Bed nuclei of the stria terminalis modulate memory consolidation via glucocorticoid-dependent and -independent circuits.

There is extensive evidence that glucocorticoid hormones enhance memory consolidation, helping to ensure that emotionally significant events are well remembered. Prior findings suggest that the anteroventral region of bed nuclei of the stria terminalis (avBST) regulates glucocorticoid release, suggesting the potential for avBST activity to influence memory consolidation following an emotionally arousing learning event. To investigate this issue, male Sprague-Dawley rats underwent inhibitory avoidance training and repeated measurement of stress hormones, immediately followed by optogenetic manipulations of either the avBST or its projections to downstream regions, and 48 h later were tested for retention. The results indicate that avBST inhibition augmented posttraining pituitary-adrenal output and enhanced the memory for inhibitory avoidance training. Pretreatment with a glucocorticoid synthesis inhibitor blocked the memory enhancement as well as the potentiated corticosterone response, indicating the dependence of the memory enhancement on glucocorticoid release during the immediate posttraining period. In contrast, posttraining avBST stimulation decreased retention yet had no effect on stress hormonal output. Subsequent experiments revealed that inhibition of avBST input to the paraventricular hypothalamus enhanced stress hormonal output and subsequent retention, whereas stimulation did not affect either. Conversely, stimulation-but not inhibition-of avBST input to the ventrolateral periaqueductal gray impaired consolidation, whereas neither manipulation affected glucocorticoid secretion. These findings indicate that divergent pathways from the avBST are responsible for the mnemonic effects of avBST inhibition versus stimulation and do so via glucocorticoid-dependent and -independent mechanisms, respectively.

Physiological behavior during stress anticipation across different chronic stress exposure adaptive models.

Anticipation of stress induces physiological, behavioral and cognitive adjustments that are required for an appropriate response to the upcoming situation. Additional research examining the response of cardiopulmonary parameters and stress hormones during anticipation of stress in different chronic stress adaptive models is needed. As an addition to our previous research, a total of 57 subjects (16 elite male wrestlers, 21 water polo player and 20 sedentary subjects matched for age) were analyzed. Cardiopulmonary exercise testing (CPET) on a treadmill was used as the laboratory stress model; peak oxygen consumption (VO2) was obtained during CPET. Plasma levels of adrenocorticotropic hormone (ACTH), cortisol, alpha-melanocyte stimulating hormone (alpha-MSH) and N-terminal-pro-B type natriuretic peptide (NT-pro-BNP) were measured by radioimmunometric, radioimmunoassay and immunoassay sandwich technique, respectively, together with cardiopulmonary measurements, 10 minutes pre-CPET and at the initiation of CPET. The response of diastolic blood pressure and heart rate was different between groups during stress anticipation (p = 0.019, 0.049, respectively), while systolic blood pressure, peak VO2 and carbon-dioxide production responses were similar. ACTH and cortisol increased during the experimental condition, NT-pro-BNP decreased and alpha-MSH remained unchanged. All groups had similar hormonal responses during stress anticipation with the exception of the ACTH/cortisol ratio. In all three groups, ΔNT-pro-BNP during stress anticipation was the best independent predictor of peak VO2 (B = 36.01, r = 0.37, p = 0.001). In conclusion, the type of chronic stress exposure influences the hemodynamic response during anticipation of physical stress and the path of hormonal stress axis activation. Stress hormones released during stress anticipation may hold predictive value for overall cardiopulmonary performance during the stress condition.

LAY SUMMARYThe study revealed differences in hormonal and hemodynamic responses during anticipation of stress between athletes and sedentary participants. Stress hormones released during stress anticipation may hold predictive value for overall cardiopulmonary performance during the stress condition.

Risk of adrenal insufficiency in patients with polymyalgia rheumatica versus patients with rheumatoid arthritis: A cross-sectional study.

