Intrinsic bioactivity of thyrotropin in human serum is inversely correlated with thyroid hormone concentrations. Application of a new bioassay using the FRTL-5 rat thyroid cell strain (original) (raw)
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Evidence for Thyroid Hormone as a Positive Regulator of Serum Thyrotropin Bioactivity
The Journal of Clinical Endocrinology & Metabolism, 2007
The aim of the study was to investigate the role of serum thyroid hormones in regulating the bioactivity of TSH. Design: We determined in vitro TSH bioactivity and glycosylation in nine patients (six females and three males, age 41.3 yr) with primary hypothyroidism before and after L-T 4 replacement, in 11 age-and sex-comparable controls (seven females and four males, age 37.6 yr), and in two thyroidectomized patients with TSH-secreting adenomas during and after L-T 4 withdrawal. Methods: In vitro TSH bioactivity was measured by a sensitive and specific bioassay based on cAMP generation by Chinese hamster ovary cells transfected with human TSH receptor. TSH glycosylation was assessed by concanavalin A lectin and ricin column affinity chromatography. Results: In vitro TSH bioactivity in hypothyroid patients was low as compared with controls (0.48 Ϯ 0.1 vs. 1.1 Ϯ 0.2; P ϭ 0.004) and increased during L-T 4 (0.48 Ϯ 0.1 vs. 0.8 Ϯ 0.1; P ϭ 0.01). A strong significant correlation (r ϭ ϩ0.80; P ϭ 0.004, Spearman) was observed between the absolute increments of serum TSH bioactivity and T 3 during L-T 4 replacement. The degree of sialylation was elevated in hypothyroid patients before treatment (47 Ϯ 2.4% vs. 29 Ϯ 4.3%; P ϭ 0.002) and decreased significantly after L-T 4 (47 Ϯ 2.4% vs. 33 Ϯ 4.3%; P ϭ 0.02). The mannose content of serum TSH in hypothyroid patients was similar to controls and did not change during L-T 4. In vitro TSH bioactivity also decreased in patients with TSH-secreting adenomas during L-T 4 withdrawal. Conclusion: These data indicate that serum thyroid hormone level is a positive regulator of TSH bioactivity.
Clinical Endocrinology, 1977
Thyroidectomized rats, kept on a low iodine diet, were killed at 60, 80 and 270 days after thyroidectomy and plasma and pituitary TSH levels measured. Pituitary TSH content was lower in the thyroidectomized rats than in the controls at 60 and 80 days, starting to increase between 60 and 80 days, and reaching hgher values than those of the controls by 270 days. Plasma TSH was higher in the thyroidectomized rats than in the controls at all the times studied, but declined markedly between 60 days (17.53 f 1.98 pg/ml) and 270 days (3.63 * 0.49 pg/ml). This decrease in plasma TSH levels was accompanied by a decrease in plasma PBI: from 0.69 * 0.08 pg/dl at 60 days to 0.06 f 0.0 1 pg/dl at 270 days. The daily injection of 1.75 pg T4/100 g body weight for 12 days in either thyroidectomized rats or normal intact rats resulted in a decline of plasma TSH levels in both groups. Pituitary TSH content increased in the thyroidectomized rats and decreased in the controls after T4 treatment. Present results agree with previous observations indicating that severe and chronic thyroid hormone deficiency is not accompanied by a progressive increase in circulating TSH levels, though an elevation is always found even in mild or subclinical forms or primary hypothyroidism. They show that in the rat this cannot be accounted for by an impairment of TSH synthesis, as previously suggested: an impairment of TSH secretion appears more probable. In primary hypothyroidism, even in mild and subclinical forms, circulating TSH levels are raised above the normal range (for a review, see Evered et aE., 1973). However, as severity or duration of hypothyroidism increases circulating TSH levels do not necessarily rise progressively. The possibility has been raised (Purves & Adams, 1960; Purves, 1964) that severe thyroid hormone deficiency has an adverse effect on the cells of the pituitary gland, possibly on TSH synthetic processes. The pituitary would thus be unable t o sustain a markedly increased TSH secretion.
