Stress-induced Hormone Research Articles

Chronic stress induces pulmonary epithelial cells to produce acetylcholine that remodels lung pre-metastatic niche of breast cancer by enhancing NETosis

BackgroundChronic stress promotes most hallmarks of cancer through impacting the malignant tissues, their microenvironment, immunity, lymphatic flow, etc. Existing studies mainly focused on the roles of stress-induced activation of systemic sympathetic nervous system and other stress-induced hormones, the organ specificity of chronic stress in shaping the pre-metastatic niche remains largely unknown. This study investigated the role of chronic stress in remodeling lung pre-metastatic niche of breast cancer.MethodsBreast cancer mouse models with chronic stress were constructed by restraint or unpredictable stress. Expressions of tyrosine hydroxylase, vesicular acetylcholine transporter (VAChT), EpCAM and NETosis were examined by immunofluorescence and confocal microscopy. mRNA and protein levels of choline acetyltransferase (ChAT), VAChT, and peptidylarginine deiminase 4 were detected by qRT-PCR and Western blotting, respectively. Immune cell subsets were analyzed by flow cytometry. Acetylcholine (ACh) and chemokines were detected by ELISA and multi chemokine array, respectively. ChAT in lung tissues from patients was examined by immunohistochemistry.ResultsBreast cancer-bearing mice suffered chronic stress metastasized earlier and showed more severe lung metastasis than did mice in control group. VAChT, ChAT and ChAT+ epithelial cells were increased significantly in lung of model mice undergone chronic stress. ACh and chemokines especially CXCL2 in lung culture supernatants from model mice with chronic stress were profoundly increased. Chronic stress remodeled lung immune cell subsets with striking increase of neutrophils, enhanced NETosis in lung and promoted NETotic neutrophils to capture cancer cells. ACh treatment resulted in enhanced NETosis of neutrophils. The expression of ChAT in lung tissues from breast cancer patients with lung metastasis was significantly higher than that in patients with non-tumor pulmonary diseases.ConclusionsChronic stress promotes production of CXCL2 that recruits neutrophils into lung, and induces pulmonary epithelial cells to produce ACh that enhances NETosis of neutrophils. Our findings demonstrate for the first time that chronic stress induced epithelial cell derived ACh plays a key role in remodeling lung pre-metastatic niche of breast cancer.

Association of GDF15 levels with body mass index and endocrine status in β-thalassaemia.

GDF15 has emerged as a stress-induced hormone, acting on the brain to reduce food intake and body weight while affecting neuroendocrine function. Very high GDF15 levels are found in thalassaemia, where growth, energy balance and neuroendocrine function are impaired. We examined the relationships between GDF15 and anthropometric measures and endocrine status in β-thalassaemia. Cross sectional study. All β-thalassaemia patients attending the thalassaemia unit of Colombo North Teaching Hospital for blood transfusions. Anthropometric data, appetite scores, circulating GDF15, IGF, thyroid and reproductive hormone levels in 103 β-thalassaemia patients were obtained. GDF15 levels were markedly elevated in thalassaemia patients (24.2-fold with β-thalassaemia major compared with healthy controls). Among patients with β-thalassaemia major, the relationship between GDF15 and body mass index (BMI) was curvilinear with all individuals with GDF15 levels above 24,000 pg/mL having a BMI below 20 kg/m2 . After adjustment for BMI, age and Tanner stage, serum IGF1 concentrations correlated negatively with GDF15 in all thalassaemia patients (β = -.027, p = .02). We found a significant positive relationship between GDF15 and gonadotropin (in both sexes) and testosterone (in males). GDF15 levels were markedly elevated in patients with β-thalassaemia and its association with BMI is consistent with the known effect of GDF15 to reduce body weight. The inverse association between GDF15 with IGF1 levels may reflect a neuroendocrine impact of GDF15 or an indirect effect via impaired nutritional state. The positive association with testosterone in males and gonadotropins in both sexes, was surprising and should prompt further GDF15 studies on the hypothalamic pituitary gonadal axis.

