Suppression Test Research Articles

Optimization of in vivo antimalarial efficacy of combinations of aqueous leaf extracts of Artemisia annua L., Vernonia amygdalina Del, and Microglossa pyrifolia (Lam.) Kuntze using factorial design.

Malaria continues to be among the leading causes of mortality in Africa including Uganda, with the emergence of parasite resistance to the first-line therapeutics (Artemisinin- based Combination Therapy). To find new therapeutics, this study has reported an in vivo antimalarial efficacy of combinations of Artemisia annua (Aa), Vernonia amygdalina (Va), and Microglossa pyrifolia (Mp) in mice model using factorial design. The Aa and Va were extracted by hot infusion, and Mp by cold maceration using distilled water. The dry extracts were screened for different phytochemicals, and later subjected to in vivo antimalarial activity using Peter's 4-day suppressive test. The 23 factorial design used Aa, Va, and Mp aqueous extracts as independent variables at two levels (-1 and 1), and the percentage chemo suppression and survival time as response variables. The data was analyzed using Design Expert 13 and GraphPad Prism employing ANOVA linear regression modelling and t-test respectively. All the extracts had alkaloids, phenols, saponins, terpenoids, cardiac glycosides, tannins, steroids, and carbohydrates. The various combinations showed chemo suppression from 41.5 to 91.0% and survival time of 19 to 23days. The first three combinations having lower levels of Aa (200mg/kg) exhibited higher chemo suppression (> 90%) compared to Artemisinin-Lumefantrine positive control at 4mg/kg with 87.5%. Lower levels of Aa in the combinations contributed to high chemo suppression while higher levels of Va prolonged survival times. Interactions between Aa and Mp showed higher chemo suppression, and that between Aa and Va increased survival time. An optimized prediction of 94.4% chemo suppression was made by the ANOVA model at lower levels of Aa and Va, and a higher level of Mp, which is similar to an experimental run which gave a response of 90. 6%. An optimum combination of the three plants as a natural herbal antimalarial therapy was obtained using factorial design, and it offers an alternative to first line Artemisinin based Combination Therapy (ACTs) as parasite resistance looms. This combination could be further developed into a standard phytopharmaceutical and subjected to Randomized Controlled Trials (RCTs).

Who and how to screen for endogenous hypercortisolism in patients with mood disorders.

A strict association exists between mood disorders and endogenous hypercortisolism, namely Cushing's syndrome (CS). Indeed, CS is characterized by a wide range of mood disorders, such as major depression, generalized anxiety, panic disorders, bipolar disorders up to psychosis, with major depression being the most frequent, with a prevalence of 50-80%, and potentially representing the clinical onset of disease. Despite this observation, the exact prevalence of hypercortisolism in patients with mood disorders is unknown and who/how to screen for endogenous hypercortisolism among patients with mood disorders is still unclear. In this context, an accurate anamnestic and clinical examination are crucial in order to identify those patients who may benefit from CS screening. In particular, the presence of specific signs and symptoms of CS, comorbidities typically associated with CS, and lack of improvement of depressive symptoms with standard treatments can further guide the decision to screen for CS. Anyhow, it is noteworthy that mood disorders represent a cause of functional activation of hypothalamic-pituitary-adrenal (HPA) axis, a condition formerly known as non-neoplastic hypercortisolism (NNH). The differential diagnosis between CS and NNH is challenging. Beyond anamnestic and clinical features, various tests, including measurement of daily urinary cortisol and late-night salivary cortisol, together with low dose-dexamethasone suppression test, are used for initial screening. However, considering their low accuracy, a definitive diagnosis may require a longitudinal follow-up along with second-line dynamic tests like combined dexamethasone-CRH test and desmopressin test. In conclusion, available data suggest the need for a comprehensive assessment and follow-up of individuals with mood disorders to detect possible underlying CS, considering the pitfalls in diagnosis and the overlap of symptoms with other conditions like NNH. Specialized centers with expertise in CS diagnosis and differential testing are recommended for accurate evaluation and management of these patients.

MÉTODOS DE DIAGNÓSTICOS DE HIPERADRENOCORTICISMO EM CÃES UMA REVISÃO NARRATIVA

The objective of this research was to investigate and evaluate the diagnostic methods used for hyperadrenocorticism in dogs by analyzing the available literature from the past 20 years. The methodology employed was a qualitative and exploratory literature review, conducted through databases such as PUBMED, MEDLINE, BVS, SCOPUS, PERIÓDICOS, BIBLIOTECA ABERTA USP, and SCIELO. Keywords such as "dogs," "canine," "hyperadrenocorticism," "endocrine," "endocrinopathy," and "Cushing" were used to identify relevant studies. The content analysis of the selected articles revealed that diagnostic methods vary according to the clinical suspicion and include detailed anamnesis, thorough clinical examination, and basic and imaging laboratory tests. The choice between suppression and stimulation hormone tests depends on the suspected origin of the condition, with the low-dose dexamethasone suppression test being highly sensitive for detecting hyperadrenocorticism, while the ACTH stimulation test is crucial for differentiating between origins. Diagnostic confirmation also involves abdominal ultrasonography to visualize the adrenal glands and identify possible masses, which is essential for guiding appropriate treatment and determining the patient’s prognosis.

Autonomous cortisol secretion promotes vascular calcification in vivo and in vitro under hyperaldosteronism.

