24-hour Cortisol Research Articles

7392 Unilateral Adrenal Embolization In Cushing Disease-A Lifesaving Emergent Procedure

Abstract Disclosure: M. Sadiq: None. B. Irshad: None. A. Haider: None. Case presentation: A 59-year-old female was diagnosed with Cushing Disease (CD) thirteen years ago with symptomatic hypercortisolism. Hypokalemia and elevated 24-hour urine cortisol (392 ug/24 hr, n 0-50 ug/24 hr) were noted at the time of diagnosis. Following LDDST, morning cortisol was 30.5 ug/dl, and HDDST showed greater than 50% suppression. A pituitary macroadenoma with bilateral cavernous sinus extension was noted on MRI Sella. Due to cavernous sinus invasion, she was not considered a surgical candidate and underwent Gamma knife radiation. 24-hour urine cortisol decreased significantly (20 ug/24 hours). Two years follow-up MRI brain showed an empty Sella and AM cortisol was noted to be normal at 12.2 ug/ dl with no evidence of AI. She was lost to follow-up and reestablished almost ten years after her initial gamma knife and was symptomatic from hypercortisolism. 24-hour urine cortisol at 85.4 mcg/24 hr, abnormal salivary cortisol x 2 (0.24 and 0.20 mcg/dl n < 0.09 mcg/dl) confirming hypercortisolism. MRI of Sella showed recurrent adenoma with bilateral sellar masses. She was referred to Neurosurgery and was started on Ketoconazole and Paseriotide once-monthly injections. She developed new onset diastolic heart failure & upper GI bleeding, requiring hospitalization. High ACTH level of 668 pg/ml (n. 6.6- 65 pg/ ml). 8 am cortisol was 107.6 ug/dl which was suppressed to 16.1 after 8 mg overnight Decadron. Repeat Gamma knife was planned but due to her decline, it was decided to do unilateral adrenal artery embolization to reduce hypercortisolism. IR-guided adrenal artery embolization of the left middle & inferior adrenal arteries was performed. She required stress dosing of HC post-embolization which was tapered off while monitoring 8 am cortisol which started to rise & 24-hour cortisol levels were noted to be normal (51.2 mcg/24 H) on post-embolization day eight. Gamma knife radiation treatment was performed a month later after which she was noted to have GWS and required Hydrocortisone 15/10 mg twice daily, which she has been taking to date. 24-hour urine cortisol remains normal at 11.8 mcg/24 h. Discussion: Treatment for CD is primarily surgical. Radiotherapy is a second-line alternative in tumors that are non-amenable to surgery. Radiotherapy takes time to achieve its full effect. Cushing Disease patients with significant hypercortisolism and resultant complications require urgent treatment. Unilateral Adrenalectomy is described in literature to curb the cortisol burden . Similarly Unilateral Adrenal artery embolization offers less invasive approach to treat patients considered unfit for surgery. Conclusion: Unilateral adrenal artery embolization can be considered a bridging treatment in CD to reduce cortisol burden and improve the metabolic profile following which a more definitive treatment such as repeat surgery or radiotherapy can lead to long-term remission. Presentation: 6/1/2024

6664 A Case of Undistinguished Congenital Adrenal Hyperplasiain a Patient with Hypertensive Emergency and Hypokalemia

Abstract Disclosure: V.L. Del Signore: None. S.T. Kaufman: None. CAH is a group of autosomal recessive disorders resulting in alterations of adrenal steroid biosynthesis. With 95% of CAH cases due to 21-hydroxylase deficiency; other causes are rare. The metabolic, phenotypic, and physiologic derangements are specific to the altered enzymatic pathways, most of which are life threatening. Identifying the enzymatic defect is crucial to treat the patient. We present a case of undifferentiated CAH in an adult resulting in significant systemic illness. A 26-year-old well virilized male presented with chief complaint of shortness of breath, lower extremity swelling, and abdominal distension for 3 weeks. He was found to have acute decompensated heart failure with LVEF 20-25%, NSTEMI, atrial fibrillation, hypertensive emergency with BP of 224/102, and potassium (K+) of 2.7 (3.5-5mmol/L). PMH included hypertension and CAH diagnosed at birth. Patient was unsure of his CAH defect. Pediatric endocrinology prescribed glucocorticoids until age 17 at which point he was told steroids were no longer required. He had been lost to follow up for 9 years. Pediatric records were unattainable. Patient remained hypokalemic and hypertensive despite aggressive K+ repletion and multiple IV antihypertensives. Endocrine work up revealed renin 0.19 (0.25- 5.82ng/mL/hr), aldosterone 4 (< or = 21ng/dL), DHEAs 97 (74-617ug/dL), FSH <0.3 (1.4 - 18.1 m[IU]/mL), LH <0.3 (1.5 - 9.3 m[IU]/mL), total testosterone 306 (250-1,100 ng/dL), SHBG 32 (10-50nmol/L), progesterone 7 (0.2-1.4 ng/mL), ACTH 345 (6-50 pg/mL), AM cortisol 4.4 (5-23 ug/dL), 17 hydroxyprogesterone 311 (32-307 ng/dL), androstenedione 1,926 (50-220 ng/dL), 11-deoxycortisol >10,000 (< or = 119 ng/dL). Cosyntropin stimulation test: 30-minute cortisol 11.1 (>18 ug/dL) and 60-minute cortisol 10.4 (>18 ug/dL). Based on clinical and lab findings a diagnosis of 11-beta hydroxylase deficiency was made. Spironolactone was started to counteract the excessive mineralocorticoid effects of deoxycorticosterone and hydrocortisone to decrease ACTH production. With this treatment, patient’s potassium and blood pressure gradually improved. IV antihypertensives were weaned as he transitioned to oral agents. This case demonstrates the importance of understanding and identifying the underlying pathophysiology of CAH to treat patients appropriately. This patient had a mineralocorticoid excess state, but adequate cortisol precursors to prevent adrenal crisis. He requires glucocorticoid therapy to prevent excessive ACTH from driving their BP and metabolic derangements. With appropriate diagnosis of 11-beta hydroxylase deficiency, patient’s excess risk of morbidity and mortality due to the downstream effects of uncontrolled CAH can be minimized. Presentation: 6/3/2024

7560 Using a Single Pre-test Cortisol Level To Reduce The Need For Dynamic Testing For Adrenal Insufficiency In A Southeast Asian Population

