New Horizons in Skeletal Physiology and Pathophysiology

ObjectiveTo review new discoveries that revisit our current thinking on the genesis of osteoporosis using hypogonadal and thyrotoxic bone loss as examples.MethodsWe focus on cell biologic, mouse genetic, and human studies that have established a direct action of the interior pituitary hormones follicle-stimulating hormone and thyrotropin on the skeleton and discuss emerging clinical evidence for a novel pituitary-bone axis in humans that bypasses master endocrine organs, namely the ovaries and thyroid gland.ResultsThe cataloguing of human mutations, the use of genetically modified mice that recapitulate human disease, and the rapid growth of genomic sciences have together had a profound impact on how basic research is translated into clinical practice. The skeleton has become a paradigm for the application of such advances to an extent that hitherto unrecognized physiologic and pathophysiologic findings have emerged. We propose that hypogonadal and thyrotoxic bone loss are not solely due to changes in the level of master hormones, but instead also arise from the direct action of anterior pituitary hormones on the skeleton.ConclusionsWe predict a pituitary-bone axis in which pituitary hormones bypass traditional endocrine targets to affect the skeleton directly with remarkable sensitivity. New therapeutic targets thus become a likely possibility. (Endocr Pract. 2010;16:874-881)     

Endocrine Complications in Patients with Gvhd

Objective: Graft-versus-host disease (GVHD) is an immune phenomenon that occurs in 30 to 70% of patients after allogeneic hematopoietic stem cell transplantation (HST). Chronic GVHD is a state of immune dysregulation wherein, depending on the severity and organ involved, patients may require prolonged treatment with additional or higher corticosteroids and other immunosuppressive agents. The objective of this study was to review the endocrine manifestations following HST that can arise as a consequence of the primary disease or its treatment, including chemotherapeutic agents, corticosteroids, radiation, or GVHD.Methods: We performed a narrative review of GVHD after HST. An English-language search for relevant studies was conducted on PubMed from inception to August 1, 2018, using the following search terms: “endocrine complications,” “bone marrow transplantation,” “graft-versus-host disease,” and “GVHD.” The reference lists of relevant studies were also reviewed.Results: Chronic GVHD may be associated with considerable pediatric growth impairment and may also contribute to thyroid gland dysfunction and thyroid cancer. These patients may also be at increased risk for low bone mineral density, reduced fertility, metabolic syndrome, and suppression of the pituitary-adrenal axis with adrenal insufficiency.Conclusion: This review indicates the importance of monitoring, diagnosing, and properly treating the endocrine complications in this population. More studies are needed to investigate the independent impact of GVHD on the endocrine system and treatment for complications.Abbreviations: BMD = bone mineral density; GH = growth hormone; GVHD = graft-versus-host disease; HST = hematopoietic stem cell transplantation; IGF-1 = insulin-like growth factor 1     

An Interesting Case of Peripheral Vascular Disease,Vascular Reperfusion,and Subsequent Development of Pain Due to Paget's Disease of Bone

ObjectiveTo present a case of Paget’s disease of bone that was unmasked after vascular reperfusion.MethodsIn this case study, we review the presentation, evaluation, diagnosis, and management of a patient with Paget’s disease and peripheral vascular disease.ResultsA 79-year-old-woman with a history of coronary artery heart disease and recent finding of a T5 compression fracture was hospitalized for evaluation of right lower extremity claudication. Angiography demonstrated a focal complete occlusion of the distal right femoral and popliteal arteries. A self-expanding stent was placed in the distal femoral and popliteal arteries. Approximately 48 hours after the procedure, the patient developed severe, right lower leg pain. On endocrine evaluation, the patient was found to have clinical signs suggesting Paget’s disease of bone, which was subsequently confirmed by imaging.ConclusionThis patient’s development of severe pain following reperfusion of distal femoral and popliteal arteries is in keeping with the known and aforementioned hypervascularity of pagetic bone. The finding of increased warmth over an area of skeletal deformation should always raise the possibility of Paget’s disease of bone.(Endocr Pract. 2013;19:e61-e63)     

