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Endocrine Reviews [journal]
- Thyroid Hormone Signaling and Homeostasis During Aging. [JOURNAL ARTICLE]
- Endocr Rev 2013 May 21.
Studies in humans and in animal models show negative correlations between thyroid hormone (TH) levels and longevity. TH signaling is implicated in maintaining and integrating metabolic homeostasis at multiple levels, notably centrally in the hypothalamus but also in peripheral tissues. The question is thus raised of how TH signaling is modulated during aging in different tissues. Classically, TH actions on mitochondria and heat production are obvious candidates to link negative effects of TH to aging. Mitochondrial effects of excess TH include reactive oxygen species and DNA damage, 2 factors often considered as aging accelerators. Inversely, caloric restriction, which can retard aging from nematodes to primates, causes a rapid reduction of circulating TH, reducing metabolism in birds and mammals. However, many other factors could link TH to aging, and it is these potentially subtler and less explored areas that are highlighted here. For example, effects of TH on membrane composition, inflammatory responses, stem cell renewal and synchronization of physiological responses to light could each contribute to TH regulation of maintenance of homeostasis during aging. We propose the hypothesis that constraints on TH signaling at certain life stages, notably during maturity, are advantageous for optimal aging.
- Tumors, IGF-2 and Hypoglycemia: Insights from the clinic, the laboratory and the historical archive. [JOURNAL ARTICLE]
- Endocr Rev 2013 May 13.
At the cellular level, the three hormone-related ligands - IGF-2, IGF-1, and insulin - all bind to four (or more) types of IGF-1 receptors and insulin receptors (IR). Each receptor has its own characteristic affinity for each ligand, a tyrosine kinase, and overlapping profiles of action in the target cells. The IGF-2 receptor (IGF-2R), in addition to binding mannose-6-phosphate containing proteins, provides an IGF-2 degradation pathway. Recent evidence suggests IGF-2R involvement also in signal transduction.Surgery, the treatment of choice, can produce a cure. For patients not cured by surgery, multiple therapies exist - for the tumor and for hypoglycemia. Potential future therapeutic approaches are sketched.Origins: From 1910-1930, hypoglycemia, insulin, insulinomas, and non-islet cell tumors were recognized. The latter third of the century witnessed the emergence of the immunoassay for insulin; the insulin-like growth factors, their binding proteins and assays to measure them; receptors for the insulin-related peptides, as well as the intracellular pathways beyond the receptor.In closing, we replace non-islet cell tumor hypoglycemia (NICTH), an outdated and misleading label, with IGF-2-oma, self-explanatory and consistent with names of other hormone-secreting tumors.
- The Regulation of Testicular Descent and the Effects of Cryptorchidism. [JOURNAL ARTICLE]
- Endocr Rev 2013 May 10.
The first half of this review examines the boundary between endocrinology and embryonic development with the aim of highlighting the way hormones and signalling systems regulate the complex morphological changes to enable the intraabdominal fetal testes to reach the scrotum. The genitofemoral ligament, or gubernaculum first enlarges to hold the testis near the groin, and then it develops limb-bud-like properties and migrates across the pubic region to reach the scrotum. Recent advances show key roles for insulin-like-hormone 3 (INSL3) in the first step, with androgen and the genitofemoral nerve involved in the second step. The mammary line may also be involved in initiating the migration.The key events in early postnatal germ cell development are then reviewed, as there is mounting evidence for this to be crucial in preventing infertility and malignancy later in life. We review the recent advances in what is known about aetiology of cryptorchidism, and summarise the syndromes where a specific molecular cause has been found. Finally we cover the recent literature on timing of surgery, the issues around acquired cryptorchidism and the limited role of hormone therapy. We conclude with some observations about the differences between animal models and baby boys with cryptorchidism.
- Novel Insights on Thyroid Stimulating Hormone Receptor Signal Transduction. [JOURNAL ARTICLE]
- Endocr Rev 2013 May 3.