Norepinephrine promotes neuronal apoptosis of hippocampal HT22 cells by up-regulating the expression of long non-coding RNA MALAT1

Stress is ever present in our modern, performance-oriented and demanding society, which causes adverse stress reactions of the body and affects health seriously. Chronic stress has been recognized as a significant risk factor leading to cognitive impairment, but the underlying mechanism is far from fully understood. Norepinephrine (NE), a pivotal stress-induced hormone, has been found to induce cell apoptosis. However, the function and the key downstream mediator of NE on the regulation of hippocampal neurons still need further exploration. In this study, we explored the role of NE in neuronal apoptosis and its association with MALAT1. Flow cytometry assay and automated western bot assay were carried out to evaluate the cell apoptosis. The data showed that the rate of apoptosis rate and the levels of apoptotic proteins (cleaved-Caspase3 and cleaved-PARP) were significantly increased in HT22 cells after a high dose of NE treatment, suggesting a facilitative role of NE on hippocampal neuronal apoptosis. Besides, a high level of NE up-regulated the expression of MALAT1 in HT22 cells. Then, a lentivirus expressing MALAT1 shRNA was constructed to investigate the role of MALAT1 in cell apoptosis and the results revealed that MALAT1 depletion decreased the cell apoptosis. Moreover, the knockdown of MALAT1 abolished the discrepancy in apoptosis between NE-treated cells and control cells. In conclusion, a high level of the stress-induced hormone NE promoted apoptosis of hippocampal neurons by elevating the expression of MALAT1. Our findings provide new experimental data supporting the epigenetic mechanisms in the regulation of stress response and may provide a potential therapeutic target for stress-related cognition dysfunction.

CORRECTION OF HORMONAL DISORDERS IN WOMEN WITH ABNOMAL UTERINE BLEEDING AND CHRONIC PSYCHO-EMOTIONAL STRESS

The aim of the research was to evaluate the effectiveness of the optimized treatment in the correction of hormonal disorders in women with abnormal uterine bleeding (AUB) and chronic psycho-emotional stress.
 Materials and methods. 100 women of reproductive age with AUB and chronic psycho-emotional stress were examined. I group included 50 patients who received complex optimized treatment, II group included 50 persons who received standard treatment. The control group included 30 healthy women without AUB and chronic psycho-emotional stress. The standard approach provided for diagnostic and therapeutic measures in accordance with the recommendations of the order of the Ministry of Health of Ukraine N 353 dated 13.04.2016. Inclusion criteria: AUB, age 18-45 years, satisfactory condition of the sample of the material from the uterine cavity for histological examination, chronic psychogenic stress, patient consent. Exclusion criteria: pregnancy, premenstrual dysphoric disorder, acute pelvic inflammatory disease, mental disorders, blood diseases associated with coagulation disorders, hypothyroidism, hyperthyroidism, hormonal adrenal tumors, chronic intestinal diseases, severe somatic pathology. Optimized treatment additionally included recommendations for lifestyle changes, melatonin, vitamin D, medicament’ correction of iron deficiency without anemia. Estradiol, follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, progesterone, prolactin, and cortisol levels were determined in all subjects.
 Results of the research. In the follicular phase of menstrual cycle after the standard treatment there is a positive dynamics of progesterone and FSH levels in the patients in the I and II groups whose concentrations reached the control group. However, LH level in patients in both groups and estradiol amount in the II group differed significantly from those in healthy women. After optimized treatment, the levels of prolactin and cortisol reached the amount of healthy women, while after the standard treatment the prolactin concentration was increased by 17.22 % (p=0.049), cortisol – by 43.84 % (p<0.001) compared with controls. In the luteal phase, the greatest correction of estradiol and progesterone concentrations in the I and II groups and prolactin level in women in the I group were determined. However, the amount of prolactin in patients of the II group remained high, exceeding the rate of healthy women by 33.64 % (p=0.007), while in the I group it corresponded to the control value. No significant changes in the concentration of FSH, LH and testosterone on the background of treatment in women of the two groups were observed, as their levels corresponded to the control group. FSH and LH levels in patients before and after the standard and optimized treatment were at the lower limit of healthy persons.
 Conclusions. The use of standard and optimized approaches in the management of patients with abnormal uterine bleeding and chronic psycho-emotional stress has been successful in normalizing in female sex hormones, but the standard approach has demonstrated an insufficient correction of stress-induced hormone levels, in contrast, the optimized treatment led to a more effective correction of all hormonal disorders.