OBJECTIVE: To determine whether patients with polymyalgia rheumatica (PMR) are more susceptible to glucocorticoid-induced adrenal insufficiency, one of the barriers to glucocorticoid tapering strategies, compared to patients with rheumatoid arthritis (RA). METHODS: This cross-sectional study included PMR and RA patients who underwent adrenocorticotropic hormone (ACTH) tests to assess adrenal function. The eligibility criteria were as follows: previous use of prednisolone (PSL) ≥ 5 mg/day, use of PSL for six consecutive months before ACTH test, and current use of PSL at 5 mg/day or less. The association between disease type (PMR vs. RA) and insufficient adrenal response was assessed using logistic regression models. RESULTS: Twenty-six of 34 (76.5%) patients with PMR and 13 of 37 (35.1%) patients with RA had insufficient adrenal response. Compared to patients with RA, patients with PMR were more likely to have insufficient adrenal response, even after adjusting for age, sex, and PSL dose (adjusted odds ratio, 6.75; 95% confidence interval, 1.78-25.60). CONCLUSION: Patients with PMR have a higher risk of glucocorticoid-induced adrenal insufficiency than patients with RA. Assessing the adrenal function in patients with PMR will contribute to establishing a more appropriate glucocorticoid reduction strategy.

The role of pro-opiomelanocortin in the ACTH-cortisol dissociation of sepsis.

BACKGROUND: Sepsis is typically hallmarked by high plasma (free) cortisol and suppressed cortisol breakdown, while plasma adrenocorticotropic hormone (ACTH) is not increased, referred to as 'ACTH-cortisol dissociation.' We hypothesized that sepsis acutely activates the hypothalamus to generate, via corticotropin-releasing hormone (CRH) and vasopressin (AVP), ACTH-induced hypercortisolemia. Thereafter, via increased availability of free cortisol, of which breakdown is reduced, feedback inhibition at the pituitary level interferes with normal processing of pro-opiomelanocortin (POMC) into ACTH, explaining the ACTH-cortisol dissociation. We further hypothesized that, in this constellation, POMC leaches into the circulation and can contribute to adrenocortical steroidogenesis. METHODS: In two human studies of acute (ICU admission to day 7, N = 71) and prolonged (from ICU day 7 until recovery; N = 65) sepsis-induced critical illness, POMC plasma concentrations were quantified in relation to plasma ACTH and cortisol. In a mouse study of acute (1 day), subacute (3 and 5 days) and prolonged (7 days) fluid-resuscitated, antibiotic-treated sepsis (N = 123), we further documented alterations in hypothalamic CRH and AVP, plasma and pituitary POMC and its glucocorticoid-receptor-regulated processing into ACTH, as well as adrenal cortex integrity and steroidogenesis markers. RESULTS: The two human studies revealed several-fold elevated plasma concentrations of the ACTH precursor POMC from the acute to the prolonged phase of sepsis and upon recovery (all p < 0.0001), coinciding with the known ACTH-cortisol dissociation. Elevated plasma POMC and ACTH-corticosterone dissociation were confirmed in the mouse model. In mice, sepsis acutely increased hypothalamic mRNA of CRH (p = 0.04) and AVP (p = 0.03) which subsequently normalized. From 3 days onward, pituitary expression of CRH receptor and AVP receptor was increased. From acute throughout prolonged sepsis, pituitary POMC mRNA was always elevated (all p < 0.05). In contrast, markers of POMC processing into ACTH and of ACTH secretion, negatively regulated by glucocorticoid receptor ligand binding, were suppressed at all time points (all p ≤ 0.05). Distorted adrenocortical structure (p < 0.05) and lipid depletion (p < 0.05) were present, while most markers of adrenocortical steroidogenic activity were increased at all time points (all p < 0.05). CONCLUSION: Together, these findings suggest that increased circulating POMC, through CRH/AVP-driven POMC expression and impaired processing into ACTH, could represent a new piece in the puzzling ACTH-cortisol dissociation.

Adrenal insufficiency in prednisolone-treated patients with polymyalgia rheumatica or giant cell arteritis-prevalence and clinical approach.

