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Recent Articles in Endocrine Reviews

Kearns AE, Khosla S, Kostenuik P
RANKL and OPG Regulation of Bone Remodeling in Health and Disease.
Endocr Rev. 2007 Dec 5;
Osteoclasts and osteoblasts dictate skeletal mass, structure, and strength via their respective roles in resorbing and forming bone. Bone remodeling is a spatially coordinated lifelong process whereby old bone is removed by osteoclasts and replaced by bone-forming osteoblasts. The refilling of resorption cavities is incomplete in many pathologic states, which leads to a net loss of bone mass with each remodeling cycle. Postmenopausal osteoporosis and other conditions are associated with an increased rate of bone remodeling, which leads to accelerated bone loss and increased risk of fracture. Bone resorption is dependent on a cytokine known as RANKL (receptor activator of nuclear factor kappa B ligand), a TNF (tumor necrosis factor) family member that is essential for osteoclast formation, activity and survival in normal and pathologic states of bone remodeling. The catabolic effects of RANKL are prevented by OPG (osteoprotegerin), a TNF receptor family member that binds RANKL and thereby prevents activation of its single cognate receptor called RANK. Osteoclast activity is likely to depend, at least in part, on the relative balance of RANKL and OPG. Studies in numerous animal models of bone disease show that RANKL inhibition leads to marked suppression of bone resorption and increases in cortical and cancellous bone volume, density and strength. RANKL inhibitors also prevent focal bone loss that occurs in animal models of rheumatoid arthritis and bone metastasis. Clinical trials are exploring the effects of denosumab, a fully human anti-RANKL antibody, on bone loss in patients with osteoporosis, bone metastasis, myeloma, and rheumatoid arthritis. [Abstract/Link to Full Text]

Ben-Jonathan N, Lapensee CR, Lapensee EW
What Can We Learn from Rodents about Prolactin in Humans?
Endocr Rev. 2007 Dec 5;
Prolactin (PRL) is a 23-kDa protein hormone that binds to a single-span membrane receptor, a member of the cytokine receptor superfamily, and exerts its action via several interacting signaling pathways. PRL is a multifunctional hormone that affects multiple reproductive and metabolic functions and is also involved in tumorigenicity. In addition to being a classical pituitary hormone, PRL in humans is produced by many tissues throughout the body where it acts as a cytokine. The objective of this review is to compare and contrast multiple aspects of PRL, from structure to regulation, and from physiology to pathology in rats, mice, and humans. At each juncture, questions are raised whether, or to what extent, data from rodents are relevant to PRL homeostasis in humans. Most current knowledge on PRL has been obtained from studies with rats, and more recently, from the use of transgenic mice. Although this information is indispensable for understanding PRL in human health and disease, there is sufficient disparity in the control of the production, distribution and physiological functions of PRL among these species to warrant careful and judicial extrapolation to humans. [Abstract/Link to Full Text]

Eizirik DL, Cardozo AK, Cnop M
The Role for Endoplasmic Reticulum Stress in Diabetes Mellitus.
Endocr Rev. 2007 Nov 29;
Accumulating evidence suggests that endoplasmic reticulum (ER) stress plays a role in the pathogenesis of diabetes, contributing to pancreatic beta-cell loss and insulin resistance. Components of the unfolded protein response (UPR) play a dual role in beta-cells, acting as beneficial regulators under physiological conditions or as triggers of beta-cell dysfunction and apoptosis under situations of chronic stress. Novel findings suggest that "what makes a beta-cell a beta-cell", i.e., its enormous capacity to synthesize and secrete insulin, is also its "Achilles heel", rendering it vulnerable to chronic high glucose and fatty acid exposure, agents that contribute to beta-cell failure in type 2 diabetes. In this review, we address the transition from physiology to pathology, namely how and why the physiological UPR evolves to a proapoptotic ER stress response and which are the defenses triggered by beta-cells against these challenges. ER stress may also link obesity and insulin resistance in type 2 diabetes. High-fat feeding and obesity induce ER stress in liver, which suppresses insulin signaling via JNK activation. In vitro data suggest that ER stress may also contribute to cytokine-induced beta-cell death. Thus, the cytokines IL-1beta and IFN-gamma, putative mediators of beta-cell loss in type 1 diabetes, induce severe ER stress through, respectively, NO-mediated depletion of ER calcium and inhibition of ER chaperones, thus hampering beta-cell defenses and amplifying the proapoptotic pathways. A better understanding of the pathways regulating ER stress in beta-cells may be instrumental for the design of novel therapies to prevent beta-cell loss in diabetes. [Abstract/Link to Full Text]

Poitout V, Robertson RP
Glucolipotoxicity: Fuel Excess and {beta}-Cell Dysfunction.
Endocr Rev. 2007 Nov 29;
Glucotoxicity, lipotoxicity, and glucolipotoxicity are secondary phenomena that are proposed to play a role in all forms of type 2 diabetes. The underlying concept is that once the primary pathogenesis of diabetes is established, probably involving both genetic and environmental forces, hyperglycemia and very commonly hyperlipidemia ensue and thereafter exert additional damaging or toxic effects on the beta-cell. In addition to their contribution to the deterioration of beta-cell function after the onset of the disease, elevations of plasma fatty acid levels that often accompany insulin resistance may, as glucose levels begin to rise outside of the normal range, also play a pathogenic role in the early stages of the disease. Because hyperglycemia is a prerequisite for lipotoxicity to occur, the term glucolipotoxicity, rather than lipotoxicity, is more appropriate to describe deleterious effects of lipids on beta-cell function. In vitro and in vivo evidence supporting the concept of glucotoxicity is first presented, as well as a description of the underlying mechanisms with an emphasis on the role of oxidative stress. Second, we discuss the functional manifestations of glucolipotoxicity on insulin secretion, insulin gene expression, and beta-cell death; and the role of glucose in the mechanisms of glucolipotoxicity. Finally, we attempt to define the role of these phenomena in the natural history of beta-cell compensation, decompensation, and failure during the course of type 2 diabetes. [Abstract/Link to Full Text]

Donath MY, St�rling J, Berchtold LA, Billestrup N, Mandrup-Poulsen T
Cytokines and {beta}-Cell Biology: from Concept to Clinical Translation.
Endocr Rev. 2007 Nov 29;
The tale of cytokines and the beta-cell is a long story, starting with in vitro discovery in 1984, evolving via descriptive and phenomenological studies to detailed mapping of the signalling pathways, gene- and protein expression patterns, molecular and biochemical effector mechanisms to in vivo studies in spontaneously diabetic and transgenic animal models. Only very recently have steps been taken to translate the accumulating compelling preclinical data into clinical trials. The aim of this chapter is to present an overview of early and recent key observations from our own groups as well as other laboratories that serve to illuminate the road from concept to clinical translation. [Abstract/Link to Full Text]