Optimal hormonal regulation when stressor cues are imperfect

The endocrine system uses information about the environment and the individual's state to regulate circulating concentrations of hormones, and then those hormones, through receptor binding, cause changes in the phenotype. How quickly individuals can up- and down-regulate their hormones can affect baseline and elevated hormone levels and presumably affects how successfully individuals can cope with a varying environment. To respond to environmental change, individuals first need to perceive and process cues about the state of the environment. Individuals may receive imperfect cues about the environment due to perceptual errors, variation in cues, or inexperience with novel stressors. In this paper we use a mathematical model to ask how these imperfect cues should affect how individuals regulate their glucocorticoid concentrations. We find imperfect cues can lead to changes in hormone regulation with individuals generally having higher baseline and lower elevated hormone levels as environmental cues become less reliable. Informational constraints and physiological constraints appear to have generally additive effects, with informational constraints having less of an impact as physiological constraints increase. Our results highlight the different means by which imperfect information can affect hormone regulation. We find that mistakes caused by imperfect cues are commonly responsible for changes in average hormone levels, but imperfect cues also cause individuals to be slower and less certain in their updated estimates of the environmental state, which affects hormone regulation. We also demonstrate the separate effects of false positive and false negative cues and how these are shaped by the relative fitness consequences of baseline and stress-induced hormone levels. Our model shows how given our assumptions imperfect stressor cues should affect endocrine flexibility and regulation, and we hope provides a piece for future conversations and models of endocrine regulation.

Neuronal circuits of stress and their dynamic interactions: a biopsychological framework

Stress alters neuroendocrine, autonomic, and behavioral processes to cope well with perceived threats that compromise subjective wellbeing. Just as the perception of risk can change the structure and function of brain circuitry, which may result in enduring behavioral changes. There needs to be a greater understanding of how the brain reacts to stress-related disorders and discern how the adaptation mechanisms of the central nervous system under acute stress, as well as how stressinduced adaptation mechanisms are altered under chronic stress conditions that may induce plasticity-related changes in the brain. During this interaction, the brain becomes more capable of resolving stress in a way that is either adaptive or maladaptive, leaving the most critical deficit in the emotion regulation associated with risk for pathological conditions. The essence of this associated risk involves the reciprocal influence between hypothalamic-pituitary-adrenal function, the relay nucleus within the amygdala reactivation, and the hippocampus as essential structures associated with the forebrain pathways mediating stress-induced hormones, and the gammaaminobutyric acid neurotransmitter system as key mechanisms of regulating stress. Understanding how related emotional experiences occur on the neural level and their impact on cognition and behavior entail tracing the interaction between the hypothalamic-pituitary-adrenal axis, the hormones released by these structures, and the neuroendocrine system's reactivity to stress. The interaction between threat-sensitive brain circuitry and the neuroendocrine stress system is crucial to understanding how related emotions arise on the neural level and their impact on cognition and behavior. The hypothalamicpituitary-adrenal axis is critical in regulating the synthesis and release of endocrine hormones through its interactions with these structures, collectively referred to as the stress response. The stress system is described in its anatomy and physiology and connections to other brain areas and endocrine systems. We explore the current evidence linking stress with pathophysiologic mechanisms implicated in stressful conditions affecting the neuronal circuitry between endocrine, metabolic, gastrointestinal, and immune systems. Examining the biopsychological contributions provides a conceptual framework for understanding the emergence of emotions and stress-related behaviors.

Glucocorticoid Induces Atrial Arrhythmogenesis via Modification of Ion Channel Gene Expression in Rats.

