Probiotic and high-fat diet: effects on pain assessment, body composition, and cytokines in male and female adolescent and adult rats.

Obesity in adolescence is increasing in frequency and is associated with elevated proinflammatory cytokines and chronic pain in a sex-dependent manner. Dietary probiotics may mitigate these detrimental effects of obesity. Using a Long-Evans adolescent and adult rat model of overweight (high fat diet - 45% kcal from fat from weaning; HFD), we determined the effect of a single strain dietary probiotic (L. plantarum 299v [Lp299v] from weaning) on the theoretically increased neuropathic injury-induced pain phenotype and inflammatory cytokines. We found that although HFD increased fat mass, it did not markedly affect pain phenotype, particularly in adolescence, but there were subtle differences in pain in adult male vs. female rats. The combination of HFD and Lp299v augmented the increase in leptin in adolescent females. There were many non-interacting, main effects of age, diet and probiotic on an array of cytokines and adipokines with adults being higher than adolescents, HFD higher than the control diet, and a decrease with probiotic compared to placebo. Of particular interest were the probiotic-induced increases in IL12p70 in female adolescents on a HFD. We conclude that a more striking pain phenotype could require a higher and longer duration caloric diet or different etiology of pain. A major strength of our study was that a single strain probiotic had a wide range of inhibiting effects on most pro-inflammatory cytokines. The positive effect of probiotic on leptin in female adolescent rats is intriguing and worthy of exploration.

Periodic hypoxia, intermittent pain, and caffeine in male and female neonatal rats: corticosterone, insulin resistance, and hepatic gene expression.

Preterm infants experience multiple stressors including periodic neonatal hypoxia, maternal/caregiver separation, and acute pain from clinical procedures. Although neonatal hypoxia or interventional pain are associated with sexually dimorphic effects that may last into adulthood, the interaction of these common preterm stressors and caffeine pretreatment remains unknown. We hypothesize that an interaction of acute neonatal hypoxia, isolation, and pain modeling the experience of the preterm infant will augment the acute stress response and that caffeine routinely given to preterm infants will alter this response. Male and female rat pups were isolated and exposed to six cycles of periodic hypoxia (10% O2) or normoxia (room air control) and/or intermittent pain by administering needle pricks (or touch control) to the paw on postnatal (PD) days 1-4. An additional set of rat pups was pretreated with caffeine citrate (80 mg/kg ip) and studied on PD1. Plasma corticosterone, fasting glucose, and insulin were measured to calculate homeostatic model assessment for insulin resistance (HOMA-IR) (index of insulin resistance). Glucocorticoid-, insulin-, and caffeine-sensitive gene mRNAs were analyzed in the PD1 liver and hypothalamus to evaluate downstream markers of glucocorticoid action. Acute pain with periodic hypoxia led to a large increase in plasma corticosterone, which was attenuated by pretreatment with caffeine. Pain with periodic hypoxia led to a 10-fold increase in hepatic Per1 mRNA expression in males, which was attenuated with caffeine. The augmentation of corticosterone and HOMA-IR at PD1 after periodic hypoxia with pain suggests early intervention to attenuate the stress response may mitigate the programming effects of neonatal stress.

Sleep restriction during opioid abstinence affects the hypothalamic-pituitary-adrenal (HPA) axis in male and female rats.

Hypothalamic-pituitary-adrenal (HPA) axis dynamics are disrupted by opioids and may be involved in substance abuse; this persists during withdrawal and abstinence and is associated with co-morbid sleep disruption leading to vulnerability to relapse. We hypothesized that chronic sleep restriction (SR) alters the HPA axis diurnal rhythm and the sexually dimorphic response to acute stressor during opioid abstinence. We developed a rat model to evaluate the effect of persistent sleep loss during opioid abstinence on HPA axis dynamics in male and female rats. Plasma ACTH and corticosterone were measured diurnally and in response to acute restraint stress in rats Before (control) compared to During subsequent opioid abstinence without or with SR. Abstinence, regardless of sleep state, led to an increase in plasma ACTH and corticosterone in the morning in males. There was a tendency for higher PM plasma ACTH during abstinence in SR males (p = 0.076). ACTH and corticosterone responses to restraint were reduced in male SR rats whereas there was a failure to achieve the post-restraint nadir in female SR rats. There was no effect of the treatments or interventions on adrenal weight normalized to body weight. SR resulted in a dramatic increase in hypothalamic PVN AVP mRNA and plasma copeptin in male but not female rats. This corresponded to the attenuation of the HPA axis stress response in SR males during opioid abstinence. We have identified a potentially unique, sexually dimorphic role for magnocellular vasopressin in the control of the HPA axis during opioid abstinence and sleep restriction.

