Low-dose Dexamethasone Suppression Research Articles

Open Surgical Thrombectomy and Coronary Stent Placement for Treatment of Aortic Thrombotic Disease in a Bitch

Background: The thrombotic aortic disease in dogs and cats is characterized by the pathological formation of blood clots that can rupture and obstruct the blood flow. Abdominal ultrasonography can identify the location and extension of thrombus in the main vasculature and using the doppler it is possible to observe the blood flow around the thrombus. Stents are expandable tube-shaped endoprosthesis characterized as a metal mesh and used to prevent or repair stenoses, allowing liquid, gas, or solids to flow. This report aims to describe the surgical and medical treatment of aortic thrombotic disease followed by coronary stents placement in a bitch.Case: An 8-year-old Shih Tzu bitch, presented for evaluation of a 1-month progressive hind limbs paresis. Nociception was present in both limbs, but the patient presented discomfort and vocalization when manipulating the pelvic limbs. A complete blood count demonstrated anemia, mild neutrophilia, and lymphopenia. Serum biochemistry found an increase in ALT, ALP, blood urea nitrogen, and CK. Abdominal ultrasonography detected mild bulging of the caudal aorta and trifurcation of the iliac arteries. Increased intraluminal echogenicity and absence of blood flow were also detected using duplex doppler. The initial medical treatment was ineffective in improving clinical signs, therefore surgical repair was performed. The aorta was isolated and clamped with Satinsky forceps and incised. The thrombus fragmented during removal. A non-compliant high-pressure balloon was used to dilated and remove small fragments of blood clots from the right and left external iliac arteries. Coronary stents of 32 mm length by 2.75 mm diameter were placed to keep both iliac arteries free. Immediately after the procedure, there was a detectable distal pulse in both hind limbs. Despite intensive medical treatment, the patient evolved to respiratory distress and died on the sixth day after surgery. At necropsy, there were thrombi in the lumen of the arteries and several organs in addition to a large hyaline thrombus occluding 80-90% of the aortic lumen and left femoral artery. In the trifurcation region, clots were present, and stents placed in the iliac arteries were also occluded.Discussion: The occurrence of aortic and iliac thrombosis is associated with several conditions, including neoplasia, chronic kidney disease, heart failure, gastric dilatation-volvulus, hypothyroidism, and hyperadrenocorticism (HAC). In this case, the underlying cause of thromboembolism was supposed to be related to an endocrine condition, since the patient had clinical signs compatible with HAC; however, the low-dose dexamethasone suppression test was borderline and further examination could not be afforded. The diagnosis of thrombosis at the iliac trifurcation was obtained through ultrasonographic examination. Computed tomographic and nuclear resonance imaging could have been applied as well. The medical management of the thromboembolic disease was based on anticoagulant therapy with both heparin and clopidogrel in association with surgical thrombectomy and coronary stents placement. Despite the efforts, the patient died shortly after the surgical procedure, which was expected since high rates of mortality and morbidity is often related to the thromboembolic ischemia. The necroscopic examination of the animal found thrombi at the stents, cranial aorta, and microscopically in several tissues. The failure to directly treat the cause of the thrombus, which could not be diagnosed in time, may negatively interfered in patient survival time. The thrombectomy and coronary stents placement reestablished the femoral pulse immediately after surgery, which has been reported in other studies. The surgical resolution of aortic thrombus should be addressed in further studies.

Influence of dental restoration under general anaesthesia on the low-dose dexamethasone suppression test in dogs

It was the aim of the study to assess the impact of a minor surgical intervention under general anaesthesia on results of a low-dose dexamethasone suppression test (LDDST) in dogs. Five clinically healthy dogs underwent a LDDST (standard protocol) prior and 1, 4, 7, 14 and 28 days after a dental restoration under general anaesthesia. All LDDSTs revealed negative results. On all test days after intervention some dogs had basal cortisol concentrations below the reference range. Accordingly, plasma cortisol concentrations 4 and 8 h after dexamethasone injection were noticeably lower than before surgery and often even below the lower detection limit of 2.0 ng/ml. The study results may indicate a suppressive effect of a minor surgery under general anaesthesia on cortisol measurements during LDDSTs. It may be speculated that this could possibly lead to false negative test results in the postsurgical period, although transfer of these results to clinical cases is subject to limitations.

The frequency of Cushing's disease, ACTH-independent Cushing's syndrome and autonomous cortisol secretion among Turkish patients with obesity.

OBJECTIVE:The frequency of Cushing’s disease (CD), ACTH-independent Cushing’s syndrome (CS) and autonomous cortisol secretion (ACS) in patients with obesity is not well known. Therefore, in the present study, we aimed to assess the frequency of CD, CS and ACS among the patients with obesity.METHODS:This study included 813 patients (683 female, mean age 46.47±14.23 yr; mean body mass index (BMI) 37.31±6.50 kg/m2). Patients with obesity were classified further to stages 1, 2, and 3, according to BMI. All patients underwent a low dose dexamethasone suppression test (LDDST). The patients with CD, CS, and ACS and patients with simple obesity were compared concerning gender, age, type-2 diabetes, hypertension (HT) and hyperlipidemia (HL).RESULTS:Forty-four (5.4%) out of 813 patients were diagnosed as CD, CS or ACS. CD, CS, and ACS were diagnosed in four (0.4%), two (0.2%), and 33 (4%) patients, respectively. When patients with CD, CS and ACS were compared to the patients with simple obesity, older age at diagnosis, the presence of stage-1 obesity, the presence of HT, and uncontrolled type-2 diabetes were more frequent in patients with CD, CS and ACS (p=0.001, p=0.007, p=0.004, and p=0.0026, respectively).CONCLUSION:The frequency of CD, CS, and ACS is high among patients with obesity. Screening for CD, CS, and ACS in patients with stage-I obesity who are older than 50 years of age with uncontrolled type-2 diabetes and HT may be a reasonable approach.