Excess psychological stress is one of the precipitating factors for paroxysmal atrial fibrillation (AF), although the involved mechanisms are still uncertain. To test a hypothesis that one of the stress-induced hormones, glucocorticoid, is involved in the pathogenesis of stress-induced AF, we investigated whether the glucocorticoid could alter the temporal profile of cardiac ion channels gene expression, thereby leading to atrial arrhythmogenesis.Dexamethasone (DEX, 1.0 mg/kg) was injected subcutaneously in Sprague-Dawley rats. At predetermined times after DEX injection (0, 1, 3, 6, 12, and 24 hours), the mRNA levels of cardiac ion channel genes (erg, KvLQT1, Kv4.3, Kv4.2, Kv2.1, Kv1.5, Kv1.4, Kv1.2, SUR2A, Kir6.2, Kir3.4, Kir3.1 Kir2.2, Kir2.1, SCN5A, and α1C) were determined using RNase protection assay. DEX induced immediate and transient increase in the mRNA level of Kv1.5 and Kir2.2 with peaks at 6 (5.0 fold) and 3 hours (3.3 fold) after DEX injection, respectively. Patch-clamp studies revealed a significantly increased current density of the corresponding current, IKur and IK1 at 6 hours after DEX injection. Simultaneously, electrophysiological study in isolated perfused hearts showed significantly increased number of repetitive atrial responses induced by single atrial extrastimulus (3.2 ± 2.4 to 26.7 ± 16.4, P = 0.004) with shorting of the refractory period (36.4 ± 4.6 to 27.4 ± 5.5 ms, P = 0.049) after DEX injection.Glucocorticoid immediately modified Kv1.5 and Kir2.2 gene expression at pretranslational levels, thus leading to effective refractory period shortening that could be arrhythmogenic. These results implied that transient glucocorticoid-induced biochemical modification of cardiac ion channels might be one of the mechanisms underlying the stress-induced paroxysmal AF.

Early stress-induced impaired microglial pruning of excitatory synapses on immature CRH-expressing neurons provokes aberrant adult stress responses.

SUMMARYSeveral mental illnesses, characterized by aberrant stress reactivity, often arise after early-life adversity (ELA). However, it is unclear how ELA affects stress-related brain circuit maturation, provoking these enduring vulnerabilities. We find that ELA increases functional excitatory synapses onto stress-sensitive hypothalamic corticotropin-releasing hormone (CRH)-expressing neurons, resulting from disrupted developmental synapse pruning by adjacent microglia. Microglial process dynamics and synaptic element engulfment were attenuated in ELA mice, associated with deficient signaling of the microglial phagocytic receptor MerTK. Accordingly, selective chronic chemogenetic activation of ELA microglia increased microglial process dynamics and reduced excitatory synapse density to control levels. Notably, selective early-life activation of ELA microglia normalized adult acute and chronic stress responses, including stress-induced hormone secretion and behavioral threat responses, as well as chronic adrenal hypertrophy of ELA mice. Thus, microglial actions during development are powerful contributors to mechanisms by which ELA sculpts the connectivity of stress-regulating neurons, promoting vulnerability to stress and stress-related mental illnesses.

Norepinephrine promotes glioma cell migration through up-regulating the expression of Twist1

BackgroundGlioma cells are characterized by high migration ability, resulting in aggressive growth of the tumors and poor prognosis of patients. It has been reported that the stress-induced hormone norepinephrine (NE) contributes to tumor progression through mediating a number of important biological processes in various cancers. However, the role of NE in the regulation of glioma migration is still unclear. Epithelial-to-mesenchymal transition (EMT) is one of the most important steps for tumor migration and metastasis. Twist1, as a key regulator of EMT, has been found to be elevated during glioma migration. But it is still unknown whether Twist1 is involved in the effect of NE on the migration of glioma cells.MethodsWound healing assay and transwell assay were conducted to evaluate the migration of glioma cells upon different treatments. The mesenchymal-like phenotype and the expression of Twist1 after NE treatment were assessed by cell diameters, real-time PCR, western blot and immunofluorescence staining. The gain-and loss-of-function experiments were carried out to investigate the biological function of Twist1 in the migration induced by NE. Finally, the clinical significance of Twist1 was explored among three public glioma datasets.ResultsIn this study, our finding revealed a facilitative effect of NE on glioma cell migration in a β-adrenergic receptor (ADRB)-dependent way. Mechanistically, NE induced mesenchymal-like phenotype and the expression of Twist1. Twist1 overexpression promoted glioma cells migration, while knockdown of Twist1 abolished the discrepancy in the migration ability between NE treated glioma cells and control cells. In addition, the clinical analysis demonstrated that Twist1 was up-regulated in malignant gliomas and recurrent gliomas, and predicted a poor prognosis of glioma patients.ConclusionsNE enhanced the migration ability of glioma cells through elevating the expression of Twist1. Our finding may provide potential therapeutic target for protecting patients with glioma from the detrimental effects of stress biology on the tumor progression.

