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controlling body mass ( Oh & Kaplan 1994 , Moreno et al . 2003 , Lanni et al . 2005 , Villicev et al . 2007 ). Decreased thyroid function seems to be related to impaired thyrotropin-releasing hormone (TRH) and thyroid-stimulating hormone (TSH) secretion
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ABSTRACT
An influence of thyrotrophin-releasing hormone (TRH) on TSH heterogeneity in close association with de-novo biosynthesis was studied in rat anterior pituitary glands. Hemipituitary glands from adult male rats were incubated in Krebs–Henseleit–glucose media containing [3H]glucosamine and [14C]alanine for 3 and 6 h in the presence or absence of 10 ng TRH per ml. Fractions of TSH in the pituitary extracts were obtained using affinity chromatography coupled with an anti-rat TSH globulin. These TSH fractions were analysed by isoelectric focusing. The control pituitary glands were composed of four component peaks (isoelectric point (pI) 8·7, 7·8, 5·3 and 2·5) of [3H]glucosamine and [14C]alanine incorporated into TSH, and the amounts of radioactivity of these components were increased with the incubation time. Of these peaks, radioactive components of pI 8·7 and 7·8 coincided with the non-radioactive TSH components measured by radioimmunoassay. Addition of TRH increased incorporation of [14C]alanine into TSH in each of the components to a greater extent than that of [3H]glucosamine. In addition, new components with pI 7·2, 6·5 and 6·2, each component corresponding to each unlabelled TSH component, were demonstrated in the presence of TRH. Because addition of TRH did not change the amounts of [14C]alanine-labelled TSH in the media, the newly formed components were assumed to be connected with protein synthesis occurring in the anterior pituitary gland, which may be specific substances in response to TRH administration. These results indicate that TRH principally elicits an increase in protein synthesis in TSH at the anterior pituitary level, resulting in an alteration of TSH heterogeneity.
J. Endocr. (1984) 103, 165–171
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ABSTRACT
It has been reported that prior exposure of thyroid tissue to TSH in vitro induces a state of refractoriness to new challenges of the hormone. We have investigated the effect of repeated TSH treatment on thyroid secretion to determine whether such refractoriness exists in vivo. The rate of thyroid secretion was estimated by measuring the rate of hydrolysis of labelled thyroglobulin from mouse thyroid glands in vitro. The thyroid glands were labelled in vivo with 131I and then cultured for 20 h in the presence of mononitrotyrosine, an inhibitor of iodotyrosine deiodinase. The rate of hydrolysis of labelled thyroglobulin was measured as the percentage of radioactivity released as free iodotyrosines and iodothyronines into the gland and the medium at the end of incubation. Thyrotrophin was administered in vivo at hourly intervals for 2–4 injections. The corresponding control group received saline injections every hour except for the last injection when they received TSH. The peak rates of thyroglobulin hydrolysis, measured 2 h following the last injection, were similar in animals receiving two, three or four TSH injections and were not different from those in the control groups. Serum tri-iodothyronine and thyroxine concentrations 2 h after the last injection were higher in the groups receiving multiple TSH injections. Thyroidal cyclic AMP accumulation in response to TSH was markedly depressed in the group receiving multiple injections compared with the group receiving a single injection of TSH in vivo. These data indicate that (1) the stimulatory effect of TSH on thyroidal secretion is not diminished by prior administration of the hormone in vivo, (2) repeated TSH administrations in vivo cause refractoriness of the adenylate cyclase response to TSH and (3) a dichotomy exists between the secretory response and the adenylate cyclase response to repeated administrations of TSH.
