Choose an application

• Reference Manager
• EndNote
• RefWorks (Direct export to RefWorks)

This eBook is a collection of articles from a Frontiers Research Topic. Frontiers Research Topics are very popular trademarks of the Frontiers Journals Series: they are collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from Original Research to Review Articles, Frontiers Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area! Find out more on how to host your own Frontiers Research Topic or contribute to one as an author by contacting the Frontiers Editorial Office: frontiersin.org/about/contact

Medicine --- Endocrinology --- thyroid --- TSH receptor --- TSH receptor autoantibodies --- Graves’ disease --- Autoimmunity --- small molecules --- TSH --- Animal Models

Choose an application

• Reference Manager
• EndNote
• RefWorks (Direct export to RefWorks)

G protein-coupled receptors (GPCRs) represent a large and physiologically important class of cell surface receptors. There are approximately 750 known GPCRs present in the human genome that can be subdivided into general classes based upon sequence homology within their transmembrane domains. Therapeutically, GPCRs represent a fertile source for the development of therapies as they are a significant percentage of our current pharmacopeia. Among the three subclasses of GPCRs, the Class A (rhodopsin-like) receptors are by far the most prevalent and extensively studied. However, within the Class A receptors, sub-families of receptors can be distinguished based upon common sequence motifs within the transmembrane domains as well as extracellular and intracellular domains. One such family of Class A receptors is characterized by multiple leucine- rich repeats within their amino- terminal domains (the Leucine-rich Repeat family (LRR)). This family of GPCRs are best represented by the glycoprotein hormone receptors (LHR, FSHR and TSHR) which have been studied extensively but also includes receptors for the peptide hormone relaxin (RXFP1 and RXFP2 (RXFP2 also binds insulin-like peptide 3)) and three other receptors (LGR4, LGR5 and LGR6). LGR4-6 were, until recently, considered orphan receptors. However, emerging data have revealed that these proteins are the receptors for a family of growth factors called R-spondins. Over the last 20 years much has been learned about LRR receptors, including the development of synthetic agonists and antagonists, new insights into signaling (including signaling bias) and the physiological role these receptors play in regulating the function of many tissues. This topic will focus on what is known concerning the regulation of these receptors, their signaling pathways, functional consequences of activation and pharmacology.

Leucine- rich repeat --- TSH --- GPCR --- R-spondin --- FSH --- Pharmacology --- LH --- Relaxin --- LRR

Choose an application

• Reference Manager
• EndNote
• RefWorks (Direct export to RefWorks)

G protein-coupled receptors (GPCRs) represent a large and physiologically important class of cell surface receptors. There are approximately 750 known GPCRs present in the human genome that can be subdivided into general classes based upon sequence homology within their transmembrane domains. Therapeutically, GPCRs represent a fertile source for the development of therapies as they are a significant percentage of our current pharmacopeia. Among the three subclasses of GPCRs, the Class A (rhodopsin-like) receptors are by far the most prevalent and extensively studied. However, within the Class A receptors, sub-families of receptors can be distinguished based upon common sequence motifs within the transmembrane domains as well as extracellular and intracellular domains. One such family of Class A receptors is characterized by multiple leucine- rich repeats within their amino- terminal domains (the Leucine-rich Repeat family (LRR)). This family of GPCRs are best represented by the glycoprotein hormone receptors (LHR, FSHR and TSHR) which have been studied extensively but also includes receptors for the peptide hormone relaxin (RXFP1 and RXFP2 (RXFP2 also binds insulin-like peptide 3)) and three other receptors (LGR4, LGR5 and LGR6). LGR4-6 were, until recently, considered orphan receptors. However, emerging data have revealed that these proteins are the receptors for a family of growth factors called R-spondins. Over the last 20 years much has been learned about LRR receptors, including the development of synthetic agonists and antagonists, new insights into signaling (including signaling bias) and the physiological role these receptors play in regulating the function of many tissues. This topic will focus on what is known concerning the regulation of these receptors, their signaling pathways, functional consequences of activation and pharmacology.

