RESUMO
The adrenal gland is a player in the Ominous Octet of obesity, which lists eight endocrine contributors to the development of obesity. Baro-adrenal axis describes the bidirectional, multifaceted link between weight homoeostasis and adrenal function, in health and disease. This communication lists the various ways in which adrenal function influences, and is impacted by, obesity.
Assuntos
Glândulas Suprarrenais , Obesidade , Humanos , Glândulas Suprarrenais/metabolismo , Glândulas Suprarrenais/fisiopatologia , Obesidade/metabolismo , Obesidade/fisiopatologiaRESUMO
BACKGROUNDMetastatic hormone-sensitive prostate cancer (mHSPC) is androgen dependent, and its treatment includes androgen deprivation therapy (ADT) with gonadal testosterone suppression. Since 2014, overall survival (OS) has been prolonged with addition of other systemic therapies, such as adrenal androgen synthesis blockers, potent androgen receptor blockers, or docetaxel, to ADT. HSD3B1 encodes the rate-limiting enzyme for nongonadal androgen synthesis, 3ß-hydroxysteroid dehydrogenase-1, and has a common adrenal-permissive missense-encoding variant that confers increased synthesis of potent androgens from nongonadal precursor steroids and poorer prostate cancer outcomes.METHODSOur prespecified hypothesis was that poor outcome associated with inheritance of the adrenal-permissive HSD3B1 allele with ADT alone is reversed in patients with low-volume (LV) mHSPC with up-front ADT plus addition of androgen receptor (AR) antagonists to inhibit the effect of adrenal androgens. HSD3B1 genotype was obtained in 287 patients with LV disease treated with ADT + AR antagonist only in the phase III Enzalutamide in First Line Androgen Deprivation Therapy for Metastatic Prostate Cancer (ENZAMET) trial and was associated with clinical outcomes.RESULTSPatients who inherited the adrenal-permissive HSD3B1 allele had more favorable 5-year clinical progression-free survival and OS when treated with ADT plus enzalutamide or ADT plus nonsteroidal antiandrogen compared with their counterparts who did not have adrenal-permissive HSD3B1 inheritance. HSD3B1 was also associated with OS after accounting for known clinical variables. Patients with both genotypes benefited from early enzalutamide.CONCLUSIONThese data demonstrated an inherited physiologic driver of prostate cancer mortality is associated with clinical outcomes and is potentially pharmacologically reversible.FUNDINGNational Cancer Institute, NIH; Department of Defense; Prostate Cancer Foundation, Australian National Health and Medical Research Council.
Assuntos
Complexos Multienzimáticos , Progesterona Redutase , Neoplasias da Próstata , Esteroide Isomerases , Masculino , Humanos , Progesterona Redutase/genética , Progesterona Redutase/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Esteroide Isomerases/genética , Idoso , Complexos Multienzimáticos/genética , Pessoa de Meia-Idade , Antagonistas de Androgênios/uso terapêutico , Benzamidas , Metástase Neoplásica , Nitrilas , Feniltioidantoína/uso terapêutico , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/antagonistas & inibidores , Taxa de Sobrevida , Glândulas Suprarrenais/patologia , Glândulas Suprarrenais/metabolismoRESUMO
We studied the effect of intramuscular injection of physostigmine and neostigmine on Na+,K+-ATPase activity in erythrocytes of rats subjected to intense physical exercise. Both anticholinesterase drugs had a significant effect on the development of the stress response, which was expressed in a decrease in the manifestation of its individual components such as the concentration of ascorbic acid in the adrenal glands, stress-related erythrocyte polycythemia, and LPO indicators. Anticholinesterase drugs reverse the stress-induced decrease in Na+,K+-ATPase activity, as well as changes in its magnesium-dependent properties. There were no changes in the activity of the studied enzyme in the erythrocyte ghosts. We associate the observed differences with the correction of the functions of the cholinergic components of the hypothalamic-pituitary-adrenal axis leading to the development of a hypoergic type stress reaction.