Spontaneous Resolution of Primary Hypercortisolism of Cushing Disease After Pituitary Hemorrhage

To describe a case of spontaneous resolution of primary hypercortisolism from Cushing disease (CD) due to pituitary apoplexy (PA). Clinical, laboratory, and pathologic information are described. A 59-year-old female presented with a headache, a 2.3 cm sellar mass with a questionable hemorrhagic component, and clinical signs of hypercortisolism. On further evaluation, she had an increased 24-hour urine free cortisol, abnormal serum cortisol during a low dose dexamethasone suppression test, and an elevated plasma adrenocorticotropic hormone (ACTH), consistent with pituitary CD. As she was being prepared for surgical resection, she was noted to have spontaneous biochemical remission associated with resolution of her symptoms of hypercortisolism, and a repeat magnetic resonance imaging scan showed shrinkage of the sellar mass. She has been managed conservatively since and remains in clinical/biochemical remission until present time, 18 months following her initial presentation. We report a case of spontaneous resolution of CD from symptomatic hemorrhage within an ACTH-secreting pituitary adenoma, or PA. This has been rarely reported in the medical literature. The fact that she did not pass through a phase of adrenal withdrawal, makes us suspect a residual functional adenoma within or around the sella which may eventually grow, causing her disease to recur, as has been reported. Hence, continued monitoring will be required.

Epidemiological, clinical, and laboratory aspects in a case series of canine hyperadrenocorticism: 115 cases (2010-2014)

ABSTRACT: Diseases’ clinical-epidemiological characterization assists in directing the diagnosis. The objective of this study was to describe epidemiological, clinical and laboratorial aspects of a case series of canine hyperadrenocorticism (HAC). One-hundred fifteen records of dogs diagnosed by the low dose dexamethasone suppression test and/or ACTH stimulation test were evaluated. Of the cases, 81.3% were HAC ACTH-dependent and 18.7% HAC ACTH-independent. Females were more affected, representing 69.3% of the cases. The mean age was 10.3±2.5 years and 64.9% were gonadectomized. Most of the patients were small size dogs, weighting less than 10kg (73.9%). The most frequent breeds were: Poodle (27%), Dachshund (17.4%), and Yorkshire Terrier (10.4%). The most frequent clinical manifestations were polyphagia (86%), polydipsia (82.6%), polyuria (80%), abdominal enlargement (82.6%), thin skin (79.1%), muscular weakness (78.3%) and panting (74.8%). However, eventually unusual HAC-associated signs would be present in some dogs in a more important way compared with the classic disease´s clinical signs. The CBC showed neutrophilia (66%), eosinopenia (58.3%) and lymphopenia (42.6%) as main hematological abnormalities. The most common findings in serum biochemistry were increased alkaline phosphatase activity (81.74%), increased ALT activity (62.6%), hypercholesterolemia (66%) and hypertriglyceridemia (54.7%). Urinalysis revealed hyposthenuria in 14.9% and isostenuria in 13.5%; besides proteinuria in 50% of the cases. Abdominal ultrasound showed bilateral adrenal hyperplasia (92.2%) with adrenal asymmetry in 20.8% of the cases, in addition to hepatomegaly (80.9%), biliary sludge (67.8%) and hepatic hyperechogenicity (47.8%). It was concluded that small size gonadectomized female dogs, mainly Poodles and Dachshunds, presented higher frequency in the population studied, and that the main changes observed in clinical and complementary tests were polyphagia, polyuria, polydipsia, abdominal enlargement, adrenal hyperplasia, increased phosphatase alkaline and hyperlipidemia. These results corroborated to a better disease characterization at Brazil. This work concluded that the population studied resembles the profile describe in European and North American epidemiologic studies, and that the HAC dog´s clinical picture looks similar worldwide.

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.

