CRH Stimulation Research Articles

Deep Venous Thrombosis in a Patient With Cushing’s Syndrome

Abstract Introduction: Cushing’s syndrome (CS) is associated with a prothrombotic state due to increased activation of several clotting factors. As such, patients are more susceptible to development of post-operative venous thrombosis. We present the case of a patient who underwent pituitary surgery for CS and subsequently developed acute lower extremity deep venous thrombosis (DVT) after stopping anticoagulation upon discharge. Case Report: A 57-year-old female presented with abdominal pain 1 month after gastric bypass surgery. She was found to have intra-abdominal abscesses and started on IV antibiotics. Upon further questioning, she endorsed 2-week history of coarse hair over chin, difficulty climbing stairs, and easy bruising. She had type 2 diabetes and hypertension, both diagnosed 2 years prior. Blood pressure was 169/88 on admission. On exam she had coarse hair on chin, central obesity, scattered ecchymoses, proximal muscle weakness, and no abdominal striae. Labs revealed potassium level of 1.9 mmol/L despite supplementation with 60 meq/day of potassium chloride. Workup showed random cortisol 45 mcg/dl, ACTH 114 pg/ml, elevated urinary free cortisol to 898.6 ug/24 hours, unsuppressed cortisol to 30.6 mcg/dL with low-dose dexamethasone and partial cortisol suppression to 11 mcg/dl with high-dose dexamethasone. MRI brain showed pituitary adenoma measuring 6 x 9 x 2 mm. CRH stimulation test showed rise of ACTH to 302 pg/ml and cortisol to 81.5 mcg/dl consistent with ACTH-dependent hypercortisolism from pituitary tumor. While hospitalized, the patient received thromboprophylaxis with SQ enoxaparin 40 mg daily. Patient was started on ketoconazole and subsequently underwent transsphenoidal resection to remove the pituitary tumor, which effectively reduced her serum cortisol levels. She was started on hydrocortisone replacement. She was discharged to a skilled nursing facility 2 weeks later. However, she did not receive thromboprophylaxis at the facility and was diagnosed with acute lower extremity DVT soon after hospital discharge. Discussion: CS is associated with increased risk of thromboembolic events. Although our patient received DVT prophylaxis in the hospital until discharge 2 weeks after surgery, she developed DVT soon after discharge. This emphasizes the increased susceptibility to development of venous thrombosis even after normalization of cortisol levels following pituitary surgery. A recent retrospective study showed that patients with CS are at higher risk of thromboembolism for approximately 30 to 60 days during the postoperative period. This case highlights that the clotting risk remains elevated in patients with CS for an extended period after successful surgery. In conclusion, patients with CS are at high risk of thromboembolism even after surgery and extended thromboprophylaxis should be considered.

The Effects of Sampling Lateralization on Bilateral Inferior Petrosal Sinus Sampling for Pediatric Cushing's Disease-A Single Endocrinology Centre Experience and Review of the Literature.

BackgroundThis study aims to analyze the diagnostic accuracy of bilateral inferior petrosal sinus sampling (BIPSS), the gold standard test for the differential diagnosis of ACTH-dependent Cushing’s syndrome (CS) in a group of pediatric patients with Cushing’s disease (CD).MethodsThis is a retrospective analysis which include 12 patients with hypercortisolemia and inconclusive pituitary MRI, who underwent bilateral inferior petrosal sinus sampling (BIPSS) and transsphenoidal surgery (TSS) from 2004 to 2020 in the Children’s Memorial Health Institute (CMHI) Warsaw, Poland. Pituitary origin of ACTH secretion was considered if baseline central to peripheral (C/P) ACTH level ratio was ≥ 2 or C/P ratio was ≥ 3 after human corticotropin-releasing hormone (hCRH) stimulation. The diagnosis was histologically confirmed in almost all cases after TSS.ResultsThe diagnostic accuracy of BIPSS reached 75% at baseline and 83.3% after CRH stimulation. The compatibility of localization of a microadenoma by BIPSS with the surgical location was 66.7%.ConclusionsOwing to its high diagnostic effectiveness, BIPSS remains the best test to differentiate CD from EAS. The indications for the procedure should be carefully considered, because EAS in the pediatric population, unlike in adults, is extremely rare. Moreover BIPSS has only limited value for indicating tumor localization.