Technical and clinical performance of six sensitive immunoradiometric assays of thyrotropin in serum
Clinical chemistry, 1987
We evaluated the analytical and clinical performance of six commercial immunoradiometric assay kits for thyrotropin (TSH) in serum in 218 subjects, with and without thyroid dysfunction. Detection limits of the six kits were lower (from 0.07 to 0.25 milli-int. unit/L) than that of conventional TSH RIA (0.7 milli-int. unit/L). Precision was adequate over a wide range of concentrations, although interassay CVs at very low concentrations were good for only two kits (7.3% and 13.1%). Results by all the kits correlated to about the same degree with the TSH RIA (r = 0.92 to 0.98). All showed a positive correlation between both the basal and post-thyroliberin (TRH)-stimulation values for TSH (r = 0.78 to 0.88), and all showed similar euthyroid reference ranges for basal concentrations of TSH. With four of the six kits we could clearly distinguish most of the hyperthyroid patients from healthy euthyroids; however, basal and post-TRH TSH values were not sufficient to discriminate among groups...
Clinical Chemistry, 1988
tivity of thyrotropin (TSH) in human serum by measuring cAMP production in FRTL-5 thyroid cells as an index of stimulation. To eliminate serum inhibitors of the cAMP response to TSH, we purified samples by mixing them with anti-TSH antibodies coupled to magnetizable particles. This method of immunoaffinity purification was simple and suitable for the measurement of a large number of samples. The detection limit of the bioassay was 3.13 milli-int. units of human TSH per liter. Intra-assay and interassay coefficients of variation ranged from 5.4 to 8.6% and from 12.6 to 21.5%, respectively. The concentrations of bioassayable TSH closely correlated with those of immunoassayable TSH, both in the immunoaffinity-purified samples (r = 0.946, p <0.001) and in the serum samples (r = 0.945, p <0.001) from 14 euthyroid subjects and 53 hypothyroid patients with Hashimoto's thyrolditis. The bioactivity-to-immunoactivity ratio was almost constant (0.84 ± 0.30; mean ± SD) over the range of concentrations of immunoassayable TSH in serum, 6.3 to 177 milli-int. units/L. We also demonstrate that the technique is applicable to measurements of bioactivities of circulating forms of immunoreactive TSH in different pathophysiological conditions.
The Journal of Clinical Endocrinology & Metabolism, 1997
Around mid-1995, the Molecular Endocrinology Laboratory of the Regional Hospital (Malaga, Spain) began detecting an increase in TSH levels in the serum of patients under study to control the treatment of hypothyroidism with levothyroxine. Over a period of 5 months, of a total of 467 hypothyroid patients treated with Levothroid, 53% had TSH levels higher than 6 U/mL. The reliability of the biochemical results was verified by duplicating 56 randomly chosen samples from all those with high TSH levels and by an external control performed in four different laboratories. The amount of levothyroxine in the tablets was analyzed by RIA, high performance liquid chromatography, and their iodine contents. The lowest levels of levothyroxine found in the 50-g Levothroid tablets were those determined by RIA, with a mean value of 32.3 g, resulting in a 35.3% loss of activity. The mean value of levothyroxine found in these same tablets by high performance liquid chromatography was 39.3 g, amounting to a 21.3% loss in activity. The iodine showed no significant loss in these tablets, with a mean experimental value of 48 g. The commercial laboratory withdrew lot J from the market, the one in which these deficiencies were found.
The Journal of Clinical Endocrinology & Metabolism, 2003
Recombinant human TSH (rhTSH) has been proposed as an alternative method to the withdrawal of thyroid hormones in the follow-up of differentiated thyroid cancer. The aim of the present study was to evaluate the influence of several demographic and anthropometric parameters [age, body weight, height, body mass index, and body surface area (BSA)] on serum peak TSH levels after rhTSH administration. rhTSH was administered to 112 patients with differentiated thyroid carcinoma according to the conventional two-dose schedule (0.9 mg/d). Serum TSH levels were measured 24 h before and after the first administration of rhTSH, and then 24, 48, and 72 h after the second administration of rhTSH. In one severely obese patient, serum peak TSH values did not reach a valid stimulation range. Serum peak TSH levels were negatively related to body weight (r ؍ ؊0.69; P < 0.0001), body mass index (r ؍ ؊0.51; P < 0.0001), and BSA (r ؍ ؊0.72; P < 0.0001). In a multivariate regression analysis including demographic and anthropometric variables, only BSA was independently associated to serum peak TSH concentrations (standardized  coefficient ؍ ؊0.721; P < 0.0001). In conclusion, body size seems to influence serum peak TSH levels after rhTSH administration. Future studies should evaluate the possibility of using personalized rhTSH doses, adjusted in relation to BSA.