Salivary Cortisol Dynamics After Mild Traumatic Brain Injury.

OBJECTIVE: To assess mild traumatic brain injury (mTBI)-related alterations in baseline (resting) salivary cortisol and cortisol reactivity to cognitive and exercise stressors, which are frequently encountered during mTBI rehabilitation and recovery. SETTING: Persons with mTBI were recruited from a level 1 trauma center emergency department. Uninjured controls (UCs) were recruited from the community. PARTICIPANTS: Participants were 37 individuals with mTBI and 24 UCs. All patients with mTBI were enrolled at 7 ± 3 days post-injury, met the American Congress of Rehabilitation Medicine definition of mTBI, and had no acute intracranial findings on clinical neuroimaging (if performed). DESIGN: A prospective cohort study design was used. All participants provided saliva samples 10 times during each of 2 visits spaced 3 weeks apart (1 week and 1 month post-injury for the mTBI group). Each visit included baseline saliva sampling and sampling to evaluate reactivity to a cognitive stressor (Paced Auditory Serial Addition Test) and physical stressor (Buffalo Concussion Treadmill Test [BCTT]). MAIN OUTCOME MEASURE: Natural log-transformed salivary cortisol was measured by enzyme immunoassay. Cortisol was predicted using a linear mixed-effects model by group (mTBI and UC), visit (1 week and 1 month), and saliva sample. RESULTS: Mean salivary cortisol was higher in the mTBI group (1.67 nmol/L [95% CI 1.42-1.72]) than in controls (1.30 nmol/L [1.12-1.47]), without an mTBI × time interaction. At 1 week, the mTBI group had greater cortisol reactivity in response to the BCTT. CONCLUSIONS: Higher cortisol in individuals with mTBI at 1 week and 1 month post-injury extends previous findings into the subacute recovery period. Furthermore, the mTBI group demonstrated a greater cortisol response to mild-to-moderate aerobic exercise (BCTT) at 1 week post-injury. Given the increasing role of exercise in mTBI rehabilitation, further research is warranted to replicate these findings and identify the clinical implications, if any, of enhanced hypothalamic-pituitary-adrenal axis responses to exercise in civilians with recent mTBI.

Interaction of chronic pain, obesity and time of day on cortisol in female human adolescents.

Adolescent obesity augments and impedes the treatment of chronic pain. This is associated with increased systemic inflammation and is more prominent in females. In addition, pain and obesity each independently affect the hypothalamic-pituitary-adrenal (HPA) axis. However, the interaction of pain and obesity on the HPA axis and the potential for sexual dimorphism in this phenomenon is not established. We hypothesized that dysregulation of the HPA axis occurs in female human adolescents with chronic pain, obesity, or the combination of the two and is associated with gonadal steroids. We measured serum cortisol, estradiol, and testosterone in 13-17-year-old adolescent females (N = 79) from venous blood drawn during the daytime (0830-1730 h) and analyzed the data in toto and partitioned by morning vs. afternoon sampling time. Subjects were categorized as healthy weight/no pain (controls; BMI = 56th percentile [37-71]), healthy weight with chronic pain, obese without pain (BMI = 97th percentile [95-99]), or the combination of obesity and chronic pain. Serum cortisol was lower with chronic pain and/or obesity compared to healthy controls and was lower with chronic pain and obesity compared to chronic pain alone (healthy weight). The lower serum cortisol in the pain alone group was more prominent in the morning compared to the afternoon. There was no relationship between serum estradiol and testosterone and study group. The decrease in the anti-inflammatory and other pain-ameliorating effects of cortisol may contribute to chronic pain and its resistance to treatment with concurrent obesity in female adolescents.

Late Night Salivary Cortisol in the diagnosis of neoplastic hypercortisolism (including cyclic Cushing's syndrome).