Cateterismo de senos petrosos inferiores y estimulación con CRH: 15 años de experiencia en un hospital de tercer nivel

BackgroundInferior petrosal sinus sampling (IPSS) is indicated in the diagnosis of adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome (CS), especially when the results of the initial diagnostic tests are discordant. ObjectiveTo describe the patients who underwent this invasive functional test in a tertiary hospital. MethodsThis was an observational study of a retrospective cohort of patients with ACTH-dependent CS and IPSS between 2004 and 2019. We determined their epidemiological, hormonal, radiological and functional characteristics, and evaluated their diagnostic capacity and optimal cut-off points to differentiate between Cushing's disease (CD) and ectopic Cushing's syndrome (ECS). Results23 patients were evaluated, of which 65.2% were women with the average age of 42 (36-62) years. ACTH secretion of pituitary origin was evident in 82.6% of the patients and of ectopic origin in 17.4%. Plasma cortisol, urinary free cortisol, and ACTH levels were higher in patients with ECS. Regarding IPSS, the baseline central/peripheral ACTH gradient detected 89.5% of patients with CD and after stimulation with CRH, 100%. The optimal cut-off points in the diagnosis of CD were 2.06 at baseline and 2.49 after CRH stimulation. ConclusiónIPSS with CRH stimulation is a test with a high diagnostic accuracy for correctly classifying patients with CD and ECS. The cut-off points of the gradients may be different from the classic ones. Therefore, we recommend that each center perform its own evaluation.

MON-178 Cyclical Cushing’s Syndrome in 12 Patients with Ectopic ACTH Secretion

Background: Cyclical Cushing’s syndrome (CCS) is characterized by alternating periods of endogenous hypercortisolism and eucortisolism. A literature survey of 60 adult patients with CCS found 15 to have ectopic ACTH secretion (EAS) (1). The duration and frequency of hypercortisolemia are unpredictable, creating a diagnostic challenge. Objective: Describe biochemical and clinical characteristics of patients with CCS due to occult or histologically proven ectopic ACTH-secreting neuroendocrine tumor (NET). Methods: We conducted a retrospective medical record review of 12 adults with EAS admitted to our institution. Inclusion required 1) evidence of ectopic ACTH tumor from biochemical testing (CRH stimulation, 8 mg dexamethasone suppression [DST], and/or inferior petrosal sinus sampling [IPSS]) or pathology results and 2) cycles of hypercortisolism (Hi-F) to eucortisolism (Eu-F) off medical treatment. Results: Average age on admission was 61 (46-79) years; 58% were women. All 12 had biochemical evidence of ACTH-dependent Hi-F. IPSS results suggested EAS in 9 patients, 8 of whom had Hi-F for more than two months, and 1 whose cycles occurred every 5 - 7 days. IPSS was consistent with Cushing’s disease (CD) in 2 patients after Hi-F of only 6 -7 weeks and one with Eu-F on admission, estimated duration < 4 weeks. DST suggested EAS in 9 patients, and CD in the one with recent Eu-F. CRH was consistent with EAS in 10 patients, but suggested CD in 2 with marginal increases in ACTH (34.5%, 38%) but not cortisol. 7 patients had ACTH-secreting tumor on pathology (5 pulmonary, 1 pancreas, 1 appendix NET), and 5 had occult presumed EAS. Time from one Hi-F episode to the next ranged from 1 week to 6 years with Hi-F duration of 3 days to 5 years. 24-hour urine free cortisol (UFC) levels were 17 - 301 times the upper reference range (RR) during Hi-F periods. During Eu-F, lowest UFCs were within RR in 9 patients and subnormal in 3. Hypokalemia occurred in 11 patients with Hi-F; increasing values paralleled movement to Eu-F. Conclusion: Patients with possible ectopic ACTH-secretion and CCS may pose a diagnostic challenge: clinical and biochemical evidence of hypercortisolemia may not be present, depending on the timing and/or duration of hypercortisolism. Furthermore, test results may inappropriately suggest Cushing’s disease if performed after less than 8 weeks of hypercortisolism, or with recent eucortisolism. Thus, weekly UFC measurement may facilitate diagnosis of cyclical Cushing’s syndrome and determine appropriate timing of dynamic testing such as inferior petrosal sinus sampling. Potassium may be a useful marker to determine when medical treatment can be tapered or stopped.1. Meinardi JR, et al. Eur J Endocrinol. 157:245, 2007.