Incidental Adrenocortical Carcinoma in Dogs: Clinical, Tomographic and Histopathological

Background: Adrenal incidentalomas are masses accidentally discovered during imaging examinations performed when there is no suspicion of adrenal disease. Even with a low prevalence, it is important to perform a reliable evaluation observing biological behavior and determining whether the hormonal activity is stimulated. Frequently, these masses are not functional, but in some cases, there is increased cortisol activity, and patients with adrenal incidentalomas may present hyperadrenocorticism. This report aims to describe the clinical, tomographic, and histopathological aspects of a case of adrenal incidentaloma detected in a routine abdominal ultrasound.Case: An 8-year-old, male, maltese dog with occasional emesis, halitosis, claudication of the left pelvic limb, and previous compensated and untreated cardiomyopathy was treated at the Veterinary Hospital of the Federal University of Mato Grosso (HOVET-UFMT). Physical examination revealed arterial hypertension and claudication, with the positive posterior drawer test suggesting rupture of the cruciate ligament. The blood count showed no alteration, and the serum biochemistry revealed a slight increase in the activity of alanine aminotransferase. In order to investigate this increase, an abdominal ultrasound was performed. Slight hepatomegaly and a heterogeneous mass of irregular edges were observed with a moderate and difficult-to-delimit vascularization of the adrenal gland. Left knee radiography raised the suspicion of rupture of the cranial cruciate ligament due to the cranial displacement of the tibia in relation to the femur. Computed tomography was performed to define the extent and delimitation of the mass, which was compatible with a tumor of the right adrenal gland characterized by the visualization of an abdominal mass between the kidneys, extending from the hepatic region to the cranial pole of the left kidney. On follow-up, the patient was reported to have diarrhea with black stools, and a low-dose dexamethasone suppression test was ordered. Unilateral adrenalectomy was recommended due to the suspicion of pheochromocytoma. During the surgical procedure, the mass adhered to the abdominal wall and the diaphragm resulting in the death of the animal. Histopathological analysis revealed a cellular proliferation of cortical adrenal cells forming multiple cell nests separated by a small amount of fibrovascular stroma. Proliferated cells were polyhedral, with densely eosinophilic cytoplasm and well-defined edges, and were occasionally vesicular. They had globular nuclei, slightly stained chromatin, and inconspicuous nucleoli. Pleomorphism, anisocytosis, and anisokaryosis were accentuated, and eight mitosis figures were observed in ten high-power fields (40×), leading to a diagnosis of adrenocortical carcinoma.Discussion: When there is no suspicion or characteristic clinical sign, and adrenal growth is observed on imaging examination, the finding may be called an incidentaloma. Here, the incidentaloma was a non-functional adrenal carcinoma, because the tests were not conclusive. Adrenal carcinomas grow by infiltrating adjacent tissues, such as the caudal vena cava. In this case, it infiltrated the abdominal wall and diaphragm. Therefore, imaging, ultrasound, and tomography examinations were important for the characterization of the adrenal incidentaloma in this dog. This adrenal incidentaloma, which was a carcinoma with metastasis to the adjacent tissues, required other hormonal tests to rule out further endocrine dysfunctions.

Hiperadrenocorticismo atípico e hipotiroidismo canino

El hiperadrenocorticismo (HAC) es una de las endocrinopatías más frecuentes en caninos, producida por la síntesis excesiva de cortisol. El HAC atípico u oculto es un síndrome caracterizado por la presentación de alteraciones clínicas, bioquímicas e imagenológicas compatibles con hipercortisolismo, pero con resultados normales en las pruebas endocrinológicas utilizadas convencionalmente para diagnóstico de HAC. Sin embargo, estos pacientes presentan elevada concentración sérica de precursores u otras hormonas corticoadrenales. El presente estudio describe el caso de una canina hembra, Bichón Frisé de 8 años de edad, epiléptica y tratada con fenobarbital, presentando signos clínicos asociados a HAC, en la que el test de supresión con dexametasona a dosis bajas y de estimulación con ACTH arrojaron valores normales. La medición de esteroides adrenales, post estimulación con ACTH, mostró elevación anormal de estrógenos y progesterona, persistiendo esta última después de que la paciente fuera esterilizada. El tratamiento con trilostano permitió la disminución de los niveles de progesterona y la resolución parcial de los signos clínicos. Sin embargo, la recuperación clínica en su totalidad sólo se obtuvo después del diagnóstico y tratamiento del hipotiroidismo concomıtante. El desafío que representa el diagnóstico del HAC atípico resalta la importancia de realizar y disponer de paneles que incluyan medición de hormonas esteroideas adrenales diferentes al cortisol, además de considerar la ocurrencia de otras enfermedades endocrinas metabólicas concomitantes.

Clinical and Clinicopathological Features in Dogs with Uncomplicated Spontaneous Hyperadrenocorticism Diagnosed in Primary Care Practice (2013-2014).

The objective of this study was to report clinical and clinicopathological abnormalities in canine spontaneous hyperadrenocorticism (HAC) and assess the relationship between patient size and those findings. A questionnaire was made available to primary care veterinarians to gather information on cases diagnosed with canine spontaneous HAC. Inclusion criteria were an adrenocorticotropic stimulation test and/or low-dose dexamethasone suppression test consistent with HAC. Exclusion criteria included concurrent systemic diseases, any clinical sign (CS) not typically associated with HAC, a urinary corticoid:creatinine ratio within reference interval, administration of steroids during the 3 mo before diagnosis, treatment with any drug causing CSs of HAC, and ongoing treatment for canine spontaneous HAC. Sixty-two cases were identified. The prevalences of various CSs were similar to those historically reported. No association between the patient weight and CSs was identified. The platelet count was negatively correlated to the weight (P = .005, r2 = 0.3). Alanine aminotransferase (P = .016, r2 = 0.17) and alkaline phosphatase (P = .05, r2 = 0.0014) activities were positively correlated to the CS ratio. In this group of dogs, CSs were not significantly different between dogs ≤20 kg and dogs >20 kg. The prevalences of various clinical findings appeared to be similar to those historically reported. Dogs with more CSs tended to have higher alanine aminotransferase and alkaline phosphatase activities.