Secondary Causes of Osteoporosis

ObjectiveTo provide an updated review of several causes of secondary osteoporosis as well as screening recommendations for these disorders.MethodsWe conducted an updated review of the literature published since 2006 on secondary causes of osteoporosis. This information has been added to the relevant data published between 1990 and 2006, which was included in our prior review from 2006. This current review also includes recent clinical guidelines recommendations.ResultsSecondary osteoporosis occurs in almost two thirds of men, more than half of premenopausal women, and about 30% of postmenopausal women. Its causes are vast, and they include hypogonadism, medications, hyperthyroidism, vitamin D deficiency, primary hyperparathyroidism, solid organ transplantation, gastrointestinal diseases, hematologic diseases, Cushing's syndrome, and idiopathic hypercalciuria. These causes have their own pathogenesis, epidemiologic features, and effects on the skeleton.ConclusionThe causes of secondary osteoporosis are numerous, and an understanding of their characteristics with respect to bone density and potential fracture risk is essential in the management of osteoporosis. A heightened awareness of the possibility of their existence is necessary to provide optimal care. (Endocr Pract. 2013;19:120-128)     

Molecular Genetic Testing in Endocrinology—A Practical Guide

ObjectiveTo discuss the factors to consider when evaluating patients with a suspected genetic endocrine disorder, so as to guide practicing endocrinologists through the process of genetic testing and result interpretation.MethodsThe author’s experience and review of appropriate literature have been used to give a personal perspective on the role of genetic testing in hereditary endocrine disorders.ResultsRecent advances in our understanding of genetics and genomics have uncovered that they have a far more important role in the pathogenesis of endocrine disease than previously appreciated. Not only are we expanding our understanding of rare mendelian disorders such as multiple endocrine neoplasia type 1 and 2, but we are also beginning to understand the clinical significance of genetic factors in the pathogenesis of common disorders such as obesity and dyslipidemia.ConclusionsIt can be difficult to appreciate the clinical significance and utility of genetic testing that is currently available, and the interpretation of genetic test results can be challenging. Decisions on whether genetic testing is needed should be made on a case-by-case basis, with the endocrinologist and geneticist working together from the outset. (Endocr Pract. 2012;18:85-89)     

Medullary Thyroid Carcinoma

ObjectiveThis review outlines advances in the diagnosis, genetic testing, and progress in medullary thyroid cancer (MTC) treatment in light of the most recent evidence.MethodsEnglish-language articles pertaining to MTC published up to 2012 were reviewed. The pertinent articles and their references were obtained and those considered relevant were reviewed for inclusion.ResultsMTC is an uncommon neuroendocrine malignancy that accounts for 5% of thyroid cancers. MTC presents in sporadic and familial forms (multiple endocrine neoplasia [MEN] 2A, MEN 2B, or familial MTC syndromes). The familial forms are secondary to germline mutations in the REarranged during Transfection (RET) proto-oncogene. Early diagnosis and treatment is paramount. Genetic testing has made possible early detection in asymptomatic carriers and high-risk patients, with early or prophylactic surgery being curative in many. All carriers of an RET mutation should be evaluated and treated surgically for MTC. The primary treatment in all patients diagnosed with MTC is total thyroidectomy with central lymph node dissection. Calcitonin and carcinoembryonic antigen levels can be used as prognostic factors and as tumor markers. If elevated, further investigation, including use of imaging modalities, may be necessary for evaluation of metastatic disease. Surgery remains the main treatment for local and locally advanced disease.ConclusionMTC is rare, but morbidity and mortality remain high if untreated. Genetic testing should be offered to all patients. Treatment of choice remains total thyroid-ectomy and central lymph node dissection. Palliative treatment for advanced disease includes surgery, radiation, standard chemotherapy, chemoembolization and more recently, targeted therapies (tyrosine kinase inhibitors). (Endocr Pract. 2013;19:703-711)     