Comparison of the effect of propofol and isoflurane on hemodynamic parameters and stress response hormones during Laparoscopic Cholecystectomy surgery.

Background and Aims:General anesthesia induces endocrine, immunologic, and metabolic responses. Anesthetic drugs affect endocrine system by changing the level of stress hormones and hemodynamic of the patient . The purpose of this study was to compare the effects of propofol and isoflurane on hemodynamic parameters and stress-induced hormones in laparoscopic cholecystectomy (LC) surgery.Material and Methods:Seventy patients of elective LC were included in this study. Patients were randomly divided into two equal groups of 35 patients; group P received propofol (70–120 μg/kg/min) and group I received isoflurane (mac: 1.28%) as anesthesia maintenance. The following parameters were monitored, checked, and recorded from preanesthesia period to 10 min after PACU entry according to a planned method: hemodynamic parameters (heart rate and mean atrial pressure), level of blood sugar, and serum epinephrine level.Results:Heart rate and mean atrial pressure changes did not show significant differences between the two groups in all stage (P > 0.05), but isoflurane group tolerated lower fluctuating changes. Blood glucose and serum epinephrine level rise in the isoflurane group were significantly higher than the propofol group (P < 0.05).Conclusion:Maintenance anesthesia by inhalation gas base on isoflurane has not shown a significant difference with total intravenous anesthesia base on propofol on hemodynamic parameter. However, propofol has a consistent effect on decreasing stress hormone and suggested for LC surgery.

Corticosterone and Glucocorticoid Receptor in the Cortex of Rats during Aging-The Effects of Long-Term Food Restriction.

Numerous beneficial effects of food restriction on aging and age-related pathologies are well documented. It is also well-established that both short- and long-term food restriction regimens induce elevated circulating levels of glucocorticoids, stress-induced hormones produced by adrenal glands that can also exert deleterious effects on the brain. In the present study, we examined the effect of long-term food restriction on the glucocorticoid hormone/glucocorticoid receptor (GR) system in the cortex during aging, in 18- and 24-month-old rats. Corticosterone level was increased in the cortex of aged ad libitum-fed rats. Food restriction induced its further increase, accompanied with an increase in the level of 11β-hydroxysteroid dehydrogenase type 1. However, alterations in the level of GR phosphorylated at Ser232 were not detected in animals on food restriction, in line with unaltered CDK5 level, the decrease of Hsp90, and an increase in a negative regulator of GR function, FKBP51. Moreover, our data revealed that reduced food intake prevented age-related increase in the levels of NFκB, gfap, and bax, confirming its anti-inflammatory and anti-apoptotic effects. Along with an increase in the levels of c-fos, our study provides additional evidences that food restriction affects cortical responsiveness to glucocorticoids during aging.

Comparison of the Effect of Propofol and Dexmedetomidine on Hemodynamic Parameters and Stress Response Hormones During Laparoscopic Cholecystectomy Surgery.

BackgroundGeneral anesthesia induces endocrine, immunologic, and metabolic responses. Anesthetic drugs affect the endocrine system by changing the level of stress hormones and hemodynamic variables of the patient.ObjectivesThe purpose of this study was to compare the effects of propofol and dexmedetomidine on hemodynamic parameters and stress-induced hormones in laparoscopic cholecystectomy (LC) surgery.MethodsSeventy patients of elective LC were included in this study. The patients were randomly assigned into two equal groups of propofol (75 µg/kg/min) and dexmedetomidine (0.5 µg/kg/hour) as anesthesia maintenance. Hemodynamic parameters (heart rate and mean atrial pressure), blood sugar, and serum epinephrine level were monitored and recorded from pre-anesthesia period to 10 min after entry to post-anesthesia care unit (PACU) according to a planned method.ResultsHeart rate and mean atrial pressure changes were significantly lower in dexmedetomidine group in all stages compared to propofol group (P < 0.001). Also, the rises in blood glucose and serum epinephrine levels in the dexmedetomidine group were significantly higher than in the propofol group (P < 0.001).ConclusionsAnesthesia maintenance by dexmedetomidine showed a significant difference in hemodynamic parameters in comparison with propofol. While dexmedetomidine had better effects on controlling hemodynamic parameters, propofol showed better effects on decreasing stress hormones, and it can be suggested for LC surgery.