Late night salivary cortisol (LNSC) is a mainstay in the diagnosis of neoplastic hypercortisolism (Cushing's syndrome) with a sensitivity and specificity of > 90% in patients with syndromic signs and symptoms. Intermittent hormonogenesis (day to day variation) is common in milder Cushing's disease whereas true cyclic Cushing's syndrome (weeks to months of tumor quiescence) is unusual. In both cases, LNSC is useful as a sensitive evaluative diagnostic tool, although its lower specificity may lead to false positive results in patients without Cushing's disease. Furthermore, intermittent hormonogenesis may lead to false negative LNSC results in patients with mild Cushing's disease. Finally, LNSC is useful as an approach to follow patients after pituitary surgery to detect a recurrence even many years after a full remission.

Opioids and pituitary function: expert opinion.

PURPOSE: Opioids are highly addictive potent analgesics and anti-allodynics whose use has dramatically increased in recent decades. The precipitous rise in opioid dependency and opioid use disorder is an important public health challenge given the risks for severely adverse health outcomes. The long-term opioid impact on hypothalamic-pituitary axes is particularly underappreciated among both endocrinologists and primary care physicians. We review the effects of opioids on hypothalamic-pituitary-target gland function and their implications for clinical practice. METHODS: Experts in hypothalamic-pituitary disorders and opioid pharmacology reviewed recently published literature and considered strategies for diagnosing and managing these opioid-induced endocrine effects. RESULTS: Opioid suppression of hypothalamic-pituitary axes can lead to hypogonadotropic hypogonadism, central adrenal insufficiency, and hyperprolactinemia. These important clinical manifestations are often under-estimated, poorly evaluated, and typically either untreated or not optimally managed. Data on biochemical testing for diagnosis and on the effect of hormone replacement in these patients is limited and prospective randomized controlled studies for guiding clinical practice are lacking. CONCLUSIONS: Patients should be informed about risks for hypogonadism, adrenal insufficiency, and hyperprolactinemia, and encouraged to report associated symptoms. Based on currently available evidence, we recommend clinical and biochemical evaluation for potential central adrenal insufficiency, central hypogonadism, and/or hyperprolactinemia in patients chronically treated with opioids as well as the use of current expert guidelines for the diagnosis and treatment of these conditions.

Lipid signatures of chronic pain in female adolescents with and without obesity.

BACKGROUND: Chronic pain in adolescence is associated with diminished outcomes, lower socioeconomic status in later life, and decreased family well-being. Approximately one third of adolescents with chronic pain have obesity compared to the general population. In obesity, lipid signals regulate insulin sensitivity, satiety, and pain sensation. We determined whether there is a distinct lipid signature associated with chronic pain and its co-occurrence with obesity in adolescents. METHODS: We performed global lipidomics in serum samples from female adolescents (N = 67, 13-17 years old) with no pain/healthy weight (Controls), chronic pain/healthy weight (Pain Non-obese), no pain/obesity (Obese), or chronic pain/obesity (Pain Obese). RESULTS: The Pain Non-obese group had lipid profiles similar to the Obese and Pain Obese groups. The major difference in these lipids included decreased lysophosphatidylinositol (LPI), lysophosphatidylcholine (LPC), and lysophosphatidylethanolamine (LPE) in the three clinical groups compared to the Control group. Furthermore, ceramides and sphingomyelin were higher in the groups with obesity when compared to the groups with healthy weight, while plasmalogens were elevated in the Pain Obese group only. CONCLUSIONS: Serum lipid markers are associated with chronic pain and suggest that specific lipid metabolites may be a signaling mechanism for inflammation associated with co-occurring chronic pain and obesity.

Team triathlon effects on physiological, psychological, and immunological measures in women breast cancer survivors.

