Zona Fasciculata Research Articles

Steroid Sulfation in Neurodegenerative Diseases.

Steroid sulfation and desulfation participates in the regulation of steroid bioactivity, metabolism and transport. The authors focused on sulfation and desulfation balance in three neurodegenerative diseases: Alzheimer´s disease (AD), Parkinson´s disease (PD), and multiple sclerosis (MS). Circulating steroid conjugates dominate their unconjugated counterparts, but unconjugated steroids outweigh their conjugated counterparts in the brain. Apart from the neurosteroid synthesis in the central nervous system (CNS), most brain steroids cross the blood-brain barrier (BBB) from the periphery and then may be further metabolized. Therefore, steroid levels in the periphery partly reflect the situation in the brain. The CNS steroids subsequently influence the neuronal excitability and have neuroprotective, neuroexcitatory, antidepressant and memory enhancing effects. They also exert anti-inflammatory and immunoprotective actions. Like the unconjugated steroids, the sulfated ones modulate various ligand-gated ion channels. Conjugation by sulfotransferases increases steroid water solubility and facilitates steroid transport. Steroid sulfates, having greater half-lives than their unconjugated counterparts, also serve as a steroid stock pool. Sulfotransferases are ubiquitous enzymes providing massive steroid sulfation in adrenal zona reticularis and zona fasciculata.. Steroid sulfatase hydrolyzing the steroid conjugates is exceedingly expressed in placenta but is ubiquitous in low amounts including brain capillaries of BBB which can rapidly hydrolyze the steroid sulfates coming across the BBB from the periphery. Lower dehydroepiandrosterone sulfate (DHEAS) plasma levels and reduced sulfotransferase activity are considered as risk factors in AD patients. The shifted balance towards unconjugated steroids can participate in the pathophysiology of PD and anti-inflammatory effects of DHEAS may counteract the MS.

Hiponatremia em ovinos no Nordeste do Brasil

ABSTRACT: Mineral deficiencies are important causes of productive losses in ruminant farming, especially in semiarid regions. This study aimed to determine Na, K, and Cl serum concentrations, plus the salivary concentrations of Na and K in sheep raised in a semiarid region of Northeastern Brazil, and to report the epidemiology, clinical and the pathological aspects of an outbreak of hyponatremia in sheep. For this, serum and salivary samples of 55 sheep were collected in 6 different farms in the region. Na, K, and Cl concentrations were determined by colorimetric test, using commercial kits in a semi-automatic biochemical analyzer. The mean serum concentrations ranged from 131.5±13.1mEq/L to 172.4±9.3mEq/L for Na, 6.28±1.3mEq/L to 13.9±1.4mEq/L for K, and 91.6±54.8mEq/L to 113.6±1.5mEq/L for Cl. The mean salivary concentrations ranged from 119.4±9.5mEq/L to 161.8±15.2mEq/L for Na, 10.1±3.1mEq/L to 22.3±2.3mEq/L for K, and the ratio Na:K ranged from 6.0±1.3mEq/L to 11.8±4.1mEq/L. These results revealed that most sheep raised in the farms in this region are marginally depleted in sodium. In one farm, sheep had severe clinical signs of Na deficiency consisting of haggard appearance, craving for salt, polydipsia, polyuria, dry cough, inappetence, pica, weakness, difficulty to rise and move, severe emaciation, and dehydration. On autopsy, the ruminal content was generally impacted, giving to the content an aspect of clay balls. Four sheep presented hypertrophy of the adrenal glands. Histopathologically, the width of the zona glomerulosa was expanded, there was loss of the architecture and loss of adrenocortical cell cords. The epithelial cells in the zona glomerulosa and fasciculata were pyramidal, and contained hypereosinophilic cytoplasm and hyperchromatic nuclei. These data demonstrate the occurrence of Na deficiency in different degrees in sheep farms in the State of Pernambuco and highlight the importance of providing NaCl to avoid outbreaks of hyponatremia.

A Chronic-Low-Dose Exposing of DEHP with OECD TG 443 Altered the Histological Characteristics and Steroidogeic Gene Expression of Adrenal Gland in Female Mice.

