Beyond the Classical Axis: Metabolic "Pressure" on the Adrenal Gland?

Objective: To study the morphofunctional features of ultrastructural changes in the cellular and extracellular structures of adrenal and thyroid glands during acute hypoxia. Methods: During the study, thyroid and adrenal glands of adult male white rats with a mass of 180-200 grams divided into 2 groups were used. In the course of the study, anatomic, histological, electron microscopic and morphometric examination methods were implemented. Results: Thus, in the comparative analysis of electron micrographs obtained from the ultrathin sections of both glands, cellular and extracellular acute dystrophic and destructive changes of adrenocytes of the adrenal gland induced by the acute hypoxia – separation of basal membranes into layers, edema of cells, hypertrophy as a compensatory reaction and vacuolation of organelles – observed at the early stage (second day) of the experiment, and on the 5th day of the experiment in thyrocytes and cytoplasmic organelles of the thyroid gland. Conclusion: As a result of the study, it can be concluded that hypobaric hypoxia affects the morphofunctional state of the adrenal and thyroid glands as the main «stress» factor, causes cellular and extracellular structural changes in the glands. Because the resistance of the adrenal and thyroid glands to hypoxia, especially strong short-term hypoxic effects, is different, the cells (adrenocytes and thyrosites), vessels and connective tissue structures of the glands respond with varying degrees of damage and changes with different morphofunctional reactions. Dystrophic and destructive changes in the adrenal gland, especially on the ultrastructural level are more pronounced, as the adrenal gland is more and more exposed to the influence of endogenous and exogenous factors compared to the thyroid gland. Keywords: Electron microscopy, thyroid gland, adrenal gland, acute hypoxia.

Localization, Transport, and Uptake of [formula omitted]-Aspartate in the Rat Adrenal and Pituitary Glands

ABSTRACTDiet manipulations during the gestation of animal models, in this case, the lipoprotein diet, mimic the alterations related to low birth weight, providing studies of the mechanisms involved in chronic disease development in later life. Our research group identified in adult male rats submitted to gestational protein restriction, increased anxiety‐like behavior, basal plasmatic corticosterone (CORT) and catecholamines elevation, and decrease of hippocampal glucocorticoid receptors (GRs), indicating dysfunction of the stress response, which is related to the sympathetic‐adrenomedullary system and the hypothalamic–pituitary–adrenal (HPA) axis alterations. Not only insults during gestation but also maternal care behavior during breastfeeding can modulate the HPA axis of the offspring, influencing its activity in adulthood. Thus, we evaluated maternal care behavior and morphological and functional parameters of the adrenal and pituitary glands in gestational protein‐restricted male rats to elucidate mechanisms that can trigger these possible alterations. Mated Wistar rats were submitted to a normal‐protein diet (NP group; 17% protein) or a low‐protein diet (LP group; 6% protein) throughout pregnancy. From the day of birth until weaning, the maternal care behavior parameters were evaluated, and at the 16th week of age, plasma, adrenal, and pituitary glands were collected for hormonal analysis by LC‐MS/MS, western blot, and immunohistochemistry. LP offspring animals showed low birth weight and recovered at weaning, indicating the effect of catch‐up growth. No difference in maternal care behavior was found between the groups, suggesting that maternal care may not influence the decrease of hippocampal GR in LP offspring. The plasma levels of 11‐dehydrocorticosterone (11‐DHC) in 21PND and 16‐week‐old LP offspring decreased, whereas the plasma levels of CORT and 11‐DHC of 8‐week‐old LP offspring increased. GR and mineralocorticoid receptors, essential to glucocorticoids' practical actions, were increased in the pituitary and adrenal glands in LP 16‐week‐old animals, indicating possible negative feedback. However, the 98.8% increase in CRH receptor and 63.3% ACTH in the pituitary of the LP offspring indicates failure of this feedback at the pituitary level. The morphometric analysis of the LP 16‐week‐old animal's adrenal gland showed an increase in medullary area, accompanied by an increase of 39.67% in NeuN, indicating an increase in medullary cellularity and an increase of 168.77% in PCNA, suggesting a cell proliferation under the demand of adrenal hyperactivity. In addition, an increase of 5‐HT1A receptor (48.69%) in the LP adrenal gland, which is associated with inhibitory catecholamine secretion, and an increase of immunostaining of 5‐HT1A and 5‐HT2A receptors differently within the pituitary lobes, suggesting modulation of the HPA axis at the pituitary level through the serotonergic innervation from hypothalamic CRH neurons. Gestation protein restriction results in adult rat offspring, morphological and functional changes in the adrenal glands, and hormonal modulations associated with stress responsively and adrenergic hyperactivity. These alterations could participate in the genesis and maintenance of hypertension in this model.