J. Endocr. (1985) 106, 153–157
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ABSTRACT
Calmodulin inhibited 125I-labelled TSH binding to the membranes of various target tissues for TSH (thyroid, epididymal fat and testis) of the guinea-pig. This inhibition was abolished by adding EGTA (1 mmol/l). Calmodulin did not inhibit the binding of 125I-labelled epidermal growth factor (EGF) to these membranes. It is suggested that the inhibitory effect of calmodulin on the binding of TSH to the receptor is specific and that this mechanism is due to the direct binding of calmodulin to receptor membranes. The ability of calmodulin to bind to the membranes was calciumsensitive while that of TSH was not. The binding of 125I-labelled calmodulin to these membranes increased significantly when the endogenous calmodulin in the membranes was removed by EGTA. It was not inhibited by a pure preparation of TSH, but it was inhibited by contaminated calmodulin in a crude TSH preparation. On the other hand, 125I-labelled TSH binding to these membranes did not change after the removal of endogenous calmodulin.
In conclusion, exogenous calmodulin has an inhibitory effect on the binding of TSH but not of EGF to the membranes of guinea-pig thyroid, epididymal fat and testis.
Journal of Endocrinology (1990) 125, 103–107
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Thyrotrophin (TSH), cyclic AMP, cyclic GMP and 1-methyl-3-isobutyl-xanthine (MIX) promoted the reassociation of isolated porcine and human thyroid cells into follicular structures in culture and stimulated the uptake of radio-iodide. Monolayer cells were present in all cultures, but in decreasing proportions as the concentration of stimulator was increased. The resting membrane potential of porcine thyroid cells cultured for 4 days in the presence of TSH was −54 ± 3·6 (mean ± s.d.) mV for follicular cells and −31 ± 2·6 mV for monolayer cells. In the absence of TSH, only monolayer cells were present and their membrane potential was −24 ± 2·0 mV. Removal of hormone by washing resulted in hyperpolarization to −70 ± 2·9 mV (follicular cells) or −59 ± 3·4 mV (monolayer cells). Subsequent replacement of TSH, or addition of cyclic AMP, MIX, prostaglandin E1 (PGE1) or long-acting thyroid stimulator immunoglobulin resulted in depolarization of previously hyperpolarized cells, to approximately the membrane potential observed before washing. Incubation in MIX resulted in enhanced sensitivity to the depolarizing effect of TSH. Cells cultured in the absence of TSH were unresponsive to TSH or other stimulators. The membrane potential of human thyroid cells behaved similarly in response to TSH, to hormone removal and replacement, and to MIX and PGE1.
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in an open or closed conformation, respectively ( Astapova & Hollenberg 2013 ). Concentrations of thyroid hormones in the circulation are regulated via the negative feedback loop by the action of thyroid-stimulating hormone (TSH). Beside these
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Thyrotropin (TSH) is secreted not as one distinct hormone, but rather as a group of isohormones which differ in their oligosaccharide composition. Although the mechanisms regulating TSH glycosylation are not fully understood, there is strong evidence that TRH plays an important role. The aim of our study was to determine the dynamic influence of TRH on TSH microheterogeneity. Sera were obtained from euthyroid volunteers (n=20) before and 30, 60, 120, 180 and 240 min after intravenous, nasal and oral administration of TRH in three independent runs (randomized order, at a time-interval of 3 weeks between each run). TSH was immuno-concentrated and analysed by isoelectric focusing (IEF) and lentil lectin affinity chromatography. TSH immunoreactivity was measured by an automated second-generation TSH immunoassay. Overall, serum TSH concentrations reached maximal values 30 min after intravenous, 60 min after nasal and 180 min after oral TRH stimulation. IEF analysis revealed 63.3+/-3.3% of pituitary standard TSH (IRP 80/558) in the neutral pH range (8>pH>6). In contrast, 30 min after TRH stimulation 80.8+/-3.7% (P<0.001) and 60 min after TRH stimulation 44.9+/-2.2% (P<0.001) of the TSH of euthyroid probands were found in this pH range, whereas 180 min after TRH stimulation 58.4+/-2.3% (P<0.001) were detected in the acidic pH range (pH<6). This shift of TSH composition in euthyroidism after TRH stimulation was confirmed by lentil lectin analysis of TSH: core-fucose content of euthyroid TSH was 73.4+/-3.8% 30 min and 22.9+/-3.2% 120 min after TRH stimulation in contrast to basal (53.3+/-1.8%; P<0.001) and pituitary standard (IRP 80/558) TSH (63.0+/-0.9%; P<0.001). In conclusion, in euthyroidism, TRH stimulation time-dependently changes the distribution pattern of the TSH isoforms from an alkaline and neutral to a more acidic one. This corresponds to the secretion of isohormones with altered bioactivity which could influence the fine-tuning of thyroid function.