OBJECTIVES: Glucocorticoid treatment is fundamental in polymyalgia rheumatica (PMR) and giant cell arteritis (GCA), but carries a risk of glucocorticoid-induced adrenal insufficiency. Adrenal insufficiency can cause reluctance to stop glucocorticoid treatment after disease remission as symptoms can resemble PMR/GCA flare. We aimed to determine the prevalence of adrenal insufficiency in prednisolone-treated patients with PMR/GCA. METHODS: We included 47 patients with PMR (n = 37), GCA (n = 1) or both (n = 9), treated with prednisolone for ≥5.4 months, current dose 2.5-10 mg/day. Adrenal function was evaluated using a corticotropin (Synacthen®) stimulation test following 48 h prednisolone pause. Two years' clinical follow-up data are provided. RESULTS: Seven patients (15%) had adrenal insufficiency, 4 (11%) of the 37 patients with PMR alone, and 3 (30%) of the 10 patients with GCA. Corticotropin-stimulated P-cortisol was significantly associated with current prednisolone dose, mean daily dose the last 3 and 6 months before testing, and basal P-cortisol, but not with total dose or treatment duration. Adrenal insufficiency occurred with all current prednisolone doses (2.5-10 mg/day). Five (71%) of the glucocorticoid-insufficient patients could discontinue prednisolone treatment; two of them recovered glucocorticoid function, whereas three still needed hydrocortisone replacement 2 years later. Two patients experienced in total four acute hospital admissions with symptoms of adrenal crises. CONCLUSION: Glucocorticoid-induced adrenal insufficiency occurred in 15% of patients with PMR/GCA. Mean prednisolone dose the last 3 months and basal P-cortisol were the best and simplest predictors of adrenal function. Most of the glucocorticoid-insufficient patients could discontinue prednisolone with appropriate treatment for adrenal insufficiency.

Identification of metabolites of peptide-derived drugs using an isotope-labeled reporter ion screening strategy.

Background Peptide-derived drugs represent an emerging class of prohibited substances in professional sports and, thus, in modern doping controls. After parental administration (e.g. subcutaneous, intravenous), these drugs undergo various metabolic processes, which degrade them to biologically active or inactive peptides. Knowledge about these metabolic processes and the hereby produced metabolites plays a key role in successful doping controls due to the effective design of analytical assays under consideration of optimal analytical targets. Unfortunately, the complexity of biological matrix (e.g. blood or urine) complicates the immediate identification of relevant metabolites due to the enormous excess of naturally occurring peptides and their degradation products. Methods In this study, a strategy employing in-vitro metabolism of stable isotope-labeled peptides producing characteristic reporter ions derived from labeled immonium ions is shown. The in-vitro experiments were performed with human skin tissue microsomes (S9), and model drugs representing prohibited peptide hormones were synacthen, insulin, and corticorelin (respectively, their stable isotope-labeled analogs). After generic sample preparation, the metabolites were identified by means of liquid chromatography (LC) coupled to high-resolution mass spectrometry (MS) in an untargeted approach. Results and conclusions For all three model peptides, several metabolic products were readily identified. While insulin and corticorelin were found to be comparably stable, synacthen was fully degraded, yielding a plethora of metabolic products. A proof of concept concerning the transferability of the obtained data was accomplished by analyzing plasma samples collected post-administration of recombinant human insulin, corroborating the presence of a skin protease-indicative insulin metabolite in vivo.

Unusual ectopic ACTH syndrome in a patient with orbital neuroendocrine tumor, resulted false-positive outcome of BIPSS:a case report.

BACKGROUND: Cushing's syndrome has been described as a complex endocrine disorder characterized with high cortisol concentration. Correct and early diagnosis of Cushing's syndrome is challenging. According to the latest guideline, bilateral inferior petrosal sinus sampling (BIPSS) is considered to be the gold standard for the differential diagnosis. However, in some unusual cases, this method may be false positive. Here, we presented a rare case of orbital neuroendocrine tumor secreting adrenocorticotrophic hormone with false positive inferior petrosal sinus sampling. CASE PRESENTATION: A 48-year-old woman was admitted to West China Hospital of Sichuan University, presenting with fatigue, whole body edema for 1 year, alopecia and skin pigmentation for 5 months. Hormonal profiles including plasma cortisol and adrenocorticotrophic hormone (ACTH) measurements and low-dose dexamethasone inhibition test suggested that the patient had Cushing's syndrome. However, during tumor location phase, the results of high-dose dexamethasone inhibition test (HDDST) contradicted desmopressin (DDAVP) stimulation test. Thus, BIPSS was employed, and its results indicated a pituitary origin. Interestingly, MRI of sellar region showed an innocent pituitary but caught a serendipitous lesion in the lateral rectus muscle of left eye, which was later proved to be an orbital neuroendocrine tumor secreting ACTH by pathological and immunohistochemical results. ACTH level of the patients was < 0.1 ng/L and cortisol level was 51.61 nmol/L 1 week after surgery. At 24 months follow-up, the patient appeared stable with no complaints nor any symptoms of Cushing's syndrome, including moon face, purple striate and central obesity. The patient's life quality also improved significantly. CONCLUSION: We reported a rare case of endogenous Cushing's syndrome due to ectopic ACTH secreting from an orbital neuroendocrine tumor. This unique case of orbital EAS suggests that orbital venous blood backflow, owning to abnormal anatomic structures, may possibly lead to false positive BIPSS results.