PURPOSE: Exercise after breast cancer diagnosis and treatment improves cancer-related outcomes, although the mechanisms involved are not clear. This study evaluated the impact of exercise on body composition, strength, endurance, quality of life (QOL), fatigue, and endocrine and inflammatory biomarkers in breast cancer survivors participating in a highly monitored, clinically supervised, moderate-intensity exercise program. The association of hormonal and inflammatory biomarkers with the observed physiological changes was assessed. METHODS: Female breast cancer survivors (BCS; n = 46) who engaged in a goal-oriented 14-week triathlon exercise training program were compared to an untrained control group of female BCS (n = 16). Psychosocial metrics, QOL, cancer-related fatigue, and exercise self-efficacy were evaluated via pre- and post-exercise intervention questionnaires. Serum estradiol and inflammatory biomarkers (C-reactive protein (CRP), sTNFR1a, estradiol, leptin, and adiponectin) were measured prior to the exercise training program start and after the completion of the goal triathlon. RESULTS: After exercise training, the exercise group had lower BMI and arm circumferences. Greater positive change was noted in the trained group for QOL, fatigue, and self-efficacy questionnaires. Functional endurance improved in the trained but not the control group. Knee and elbow strength were not different between the groups, except that knee flexion at 180 degrees∙sec-1 was higher in trained. The only significantly different biomarker was adiponectin, which decreased in the trained group. CONCLUSIONS: Group triathlon exercise training may be beneficial to BCS by significantly improving their psychosocial measures, functional endurance, and BMI.

Insulin sensitivity, leptin, adiponectin, resistin, and testosterone in adult male and female rats after maternal-neonatal separation and environmental stress.

Care of premature infants often requires parental and caregiver separation, particularly during hypoxic and hypothermic episodes. We have established a neonatal rat model of human prematurity involving maternal-neonatal separation and hypoxia with spontaneous hypothermia prevented by external heat. Adults previously exposed to these neonatal stressors show a sex difference in the insulin and glucose response to arginine stimulation suggesting a state of insulin resistance. The current study used this cohort of adult rats to evaluate insulin resistance [homeostatic model assessment of insulin resistance (HOMA-IR)], plasma adipokines (reflecting insulin resistance states), and testosterone. The major findings were that daily maternal-neonatal separation led to an increase in body weight and HOMA-IR in adult male and female rats and increased plasma leptin in adult male rats only; neither prior neonatal hypoxia (without or with body temperature control) nor neonatal hypothermia altered subsequent adult HOMA-IR or plasma adiponectin. Adult male-female differences in plasma leptin were lost with prior exposure to neonatal hypoxia or hypothermia; male-female differences in resistin were lost in the adults that were exposed to hypoxia and spontaneous hypothermia as neonates. Exposure of neonates to daily hypoxia without spontaneous hypothermia led to a decrease in plasma testosterone in adult male rats. We conclude that neonatal stressors result in subsequent adult sex-dependent increases in insulin resistance and adipokines and that our rat model of prematurity with hypoxia without hypothermia alters adult testosterone dynamics.

Effect of a melanocortin type 2 receptor (MC2R) antagonist on the corticosterone response to hypoxia and ACTH stimulation in the neonatal rat.

The adrenal stress response in the neonatal rat shifts from ACTH-independent to ACTH-dependent between postnatal days 2 (PD2) and 8 (PD8). This may be due to an increase in an endogenous, bioactive, nonimmunoreactive ligand to the melanocortin type 2 receptor (MC2R). GPS1574 is a newly described MC2R antagonist that we have shown to be effective in vitro. Further experimentation with GPS1574 would allow better insight into this seemingly ACTH-independent steroidogenic response in neonates. We evaluated the acute corticosterone response to hypoxia or ACTH injection following pretreatment with GPS1574 (32 mg/kg) or vehicle for GPS1574 in PD2, PD8, and PD15 rat pups. Pretreatment with GPS1574 decreased baseline corticosterone in PD2 pups but increased baseline corticosterone in PD8 and PD15 pups. GPS1574 did not attenuate the corticosterone response to hypoxia in PD2 pups and augmented the corticosterone response in PD8 and PD15 pups. GPS1574 augmented the corticosterone response to ACTH in PD2 and PD15 pups but had no significant impact on the response in PD8 pups. Baseline adrenal Mrap and Star mRNA increased from PD2 to PD15, whereas Mrap2 mRNA expression was low and did not change with age. The data suggest that GPS1574 is not a pure MC2R antagonist, but rather acts as a biasing agonist/antagonist. Its ability to attenuate or augment the adrenal response may depend on the ambient plasma ACTH concentration and/or developmental changes in early transduction steroidogenic pathway genes.