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SUMMARY
Experimental analysis of the rat's hypothalamic-hypophysial-thyroid system, utilizing stereotaxic, radiometric, histochemical, and bioassay procedures, indicated that electrolytic lesions in the anterior and tuberal portions of the hypothalamus altered thyrotrophic hormone (TSH) secretion in the adenohypophysis and reduced thyroid function (histology and 131I release from the gland). Inhibition of thyroidal radio-iodine release was found within 2 weeks after hypothalamic destruction and was greater in rats which became obese. Significant reduction in titres of circulating TSH also occurred. TSH concentration in the smaller pituitaries of animals in which lesions had been made remained normal, but total hormonal stores decreased.
Thyroxine and triiodothyronine suppressed markedly and equally TSH secretion in the adenohypophyses of operated and intact rats; triiodothyronine was more potent (about 5:1). Hypothalamic damage did not prevent the re-accumulation of TSH in pituitaries previously depleted of their hormone by propylthiouracil; pituitary TSH concentrations rebounded to supranormal levels, but titres in blood decreased to subnormal values. The physiological and histochemical changes induced in the adenohypophyses of rats with lesions strongly implicated the basophils (β cells) in the genesis of TSH. All anterior pituitary cell types were affected in hypothalamic deficiency, but only the β basophils persisted when TSH stores were high, or disappeared when the pituitary was depleted of TSH with exogenous thyroid hormone.
The experimental results indicated that the hypothalamus modulates the activity of the pituitary-thyroid system by influencing production and release of TSH by the pituitary. Hypothalamic regulation of TSH secretion exists for normal conditions as well as for those situations in which enhanced TSH secretion is required. The maintenance of abundant TSH reserves in the adenohypophysis, their depletion after thyroid hormone, and their re-accumulation after goitrogen withdrawal, nevertheless revealed: (1) that the 'isolated' rat pituitary possesses a good measure of autonomous TSH function; (2) that thyroid hormone can act directly on the adenohypophysis independently of the hypothalamus; and (3) that the basic thyroid-pituitary servomechanism is systemically controlled by circulatory levels of thyroid hormone and is not under neural domination.
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Department of Diabetes and Endocrinology, Department of Medicine, Ophthalmology and Visual Sciences, Internal Medicine, King's College London School of Medicine, London, UK
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Department of Diabetes and Endocrinology, Department of Medicine, Ophthalmology and Visual Sciences, Internal Medicine, King's College London School of Medicine, London, UK
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) ( Perros & Krassas 2009 , Bahn 2010 , Naik et al . 2010 ). In GD, thyroid-stimulating antibodies (TSAbs) directed against the TSH receptor (TSHR) activate the thyroid gland, leading to excessive production of thyroid hormone and thyrotoxicosis ( Rees
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ABSTRACT
A new preparative procedure is described for the efficient purification of LH and TSH from frozen human pituitary glands. LH and TSH were isolated simultaneously from crude preparations by hydrophobic-interaction chromatography followed by separation and purification by reverse-phase high-performance liquid chromatography in a single step. Highly purified hormones were prepared in good yields (45 mg LH and 20 mg TSH/1000 glands) and with high biological activities; the potencies of purified LH and TSH were 5·8 × NIH-LH-S1 equivalent in an ovarian ascorbic acid depletion assay and 7·1 U/mg against human TSH MRC Research Standard (T1 70/9) in the McKenzie assay respectively. Cross-contamination by other glycoprotein hormones was low.
Journal of Endocrinology (1990) 125, 493–500