Autonomous cortisol secretion (ACS) is not uncommon in patients with primary aldosteronism (PA). However, the cardiovascular burden of ACS due to its dysregulated cortisol secretion remains poorly understood. Thus, we examined the effects of ACS on vascular calcification in a hyperaldosteronism environment in vitro and in vivo. A total of 339 patients with PA with adrenal incidentaloma and low-dose dexamethasone suppression test data (cutoff level: cortisol > 1.8 μg/dL) from a prospectively maintained database were enrolled; abdominal aortic calcification (AAC) scores were quantitatively estimated. Human aortic smooth muscle cells (HAOSMCs) were used as in vitro model of vascular calcification. In this study, 65 of the 339 patients with PA had ACS; 274 did not. Patients with PA/ACS had a higher AAC score (1171.0 ± 2434.0 vs. 489.5 ± 1085.3, P = 0.012) than patients without ACS. ACS was independently associated with AAC score (β = 0.139, P = 0.004) in multivariate analysis, and post-suppression cortisol level was significantly correlated with the AAC score (P = 0.004). In the HAOSMC model, co-treatment with cortisol synergistically stimulated alkaline phosphatase activity and calcium deposition in a hyperaldosteronism environment. The stimulatory effect of cortisol was abolished by the mineralocorticoid receptor (MR) antagonist eplerenone, but not glucocorticoid receptor antagonist mifepristone, indicating a MR-dependent mechanism. In conclusion, the presence of ACS is associated with heavier vascular calcification in patients with PA. Aldosterone and cortisol synergistically activate HAOSMC calcification via MR signaling, via a process that can be attenuated by eplerenone.

Active micro-vibration isolation system for adaptive vibration suppression tests using piezoelectric stack actuator

An active micro-vibration isolation system for adaptive vibration suppression using piezoelectric stack actuators is presented, along with the discrete time modelling method, real-time adaptive controller design, and hardware implementation. The system comprises piezoelectric stack actuators, capacitive displacement sensors, power amplifiers, signal conditioners, and a real-time computer. A discrete asymmetric Bouc-Wen model is developed to characterize the nonlinear behavior of the piezoelectric stack actuators. System identification is conducted using an improved particle swarm optimization method, specifically the Hybrid PSO-Jaya algorithm, which sequentially integrates the PSO algorithm with the Jaya algorithm. Additionally, an improved adaptive filtering algorithm employing affine projection, referred to as the FXAPA algorithm, is introduced to facilitate real-time control. The efficacy of the proposed active micro-vibration isolation technology is validated through micro-vibration suppression tests.

Design, synthesis, and in vitro and in vivo biological evaluation of triazolopyrimidine hybrids as multitarget directed anticancer agents.

In response to the urgent need for new anti-proliferative agents, four novel series of triazolopyrimidine compounds (7a-e, 9a-d, 11a-f, and 13a-e) were synthesized and evaluated for in vitro anticancer efficacy against HCT116, HeLa, and MCF-7 cell lines. Compound 13c emerged as the most potent, with IC50 values of 6.10, 10.33, and 2.42 μM respectively, while 11e and 7c also showed strong activity. In multi-target suppression tests, 13c exhibited the highest inhibition against EGFR, TOP-II, HER-2, and ARO (IC50: 0.087, 31.56, 0.078, and 0.156 μM, respectively). Flow cytometry revealed 13c's ability to suppress the S-phase cell population in MCF-7 cells. In vivo studies of 13c demonstrated significant tumor growth inhibition, comparable to the positive control. Molecular docking studies supported the experimental findings, confirming the binding of the novel motifs to the target enzymes' active sites. This comprehensive evaluation highlights the potential of these triazolopyrimidine compounds, particularly 13c, as promising anticancer agents, warranting further investigation.

Autonomous cortisol secretion in patients with primary aldosteronism is associated with left ventricular hypertrophy and diastolic dysfunction

Abstract Background and Aims: Autonomous cortisol secretion (ACS) constitutes a significant portion of patients diagnosed with primary aldosteronism (PA) and is potentially linked to adverse cardiovascular outcomes. This study aimed to explore the impact of ACS on cardiac remodeling and diastolic dysfunction in PA patients. Methods We prospectively enrolled 567 PA patients from March 2000 to March 2023. ACS was defined as a cortisol level >1.8 μg/dL after a 1 mg dexamethasone suppression test (DST). Clinical, biochemical, and echocardiographic data were collected at baseline and during one-year follow-up after targeted treatments including adrenalectomy and mineralocorticoid receptor antagonist administration. Results In this prospective cohort, 21.5% of PA patients had concurrent ACS. PA patients with ACS were older and had a higher prevalence of diabetes. They also exhibited significantly higher left ventricular mass index (LVMI) and worse diastolic function (E/e'). Baseline post-1 mg DST cortisol levels positively correlated with baseline LVMI and E/e' in restricted cubic spline analysis. Multivariable linear regression analysis showed that ACS presence was significantly associated with higher LVMI and worse E/e' after adjusting for significant variables. Among patients who underwent adrenalectomy, both those with and without ACS showed significant improvements in LVMI and E/e'. Patients who received mineralocorticoid receptor antagonist treatment also showed significant improvement in E/e', irrespective of ACS presence. However, significant LVMI improvement was observed only in PA patients without ACS who received mineralocorticoid receptor antagonist treatment. Conclusions The presence of ACS in PA patients was associated with worse left ventricular hypertrophy and diastolic dysfunction. Adrenalectomy and mineralocorticoid receptor antagonist treatment partially reversed cardiac remodeling in PA patients with ACS.

