Variation of pituitary thyrotropin reserve with different dosages of thyrotropin-releasing hormine (TRH) -- mode of failure of pituitary thyrotropin reserve.
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Elimination kinetics of maternally derived thyrotropin receptor-blocking antibodies in a newborn with significant thyrotropin elevation.
OBJECTIVE: To determine the course of maternally derived elevations in thyrotropin-binding inhibitory immunoglobulins in a neonate. DESIGN: Case report. SETTING: University pediatric endocrinology clinic and endocrine immunology laboratory in Ohio. PARTICIPANTS: An infant with elevated thyrotropin levels but near-normal total thyroxine levels, and her mother. INTERVENTIONS: None. MEASUREMENTS/MAIN RESULTS: Thyroid hormone, thyrotropin, and thyrotropin-blocking immunoglobulin concentrations were serially measured in a woman and her infant, who was found to have elevated thyrotropin levels (234 mU/L) and borderline low thyroxine levels (95 nmol/L). As infant thyroxine concentrations remained normal (125 to 145 nmol/L), no thyroxine supplementation was given. Thyrotropin levels decreased concomitantly with thyrotropin-blocking inhibitory immunoglobulin levels, and normalized by day 56 of life. The apparent elimination half-life of thyrotropin-blocking immunoglobulins was 7.5 days. CONCLUSIONS: The observed parallel elimination kinetics suggest that the thyrotropin receptor antibody acts as a thyrotropin antagonist, resulting in compensatory thyrotropin elevations. The duration of such elevations may be predicted on the basis of such elimination.
Autoantibodies↗
Experimental exophthalmos. Binding of thyrotropin and an exophthalmogenic factor derived from thyrotropin to retro-orbital tissue plasma membranes.
Biologically active preparations of 125I-thyrotropin, [3H]thyrotropin, and the [3H]exophthalmogenic factor derived from thyrotropin by partial pepsin digestion have been used to study the binding properties of the thyrotropin receptor on guinea pig retro-orbital tissue plasma membranes. In regard to the optimal conditions of binding, pH, buffer, salt concentrations, and temperature, these properties are the same as those described in any accompanying report concerning thyrotropin binding to bovine thyroid plasma membranes (Tate, R.L., Schwartz, H.I., Holmes, J.M., Kohn, L.D., and Winand, R.J. (1975) J. Biol. Chem. 250, 6509-6515). In addition, thyrotropin receptors on the retro-orbital tissue plasma membranes are similar to thyrotropin receptors on bovine thyroid plasma membranes in their apparent negative cooperativity and in their relative affinities for luteinizing hormone, the beta subunit of thyrotropin, and the alpha subunit of thyrotropin. In contrast, gamma-globulin from patients with malignant exophthalmos enhances binding when added to incubation mixtures containing the retro-orbital tissue plasma membranes but not when added to those containing thyroid plasma membranes. Normal gamma-globulin and gamma-globulin from Graves' disease patients without exophthalmos do not have this property. The gamma-globulin itself does not bind to the membrane except in the presence of thyrotropin or its exophthalmogenic factor derivative. Tryptic digestion of the retro-orbital tissue membranes releases specific thyrotropin and exophthalmogenic factor binding activity into the supernatant phase. Chromatography on Sephadex G-100 indicates that this trypsin-released receptor activity has a molecular weight of 75,000 or greater, rather than 15,000 to 30,000 for the trypsin-released receptor activity from bovine thyroid membranes (Tate, R.L., Schwartz, H.I., Holmes, J.M., Kohn, L.D., and Winand, R.J. (1975) J. Biol. Chem. 250, 6509-6515).
Animals↗
Plasma somatostatin correlates with blunted thyrotropin secretion after stimulation by thyrotropin-releasing hormone in critical illness.
To clarify whether plasma somatostatin affects thyrotropin secretion in critical illness, plasma somatostatin and thyrotropin responses to thyrotropin-releasing hormone were studied in forty-three critically ill patients. High somatostatin levels were associated with blunted thyrotropin secretion in critically ill patients. There was an inverse correlation between plasma somatostatin levels and the maximum increment of thyrotropin after stimulation by thyrotropin-releasing hormone. Decreased somatostatin and increased thyrotropin secretion before discharge from the intensive care unit were demonstrated in survivors. On the other hand, non-survivors maintained high somatostatin levels and had blunted thyrotropin secretion during their intensive care admission. These results suggest that high plasma somatostatin levels may play a role in the blunted thyrotropin secretion observed in critical illness.