The blockade of corticotropin-releasing factor 1 receptor attenuates anxiety-related symptoms and hypothalamus-pituitary-adrenal axis reactivity in mice with mild traumatic brain injury.

Recent studies have shown that mild traumatic brain injury (mTBI) is associated with higher risk for anxiety-related disorders. Dysregulation in the hypothalamus-pituitary-adrenal (HPA) axis following mTBI has been proposed to be involved in the development of neurobehavioral abnormalities; however, the underlying mechanisms are largely unknown. The aim of this study was to determine whether the corticotropin-releasing-factor-1 (CRF-1) receptor is involved in the regulation of anxiety-related symptoms in a mouse model of mTBI. Animals with or without mTBI received intracerebroventricular injections of a CRF-1 receptor agonist (CRF; 0.01 nmol/mouse) or antagonist (antalarmin; 1 µg/mouse) for 5 days, and then the animals were subjected to anxiety tests (light-dark box and zero maze). The levels of adrenocorticotropic hormone and corticosterone, the most important markers of HPA axis, were also measured after behavioral tests. Our results indicated that mTBI-induced anxiety-related symptoms in mice through increased levels of adrenocorticotropic hormone and corticosterone, showing HPA axis hyperactivity. Interestingly, activation of CRF receptor by a subthreshold dose of CRF resulted in significant increases in anxiety-like behaviors and HPA axis response to stress, whereas blockade of CRF receptors by a subthreshold dose of antalarmin decreased anxiety-related symptoms and HPA axis response to stress in mTBI-induced mice. Collectively, these findings suggest that the CRF-1 receptor plays an important role in the regulation of anxiety-related behaviors following mTBI induction in mice and support the hypothesis that blockade of the CRF-1 receptor may be a promising therapeutic target for anxiety-related disorders in patients with TBI.

Quercetin mitigates anxiety-like behavior and normalizes hypothalamus-pituitary-adrenal axis function in a mouse model of mild traumatic brain injury.

Mild traumatic brain injury (mTBI) is a major public health risk for developing anxiety-related disorders and hypothalamus-pituitary-adrenal (HPA) axis dysregulation in humans. Extensive research has shown that dietary intake or supplementation of the natural flavonoid quercetin might be useful for treating anxiety-related symptoms. The objectives of this study were to determine whether quercetin treatment can attenuate anxiogenic-like behaviors and normalize HPA axis function in mice with mTBI. Animals subjected to mTBI were treated daily with quercetin (50 mg/kg) or diazepam (positive control, 3 mg/kg) for 14 days. Four behavioral tests (open field, plus maze, light-dark box, and zero maze) were used to assess anxiety-related behaviors in mice. To evaluate HPA axis function, adrenocorticotropic hormone and corticosterone were measured in the serum of mice after the anxiety tests. Quercetin treatment was found to significantly reduce anxiety-like behaviors in mTBI-induced mice. A strength of this study is the consistency of results among anxiety tests. The dysregulation of the HPA axis in mTBI-induced mice treated with quercetin was also attenuated, with decreased levels of adrenocorticotropic hormone and corticosterone. The effects of quercetin were comparable with those of diazepam treatment. Taken together, these results suggest that quercetin might be useful for treating anxiety-related symptoms and HPA axis hyperreactivity in patients with mTBI.

Effect of chronic corticosterone treatment on expression and distribution of serotonin 5-HT7 receptors in rat adrenal glands.