The purpose of this study is to determine the effects of low and high dose of carbendazim on the level of certain hormones and endocrine glands (thyroid, parathyroid, adrenal and pituitary glands) of male rats. Carbendazim is a systemic fungicide with activity against a number of plant pathogens. In this study, daily doses of 0, 150, 300 and 600 mg/kg per day carbendazim were applied to male rats by gavage for 15 weeks. At the end of the experiment, T3, T4, TSH, ACTH and GH levels in rat serum were analysed. Thyroid, parathyroid, adrenal and pituitary glands of rats were taken. A significant increase was observed in serum T3 levels of the rats, which were exposed to 300 mg/kg per day carbendazim doses, compared to the serum T3 levels of the control group. There were no differences between the control and carbendazim-treated group of rats regarding serum TSH, T4, ACTH and growth hormone levels. This showed us that carbendazim caused histopathological damages in thyroid, parathyroid and adrenal glands of rats. No changes were observed in pituitary glands of treated rats. These results suggest that a high quantity of subchronic carbendazim exposure affects thyroid, parathyroid and adrenal glands.

The aimof the studywas to study the characteristic features of ultrastructural changes in the cellular and extracellular matrix of the adrenal and thyroid glands in chronic hypoxia.Materials and methods.The study used the thyroid and adrenal glands of healthy adult male white rats weighing 180-200 g. The anatomical, histological, histochemical, electron microscopic and morphometric methods were used.Results.We found that the response of thyroid and adrenal cells to hypoxia is different. So, since the processes of proliferation in the cells of the thyroid gland occur faster and earlier, all tissues are restored on the 15th day of the experiment in the thyroid gland, and in the adrenal gland are restored only on the 30th day of the experiment. And this can be regarded as a higher degree of sensitivity of the adrenal glands to hypoxia, which is a stronger stress factor than the thyroid gland.Summary.The structures of the thyroid gland adapt to long-term hypoxia earlier, and responds to this with ultrastructural rearrangement – hyperplasia, hypertrophy and proliferation of thyrocytes.

Melanocortin 2 receptor accessory protein (MRAP) is a single transmembrane domain accessory protein and a critical component of the hypothamo-pituitary-adrenal axis. MRAP is highly expressed in the adrenal gland and is essential for adrenocorticotropin hormone (ACTH) receptor expression and function. Human loss-of-function mutations in MRAP cause familial glucocorticoid (GC) deficiency (FGD) type 2 (FGD2), whereby the adrenal gland fails to respond to ACTH and to produce cortisol. In this study, we generated Mrap-null mice to study the function of MRAP in vivo. We found that the vast majority of Mrap−/− mice died at birth but could be rescued by administration of corticosterone to pregnant dams. Surviving Mrap−/− mice developed isolated GC deficiency with normal mineralocorticoid and catecholamine production, recapitulating FGD2. The adrenal glands of adult Mrap−/− mice were small, with grossly impaired adrenal capsular morphology and cortex zonation. Progenitor cell differentiation was significantly impaired, with dysregulation of WNT4/β-catenin and sonic hedgehog pathways. These data demonstrate the roles of MRAP in both steroidogenesis and the regulation of adrenal cortex zonation. This is the first mouse model of isolated GC deficiency and reveals the role of MRAP in adrenal progenitor cell regulation and cortex zonation.—Novoselova, T. V., Hussain, M., King, P. J., Guasti, L., Metherell, L. A., Charalambous, M., Clark, A. J. L., Chan, L. F. MRAP deficiency impairs adrenal progenitor cell differentiation and gland zonation.

Angiotensin-converting enzyme type 2 and aldosterone synthesis: beyond the renin--angiotensin--aldosterone system and closer to the clinic.

