• Central adrenal insufficiency in children and adolescents
• Animal models of endocrine disruption
• Animal models of endometriosis: Replicating the aetiology and symptoms of the human disorder
• Diagnosis and management of hyperthyroidism from prenatal life to adolescence
• Diagnosis and management of postnatal fetal growth restriction
• Imaging endocrinology in animal models of endocrine disease
• Genetically modified mouse models to investigate thyroid development, function and growth
• Translational Studies Provide Insights for the Etiology and Treatment of Cortical Bone Osteoporosis
• Mouse models of peripheral metabolic disease
• Evidence from animal models on the pathogenesis of PCOS
• Mouse models for the analysis of gonadotropin secretion and action
• Preface
• Thyrotropin receptor, still much to be learned from the patients
• An orphan G-protein-coupled receptor causes human gigantism and/or acromegaly: Molecular biology and clinical correlations
• Translational studies provide insights for the etiology and treatment of cortical bone osteoporosis
• G-protein-coupled receptors (GPCRs) in the treatment of diabetes: Current view and future perspectives
• Novel mechanisms of G-protein-coupled receptors functions: AT1 angiotensin receptor acts as a signaling hub and focal point of receptor cross-talk
• Pathophysiology of melanocortin receptors and their accessory proteins
• Internalization of G-protein-coupled receptors: Implication in receptor function, physiology and diseases
• Aberrant G-protein coupled hormone receptor in adrenal diseases
• Multiple hormone resistance and alterations of G-protein-coupled receptors signaling
• Pharmacogenetics of G-protein-coupled receptors variants: FSH receptor and infertility treatment
• The kisspeptin receptor: A key G-protein-coupled receptor in the control of the reproductive axis
• WITHDRAWN: Pharmacogenetics of osteoporosis
• Genetic and non iodine-related factors in the cause of nodular goitre
• Editorial Board

Central adrenal insufficiency in children and adolescents

Central adrenal insufficiency (CAI) is a life-threatening condition caused by either pituitary disease (secondary adrenal insufficiency) or impaired hypothalamic function with inadequate CRH production (tertiary adrenal insufficiency). ACTH deficiency may be isolated or, more frequently, occur in conjunction with other pituitary hormone deficiencies and midline defects. Genetic mutations of the TBX19 causing isolated CAI are rare but a number of genes encoding transcription factors involved in hypothalamic-pituitary gland development, as well as other genes including POMC and PC1, are associated with ACTH deficiency.

Animal models of endocrine disruption

Endocrine disrupting chemicals (EDCs) are compounds that alter the structure and function of the endocrine system and may be contributing to disorders of the reproductive, metabolic, neuroendocrine and other complex systems. Typically, these outcomes cannot be modeled in cell-based or other simple systems necessitating the use of animal testing. Appropriate animal model selection is required to effectively recapitulate the human experience, including relevant dosing and windows of exposure, and ensure translational utility and reproducibility.

Animal models of endometriosis: Replicating the aetiology and symptoms of the human disorder

Endometriosis is a chronic incurable disorder that affects 1 in 10 women of reproductive age: associated symptoms include chronic pain and infertility. The aetiology of endometriosis remains poorly understood but patients, clinicians and researchers are all in agreement that new non-surgical therapies are urgently needed to reduce the severity of symptoms. Preclinical testing of drugs requires the development and validation of models that recapitulate the key features of the disorder. In this review we describe the best-validated animal models (primate, rodent, xenograft) and their contributions to our understanding of the factors underpinning the development of symptoms.

Diagnosis and management of hyperthyroidism from prenatal life to adolescence

Hyperthyroidism in children is a rare heterogeneous syndrome characterized by excessive thyroid hormone production. Its manifestations differ according to disease severity. For all forms of hyperthyroidism, treatment aims to restore a euthyroid state, enabling the child to demonstrate appropriate metabolism, growth, and neurocognitive development. Graves? disease is the most frequent cause of hyperthyroidism in children. Treatment modalities include antithyroid drugs, with the advantage that prolonged treatment for several years can be followed by freedom from medical intervention in about 40-50% of cases.