The Journal of Clinical Endocrinology & Metabolism, 2014
Context: TSH has been shown in vitro to increase conversion of T 4 to T 3 and to preferentially increase thyroidal T 3 secretion. Whether or not these effects are significant in vivo, other than in obesity, is unclear. Objective: To test whether the incremental relationships between free T 4 (FT4), free T 3 (FT3), and TSH are compatible with TSH enhancement of a preferential increase in serum FT3. Design and Setting: A large database of pediatric and adolescent thyroid test results drawn in community clinics from children and adolescents without known thyroid disease was analyzed. Patients and Methods: Results of FT3, FT4, and TSH were studied anonymously. They were crossed with electronic charts to exclude a history of positive thyroid autoantibodies and use of thyroid hormone preparations, antithyroid medication, or drugs known to affect thyroid function. All samples from patients appearing more than once in the database were removed. After exclusions, 3276 samples remained. FT4, FT3, and the FT3/FT4 ratios were correlated with TSH for the entire group, and the same parameters were segregated by TSH quartile. Results were stratified for body mass index and studied separately in a normal-weight subgroup. Main Outcome Measures: Stepwise correlations of FT4, FT3, and FT3/FT4 ratios with TSH. Results: There was a significant positive linear correlation of TSH with FT3 and FT3/FT4 ratios (R ϭ 0.12; P Ͻ .0001 in both), but not with FT4. Conclusion: Within the near-euthyroid range, increasing TSH levels are associated with increasing FT3 levels, without an increase in FT4. This provides in vivo support for TSH enhancing preferentially T 3 production and/or secretion.
Frontiers in Endocrinology, 2022
In recent years evidence has accumulated supporting a revised view of the nature of euthyroidism and the biomarkers of thyroid function. Within the normal range, variations in thyroid hormone levels are associated with variations in clinical parameters and outcomes. There are therefore no readily identified individually specific optimum levels of thyroid hormones for any individual. Levels around the middle of the normal population range may best reflect euthyroidism. These levels may have evolutionary advantages on the basis that adverse outcomes often increase with divergence from such levels, and physiological processes tend to minimise such inter-individual and intra-individual divergence. In populations of predominantly untreated individuals, levels of thyroid hormones and in particular levels of free thyroxine (FT4) correlate more often with clinical parameters than do levels of thyrotropin (TSH). Levels of thyroid hormones may therefore be regarded as the best available biomarkers of euthyroidism and dysthyroidism. It follows that 'subclinical hypothyroidism' (normal FT4/raised TSH levels), rather than being an accurate marker of peripheral tissue hypothyroidism is more a marker of decreased thyroid reserve and prognosis. The recent evidence suggests that treatment of hypothyroxinemia, regardless of the TSH level, and monitoring therapy using FT4 and/ or triiodothyronine levels, depending on the replacement regime, may result in more successful treatment of hypothyroidism than relying on thyrotropin levels for patient selection and subsequent treatment monitoring. The equivalents of mid-range levels of thyroid hormones (especially FT4), adjusted by individual comorbidity concerns, may be rational general replacement targets. These implications of the new evidence may create opportunities for novel trials of thyroid replacement therapy.
The Journal of Clinical Endocrinology & Metabolism, 2004
The effect of recombinant human TSH (rhTSH) on thyroid function and ultrasonically determined thyroid volume was investigated in nine healthy euthyroid male volunteers. Each received either 0.9 mg rhTSH or isotonic saline in a randomized order, and thyroid volume and function were closely monitored during the following 28 d. No significant changes were observed after saline injection. After rhTSH stimulation, the median serum TSH increased from 2.03 mU/liter (range, 0.99 -3.07 mU/liter) to more than 200 mU/liter (range, 78.9 to >200.0 mU/liter) after 4 h, with a subsequent rapid decline. Mean (؎SEM) serum free T 4 and free T 3 peaked at 48 h with levels 204.7 ؎ 26.1% and 226.9 ؎ 31.4%, respectively, above baseline (P < 0.001). Twenty-four hours after rhTSH stimula-tion, mean (؎SEM) thyroid volume was significantly increased by 23.3 ؎ 5.8% (P ؍ 0.003) and after 48 h by 35.5 ؎ 18.4% (P ؍ 0.02). On d 4 the mean thyroid enlargement had reverted to baseline values. One individual developed a 90-ml tender thyroid enlargement (initially 21 ml) 36 h after rhTSH administration, associated with a very high level of serum thyroglobulin. It is concluded that 0.9 mg rhTSH may result in a profound stimulation of not only thyroid function but also of thyroid size, appearing in the period 1-4 d after injection. Further dose-response studies are needed to clarify the potential hazards before routine use, for example in the context of 131 I therapy and goiter. (J Clin Endocrinol