Background: Since chinchilla (Chinchilla lanigera) is frequently used as a laboratory animal, satisfactory data about the imaging anatomical appearance of its adrenal glands, such as their anatomical location and closeness with other abdomi­nal soft tissue and vessels, are important. The aim of this study to determine anatomical features of the chinchilla adrenal gland’s using computed tomography and magnetic resonance imaging. Materials, Methods & Results: We used 12 chinchillas (6 males and 6 females), aged 18 months. The animals were in supine recumbency when contrast-enhanced computed tomography (CT) was performed. Transverse, sagittal and dorsal images of the adrenal glands were obtained with iodinated contrast medium, and 3D reconstruction of the obtained images was applied. The craniocaudal (CrCc - length), dorsoventral (DV - height) and lateromedial (LM - width) diameters were measured using an electronic calliper. Magnetic resonance imaging was performed, and coronal T1-weighted images were obtained. The transverse CT anatomical image at the level of the 3rd lumbar vertebra demonstrated the location of the both adrenal glands in accordance with the grey-white scale’s variation. The right adrenal gland was hypo-attenuated and elliptic compared to the right kidney and in close contact to it and to the caudal vena cava. The left adrenal gland was oval and at a distance to the abdominal aorta. The dorsal MRI anatomical study of the chinchilla’s abdominal organs at a distance of 10 mm from the spine and in a T1-weighted sequence showed that both adrenal glands were retroperitoneal organs. Discussion: Post-contrasted CT defined the topography of both glands. The right adrenal gland has an oval shape and is cranially situated to the left gland, whose shape is cylindrical and elongated. The LM diameter of the right gland is higher than that measured in the left gland. Both DV and CrCc diameters of the right gland are lower compared to those of the left gland. The right adrenal gland is in close contact to the caudal vena cava, the right kidney and the liver, and the left adrenal gland is in a distance to the abdominal aorta. The right adrenal gland was close to the caudal vena cava and the right kidney and medially to the left kidney. The successful comparative analysis of the images in 3D reconstruction and post-contrast CT in 2D allowed us to conclude that 3D reconstruction is suitable to obtain detailed information in a sum­mary form regarding the closeness of the glands and their shape, mainly because the results are in a real time and highly comprehensive. Our data are in in agreement with previous findings about the advantages of 3D reconstruction. The research algorithm applied was based on the dorsal visualization of the glands in T1-weighted sequence, achieving a comprehensive and high-quality MRI imaging of the examined organs in chinchillas. Both adrenal glands were retroperitoneal organs and with low signal. The dorsal MRI anatomical study of the chinchilla’s abdominal organs at a distance of 10 mm from the spine and in a T1-weighted sequence showed the whole profile of the right and left glands and the cranial position of the right gland to the left one, the close contact between the right gland and the kidney and the distance between the left gland and the left kidney. The MRI results are detailed and comprehensive for interpretation. In conclusion, the results of the present study are comprehensive, detailed and with high resolution. We present data for the anatomical relationships of the studied organs, their shape and macrometric parameters, concluding that the above mentioned modalities are very important tools for studying the chinchilla’s adrenal glands to create a morphological base, which is necessary to inves­tigate specific diseases. Keywords: adrenal glands, chinchilla, CT, imaging anatomy, MRI, 3D reconstruction

Adrenal glands in Cushing's disease (CD) range from normal to showing diffuse enlargement in most cases. The finding of nodular lesions has been reported, but information about prevalence and evolution is described in few reports. To investigate the prevalence of nodular adrenal glands in patients with CD and assess its evolution after disease remission. We assessed 41 CD patients' abdominal computed tomography (CT) scans obtained during the active phase of the disease and evaluated the dynamics of ACTH and cortisol secretion. CT was repeated after disease remission in patients with adrenal nodules. Fifteen of 41 patients had nodular and the remaining 26 had normal or enlarged adrenal glands. Patients with nodules were older (45.1 ± 8.8 vs 36.9 ± 12.7 yr; p=0.03) and had longer-standing disease (57.3 ± 56.9 vs 32.9 ± 29.1 months; p=0.05) than patients with normal/enlarged adrenal glands. ACTH (45.4 ± 21.3 vs 70.5 ± 39.1 pg/ml; p=0.04) and urinary free cortisol levels (606.1 ± 512.3 vs 301.0 ± 224.7 μg/day, p=0.01) were significantly lower in patients with adrenal nodules while there were no differences between the groups in terms of dynamic tests results. Post-operative follow-up showed regression or shrinkage of the nodules in 8 out of 10 patients in disease remission. We found that adrenal nodular glands are a frequent finding in CD in particular in older patients and in those with a longerstanding disease. Nevertheless, a high percentage of nodules regression or shrinking was evidenced in our series after disease remission.