Diagnosis and management of postnatal fetal growth restriction

Fetal growth restriction (FGR) can result from multiple causes, such as genetic, epigenetic, environment, hormonal regulation, or vascular troubles and their potential interaction. The physiopathology of FGR is not yet fully elucidated, but the insulin-like growth factor system is known to play a central role. Specific clinical features can lead to the identification of genetic syndromes in some patients. FGR leads to multiple global health concerns, from the perinatal period, with higher morbidity/mortality, through infancy, with neurodevelopmental, growth, and metabolic issues, to the onset of puberty and later in life, with subfertility and elevated risks of cardiovascular and kidney diseases.

Imaging endocrinology in animal models of endocrine disease

Endocrine organs secrete a variety of hormones involved in the regulation of a multitude of body functions. Although pancreatic islets were discovered at the turn of the 19th century, other endocrine glands remained commonly described as diffuse endocrine systems. Over the last two decades, development of new imaging techniques and genetically-modified animals with cell-specific fluorescent tags or specific hormone deficiencies have enabled in vivo imaging of endocrine organs and revealed intricate endocrine cell network structures and plasticity.

Genetically modified mouse models to investigate thyroid development, function and growth

The thyroid gland produces thyroid hormones (TH), which are essential regulators for growth, development and metabolism. The thyroid is mainly controlled by the thyroid-stimulating hormone (TSH) that binds to its receptor (TSHR) on thyrocytes and mediates its action via different G protein-mediated signaling pathways. TSH primarily activates the Gs-pathway, and at higher concentrations also the Gq/11-pathway, leading to an increase of intracellular cAMP and Ca2+, respectively. To date, the physiological importance of other G protein-mediated signaling pathways in thyrocytes is unclear.

Translational Studies Provide Insights for the Etiology and Treatment of Cortical Bone Osteoporosis

Increasing attention is being focused on the important contributions of cortical bone to bone strength, fractures and osteoporosis therapies. Recent progress in human genome wide association studies in combination with high-throughput mouse gene knock out phenotyping efforts of multiple genes and advanced conditional gene inactivation in mouse models have successfully identified genes with crucial roles in cortical bone homeostasis. Particular attention in this review is given to genes, such as WNT16, POSTN and SFRP4, that differentially affect cortical and trabecular bone architecture.

Mouse models of peripheral metabolic disease

Metabolic disease risk is driven by defects in the function of cells that regulate energy homeostasis, as well as altered communication between the different tissues or organs that these cells occupy. Thus, it is desirable to use model organisms to understand the contribution of different cells, tissues and organs to metabolism. Mice are widely used for metabolic research, since well-characterised mouse strains (in terms of their genotype and phenotype) allow comparative studies and human disease modelling.

Evidence from animal models on the pathogenesis of PCOS

Polycystic ovarian syndrome (PCOS) is the most common endocrine condition in women, and is characterized by reproductive, endocrine and metabolic features. However, there is no simple unequivocal diagnostic test for PCOS, its etiology remains unknown and there is no cure. Hence, the management of PCOS is suboptimal as it relies on the ad hoc empirical management of its symptoms only. Decisive studies are required to unravel the origins of PCOS, but due to ethical and logistical reasons these are not possible in humans.

Mouse models for the analysis of gonadotropin secretion and action

Gonadotropins are pituitary gonadotrope-derived glycoprotein hormones. They act by binding to G-protein coupled receptors on gonads. Gonadotropins play critical roles in reproduction by regulating both gametogenesis and steroidogenesis. Although biochemical and physiological studies provided a wealth of knowledge, gene manipulation techniques using novel mouse models gave new insights into gonadotropin synthesis, secretion and action. Both gain of function and loss of function mouse models for understanding gonadotropin action in a whole animal context have already been generated.

