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Concept: Adrenal gland

171

Most species living in temperate zones adapt their physiology and behavior to seasonal changes in the environment by using the photoperiod as a primary cue. The mechanisms underlying photoperiodic regulation of stress-related functions are not well understood. In this study, we analyzed the effects of photoperiod on the hypothalamic-pituitary-adrenal axis in photoperiod-sensitive Fischer 344 rats. We first examined how photoperiod affects diurnal variations in plasma concentrations of adrenocorticotropic hormone (ACTH) and corticosterone. ACTH levels did not exhibit diurnal variations under long- and short-day conditions. On the other hand, corticosterone levels exhibited a clear rhythm under short-day condition with a peak during dark phase. This peak was not observed under long-day condition in which a significant rhythm was not detected. To analyze the mechanisms responsible for the photoperiodic regulation of corticosterone rhythms, ACTH was intraperitoneally injected at the onset of the light or dark phase in dexamethasone-treated rats maintained under long- and short-day conditions. ACTH induced higher corticosterone levels in rats examined at dark onset under short-day condition than those maintained under long-day condition. Next, we asked whether melatonin signals are involved in photoperiodic regulation of corticosterone rhythms, and rats were intraperitoneally injected with melatonin at late afternoon under long-day condition for 3 weeks. However, melatonin injections did not affect the corticosterone rhythms. In addition, photoperiodic changes in the amplitude of corticosterone rhythms were also observed in melatonin-deficient C57BL/6J mice, in which expression profiles of several clock genes and steroidgenesis genes in adrenal gland were modified by the photoperiod. Our data suggest that photoperiod regulates corticosterone rhythms by altered adrenal sensitivity through melatonin-independent mechanisms that may involve the adrenal clock.

Concepts: Adrenocorticotropic hormone, Circadian rhythm, Adrenal gland, ACTH stimulation test, Cortisol, Anterior pituitary, Hypothalamus, Adrenal cortex

151

The purpose of this prospective study was to establish the ultrasonographic characteristics of the dimension of the right pancreatic lobe with that of the associated anatomic landmarks in healthy dogs. Ultrasonographic examinations were performed on 25 dogs. The thickness of the right pancreatic lobe was compared with that of mural thickness of duodenum, diameters of duodenum, pancreatic duct, abdominal aorta, portal vein, caudal vena cava, and length and width of the right kidney and right adrenal gland. The correlation between each pancreatic parameter and the dimensions of the anatomical landmarks were assessed using linear regression analysis and Pearson’s correlation coefficient ® test. Significant, but weak linear correlations were observed between thickness of right pancreatic lobe with that of duodenum mural thickness (r=0.605, R(2)=0.339, P=0.001); duodenum diameter (r=0.573, R(2)=0.299, P=0.003); and right adrenal gland length (r=0.508, R(2)=0.052, P=0.01). There was no significant dimensional relationship with other selected anatomic landmarks. The ratio between the thickness of right pancreatic lobe and the mural thickness of duodenum, diameter of duodenum and length of right adrenal gland were 2.88 ± 0.53, 1.27 ± 0.27, and 0.81 ± 0.15, respectively. Calculating the ratio of thickness of the right pancreatic lobe with the dimension of significantly correlated anatomic landmarks is a useful and simple method for evaluating the size of the right pancreatic lobe in dogs in clinical practice.

Concepts: Kidney, Abdominal aorta, Covariance and correlation, Adrenal gland, Pancreas, Spearman's rank correlation coefficient, Correlation and dependence, Pearson product-moment correlation coefficient

28

Patients with Congenital adrenal hyperplasia due to partial deficiency in the enzyme 21-hydroxlyase can present in childhood or adolescence with signs of adrenal androgen excess. Strategies to reduce the impact of androgen excess in females include cosmetic measures as well as antiandrogens and agents such as the combined oral contraceptive pill. Glucocorticoid may not be appropriate straightaway but can be introduced if other measures are ineffective or when pregnancy is planned.

Concepts: Adolescence, Congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency, Adrenal gland, Congenital adrenal hyperplasia, Testosterone, Androgen, Adrenal cortex, Combined oral contraceptive pill

27

Hibernomas are uncommon benign lipomatous tumors which show differentiation toward brown fat. To our knowledge, only one case of adrenal hibernoma has been previously reported. We describe a 55-year-old woman showing an incidental, 1.7cm-hibernoma associated with a 2.6cm-cortical adenoma producing primary hyperaldosteronism (Conn’s syndrome), both in the left adrenal gland. The hibernoma was composed predominantly of univacuolated mature fat cells admixed with small vessels. Scattered areas composed of large multivacuolated pale cells with central or paracentral nuclei, mimicking lipoblasts, accounting for less than 30% of the tumor, were found. These cells lacked nuclear hyperchromasia or marked atypia, were S100-positive, and showed numerous mitochondria reactive with the anti-mitochondrial antibody. A diagnosis of lipoma-like hibernoma was made. Pathologists should be aware of this variant of hibernoma to avoid misdiagnosis and excessive treatment.

