Glucocorticoid Replacement Research Articles

Proof of concept for a superior therapeutic index of corticosterone compared with hydrocortisone in patients with congenital adrenal hyperplasia.

Outcomes are poor for patients with congenital adrenal hyperplasia (CAH), in part due to the supraphysiological glucocorticoid doses required to control adrenal androgen excess. Hydrocortisone (i.e. cortisol) is the recommended glucocorticoid for treatment of CAH. However, the other endogenous glucocorticoid in humans, corticosterone, is actively transported out of metabolic tissues such as adipose tissue and muscle, so we hypothesized that corticosterone could control adrenal androgens while causing fewer metabolic adverse effects than hydrocortisone. Thirteen patients (8 female, 5 male) with CAH due to 21-hydroxylase deficiency completed a randomised placebo-controlled crossover study comparing 5h intravenous infusions of either hydrocortisone, corticosterone or placebo. 6-6[2H]2-glucose and 1,1,2,3,3-[2H]5-glycerol were infused to measure glucose and glycerol kinetics, and blood samples were collected throughout. Subcutaneous abdominal adipose tissue biopsies were obtained at the end of each infusion. During the infusion, corticosterone and hydrocortisone similarly reduced ACTH, 17α-hydroxyprogesterone, androstenedione, and testosterone (in females only) compared with placebo. Despite achieving circulating corticosterone concentrations ∼2.5-fold higher than hydrocortisone, by T+300 minutes hydrocortisone but not corticosterone increased glucose and insulin concentrations and reduced 6-6-[2H]2-glucose clearance compared with placebo. Hydrocortisone increased mRNA levels of the glucocorticoid regulated transcript PER1 in adipose to a greater extent than corticosterone. Corticosterone acutely controls biochemical markers of androgen excess similarly to hydrocortisone but without inducing markers of glucocorticoid 'toxicity' in CAH. These data demonstrate proof of concept that corticosterone may be a safer glucocorticoid replacement than current medications, although further research is required to assess the longer-term effects of corticosterone replacement.

6545 Weekly Somapacitan Reduces Serum C-reactive Protein Levels in Adult Patients with Growth Hormone Deficiency

Abstract Disclosure: Y. Seki: None. S. Morimoto: None. M. Ikemoto: None. N. Takano: None. K. Yamashita: None. K. Bokuda: None. D. Watanabe: None. A. Ichihara: None. Background: Adult growth hormone deficiency (GHD) is known to be associated with increased inflammation. Our previous research revealed a significant association between GHD and elevated serum C-reactive protein (CRP) levels. Limited studies have demonstrated a significant association between GH replacement therapies and CRP levels; only two reports showed a significant reduction in serum CRP levels with daily somatropin. This study aimed to investigate the effects of weekly somapacitan on serum CRP levels in adult patients with GHD. Methods: We prospectively observed serum CRP levels as the primary outcome before and 6 months after somapacitan treatment in adult patients with GHD with no history of GH supplementation therapy within the past 6 months. Secondary outcomes included anthropometric data, IGF-1 levels, and kidney and liver functions. The somapacitan dose was titrated based on IGF-1 levels during the 6-month treatment period. Results: Eight adult patients (mean age 50±17, male 4 [50%]) with GHD received weekly somapacitan treatment. Of the patients, 2 (25%) had ACTH deficiency, 2 (25%) had TSH deficiency, and 2 (25%) had gonadotropin deficiency. Two patients (25%) were on glucocorticoid replacement. The somapacitan dose at 6 months was 1.9 (1.5-2.6) mg/week. Weekly somapacitan significantly increased serum IGF-1 level (48 [29-122] to 125 [63-205] ng/mL, P = 0.001) and IGF-1 SD score (-3.3 [-5.3-0.9] to -0.7 [-3.0-0.8], P = 0.008) and significantly decreased serum CRP level (0.243 [0.056-0.464] to 0.093 [0.036-0.290] ng/mL, P = 0.008). However, it did not affect body weight (80.6±11.6 to 79.8±10.5 kg, P = 0.67) or serum creatinine (0.74±0.13 to 0.68±0.21 mg/dL, P = 0.35) and alanine aminotransferase (60 [20-99] to 48 [21-85] U/L, P = 0.23) levels. Changes in CRP levels were significantly correlated with changes in IGF-1 levels (rs = -0.83, P = 0.010) and IGF-1 SD scores (rs = -0.79, P = 0.021). Conclusion: GH supplementation therapy with weekly somapacitan reduced serum CRP levels in adult patients with GHD without affecting body composition or kidney and liver functions. Presentation: 6/3/2024