Preface

G-protein-coupled receptors (GPCR) constitute the largest family of receptors, sharing about 4% of human genome, and allow cells to sense extracellular signals. These signals include a variety of stimuli, such as light, odorants, neurotransmitters, hormones, metal ions, amino acids and other hydrophilic molecules. Upon agonist activation, the first wave of GPCR signalling is initiated by the dissociation of the heterotrimeric G proteins followed by modulation of a wide signalling spectra, including second messenger generation, activation of cytoplasmic tyrosine kinases, regulation of ion channels or transactivation of growth factor receptors.

Thyrotropin receptor, still much to be learned from the patients

In the absence of crystal available for the full-length thyrotropin receptor, knowledge of its structure and functioning has benefitted from the identification and characterization of mutations in patients with various thyroid dysfunctions. The characterization of activating mutations has contributed to the elaboration of a model involving the extracellular domain of the receptor as an inverse tethered agonist which, upon binding of the ligand, relieves the transmembrane domain from an inhibiting interaction and activates it.

An orphan G-protein-coupled receptor causes human gigantism and/or acromegaly: Molecular biology and clinical correlations

X-linked acrogigantism (X-LAG) is a recently described form of familial or sporadic pituitary gigantism characterized by very early onset GH and IGF-1 excess, accelerated growth velocity, gigantism and/or acromegaloid features. Germline or somatic microduplications of the Xq26.3 chromosomal region, invariably involving the GPR101 gene, constitute the genetic defect leading to X-LAG. GPR101 encodes a class A G protein-coupled receptor that activates the 3?,5?-cyclic adenosine monophosphate signaling pathway.

Translational studies provide insights for the etiology and treatment of cortical bone osteoporosis

Increasing attention is being focused on the important contributions of cortical bone to bone strength, fractures and osteoporosis therapies. Recent progress in human genome wide association studies in combination with high-throughput mouse gene knockout phenotyping efforts of multiple genes and advanced conditional gene inactivation in mouse models have successfully identified genes with crucial roles in cortical bone homeostasis. Particular attention in this review is given to genes, such as WNT16, POSTN and SFRP4, that differentially affect cortical and trabecular bone architecture.

G-protein-coupled receptors (GPCRs) in the treatment of diabetes: Current view and future perspectives

G-protein coupled receptors (GPCRs) represent the largest receptor family in the genome and are of great interest for the design of novel drugs in a wide variety of diseases including neurologic disorders, obesity and Type 2 diabetes mellitus. The latter is a chronic disease characterized by insulin resistance and impaired insulin secretion, affecting >400 million patients worldwide.Here we provide an overview on: a) The molecular basis of GPCR signalling and of its involvement in the regulation of insulin secretion and of glucose homeostasis; b) the role of GPCRs in type 2 diabetes pathophysiology and as therapeutic targets of current and future glucose-lowering drugs.

Novel mechanisms of G-protein-coupled receptors functions: AT1 angiotensin receptor acts as a signaling hub and focal point of receptor cross-talk

AT1 angiotensin receptor (AT1R), a prototypical G protein-coupled receptor (GPCR), is the main receptor, which mediates the effects of the renin-angiotensin system (RAS). AT1R plays a crucial role in the regulation of blood pressure and salt-water homeostasis, and in the development of pathological conditions, such as hypertension, heart failure, cardiovascular remodeling, renal fibrosis, inflammation, and metabolic disorders. Stimulation of AT1R leads to pleiotropic signal transduction pathways generating arrays of complex cellular responses.

Pathophysiology of melanocortin receptors and their accessory proteins

The melanocortin receptors (MCRs) and their accessory proteins (MRAPs) are involved in regulation of a diverse range of endocrine pathways. Genetic variants of these components result in phenotypic variation and disease. The MC1R is expressed in skin and variants in the MC1R gene are associated with ginger hair color. The MC2R mediates the action of ACTH in the adrenal gland to stimulate glucocorticoid production and MC2R mutations result in familial glucocorticoid deficiency (FGD). MC3R and MC4R are involved in metabolic regulation and their gene variants are associated with severe pediatric obesity, whereas the function of MC5R remains to be fully elucidated.

