Cushing's Syndrome Research Articles

9363 Spontaneous Cushing Disease Remission Induced By Pituitary Apoplexy

Abstract Disclosure: J.E. Esquivel Vargas: None. F. Ruiz Salazar: None. A.B. Santos Rojo: None. Background: Spontaneous remission of Cushing disease is rare, and it is mainly due to apoplexy of a pituitary tumor. Clinical case: 14-year-old female presented with clinical features of Cushing syndrome. Initial tests were consistent with Cushing disease (CD): elevated 24h urinary cortisol (235µg/24h, n<90µg/24h), abnormal 1 mg dexamethasone overnight test (cortisol after 1 mg dex 3.4µg/dL, n<1.8µg/dL), and elevated ACTH-concentrations (83.5 pg/mL, n 10-60pg/mL). Pituitary adenoma was suspected, and the patient was referred for a transsphenoidal resection of the adenoma. While waiting for surgery the patient presented to the Emergency department with a headache and clinical signs of meningism. Computed axial tomography of the central nervous system was performed, and no structural alterations were found. The symptoms subsided with analgesia. One month later she presented again to the Emergency department with clinical findings of acute adrenal insufficiency (cortisol level of 4.06 µg/dL), and she was noted to have spontaneous biochemical remission associated with resolution of her symptoms of hypercortisolism. Nuclear magnetic resonance imaging was performed describing a 2.6 x 1.8mm hypointense pituitary lesion, suggestive of cerebrospinal fluid, which could be a remnant of a pituitary microadenoma. For that reason, spontaneous CD remission induced by pituitary apoplexy (PA) was diagnosed. The patient has been managed conservatively since the diagnosis and remains in clinical and biochemical remission until the present time after 10 months of follow up. Conclusion: There are 3 unique aspects of our case: the early age of onset of symptoms, the spontaneous remission of CD due to PA which has been rarely reported in the medical literature, and the patient presented a microadenoma because there are less than 10 clinical case reports of PA associated with microadenoma. Presentation: 6/1/2024

7667 Cushing’s Puzzle: Echinococcal Pituitary Cyst In A Rare Encounter

Abstract Disclosure: E. Sari: None. F. Erenler: None. Introduction: Echinococcus is a rare parasitic infection endemic in the Mediterranean, Middle East, South America and Africa, which can cause cystic disease in several organs. Central nervous system involvement is known to comprise 1-2% of all cystic echinococcal disease. Hereby, we report a case of an opportunistic pituitary echinococcus infection in a patient with hypercortisolism due to adrenocortical adenoma with initial misdiagnosis of Cushing’s disease. Clinical Case: A 40-year-old South American female with poorly controlled T2DM on oral agents and hypertension presented to the ER with abdominal pain and subsequent CT of the abdomen with contrast showed a right adrenal mass measuring up to 2.8 cm. A follow up CT with adrenal protocol confirmed 3.3 cm right adrenal mass, 46 HU in precontrast images with >50% washout. Review of records revealed that a recent MRI brain with contrast was performed for headache evaluation and showed an incidental 5x7x4 mm lesion in the pituitary gland. Endocrinology evaluation revealed 24-hour urine volume 1800 mL, elevated free cortisol levels 277.6 mcg/24hr (RR: 4.0-50.0 mcg/24hr), creatinine of 0.67g/24hr (RR: 0.50-2.15g/24hr). 1 mg dexamethasone suppression test showed AM cortisol of 28.7 mcg/dL. ACTH was elevated at 67 pg/mL (RR: 6-50 pg/mL). FSH, LH, and GH were normal. Presumed diagnosis of ACTH-dependent hypercortisolism was made and she underwent bilateral inferior petrosal sinus sampling with confirmed successful cannulation but this was inconclusive due to low ACTH levels. Follow-up MRI of the pituitary gland showed T1 bright, T2 isointense circumscribed lesion measuring 7x6x3 mm at anterior pituitary gland with a thin rim of peripheral enhancement consistent with cystic features. She underwent transsphenoidal resection of the pituitary lesion and the pathology specimen showed parasites consistent with echinococcosis. Infectious disease was consulted, and the patient started on albendazole. Post-operative laboratory evaluation was notable for persistently elevated AM cortisol, 24-hour urine free cortisol levels, and low ACTH levels, confirming ACTH independent hypercortisolism. She underwent right adrenal nodule resection and pathology was consistent with adrenocortical adenoma. Post-adrenalectomy AM cortisol levels were < 2 mcg/dL, indicating the resolution of hypercortisolism along with substantiating the diagnosis of primary adrenocortical hyperfunction. Conclusion: To the best of our knowledge, this is the first case report of an opportunistic echinococcus infection presenting as a pituitary lesion in the setting of Cushing Syndrome. We would like to highlight the importance of recognizing opportunistic infections, including Echinococcus as a potential etiology in the setting of hypercortisolism, especially for patients from endemic regions. Presentation: 6/2/2024