Assuntos
Inibidores da Colinesterase , Eritrócitos , Neostigmina , Condicionamento Físico Animal , Fisostigmina , Ratos Wistar , ATPase Trocadora de Sódio-Potássio , Animais , ATPase Trocadora de Sódio-Potássio/metabolismo , Ratos , Inibidores da Colinesterase/farmacologia , Eritrócitos/efeitos dos fármacos , Eritrócitos/enzimologia , Eritrócitos/metabolismo , Masculino , Fisostigmina/farmacologia , Neostigmina/farmacologia , Estresse Fisiológico/efeitos dos fármacos , Ácido Ascórbico/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Glândulas Suprarrenais/efeitos dos fármacos , Glândulas Suprarrenais/metabolismo , Glândulas Suprarrenais/enzimologia , Membrana Eritrocítica/efeitos dos fármacos , Membrana Eritrocítica/metabolismoRESUMO
BACKGROUND: Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of Cushing's syndrome. Individuals with PBMAH and glucose-dependent insulinotropic polypeptide (GIP)-dependent Cushing's syndrome due to ectopic expression of the GIP receptor (GIPR) typically harbor inactivating KDM1A sequence variants. Primary unilateral macronodular adrenal hyperplasia (PUMAH) with concomitant glucocorticoid and androgen excess has never been encountered or studied. METHODS: We investigated a woman with a large, heterogeneous adrenal mass and severe adrenocorticotropic hormone-independent glucocorticoid and androgen excess, a biochemical presentation typically suggestive of adrenocortical carcinoma. The patient presented during pregnancy (22nd week of gestation) and reported an 18-month history of oligomenorrhea, hirsutism, and weight gain. We undertook an exploratory study with detailed histopathological and genetic analysis of the resected adrenal mass and leukocyte DNA collected from the patient and her parents. RESULTS: Histopathology revealed benign macronodular adrenal hyperplasia. Imaging showed a persistently normal contralateral adrenal gland. Whole-exome sequencing of 4 representative nodules detected KDM1A germline variants, benign NM_001009999.3:c.136G > A:p.G46S, and likely pathogenic NM_001009999.3:exon6:c.865_866del:p.R289Dfs*7. Copy number variation analysis demonstrated an additional somatic loss of the KDM1A wild-type allele on chromosome 1p36.12 in all nodules. RNA sequencing of a representative nodule showed low/absent KDM1A expression and increased GIPR expression compared with 52 unilateral sporadic adenomas and 4 normal adrenal glands. Luteinizing hormone/chorionic gonadotropin receptor expression was normal. Sanger sequencing confirmed heterozygous KDM1A variants in both parents (father: p.R289Dfs*7 and mother: p.G46S) who showed no clinical features suggestive of glucocorticoid or androgen excess. CONCLUSIONS: We investigated the first PUMAH associated with severe Cushing's syndrome and concomitant androgen excess, suggesting pathogenic mechanisms involving KDM1A.
Assuntos
Síndrome de Cushing , Histona Desmetilases , Humanos , Feminino , Adulto , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Síndrome de Cushing/genética , Síndrome de Cushing/patologia , Síndrome de Cushing/metabolismo , Glucocorticoides , Gravidez , Androgênios/metabolismo , Glândulas Suprarrenais/patologia , Glândulas Suprarrenais/metabolismo , Glândulas Suprarrenais/diagnóstico por imagem , Hiperplasia Suprarrenal Congênita/genética , Hiperplasia Suprarrenal Congênita/complicações , Hiperplasia Suprarrenal Congênita/patologia , Hiperplasia Suprarrenal Congênita/metabolismoRESUMO
Dynamins are large GTPases whose primary function is not only to catalyze membrane scission during endocytosis but also to modulate other cellular processes, such as actin polymerization and vesicle trafficking. Recently, we reported that centronuclear myopathy associated dynamin-2 mutations, p.A618T, and p.S619L, impair Ca2+-induced exocytosis of the glucose transporter GLUT4 containing vesicles in immortalized human myoblasts. As exocytosis and endocytosis occur within rapid timescales, here we applied high-temporal resolution techniques, such as patch-clamp capacitance measurements and carbon-fiber amperometry to assess the effects of these mutations on these two cellular processes, using bovine chromaffin cells as a study model. We found that the expression of any of these dynamin-2 mutants inhibits a dynamin and F-actin-dependent form of fast endocytosis triggered by single action potential stimulus, as well as inhibits a slow compensatory endocytosis induced by 500 ms square depolarization. Both dynamin-2 mutants further reduced the exocytosis induced by 500 ms depolarizations, and the frequency of release events and the recruitment of neuropeptide Y (NPY)-labeled vesicles to the cell cortex after stimulation of nicotinic acetylcholine receptors with 1,1-dimethyl-4-phenyl piperazine iodide (DMPP). They also provoked a significant decrease in the Ca2+-induced formation of new actin filaments in permeabilized chromaffin cells. In summary, our results indicate that the centronuclear myopathy (CNM)-linked p.A618T and p.S619L mutations in dynamin-2 affect exocytosis and endocytosis, being the disruption of F-actin dynamics a possible explanation for these results. These impaired cellular processes might underlie the pathogenic mechanisms associated with these mutations.