Internalization of G-protein-coupled receptors: Implication in receptor function, physiology and diseases

G protein-coupled receptors (GPCRs) are the largest family of membrane receptors and mediate the effects of numerous hormones and neurotransmitters. The nearly 1000 GPCRs encoded by the human genome regulate virtually all physiological functions and are implicated in the pathogenesis of prevalent human diseases such as thyroid disorders, hypertension or Parkinson's disease. As a result, 30?50% of all currently prescribed drugs are targeting these receptors. Once activated, GPCRs induce signals at the cell surface.

Aberrant G-protein coupled hormone receptor in adrenal diseases

The regulation of cortisol or aldosterone production when ACTH of pituitary origin or the renin-angiotensin systems are suppressed in primary adrenal Cushing's syndrome or in primary aldosteronism is exerted by diverse genetic and molecular mechanisms. In addition to recently identified mutations in various genes implicated in the cyclic AMP or ion channel pathways, steroidogenesis is not really autonomous as it is frequently regulated by the aberrant adrenocortical expression of diverse hormone receptors, particularly G-protein coupled hormone receptors (GPCR) which can substitute for the normal function of ACTH or angiotensin-II.

Multiple hormone resistance and alterations of G-protein-coupled receptors signaling

Metabolic disorders deriving from the non-responsiveness of target organs to hormones, which manifest clinically similar to the deficiency of a given hormone itself, derive from molecular alterations affecting specific hormone receptors.Pseudohypoparathyroidism (PHP) and related disorders exemplify an unusual form of hormone resistance as the underlying molecular defect is a partial deficiency of the ? subunit of the stimulatory G protein (Gs?), a key regulator of cAMP signaling pathway, or, as more recently described, of downstream effector proteins of the same pathway, such as PKA regulatory subunit 1A (R1A) and phosphodyestarase type 4D (PDE4D).

Pharmacogenetics of G-protein-coupled receptors variants: FSH receptor and infertility treatment

Infertility treatment may represent a paradigmatic example of precision medicine. Follicle-stimulating hormone (FSH) has been proposed as a valuable therapeutic option both in males and in females, even if a standardized approach is far to be established. To date, several genetic mutations as well as polymorphisms have been demonstrated to significantly affect the pathophysiology of FSH-FSH receptor (FSHR) interaction, although the underlying molecular mechanisms remain unclear. This review aims to highlight possible aspects of FSH therapy that could benefit from a pharmacogenetic approach, providing an up-to-date overview of the variability of the response to FSH treatment in both sexes.

The kisspeptin receptor: A key G-protein-coupled receptor in the control of the reproductive axis

The kisspeptin receptor, Kiss1R, also known as Gpr54, is a G protein-coupled receptor (GPCR), deorphanized in 2001, when it was recognized as canonical receptor for the Kiss1-derived peptides, kisspeptins. In 2003, inactivating mutations of Kiss1R gene were first associated to lack of pubertal maturation and hypogonadotropic hypogonadism in humans and rodents. These seminal findings pointed out the previously unsuspected, essential role of Kiss1R and its ligands in control of reproductive maturation and function.

WITHDRAWN: Pharmacogenetics of osteoporosis

The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.beem.2014.07.004.The duplicate article has therefore been withdrawn.

Genetic and non iodine-related factors in the cause of nodular goitre

Genetic and a large number of environmental non-iodine-related factors play a role in the cause of nodular goitre. Most evidence for the influence of genetic and environmental factors in the cause of goitre is from cross-sectional, population-based studies. Only a few studies have included prospective data on risk factors for nodular goitre, although few prospective data are available on the effect of iodine and tobacco smoking on goitre development. When studying this issue, it is important to realize that goitre is not one single phenotype.

Editorial Board