Phthalates and their metabolites are well-known endocrine disrupting chemicals. Di-(2-ethylhexyl) phthalate (DEHP) has been widely used in industry and the exposing possibility to adult is high. In this study, DEHP was treated (133 μg/L and 1,330 μg/L in drinking water) according to the OECD test guideline 443 to mature female mice and their adrenal gland were examined for histological characteristics and steroidogenic gene expression. The wet weight of the adrenal gland was increased in all administrated groups compared to control. The diameter of zona fasciculata (ZF) was increased by DEHP in both outer ZF and inner ZF but there was no difference in morphology of the cells and arrangements into zona between groups. In addition, the arrangement of extracellular matrix was not different between control and DEHP groups. CYP11B1 was mainly localized at ZF and the intensity was not different between groups. DAX1 was localized in zona glomerulosa (ZG) and ZF, and its expression levels were decreased by DEHP administration. Its level was lower in DEHP133 group than DEHP1330 group. On the other hand, CYP17A1 was localized in ZG of DEHP1330 group. These results suggest that chronic low-dose DEHP exposing may modify the microstructure and function of the adrenal cortical cortex.

Effect of induced hepatic ischemia–reperfusion on the adrenal cortex of adult male albino rats and the possible protective role of L-arginine: Biochemical, histological and immunohistochemial study

Hepatic ischemia reperfusion injury (IRI) takes place through liver transplantation. Hepatic IRI might seriously affect liver function and is reported to be accountable for 15 % of organ failure and could result in multi-organ dysfunction syndrome (MODS) that lead to high rates of morbidity and mortality. L-arginine (L-Arg) could reduce hepatic IRI via different mechanisms Objective: To estimate the effect of hepatic ischemic reperfusion (I/R) and the possible protective effect of L-Arg. on the adrenal cortex. Materials & Methods: Thirty two albino rats were utilized in the current work. The animals split to Sham-Operation, L-Arg , ischemic reperfusion, I/R group and I/R and L-Arg group. Then, at the assigned time, blood samples were assembled for biochemical study. Histological and immunohistochemical studies were performed on the adrenal tissueResults: The adrenal cortex of I/R group exhibited architecture loss of the three zones. Zona glomerulosa cells showed small pyknotic nuclei and vacuolated cytoplasm. Zona fasciculata cells appeared ballooned with small pyknotic nuclei. Also, karyolitic nuclei were seen. zona reticularis cells showed pyknotic nuclei and vacuolated cytoplasm and separated by congested blood sinusoids. Hyaline material depositions were seen. Biochemical study revealed a marked increase in serum levels of liver enzymes, excess in the MDA level and a marked reduction in the CAT level compared to control group. These changes were ameliorated by L-Arg.Conclusion: hepatic I/R has been proved to induce histological changes of the adrenal cortex which could be ameliorated by administration of L-Arg. Therefore, For inhibiting or reducing hepatic IRI through liver surgery, an effective method is urgently required.

Dichlorodiphenyltrichloroethane and the Adrenal Gland: From Toxicity to Endocrine Disruption.

Endocrine disruptors are exogenous compounds that pollute the environment and have effects similar to hormones when inside the body. One of the most widespread endocrine disruptors in the wild is the pesticide dichlorodiphenyltrichloroethane (DDT). Toxic doses of DDT are known to cause cell atrophy and degeneration in the adrenal zona fasciculata and zona reticularis. Daily exposure in a developing organism to supposedly non-toxic doses of DDT have been found to impair the morphogenesis of both the cortex and the medulla of the adrenal glands, as well as disturbing the secretion of hormones in cortical and chromaffin cells. Comparison of high and very low levels of DDT exposure revealed drastic differences in the morphological and functional changes in the adrenal cortex. Moreover, the three adrenocortical zones have different levels of sensitivity to the disruptive actions of DDT. The zona glomerulosa and zona reticularis demonstrate sensitivity to both high and very low levels of DDT in prenatal and postnatal periods. In contrast, the zona fasciculata is less damaged by low (supposedly non-toxic) exposure to DDT and its metabolites but is affected by toxic levels of exposure; thus, DDT exerts both toxic and disruptive effects on the adrenal glands, and sensitivity to these two types of action varies in adrenocortical zones. Disruptive low-dose exposure leads to more severe affection of the adrenal function.

Histological, transmission electron microscopic, and immunohistochemical study of the adrenal gland in the Persian squirrel (Sciurus anomalus).