Biondi B, Cooper DS
The Clinical Significance of Subclinical Thyroid Dysfunction.
Endocr Rev. 2007 Nov 8;
Subclinical thyroid disease (SCTD) is defined as serum FT4 and FT3 levels within their respective reference ranges in the presence of abnormal serum thyrotropin-stimulating hormone levels. Subclinical thyroid disease is being diagnosed more frequently in clinical practice in young and middle-aged people as well as in the elderly. However, the clinical significance of subclinical thyroid dysfunction is much debated. Subclinical hyper- and hypothyroidism can have repercussions on the cardiovascular system and bone, as well as on other organs and systems. However, the treatment and management of SCTD and population screening are controversial despite the potential risk of progression to overt disease, and there is no consensus on the thyroid hormone and thyrotropin cutoff values at which treatment should be contemplated. Opinions differ regarding tissue effects, symptoms and signs, and the cardiovascular risk. Here we critically review the data on the prevalence and progression of SCTD, its tissue effects, and its prognostic implications. We also examine the mechanisms underlying tissue alterations in SCTD and the effects of replacement therapy on progression and tissue parameters. Lastly, we address the issue of the need to treat slight thyroid hormone deficiency or excess in relation to the patient's age. [Abstract/Link to Full Text]

Hill JO
Understanding and addressing the epidemic of obesity: an energy balance perspective.
Endocr Rev. 2006 Dec;27(7):750-61.
The intent of this paper is to address the obesity epidemic, which is a term used to describe the sudden and rapid increase in obesity rates that began in the 1980s and continues unabated today. Since 1980, the entire population, regardless of starting weight, is gradually gaining weight. This has led to escalating obesity rates and to obesity being considered one of the most serious public health challenges facing the world. At one level, the obesity epidemic is a classic gene-environment interaction where the human genotype is susceptible to environmental influences that affect energy intake and energy expenditure. It is also a problem of energy balance. Understanding the etiology of obesity requires the study of how behavioral and environmental factors have interacted to produce positive energy balance and weight gain. Reversing the epidemic of obesity will require modifying some combination of these factors to help the population achieve energy balance at a healthy body weight. While body weight is strongly influenced by biological and behavioral factors, changes in the environment promoting positive energy balance have been most responsible for the obesity epidemic. Our best strategy for reversing the obesity epidemic is to focus on preventing positive energy balance in the population through small changes in diet and physical activity that take advantage of our biological systems for regulating energy balance. Simultaneously, we must address the environment to make it easier to make better food and physical activity choices. This is a very long-term strategy for first stopping and then reversing the escalating obesity rates, but one that can, over time, return obesity rates to pre-1980s levels. [Abstract/Link to Full Text]

Farooqi S, O'Rahilly S
Genetics of obesity in humans.
Endocr Rev. 2006 Dec;27(7):710-18.
Considerable attention has focused on deciphering the hypothalamic pathways that mediate the behavioral and metabolic effects of leptin. We and others have identified several single gene defects that disrupt the molecules in the leptin-melanocortin pathway causing severe obesity in humans. In this review, we consider these human monogenic obesity syndromes and discuss how far the characterization of these patients has informed our understanding of the physiological role of leptin and the melanocortins in the regulation of human body weight and neuroendocrine function. [Abstract/Link to Full Text]

Foster-Schubert KE, Cummings DE
Emerging therapeutic strategies for obesity.
Endocr Rev. 2006 Dec;27(7):779-93.
The rising tide of obesity is one of the most pressing health issues of our time, yet existing medicines to combat the problem are disappointingly limited in number and effectiveness. Fortunately, a recent burgeoning of mechanistic insights into the neuroendocrine regulation of body weight provides an expanding list of molecular targets for novel, rationally designed antiobesity pharmaceuticals. In this review, we articulate a set of conceptual principles that we feel could help prioritize among these molecules in the development of obesity therapeutics, based on an understanding of energy homeostasis. We focus primarily on central targets, highlighting selected strategies to stimulate endogenous catabolic signals or inhibit anabolic signals. Examples of the former approach include methods to enhance central leptin signaling through intranasal leptin delivery, use of superpotent leptin-receptor agonists, and mechanisms to increase leptin sensitivity by manipulating SOCS-3, PTP-1B, ciliary neurotrophic factor, or simply by first losing weight with traditional interventions. Techniques to augment signaling by neurochemical mediators of leptin action that lie downstream of at least some levels of obesity-associated leptin resistance include activation of melanocortin receptors or 5-HT2C and 5-HT1B receptors. We also describe strategies to inhibit anabolic molecules, such as neuropeptide Y, melanin-concentrating hormone, ghrelin, and endocannabinoids. Modulation of gastrointestinal satiation and hunger signals is discussed as well. As scientists continue to provide fundamental insights into the mechanisms governing body weight, the future looks bright for development of new and better antiobesity medications to be used with diet and exercise to facilitate substantial weight loss. [Abstract/Link to Full Text]

Murphy KG, Dhillo WS, Bloom SR
Gut peptides in the regulation of food intake and energy homeostasis.
Endocr Rev. 2006 Dec;27(7):719-27.
Gut hormones signal to the central nervous system to influence energy homeostasis. Evidence supports the existence of a system in the gut that senses the presence of food in the gastrointestinal tract and signals to the brain via neural and endocrine mechanisms to regulate short-term appetite and satiety. Recent evidence has shown that specific gut hormones administered at physiological or pathophysiological concentrations can influence appetite in rodents and humans. Gut hormones therefore have an important physiological role in postprandial satiety, and gut hormone signaling systems represent important pharmaceutical targets for potential antiobesity therapies. Our laboratory investigates the role of gut hormones in energy homeostasis and has a particular interest in this field of translational research. In this review we describe our initial studies and the results of more recent investigations into the effects of the gastric hormone ghrelin and the intestinal hormones peptide YY, pancreatic polypeptide, glucagon-like peptide-1, and oxyntomodulin on energy homeostasis. We also speculate on the role of gut hormones in the future treatment of obesity. [Abstract/Link to Full Text]

Cone RD
Studies on the physiological functions of the melanocortin system.
Endocr Rev. 2006 Dec;27(7):736-49.
The melanocortin system refers to a set of hormonal, neuropeptidergic, and paracrine signaling pathways that are defined by components that include the five G protein-coupled melanocortin receptors; peptide agonists derived from the proopiomelanocortin preprohormone precursor; and the endogenous antagonists, agouti and agouti-related protein. This signaling system regulates a remarkably diverse array of physiological functions including pigmentation, adrenocortical steroidogenesis, energy homeostasis, natriuresis, erectile responses, energy homeostasis, and exocrine gland secretion. There are many complex and unique aspects of melanocortin signaling, such as the existence of endogenous antagonists, the agouti proteins, that act at three of the five melanocortin receptors. However, there is an aspect of melanocortin signaling that has facilitated highly reductionist approaches aimed at understanding the physiological functions of each receptor and peptide: in contrast to many peptides, the melanocortin agonists and antagonists are expressed in a limited number of very discrete locations. Similarly, the melanocortin receptors are also expressed in a limited number of discrete locations where they tend to be involved in rather circumscribed physiological functions. This review examines my laboratory's participation in the cloning of the melanocortin receptors and characterization of their physiological roles. [Abstract/Link to Full Text]

