Glucocorticoid Replacement Therapy Research Articles

Redefining ITT cortisol thresholds on Abbott platforms to prevent misdiagnosis of adrenal insufficiency.

Adrenal insufficiency (AI) is a life-threatening condition which requires long term glucocorticoid replacement. The insulin tolerance test (ITT) is the current gold standard test for diagnosis of secondary AI, but the widely accepted cut-off value of a peak cortisol of less than 500 nmol/L assumes that anyone who does not reach this value has AI and thus requires full replacement. The cut-off used to diagnose AI is also founded on outdated assays. Use of this cut-off in an era of more specific immunoassays therefore risks misdiagnosis, subsequent unnecessary glucocorticoid exposure and associated adverse effects with increased mortality risk. This retrospective analysis assessed 300 ITT cortisol responses using the Abbott Architect and Alinity analyser platforms in patients with suspected AI over a period of 12 years (August 2010 to January 2022), at a tertiary centre. Patients were classified as having AI or not, based on a comprehensive clinical review of electronic patient records from the point of test to the present day by a panel of pituitary and adrenal specialists. Using the current institutional cut-off value of 500 nmol/L, receiver operating characteristic analysis identified a 100.0% sensitivity and 43.6% specificity (area under the curve 0.979). Using a lower cortisol threshold value of 416 nmol/L on the Abbott analyser platform maintained a sensitivity of 100.0% and improved the specificity to 86.7%. This data supports lowering the Abbott analyser ITT peak cortisol threshold to 416 nmol/L. Use of this improved cut-off avoids unnecessary glucocorticoid replacement therapy in 104 (34.7%) of individuals in this study. All patients remained well with at least 1 year longitudinal follow up of glucocorticoid replacement.

Exploring sexual function in adrenal insufficiency: findings from the Dual RElease hydrocortisone versus conventionAl glucocorticoid replaceMent therapy in hypocortisolism (DREAM) trial.

Data on sexual function in patients with adrenal insufficiency are scarce and largely controversial. To investigate sexual dysfunction in patients with primary and secondary adrenal insufficiency and the effects of switching to once-daily dual-release hydrocortisone on sexual function in outcome assessors blinded, randomized, multicenter, active comparator clinical trial. Eighty-nine adrenal insufficiency patients on conventional, multiple daily doses of glucocorticoid replacement, enrolled in the Dual RElease hydrocortisone versus conventionAl glucocorticoid replaceMent in hypocortisolism (DREAM) trial, were randomly assigned to continue their therapy or to switch to an equivalent dose of dual-release hydrocortisone. Sixty-three patients (34 women) consented to sex steroid measurements and questionnaires completion for quality of life (Addison's disease-specific quality-of-life questionnaire) and sexual function evaluation (female sexual function index for women, International Index of Erectile Function-Erectile Function for men) at baseline and 24weeks after randomization. At baseline, sexual dysfunction was observed in 41% of women and 59% of men with adrenal insufficiency. In both sexes, no associations were found between sexual function and hormone levels, whereas Addison's disease-specific quality-of-life questionnaire total and fatigue domain scores positively correlated with total female sexual function index and International Index of Erectile Function-Erectile Function scores. At 24weeks, there was no significant difference either in sexual function or sex steroid levels between study groups. In the dual-release hydrocortisone group, the variation in the female sexual function index desire domain score was positively associated with the change in Addison's disease-specific quality-of-life questionnaire's symptom domain score (ρ=0.478, p=0.045). Sexual dysfunction is common in adrenal insufficiency patients and is likely explained by multiple factors. dual-release hydrocortisone treatment is not directly associated with sexual function improvement, but an indirect effect mediated by quality-of-life amelioration cannot be excluded.

Salivary Cortisol Measurement Contamination After Oral Hydrocortisone: A Randomized Crossover Trial.

The study aimed to evaluate salivary cortisol (SC) contamination and determine the associated factors in secondary adrenal insufficiency (SAI) patients treated with hydrocortisone (Hc). A randomized crossover trial involved SAI patients. SC was measured before the morning Hc dose, then at one, two, and four hours after. The procedure was performed twice on two days of a week: one day while taking Hc in tablet form (tablet set) and one day while taking Hc in capsule form (capsule set). Area under the curve (AUC) of SC levels over time was calculated in each participant for the two sets. SC contamination was defined as AUCtablet above the 95th percentile of AUCcapsule. Thirty-four patients (24 females and 10 males) with a median age of 48 years were enrolled. Post-Hc dose SC levels were higher in tablet than in capsule set, particularly at one hour. Prevalence and extent of SC contamination were estimated to 32% and 88%, respectively. In capsule set, SC measured two hours after Hc intake showed the strongest correlation with AUC (r=0.88, p<0.001). In multivariate analysis, serum potassium≥3.9 mEq/l was the only predictor for SC contamination [multi-adjusted OR (95% CI): 7.1 (1.4-36.1); p=0.018]. SC measured during the two hours after Hc intake is inaccurate for glucocorticoid replacement therapy assessment in SAI patients treated with Hc in tablet form.