The frequency of Cushing's disease, ACTH independent Cushing's syndrome, and autonomous cortisol secretion among turkish patients with obesity

OBJECTIVE The frequency of Cushing's disease (CD), ACTH-independent Cushing's syndrome (CS) and autonomous cortisol secretion (ACS) in patients with obesity is not well known. Therefore, in the present study, we aimed to assess the frequency of CD, CS and ACS among the patients with obesity. METHODS This study included 813 patients (683 female, mean age 46.47±14.23 yr; mean body mass index (BMI) 37.31±6.50 kg/m2). Patients with obesity were classified further to stages 1, 2, and 3, according to BMI. All patients underwent a low dose dexamethasone suppression test (LDDST). The patients with CD, CS, and ACS and patients with simple obesity were compared concerning gender, age, type-2 diabetes, hypertension (HT) and hyperlipidemia (HL). RESULTS Forty-four (5.4%) out of 813 patients were diagnosed as CD, CS or ACS. CD, CS, and ACS were diagnosed in four (0.4%), two (0.2%), and 33 (4%) patients, respectively. When patients with CD, CS and ACS were compared to the patients with simple obesity, older age at diagnosis, the presence of stage-1 obesity, the presence of HT, and uncontrolled type-2 diabetes were more frequent in patients with CD, CS and ACS (p=0.001, p=0.007, p=0.004, and p=0.0026, respectively). CONCLUSION The frequency of CD, CS, and ACS is high among patients with obesity. Screening for CD, CS, and ACS in patients with stage-I obesity who are older than 50 years of age with uncontrolled type-2 diabetes and HT may be a reasonable approach.

MON-414 The Case of a Dual-Secreting Pituitary Macroadenoma

Introduction: Pituitary adenomas are estimated to occur in 17% of the population (1 in 600 persons).1 One-half of pituitary adenomas secrete a distinct hormone, most often prolactin, GH or ACTH.1 Prolactinomas are the most common, 50% of functional pituitary tumors and 40% of pituitary tumors overall.1 Exceedingly rare are dual-secreting pituitary adenomas. We aim to describe a pituitary macroadenoma secreting both prolactin and ACTH with significant mass effect. Clinical Case: An 87-year-old female was seen in Endocrine clinic for bitemporal hemianopsia and fatigue in October 2017. A brain MRI revealed a 2.0 x 1.1 x 1.2 cm pituitary mass displacing the optic chiasm and left optic nerve. She denied any headaches, galactorrhea, weight or appetite changes. Her physical exam was only notable for visual field defects. Her prolactin was 591 ng/mL (n 5-23 ng/mL) and 395 ng/mL after a dilution test. Her ACTH was 103 pg/ml (n 6-58 pg/mL) and cortisol 15 ug/dl at baseline. After a low-dose (1 mg) dexamethasone suppression test, ACTH was 32 pg/ml and cortisol was 5.1 ug/dl (cutoff 1.8 ug/dl). A high-dose (8 mg) dexamethasone test suppressed ACTH to 3.7 pg/mL and cortisol to 0.9 ug/dl. Her TSH was 0.64 uIU/mL (n 0.30-4.50 uIU/mL) with a total T4 of 0.6 ng/dL (n 0.6-1.5 ng/dL). The patient was deemed a poor Neurosurgical candidate due to her age and comorbidities. She was started on Levothyroxine and Cabergoline. Over time with medical management, her vision loss and fatigue improved. Her prolactin level reduced from 591 ng/mL to 209 ng/mL after 2 months. On repeat brain imaging in February 2018, the macroadenoma was stable in size. Discussion: Our case is unique as it describes a pituitary macroadenoma with concurrent secretion of prolactin and ACTH. She presented with subclinical Cushing’s disease given her test results, no symptoms, and normal exam. Gradual growth of the adenoma led to pituitary compression and a secondary hypothyroidism. While the adenoma was stable in size, resolution of her visual field defect indicates some treatment response. Dual-secreting pituitary adenomas are rare. In a 6-year study at UCSF, 22 of 593 patients diagnosed with pituitary adenomas had dual GH and prolactin secretion (3.7%).2 As for coexistent ACTH and prolactin tumor secretion, very few cases have been reported.3Conclusion: Neuroendocrine tumors have the potential for significant morbidity due to potent endocrine effects and critical mass effect as seen in our patient.1 Early diagnosis and treatment is critical to reduce morbidity and mortality of this disease.