Abstract Disclosure: V. Ramadoss: None. L. Tan: None. A.E. Teo: None. K. Lazarus: None. K. Meeran: None. D. Deepak: None. L. Ong: None. C. Khoo: None. P. Eng: None. Introduction: The Short Synacthen Test (SST) is widely used in clinical practice to assess Adrenal Insufficiency (AI). Despite its relative ease of administration, Synacthen use is limited by its availability and its administration demands supervision by experienced staff, resulting in increased testing cost. A single measurement of serum cortisol has been shown to predict AI, but the suggested threshold varies according to the patient cohort studied, assay variation and the prevalence of the condition relative to the size of population tested. This study aims to (a) identify a threshold cortisol level to screen for AI in a South-East Asian population and (b) to determine the utility of a stimulated 60-minute cortisol level in the diagnosis of AI. Methods: This is a retrospective analysis of SSTs (250 micrograms) performed in our institution between 28th February 2022 to 28th February 2023. Serum cortisol in our institution was measured by Abbott Alinity analysers. We defined a normal response as a stimulated cortisol value of ≥ 420nmol/L at either 30-minutes, 60-minutes, or at both time points. Logistic regression analysis was performed to predict normal responses based on baseline cortisol level. Results: Median cortisol level at baseline, 30-minutes, and 60-minutes after Synacthen stimulation were 254 (IQR 191-320) nmol/L, 499 (IQR 415 -585) nmol/L, 574 (IQR 476 -662) nmol/L respectively. A total of 785 SSTs were performed, out of which 83.1% were normal and 16.9% were abnormal. Of the 785 SSTs, 55 (7.0%) would have failed if only the 30-minute cortisol was assessed without the 60-minute value, whereas 10 (1.4%) would have failed if only the 60-minute cortisol was assessed without the 30-minutes value. An early morning basal cortisol (0800am to 1200pm) cut-off of <300nmol/L identified subnormal cortisol with 95.0% sensitivity and an afternoon cortisol (1200pm to 1700) of < 312nmol/L achieved 95.2% sensitivity. A basal cortisol level of < 100nmol/L will confirm AI with 97.3% specificity. Using a basal cortisol level of ≥ 300nmol/L, 94.8% of individuals go on to pass the SST. Use of this basal cortisol value would avoid 252 (32.1%) SSTs. Conclusion: A single measurement of basal cortisol of ≥ 300nmol/L has the potential to exclude AI with 95% sensitivity on Abbott Alinity platform in our cohort of patients. Using a threshold cortisol level of 300nmol/L, at least 32% of the SSTs could be avoided. This would have improved patients experience with cost savings implications. Furthermore, a stimulated 60-minute cortisol level identifies 55 (7%) of individuals who would otherwise be misclassified as AI, thereby avoiding unnecessary long-term glucocorticoid replacement. Presentation: 6/1/2024

7385 Prevalence of Central Hypothyroidism in Cushing Syndrome and Thyroid Function Tests After Cushing Treatment

Abstract Disclosure: T. Kunavisarut: None. A. Sriwijitkamol: None. Cushing syndrome can be associated with thyroid dysfunction. We investigated the association between Cushing syndrome and thyroid dysfunction. We conducted a retrospective study at Siriraj Hospital in Thailand and analyzed thyroid function tests in 80 Cushing's patients. The inclusion criteria were patients diagnosed with Cushing syndrome with thyroid function tests recorded at diagnosis of Cushing syndrome. Patients who had an abnormal thyroid function test at diagnosis of Cushing syndrome must have a thyroid function test after treatment of Cushing syndrome. Of the 80 patients, sixty-five patients (81.2%) had normal thyroid function at diagnosis, 12 patients (15%) had central hypothyroidism and three patients (3.8%) had subclinical hyperthyroidism.Interestingly, among 12 patients who had central hypothyroidism, eight patients (66.7%) were diagnosed with Cushing disease. Three patients (25%) were diagnosed with adrenal Cushing syndrome and one patient (8.3%) was diagnosed with ectopic Cushing syndrome. This finding suggested that central hypothyroidism may not be exclusively due to the mass effect of the pituitary tumor on the normal pituitary because adrenal Cushing syndrome and ectopic Cushing syndrome can also cause central hypothyroidism. Among 12 patients with central hypothyroidism at diagnosis of Cushing syndrome, nine patients (75%) normalized their thyroid function after remission of Cushing syndrome without Levothyroxine replacement. Moreover, patients with central hypothyroidism had significantly higher median 24-hour urine-free cortisol levels than euthyroid patients (1030.5 ug/day vs. 404.5 ug/day, p=0.017), indicating a potential correlation between cortisol excess and low FT4 levels. These findings suggest that hypercortisolism in Cushing syndrome can suppress the hypothalamic-pituitary-thyroid axis, but this suppression is often reversible with successful Cushing's treatment. This study highlights the importance of central hypothyroidism, which can occur in all types of Cushing syndrome. If the patients did not have hypothyroid symptoms, Levothyroxine replacement may not be necessary. For patients who already received Levothyroxine and had normal thyroid function tests, Levothyroxine can be carefully tapered and potentially discontinued because successful Cushing syndrome treatment can ultimately normalize thyroid function tests. Presentation: 6/1/2024

