Severe Hypercortisolemia Research Articles

Successful management of refractory Cushing's disease with severe hypercortisolemia using etomidate and temozolomide in post-surgical failure.

Corticotropinomas account for 20% of all aggressive pituitary tumors and pituitary carcinomas and are associated with high mortality. These tumors not only cause neurovascular compromise but can also be fatal due to severe hypercortisolemia itself. Although surgery is considered the primary treatment modality, it is often partially successful or unsuccessful. Moreover, these tumors frequently recur and may be resistant to conventional treatments, including surgery and radiotherapy. Therefore, early multimodal treatment and regular follow-up are necessary. We present a case of aggressive Cushing's disease managed with combined temozolomide therapy and radiotherapy following an unsuccessful transsphenoidal surgery, resulting in significant long-term radiological and biochemical remission. In addition, etomidate infusion was administered to achieve rapid cortisol reduction, highlighting its role as a bridging therapy to other modalities in treating life-threatening and severe hypercortisolemia outside an intensive care setting.

An aggressive Cushing's syndrome originating from a rare thymic neuroendocrine tumor, controlled successfully with fluconazole and octreotide therapy before surgery.

Cushing's syndromes (CSs) due to the thymic neuroendocrine tumors are rarely seen. Here, a case of ectopic CS originating from an atypical neuroendocrine tumor has been presented. A 49-year-old woman was hospitalized with symptoms of fatigue, chest pressure, dyspnea, muscle weakness, and resistant hypertension. There was marked hyperpigmentation in the whole-body surface suggestive of adrenocorticotropic hormone (ACTH) excess and there were physical features of CS. There was deep hypokalemia. Basal hormone profile, dexamethasone suppression tests, midnight cortisol, and 24-hour urine cortisol levels were suggestive of ectopic CS. The pituitary magnetic resonance imaging revealed a 5 mm cystic lesion and the patient refused inferior petrosal sinus sampling. Thorax computerized tomography showed an anterior mediastinal mass. A fluorodeoxyglucose-positron emission tomography showed the same mediastinal lesion (suvmax: 11.4), and no other tumor focus was detected. There was an aggressive cortisol excess causing acute respiratory distress syndrome, making it difficult to perform the surgery. We immediately started fluconazole and octreotide therapy and were successful in lowering the cortisol level. Then a complete resection of the tumor had been able to be surgically performed and tumor cells showed strong cytoplasmic immunopositivity with ACTH. A definitive diagnosis of "ACTH secreting atypical thymic carcinoid tumor" was rendered based on the histopathological and immunohistochemical features. There was only surrounding vessel invasion, and no lymphoid or other organ metastases were detected. As there were surrounding vessel invasions, a two-cycle regimen cisplatin-etoposide chemotherapy and radiotherapy were employed. After surgical and medical therapy, the cortisol and ACTH levels turned to normal. The patient is in biochemical and clinical remission and has no tumor recurrence yet. Ectopic ACTH-producing thymic carcinoids are rare but life-threatening tumors because of the underlying malignancy and severe hypercortisolemia. It is important to consider this disease and perform appropriate treatment at the right time. Today, surgery is the standard therapeutic modality if it is possible to perform, but there is not a clear and constant recommendation for nonsurgical therapeutic modalities. Further studies are needed for the optimal treatment strategies.