Sensitized stress-induced corticosterone (CORT) secretion in chronically stressed rats involves 5-HT7 receptor activation. The effect of 14-day chronic CORT and vehicle (VEH) administration on 5-HT7 receptor expression in adrenal glands, adrenal 5-HT content, and adrenocorticotropic hormone and CORT secretion was analysed. On day 15, VEH- and CORT-treated animals were perfused or decapitated without stress exposure (0 min) or after 10 and 30 min of restraint for collection of trunk blood and tissues. 5-HT7 receptor-like immunoreactivity (5-HT7R-LI), 5-HT7 receptor protein, and mRNA levels were determined by immunohistochemistry, Western blot, and reverse transcription polymerase chain reaction assays, respectively; 5-HT levels and hormones were quantified using HPLC and ELISA kits, respectively. An undisturbed control group was included for most experimental comparisons. Chronic CORT strongly increased 5-HT7R-LI in the outer adrenal cortex, as well as 5-HT7 receptor protein and mRNA in whole adrenal glands; adrenal 5-HT content also increased in these animals. Decreased adrenocorticotropic hormone and CORT secretion at 30 min of restraint occurred in CORT-treated rats. The results support the notion that chronic stress-induced increase of adrenocortical 5-HT7 receptors and adrenal 5-HT content is a glucocorticoid-dependent phenomenon; the development of magnified stress-induced 5-HT7 receptor-mediated CORT responses in chronically stressed animals nevertheless likely involves additional mechanisms.

Effects of Boxing Matches on Metabolic, Hormonal, and Inflammatory Parameters in Male Elite Boxers.

Background and objectives: Boxing is a popular combat sport that requires high intensity and cooperation. However, there are limited data about the influence of boxing matches on blood parameters. The purpose of the present study was to investigate the match-induced changes in the metabolic, hormonal, and inflammatory status in male elite boxers. Materials and methods: High-level 20 male boxers with more than 5 years experience in boxing voluntarily participated in this study. Venous blood samples of the boxers, before and after combat, were taken for determination of the plasma parameters. Results: Our results indicated that a 9-min boxing match caused significant increases in plasma energy fuels (glucose and lactate), metabolic hormones (insulin, adrenocorticotropic hormone (ACTH), cortisol, and growth hormone), inflammatory markers (interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α)), muscle damage indicators (alanine aminotransferase (ALT) and aspartate aminotransferase (AST)), and oxidative stress marker (SOD). A decrease in total oxidant status (TOS) was also considered. However, there were no significant alterations in the plasma levels of androgenic hormone (free and total testosterone), anabolic hormone (IGF-1), lipids (total cholesterol, triglyceride, high-density lipoprotein (HDL), and low-density lipoprotein (LDL)), kidney function markers (creatinine and urea), and minerals (iron (Fe) and magnesium (Mg)). Conclusion: Elevations in the level of energy fuels and metabolic hormones of the boxers could be taken as a reflection of high-energy turnover during combat performance. The increases in inflammatory and tissue damage indicators may possibly be an indication of traumatic injury. Understanding the biochemical changes that occur during boxing match could be valuable to optimize the performance improvement of the athletes.

Burnout Syndrome in Physicians-Psychological Assessment and Biomarker Research.

Background and objectives: Burnout is a syndrome typically occurring in work environments with continuous and chronic stress. Physicians are at increased risk for burnout, as a result of 24-hour work, delayed work-life balance gratification, and the challenges associated with patient care. The aim of the present study was to evaluate the psychological parameters of burnout symptoms in relation to biomarkers of stress among physicians with different medical specialties. Materials and methods: A total of 303 physicians were contacted as potential participants. A comparison group of 111 individuals working outside medicine was used as a control to verify the results. The physicians were specialists in internal medicine, general surgery, pathology, and primary care. Serum cortisol, salivary cortisol, adrenocorticotropic hormone (ACTH), insulin (IRI), and prolactin levels were analyzed by chemiluminescence enzyme immunoassay (Access 2, Beckman Coulter). Fasting glucose in serum and glycated hemoglobin (HbA1C) in whole blood were measured using the automatic analyzer AU 480 Beckman Coulter system. Symptoms of burnout were measured with the Maslach Burnout Inventory (MBI). Results: The group with burnout presented significantly higher levels of serum and saliva cortisol, ACTH, prolactin, fasting glucose, and HbA1C compared with the control group. The correlation analysis between biomarkers showed a positive correlation with moderate strength between serum and saliva cortisol (r = 0.516, p = 0.01),as well as serum and saliva cortisol with ACTH (r = 0.418; r = 0.412, p = 0.01) and HbA1C (r = 0.382; r = 0.395, p = 0.01). A weak positive correlation was found between serum and saliva cortisol with prolactin (r = 0.236; r = 0.267, p < 0.01) and glucose (r = 0.271; r = 0.297, p < 0.01). In the multiple logistic regression model, saliva cortisol, HbA1C, and age were significantly associated with burnout (chi-square = 16.848, p < 0.032). Conclusion: Our findings demonstrated the interest of exploring biomarkers of stress related to burnout in health professionals.