Cushing's syndrome: from physiological principles to diagnosis and clinical care.

The physiological control of cortisol synthesis in the adrenal cortex involves stimulation of adrenocorticotrophic hormone (ACTH) by hypothalamic corticotrophin-releasing hormone (CRH) and then stimulation of the adrenal by ACTH. The control loop of the hypothalamic-pituitary-adrenal (HPA) axis is closed by negative feedback of cortisol on the hypothalamus and pituitary. Understanding this system is required to master the diagnosis, differential diagnosis and treatment of endogenous hypercortisolism--Cushing's syndrome. Endogenous Cushing's syndrome is caused either by excess ACTH secretion or by autonomous cortisol release from the adrenal cortex. Diagnosis of cortisol excess exploits three physiological principles: failure to achieve the normal nadir in the cortisol diurnal rhythm, loss of sensitivity of ACTH-secreting tumours to cortisol negative feedback, and increased excretion of free cortisol in the urine. Differentiating a pituitary source of excess ACTH (Cushing's disease) from an ectopic source is accomplished by imaging the pituitary and sampling for ACTH in the venous drainage of the pituitary. With surgical removal of ACTH or cortisol-secreting tumours, secondary adrenal insufficiency ensues because of the prior suppression of the HPA axis by glucocorticoid negative feedback. Medical therapy is targeted to the anatomical location of the dysregulated component of the HPA axis. Future research will focus on new diagnostics and treatments of Cushing's syndrome. These are elegant examples of translational research: understanding basic physiology informs the development of new approaches to diagnosis and treatment. Appreciating pathophysiology generates new areas for inquiry of basic physiological and biochemical mechanisms.

Renin knockout rat: control of adrenal aldosterone and corticosterone synthesis in vitro and adrenal gene expression.

The classic renin-angiotensin system is partly responsible for controlling aldosterone secretion from the adrenal cortex via the peptide angiotensin II (ANG II). In addition, there is a local adrenocortical renin-angiotensin system that may be involved in the control of aldosterone synthesis in the zona glomerulosa (ZG). To characterize the long-term control of adrenal steroidogenesis, we utilized adrenal glands from renin knockout (KO) rats and compared steroidogenesis in vitro and steroidogenic enzyme expression to wild-type (WT) controls (Dahl S rat). Adrenal capsules (ZG; aldosterone production) and subcapsules [zona reticularis/fasciculata (ZFR); corticosterone production] were separately dispersed and studied in vitro. Plasma renin activity and ANG II concentrations were extremely low in the KO rats. Basal and cAMP-stimulated aldosterone production was significantly reduced in renin KO ZG cells, whereas corticosterone production was not different between WT and KO ZFR cells. As expected, adrenal renin mRNA expression was lower in the renin KO compared with the WT rat. Real-time PCR and immunohistochemical analysis showed a significant decrease in P450aldo (Cyp11b2) mRNA and protein expression in the ZG from the renin KO rat. The reduction in aldosterone synthesis in the ZG of the renin KO adrenal seems to be accounted for by a specific decrease in P450aldo and may be due to the absence of chronic stimulation of the ZG by circulating ANG II or to a reduction in locally released ANG II within the adrenal gland.

Adrenocortical sensitivity to ACTH in neonatal rats: correlation of corticosterone responses and adrenal cAMP content.

A coordinated hypothalamic-pituitary-adrenal axis response is important for the survival of newborns during stress. We have previously shown that prior to postnatal day (PD) 5, neonatal rats exposed to hypoxia (one of the most common stressors effecting premature neonates) exhibit a large corticosterone response with a minimal increase in immunoassayable plasma ACTH and without a detectable increase in adrenal cAMP content (the critical second messenger). To explore the phenomenon of ACTH-stimulated steroidogenesis in the neonate, we investigated the adrenal response to exogenous ACTH in the normoxic neonatal rat. Rat pups at PD2 and PD8 were injected intraperitoneally with porcine ACTH at low, moderate, or high doses (1, 4, or 20 µg/kg body wt). Trunk blood and whole adrenal glands were collected at baseline (before injection) and 15, 30, or 60 min after the injection. ACTH stimulated corticosterone release in PD2 and PD8 pups. In PD2 pups, plasma corticosterone at baseline and during the response to ACTH injection was greater than values measured in PD8 pups, despite lower adrenal cAMP content in PD2 pups. Specifically, the low and moderate physiological ACTH doses produced a large corticosterone response in PD2 pups without a change in adrenal cAMP content. At extremely high, pharmacological levels of plasma ACTH in PD2 pups (exceeding 3,000 pg/ml), an increase in adrenal cAMP was measured. We conclude that physiological increases in plasma ACTH may stimulate adrenal steroidogenesis in PD2 pups through a non-cAMP-mediated pathway.