Chronic cortisol differentially impacts stem cell-derived astrocytes from major depressive disorder patients

Major depressive disorder (MDD) is a prevalent psychiatric disorder, and exposure to stress is a robust risk factor for MDD. Clinical data and rodent models have indicated the negative impact of chronic exposure to stress-induced hormones like cortisol on brain volume, memory, and cell metabolism. However, the cellular and transcriptomic changes that occur in the brain after prolonged exposure to cortisol are less understood. Furthermore, the astrocyte-specific contribution to cortisol-induced neuropathology remains understudied. Here, we have developed an in vitro model of “chronic stress” using human induced pluripotent stem cell (iPSC)-derived astrocytes treated with cortisol for 7 days. Whole transcriptome sequencing reveals differentially expressed genes (DEGs) uniquely regulated in chronic cortisol compared to acute cortisol treatment. Utilizing this paradigm, we examined the stress response transcriptome of astrocytes generated from MDD patient iPSCs. The MDD-specific DEGs are related to GPCR ligand binding, synaptic signaling, and ion homeostasis. Together, these data highlight the unique role astrocytes play in the central nervous system and present interesting genes for future study into the relationship between chronic stress and MDD.

Baseline and stress-induced prolactin and corticosterone concentrations in a species with female offspring desertion – The case of Whiskered Tern Chlidonias hybrida

To understand the proximate mechanisms regulating brood desertion, we studied hormonal and behavioural stress responses during the chick-rearing period in adult Whiskered Terns (Chlidonias hybrida), a socially monogamous, semi-precocial species with prolonged post-fledging parental care. In contrast to males, almost all females of this species desert during the chick-rearing and post-fledging periods. Because of the expected link between corticosterone, prolactin and parental investment, we hypothesized that males and females should differ in circulating prolactin and corticosterone concentrations. Baseline hormone concentrations did not differ between males and females. In both sexes, prolactin and corticosterone concentrations decreased and increased in response to acute stress (30 min after capture), respectively. Baseline and stress-induced prolactin concentrations decreased significantly in both sexes with advancing brood age. As expected, males had significantly higher stress-induced prolactin concentrations than females. None of the nine males released after being held in captivity for 24 h deserted, whereas four (29%) of the 14 females kept in captivity for 24 h did so. Altogether, these results suggest that higher prolactin concentrations may be involved in the maintenance of parental care under stress. However, there was no statistically significant difference in stress-induced hormone levels between males, females that deserted and those that returned to the nest after prolonged stress (24 h). Our data indicate that males are probably more resistant to stress as regards the continuation of parental care. The pattern of male and female behavioural and hormonal responses to stress partially predicts their behaviour in terms of natural desertion.

Jasmonates, Ethylene and Brassinosteroids Control Adventitious and Lateral Rooting as Stress Avoidance Responses to Heavy Metals and Metalloids.

Developmental and environmental signaling networks often converge during plant growth in response to changing conditions. Stress-induced hormones, such as jasmonates (JAs), can influence growth by crosstalk with other signals like brassinosteroids (BRs) and ethylene (ET). Nevertheless, it is unclear how avoidance of an abiotic stress triggers local changes in development as a response. It is known that stress hormones like JAs/ET and BRs can regulate the division rate of cells from the first asymmetric cell divisions (ACDs) in meristems, suggesting that stem cell activation may take part in developmental changes as a stress-avoidance-induced response. The root system is a prime responder to stress conditions in soil. Together with the primary root and lateral roots (LRs), adventitious roots (ARs) are necessary for survival in numerous plant species. AR and LR formation is affected by soil pollution, causing substantial root architecture changes by either depressing or enhancing rooting as a stress avoidance/survival response. Here, a detailed overview of the crosstalk between JAs, ET, BRs, and the stress mediator nitric oxide (NO) in auxin-induced AR and LR formation, with/without cadmium and arsenic, is presented. Interactions essential in achieving a balance between growth and adaptation to Cd and As soil pollution to ensure survival are reviewed here in the model species Arabidopsis and rice.