BackgroundThe peptide CART is widely expressed in central and peripheral neurons, as well as in endocrine cells. Known peripheral sites of expression include the gastrointestinal (GI) tract, the pancreas, and the adrenal glands. In rodent pancreas CART is expressed both in islet endocrine cells and in nerve fibers, some of which innervate the islets. Recent data show that CART is a regulator of islet hormone secretion, and that CART null mutant mice have islet dysfunction. CART also effects GI motility, mainly via central routes. In addition, CART participates in the regulation of the hypothalamus-pituitary-adrenal-axis. We investigated CART expression in porcine pancreas, GI-tract, adrenal glands, and thyroid gland using immunocytochemistry.ResultsCART immunoreactive (IR) nerve cell bodies and fibers were numerous in pancreatic and enteric ganglia. The majority of these were also VIP IR. The finding of intrinsic CART containing neurons indicates that pancreatic and GI CART IR nerve fibers have an intrinsic origin. No CART IR endocrine cells were detected in the pancreas or in the GI tract. The adrenal medulla harboured numerous CART IR endocrine cells, most of which were adrenaline producing. In addition CART IR fibers were frequently seen in the adrenal cortex and capsule. The capsule also contained CART IR nerve cell bodies. The majority of the adrenal CART IR neuronal elements were also VIP IR. CART IR was also seen in a substantial proportion of the C-cells in the thyroid gland. The majority of these cells were also somatostatin IR, and/or 5-HT IR, and/or VIP IR.ConclusionCART is a major neuropeptide in intrinsic neurons of the porcine GI-tract and pancreas, a major constituent of adrenaline producing adrenomedullary cells, and a novel peptide of the thyroid C-cells. CART is suggested to be a regulatory peptide in the porcine pancreas, GI-tract, adrenal gland and thyroid.

During the staphylococcal infection, changes in the interaction of glandular cells, dystrophic and disorganizing pathologies in tissues, especially acute structural and hemodynamic changes in the stroma of the glands in the pituitary-adrenal-thyroid system, develop from the first day of the experiment. At the end of the experiment, on the background of a decrease in exudative processes, fibroplastic reactions are significantly activated, resulting in signs of incomplete regeneration – mainly sclerotic processes and cystic-atrophic changes in the parenchyma. Structural changes in tissues in the early stages of staphylococcal infection and the dynamics of development are characterized by specific symptoms in each of the glands. Since the pituitary gland is exposed to endogenous and exogenous factors earlier and more often than the adrenal glands, and the adrenal glands are earlier than the thyroid gland, dystrophic and destructive changes in the pituitary and adrenal glands are more pronounced at the early stage of the experiment. These morphological changes can change the hormonal status of the body and lead to dysfunction of the endocrine system as a whole – a decrease in the functional activity of the glands to some extent, and even inhibition of adenohypophyseal cells. Key words: staphylococcal infection, peritonitis, pituitary, adrenal and thyroid glands

Young adult male domestic pigeons were exposed to artificial long photoperiod (LP, 200 watt; 20 hr light, L : 4 hr dark, D), short photoperiod (SP; 4 L : 20 D) and administration of exogenous testosterone propionate (TP) at a daily dose of 1 mg/100 g body weight for 60 consecutive days in primary breeding and regressive phases-I. Administration of TP in LP and SP during primary breeding phase decreased both the adrenal and pineal gland weight. In the TP–LP treatment during breeding phase, adreno-cortical cord width, nuclear diameter of sub-capsular zone (SCZ), central zone (CZ), and pinealocytes decreased significantly. Cholesterol, ascorbic acid level, and side-chain cleavage enzyme (SCC) within the CZ regions also decreased. Lipid granules increased in the SCZ but decreased in the CZ region, and alkaline and acid phosphatases levels increased significantly. Dark and broad cristae and numbers of mitochondria (mt) decreased within the adreno-cortical regions. But lipid droplets and rough endoplasmic reticulum (rER) increased. Large numbers of dark and dead mitochondria and less number of free ribosomes were also found within the pinealocytes cytoplasm. Whereas, in TP–SP treatment groups during breeding phase, weight of adrenal and pineal glands decreased. Alkaline and acid phophatases levels also decreased. But, cholesterol and ascorbic acid level and intensity of lipids droplets increased within the SCZ region. On the other hand, owing to TP–LP treatment during regressive phase-I, weight of adrenal gland, adreno-cortical cord widths, and nuclear diameter of SCZ and CZ regions increased significantly. High intensities of SCC enzymes were found in both the SCZ and CZ regions as well. Lipid droplets and rER decreased but mitochondria increased in the adreno-cortical region. Cholesterol and ascorbic acid level and intensity of lipids droplets in both the SCZ and CZ regions decreased. But alkaline and acid phophatases levels increased. And weight of pineal gland and its nuclear diameter decreased. Here, free ribosomes and the number of mitochondria decreased. In the TP-SP treatment groups, there is no major change within the adrenal gland, adrenocortical regions, and SCC enzymes. Intensity of lipids droplets increased within the CZ region. The nuclear diameters of pinealocytes were smaller than control. Cholesterol and ascorbic acid levels also decreased and alkaline and acid phophatases levels increased when compared to that in control. The number of mitochondria, smooth endoplasmic reticulum (sER), and Golgi complex was the same as in control groups in both the adrenal and pineal glands. But mitochondria and rER increased in both the adrenal and pineal gland cytoplasm. The present studies on the male domestic pigeons clearly indicate that the activities of the adrenal and pineal glands during the regressive phases-I showed a clear relationship with the breeding birds. However, TP treatment in the birds during breeding phases showed some depressive results due to melatonin rhythm like the non-breeding or regressive phase of adult birds.