APACHE↗
In Chinese hamster ovary K1 cells dog and human thyrotropin receptors activate both the cyclic AMP and the phosphatidylinositol 4,5-bisphosphate cascades in the presence of thyrotropin and the cyclic AMP cascade in its absence.
Thyrotropic hormone, through its human thyrotropin receptor, activates both the cyclic AMP and the phosphatidylinositol 4,5-bisphosphate-phospholipase-C cascades in human thyroid cells and in Chinese hamster ovary cells (CHO-K1) expressing this receptor. However, thyrotropin only activates the cyclic-AMP cascade in dog thyroid cells. In order to establish whether this different pattern of responses reflects a different structure of the human and dog thyrotropin receptors, CHO-K1 cells were permanently transfected with a plasmid coding for one or the other receptor. For various levels of receptor expression, CHO-K1 cells expressing either receptor presented qualitatively similar cyclic AMP and inositol phosphates responses to thyrotropin. This suggests that the difference in the response of the dog and human thyroid to thyrotropin involves elements of the phosphatidylinositol 4,5-bisphosphate cascade downstream of the receptor. In CHO-K1 cells overexpressing the thyrotropin receptor, the basal level of cyclic AMP was raised, suggesting a constitutive activity of the wild-type receptor. This was confirmed in COS-7 cells transiently expressing the human or dog thyrotropin receptors, the basal cyclic AMP levels of these cells increased in parallel with thyrotropin binding. This spontaneous activity of the thyrotropin receptor may have physiological and pathological consequences.
Animals↗
Relationship of gangliosides to the structure and function of thyrotropin receptors: their absence on plasma membranes of a thyroid tumor defective in thyrotropin receptor activity.
Plasma membranes derived from rat thyroid tumor (1-8R) which is unresponsive to thyrotropin but is responsive to dibutyryl adenosine 3':5'-cyclic monophosphate bind less than 20% of the [125I] thyrotropin which can be bound to plasma membranes from normal rat thyroids under conditions which optimize tumor membrane binding relative to normal thyroid membranes. In addition, the binding is different from thyrotropin binding to normal thyroid membranes both in its altered sensitivity to changes in hydrogen ion concentration and in a decreased sensitivity to competition by unlabeled thyrotropin. This reduced capacity to bind [125I] thyrotropin cannot be attributed to degradation of the hormone by membrane-associated proteases. Although the supernatant phase of the thyroid tumor homogenates contains a soluble component which inhibits [125I] thyrotropin binding to thyrotropin receptors on plasma membranes, its level is the same as in homogenates of normal thyroid tissue. Trypsin digestion does not expose thyrotropin receptors in a manner analogous to that seen in normal thyroid tissue. The major ganglioside in the tumor membranes is N-acetylneuraminylgalactosylglucosylceramide and the membranes lack the N-acetylgalactosaminyltransferase required for the synthesis of more complex gangliosides. In contrast, the normal rat thyroid membranes contain more complex gangliosides such as galactosyl-N-acetylgalactosaminyl-[N-acetylneuraminyl]-galactosylglucosylceramide and N-acetylneuraminylgalactosyl-N-acetylgalactosaminyl-[N-acetylneuraminyl]-galactosylglucosyl ceramide as well as the glycosyltransferase activities required for their syntheses. Galactosyl-N-acetylgalactosaminyl-[N-acetylneuraminyl]-galactosylglucosylceramide can also be detected in normal membranes, but not in tumor membranes, by selective labeling with galactose oxidase (D-galactose: oxygen 6-oxidoreductase, EC 1.1.3.9) and [3H] sodium borohydride. These results support the hypothesis that gangliosides are important structural or functional components of thyrotropin receptors on thyroid plasma membranes.
Animals↗
Thyrotropin-ganglioside interactions and their relationship to the structure and function of thyrotropin receptors.