8117 Late-night Salivary Cortisol in the Diagnosis of Cushing's Disease Recurrence

Abstract Disclosure: A.E. Alexandre: None. P.C. Elias: None. M. De Castro: None. L.M. Mermejo: None. D.C. Aragon: None. A.C. Moreira: None. Cushing’s Disease (CD) remission following transsphenoidal surgery (TSS) is most often defined by low morning cortisol levels and the requirement of glucocorticoid (GC) replacement therapy. However, CD recurrence is not a well studied event. There is no standard definition of remission criteria and no accurate cutoff for biochemical tests on CD recurrence. Late-night salivary cortisol (LNSC) has been shown to have higher accuracy in confirming CD recurrence than urinary free cortisol and dexamethasone suppression test (DST). However, few studies addressed LNSC performance following remission after TSS. The study aimed to establish cutoff values of LNSC with higher sensitivity (S) and specificity (E) in CD recurrence diagnosis.In a retrospective cohort study of 65 patients with remitted CD after TSS, remission was defined as improvement of sign and symptoms related to CD and a plasma cortisol <5mcg/dL in 30 days following TSS. Eleven patients progressed to permanent adrenal insufficiency and were excluded from the study. All 54 patients had at least four LNSC sampling and a minimal follow-up of 24 months after TSS. LNSC was determined by RIA. A cutoff value of 270 ng/dl for LNSC is used for the diagnosis of CD. Patients were divided in three different groups: Overt Recurrence (OR): elevated LNSC and worsening of CD`s signs and symptoms. Remission (RM): normal LNSC and no clinical signs of CD recurrence. Biochemical Recurrence (BR): at least 2 elevated biochemical parameters (LNSC or DST) but no worsening of signs and symptoms associated with CD. The mean of the 2 LNSC last values when OR was diagnosed and the mean of 2 LNSC last values of follow up for RM patients were used to estimate the accuracy of LNSC for diagnosing recurrence using a ROC curve (AUC) and its 95% confidence interval. Of the 54 patients included, 46 females; 8 males; mean age at diagnosis: 32 years, (5 – 58 yrs); mean time of follow-up: 12.8 years (4 – 31.7 yrs). Thirteen were classified as OR, 18 as RM and 23 as BR; and mean time of GC use after TSS was: 8.7; 34 and 17 yrs, respectively, significantly lower in OR compared to RM (p:0.046). A LNSC cutoff value of 272 mcg/dL had sensitivity of 85% and specificity of 95% (AUC: 0.97; 95% IC = [0.93; 1,00]) for CD recurrence diagnosis. BR patients presented LSNC fluctuation along follow-up.LNSC is a useful tool for CD recurrence screening. Setting LSNC specific assay cutoff values might be needed. LSNC cutoff values were similar for the initial CD diagnosis, as well as for CD recurrence diagnosis. Shorter time of GC replacement may be an important predictor of CD recurrence. Patients with BR should be followed more carefully as they may be at higher risk of recurrence. Multiple LNSC sampling on successive days can be easily performed and may detect subtle changes in cortisol rhythm. Presentation: 6/1/2024

7286 Higher Order Associations Linking Tryptophan, Kynurenine, And Tyrosine As Serum Markers Of Glucocorticoid Downstream Action In Adipose Tissue

Abstract Disclosure: K. Bennett: None. T. Garner: None. D. Chantzichristos: Speaker; Self; Sanofi, Takeda. P. Jansson: None. A. Stevens: None. G. Johannsson: Consulting Fee; Self; Novo Nordisk, Shire, AstraZeneca. Speaker; Self; Novo Nordisk, Pfizer, Inc.. Introduction: Treatment of Adrenal Insufficiency (AI) by glucocorticoid (GC) replacement therapy is mainly guided by clinical judgement, as there is no biomarker of GC action to individualise its dosage. Hypergraphs are networks modelling higher order associations (HOAs), which are interactions between more than two ‘omic elements. The aim of this study was to use hypergraphs to identify serum markers that reflect the action of GCs in adipose tissue (AT). Methods: In a randomised, cross-over trial, 10 patients with primary AI received saline i.v. (GC withdrawal), or circadian infusion of hydrocortisone (GC exposure), with > 2 weeks apart. After 26 hours (8AM), AT biopsy and PBMCs were collected for transcriptomic analysis, and abdominal subcutaneous microdialysis and PBMCs were collected for metabolomic profiling using LC/MS. Hypergraph models were generated to integrate serum and AT transcriptomics and metabolomics, identifying clusters of putatively causally linked metabolites which could represent serum markers of downstream GC action in AT. Hypergraph structure was assessed in AT and serum using entropy to infer associations within pre-defined metabolic pathways. Differences in entropy between the interventions was measured using Bayes Factor. Univariate ROC curve analysis was used to calculate AUCs for the serum markers. Results: In AT dialysate, 22 metabolites were identified as significantly different between GC exposure and withdrawal states. These included metabolites found in lipolysis and proteolysis pathways, such as acyl carnitines, lysophosphatidylcholines, fatty acids, and peptide derivatives. Nine metabolites were significantly different between the interventions in the serum. DEGs in AT (n=2048) were found to be enriched in metabolic pathways. Hypergraphs were used to refine clusters in the serum based on their HOAs with AT differentially expressed genes and metabolites. Tryptophan, Kynurenine, and Tyrosine clustered together, demonstrating a relationship between their expression in serum, and the metabolomic and transcriptomic profile of AT. These HOAs were shared with cortisol in the exposure intervention, but not in GC withdrawal, suggesting GC dependent regulation. All 3 metabolites had AUC-ROCs > 0.8, with Kynurenine performing the best at 0.86. Tissue specific differences were seen in the entropy of metabolic pathways between GC exposure and withdrawal, with similar changes seen in lipid and proteolysis pathways, but no difference seen in serum in carbohydrate and amino acid biosynthesis. Conclusions: During near physiological exposure, we identified changes to hypergraph structure and metabolite concentrations in lipid, protein, and carbohydrate pathways in AT and serum, compared to GC withdrawal. Hypergraph integration of multi-omic data identified tryptophan, kynurenine, and tyrosine as potential serum markers reflecting GC action in AT. Presentation: 6/3/2024