Assuntos
Células Cromafins , Dinamina II , Endocitose , Exocitose , Mutação , Miopatias Congênitas Estruturais , Células Cromafins/metabolismo , Endocitose/fisiologia , Endocitose/genética , Dinamina II/genética , Dinamina II/metabolismo , Animais , Exocitose/fisiologia , Miopatias Congênitas Estruturais/genética , Miopatias Congênitas Estruturais/patologia , Miopatias Congênitas Estruturais/metabolismo , Mutação/genética , Bovinos , Humanos , Actinas/metabolismo , Actinas/genética , Células Cultivadas , Técnicas de Patch-Clamp , Glândulas Suprarrenais/metabolismo , Glândulas Suprarrenais/patologiaRESUMO
Rising temperatures and intensified agricultural practices have heightened heat stress (HS)-related challenges in poultry farming, notably heat-induced sudden death in chickens. Wenchang chickens, recognized for their heat resistance, have emerged as the potential candidates for improving the economic efficiency of poultry farming. The adrenal gland plays a crucial role in preventing HS-induced heart failure sudden death by secreting hormones. However, little is known about the damage to and resilience of Wenchang chicken adrenal glands during HS. In this study, 34 healthy Wenchang chickens with similar weights were selected for formal experimentation, with 10 as the control group (Con). Following a single exposure to acute HS of 42 ± 1°C and 65% relative humidity for 5 h, 15 deceased individuals formed the HS death (HSD) group, and 9 survived comprised the HS survival (HSS) group. ELISA revealed significant higher (P < 0.05) levels of COR and NE in the HSS and the lowest levels of CORT and EPI in the HSD. Histopathological analysis indicated major degeneration in HSS cortical and chromaffin cells and extensive cell necrosis (nuclear pyknosis) in HSD. Proteomic analysis identified 572 DEPs in HSD vs. Con and 191 DEPs in HSS vs. Con. Bioinformatics highlighted ER protein processing, especially ERAD as a key pathway for heat stress resistance (HSR) in the adrenal gland, with HSPH1, DNAJA1, HSP90AA1, HSPA8 and HERPUD1 identified as regulating key molecules. Western blotting validated significantly higher (P < 0.01) protein levels in both HSS and HSD compared to the Con. Immunohistochemical staining showed increased cytoplasmic HSPH1-positive signal intensity under HS and enhanced HSP90AA1 nuclear signals, strongest in HSS. In summary, HS induces pathological damage in Wenchang chicken adrenal glands, affecting hormone secretion, and various heat shock proteins play crucial roles in cellular resistance. These results elucidate the biological basis of HSR in Wenchang chickens from the perspective of the adrenal gland and provide necessary research foundations for enhancing economic performance of various broilers in high-heat environments and screening drugs for HS treatment.
Assuntos
Glândulas Suprarrenais , Proteínas Aviárias , Galinhas , Resposta ao Choque Térmico , Proteômica , Animais , Galinhas/fisiologia , Glândulas Suprarrenais/metabolismo , Resposta ao Choque Térmico/fisiologia , Proteínas Aviárias/metabolismo , Proteínas Aviárias/genética , Masculino , Temperatura AltaAssuntos
Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Colesterol , Animais , Humanos , Camundongos , Glândulas Suprarrenais/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Colesterol/metabolismo , Colesterol/biossíntese , Esteroides/biossíntese , Esteroides/metabolismoRESUMO
We studied the effect of enteral administration of GABA on the gastric mucosa in male Wistar rats (n=47) with modeled metabolic stress (food deprivation for 9 days with free access to water). The relative weights of the adrenal glands and thymus were determined, and histological examination of the stomach was performed. In control rats, modeling the metabolic stress was accompanied by the development of erosive damage to the gastric mucosa related to blood supply disturbances. Administration of GABA prevented erosions and exhibited a pronounced gastroprotective effect. Thus, administration of GABA can be a promising method for the prevention and treatment of erosive gastric lesions associated with metabolic stress.
