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Journal of Molecular Medicine (Berlin,... Nov 2021The adrenal gland and its hormones regulate numerous fundamental biological processes; however, the impact of hypoxia signaling on adrenal function remains poorly...
The adrenal gland and its hormones regulate numerous fundamental biological processes; however, the impact of hypoxia signaling on adrenal function remains poorly understood. Here, we reveal that deficiency of HIF (hypoxia inducible factors) prolyl hydroxylase domain protein-2 (PHD2) in the adrenal medulla of mice results in HIF2α-mediated reduction in phenylethanolamine N-methyltransferase (PNMT) expression, and consequent reduction in epinephrine synthesis. Simultaneous loss of PHD2 in renal erythropoietin (EPO)-producing cells (REPCs) stimulated HIF2α-driven EPO overproduction, excessive RBC formation (erythrocytosis), and systemic hypoglycemia, which is necessary and sufficient to enhance exocytosis of epinephrine from the adrenal medulla. Based on these results, we propose that the PHD2-HIF2α axis in the adrenal medulla regulates the synthesis of epinephrine, whereas in REPCs, it indirectly induces the release of this hormone. Our findings are also highly relevant to the testing of small molecule PHD inhibitors in phase III clinical trials for patients with renal anemia. KEY MESSAGES: HIF2α and not HIF1α modulates PNMT during epinephrine synthesis in chromaffin cells. The PHD2-HIF2α-EPO axis induces erythrocytosis and hypoglycemia. Reduced systemic glucose facilitates exocytosis of epinephrine from adrenal gland.
Topics: Adrenal Medulla; Animals; Basic Helix-Loop-Helix Transcription Factors; Calcium; Epinephrine; Erythropoietin; Female; Hypoglycemia; Hypoxia-Inducible Factor-Proline Dioxygenases; Male; Mice, Transgenic; Phenylethanolamine N-Methyltransferase; Polycythemia; Tumor Cells, Cultured
PubMed: 34480587
DOI: 10.1007/s00109-021-02121-y -
Endocrine-related Cancer Jun 2017Tumourigenesis is a relatively common event in endocrine tissues. Currently, specific guidelines have been developed for common malignant endocrine tumours, which also... (Review)
Review
Tumourigenesis is a relatively common event in endocrine tissues. Currently, specific guidelines have been developed for common malignant endocrine tumours, which also incorporate advances in molecular targeted therapies (MTT), as in thyroid cancer and in gastrointestinal neuroendocrine malignancies. However, there is little information regarding the role and efficacy of MTT in the relatively rare malignant endocrine tumours mainly involving the adrenal medulla, adrenal cortex, pituitary, and parathyroid glands. Due to the rarity of these tumours and the lack of prospective studies, current guidelines are mostly based on retrospective data derived from surgical, locoregional and ablative therapies, and studies with systemic chemotherapy. In addition, in many of these malignancies the prognosis remains poor with individual patients responding differently to currently available treatments, necessitating the development of new personalised therapeutic strategies. Recently, major advances in the molecular understanding of endocrine tumours based on genomic, epigenomic, and transcriptome analysis have emerged, resulting in new insights into their pathogenesis and molecular pathology. This in turn has led to the use of novel MTTs in increasing numbers of patients. In this review, we aim to present currently existing and evolving data using MTT in the treatment of adrenal, pituitary and malignant parathyroid tumours, and explore the current utility and effectiveness of such therapies and their future evolution.