6568 A Novel Case of Liddle Syndrome in Siblings: Insights into a Rare Genetic Mutation

Abstract Disclosure: A.B. Humrickhouse: None. M. Peltsverger: None. Introduction: Liddle syndrome (LS) is an inherited form of hypertension caused by a mutation in the epithelialsodium channel (ENaC). This condition is characterized by hypertension (HTN), hypokalemia,hyporeninemia, and metabolic alkalosis, although clinical presentation can vary. Asymptomaticearly-onset HTN is common, and if left undiagnosed, it can lead to advanced renal disease,cardiovascular complications, stroke, and even sudden death. Treatment typically involves theadministration of ENaC blockers such as amiloride and triamterene. We present a novel case ofLS in two siblings resulting from a missense mutation in the SCNN1B gene. Case Presentation: The patient is a 24-year-old Hispanic female who presented for evaluation of poorly controlledHTN and severe hypokalemia of 2.9 mmol/L during the first trimester of pregnancy. She wasdiagnosed with HTN at age eighteen. The family history was notable for resistant HTN in herfather and younger brother. Biochemical evaluation revealed normal plasma-free metanephrinesand 24-hour urine-free cortisol. Low plasma renin activity (0.530 ng/mL/hr) and aldosterone(<1.0 ng/dL) were detected on multiple tests. The urine-free cortisol-to-cortisone ratio was <0.5,excluding the diagnosis of apparent mineralocorticoid excess syndrome. The diagnosis of LS wasconfirmed by genetic analysis, which identified a novel heterozygous mutation, c.1859 A>G(Tyr620Cys), in the SCNN1B gene, which had not been reported in the literature to date. Thesame mutation was identified in her brother. The patient was treated with a high dose ofamiloride (15 mg daily), which controlled her HTN and hypokalemia throughout her pregnancy. Discussion: LS is an autosomal dominant disorder with genetic heterogeneity. It is characterized by HTN,low plasma aldosterone and renin activity, and increased potassium excretion. This leads tohypokalemia and metabolic alkalosis. LS is caused by germline mutations found in theSCNN1A, SCNN1B, and SCNN1G genes, which encode the alpha, beta, and gamma subunits ofthe ENaC channel. These mutations lead to enhanced sodium reabsorption in the kidneys,independent of aldosterone. Our patient was diagnosed with hypertension at the age of 18.However, the diagnosis of LS was not made until six years later when she presented during herfirst trimester of pregnancy. Treatment with amiloride effectively controlled her hypertension andhypokalemia, which allowed her to deliver a healthy child. Amiloride was also prescribed for thepatient's brother. A combination of biochemical analysis and genetic testing enables a betterunderstanding of the various clinical presentations, ensuring appropriate treatment andprevention of end-organ damage. Genetic counseling is essential for families affected by LS. Presentation: 6/1/2024

A-080 Morning Cortisol for Rule-in and Rule-out of Adrenal Insufficiency in an Asian Population

Abstract Background Short ACTH stimulation (Synacthen) tests are performed to investigate for adrenal insufficiency. Previous work suggests that morning cortisol concentrations can be used to rule in or out adrenal insufficiency to avoid performance of a Synacthen test. This study aimed to determine the optimal cortisol concentration for rule-in or rule-out adrenal insufficiency based on 30-minute cortisol (COR30) for adequate response using the assay-specific cut-off from The Endocrine Society of Australia/The Australasian Association for Clinical Biochemistry and Laboratory Medicine/The Royal College of Pathologists of Australasia (ESA/AACB/RCPA) Harmonization of Endocrine Dynamic Testing - Adult (HEDTA), in an Asian population. Methods Synacthen tests performed at our institution from 2012-2024, with a baseline cortisol between 6 and 10 am (COR0(6-10)), were extracted from the laboratory database. Plasma cortisol concentrations were measured by Beckman Coulter DxI 800. Synacthen tests were classified as adequate or inadequate based on the Beckman Coulter specific HEDTA cut-off for COR30 of 420 nmol/L. Performance characteristics (sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and area under receiver operator characteristic (AUROC) curve) of COR0(6-10) concentrations to predict adequate or inadequate response were calculated using Microsoft Excel. Results 4609 Synacthen tests were included, 77% of which had adequate Synacthen response. COR0(6-10) >300 nmol/L could exclude inadequate COR30 response with sensitivity 95%, specificity 48%, PPV 35%, NPV 97%; and COR0(6-10) >364 nmol/L had sensitivity 99%, specificity 29%, PPV 29%, NPV 99%. COR0(6-10) <155 nmol/L could rule-in inadequate COR30 response with sensitivity 53%, specificity 95%, PPV 76%, NPV 87%; and COR0(6-10) <97 nmol/L had sensitivity 35%, specificity 99%, PPV 91%, NPV 84%. AUROC of COR0(6-10) for adequate COR30 response was 0.86. If patients with COR0(6-10) <97 nmol/L and >300 nmol/L did not proceed to Synacthen testing, up to 46% of tests could be avoided, while keeping misclassification under 5%. Conclusions Morning cortisol cut-offs were determined for rule-in and rule-out of adrenal insufficiency in an Asian population. Patients with morning cortisol >300 nmol/L or <97 nmol/L may be able to avoid Synacthen testing unless there is a strong suspicion of clinical discordance. Such a testing strategy could significantly decrease the number of Synacthen tests while keeping misclassification to a minimum.

Abstract P218: Resistant hypertension is associated with elevated 24-hour cortisol to cortisone ratios in black patients.

Background: RHTN is defined as blood pressure above goal despite using ≥3 antihypertensive medications. Patients with RHTN are at an increased risk for cardiovascular (CVD) compared to those with more easily controlled hypertension (HTN). Blacks With RHTN are at a specifically high risk for CVD. Mineralocorticoid receptor activation has been found as an important mechanism of RHTN. However, aldosterone levels are not different in blacks versus whites. The role of 24-hour cortisol-to-cortisone ratios in this group has not been investigated. Methods: We conducted a cross-sectional analysis of a large cohort of 2397 black and white patients with RHTN who were referred to the RHTN Clinic at the University of Alabama at Birmingham and who underwent 24-hour urine collection including cortisol and cortisone. Patients with HTN served as a control group. Results: Black patients with RHTN compared to whites had a trend to higher 24h cortisol levels (17.7±27.6 vs 16.9±14.9, p =0.70, significantly lower 24h cortisone levels (60.45±37.7 vs 75.3±40.0, p 0.000234), and significantly higher 24h cortisol-to-cortisone ratios (0.23±0.14 vs 0.20 ±0.10, p=0.027). They were younger (53.3±11.6 vs 59.4±12.9 years), more obese (BMI 34.9±7.6 vs 30.8±6.1 kg/m2, p<0.001), had earlier onset of HTN (35.6±12.5 vs 41.4±11.6 years of age, p<0.001), higher 24-hour urinary sodium excretion (188.2±92.5 vs 174.9±83.1 mmol, p=0.006) and lower potassium excretion (54.5 ±28.6 vs 65.5 ±30.5 mmol, p<0.001). Furthermore, they had a significantly higher rate of heart failure (p=0.000455) and diabetes (p=0.0006). Conclusion: Cortisol dysregulation and a higher cortisol-to-cortisone ratio as an index of 11beta HSD2 activity may play a role in black patients with RHTN and may be related to adverse outcomes in this population.

Efficacy and Safety of Levoketoconazole in Managing Cushing's Syndrome: A Systematic Review.