Impact of Cortisol-Cosecretion on Adrenal Venous Sampling Results in Primary Aldosteronism: Study of 225 Cases

Background/Objectives: Mild autonomous cortisol secretion (MACS) can coexist with primary aldosteronism (PA). The purpose of our study was to evaluate whether (MACS) influences parameters analyzed during adrenal venous sampling (AVS) in patients with PA. Methods: Patients with PA from the SPAIN-ALDO Registry and the German Conn’s Registry with available 1 mg-dexamethasone suppression test (DST) and AVS were included. MACS was defined as a post-DST cortisol > 1.8 µg/dL in the absence of specific signs and symptoms of Cushing’s syndrome. Results: Two-hundred and twenty-five patients were included, 98 (43.6%) of whom had concomitant MACS. The mean age was 54 ± 10 years and 37.3% were women. AVS was performed by simultaneous catheterization of both adrenal veins and analysis of basal samples in 157 patients (69.8%), with both basal and post-ACTH samples in 15 patients (6.7%), and during continuous ACTH infusion in 53 patients (23.6%). AVS was considered technically unsuccessful in 40 cases (17.8%), suggesting unilateral secretion in 106 (47.1%) and bilateral secretion in 79 (35.1%). We did not find significant differences in the percentage of unilateral and bilateral results, cortisol, corrected aldosterone, or selectivity indices in the dominant and non-dominant veins, nor in the lateralization index or the contralateral suppression index between patients with and without MACS. They also had similar rates of surgical treatment and biochemical and clinical response. Conclusions: Although pathophysiological reasoning suggests that MACS could hinder AVS identification of unilateral forms of PA, our data suggest that such interference, if it exists, is of moderate clinical relevance.

Long-term outcome of unilateral adrenalectomy for primary bilateral macronodular adrenal hyperplasia.

Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a form of Cushing's syndrome (CS) characterized by heterogeneous cortisol secretion and clinical comorbidities. Previously, bilateral adrenalectomy was the standard treatment for PBMAH, but this approach carried a high risk of primary adrenocortical insufficiency. In recent decades, unilateral adrenalectomy (U-Adx) has emerged as an effective alternative. However, limited research exists on its postoperative efficacy and prognostic predictors. Therefore, the present study aimed to investigate the long-term effectiveness and prognostic predictors of U-Adx in treating PBMAH. A total of 61 patients with PBMAH diagnosis who underwent U-Adx at a single center between 2004 and 2022 were retrospectively evaluated. Patients were categorized into persistent hypercortisolism and remission groups based on postoperative biochemical outcomes at the last follow-up (>12 months after U-Adx). Clinical characteristics, comorbidities, plasma adrenocorticotropic hormone (ACTH), serum cortisol, and 24-h urinary-free cortisol (24-h UFC) levels were analyzed pre- and postoperatively. We further examined whether baseline plasma ACTH, serum cortisol, 24-h UFC levels, and the inhibition of cortisol and 24-h UFC after a low-dose dexamethasone suppression test (LDDST) could predict non-remission following U-Adx. Additionally, we explored the improvements in hypertension, abnormal glucose metabolism, osteoporosis, and other complications in patients with PBMAH post-U-Adx. After U-Adx, 22 of the 45 patients (48.89%) achieved initial remission within 6 months. At the last follow-up, 25 of the 45 patients underwent all required biochemical tests and cortisol assessment tests, among which eight of 25 (32.00%) were in remission and 17 of 25 (68.00%) were experiencing persistent hypercortisolism. Moreover, five of those 25 patients exhibited recurrence after initial remission. Baseline 24-h UFC level > 2 times the upper limit of normal (2ULN) and unsuppressed 24-h UFC after LDDST may predict persistent hypercortisolism postoperatively. Lastly, long-term postoperative follow-up revealed that hypertension decreased with hypercortisolism remission, whereas osteoporosis worsened with persistent hypercortisolism. The short-term remission rate of hypercortisolism was 48.89% in patients with PBMAH treated with U-Adx, while a long-term remission rate of 32.00% was achieved after a median follow-up of 38.58 months. Furthermore, this finding suggests that baseline 24-h UFC level > 2ULN and unsuppressed 24-h UFC after LDDST predict persistent hypercortisolism in the long-term post-U-Adx. Finally, U-Adx improved cortisol circadian rhythm alterations and ACTH suppression in the patients in the remission group, thereby substantially alleviating hypertension and delaying the development of osteoporosis linked to PBMAH.

Primary Bilateral Macronodular Adrenal Hyperplasia: A Case Series from a Tertiary Hospital

Introduction: Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare etiology of Cushing’s syndrome characterized by the presence of multiple adrenal macronodules and variable levels of cortisol excess. Its pathogenesis is complex, involving mechanisms such as aberrant hormone receptors, adrenal paracrine ACTH production, and genetic germline pathogenic variants. However, management is not well established. Methods: This was a retrospective, observational study. We evaluated patients with PBMAH at our tertiary center. We aimed to describe the clinical, hormonal, and radiological characteristics; treatment approaches; and outcomes. Results: Twenty patients were included in this study. Patients had a mean age at diagnosis of PBMAH of 56.1 ± 11.1 years, and 10 patients (50.0%) were females. Most cases were initially investigated for adrenal incidentalomas. Median 8:00 a.m. serum cortisol after 1 mg dexamethasone overnight suppression test was 223.5 (73.1–698.6) nmol/L (8.11 [2.65–25.3] µg/dL), late-night salivary cortisol was 1.48 (0.765–3.21) times the upper limit of normal (ULN), and 24 h-UFC was 1.61 (0.42–3.64) times the ULN. One patient presented with the co-secretion of cortisol and aldosterone. Mean total adrenal size was 98.5 ± 25.6 mm, and the largest nodule size was 32.1 ± 9.09 mm. In six (31.6%) patients, the largest nodule had an attenuation higher than 10 HU. Germline pathogenic variants in ARMC5 were found in four (50.0%) of the eight tested patients who underwent genetic testing. Treatment strategies varied, with unilateral adrenalectomy often successfully controlling hypercortisolism in five (83.3%) of 6 patients with modest excess cortisol secretion. For mild autonomous cortisol secretion, active surveillance of comorbidities and appropriate treatment were not associated with progression of cortisol secretion after a median follow-up of 34.0 (10.5–83.0) months. Conclusion: This study underscores the need for personalized management strategies and identifies areas for future research to optimize the care of patients with PBMAH.

The Influence of Remnant Cholesterol on Cardiovascular Risk and Mortality in Patients with Non-Functional Adrenal Incidentalomas and Mild Autonomous Cortisol Secretion: A Retrospective Cohort Study.