Hormonal Status and Cognitivo-Emotional Profile in Real-Life Patients With Neuropathic Pain: A Case Control Study.

BACKGROUND: The specific impact of neuropathic pain and recommended neuropathic pain treatments on the hormonal and immune status of patients has been so far poorly explored. This study aimed at studying, in real life, the hypothalamic-pituitary-adrenal axis and the cytokine profile of patients with neuropathic pain. It also explored their links with cognition, emotion, quality of life, and drug treatment. METHODS: This prospective study (clinicaltrials.gov NCT01543425) included 60 patients with neuropathic pain and 60 age- and gender-matched healthy volunteers after obtaining signatures of informed consent. A number of parameters were measured: adrenocorticotropic hormone, cortisol, cortisol awakening response, dehydroepiandrosterone sulphate, sex hormone binding globulin, testosterone, 17-ß-estradiol, progesterone, luteinizing hormone, follicle-stimulating hormone, cytokines, brain-derived neurotrophic factor, and vitamin D. Psychological parameters were assessed by questionnaires. RESULTS: Patients with neuropathic pain had lower levels of adrenocorticotropic hormone (P = 0.009) and dehydroepiandrosterone sulphate (P < 0.001) than controls, and the cortisol awakening response was impaired. Patients were more depressed and anxious (P < 0.001) and had a diminished quality of life (P < 0.001), which was influenced by cytokines (P = 0.0067) and testosterone (P = 0.028). Antidepressants and antiepileptics appeared to interfere with testosterone and cognitivo-emotional domains. CONCLUSION: An impairment of the hormonal status and of the immune system was observed in patients. It identified testosterone as a potential pivotal mediator between antidepressants/antiepileptics and quality of life. Further studies must address the exact impact of different types of drugs on central effects, of gender differences, and of the immune system of neuropathic pain.

UTILITY OF A SINGLE LATE-NIGHT PLASMA CORTISOL AND ACTH FOR THE DIAGNOSIS OF CUSHING SYNDROME.

OBJECTIVE: To evaluate the diagnostic efficacy of various screening tests for the diagnosis of Cushing syndrome (CS). METHODS: Thirty-five patients with CS and 16 patients of pseudo-CS were enrolled. Assessment of 24-h urinary free cortisol (UFC), late-night salivary cortisol (LNSC), overnight dexamethasone suppression test (ONDST), late-night plasma cortisol (LNPC), and adrenocorticotropic hormone (ACTH) on outpatient basis, and during sleep as well as in awake state after 48 hours of hospital admission. RESULTS: We found that 24-h UFC performed the best among the screening tests with sensitivity, specificity and areas under the curve (AUCs) of 96.0%, 99%, and 0.988, respectively, at a cut-off of 144.6 µg/24 h. A cut-off of 10.5 nmol/L for LNSC had sensitivity 85.7%, specificity 88.2%, and an AUC of 0.897. A cut-off of 412.4 nmol/L for LNPC on outpatient basis had sensitivity 88.2%, specificity 91.2%, and an AUC of 0.957. Cut-offs of 215 and 243.3 nmol/L for LNPC during sleep and awake states after acclimatization had sensitivity, specificity, and an AUC of 94.1%, 88.2%, and 0.958, respectively. An ONDST cut-off of 94.6 nmol/L provided sensitivity, specificity, and an AUC of 96.0%, 99.03% and 0.995, respectively. A cut-off of 30.3 pg/mL for late-night ACTH on outpatient basis had sensitivity 67.6%, specificity 99.9%, and an AUC 0.796.A cut-off of 22.6 pg/mL for ACTH during sleep state after acclimatization had sensitivity, specificity, and an AUC of 73.5%, 99.2%, and 0.827, respectively. CONCLUSION: UFC is the best screening test for CS. Furthermore, single measurements of LNPC and ACTH help to establish the diagnosis and ACTH dependency of CS in the majority of patients with CS. ABBREVIATIONS: ACTH = adrenocorticotropic hormone AUC = area under the curve CRH = corticotropin-releasing hormone CS = Cushing syndrome ECLIA = electrochemiluminescence immuno-assay LDDST = low-dose dexamethasone suppression test LNPC = late-night plasma cortisol LNSC = late-night salivary cortisol ONDST = overnight dexamethasone suppression test RIA = radio-immuno assay UFC = urinary free cortisol.