THU017 Severe Hypercortisolemia- A Biological Time Bomb

Abstract Disclosure: U. Munasinghe: None. S. Pittampalli: None. D. Das: None. V. Pattan: None. Cushing's disease, the most common cause of endogenous Cushing syndrome, is usually insidious and has less severe hypercortisolemia than ectopic Cushing's. 73 yr.old female with hypertension, hyperlipidemia, T2DM, and OSA on anticoagulation for recent pulmonary embolism, presented with recurrent hypokalemia and proximal muscle weakness of 3 months duration. She denied visual symptoms and headaches. BP was 158/90 mmHg, HR 92 bpm, and BMI 34.9. She had a round face with ruddy complexion, extensive bruising on her upper extremities and proximal muscle weakness. Laboratory tests showed serum bicarbonate 26 mmol/l (22-29), sodium 140 mmol/L (136-145), potassium 2.0 mom/L (3.4- 5.1), chloride 106 mmol/L (98-107), glucose 164 mg/dl. Hemoglobin A1c 9.6 %, random cortisol 46.2mcg/dL, ACTH 72.4 pg/ml (7.2-63.3), late-night salivary cortisol sample was inadequate to assess, 24-hour urine cortisol 1802 ug/24 hr (6-42). Prolactin level was 14.6 ng/ml(4.7-23.3), IGF-1 62 ng/dl (48-191), GH 0.12 ng/ml (0-3.61), FSH< 0.3 mU/ml (25.8-134.8), TSH 0.193 u/ml (0.27-4.2), Ft4 1.1 ng/dl (0.93-1.7), alpha subunit <0.15 ng/ml (<3.56). She had non-suppressed cortisol of 44.3 mcg/dL and ACTH of 113 pg/mL after overnight 8mg dexamethasone suppression test. CT angiogram chest did not reveal any pathology. MRI pituitary revealed pituitary adenoma measuring 9 x 8 mm. IPSS with desmopressin stimulation showed IPSS to peripheral prolactin ratio was greater than 1.8 verifying successful catheterization. Her central to peripheral ACTH gradient was >2 before stimulation confirming pituitary source. Her ACTH concentration gradient >1.4 between 2 sinuses lateralizing the lesion to the right. The patient was started on Osilodrostat 2mg bid for control of hypercortisolemia and subsequently treated with transsphenoidal resection of the pituitary adenoma. Surgical pathology was consistent with densely granulated corticotrophin adenoma. Initial presentation of recurrent hypokalemia, proximal muscle weakness, pulmonary embolism and severe hypercortisolemia was suspicious for ectopic Cushing’s but after initial chest imaging was negative for ectopic pathology, MRI and subsequent IPSS helped with timely diagnoses and management. Severe hypercortisolemia is an endocrine emergency carrying high mortality. Expedited diagnoses, control of hypercortisolemia, anticoagulation and antibiotic prophylaxis can be life saving before definitive treatment can be done. Presentation: Thursday, June 15, 2023

Medical Therapies in Functioning Pituitary Neuroendocrine Tumors(PitNETs)

Transsphenoidal surgery is the first-line treatment for most functioning pituitary neuroendocrine tumors(PitNETs). Medical therapies are usually chosen for patients with residual or refractory tumors after surgery or contraindications to surgery. Dopamine agonists(DA)are the first-line treatment for prolactinomas. Somatostatin analogs are the first line of therapy for GH- and TSH-producing PitNETs. In severe hypercortisolemia due to ACTH-producing PitNETs, adrenal enzyme inhibitors such as 11β-hydroxylase inhibitors should be started immediately, as marked hypercortisolemia leads to serious opportunistic infections. Pasireotide and DA are usually administered to treat mild hypercortisolemia. Based on the histological pattern of secretory granules, somatotroph, lactotroph, and corticotroph tumors can be divided into two subtypes: densely granulated and sparsely granulated. Densely granulated lactotroph tumors tend to be resistant to DA. In contrast, densely granulated somatotroph and corticotroph tumors express high levels of somatostatin receptors and are more responsive to somatostatin analogs. Since ACTH-producing PitNETs express SSTR5 without SSTR2, the second-generation somatostatin analog, pasireotide, is effective against ACTH-producing PitNETs.

ODP245 Syndrome of Diabetic Ketoalkalosis due to Severe Hypercortisolemia: A Case Series