Background: Increased cardiovascular risk has been described in individuals with adrenal incidentalomas. The aim of the present study is to assess the effect of remnant cholesterol (RC) on the cardiovascular risk and mortality of patients with adrenal incidentalomas. Methods: A retrospective cohort study was conducted with patients with adrenal incidentalomas between 2001 and 2024. One hundred thirty-seven patients (mean age of 61.2 ± 11.5 years; 56.6% women) with non-functioning adrenal incidentalomas and with mild autonomous cortisol secretion (MACS) (cortisol post-dexamethasone suppression test ≥1.8 µg/mL) were included. The patients were divided into two groups using 30 mg/dL as the cut-off for RC. Logistic regression models were used to study the impact of RC on major adverse cardiovascular events and mortality (MACEs). Results: Patients with RC ≥ 30 mg/dL exhibited a higher prevalence of type 2 diabetes mellitus (T2D) (p < 0.001), lower HDL-C (p < 0.001) and LDL-C (p = 0.025) levels, a higher frequency of treatment with statins (p = 0.032), and a higher rate of non-fatal major cardiovascular events (p = 0.038) and MACEs (p = 0.038). Patients with MACS showed no differences in RC or complications during the follow-up. The relative risk of high RC was 2.65 (1.04-6.77) for cardiovascular events and 2.27 (1.05-4.92) for MACEs, with p < 0.05 in both cases. The only variables independently affecting MACEs were age ([odds ratio] OR = 1.13 [p = 0.004]), female sex (OR = 0.20; p = 0.016), LDL-C (OR = 1.02; p = 0.029), and RC (OR = 1.06; p = 0.014). T2D and HDL-C were not independently associated with MACEs. Conclusions: RC ≥30 mg/dL in patients with adrenal incidentalomas was associated with a higher prevalence of T2D, lower HDL-C levels, and a higher risk of MACEs. MACS was not associated with RC or MACEs during the follow-up.

6426 Pregnancy-induced ACTH-independent Cushing Syndrome: A Rare Phenomenon Secondary To Aberrant Receptors On Adrenal Glands

Abstract Disclosure: K. Manglani: None. S.T. Sharma: None. Pregnancy-induced hypercortisolism is a rare phenomenon with very few cases reported in the literature. The pathogenesis is thought to be secondary to the expression of aberrant LH/hCG receptors on the adrenal gland that stimulate cortisol production in pregnancy. We present a case of a 31-year-old female with no past comorbidities until her first pregnancy in 2017 when she gained around 50lbs, developed violaceous striae, acne, hirsutism, depression with suicidal ideation for which she was hospitalized twice, and underwent emergent C-section at 34 weeks’ gestation due to pre-eclampsia. She was referred to the Endocrinology clinic post-delivery, and screening for Cushing syndrome was negative at that time: 24-hour urinary free cortisol (UFC), late-night salivary cortisol (LNSC) and 1-mg dexamethasone (dex) suppression test (DST) were normal. She presented again in 2020 during her second pregnancy at 14 weeks gestation, with 20lb weight gain in the first trimester, acne, hirsutism, and easy bruising. Labs showed cortisol of 22.4 mcg/dL (6.2-19.4), ACTH &amp;lt;1.5 pg/mL, total testosterone 168 ng/dL (8-48), androstenedione 751 ng/dL (41-262), DHEAS 91.2 mcg/dL (84.8-378), 24-hour UFC 277 mcg/day (6-42), LNSC 0.671 mcg/dL, 1mg DST with post-dex cortisol 24 mcg/dL (dex level 58 ng/dL), and 8-mg DST with post-dex cortisol level of 28.2 mcg/dL (dex level 457 ng/dL). Testing was consistent with ACTH-independent Cushing syndrome. Ultrasound and MRI of the abdomen/pelvis showed normal adrenal glands with no hyperplasia or mass. Given worsening hypercortisolism and her course during a prior pregnancy, medical treatment with metyrapone was initiated. We started at a dose of 500 mg daily and gradually increased to 1500 mg with close monitoring of her blood pressure and cortisol levels. She underwent vaginal delivery at 38 weeks’ gestation, and the baby required a brief stay in the NICU for respiratory distress but was otherwise doing well. The patient developed secondary adrenal insufficiency post-delivery requiring hydrocortisone, with recovery of her HPA axis in around 10 weeks. Since then, she has been off hydrocortisone with normal UFC, ACTH, and cortisol levels. This case enables discussion regarding the underlying etiology, diagnostic difficulties, and management of this rare condition. Although the exact etiology is unknown, the postulated mechanism is aberrant LH/hCG receptor expression given the patient’s presentation during each pregnancy, normal cortisol levels between both pregnancies, and a brief period of adrenal insufficiency post-delivery. Management of hypercortisolism during pregnancy remains challenging. Metyrapone, a steroidogenesis inhibitor, can be considered for control of hypercortisolemia during pregnancy (off-label) in select cases to prevent maternal and fetal complications. Presentation: 6/1/2024