8424 Complex Management Of Adrenal Insufficiency In Pregnancy: A Challenging Case

Abstract Disclosure: T. Avanessian: None. H. Alsamarraie: None. Background: Physiologic changes, including changes in the HPA axis and RAAS, during pregnancy pose challenges in the management of adrenal insufficiency in pregnant women. This case report discusses the management of adrenal insufficiency in a young primigravida female with Addison’s disease. Clinical Case: At 19.5 weeks of gestation, a 26-year-old primigravida, previously diagnosed with Addison’s disease 5 years ago, presented to an acute care center for syncopal episodes. The pregnancy had been complicated by persistent nausea and vomiting, labeled as hyperemesis gravidarum, and recurrent syncopal episodes, resulting in 6 ED visits and 3 hospitalizations, with symptoms improving each time after IV hydration and then returning within a few days. At presentation, the patient reported lightheadedness, sweating, palpitations, dyspnea, fatigue, nausea, vomiting, and a 10 lb weight loss since the beginning of pregnancy. The pre-pregnancy regimen was hydrocortisone 10 mg in the morning and 5 mg in the afternoon, with fludrocortisone 0.1mg daily. At 8 weeks of gestation, due to increased fatigue and hypotension, the hydrocortisone dose was doubled, while fludrocortisone was continued the same. During admission, blood pressure ranged from 67/37 to 90/56 mmHg, and heart rate ranged between 93-103 bpm. On labs, electrolytes were normal, and the serum renin level was elevated at 5.803 ng/ml/hr (0.167-5.380). Treatment included IV hydration and hydrocortisone 40 mg in the morning and 20 mg in the afternoon. Despite symptom improvement, blood pressure remained low. Thus, fludrocortisone was increased to 0.1 mg twice daily. Within 3 days, all symptoms improved, allowing for the down-titration of the hydrocortisone dose. The patient was discharged with hydrocortisone 30 mg at 8 AM, 10 mg at 3 PM, 5 mg at 7 PM, and fludrocortisone at 0.1 mg twice daily. Conclusion: Managing symptoms of adrenal insufficiency during pregnancy is challenging due to the overlap of symptoms and signs with physiologic manifestations of pregnancy. The use of biochemical testing is limited, given the physiological activation of RAAS and progressive increases in renin, CRH, ACTH (from both pituitary and placental sources), and cortisol during pregnancy. Monitoring mineralocorticoid requirements is further complicated by physiological changes in blood pressure and interstitial fluid status. While some literature suggests that adjusting fludrocortisone may not be necessary, as an increase in glucocorticoid dose can compensate, determining the correct dose of glucocorticoid and mineralocorticoid replacement should be tailored to each patient and their specific symptoms.

7829 Hydrocortisone Vs Prednisone During Recovery Following Surgical Cure For Endogenous Hypercortisolism: A Longitudinal Observational Study

Abstract Disclosure: R. Sandooja: None. J. Saini: None. R. Gregg garcia: None. C. Zhang: None. S. Achenbach: None. E. Atkinson: None. J. Van Gompel: None. W.F. Young: None. I. Bancos: None. Hydrocortisone vs Prednisone During Recovery Following Surgical Cure for Endogenous Hypercortisolism: A Longitudinal Observational Study Introduction: Glucocorticoid withdrawal syndrome (GWS) is a constellation of symptoms that occurs after successful surgery for endogenous hypercortisolism. The objective of this study is to compare hydrocortisone versus prednisone on GWS symptoms. Methods: Study design: Single-center prospective longitudinal cohort study, 2019-2023. Participants: Adults with Cushing syndrome (CS) and mild autonomous cortisol secretion (MACS) with post-operative adrenal insufficiency treated with either hydrocortisone or prednisone for glucocorticoid replacement. Measurements: Clinical and biochemical severity scores for hypercortisolism were calculated. Quality of life (QOL) was assessed using Short Form-36 (SF-36) and Cushing QOL surveys. GWS was assessed using weekly AddiQoL surveys for the first 12 weeks after surgery. Results: Of 131 patients, 91 (69%) patients were treated with hydrocortisone and 40 (31%) with prednisone. No differences in age (median age 51 vs 53 years, P=0.62), sex (84 vs 85% women, P=0.83), etiology of hypercortisolism (ACTH-dependent: 44% vs 48%, P=0.26), clinical severity of hypercortisolism (median score 13 vs 12, P=0.97), or biochemical severity of hypercortisolism (median score of 6 in both, P=0.31) were noted between groups. When assessed at 4-, 8-, and 12-weeks post-surgery, the prevalence and trajectory of symptoms (fatigue, myalgias/arthralgias, sleep, headaches, nausea, weakness) were similar in patients treated with hydrocortisone and prednisone (P>0.05 for all). However, patients treated with prednisone were less likely to report mood changes (8.5% vs 20.9%, P= 0.004) compared to those treated with hydrocortisone. When compared to the presurgical baseline, the overall Cushing QOL score 12 weeks post-surgery improved in both groups (mean delta 8.9 vs 13.0, P=0.21). No differences in the hydrocortisone vs prednisone treatment were found in the SF-36 physical component score (mean delta of -1.7 vs 0.3, P=0.23) and SF-36 mental component score (mean delta 2.3 vs 5.0, P=0.22). Using multivariable analysis, age (estimate 0.22, P= 0.005), clinical severity score (estimate -0.73, P<0.001), female sex (estimate -5.45, P= 0.046) but not glucocorticoid type (estimate -0.06, P=0.98) were associated with the overall GWS symptom burden at 12 weeks. Conclusion: Use of prednisone after curative surgery for hypercortisolism was associated with lower mood symptoms, but did not impact the overall severity or trajectory of other symptoms associated with GWS. Baseline clinical severity of hypercortisolism, age, and female sex were associated with GWS burden. Presentation: 6/1/2024

12575 Exploring Patient And Parent Perceptions Of Administering Hydrocortisone Injection During Adrenal Crisis: A Cross-Sectional Study