Abstract Introduction Decompensated diabetes (DM) precoma/comas states are major causes of hospital morbidity and mortality. These commonly include diabetic ketoacidosis (DKA), diabetic hyperglycemic hyperosmolar syndrome (DHHS), diabetic hypoglycemia coma (DHC) and diabetic lactic acidosis (DLA). Another less common decompensated DM precoma/coma state to be aware of is Diabetic ketoalkalosis (DKAL). We present two cases of DKAL due to severe hypercortisolemia (HCS) from ectopic Cushing's syndrome (ECS). Clinical cases; Case 1 was a 61 yr old AA woman with suboptimally managed type 2 DM who had been admitted for DKA 2 months before. She had marked hyperglycemia (blood glucose >500mg/dl) on repeated measures (RMs) and chronic diarrhea with tachypnea and altered mental status (AMS). She had heavy tobacco abuse and work up revealed a right lung mass biopsy of which showed a malignant neuroendocrine tumor presumed to be malignant bronchial carcinoid. Her initial lab tests showed marked metabolic alkalosis with severe hypokalemia and elevated anion gap, ketonemia and ketonuria. Presentation was typical of DKAL and subsequent work up showed ECS with serum cortisol > 110 (n; 4.3-22.4ug/dl) on RMs and serum ACTH 377-480 (n; 0/46pg/ml). Her metabolic derangements were corrected and HCS managed with mild impact using ketaconazole and octreotide but she died within a month of admission with intractable septic shock despite parenteral antimicrobials. Case 2 was a 46 yr old Hispanic man with heavy tobacco abuse admitted on account of AMS, tachypnea and upper abdominal pain. He had severe hyperglycemia (blood glucose >750mg/dl on RMs) though not known to have DM. HBA1c was > 15% indicating undiagnosed DM. Initial lab tests showed marked respiratory and metabolic alkalosis, marked hyponatremia, hypokalemia, hypo-osmolality but with ketonemia and ketonuria. Presentation was consistent with DKAL. Work up showed a left lung lesion with pleural effusion shown to be small cell carcinoma of the lung. He was also found to have profound HCS (serum cortisol >150ug/d; on RMs) confirmed due to ECS with serum ACTH, 1500-1800pg/ml. Metabolic derangements were corrected and he was started on ketoconazole and etomidate to correct HCS with little response. Elective bilateral adrenalectomy was planned but patient abruptly discharged himself AMA. He was readmitted ∼ 3 weeks later with a massive pulmonary embolism and acute respiratory failure from which he never recovered. He died ∼ 2 months later. Discussion + Conclusions DKAL is an uncommon but important potential acute presentation of decompensated DM. Early recognition and management requires close attention to the acid-base and electrolyte derangements that often accompany it. Among the many possible causes of DKAL severe HCS is an important possibility to be consider. Rapid diagnosis and institution of aggressive therapy of HCS is crucial as it often has high morbidity and mortality potential. Presentation: No date and time listed

A Rare Cause of Hypokalemia: Ectopic ACTH Syndrome

The most common cause of adrenocorticotropic hormone (ACTH)-dependent Cushing’s syndrome is a benign ACTH-producing pituitary tumour or, less frequently, ectopic ACTH production from non-pituitary tumours. Ectopic ACTH syndrome occurs more commonly in men and usually presents after 40 years. It is most commonly associated with small cell lung cancer. Although this syndrome is associated with severe hypercortisolemia, some findings of Cushing’s syndrome, such as central obesity, may not be observed due to underlying malignant diseases. In these cases, rapid metabolic disruption, anorexia, myopathy, glucose intolerance, hypokalemic alkalosis, and hyperpigmentation accompany the patients’ clinical condition. In the current case report, we aimed to emphasize that ectopic ACTH syndrome should be kept in mind in the differential diagnosis, especially in the presence of hypokalemia accompanying hypertension and proximal muscle weakness, if the patient also has progressive weight loss.

Pharmacological management of severe Cushing's syndrome: the role of etomidate.

Cushing’s syndrome (CS) is an endocrine disease characterized by excessive adrenocortical steroid production. One of the mainstay pharmacological treatments for CS are steroidogenesis enzyme inhibitors, including the antifungal agent ketoconazole along with metyrapone, mitotane, and aminoglutethimide. Recently, osilodrostat was added to this drug class and approved by the US Food and Drug Administration (FDA) for the treatment of Cushing’s Disease. Steroidogenesis enzyme inhibitors inhibit various enzymes along the cortisol biosynthetic pathway and may be used preoperatively to lower cortisol levels and reduce surgical risk associated with tumor resection or postoperatively when surgery and/or radiation therapies are not curative. Because their selectivities for steroidogenic enzymes vary, they may even be administered in combination to achieve relatively rapid control of severe hypercortisolemia. Unfortunately, all currently available inhibitors are accompanied by serious adverse side effects that limit dosing and often result in treatment failures. Although more commonly known as a general anesthetic induction agent, etomidate is another member of the steroidogenesis enzyme inhibitor drug class. It suppresses cortisol production primarily by inhibiting 11β-hydroxylase and is the only inhibitor that may be given parenterally. However, the sedative-hypnotic actions of etomidate limit its use as an acute management option for CS. Thus, some have recommended that it be used only in intensive care settings. In this review, we discuss the initial development of etomidate as an anesthetic agent, its subsequent development as a treatment for CS, and the recent advances in dosing and drug development that dissociate sedative-hypnotic and adrenostatic drug actions to facilitate CS treatment in non-critical care settings.