Trujillo ME, Scherer PE
Adipose tissue-derived factors: impact on health and disease.
Endocr Rev. 2006 Dec;27(7):762-78.
The endocrine functions of the adipose organ are widely studied at this stage. The adipose organ, and in particular adipocytes, communicate with almost all other organs. Although some adipose tissue pads assume the functions as distinct "miniorgans," adipocytes can also be present in smaller numbers interspersed with other cell types. Although fat pads have the potential to have a significant systemic impact, adipocytes may also affect neighboring tissues through paracrine interactions. These local or systemic effects are mediated through lipid and protein factors. The protein factors are commonly referred to as adipokines. Their expression and posttranslational modifications can undergo dramatic changes under different metabolic conditions. Due to the fact that none of the mutations that affect adipose tissue trigger embryonic lethality, the study of adipose tissue physiology lends itself to genetic analysis in mice. In fact, life in the complete absence of adipose tissue is possible in a laboratory setting, making even the most extreme adipose tissue phenotypes genetically amenable to be analyzed by disruption of specific genes or overexpression of others. Here, we briefly discuss some basic aspects of adipocyte physiology and the systemic impact of adipocyte-derived factors on energy homeostasis. [Abstract/Link to Full Text]

Handschin C, Spiegelman BM
Peroxisome proliferator-activated receptor gamma coactivator 1 coactivators, energy homeostasis, and metabolism.
Endocr Rev. 2006 Dec;27(7):728-35.
Many biological programs are regulated at the transcriptional level. This is generally achieved by the concerted actions of several transcription factors. Recent findings have shown that, in many cases, transcriptional coactivators coordinate the overall regulation of the biological programs. One of the best-studied examples of coactivator control of metabolic pathways is the peroxisome proliferator-activated receptor coactivator 1 (PGC-1) family. These proteins are strong activators of mitochondrial function and are thus dominant regulators of oxidative metabolism in a variety of tissues. The PGC-1 coactivators themselves are subject to powerful regulation at the transcriptional and posttranslational levels. Recent studies have elucidated the function of the PGC-1 coactivators in different tissues and have highlighted the implications of PGC-1 dysregulation in diseases such as diabetes, obesity, cardiomyopathy, or neurodegeneration. [Abstract/Link to Full Text]

Ohnemus U, Uenalan M, Inzunza J, Gustafsson JA, Paus R
The hair follicle as an estrogen target and source.
Endocr Rev. 2006 Oct;27(6):677-706.
For many decades, androgens have dominated endocrine research in hair growth control. Androgen metabolism and the androgen receptor currently are the key targets for systemic, pharmacological hair growth control in clinical medicine. However, it has long been known that estrogens also profoundly alter hair follicle growth and cycling by binding to locally expressed high-affinity estrogen receptors (ERs). Besides altering the transcription of genes with estrogen-responsive elements, 17beta-estradiol (E2) also modifies androgen metabolism within distinct subunits of the pilosebaceous unit (i.e., hair follicle and sebaceous gland). The latter displays prominent aromatase activity, the key enzyme for androgen conversion to E2, and is both an estrogen source and target. Here, we chart the recent renaissance of estrogen research in hair research; explain why the hair follicle offers an ideal, clinically relevant test system for studying the role of sex steroids, their receptors, and interactions in neuroectodermal-mesodermal interaction systems in general; and illustrate how it can be exploited to identify novel functions and signaling cross talks of ER-mediated signaling. Emphasizing the long-underestimated complexity and species-, gender-, and site-dependence of E2-induced biological effects on the hair follicle, we explore targets for pharmacological intervention in clinically relevant hair cycle manipulation, ranging from androgenetic alopecia and hirsutism via telogen effluvium to chemotherapy-induced alopecia. While defining major open questions, unsolved clinical challenges, and particularly promising research avenues in this area, we argue that the time has come to pay estrogen-mediated signaling the full attention it deserves in future endocrinological therapy of common hair growth disorders. [Abstract/Link to Full Text]

Yang SN, Berggren PO
The role of voltage-gated calcium channels in pancreatic beta-cell physiology and pathophysiology.
Endocr Rev. 2006 Oct;27(6):621-76.
Voltage-gated calcium (CaV) channels are ubiquitously expressed in various cell types throughout the body. In principle, the molecular identity, biophysical profile, and pharmacological property of CaV channels are independent of the cell type where they reside, whereas these channels execute unique functions in different cell types, such as muscle contraction, neurotransmitter release, and hormone secretion. At least six CaValpha1 subunits, including CaV1.2, CaV1.3, CaV2.1, CaV2.2, CaV2.3, and CaV3.1, have been identified in pancreatic beta-cells. These pore-forming subunits complex with certain auxiliary subunits to conduct L-, P/Q-, N-, R-, and T-type CaV currents, respectively. beta-Cell CaV channels take center stage in insulin secretion and play an important role in beta-cell physiology and pathophysiology. CaV3 channels become expressed in diabetes-prone mouse beta-cells. Point mutation in the human CaV1.2 gene results in excessive insulin secretion. Trinucleotide expansion in the human CaV1.3 and CaV2.1 gene is revealed in a subgroup of patients with type 2 diabetes. beta-Cell CaV channels are regulated by a wide range of mechanisms, either shared by other cell types or specific to beta-cells, to always guarantee a satisfactory concentration of Ca2+. Inappropriate regulation of beta-cell CaV channels causes beta-cell dysfunction and even death manifested in both type 1 and type 2 diabetes. This review summarizes current knowledge of CaV channels in beta-cell physiology and pathophysiology. [Abstract/Link to Full Text]

de Groot JW, Links TP, Plukker JT, Lips CJ, Hofstra RM
RET as a diagnostic and therapeutic target in sporadic and hereditary endocrine tumors.
Endocr Rev. 2006 Aug;27(5):535-60.
The RET gene encodes a receptor tyrosine kinase that is expressed in neural crest-derived cell lineages. The RET receptor plays a crucial role in regulating cell proliferation, migration, differentiation, and survival through embryogenesis. Activating mutations in RET lead to the development of several inherited and noninherited diseases. Germline point mutations are found in the cancer syndromes multiple endocrine neoplasia (MEN) type 2, including MEN 2A and 2B, and familial medullary thyroid carcinoma. These syndromes are autosomal dominantly inherited. The identification of mutations associated with these syndromes has led to genetic testing to identify patients at risk for MEN 2 and familial medullary thyroid carcinoma and subsequent implementation of prophylactic thyroidectomy in mutation carriers. In addition, more than 10 somatic rearrangements of RET have been identified from papillary thyroid carcinomas. These mutations, as those found in MEN 2, induce oncogenic activation of the RET tyrosine kinase domain via different mechanisms, making RET an excellent candidate for the design of molecular targeted therapy. Recently, various kinds of therapeutic approaches, such as tyrosine kinase inhibition, gene therapy with dominant negative RET mutants, monoclonal antibodies against oncogene products, and nuclease-resistant aptamers that recognize and inhibit RET have been developed. The use of these strategies in preclinical models has provided evidence that RET is indeed a potential target for selective cancer therapy. However, a clinically useful therapeutic option for treating patients with RET-associated cancer is still not available. [Abstract/Link to Full Text]

Pissios P, Bradley RL, Maratos-Flier E
Expanding the scales: The multiple roles of MCH in regulating energy balance and other biological functions.
Endocr Rev. 2006 Oct;27(6):606-20.
Melanin-concentrating hormone (MCH) is a cyclic peptide originally identified as a 17-amino-acid circulating hormone in teleost fish, where it is secreted by the pituitary in response to stress and environmental stimuli. In fish, MCH lightens skin color by stimulating aggregation of melanosomes, pigment-containing granules in melanophores, cells of neuroectodermal origin found in fish scales. Although the peptide structure between fish and mammals is highly conserved, in mammals, MCH has no demonstrable effects on pigmentation; instead, based on a series of pharmacological and genetic experiments, MCH has emerged as a critical hypothalamic regulator of energy homeostasis, having effects on both feeding behavior and energy expenditure. [Abstract/Link to Full Text]