No systematic review has holistically analysed the efficacy and safety of levoketoconazole, a novel purified 2S,4R enantiomer of ketoconazole, believed to be 15- to 25-fold more potent than ketoconazole for managing Cushing's syndrome (CS). We undertook this meta-analysis to address this knowledge gap. Electronic databases were searched for studies involving patients with CS receiving levoketoconazole in the intervention arm. The primary outcome was to evaluate changes in mean 24-hour urine-free cortisol (mUFC) levels. Secondary outcomes were to evaluate alterations in cortisol and adverse events. SONICS study showed that normalisation of mUFC was seen in 61%, 55%, and 41% of the patients at the end of 6, 9, and 12 months therapy, respectively. The LOGICs study showed that withdrawal of levoketoconazole was associated with a significant increase in mUFC from 81.3 ± 35.7 to 220.8 ± 333.5 nmol/24h. The late-night salivary-cortisol (LNSC) increase during the drug withdrawal phase was 2.6 nmol/L in the placebo group (PG) compared to 2.2 nmol/L in the levoketoconazole group (LG) (P < 0.05). Re-initiation of levoketoconazole in original LG was associated with a decrease in mUFC from 224.3 ± 341.3 to 135.6 ± 87.3 nmol/24h. Initiation of levoketoconazole in the original PG was associated with a decrease in mUFC from 537.9 ± 346.0 to 141.3 ± 130.3 nmol/24h. Normalisation of mUFC was observed in 50.0% patients in LG compared to 4.5% in the placebo group. The median time for the response was 25 days. The median time to loss of therapeutic response was significantly shorter for PG (24 days) compared to LG (62 days) (P < 0.0001). Levoketoconazole has good efficacy and safety in CS. Bigger and longer studies are warranted to establish its superiority over ketoconazole.

Determination of cortisol cut-off limits and steroid dynamics in the ACTH stimulation test: a comparative analysis using Roche Elecsys Cortisol II immunoassay and LC-MS/MS

PurposeMeasurement of cortisol concentrations is method dependent. The study aimed to establish assay-specific cut-off limits for cortisol after adrenocorticotropic hormone (ACTH) stimulation, comparing Roche Elecsys Cortisol II immunoassay to liquid chromatography-mass spectrometry (LC-MS/MS), and to assess the impact of patient characteristics, estrogen containing oral contraceptives as well as relation to other adrenocortical steroid hormone dynamics.MethodsOne hundred healthy participants underwent a 250 μg ACTH-test, with plasma samples analyzed using ElecsysCortI, ElecsysCortII, and LC-MS/MS. Cortisone, corticosterone, 17-OH-progesterone, dehydroepiandrosterone sulfate (DHEAS), androstenedione, and testosterone were additionally analyzed with LC-MS/MS. Cut-off limit for a normal cortisol response to the ACTH-test was defined as: 2.5th percentile–1.96 × SE.ResultsElecsysCort II measured cortisol concentrations 21% (95% CI: 19–22%) lower than ElecsysCort I. Cut-off limits for cortisol 30 and 60 min after ACTH were 426 and 485 nmol/L (ElecsysCort II) and 411 and 470 nmol/L (LC-MS/MS). Cut-offs were unaffected by gender, or body-composition. The ACTH-test resulted in significantly increased adrenocortical steroid hormones, except for decreased cortisone concentrations (both sexes), and decreased testosterone in men (1.9 nmol/L, 95% CI: 1.3–2.5). Testosterone was increased in women (0.07 nmol/L, 95% CI: 0.02–0.13).ConclusionElecsysCort II has high analytical performance and yields significantly lower cortisol concentrations than prior polyclonal immunoassays. This clinically relevant difference underscores the necessity for revised cut-off limits for improved diagnostic precision. Suggested 30-minute cortisol cutoff limits are 411 nmol/L (LC-MS/MS) and 426 nmol/L (ElecsysCort II). Adrenocortical steroids increased upon ACTH stimulation, except for cortisone in both sexes and testosterone in men, both of which decreased.

Choroidal Thickness in Mild Autonomous Cortisol Secretion.

To evaluate the patients with mild autonomous cortisol secretion (MACS) by means of choroidal thickness (CT) and also investigate whether CT may be a diagnostic tool in the management of MACS or not. Twenty-seven patients with MACS and 25 age-sex-matched healthy controls were enrolled in this cross-sectional comparative study. All the participants underwent CT measurement by using Spectralis optical coherence tomography (Heidelberg Engineering, Heidelberg, Germany) with enhanced deep imaging mode at the subfoveal, 500-1000-1500 µm nasal and 500-1000-1500 µm temporal to the foveola. The groups were similar in terms of spherical equivalence, age and axial lengths. The mean CT was significantly thicker in patients with MACS than controls in all measurement quadrants (p<0.001). There was no significant correlation between CT, size of the adenoma, basal cortisol, 1mg dexamethasone suppression test, salivary cortisol, 24-hour total urine-free cortisol, ACTH and DHEAS levels. However, 2 mg dexamethasone suppression test results were found to be significantly correlated with CT in temporal 500-1000 and 1500 µm quadrants (r=0.436, p=0.023, r=0.443, p=0.021 and r=0.488, p=0.010, respectively). Five (18.5%) eyes had pachychoroid pigment epitheliopathy in the MACS group. CT increases in patients with MACS and those tend to have pachychoroid pigment epitheliopathy more frequent than healthy individuals. A thicker choroid in the patients with MACS may be a novel biomarker both as a diagnostic tool for the degree of hypercortisolemia and cortisol-related comorbidity.

CHOROIDAL AND RETINAL ABNORMALITIES IN CUSHING SYNDROME: Correlation with the Cortisol Level.

To investigate the structure and blood flow of the retina and choroid in Cushing syndrome and their relationship with cortisol levels. A consecutive series of patients with Cushing syndrome with adrenocortical carcinoma were included in this study. Cortisol levels gradually returned to normal after adrenalectomy. Optical coherence tomography and optical coherence tomography angiography were used to assess patients with Cushing syndrome before and after the surgery for retina and choroid. Correlation analysis was performed between cortisol level and fundus changes. Compared with normal cortisol levels, patients with Cushing syndrome had significantly lower central macular thickness with increased cortisol level (220.82 ± 16.59 µ m and 223.68 ± 15.78 µ m, P = 0.019). However, the central choroidal thickness was higher with increased cortisol level (255.18 ± 105.89 µ m and 205.94 ± 87.04 µ m, P < 0.001). The choriocapillaris flow area was higher with increased cortisol level (2.05 ± 0.14 mm 2 and 2.00 ± 0.13 mm 2 , P = 0.02). The change of choriocapillaris flow area was correlated with the score of Huaxi Emotional-distress Index and 24-hour urine-free cortisol (24h-UFC). The increased cortisol level was correlated with lesser central macular thickness and thicker central choroidal thickness. The decrease of choriocapillaris flow area was correlated with 24h-UFC, indicating the effect of increased cortisol level on choroidal vessels.