Ectopic Cushing’s Syndrome and Severe Hypocalcemia Due to Medullary Thyroid Cancer Responsive to Selpercatinib

Introduction: Cushing’s syndrome (CS) due to ectopic ACTH production from medullary thyroid carcinoma (MTC) is characterized by rapid progression of disease, leading to hyperglycemia and hypokalemia. However, hypercortisolemia leading to hypocalcemia is rarely seen. Initiation of selpercatinib greatly improved hypocalcemia and ectopic CS in this case. Clinical Case: A 41-year-old man with a history of MTC (variant RET p.M918T) post thyroidectomy in 2018 developed progressive weight gain, lower extremity edema, weakness, new onset diabetes, severe refractory hypocalcemia and hypokalemia requiring multiple hospitalizations. On initial presentation to our institution, he was lethargic, had multiple ecchymoses, peripheral edema and proximal myopathy. Laboratory evaluation revealed Ca 5.4 mg/dL (NR 8.9 - 10.3), albumin 3 g/dL (NR 3.5 - 5.1), iPTH 1.4 pmol/L (NR 1.6 - 6.9), 25-OH vitamin D 23 pg/mL (NR 25–80) while taking elemental calcium 1500 mg every 6h, calcitriol 0.25 mcg/d and vitamin D3 1000 IU/d. Serum cortisol measured at 9:30 pm was 136 ug/dL (NR 2.5–11.9), ACTH 1,145 pg/mL (NR 7.2–63.3) and 24-h UFC 27,629 ug/d consistent with CS due to ectopic ACTH production. Calcitonin and CEA were 18,687 pg/mL (NR 0–7.5) and 3,766 ng/mL (NR 0–4.7). CT abdomen revealed numerous bilateral liver lesions and bilateral adrenal hyperplasia. In addition to high doses of oral calcium and calcitriol, he required calcium drip up to 1.5mg/kg/hr for about 1 week. He simultaneously began cabozantinib, ketoconazole and metyrapone. Hospital course was complicated by infections and recurrent scrotal bleeding, so he was switched to selpercatinib. Two days after starting selpercatinib, ketoconazole was discontinued, and metyrapone has been gradually reduced. Most recent calcitonin was 149 pg/mL, CEA 97.8 ng/mL and 24-h UFC 10 ug/d on metyrapone 250 mg twice daily. Similarly, refractory hypocalcemia greatly improved, last serum Ca was 8.3 mg/dL on elemental calcium 480 mg/d. He has made significant clinical gains and has returned home from rehab. Clinical Lesson: Hypocalcemia is rarely described as a complication in patients with CS. Our patient had underlying hypoparathyroidism and vitamin D deficiency; however, hypocalcemia was initially refractory to high doses of calcium and calcitriol and only improved with treatment of CS. We suspect hypercortisolemia impaired 25 to 1,25 D activation, thereby reducing calcium absorption, and likely inducing hypercalciuria. These deleterious effects of severe hypercortisolemia combined with underlying hypoparathyroidism led to severe and refractory hypocalcemia requiring repeated admissions, and only improved once his ectopic CS due to MTC was recognized and controlled. The RET kinase inhibitor, selpercatinib, induced a rapid decline in calcitonin, CEA and ACTH levels, and with metyrapone, enabled control of hypercortisolemia and its complications.

MON-914 Ectopic ACTH Syndrome Caused by Adenocarcinoma of Lung - a Rare Association with Rare Complication