Turgeon JL, Carr MC, Maki PM, Mendelsohn ME, Wise PM
Complex actions of sex steroids in adipose tissue, the cardiovascular system, and brain: Insights from basic science and clinical studies.
Endocr Rev. 2006 Oct;27(6):575-605.
Recent publications describing the results of the Women's Health Initiative (WHI) and other studies reporting the impact of hormone therapy on aging women have spurred reexamination of the broad use of estrogens and progestins during the postmenopausal years. Here, we review the complex pharmacology of these hormones, the diverse and sometimes opposite effects that result from the use of different estrogenic and progestinic compounds, given via different delivery routes in different concentrations and treatment sequence, and to women of different ages and health status. We examine our new and growing appreciation of the role of estrogens in the immune system and the inflammatory response, and we pose the concept that estrogen's interface with this system may be at the core of some of the effects on multiple physiological systems, such as the adipose/metabolic system, the cardiovascular system, and the central nervous system. We compare and contrast clinical and basic science studies as we focus on the actions of estrogens in these systems because the untoward effects of hormone therapy reported in the WHI were not expected. The broad interpretation and publicity of the results of the WHI have resulted in a general condemnation of all hormone replacement in postmenopausal women. In fact, careful review of the extensive literature suggests that data resulting from the WHI and other recent studies should be interpreted within the narrow context of the study design. We argue that these results should encourage us to perform new studies that take advantage of a dialogue between basic scientists and clinician scientists to ensure appropriate design, incorporation of current knowledge, and proper interpretation of results. Only then will we have a better understanding of what hormonal compounds should be used in which populations of women and at what stages of menopausal/postmenopausal life. [Abstract/Link to Full Text]

Cools M, Drop SL, Wolffenbuttel KP, Oosterhuis JW, Looijenga LH
Germ cell tumors in the intersex gonad: old paths, new directions, moving frontiers.
Endocr Rev. 2006 Aug;27(5):468-84.
The risk for the development of germ cell tumors is an important factor to deal with in the management of patients with disorders of sex development (DSD). However, this risk is often hard to predict. Recently, major progress has been made in identifying gene-products related to germ cell tumor development (testis-specific protein-Y encoded and octamer binding transcription factor 3/4) and in recognizing early changes of germ cells (maturation delay, preneoplastic lesions, and in situ neoplasia). The newly recognized "undifferentiated gonadal tissue" has been identified as a gonadal differentiation pattern bearing a high risk for the development of gonadoblastoma. It is expected that the combination of these findings will allow for estimation of the risk for tumor development in the individual patient (high risk/intermediate risk/low risk). This article reviews the recent literature regarding the prevalence of germ cell tumors in patients with DSD. Some major limitations regarding this topic, including a confusing terminology referring to the different forms of intersex disorders and unclear criteria for the diagnosis of malignant germ cells at an early age (maturation delay vs. early steps in malignant transformation) are discussed. Thereafter, an overview of the recent advances that have been made in our knowledge of germ cell tumor development and the correct diagnosis of early neoplastic lesions in this patient population is provided. A new classification system for patients with DSD is proposed as a tool to refine our insight in the prevalence of germ cell tumors in specific diagnostic groups. [Abstract/Link to Full Text]

Gillam MP, Molitch ME, Lombardi G, Colao A
Advances in the treatment of prolactinomas.
Endocr Rev. 2006 Aug;27(5):485-534.
Prolactinomas account for approximately 40% of all pituitary adenomas and are an important cause of hypogonadism and infertility. The ultimate goal of therapy for prolactinomas is restoration or achievement of eugonadism through the normalization of hyperprolactinemia and control of tumor mass. Medical therapy with dopamine agonists is highly effective in the majority of cases and represents the mainstay of therapy. Recent data indicating successful withdrawal of these agents in a subset of patients challenge the previously held concept that medical therapy is a lifelong requirement. Complicated situations, such as those encountered in resistance to dopamine agonists, pregnancy, and giant or malignant prolactinomas, may require multimodal therapy involving surgery, radiotherapy, or both. Progress in elucidating the mechanisms underlying the pathogenesis of prolactinomas may enable future development of novel molecular therapies for treatment-resistant cases. This review provides a critical analysis of the efficacy and safety of the various modes of therapy available for the treatment of patients with prolactinomas with an emphasis on challenging situations, a discussion of the data regarding withdrawal of medical therapy, and a foreshadowing of novel approaches to therapy that may become available in the future. [Abstract/Link to Full Text]

Sch�ffler A, M�ller-Ladner U, Sch�lmerich J, B�chler C
Role of adipose tissue as an inflammatory organ in human diseases.
Endocr Rev. 2006 Aug;27(5):449-67.
Reviews on the inflammatory role of adipose tissue outside the field of metabolism are rare. There is increasing evidence provided by numerous basic research studies from nearly all internal medicine subspecializations that adipocytes and adipocytokines are involved in primary inflammatory processes and diseases. Therefore, it is the aim of the present review to discuss and to summarize the current knowledge on the inflammatory role of adipocytokines and special types of regional adipocytes such as retroorbital, synovial, visceral, subdermal, peritoneal, and bone marrow adipocytes in internal medicine diseases. Future clinical and therapeutic implications are discussed. [Abstract/Link to Full Text]

Wang H, Dey SK, Maccarrone M
Jekyll and hyde: two faces of cannabinoid signaling in male and female fertility.
Endocr Rev. 2006 Aug;27(5):427-48.
Mammalian reproduction is a complicated process designed to diversify and strengthen the genetic complement of the offspring and to safeguard regulatory systems at various steps for propagating procreation. An emerging concept in mammalian reproduction is the role of endocannabinoids, a group of endogenously produced lipid mediators, that bind to and activate cannabinoid receptors. Although adverse effects of cannabinoids on fertility have been implicated for years, the mechanisms by which they exert these effects were not clearly understood. With the identification of cannabinoid receptors, endocannabinoid ligands, their key synthetic and hydrolytic pathways, and the generation of mouse models missing cannabinoid receptors, a wealth of information on the significance of cannabinoid/endocannabinoid signaling in spermatogenesis, fertilization, preimplantation embryo development, implantation, and postimplantation embryonic growth has been generated. This review focuses on various aspects of the endocannabinoid system in male and female fertility. It is hoped that a deeper insight would lead to potential clinical applications of the endocannabinoid signaling as a target for correcting infertility and improving reproductive health in humans. [Abstract/Link to Full Text]