Leucine- rich repeat --- TSH --- GPCR --- R-spondin --- FSH --- Pharmacology --- LH --- Relaxin --- LRR

Choose an application

• Reference Manager
• EndNote
• RefWorks (Direct export to RefWorks)

This eBook is a collection of articles from a Frontiers Research Topic. Frontiers Research Topics are very popular trademarks of the Frontiers Journals Series: they are collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from Original Research to Review Articles, Frontiers Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area! Find out more on how to host your own Frontiers Research Topic or contribute to one as an author by contacting the Frontiers Editorial Office: frontiersin.org/about/contact

Medicine --- Endocrinology --- signal transduction --- ACTH --- G protein --- beta-arrestin --- sertolli cells --- gonadotroph cell --- myometrium contractility --- TSH receptor

Choose an application

• Reference Manager
• EndNote
• RefWorks (Direct export to RefWorks)

The discovery of the negative feedback of thyroid hormones on pituitary thyroid-stimulating hormone (TSH) secretion, a classical endocrine feedback control system, has shaped diagnosis and treatment of thyroid disease for the last decades. Based on this concept, a unique diagnostic category of subclinical thyroid disorders was introduced, being defined exclusively by an abnormal TSH response in the presence of thyroid hormone concentrations within the reference range. Although this approach was able to deliver a conceptually straightforward disease definition problems surfaced in clinical practice as neither the diagnostic reference range nor the appropriate threshold for initiating substitution treatment are universally agreed upon for subclinical thyroid disorders. The situation is further aggravated by the so-called syndrome T, which comprises a substantial but heterogeneous group of L-T4 treated patients with hypothyroidism with reduced quality of life despite “normal” TSH values.

A limited understanding of the physiological relationships between TSH and thyroid hormones may be a main reason for clinical difficulties in dealing with the causes of syndrome T and tailoring substitution therapy for hypothyroid patients with subclinical thyroid disorders.

Feedback regulation has recently been shown to be much more complex than previously assumed. The concept of homeostatic control has also been extended to include the lesser known but equally important allostatic thyroid regulation.The latter aims at adaptive homeostasis or stability through changing setpoints and modulating structural parameters of feedback control, as may be appropriate to adapt to a vast array of conditions spanning from fetal life, aging, pregnancy, exercise, starvation, obesity, psychiatric disorders to the severe non-thyroidal illness syndrome.

A better understanding of homeostatic and allostatic mechanisms, which govern the behaviour of pituitary-thyroid feedback control, is on the horizon. This promises to improve the diagnostic utility of laboratory methods, laying the foundation for personalised methods to optimise dosage and modality of substitution therapy. The emerging new world of thyroid physiology is reflected on the side of clinical medicine in a new, relational paradigm for diagnosis and treatment.

Considerable progress has been made in this respect in the following key areas:

• the significance of complementary information processing structures within the feedback loop, in particular ultrashort feedback of TSH on its own secretion and the action of a TSH-T3 shunt unburdening the thyroid from T4 synthesis in imminent thyroid failure,

• the unravelling of spatio-temporal dynamics of hormone concentrations ranging from ultradian to circannual rhythms and including hysteresis effects,

• the emergence of “non-canonical” mechanisms of thyroid hormone signalling beyond transcriptional control of gene expression,

• the physiological actions of thyronine metabolites, which have been previously regarded as biologically inactive, such as thyronamines and iodothyroacetates,

• the characterisation of distinct patterns in the adaptive processes to stress and strain and their conclusive explanation through reactions to type 1 and type 2 allostatic load.

This collective volume contains the contributions to the Research Topic “Homeostasis and Allostasis of Thyroid Function”, which was originally published by the journal Frontiers in Endocrinology. Authored by an international team of experts from three continents ,the book provides a comprehensive overview on thyroid control from recent research in basic, computational and clinical thyroidology. Many aspects addressed here can be expected to stimulate future research. A more comprehensive view and better integration of in-vitro, in-silico and in-vivo investigations will be invaluable in paving the way to this new world of thyroidology.

relational stability --- Thyronamines --- TSH-T3 Shunt --- thyroid allostasis --- precision medicine --- Stratified Medicine --- 3-T1AM --- Hypothyroidism --- Thyroid homeostasis --- Hysteresis