This research was aimed to present the histological and ultrastructure properties of the adrenal gland in the Persian squirrel. Two male and female animals were included in the study. The adrenal gland was bean-shaped and located on the cranial pole of kidney. The enveloping capsule was dense connective tissue that reacted positively with Periodic-Acid Schiff (PAS) and Masson trichrome stainings. The parenchyma of the gland consisted of two-part, namely cortex and medulla; the cortex had three layers: zona glomerulosa (ZG), zona fasciculata (ZF), and zona reticularis (ZR). The cells of the ZG were mainly spherical and ovoid with circular arrangement and few lipid droplets in TEM micrographs. The cells of the ZF were columnar and spherical that were arranged in cord-like rows. Transmission electron microscopy (TEM) indicated conspicuous lipid droplets and mitochondria in this zone. The cells of the ZR were arranged in a tangled networks and were almost similar to those in the ZF. TEM images showed fewer lipid vesicles in the ZR compared to the ZF and ZG. Chromaffin cells were located in the medulla of the adrenal gland in two layers. TEM images showed that some of them were smaller and contained fewer secretory granules; other cells were larger and contained more electron-dense secretory granules. Immunofluorescence staining showed that steroidogenic factor 1 (SF1) expressed from cortex to the corticomedullary junction (CMJ) and tyrosine hydroxylase (TH) expressed in the medulla. In conclusion, the results indicated both similarities and differences between the adrenal gland of the Persian squirrel and other animals such as mammals and rodents.

Effects of castration on IFN-γ and TNF-α expression in the adrenal gland of Angora goat

In the adrenal gland, there is a mutual interaction between the cells in the cortex and medulla and the cells of the immune system. Sex hormones regulate immune cell functions as well as reproductive and metabolic processes throughout life. Interferon-gamma (IFN-γ) is a cytokine that regulates the maturation and differentiation of many cell types. Tumor necrosis factor-alpha (TNF-α) is a multifunctional cytokine that plays an important role in various physiological and pathophysiological processes and orchestrates cytokines. This study was conducted to investigate the effects of castration on the expression of IFN-γ and TNF-α in the adrenal gland of Angora goat. A total of 16 Angora goat kids were used as material for the study. Healthy animals were selected for the study by clinical examination. At an average age of 75 days, eight animals were randomly selected from the institute herd and castrated. 85 days after castration (after approximately 160 days old), eight control and eight castrated Angora goats were slaughtered and their adrenal glands were removed. In the analysis of each group, IFN-γ expression was found in the cytoplasm of cells in the adrenal cortex and medulla. The adrenal glands of the castrated group showed a decrease in IFN-γ expression in the zona fasciculata. A distinct brown staining was seen in the cytoplasm of TNF-α-positive responsive secretory cells. TNF-α expression was found to be increased in the zona glomerulosa, zona fasciculata and zona reticularis of the adrenal gland in the castrated group. Accordingly, androgen hormone deficiency was able to increase TNF-α expression, whereas it did not significantly affect IFN-γ expression in the adrenal tissue of the Angora goat.

Obesogenic and histopathological effect of monosodium glutamate on the adrenal gland of maternal and postnatal albino rats

Monosodium glutamate (MSG) is a flavoring food additive that’s found in many foods like chips, and fast foods. The aim of this study was to demonstrate the injurious effects of MSG on the adrenals of the female albino rats and its potentiality to cross the placental barrier carrying its injurious effects to their pups. Twenty-five female albino rats weighing about (200) g were mated then separated into two groups. The control group (10 rats), and MSG-treated Group(15 rats) received 10 g/kg MSG orally, dissolved in water at a concentration of 5 g/100 ml, starting on day 7 to 20 day of gestation.A day after delivery, animals were weighed, blood samples collected then sacrificed, and the adrenals were collected and examined by the light and electron microscope. Statistically, there was a significant increase in the body weight and decrease in adrenal weight of MSG-treated mothers and their pups, as well as a decrease in the corticosterone level in MSG-treated mothers. Histologically, MSG-treated mothers and pups showed many degenerative changes, with thinning of the capsule that was confirmed by Masson trichrome stain, a disorganized structure of Zona Golmeruloza and Zona Fasciculata, and areas of shedding and hemorrhage were noticed. Shrunken nuclei and degenerated mitochondria with disrupted cristae and penetration of the lipid droplets to form “myelin-like” structures were noticed by E/M examination. The study concluded that MSG had an unwholesome effect on the structure of the adrenal tissue of both pregnant rats and their pups

Microscopic features of the rat adrenal gland associated with chronic codeine phosphate administration.

