Hydrocortisone Replacement Research Articles

A quantitative modeling framework to understand the physiology of the hypothalamic-pituitary-adrenal axis and interaction with cortisol replacement therapy.

Congenital adrenal hyperplasia (CAH) is characterized by impaired adrenal cortisol production. Hydrocortisone (synthetic cortisol) is the drug-of-choice for cortisol replacement therapy, aiming to mimic physiological cortisol circadian rhythm. The hypothalamic-pituitary-adrenal (HPA) axis controls cortisol production through the pituitary adrenocorticotropic hormone (ACTH) and feedback mechanisms. The aim of this study was to quantify key mechanisms involved in the HPA axis activity regulation and their interaction with hydrocortisone therapy. Data from 30 healthy volunteers was leveraged: Endogenous ACTH and cortisol concentrations without any intervention as well as cortisol concentrations measured after dexamethasone suppression and single dose administration of (i) 0.5-10mg hydrocortisone as granules, (ii) 20mg hydrocortisone as granules and intravenous bolus. A stepwise model development workflow was used: A newly developed model for endogenous ACTH and cortisol was merged with a refined hydrocortisone pharmacokinetic model. The joint model was used to simulate ACTH and cortisol trajectories in CAH patients with varying degrees of enzyme deficiency, with or without hydrocortisone administration, and healthy individuals. Time-dependent ACTH-driven endogenous cortisol production and cortisol-mediated feedback inhibition of ACTH secretion processes were quantified and implemented in the model. Comparison of simulated ACTH and cortisol trajectories between CAH patients and healthy individuals showed the importance of administering hydrocortisone before morning ACTH secretion peak time to suppress ACTH overproduction observed in untreated CAH patients. The developed framework allowed to gain insights on the physiological mechanisms of the HPA axis regulation, its perturbations in CAH and interaction with hydrocortisone administration, paving the way towards cortisol replacement therapy optimization.

Linear growth in children and adolescents with congenital adrenal hyperplasia.

Congenital adrenal hyperplasia (CAH) is a relatively common disorder and one of the most challenging conditions seen by pediatric endocrinologists. Poor linear growth in CAH has been recognized for many years. There are new insights to explain this abnormality and shed light on strategies to promote normal growth. Published data suggest that the dose of hydrocortisone during two critical periods of rapid growth, namely infancy and at puberty, has a fundamental effect on growth velocity, and by definition adult height. To prevent over-treatment, hydrocortisone dosage should remain within the range of 10-15 mg/m 2 body surface area per day. Precursor steroids such as 17-hydroxy progesterone (17OHP) should not be suppressed to undetectable levels. In fact, 17OHP should always be measurable, as complete suppression suggests over-treatment. CAH is a challenging disorder. High-quality compliance within the consultation setting, with the patient seeing the same specialist at every visit, will be rewarded by improved long-term growth potential. Quality auxological monitoring can avoid phases of growth suppression. New therapy with CRH receptor antagonists may lead to a more nuanced approach by allowing fine tuning of hydrocortisone replacement without the need to suppress ACTH secretion.

Abstract PS14-03: Delayed and post-treatment immune toxicities in patients with breast cancer receiving immune checkpoint inhibitors

Abstract Background: Immune checkpoint inhibitors (ICI) have improved outcomes in patients (pts) with breast cancer, however identification and management of immune-related adverse events (irAE) remains challenging. Delayed irAE have been observed, occurring even after ICI cessation. Prior analyses of delayed irAE have focused on patients with melanoma, lung, and head & neck cancer but data in patients with breast cancer are lacking. Methods: We identified pts with breast cancer who received ICI at our institution between 2012 and 2022 using pharmacy administration records. Charts were reviewed for delayed and post-treatment irAE. Delayed irAE were defined as occurring >90 days after ICI start; post-treatment irAE were defined as occurring >60 days after ICI discontinuation. Events were categorized as irAE if provider notes indicated that the toxicity was related to or possibly related to ICI. Results: 320 consecutive pts with breast cancer (219 metastatic, 96 localized disease) underwent treatment with ICI, of which 79 (25%) developed delayed irAE (40 with metastatic disease, 39 with localized disease). 54 pts had triple negative breast cancer (TNBC), 22 had hormone receptor positive (HR+) disease, and 4 had HER2+ disease. 44 pts received ICI on a clinical trial. The median number of ICI doses was 8, and the median length of follow-up after the first ICI infusion with 29 months. For delayed iRAE, median time to onset was 183 days (range 91-1800 days) with a total of 103 delayed irAE events (see table). 24 pts (7.5%) developed a post-treatment irAE with a total of 27 events. For post-treatment irAE, median time to onset was 112 days after ICI cessation (range 69-1100 days) and median time on ICI was 63 days (range 22-1724 days). 11 of 24 patients who experienced a post-treatment irAE also experienced an irAE while on treatment. Hypothyroidism, colitis, adrenal insufficiency, and hepatitis were the most common irAE at all time points. Rash primarily occurred while still on ICI. All irAE at any time point either self-resolved, resolved with systemic steroids, or continued with indefinite hormone replacement. 45 irAE required systemic steroids, not including hydrocortisone replacement for adrenal insufficiency. There were no grade 4 or 5 irAEs. Conclusions: This is the first evaluation of delayed/post-treatment irAE in a large cohort of patients with breast cancer. 79 pts (25%) experienced delayed irAEs occurring ≥ 90 days after ICI start, with median time to onset of 183 days. 89% of patients with delayed irAE also experienced an irAE at an earlier time point, indicating that early irAE may be a risk for delayed irAE. 24 pts (7.5%) experienced post-treatment irAE with median onset of 121 days after ICI cessation. Diagnosis of delayed irAE requires heightened awareness and prompt treatment. Future work is needed to identify key clinical and molecular markers that predict risk for delayed irAE to better inform treatment & monitoring. Table. Parameter Number of pts (%) Total pts receiving an ICI 320 Delayed irAE 79 (25) >1 delayed irAE 21 (27% of pts with delayed irAE) Patients with delayed irAEs who also had irAE occurring < 90 days after ICI start 70 (89% of pts with delayed irAE) Post-treatment irAE 24 (7.5) Types of delayed irAE (>90 days after ICI start) Any Grade Grade 3 Hypothyroidism 24 (23) 1 (1) Colitis/Diarrhea 19 (18) 3 (3) Rash 14 (14) 0 Adrenal Insufficiency/Hypophysitis 11 (11) 4 (4) Hepatitis 10 (10) 3 (3) Pneumonitis 4 (4) 1 (1) Arthralgia 4 (4) 0 Diabetes mellitus 3 (3) 0 Mucositis 2 (2) 1 (1) Neuropathy 2 (2) 0 Neutropenia 2 (2) 1 (1) Bronchitis 1 (1) 0 Fever 1 (1) 0 Neuromuscular Weakness 1 (1) 0 Autoimmune Hemolytic Anemia 1 (1) 1 (1) Myocarditis 1 (1) 1 (1) Acid Reflux 1 (1) 0 Sarcoidosis 1 (1) 0 Vitiligo 1 (1) 0 Types of post-treatment irAE (>60 days post ICI cessation) Any Grade Grade 3 Hypothyroidism 7 (26) 2 (7) Colitis 7 (26) 3 11) Adrenal Insufficiency/Hypophysitis 6 (22) 1 (4) Hepatitis 4 (15) 3 (11) Arthralgia 1 (4) 0 Neuropathy 1 (4) 0 Neutropenia 1 (4) 1 (4) Rash 1 (4) 0 Citation Format: Saya Jacob, Samantha Fisch, Carolyn Face, Laura Huppert, Zoe Quandt, Laura Quintal, Michelle Melisko, Melanie Majure, Jo Chien, Anne Blaes, Hope Rugo. Delayed and post-treatment immune toxicities in patients with breast cancer receiving immune checkpoint inhibitors [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS14-03.