Abstract Disclosure: S.V. Llahana: None. J. Anhony: Employee; Self; Solution Medical LLC. Background: Adrenal insufficiency (AI) necessitates lifelong glucocorticoid replacement therapy for most patients, with parenteral hydrocortisone crucial for managing adrenal crisis, a potentially life-threatening complication. Despite this, approximately 1 in 6-12 patients are hospitalised at least once a year, while 1 in 200 patients die from a potentially preventable adrenal crisis. While timely self-administration of hydrocortisone mitigates these risks, the complexity of current injection devices, requiring up to 20 steps to administer, often impedes effective self-treatment. Evidence shows that although 70% of patients possess emergency hydrocortisone injection kits, only 19% have received training for self-administration. Aim: This study aimed to investigate the experiences and perceptions of patients with AI and their caregivers regarding the usage of Solu-Cortef Act-O-Vial (parenteral hydrocortisone) for adrenal crisis management. Methods: A cross-sectional online survey was conducted, involving participants recruited through USA-based patient advocacy groups, CARES Foundation and Adrenal Insufficiency United. Participants provided insights into factors influencing their ability to manage adrenal crisis using Solu-Cortef Act-O-Vial. Content analysis generated themes, which were quantitatively analyzed using SPSS descriptive statistics and correlations. Results: The survey encompassed 689 patients and caregivers. Content analysis revealed eighteen themes across three domains: patient-based factors, external influences, and emotional aspects. Predominant themes, identified by over 80% of participants, included the complexity of the hydrocortisone device, the necessity for assistance during adrenal crisis episodes, and emotional distress due to fear associated with injection. Conclusion: This study underscores the necessity for a simpler injection device to enhance patient self-confidence and self-administration ability. Heightened awareness among healthcare professionals and the public regarding adrenal crisis is imperative for timely management and prevention of avoidable hospital admissions. Presentation: 6/3/2024

7648 Bilateral Adrenal Hemorrhage After Laminectomy: A Rare Complication

Abstract Disclosure: M. Rizk: None. S. Sharma: None. H. Qadeer: None. R. Paudel: None. C. Sherpa: None. Introduction: Bilateral Adrenal Hemorrhage (BAH) is an exceedingly uncommon complication of laminectomy, with few cases reported in the literature. In patients with history of any surgical procedure who present with unexplained symptoms of abdominal pain, back pain, hypotension, fever, confusion, or electrolyte abnormalities especially hyponatremia, acute adrenal insufficiency (AI) should be highly suspected. We herein describe a case of BAH following laminectomy. Clinical Case: 63-year-old male with past medical history of hypertriglyceridemia was admitted for post traumatic L1 burst fracture and was treated with T11-L3 fusion and T12-L3 laminectomy. The patient had normal bilateral adrenal glands after the fall on CT thoracic/lumbar spine imaging. The course was complicated by thrombocytopenia initially thought to be induced by therapeutic heparin since heparin antibody was positive. Serotonin-release assay returned negative weeks later ruling out heparin induced thrombocytopenia. Two weeks later, he developed unexplained tachycardia and CT angiogram was done which showed segmental pulmonary embolism and bilateral adrenal nodules measuring at least 3.9 cm on right side and 3.3 cm on left side. He was treated with Eliquis and was discharged home. Two weeks later, he was readmitted with weight loss of 30 lbs, weakness and altered mental status. His vital signs were significant for hypotension and tachycardia. Initial work up showed profound hyponatremia (sodium 121 mEq/L), hyperkalemia (potassium 6.1 mEq/L), hypoglycemia (Glucose 58 mg/dL), hypercalcemia (calcium 11.7 mg/dL) and acute kidney injury (creatinine 2.58 mg/dL). Repeat CT scan of chest/abdomen/pelvis without contrast showed bilateral hyperdense 4 cm adrenal mass/hematoma. Since initial CT of thorax/spine done after the fall showed normal adrenal glands, the new bilateral hyperdense adrenal masses noted post procedure is suggestive of adrenal hemorrhage/hematoma. Undetectable cortisol and high ACTH confirmed AI. Patient was treated with stress dose hydrocortisone followed by slow taper. MRI of pituitary gland showed partial empty Sella however since ACTH was high, empty sella was only an incidental finding and not the cause of AI. He is maintained on hydrocortisone 15 mg in the morning and 5 mg in the evening plus fludrocortisone 0.1 mg daily. His fatigue has improved, he is gaining weight and electrolytes are normal. Conclusions: This case report emphasizes the significance of timely diagnosis and management of BAH, which leads to primary AI. BAH is a rare complication following laminectomy. Clinicians should be aware of this possibility and consider it in the differential diagnosis of postoperative abdominal pain and electrolyte abnormalities, especially hyponatremia. Timely recognition and high index of suspicion should prompt empiric glucocorticoid replacement to decrease mortality. Presentation: 6/1/2024

7038 Continuous Subcutaneous Hydrocortisone Infusion Is Practical And Effective In Select Patients With Adrenal Insufficiency