Use of the Buffalo Concussion Treadmill Test in community adult patients with mild traumatic brain injury.

BACKGROUND: The Buffalo Concussion Treadmill Test (BCTT) is used to establish exercise tolerance for rehabilitation and identify injury subtypes for youth athletes after mild traumatic brain injury (mTBI). Its utility in adult community members is unknown. OBJECTIVE: Primary: To describe how adults with and without mTBI tolerate the BCTT. Secondary: To explore relationships between baseline factors, mTBI-related symptoms, and BCTT duration. DESIGN: Prospective, observational, longitudinal. SETTING: Academic medical center. PARTICIPANTS: Thirty-seven adults treated in a level 1 trauma center emergency department with mTBI; 24 uninjured controls (UC). INTERVENTIONS: N/A. MAIN MEASURES: Participants completed two visits 3 weeks apart (1 week and 1 month after mTBI) including a 15-minute BCTT, the Rivermead Post Concussion Symptoms Questionnaire (RPQ), and preinjury International Physical Activity Questionnaire. Analyses characterized BCTT response and associations between baseline factors, RPQ scores, and BCTT duration. RESULTS: Persons with mTBI discontinued earlier than UC at 1-week postinjury using standard discontinuation criteria for exercise intolerance. The percentage of mTBI participants with signs of possible mTBI-related intolerance was 55.6% at 1 week (36.1% for mTBI-related symptom exacerbation, 19.4% for exertion/fatigue before reaching 85% of one's age-predicted maximum heart rate [HR]) and 48.0% at 1 month (40.0% mTBI-related symptom exacerbation, 8.0% exertion without reaching the target HR). Thirty percent of UCs completed the BCTT at both assessments. UCs met discontinuation criteria for increased nonspecific symptoms (eg, pain/general discomfort and increased Visual Analog Scale ratings; 39-61%) and physical exertion (9-26%). Shorter duration was associated with higher body mass index (r = -0.42 - -0.45), shorter height (r = 0.22-0.29), female gender (r = -0.26 - -0.27), and greater RPQ symptoms (r = -0.28 - -0.47). CONCLUSION: The BCTT exacerbates mTBI-related symptoms in adult community members. Participant characteristics and noninjury factors influence performance. The findings imply the BCTT could be useful in clinical assessments of adults with mTBI. Interpretation should account for the unique characteristics of nonathletes.

Differences in Fluid, Electrolyte, and Energy Balance in C57BL/6J Mice (Mus musculus) in Metabolic Caging at Thermoneutral or Standard Room Temperatures.

The Guide for the Care and Use of Laboratory Animals recommends mice be pair or group housed and provided with nesting materials. These provisions support social interactions and are also critical for thermoregulatory behaviors such as huddling and burrowing. However, studies of fluid and electrolyte balance and digestive function may involve use of metabolic caging (MC) systems in which mice are housed individually on wire-mesh floors that permit quantitative collection of urine and feces. MC housing prevents mice from performing their typical huddling and burrowing behaviors. Housing in MC can cause weight loss and behavioral changes in rodents. Here, we tested the hypothesis that MC housing of mice at standard room temperature (SRT, 22 to 23 °C) exposes them to cold stress, which causes metabolic changes in the mice as compared with standard housing. We hypothesized that performing MC studies at a thermoneutral temperature (TNT, 30 °C) would minimize these changes. Fluid, electrolyte, and energy balance and body composition were assessed in male and female C57BL/6J mice housed at SRT or TNT in MC, static microisolation cages, or a multiplexed metabolic phenotyping system designed to mimic static microisolation cages (Promethion, Sable Systems International). In brief, as compared with MC housing at SRT, MC housing at TNT was associated with lower food intake and energy expenditure, absence of weight loss, and lower urine and fecal corticosterone levels. These results indicate that housing in MC at SRT causes cold stress that can be mitigated if MC studies are performed at TNT.