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.

Acute heart failure in a neonate

The male patient, one day old, was admitted to the hospital due to hypoglycemia accompanied by apnea appearing six hours after birth. The patient had transient hypoglycemia early after birth, and acute heart failure suddenly occurred on the eighth day after birth. Laboratory tests showed significantly reduced levels of adrenocorticotropic hormone and cortisol, and pituitary magnetic resonance imaging was normal. Genetic testing results showed that the patient had probably pathogenic compound heterozygous mutations of the TBX19 gene (c.917-2A>G+c.608C>T), inherited respectively from the parents. The patient was conclusively diagnosed with congenital isolated adrenocorticotropic hormone deficiency caused by mutation of the TBX19 gene. Upon initiating hydrocortisone replacement therapy, cardiac function rapidly returned to normal. After being discharged, the patient continued with the hydrocortisone replacement therapy. By the 18-month follow-up, the patient was growing and developing well. In neonates, unexplained acute heart failure requires caution for possible endocrine hereditary metabolic diseases, and timely cortisol testing and genetic testing should be conducted.

Newborn screening-detected 21-hydroxylase deficiency: growth pattern is not associated with the genotype.

Normalizing growth in children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD-CAH) requires a long-term maintenance of a fragile balance between hydrocortisone (HC) replacement and androgen suppression. The growth pattern in children with 21OHD-CAH diagnosed by clinical symptoms has been evaluated in numerous retrospective studies. The aim of this study was to evaluate growth of patients with 21OHD-CAH detected by newborn screening (NBS), prior to clinical symptoms. Nation-wide NBS for 21OHD-CAH was implemented in the Czech Republic in 2006. Since then, 1,317,987 neonates were screened (2006-2017) and 21OHD-CAH was confirmed in 108 patients. Growth was evaluated as height-standard deviation score (SDS) at regular time-points, related to bone age and compared to recent population standards. In 88 patients, available data allowed long-term evaluation of growth, HC and fludrocortisone doses (in half-year intervals), with a median observation period of ten years. Body height in affected children was shorter between years 1-9 of life with a nadir at age 1-3 years. Their height did not differ from general population at the age 10-12 years. There were not found differences according to 21OHD-CAH severity. NBS is an effective secondary prevention tool for the early detection of 21OHD-CAH which improves growth patterns. A significant growth deceleration was observed during infancy and early childhood periods but with following height normalization. Growth pattern was not associated with the genotype of 21OHD, if patients have been detected by NBS.