Toward an integrative view of Optineurin functions

This review highlights recent advances in our understanding of the mechanisms of Optineurin (Optn) action and its implication in diseases. Optn has emerged as a key player regulating various physiological processes, including membrane trafficking, protein secretion, cell division and host defense against pathogens. Furthermore, there is growing evidence for an association of Optn mutations with human diseases such as primary open-angle glaucoma, amyotrophic lateral sclerosis and Paget’s disease of bone. Optn functions depend on its precise subcellular localization and its interaction with other proteins. Here, we review the mechanisms that allow Optn to ensure a timely and spatially coordinated integration of different physiological processes and discuss how their deregulation may lead to different pathologies.     

Targeted Therapy for Endocrine Cancer: The Medullary Thyroid Carcinoma Paradigm

ObjectiveTo provide an overview of a new approach for treatment of medullary thyroid carcinoma (MTC) and other endocrine tumors.MethodsThis review compiles recent information from the medical literature and scientific meetings focused on the use of tyrosine kinase inhibitors (TKIs) for the treatment of MTC and other endocrine tumors.ResultsThe elucidation during the past 2 decades of multiple genetic abnormalities in endocrine tumors has provided specific targets for therapy. The identification of activating mutations of the RET tyrosine kinase receptor in both hereditary and sporadic MTC makes this malignant disease an excellent model for examination of the effect of a group of small organic molecule TKIs for treatment of metastatic MTC. Clinical trials with several TKIs targeting RET and other tyrosine kinase receptors have shown positive results with generally tolerable toxicity. Approximately one-third to one-half of patients with MTC have a reduction in tumor size of 0% to 50%, with the longest treatment duration of approximately 4 years. The most common treatment-related toxic effects are cutaneous effects, nausea, and diarrhea. Cardiovascular toxicity, such as hypertension, prolongation of the corrected QT interval, or heart failure, is uncommon but may be serious.ConclusionDespite promising initial results, these studies are in their early stages, and none of these therapies is currently approved by the US Food and Drug Administration for treatment in the United States. These studies highlight the potential for targeting endocrine cancer signaling pathways and provide a paradigm for treatment of endocrine cancer. (Endocr Pract. 2009;15:597-604)     

骨钙素对能量代谢调节的研究进展

研究表明,骨钙素(osteocalcin)是由骨骼中成熟的成骨细胞合成并分泌的一种非胶原蛋白质,在骨骼的合成和重建过程中起着重要作用。近年来研究显示,骨骼亦可作为一种分泌器官,通过分泌骨钙素,作用于胰腺、脂肪、睾丸等器官,调节能量代谢、雄性生殖能力。此外,临床研究表明,骨钙素与糖尿病、心血管疾病等也有着密切的联系。因此,本文一方面概述了骨钙素的基本特征,另一方面着重介绍了骨钙素在调节能量代谢等方面的研究进展,以便为治疗糖尿病等代谢性疾病提供新的治疗靶点。     

Anabolic Therapy and Optimal Treatment Sequences for Patients With Osteoporosis at High Risk for Fracture

Objective: Provide an update regarding anabolic medications for osteoporosis, which are often considered to be the last resort for patients with osteoporosis, after multiple fractures have already occurred and other medications have already been administered.Methods: Literature review and discussion.Results: Recent pivotal trial data for anabolic agents and randomized trials comparing anabolic and antiresorptive medications suggest that three anabolic agents (teriparatide, abaloparatide, and romosozumab) reduce nonvertebral and vertebral fractures faster and to a greater extent than potent antiresorptive treatments. Furthermore, bone density accrual is maximized when patients are given anabolic agents first, followed by potent antiresorptive therapy. Since total hip bone density during or after osteoporosis treatment has emerged as an excellent surrogate for future fracture risk, attaining a greater hip bone mineral density is a treatment goal for high-risk osteoporosis patients.Conclusion: This review defines the highest-risk patients and summarizes the rationale for the evolving role of anabolic therapy in the management of postmenopausal women at high risk for fracture.Abbreviations: ACTIVE = Abaloparatide Comparator Trial in Vertebral Endpoints; ARCH = Active Controlled Fracture Study in Postmenopausal Women with Osteoporosis at High Risk; BMD = bone mineral density; FRAME = Fracture Study in Postmenopausal Women with Osteoporosis; FRAX = Fracture Risk Assessment Tool; PTH = parathyroid hormone; TBS = trabecular bone score     