SUN-397 A Rare Case of Ectopic Adrenocorticotropic Hormone (ACTH) Syndrome Due to Thymic Large Cell Neuroendocrine Carcinoma Presenting as Severe Hypokalemia in a Taiwanese Man

Background Ectopic ACTH syndrome (EAS) represented 5% of Cushing syndrome. EAS is rapid onset, severe, associated with hypercortisolism related life-threatening infections and hypokalemia. In 60% of cases, the tumor is located in intrathoracic organ (lung, bronchus and thymus). Large cell neuroendocrine tumor of thymus secreting ACTH is a high grade, aggressive, poor prognosis and only few case reports in literature. Here we report a case of thymic LCNEC related EAS, which presented as severe hypokalemia, metabolic alkalosis and muscle weakness. Clinical Case A 71-year-old man presented with 12-kg weight loss, progressive generalized weakness and bilateral legs edema for two months.He has medical histories of hypertension and diabetes mellitus. Physical examination revealed generalized weakness without Cushingoid appearance. Laboratory examination showed metabolic alkalosis and severe hypokalemia (1.7 mmol/L, range 3.4-4.7).Hypokalemia work-up showed high morning ACTH 497 pg/mL (normal <46.0), cortisol 87.8 μg/dL (range 3.7-19.4), and normal limits of other pituitary hormones. Cushing syndrome survey showed lack of ACTH/cortisol circadian rhythm, markedly increased 24h urinary free cortisol excretion on two consecutive days ( 21429, 17061 μg). Low-dose and high-dose dexamethasone suppression tests showed non-suppressible. Ovine corticotrophin-releasing hormone stimulation test and desmopressin (DDAVP) test showed ectopic ACTH source. Pituitary MRI revealed negative findings. Bilateral inferior petrosal sinus sampling showed no central-to-peripheral ACTH gradient. Ectopic ACTH syndrome was impressed. Etomidate continuous infusion was prescribed.Fournier gangrene of left scrotum occurred during hospitalization and antibiotic and surgical treatment were given. Chest CT scan revealed tiny lobulated nodule in left lower lung field and soft tissue nodule in prevascular of mediastium. In-111 Octreoscan revealed several nodular lesions with increased In-111 uptake in the paraortic and prevascular region considering neuroendocrine tumor. Anterior mediastinal tumor excision was performed and histopathological report showed large cell neuroendocrine carcinoma of thymus with mitotic count 13/10 HPF and positive immunohistochemical stain for synaptophysin, chromogranin, DD-56, SSTR2 and ACTH. Sandostain LAR injection was administered afterward. Unfortunately, tumor progression with hypercortisolemia occurred after 6 months . External radiation and systemic chemotherapy were performed later. Clinical Lessons Although rare, Cushing syndrome must be considered in differential diagnosis of hypokalemia like our case, a challenging case of EAS. Early diagnosis and treatment was important to avoid life-threatening infections and metabolic complications. Moreover recurrence free survival with Sandostain LAR alone was only 6 months for LCNEC.

SAT-223 Insights into Ovarian Hyperandrogenism: Lessons from Two Unusual Cases

Introduction: The majority of cases with postmenopausal hyperandrogenism have a benign etiology such as ovarian hyperthecosis, hilus cell hyperplasia, ovarian or adrenal tumors. Determining adrenal versus ovarian OR tumorous versus nontumorous causes of hyperandrogenism can be tricky. Here we report two very different cases associated with ovarian hyperthecosis. Case 1: The 73 year old obese female with a history of prediabetes, hysterectomy and breast cancer presented with severe hirsutism and virilization over 5 years. Testosterone levels per LC/MS were between 200-350 ng/dL and rose further during a 2d LDDST (Low Dose Dexamethasone Suppression Test), while cortisol and DHEA-S suppressed appropriately. Imaging was negative for an adrenal or ovarian mass. Based on the biochemical data, we suspected a tumorous ovarian source of androgen excess despite negative imaging findings. The patient underwent salpingo-oophorectomy which revealed small bilateral steroid cell tumors (0.7-0.9 cm) in the setting of bilateral focal hyperthecosis and hilus cell hyperplasia. Postoperative testosterone levels fell to 14 ng/dL. Case 2: The 53 year old obese female with a history of diabetes and PCOS presented with progressive male pattern hair loss, acne and acanthosis nigricans over 3-5 years. Her testosterone levels per LC/MS were between 100-150 ng/dL. During LDDST, cortisol and DHEA-S suppressed appropriately, testosterone increased further. Imaging was again negative for an adrenal or ovarian mass. Following this workup, the patient was treated with a GnRH analogue which resulted in complete testosterone suppression, regression of acanthosis nigricans and scalp hair regrowth. She later underwent salpingo-oophorectomy which showed only a few scattered, minute clusters of luteinizing theca cells in both ovaries, no tumor was identified. Lessons: These cases illustrate that imaging often fails to detect small ovarian tumors, stressing the need for additional diagnostic markers such as LDDST. Based on their case series, Kaltsas et al. suggested that lack of testosterone suppression during LDDST ruled out a nontumorous androgen source (1). However, this was not true for case 2 presented here: Testosterone remained non-suppressed during LDDST, yet she did not have an androgen-producing tumor, but mild hyperthecosis. Notably, her testosterone levels were <150 ng/dL. In summary, we propose that testosterone levels >150 ng/dL PLUS absent testosterone suppression during LDDST might be suggestive of androgen-producing tumors. Furthermore, therapy with GnRH can be an alternative to surgery in cases with ovarian hyperandrogenism.