Basal cortisol in relation to metyrapone confirmation in predicting adrenal insufficiency after pituitary surgery

PurposePituitary surgery can lead to post-surgical adrenal insufficiency with the need for glucocorticoid replacement and significant disease related burden. In patients who do not receive hydrocortisone replacement before surgery, at our center, an early morning plasma cortisol concentration using a cut-off value of 450 nmol/L 3 days after surgery (POD3) is used to guide the need for hydrocortisone replacement until dynamic confirmatory testing using metyrapone. The aim of this study was to critically assess the currently used diagnostic and treatment algorithm in patients undergoing pituitary surgery in our pituitary reference center.MethodsRetrospective analysis of all patients with a POD3 plasma cortisol concentration < 450 nmol/L who received hydrocortisone replacement and a metyrapone test after 3 months. Plasma cortisol concentration was measured using an electrochemiluminescence immunoassay (Roche). All patients who underwent postoperative testing using metyrapone at Amsterdam UMC between January 2018 and February 2022 were included. Patients with Cushing’s disease or those with hydrocortisone replacement prior to surgery were excluded.ResultsNinety-five patients were included in the analysis. The postoperative cortisol concentration above which no patient had adrenal insufficiency (i.e. 11-deoxycortisol > 200 nmol/L) was 357 nmol/L (Sensitivity 100%, Specificity 31%, PPV:32%, NPV:100%). This translates into a 28% reduction in the need for hydrocortisone replacement compared with the presently used cortisol cut-off value of 450 nmol/L.ConclusionEarly morning plasma cortisol cut-off values lower than 450 nmol/L can safely be used to guide the need for hydrocortisone replacement after pituitary surgery.

O-02 Inactivation of KDM1A with the concurrent presence of MGUS in a patient with GIP-dependent Cushing's syndrome and the vanishing effect of octreotide therapy

Abstract Introduction Glucose-dependent insulinotropic peptide (GIP)-dependent primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of Cushing's syndrome. It has germline genetic predisposition and requires for personalized approaches to investigation and therapy. We aimed to present the rare case of a GIP-dependent PBMAH patient with unusually severe cortisol secretion and a KDM1A inactivation with an accompanying haematological co-morbidity related to that mutation. Clinical Case A 41-year-old woman presented with a 5-kg weight gain in last 6 months, irritability and fatique. Physical examination revealed elevated blood pressure, increased supraclavicular fat pads, and abdominal obesity. The cortisol level was 25.9 (6.7-22.6) µg/dL in the morning, 16.9 µg/dL in the late night, and 6.5 µg/dL in the morning after an overnight 1 mg of dexamethasone. Urinary free cortisol (UFC) level was also elevated to 2150 (58-403) µg/24-h. The early morning plasma ACTH level was 1.5 (7-63) pg/mL. Abdominal imaging revealed 29×23 mm adenomas on the right and 46×35 mm on the left with high fat content. Cortisol was stimulated by the administration of mixed meals (+537%) but not by TRH, GnRH, metoclopramide or upright posture. The response to mixed meals was blunted by pretreatment with subcutaneous 100 mg octreotide. Following the patient's diagnosis of GIP-dependent PBMAH, octreotide LAR therapy was initiated. Although inducing a significant acute suppression of UFC and improvement in symptoms during the first 3 months, the UFC began to rise due to the resistance in the following period (Figure 1). After 9 months of octreotide LAR treatment, left adrenalectomy was performed according to the adrenal volumetric assessment. Histopathology was reported as diffuse macronodular adrenal hyperplasia without internodular atrophy. Even though the patient had a unilateral adrenalectomy, adrenal insufficiency occurred in the postoperative period. Subsequently, the patient has been closely monitored and followed up with a physiological, divided-dose hydrocortisone replacement regimen for 7 months. A germline heterozygous variant in the KDM1A gene in the patient's blood sample and a recurrent deletion in the short p arm of chromosome 1 harboring the KDM1A locus in the adrenal sample were identified. When screened for diseases associated with the KDM1A mutation, monoclonal gammopathy of undetermined significance (MGUS) was detected in the patient with mild anemia, and genetic counseling was also provided. Conclusion The management of GIP-dependent PBMAH remains controversial, and further therapeutic options are under investigation. Due to the very limited number of case reports and the heterogeneous nature of the disease, special features of our case, which are severe cortisol excess, accompanying MGUS, the vanishing effect of octreotide, and adrenal insufficiency after unilateral adrenalectomy, might contribute to the existing literature.Figure 1.Urinary free cortisol levels following octreotide therapyUFC: Urinary free cortisol, ULN: Upper limit normal, LAR: Long acting release

O-04 A diagnostic riddle of an adrenal incidentaloma

Abstract Clinical case A 78-year-old male underwent preoperative CT as transcatheter aortic valve implantation was planned. In addition to a 6 cm incidental mass in the right adrenal, it also revealed unspecific pulmonary nodules. The patient was referred to the Endocrine unit. Non-contrast adrenal CT demonstrated a heterogenous 6 cm tumor, &amp;lt; 10 HU. The patient had a history of psoriasis, type 2 diabetes mellitus, hypertension, chronic kidney disease, atrial fibrillation, peripheral artery disease, aortic stenosis and coronary artery disease. Clinical examination revealed no signs of Cushing's syndrome. First, normal blood metanephrine/normetanephrine concentrations confirmed that pheochromocytoma was ruled out. The possibility of a metastatic tumor mass was investigated by tumor biopsy, histopathology was compatible with an adrenocortical neoplasm, Ki67 2%. Further laboratory work-up is given in Table 1. How should the laboratory findings be interpreted? Primary aldosteronism was ruled out. Cortisol was not suppressed on 1mg DST, in contrast to perfectly normal 24h urinary free cortisol. Late night salivary cortisol (LNSC) was markedly increased, 1210 nmol/l and low ACTH concentration further suggested true hypercortisolism. Does the patient suffer from hypercortisolism? The patient had no clinical signs of Cushing syndrome, albeit cardiometabolic diseases. False positive DST and LNSC results were suspected. Indeed, the patient was using 1% hydrocortisone lip lotion. On repeat screening after discontinuation of hydrocortisone, LNSC was 3.8 nmol/l, and DST remained positive (258nmol). The patient was diagnosed with autonomous cortisol excess (MACS) (1). Should the patient undergo surgery for the right adrenal mass? MACS in combination with relevant co-morbidities and large tumor size indicated surgery (1), which the patient consented to. After surgery, cortisol concentrations remained suppressed which prompted hydrocortisone replacement therapy. Final pathology review classified the tumor as an adenoma, Weiss Score 0/9 and Ki-67 2%. Conclusion False positive cortisol screening tests are common and must be ruled out before surgery. For DST, common explanations are exogenous glucocorticoid use, drugs that accelerate dexamethasone metabolism and estrogen induced increase in CBG. The most common pitfalls for LNSC are deranged circadian rhythm and exogenous hydrocortisone. Reference (1). Fassnacht el al. European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas. European Journal of Endocrinology,2023; 189(1): G1–G42.Table 1

Hypopituitarism due to CNS Aspergillus Infection.