Nerves in the Tumor Microenvironment: Origin and Effects.

Studies have reported the vital role of nerves in tumorigenesis and cancer progression. Nerves infiltrate the tumor microenvironment thereby enhancing cancer growth and metastasis. Perineural invasion, a process by which cancer cells invade the surrounding nerves, provides an alternative route for metastasis and generation of tumor-related pain. Moreover, central and sympathetic nervous system dysfunctions and psychological stress-induced hormone network disorders may influence the malignant progression of cancer through multiple mechanisms. This reciprocal interaction between nerves and cancer cells provides novel insights into the cellular and molecular bases of tumorigenesis. In addition, they point to the potential utility of anti-neurogenic therapies. This review describes the evolving cross-talk between nerves and cancer cells, thus uncovers potential therapeutic targets for cancer.

GDF15 is elevated in conditions of glucocorticoid deficiency and is modulated by glucocorticoid replacement

CONTEXT GDF15 is a stress-induced hormone acting in the hindbrain that activates neural circuitry involved in establishing aversive responses and reducing food intake and body weight in animal models. Anorexia, weight loss, nausea and vomiting are common manifestations of glucocorticoid deficiency, and we hypothesized that glucocorticoid deficiency may be associated with elevated levels of GDF15. OBJECTIVE To determine the impact of primary adrenal insufficiency (PAI) and glucocorticoid replacement on circulating GDF15 levels. METHODS AND RESULTS We measured circulating concentrations of GDF15 in a cohort of healthy volunteers and Addison's disease patients following steroid withdrawal. Significantly higher GDF15 (mean ± standard deviation [SD]) was observed in the Addison's cohort, 739.1 ± 225.8 pg/mL compared to healthy controls, 497.9 ± 167.7 pg/mL (P = 0.01). The effect of hydrocortisone replacement on GDF15 was assessed in 3 independent PAI cohorts with classical congenital adrenal hyperplasia or Addison's disease; intravenous hydrocortisone replacement reduced GDF15 in all groups. We examined the response of GDF15 to increasing doses of glucocorticoid replacement in healthy volunteers with pharmacologically mediated cortisol deficiency. A dose-dependent difference in GDF15 (mean ± SD) was observed between the groups with values of 491.0 ± 157.7 pg/mL, 427.0 ± 152.1 pg/mL and 360 ± 143.1 pg/mL, in the low, medium and high glucocorticoid replacement groups, respectively, P < .0001. CONCLUSIONS GDF15 is increased in states of glucocorticoid deficiency and restored by glucocorticoid replacement. Given the site of action of GDF15 in the hindbrain and its effects on appetite, further study is required to determine the effect of GDF15 in mediating the anorexia and nausea that is a common feature of glucocorticoid deficiency.

OR03-04 The Study of Cell Senescence in Cortisol-Producing Adrenocortical Adenomas