Evaluation of a Novel General Pituitary Hormone Score to Evaluate the Function of the Residual Anterior Pituitary (Adenohypophysis) in Patients Following Surgery for Pituitary Adenoma.

BACKGROUND The aim was to develop and assess a general pituitary hormone score to evaluate the function of the anterior pituitary (adenohypophysis) in patients following resection of pituitary adenomas. MATERIAL AND METHODS Sixty-six patients with pituitary null cell macroadenoma (1-3 cm diameter) (N=38) and pituitary null cell giant adenoma (≥3 cm diameter) (N=28) had preoperative and postoperative data including magnetic resonance imaging (MRI) and measurement of six pituitary hormones levels, adrenocorticotropic hormone (ACTH), growth hormone (GH), thyroid-stimulating hormone (TSH), prolactin (PRL), follicle-stimulating hormone (FSH), and luteinizing hormone (LH). The postoperative general pituitary hormone score, for 57 patients who underwent subtotal resection (>60%) and nine patients who underwent partial resection (≤60%), was 1-5 for each hormone level (score range, 6-30). RESULTS ACTH, GH, TSH, PRL, FSH, and LH levels in 38 patients with pituitary null cell macroadenoma were not statistically different from the 28 patients with pituitary null cell giant adenoma; the general pituitary hormone score in the former group was significantly increased compared with the latter group (P<0.05). ACTH, GH, TSH, PRL, FSH, and LH levels in the 57 patients with subtotal tumor resection were not significantly different from the nine patients with partial tumor resection; the general pituitary hormone score in the former group was significantly reduced compared with the latter group (P<0.05). CONCLUSIONS A general pituitary hormone score was developed that might be relevant to the evaluation of pituitary function following surgical resection of pituitary null cell macroadenoma and giant adenoma.

Hypertensive crisis in pregnancy due to a metamorphosing pheochromocytoma with postdelivery Cushing's syndrome.

Pheochromocytomas in pregnancy are rare but potentially lethal. Even rarer is the combination of pheochromocytoma in pregnancy with subsequent development of ectopic Cushing's syndrome. We report a 36-year-old woman, previously diagnosed with essential hypertension, who developed severe hypertension in pregnancy complicated by insulin-dependent gestational diabetes. A cesarean section was performed at 32 weeks following a hypertensive crisis after routine administration of betamethasone. Postnatal persistence of signs and symptoms of catecholamine excess led to the diagnosis of a left adrenal pheochromocytoma. Between diagnosis and planned tumor removal, the patient developed signs and symptoms of Cushing's syndrome (facial edema and hirsutism, myopathy and fatigue). Biochemical testing confirmed hypercortisolism with extremely elevated levels of plasma adrenocorticotropin, urinary cortisol and multiple steroids of a plasma panel that were all normal at previous testing. The previously noradrenergic tumor also started producing epinephrine. Histopathological examination confirmed the pheochromocytoma, which was also immunohistochemically positive for adrenocorticotropin. Full post-surgical recovery was sustained with normal blood pressure and biochemical findings after one year. This report not only underlines the chameleon behavior of pheochromocytoma but also illustrates its potential for a metamorphosing presentation. Corticosteroid administration in pregnancy requires a cautious approach in patients with hypertension.

[The hormonal indices of hypophysis-adrenal glands system in combatants during missions to "trouble spots".]

The officials of the Interior Ministry of Russia usually perform their duties in extreme and quite often emergency conditions. The hypophysis-adrenal glands system of regulation mainly contributes into supporting formation of mechanisms of compensation of these exposures. The purpose of study is to analyze alterations of content of adrenocorticotropic hormone, cortisol, adrenaline and noradrenaline in officials of the Interior Ministry sent on a mission to territories with local military conflict (the Northern Caucasus) to support public order. The study results demonstrated that during first two months of mission a significant increasing of level of analyzed hormones occurs. This is a proper reaction to changed conditions of environment. These alterations correspond to main propositions of the general adaptation syndrome theory. However, further observation in dynamics of mission established presence of signs of imbalance of secretion of hormones in hypophysis-adrenal glands system. The long-lasting conserving high content of both of adrenocorticotropic hormone and cortisol till the end of mission was established. At the same time, content of hormones of "fast response" to extreme factors of environment (adrenaline, noradrenaline) occurred to be as higher as at the beginning of mission. Such occurrences result in disorder of regulation of inter hormonal relationships that correspondingly is a factor of decreasing of vital stress resistance of organism. The main directions of organizational medical character are proposed within th framework of activities supporting resistance of organism to conditions of extreme impact of emergency situations and decreasing risk of development of pathological conditions.