A 59-year-old man was admitted to our hospital with hyponatremia. An endocrine examination indicated panhypopituitarism, and magnetic resonance imaging revealed a mass-like lesion in the pituitary gland. Sinus endoscopy revealed a fungal mass in the sphenoid sinus, and the patient was diagnosed with hypopituitarism due to aspergillosis of the central nervous system (CNS). The patient's hyponatremia resolved with hydrocortisone replacement. Although the right internal carotid artery was eventually occluded, antifungal medications were administered for the aspergillosis, and the patient's general condition improved. The patient's CNS lesions have remained under control since discharge. This is the first case to suggest that ACTH secretion may be relatively preserved in Aspergillus-induced hypopituitarism.

Predictor of Steroid Replacement Duration after Removal of Cortisol-producing Adenoma.

Objective Cortisol-producing adenoma (CPA) is a major subtype of functional adrenal tumors. CPAs are generally treated with adrenalectomy; however, it is difficult to predict the ideal duration of glucocorticoid replacement after resection. This study explored pre-operative factors predictive of glucocorticoid replacement therapy duration after CPA resection. Mehtods This multicenter retrospective observational study was conducted as part of the Advancing Care and Pathogenesis of Intractable Adrenal Diseases in Japan (ACPA-J) from January 2006 to December 2015. Patients This study was conducted at 10 referral centers and included 124 patients who received hydrocortisone replacement therapy after adrenalectomy for CPA. Results The median duration of replacement therapy was 12 (interquartile range, 5-24) months. In the single regression analysis, the sex (P=0.04), morning ACTH level (P=0.02), morning serum cortisol level (P=0.003), midnight serum cortisol level (P<0.001), serum cortisol level after a 1-mg dexamethasone suppression test (P<0.001), presence of lumbar compression fracture (P=0.015), and Cushingoid appearance (P<0.001) were all significantly associated with the replacement therapy duration. In multiple regression analyses, the midnight serum cortisol level and presence of lumbar compression fracture were significantly correlated with the replacement therapy duration after adjusting for other parameters. Conclusion Our results suggest that high midnight serum cortisol levels, which cause persistent suppression of the HPA axis, contribute to a delay in HPA axis recovery. Lumbar compression fracture is an important symptom that reflects the severity and persistence of cortisol secretion.

Major immunophenotypic abnormalities in patients with primary adrenal insufficiency of different etiology.

Patients with primary adrenal insufficiency (PAI) suffer from increased risk of infection, adrenal crises and have a higher mortality rate. Such dismal outcomes have been inferred to immune cell dysregulation because of unphysiological cortisol replacement. As the immune landscape of patients with different types of PAI has not been systematically explored, we set out to immunophenotype PAI patients with different causes of glucocorticoid (GC) deficiency. This cross-sectional single center study includes 28 patients with congenital adrenal hyperplasia (CAH), 27 after bilateral adrenalectomy due to Cushing's syndrome (BADx), 21 with Addison's disease (AD) and 52 healthy controls. All patients with PAI were on a stable GC replacement regimen with a median dose of 25 mg hydrocortisone per day. Peripheral blood mononuclear cells were isolated from heparinized blood samples. Immune cell subsets were analyzed using multicolor flow cytometry after four-hour stimulation with phorbol myristate acetate and ionomycin. Natural killer (NK-) cell cytotoxicity and clock gene expression were investigated. The percentage of T helper cell subsets was downregulated in AD patients (Th1 p = 0.0024, Th2 p = 0.0157, Th17 p < 0.0001) compared to controls. Cytotoxic T cell subsets were reduced in AD (Tc1 p = 0.0075, Tc2 p = 0.0154) and CAH patients (Tc1 p = 0.0055, Tc2 p = 0.0012) compared to controls. NKCC was reduced in all subsets of PAI patients, with smallest changes in CAH. Degranulation marker CD107a expression was upregulated in BADx and AD, not in CAH patients compared to controls (BADx p < 0.0001; AD p = 0.0002). In contrast to NK cell activating receptors, NK cell inhibiting receptor CD94 was upregulated in BADx and AD, but not in CAH patients (p < 0.0001). Although modulation in clock gene expression could be confirmed in our patient subgroups, major interindividual-intergroup dissimilarities were not detected. In patients with different etiologies of PAI, distinct differences in T and NK cell-phenotypes became apparent despite the use of same GC preparation and dose. Our results highlight unsuspected differences in immune cell composition and function in PAI patients of different causes and suggest disease-specific alterations that might necessitate disease-specific treatment.