Assuntos
Mucosa Gástrica , Ratos Wistar , Estresse Fisiológico , Ácido gama-Aminobutírico , Animais , Masculino , Ácido gama-Aminobutírico/metabolismo , Ácido gama-Aminobutírico/farmacologia , Ratos , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Estresse Fisiológico/efeitos dos fármacos , Glândulas Suprarrenais/efeitos dos fármacos , Glândulas Suprarrenais/metabolismo , Glândulas Suprarrenais/patologia , Timo/efeitos dos fármacos , Timo/patologia , Timo/metabolismo , Privação de Alimentos , Úlcera Gástrica/metabolismo , Úlcera Gástrica/patologia , Úlcera Gástrica/prevenção & controle , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/tratamento farmacológicoRESUMO
Multiple sclerosis (MS) is a chronic inflammatory disease that affects the central nervous system, usually diagnosed during the reproductive period. Both MS and its commonly used animal model, experimental autoimmune encephalomyelitis (EAE), exhibit sex-specific features regarding disease progression and disturbances in the neuroendocrine and endocrine systems. This study investigates the hypothalamic-pituitary-adrenal (HPA) axis response of male and female Dark Agouti rats during EAE. At the onset of EAE, Crh expression in the hypothalamus of both sexes is decreased, while males show reduced plasma adrenocorticotropic hormone levels. Adrenal gland activity is increased during EAE in both males and females, as evidenced by enlarged adrenal glands and increased StAR gene and protein expression. However, only male rats show increased serum and adrenal corticosterone levels, and an increased volume of the adrenal cortex. Adrenal 3ß-HSD protein and progesterone levels are elevated in males only. Serum progesterone levels of male rats are also increased, although testicular progesterone levels are decreased during the disease, implying that the adrenal gland is the source of elevated serum progesterone levels in males. Our results demonstrate a sex difference in the response of the HPA axis at the adrenal level, with male rats showing a more pronounced induction during EAE.
Assuntos
Encefalomielite Autoimune Experimental , Sistema Hipotálamo-Hipofisário , Sistema Hipófise-Suprarrenal , Animais , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Feminino , Masculino , Sistema Hipófise-Suprarrenal/metabolismo , Ratos , Sistema Hipotálamo-Hipofisário/metabolismo , Corticosterona/sangue , Hormônio Adrenocorticotrópico/sangue , Glândulas Suprarrenais/metabolismo , Glândulas Suprarrenais/patologia , Caracteres Sexuais , Progesterona/sangueRESUMO
Objective: To evaluate the function of serum dehydroepiandrosterone sulfate (DHEAS) in adult adrenal space-occupying lesions. Methods: In this cross-sectional study, 395 patients with adrenal space-occupying lesions who had their DHEAS levels measured were collected from the First Medical Center of Chinese PLA General Hospital from January 2010 to June 2021. They were divided into the adrenal Cushing syndrome (ACS) group (n=100) and non-ACS group (n=295). The former was divided into the cortisol-producing adrenal adenoma (CPA) group (n=67) and primary bilateral macronodular adrenal hyperplasia (PBMAH) group (n=33). Clinical data of each group were collected and compared among groups by independent samples t-test, chi-square test, and Mann-Whitney U test. Serum DHEAS ratio corrected for age and sex was further constructed to identify the receiver operating characteristic curve and the optimal tangent point value for different adrenal occupation. Results: Patients in the ACS group were younger (44.9±13.7 vs. 49.9±12.5, P=0.001); had a larger proportion of women (79/100 vs.139/295, P=0.001); and had higher cortisol levels [8â¶00Am, 497.31 (343.52, 606.50) vs. 353.11 (267.50, 487.91) nmol/L, P<0.001] than those in the non-ACS group. The serum DHEAS level and ratio in the ACS group were significantly lower than those in the non-ACS group [0.50 (0.40, 1.21) vs. 2.68 (1.56, 4.32) µmol/L, 1.00 (0.43, 1.68) vs. 3.17 (2.21, 4.54), both P<0.001]. When the serum DHEAS ratio cut-off point was 1.29, the sensitivity and specificity for differential diagnosis of ACS and non-ACS were 72.0% and 91.5% respectively. The ratio of DHEAS in the CPA group was lower [0.58 (0.27, 1.05) vs. 1.14 (1.04, 2.40), P<0.001] than that in the PBMAH group. When the serum DHEAS ratio cut-off point was 0.99, the sensitivity and specificity for differential diagnosis of CPA and PBMAH were 64.2% and 81.2% respectively. Conclusion: Corrected age-sex DHEAS ratio can assist in the functional assessment of adrenal space-occupying lesions.