Concepts: DNA, Primary aldosteronism, Adipose tissue, Oncology, Lipoma, Benign tumor, Hyperaldosteronism, Adrenal gland

27

Inflammation in the course of systemic inflammatory response syndrome (SIRS) or sepsis often results in dysregulation of the hypothalamic-pituitary-adrenal axis; however, the underlying mechanisms are not well understood. The adrenal gland is highly vascularized; thus, we hypothesized that endothelial dysfunction may actively participate in inflammation-related adrenal insufficiency. To address this hypothesis, we used the properties of developmental endothelial locus-1 (Del-1), which is an endothelial-derived anti-inflammatory factor that antagonizes integrin-dependent leukocyte adhesion. Here we identified that Del-1 is expressed in the adrenal gland and that its expression was down-regulated upon SIRS induction by systemic lipopolysaccharide administration. Furthermore, we observed increased leukocyte accumulation, inflammation, and higher apoptosis in the adrenal glands of Del-1-deficient mice as compared with wild-type mice. Strikingly, Del-1 deficiency was also associated with reduced corticosterone and ACTH levels 24 hours after lipopolysaccharide administration. Together, these data suggest that Del-1 may act as a gatekeeper of adrenal gland inflammation and may regulate the integrity of the hypothalamic-pituitary-adrenal axis stress response, thereby modulating adrenal (dys)function in the course of SIRS.

Concepts: Immune system, Adrenal gland, Sepsis, Adrenal cortex, Aldosterone, Systemic inflammatory response syndrome, Cortisol, Inflammation

26

Abstract Androstenedione is a common precursor of sex steroids produced and secreted in the human adrenal gland and produced by 3β-hydroxysteroid dehydrogenase (3βHSD), 17β-hydroxylase/17,20-lyase (CYP17) and cytochrome b5 (CYB5A). 3βHSD is expressed in the zona glomerulosa (ZG) and fasciculata (ZF), CYP17 in the ZF and zona reticularis (ZR) and CYB5A in the ZR, respectively. We previously demonstrated the presence of cortical parenchymal cells co-expressing 3βHSD and CYB5A with hybrid features of both ZF and ZR in human adrenal cortex and hypothesized that these cells may play an important role in androstenedione production in human adrenal gland. Age-related morphologic development of these hybrid cells has, however, not been studied. Therefore, in this study, 48 human adrenal specimens from various age groups were retrieved. Double-immunohistochemical analyses were used in order to study the correlation between this hybrid cell type and age. In both male and female adrenal cortex, the means of total adrenocortical area, the area positive for CYB5A and its ratio reached highest peak in the 21-40-year-old (y.o.) group. The greatest overlap between 3βHSD and CYB5A in both total and relative area was present in the 13-20 y.o. group. For all the markers mentioned above, statistically significant differences were detected among the different age groups examined (p < 0.05). These findings indicated that both area and ratio of 3βHSD and CYB5A double positive cells, which could represent the hybrid cells of ZF and ZR, are correlated with human adrenal development and could subsequently influence age-related serum androstenedione levels.

Concepts: Androgen, Aldosterone, Abdomen, Adrenal gland, Glands, Testosterone, Endocrine system, Adrenal cortex

26

Objective: To describe that Topiramate may well be a cause of false positive in Overnight 1 mg dexamethasone suppression test (DST) for hypercortisolism screening.Methods: We present a case in which topiramate induced dexamethasone metabolism showing a false positive in DST.Results: A 44 year-old woman, with an incidentally found adenoma in the right adrenal gland, underwent a DST for hypercortisolism screening. The patient was taking topiramate prescribed by a psychiatrist for an affective disorder and insufficient suppression of cortisol (11.9 mcg/dl) was observed. Free cortisol in 24-hour urine was normal and insufficient suppression was established in a second determination (9.3 mcg/dl). Finally, her psychiatrist switched her treatment from topiramate to bupropion and measures were repeated. When she was not taking topiramate correct suppression with 1 mg of dexamethasone was obtained (1.7 mcg/dl) and free cortisol in 24 hour urine was again normal, thereby excluding the presence of hypercortisolism. On reviewing the literature, topiramate was not found to have been previously described as a cause of a false positive in DST, but it was proposed as a cause of hypoadrenalism in a patient taking oral corticosteroid replacement because its capacity to induce dexamethasone metabolism.Conclusion: Topiramate treatment may well be a cause of false positive in dexamethasone suppression tests and its presence should be taken into consideration when performing DST.