The ERV3 locus at chromosome 7q11 is a much studied human endogenous retroviral (HERV) sequence, owing to an env open reading frame (ORF) and placental RNA and protein expression. An analysis of the human genome demonstrated that ERV3 is one of a group of 41 highly related elements (ERV3-like HERVs) which use proline, isoleucine, or arginine tRNA in their primer binding sites. In addition to elements closely related to ERV3, the group included the previously known retinoic acid-inducible element, RRHERVI, also referred to as HERV15, but was separate from the related HERV-E elements. The ERV3-like elements are defective. The only element with an ORF among gag, pro, pol, and env genes was the env ORF of the original ERV3 locus. A search in dbEST revealed ERV3 RNA expression in placenta, skin, carcinoid tumor, and adrenal glands. Expression was also studied with newly developed real-time quantitative PCRs (QPCR) of ERV3 and HERV-E(4-1) env sequences. Results from a novel histone 3.3 RNA QPCR result served as the expression control. QPCR results for ERV3 were compatible with previously published results, with a stronger expression in adrenal gland and placenta than in 15 other human tissues. The expression of the envelope (env) of ERV3 at chromosome 7q11 was also studied by using stringent in situ hybridization. Expression was found in corpus luteum, testis, adrenal gland, Hassal's bodies in thymus, brown fat, pituitary gland, and epithelium of the lung. We conclude that ERV3 env is most strongly expressed in adrenal and sebaceous glands as well as in placenta.

Context: Adrenal glands locate at the retroperitoneal space and could be affected their positions by some factors. Adrenal glands being surrounded by visceral adipose tissue (VAT), we have hypothesized that the VAT amount influences the position of adrenal glands in cranial-caudal direction. In patients with primary aldosteronism (PA), comprehending the position of adrenal glands in cranial-caudal direction might be useful to predict the position of adrenal veins before performing adrenal venous sampling.Objectives: To clarify the influence of VAT amount on the position of adrenal glands, we investigated the correlation of visceral fat parameters with the position difference of adrenal glands in cranial-caudal direction in patients with PA.Materials and methods: This retrospective observational study included patients with PA according to the guidelines of both the Japan Endocrine Society and the Japan Society of Hypertension. Those with adrenal tumors more than 10 mm in diameter in computed tomography (CT) were excluded. We measured the position difference of the adrenal glands in cranial-caudal direction, from the top of right adrenal gland to the top of left adrenal gland by CT. We correlated visceral fat percentage (VF%), visceral fat area (VFA), and subcutaneous fat area (SCFA) evaluated by CT studies with the position difference of adrenal glands in cranial-caudal direction.Results: We analyzed 150 patients [male (n = 50), female (n = 100)]. Patients’ characteristics: Age was 54.8 ± 11.4, body mass index 24.9 ± 3.8 kg/m2, plasma aldosterone concentration 133.5 [101–176] pg/ml, plasma renin activity 0.3 [0.2–0.5] ng/ml/h, VF% 25.8 [19.8–33.6] %, VFA 88.3 [60.9–125.0] cm2, and SCFA was 147.4 [105.6–193.4] cm2 (mean ± SD, or median [interquartile range]). The position difference of adrenal glands in cranial-caudal direction was 9.7 ± 10.0 mm. In 120 patients (80.0%), left adrenal glands locate at the upper position comparing to right adrenal glands. In 19 patients (12.7%), right adrenal glands were positioned at the upper comparing to left adrenal glands. A positive correlation of VF%, VFA with the position difference of adrenal glands in cranial-caudal direction were shown (r = 0.451, p < 0.001, r = 0.426, p < 0.001, respectively). No significant correlation of SCFA with the position difference of adrenal glands in cranial-caudal direction was shown (r = 0.122, p = 0.139). In patients with more VAT amount, right adrenal glands locate at the upper position comparing to left adrenal glands. In patients with less VAT amount, left adrenal glands locate at the upper position comparing to right adrenal glands.Conclusions: Regardless of the variation of the position of adrenal gland on each side, the correlation was found between VAT and the position difference of adrenal glands in cranial-caudal direction in PA.

COVID-19 targets human adrenal glands