SAT-263 A Vicious Cycle of Hypercortisolism - Cyclical Cushing’s Syndrome

Background: Cyclical Cushing’s syndrome (CS) is described as periods of excess cortisol secretion interspersed with low or normal cortisol. The generally acceptable criteria for diagnosis is demonstration of 3 peaks and 2 troughs in cortisol secretion but, in practice, patterns and duration of cycles are unpredictable and can present a significant diagnostic challenge. Here, we present a case series of three patients who did not meet the published criteria but had pathological confirmation of ACTH-dependent CS. Clinical Case: Two women (A: 30 year-old, B: 40 year-old), and one man (C: 30 year-old) presented to the Pituitary Center for second/third opinions regarding CS. All patients had significant central weight gain. Patient A described cycles of rapid weight gain and loss, fluctuating facial and leg swelling, anxiety and darkening of stretch marks or scars punctuated with episodes of fatigue, lightheadedness and nausea. Patients B and C reported cyclical leg swelling, facial redness and acne. These patients had additional clinical signs of Cushingoid facies, dorsocervical and supraclavicular fat pads. Patient C had violaceous striae.Multiple tests for CS were performed: 1 mg overnight dexamethasone suppression test, two midnight salivary cortisols, and 24h urine free cortisol (UFC). All testing was normal, with a few exceptions. Patient A had an isolated midnight salivary cortisol elevated to 0.426 (<0.112 ug/dL). Patient C had two mildly elevated 24h UFC collections of 1.4 times upper limit of normal corresponding with his cycles of peripheral edema and acne. Patient B had completely negative testing. In all 3 patients, ACTH levels were not suppressed but also not elevated. Random serum DHEA-S levels were elevated in patients A and B.Patients A and C were found to have possible pituitary microadenomas on MRI with dynamic contrast. Patient B’s MRI was negative but inferior petrosal sinus sampling revealed a markedly elevated tumoral level of ACTH of >62,500 pg/mL with CRH stimulation. All 3 patients underwent endoscopic transsphenoidal resection by an expert pituitary surgeon with no post-operative complications in patients A & B, but development of partial diabetes insipidus in patient C. In patients A & C, pathology revealed corticotroph hyperplasia while patient B was found to have a corticotroph adenoma. Patients A & B persisted to have symptoms of hypercortisolism, opted to undergo bilateral adrenalectomy and pathology showed diffuse adrenocortical hyperplasia for both. Conclusion: Cyclical CS is likely underdiagnosed because of difficulty in obtaining biochemical confirmation even with strong clinical suspicion of CS. DHEA-S has a long half-life as well as minimal diurnal variation, and could be an additional clue in patients with suspected pituitary source of cyclical hypercortisolism. Ultimately, clinical concern should drive further diagnostic imaging and management.

SAT-142 Periodic Cushing Syndrome in a Patient with an Intestinal Neuroendocrine Tumor (NET). A Novel Case Report

Introduction A major diagnostic enigma regarding ACTH-dependent Cushing syndrome is the distinction between the source of ACTH, which may have either a pituitary or ectopic origin. We present the first described patient with cyclic Cushing syndrome caused by an intestinal neuroendocrine tumour (NET) detected by 68GA-DOTATATE PET-CT, despite functional tests that were indicative of pituitary Cushing disease. Clinical Case A 53-year old man was admitted to outpatient clinic because of muscle weakness. His phenotype and clinical findings (progressively worsening upper and lower limb weakness, emotional disturbances, easy bruising, a Buffalo hump, prediabetes and leucocytosis) led to the diagnosis of Cushing syndrome. Initial laboratory tests established the diagnosis with an abnormal diurnal cortisol and ACTH secretion (night cortisol F: 22.1μg / dl), absence of suppression with dexamethasone 1mg and increased free urinary free cortisol 24h (243.5μg /24h). Abdominal CT scanning revealed a left-sided adrenal adrenocortical adenoma 1.5 mm in max diameter. Pituitary MRI and somatostatin scintigraphy were normal. Low dexamethasone suppression test was indicative of Cushing (F: 14μg / dl) followed by a combined CRH stimulation test during bilateral inferior petrosal sinus sampling. Pituitary / peripheral ACTH ratio pre-infusion of CRH and 3 min after CRH infusion was compatible with right-sided pituitary origin of ACTH hypersecretion. Pending the results of the laboratory, the patient showed a remission of his symptoms along with a laboratory-confirmed recession of active hypercortisolaemia (LDDST test), and this led to the suspicion of periodic Cushing syndrome. The patient was followed with clinical and laboratory examinations weekly, with recurrence of symptoms 2 months later followed by a new remission 3 months later. A PETGA CT SCAN with 68GA-HA-DOTATATE was performed, which showed an increased uptake of the radioisotope in the small intestine. A surgical excision of the affected small bowel region was performed according to the guidelines for intestinal NETs. Histology confirmed the existence of a well-differentiated neuroendocrine neoplasm of the small intestine of 1.1 cm diameter, grade 1 (WHO 2010). Immunophenotype was positive for serotonin and ACTH. Postoperatively, the patient showed a complete remission of symptomatology and regression of hypercortisolaemia over a 18-month period. Follow-up abdominal MRI and 68GA-HA-DOTATATE revealed no pathological findings. Conclusion: Our patient is the first case of ectopic Cushing disease caused by intestinal NET. The differential diagnosis between pituitary and ectopic Cushing syndrome due to ACTH or CRH hypersecretion is not easy and frequently complicated by the periodicity of the disease. In patients with no visible pituitary lesions on MRI we suggest further investigation for ectopic ACTH- driven Cushing syndrome.

Olfactory neuroblastoma (esthesioneuroblastoma) presenting as ectopic ACTH syndrome: always follow your nose.