Gangliosides inhibit 125I-labeled thyrotropin binding to the thyrotropin receptors on bovine thyroid plasma membranes, on guinea pig retro-orbital tissue plasma membranes, and on human adipocyte membranes. This inhibition by gangliosides is critically altered by the number and location of the sialic acid residues within the ganglioside structure, the efficacy of inhibition having the following order: GD1b greater than GT1 greater than GM1 greater than GM2 = GM3 greater than GD1a. The inhibition results from the interaction of thyrotropin and gangliosides, rather than the interaction of membrane and gangliosides. Fluorescence studies show that the inhibition is associated with a distinct conformational change of the thyrotropin molecule and that the progression from a "noninhibitory conformation" to an "inhibitory conformation" parallels exactly the order of effectiveness in inhibiting 125I-labeled thyrotropin binding. The ganglioside inhibition of 125I-labeled thyrotropin binding appears to be hormonally specific in that it is not affected by albumin, glucagon, insulin, prolactin, follicle-stimulating hormone, growth hormone, or corticotropin. The possibility that a ganglioside or ganglioside-like structure is a component of the thyrotropin receptor is suggested by the finding that gangliosides more complex than N-acetylneuraminylgalactosylglucosylceramide are present in bovine thyroid membranes in much higher quantities than have been previously found in extraneural tissue. The finding that the B component of cholera toxin, which also interacts with gangliosides, has a peptide sequence in common with the beta subunit of thyrotropin, suggests that thyrotropin and cholera toxin may be analogous in their mode of action on the membrane.
Adipose Tissue↗
The interaction of radioiodinated thyrotropin with human plasma membranes from normal and diseased thyroid glands. Relation of thyrotropin binding to adenylate cyclase activity.
Plasma membranes have been purified from homogenates of normal human thyroid glands and multinodular euthyroid and Graves' goitres by discontinuous sucrose gradient centrifugation. Preparations of reasonable purity were obtained containing specific binding sites for thyrotropin and thyrotropin-sensitive adenylate cyclase. Optimum conditions for 125I-labeled thyrotropin binding were pH 7.8 and 37 degrees C. Sodium ions and concentration of Tris above 20 mM reduced thyrotropin binding. Human plasma membranes showed no species specificity toward thyrotropins from 3 different species (ox, hog and man). Displacement curves of I125-labeled bovine thyrotropin by unlabeled hormones was in the order of increasing concentrations of bovine, porcine and human highly purified thyrotropins and was inversely related to the specific biological activity of these preparations as determined by the bioassay in the mouse. Analysis of the interaction between membranes and 125I-labeled thyrotropin resulted in curvilinear Scatchard plots which can indicate the presence of two types of sites with high affinity -- low capacity (KD = 5 nM) and low affinity -- high capacity (KD = 500 nM) or site -- site interaction of the negative cooperativity type. No significant difference in binding site characteristics was found in normal and diseased glands (multinodular and Graves' goitres). A good correlation was found at equilibrium and in the conditions of adenylate cyclase assay between receptor occupancy and cyclase activation by b-thyrotropin.
Adenylyl Cyclases↗
Influence of human anti-mouse antibodies on thyrotropin in-vitro analysis: a comparison of 6 thyrotropin IRMA kits.
OBJECTIVE: The aim of the study was to evaluate the influence of human anti-mouse antibodies on the measurement of thyrotropin. INVESTIGATIONS: Samples from 11 patients with measureable human anti-mouse antibody titres (19 micrograms/l-3880 micrograms/l) after radioimmuno-scintigraphy were analysed with 6 different thyrotropin immuno-radiometric assay kits (IRMA). Each sample was analysed in the routine way (sample influenced by human anti-mouse antibodies), as well as after incubation with murine immunoglobulin to precipitate human anti-mouse antibodies (samples not influenced by human anti-mouse antibodies). RESULTS: Two kits showed clear deviations of measured thyrotropin levels when the human anti-mouse antibody titres were higher than 1350 micrograms/l. A third kit was influenced to a lesser extent by human anti-mouse antibodies. Three of the 6 investigated thyrotropin IRMA kits produced thyrotropin values that were unaffected by the presence of elevated human anti-mouse antibodies. In comparison with former studies after immunotherapy, the thyrotropin deviations were marginal. However, differences were found between the commercially available thyrotropin assays. According to the results of this study only three out of the six investigated kits were unaffected by human anti-mouse antibodies. CONCLUSION: Since thyrotropin is one of the key quantities for the endocrinologist dealing with the thyroid gland, every laboratory should ensure high quality thyrotropin assays by critically analysing their method for human anti-mouse antibody.