Topics: Adrenal Gland Neoplasms; Animals; Humans; Molecular Targeted Therapy; Paraganglioma; Parathyroid Neoplasms; Pheochromocytoma; Pituitary Neoplasms
PubMed: 28400402
DOI: 10.1530/ERC-16-0542 -
Endocrine-related Cancer Jan 2023Mitochondrial DNA (mtDNA) alterations have been reported in different types of cancers and are suggested to play important roles in cancer development and metastasis.... (Review)
Review
Mitochondrial DNA (mtDNA) alterations have been reported in different types of cancers and are suggested to play important roles in cancer development and metastasis. However, there is little information about its involvement in pheochromocytomas and paragangliomas (PCCs/PGLs) formation. PCCs and PGLs are rare endocrine tumors of the chromaffin cells in the adrenal medulla and extra-adrenal paraganglia that can synthesize and secrete catecholamines. Over the last 3 decades, the genetic background of about 60% of PCCs/PGLs involving nuclear DNA alterations has been determined. Recently, a study showed that mitochondrial alterations can be found in around 17% of the remaining PCCs/PGLs. In this review, we summarize recent knowledge regarding both nuclear and mitochondrial alterations and their involvement in PCCs/PGLs. We also provide brief insights into the genetics and the molecular pathways associated with PCCs/PGLs and potential therapeutical targets.
Topics: Humans; DNA, Mitochondrial
PubMed: 36219865
DOI: 10.1530/ERC-22-0217 -
Endocrine Pathology Jun 2021Abdominal paragangliomas and pheochromocytomas (PPGLs) are rare neuroendocrine tumors of the infradiaphragmatic paraganglia and adrenal medulla, respectively. Although... (Review)
Review
Abdominal paragangliomas and pheochromocytomas (PPGLs) are rare neuroendocrine tumors of the infradiaphragmatic paraganglia and adrenal medulla, respectively. Although few pathologists outside of endocrine tertiary centers will ever diagnose such a lesion, the tumors are well known through the medical community-possible due to a combination of the sheer rarity, their often-spectacular presentation due to excess catecholamine secretion as well as their unrivaled coupling to constitutional susceptibility gene mutations and hereditary syndromes. All PPGLs are thought to harbor malignant potential, and therefore pose several challenges to the practicing pathologist. Specifically, a responsible diagnostician should recognize both the capacity and limitations of histological, immunohistochemical, and molecular algorithms to pinpoint high risk for future metastatic disease. This focused review aims to provide the surgical pathologist with a condensed update regarding the current strategies available in order to deliver an accurate prognostication of these enigmatic lesions.
Topics: Adrenal Gland Neoplasms; Biomarkers, Tumor; Humans; Immunohistochemistry; Paraganglioma; Pathology, Molecular; Pheochromocytoma
PubMed: 33768452
DOI: 10.1007/s12022-021-09675-0 -
Stress (Amsterdam, Netherlands) Sep 2016In this review, nonassociative learning is advanced as an organizing principle to draw together findings from both sympathetic-adrenal medullary and... (Review)
Review
In this review, nonassociative learning is advanced as an organizing principle to draw together findings from both sympathetic-adrenal medullary and hypothalamic-pituitary-adrenocortical (HPA) axis responses to chronic intermittent exposure to a variety of stressors. Studies of habituation, facilitation and sensitization of stress effector systems are reviewed and linked to an animal's prior experience with a given stressor, the intensity of the stressor and the appraisal by the animal of its ability to mobilize physiological systems to adapt to the stressor. Brain pathways that regulate physiological and behavioral responses to stress are discussed, especially in light of their regulation of nonassociative processes in chronic intermittent stress. These findings may have special relevance to various psychiatric diseases, including depression and post-traumatic stress disorder (PTSD).
Topics: Adaptation, Physiological; Animals; Depression; Humans; Hypothalamo-Hypophyseal System; Learning; Pituitary-Adrenal System; Stress Disorders, Post-Traumatic; Stress, Psychological
PubMed: 27294884
DOI: 10.1080/10253890.2016.1192120 -
Laboratory Animals Jun 2022Mice and rats are among the most used laboratory animals. They share numerous similarities along with differences, some yet unexplored. One of them is the morphometry of...