ACTH-dependent hypercortisolism is caused by an ectopic ACTH syndrome (EAS) in 20% of cases. We report a rare cause of EAS in a 41-year-old woman, presenting with clinical features of Cushing's syndrome which developed over several months. Biochemical tests revealed hypokalemic metabolic alkalosis and high morning cortisol and ACTH levels. Further testing, including 24-hour urine analysis, late-night saliva and low-dose dexamethasone suppression test, confirmed hypercortisolism. An MRI of the pituitary gland was normal. Inferior petrosal sinus sampling (IPSS) revealed inconsistent results, with a raised basal gradient but no rise after CRH stimulation. Additional PET-CT showed intense metabolic activity in the left nasal vault. Biopsy of this lesion revealed an unsuspected cause of Cushing's syndrome: an olfactory neuroblastoma (ONB) with positive immunostaining for ACTH. Our patient underwent transnasal resection of the tumour mass, followed by adjuvant radiotherapy. Normalisation of cortisol and ACTH levels was seen immediately after surgery. Hydrocortisone substitution was started to prevent withdrawal symptoms. As the hypothalamic-pituitary-axis slowly recovered, daily hydrocortisone doses were tapered and stopped 4 months after surgery. Clinical Cushing's stigmata improved gradually. Ectopic ACTH syndrome can originate from tumours outside the thoracoabdominal region, like the sinonasal cavity. The diagnostic accuracy of IPSS is not 100%: both false positives and false negatives may occur and might be due to a sinonasal tumour with ectopic ACTH secretion. Olfactory neuroblastoma (syn. esthesioneuroblastoma), named because of its sensory (olfactory) and neuroectodermal origin in the upper nasal cavity, is a rare malignant neoplasm. It should not be confused with neuroblastoma, a tumour of the sympathetic nervous system typically occurring in children. If one criticises MRI of the pituitary gland because of ACTH-dependent hypercortisolism, one should take a close look at the sinonasal field as well.

Early postoperative HPA-axis testing after pituitary tumor surgery: reliability and safety of basal cortisol and CRH test

PurposeTo assess the reliability and safety of a postsurgical evaluation strategy of adrenal function using CRH stimulation and basal cortisol concentrations after transsphenoidal pituitary surgery.MethodsRetrospective cohort study of all patients undergoing endoscopic transsphenoidal surgery from 2010 to 2017, in whom early postoperative basal cortisol and/or CRH-stimulated cortisol secretion were available, including confirmation of adrenal function during follow-up. Patients with Cushing’s disease were excluded. Optimal test performances were assessed using ROC analysis.ResultsA total of 156 patients were included. Sensitivity and specificity of the CRH test were 78% and 90%, respectively, and 86% and 92% for basal cortisol, respectively, using an optimal cutoff of 220 nmol/L. Eight patients had false-negative test results with the CRH test (normal test but adrenal insufficient at follow-up), and six patients with basal cortisol, the majority of which had multiple pituitary hormone deficiencies and fluid imbalances. No clinical adverse events occurred in patients with false-negative test results. The diagnostic performance of a single basal cortisol measurement was superior to the CRH test.ConclusionsThe early postoperative basal cortisol is a safe and simple measurement to guide (dis)continuation of hydrocortisone replacement. However, disturbing factors, e.g., sodium balance disorders, contraceptives, untreated hypopituitarism, and illness impact the interpretation and in those cases this measure is unreliable. We propose an algorithm in which hydrocortisone replacement at discharge is based on basal cortisol <220 nmol/L on postoperative day 2 or 3 in a stable condition.

Correlation between responsiveness to CRH stimulation test in Cushing's disease patients and USP8 mutational status

Correlation between responsiveness to CRH stimulation test in Cushing's disease patients and USP8 mutational status

SUN-368 Fatty Hypertrophy of the Hip as a Clinical Manifestation of Cushing Syndrome