Lost in the crowd: identifying targetable MHC class I neoepitopes for cancer immunotherapy

ABSTRACT

Introduction: The recent development of checkpoint blockade immunotherapy for cancer has led to impressive clinical results across multiple tumor types. There is mounting evidence that immune recognition of tumor derived MHC class I (MHC-I) restricted epitopes bearing cancer specific mutations and alterations is a crucial mechanism in successfully triggering immune-mediated tumor rejection. Therapeutic targeting of these cancer specific epitopes (neoepitopes) is emerging as a promising opportunity for the generation of personalized cancer vaccines and adoptive T cell therapies. However, one major obstacle limiting the broader application of neoepitope based therapies is the difficulty of selecting highly immunogenic neoepitopes among the wide array of presented non-immunogenic HLA ligands derived from self-proteins.

Areas covered: In this review, we present an overview of the MHC-I processing and presentation pathway, as well as highlight key areas that contribute to the complexity of the associated MHC-I peptidome. We cover recent technological advances that simplify and optimize the identification of targetable neoepitopes for cancer immunotherapeutic applications.

Expert commentary: Recent advances in computational modeling, bioinformatics, and mass spectrometry are unlocking the underlying mechanisms governing antigen processing and presentation of tumor-derived neoepitopes.     

Evaluation of Secondary Causes of Bone Loss in a Primary Care Setting

ObjectiveTo evaluate the clinical and laboratory work-up for secondary causes of bone loss in a primary care setting.MethodsWe conducted a retrospective review of medical records of 100 patients with either osteoporosis or osteopenia, who presented to a university-based primary care clinic. Patients with chronic kidney disease or a history of organ transplantation were excluded, as were premenopausal women.ResultsAge at menopause was ascertained in 43% of female patients. Only 2% of patients were asked specifically about symptoms of malabsorption, whereas a history of malignant disease or its treatment was elicited from 24%. Of the overall study group, 50% were asked about a history of thyroid disease and 18% about a history of liver disease. Testicular examination was documented in 40% of male patients. Serum calcium and creatinine, complete blood cell count, and thyroid function tests were evaluated in 100% of patients. Vitamin D status was assessed in only 1 patient; no study patient had a 24-hour urine collection for determination of calcium excretion. Serum parathyroid hormone was measured in 7% and serum phosphorus in 10% of patients. Sixty percent of male patients had their testosterone levels assessed. Although the serum creatinine level was determined in all patients, only 1% had a formal estimation of the creatinine clearance or glomerular filtration rate.ConclusionThe evaluation of secondary causes of bone loss was notably inadequate in our study population. Because most patients with osteoporosis or osteopenia are managed in the primary care setting, a distinct need exists for consensus guidelines and recommendations from professional endocrine organizations to advise primary care physicians in the appropriate diagnostic evaluation for secondary causes of bone loss in such patients. (Endocr Pract. 2009;15:410-414)     

Does Testosterone Therapy Increase the Risk of Prostate Cancer?