The golden ratio for cortisol replacement

The golden ratio for cortisol replacement

SAT291 Remote Monitoring Of Biometric, Proteomic, And Patient-reported Outcomes In Adrenal Insufficiency

Abstract Disclosure: A. Ben-Shlomo: None. B. Chazarin: None. G. Gresham: None. M. Choudhary: None. K. Barnhill: None. K. Haptonstall: None. J. Van Eyk: None. Background: Damaged hypothalamic-pituitary adrenal axis may result in adrenal insufficiency (AI) and require hydrocortisone replacement. Currently, there are no biometric or circulating biomarkers to assess hydrocortisone replacement adequacy. Dosing is based on symptomatology, often resulting in over- or undertreatment. Methods: We used remote monitoring precision health solutions to identify AI molecular and biometric biomarkers over 2 weeks. Using remote sampling devices (Mitra Neoteryx), 10-µL dried blood samples were collected weekly for protein analysis by AI subjects before and 5 hours after daily hydrocortisone doses and age- and sex matched adrenal sufficient (AS) subjects at approximately the same times. Continuous physical activity were measured with a wearable biosensor (Fitbit Charge HR) along with remote systolic (SBP) and diastolic (DBP) blood pressure and heart rate (HR) (Omron Evolv). Self-reported AddiQoL questionnaires were completed twice daily. For biometric endpoints and questionnaires, data are summarized as mean ± SD using two-sided t-tests, where a p value &amp;lt;0.05 is considered statistically significant. For proteomic analysis, median value was calculated, and statistical testing identified differentially expressed proteins (DEPs; FDR&amp;lt;5%). Results: Fifteen AI (6 primary AI [PAI] and 9 secondary AI [SAI] and 15 AS subjects completed the study. AI group mean age was 46.3±15.7 and AS was 41.7±13.2. In both groups, 80% were female. Adherence to home monitoring was 100% in AI subjects and &amp;gt;90% in AS (13/15 assessable for biometrics (activity and BP) and 14/15 for AddiQoL). SBP was lower in PAI (106.2±7.9/68.3±7.6 [n=5]) vs SAI (119.1±15.3/71.1±8.9 [n=8]; p=0.04). Nighttime BP (22:00-05:00) for both PAI (102.3±7.8/68.5±7.9) and SAI (101.2±8.2/63.8±9) were significantly lower than AS (115.5±15.6; p=0.04 and p=0.02, respectively). AI heart rate was lower vs AS at night (61.4±11.6 [n=13] vs 72.5±11.1 [n=11]; p=0.01), especially in PAI (57.7±5 [n=5]; p=0.001). Average daily activity was higher in AS than AI as measured by steps (9010 vs 7787; p=0.02), miles (3.94 vs 3.36; p=0.03) and stair flights (14.19 vs 9.85; p=0.01). On AddiQoL, AI subjects scored lower than AS subjects (126.8±18.1 vs 143.3±14.9, respectively; p&amp;lt;0.0001). Across all dried blood samples, 444 proteins were quantified. Comparing AI vs AS, 78 were identified before morning hydrocortisone dose vs 88 before afternoon dose. Forty-nine DEPs were commonly identified and showed the same regulation trends. Nine DEPs before and 18 DEPs after morning and afternoon dosing, respectively, were identified in AI. None of these DEPs were common, indicating potential blood proteome signature changes in the morning and in the afternoon. Conclusion: Remote monitoring of biometrics and blood proteome in AI is feasible and informative and may identify biomarkers to optimize hydrocortisone replacement therapy. Presentation: Saturday, June 17, 2023

SAT327 A Curious Case of Immune Checkpoint Inhibitor Induced Hypophysitis with Transient ACTH-dependent Hypercortisolism

Abstract Disclosure: M. Shi: None. F. AlRubaish: None. N. Gupta: None. V. Larouche: None. S. Christopoulos: None. The use of immune checkpoint inhibitors (ICI) has increased exponentially over the last decade as these agents have shown to substantially improve the prognosis in multiple advanced malignancies. Despite these important clinical benefits, ICI are associated with many immune-related adverse events (irAE). Endocrinopathies are the most frequent irAE and include autoimmune thyroid disorders, hypophysitis and primary adrenal insufficiency. These endocrinopathies often require long-term surveillance and hormone supplementation. We report a relatively novel irAE case of transient central hypercortisolism that progressed to hypopituitarism. A 72-year-old woman with metastatic melanoma on combined ICI therapy of nivolumab-ipilimumab developed subclinical hyperthyroidism (TSH &amp;lt;0.02 mU/L [reference range (RR) 0.40-4.50 mU/L]; FT4 20.2 pmol/L [RR 9.0-26.0 pmol/L]) eight weeks following initiation of her immunotherapy. At week 11, she was found to have refractory hypokalemia (initial potassium at presentation 2.3 mmol/L RR 3.5-5.5 mmol/L) and metabolic alkalosis (pH 7.57 [RR 7.35-7.45]; bicarbonate 39 mmol/L [RR 22-31 mmol/L]). Physical exam was unremarkable for Cushingoid features. Subsequent investigations revealed central hypothyroidism (TSH 0.02 mU/L [RR 0.40-4.50 mU/L]; FT4 8.1 pmol/L [RR 9.0-26.0 pmol/L]) and levothyroxine replacement was started. She also had evidence of hypogonadotropic hypogonadism (FSH 4.2 U/L [postmenopausal RR 25.8-143.9 U/L]; LH 1.5 U/L [postmenopausal RR 13.2-45.7U/L]) and central hypercortisolism with a morning cortisol of 1082 nmol/L [RR 172-497 nmol/L] and an ACTH level of 18.3 pmol/L [RR 1.6-13.9 pmol/L]. The low dose dexamethasone suppression test was not suppressed (morning cortisol at 983 nmol/L). She underwent imaging studies of her abdomen and brain which revealed normal adrenal and pituitary glands, respectively. Close pituitary function monitoring during endocrinology follow-up revealed persistent elevation of cortisol and ACTH levels until week 15, then a subsequent decline in both cortisol and ACTH levels for which she started hydrocortisone replacement. Further follow-up blood work revealed morning cortisol levels below 50 nmol/L [RR 172-497 nmol/L] with undetectable ACTH levels from week 16 onwards. The hydrocortisone and levothyroxine replacement were continued, and the patient remained asymptomatic throughout her follow-ups. This case highlights that a transient episode of ACTH dependent hypercortisolism may be an early marker prior to the development of central adrenal insufficiency from ICI-related destructive immune hypophysitis. Furthermore, our report highlights that physicians and other healthcare professionals should remain vigilant in monitoring laboratory progression in these patients, as early recognition facilitated timely management in our patient and prevented complications. Presentation: Saturday, June 17, 2023