Abstract Disclosure: J.E. Lee: None. O. Hamidi: None. S. Mirfakhraee: None. Continuous subcutaneous hydrocortisone infusion (CSHI) via insulin pump is an alternative therapy for treating patients with adrenal insufficiency (AI) and allows for adjustable hydrocortisone delivery to provide more physiologic glucocorticoid replacement. Retrospective case series of 9 patients on CSHI showed a reduction in total daily dose of glucocorticoid by 34% and a decrease in hospitalization admissions due to adrenal crisis by 50%. In a double-blind placebo-controlled study, CSHI in patients with primary AI did not demonstrate benefit in subjective health status metrics compared to oral hydrocortisone; however, patients had good baseline subjective health scores. Due to a scarcity of data, CSHI is likely underutilized in patients who may benefit from this individualized therapy. Our research objectives were to analyze the change in total daily glucocorticoid dose, number of adrenal crises events and hospitalization days, glucocorticoid-related comorbidities, and quality of life of patients transitioned to CSHI. We performed a single-center, retrospective longitudinal follow-up study in 23 consecutive patients (87% women, median age 40 years at time of CSHI initiation) treated with CSHI between 2015 and 2023. Types of adrenal insufficiency were 48% secondary AI, 35% glucocorticoid induced AI, and 17% primary AI. CSHI delivery settings were generated by a formula that we derived using each patient’s daily oral glucocorticoid dose and preferred waking time. Median time from AI diagnosis to CSHI implementation was 41 months, and median duration of CSHI was 25 months. Total daily dose of glucocorticoid (in hydrocortisone equivalent) before CSHI vs during CSHI decreased from 30.0mg (15.0mg to 80.0mg) to 26.6mg (14.4mg to 200.5mg) (p= 0.45). Median number of adrenal crisis events decreased from 1 (0 to 13) to 0 (0 to 38) (p=0.25), and hospitalization days due to adrenal crisis decreased from 2 (0 to 46) to 0 (0 to 58) (p=0.53). No significant differences were noted for change in weight, blood pressure, diabetes, cardiovascular and cerebrovascular events, total cholesterol, LDL, and triglyceride levels. Median HDL decreased from 59 to 51 (p=0.01). In terms of subjective health status, 10 patients completed SF-36 survey while on CSHI. Significant impairments were noted in physical health, vitality, and general health with median score less than 40. At the conclusion of the study, 20 patients (87%) preferred CSHI therapy. Only 3 patients stopped CSHI for reasons of inconvenience, skin irritation at pump site, and better symptom control on oral therapy. No significant CSHI-related safety concerns were noted. In conclusion, CSHI is a safe and effective way to deliver individualized therapy to patients with difficult to control AI. CSHI led to reduction in glucocorticoid exposure and fewer adrenal crisis events and hospitalization days due to adrenal crisis. Presentation: 6/1/2024

12670 CHAMPAIN Study: Initial Results From A Phase II Study Of Efficacy, Safety And Tolerability Of Modified-release Hydrocortisones: Chronocort® (Efmody®) Versus Plenadren®, In Primary Adrenal Insufficiency

Abstract Disclosure: A. Prete: Research Investigator; Self; Diurnal. V. Theiler-Schwetz: Research Investigator; Self; Diurnal. W. Arlt: Research Investigator; Self; Diurnal. I.O. Chifu: Research Investigator; Self; Diurnal. B. Harbeck: Research Investigator; Self; Diurnal. C. Napier: Research Investigator; Self; Diurnal. J.D. Newell-Price: Research Investigator; Self; Diurnal. A. Rees: Research Investigator; Self; Diurnal. N. Reisch: Research Investigator; Self; Diurnal. G.K. Stalla: Research Investigator; Self; Diurnal. N. Aslam: Employee; Self; Diurnal. H. Coope: Employee; Self; Diurnal. K. Maltby: Employee; Self; Diurnal. J. Porter: Employee; Self; Diurnal. J. Quirke: Employee; Self; Diurnal. R.J. Ross: Consulting Fee; Self; Diurnal. Background: Current glucocorticoid replacement regimens for patients with primary adrenal insufficiency (PAI) mean patients wake with either low or undetectable cortisol levels[1], associated with fatigue and a reduced quality of life (QoL)2. Plenadren® (Takeda, UK) is a once-daily modified-release formulation of hydrocortisone that replaces daytime cortisol levels whereas Chronocort® (modified-release hydrocortisone hard capsules, Diurnal, UK) when taken twice-daily, has been shown to replicate the normal overnight rise in serum cortisol concentration and provide physiological levels throughout the day. We have undertaken a double-blind, double-dummy, two-way cross-over, randomised, phase II study of efficacy, safety and tolerability of modified-release hydrocortisones: Chronocort® Versus Plenadren®. Aim: To test the hypothesis that Chronocort® provides more physiological waking cortisol levels than Plenadren®. Methodology: The study was conducted across 8 sites in the UK and Germany. Male and female patients, aged ≥18 with confirmed PAI (defined as morning pre-dose cortisol <50 nMol/l) on stable therapy over the preceding three months and not currently treated with Chronocort®/Plenadren®. Participants with congenital adrenal hyperplasia (CAH), secondary or tertiary AI were excluded. Each participant was randomised on a 1:1 basis to either; treatment sequence I (Chronocort® first) or treatment sequence II (Plenadren® first) taking a 25mg total daily dose for 4 weeks; either Plenadren® 25mg in the morning or Chronocort® 10mg in the morning and 15mg at night with the associated dummy preparation followed immediately by the other treatment. The pre-dose morning serum cortisol level was assayed at baseline and after each treatment period. A physiological morning cortisol level was defined as a pre-dose level of >140nMol/L. Secondary measures included: morning fatigue measured using the Multidimensional Assessment of Fatigue (MAF) questionnaire and the PROMIS® 7b questionnaire; QoL was assessed using the EuroQol 5-level Standardised Health Questionnaire (EQ-5D-5L™); Health-related Quality of Life in Addison’s disease (AddiQoL) questionnaire and the 36-Item Short Form Health Survey (SF-36®) questionnaire. Results: Of 49 evaluable participants with PAI, 45 achieved a physiological morning cortisol after four weeks of Chronocort® compared with 2 after four weeks of Plenadren® (P<0.0001). The mean (standard deviation) waking cortisol was 422.85 (203.50) vs 36.98 (113.87), respectively. Conclusion: Chronocort® provides more physiological waking cortisol levels than Plenadren®. Further analysis will test the hypothesis that waking with physiological cortisol levels improves fatigue and QoL in patients with PAI. 1.Mah PM, et al. Clin Endocrinol (Oxf). 2004;61(3):367-75.2.Wichers M, et al. Clin Endocrinol (Oxf). 1999;50(6):759-65. Presentation: 6/3/2024

8295 Development of Type 1 Diabetes and Primary Adrenal Insufficiency Secondary to Immunotherapy Treatment for Chordoma in a Patient With Hypopituitarism