Giant Basal Cell Carcinomas Express Neuroactive Mediators and Show a High Growth Rate: A Case-Control Study and Meta-Analysis of Etiopathogenic and Prognostic Factors.

BACKGROUND: Giant basal cell carcinomas (GBCCs), (BCC ≥ 5 cm), are often painless, destructive tumors resulting from poorly understood patient neglect. OBJECTIVES: To elucidate etiopathogenic factors distinguishing GBCC from basal cell carcinoma (BCC) and identify predictors for disease-specific death (DSD). METHODS: Case-control study examining clinicopathologic and neuroactive factors (ß-endorphin, met-enkephalin, serotonin, adrenocorticotropic hormone, and neurofilament expression) in GBCC and BCC. Systematic literature review to determine DSD predictors. RESULTS: Thirteen GBCCs (11 patients) were compared with 26 BCCs (25 patients). GBCC significantly differed in size, disease duration, and outcomes; patients were significantly more likely to live alone, lack concern, and have alcoholism. GBCC significantly exhibited infiltrative/morpheic phenotypes, perineural invasion, ulceration, and faster growth. All neuromediators were similarly expressed. Adenoid phenotype was significantly more common in GBCC. Adenoid tumors expressed significantly more ß-endorphin (60% vs. 18%, P = 0.01) and serotonin (30% vs. 4%, P = 0.02). In meta-analysis (n ≤ 311: median age 68 years, disease duration 90 months, tumor diameter 8 cm, 18.4% disease-specific mortality), independent DSD predictors included tumor diameter (cm) (hazard ratio (HR): 1.12, P = 0.003), bone invasion (HR: 4.19, P = 0.015), brain invasion (HR: 8.23, P = 0.001), and distant metastases (HR: 14.48, P = 0.000). CONCLUSIONS: GBCC etiopathogenesis is multifactorial (ie, tumor biology, psychosocial factors). BCC production of paracrine neuromediators deserves further study.

The quantitative evaluation of the immunohistochemical expression of the pituitary adenomas.

BACKGROUND: The aim of this study was to evaluate morphometrically the pituitary adenomas immunoexpression. METHODS: The cases of 72 patients were analyzed, who underwent transsphenoidal surgery for pituitary adenomas. Subsequently, the immunohistochemical pituitary hormone panel was applied including alpha- subunit of the glycoprotein hormones. Immunohistochemical sections were analyzed quantitatively with the help of morphometric grid. The percentage rate of the immunoexpression was calculated separately for every single hormone. RESULTS: As a result, 22 monohormonal adenomas (30.56%), 21 plurihormonal adenomas (29.17%), 21 immunonegative adenomas (29.17%) and 8 unreliable cases (11.11%) were recognized. The immunopositivity for particular hormones was found as follows: PRL and GH (25% each), α-SU (22.22%), ACTH (13.89%), LH and FSH (12.5% each), and TSH (5.56%). An average percentage of immunoexpression in each positive staining groups occurred as follows: for PRL - 59.98%, for GH - 53.97%, for ACTH - 39.21%, for TSH - 25.05%, for LH - 37.3%, for FSH - 54.66%, for α-SU - 45.71. CONCLUSION: The morphometrical method utilizing the immunoexpression index introduced in this study provided a very precise recognition of pituitary adenomas pathology. This method may limit the subjectivity of a single researcher and enable better comparison of the studies. The plurihormonality is a common phenomenon, and immunohistochemical staining for all adenohypophyseal hormones is obligatory in order to classify pituitary adenomas correctly. The awareness of an operating neurosurgeon of the importance of meticulous collecting histopathological material, especially in microadenoma cases, has essential impact on further neuropathological evaluation and possibility of immunohistochemical staining.