Adult↗
Negative correlation between the conversion of thyrotropin receptor-bound blocking type thyrotropin receptor antibody to the stimulating type by anti-human IgG antibodies and the biological activity of blocking type thyrotropin receptor antibody.
It has been reported that receptor-bound blocking type TSH receptor antibody (TRAb) can be converted to the stimulating type by anti-human IgG antibodies. To evaluate the relationship between the conversion of receptor-bound blocking type TRAb to the stimulating type and the biological activity of blocking type TRAb, we compared converting activities of blocking type TRAb from 10 patients with primary nongoitrous hypothyroidism with both the doses of blocking type TRAb which show 50% inhibition of 125I-bTSH binding to the TSH receptor and those which show 50% inhibition of TSH-stimulated cAMP production in cultured rat thyroid cells (FRTL-5). The additions of anti-human IgG antibody to FRTL-5 cell-bound blocking IgGs resulted in the increase in cAMP production in a dose-dependent manner and the converting activities (percent increase of cAMP production) also depended on the doses of blocking IgGs. The converting activities were significantly correlated with the doses of blocking IgGs which showed 50% inhibition of 125I-bTSH binding to the TSH receptor (r = 0.71, p = 0.011). And these converting activities were also significantly correlated with the doses of blocking IgGs which showed 50% inhibition of TSH-stimulated cAMP increase (r = 0.81, p = 0.002), and were negatively correlated with thyroid stimulation blocking antibody activities (r = 0.58, p = 0.02). We have demonstrated that all cell-bound blocking type TRAb were converted to the stimulating type by anti-human IgG antibody and the degree of conversion was negatively correlated with the biological activity of blocking type TRAb.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Relationship of thyrotropin to exophthalmos-producing substance: formation of an exophthalmos-producing factor by pepsin digestion of mouse pituitary tumor and human thyrotropin preparations.
The present report demonstrates that mouse tumor thyrotropin preprarations have exophthalmogenic activity. In addition it shows that the exophthalmogenic activity of mouse tumor thyrotropin can be increased by partial pepsin digestion, whereas the thyroid stimulating activity of mouse tumor thyrotropin is rapidly destroyed by such treatment. Thus, after 30 min of pepsin digestion, mouse tumor thyrotropin has 130% of its initial exophthalmogenic action but only 10% of its thyroid stimulating activity. Preparations of human thyrotropin are similarly sensitive to partial pepsin digestion, i.e., there is a rapid destruction of thyroid stimulating activity but a very much slower destruction of exophthalmogenic activity. Thus, after 30 min of pepsin digestion, preparations of human thyrotropin retain 80% of their exophthalmogenic activity but only 20-30% of their thyroid stimulating action. Since these results are analogous to those obtained in studies of the partial pepsin digestion of bovine thyrotropin (1), partial pepsin digestion of both purified human and purified mouse tumor thyrotropin preparations should yield an exophthalmogenic fragment of the TSH molecule devoid of thyroid stimulating action.
Animals↗
Stimulation of adenylate cyclase activity in retro-orbital tissue membranes by thyrotropin and an exophthalmogenic factor derived from thyrotropin.
Retro-orbital tissue membranes have been shown to have adenylate cyclase activity which can be stimulated by thyrotropin and by an exophthalmogenic factor derived from the thyrotropin molecule by partial pepsin digestion. This stimulable activity is maximal after 15 min and is optimal in the presence of 3 mM magnesium and 1.5 mM ATP. Calcium salts are exquisitely inhibitory to the hormonal stimulation; sodium, lithium, and ammonium salts are significantly less inhibitory. Thyrotropin and the exophthalmogenic factor induce similar maximal levels of stimulation but a 4- to 5-fold higher concentration of exophthalmogenic factor is required to achieve this level. Fluoride stimulates adenylate cyclase activity 2- to 3-fold higher than either thyrotropin or the exophthalmogenic factor; thyrotropin, luteinizing hormone, the beta subunit of thyrotropin, and the alpha subunit of thyrotropin have relative activities for stimulation of cyclase activity of 100:2:2 less than 0.5. Several other polypeptide and glycoprotein hormones have no effect. The gamma-globulin from patients with malignant exophthalmos has no significant effect on cyclase activity either alone or in the presence of maximal levels of thyrotropin or the exophthalmogenic factor; this gamma-globulin does, however, stimulate cyclase activity at submaximal hormone levels. Trypsin not only destroys the hormone-stimulable adenylate cyclase activity on retro-orbital tissue plasma membranes, but also destroys it on the 15,000 to 30,000 molecular weight receptor fragment released from the membranes by the tryptic action.