Abstract Disclosure: P. Kesavan Chary: None. J.M. Silverstein: None. Background: Cranio-cervical chordomas are rare locally aggressive, invasive, and slow-growing bone neoplasms. Treatment involves a combination of excision and radiation therapy, and sometimes immunotherapy for recurrent disease. Endocrine-related toxicities from immune checkpoint inhibitors are well recognized and include autoimmune thyroid disease, hypophysitis, and less commonly, type 1 diabetes mellitus (T1DM) and primary adrenal insufficiency (PAI). We present a case of a patient with hypopituitarism secondary to a recurrent and aggressive skull base chordoma with leptomeningeal spread who developed T1DM and PAI after treatment with nivolumab, an anti-programmed cell death-1 (PD-1) monoclonal antibody. Diagnosis of PAI was delayed because patient was on hydrocortisone replacement for secondary adrenal insufficiency. Case Report: A 38 year old male with history of primary hypothyroidism underwent endoscopic endonasal transsphenoidal resection and adjuvant proton beam radiation therapy for a sellar chordoma after presenting with diplopia. Testing was consistent with hypopituitarism and the patient was started on hydrocortisone, levothyroxine, and testosterone replacement. Due to recurrent disease and leptomeningeal spread, he subsequently underwent three additional surgeries and two courses of gamma knife radiosurgery. Five months after starting systemic therapy with nivolumab, the patient developed insulin dependent diabetes presumed to be T1DM secondary to immunotherapy. He was continued on nivolumab, and six months into treatment developed hyperkalemia and hyponatremia requiring inpatient admission. He was treated with diuretics and fluid restriction initially without improvement in his electrolyte abnormalities although he remained relatively asymptomatic. Laboratory evaluation showed a renin activity of 66 ng/mL/H and aldosterone < 4.0 ng/dL (<= 21) with sodium of 128 mmol/L (135-145) and potassium 5.8 mml/L (3.3-4.9). Due to suspicion for PAI secondary to checkpoint-inhibitor induced adrenalitis, 21-hydroxylase antibody was checked and was positive. It was felt that the patient had not had other signs or symptoms classic for PAI such as nausea and/or vomiting because he had already been on glucocorticoid replacement for his hypopituitarism. Ultimately, the patient was started on fludrocortisone, with resolution of his hyponatremia and hyperkalemia. Conclusion: Adrenal insufficiency from immunotherapy is most commonly caused by hypophysitis. T1DM and PAI due to adrenalitis are less common. In patients on steroid replacement for hypopituitarism, the development of electrolyte abnormalities with or without symptoms in a patient on immunotherapy should raise the suspicion for rarer endocrine side effects such as primary adrenal insufficiency. Presentation: 6/3/2024

12484 Safety And Pharmacokinetics Of Anti-ACTH Antibody Lu AG13909 In Patients With Classic Congenital Adrenal Hyperplasia: Phase 1 Open-label, Multiple-Ascending-Dose Trial Protocol

Abstract Disclosure: U. Srirangalingam: Advisory Board Member; Self; Lundbeck. Consulting Fee; Self; Diurnal. Research Investigator; Self; Neurocrine. A. Velusamy: Consulting Fee; Self; Novo Nordisk. M. Binderup: Employee; Self; H. Lundbeck A/S. B. Baker: Employee; Self; H. Lundbeck A/S. M. Folden Flensburg: Employee; Self; H. Lundbeck A/S. L. Pickering Boserup: Employee; Self; H. Lundbeck A/S. J. Luthman: Employee; Self; H. Lundbeck A/S. H. Benecke: Employee; Self; H. Lundbeck A/S. R.J. Auchus: Consulting Fee; Self; Neurocrine Biosciences, Diurnal, Corcept Therapeutics, Recordati Rare Diseases, Crinetics Pharmaceuticals, Quest Diagnostics, Xeris Pharmaceuticals, Novo Nordisk, H. Lundbeck A/S, Sparrow Pharmaceuticals. Research Investigator; Self; Adrenas Therapeutics, Spruce Biosciences, Neurocrine Biosciences, Diurnal, Corcept Therapeutics, Recordati Rare Diseases, Crinetics Pharmaceuticals. Introduction: Classic congenital adrenal hyperplasia (CAH) is a rare, autosomal recessive disorder characterized by cortisol and aldosterone deficiency, elevated adrenocorticotropic hormone (ACTH) and subsequent hyperandrogenemia, most commonly due to 21-hydroxylase deficiency. Balancing physiological glucocorticoid replacement and control of hyperandrogenism remains a challenge with the risk of long-term consequences of glucocorticoid overtreatment. Lu AG13909 is a novel, high-affinity, anti-ACTH monoclonal antibody that neutralizes ACTH-induced signaling. In preclinical models, Lu AG13909 dose-dependently and persistently reduced plasma corticosterone and cortisol concentrations. No adverse effects were observed after 6 months of intravenous dosing every 2 weeks in cynomolgus monkeys. Here, we describe the ongoing first-in-human trial of Lu AG13909, investigating the safety, tolerability, pharmacokinetic (PK) properties, and pharmacodynamic (PD) effects of Lu AG13909 in adults with classic CAH. Methods: This is a Phase 1, open-label, multiple-ascending-dose trial with intra-participant dose escalation (EUCT #2023-503711-15-00). The trial enrolls men and women with classic CAH aged between ≥18 and ≤70 years under stable glucocorticoid and mineralocorticoid dosing, with morning 17-hydroxyprogesterone >4 times the upper limit of normal. Each participant receives up to 6 doses of Lu AG13909 every 28-35 days at increasing dose levels. The trial consists of 2 parts: Part A has a 3+3 design, in which 3 participants are given a certain dose, and escalation to the next dose is based on a 28-day safety observation period. Part B explores the pharmacologically relevant Lu AG13909 doses identified in Part A in a larger number of participants. The aim is for a total of 12 participants to receive each of the dose levels identified as relevant. Outcomes The primary safety and tolerability endpoints include adverse events and clinical safety tests. PK endpoints include maximum observed exposure and area under the Lu AG13909 concentration-time curve in a dosing interval. The PD endpoints are the relative reductions in morning 17-hydroxyprogesterone, androstenedione, and unbound ACTH, from baseline to the day after each Lu AG13909 dose. Conclusions This innovative, multi-dose, intra-participant dose escalation trial design was developed specifically for the rare classic CAH population, who have a high unmet medical need due to the challenges with current glucocorticoid treatment. The aim of the trial is to gather safety, PK, and PD data while minimizing participant risk and burden. Data from this trial will reinforce the development of Lu AG13909 as a novel treatment strategy in conditions characterized by increased levels of ACTH, such as classic CAH and Cushing disease. Presentation: 6/3/2024