Multivariable Model to Predict an ACTH Stimulation Test to Diagnose Adrenal Insufficiency Using Previous Test Results.

The adrenocorticotropin hormone stimulation test (AST) is used to diagnose adrenal insufficiency, and is often repeated in patients when monitoring recovery of the hypothalamo-pituitary-adrenal axis. To develop and validate a prediction model that uses previous AST results with new baseline cortisol to predict the result of a new AST. This was a retrospective, longitudinal cohort study in patients who had undergone at least 2 ASTs, using polynomial regression with backwards variable selection, at a Tertiary UK adult endocrinology center. Model was developed from 258 paired ASTs over 5 years in 175 adults (mean age 52.4 years, SD 16.4), then validated on data from 111 patients over 1 year (51.8, 17.5) from the same center, data collected after model development. Candidate prediction variables included previous test baseline adrenocorticotropin hormone (ACTH), previous test baseline and 30-minute cortisol, days between tests, and new baseline ACTH and cortisol used with calculated cortisol/ACTH ratios to assess 8 candidate predictors. The main outcome measure was a new test cortisol measured 30 minutes after Synacthen administration. Using 258 sequential ASTs from 175 patients for model development and 111 patient tests for model validation, previous baseline cortisol, previous 30-minute cortisol and new baseline cortisol were superior at predicting new 30-minute cortisol (R2 = 0.71 [0.49-0.93], area under the curve [AUC] = 0.97 [0.94-1.0]) than new baseline cortisol alone (R2 = 0.53 [0.22-0.84], AUC = 0.88 [0.81-0.95]). Results of a previous AST can be objectively combined with new early-morning cortisol to predict the results of a new AST better than new early-morning cortisol alone. An online calculator is available at https://endocrinology.shinyapps.io/sheffield_sst_calculator/ for external validation.

OR30-01 Waking Salivary 11-hydroxyandrostenedione And Cortisone As A Novel Non-invasive Test For Adrenal Insufficiency

Abstract Disclosure: N.R. Lawrence: None. B.G. Keevil: None. C. Elder: None. J. Fearnside: None. S. Caunt: None. S. Dixon: None. J.D. Newell-Price: Consulting Fee; Self; Diurnal, Recordati, Crinetics, HRA Pharma. R.J. Ross: Employee; Self; Diurnal. M. Debono: None. Background: The ACTH (Cosyntropin) stimulation test (AST) is the reference standard for diagnosis of adrenal insufficiency. We have demonstrated recently that home waking salivary cortisone accurately predicts the ACTH stimulation test outcome and confirms or excludes adrenal insufficiency in 70% of high-risk patients (in press: Home Waking Salivary Cortisone to Screen for Adrenal Insufficiency NEJM Evidence). 11-hydroxyandrostenedione (11-OHA4) is a weak adrenal androgen whose synthesis is dependent on CYP11B1. Since ACTH drives steroidogenesis, and adrenal androgens are low in patients with adrenal insufficiency, we hypothesised that waking 11-OHA4 could also predict adrenal status. Methods: A prospective, diagnostic accuracy study of waking salivary cortisone was performed in 173 patients at high risk of AI. All patients collected a salivary sample on waking, and then attended the endocrine clinic for an AST with the 30-minute cortisol used to diagnose AI. Salivary cortisone and 11-OHA4 was measured in the waking salivary sample. Biomarker discrimination was assessed by calculation of area under the curve (AUC) of the receiver operator characteristics (ROC) plot. Equivocal results were defined to maintain a sensitivity of 95% and specificity of 95%, and percentage of AST saved by calculating the number of AST needed if used only in equivocal cases. Results: The median (IQR) for 11-OHA4 for patients with AI and no AI was 55 (45 to 110) pmol/l vs 508 (255 to 765) pmol/l; p&amp;lt;0.0001. Salivary 11-OHA4 on waking was highly predictive of adrenal insufficiency (R2=0.63, ROC AUC 0.94), similar to waking salivary cortisone alone (R2=0.65, AUC 0.94). Waking 11-OHA4 performed better than either serum cortisol (R2=0.65, AUC 0.88) or salivary cortisone (R2=0.74, AUC 0.93) collected at the baseline of the AST. Combining both waking salivary 11-OHA4 with waking salivary cortisone further improved discrimination (R2=0.70, AUC 0.96), and using this combination would mean that 78% of ACTH-stimulation tests could be avoided. Conclusion: Waking salivary 11-OHA4 can accurately predict AI with similar discriminatory value as waking salivary cortisone. Combining waking 11-OHA4 with waking salivary cortisone improves discrimination for adrenal insufficiency, is a simple non-invasive test that can be used widely in clinical practice in the ambulatory setting, and obviates the need for AST in 78% of cases with greater patient convenience and lower costs. Presentation: Sunday, June 18, 2023

FRI697 Severe Hypocalcemia Due To Idiopathic Hypoparathyroidism In An Elderly Female