Course of COVID-19 infection in patients with congenital adrenal hyperplasia.

Patients with primary adrenal insufficiency due to congenital adrenal hyperplasia (CAH) are at risk for adrenal crisis during infectious illnesses. Increased risk of infection including COVID-19 has been variably reported. To evaluate COVID-19 illness outcomes and stress dose practices in a large cohort of patients with CAH during the first two years of the pandemic and compare observations of COVID-19 infection in patients with CAH to the general USA population. Between March 2020 and November 2022, patients with CAH followed at the National Institutes of Health Clinical Center were queried about COVID-19 infection during their routine visits. Cases of COVID-19 were compared to controls. COVID-19 infection rates and symptoms were compared to general USA population data from the Centers for Disease Control and Prevention. Of 168 patient visits, there were 54 (32%) cases of COVID-19 infection, and 15 (28%) were pediatric. Overall an association was found between acquiring COVID-19 and obesity (p=0.018), and adults acquiring COVID-19 were on lower doses of fludrocortisone (p=0.008). Fewer cases of COVID-19 infection were reported in those receiving hydrocortisone or modified-release hydrocortisone compared to longer acting glucocorticoids (p=0.0018). In our CAH population, the pattern of COVID-19 infection rates and COVID-related symptomatology were similar to those observed in the general USA population. Most patients with the presumed alpha variant reported anosmia and ageusia, while gastrointestinal symptoms were commonly reported during the delta and omicron waves. Stress dosing occurred in 30/54 cases, and 7 received parenteral hydrocortisone. Two hospitalizations occurred; one pediatric and one adult, both with co-morbidities. There were 5 emergency room visits and no reported deaths. Patients with CAH with close follow-up do not appear to be at increased risk of acquiring COVID-19 or to have a more severe course of COVID-19 compared to the general USA population. Obesity may increase risk of acquiring COVID-19 in patients with CAH, and overall infection risk may be lower in those receiving short-acting and circadian glucocorticoid replacement therapy. Established age-appropriate guidelines for stress dosing during infectious illnesses should be used for patients with CAH and COVID-19. COVID-19 specific guidelines are not indicated. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT00250159.

Prediction of adrenal insufficiency after pituitary surgery: a retrospective study using beckman access cortisol assay.

Identifying patients requiring glucocorticoid replacement therapy after pituitary surgery is challenging as the tests commonly used for the diagnosis of secondary adrenal insufficiency (SAI) are not recommended in the immediate postoperative period. There are controversial data on the role of postoperative days' morning cortisol, with no specific data for each cortisol assay. The aim of this study is to investigate the reliability of 8.00 a.m. cortisol of the first and second postoperative days in predicting SAI. Data of patients underwent pituitary surgery in Humanitas Research Hospital in Italy, from March 2017 to August 2022, were retrospectively analyzed. Definitive diagnosis of SAI was made through ACTH test 1µg six weeks after surgery. Cortisol was measured through Beckman Access Cortisol and the diagnosis of SAI was made if cortisol peak was below 14.8µg/dL (408 nmol/L) at 30 or 60min after stimulus. Of the sixty-four patients enrolled, seven developed SAI. The ROC curves demonstrated that both first- and second-day postoperative 8.00 a.m. cortisol predict SAI (AUC 0.94 and 0.95, respectively). The optimal thresholds were 15.6µg/dL (430.3 nmol/L; accuracy 89%) for the first day and 11.5µg/dL (317.2 nmol/L, accuracy 81%) for the second day. Patients who developed SAI had larger tumors (p = 0.004) and lower fT4 (p = 0.038) before surgery. Clinicians might rely on the first- and second- postoperative days 8.00 a.m. cortisol to identify patients to discharge with glucocorticoid replacement therapy waiting for the confirmation of SAI through the ACTH test.

Clinical profile and growth pattern of children with congenital adrenal hyperplasia attending endocrine clinic, in a tertiary care center, South India

Background: Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders that result from the deficiency of one of several enzymes involved in the steroidogenic pathway for cortisol or aldosterone biosynthesis. Glucocorticoid replacement therapy, though largely effective in managing crises and limiting virilization, is far from perfect. Aims and Objectives: The aims and objectives of the study are to study the clinical profile and association between type of disease and glucocorticoid dosage with the growth of children with CAH attending pediatric and endocrinology outpatient department in a tertiary care hospital. Materials and Methods: This is a prospective observational study. All children who were newly diagnosed and old cases of CAH were consecutively recruited. Background details of the patient including sociodemographic data were obtained by a structured pro forma. Medical history and details of treatment were obtained from previous records. Patients were then followed up 6 monthly for 1 year and height and height velocity were obtained. Results: This study included 33 children (23 salt wasting [SW] and 10 simple virilizing [SV] CAH). Mean age was 6.3 ± 4.3 years. Among SW CAH, while 83.3% of male babies presented with adrenal crises while only 20% of the female babies went for a crisis, because most of them were diagnosed by the presence of ambiguous genitalia. Among SV patients, all females presented with ambiguous genitalia and males presented with precocious puberty. The overall height standard deviation was 0.8 ± 1.2 with a greater growth faltering in those taking higher doses of hydrocortisone. Growth was compromised more in SW CAH than in SV CAH. Conclusion: Growth in CAH is less compared to normal population and many factors including glucocorticoid dose and type of disease determine the growth and final height.