Assuntos
Neoplasias das Glândulas Suprarrenais , Síndrome de Cushing , Sulfato de Desidroepiandrosterona , Humanos , Sulfato de Desidroepiandrosterona/sangue , Estudos Transversais , Adulto , Síndrome de Cushing/sangue , Síndrome de Cushing/diagnóstico , Pessoa de Meia-Idade , Neoplasias das Glândulas Suprarrenais/sangue , Neoplasias das Glândulas Suprarrenais/diagnóstico , Glândulas Suprarrenais/metabolismo , Hidrocortisona/sangue , Curva ROC , Masculino , FemininoRESUMO
SCOPE: The aim of this study is to investigate the effect of time-of-day on serum hormones and gene expression in adrenal glands, studying the impact of sex, obesogenic diet, and timing of proanthocyanidins administration, with a focus on glucocorticoids synthesis by this gland. METHODS AND RESULTS: Female and male rats, assigned to a standard chow or a cafeteria diet-fed group, receive a daily oral dose of a grape seed proanthocyanidin extract (GSPE), or a vehicle (when light is turned on, or when light is turned off). Corticosterone, estradiol, and testosterone serum levels, and the expression analysis of clock genes and genes related to corticosterone synthesis pathway, are assessed. Serum hormone levels exhibited a marked time-of-day effect also see in the expression of scavenger receptor class B member 1 (Scarb1) and cyp11b genes. The correlation between these two genes and period circadian regulator 2 (Per2) is also extended to other clock genes, although to a lesser extent: cryptochrome (Cry) and nuclear receptor subfamily 1 group D member 1 (Rev-erba). CONCLUSION: The strong correlations found suggest an important role of local Per2 (but also of Cry and Rev-erbA) in regulating the expression of the enzymes involved in the corticosterone synthesis pathway. The expression of clock genes in adrenals is influenced by sex and diet but not by GSPE.
Assuntos
Glândulas Suprarrenais , Corticosterona , Extrato de Sementes de Uva , Proantocianidinas , Testosterona , Animais , Corticosterona/sangue , Masculino , Proantocianidinas/farmacologia , Feminino , Glândulas Suprarrenais/metabolismo , Glândulas Suprarrenais/efeitos dos fármacos , Extrato de Sementes de Uva/farmacologia , Testosterona/sangue , Estradiol/sangue , Receptores Depuradores Classe B/genética , Receptores Depuradores Classe B/metabolismo , Ratos Wistar , Dieta/métodos , Esteroide 11-beta-Hidroxilase/genética , Esteroide 11-beta-Hidroxilase/metabolismo , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , Ratos , Criptocromos/genética , Criptocromos/metabolismoRESUMO
Hypertension affects one-third of the adult population worldwide, with primary aldosteronism (PA) accounting for at least 5-10% of these cases. The aldosterone synthase enzyme (CYP11B2) plays a pivotal role in PA manifestation, as increased expression of CYP11B2 leads to excess aldosterone synthesis. Physiological expression of CYP11B2 in humans is normally limited to cells of the adrenal zona glomerulosa under tight homeostatic regulation. In PA, however, there are CYP11B2-positive lesions in the adrenal cortex that autonomously secrete aldosterone, highlighting the dysregulation of adrenal cortex zonation and function as a key aspect of PA pathogenesis. Thus, this review aims to summarize the development of the adrenal glands, the key regulators of adrenal cortex homeostasis, and the dysregulation of this homeostasis. It also discusses the development of CYP11B2 inhibitors for therapeutic use in patients with hypertension, as well as the current knowledge of the effects of CYP11B2 inhibition on adrenal cortex homeostasis and cell fate. Understanding the control of adrenal cell fate may offer valuable insights into both the pathogenesis of PA and the development of alternative treatment approaches for PA.