Adenylyl Cyclases↗
Decreased receptor binding of biologically inactive thyrotropin in central hypothyroidism. Effect of treatment with thyrotropin-releasing hormone.
Previous studies have suggested that certain cases of idiopathic central hypothyroidism of hypothalamic origin may result from the secretion of biologically inactive thyrotropin. To investigate this possibility and to define the mechanism of defective hormone action, we measured the adenylate cyclase-stimulating bioactivity (B) and receptor-binding (R) activity of purified immunoreactive serum thyrotropin (I) from seven patients with hypothalamic hypothyroidism. We found a strikingly decreased R/I ratio (less than 0.15) in patients as compared with controls (0.6 to 2.7) and a similarly decreased B/I ratio (less than 0.2 vs 2.8 to 5.6). After acute injection of thyrotropin-releasing hormone (TRH, 200 micrograms intravenously), the R/I ratio increased in two of three patients, but the B/I ratio became normal in only one. After administration of TRH for 20 to 30 days, an increase in immunoreactive serum thyrotropin was observed in all patients. Moreover, both ratios returned to normal in all but one patient, who had apparent desensitization. The increase in the amount and bioactivity of secreted thyrotropin after long-term TRH therapy resulted in enhanced secretion of serum thyroid hormones in all patients studied. We conclude that in certain cases of hypothalamic hypothyroidism, secreted thyrotropin lacks biologic activity because of impaired binding to its receptor; TRH treatment can correct both defects. These data suggest that TRH regulates not only the secretion of thyrotropin but also its specific molecular and conformational features required for hormone action.
Adult↗
Effects of thyrotropin and thyroid hormones in vivo on thyroid responsiveness to thyrotropin in vitro.
The thyroid gland of rats fed propylthiouracil is known to be unresponsive in vitro to thyrotropin; to investigate further the underlying mechanism groups of rats were variously treated with propylthiouracil and thyroid hormone or subjected to hypophysectomy. In vitro responsiveness of the thyroids was tested by measuring an increase in the concentration of c AMP when thyrotropin or prostaglandin E1 was added to the medium. Results showed that responsiveness to thyrotropin partially returned with rats fed prophylthiouracil and hypophysectomized 5, but not 2, days before death; hypophysectomy of normal rats led to increased in vitro responsiveness to thyrotropin and this was partially reversed by injections of thyrotropin for a week before death. Administration of thyroid hormone had little effect in these investigations and in vitro responsiveness to prostaglanding E1 was not consistently influenced by any of the in vivo regimens. From this experience we conclude that, at least as studied in vitro, circulating thyrotropin has a significant role in modulating responsiveness of the thyroid to thyrotropin.
3',5'-Cyclic-AMP Phosphodiesterases↗
Pituitary-thyroid responsiveness to intramuscular thyrotropin-releasing hormone based on analyses of serum thyroxine, tri-iodothyronine and thyrotropin concentrations.
To develop a test of pituitary-thyroid responsiveness to thyrotropin-releasing hormone that would obviate the need for measuring serum thyrotropin, we determined serum thyrotropin, thyroxine, and tri-iodothyronine concentrations before and at frequent intervals after the intramuscular administration of 2 mg of thyrotropin-releasing hormone in normal subjects and in patients with a variety of thyroid disorders. In specimens obtained four and five hours after administration of the hormone to normal subjects, serum thyroxine concentration increased 2.4 plus or minus 0.7 mug per 100 ml (mean plus or minus S.D.) over base-line values, the magnitude of increase being greater than 1.5 mug per 100 ml in 32 of 34 subjects. Serum thyroxine concentrations after administration of thyrotropin-releasing hormone did not increase in 11 hyperthyroid patients. Of 13 with hypothyroidism, increases in 12 were 0 to 0.7 mug per 100 ml; in one the increment was 1.2 mug per 100 ml. Measurement of the serum thyroxine response to intramuscular thyrotropin-releasing hormone will usually suffice to determine the integrity of the hypothalamic-pituitary-thyroid complex.