Current Update on the Management and Treatment of Congenital Adrenal Hyperplasia

Congenital Adrenal Hyperplasia (CAH) comprises a set of inherited conditions marked by enzymatic deficiencies within the adrenal steroidogenesis pathway, resulting in compromised cortisol synthesis and, in certain instances, heightened androgen production. Congenital adrenal hyperplasia (CAH) arises from autosomal recessive genetic mutations affecting enzymes crucial for the adrenal glands’ biochemical synthesis of glucocorticoids, mineralocorticoids, or sex steroids from cholesterol. The majority of these conditions result in either excessive or deficient production of sex steroids, potentially influencing the development of primary or secondary sex characteristics in affected infants, children, or adults. The management and treatment of CAH are geared towards optimizing hormonal equilibrium, averting adrenal crises, and addressing associated comorbidities. This review presents an updated survey of contemporary approaches to CAH management, encompassing glucocorticoid and mineralocorticoid replacement therapies, along with strategies to alleviate androgen excess. Furthermore, it is required that we look into emerging treatments, including novel pharmaceutical interventions and advancements in genetic and reproductive technologies. The complexities and possibilities inherent in the comprehensive care of individuals with CAH, involving collaboration among endocrinologists, geneticists, and reproductive specialists, are also examined. This review presents an updated survey of contemporary approaches to CAH management, encompassing glucocorticoid and mineralocorticoid replacement therapies, along with strategies to alleviate androgen excess. By scrutinizing recent advancements, this abstract provides valuable insights into the dynamic landscape of CAH management, emphasizing the imperative for sustained research efforts to augment the well-being of affected individuals.

Adrenal Cushing's syndrome in children.

Adrenal Cushing's syndrome is a rare cause of endogenous hypercortisolism in neonatal and early childhood stages. The most common causes of adrenal CS are hyperfunctioning adrenal tumours, adenoma or carcinoma. Rarer causes are primary bilateral macronodular adrenal hyperplasia (PBAMH), primary pigmented adrenocortical disease (PPNAD) and McCune Albright syndrome. The diagnosis represents a challenge for clinicians. In cases of clinical suspicion, confirmatory tests of hypercortisolism should be performed, similarly to those performed in adults. Radiological imaging should be always combined with biochemical confirmatory tests, for the differential diagnosis of adrenal CS causes. Treatment strategies for adrenal CS include surgery and in specific cases medical drugs. An adequate treatment is associated to an improvement of growth, bone health, reproduction and body composition from childhood into and during adult life. After cure, lifelong glucocorticoid replacement therapy and endocrine follow-up are required, notably in patients with Carney's complex disease.

X-linked adrenoleukodystrophy and primary adrenal insufficiency.

X-linked adrenoleukodystrophy (X-ALD; OMIM:300100) is a progressive neurodegenerative disorder caused by a congenital defect in the ATP-binding cassette transporters sub-family D member 1 gene (ABCD1) producing adrenoleukodystrophy protein (ALDP). According to population studies, X-ALD has an estimated birth prevalence of 1 in 17.000 subjects (considering both hemizygous males and heterozygous females), and there is no evidence that this prevalence varies among regions or ethnic groups. ALDP deficiency results in a defective peroxisomal β-oxidation of very long chain fatty acids (VLCFA). As a consequence of this metabolic abnormality, VLCFAs accumulate in nervous system (brain white matter and spinal cord), testis and adrenal cortex. All X-ALD affected patients carry a mutation on the ABCD1 gene. Nevertheless, patients with a defect on the ABCD1 gene can have a dramatic difference in the clinical presentation of the disease. In fact, X-ALD can vary from the most severe cerebral paediatric form (CerALD), to adult adrenomyeloneuropathy (AMN), Addison-only and asymptomatic forms. Primary adrenal insufficiency (PAI) is one of the main features of X-ALD, with a prevalence of 70% in ALD/AMN patients and 5% in female carriers. The pathogenesis of X-ALD related PAI is still unclear, even if a few published data suggests a defective adrenal response to ACTH, related to VLCFA accumulation with progressive disruption of adrenal cell membrane function and ACTH receptor activity. The reason why PAI develops only in a proportion of ALD/AMN patients remains incompletely understood. A growing consensus supports VLCFA assessment in all male children presenting with PAI, as early diagnosis and start of therapy may be essential for X-ALD patients. Children and adults with PAI require individualized glucocorticoid replacement therapy, while mineralocorticoid therapy is needed only in a few cases after consideration of hormonal and electrolytes status. Novel approaches, such as prolonged release glucocorticoids, offer potential benefit in optimizing hormonal replacement for X-ALD-related PAI. Although the association between PAI and X-ALD has been observed in clinical practice, the underlying mechanisms remain poorly understood. This paper aims to explore the multifaceted relationship between PAI and X-ALD, shedding light on shared pathophysiology, clinical manifestations, and potential therapeutic interventions.