9341 CHAMPAIN Study: Initial Results From A Phase II Study Of Efficacy, Safety And Tolerability Of Modified-release Hydrocortisones: Chronocort® (Efmody®) Versus Plenadren®, In Primary Adrenal Insufficiency

Abstract Disclosure: A. Prete: Research Investigator; Self; Diurnal. V. Theiler-Schwetz: Research Investigator; Self; Diurnal. W. Arlt: Research Investigator; Self; Diurnal. I.O. Chifu: Research Investigator; Self; Diurnal. B. Harbeck: Research Investigator; Self; Diurnal. C. Napier: Research Investigator; Self; Diurnal. J.D. Newell-Price: Research Investigator; Self; Diurnal. A. Rees: Research Investigator; Self; Diurnal. N. Reisch: Research Investigator; Self; Diurnal. G.K. Stalla: Research Investigator; Self; Diurnal. N. Aslam: Employee; Self; Diurnal. H. Coope: Employee; Self; Diurnal. K. Maltby: Employee; Self; Diurnal. J. Porter: Employee; Self; Diurnal. J. Quirke: Employee; Self; Diurnal. R.J. Ross: Consulting Fee; Self; Diurnal. Background: Current glucocorticoid replacement regimens for patients with primary adrenal insufficiency (PAI) mean patients wake with either low or undetectable cortisol levels[1], associated with fatigue and a reduced quality of life (QoL)2. Plenadren® (Takeda, UK) is a once-daily modified-release formulation of hydrocortisone that replaces daytime cortisol levels whereas Chronocort® (modified-release hydrocortisone hard capsules, Diurnal, UK) when taken twice-daily, has been shown to replicate the normal overnight rise in serum cortisol concentration and provide physiological levels throughout the day. We have undertaken a double-blind, double-dummy, two-way cross-over, randomised, phase II study of efficacy, safety and tolerability of modified-release hydrocortisones: Chronocort® Versus Plenadren®. Aim: To test the hypothesis that Chronocort® provides more physiological waking cortisol levels than Plenadren®. Methodology: The study was conducted across 8 sites in the UK and Germany. Male and female patients, aged ≥18 with confirmed PAI (defined as morning pre-dose cortisol <50 nMol/l) on stable therapy over the preceding three months and not currently treated with Chronocort®/Plenadren®. Participants with congenital adrenal hyperplasia (CAH), secondary or tertiary AI were excluded. Each participant was randomised on a 1:1 basis to either; treatment sequence I (Chronocort® first) or treatment sequence II (Plenadren® first) taking a 25mg total daily dose for 4 weeks; either Plenadren® 25mg in the morning or Chronocort® 10mg in the morning and 15mg at night with the associated dummy preparation followed immediately by the other treatment. The pre-dose morning serum cortisol level was assayed at baseline and after each treatment period. A physiological morning cortisol level was defined as a pre-dose level of >140nMol/L. Secondary measures included: morning fatigue measured using the Multidimensional Assessment of Fatigue (MAF) questionnaire and the PROMIS® 7b questionnaire; QoL was assessed using the EuroQol 5-level Standardised Health Questionnaire (EQ-5D-5L™); Health-related Quality of Life in Addison’s disease (AddiQoL) questionnaire and the 36-Item Short Form Health Survey (SF-36®) questionnaire. Results: Of 49 evaluable participants with PAI, 45 achieved a physiological morning cortisol after four weeks of Chronocort® compared with 2 after four weeks of Plenadren® (P<0.0001). The mean (standard deviation) waking cortisol was 422.85 (203.50) vs 36.98 (113.87), respectively. Conclusion: Chronocort® provides more physiological waking cortisol levels than Plenadren®. Further analysis will test the hypothesis that waking with physiological cortisol levels improves fatigue and QoL in patients with PAI. 1.Mah PM, et al. Clin Endocrinol (Oxf). 2004;61(3):367-75.2.Wichers M, et al. Clin Endocrinol (Oxf). 1999;50(6):759-65. 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