Cozar-Castellano I, Fiaschi-Taesch N, Bigatel TA, Takane KK, Garcia-Oca�a A, Vasavada R, Stewart AF
Molecular control of cell cycle progression in the pancreatic beta-cell.
Endocr Rev. 2006 Jun;27(4):356-70.
Type 1 and type 2 diabetes both result from inadequate production of insulin by the beta-cells of the pancreatic islet. Accordingly, strategies that lead to increased pancreatic beta-cell mass, as well as retained or enhanced function of islets, would be desirable for the treatment of diabetes. Although pancreatic beta-cells have long been viewed as terminally differentiated and irreversibly arrested, evidence now indicates that beta-cells can and do replicate, that this replication can be enhanced by a variety of maneuvers, and that beta-cell replication plays a quantitatively significant role in maintaining pancreatic beta-cell mass and function. Because beta-cells have been viewed as being unable to proliferate, the science of beta-cell replication is undeveloped. In the past several years, however, this has begun to change at a rapid pace, and many laboratories are now focused on elucidating the molecular details of the control of cell cycle in the beta-cell. In this review, we review the molecular details of cell cycle control as they relate to the pancreatic beta-cell. Our hope is that this review can serve as a common basis and also a roadmap for those interested in developing novel strategies for enhancing beta-cell replication and improving insulin production in animal models as well as in human pancreatic beta-cells. [Abstract/Link to Full Text]

Daftary GS, Taylor HS
Endocrine regulation of HOX genes.
Endocr Rev. 2006 Jun;27(4):331-55.
Hox genes have a well-characterized role in embryonic development, where they determine identity along the anteroposterior body axis. Hox genes are expressed not only during embryogenesis but also in the adult, where they are necessary for functional differentiation. Despite the known function of these genes as transcription factors, few regulatory mechanisms that drive Hox expression are known. Recently, several hormones and their cognate receptors have been shown to regulate Hox gene expression and thereby mediate development in the embryo as well as functional differentiation in the adult organism. Estradiol, progesterone, testosterone, retinoic acid, and vitamin D have been shown to regulate Hox gene expression. In the embryo, the endocrine system directs axial Hox gene expression; aberrant Hox gene expression due to exposure to endocrine disruptors contributes to the teratogenicity of these compounds. In the adult, endocrine regulation of Hox genes is necessary to enable such diverse functions as hematopoiesis and reproduction; endocrinopathies can result in dysregulated HOX gene expression affecting physiology. By regulating HOX genes, hormonal signals utilize a conserved mechanism that allows generation of structural and functional diversity in both developing and adult tissues. This review discusses endocrine Hox regulation and its impact on physiology and human pathology. [Abstract/Link to Full Text]

L�pez-Soriano J, Chiellini C, Maffei M, Grimaldi PA, Argil�s JM
Roles of skeletal muscle and peroxisome proliferator-activated receptors in the development and treatment of obesity.
Endocr Rev. 2006 May;27(3):318-29.
Metabolic disturbances associated with alterations in lipid metabolism, such as obesity, type 2 diabetes, and syndrome X, are becoming more and more prominent in Western societies. Despite extensive research in such pathologies and their molecular basis, we are still far from completely understanding how these metabolic perturbations are produced and interrelate and, consequently, how to treat them efficiently. The discovery that adipose tissue is, in fact, an endocrine tissue able to secrete active molecules related to lipid homeostasis--the adipokines--has dramatically changed our understanding of the molecular events that take place in such diseases. This knowledge has been further improved by the discovery of peroxisome proliferator-activated receptors and their ligands, at present commonly used for the clinical treatment of lipid disturbances. However, a key point remains to be solved, and that is the role of muscle lipid metabolism, notably because of the main role played by this tissue in the development of such pathologies. In addition, a reciprocal regulation between adipose tissue and skeletal muscle has been proposed. New discoveries on the role of peroxisome proliferator-activated receptor-delta in skeletal muscle functions as well as the secretory capabilities of muscle, now considered as an endocrine tissue, have changed the general point of view on lipid homeostasis, opening new and promising doors for the treatment of lipid disorders. [Abstract/Link to Full Text]

Woodhouse LJ, Mukherjee A, Shalet SM, Ezzat S
The influence of growth hormone status on physical impairments, functional limitations, and health-related quality of life in adults.
Endocr Rev. 2006 May;27(3):287-317.
The availability of recombinant human GH and somatostatin analogs has resulted in widespread treatment for adults with GH deficiency (GHD) and those with GH excess (acromegaly). Despite being at opposite ends of the spectrum in terms of their GH/IGF-I axis, both of these populations experience overlapping somatic impairments. Adults with untreated GHD have low circulating levels of IGF-I that manifest as altered body composition with increased fat and reduced lean body and skeletal muscle mass. At the other end of the spectrum, adults with GH excess, who have elevated levels of IGF-I, also have altered body composition. Impairments that result from disorders of either GHD or GH excess are both associated with increased functional limitations, such as reduced ability to walk quickly for prolonged periods, and poorer health-related quality of life (HR-QoL). Adults with untreated GHD and GH excess both commonly complain of excessive fatigue that seems to be associated more with impaired aerobic than muscular performance. Several studies have documented that administration of GH or somatostatin analogs to adults with GHD or GH excess, respectively, ameliorates abnormal biochemical profile and the associated somatic impairments. However, whether these improvements translate into improved physical function in adults with GHD or GH excess remains largely unknown, and their impact on HR-QoL controversial. Review of placebo-controlled trials to date suggests that GH and somatostatin analogs have greater effects on gas exchange and aerobic performance than as anabolic agents on skeletal muscle mass and function. Future investigations should include dose-response studies to establish the optimal combination of pharmacological agents plus exercise required to improve not only biochemical markers but also physical function and HR-QoL in adults with GHD or GH excess. [Abstract/Link to Full Text]

Cohen PE, Pollack SE, Pollard JW
Genetic analysis of chromosome pairing, recombination, and cell cycle control during first meiotic prophase in mammals.
Endocr Rev. 2006 Jun;27(4):398-426.
Meiosis is a double-division process that is preceded by only one DNA replication event to produce haploid gametes. The defining event in meiosis is prophase I, during which chromosome pairs locate each other, become physically connected, and exchange genetic information. Although many aspects of this process have been elucidated in lower organisms, there has been scant information available until now about the process in mammals. Recent advances in genetic analysis, especially in mice and humans, have revealed many genes that play essential roles in meiosis in mammals. These include cell cycle-regulatory proteins that couple the exit from the premeiotic DNA synthesis to the progression through prophase I, the chromosome structural proteins involved in synapsis, and the repair and recombination proteins that process the recombination events. Failure to adequately repair the DNA damage caused by recombination triggers meiotic checkpoints that result in ablation of the germ cells by apoptosis. These analyses have revealed surprising sexual dimorphism in the requirements of different gene products and a much less stringent checkpoint regulation in females. This may provide an explanation for the 10-fold increase in meiotic errors in females compared with males. This review provides a comprehensive analysis of the use of genetic manipulation, particularly in mice, but also of the analysis of mutations in humans, to elucidate the mechanisms that are required for traverse through prophase I. [Abstract/Link to Full Text]