Abstract 13014: Cardiac Arrhythmias, Hypotension and Need for Vasopressors Following Admissions for Addisonian Crisis; an Analysis via the 2016-2020 National Inpatient Sample

Introduction: Addisonian crisis(AC) is a life-threatening complication secondary to acute adrenal insufficiency. Various cardiac arrhythmias and complications can be seen during such episodes. While fluids and glucocorticoid replacement therapies are the main steps in management, critically ill patients often also require vasopressors (VP) to maintain an adequate Mean Arterial Pressure. Methods: We queried adults with AC from the 2016-2020 National Inpatient Sample. The incidence of several cardiac arrhythmias and cardiac events was estimated. The need for VP among hypotensive cases and their impact on mortality were also analyzed. Results: There were 28430 adult cases of AC with a mean age was 55.59 years (SEM 0.106) and involved predominantly females (62.9% of all cases). Several cardiac arrhythmias were also reported, such as atrial fibrillation (12.6%), supraventricular tachycardia (1.7%), ventricular tachycardia (1.5%), ventricular fibrillation (1.8%), and atrial flutter (1.8%). A diagnosis of hypotension was also reported in 23.2% (6590 cases) of cases, while 16.7% (4755 cases) had hyperkalemia. Among patients with hypotension, 305 (4.6%) cases also needed VP. Higher use of VP in hypotensive cases was observed among Hispanics (vs. Whites, aOR 1.772, 95% CI 1.195-2.627), Males (aOR1.826, 95% CI 1.407-2.371, p&lt;0.01), history of hypertension (aOR1.670, 95% CI 1.232-2.263, p&lt;0.01), prior stroke (aOR 1.741, 95% CI 1.111-2.726, p=0.015), or cirrhosis (aOR 2.185, 95% CI 1.084-4.406, p=0.029). Hypotensive patients requiring the use of VP were older (mean age 62.10 vs. 55.53 years, p&lt;0.01), and with a higher mean Charlson Comorbidity Index (CCI) score (mean score 4.44 vs. 2.97, p&lt;0.01) than those not requiring VP. Overall, 18.0% of hypotensive patients using VP died (vs. 2.2% not requiring VP, aOR 4.950, 95% CI 2.974-8.238, p&lt;0.01). Conclusions: AC presents with multiple cardiac arrhythmias. VP use in hypotensive cases was more common in Hispanics, Males, patients with a history of hypertension, stroke, or cirrhosis. Hypotensive patients requiring VP were also sicker and had a higher mortality rate. Thus, AC management and diagnosis must be prompt to reduce the odds of mortality.

Postoperative hypothalamic-pituitary dysfunction and long-term hormone replacement in patients with childhood-onset craniopharyngioma.

Hypothalamic-pituitary axis dysfunction is a common complication in post-operative craniopharyngioma(CP) patients, and it greatly impacts the long-term quality of life of such patients. To better understand the effects of postoperative hypothalamic-pituitary dysfunction and long-term hormone replacement therapy in patients with childhood CP, we assessed approximately 200 patients with childhood-onset CP postoperatively. Clinical details of patients with childhood-onset CP who underwent sellar tumor resection in Beijing Children's Hospital and Beijing Tiantan Hospital from 2018 to 2019 were retrieved retrospectively. The participants were followed up to assess the effects of post-operative long-term hormone replacement therapy and assess the tumor recurrence rate. The median age of admission was 8.1 (1.8, 14.3) years. Headache (45.5%), visual impairment (39.5%), and nausea (33.0%) were the most common clinical manifestations. ACP accounted for 95% of all CP cases. The incidence of central adrenal insufficiency and central hypothyroidism within the first week after surgery was 56.2% and 70.3%, respectively. At the same time 85.5% of the patients required at least one dose of desmopressin to control urine output. Total survival and tumor recurrence rates were 98.6% and 26.1%, respectively, with a median follow-up time of 29.7 (19.0, 40.3) months. During the follow-up period, 28.1% patients met the diagnostic criteria for short stature, while 54.4% fit the criteria for obesity. In addition, 94.4% of the patients were taking at least one kind of hormone substitution, and 74.7% were taking three or more. The prevalence of levothyroxine, glucocorticoid, desmopressin, and growth hormone replacement therapy was 87.3%, 77.5%, 78.9% and 31.0%, respectively. The proportion of patients treated with the substitutive combination of levothyroxine, hydrocortisone, and desmopressin was 54.9%. This study is a large-sample systematic postoperative endocrine function evaluation of patients with childhood-onset CP. Due to the high prevalence of post-operative hypothalamic-pituitary dysfunction, patients with CP usually require long-term multiple hormone substitution therapy. Individualized management and accurate hormone replacement dosage for postoperative childhood-onset CP patients are of great importance.