6606 Connshing Syndrome: An Uncommon Presentation Of Bilateral Adrenal Mass

Abstract Disclosure: C.S. Botero Suarez: None. N. Meda: None. K. Lamar: None. S.K. Suryanarayanan: None. Introduction: Mild autonomous hypersecretion of cortisol in the underlying setting of hyperaldosteronism has been described before and coined the term Connshing Syndrome. Even though it was described in 1979, recently W. Arlt et al in 2017 revived interest in the topic of Connshing Syndrome represents a distinct entity among PA (primary hyperaldosteronisms). We present a case of bilateral adrenal mass associated with mild autonomous hypersecretion of cortisol as well as the development of primary aldosteronism. Case Description: A 62-year-old male with a medical history of hyperlipidemia, hypertension, spontaneous hypokalemia, and T2DM was referred to the clinic due to concerns for hyperaldosteronism. Exam was unremarkable for signs of hypercortisolism. Blood pressure in the clinic was 143/88 mmHg, pulse 81 bpm, weight 105.4 Kg (231.8 lbs.), and a BMI of 28 kg/m2. A non-contrast abdominal CT performed, showed a 2.9 x.1.4 cm right adrenal lipid-rich adenoma with -3.7 HU, as well as a left adrenal lipid-rich adenoma of 1.8 x 1.3 x cm and -7.7 HU. A hormonal workup showed normal plasma metanephrines, an aldosterone of 39 ng/dL, plasma renin activity 0.16 ng/mL/h, and aldosterone/PRA ratio of 243. The patient underwent 1 mg dexamethasone suppression test which resulted in an ACTH <5 pg/mL, dexamethasone level of 288 ng/dL, and cortisol of 1.9 mcg/dL. AVS with Cosyntropin was performed (see Table 1). Right sided adrenalectomy is being considered but the identification of possible lateralization of cortisol is being considered. Discussion: Surgical management is usually preferred treatment modality for both unilateral PA and MACS, but identification of lateralization of both cortisol and aldosterone can be difficult. Although identifying lateralization of aldosterone with Cosyntropin-stimulated AVS is well understood, lateralization of cortisol production is not well understood. Johnson et. all have suggested the use of adrenal venous sampling with dexamethasone suppression as well as measurement of epinephrine levels to identify the source of hypercortisolism. They demonstrated identification of cortisol lateralization with adrenal vein sampling with specificity of 95 – 100% for unilateral disease utilizing a AV/IVC cortisol ratio > 9 and a cortisol lateralization ratio (CLR) of > 2.3. Although our case had a Cosyntropin-stimulated AVS showing clear lateralization of aldosterone production to the right adrenal, the lateralization of cortisol production is yet unknown and AVS with dexamethasone suppression is being considered. Although the treatment considerations are traditionally utilizing the guidelines for both PA and Cushing Syndrome guidelines respectively, very little is known when there are divergence of autonomous secretion amongst the bilateral adrenal masses and more studies are needed to clarify the long-term treatment considerations. 1 Presentation: 6/3/2024