Effects of age on ACTH, corticosterone, glucose, insulin, and mRNA levels during intermittent hypoxia in the neonatal rat.

Apnea, the temporary cessation of respiratory airflow, is a common cause of intermittent hypoxia (IH) in premature infants. We hypothesized that IH elicits a stress response and alters glucose homeostasis in the neonatal rat. Rat pups were studied on postnatal day (PD) 2, 8, 10, 12, and 14. Pups were exposed to normoxia (control) or six cycles consisting of 30-s exposures to hypoxia (FiO2 = 3%) over a 60-min period. Blood samples were obtained at baseline, after the third cycle (~30 min), and after the sixth cycle (~60 min). Tissue samples were collected following the sixth cycle. Plasma ACTH, corticosterone, glucose, and insulin were analyzed at all ages. Hypothalamic, pituitary, and adrenal mRNA expression was evaluated by quantitative PCR in PD2, PD8, and PD12 pups. Exposure to IH elicited significant increases in plasma ACTH and corticosterone at all ages studied. The largest increase in corticosterone occurred in PD2 pups, despite only a very small increase in plasma ACTH. This ACTH-independent increase in corticosterone in PD2 pups was associated with increases in adrenal Ldlr and Star mRNA expression. Additionally, IH caused hyperglycemia and hyperinsulinemia at all ages. We conclude that IH elicits a significant pituitary-adrenal response and significantly alters glucose homeostasis. Furthermore, the quantitative and qualitative characteristics of these responses depend on developmental age.

Recognition of Nonneoplastic Hypercortisolism in the Evaluation of Patients With Cushing Syndrome.

The evaluation of suspected hypercortisolism is one of the most challenging problems in medicine. The signs and symptoms described by Dr Harvey Cushing are common and often create diagnostic confusion to even experienced endocrinologists. Cushing syndrome is classically defined as neoplastic hypercortisolism resulting from an ACTH-secreting tumor or from autonomous secretion of excess cortisol associated with benign or malignant adrenal neoplasia. The increasing recognition of the negative cardiometabolic effects of mild cortisol excess without overt physical signs of Cushing syndrome has led to more screening for endogenous hypercortisolism in patients with adrenal nodular disease, osteoporosis, and the metabolic syndrome. However, sustained or intermittent activation of the dynamic hypothalamic-pituitary-adrenal axis caused by chemical (alcohol), inflammatory (chronic kidney disease), psychologic (major depression), and physical (starvation/chronic intense exercise) stimuli can result in clinical and/or biochemical features indistinguishable from neoplastic hypercortisolism. Nonneoplastic hypercortisolism (formerly known as pseudo-Cushing syndrome) has been recognized for more than 50 years and often causes diagnostic uncertainty. This expert consultation describes two patients with features of Cushing syndrome who were referred for inferior petrosal sinus sampling for the differential diagnosis of ACTH-dependent hypercortisolism. Both patients were discovered to have nonneoplastic hypercortisolism: one from a covert alcohol use disorder and the other to chronic kidney disease. This consultation emphasizes the value of a good history and physical examination, appropriate laboratory testing, and the desmopressin acetate stimulation test to aid in distinguishing neoplastic from nonneoplastic hypercortisolism.

A New Approach - Home Waking Salivary Cortisone to Screen for Adrenal Insufficiency.

Adrenal insufficiency is a common and potentially life-threatening endocrine disorder that can be drug induced or endogenous and of adrenal (primary) or pituitary/hypothalamic (secondary/tertiary) origin.1,2 Of particular concern in drug-induced disease is the patient with glucocorticoid- or opioid-induced adrenal insufficiency. Adrenal insufficiency of any cause is typically diagnosed biochemically with a subnormal morning serum cortisol (the circadian, awakening peak) and serum dehydroepiandrosterone sulfate, followed by or simultaneously with an assessment of the acute (30 and 60 minutes) serum cortisol response to injected synthetic corticotropin (ACTH[1-24]), if clinically indicated.