Salt-Wasting Congenital Adrenal Hyperplasia in A 2-Year-Old Patient

Congenital Adrenal Hyperplasia (CAH) is an autosomal recessive disorder due to deficiencies of enzymes involved in steroidogenesis in the adrenal cortex. It is known that 90% of CAH are due to 21-hydroxylase enzyme deficiency caused by mutation of the CYP21A2 gene. A female patient aged two years and one month old was reported with a diagnosis of salt-wasting CAH. The diagnosis was based on complaints of genital enlargement since birth. The patient had developed repeated vomiting and severe dehydration since newborn. The patient was diagnosed with CAH and under treatment with glucocorticoid replacement therapy by a pediatrician since the age of 5 months. Body height/age &lt; -3 Standard Deviation (SD) of the Z-score chart (very short stature) and ambiguous genitalia were reported. Laboratory tests indicated thrombocytosis (795x103/uL), mild hyperkalemia (5.4 mmol/L), and increased testosterone (110.1 ng/dL). Bone age study affirmed an advanced bone age. History of increased 17-hydroxyprogesterone (109.19 ng/mL) and decreased morning serum cortisol levels (1.7 ug/dL). History of gynecological ultrasonography (USG) showed uterus, no bilateral testicular structure, hyperplasia of the left adrenal gland, and suggestive of genital ambiguity. The 21-hydroxylase deficiency causes a decrease in aldosterone and cortisol and an increase in androgens. Hypoaldosteronism causes hypovolemia, hyponatremia and hyperkalemia. Hypocortisolime causes hypoglycemia, decreased response to infection, and stress. Hyperandrogenism causes virilization of the genitalia and short stature in patients. A female patient aged two years and one month old was reported with a salt-wasting congenital adrenal hyperplasia diagnosis. Chromosome analysis was the recommended test in this case.

Bilateral Cortical-sparing Adrenalectomy for the Treatment of Bilateral Aldosterone-producing Adenomas

Abstract Aldosterone-producing adenoma (APA) is 1 of the major subtypes of primary aldosteronism (PA). Although most APA occurs unilaterally, bilateral APAs have rarely been documented. Because of its rarity, optimal management of patients with bilateral APAs has not been established. Here, we report a case of bilateral APAs that was successfully treated with simultaneous bilateral cortical-sparing surgery. A 44-year-old Japanese woman was referred to us for the evaluation of PA. She had typical clinical characteristics of PA, including hypertension, hypokalemia, and high plasma aldosterone concentration with suppressed renin. She was diagnosed as having PA based on the results of confirmatory testing. Computed tomography revealed bilateral adrenal nodules with diameters of 17 and 10 mm on the right and left adrenal gland, respectively. Adrenal venous sampling indicated excess aldosterone production from bilateral adrenal lesions. She underwent simultaneous bilateral laparoscopic partial adrenalectomy that normalized her blood pressure and serum potassium levels. Aldosterone synthase immunohistochemistry on the resected adrenal tumor tissue confirmed the diagnosis of bilateral APAs. Long-term postsurgical follow-up data suggest cure of the disease without the need for glucocorticoid replacement therapy. Bilateral cortical-sparing adrenalectomy appears to be a viable treatment option at least for selected patients with bilateral APAs.

Bone Microarchitecture and Volumetric Mineral Density Assessed by HR-pQCT in Patients with 21- and 17α-Hydroxylase Deficiency.

Due to disturbances in hormones and long-term glucocorticoid replacement therapy (GRT), congenital adrenocortical hyperplasia (CAH) patients are at risk of impaired bone structure and metabolism. This cross-sectional, case-control study aims to investigate for the first time bone microarchitecture features in 21-hydroxylase deficiency (21OHD; N = 38) and 17α-hydroxylase deficiency (17OHD; N = 16) patients using high-resolution peripheral quantitative computed tomography (HR-pQCT) by matching the same sex and similar age [21OHD vs. control: 29.5 (24.0-34.3) vs. 29.6 (25.9-35.2) years; 17OHD vs. controls: 29.0 (21.5-35.0) vs. 29.7 (24.6-35.3) years] with healthy controls (1:3). All patients underwent HR-pQCT scans of the nondominant radius and tibia, and had received GRT. Compared with corresponding controls, 17OHD cases had higher height (P < 0.001), weight (P = 0.013) and similar body mass index (BMI), while 21OHD had lower height (P < 0.001), similar weight and higher BMI (P < 0.001). 17OHD and 21OHD patients demonstrated various significant bone differences in most HR-pQCT indices, suggesting abnormalities in bone microarchitectures from healthy people. Further correlation analyses revealed that some characteristics, such as height and hormones, may contribute to the bone differences in HR-pQCT indices between two diseases. However, treatment dosage and time were not correlated, indicating that the current glucocorticoid doses may be within safety limits for bone impairment. Overall, our study for the first time revealed changes of bone microarchitecture in CAH patients and their potential relations with clinical characteristics. Further longitudinal researches are required to confirm these findings.

Glucocorticoid Replacement for Adrenal Insufficiency and the Development of Non-Alcoholic Fatty Liver Disease.