ObjectiveTo review factors affecting use of testosterone therapy for hypogonadism including the persistent controversial link between testosterone therapy and prostate cancer.MethodsWe reviewed studies investigating the relationship between testosterone therapy and prostate cancer progression and summarized strategies for hypogonadism management and prostate monitoring.ResultsTrials of up to 36 months in length and longitudinal studies consistently fail to demonstrate an increased prostate cancer risk associated with increased testosterone levels. No evidence of an associated relationship between exogenous testosterone therapy and prostate cancer has emerged from clinical trials or adverse event reports. It does not appear that exogenous testosterone accumulates in the prostate or provokes major biologic change in the prostate gland. In addition, preliminary evidence indicates that low endogenous testosterone may confer an increased risk of prostate cancer.ConclusionsMounting evidence demonstrates that there is a lack of association between testosterone therapy and prostate cancer progression. Testosterone therapy may be prescribed for men for whom it was once not considered. Careful monitoring of patients with hypogonadism who are receiving testosterone therapy is imperative. Well-designed, large-scale prospective clinical trials are necessary to adequately address prostate safety in hypogonadal men receiving testosterone therapy. (Endocr Pract. 2008;14:904-911)     

Metastatic Burkitt's Lymphoma Presenting as Diabetes Insipidus

ObjectiveTo present the first reported case of metastatic Burkitt's lymphoma with a single central nervous system (CNS) metastasis to the pituitary stalk.MethodsWe provided details of the case presentation and review the literature.ResultsAlthough other malignancies are known to metastasize to the pituitary, and diabetes insipidus is often the presenting symptom, there has not been a previously reported case of Burkitt's lymphoma with a single CNS metastasis to the pituitary.ConclusionA careful history and an endocrine review of systems may aid early identification of pituitary or central nervous system metastases. (Endocr. Pract. 2013; 19:e102-e104)     

Guías de práctica clínica para la evaluación y tratamiento de la osteoporosis asociada a enfermedades endocrinas y nutricionales

ObjectiveTo provide practical recommendations for evaluation and treatment of osteoporosis associated to endocrine diseases and nutritional conditions.ParticipantsMembers of the Bone Metabolism Working Group of the Spanish Society of Endocrinology, a methodologist, and a documentalist.MethodsRecommendations were formulated according to the GRADE system (Grading of Recommendations, Assessment, Development, and Evaluation) to describe both the strength of recommendations and the quality of evidence. A systematic search was made in MEDLINE (Pubmed), using the following terms associated to the name of each condition: AND “osteoporosis”, “fractures”, “bone mineral density”, and “treatment”. Papers in English with publication date before 18 October 2011 were included. Current evidence for each disease was reviewed by two group members, and doubts related to the review process or development of recommendations were resolved by the methodologist. Finally, recommendations were discussed in a meeting of the Working Group.ConclusionsThe document provides evidence-based practical recommendations for evaluation and management of endocrine and nutritional diseases associated to low bone mass or an increased risk of fracture. For each disease, the associated risk of low bone mass and fragility fractures is given, recommendations for bone mass assessment are provided, and treatment options that have shown to be effective for increasing bone mass and/or to decreasing fragility fractures are listed.     

Xanthogranuloma as an Unsuspected Cause of Idiopathic Central Diabetes Insipidus

ObjectiveTo demonstrate that xanthogranuloma is a rare cause of idiopathic central diabetes insipidus in the early phase of the disease and that it presents as a suprasellar mass at a later stage. In addition, we emphasize the importance of identifying the cause of idiopathic central diabetes insipidus and review the literature concerning endocrine disturbance in central xanthogranuloma.MethodsReview of recently published case reports of central xanthogranuloma with endocrine disorders. The case of a 35-year-old man who presented with a very large suprasellar mass is also reported. The patient was diagnosed with idiopathic central diabetes insipidus 20 years ago with normal brain magnetic resonance imaging.ResultMost cases of this disease present as supra-or parasellar masses with endocrine involvement, the most common of which (in approximately 75% of patients) is sex hormone deficiency. Diabetes insipidus was found in 65% of patients.ConclusionXanthogranuloma should be in the differential diagnosis of idiopathic central diabetes insipidus and sellar and parasellar masses. A detailed skin examination is very important in making the diagnosis of central diabetes insipidus. (Endocr Pract. 2014;20:e42-e46)     

