Targeting thyroid diseases with TSH receptor analogs

Galofré, Juan Carlos; Chacón, Ana M.; Latif, Rauf

doi:10.1016/j.endoen.2014.01.001

Cited by 3 publications

(9 citation statements)

References 41 publications

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“…Recent neuroendocrine research has generated a large array of hormone analogs, such as TRH analogs , TSH analogs , and prolactin analogs . Although these were tested in humans and in animals for multiple extracutaneous disorders, it remains largely unstudied how these available analogs impact on human skin physiology and pathology.…”

Section: Neuroendocrine Controls Of Keratin Expression May Be Clinicamentioning

confidence: 99%

Harnessing neuroendocrine controls of keratin expression: A new therapeutic strategy for skin diseases?

Ramot

Paus

2014

BioEssays

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Human skin produces numerous neurohormones and neuropeptides. Recent evidence has shown that the neuroendocrine regulation of human skin biology also extends to keratins, the major structural components of epithelial cells. For example, thyrotropin-releasing hormone, thyrotropin, opioids, prolactin, and cannabinoid receptor 1-ligands profoundly modulate human keratin gene and protein expression in human epidermis and/or hair follicle epithelium in situ. Since selected keratins are now understood to exert important regulatory functions beyond mechanical stability, we argue that neuroendocrine pathways of keratin regulation are important for maintaining skin and hair follicle homeostasis. This invites innovative neuroendocrine therapeutic interventions for skin disorders characterized by abnormal keratin expression, ranging from psoriasis to genodermatoses, and for promoting skin wound healing and hair growth. This strategy can be probed in simple, but instructive and readily available human skin and hair follicle organ culture assays as ideal models for exploring this new neuroendocrine frontier in translational epithelial biology.

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Section: Neuroendocrine Controls Of Keratin Expression May Be Clinicamentioning

confidence: 99%

Harnessing neuroendocrine controls of keratin expression: A new therapeutic strategy for skin diseases?

Ramot

Paus

2014

BioEssays

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“…In contrast to these GPCR examples, little is known yet concerning the mechanisms as well as the functional and physiological relevance of the constitutive wt TSHR activity. Physiologically the human wt TSHR expresses high CA, which leads to stimulation of follicular cell proliferation [ 15 ] . Thus, the physiologically high constitutive wt TSHR activity could have an infl uence on maintenance of metabolic activity or also on conserving body heat and promoting thermogenesis in humans [ 16 ] .…”

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confidence: 99%

“…For several of the aff ected GPCRs no inverse agonists are currently available. In case of nonautoimmune hyperthyroidism (NAH) induced by constitutively activating somatic or germline TSHR mutations, inverse agonists could decrease or reverse TSHR activity [ 15 ] . Thus, TSHR inverse agonists could become an alternative therapeutic strategy to the current therapies for patients with NAH (caused by hot thyroid nodules or germline TSHR mutations) like surgery or radioiodine therapy and antithyroid drugs, which often cause adverse reactions.…”

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confidence: 99%

“…Thus, TSHR inverse agonists could become an alternative therapeutic strategy to the current therapies for patients with NAH (caused by hot thyroid nodules or germline TSHR mutations) like surgery or radioiodine therapy and antithyroid drugs, which often cause adverse reactions. Since the wt TSHR expresses high CA, which stimulates follicular cell proliferation, it can be assumed that this process could promote the growth of follicular thyroid cancer cells [ 15 ] . Therefore, TSHR inverse agonists may well have a therapeutic potential for patients with thyroid cancer by inhibiting basal receptor signaling [ 15 ] .…”

mentioning

confidence: 99%

“…Since the wt TSHR expresses high CA, which stimulates follicular cell proliferation, it can be assumed that this process could promote the growth of follicular thyroid cancer cells [ 15 ] . Therefore, TSHR inverse agonists may well have a therapeutic potential for patients with thyroid cancer by inhibiting basal receptor signaling [ 15 ] . This approach could be superior to suppressive therapy [ 15 ] which "only" decreases the ligand TSH, but not the high constitutive wt TSHR activity which is independent of the physiological TSH concentration.…”