Karavitaki N, Cudlip S, Adams CB, Wass JA
Craniopharyngiomas.
Endocr Rev. 2006 Jun;27(4):371-97.
Craniopharyngiomas are rare, mainly sellar/parasellar, epithelial tumors diagnosed during childhood or adult life. Histologically, two primary subtypes have been recognized (adamantinomatous and papillary) with an as yet, unclarified pathogenesis. They may present with a variety of manifestations (neurological, visual, and hypothalamo-pituitary). Despite their benign histological appearance, they often show an unpredictable growth pattern, which, combined with the lack of randomized studies, poses significant difficulties in the establishment of an optimal therapeutic protocol. This should focus on the prevention of recurrence(s), improvement of survival, reduction of the significant disease and treatment-related morbidity (endocrine, visual, hypothalamic, neurobehavioral, and cognitive), and preservation of the quality of life. Currently, surgical excision followed by external beam irradiation, in cases of residual tumor, is the main treatment option. Intracystic irradiation or bleomycin, stereotactic radiosurgery, or radiotherapy and systemic chemotherapy are alternative approaches; their place in the management plan remains to be assessed in adequately powered long-term trials. Apart from the type of treatment, the identification of clinical and imaging parameters that will predict patients with a better prognosis is difficult. The central registration of patients with these challenging tumors may provide correlates between treatments and outcomes and establish prognostic factors at the pathological or molecular level that may further guide us in the future. [Abstract/Link to Full Text]

Nigro J, Osman N, Dart AM, Little PJ
Insulin resistance and atherosclerosis.
Endocr Rev. 2006 May;27(3):242-59.
The epidemic of obesity in the developed world over the last two decades is driving a large increase in type 2 diabetes and consequentially setting the scene for an impending wave of cardiovascular morbidity and mortality. It is only now being recognized that the major antecedent of type 2 diabetes, insulin resistance with its attendant syndrome, is the major underlying cause of the susceptibility to type 2 diabetes and cardiovascular disease. In metabolic tissues, insulin signaling via the phosphatidylinositol-3-kinase pathway leads to glucose uptake so that in insulin resistance a state of hyperglycemia occurs; other factors such as dyslipidemia and hypertension also arise. In cardiovascular tissues there are two pathways of insulin receptor signaling, one that is predominant in metabolic tissues (mediated by phosphatidylinositol-3-kinase) and another being a growth factor-like pathway (mediated by MAPK); the down-regulation of the former and continued activity of the latter pathway leads to atherosclerosis. This review addresses the metabolic consequences of the insulin resistance syndrome, its relationship with atherosclerosis, and the impact of insulin resistance on processes of atherosclerosis including insulin signaling in cells of the vasculature. [Abstract/Link to Full Text]

Hillhouse EW, Grammatopoulos DK
The molecular mechanisms underlying the regulation of the biological activity of corticotropin-releasing hormone receptors: implications for physiology and pathophysiology.
Endocr Rev. 2006 May;27(3):260-86.
The CRH receptor (CRH-R) is a member of the secretin family of G protein-coupled receptors. Wide expression of CRH-Rs in the central nervous system and periphery ensures that their cognate agonists, the family of CRH-like peptides, are capable of exerting a wide spectrum of actions that underpin their critical role in integrating the stress response and coordinating the activity of fundamental physiological functions, such as the regulation of the cardiovascular system, energy balance, and homeostasis. Two types of mammal CRH-R exist, CRH-R1 and CRH-R2, each with unique splicing patterns and remarkably distinct pharmacological properties, but similar signaling properties, probably reflecting their distinct and sometimes contrasting biological functions. The regulation of CRH-R expression and activity is not fully elucidated, and we only now begin to fully understand the impact on mammalian pathophysiology. The focus of this review is the current and evolving understanding of the molecular mechanisms controlling CRH-R biological activity and functional flexibility. This shows notable tissue-specific characteristics, highlighted by their ability to couple to distinct G proteins and activate tissue-specific signaling cascades. The type of activating agonist, receptor, and target cell appears to play a major role in determining the overall signaling and biological responses in health and disease. [Abstract/Link to Full Text]

Recent Articles in Endocrinology

Svendsen AM, Vrecl M, Ellis TM, Heding A, Kristensen JB, Wade JD, Bathgate RA, De Meyts P, N�hr J
Cooperative binding of insulin-like peptide 3 to a dimeric relaxin family peptide receptor 2.
Endocrinology. 2007 Dec 6; .
Insulin-like peptide 3 (INSL3) binds to a G-protein-coupled receptor (GPCR) called relaxin family peptide receptor 2 (RXFP2). RXFP2 belongs to the leucine-rich repeat (LRR)-containing subgroup (LGRs) of class A GPCRs. Negative cooperativity has recently been demonstrated in other members of the LGR subgroup. In this work, the kinetics of INSL3 binding to HEK293 cells stably transfected with RXFP2 (HEK293-RXFP2) have been investigated in detail in order to study if negative cooperativity occurs and if this receptor functions as a dimer. Our results show that negative cooperativity is present, and that INSL3-RXFP2 binding shows both similarities and differences with insulin binding to the insulin receptor. A dose-response curve for the negative cooperativity of INSL3 binding had a reverse bell-shape reminiscent of that seen for the negative cooperativity of insulin binding to its receptor. This suggests that binding of INSL3 may happen in a trans- rather than in a cis way in a receptor dimer. BRET(2) experiments confirmed that RXFP2 forms constitutive homodimers. Heterodimerization between RXFP2 and RXFP1 was also observed. [Abstract/Link to Full Text]

Hong MH, Sun H, Jin CH, Chapman M, Hu J, Chang W, Burnett K, Rosen J, Negro-Vilar A, Miner JN
Cell-specific activation of the human skeletal {alpha}-actin by androgens.
Endocrinology. 2007 Dec 6;
Although it is evident that androgens increase muscle mass and strength, little is known about the critical molecular targets of androgens in skeletal muscle. In rodents, the skeletal alpha-actin gene is a tissue-specific gene only expressed in the levator ani, and other skeletal muscles, but not in the prostate or preputial gland, the well-known androgen target tissue. We have identified tissue-specific androgen-regulated genes in the skeletal muscle in rats following oral administration of androgens and focused on androgen-dependent up-regulation of the skeletal alpha-actin gene. To investigate the mechanism of action, an in vitro system with various cell lines and a series of deletion mutants of the alpha-actin promoter were utilized. The human skeletal alpha-actin promoter was activated by androgens in the muscle cell line C2C12, but not in the liver, prostate or breast cancer cell lines where exogenous human androgen receptor expressed. The sequence of the promoter is sufficient for cell-specific androgen response, providing a model for the tissue specificity demonstrated in vivo. Using a series of deletion mutants, the androgen response can be maintained using just the proximal promoter region. The importance of androgen regulation of this small portion of the human skeletal alpha-actin promoter was demonstrated by the correlation between muscle and the alpha-actin promoter activity for an array of selective androgen receptor modulators (SARMs), including an orally active SARM LGD2226. Taken together, the results suggest that the regulation of skeletal alpha-actin by androgens/SARMs may represent an important model system for understanding androgen anabolic action in the muscle. [Abstract/Link to Full Text]