8688 Pseudopheochromocytoma Due To Severe Obstructive Sleep Apnea

Abstract Disclosure: L.M. José: None. M. Ataide: None. F. Aratani: None. S. Beeby: None. G.F. Fagundes: None. F. Coelho: None. F. Ledesma: None. A. Latronico: None. B.B. Mendonca: None. M.C. Fragoso: None. M.Q. Almeida: None. Background: Obstructive sleep apnea (OSA) represents an independent risk factor for cardiovascular disease, and it is associated with a wide range of conditions, such as resistant hypertension and primary aldosteronism (PA). Patients with sleep apnea have a higher sympathetic activity during wakefulness due to chronic hypoxia. We present the case of pseudopheochromocytoma caused by severe OSA in an obese patient with RH and PA.Clinical Case: A 58-year-old female Brazilian patient was referred to an endocrinologist to investigate a 1.8 cm right adrenal nodule at computed tomography (CT) performed to investigate abdominal pain. Her medical history includes resistant hypertension diagnosed at 27 years of age, type 2 diabetes, dyslipidemia, Class II obesity, a previous acute myocardial infarction, and severe OSA (apnea-hypopnea index 61.6/hour). She has used irregularly the continuous positive airway pressure (CPAP) therapy at night. She is currently using carvedilol 50 mg bid, chlorthalidone 25 mg, olmesartan 40 mg, amlodipine 10 mg, spironolactone 50 mg, clonidine 0.2 mg tid, hydralazine 50 mg every 6 hours, acetylsalicylic acid 100 mg, atorvastatin 80 mg, and metformin XR 1000 mg. At physical examination, she had BMI 37 kg/m2, BP 150 x 90 mmHg, HR 64 bpm, and no signs of Cushing syndrome. Abdominal CT revealed a right adrenal nodule measuring 1.8 cm with 18 Hounsfield unit (HU) in the pre-contrast phase, reaching a density of 117 HU at the arterial phase and showing an absolute washout of 65% and a relative washout of 56%. A nodular thickening of 1.4 cm (-4 HU) at the left adrenal gland was also displayed at CT scan. Hormone evaluation showed basal cortisol 7 µg/dL, ACTH 15.7 pg/mL, DHEAS 1152 ng/mL (189-2050 ng/mL), 1 mg overnight dexamethasone suppression test 2.3 ug/dL, aldosterone 9.9 ng/dL, direct renin concentration 36.8 uIU/mL, plasma metanephrines 0.3 nmol/L (&amp;lt;0.5 nmol/L) and plasma normetanephrines 1.3 nmol/L (&amp;lt;0.9 nmol/L). It was not possible to change anti-hypertensive medications to investigate PA. A 0.3 mg clonidine suppression test did not suppress normetanephrine levels, confirming the biochemical diagnosis of pheochromocytoma. Then, alpha-blockade with doxazosin 4 mg was started and the patient underwent right adrenalectomy. Pathological examination revealed an adenoma with immunohistochemistry positive for CYP11B2. BP control was achieved with only two medications and aldosterone decreased to 3 ng/dL confirming PA. Plasma normetanephrine levels remained elevated post-surgery and only normalized after the CPAP regular use.Clinical lessons: Chronic activation of sympathetic autonomic drive in OSA can increase norepinephrine and normetanephrine levels. OSA is a very prevalent disease and it is frequently associated with RH. Therefore, OSA should be considered a possible cause of pseudopheochromocytoma in hypertensive patients. Presentation: 6/3/2024

8528 An Unusual Case Of Adrenal Hemorrhage As An Initial Manifestation Of Castleman Disease In A 29 yo Male With Unsuspected Late-Onset Congenital Adrenal Hyperplasia

Abstract Disclosure: L.M. Martel: None. F. Mercier: None. S. Parisien-La Salle: None. A. Lacroix: None. A. Liberman: None. N. Bettache: None. H. Olney: None. I. Bourdeau: None. Background: Castleman disease is a lymphoproliferative disorder with no clear etiology. We report the case of a 29 yo man presenting with an adrenal hemorrhage as initial manifestation of Castleman disease and unsuspected late-onset congenital adrenal hyperplasia. Clinical case: A 29-year-old male with no significant past medical history except for unilateral orchiectomy at 1 year-old for a possible testicular mass was referred to our adrenal clinic for a 6,2x7,5 cm left adrenal mass showing at CT scan necrosis and an hemorrhagic component (HU52). The patient presented initially with acute left abdominal pain. The adrenal mass showed at peripheral high uptake at PET-FDG (SUVmax 5,3) with no central uptake. His physical exam was unremarkable except for obesity. The hormonal work-up for the adrenal mass revealed normal metanephrines, and normal 1mg-dexamethasone suppression test with morning cortisol of 18 nmol/L (N&amp;lt;50). Further hormonal investigations based on the high adrenal mass uptake and possible adrenocortical carcinoma included: 17-OH Progesterone: 7.7 nmol/L (N:1.1-7.0), Androstenedione: 14.1 nmol/L (N: 1.5-9.0), Testosterone: 11.3 nmol/L (N: 9.0-28.3) and DHEAS: 3.6 umol/L (2.3-18.7). The ACTH levels were increased at 21.2 pmol/L (N:2-11) with morning cortisol of 220 nmol/L. During the consultation, the patient reported a pleuritic chest pain and underwent an urgent CT pulmonary angiography showing a pulmonary embolism with lung infarction in addition to mediastinal lymphadenopathy (biopsy negative) and a mass in his thymus. He underwent thymectomy and the pathology report described Castleman disease (hyaline vascular type). Taking into account the increased level of 17-OH progesterone, we performed an ACTH stimulation test (250 mcg) that showed an increase of cortisol levels from 333nmol/L to 874nmol/L at 60 minutes and of 17OH Progesterone levels from 5.2nmol/L to 44.2nmo/L excluding adrenal insufficiency, but confirming the diagnosis of late-onset congenital adrenal hyperplasia. Genetic analyses: After written consent, the patient underwent genetic analysis of the CYP21A2 gene by direct sequencing and MLPA. The analyses revealed a heterozygous pathogenic variant in the CYP21A2 gene (c.293-13A/C&amp;gt;G). No other genetic variant was identified in the gene. Follow-up: Subsequent adrenal MRIs showed decreasing size of the left adrenal mass; 3 cm at 3 months, 2 cm at 6 months and no residual mass was seen at 9 months supporting the diagnosis of adrenal hemorrhage. Conclusion: To our knowledge, we report a first case of Castleman disease presenting with adrenal hemorrhage as initial symptom with the association of late-onset congenital adrenal hyperplasia. The possible link between these diseases remains to be explored. Presentation: 6/3/2024