Codeine is an opioid analgesic and antitussive that has been widely abused. Some adverse effects noted with its abuse include adrenocortical insufficiency and activation of the hypothalamic-pituitary-adrenal axis. The structural basis for these dysfunctions is not clearly understood. Twenty-five adult male rats were used for the study. They were divided into intervention and control groups that were administered 40 mg/kg of codeine phosphate and normal saline respectively by gavage daily for 50 days. Subsequently, both groups were given normal saline for a further fourteen days to note recovery changes. At day 0, 50 and 64, rats were randomly selected from both groups, euthanized and adrenal glands harvested for histological processing and analysis. At day 50 of codeine administration, the adrenal glands demonstrated an increase in zona fasciculata thickness but a decrease in zona reticularis thickness. Lower values were noted in the volume density of zona reticularis and cells count of the medulla in the experimental compared to the control groups (P-value<0.05). The experimental group also showed an increase in vascularization and connective tissue in the glands. After 14 days of recovery, most of the changes observed in experimental animals were reversed and the adrenal glands in both groups had similar features. A decrease in cell count of the adrenal medulla was however observed (P-value<0.05). In conclusion administration of codeine phosphate causes discernible changes in the microscopic structure of the adrenal gland, most of which appear to be reversed after two weeks recovery period.

Effects of Estrogen and Exercise Stress on Adrenal Glands of Male Rats

Consciously done exercises are beneficial for human health. However, unconscious and wrong practices (medication use, etc…) can cause various injuries and permanent damage to the human body. For reasons such as increasing muscle mass and/or to getting more performance, taking steroid hormones disrupts overall body hormone balance. Effects of exercise on oxygen and energy metabolism and estrogen as an exogenous steroid have significant effects on the adrenal gland. The aim of this study was to see the effects of 17b-estradiol on surrenal glands of rats that is put through regular physical exercises.&#x0D; 36 male Sprague-Dawley rats between the weights 220-250 gr, were put into thermal-controlled room with day-night cycles to stimulate an optimal day for the subjects. The experiment was modeled by dividing 36 animals into 6 groups in total according to the control, exercising and estrogen administration criteria. Experimental group animals received daily doses of 10 μg/kg/day 17-β-estradiol during 30 days. Also exercises group animals ran at 20 m/min on a 15% grade for 90 minutes and rest 34 minutes. Then, TUNNEL and Hematoxylen &amp; Eosin staining were performed to measure the damage on the adrenal glands.&#x0D; In group 2, dense presence of degenerative fibroblasts and inflammatuary cells infiltration in zona fasciculata were significantly different. In group 3, the degenerative areas were significant in all adrenal cortex zones. In group 4, necrotic areas were determined in zona reticularis. In group 5, zona fasciculata was severely degenerated. With group 6, Sinusoidal features were completely lost in zona reticularis. The results strongly show that exercise may affect the zona glomerulase in short time period. As a result, exposure to exercise and exercise stress with external administration of estradiol may cause cellular degeneration especially zona fasciculata and zona reticularis in the adrenal gland.

Cellular Senescence in Human Aldosterone-Producing Adrenocortical Cells and Related Disorders.

In situ cortisol excess was previously reported to promote cellular senescence, a cell response to stress, in cortisol-producing adenomas (CPA). The aim of this study was to explore senescence pathways in aldosterone-producing cells and related disorders, and the influence of aldosterone overproduction on in situ senescence. We analyzed 30 surgical cases of aldosterone-producing adenoma (APA), 10 idiopathic hyperaldosteronism (IHA) and 19 normal adrenals (NA). CYP11B2 and senescence markers p16 and p21 were immunolocalized in all those cases above and results were correlated with histological/endocrinological findings. In the three cohorts examined, the zona glomerulosa (ZG) was significantly more senescent than other corticosteroid-producing cells. In addition, the ZG of adjacent non-pathological adrenal glands of APA and IHA had significantly higher p16 expression than adjacent non-pathological zona fasciculata (ZF), reticularis (ZR) and ZG of NA. In addition, laboratory findings of primary aldosteronism (PA) were significantly correlated with p21 status in KCNJ5-mutated tumors. Results of our present study firstly demonstrated that non-aldosterone-producing cells in the ZG were the most senescent compared to other cortical zones and aldosterone-producing cells in PA. Therefore, aldosterone production, whether physiological or pathological, could be maintained by suppression of cell senescence in human adrenal cortex.