FRI261 A Case Of Cushing Syndrome And Hyperandrogenism Secondary To An Adrenal Cortical Oncocytoma

Abstract Disclosure: E. Hall: None. S. Gupta: None. J. Lee: None. Background: Adrenal cortical oncocytomas are rare neoplasms that are often non-functional, but there have been case reports of associated hypercortisolism, hyperandrogenism, and in even rarer cases, multiple hormonal excesses. Clinical Case: A 30 year old woman with history of hypertension, prediabetes and obesity presented with 3 years of oligomenorrhea, hirsutism, weight gain, and voice deepening. She did not take any medications and had no family history of endocrine diseases. Labs revealed hyperandrogenism: elevated total testosterone of 390 ng/dL and 435 ng/dL (nl 6-82), suppressed FSH of 0.2 mIU/mL (nl 1.7-21.5) and LH of &amp;lt;0.1 mIU/mL (nl 1.0-95.6), normal DHEA-S of 290 ug/dL (nl 98.8-340). Morning 17-hydroxyprogesterone was elevated to 944 ng/dL and increased to 1031 ng/dL (nl 23-431) on ACTH stimulation test, which did not meet diagnostic criteria for non-classical congenital adrenal hyperplasia. Also, genetic testing for CYP21A2 gene mutations was negative. Pelvic ultrasound was unremarkable. CT of the adrenal glands showed a 4.6 x 3.8 x 4.4 cm mildly heterogeneous left adrenal mass that measured 35 HU on non-contrast images with absolute washout of 50% and relative washout of 31%. The mass was concerning for malignancy based on HU &amp;gt;20, size &amp;gt;4cm, and 50% contrast washout (borderline). Overnight 1mg dexamethasone suppression test showed non-suppressed morning cortisol of 7.1 ug/dL (nl &amp;lt;1.8), with dexamethasone level of 246 ng/dL (nl 180-550) and ACTH of &amp;lt;5 pg/ml (nl 6-50). Twenty four hour urinary free cortisol level was slightly elevated to 52.3 mcg/24h (nl 4-50). Plasma metanephrines and aldosterone/renin ratio were normal. The patient underwent left laparoscopic adrenalectomy without complications. Pathology was consistent with adrenal cortical oncocytoma. Post-operatively, morning cortisol was &amp;lt;0.3 ug/dL, so she was started on hydrocortisone replacement twice daily but was tapered off within three months. Three weeks after surgery, total testosterone was &amp;lt;8 ng/dL. Two months after surgery, her menstrual cycles resumed. Fifteen months after surgery, she had regular menstrual cycles, 20 lb weight loss, resolution of hirsutism, hypertension and prediabetes. Conclusions: Adrenal cortical oncocytomas are rare tumors of the adrenal glands that should be considered in the differential for large adrenal tumors that appear suspicious for malignancy on imaging. They may or may not be functional, and in this case, the tumor secreted both androgens and cortisol. Although androgen-secreting tumors are frequently malignant, such as adrenocortical carcinomas, androgen-secreting oncocytomas are generally considered benign. However, there have been rare reports of malignant oncocytomas and oncocytomas of uncertain malignant potential. Presentation: Friday, June 16, 2023

FRI248 A Case of Cyclic Cushing’s Disease With No Peripheral ACTH Response But A Marked Inferior Petrosal Sinus ACTH Response After Desmopressin Administration