8475 Automated Insulin Delivery System with Concentrated Regular U500 Insulin in Cushing Syndrome

Abstract Disclosure: F. Erenler: None. J. Aurora: None. Background: Concentrated regular U-500 (U-500R) insulin is commonly used in patients with T2DM, who are highly insulin-resistant, requiring more than 200 units of insulin per day. Utilizing U-500R reduces the number of daily injections, decreases injection volume, and improves cost effectiveness. There has been a case report with U-500R in an automated insulin delivery (AID) system with successful results (1). To our knowledge there is no data on AID system use in Cushing patients with T2DM using U-500R. We present a case of a patient with Cushing Syndrome (CS) with poor BG control using &amp;gt;250 units/day of SC U-500R with improved BG control after switching to Omnipod 5 AID system. Clinical Case: A 57 y.o. male initially presented with hypogonadotropic hypogonadism and subsequently diagnosed with ACTH-dependent CS, which is complicated by obesity, uncontrolled T2DM, lower extremity wounds, and DVTs. He was diagnosed with CS with multiple abnormal 1 mg dexamethasone suppression tests (DST) (max AM cortisol 5.9 mcg/dL; RR &amp;lt;1.8 mcg/dL, dexamethasone level 300), elevated urine free cortisol (UFC) (max UFC/Cr 77.6 mcg/mg/L; RR: 5-64 mcg/24-hr) and elevated salivary cortisol (max cortisol 0.2 mcg/dL; RR: &amp;lt;0.09 mcg/dL). He had suppressed cortisol with 8 mg DST. An MRI sella showed left-sided hypoechoic 0.9 cm mass. Desmopressin (DDAVP) stimulation test and Ga-68 DOTATATE-PET scan were negative. As a result of his abnormal MRI sella and elevated cortisol, he underwent transsphenoidal surgery of the left pituitary. Pathology was non-diagnostic for a pituitary adenoma. Post-op 24-hr UFC and 1 mg DST levels remained high. DDAVP stimulation test and Ga-68 DOTATATE-PET were repeated post-op and were negative. Due to complications of CS, he was initially treated with cabergoline, but switched to osilodrostat due to intolerances. He is currently on 2 mg BID dose and 24-hr UFC has been normal since then (UFC 20 mcg/L, Cr 0.67 mg, UFC/Cr 12 mcg/mg/L). He continued to have uncontrolled hyperglycemia despite normalization of UFC. On his CGM data, he was in target range (70-180 mg/dL) 5% of the time despite using U-500R 95 units SC TID. Given his severe hyperglycemia and insulin resistance, he was switched to an AID system with U-500R and his time in target range improved over 60% after a month of use and his total daily dose of insulin decreased to less than 200 units. Conclusion: U-500R proved to be safe and effective with Omnipod 5 AID. To our knowledge, this is the first reported patient with CS using U-500R with Omnipod 5 AID. In patients without CS, the AID algorithm continuously kept BG well below the set target, especially overnight. Notably, our patient did not have this overnight hypoglycemia trend, which should be expected with his disease. We are hoping to increase the awareness of U-500R with AID systems, especially for patients with incurable CS. Reference:1.Aurora J Jr, Saraswat A. J Endocr Soc. 2023;7(Suppl 1):bvad114.873. Presentation: 6/3/2024

8790 A Case Of Ectopic Cushing’s Syndrome Secondary To Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH)

Abstract Disclosure: T. Goettemoeller: None. R. Lopez Fanas: None. K. Cedeno: None. A. Manavalan: None. Introduction: Ectopic Cushing’s syndrome is a rare disease accounting for &amp;lt;20% of cases of endogenous Cushing’s syndrome. DIPNECH is a poorly understood lung disease characterized by abnormal proliferation of neuroendocrine cells in the bronchial mucosa. It can be a precursor to pulmonary carcinoid tumors and has rarely been associated with ACTH production. Clinical Case: A 70-year-old female with intellectual disability and hypertension presented with diffuse edema and weakness. Examination was notable for hypertension, anasarca, and hirsutism. In addition to hypokalemia and metabolic alkalosis, hypercortisolism was observed: random serum cortisol - 50.1 ug/dL, late-night salivary cortisol - 1.72 mcg/dL (normal &amp;lt; 0.09 mcg/dL) and 24-hour urine free cortisol - 1,845.9 mcg (normal: 4.0 – 50.0 mcg/24h). Cortisol level remained &amp;gt; 25 ug/dL after high-dose dexamethasone suppression test. Ketoconazole was initiated and titrated to achieve normal 24-hour urine free cortisol levels and spironolactone was added to manage hypokalemia. An MRI of the sella and pituitary was unremarkable while an abdomen and chest CT identified a 2.5 cm well-circumscribed right middle lobe pulmonary nodule and mild thickening of the bilateral adrenal glands. A gallium-DOTATATE scan revealed a 2.1 cm right middle lobe pulmonary nodule with mildly increased uptake. A transbronchial biopsy of the right middle lobe nodule confirmed a carcinoid tumor. Immunohistochemistry (IHC) staining was positive for CHR, SYN, CD56, and AE1/3. Ki-67 stain showed a low proliferative index. A right middle lobectomy was performed with pathology revealing two typical carcinoid tumors measuring 2.8 and 0.7 cm each, with multiple carcinoid tumorlets and foci of neuroendocrine cell hyperplasia consistent with DIPNECH. IHC staining for ACTH was positive in the carcinoid tumors and tumorlets. Four days after surgery, AM cortisol was 8.1 ug/dL and potassium levels and blood pressure normalized off ketoconazole and spironolactone. The patient was discharged, but was readmitted a month later for anasarca, lethargy, hypokalemia, and metabolic alkalosis. A recurrence of Cushing’s syndrome was confirmed, and medical therapy was resumed. A chest CT revealed post-surgical changes. Her course was complicated by an aspiration event, septic shock, PEA arrest, resuscitation, and intubation. The patient’s care was ultimately transitioned to hospice. Conclusion: Florid Cushing’s syndrome due to ectopic ACTH production associated with DIPNECH is an exceedingly rare condition. Early recognition and treatment are crucial to prevent the numerous complications that may arise, and close follow-up after tumor removal is critical to ensure continued remission has been achieved. Presentation: 6/1/2024