INTRODUCTION Ectopic ACTH constitutes 5-10% of ACTH dependent Cushing’s syndrome. Evolution of symptoms can be rapid. Cortisol & ACTH is usually higher as compared to Cushing’s disease. Imaging studies should be obtained for localization of the source of ACTH. Here, we present a case of Cushing’s syndrome caused by ectopic ACTH production caused by adenocarcinoma lung, which has very rarely been associated with this syndrome CASE A 52-year-old male presented with 3-month H/O bilateral pedal edema & puffiness of face. He noticed bruises over his trunk & darkening of face for 2 months. There was a recent worsening of his HTN (requiring 3 antihypertensives) & recently diagnosed with DM. On examination patient had cushingoid features, acne and ecchymosis. BP - 166/110 mm Hg. Proximal myopathy, Pedal edema, clubbing & cervical lymphadenopathy was present (largest node - 2.5cm). Fasting & postprandial blood sugars were 190 & 285 mg/dl respectively. Serum K+ was 3.0 meq/L (3-5-5.0meq/L), 11pm serum cortisol was 51.6 mcg/dl (cutoff < 7,5mcg/dl), 8 am cortisol after overnight 1mg dexamethasone was 60.7 mcg/dl (cutoff<1.8mcg/dl). Serum ACTH(8am) - 178 pg/ml.(>20 pg/ml-ACTH dependent Cushing’s) Biopsy of neck node revealed poorly differentiated adenocarcinoma. PET scan showed left lung upper & lower lobe masses. A diagnosis of ectopic ACTH syndrome was made, the source of which was adenocarcinoma of lung, which has been very rarely reported to be associated with it. Oral ketoconazole was started followed by Chemotherapy with paclitaxel & carboplatin. Within the next 7 days patient developed pleural effusion, neutropenia & worsened rapidly. BAL revealed Nocardia species, known to be associated with hypercortisolism. He was treated with appropriate antibiotics & supportive treatment but succumbed to septic shock. CONCLUSION If a patient presents with rapidly evolving symptoms of Cushing’s syndrome, ectopic ACTH syndrome should be considered. The presence of wasting and weight loss, hypokalemic alkalosis, pedal edema & marked hyperpigmentation should also alert towards the diagnosis. Histopathological confirmation of malignancy is important, as in our case with ectopic ACTH where the source was an adenocarcinoma of the lung, of which only 5 cases have been reported till now (Ectopic ACTH more commonly associated with SCLC). Finally, in cases of severe hypercortisolemia, there should be a high index of suspicion for opportunistic infections including invasive fungal infections, Nocardiosis etc, so that specific antibiotic therapy can be initiated. Typical features like fever, leukocytosis can be absent. Treatment of underlying hypercortisolism with surgical/medical management prior to initiation of chemotherapy has been shown to reduce the frequency of infections.

Improvement in cognitive impairment following the successful treatment of endogenous Cushing\u2019s syndrome-a case report and literature review

BackgroundEndogenous Cushing’s syndrome, a rare endocrine disorder, characterised by chronic cortisol hypersecretion, results in neuropsychiatric disturbances and in cognitive deficits, which are only partially reversible after the biochemical remission of the disease.Case presentationWe report a case of a woman with a profound cognitive deficit and a gradual functional decline caused by Cushing’s disease of at least 10 years duration. The neurosurgical resection of her 2 mm adrenocorticotropic hormone (ACTH) secreting pituitary microadenoma resulted in a successful resolution of the patient’s hypercortisolism and a significant recovery of her neurocognitive function. The patient’s progress was evaluated using serial clinical observations, functional assessments, Mini-Mental Status exams and through the formal neuropsychological report. Furthermore, the patient’s recovery of her neurocognitive function was reflected by a sustained improvement in the patient’s specific structural brain abnormalities on radiological imaging.ConclusionsThis report illustrates the importance of early detection and treatment of Cushing’s syndrome in order to prevent neurocognitive impairment and neuropsychiatric disorders which are associated with an endogenous cortisol hypersecretion. The long term adverse effects of severe hypercortisolaemia on brain function and the pathophysiological mechanisms responsible for the structural and functional changes in brain anatomy due to glucocorticoid excess are reviewed.