SUN-392 Severe Idiopathic Intracranial Hypertension with Papilledema after Surgical Treatment of Cushing's Due to an Adrenal Adenoma

Background: It has been rarely reported that patients may develop idiopathic intracranial hypertension (IIH) after treatment of Cushing’s disease. We present a first known case of a patient with IIH after treatment of Cushing’s due to an adrenal adenoma. Clinical case: A 29-year-old female presented with 50 lb weight gain over the prior 2 years. She also had facial acne and hirsutism. Menses were regular. Her only medicine was norelgestromin-ethinyl estradiol 50-35 mcg/24hr patch for contraception. On exam she was normotensive with a BMI of 36kg/m2, generalized obesity, facial acne scars, and dark abdominal striae. Pelvic ultrasound revealed polycystic ovaries and small myomas. Extensive blood testing was normal including DHEAS, IGF-1, 17-hydroxyprogesterone, prolactin, TSH, testosterone and HgbA1C. However, her 24-hour urinary free cortisol (UFC) and two late night salivary cortisols were elevated with a suppressed ACTH (UFC 85.9 with normal range 4-50 mcg/24hr, salivary cortisols 0.24 and 0.18 with normal range 0.01-0.09 mcg/dl). Low dose dexamethasone suppression test revealed non suppressibility of cortisol (cortisol 16 mcg/dl). CT abdomen demonstrated a 3.6 x 3.2 x 3.0 cm left adrenal mass with benign characteristics. The patient underwent left adrenalectomy. Pathology confirmed adrenal cortical adenoma. At her one month post-op visit the patient was tearful and fatigued. Her cortisol level was 1.9mcg/dl after holding hydrocortisone for 24 hours. An additional 5 mg hydrocortisone was added midday to her discharge dose of 10 mg in the AM and 5 mg in the PM. She felt well immediately after the dose increase. Three months post-op her weight had decreased by 10 lbs. The hydrocortisone dose was decreased by 2.5 mg. Several days later she noticed daily episodes of transient vision loss with postural changes. She waited 1 month before seeking medical attention and then saw an ophthalmologist who diagnosed papilledema, confirmed by MRI and MRV of the brain, which were otherwise normal. A neurologist prescribed Diamox 500mg tid for presumed intracranial hypertension and referred her for lumbar puncture. The hydrocortisone was increased back to 10mg/5mg/5mg daily. She stopped the Diamox due to unremitting symptoms and inability to tolerate the medication. Three weeks later she presented to ED with progressive visual loss. Lumbar puncture had an increased opening pressure of 32 mm of H2O with normal CSF analysis. She was restarted on Diamox at a lower dose and improved 1 month later. Conclusion: There have been less than a dozen cases of IHH reported in patients treated for Cushing’s disease, 2 after withdrawal from inhaled glucocorticoids, and 2 with adrenal insufficiency. The cause is believed to be multifactorial, likely related to relative decrease in cortisol after surgical resection. This case is the first report of a patient with IIH after treatment for Cushing’s due to an adrenal adenoma.

MON-435 The Responsiveness To Ddavp Test Predicts Usp8 Mutation In Patients With Cushing's Disease

Background: Desmopressin test (DT) is useful for the diagnosis of Cushing’s disease (CD). Approximately 80% of patients with CD respond in DT; however, the clinical significance remains unclear. Objective: To clarify the clinical significance of the responsiveness to DT in CD. Patients and Methods: This is a retrospective multi-center study. Thirty-five patients with CD who underwent DT (29 women and 6 men, age 40 ± 15 years) between 2014 and 2018 in Kobe university hospital or Toranomon hospital were included. A method of single intravenous injection of desmopressin (4μg) were used as previously described (1). Patients were divided into two groups by the responsiveness to DT; DT (+), whose ACTH increased to 1.5-folds or more during the DT (n = 20) and DT (-), whose response was less than 1.5-folds (n = 14). Following clinical parameters; age, gender, serum ACTH level, cortisol level (F), F in low dose dexamethasone suppression test, F in high dose dexamethasone suppression test, 24 hour urinary free cortisol (UFC), tumor diameter, Knosp grades, and USP8 mutation were compared between DT(+) and DT(-). Results: While serum ACTH, F, UFC and tumor size did not show any differences between these two groups, the responder was more predominant in women than men (68% vs. 17%, p = 0.028). Intriguingly, the responsiveness to DT was significantly greater in USP8 mutation-positive group (n = 15) than that in wild-type group (n = 6) (median (range); 3.0 (1.0-6.7) vs. 1.3 (1.1-1.6) folds, p = 0.010). When cutoff value is defined as 1.6-folds, the responsiveness to DT predicts the presence of USP8 mutation in the sensitivity of 80% and specificity of 100%. Conclusions: The responsiveness to DT was greater in female patients with CD. DT can predict the presence of USP8 mutation in a high specificity. These results suggest that the underlying mechanisms associated with USP8 mutation may affect the expression of V1b or V2 receptor. Reference (1) Y. Sakai, et al., Endocr J 1997;44:687-695.