Abstract Disclosure: M. Guay-Gagnon: None. R. Cheng: None. N. Younes: None. A. La Fontaine: None. S. Larose: None. É. Thérasse: None. C. Beauregard: None. A. Lacroix: None. Background: Desmopressin is commonly used for the diagnosis of Cushing’s disease (CD) especially when CRH is unavailable. We report a case of CD with no peripheral ACTH response but with an unexpectedly marked ACTH and prolactin (PRL) response in inferior petrosal sinus sampling (IPSS) performed with desmopressin. Following failure of pituitary surgery, cabergoline was introduced, which rapidly induced central adrenal insufficiency (AI). Case Report: A 32-y.o. man was referred to our center for Cushing’s syndrome (CS). Over the last years he had developed diabetes, hypertension, hypokalemia, osteoporosis, obesity, and an overt Cushingoid appearance. Morning cortisol was variable with values up to 8065 nmol/L (292 μg/dL) with elevated ACTH of 63 pmol/L (285 pg/mL). The 1 mg dexamethasone suppression test (DST), 24-hour urinary free cortisol (up to 422 x ULN) and bedtime salivary cortisol (up to 74 x ULN) were elevated. The 4 mg IV DST showed partial cortisol suppression, but a very elevated value of 3750 nmol/L (136 μg/dL) the following morning. Desmopressin (10 mcg IV) stimulation test showed no response: ACTH went from 3.8 pmol/L (17.3 pg/mL) to 3.9 pmol/L, and cortisol, from 688 nmol/L (25 μg/dL) to 622 nmol/L. Pituitary MRI, thoracic CT and DOTATATE PET/CT identified no lesion; abdominal CT showed bilateral adrenal hyperplasia. IPSS with desmopressin stimulation identified a pituitary origin with central/peripheral (C/P) ACTH ratios that rose from 7.1 to 34.2 on the left. PRL increased by 83% in left IPSS after desmopressin, while peripheral ACTH and PRL remained stable. During pituitary exploration, the surgeon suspected a tumor on the left, but pathology showed normal pituitary tissue. Hypercortisolism persisted with partial DI requiring oral desmopressin, and cabergoline 0.5 mg twice weekly was initiated. Two weeks later, he was admitted with nausea, vomiting, lethargy, hypotension, hyponatremia, hyperkalemia and a negative septic evaluation. Morning cortisol was 233 nmol/L (8.4 μg/dL), abnormally low in this context. His condition resolved with IV hydrocortisone and fluid resuscitation. ACTH was not measured initially but was 2 x ULN a few weeks later and 4 mg IV DST showed an early cortisol and ACTH rebound. In view of recurrent hypercortisolism, the patient underwent bilateral adrenalectomy resulting in rapid clinical remission. Under hydrocortisone replacement, his most recent ACTH was 21 pmol/L. Conclusions: This is the first report of a petrosal sinus ACTH response to desmopressin without any peripheral response, suggesting a central source of ACTH. Thus, the use of desmopressin during IPSS should still be attempted in patients with no prior peripheral response. It is unclear whether the acute AI episode was due to a combination of nadir of cyclic CD or partial apoplexy and response to cabergoline of a residual corticotroph tumor with desmopressin induced prolactin co-secretion. Presentation: Friday, June 16, 2023

FRI343 A Case Of Postpartum Adrenal Crisis Secondary To Empty Sella

Abstract Disclosure: A. Alzenaidi: None. Empty sella occurs when the pituitary gland appears shrunken or invisible and CSF fills the sella turcica space. It is commonly defined in the radiology literature as an incidental finding of no clinical significance, but an association with sequalae of lymphocytic hypophysitis (LH) was observed in a mouse model of the disease. However, patient data on the development of empty sella are scant and present later in life.To our knowledge, this is the second case of postpartum empty sella with clinically suspected LH and early presentation within 2 yr postpartum. A 31-year-old woman presented to our endocrine clinic for pituitary evaluation. She was 16 months post-spontaneous vaginal delivery with no history of excessive bleeding or blood transfusion. Her pregnancy was uneventful except for headache without visual changes after the thirty-fifth week, which improved with nasal steroid spray. Four to six weeks postpartum, she presented to her primary care physician with palpitations, fatigue and weight loss. Labs showed TSH, 0.001 mIU/mL (0.3-4.2); free T4, 30.98 pmol/L (9-19); free T3, 23.04 pmol/L (2.6-5.7); and thyroid peroxidase antibodies, 512.6 IU/mL (&amp;lt;5.6). Thyroid function tests improved after a short course of carbimazole, although without significant improvement of her symptoms. At 10 months postpartum, she presented to the ED with worsening fatigue, weight loss, vomiting and dizziness. Further history revealed oligomenorrhea and an inability to lactate since delivery. On exam, her heart rate was 100 b/m, respiratory rate was 20 b/m, BP was 90/50 mmHg, and temperature was 38.8 C. Labs showed WBC, 4.26 x 103/µL (4-11); Hb, 9.9 g/dL (11.8-14.8); PLT, 181 x 103/µL (150-450); Na, 136 mEq/L (135-145); K, 3.6 mEq/L (3.5-5.1); HCO3, 20 mmol/L (22-29); creatinine, 62 µmol/L (49-90); lactate, 0.82 mmol/L (0.5-2.2); FSH, 6.16 IU/L; prolactin, &amp;lt; 12.6 mIU/L (110-564) (prolactin prepregnancy was 233 mIU/L); TSH, 6.7 (0.3-4.2); free T4, &amp;lt;5.15 pmol/L (9-19); ACTH, 0.22 pmol/L (1.03-10.73); cortisol, 50.3 nmol/L (1.82 µg/dl); and peak cortisol after 250 mcg ACTH stimulation test, 223.5 nmol/L (8.1 µg/dl). She was treated with intravenous fluids and hydrocortisone. Pituitary MRI showed marked compression of the pituitary tissue with concave superior margins due to partially empty sella. She was maintained only on hydrocortisone replacement. During follow-up, her menstrual cycle resumed regularly, and fatigue and thyroid function improved (TSH, 2.65 µIU/ml; free T4, 12.13 pmol/L). Our patient had autoimmune thyroiditis with positive TPO antibodies, and it is possible that she had coexistent LH. LH typically presents as a pituitary mass; however, our patient had empty sella.In conclusion, the development of empty sella in this case suggests that postpartum atrophy of the pituitary gland can be life threatening if associated with hypopituitarism. Early recognition could prevent serious consequences. Presentation: Friday, June 16, 2023