Assuntos
Glândulas Suprarrenais , Aldosterona , Citocromo P-450 CYP11B2 , Hiperaldosteronismo , Humanos , Aldosterona/metabolismo , Aldosterona/biossíntese , Citocromo P-450 CYP11B2/metabolismo , Hiperaldosteronismo/metabolismo , Hiperaldosteronismo/patologia , Glândulas Suprarrenais/metabolismo , Animais , Córtex Suprarrenal/metabolismo , Córtex Suprarrenal/citologia , Hipertensão/metabolismo , Hipertensão/patologia , Zona Glomerulosa/metabolismo , Diferenciação Celular , HomeostaseRESUMO
The human adrenal gland is a complex endocrine tissue. Studies on adrenal renewal have been limited to animal models or human foetuses. Enhancing our understanding of adult human adrenal homeostasis is crucial for gaining insights into the pathogenesis of adrenal diseases, such as adrenocortical tumours. Here, we present a comprehensive cellular genomics analysis of the adult human normal adrenal gland, combining single-nuclei RNA sequencing and spatial transcriptome data to reconstruct adrenal gland homeostasis. As expected, we identified primary cells of the various zones of the adrenal cortex and medulla, but we also uncovered additional cell types. They constitute the adrenal microenvironment, including immune cells, mostly composed of a large population of M2 macrophages, and new cell populations, including different subpopulations of vascular-endothelial cells and cortical-neuroendocrine cells. Utilizing spatial transcriptome and pseudotime trajectory analysis, we support evidence of the centripetal dynamics of adrenocortical cell maintenance and the essential role played by Wnt/ß-catenin, sonic hedgehog, and fibroblast growth factor pathways in the adult adrenocortical homeostasis. Furthermore, we compared single-nuclei transcriptional profiles obtained from six healthy adrenal glands and twelve adrenocortical adenomas. This analysis unveiled a notable heterogeneity in cell populations within the adenoma samples. In addition, we identified six distinct adenoma-specific clusters, each with varying distributions based on steroid profiles and tumour mutational status. Overall, our results provide novel insights into adrenal homeostasis and molecular mechanisms potentially underlying early adrenocortical tumorigenesis and/or autonomous steroid secretion. Our cell atlas represents a powerful resource to investigate other adrenal-related pathologies.
Assuntos
Glândulas Suprarrenais , Homeostase , Transcriptoma , Humanos , Transcriptoma/genética , Glândulas Suprarrenais/metabolismo , Homeostase/genética , Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/metabolismo , Neoplasias do Córtex Suprarrenal/patologia , Adulto , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/metabolismo , Neoplasias das Glândulas Suprarrenais/patologiaRESUMO
The distribution of CYP11B2-positive or aldosterone producing adrenocortical cells in human fetuses and children and their age-dependent changes has not been studied. We aimed to explore the changes of aldosterone biosynthesis and age-related histological alterations of the zona glomerulosa in human adrenal gland during fetal and pediatric periods. We first reviewed 125 fetal and pediatric autopsy cases and retrieved 78 adrenals from 70 cases. CYP11B2 immunohistochemistry and quantitative image analysis of its results were performed in all adrenal glands. The ratio of the definitive zone (DZ) or zona glomerulosa (ZG) / the whole adrenocortical areas started to increase in the 2nd trimester, subsequently decreased in the 3rd, increased after birth, peaked in infancy, and then gradually decreased. The ratio of CYP11B2-positive / whole adrenocortical areas remained low during the fetal period but increased after birth, peaked at infancy, and then decreased. The ratio of CYP11B2-positive / DZ or ZG areas and CYP11B2-positive areas / depth of DZ or ZG demonstrated a distinctive bimodal pattern, with one peak in the fetal period and another in the neonatal period to infancy. This is the first study to perform quantitative analysis of the distribution of CYP11B2-positive cells, the histological DZ or ZG, and the development of aldosterone biosynthesis in human adrenal glands during fetal and pediatric periods.