6436 Adrenal Venous Congestion Clinically Mimicking Carcinoma In A Large Degenerated Adrenocortical Adenoma

Abstract Disclosure: K. Ishiwata: None. S. Suzuki: None. S. Watanabe: None. Y. Yamazaki: None. H. Sasano: None. K. Yokote: None. Introduction: A large heterogenous adrenal tumor is often malignant. Only eight reported cases of adrenal adenoma harboring hemorrhage or venous thrombosis have been reported but their details not. We encountered a case of large degenerated adrenocortical adenoma harboring adrenal venous congestion mimicking adrenocortical carcinoma. Case: Adrenal tumor was incidentally detected in a 71-year-old woman with a history of hypertension, dyslipidemia, and osteoporosis in her regular health check-up. Abdominal CT and MRI demonstrated a heterogenous mass measuring 7.6 cm with peripheral enhancement in the left adrenal gland. [1]3[1]I-adosterol scintigraphy revealed accumulation only in the left tumor margins with no accumulation in [1]8F-FDG-PET scan. Results of endocrinologic evaluation were consistent with subclinical Cushing syndrome. The large size and heterogeneous nature of the mass clinically suggested adrenocortical malignancy, and left laparoscopic adrenalectomy was subsequently performed. The resected left adrenal lesion was encapsulated and measured 6.5 x 6.3 x 5.8 cm appearing almost black and partially yellow on the cut surface. Microscopically, the nodule was composed of SF-1 positive, clear cortical cells with abundant hyaline stroma containing numerous dilated veins with CD31/34-positive endothelial cells, and no foci of necrosis or hemorrhage were detected. The tumor cells above were positive for steroidogenic enzymes including CTP17, HSD3β and CYP11B1 but negative for CYP11B2. Ki-67 labeling index was <2% in the tumor. The criteria of Weiss (0 out of 9) revealed that the tumor was cortisol-producing adrenocortical adenoma. Discussion: In this case, clusters of SF1-positive cortisol producing adrenocortical adenoma cells were present in the hyalinized stroma containing many dilated blood vessels. These findings indicated that those histological features were caused by ischemic degeneration due to intratumoral circulatory disturbance, which clinically simulated adrenocortical carcinoma. Conclusion: We have experienced a very rare case of cortisol-producing adrenocortical adenoma with adrenal venous congestion, resulting in marked enlargement of the lesion. Presentation: 6/3/2024

6564 A Case Of Severe Hypercalcemia In Carney's Complex

Abstract Disclosure: J. Chippior: None. M. Rayan: None. L. Wright: None. L.S. Kirschner: Grant Recipient; Self; Medpace, Sparrow, Corcept Therapeutics, Corcept, Spruce, CinCor, Crinetics, Adrenas. S.W. Ing: Grant Recipient; Self; Alexion Pharmaceuticals, Inc., Amgen Inc, Radius Health, Inc, Takeda, Ultragenyx, Amolyt, Bridge Bio. Carney complex is a rare syndrome with fewer than 750 reported cases, characterized by lentigniosis, myxomas, and the occurrence of both endocrine and non-endocrine tumors. An inactivating mutation PRKAR1A, which encodes for the type 1A regulatory subunit of Protein kinase A, is responsible for over 70% of familial cases and 37% of sporadic cases. A 31-year-old female with a history of Carney complex, Cushing syndrome due to primary pigmented nodular adrenocortical disease (PPNAD), facial lentigines, spinal Schwannomas, and recent ischemic stroke secondary to embolization of a cardiac atrial myxoma, was transferred to our medical center for hyperemesis and severe hypercalcemia. Albumin-corrected serum calcium measured 15.4 mg/dL (8.6-10.5 mg/dL), ionized calcium 7.8 mg/dL (4.6-5.3 mg/dL) associated with suppressed PTH, normal PTH-related protein, and elevated bone turnover markers, C-telopeptide 4,273 pg/ml (150-635) and Procollagen Type 1 N-terminal Propeptide 222 mcg/L (19-83). Evaluation for etiology of hypercalcemia revealed elevated 1,25 dihydroxy vitamin D at 107.0 pg/ml (20-79) and elevated interleukin-6 at 11 pg/ml (<6.4). IL-6 is expressed by cardiac myxomas. Serum angiotensin-converting enzyme level was 50 U/L (16-85) and infectious workup was negative for potential granulomatous causes of elevated calcitriol (including testing for tuberculosis, histoplasma, blastomyces, bartonella, and coccidioides). CT angiogram of the abdomen and pelvis (completed in preparation of atrial myxoma resection) revealed ground-glass opacities in bilateral posterior lung fields and multiple pulmonary nodules, with the largest measuring 8 mm. After treatment with aggressive intravenous fluid resuscitation, intramuscular calcitonin, and intravenous zoledronic acid, corrected calcium normalized to 9.4 mg/dL at discharge. Urinary cortisol was 6.2 mcg per 24-hr (3.5-45), for which she started hydrocortisone 20 mg daily to treat suspected adrenal insufficiency as excess cortisol secretion in PPNAD may be episodic. Thus remission of hypercortisolism may have unmasked an underlying hypercalcemia, and adrenal insufficiency itself may have contributed to this finding. She had excision of left atrial myxoma and has continued to exhibit normal calcium levels on steroid replacement therapy. Repeat chest CT to further characterize these pulmonary findings is planned. This case illustrates a unique constellation of endocrine features associated with severe hypercalcemia in Carney complex. Presentation: 6/1/2024

Disruptions to protein kinase A localization in adrenal pathology.