MON-317 Ectopic Cushing's Syndrome Due to Prostate Cancer: A Case Series

Background: The introduction of chemotherapy and androgen receptor signaling inhibitors to patients with newly diagnosed metastatic or castration resistant prostate cancer has resulted in longevity and improved quality of life. However, as the disease transitions to a more resistant clinical state despite multiple agents, there has been, in some patients, the emergence of a more aggressive form of the disease with adrenocorticotropic hormone (ACTH) production due to either small cell or neuroendocrine features. These subtypes of prostate cancer are behaviorally unique and can manifest with clinical symptoms and laboratory abnormalities due to severe hypercortisolemia that portend rapid clinical decline if not death. In order to facilitate early recognition and treatment of this rare clinical syndrome, we describe several cases of ectopic ACTH-dependent Cushing’s syndrome that were associated with this histologic entity and were not easily identified despite refractory hypokalemia and hypertension. Methods: Through a dataline search we identified 10 cases of prostate cancer with ectopic ACTH-dependent Cushing’s syndrome treated at MSKCC over the past 20 years. Data were abstracted from patients' medical records, including clinical course, histopathology and response to therapy. Results: Mean age at presentation was 66 years (range 58 to 80). 9 of 10 patients reported prior tobacco use. 7 of 10 patients had prostate adenocarcinoma prior to diagnosis of ectopic Cushing’s, and 9 of 10 patients had a Gleason score >7. When available, tumor pathology showed small cell or high grade neuroendocrine carcinoma, but despite elevated plasma ACTH levels, not all tumors had immunohistochemistry that was positive for ACTH. Spontaneous hypokalemia was present in all 10 patients, and presenting signs of Cushing’s syndrome were most commonly hypokalemia or resistant hypertension. One patient had hypertensive urgency and two developed psychosis. Median survival was ~2.5 months after the development of Cushing’s syndrome. Four patients died of complications from progressive tumor growth, and three died of complications due to infections, including PCP, aspergillus lung infection, mold lung infection, cellulitis/fasciitis, and mastoiditis. Three died of unclear causes. Conclusions: Prostate cancer that evolves into an ACTH-secreting neuroendocrine phenotype is a rare entity that is associated with high risk for infections, refractory hypokalemia, and poor survival. Further clinical and pathological characterization is needed to ensure early recognition and appropriate treatment interventions for these patients.

Continuous Etomidate Infusion for the Management of Severe Cushing Syndrome: Validation of a Standard Protocol.

ObjectiveDemonstrate the safety and efficacy of a standardized intravenous etomidate infusion protocol in normalizing cortisol levels in patients with severe and life-threatening hypercortisolism.MethodsA retrospective case series of seven patients representing nine episodes of severe hypercortisolism at two large academic medical centers was conducted. Patients were included in this series if they received an etomidate infusion for the treatment of severe and life-threatening hypercortisolism. The etomidate infusion was administered via a newly developed protocol designed to safely reduce cortisol levels until more long-term medical or definitive surgical therapy could be instituted.ResultsSeven patients representing nine episodes received etomidate treatment. In eight of nine episodes of therapy, rapid control of hypercortisolemia was achieved, generally defined as a serum cortisol level of 10 to 20 µg/dL. Patients with a median baseline cortisol of 105 µg/dL (range, 32 to 245 µg/dL) achieved a median nadir serum cortisol of 15.8 µg/dL (range, 6.9 to 27 µg/dL) after a median of 38 hours (range, 26 to 134 hours).ConclusionsA standardized continuous intravenous etomidate infusion protocol is a safe and effective means of achieving a serum cortisol level of 10 to 20 µg/dL in patients with severe hypercortisolemia.

Etomidate for the management of severe hypercortisolaemia in different clinical scenarios - a case series

Etomidate for the management of severe hypercortisolaemia in different clinical scenarios - a case series

Decreased prefrontal functional brain response during memory testing in women with Cushing’s syndrome in remission

Neurocognitive dysfunction is an important feature of Cushing’s syndrome (CS). Our hypothesis was that patients with CS in remission have decreased functional brain responses in the prefrontal cortex and hippocampus during memory testing. In this cross-sectional study we included 19 women previously treated for CS and 19 controls matched for age, gender, and education. The median remission time was 7 (IQR 6–10) years. Brain activity was studied with functional magnetic resonance imaging during episodic- and working-memory tasks. The primary regions of interest were the prefrontal cortex and the hippocampus. A voxel-wise comparison of functional brain responses in patients and controls was performed. During episodic-memory encoding, patients displayed lower functional brain responses in the left and right prefrontal gyrus (p<0.001) and in the right inferior occipital gyrus (p<0.001) compared with controls. There was a trend towards lower functional brain responses in the left posterior hippocampus in patients (p=0.05). During episodic-memory retrieval, the patients displayed lower functional brain responses in several brain areas with the most predominant difference in the right prefrontal cortex (p<0.001). During the working memory task, patients had lower response in the prefrontal cortices bilaterally (p<0.005). Patients, but not controls, had lower functional brain response during a more complex working memory task compared with a simpler one. In conclusion, women with CS in long-term remission have reduced functional brain responses during episodic and working memory testing. This observation extends previous findings showing long-term adverse effects of severe hypercortisolaemia on brain function.