Background: Increased fat deposition is a hallmark of exogenous and endogenous hypercortisolism (Cushing’s syndrome, CS). Fat accumulates not only in the abdomen and liver, but also in unusual locations such as the temporal and supraclavicular fossae, intrascapular fat pads and spinal epidural space (1). Here we describe, to our knowledge, the first report of intracapsular fat deposition at the hip in a patient (pt) with CS. Case Presentation: A 47 year old African American male presented with a six year history of diabetes and hypertension. He also reported abdominal weight gain, moodiness, facial flushing, blurry vision, fatigue, joint aches (especially knee and hips), muscle weakness leading to falls, difficulty with ambulation, straie, and decreased memory. Physical exam on admission revealed a rounded face with bitemporal fat pads, supraclavicular and dorsocervical fat pads, central obesity, +1 pitting edema of the lower extremities, 4/5 strength in shoulders and hips, ankle flexion and hand grip strength 5/5, wide violaceous striae on the abdomen. Biochemical evaluation revealed urine free cortisol 1460.8 and 1031.2 mcg/24h (ref: 3.5-45 mcg/24h), and plasma ACTH levels of 51.3-158 pg/ml (ref:5-46pg/ml). Pituitary MRI showed an 8mm lesion, CRH stimulation test showed 52% increase in cortisol level (29.8 to 43.1 mcg/dl) and a 79% increase in ACTH level, (95.9 to 175 pg/ml), suggestive of Cushing’s disease. However, cortisol increased by 41% after 8mg dexamethasone (23.2 to 32.8 mcg/dL), and IPSS also was consistent with an ectopic source of ACTH. A 10mm right hilar lesion was identified by CT, MRI, and 68Ga-DOTATATE. While awaiting surgical resection, pt was treated with ketoconazole and metyrapone. Three weeks after initiation of medical therapy, pt reported new unprovoked bilateral hip pain with antalgic gait. MRI hip revealed only bilateral symmetric intracapsular fat abutting the superolateral aspects of the femur in the subcapital region. There was no evidence of avascular necrosis of bone, osteoarthritis, or collagen tear. Physiatry evaluation reported functional hip strength in the 4- range, hip extension bilaterally 2+, unchanged ability from a prior admission to stand from sitting position without the use of upper extremities, and ability to ambulate independently across a room, but necessary use of a single point cane for longer distances. Physical therapy noted a decline in his mobility status since last visit, and recommended use of a wheeled walker. Discussion: This is the first time we have identified a patient with increased fat in the hip joint explained by no other comorbidities other than Cushing’s Syndrome. This new finding adds another unusual location for increased adipose in the clinical presentation of patients with CS. Further studies are needed to better assess the correlation between the finding of intracapsular hip fat, pain and hypercortisolism.

Two cases of traumatic isolated ACTH deficiency

Case 1: A 65- year-old man was accidentally injured by wooden hammer on his top of head on 34 years before. He was suffered from vomiting, diarrhea and hypotension, and the laboratory examination revealed increased CRP level, hyponatremia and decreased plasma cortisol and ACTH levels, suggesting isolated ACTH deficiency and Crohn disease diagnosed by colonoscopic biopsy, and finally transferred to University Hospital. LH-RH, TRH, CRH and GHRP stimulation tests showed normal response of plasma pituitary hormones except for no response of plasma ACTH and cortisol levels by CRH stimulation. ACTH stimulation test showed no response of plasma cortisol levels although hydrocotisone replacement therapy had already been started. MRI imaging showed bottom of anterior lobe was crushed and pituitary gland was atrophied, which suggested brain might be injured by any strong trauma.

Paraneoplastic Cushing Syndrome: A Sign of Occult Malignancy

SESSION TITLE: Metastatic and Other Primary Lung Tumors SESSION TYPE: Affiliate Case Report Poster PRESENTED ON: Tuesday, October 31, 2017 at 01:30 PM - 02:30 PM INTRODUCTION: Cushing Syndrome (CS) results from prolonged hypercortisolism. While often caused by iatrogenic administration of exogenous steroids or Cushing Disease, CS is also rarely caused by secretion of ACTH from ectopic sources, such as malignancies. Though rare - with ectopic ACTH secretion (EAS) accounting for only >15% of endogenous CS cases - diagnosis of CS can lead to earlier discovery of occult malignancy and increase potential for successful treatment. Clinicians therefore need a high degree of suspicion when faced with such presentations. CASE PRESENTATION: 57-yo man with CKD, CAD, HTN, DM and a long smoking history was admitted with respiratory failure due to CAP with dyspnea, weight gain, abdominal distention, and extremity weakness x 1 month. Physical exam showed reduced breath sounds over his right lower lung fields and abdominal obesity, but no Cushingoid appearance. He had marked refractory HTN. Labs showed profound hypokalemia with metabolic alkalosis, hypoxemia, hypercapnia and leukocytosis. CXR showed a right pleural effusion and basilar infiltrate. Elevated serum cortisol and ACTH levels helped diagnose CS. Abdominal CT showed no adrenal mass. Lab tests ruled out pheochromocytoma. A negative dexamethasone suppression test led to suspicion for EAS. CT Chest showed a mass with RML bronchial obstruction, mediastinal LAD and bilateral noncalcified lung nodules concerning for metastatic disease. While pleural fluid analysis showed a transudative effusion and microbiology was negative, cytology showed atypical cells suspicious for malignancy. Biopsy of the RML mass allowed for a unifying diagnosis of small cell carcinoma (SCLC) as the cause of the paraneoplastic CS. Chemotherapy was promptly started. DISCUSSION: Current standard practice for CS diagnostic work-up includes 8 mg dexamethasone suppression and CRH stimulation tests, inferior petrosal sinus sampling (IPPS), and imaging including CT, MRI, octreotide scans and venous sampling. In cases of EAS, the majority did not respond to CRH stimulation or dexamethasone suppression. IPPS was found most likely to identify the disease. Hypercortisol control treatments range from medications such as ketoconazole, metyrapone, or etomidate to surgical bilateral adrenalectomy. The highest rate of cure, up to 65%, came with the surgical removal of the ectopic ACTH-secreting neoplasm though recurrence was a possible complication. While cure in nonsurgical candidates is relatively rare, survival was common except in those cases of paraneoplastic CS caused by aggressive diseases. CONCLUSIONS: Though rare and difficult to recognize, Paraneoplastic CS may be the first sign of malignancy. While the source of EAS may be benign, it can be seen with SCLC, gastrinoma, medullary thyroid cancer and other such aggressive malignancies. Early identification may be lifesaving. Reference #1: Bertherat J. Cushing syndrome due to ectopic ACTH secretion. Orpha Net. 2012; ORPHA:99889 DISCLOSURE: The following authors have nothing to disclose: Vandana Pai, Kim Phung Nguyen, Jennifer Treece, Badar Siddiqui, Lisa McKinney-Smith No Product/Research Disclosure Information