9360 Evaluating The More Accurate Indicator Of Kidney Function In Mild Autonomous Cortisol Secretion: EGFR Creatinine Versus EGFR Cystatin

Abstract Disclosure: L. Rahimi: None. J. Saini: None. E. Atkinson: None. S. Achenbach: None. A. Kattah: None. I. Bancos: None. Introduction: Patients with mild autonomous cortisol secretion (MACS) have higher prevalence of cardiovascular comorbidities including chronic kidney disease. However, considering that patients with MACS may have relative skeletal muscle atrophy, it is unclear whether the creatine-based assessment of kidney function is accurate in this population. Objective: To characterize the differences in assessing estimated glomerular filtration rate using cystatin (eGFRcys) versus creatinine (eGFRcre) in patients with MACS versus referent subjects. Methods: Cross-sectional single-center study, 2019-2022. MACS was defined as serum cortisol concentration &amp;gt;1.8 mcg/dL after the 1 mg overnight dexamethasone suppression test (DST). For each patient, eGFRcre, eGFRcys and eGFRcre/eGFRcys ratio were measured and compared between the two groups. Body composition was measured by DXA scan. The Kruskal-Wallis test was used to compare measurements between groups. Result: A total of 37 patients with MACS (median age 59 years (interquartile range, IQR 47-67), 25 (68%) women) and 45 referent subjects (median age 57 years (IQR 51-66), 30 (67%) women) were included. The distribution of BMI, total body fat mass and total body lean mass were similar between the two groups. In the MACS cohort, the median cortisol following 1-mg DST was 3.0 ug/dL (IQR, 2.2-4.0). While assessment of kidney function with eGFRcre showed no differences between patients with MACS and referent subjects (median 85.1 vs 87.0 ml/min/1.73m2, P=0.431), kidney function using eGFRcys was lower in MACS (median 78.0 vs 89.3 ml/min/1.73m2 in referents, P&amp;lt;0.014), resulting also in a higher eGFRcre/eGFRcys ratio (median 1.07 vs 0.97 in MACS vs referents, P=0.053). After adjusting for age, sex, and BMI, a higher 1 mg DST cortisol level in the MACS cohort was associated with a higher eGFRcre/eGFRcys ratio (Spearman correlation coefficient of 0.35, P = 0.042). Lower eGFRcys was associated with higher fat mass (Spearman correlation of -0.26, P = 0.023), and a higher eGFRcre/eGFRcys ratio showed a trend towards lower lean mass (Spearman correlation of -0.20, P = 0.081). Conclusion: Creatinine-based eGFR assessment in patients with MACS underestimates the degree of kidney dysfunction, likely due to underlying skeletal muscle atrophy. eGFRcys is a more accurate indicator of kidney function in patients with hypercortisolism. Presentation: 6/1/2024

9388 Unusual Case Of Ectopic Adrenocorticotropic Hormone Syndrome Secondary To Non-small Cell Lung Cancer

Abstract Disclosure: A. TakallooBakhtiari: None. G.L. Nunlee-Bland: None. V. Ganta: None. A. Zenebe: None. H. Abdalla: None. A. Elobeid: None. W.A. Odonkor: None. Introduction: Ectopic adrenocorticotropic hormone syndrome (EAS) is a rare condition due to adrenocorticotropic hormone (ACTH) release from non-pituitary tumors. It increases the mortality of affected patients thus finding and removal of the ACTH-producing source allows for curing or reduction of symptoms and serum cortisol levels. The most common cause of EAS is lung cancer. Cushing syndrome (CS) due to EAS is an uncommon paraneoplastic phenomenon in non-small cell lung cancer. Clinical case: The patient is an 80-year-old man with a past medical history of hypertension, dementia, stroke, schizophrenia, and recently diagnosed lung adenocarcinoma. He presented with a few weeks history of dysuria and generalized fatigue. There was no family history for any endocrine disorders. He has a 40 pack-year history of tobacco use. He denied alcohol or illicit drug use. Upon initial evaluation, VS: BP 155/95 mmHg, HR 82 beats/min, Ht 77 inches, Wt 125 lb with a BMI 14.7 Kg/m2. He had no typical symptoms of CS. A physical exam showed a cachectic man with no other remarkable findings. Laboratory tests on admission showed severe hypokalemia of 1.8 mEq/L (3.5-5 mEq/L) with hypochloremic metabolic alkalosis. (bicarbonate 45 mEq/L (22-28 mEq/L) and chloride 79 mEq/L (96-106 mEq/L)). Patient was normoglycemic with HbA1c of 5.0%. Random morning cortisol was 55 μg/dL (13-24 μg/dL). Supine renin and aldosterone levels were 0.45 ng/ml/h (0.25-5.8 ng/ml/h) and 1.0 ng/dL (3-16 ng/dL), respectively, excluding hyperaldosteronism. Beside urinary tract infection, other biochemical workup revealed elevated 24-h urinary free cortisol level 5233 mcg/24h (4.0-50.0 mcg/24h) with creatinine 0.7 g/24h (0.5-2.15 g/24h). Failure to suppress cortisol with low dose dexamethasone suppression test (LDDST) was evident: morning cortisol &amp;gt;60.0 g/dL , with concurrent serum dexamethasone 299 ng/dL (180-550 ng/dL). Plasma ACTH level was elevated 327 pg/ml (6-50 pg/ml), favoring ACTH-dependent CS. A magnetic resonance imaging (MRI) of the sella and computed tomography (CT) of the abdomen did not show pituitary or adrenal masses. Therefore, a diagnosis of ectopic CS due to lung cancer was established. Pathology of the lung mass showed tumor cells were negative for synaptophysin, chromogranin, and CD52. The immunohistochemically findings support primary adenocarcinoma of the lung. Patient refused surgical or medical treatment and was discharged to a hospice facility. Conclusion: The clinical presentation of EAS ranges from the abrupt onset of the signs and symptoms of severe hypercortisolism, including hypertension, hypokalaemia, metabolic alkalosis as in our patient to the gradual and slow onset of the classical signs and symptoms of CS. Though EAS with adenocarcinoma of the lung is rare, it is important to consider it within the differential diagnosis of any adenocarcinoma of the lung presenting with the relevant symptoms. Presentation: 6/3/2024