The thyrotropin or thyroid stimulating hormone receptor (TSHR) is a member of the glycoprotein hormone receptors (GPHRs), a sub-family of family A G-protein coupled receptors (GPCRs). The TSHR is of great importance for the growth and function of the thyroid gland. The TSHR and its endogenous ligand TSH are pivotal proteins with respect to a variety of physiological functions and malfunctions. The molecular events of TSHR regulation can be summarized as a process of signal transduction, including signal reception, conversion and amplification. The steps during signal transduction from the extra- to the intracellular sites of the cell are not yet comprehensively understood. However, essential new insights have been achieved in recent years on the interrelated mechanisms at the extracellular region, the transmembrane domain and intracellular components. This review contains a critical summary of available knowledge of the molecular mechanisms of signal transduction at the TSHR, for example, the key amino acids involved in hormone binding or in the structural conformational changes that lead to G-protein activation or signaling regulation. Aspects of TSHR oligomerization, signaling promiscuity, signaling selectivity, phenotypes of genetic variations and potential extra-thyroidal receptor activity are also considered, as these are relevant to an understanding of the overall function of the TSHR, including physiological, pathophysiological and pharmacological perspectives. Directions for future research are discussed.
- New Insights Into the Role of Sequestosome 1/p62 Mutant Proteins in the Pathogenesis of Paget's Disease of Bone. [JOURNAL ARTICLE]
- Endocr Rev 2013 Apr 23.
Paget's disease of bone (PDB) is characterized by focal areas of aberrant and excessive bone turnover, specifically increased bone resorption and disorganized bone formation. Germline mutations in the sequestosome 1/p62 (SQSTM1/p62) gene are common in PDB patients, with most mutations affecting the ubiquitin-associated domain of the protein. In vitro, osteoclast precursor cells expressing PDB-mutant SQSTM1/p62 protein are associated with increases in nuclear factor κB activation, osteoclast differentiation, and bone resorption. Although the precise mechanisms by which SQSTM1/p62 mutations contribute to disease pathogenesis and progression are not well defined, it is apparent that as well as affecting nuclear factor κB signaling, SQSTM1/p62 is a master regulator of ubiquitinated protein turnover via autophagy and the ubiquitin-proteasome system. Additional roles for SQSTM1/p62 in the oxidative stress-induced Keap1/Nrf2 pathway and in caspase-mediated apoptosis that were recently reported are potentially relevant to the pathogenesis of PDB. Thus, SQSTM1/p62 may serve as a molecular link or switch between autophagy, apoptosis, and cell survival signaling. The purpose of this review is to outline recent advances in understanding of the multiple pathophysiological roles of SQSTM1/p62 protein, with particular emphasis on their relationship to PDB, including challenges associated with translating SQSTM1/p62 research into clinical diagnosis and treatment.
- 11β-Hydroxysteroid Dehydrogenase 1: Translational and Therapeutic Aspects. [JOURNAL ARTICLE]
- Endocr Rev 2013 Apr 23.
11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) interconverts the inactive glucocorticoid cortisone and its active form cortisol. It is widely expressed and, although bidirectional, in vivo it functions predominantly as an oxoreductase, generating active glucocorticoid. This allows glucocorticoid receptor activation to be regulated at a prereceptor level in a tissue-specific manner. In this review, we will discuss the enzymology and molecular biology of 11β-HSD1 and the molecular basis of cortisone reductase deficiencies. We will also address how altered 11β-HSD1 activity has been implicated in a number of disease states, and we will explore its role in the physiology and pathologies of different tissues. Finally, we will address the current status of selective 11β-HSD1 inhibitors that are in development and being tested in phase II trials for patients with the metabolic syndrome. Although the data are preliminary, therapeutic inhibition of 11β-HSD1 is also an exciting prospect for the treatment of a variety of other disorders such as osteoporosis, glaucoma, intracranial hypertension, and cognitive decline.
- The Osteocyte: An Endocrine Cell and More. [JOURNAL ARTICLE]
- Endocr Rev 2013 Apr 26.
Few investigators think of bone as an endocrine gland, even after the discovery that osteocytes produce circulating fibroblast growth factor 23 (FGF23) that targets the kidney and potentially other organs. In fact, until the last few years, osteocytes were perceived by many as passive, metabolically inactive cells. However, exciting recent discoveries have shown that osteocytes encased within mineralized bone matrix are actually multifunctional cells, with many key regulatory roles in bone and mineral homeostasis. In addition to serving as endocrine cells and regulators of phosphate homeostasis, these cells control bone remodeling through regulation of both osteoclasts and osteoblasts, are mechanosensory cells that coordinate adaptive responses of the skeleton to mechanical loading, and also serve as a manager of the bone's reservoir of calcium. Osteocytes must survive for decades within the bone matrix, making them one of the longest lived cells in the body. Viability and survival are therefore extremely important to ensure optimal function of the osteocyte network. As we continue to search for new therapeutics, in addition to the osteoclast and the osteoblast, the osteocyte should be considered in new strategies to prevent and treat bone disease.