Cell signaling fidelity requires specificity in protein-protein interactions and precise subcellular localization of signaling molecules. In the case of protein phosphorylation, many kinases and phosphatases exhibit promiscuous substrate pairing and therefore require targeting interactions to modify the appropriate substrates and avoid cross-talk among different pathways. In the past 10 years, researchers have discovered and investigated how loss of specific interactions and subcellular targeting for the protein kinase A catalytic subunit (PKAc) lead to cortisol-producing adenomas and the debilitating stress disorder adrenal Cushing's syndrome. This article reviews classical studies regarding PKA localization in glucocorticoid-producing adrenal cells and synthesizes recent evidence of disrupted PKA localization and selective regulatory interactions in adrenal pathology.

Screening for endogenous hypercortisolism in patients with osteoporosis and fractures: why, when and how.

Skeletal comorbidities are frequent and clinically relevant findings in Cushing's syndrome (CS) since an uncoupled suppressed bone formation and enhanced bone resorption leads to a marked skeletal damage with a rapid increase of fracture risk. Reduced Bone Mineral Density (BMD) has been consistently reported and osteopenia or osteoporosis are typical findings in patients with CS. Vertebral Fractures (VFs) are frequently reported and may occur even in patients with an only mild reduction of BMD. Since CS is diagnosed late due to often difficult biochemical and radiological confirmation as well as to signs and symptoms common in other much more frequent diseases an approach suggested for overcoming underdiagnosis is to screen patients with manifestations which may overlap with those of CS such as arterial hypertension, diabetes mellitus and osteoporosis. Our review will focus on the rationale and best practice for screening osteoporotic patients for CS.

Blood DNA methylation of CRF and its association with amygdala volume and mood in Cushing’s syndrome

ObjectiveThe impact of chronic exposure to stress or glucocorticoids on psychiatric symptoms has been exemplified by cases of iatrogenic or endogenous hypercortisolism such as Cushing’s syndrome (CS). The amygdala plays an important role in mediating both stress and affective responses, and one of the key factors that link stress response and psychiatric symptoms is the corticotropin-releasing factor (CRF). Epigenetic changes, especially those occurring on CpG dinucleotides in DNA of glucocorticoid target genes in blood, have been previously implicated as potential predictors of glucocorticoid-related events in the central nervous system (CNS). In this study, we examined amygdala volume and mood symptoms in CS patients and aimed at evaluating whether these parameters were associated with blood DNA methylation of CRF.MethodsIn this cross-sectional study, 32 CS patients and 32 healthy controls matched for age, sex, and years of education underwent an MRI scan, a Beck Depression Inventory-II, and a State-Trait Anxiety Inventory. Genomic DNA extracted from total leukocytes were used for DNA methylation analysis of several CpG dinucleotides at the CRF promoter region.ResultsSignificant associations between CRF methylation vs. amygdala volume (CpG-1, P = 0.006) and depression scores (CpG-2, P = 0.01) were found. To assess whether the promoter CpG methylation has functional consequences, we examined RNA and DNA extracted from non-CS, postmortem amygdala tissues. A significant association between CpG methylation and gene expression (CpG-1, P = 0.004) was observed.ConclusionThese results demonstrate that methylation levels of the CRF promoter CpGs are associated with amygdala volume in CS and related mood symptoms. Methylation levels may also be associated with CRF expression. This finding supports the feasibility of using epigenetic patterns in blood as a surrogate for assessing GC-related pathologies in the brain.

Who and how to screen for endogenous hypercortisolism in type 2 diabetes mellitus or obesity.