6453 Cushing Syndrome And Bilateral Adrenal Incidentalomas In A Patient With Mucopolysaccharidosis

Abstract Disclosure: D. John: None. M. Kinaan: None. TITLE Cushing Syndrome &amp; Bilateral Adrenal Incidentalomas in a patient with Mucopolysaccharidosis Affiliation of Authors Dieula John M.D., M.B.A.,a,b Mustafa Kinaan M.D.,a,baEndocrinology, Diabetes, and Metabolism Fellowship, UCF HCA Healthcare GME, Orlando, FL. bDepartment of Internal Medicine, UCF College of Medicine, Orlando, FL. This research was supported (in whole or in part) by HCA Healthcare and/or an HCA Healthcare affiliated entity. The views expressed in this publication represent those of the author(s) and do not necessarily represent the official views of HCA Healthcare or any of its affiliated entities. Introduction: Mucopolysaccharidoses (MPS) is a group of hereditary and incurable storage diseases characterized by a deficiency of enzymes involved in the metabolism of glycosaminoglycans (GAGs) at the lysosomal level. MPS are usually inherited in autosomal recessive or x-linked pattern. MPS affects functioning of the cells, tissues and organs where the GAGs products typically accumulate. This can result in neurologic, developmental, and neoplastic issues. While endocrine disturbances in MPS have been reported, the literature on hypercortisolism and adrenal masses in MPS is limited. We present a case of a patient with MPS diagnosed with Cushing Syndrome (CS) as part of evaluation for adrenal incidentalomas. Case Description: A 50 year old male with a medical history of MPS, DVT, and developmental delay presented to our clinic accompanied by his mother for evaluation of adrenal incidentalomas. CT abdomen incidentally showed a left adrenal non-calcified, non-hemorrhagic mass measuring 3.9 x 3.6 cm with a pre-contrast attenuation of 45 Hounsfield units. Delayed washout was not obtained, and washout calculation couldn’t be performed. These radiologic features were suspicious for malignancy. Repeat CT with adrenal protocol showed left adrenal mass measuring 4.5 x 3.9 cm with central necrosis, unenhanced attenuation of 42 HU, and no drop-in attenuation on delayed phase indicating poor absolute and relative washout. There was also a right adrenal mass measuring up to 2.2 cm 54.5% absolute washout and 39.0% relative washout. Biochemical workup showed no pheochromocytoma, hyperaldosteronism, or adrenal hyperandrogenism. However, his dex suppression test was consistent with ACTH-independent CS. The patient was referred to an endocrine surgeon. We anticipate more information to be available based on the pathology of the excised tumor following his urgent surgery. Conclusion: MPS diseases are extremely rare and their effects on the endocrine system in general, and the adrenal gland specifically, is limited. Our case would serve as the first reported case of CS in MPS patient based on our literature search. In addition, we’ll discuss the pathology findings once the tumor is excised and highlight the connection between the adrenal mass and this lysosomal storage disease. Presentation: 6/3/2024

7859 Primary Hyperaldosteronism And Mild Autonomous Cortisol Secretion (MACS) In Adrenal Incidentaloma

Abstract Disclosure: K. Chanturishvili: None. Q. Gvazava: None. N. Zavrashvili: None. An adrenal incidentaloma is a mass lesion greater than 1 cm in diameter, discovered by radiologic examination, performed for another reason. Widespread use of imaging studies in everyday clinical practice has led to the increased rates of adrenal incidentalomas. Two main questions arise after discovering adrenal mass: is it malignant or benign, and is the mass hormonally active?We present a case of a 55 years old male, with a history of obesity (BMI 35).He had no significant past medical history and was not taking any medications.He presented to our clinic with an upper respiratory tract infection and shortness of breath. Chest CT was done to evaluate for possible pneumonia, where 46 x 30 cm adrenal incidentaloma with -5 HU was discovered.He was referred to our department for endocrine evaluation.Initial assessment revealed previously unknown hypertension with left ventricular hypertrophy. Laboratory workup revealed high aldosterone, suppressed renin, low normal ACTH and DHEA-S, positive 1-mg overnight dexamethasone suppression test (DST- 2.66 ug/dL) and 8-mg DST (2.26 ug/dL).Additionally, the metabolic panel showed prediabetes and hyperlipidemia.Diagnosis of adrenal macroadenoma with cortisol and aldosterone co-secretion was made.Unilateral adrenalectomy was planned. Possible postoperative adrenal insufficiency has been established. Recommendation for proper glucocorticoid coverage was given.In conclusion, evaluation of the functional status of adrenal tumors is essential to uncover hidden medical issues, as s well as to properly guide the patient for intra and postoperative management, avoiding the risks of adrenal insufficiency with proper glucocorticoid coverage. Surgical management of hormonally active adrenal incidentalomas, especially larger &amp;gt;2.4 cm, has potential benefit of improving and preventing metabolic abnormalities: hyperglycemia, dyslipidemia as well as comorbidities such as obesity, hypertension and osteoporosis. Presentation: 6/1/2024