FRI196 Non-Hemorrhagic Adrenal Infarction in Pregnancy with Tuberous Sclerosis

Abstract Disclosure: A. Mahaldar: None. H. Al Jumaili: None. S.R. Campbell: None. M.Z. Baker: None. Background: Non hemorrhagic adrenal infarction is a rare diagnosis in pregnancy with less than 20 cases reported in literature so far. No cases have been reported in patients with tuberous sclerosis. Most patients present with abdominal pain. Clinical Case: 29 year old woman G2P1 presented at 35 weeks gestation with right upper quadrant pain. She reported two episodes of dizziness in first trimester but otherwise had an uneventful pregnancy prior to presentation. First pregnancy was uncomplicated. Past medical history included asymptomatic tuberous sclerosis. No previous history of blood clots. Physical examination revealed a distended abdomen appropriate for gestational age and right upper quadrant tenderness to palpation. Initial laboratory data was unremarkable except for leukocytosis with WBC 16.6 k/mm3 (4-11 k/mm3). Normal electrolytes and liver function tests. Abdominal ultrasound revealed cholelithiasis without evidence of acute cholecystitis and unremarkable renal findings. CT abdomen pelvis with contrast showed thickening with surrounding stranding of right adrenal gland suggesting acute adrenal infarction and multiple pancreatic cysts. 8 am cortisol was 4.9 mcg/dl (4.1-16.6 mcg/dl) and ACTH was 23 pg/ml (7.2-63.3 pg/ml). Patient had received 2 doses of betamethasone due to concern for preterm delivery at 48 hours and 36 hours prior to this blood draw. Hypercoagulable panel was sent prior to starting enoxaparin. Elevated Factor VIII &amp;gt;150% (50 to 150%) was noted as expected in pregnancy. Lupus anticoagulant was weakly positive with LA sensitive PTT 50.1 (0 to 51.9 sec). Anticardiolipin antibody and beta 2 glycoprotein antibody were normal. Patient was treated with hydrocortisone 15 mg by mouth daily and full dose enoxaparin for anticoagulation. At one month follow up 8 am cortisol was 24 mcg/dl. Hydrocortisone replacement was discontinued. Labor was uncomplicated with vaginal delivery at 38 weeks gestation. Day 1 postpartum at 7:30 AM cortisol was 20.94 mcg/dl. Patient was discharged home in a stable condition with continued anticoagulation with enoxaparin and no further hydrocortisone treatment. Conclusion: We present a case of non hemorrhagic adrenal infarction in a pregnant patient with tuberous sclerosis. Adrenal infarction without hemorrhage is rare. Anatomy of adrenal gland makes it prone to microvascular thrombosis and infarction in a thrombotic state because of single draining vein for venous drainage. Pregnancy as a hypercoagulable state has been previously associated with non hemorrhagic adrenal infarction in few case reports. Whether tuberous sclerosis played any role in our patient’s pathogenesis remains unclear as there are no data or case reports linking the two. In conclusion, the diagnosis of non hemorrhagic adrenal infarction needs to be considered in hypercoagulable or pregnant patients presenting with abdominal pain. Presentation: Friday, June 16, 2023

FRI243 Hypertension And Virilization In A 4 Year Old Female

Abstract Disclosure: E. Ismail: None. J.L. Miller: None. A.V. Bernier: None. Background: Congenital adrenal hyperplasia (CAH) is the most common cause of virilization of an XX female neonate. More than 95% of CAH cases are due to 21 hydroxylase deficiency which is detected in the newborn screen by detection of elevated 17 hydroxyprogesterone (17 OHP). 11 beta hydroxylase deficiency (11 BOHD) is the second most common cause of CAH, but considered extremely rare accounting for only 0.2-8% of cases. 11-BOHD is not part of the newborn screen, as it does not present with life-threatening salt wasting crisis. Hypertension (HTN) is observed in 2/3 of cases and is due to mineralocorticoid excess in the form of deoxycorticosterone (DOC). Therefore, 11-BOHD should be strongly considered in a virilized female with HTN and accelerated growth. Clinical case: 4-year-old female admitted for evaluation of severe persistent HTN. She had surgical repair of posterior labial fusion at 5 months of age. She was seen at 21 months of age for concerns of precocious puberty and virilization. Her work up included XX karyotype, 17 OHP and electrolytes within normal limits, however, she had an elevated DHEAS and testosterone level, with a bone age of 5 years at 21 months of age. Hypertension was recorded at the visit, but she was lost to follow up. At a primary care appointment her blood pressure was notably elevated, so she was sent to the ED. On admission, she was found to have both weight and height &amp;gt;99% for age, hyperpigmentation of gums and scars, and virilization (clitoromegaly with tanner 3 pubic hair). She had no thelarche. Initial hormonal evaluation revealed prepubertal gonadotropins, low aldosterone and low plasma renin activity. High dose ACTH stimulation test revealed elevated 11 deoxycortisol and 11 deoxycorticosterone levels. Her peak stimulated cortisol was inadequate at 8.7 mcg/dl (normal=&amp;gt;18 mcg/dl). Genetic testing for CAH revealed compound heterozygosity for 2 variants in the CYP11B1 gene, confirming the diagnosis of 11-BOHD. She was started on hydrocortisone replacement (12 mg/m2/day) and required spironolactone to achieve adequate blood pressure control. At the time of diagnosis, her father reported that he also had hypertension before 10 years of age, as well as early puberty, and significantly darker skin color than his family members. Conclusions: The HTN seen with 11-OHD is associated with suppressed aldosterone/renin activity and hypokalemia and is responsive to glucocorticoid therapy. However, this cause of CAH is not included in the newborn screen so can go unrecognized until features of virilization and rapid growth with bone age advancement are noted. If HTN is persistent despite glucocorticoid treatment, spironolactone is the preferred antihypertensive, as it is both a mineralocorticoid and androgen receptor antagonist. This case serves as a reminder to pay attention to BP at every clinic visit. Presentation: Friday, June 16, 2023