Belo NO, Sairam MR, Dos Reis AM
Impairment of the natriuretic peptide system in follitropin receptor knockout mice and reversal by estradiol: implications for obesity-associated hypertension in menopause.
Endocrinology. 2007 Dec 6;
Estrogen is considered a major regulator of adipose tissue in females. Estrogen increases circulating levels of Atrial Natriuretic Peptide (ANP), a hormone with renal and cardiovascular effects. The aim of this study was to determine the status of Natriuretic Peptide System in female follitropin-receptor knockout mice (FORKO) that could be associated with obesity and hypertension observed in these mutants. Furthermore, estradiol treatment was used to reverse alterations observed. FORKO and Wild-type (WT) mice received daily injections of Estradiol (E2) for 4 days. On the 5th day, blood was collected for determination of plasma ANP levels and selected tissues were collected for determination of ANP, natriuretic peptide receptor type-A (NPR-A) and type-C (NPR-C) gene expression by RT-PCR and binding of (125)I-ANP by autoradiography. At five months of age, FORKO were heavier and had more adipose tissue than WT. FORKO had lower plasma ANP levels and atrial ANP gene expression, and higher renal and adipocyte NPR-C gene expression than WT. E2 treatment reduced weight gain and increased atrial ANP synthesis as well as decreased ANP clearance receptors, resulting in elevation of circulating ANP level. In conclusion, this study shows that FORKO females have an impaired natriuretic peptide system, which may contribute to the susceptibility of FORKO to developing age-related hypertension previously shown in these animals. This study establishes a relation between estrogen, adipose tissue and ANP, which may have important implications in menopausal women. [Abstract/Link to Full Text]

Montessuit C, Papageorgiou I, Lerch R
Nuclear receptors agonists improve insulin responsiveness in cultured cardiomyocytes through enhanced signaling and preserved cytoskeletal architecture.
Endocrinology. 2007 Dec 6;
Insulin resistance is the failure of insulin to stimulate the transport of glucose into its target cells. A highly regulatable supply of glucose is important for cardiomyocytes to cope with situations of metabolic stress. We recently observed that isolated adult rat cardiomyocytes become insulin resistant in vitro. Insulin resistance is combated at the whole body level with agonists of the nuclear receptor complex PPARgamma/RXR. We investigated the effects of PPARgamma/RXR agonists on the insulin-stimulated glucose transport and on insulin signaling in insulin-resistant adult rat cardiomyocytes. Treatment of cardiomyocytes with ciglitazone, a PPARgamma agonist, or 9-cis retinoic acid (RA), a RXR agonist, increased insulin- and metabolic stress-stimulated glucose transport, while agonists of PPARalpha or PPARbeta/delta had no effect. Stimulation of glucose transport in response to insulin requires the phosphorylation of the signaling intermediate Akt on the residues Thr308 and Ser473 and, downstream of Akt, AS160 on several Thr and Ser residues. Phosphorylation of Akt and AS160 in response to insulin was lower in insulin resistant cardiomyocytes. However, treatment with 9-cis RA markedly increased phosphorylation of both proteins. Treatment with 9-cis RA also led to better preservation of microtubules in cultured cardiomyocytes. Disruption of microtubules in insulin-responsive cardiomyocytes abolished insulin-stimulated glucose transport and reduced phosphorylation of AS160, but not Akt. Metabolic stress-stimulated glucose transport also involved AS160 phosphorylation in a microtubule dependent manner. Thus the stimulation of glucose uptake in response to insulin or metabolic stress is dependent in cardiomyocytes on the presence of intact microtubules. [Abstract/Link to Full Text]

Oliveira JF, Henkes LE, Ashley RL, Purcell SH, Smirnova NP, Veeramachaneni DN, Anthony RV, Hansen TR
Expression of ISGs in extrauterine tissues during early pregnancy in sheep is the consequence of endocrine IFN-{tau} release from the uterine vein.
Endocrinology. 2007 Dec 6;
The ruminant conceptus synthesizes and secretes interferon-tau (IFN-tau), which presumably acts via an intra-uterine paracrine mechanism to signal maternal recognition of pregnancy. The aims of this study were to determine: if Interferon-Stimulated Genes (ISGs), such as ISG15 and OAS-1 are differentially expressed in blood cells circulating in the uterus of ewes; if extrauterine components of the reproductive tract, such as the corpus luteum (CL) also express mRNA for these ISGs; and if antiviral activity is greater in uterine vein than in uterine artery during early pregnancy. The concentrations of mRNA for both ISGs were significantly greater (P<0.0001) in endometrium and jugular blood of 15-day pregnant ewes than in nonpregnant ewes. ISG15 and OAS-1 mRNA concentrations were also greater (P<0.05) in CL from 15-day pregnant ewes than in nonpregnant ewes. Immunohistochemistry revealed intense staining for ISG15 in large luteal cells on day 15 of pregnancy. Blood cells from uterine artery and vein of 15-day pregnant ewes had similar ISG15 and OAS-1 mRNA concentrations, suggesting that these cells were not conditioned by IFN-tau within the uterus. By using an antiviral assay, uterine venous blood was found to contain 500-1000-fold higher concentrations of bioactive IFN-tau than in uterine arterial blood on day 15 of pregnancy. It is concluded that uterine vein releases IFN-tau, which induces ISGs in extrauterine tissues such as the CL during the time of maternal recognition of pregnancy. [Abstract/Link to Full Text]

Augustine RA, Grattan DR
Induction of central leptin resistance in hyperphagic pseudopregnant rats by chronic prolactin infusion.
Endocrinology. 2007 Dec 6;
Pregnancy in rats is associated with hyperphagia, increased fat deposition and elevated plasma leptin concentrations. Elevated leptin would be expected to inhibit food intake, but hypothalamic leptin resistance develops around midpregnancy, allowing hyperphagia to be maintained and excess energy to be stored as fat in preparation for future metabolic demands of lactation. To investigate the hormonal mechanisms inducing leptin resistance during pregnancy, the anorectic response to leptin was examined during pseudopregnancy. Pseudopregnant rats have identical hormonal profiles to early pregnancy, but no placenta formation, allowing differentiation of maternal and placental hormone effects on appetite. To investigate the effect of leptin on food intake, day 9 pseudopregnant rats were injected with leptin (4 microg) via an intracerebroventricular (icv) cannula, and then food intake measured 24 hours later. Pseudopregnant rats were hyperphagic but had normal anorectic responses to leptin. We therefore hypothesized that a longer exposure time to high concentrations of progesterone might be required to mimic the leptin resistance that occurs on day 14 of pregnancy. Pseudopregnant rats were given progesterone to prolong pseudopregnancy beyond the time that leptin resistance develops during pregnancy. However, rats remained responsive to icv leptin. To model the placental lactogen secretion that occurs during pregnancy, pseudopregnant rats were given progesterone and chronic icv ovine prolactin (oPRL) infusion. Central icv injection of leptin had no effect on food intake in pseudopregnant rats receiving chronic oPRL. These results suggest that chronically high lactogen levels, secreted by the placenta during the second half of pregnancy, induce central leptin resistance. [Abstract/Link to Full Text]

