- Klinefelter syndrome - integrating genetics, neuropsychology and endocrinology. [Journal Article]
- EREndocr Rev 2018 Feb 09
- Although first identified over 70 years ago, Klinefelter syndrome (KS) continue to pose significant diagnostic challenges, as many patients are still misdiagnosed, or remain undiagnosed. In fact, as ...
Although first identified over 70 years ago, Klinefelter syndrome (KS) continue to pose significant diagnostic challenges, as many patients are still misdiagnosed, or remain undiagnosed. In fact, as few as 25% of KS patients are accurately diagnosed, and most of these diagnoses are not made until adulthood. Classic characteristics of KS include small testes, infertility, hypergonadothropic hypogonadism, and cognitive impairment. However, the pathophysiology behind KS is not well understood, although genetic effects are also thought to play a role. For example, recent developments in genetics and genomics point to a fundamental change in our understanding of KS, with global epigenetic and RNA expression changes playing a central role for the phenotype.KS is also associated with more general health markers, including higher morbidity and mortality rates, and lower socio-economic status (which likely affects both morbidity and mortality). In addition, hypogonadism is associated with greater risk of of metabolic syndrome, type 2 diabetes, cardiovascular disease, breast cancer, and extragonadal germ cell tumors. Medical treatment typically focuses on testosterone replacement therapy (TRT), although the effects of this therapy has not been studied rigorously, and future studies need to evaluate the effects of TRT on metabolic risk and neurocognitive outcomes.This review presents a comprehensive, interdisciplinary examination of recent developments in genetic, endocrine and neurocognitive science, including the study of animal models regarding KS. It also provides a number of recommendations for improving the effectiveness of research and clinical practice, including neonatal KS screening programs, and a multidisciplinary approach to KS treatment from childhood until senescence.
- Extracellular Vesicles in Human Reproduction in Health and Disease. [Journal Article]
- EREndocr Rev 2018 Jan 30
- Extensive evidence suggests that the release of membrane enclosed compartments, more commonly known as extracellular vesicles (EVs), is a potent newly identified mechanism of cell-to-cell communicati...
Extensive evidence suggests that the release of membrane enclosed compartments, more commonly known as extracellular vesicles (EVs), is a potent newly identified mechanism of cell-to-cell communication both in normal physiology and in pathological conditions. This article specifically reviews evidence about the formation and release of different EVs, their definitive markers and cargo content in reproductive physiological processes, and their capacity to convey information between cells through the transfer of functional protein and genetic information to alter phenotype and function of recipient cells associated with reproductive biology. In the male reproductive tract, epididymosomes and prostasomes participate in regulating sperm motility activation, capacitation and acrosome reaction. In the female reproductive tract, follicular fluid, oviduct/tube and uterine cavity EVs are considered as vehicles to carry information during oocyte maturation, fertilization and embryo-maternal cross talk. EVs via their cargo might be also involved in the triggering, maintenance and progression of reproductive and obstetric related pathologies such as endometriosis, polycystic ovarian syndrome, pre-eclampsia, gestational diabetes, and erectile disfunction. We provide here, the current knowledge on the present and future use of EVs not only as biomarkers, but also as therapeutic targeting agents, mainly as vectors for drug/compounds delivery into target cells/tissues.
- 11β-HSD 1 in human fetal membranes as a potential therapeutic target for preterm birth. [Journal Article]
- EREndocr Rev 2018 Jan 29
- Human parturition is a complex process involving interactions between the myometrium and signals derived from the placenta, fetal membranes and fetus. Signals originating from fetal membranes are cru...
Human parturition is a complex process involving interactions between the myometrium and signals derived from the placenta, fetal membranes and fetus. Signals originating from fetal membranes are crucial components that trigger parturition, which is clearly illustrated by the labor-initiating consequence of membrane rupture. It has been recognized for a long time that among fetal tissues in late gestation the fetal membranes possess the highest capacity for cortisol regeneration by 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1). However, the exact role of this unique feature remains a mystery. Accumulating evidence indicates that this extra-adrenal source of cortisol may serve as an upstream signal for critical events in human parturition, including enhanced prostaglandin and estrogen synthesis as well as extracellular matrix remodeling. This may explain why such high capacity for cortisol regeneration develops in human fetal membranes at late gestation. Therefore, inhibition of 11β-HSD1 may provide a potential therapeutic target for prevention of preterm birth. This review summarizes the current understanding of the functional role of cortisol regeneration by 11β-HSD1 in human fetal membranes.
- Sexual Dimorphism and the Origins of Human Spinal Health. [Journal Article]
- EREndocr Rev 2018 Jan 29
- Recent observations indicate that the cross-sectional area (CSA) of vertebral bodies are on average 10% smaller in healthy newborn girls than in newborn boys - a striking difference that increases du...