The current review aims to summarize and discuss the prevalence of confirmed hypercortisolism in patients with diabetes mellitus or obesity, analysing the screening tests used and their accuracy, in order to better identify whether patients with diabetes mellitus and obesity should be screened for Cushing's syndrome (CS) and how. A narrative review was performed including publications focusing on the current knowledge on prevalence of confirmed hypercortisolism in patients with type 2 diabetes mellitus (T2DM) or obesity and on screening tests used to detect CS. The studies reviewed suggest that the prevalence of CS in patients with T2DM is variable, ranging from 0.6 to 9.3%. The most used screening test is the overnight cortisol after 1mg of dexamethasone suppression test (DST), with a false positive rate ranging from 3.7 to 21%. The prevalence of CS among obese patients is generally about 1%, except for two studies which reported higher prevalence. For obese patients, 1mg DST and late-night salivary cortisol are the most accurate screening tests for CS. Clinical expertise remains the mainstay to identify which subjects should be screened for CS. The evaluation of the clinical stigmata of CS and the combination with clinical comorbidities typical of CS are the stronger predictors of CS. In addition, we could hypothesize that in patients with T2DM, overnight 1mg DST is the more accurate screening test for CS. By contrast, in patients with obesity both LNSC and overnight 1mg DST could be equally used for the screening of hypercortisolism.

Unusual infections and thrombotic events in Cushing's syndrome.

The diagnosis of Cushing's syndrome requires a high degree of suspicion, especially in patients in whom typical features are overshadowed by other ailments. These include, among others, widespread opportunistic infections or sepsis and venous or arterial thromboembolism.This Review will summarize available data on patients presenting with severe infections or thrombotic events and the best approach to diagnosis.

Interim analysis from prospective, multi-country, post-authorization safety study of patients with endogenous Cushing's syndrome treated with Ketoconazole HRA, using the existing European Registry on Cushing's syndrome (ERCUSYN), to assess safety and effectiveness

Interim analysis from prospective, multi-country, post-authorization safety study of patients with endogenous Cushing's syndrome treated with Ketoconazole HRA, using the existing European Registry on Cushing's syndrome (ERCUSYN), to assess safety and effectiveness

8273 ACTH-Dependent Cushing's Syndrome due to Metastatic Cervical Cancer: A Case Report

8273 ACTH-Dependent Cushing's Syndrome due to Metastatic Cervical Cancer: A Case Report

8214 Adrenocortical Oncocytic Neoplasm Presenting As Cushing's Syndrome: A Case Report

8214 Adrenocortical Oncocytic Neoplasm Presenting As Cushing's Syndrome: A Case Report

Therapeutic and prognosis of Cushing's syndrome: A multicenter retrospective study

Therapeutic and prognosis of Cushing's syndrome: A multicenter retrospective study

An Overlooked Disease: Minimal Autonomous Cortisol Secretion (MACS). A Narrative Review.

A far more common disease than Cushing's syndrome is subclinical hypercortisolism or mild autonomous cortisol secretion (MACS), with an overall prevalence of 0.2-2%. This review aims to shed light on the prevalence, screening and diagnostic criteria, comorbidities, and management of Mild Autonomous Cortisol Secretion (MACS). Studies eligible targeted MACS regarding prevalence, screening, comorbidities, management, and clinical outcome. This is a mini-review. IRB approval was not needed. The 1 mg Dexamethasone suppression test (DST) remains the first screening test. MACS is associated with adverse cardiometabolic and renal outcomes, osteoporosis and osteopenia, immunodeficiency, depression, coagulopathy, and sarcopenia. Surgery is the gold standard treatment. Medical therapy is recommended when surgery is contraindicated or not feasible. Clinically silent hypercortisolism is a frequent entity that necessitates early detection and treatment. The production of cortisol should be looked at as a spectrum where subtle, undetectable levels can still be produced. They know its association with adverse health outcomes. MACS is no longer considered an asymptomatic disorder; repeated hormonal and functional tests are crucial to prevent multiorgan damage.

Sensitivity of static and dynamic assays in the confirmation of Cushing's syndrome

Sensitivity of static and dynamic assays in the confirmation of Cushing's syndrome

8598 Heterogeneous course of ectopic Cushing's syndrome (EAS) - does the location of the primary tumor affect the clinical picture and the outcome?

8598 Heterogeneous course of ectopic Cushing's syndrome (EAS) - does the location of the primary tumor affect the clinical picture and the outcome?

ACTH-independent Cushing syndrome related to retroperitoneal liposarcoma: A case report

ACTH-independent Cushing syndrome related to retroperitoneal liposarcoma: A case report

Ectopic Cushing Syndrome: A Diagnostic Anomaly of Malignancy

Ectopic Cushing Syndrome: A Diagnostic Anomaly of Malignancy

7713 Remission of Ectopic Cushing Syndrome Due to Medullary Thyroid Cancer with Selpercatinib

7713 Remission of Ectopic Cushing Syndrome Due to Medullary Thyroid Cancer with Selpercatinib