Corticotrophin-releasing hormone stimulation tests for the infants with relative adrenal insufficiency.

Very low birthweight (VLBW) infants are considered to be vulnerable to relative adrenal insufficiency (RAI); however, diagnosis is difficult in some clinical settings. Considering this background, it is necessary to establish a diagnosis of RAI in preterm infants. In this study, we attempted to clarify the difference in response to CRH stimulation tests for preterm infants with or without RAI. Between June 2009 and December 2015, we performed CRH stimulation tests for preterm infants born at a gestational age of <30weeks at around 2weeks of age. Retrospectively, subjects were classified into two groups: infants with RAI (n=9) or without RAI (n=17) based on the clinical symptoms and responsiveness to hydrocortisone. We found no difference in base or peak serum cortisol levels related to CRH stimulation tests between the two groups; however, delta cortisol levels and responsive ratio (peak-to-base ratio) were significantly reduced in infants with RAI. 140nmol/L for delta cortisol or 1.5 times for peak-to-base ratio may be cut-off levels in preterm infants. This study provides evidence that base cortisol levels of preterm infants with RAI were not different from those without RAI; however, CRH stimulation tests may be a useful tool for the diagnosis of RAI in preterm infants.

Effects of mitotane on the hypothalamic-pituitary-adrenal axis in patients with adrenocortical carcinoma.

Mitotane, a drug used to treat adrenocortical cancer (ACC), inhibits multiple enzymatic steps of adrenocortical steroid biosynthesis, potentially causing adrenal insufficiency. Recent studies in vitro have also documented a direct inhibitory effect of mitotane at the pituitary level. The present study was aimed to assess the hypothalamic-pituitary-adrenal axis in patients with ACC receiving mitotane. We prospectively enrolled 16 patients on adjuvant treatment with mitotane after radical surgical resection of ACC, who underwent standard hormone evaluation and h-CRH stimulation. A group of 10 patients with primary adrenal insufficiency (PAI) served as controls for the CRH test. We demonstrated a close correlation between cortisol-binding globulin (CBG) and plasma mitotane levels, and a non-significant trend between mitotane dose and either serum or salivary cortisol in ACC patients. We did not find any correlation between the dose of cortisone acetate and either ACTH or cortisol levels. ACTH levels were significantly higher in patients with PAI than that in patients with ACC, both in baseline conditions (88.99 (11.04-275.00) vs 24.53 (6.16-121.88) pmol/L, P = 0.031) and following CRH (158.40 (34.32-275.00) vs 67.43 (8.8-179.52) pmol/L P = 0.016). The observation of lower ACTH levels in patients with ACC than that in patients with PAI, both in basal conditions and after CRH stimulation, suggests that mitotane may play an inhibitory effect on ACTH secretion at the pituitary levels. In conclusion, the present study shows that mitotane affects the HPA axis at multiple levels and no single biomarker may be used for the assessment of adrenal insufficiency.

Identification of a novel interaction between corticotropin releasing hormone (Crh) and macroautophagy.

In inflammatory bowel disease (IBD), compromised restitution of the epithelial barrier contributes to disease severity. Owing to the complexity in the pathogenesis of IBD, a variety of factors have been implicated in its progress. In this study, we report a functional interaction between macroautophagy and Corticotropin Releasing Hormone (Crh) in the gut. For this purpose we used DSS colitis model on Crh −/− or wild-type (wt) with pharmacological inhibition of autophagy. We uncovered sustained basal autophagy in the gut of Crh −/− mice, which persisted over the course of DSS administration. Autophagy inhibition resulted in partial rescue of Crh −/− mice, while it increased the expression of Crh in the wt gut. Similarly, Crh deficiency was associated with sustained activation of base line autophagy. In vitro models of amino acid deprivation- and LPS-induced autophagy confirmed the in vivo findings. Our results indicate a novel role for Crh in the intestinal epithelium that involves regulation of autophagy, while suggesting the complementary action of the two pathways. These data suggest the intriguing possibility that targeting Crh stimulation in the intestine may provide a novel therapeutic approach to support the integrity of the epithelial barrier and to protect from chronic colitis.