- Thyrotropin Secretion Patterns in Health and Disease. [JOURNAL ARTICLE]
- Endocr Rev 2013 Apr 10.
Thyroid hormones are extremely important for metabolism, development and growth during the life time. The hypothalamo-pituitary-thyroid (HPT) axis is precisely regulated for these purposes. Much of our knowledge of this hormonal axis is derived from experiments in animals and mutations in man. This review examines the HPT-axis particularly in relation to the regulated 24-hour serum TSH concentration profiles in physiological and pathophysiological conditions, including obesity, primary hypothyroidism, pituitary diseases, psychiatric disorders and selected neurological diseases. Diurnal TSH rhythms can be analyzed with novel and precise techniques, e.g. operator-independent deconvolution and approximate entropy. These approaches provide indirect insight in the regulatory components in pathophysiological conditions.
- Molecular Characteristics of Malignant Ovarian Germ Cell Tumors and Comparison With Testicular Counterparts: Implications for Pathogenesis. [JOURNAL ARTICLE]
- Endocr Rev 2013 Apr 10.
This review focuses on the molecular characteristics and development of rare malignant ovarian germ cell tumors (mOGCTs). We provide an overview of the genomic aberrations assessed by ploidy, cytogenetic banding, and comparative genomic hybridization. We summarize and discuss the transcriptome profiles of mRNA and microRNA (miRNA), and biomarkers (DNA methylation, gene mutation, individual protein expression) for each mOGCT histological subtype. Parallels between the origin of mOGCT and their male counterpart testicular GCT (TGCT) are discussed from the perspective of germ cell development, endocrinological influences, and pathogenesis, as is the GCT origin in patients with disorders of sex development. Integrated molecular profiles of the 3 main histological subtypes, dysgerminoma (DG), yolk sac tumor (YST), and immature teratoma (IT), are presented. DGs show genomic aberrations comparable to TGCT. In contrast, the genome profiles of YST and IT are different both from each other and from DG/TGCT. Differences between DG and YST are underlined by their miRNA/mRNA expression patterns, suggesting preferential involvement of the WNT/β-catenin and TGF-β/bone morphogenetic protein signaling pathways among YSTs. Characteristic protein expression patterns are observed in DG, YST and IT. We propose that mOGCT develop through different developmental pathways, including one that is likely shared with TGCT and involves insufficient sexual differentiation of the germ cell niche. The molecular features of the mOGCTs underline their similarity to pluripotent precursor cells (primordial germ cells, PGCs) and other stem cells. This similarity combined with the process of ovary development, explain why mOGCTs present so early in life, and with greater histological complexity, than most somatic solid tumors.
- Evolving Approaches to Patients with Advanced Differentiated Thyroid Cancer. [JOURNAL ARTICLE]
- Endocr Rev 2013 Apr 10.
Advanced differentiated thyroid cancer (DTC), defined by clinical characteristics including gross extrathyroidal invasion, distant metastases, radioiodine (RAI) resistance, and avidity for 18-fluorodeoxyglucose (positron emission tomography-positive), is found in approximately 10-20% of patients with DTC. Standard therapy (surgery, RAI, TSH suppression with levothyroxine) is ineffective for many of these patients, as is standard chemotherapy. Our understanding of the molecular mechanisms leading to DTC and the transformation to advanced DTC has rapidly evolved over the past 15-20 years. Newer targeted therapy, specifically inhibitors of intracellular kinase signaling pathways, and cooperative multicenter clinical trials have dramatically changed the therapeutic landscape for patients with advanced DTC. In this review focusing on morbidities, molecules, and medicinals, we present a patient with advanced DTC, explore the genetics and molecular biology of advanced DTC, and review evolving therapies for these patients including multikinase inhibitors, selective kinase inhibitors, and combination therapies.