Human Adrenal Cortical Zone Changes With Aging

Background: Previous adrenal morphological studies have shown that the zona reticularis (ZR) and the zona glomerulosa (ZG) decrease in size with aging. Although several lines of evidence indicate that the hypothalamic-pituitary-adrenal axis becomes hyperactive in elderly, little is known about age-related transformations of the adrenal zona fasciculata (ZF). Objectives: To investigate the morphological and functional changes of the adrenal cortex across the adult life span, with emphasis on: 1) the understudied ZF, and 2) potential sexual dimorphisms. Methods: We used immunohistochemistry to evaluate the expression of several cortical proteins: aldosterone synthase (CYP11B2), visinin-like protein 1 (VSNL1), 3β-hydroxysteroid dehydrogenase type II (HSD3B2), 11β-hydroxylase (CYP11B1) and cytochrome b5 type A (CYB5A). The ZF area was estimated by subtracting the VSNL1-positive (a ZG marker) area from the HSD3B2-expressing area (ZG and ZF). All captured images were quantitated by ImageJ. In addition, we employed liquid chromatography-tandem mass spectrometry to quantify the morning serum concentrations of 6 steroids: cortisol, 11-deoxycortisol (11dF), 17α-hydroxyprogesterone (17OHP4), 11-deoxycorticosterone (DOC), corticosterone, and androstenedione (A4). The Mann-Whitney U test and Spearman’s rank correlation coefficients were used for statistical analysis, as appropriate. Results: We included 60 adrenal glands from 30 men and 30 women, with ages between 18–86 years. The total cortical area was positively correlated with age (r=0.34, p=0.008), and this association was significant only in men (p=0.02). Both the total (VSNL1-positive) and functional ZG (CYP11B2-positive) areas declined abruptly with aging in men (r=-0.57 and -0.76, p=0.001 and p<0.0001, respectively), but not women (p=0.06 and 0.27, respectively). The CYB5A-positive area, marking the ZR, correlated negatively with age (r=-0.76, p<0.0001) in both sexes. In contrast, the estimated ZF area showed a strong positive correlation with age both in men (r=0.59, p=0.0006) and women (r=0.49, p=0.007), while CYP11B1-positive area remained stable across ages (p=0.86). Finally, we measured morning levels of 6 steroids in 149 men and 149 women, with ages between 21–95 years, matched for age and body mass index. Serum cortisol, corticosterone, and DOC levels remained relatively stable across ages (p=0.38, 0.64 and 0.25, respectively), while 11dF levels increased slightly with age (r=0.16 and p=0.007), particularly so in men (p=0.005). Expectedly, 17OHP4 and A4 declined with aging (r=-0.37 and -0.37, p<0.0001 for both). Conclusions: In contrast with the ZG and ZR, the ZF and the total adrenal cortex area enlarge with aging. An abrupt decline of the ZG occurs with age in men, but not in women, possibly contributing to sexual dimorphism in cardiovascular risk.

The Functional Glomerulosa Cells Define the Unicity of the Adult Human Adrenal Cortex