Efficacy of single serum cortisol reading obtained between 9 AM and 10 AM as an index of adrenal function in children treated with glucocorticoids or synthetic adrenocorticotropic hormone.

.To find a simple method to screen for iatrogenic childhood adrenal insufficiency, we retrospectively examined the results of CRH stimulation tests performed 212 times on 111 subjects (68 males; age at commencement of initial treatment ranged 0.0–19.8 yr; median age, 5.8 yr). Before the commencement of this study, 97 subjects had been treated with glucocorticoids and 14 subjects with West syndrome had been treated with synthetic adrenocorticotropic hormone. Duration of the primary treatment ranged from 15 to 2150 days. CRH stimulation tests were conducted between 09:00 AM and 10:00 AM and peak cortisol values less than 15 µg/dL were considered indicative of adrenal insufficiency. The receiver operating characteristic curve showed that the optimal basal serum cortisol cut-off values when screening for adrenal suppression ranged from 5.35 to 5.80 µg/dL depending on the primary disease. All subjects having a serum cortisol value of less than 2.3 µg/dL had insufficient adrenal function while all subjects having greater than 11 µg/dL had intact adrenal function. We concluded that single serum cortisol values obtained between 09:00 AM and 10:00 AM had the potential to serve as an index of adrenal function in children treated with glucocorticoids or synthetic adrenocorticotropic hormone.

The Effect of Sex and Irritable Bowel Syndrome (IBS) on the Integrated Hypothalamic-Pituitary-Adrenal (HPA) Axis Response to Hormone Challenge

Introduction: Irritable bowel syndrome (IBS), a stress-related and female-predominant disorder, is associated with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. Men and women have different HPA response to hormone challenge and stress. IBS-related changes in the HPA response to corticotropin-releasing factor (CRF) and adrenocorticotrophic hormone (ACTH) differ by sex and can be affected by early adverse life events (EALs).(Adeyemo, Gastro 2015) Aims of this study were to create measures of the integrated response to hormone challenge through factor analysis of the response to CRF and ACTH and to determine the effect of sex and IBS status on these measures. Methods: Rome III+ IBS patients and healthy controls (HCs) underwent CRH (1μg/kg ovine) and ACTH (250μg) stimulation with serial plasma ACTH and cortisol levels. Baseline, area under the curve with respect to the minimum value (AUCi), rise and decline slopes were included in the factor analysis. Factors were extracted by principal components (threshold of eigenvalue>1), followed by Varimax rotation. Differences in factor scores (regression method) were determined with linear models controlling for Age and BMI. Results: Participants (Table 1) were 46 IBS patients (63% women) and 49 HCs (53% women). Factor structure is shown in Table 2. Based on the variables with the highest loadings, the factors can be described as: 1: ACTH response to CRF; 2: Cortisol response to CRF & ACTH; 3: Baseline PM ACTH & cortisol; and 4: Low AM cortisol & fast decline of ACTH stimulated cortisol. Factor scores by IBS and sex are shown in Figure 1. For all factors, IBS-related changes were opposite in men (M) vs. women (F) Cortisol response was higher in IBS M vs. HC M (p=0.041). Baseline PM ACTH and cortisol (Factor 3) scores were higher in M vs. F (p=0.0008), with M>F within both IBS and HC. There was a trend for higher Cortisol response in EAL vs. No EAL among M (p=0.08). There was a correlation between the number physical abuse-related EALs and Cortisol (r=0.2908, p=0.0080). There was no correlation with factors and IBS symptoms or pain.Figure 1Table 1: Participant CharacteristicsTable 2: Factor StructureConclusion: IBS-related HPA changes differ by sex. These results suggest the presence of an IBS endophenotype characterized by men with enhanced cortisol response and a history of physical abuse. Supported by NIH grants: P50 DK064539 and T32 DK07180-40.