Assuntos
Aldosterona , Citocromo P-450 CYP11B2 , Feto , Zona Glomerulosa , Humanos , Citocromo P-450 CYP11B2/metabolismo , Citocromo P-450 CYP11B2/genética , Aldosterona/biossíntese , Aldosterona/metabolismo , Lactente , Zona Glomerulosa/metabolismo , Feminino , Pré-Escolar , Feto/metabolismo , Masculino , Recém-Nascido , Criança , Glândulas Suprarrenais/metabolismo , Glândulas Suprarrenais/embriologia , Adolescente , GravidezAssuntos
Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Colesterol , Colesterol/metabolismo , Colesterol/biossíntese , Animais , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Humanos , Glândulas Suprarrenais/metabolismo , Esteroides/biossíntese , Esteroides/metabolismo , CamundongosRESUMO
BACKGROUND: The effect of coronavirus disease 2019 (COVID-19) on adrenal endocrine metabolism in critically ill patients remains unclear. This study aimed to investigate the alterations in adrenal steroidogenic activity, elucidate underlying mechanisms, provide in situ histopathological evidence, and examine the clinical implications. METHODS: The comparative analyses of the adrenal cortices from 24 patients with fatal COVID-19 and 20 matched controls were performed, excluding patients previously treated with glucocorticoids. SARS-CoV-2 and its receptors were identified and pathological alterations were examined. Furthermore, histological examinations, immunohistochemical staining and ultrastructural analyses were performed to assess corticosteroid biosynthesis. The zona glomerulosa (ZG) and zona fasciculata (ZF) were then dissected for proteomic analyses. The biological processes that affected steroidogenesis were analyzed by integrating histological, proteomic, and clinical data. Finally, the immunoreactivity and responsive genes of mineralocorticoid and glucocorticoid receptors in essential tissues were quantitatively measured to evaluate corticosteroid responsiveness. FINDINGS: The demographic characteristics of COVID-19 patients were comparable with those of controls. SARS-CoV-2-like particles were identified in the adrenocortical cells of three patients; however, these particles did not affect cellular morphology or steroid synthesis compared with SARS-CoV-2-negative specimens. Although the adrenals exhibited focal necrosis, vacuolization, microthrombi, and inflammation, widespread degeneration was not evident. Notably, corticosteroid biosynthesis was significantly enhanced in both the ZG and ZF of COVID-19 patients. The increase in the inflammatory response and cellular differentiation in the adrenal cortices of patients with critical COVID-19 was positively correlated with heightened steroidogenic activity. Additionally, the appearance of more dual-ZG/ZF identity cells in COVID-19 adrenals was in accordance with the increased steroidogenic function. However, activated mineralocorticoid and glucocorticoid receptors and their responsive genes in vital tissues were markedly reduced in patients with critical COVID-19. INTERPRETATION: Critical COVID-19 was characterized by potentiated adrenal steroidogenesis, associated with increased inflammation, enhanced differentiation and elevated dual-ZG/ZF identity cells, alongside suppressed corticosteroid responsiveness. These alterations implied the reduced effectiveness of conventional corticosteroid therapy and underscored the need for evaluation of the adrenal axis and corticosteroid sensitivity.