Hadjiyanni I, Baggio LL, Poussier P, Drucker DJ
Exendin-4 modulates diabetes onset in non obese diabetic mice.
Endocrinology. 2007 Dec 6;
Activation of the glucagon-like peptide-1 receptor is associated with expansion of beta-cell mass due to stimulation of cell proliferation and induction of anti-apoptotic pathways coupled to beta-cell survival. Although the GLP-1R agonist Exenatide (exendin-4) is currently being evaluated in subjects with type 1 diabetes, there is little information available about the efficacy of GLP-1R activation for prevention of experimental type 1 diabetes. We examined the consequences of exendin-4 (Ex-4) administration (100 ng once daily and 2 microg twice daily) on diabetes onset in NOD mice beginning at either 4 or 9 weeks of age prior to the onset of diabetes. Ex-4 treatment for 26 weeks (2 microg twice daily) initiated at 4 weeks of age delayed the onset of diabetes (P = 0.007). Ex-4-treated mice also exhibited a significant reduction in insulitis scores, enhanced beta-cell mass and improved glucose tolerance. Although GLP-1R mRNA transcripts were detected in spleen, thymus, and lymph nodes from NOD mice, Ex-4 treatment was not associated with significant changes in the numbers of CD4+ or CD8+ T cells, or B cells in the spleen. However, Ex-4 treatment resulted in an increase in the number of CD4+ and CD8+ T cells in the lymph nodes and a reduction in the numbers of CD4+CD25+Foxp3+ Regulatory T cells in the thymus but not in lymph nodes. These findings demonstrate that sustained GLP-1R activation in the absence of concomitant immune intervention may be associated with modest but significant delay in diabetes onset in a murine model of type 1 diabetes. [Abstract/Link to Full Text]

Nagashima T, Maruyama T, Uchida H, Kajitani T, Arase T, Ono M, Oda H, Kagami M, Masuda H, Nishikawa S, Asada H, Yoshimura Y
Activation of SRC kinase and phosphorylation of STAT5 are required for decidual transformation of human endometrial stromal cells.
Endocrinology. 2007 Dec 6;
Progesterone induces decidual transformation of estrogen-primed human endometrial stromal cells (hESCs), critical for implantation and maintenance of pregnancy, through activation of many signaling pathways involving protein kinase A and STAT5. We have previously shown that activation of SRC kinase is closely associated with decidualization and that SRC is indispensable for maximal decidualization in mice. To address whether SRC kinase activity is essential for decidualization in humans, hESCs were infected with adenoviruses carrying EGFP alone (Ad-EGFP), a kinase-inactive dominant negative mutant (Ad-SRC/K295R), or an inactive autophosphorylation site mutant (Ad-SRC/Y416F). The cells were cultured in the presence of estradiol and progesterone (EP) to induce decidualization, and subjected to RT-PCR, immunoblot, and ELISA analyses. Ad-EGFP-infected hESCs exhibited decidual transformation and up-regulation of decidualization markers including IGF binding protein 1 (IGFBP1) and prolactin in response to 12-day treatment with EP. In contrast, hESCs infected with Ad-SRC/K295R remained morphologically fibroblastoid without production of IGFBP1 and prolactin even after EP treatment. Ad-SRC/Y416F displayed similar but less inhibitory effects on decidualization compared to Ad-SRC/K295R. During decidualization, STAT5 was phosphorylated on tyrosine 694, a well-known SRC phosphorylation site. Phosphorylation was markedly attenuated by Ad-SRC/K295R, but not Ad-EGFP. These results indicate that the SRC-STAT5 pathway is essential for decidualization of hESCs. [Abstract/Link to Full Text]

Prast J, Saleh L, Husslein H, Sonderegger S, Helmer H, Kn�fler M
Human chorionic gonadotrophin stimulates trophoblast invasion through ERK and AKT signalling.
Endocrinology. 2007 Dec 6;
Chorionic gonadotrophin (CG) is indispensable for human pregnancy since it controls implantation, decidualisation and placental development. However, its particular role in the differentiation process of invasive trophoblasts has not been fully unravelled. Here, we demonstrate that the hormone promotes trophoblast invasion and migration in different trophoblast model systems. RT-PCR and Western blot analyses revealed expression of the LH/CG receptor in trophoblast cell lines and different trophoblast primary cultures. In vitro, CG increased migration and invasion of trophoblastic SGHPL-5 cells through uncoated and Matrigel-coated transwells, respectively. The hormone also increased migration of first trimester villous explant cultures on collagen I. Proliferation of the trophoblast cell line and of villous explant cultures measured by cumulative cell numbers and in situ BrdU labelling, respectively, was unaffected by CG. Addition of the hormone activated ERK-1/2 and AKT in SGHPL-5 cells and pure, extravillous trophoblasts. Inhibition of MEK/ERK and PI3K/AKT blocked phosphorylation of the kinases and attenuated CG-dependent invasion of SGHPL-5 cells. Similarly, the inhibitors decreased hormone-stimulated migration in villous explant cultures. Western blot analyses and gelatin zymography suggested that CG increased MMP-2 protein levels and activity in both culture systems. Inhibition of ERK or AKT diminished CG-induced MMP-2 expression. In summary, the data demonstrate that CG promotes trophoblast invasion and migration through activation of ERK and AKT signalling involving their downstream effector MMP-2. Since the increase of CG during the first trimester of pregnancy correlates with rising trophoblast motility, the hormone could be a critical regulator of the early invasion process. [Abstract/Link to Full Text]

Edwards SJ, Reader KL, Lun S, Western A, Lawrence S, McNatty KP, Juengel JL
The co-operative effect of GDF9 and BMP15 on granulosa cell function is modulated primarily through BMP Receptor II.
Endocrinology. 2007 Dec 6;
Growth and differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15, GDF9B) are oocyte-derived proteins essential for the growth and function of ovarian follicles. Moreover, ovine (o) GDF9 and oBMP15 co-operate to increase both (3)H-thymidine incorporation and alpha-inhibin production, and to inhibit progesterone production by rat or ovine granulosa cells. Although the receptors through which these proteins act individually have been determined, the receptor(s) involved in mediating the co-operative effects of GDF9 and BMP15 is (are) unknown. In this study, the effects of the extracellular domains of the Type I and Type II TGFbeta receptors on (3)H-thymidine incorporation by rat granulosa cells stimulated by oGDF9 and oBMP15 were investigated. Stimulation of (3)H-thymidine incorporation was completely blocked by the BMP receptor II (BMPRII) extracellular domain but unaffected by any other Type II or any Type I receptor. These results suggest that the initial interaction of oGDF9 and oBMP15 is with BMPRII and that a type I receptor is either recruited or already associated with BMPRII in order to mediate the cooperative effects of these growth factors. [Abstract/Link to Full Text]

Vulliemoz NR, Xiao E, Xia-Zhang L, Rivier J, Ferin M
Astressin B, a non selective CRH receptor antagonist, prevents the inhibitory effect of Ghrelin on LH pulse frequency in the ovariectomized rhesus monkey.
Endocrinology. 2007 Dec 6;
Administration of ghrelin, a key peptide in the regulation of energy homeostasis, has been shown to decrease LH pulse frequency while concomitantly elevating cortisol levels. Because increased endogenous CRH release in stress is associated with an inhibition of reproductive function, we have tested here whether pulsatile LH decrease following ghrelin may reflect an activated HPA axis and be prevented by a CRH antagonist. After a 3h baseline LH pulse frequency monitoring, 5 adult OVX rhesus monkeys received a 5h- saline (protocol 1) or ghrelin infusion (100microg bolus followed by 100microg/h, protocol 2). In protocols 3 and 4, animals were given astressin B, a non specific CRH receptor antagonist (0.45mg/kg im), 90 min prior to ghrelin or saline infusion. Blood samples were taken every 15 min for LH measurements, while cortisol and GH were measured every 45 min. Mean LH pulse frequency during the 5h ghrelin infusion was significantly lower than in all other treatments (p<0.05) and when compared to the baseline period (p<0.05). Pretreatment with astressin B prevented the decre