Glucocorticoid excess is a known risk factor for non-alcoholic fatty liver disease (NAFLD). Our objective was to analyse the impact of glucocorticoid replacement therapy on the development of NAFLD and NAFLD-related fibrosis and, therefore, on cardiovascular as well as hepatic morbidity in patients with adrenal insufficiency. Two hundred and fifteen individuals with primary (n = 111) or secondary (n = 104) adrenal insufficiency were investigated for hepatic steatosis and fibrosis using the fatty liver index (FLI), NAFLD fibrosis score (NAFLD-FS), Fibrosis-4 Index (FiB-4) plus sonographic transient elastography. Results were correlated with glucocorticoid doses and cardiometabolic risk parameters. The median dose of hydrocortisone equivalent was 20 mg daily, with a median therapy duration of 15 years. The presence and grade of hepatic steatosis and fibrosis were significantly correlated with cardiometabolic risk factors. We could not find any significant correlations between single, daily or cumulative doses of glucocorticoids and the grade of liver steatosis, nor with fibrosis measured via validated sonographic techniques. In patients with adrenal insufficiency, glucocorticoid replacement within a physiological range of 15-25 mg hydrocortisone equivalent per day does not appear to pose an additional risk for the development of NAFLD, subsequent liver fibrosis, or the cardiovascular morbidity associated with these conditions.

THU609 Timeline For Undetectable Mitotane Plasma Levels In Adrenocortical Carcinoma Patients After Stopping Treatment

Abstract Disclosure: N. Younes: None. P. Hétu: None. A. Lacroix: None. I. Bourdeau: None. Background: Mitotane (o,p’DDD) is an adrenolytic steroidogenesis inhibitor recommended in the treatment of adrenocortical carcinoma (ACC) with a high risk of recurrence. Mitotane has a long plasma elimination half-life, because of its highly lipophilic properties. Objectives: To further explore time to reach undetectable mitotane plasma levels (UM) in treated ACC patients after stopping the medication. Methods: We retrospectively analyzed the medical files of 13 adult patients with ACC who were treated with mitotane during at least 24 months, between 2006 and 2020, in our center. We calculated the duration in months for plasma concentrations of mitotane to be undetectable, from the time of cessation of mitotane in all 13 patients. Baseline demographic characteristics of patients and baseline tumor characteristics were recorded, along with the maximal dose of mitotane used. We also explored the time it took patients to be able to stop glucocorticoid and/or mineralocorticoid replacement therapy following mitotane cessation. Results: The mean age at diagnosis of ACC was 48.2 ± 14.9 years and 69.2% of patients were female. Patients weighted 78.2 ± 27.2 Kg. The mean tumor size and proliferation index Ki67 were 8.1 ± 4.3 cm and 13.3 ± 7.3%. None of the patients had metastasis at diagnosis. They were treated with a mean of 4 ± 2 g of mitotane daily, for 33.5 ± 9 months. Only one patient never had documented therapeutic mitotane range (between 14 and 20 mg/L) during treatment. The time to UM from the time of mitotane cessation was 13.2 ± 7.1 months. All 13 patients were taking glucocorticoid replacement therapy and 5 were able to completely withdraw hydrocortisone 39 ± 14.5 months after stopping mitotane treatment. Only 2 patients out of the 6 patients that were on mineralocorticoid replacement therapy, were able to stop after 34.2 and 59.7 months, respectively. There was no significant relationship found between the duration of exposure to mitotane and the time to UM (p=0.82). On simple linear regression, patients’ weight explained 80% of variance of time to UM. There was a positive relationship between patients’ weight and time to UM (standardized coefficient beta 0.89, p &amp;lt;0.0001). On multiple linear regression, patients’ weight was an independent predictor of time to UM. Conclusion: Mitotane can take up to 13 months to become undetectable in patients’ plasma after cessation. In our cohort, it is mainly influenced by increased weight but not by duration of exposure to the drug. Presentation: Thursday, June 15, 2023

SAT296 Ambulatory 24-hour Tissue Microdialysis Of Cortisol And Metabolites, A Tool For Precision Management In Addison’s Disease