Abstract The zonation of the human adrenal cortex has long been established morphologically and histologically as three distinct layers of cells. The outer zona glomerulosa (ZG) comprises densely packed cells arranged in clusters that produce aldosterone; the zona fasciculata (ZF) is composed of cells with large cytoplasm, containing lipid droplets arranged in radial columns that synthetize cortisol; and the zona reticularis is composed of compact and pigmented cells producing androgens. The main purpose of this work was to study the expression of aldosterone synthase (CYP11B2 which catalyzes the last steps of aldosterone synthesis) and 11β-hydroxylase (CYP11B1 which catalyzes the last step of cortisol synthesis) in normal adrenal glands to address issues regarding the zonation and the fate of the cells constitutive of each zone through the expression of Ki-67 and cleaved Caspase-3. Thirty eight normal human adrenals (16 females, 22 males, ranging in age from 22 to 81 years old with a median age of 52 years old) were obtained from brain-dead organ donors (kindly provided by the Organ Transplant Clinics, University Hospital of Rouen). As early as 22 years old, we found that the histological ZG (h-ZG) does not correspond to the functional ZG (f-ZG) expressing CYP11B2. Moreover, the h-ZG CYP11B2- cells were CYP11B1+ showing that these cells ascribed to the h-ZG are in fact cortisol producing cells. The progressive replacement of CYP11B2+ cells by CYP11B1+ cells in the h-ZG might demonstrate the role of the extracellular matrix in the morphological maintenance of the adrenal cortex. Our analysis also showed that steroidogenic cells were either CYP11B1 or CYP11B2 positive. By immunofluorescence, we observed in many cases isolated or clusters of CYP11B2+ cells located deeply in the h-ZF and sometimes in the vicinity of the central vein. We were able to show that those cells were probably issued from CYP11B2+ cell clusters located in h-ZG which migrated centripetally. Ki-67 immunoreactivity was highly variable and observed throughout the entire cortex. We also found a positive correlation between the steroidogenic and endothelial cells proliferation. It is interesting to note that some Ki-67+ cells located in the h-ZG were CYP11B1+. Cortical cells positive for cleaved Caspase-3 were extremely rare but detected in all zones when present. These findings challenge the classic view of lineage conversion of differentiated ZG cells and show a new pathway where the CYP11B2+ cells migrate without changing their phenotype.

Mechanisms for establishment of GABA signaling in adrenal medullary chromaffin cells.

γ-Aminobutyric acid (GABA) is thought to play a paracrine role in adrenal medullary chromaffin (AMC) cells. Comparative physiological and immunocytochemical approaches were used to address the issue of how the paracrine function of GABA in AMC cells is established. GABAA receptor Cl- channel activities in AMC cells of rats and mice, where corticosterone is the major glucocorticoid, were much smaller than those in AMC cells of guinea-pigs and cattle, where cortisol is the major. The extent of enhancement of GABAA receptor α3 subunit expression in rat pheochromocytoma (PC12) cells by cortisol was larger than that by corticosterone in parallel with their glucocorticoid activities. Thus, the species difference in GABAA receptor expression may be ascribed to a difference in glucocorticoid activity between corticosterone and cortisol. GABAA receptor Cl- channel activity in mouse AMC cells was enhanced by allopregnanolone, as noted with that in guinea-pig AMC cells, and the enzymes involved in allopregnanolone production were immunohistochemically detected in the zona fasciculata in both mice and guinea pigs. The expression of glutamic acid decarboxylase 67 (GAD67), one of the GABA synthesizing enzymes, increased after birth, whereas GABAA receptors already developed at birth. Stimulation of pituitary adenylate cyclase-activating polypeptide (PACAP) receptors, but not nicotinic or muscarinic receptors, in PC12 cells, resulted in an increase in GAD67 expression in a protein-kinase A-dependent manner. The results indicate that glucocorticoid and PACAP are mainly responsible for the expressions of GABAA receptors and GAD67 involved in GABA signaling in AMC cells, respectively.

Cellular mechanisms of impaired mineralocorticoid and glucocorticoid production by endocrine disruptor DDT