SUN-380 A Case of Cushing Syndrome

Introduction: Cushing's syndrome is characterized by over-secretion of cortisol. Etiologies of Cushing’s syndrome can be ACTH dependent or independent. This highlights a case of ACTH independent Cushing’s secondary to an adrenal lesion. Clinical case: A 28 year old lady presents to Endocrine clinic for evaluation of secondary amenorrhea for 2 years. She was previously evaluated by a gynecologist who performed a progesterone challenge test with no response. The patient reports mild acne during adolescence but denies excess hair growth, or voice deepening. She notes weight gain primarily distributed in her abdomen and face. She reports fatigue, anxiety, easy bruising, intermittent headaches as well as some polydipsia and polyuria. She is not experiencing peripheral muscle weaknessm galactorrhea, or problems with peripheral vision. Her medications are fish oil, multivitamin, and probiotic. Physical exam is notable for BMI of 21.7 kg/m2, round face with increased facial plethora, and an increased posterior fat pad. Significant labs include DHEA sulfate 15mcg/dL (18-391mcg/dL), FSH 6.3mlU/mL, estradiol <15pg/mL for a non-premenopausal woman (19-357pg/mL), total testosterone 3ng/dL (2-45ng/dL), prolactin 25.9 ng/dL (3.0-30 ng/dL). Her ACTH is <5pg/mL (6-50pg/mL) and AM cortisol followed by 1 mg dexamethasone of 22.9mcg/dL (<2.0mcg/dL). Repeat low dose dexamethasone suppression test is significant for AM cortisol 20.7 mcg/dL (4-22mcg/dL) and dexamethasone 258ng/dL. CT Abdomen is performed revealing a left sided adrenal mass. The patient undergoes unilateral adrenalectomy with pathology demonstrating an adrenal cortical adenoma. Her post-operative midnight salivary cortisol levels are appropriately low. Given some symptoms of adrenal insufficiency of dizziness and weakness she undergoes a slow hydrocortisone taper. Her menstrual cycles gradually return, facial plethora and sites of abnormal fat deposition resolve. She reports a significant improvement in her psychological wellbeing with decreased anxiety and increased functionality. Conclusion: The signs and symptoms of Cushing’s syndrome are attributable to the presence of hypercortisolism. While there are signs highly suggestive of Cushing’s syndrome including central obesity with wasting of the extremities, increased dorsocervical fat pad, easy bruising and wide purple striae, symptoms can be subtle, leading to a delay in diagnosis. Our patient presented with a complaint of amenorrhea. Menstrual irregularities are very common in women with Cushing’s syndrome. These symptoms are due to suppression of gonadotropin-releasing hormone secretion secondary to hypercortisolemia, with resultant decrease in levels of FSH and LH. A high level of suspicion is important in order to diagnose Cushing’s syndrome as curative treatment leads to a significant improvement in morbidity and the patient’s quality of life.

SUN-454 Rationale and Methods for a Phase II Trial Evaluating Osilodrostat in Pediatric Patients with Cushing's Disease

Background: Cushing’s disease (CD) is a rare disease associated with significant morbidity and mortality, with 2-5 new cases per million per year, of which 10% occur in children (Stratakis CA. Endocrinol Metab Clin North Am 2012;41:793-803). In children, CD presents with a combination of weight gain and slowed linear growth. First-line surgery is the treatment of choice for most patients, with a success rate of 60-98% in pediatric patients if performed by an expert pituitary surgeon (Keil MF. J Clin Endocrinol Metab 2013;98:2667-78). When surgery is not successful, patients require additional pharmacologic interventions, which are currently limited in children. Osilodrostat is a potent oral 11β-hydroxylase inhibitor in clinical development for the treatment of CD. This Phase II, multicenter, open-label, non-comparative study will evaluate the pharmacokinetics (PK), pharmacodynamics and safety/tolerability of osilodrostat in patients aged 6-<18 years with Cushing’s disease (clinicaltrials.gov identifier: NCT03708900). Methods: This single-arm study will enroll 12 evaluable patients aged 6-<18 years with confirmed CD for whom pituitary surgery is not an option, for whom surgery has failed, or who are awaiting surgery. CD will be confirmed by the clinical criteria of decreasing growth percentiles with increasing weight (defined by height SDS <0, BMI SDS >0, and a strong clinical suspicion of CD), an abnormal low-dose dexamethasone suppression test, measurable morning ACTH levels, and two 24-hour UFC measurements >1.3 x ULN. This study consists of two phases: a 12-week core phase and an optional 9-month extension period for patients who obtain a clinical benefit from osilodrostat as judged by the investigator. The primary objective is to assess the PK (Cmax and Ctrough) of osilodrostat during the 12-week core study. A secondary objective is to assess the proportion of patients with normal mean UFC (mUFC; determined from two 24-hour UFC samples) at weeks 6 and 12. Other secondary objectives include: assessment of safety and tolerability up to week 12 of the core phase and up to month 12 of the extension phase; assessment of efficacy up to month 12. The starting dose of osilodrostat will be 1 mg once daily and 1 mg twice daily for patients weighing <60 kg and ≥60 kg, respectively. The dose may be titrated based on mUFC response. PK parameter estimates will be calculated by pooling individual plasma osilodrostat concentration-time data and analyzed using non-compartmental analysis. Conclusion: This Phase II, multicenter, open-label, non-comparative study will be the first study of osilodrostat in pediatric patients with CD. The results of this study may allow further clinical development of osilodrostat in children with CD.