Recent observations indicate that the cross-sectional area (CSA) of vertebral bodies are on average 10% smaller in healthy newborn girls than in newborn boys - a striking difference that increases during infancy and puberty, and is greatest by the time of sexual and skeletal maturity. The smaller vertebral CSA in females is associated with greater spinal flexibility, and could represent the human adaptation to fetal load in bipedal posture. Unfortunately, it also imparts a mechanical disadvantage that increases stress within the vertebrae for all physical activities. This review summarizes the potential endocrine, genetic, and environmental determinants of vertebral cross-sectional growth and current knowledge on the association between the small female vertebrae and increased risk for a broad array of spinal conditions across the lifespan.
- X-linked hypophosphatemia and FGF23-related hypophosphatemic diseases -Prospect for new treatment. [Journal Article]
- EREndocr Rev 2018 Jan 26
- Phosphate plays essential roles in many biological processes, and the serum phosphate level is tightly controlled. Chronic hypophosphatemia causes impaired mineralization of the bone matrix and resul...
Phosphate plays essential roles in many biological processes, and the serum phosphate level is tightly controlled. Chronic hypophosphatemia causes impaired mineralization of the bone matrix and results in rickets and osteomalacia. Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that regulates phosphate metabolism. FGF23 excess induces hypophosphatemia via impaired phosphate reabsorption in the renal proximal tubules and decreased phosphate absorption in the intestines. There are several types of genetic and acquired form of FGF23-related hypophosphatemic diseases. Among these diseases, X-linked hypophosphatemia (XLH), which is caused by inactivating mutations in the phosphate-regulating endopeptidase homolog, X-linked (PHEX) gene, is the most prevalent form of genetic FGF23-related hypophosphatemic rickets. Another clinically relevant form of FGF23-related hypophosphatemic disease is tumor-induced osteomalacia (TIO), a paraneoplastic syndrome associated with FGF23-producing tumors. A combination of active vitamin D and phosphate salts is the current medical therapy used to treat patients with XLH and inoperative TIO. However, this therapy has certain efficacy- and safety-associated limitations. Several measures to inhibit FGF23 activity have been considered as possible new treatments for FGF23-related hypophosphatemic diseases. In particular, a humanized monoclonal antibody for FGF23 (burosumab) is a promising treatment in patients with XLH and TIO. This review will focus on the phosphate metabolism and the pathogenesis and treatment of FGF23-related hypophosphatemic diseases.
- The versatile tanycyte: a hypothalamic integrator of reproduction and energy metabolism. [Journal Article]
- EREndocr Rev 2018 Jan 17
- The fertility and survival of an individual rely on the ability of the periphery to promptly, effectively and reproducibly communicate with brain neural networks that control reproduction, food intak...
The fertility and survival of an individual rely on the ability of the periphery to promptly, effectively and reproducibly communicate with brain neural networks that control reproduction, food intake and energy homeostasis. Tanycytes, a specialized glial cell type lining the wall of the third ventricle in the median eminence of the hypothalamus, appear to act as the linchpin of these processes by dynamically controlling the secretion of neuropeptides into the portal vasculature by hypothalamic neurons and regulating blood-brain and blood-cerebrospinal fluid exchanges, both processes that depend on the ability of these cells to adapt their morphology to the physiological state of the individual. In addition to their barrier properties, they possess the ability to sense blood glucose levels, and play a fundamental and active role in shuttling circulating metabolic signals to hypothalamic neurons that control food intake. Moreover, accumulating data suggest that, in keeping with their putative descent from radial glial cells, tanycytes are endowed with neural stem cell properties and may respond to dietary or reproductive cues by modulating hypothalamic neurogenesis. Tanycytes could thus constitute the missing link in the loop connecting behavior, hormonal changes, signal transduction, central neuronal activation and, finally, behavior again. In this paper, we will examine these recent advances in the understanding of tanycytic plasticity and function in the hypothalamus, and the underlying molecular mechanisms. We will also discuss the putative involvement and therapeutic potential of hypothalamic tanycytes in metabolic and fertility disorders.
- The extending spectrum of NPC1-related human disorders: from Niemann-Pick C1 Disease to obesity. [Journal Article]
- EREndocr Rev 2018 Jan 09
- The Niemann-Pick C1 (NPC1) protein regulates the transport of cholesterol and fatty acids from late endosomes / lysosomes and has a central role in maintaining lipid homeostasis. NPC1 loss-of-functio...
The Niemann-Pick C1 (NPC1) protein regulates the transport of cholesterol and fatty acids from late endosomes / lysosomes and has a central role in maintaining lipid homeostasis. NPC1 loss-of-function mutations in humans cause NPC1 disease, a rare autosomal-recessive lipid-storage disorder characterized by progressive and lethal neurodegeneration, liver and lung failure, due to cholesterol infiltration. In humans, genome wide association studies (GWAS) and post-GWAS reports highlight the implication of common variants in NPC1 in adult-onset obesity, body fat mass, and type 2 diabetes. Heterozygous human carriers of rare loss-of-function coding variants in NPC1 display an increased risk of morbid adult obesity. These associations have been confirmed in mice models, showing an important interaction with high-fat diet. Here we describe the current state of knowledge for NPC1 variants in relation to pleotropic effects on metabolism. We provide evidence that NPC1 may predispose to common metabolic diseases by modulating steroid hormone synthesis and / or lipid homeostasis. We also propose several important directions of research to further define the complex roles of NPC1 in metabolism. This review emphasizes the contribution of NPC1 to obesity and its metabolic complications.