Adult↗
Adenosine 3',5'-monophosphate modulates thyrotropin receptor clustering and thyrotropin activity in culture.
A biologically active rhodamine conjugate of thyrotropin binds at 4 degrees C to diffusely distributed membrane thyrotropin receptors which patch and become endocytosed into thyroid cells in a temperature-sensitive process. When the cells are first incubated with 8-bromo-cyclic adenosine monophosphate at 37 degrees C, the conjugate also binds to clustered receptors at 4 degrees C. Furthermore, 8-bromo-cyclic adenosine monophosphate reduces the amount of adenosine 3',5'-monophosphate (cyclic AMP) induced by thyrotropin. Hence, increased intracellular cyclic AMP induces receptor patching and reduces the concentration of cyclic AMP normally induced by thyrotropin. This suggests that cyclic AMP acts both as the second messenger of thyrotropin and also as the regulator of the level of thyrotropin receptors.
8-Bromo Cyclic Adenosine Monophosphate↗
Thyroglobulin is a more sensitive indicator of iodine deficiency than thyrotropin: development and evaluation of dry blood spot assays for thyrotropin and thyroglobulin in iodine-deficient geographical areas.
Immunometric assays were developed for thyrotropin and thyroglobulin using time-resolved fluorescence as the measurement signal. The assays were suitable for measurements in serum/plasma or in dry blood spots (3 mm diameter). Both assays have acceptable coefficients of variation for dry blood spots (intra-assay median CV < 10%, interassay CV < 15%) in the concentration range of interest (thyrotropin 3-250 mU/l, thyroglobulin 10-500 micrograms/l). The relatively high CV values are not only due to the assay design but also the inhomogeneity of the samples used. For serum samples the median intra-assay CV was < 3% for thyrotropin in the range 0.1-50 mU/l and for thyroglobulin between 2 and 500 micrograms/l. The corresponding inter-assay CV were less than 5%. The assays were evaluated in field studies carried out under auspices of International Council for Control of Iodine Deficiency Disorders (ICCIDD) with the support of UNICEF in Algeria, Peru, India and Zimbabwe, and were found to be practical inasmuch as dry blood spot samples could be transported without special precautions for up to 5-6 weeks without significant loss in immunoreactivity. This agrees with other findings. The results showed that serum thyroglobulin levels are a more sensitive indicator of iodine deficiency than thyrotropin; elevated thyroglobulin levels were found in 182/304 children in Zimbabwe compared with elevated thyrotropin level in 28/304 cases. 213/304 children had enlarged thyroid glands. The cut-off levels used here were 4.5 mU/l thyrotropin and 20 micrograms/l for thyroglobulin, both in whole blood. The assays proved useful for assessing the efficacy of iodine therapy, either by oral dosage or intramuscularly (iodised oil).(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Enhanced thyrotropin response to thyrotropin releasing hormone in boys at risk for development of alcoholism. Preliminary findings.
Alcoholism is three times more prevalent in men than in women. We studied responses of thyrotropin to protirelin (thyrotropin releasing hormone) in nine sons and eight daughters of patients with familial alcoholism and in eight control boys and seven control girls. Basal and protirelin stimulated triiodothyronine, prolactin, and growth hormone concentrations were also measured. The controls were matched for age, sex, and past alcohol exposure with the index children. The sons of familial alcoholics had significantly higher basal thyrotropin levels, peak thyrotropin levels, and thyrotropin areas under the curve than did the control boys. The daughters of patients with familial alcoholism showed no differences from the control girls. Analyses of triiodothyronine, prolactin, and growth hormone concentrations revealed no differences between the index children and controls. We believe that this is the first report of a male-limited neuroendocrine difference between children of alcoholics and control children. Further studies are needed to elucidate the clinical significance of our preliminary findings.
Adolescent↗