Abstract Disclosure: I. Botusan: None. K. Berinder: None. P. Methlie: None. T. Upton: None. E. Zavala: None. K. Simunkova: None. D.A. Vassiliadi: None. I. Marinelli: None. G.M. Russell: None. M.A. Grytaas: None. S. Tsagarakis: None. S.L. Lightman: None. E.S. Husebye: None. O. Kampe: None. M. Oksnes: None. S. Bensing: None. Background: The autoimmune attack on the adrenals in AD (Addison’s disease) results in lack of the vital hormones cortisol and aldosterone, rendering AD patients dependent on life-long hormone replacement therapy. Current therapies cannot replicate the physiological well-tuned, circadian and ultradian hormonal oscillations properly, probably contributing to increased mortality, morbidity and reduced quality of life. No established biomarker for treatment monitoring exists hampering treatment optimization. Ambulatory 24-hour dynamic steroid profiling may represent a novel therapy-monitoring tool, providing new insights in different replacement therapy regimes. Aim: We aimed to assess 24-hour profiles of free cortisol and metabolites in patients with AD on different glucocorticoid replacement therapies (GRT) and compare the results with healthy volunteers (HV). Material and methods: The study includes 41 patients with AD on different GRT regimes (hydrocortisone, cortisone acetate, modified release hydrocortisone) and 214 healthy participants. Twenty minute microdialysis fractions were collected ambulatory from abdominal subcutaneous tissue over 24 hours using a novel and portable microdialysis fraction collector (U-RHYTHM). Steroid hormones were analyzed by ultrasensitive liquid chromatography tandem mass spectroscopy (LC-MS/MS). Dynamic biomarkers were used to define hormone parameters in both healthy and hormone-replaced participants, and to assess the “time in range” for patients on GRT compared with the profiles of healthy controls. Results: Free cortisol and cortisone levels were measurable in all AD patients, while 18- hydroxycortisol, and corticosterone were detected only in a few AD patients suggesting the persistence of residual adrenal function. Lower cortisol levels during night were observed in AD compared with controls. Ambulatory 24-hour dynamic steroid profiling revealed marked interindividual variations partially depending on the type of GRT and dosing-regime. Conclusions: The 24-hour profiles of free cortisol and cortisone differs between patients with AD and healthy volunteers. Ambulatory 24-hour microdialysis samplings may provide a novel dynamic tool to monitor GRT in AD providing opportunity for individual dose adjustment. Presentation: Saturday, June 17, 2023

THU531 A Case Of Cushing Syndrome Due To Ectopic ACTH Secreting Lung Neuroendocrine Tumor Treated With Cryoablation

Abstract Disclosure: S. Paknikar: None. J. McHugh: None. K. Rachmasari: None. I. Bancos: None. Introduction: Ectopic secretion of adrenocorticotropic hormone (ACTH) is a rare and severe form of Cushing Syndrome (CS) that requires an urgent specialized approach for diagnosis and management. Clinical Case: A 50-year-old woman was referred to endocrinology due to concern for CS. Over the previous year she had developed progressive weakness, edema, weight gain with abdominal fat redistribution, hypertension, and multiple compression fractures. On exam, she had a profound proximal myopathy, reported 10/10 pain along the spine, and was hypertensive (170/105 mm Hg) with normal other vitals. The patient's sodium was 141mmol/L [reference range 135-145 mmol/ L], potassium 4.1 mmol/L [3.6-5.2 mmol/L] while on spironolactone, and creatinine was 0.57 mg/dL [0.59-1.04 mg/dL]. Due to the severity of her symptoms, she was admitted to the hospital. Hormonal work up was consistent with an ACTH dependent CS: ACTH was 121pg/mL [7.2-63 pg/mL] and 24-hour urine cortisol was 645 mcg/24 hr [3.5-45 mcg/24 hr]. Workup for ACTH secreting tumor included a pituitary MRI which showed a 3 mm area of delayed enhancement in the pituitary gland, felt to be artifactual. A chest computed tomography (CT) showed a 1.3 cm low-density nodule in the right upper lobe concerning for a neuroendocrine tumor. A Gallium-68 DOTATATE Positron emission tomography/CT scan was performed and demonstrated that the nodule was highly DOTATATE avid (Krenning score of 3, scale of 0-4). These findings supported a diagnosis of ectopic CS caused by an ACTH secreting lung neuroendocrine tumor. Management of ectopic CS was twofold: addressing the underlying ACTH secreting lesion and urgent treatment of hypercortisolism and its consequences. In this case, this was achieved with CT-guided cryoablation of the right upper lobe nodule. The ACTH levels were monitored postoperatively, and when decreased (9.3pg/mL [ 7.2-63 pg/mL], glucocorticoid replacement therapy was initiated. As a result of prolonged hypercortisolism, the patient experienced multiple compression fractures and debility. Physical therapy was recommended for recovery from the compression fractures as well as proximal myopathy. Enoxaparin was initiated due to risk of venous thromboembolism from CS. From an osteoporosis standpoint, she was continued on calcium and vitamin-D supplementation and treated with weekly alendronate. Her hypertension improved allowing medication reduction. Postoperatively, she received education on adrenal insufficiency and biochemical monitoring for adrenal insufficiency recovery was implemented. Conclusion: Ectopic ACTH secreting tumors represent a rare cause of CS and effective management requires consideration of medical comorbidities to determine the approach: surgical, cryoablative, or medical therapy alone, mitigation of Cushing syndrome sequelae, and prompt recognition and treatment of glucocorticoid withdrawal. Presentation: Thursday, June 15, 2023

SAT338 Desmopressin Stimulation Test As A Valuable Tool In Establishing Cushing Syndrome Etiology