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Controversial Constitutive TSHR Activity: Patients, Physiology, and In Vitro Characterization

et al. 2014

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G protein-coupled receptors constitute a large family of transmembrane receptors, which activate cellular responses by signal transmission and regulation of second messenger metabolism after ligand binding. For several of these receptors it is known that they also signal ligand-independently. The G protein-coupled thyroid stimulating hormone receptor (TSHR) is characterized by a high level of constitutive activity in the wild type state. However, little is known yet concerning the physiological relevance of the constitutive wild type TSHR activity. Certainly, knowledge of the physiological relevance of constitutive wild type receptor activity is necessary to better understand thyroid physiology and it is a prerequisite for the development of better therapies for nonautoimmune hyperthyroidism and thyroid cancer. Based on a literature search regarding all published TSHR mutations, this review covers several mutations which are clearly associated with a hyperthyroidism-phenotype, but interestingly show a lack of constitutive activity determined by in vitro characterization. Possible reasons for the observed discrepancies between clinical phenotypes and in vitro characterization results for constitutive TSHR activity are reviewed. All current in vitro characterization methods for constitutive TSHR mutations are "preliminary attempts" and may well be revised by more comprehensive and even better approaches. However, a standardized approach for the determination of constitutive activity can help to identify TSHR mutations for which the investigation of additional signaling mechanisms would be most interesting to find explanations for the current clinical phenotype/in vitro discrepancies and thereby also define suitable methods to explore the physiological relevance of constitutive wild type TSHR activity.

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Evaluation of the role of thyroid scintigraphy in the differential diagnosis of thyrotoxicosis

Perdomo

García‐Goñi

Sancho

et al. 2020

Clinical Endocrinology

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Objective A differential diagnosis of thyrotoxicosis is crucial as the treatment of the main causes of this condition can vary significantly. Recently published diagnostic guidelines on thyrotoxicosis embrace the presence of thyrotropin receptor (TSH‐R) antibodies (TRAb) as the primary and most important diagnostic step. The application of diagnostic algorithms to aid in the treatment of hyperthyroidism supports using thyroid radionuclide scintigraphy (TRSt) in baffling clinical scenarios, when TRAb are absent or when third‐generation TRAb are not available. First‐generation TRAb measurement may have limitations. Consequently, patients with thyrotoxicosis and first‐generation TRAb results may be misdiagnosed and consequently improperly treated. Our purpose was to compare first‐generation TRAb values to TRSt in the differential diagnosis of hyperthyroidism. Methods We conducted a retrospective study of 201 untreated outpatients with overt or subclinical hyperthyroidism on whom first‐generation TRAb and TRSt had been performed at the time of diagnosis. Histological specimens were analysed in patients who had previously undergone thyroid surgery at our centre. SPSS 20.0 was used in statistical analysis. Results Seventy‐three out of 201 (36.3%) patients had positive TRAb. A diffuse uptake was present in 83.5% (61/73), whereas 13.7% (10/73) had a heterogeneous uptake and 2.7% (2/73) had an absent uptake. Thirty out of 91 (33%) patients with diffuse uptake were negative for positive TRAb and were diagnosed with Graves’ disease. Analysis of 37 histological specimens indicated that TRSt had greater accuracy (81% vs 75.7%) and specificity (79.2% vs 57.1%) when compared to TRAb in the differential diagnosis of thyrotoxicosis. However, TRSt sensitivity was inferior to TRAb (84.6% vs 92.3%). Conclusions Our study endorses that initial differential diagnosis of thyrotoxicosis should not be based solely on first‐generation TRAb as this approach may leave nearly 20% of the patients misdiagnosed and, consequently, improperly treated. Our results underscore that thyroid scintigraphy should also be performed when only first‐generation TRAb assays are available during the initial differential diagnosis of thyrotoxicosis.

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Targeting thyroid diseases with TSH receptor analogs

Cited by 3 publications

References 41 publications

Harnessing neuroendocrine controls of keratin expression: A new therapeutic strategy for skin diseases?

Harnessing neuroendocrine controls of keratin expression: A new therapeutic strategy for skin diseases?

Controversial Constitutive TSHR Activity: Patients, Physiology, and In Vitro Characterization

Evaluation of the role of thyroid scintigraphy in the differential diagnosis of thyrotoxicosis

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