245 Evidence for a New Mechanism Underlying Persistent Visceral Hypersensitivity and Increased Permeability in a Model of Post-Infectious IBS

and cortisol responses to stimulation with CRH and ACTH: 1) differ between IBS patients and healthy controls (HCs), 2) are affected by sex and EALs, 3) are associated with GR mRNA expression. Methods: Male and female Rome III+ IBS patients and HCs underwent CRH (1μg/kg ovine) and ACTH (250μg) stimulation tests with serial plasma ACTH and cortisol levels measured. GR mRNA levels were measured from peripheral blood mononuclear cells using real-time PCR. Presence of EALs <18 yrs of age was measured with the Trauma History questionnaire. Linear mixed effects models were used to compare ACTH and cortisol response measured across time between groups with a knot at the peak of the curve to model the rates of change from baseline to peak (rise) and from peak to the last time point (decline). Area under the curve (AUC) was also measured. Results: 60 IBS patients (65%F, mean age 33yrs) and 56 HCs (52%F, mean age 31yrs) underwent hormone stimulation studies. 74 IBS (65%F, mean age 33yrs) and 69 HCs (52%F, mean age 33yrs) had GR mRNA expression levels. A subset (37 IBS, 28 HCs) had both hormone stimulation and GR mRNA studies. 34 (60%) IBS patients and 27 (48%) HCs had +EAL. CRH stimulation test: IBS patients showed a slower rate of decline from peak ACTH levels than HCs (p<0.05). Women with IBS had a slower rate of decline of ACTH (p=0.01) and cortisol (p=0.001) than men with IBS. ACTH stimulation test: Cortisol responses were similar in IBS and HCs, likely due to a significant interaction between IBS and sex (p<0.001). Within women, IBS had a lower cortisol response (AUC) than HCs. In contrast, in men, IBS had a greater cortisol response than HCs. GR mRNA expression: Levels were lower in IBS vs HCs (p= 0.03), which was mainly seen within men. Lower GR mRNA levels were associated with faster rise in ACTH and cortisol responses (p=0.01-0.03). EAL did not have a significant effect on hormone responses. Conclusion: HPA axis response was dysregulated in IBS. The enhanced HPA axis response was associated with downregulation of the GR mediated negative feedback system. Sex differences in the stress response may play a role in the female predominance of IBS.

Ectopic adrenocorticotropic hormone and corticotropin-releasing hormone co-secreting tumors in children and adolescents causing cushing syndrome: a diagnostic dilemma and how to solve it.

Ectopic ACTH/CRH syndrome is a rare cause of Cushing syndrome (CS), especially in children. The localization, work-up, and management of ACTH/CRH-secreting tumors are discussed. A retrospective study was conducted of patients under 21 years of age evaluated at the National Institutes of Health (NIH) for CS and diagnosed with ectopic ACTH/CRH-secreting tumors during the period 2009-2014. Seven patients with ectopic ACTH/CRH CS are included in this study with a median age 13.6 years (range 1-21), and 3 are female. Clinical, biochemical, radiological features, treatment, and histological findings are described. Seven patients were found to have ACTH/CRH-secreting tumors, all with neuroendocrine features. The site of the primary lesion varied: pancreas (3), thymus (2), liver (1), right lower pulmonary lobe (1). PATIENTS underwent biochemical evaluation for CS, including diurnal serum cortisol and ACTH levels, urinary free cortisol levels (UFC), and CRH stimulation tests. All patients underwent radiological investigations including MRI, CT, and PET scan; imaging with octreotide and 68 gallium DOTATATE scans were performed in individual cases. Five patients underwent inferior petrosal sinus sampling; 4 patients had sampling for ACTH and CRH levels from additional sites. Three patients underwent trans-sphenoidal surgery (TSS), and 3 patients required bilateral adrenalectomy. Three patients (43%) died due to metastatic disease, demonstrating the high mortality rate. One of the unique findings in these seven patients is that in each case, their neuroendocrine tumors were ultimately proven to be co-secreting ACTH and CRH. This explains the enigmatic presentation, in which 3 patients initially thought to have Cushing's disease (CD) with corresponding pituitary hyperplasia underwent TSS prior to the correct localization of the causative tumor. Ectopic ACTH/CRH co-secreting tumors are extremely rare in children and adolescents. The diagnosis of this condition is frequently missed and is sometimes confused with CD due to the effect of CRH on the pituitary.

Single serum cortisol values at 09:00 h can be indices of adrenocortical function in children with Kawasaki disease treated with intravenous immunoglobulin plus prednisolone.

Combination treatment with intravenous immunoglobulin (IVIG) plus prednisolone is effective for prevention of cardiovascular complications in children with Kawasaki disease (KD). However, administration of prednisolone for approximately 20 d in this regimen causes adrenocortical suppression in a high proportion of treated children. To establish a simple method to screen for this suppression, we performed a prospective study on 72 children with KD treated with this regimen in our institution from February 2012 to March 2014. By performing ROC analysis of 21 initial patients treated between February and June 2012, a serum cortisol value at 09:00 h of 5 mcg/dL was established as a threshold for intact adrenocortical function, which is equivalent to a peak serum cortisol value of higher than 15 mcg/dL in the CRH stimulation test. Then, we applied this screening test to 51 subsequent patients treated between July 2012 and March 2014. Approximately 90% of the patients with morning serum cortisol values above 5 mcg/dL 2 to 6 mo after the cessation of initial prednisolone treatment had peak serum cortisol values exceeding 15 mcg/dL, suggesting the efficacy of this approach.