Concepts: Adrenal insufficiency, Corticosteroid, Adrenal cortex, Cushing's syndrome, Adrenal gland, Dexamethasone, Dexamethasone suppression test, Cortisol

22

Empathy for another’s physical pain has been demonstrated in humans [1] and mice [2]; in both species, empathy is stronger between familiars. Stress levels in stranger dyads are higher than in cagemate dyads or isolated mice [2, 3], suggesting that stress might be responsible for the absence of empathy for the pain of strangers. We show here that blockade of glucocorticoid synthesis or receptors for adrenal stress hormones elicits the expression of emotional contagion (a form of empathy) in strangers of both species. Mice and undergraduates were tested for sensitivity to noxious stimulation alone and/or together (dyads). In familiar, but not stranger, pairs, dyadic testing was associated with increased pain behaviors or ratings compared to isolated testing. Pharmacological blockade of glucocorticoid synthesis or glucocorticoid and mineralocorticoid receptors enabled the expression of emotional contagion of pain in mouse and human stranger dyads, as did a shared gaming experience (the video game Rock Band) in human strangers. Our results demonstrate that emotional contagion is prevented, in an evolutionarily conserved manner, by the stress of a social interaction with an unfamiliar conspecific and can be evoked by blocking the endocrine stress response.

Concepts: Behavior, Video game, Empathy, Gene, Adrenal cortex, Hormone, Adrenal gland, Psychology

14

Primary and secondary hypertension are major risk factors for cardiovascular disease, the leading cause of death worldwide. Elevated secretion of aldosterone resulting from primary aldosteronism (PA) is a key driver of secondary hypertension. Here, we report an unexpected role for the ubiquitin ligase Siah1 in adrenal gland development and PA. Siah1a-/- mice exhibit altered adrenal gland morphology, as reflected by a diminished X-zone, enlarged medulla, and dysregulated zonation of the glomerulosa as well as increased aldosterone levels and aldosterone target gene expression and reduced plasma potassium levels. Genes involved in catecholamine biosynthesis and cAMP signaling are upregulated in the adrenal glands of Siah1a-/- mice, while genes related to retinoic acid signaling and cholesterol biosynthesis are downregulated. Loss of Siah1 leads to increased expression of the Siah1 substrate PIAS1, an E3 SUMO protein ligase implicated in the suppression of LXR, a key regulator of cholesterol levels in the adrenal gland. In addition, SIAH1 sequence variants were identified in patients with PA; such variants impaired SIAH1 ubiquitin ligase activity, resulting in elevated PIAS1 expression. These data identify a role for the Siah1-PIAS1 axis in adrenal gland organization and function and point to possible therapeutic targets for hyperaldosteronism.

Concepts: Mineralocorticoid, Proteasome, Adrenal medulla, Aldosterone, Adrenal gland, Gene, Cortisol, Cholesterol

11

Glucocorticoids (GCs) are secreted in an ultradian, pulsatile pattern that emerges from delays in the feedforward-feedback interaction between the anterior pituitary and adrenal glands. Dynamic oscillations of GCs are critical for normal cognitive and metabolic function in the rat and have been shown to modulate the pattern of GC-sensitive gene expression, modify synaptic activity, and maintain stress responsiveness. In man, current cortisol replacement therapy does not reproduce physiological hormone pulses and is associated with psychopathological symptoms, especially apathy and attenuated motivation in engaging with daily activities. In this work, we tested the hypothesis that the pattern of GC dynamics in the brain is of crucial importance for regulating cognitive and behavioral processes. We provide evidence that exactly the same dose of cortisol administered in different patterns alters the neural processing underlying the response to emotional stimulation, the accuracy in recognition and attentional bias toward/away from emotional faces, the quality of sleep, and the working memory performance of healthy male volunteers. These data indicate that the pattern of the GC rhythm differentially impacts human cognition and behavior under physiological, nonstressful conditions and has major implications for the improvement of cortisol replacement therapy.

Concepts: Hormone, Adrenal cortex, Brain, Hypothalamus, Cognition, Adrenal gland, Cortisol, Psychology