Abstract Disclosure: K.A. Chopra: None. Most cases of acquired hypoparathyroidism in adulthood occur after neck surgery or radiation. However, idiopathic cases, although rare, do occur in elderly patients and should be a diagnosis of exclusion after thorough investigation. 76-year-old female with a history of chronic kidney disease, anemia of chronic disease, and hypertension presented with fatigue. Labs showed calcium (Ca) 5.7(RR 8.4-10.2 mg/dL), albumin 3.5(RR 3.5-5 g/dL), magnesium 2(RR 1.6-2.5 mg/dL), phosphorus 7.8(RR 2.5-4.4 mg/dL), parathyroid hormone 9(RR 15-75 pg/mL), 25-hydroxyvitamin D 32(RR 12-99 ng/mL). Patient denied history of neck surgery or radiation. Patient denied nephrolithiasis, perioral numbness, paresthesias, family history of hypoparathyroidism. Physical exam notable for positive Chvostek sign. Neck ultrasound unremarkable, no evidence of infiltrative disease. Urine Ca was low at 6 mg/24 hour(RR 100-300 mg/24hr). ACE level 10 nmol/ml/min(RR&amp;lt;40 nmol/ml/min) and 1,25 dihydroxyvitamin D level 12(RR 18-78 pg/mL) making sarcoidosis or granulomatous disease unlikely. HIV screen negative and interferon gamma response to mycobacterium tuberculosis antigens was not detected. Ferritin elevated at 300(RR 12-150 ng/mL) but transferrin saturation was 15%(RR 15-55%), not consistent with hemochromatosis. Antiparathyroid antibodies were negative. Patient denied mucocutaneous candidiasis, however testing for underlying autoimmune polyglandular syndrome type 1 (APS type 1) and adrenal insufficiency was completed with cosyntropin stimulation test. Patient had normal response to cosyntropin with baseline cortisol 20.1 (RR 6-18.4 ug/dL) and ACTH 37.7(RR&amp;lt;52 pg/mL), 30 minute cortisol 27(RR 6-18.4 ug/dL) and 60 minute cortisol 37(RR 6-18.4 ug/dL). Patient was treated with Ca gluconate infusion (100 ml of 10% Ca gluconate in 1000 mL of normal saline) at 30 ml/hr and Ca level gradually improved. Once Ca level was greater than 8.0(RR 8.4-10.2 mg/dL), Ca drip was discontinued. Due to patient’s lack of prior neck surgery history, lack of evidence of infiltrative conditions, negative antiparathyroid antibodies, normal adrenal function (unlikely APS type 1), lack of family history, and low urine Ca (unlikely activating mutation of Ca sensing receptor), patient’s hypoparathyroidism was considered idiopathic. Patient was discharged on oral Ca carbonate, Ca acetate, and calcitriol tablets. On follow up, patient had Ca 8.5(RR 8.4-10.2 mg/dL) with symptom improvement. Although hypocalcemia is commonly encountered, it is rare to see severe hypocalcemia in an elderly patient due to hypoparathyroidism without a history of neck surgery or radiation. Therefore, it is vitally important to conduct a thorough investigation to rule out underlying causes before diagnosing idiopathic hypoparathyroidism as highlighted in our case to guide future treatment and optimize patient health. Presentation: Friday, June 16, 2023

SAT627 Is Cyberknife Stereotactic Radiosurgery Effective For Treating Cushing’s Disease?

Abstract Disclosure: G. Wintermyer: None. E. Villanueva: None. Patients with pituitary adenoma can often present with endocrine abnormalities. Transsphenoidal surgery(TSS) is the “gold standard” treatment. In patients with recurrent or post-surgery remaining adenoma, stereotactic radiosurgery with CyberKnife (CKRS) has demonstrated to be a good adjuvant therapy. Occasionally patients develop hypopituitarism and adrenal insufficiency (AI) post CKRS. Here is a patient with ACTH-secreting pituitary adenoma with Cushing’s disease who developed remission afterCKRS:52-year-old-male with PMHx of T2DM, hypothyroidism, HTN presented to hospital complaining of fatigue, ataxia, 40-lbs weight loss over four months and mood changes. Due to ataxia, CT of the head was done which revealed an Empty Sella. During the workup, ACTH and cortisol were detected 131 pg/mL and 37.5 ug/dL respectively. After ruling out life-threatening medical conditions, he was discharged with endocrinology referral for Empty Sella syndrome (ESS) and elevated ACTH. During endocrinology evaluation, patient was sent for testosterone, LH, FSH, ACTH, AM cortisol, prolactin and DHEAS tests. Results were as follows: elevated ACTH (91 pg/mL) and Cortisol (33.5ug/dL), elevated DHEAS (401 ug/dL) and prolactin (15 NG/dL), low testosterone (72 NG/dL), within appropriately low LH and FSH. Later, PM Salivary cortisol level, Dexamethasone suppression test(DST), and urine free cortisol (UFC) level were tested. He had pituitary MRI concurrently. Salivary cortisol and UFC were high. There was no suppression of cortisol level after DST. Pituitary MRI demonstrated pituitary tumor. He was diagnosed with Cushing’s disease and was referred to neurosurgery for pituitary tumor TSS. Patient was started on Ketoconazole prior to surgery. Pathology confirmed ACTH-secreting pituitary adenoma. After surgery, Cortisol level normalized, and the patient regained his energy. Post-surgery MRI showed complete resection of adenoma. Ketoconazole was discontinued post-operatively. Two years later, during routine workup, there were elevations in 24-hour and PM salivary cortisol levels. The patient was asymptomatic. He failed his DST. Repeat pituitary MRI showed small hypo enhancement at the bottom of Sella suspicious for pituitary adenoma recurrence. The patient underwent CKRS. Cortisol level and pituitary axis activity remained normal since CKRS. No change was noted in the six-month and one-year surveillance MRI. Even though TSS is a “gold standard” treatment for pituitary adenoma, the likelihood of remaining residues or recurrence of the tumor is high. Frequent pituitary hormone checks can detect recurrence of adenoma before emerging symptoms. CKRS should be considered as a therapeutic option for recurrent adenoma. Clinicians should frequently check patients for hypopituitarism and AI post-CKRS. Clinicians should also recognize that ESS may contribute to MRI-negative Cushing’s disease. Presentation: Saturday, June 17, 2023

OR30-03 High Resolution Daily Profiles Of Tissue Adrenal Steroids By Portable Automated Collection