- "Evaluating Causality of Gut Microbiota in Obesity and Diabetes in Humans". [Journal Article]
- EREndocr Rev 2017 Dec 22
- The pathophysiology of obesity and obesity-related diseases such as type 2 diabetes mellitus (T2DM) is complex and driven by many factors. One of the most recently identified factors in development o...
The pathophysiology of obesity and obesity-related diseases such as type 2 diabetes mellitus (T2DM) is complex and driven by many factors. One of the most recently identified factors in development of these metabolic pathologies is the gut microbiota. The introduction of affordable, high-throughput sequencing technologies has significantly expanded our understanding of the role of the gut microbiome in modulation of host metabolism and (cardio)metabolic disease development. Nevertheless, evidence for a role of the gut microbiome as causal, driving factor in disease development mainly originates from studies in mouse models: data showing causality in humans is scarce. In this review, we will discuss the quality of evidence supporting a causal role for the gut microbiome in the development of obesity and diabetes, in particular T2DM, in humans. Considering overlap in potential mechanisms, the role of the gut microbiome in type 1 diabetes mellitus will also be addressed. We will elaborate on factors that drive microbiome composition in humans and discuss how alterations in microbial composition or microbial metabolite production contribute to disease development. Challenging aspects in determining causality in humans will be postulated together with strategies that might hold potential to overcome these challenges. Furthermore, we will discuss means to modify gut microbiome composition in humans to help establish causality and discuss systems biology approaches that might hold the key to unravel the role of gut microbiome in obesity and T2DM.
- Hormonal Contraception and HIV-1 Acquisition: Biological Mechanisms. [Journal Article]
- EREndocr Rev 2018 Feb 01; 39(1):36-78
- Access to effective affordable contraception is critical for individual and public health. A wide range of hormonal contraceptives (HCs), which differ in composition, concentration of the progestin c...
Access to effective affordable contraception is critical for individual and public health. A wide range of hormonal contraceptives (HCs), which differ in composition, concentration of the progestin component, frequency of dosage, and method of administration, is currently available globally. However, the options are rather limited in settings with restricted economic resources that frequently overlap with areas of high HIV-1 prevalence. The predominant contraceptive used in sub-Saharan Africa is the progestin-only three-monthly injectable depot medroxyprogesterone acetate. Determination of whether HCs affect HIV-1 acquisition has been hampered by behavioral differences potentially confounding clinical observational data. Meta-analysis of these studies shows a significant association between depot medroxyprogesterone acetate use and increased risk of HIV-1 acquisition, raising important concerns. No association was found for combined oral contraceptives containing levonorgestrel, nor for the two-monthly injectable contraceptive norethisterone enanthate, although data for norethisterone enanthate are limited. Susceptibility to HIV-1 and other sexually transmitted infections may, however, be dependent on the type of progestin present in the formulation. Several underlying biological mechanisms that may mediate the effect of HCs on HIV-1 and other sexually transmitted infection acquisition have been identified in clinical, animal, and ex vivo studies. A substantial gap exists in the translation of basic research into clinical practice and public health policy. To bridge this gap, we review the current knowledge of underlying mechanisms and biological effects of commonly used progestins. The review sheds light on issues critical for an informed choice of progestins for the identification of safe, effective, acceptable, and affordable contraceptive methods.
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- Diagnostic Utility of Molecular and Imaging Biomarkers in Cytological Indeterminate Thyroid Nodules. [Journal Article]
- EREndocr Rev 2018 Jan 02
- Indeterminate thyroid cytology (Bethesda III and IV) corresponds to follicular-patterned benign and malignant lesions, which are particularly difficult to differentiate on cytology alone. As approxim...
Indeterminate thyroid cytology (Bethesda III and IV) corresponds to follicular-patterned benign and malignant lesions, which are particularly difficult to differentiate on cytology alone. As approximately 25% of these nodules harbor malignancy, diagnostic hemithyroidectomy is still custom. However, advanced preoperative diagnostics are rapidly evolving.This review provides an overview of additional molecular and imaging diagnostics for indeterminate thyroid nodules in a pre-operative clinical setting, including considerations regarding cost-effectiveness, availability, and feasibility of combining techniques. Addressed diagnostics include gene mutation analysis, microRNA, immunocytochemistry, ultrasonography, elastosonography, CT, sestamibi scintigraphy, FDG-PET and diffusion-weighted MRI.The best rule-out tests for malignancy were the Afirma® GEC and FDG-PET. The most accurate rule-in test was sole BRAF mutation analysis. No diagnostic had both near-perfect sensitivity and specificity, and estimated cost-effectiveness. Molecular techniques are rapidly advancing. However, given the currently available techniques a multimodality stepwise approach likely offers the most accurate diagnosis, sequentially applying one sensitive rule-out test and one specific rule-in test. Geographical variations in cytology (e.g. Hürthle cell neoplasms) and tumor genetics strongly influence local test performance and clinical utility. Multidisciplinary collaboration and implementation studies can aid the local decision for one or more eligible diagnostics.