Developmental exposure to persistent endocrine disruptors is of a great concern. Affection of adrenal hormones production by low-dose exposure to dichlorodiphenyltrichloroethane (DDT) has been revealed recently. Objective of the research – investigation of ultrastructural mechanisms of impaired mineralocorticoid and glucocorticoid production after prenatal and postnatal exposure to endocrine disruptor DDT. Male Wistar rats exposed to low doses of DDT during prenatal and postnatal development were studied. Aldosterone and corticosterone levels in serum were measured by enzyme-linked immunosorbent assay, histological examination and electron microscopy of the adrenals were performed. Pubertal rats, developmentally exposed to low doses of DDT, demonstrated lowered aldosterone and elevated corticosterone serum levels. After puberty the rats showed tendency to normalization of hormones’ production. Morphological examination of the adrenals revealed less developed zona glomerulosa in pubertal period and its relative hyperplasia after puberty. Microcirculatory disorders and focal cell death were observed in outer zona fasciculata. Electron microscopy of glomerulosa cells found signs of suppressed secretory activity in pubertal period and no significant reduction of mitochondria size in adult rats. Total number of mitochondria in 1 µm2 of cytoplasm and percent of mitochondria with swollen matrix were diminished compared to the control. Cells of inner zona fasciculata demonstrated increased functional activity. Age-dependent changes in fine structure of fasciculata cells were similar to the control, but were more pronounced. In this way, cellular mechanism of impaired mineralocorticoid production in rats prenatally and postnatally exposed to low doses of endocrine disruptor DDT, are insufficient mitochondrion function and impaired reorganization of mitochondrial apparatus, which occurs during pubertal period. Mechanisms of elevated glucocorticoid secretion are attributed to enhanced function of mitochondria in fasciculata cells.

Adrenal cortex development and related disorders leading to adrenal insufficiency

The adult human adrenal cortex produces steroid hormones that are crucial for life, supporting immune response, glucose homeostasis, salt balance and sexual maturation. It consists of three histologically distinct and functionally specialized zones. The fetal adrenal forms from mesodermal material and produces predominantly adrenal C19 steroids from its fetal zone, which involutes after birth. Transition to the adult cortex occurs immediately after birth for the formation of the zona glomerulosa and fasciculata for aldosterone and cortisol production and continues through infancy until the zona reticularis for adrenal androgen production is formed with adrenarche. The development of this indispensable organ is complex and not fully understood. This article gives an overview of recent knowledge gained of adrenal biology from two perspectives: one, from basic science studying adrenal development, zonation and homeostasis; and two, from adrenal disorders identified in persons manifesting with various isolated or syndromic forms of primary adrenal insufficiency.

The Age-Dependent Changes of the Human Adrenal Cortical Zones Are Not Congruent.

While previous studies indicate that the zonae reticularis (ZR) and glomerulosa (ZG) diminish with aging, little is known about age-related transformations of the zona fasciculata (ZF). To investigate the morphological and functional changes of the adrenal cortex across adulthood, with emphasis on (i) the understudied ZF and (ii) sexual dimorphisms. We used immunohistochemistry to evaluate the expression of aldosterone synthase (CYP11B2), visinin-like protein 1 (VSNL1), 3β-hydroxysteroid dehydrogenase type II (HSD3B2), 11β-hydroxylase (CYP11B1), and cytochrome b5 type A (CYB5A) in adrenal glands from 60 adults (30 men), aged 18 to 86. Additionally, we employed mass spectrometry to quantify the morning serum concentrations of cortisol, 11-deoxycortisol (11dF), 17α-hydroxyprogesterone, 11-deoxycorticosterone, corticosterone, and androstenedione in 149 pairs of age- and body mass index-matched men and women, age 21 to 95 years. The total cortical area was positively correlated with age (r = 0.34, P = 0.008). Both the total (VSNL1-positive) and functional ZG (CYP11B2-positive) areas declined with aging in men (r = -0.57 and -0.67, P < 0.01), but not in women. The CYB5A-positive area declined with age in both sexes (r = -0.76, P < 0.0001). In contrast, the estimated ZF area correlated positively with age in men (r = 0.59, P = 0.0006) and women (r = 0.49, P = 0.007), while CYP11B1-positive area remained unchanged across ages. Serum cortisol, corticosterone, and 11-deoxycorticosterone levels were stable across ages, while 11dF levels increased slightly with age (r = 0.16, P = 0.007). Unlike the ZG and ZR, the ZF and the total adrenal cortex areas enlarge with aging. An abrupt decline of the ZG occurs with age in men only, possibly contributing to sexual dimorphism in cardiovascular risk.