Mice and rats are among the most used laboratory animals. They share numerous similarities along with differences, some yet unexplored. One of them is the morphometry of their adrenal glands, whose characteristics may be related to differences in energy management, immune response, drug metabolism, behaviour and temperament. The present study tries to fill this knowledge gap with the evaluation and comparison of adrenal gland anatomical/morphometric parameters of mice and rats. In groups of 10 ( = 10) adult, male and female BALB/c mice and Wistar rats, one in every 20 sections transverse to the longitudinal axis of the gland was used for measuring entire gland area, capsule, entire cortex, cortex zones and medulla with the aid of an image analysis system and subjected to statistical analysis. Quotients of the individual areas were calculated and comparison between the resulting ratios was performed. Gland length and volume were also calculated. Statistically significant differences were revealed between the rat female and male cortex area, rat and mouse medulla/cortex, medulla/gland, zona glomerulosa/cortex and cortex/gland ratios, male and female rats' medulla/cortex, medulla/gland, capsule/gland, zona glomerulosa/cortex, zona reticularis/cortex and zona glomerulosa/zona fasciculata ratios, length and volume. The correlation evaluation revealed that in male rats and in female mice the larger medulla area was accompanied by a larger cortex area and vice versa. In general, a larger cortex area was accompanied by larger areas of cortex zones. The collected data and the revealed differences can possibly contribute to the understanding of the physiology of the two species.
Topics: Adrenal Glands; Adrenal Medulla; Animals; Female; Male; Rats; Rats, Wistar
PubMed: 34541948
DOI: 10.1177/00236772211044352 -
Vitamins and Hormones 2024The adrenal glands are key components of the mammalian endocrine system, helping maintain physiological homeostasis and the coordinated response to stress. Each adrenal... (Review)
Review
The adrenal glands are key components of the mammalian endocrine system, helping maintain physiological homeostasis and the coordinated response to stress. Each adrenal gland has two morphologically and functionally distinct regions, the outer cortex and inner medulla. The cortex is organized into three concentric zones which secrete steroid hormones, including aldosterone and cortisol. Neural crest-derived chromaffin cells in the medulla are innervated by preganglionic sympathetic neurons and secrete catecholamines (epinephrine, norepinephrine) and neuropeptides into the bloodstream, thereby functioning as the neuroendocrine arm of the sympathetic nervous system. In this article we review serotonin (5-HT) and the serotonin transporter (SERT; SLC6A4) in the adrenal gland. In the adrenal cortex, 5-HT, primarily sourced from resident mast cells, acts as a paracrine signal to stimulate aldosterone and cortisol secretion through 5-HT/5-HT receptors. Medullary chromaffin cells contain a small amount of 5-HT due to SERT-mediated uptake and express 5-HT receptors which inhibit secretion. The atypical mechanism of the 5-HT receptors and interaction with SERT fine tune this autocrine pathway to control stress-evoked catecholamine secretion. Receptor-independent signaling by SERT/intracellular 5-HT modulates the amount and kinetics of transmitter release from single vesicle fusion events. SERT might also influence stress-evoked upregulation of tyrosine hydroxylase transcription. Transient signaling via 5-HT receptors during embryonic development can limit the number of chromaffin cells found in the mature adrenal gland. Together, this emerging evidence suggests that the adrenal medulla is a peripheral hub for serotonergic control of the sympathoadrenal stress response.
Topics: Animals; Humans; Serotonin; Serotonin Plasma Membrane Transport Proteins; Aldosterone; Hydrocortisone; Adrenal Glands; Mammals
PubMed: 38408804
DOI: 10.1016/bs.vh.2023.06.002 -
Journal of Toxicologic Pathology Jul 2015The adrenal gland has characteristic morphological and biochemical features that render it particularly susceptible to the actions of xenobiotics. As is the case with... (Review)
Review
The adrenal gland has characteristic morphological and biochemical features that render it particularly susceptible to the actions of xenobiotics. As is the case with other endocrine organs, the adrenal gland is under the control of upstream organs (hypothalamic-pituitary system) in vivo, often making it difficult to elucidate the mode of toxicity of a test article. It is very important, especially for pharmaceuticals, to determine whether a test article-related change is caused by a direct effect or other associated factors. In addition, antemortem data, including clinical signs, body weight, food consumption and clinical pathology, and postmortem data, including gross pathology, organ weight and histopathologic examination of the adrenal glands and other related organs, should be carefully monitored and evaluated. During evaluation, the following should also be taken into account: (1) species, sex and age of animals used, (2) metabolic activation by a cytochrome P450 enzyme(s) and (3) physicochemical properties and the metabolic pathway of the test article. In this review, we describe the following crucial points for toxicologic pathologists to consider when evaluating adrenal toxicity: functional anatomy, blood supply, hormone production in each compartment, steroid biosynthesis, potential medulla-cortex interaction, and species and gender differences in anatomical features and other features of the adrenal gland which could affect vulnerability to toxic effects. Finally practical approaches for evaluating adrenal toxicity in nonclinical safety studies are discussed.