Abstract Disclosure: T. Upton: None. E. Zavala: None. P. Methlie: None. M. Oksnes: None. M.A. Grytaas: None. K. Simunkova: None. S. Bensing: None. I. Botusan: None. K. Berinder: None. D.A. Vassiliadi: None. O. Kampe: None. S. Tsagarakis: None. E.S. Husebye: None. G.M. Russell: None. S.L. Lightman: None. Background: Rhythms are intrinsic to endocrine systems, and disruption of these hormone oscillations occurs at very early stages of disease. Since adrenal hormones are secreted with both circadian and ultradian periods, conventional single time point measures provide limited information about rhythmicity, and crucially do not provide information during sleep when many hormones fluctuate from nadir to peak concentrations. If blood sampling is attempted overnight this necessitates admission to a clinical research unit, can be stressful and disturbs normal sleep. Aim: To obtain automated ambulatory 24-hour profiles of adrenal steroids in healthy human subcutaneous tissue to characterize healthy variability without blood sampling. Methods: We used microdialysis, an ambulatory fraction collector and liquid-chromatography mass-spectrometry to obtain 72-point profiles of tissue free adrenal steroids over 24 hours in n=214 healthy volunteers. For validation, we compared tissue against plasma measurements in n=7 inpatient healthy volunteers. We used stationery statistics, time series analyses, and mathematical methods to characterise interindividual and intraindividual variability of these hormones at different times of the day. Results: There were no serious adverse events, and the method was well tolerated, allowing almost all normal activities to continue. In addition to cortisol, we identified daily and ultradian variation in free cortisone, corticosterone, 18-OHF, aldosterone, THF, and aTHF. Rhythmic hormones were highly correlated when measured across the day, especially cortisol with 18OHF (rs = 0.99), cortisol with cortisone (rs = 0.96) and cortisol and 18-OHF with corticosterone (rs = 0.96-0.97). There was a very strong correlation between mean values of cortisol and 18OHF with aldosterone (rs = 0.91-0.93), but aldosterone profiles were characterized by high interindividual variability. Tissue 18-OHF was the most highly correlated with plasma cortisol (rs 0.89, range 0.74—0.97, p&amp;lt;0.001), and 18-OHF phase was advanced with respect to tissue cortisol. The ratio of tissue cortisol:cortisone exhibited a stronger daily rhythm than in plasma, with cortisol concentrations often falling below cortisone in the late afternoon and early part of sleep.Using the data, we computed mathematically defined metrics (“dynamic biomarkers”) stratified by sex, age, and BMI to quantify individual variability of hormone rhythms. Provisional analysis suggests no evidence for an effect of sex on cortisol or 18OHF, but evidence for a small effect of BMI on total 24-hour cortisol, 18OHF, corticosterone, and aldosterone. Conclusions: These data provide, for the first time, an insight into the dynamics of adrenal steroids in tissue in real world setting and will serve normative reference data for establishing novel and improved biomarkers of endocrine disease. Presentation: Sunday, June 18, 2023

THU605 Impact Of Abnormal Circadian Cortisol Secretion On Bone Metabolism In Patients With Mild Autonomous Cortisol Secretion

Abstract Disclosure: J. Saini: None. R. Nathani: None. S. Singh: None. V. Fell: None. E. Atkinson: None. S. Achenbach: None. S. Khosla: None. I. Bancos: None. Background: Previous studies reported that both cortisol secretion and bone metabolism biomarkers follow a circadian pattern of secretion. Patients with mild autonomous cortisol secretion (MACS) demonstrate an increased risk of fractures. As most patients with MACS do not have increased cortisol production, we hypothesized that abnormal circadian cortisol secretion is associated with impaired bone metabolism. Objective: To compare the circadian secretory pattern of bone metabolism biomarkers in relation to cortisol circadian secretion in patients with MACS versus referent subjects. Methods: We conducted a pilot cross-sectional study of patients with MACS and referent subjects. MACS was diagnosed in patients with adrenal adenomas based on an abnormal 1 mg dexamethasone suppression test (cortisol &amp;gt;1.8 mcg/dL). Referent subjects with available abdominal imaging within 5 years and adrenal disorder were recruited from the community. Participants were admitted to the clinical research unit for blood sampling every 2 hours over 24h period. Measurements included total and free cortisol, calcium, parathyroid hormone (PTH), osteocalcin, amino-terminal propeptide type 1 collagen (PINP), and carboxy-terminal telopeptide of type 1 collagen (CTX). Subjects with disorders or medication affecting bone metabolism were excluded. Time periods of blood draw were categorized into the morning (6 to 12 hours), afternoon (14-18 hours) and night (20-2 hours). Delta (morning measurements/afternoon measurements) was calculated. Results: Subjects included 12 patients with MACS (median age 57, IQR 48-67, 83% women) and 10 referent subjects (median age 57, IQR 50-63, 80% women). The 24-hour area under the curve for total (10342 vs 9090 mcg/dL, p=0.468) and free cortisol (437 vs 329 mcg/dL, p=0.086) was no different between patients with MACS and referent subjects. However, the mean night total (6.7 vs 4.3 mcg/dL, p=0.056) and free cortisol (0.2 vs 0.1 mcg/dL, p=0.035) was higher in MACS vs referent subjects. The area under the curve for calcium, phosphorus, CTX, osteocalcin and PINP were similar between patients and referent subjects, however, the area under the curve for PTH was higher in patients vs referent subjects (mean 64179 vs 42602 pg/mL, p=0.021). Both delta total cortisol (mean 8.6 vs 5.5, p=0.01) and delta PTH (mean -1.5 vs 4.2, p=0.051) was higher in referent subjects vs patients with MACS. Conclusion: When compared to referent subjects, patients with MACS have similar 24-hour cortisol production but demonstrate an increase in night-time cortisol secretion and a blunting of diurnal cortisol (lower morning/afternoon cortisol). Patients with MACS have higher PTH production overall, as well as an abnormal diurnal PTH secretion. Noted abnormalities in PTH may contribute to the MACS-associated impairment in bone health. Presentation: Thursday, June 15, 2023

FRI255 Polyglandular Autoimmune Syndrome Type 2 Presenting With Severe Hyponatremia