Abstract Disclosure: A. Aponte Velez: None. A. Figueroa Cruz: None. M.M. Mangual Garcia: None. Hypercortisolism diagnosis may be challenging based on its nonspecific signs and symptoms. The challenge continues when establishing the etiology of Cushing’s syndrome (CS). Based on ACTH levels, which are episodic and can provide equivocal results, further testing is guided to determine pituitary, adrenal or ectopic etiology. Various approaches have been proposed to assess ACTH dependent CS with negative pituitary imaging leading to recommend invasive procedures such as IPSS. This procedure is not widely available and can lead to conflicting results which does not always assist in selecting appropriate therapy. Data on the use of desmopressin stimulation test has suggested a limited role in distinguishing etiology of CS. It is mostly recommended to distinguish Cushing Disease from ectopic secretion, but it can provide further information. A 30 year old female with medical history of arterial hypertension, prediabetes and hypothyroidism was referred due to inconclusive etiology of hypercortisolism. Patient reported a 1.5 year onset of worsening fatigue, lower extremity edema, hair loss, violaceous abdominal striae and easy bruising. Physical exam remarkable for an overweight patient, with elevated blood pressure, moon facies, abdominal violaceous striae &amp;gt;1cm, ecchymosis, dorsocervical fat pad, increased abdominal adiposity and proximal muscle weakness. Hypercortisolism was confirmed biochemically with elevated late night salivary cortisol test, urinary free cortisol and 1mg dexamethasone suppression test. ACTH was found inappropriately normal (19-33 pg/mL) suggestive of ACTH dependent CS. ACTH levels raised suspicion for pituitary etiology, for which brain MRI was performed twice and was found negative for pituitary adenoma. Further laboratories revealed low DHEA-S (7mcg/dL) that on the contrary suggested adrenal etiology. Based on this scenario, patient underwent desmopressin stimulation test without an increase in ACTH or cortisol levels suggestive of adrenal source of hypercortisolism. Adrenal CT scan with and without contrast demonstrated right adrenal mass with defined borders, approximately 2cm in diameter, and contrast enhancement with 65% washout. Patient underwent successful right unilateral adrenalectomy. She was started on glucocorticoid replacement therapy with improvement in clinical symptoms, weight loss and control of hypertension and prediabetes. Postoperative evaluation revealed suppressed cortisol levels, and no electrolyte imbalances. This case describes the challenge of determining the etiology of CS using a combination of endocrine tests and imaging. Owing to increased mortality of untreated CS, it is essential for adequate identification of cause for curative therapy. We promote a non-invasive approach using the desmopressin stimulation test for successful identification in patients with discordant serum and imaging results. Presentation: Saturday, June 17, 2023

FRI256 The Clinical Impacts Of Bi-allelic Germline Pathogenic Variant In TP53 In Two Patients With Li-Fraumeni Syndrome

Abstract Disclosure: V. Petry: None. D. Cohn: None. R.R. Oppenheimer: None. M.D. Estevez-Diz: None. A. Latronico: None. B.B. Mendonca: None. M.Q. Almeida: None. M.C. Fragoso: None. Background: Li-Fraumeni syndrome is an autosomal dominant cancer predisposition due to a heterozygous germline TP53 mutation. This mutation is related to different types of cancer; mainly adrenocortical carcinomas (ACC), soft tissues and bone sarcomas, breast cancer, choroid plexus carcinoma and leukemias at early ages. Although little is known about the impact of this TP53 variant in the homozygous form. Methods: We described the clinical presentation and the follow-up of 2 patients with a TP53 (p.R337H) homozygous pathogenic variant inherited from their parents. Case 1: A two year old patient presented with a headache, vomiting and nuchal stiffness, and was taken to the ER where she had a CNS CT scan. The CT scan revealed a mass located at left intraventricular region She then had surgery to remove the tumor and the histological finding confirmed the diagnosis of choroid plexus carcinoma. She underwent adjuvant systemic chemotherapy Headstart III protocol. This was the first case of cancer within this family. The child was seen by a medical geneticist and a genetic test revealed a homozygous pathogenic variant (p.R337H) in TP53. Afterwards her parents were tested and both were heterozygous for the p.R337H mutation. The patient is now 4 years old and free of oncologic disease. Case 2: A 9 months old female patient presented with Cushing´s syndrome and heterosexual precocious puberty. The MRI revealed a right adrenal tumor and she underwent laparoscopic adrenalectomy. Oral hydrocortisone was initiated postoperatively as glucocorticoid replacement therapy and was gradually tapered off over 6 months. Both parents of the patient were heterozygous for the p.R337H mutation in TP53 and they reported several cases of cancer within the family. The patient inherited both mutated alleles TP53 p.R337H. She had normal puberty development and she reached the target height. The patient did not develop further neoplasms during long-term follow-up (23 years). Conclusions: We described 2 cases with a biallelic pathogenic variant in TP53 (p.R337H) who were diagnosed with cancer at early ages and who did not develop further neoplasms during the follow-up period. There is a previous case description in the literature of a patient with a homozygous p.R337H mutation in TP53 who developed ACC at an early age and he did not develop other neoplasms during 8 years of follow-up. These two cases draw your attention to the early age for the development of choroid plexus carcinoma and adrenocortical tumors as well as the published case by Giacomazzi et al. Whether the bi-allelic pattern of the TP53 variant influences the tumor’s behavior remains unclear, there are potentially broad implications for clinical surveillance and genetic counseling for patients and their families. Presentation: Friday, June 16, 2023