PubMed: 26441474
DOI: 10.1293/tox.2015-0025 -
Stem cells, evolutionary aspects and pathology of the adrenal medulla: A new developmental paradigm.Molecular and Cellular Endocrinology Dec 2020The mammalian adrenal gland is composed of two main components; the catecholaminergic neural crest-derived medulla, found in the center of the gland, and the... (Review)
Review
The mammalian adrenal gland is composed of two main components; the catecholaminergic neural crest-derived medulla, found in the center of the gland, and the mesoderm-derived cortex producing steroidogenic hormones. The medulla is composed of neuroendocrine chromaffin cells with oxygen-sensing properties and is dependent on tissue interactions with the overlying cortex, both during development and in adulthood. Other relevant organs include the Zuckerkandl organ containing extra-adrenal chromaffin cells, and carotid oxygen-sensing bodies containing glomus cells. Chromaffin and glomus cells reveal a number of important similarities and are derived from the multipotent nerve-associated descendants of the neural crest, or Schwann cell precursors. Abnormalities in complex developmental processes during differentiation of nerve-associated and other progenitors into chromaffin and oxygen-sensing populations may result in different subtypes of paraganglioma, neuroblastoma and pheochromocytoma. Here, we summarize recent findings explaining the development of chromaffin and oxygen-sensing cells, as well as the potential mechanisms driving neuroendocrine tumor initiation.
Topics: Adrenal Gland Diseases; Adrenal Medulla; Animals; Biological Evolution; Cell Differentiation; Humans; Neural Crest; Stem Cells
PubMed: 32818585
DOI: 10.1016/j.mce.2020.110998 -
Journal of Clinical Medicine Aug 2018Pheochromocytoma (PCC) and sympathetic paraganglioma (PGL) are rare neuroendocrine tumors characterized by catecholamine production in the adrenal medulla and... (Review)
Review
Pheochromocytoma (PCC) and sympathetic paraganglioma (PGL) are rare neuroendocrine tumors characterized by catecholamine production in the adrenal medulla and extra-adrenal paraganglia. PCC and PGL (PPGL) with metastasis was termed malignant PPGL. However, the distinction between "benign" and "malignant" PPGLs has been debated. Currently, all PPGLs are believed to have some metastatic potential and are assigned malignant tumors (ICD-O/3) by the WHO Classification of Endocrine Organs (2017, 4th edition). Therefore, the previous categories benign and malignant PPGL have been eliminated in favor of risk stratification approach. The Grading of Adrenal Pheochromocytoma and Paraganglioma (GAPP) is a tool for risk stratification for predicting metastasis and the prognosis of patients. At least 30% of PPGLs are hereditary, with 20 genes identified and genotype-phenotype correlations clarified. Of these genes, and have been well investigated and are the primary cause of bilateral PCC. In addition, mutation of succinate dehydrogenase gene subunits and are strongly correlated with extra-adrenal location, younger age, multiple tumors, metastasis and poor prognosis. Disease stratification by catecholamine phenotype and molecular profiling correlates with histological grading by GAPP. PPGLs should be understood comprehensively based on clinical, biochemical, molecular and pathological data for patient care. A flow chart for pathological diagnosis is included.
PubMed: 30150569
DOI: 10.3390/jcm7090242