Abstract Disclosure: A. West: None. A.N. Davis: None. A. Warner: None. S. Salcin: None. Introduction: Polyglandular autoimmune syndrome type 2 (PAS-2) is a polygenic autoimmune syndrome which presents with two or more specific autoimmune manifestations. The combination of Addison’s disease and Hashimoto’s thyroiditis has been referred to as Schmidt Syndrome. Treatment of hypothyroidism without recognition of concomitant adrenal insufficiency may result in exacerbation of adrenal insufficiency (AI). We present a case of PAS-2 presenting with severe hyponatremia. Case: A 28-year-old male presented to an outside hospital with fatigue and weakness. His sodium was 121mEq/L and TSH &amp;gt;356mcIU/mL, and he was admitted for management of hyponatremia. He was started on oral levothyroxine, urea tablets, and fluid restriction. In the weeks following discharge, the patient had worsening fatigue, weakness, dizziness, nausea, and weight loss, and he presented to our ED. His vital signs were stable without tachycardia or hypotension. He was lethargic but fully oriented. Hyperpigmented areas of the tongue and nose were noted. Laboratory evaluation revealed sodium 111mEq/L, potassium 4.5mEq/L, TSH 43.56 (0.4-4.7mcIU/mL), and free T4 of 1.12 (0.58-1.76ng/dL). He was admitted to the medical intensive care unit for management of severe hyponatremia. Repeat sodium was 112mEq/L with serum cortisol 4.57mcg/dL. Hypertonic saline was given without improvement in hyponatremia. Cortisol level was determined to be inappropriately normal in the setting of severe hyponatremia. Cosyntropin stimulation test was performed with baseline, 30 minute, and 60 minute cortisol levels of 5.31, 6.17, and 6.26, respectively, consistent with AI. ACTH level was not obtained due to the blood sample being hemolyzed. Other results include positive 21-hydroxylase antibody, TPO antibody &amp;gt;900 IU/mL, and undetectable GAD 65 antibody. He received IV stress dose steroids with resolution of his symptoms and his hyponatremia. Oral hydrocortisone replacement therapy was started prior to discharge. Discussion: Patients with one autoimmune endocrinopathy are at risk of developing a second one. Our patient’s hyponatremia was initially attributed to his hypothyroidism without recognition of concomitant AI. Early diagnosis of AI is important prior to initiation of levothyroxine, as treatment of hypothyroidism may exacerbate AI. The sodium level in our patient worsened from 121mEq/L at the previous admission to 111mEq/L when he presented to our hospital, related to worsening of his AI while being treated for his hypothyroidism. Timely diagnosis of associated AI requires high index of suspicion in such patients, particularly in patients with signs or symptoms which may overlap with hypothyroidism, such as hyponatremia in our patient. AI should be considered in any patient who presents with hyponatremia, even those who lack other classic features such as hypotension, hyperkalemia, and hypoglycemia. Presentation: Friday, June 16, 2023

FRI268 Late Onset Polyglandular Autoimmune Syndrome Type 2

Abstract Disclosure: M.S. Nicholson: None. A. Barnett: None. A 66-year old white female was admitted for weakness, acute kidney injury, and hypotension. This is her 3rd hospital or ER visit in the last 12 months for similar complaints. She has a 25 year history of type 2 diabetes on insulin and oral therapy and 30 year history of hypothyroidism on levothyroxine 75 mcg daily. She was on oral estrogen replacement therapy for post-menopausal symptoms with a hysterectomy in her early 50s. She has a sister with type 2 diabetes on oral meds and hypothyroidism. She has a brother with type 1 diabetes. Her serum sodium was 135 mmol/L (135-145), potassium was 5.4 mEq/L (3.5 -5.1), and calcium was 9.2 (8.5-10.1). Her Creatinine was 1.2 with a GFR of 48. A random cortisol in the ED was 9.2 (no ref range). Blood pressure was low and she was tachycardic and her weight was 68 kg. She was a well developed female with a a tanned complexion. Areas of vitiligo were noted on her arms. A cosyntropin stimulation test was done midday with a baseline, 30, and 60 minute cortisol levels of 9.2, 8.8, and 9.3 respectively. Baseline ACTH was 877.6 pg/mL (7.2-63.6). Her TSH was 4.09 mIU/mL (0.358-3.74) and free T4 was 1.29 ng/dL (0.76-1.46). DHEA-S was 14 mcg/dL (13-130). She was started on stress dose steroids with rapid improvement in BP, hyponatremia, and symptoms. GAD-65 antibodies were above 250 IU/mL and 21-hydroxylase antibodies were positive. Her TPO antibodies were negative. Non-insulin diabetes medications were stopped and she was discharged home after stabilization on prednisone 5 mg daily and fludrocortisone 0.1 mg daily. This patient has an atypical presentation of polyglandular autoimmune syndrome type 2 (PAS2). She presented with an Addisons crisis at the age of 66. She was already diagnosed with hypothyroidism and insulin requiring diabetes and evidence of vitiligo. A majority of patients with PAS2 are female and present in their 20s to 40s with primary adrenal insufficiency and primary hypothyroidism. Her initial manifestation was hypothyroidism and then diabetes and vitiligo with adrenal insufficiency many years later. Her random cortisol was not suppressed and this lead to a delay in her diagnosis. This was likely due to oral estrogen therapy raising cortisol-binding globulin. Her elevated baseline ACTH and lack of response to ACTH stimulation confirmed her diagnosis of primary adrenal insufficiency. An ACTH stimulation test was repeated as an outpatient with similar response. This case highlights the importance of provocative testing for adrenal disorders and testing for autoimmune causes of endocrine disorders when patients are not responding as expected. Presentation: Friday, June 16, 2023

Anorexia nervosa and adrenal hormones: a systematic review and meta-analysis.

Anorexia nervosa is a primary psychiatric disorder characterized by self-induced negative energy balance. A number of hormonal responses and adaptations occur in response to starvation and low body weight including changes in adrenocortical hormones. Our objective was to systematically review adrenocortical hormone levels in anorexia nervosa. We searched MEDLINE and EMBASE for studies that reported at least one adrenocortical hormone, including dehydroepiandrosterone (DHEA), DHEA-sulphate (DHEA-S), progesterone, 17-hydroxyprogesterone, pregnenolone, cortisol (serum, urine, cerebrospinal fluid, and hair sample), aldosterone, androstenedione, and testosterone in patients with anorexia nervosa and normal-weight healthy controls from inception until October 2021. Means and standard deviations for each hormone were extracted from the studies to calculate a mean difference (MD). A pooled MD was then calculated by combining MDs of each study using the random-effects model. We included a total of 101 studies with over 2500 females with anorexia nervosa. Mean cortisol levels were significantly higher in anorexia nervosa as compared to normal-weight controls for multiple forms of measurement, including morning cortisol, 12-hour and 24-hour pooled serum cortisol, 24-hour urine cortisol, and after an overnight dexamethasone suppression test. In contrast, mean serum total testosterone and DHEA-S levels were significantly lower among patients with anorexia nervosa. Women with anorexia nervosa have higher cortisol levels and lower DHEA-S and testosterone levels compared to women without anorexia nervosa. This finding is important to consider when evaluating low-weight women for disorders involving the adrenal axis, especially Cushing's syndrome.