Bowel perforation complicating an ACTH-secreting phaeochromocytoma.

SummaryACTH-secreting phaeochromocytoma (ASP) is a rare cause of ACTH-dependent Cushing’s syndrome (CS). We report the case of a 63-year-old female presenting with CS secondary to an ASP complicated by bowel perforation. This case report highlights ASP as an uncommon but important cause of ectopic ACTH secretion (EAS). There have been 29 cases of ASP, all of which were unilateral and benign, but associated with significant complications. Patients presenting with ASP have the potential for cure with unilateral adrenalectomy. Given this promising prognosis if recognised, ASP should be considered in the diagnostic workup of ACTH-dependent CS. As this case demonstrates, gastrointestinal complications can arise from severe hypercortisolaemia associated with CS. Early medical and surgical intervention is imperative as mortality approaches 50% once bowel perforation occurs.Learning pointsConsider phaeochromocytoma in the diagnostic workup of ACTH-dependent CS; screen with plasma metanephrines or urinary catecholamines.Serial screening may be required if ACTH-secreting phaeochromocytoma is suspected, as absolute levels can be misleading.Early catecholamine receptor blockade and adrenal synthesis blockade may avoid the need for rescue bilateral adrenalectomy in ACTH-secreting phaeochromocytoma.Consider early medical or surgical management when gastrointestinal features are present in patients with CS, as bowel perforation due to severe hypercortisolaemia can occur and is associated with significant mortality.

OVERCOMING TREATMENT RESISTANCE IN A PATIENT WITH PSYCHOTIC MAJOR DEPRESSION AND SEVERE HYPERCORTISOLEMIA: A CLINICAL CASE PRESENTATION AND A LITERATURE REVIEW

In patients with major depression, there is well-known dysregulation of the HPA axis, including GR resistance, hypercortisolism, aberrant negative cortisol feedback, presenting itself as positive standard 1 mg dexamethasone suppression test, absence of nighttime cortisol suppression. Those HPA axis disturbances are more pronounced in cases with severe depression, and/or with melancholic features or psychosis, and in cases where treatment resistance is documented or suspected. Severe HPA axis disturbances may themselves predispose patients to treatment resistance or be the main reason for it. One method to overcome treatment resistance in such cases is using antiglucocorticoid therapy (for example, inhibitors of cortisol biosynthesis, like ketoconazole, or GR antagonist mifepristone, or a short course of high-dose synthetic glucocorticoid dexamethasone to suppress the HPA axis overactivity). In this article, we present a case in which the treatment resistance in a patient with severe psychotic major depression and severe hypercortisolemia was successfully overcomed by sequential use of high-dose dexamethasone (20 mg/day x 4 days) and high-dose mifepristone (600 mg/day for 14 days).

Hypercortisolaemia due to ectopic adrenocorticotropic hormone secretion by a nasal paraganglioma: a case report and review of the literature

BackgroundAdrenocorticotropic hormone-producing extraadrenal paragangliomas are extremely rare. We present a case of severe hypercortisolemia due to ectopic adrenocorticotropic hormone secretion by a nasal paraganglioma.Case presentationA 70-year-old Caucasian woman was emergently admitted to our department with supraventricular tachycardia, oedema of face and extremities and hypertensive crisis. Initial laboratory evaluation revealed severe hypokalemia and hyperglycemia without ketoacidosis, although no diabetes mellitus was previously known. Computed tomography revealed a large tumor obliterating the left paranasal sinus and a left-sided adrenal mass. After cardiovascular stabilisation, a thorough hormonal assessment was performed revealing marked adrenocorticotropic hormone-dependent hypercortisolism. Due to the presence of a cardiac pacemaker magnetic resonance imaging of the hypophysis was not possible. [68Ga-DOTA]-TATE-Positron-Emission-Tomography was performed, showing somatostatin-receptor expression of the paranasal lesion but not of the adrenal lesion or the hypophysis. The paranasal tumor was resected and found to be an adrenocorticotropic hormone-producing paraganglioma of low-proliferative rate. Postoperatively the patient became normokaliaemic, normoglycemic and normotensive without further need for medication. Genetic testing showed no mutation of the succinatdehydrogenase subunit B- and D genes, thus excluding hereditary paragangliosis.ConclusionDetection of the adrenocorticotropic hormone source in Cushing’s syndrome can prove extremely challenging, especially when commonly used imaging modalities are unavailable or inconclusive. The present case was further complicated by the simultaneous detection of two tumorous lesions of initially unclear biochemical behaviour. In such cases, novel diagnostic tools - such as somatostatin-receptor imaging - can prove useful in localising hormonally active neuroendocrine tissue. The clinical aspects of the case are discussed and relevant literature is reviewed.