Celiac Disease and the Endocrinologist: a Diagnostic Opportunity

ObjectiveTo review the association of celiac disease and various endocrine disorders and present the related clinical experience of a 3-physician adult endocrinology practice.MethodsWe provide an overview of the pertinent literature, discuss the clinical manifestations, genetics, and pathogenesis of celiac disease, and describe our clinical experience during a 5-year period.ResultsCeliac disease has been associated with numerous disorders, including several conditions treated by endocrinologists—type 1 diabetes mellitus, autoimmune thyroid disease, Addison disease, osteomalacia, secondary hyperparathyroidism, vitamin D or iron deficiency, fertility problems, hypogonadism in men, and autoimmune hypopituitarism. After our clinical awareness was raised about these potential comorbidities, 18 patients were newly diagnosed with celiac disease in our clinical practice during a 5-year interval. All patients had been referred for endocrine evaluation or were undergoing follow- up for ongoing management of endocrine disorders. When a “celiac-associated” endocrine disorder coexists with other factors associated with celiac disease, we recommend performance of IgA class antibody testing, and either antiendomysial or anti-tissue transglutaminase antibodies provide high specificity and sensitivity for the diagnosis of celiac disease.ConclusionEndocrinologists have an opportunity to diagnose celiac disease, a relatively common disorder with profound clinical implications that can often be associated with various endocrinopathies. (Endocr Pract. 2008;14: 381-388)     

Endocrine Disturbances in Empty Sella Syndrome: Case Reports and Review of Literature

ObjectiveTo report 5 cases of empty sella syndrome (ESS) manifesting with various degrees of pituitary dysfunction.MethodsWe describe the initial manifestations in 5 patients with primary ESS and in previous cases of ESS reported in the English language literature.ResultsReview of our recent medical records identified 5 patients referred for evaluation of pituitary deficiencies in whom ESS was diagnosed. Glucocorticoid replacement was required in 3 patients, 2 of whom presented initially with symptoms of severe glucocorticoid deficiency. In each case, magnetic resonance imaging of the brain demonstrated an empty sella.ConclusionOur cases suggest that endocrine abnormalities are not rare as the initial manifestation of ESS and that, contrary to many studies in the literature, the endocrine abnormalities may be quite severe. (Endocr Pract. 2005;11:120-124)     

Application of Molecular Biology and Genetics in Endocrinology

ObjectiveTo review the growing impact of molecular biology and genetics on clinical endocrinology.MethodsMedical literature, databases, and Web sites describing genetics and genomic medicine with relevance for clinical endocrinology were reviewed.ResultsMany monogenic disorders can now be explained at the molecular level and the diagnosis can be established through mutational analysis. The ability to establish a molecular diagnosis is relevant for carrier detection and genetic counseling. In contrast to the significant advances in monogenic disorders, the current knowledge about the genetic components contributing to the pathogenesis of complex disorders is still relatively modest and is a major focus of current research efforts. Molecular biology already has an important impact on therapy in endocrine disorders. A broad spectrum of recombinant peptides and proteins are used in daily practice, eg, insulin and insulin analogues. Moreover, the increasingly detailed understanding of the molecular pathogenesis of cancer is leading to the development of novel and more specific inhibitors. While genetic testing has many advantages, it is important that physicians and patients are aware of potential limitations. They include, among others, technical limitations and allelic and nonallelic heterogeneity. These limitations need to be discussed in detail with patients and relatives, and it is often useful to involve a genetic counselor before obtaining informed consent by the individuals undergoing testing.ConclusionMolecular biology and genetics play an increasingly important role for the diagnosis and therapy of endocrine disorders. Challenges for the future include the elucidation of the genetic components contributing to complex disorders, eg, diabetes mellitus type 2, and the development of cheaper and comprehensive DNA sequencing technologies. Lastly, it is important that there is continuing attention directed towards the ethical, social, and legal aspects surrounding genetic medicine. (Endocr Pract, 2007;13: 534-541)