Introduction Aging is associated with the pathogenesis of many endocrine disorders such as cardiovascular diseases and diabetes. Cell senescence has been reported as one of their mechanisms. In addition, stress responsiveness has been reported to be associated with cell senescence. In addition, some genetic abnormalities such as mitochondrial DNA (mtDNA) damages or telomere shortening, have been detected in some endocrine disorders. Cortisol is a well-known stress-induced hormone and closely associated with aging. We previously reported that cortisol-producing adenoma (CPA) more abundantly expressed cell senescent markers such as p16 and p21 than other hormone-producing adrenocortical adenomas. However, the detailed pathophysiology of cell senescence and its association with histological features in CPAs have remained virtually unknown. Therefore, we analyzed cell senescent markers (telomere length, mtDNA copy number, mtDNA deletion and p16 and p21 immunoreactivity) and analyzed their correlation with clinicopathological factors in CPA patients. Methods & Materials Forty CPA cases was immunohistochemically evaluated. Twenty CPA, ten adjacent ZF and six non-functional adenoma (NFA) were examined for mtDNA abnormalities. mtDNA deletion was evaluated by nested-PCR and mtDNA copy number and telomere length were measured using real-time PCR. Results p21 immunoreactivity was significantly higher in CPA than that of adjacent ZF (P=0.0001) and significantly inversely correlated with tumor size (P=0.0004). Telomere length was much longer in CPA than that in adjacent ZF(P=0.0038), and NFA (P=0.0018). mtDNA copy number of NFA was significantly higher than that of CPA and adjacent ZF (P=0.0038). mtDNA copy number of compact cells was significantly higher than that of clear cells (P=0.0432). mtDNA copy number of compact cells was positively correlated with urinary free cortisol (UFC) (P=0.0428) and plasma cortisol (F) (P=0.0609). mtDNA copy number of clear cells were inversely correlated with F (0.0497). 4977 bp mtDNA deletion was more frequently detected in CPA (54%) and in adjacent ZF (50%) than in NFA (17%). Discussion Results of our present study did reveal that CPA harbored more senescent phenotype as demonstrated by abundant p16 and p21, marked telomere shortening, frequent mtDNA 4977bp deletion and relatively low mtDNA copy number, possibly caused by long-term exposure of excessive cortisol in situ compared to NFA. In addition, clear tumor cells could represent more senescent histological phenotype because of their lower mtDNA copy numbers. This is the first study to demonstrate that compact tumor cells were biologically more active than clear tumor cells and could reflect clinical cortisol biosynthesis, resulting in marked functional intratumoral heterogeneity in CPAs.

Prolactin is related to incubation constancy and egg temperature following a disturbance in a precocial bird

To maximize fitness, parents may trade-off time and energy between parental care and self-maintenance. In vertebrates, prolactin and corticosterone are two important hormones that regulate parental investment because they stimulate parental care and mobilize energy, respectively. Further, concentrations of both hormones change in response to disturbances. One of the most important parental care behaviors in birds is incubation, since small changes in egg temperature have large effects on offspring. We investigated how prolactin and corticosterone may mediate parental incubation constancy (i.e., the daily amount of time spent incubating eggs) and regulation of egg temperature. We collected blood samples from female wood ducks (Aix sponsa) near the start and end of the incubation period to measure baseline and stress-induced (30 min after capture and restraint) hormone concentrations. We also quantified incubation constancy and egg temperature using artificial egg temperature loggers. As expected, prolactin decreased and corticosterone increased after 30 min of capture and restraint. Corticosterone concentrations (baseline and stress-induced) were negatively related to body mass, but were not related to incubation constancy. In contrast, prolactin concentrations (baseline and stress-induced) were higher at the end than the start of the incubation period, and stress-induced prolactin concentrations were positively related to incubation constancy following a nest disturbance (i.e., capture). Further, prolactin (baseline and stress-induced) concentrations were positively related to egg temperatures, but only after the disturbance. These results suggest that prolactin may be associated with the regulation of parental incubation constancy and resulting heat-transfer after a disturbance, which may ultimately affect offspring development.

Octopamine mobilizes lipids from honey bee (Apis mellifera) hypopharyngeal glands.

Recent widespread honey bee (Apis mellifera) colony loss is attributed to a variety of stressors, including parasites, pathogens, pesticides and poor nutrition. In principle, we can reduce stress-induced declines in colony health by either removing the stressor or increasing the bees' tolerance to the stressor. This latter option requires a better understanding than we currently have of how honey bees respond to stress. Here, we investigated how octopamine, a stress-induced hormone that mediates invertebrate physiology and behavior, influences the health of young nurse-aged bees. Specifically, we asked whether octopamine induces abdominal lipid and hypopharyngeal gland (HG) degradation, two physiological traits of stressed nurse bees. Nurse-aged workers were treated topically with octopamine and their abdominal lipid content, HG size and HG autophagic gene expression were measured. Hemolymph lipid titer was measured to determine whether tissue degradation was associated with the release of nutrients from these tissues into the hemolymph. The HGs of octopamine-treated bees were smaller than control bees and had higher levels of HG autophagy gene expression. Octopamine-treated bees also had higher levels of hemolymph lipid compared with control bees. Abdominal lipids did not change in response to octopamine. Our findings support the hypothesis that the HGs are a rich source of stored energy that can be mobilized during periods of stress.