Pituitary tumors

Pituitary adenomas are the most common intrasellar tumors. With the exception of prolactinomas, first-line treatment is almost always surgical. Prolactinomas are usually treated with dopamine agonists such as cabergoline or bromocriptine. Somatostatin analogues, such as octreotide and lanreotide, can be adjunctive to surgical therapy in acromegaly, although they can be used as primary therapy in selected cases. Pegvisomant, a growth hormone receptor antagonist, is reserved for acromegalic patients who are resistant to treatment with somatostatin analogues. No effective medical therapy is available for adenomas that secrete adrenocorticotropic hormone, and occasionally bilateral adrenalectomy is required to resolve severe hypercortisolemia. Radiation therapy (fractionated or radiosurgery) can be used for residual or recurrent pituitary tumors. Asymptomatic, nonfunctioning pituitary adenomas may be followed without any intervention, but surgery is typically indicated if there are symptoms of mass effect on the optic chiasm or endocrine dysfunction. In the hands of an experienced pituitary neurosurgeon, the prognosis for endocrinologic recovery and visual improvement is good.

A novel use of etomidate for intentional adrenal suppression to control severe hypercortisolemia in childhood*

To describe a novel use for etomidate in critically ill children. Etomidate induction of anesthesia in children is controversial due to adrenal suppression; we review this controversy and describe a therapeutic application of this "side effect" using a continuous etomidate infusion in pediatric intensive care to deliberately suppress critically elevated endogenous cortisol. Case report. A tertiary pediatric intensive care unit. A 6-year-old boy with severe, life-threatening hypercortisolemia secondary to Cushing's disease. Admission to pediatric intensive care unit, before bilateral adrenalectomies, to facilitate etomidate infusion to reduce endogenous hypercortisolemia, as first-line treatment with metyrapone and ketoconazole had failed. Continuous intravenous etomidate at 0.08 mg/kg/hr decreased serum cortisol from 1200 to 250 nmol/L within 48 hours. Once etomidate and hydrocortisone therapy provided stable serum cortisol levels, bilateral laparoscopic adrenalectomies were undertaken. A perioperative cortisol surge was seen, but to a much lower peak than expected without prior etomidate suppression. The adrenal suppression caused by etomidate, so controversial in the care of the critically ill at present, can be therapeutically used for short-term control of severe hypercortisolemia in children.

Ectopic ACTH syndrome

Ectopic adrenocorticotropic secretion (EAS) is responsible for 12-17% of cases of Cushing's syndrome (CS) and covers a range of tumours, from undetectable benign lesions to widespread metastases. The syndrome is often associated with severe hypercortisolaemia, which aggravates the underlying condition. EAS requires a complete workup that includes the establishment of endogenous CS, diagnosis of adrenocorticotropic hormone (ACTH) dependency, localization of the source of ACTH secretion and rapid biochemical control of hypercortisolaemia. Dynamic endocrine tests should include inferior petrosal sinus sampling with CRH stimulation. Localization studies depend on the availability of reliable high-resolution cross-sectional imaging. This systematic review of the largest published series of patients with EAS (over 380 patients) reveals the common trends in the prevalence and management of this syndrome. The concept of 'occult' EAS has been revisited and the terms 'overt' and 'covert' EAS introduced. In addition to small cell lung carcinoma, the most common causes of ectopic EAS are bronchial carcinoids, thymic tumours, islet cell tumour of the pancreas, medullary thyroid carcinomas, and phaeochromocytomas. Their prevalence and the best localization modalities are presented. Medical and surgical management is discussed on the basis of the extensive experience of major referral centres.