Assuntos
Corticosteroides , COVID-19 , Estado Terminal , Humanos , COVID-19/metabolismo , Masculino , Feminino , Pessoa de Meia-Idade , Corticosteroides/uso terapêutico , Corticosteroides/biossíntese , Idoso , SARS-CoV-2 , Zona Fasciculada/metabolismo , Zona Fasciculada/efeitos dos fármacos , Receptores de Glucocorticoides/metabolismo , Adulto , Córtex Suprarrenal/metabolismo , Córtex Suprarrenal/efeitos dos fármacos , Córtex Suprarrenal/patologia , Zona Glomerulosa/metabolismo , Zona Glomerulosa/efeitos dos fármacos , Zona Glomerulosa/patologia , Glândulas Suprarrenais/metabolismo , Glândulas Suprarrenais/efeitos dos fármacosRESUMO
BACKGROUND: Asthma is routinely treated with inhaled corticosteroids (ICS). Asthma patients on ICS are at increased risk of adrenal suppression, a potentially serious effect of long-term glucocorticoid exposure; however, this relationship is poorly understood. Therefore, this study aims to identify metabolite biomarkers related to adrenal suppression in asthma patients taking ICS. METHODS: A total of 571 urine metabolites from 200 children with asthma on ICS in the Pharmacogenetics of Adrenal Suppression with Inhaled Steroids (PASS) cohort were profiled. Samples were grouped by peak plasma cortisol measurement as adrenal sufficient (>350 nmol/L) or insufficient (≤350 nmol/L) (outcome). Regression and discriminant-based statistical models combined with network analyses were utilized to assess relationships between metabolites and the outcome. Finally, prioritized metabolites were validated using data from an ancillary study of the Childhood Asthma Management (CAMP) cohort with similar characteristics to PASS. RESULTS: Ninety metabolites were significantly associated with adrenal suppression, of which 57 also could discriminate adrenal status. While 26 metabolites (primarily steroids) were present at lower levels in the adrenal insufficient patients, 14 were significantly elevated in this group; the top metabolite, mannitol/sorbitol, was previously associated with asthma exacerbations. Network analyses identified unique clusters of metabolites related to steroids, fatty acid oxidation, and nucleoside metabolism, respectively. Four metabolites including urocanic acid, acetylcarnitine, uracil, and sorbitol were validated in CAMP cohort for adrenal suppression. CONCLUSIONS: Urinary metabolites differ among asthma patients on ICS, by adrenal status. While steroid metabolites were reduced in patients with poor adrenal function, our findings also implicate previously unreported metabolites involved in amino acid, lipid, and nucleoside metabolism.
Assuntos
Corticosteroides , Asma , Metabolômica , Humanos , Asma/tratamento farmacológico , Asma/urina , Asma/sangue , Asma/diagnóstico , Criança , Masculino , Feminino , Administração por Inalação , Metabolômica/métodos , Corticosteroides/administração & dosagem , Corticosteroides/uso terapêutico , Biomarcadores/urina , Biomarcadores/sangue , Adolescente , Metaboloma/efeitos dos fármacos , Insuficiência Adrenal/diagnóstico , Insuficiência Adrenal/sangue , Insuficiência Adrenal/urina , Insuficiência Adrenal/etiologia , Insuficiência Adrenal/tratamento farmacológico , Pré-Escolar , Hidrocortisona/sangue , Hidrocortisona/urina , Glândulas Suprarrenais/metabolismo , Glândulas Suprarrenais/efeitos dos fármacos , Estudos de CoortesRESUMO
Recognizing the limitations of current therapies for Addison's disease, novel treatments that replicate dynamic physiologic corticosteroid secretion, under control of ACTH, are required. The aim of these experiments was to evaluate the feasibility of adrenocortical cell transplantation (ACT) in a large animal model, adapting methods successfully used for intracutaneous pancreatic islet cell transplantation, using a fully biodegradable temporizing matrix. Autologous porcine ACT was undertaken by bilateral adrenalectomy, cell isolation, culture, and intracutaneous injection into a skin site preprepared using a biodegradable temporizing matrix (BTM) foam. Hydrocortisone support was provided during adrenocortical cell engraftment and weaned as tolerated. Blood adrenocortical hormone concentrations were monitored, and the transplant site was examined at endpoint. Outcome measures included cellular histochemistry, systemic hormone production, and hydrocortisone independence. Transplanted adrenocortical cells showed a capability to survive and proliferate within the intracutaneous site and an ability to self-organize into discrete tissue organoids with features of the normal adrenal histologic architecture. Interpretation of systemic hormone levels was confounded by the identification of accessory adrenals and regenerative cortical tissue within the adrenal bed postmortem. Corticosteroids were unable to be completely ceased. ACT in a large animal model has not previously been attempted, yet it is an important step toward clinical translation. These results demonstrate rhe potential for ACT based on the development of adrenal organoids at the BTM site. However, the inability to achieve clinically relevant systemic hormone production suggests insufficient function, likely attributable to insufficient cells through delivered dose and subsequent proliferation.