SAT-LB077 Remission and Mortality Rates in Patients with Cushing Disease According to Their Tumor Size

Objective It has been reported that Cushing’s disease due to macroadenoma is characterized by different biochemical features compared with microadenoma. We aimed to analyze and compare the clinical and biochemical features of patients with micro and macroadenomas causing Cushing disease. Methods We conducted a retrospective review of electronic and paper medical records that included 139 patients (108 microdenomas and 40 macroadenomas) with Cushing disease diagnosis who were studied and treated at the (undisclosed), in Mexico City from 2000 to 2017. Clinical characteristics, biochemical analysis of hypercorticolism, pituitary imaging findings, treatment modalities, remission as well as mortality rates were recorded. Results The mean age was 32.5 years (range 24-37) for microadenoma and 30.0 years (range 23-38) for macroadenoma (p=0.65). Female predominance was seen both in microadenoma (91.7%) and macroadenoma (87.1%) patients. Biochemical analysis of hypercortisolism including basal cortisol, ACTH, 24-hour urinary cortisol levels, and responsivity to low-dose dexamethasone suppression were similar between both groups. Remission and mortality rates after initial pituitary surgery for microadenoma and macroadenoma were 82.5 vs 17.5% (p=0.049) and 40.0% vs 60.0% (p=0.024), respectively. Using log-rank test we confirmed higher remission rates in microadenomas (p=0.049) and higher mortality risk with macroadenomas (p=0.024). Conclusion Our study suggest that patients with microadenomas showed better remission rates and lower mortality than those cases with macroadenomas, despite similar biochemical activity and treatment for CD. Therefore, further research is mandatory to identify those risk factors that gave different prognosis Reference Aydin, K & Dagdelen, S & Ozgen, Burce & Oruckaptan, H & Soylemezoglu, F & Erbas, T. (2014). Pituitary Corticotroph Microadenomas Versus Macroadenomas Causing Cushing’s Disease. Journal für Klinische Endokrinologie und Stoffwechsel. 7. 358-362. Keywords Cushing’s disease, corticotroph macroadenoma, corticotroph microadenoma Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Androgen-Secreting Ovarian Tumors.

About 1% of ovarian tumors that comprise testicular cell types can cause hyperandrogenism followed by characteristic virilization. Androgenic group of tumors originated mainly from sex-cord stromal ovarian tumors are including steroid cell tumors, Leydig tumors, granulosa cell tumors, Sertoli cell tumors, Sertoli-Leydig cell tumors, gonadoblastomas, and some other rare forms as ovarian metastases from neuroendocrine tumors. Germline or somatic mutations in some genes like DICER1, STK11, and FOXL2 are associated with the development of some sex cord-stromal ovarian tumors. Basal serum testosterone concentrations above 7 nmol/L could indicate an androgen-secreting tumor. Other ovarian and adrenal androgens should be determined and functional endocrine testing including low-dose dexamethasone suppression test, gonadotrophin-releasing hormone (GnRH) agonist test, imaging methods, and selective venous sampling should be performed. Surgery is the first-line treatment for most of the tumors. Women who are not good surgical candidates could benefit from use of GnRH agonist to control hyperandrogenism. In some cases, chemotherapy and/or radiation therapy is required while some tumors respond on antiangiogenic agents used alone or in combination with chemotherapy. Metabolic implications and long-term outcomes of ovarian androgen-secreting tumors are unknown and require more detailed follow-up in multicentric and longitudinal clinical studies.

Clinical analysis of bilateral macronodular adrenal hyperplasia

Objective To investigate the clinical characteristics in patients with bilateral macronodular adrenal hyperplasia (BMAH). Methods We enrolled 357 patients with adrenal tumors including 42 BMAH, 167 cortisol-producing adrenal adenoma (CPA), and 148 non-functional adenomas (NFA). The clinical manifestations, hormonal explorations and complications were compared among groups. Results (1) Age at diagnosis of BMAH group was significantly higher than that of CPA group [(53.7±8.3 vs 41.1±13.1)years], female proportion of BMAH group was lower that that of CPA group(54.8% vs 88.0%, P<0.01). Both were similar to NFA group. (2) Compared to NFA group, metabolic abnormalities were severer in BMAH and CPA groups. Prevalence of hypertension, diabetes mellitus, and hypokalemia were the highest in BMAH group. (3) BMAH patients had lower midnight serum cortisol, 24 hour urine free cortisol, and adrenocorticotrophic hormone levels than CPA patients (P=0.008, 0.010, and P=0.001, respectively). The suppression rate of serum cortisol after low-dose dexamethasone suppression test was significantly higher in BMAH group (P=0.005). Conclusion BMAH patients were at higher age at diagnosis. Although hypercortisolism in BMAH patients is relatively slight, metabolic abnormalities are more severe. Besides functional diagnosis, physicians should pay more attention to the assessment of complications related to hypercortisolism. (Chin J Endocrinol Metab, 2018, 34: 1010-1014) Key words: Bilateral macronodular adrenal hyperplasia; Cortisol-producing adrenal adenoma; Non-functional adenomas; Adrenal Cushing′s syndrome