The Comprehensive Morphological Criteria for the Diagnosis of Subclinical Bacterial Maternal-Fetal Infection in Offspring

The paper presents study materials devoted to determining the morphofunctional state of progeny’s organs developed under subclinical bacterial maternal-fetal infection (MFI) in order to define the comprehensive diagnostic criteria of this pathology. The rat models of subclinical MFI caused separately by E. coli, S. aureus, and K. pneumoniae were used, the set of diagnostic tools (histopathological staining of paraffin sections of aorta (AO), pulmonary artery (PA), thyroid (TG), and adrenal glands (AG), liver (LV) of fetuses with H&amp;E, Mallory’s trichrome and Van Gieson's methods, optical microscopy, morphometry, and immunofluorescence with the use of ImageJ software) was applied. Statistical analysis was performed in Microsoft Excel 365 and R. Depending on the organ, the null hypothesis was rejected when p&lt;0.05 or p&lt;0.001. The assemblage of statistically significant diagnostic parameters of the subclinical MFI damaging effect in offspring’s organism was determined: for AO and PA – endotheliocyte’s height, the optical density of fluorescence (ODF) of CD34-positive cells, type III and IV collagens; for TG – thyrocyte’s height, nuclear-cytoplasmic ratio (NCR), follicle’s square, T4 OD; for AG – adrenocorticocytes’ density in zona glomerulosa, adrenocorticocyte’s NCR, cortisol ODF in zona fasciculata; for LV - hepatocytes’ density, NCR, the absolute number of IL-6 producing cells. Conclusion: in this study, we have proved the presence of pathomorphological substrate and defined dynamics of morphofunctional changes forming in the fetal organism under the bacterial MFI that enables the use of obtained values as diagnostic criteria of this pathology.

The Adrenal Cortex, an Underestimated Site of SARS-CoV-2 Infection.

BackgroundThe majority of the critically ill patients may have critical illness-related corticosteroid insufficiency (CIRCI). The therapeutic effect of dexamethasone may be related to its ability to improve cortical function. Recent study showed that dexamethasone can reduce COVID-19 deaths by up to one third in critically ill patients. The aim of this article is to investigate whether SARS-CoV-2 can attack the adrenal cortex to aggravate the relative adrenal insufficiency.MethodsWe summarized the clinical features of COVID-19 reported in currently available observational studies. ACE2 and TMPRSS2 expression was examined in human adrenal glands by immunohistochemical staining. We retrospectively analyzed serum cortisol levels in critically ill patients with or without COVID-19.ResultsHigh percentage of critically ill patients with SARS-COV-2 infection in the study were treated with vasopressors. ACE2 receptor and TMPRSS2 serine protease were colocalized in adrenocortical cells in zona fasciculata and zona reticularis. We collected plasma cortisol concentrations in nine critically ill patients with COVID-19. The cortisol levels of critically ill patients with COVID-19 were lower than those in non-COVID-19 critically ill group. Six of the nine COVID-19 critically ill patients had random plasma cortisol concentrations below 10 µg/dl, which met the criteria for the diagnosis of CIRCI.ConclusionWe demonstrate that ACE2 and TMPRSS2 are colocalized in adrenocortical cells, and that the cortisol levels are lower in critically ill patients with COVID-19 as compared to those of non-COVID-19 critically ill patients. Based on our findings, we recommend measuring plasma cortisol level to guide hormonal therapy.

СТРУКТУРНО-ФУНКЦИОНАЛЬНЫЕ ПРОЯВЛЕНИЯ ОСТРОГО И ХРОНИЧЕСКОГО ГРАВИТАЦИОННОГО СТРЕССА В НАДПОЧЕЧНИКЕ

Optical and electron microscopy, quantitative cytochemistry and morphometric analysis were used to look into structural and functional transformations in the bloodstream, adrenal cortex corticosterocytes and adrenal brain cells in consequence of exposure to modeled acute and chronic gravitational stresses (AGS and CGS respectively). AGS caused adrenal hyperemia, hypertrophy of the zona fasciculata, elevated activity of enzymes involved in mitochondrial and extramitochondrial oxidation, and secretion of undissolved catecholamine granules in the capillary bloodstream. CGS depressed mitochondrial oxidation, activated glycolysis, produced destructive changes in corticosteroids, and LED lipid droplets in capillary lumen. From capillaries the fat droplets traveled further to the brain sinusoids where they deposited together with blood corpuscles (erythrocytes primarily) and formed microcirculation impairing microemboli. Thereupon we assume that the source of lipid droplets under the full-strength gravitational stress is intermediate products of corticoid synthesis in conditions of mitochondria destruction and disturbed mitochondrial metabolism in cells of the fasciculata and glomerulosa zones.