two cases of the chromatin positive variety of ovarian dysgenesis (XO/XX mosaicism) associated with hGH deficiency and marginal impairment of other hypothalamic‐pituitary functions

Plasma hGH response to provocative tests (insulin-induced hypoglycaemia and arginine infusion) appears normal in Turner's syndrome. Two cases are reported of the chromatin positive variety of ovarian dysgenesis (XO/XX mosaicism) with unusual absence of plasms hGH response to provocative tests (arginine infusion, insulin-induced hypoglycaemia). Study of other pituitary functions supports the view that a hypothalamic-pituitary impairment is present in these cases. In fact, in these cases we observed low values of gonadotrophin excretion and limited responses of plasma ACTH and plasma corticosteroids to provocative tests (insulin-induced hypoglycaemia, metopyrone). Moreover, markedly abnormal plasma TSH response to TRF was observed in Case 2. The results are discussed with reference to the significance of this rare association.