7839 Assess Management of Adrenal Insufficiency in Melanoma Patients Treated with Cancer Immunotherapy

Abstract Disclosure: W. Lin: None. L. Min: None. Despite high prevalent of adrenal insufficiency in melanoma patients treated with cancer immunotherapy, no study has examined the management of adrenal insufficiency in these patients. We performed this retrospective, longitudinal cohort study at Mass General Brigham, Boston, aims to characterize the management of adrenal insufficiency in melanoma patients. Patients were identified through our RPDR search tool, and medical record reviews were conducted. Three patient groups were analyzed: Melanoma with secondary adrenal insufficiency group (Mel_SAI, n=74), Melanoma matched control group (Mel_Con, n=69), and Pituitary macroadenoma-related adrenal insufficiency matched control group (Pit_Con, n=37). We compared self-perceived quality of life, glucocorticoid replacement dose, and clinic visit. Mel_SAI patients exhibited significantly higher incidences of anxiety (43.1%, 95%CI: 32.3-54.6), fatigue (73.6%, 95%CI: 62.4-82.4), pain (58.3%, 95%CI: 46.8-69.0), and insomnia (36.1%, 95%CI: 26.0-47.6), as compared to Pit_Con group (21.6%, 11.4-37.2; 24.3, 13.4-40.1; 29.7%, 17.5-45.8; 5.4%, 1.5-17.7, respectively). The initial hydrocortisone dose was higher for Mel_SAI (30mg qd, 95%CI: 20.5-25.1) compared to Pit_Con (15mg qd, 95%CI: 12.8-18.3). Additionally, the Mel_SAI group had fewer endocrinology clinic visits (3, 95%CI: 3.40-5.04) than the Pit_Con group (9, 95%CI: 7.35-10.9). Subgroup analysis indicated a higher mortality risk (HR 2.61, 95% CI 1.11-6.13) in Mel_SAI patients with fewer than three endocrinology visits over five years. Compared to the Mel_Con group, Mel_SAI patients also showed higher incidences of fatigue (71.6%, 95%CI: 60.5-80.6; Mel_Con: 55.1%, 95%CI: 43.4%-66.2%), but lower rates of depression (25.7%, 95%CI: 17.1-36.7; Mel_Con: 43.5%, 95%CI: 32.4-55.2) and appetite loss (24.3%, 95%CI: 16.0-35.2; Mel_Con: 47.8%, 95%CI: 36.4-59.4). No significant difference in other self-perspective symptoms. Furthermore, Mel-SAI patients had more oncological clinic visits (71, 95%CI: 74.0-109.2) than those in the Mel_Con group (41, 95%CI: 42.1-64.1). Our study suggests that most self-perceived quality of life in the Mel_SAI group is related to melanoma rather than adrenal insufficiency. Therefore, a higher initiating dose of hydrocortisone in melanoma patients with adrenal insufficiency may not be necessary. However, increasing endocrine clinic visits in cancer patients with cancer immunotherapy-related adrenal insufficiency may improve their survival outcomes. Presentation: 6/3/2024

7692 Morning Cortisol Levels In Patients With Established Primary Adrenal Insufficiency

Abstract Disclosure: A. Prete: Research Investigator; Self; Diurnal. V. Theiler-Schwetz: Research Investigator; Self; Diurnal. W. Arlt: Research Investigator; Self; Diurnal. I.O. Chifu: Research Investigator; Self; Diurnal. B. Harbeck: Research Investigator; Self; Diurnal. C. Napier: Research Investigator; Self; Diurnal. J.D. Newell-Price: Research Investigator; Self; Diurnal. A. Rees: Research Investigator; Self; Diurnal. N. Reisch: Research Investigator; Self; Diurnal. G.K. Stalla: Research Investigator; Self; Diurnal. N. Aslam: Employee; Self; Diurnal. H. Coope: Employee; Self; Diurnal. K. Maltby: Employee; Self; Diurnal. J. Porter: Employee; Self; Diurnal. J. Quirke: Employee; Self; Diurnal. R.J. Ross: Consulting Fee; Self; Diurnal. Background: Primary adrenal insufficiency (PAI) is rare: prevalence ∼100-140/million and incidence 4:1 000 000/year in Western societies [1]. The diagnosis of PAI is suggested by an early-morning cortisol <140 nmol/L (5 µg/dL) [1]. The commonest cause in adults is autoimmunity (∼90% in Western countries) and it is generally considered progressive once the diagnosis is made, although it has been reported that residual cortisol secretion is present in ∼30% of patients 2. We have developed a modified-release formulation of hydrocortisone to replace the physiological cortisol circadian rhythm and are undertaking a Double-Blind, Double-Dummy, Two-Way Cross-Over, Randomised, Phase II Study of Modified-Release Hydrocortisones: Chronocort® Versus Plenadren® in PAI. During recruitment, we were surprised by the number of patients who were ineligible as they had detectable morning cortisol levels. Methods: Main inclusion criteria: Participants with known PAI on stable glucocorticoid replacement therapy and an early morning pre-dose cortisol <50 nmol/L (1.8 µg/dl). Baseline serum cortisol was taken at ∼0700h and measured in a central laboratory by ADVIA Centaur® immunoassay with the lower limit of detection <14nmol/l (<0.5 µg/dL). Results: 86 patients with PAI (autoimmune aetiology in 71), median age 52 years (range 20-73), 60 female, were screened in 8 centres in UK and Germany. 18 (21%) patients were excluded from the study based on morning cortisol >50 nmol/L (1.8 µg/dL), and of those 68 patients who qualified on the main inclusion criteria 51 (59% of screened) had a cortisol <14 nmol/L (<0.5 µg/dL). Of the 18 patients (autoimmune aetiology in 10) excluded based on their morning cortisol level, 9 (50%) were female and 11 (13% of screened), had morning cortisol ≥140 nmol/L (5.0 µ/dL). 12 patients with morning cortisol of >50nmol/L (1.8 µ/dL) were retested and only 2 then qualified; their initial morning cortisol levels were 70 and 51 nmol/L. In patients retested the median difference between retest and the initial sample was 13 nmol/L (range 1-421 nmol/L). Conclusions: In patients with an established diagnosis of PAI, the majority had undetectable morning cortisol, but cortisol was detectable in 41% of patients and above 140 nmol/L in 13% confirming previous publications 2. Retesting patients with a cortisol >50nmol/L showed very similar results suggesting that the detectable cortisol was not an artefact and likely due to background cortisol secretion. 1. Bornstein SR, et al. J Clin Endocrinol Metab 2016;101:364-89.2.Pearce SHS, et al. European Journal of Endocrinology (2021) 184, R61–R67 Presentation: 6/1/2024

7412 A Case of Exogenous Cushing Syndrome in a Patient with History of Acromegaly Status Post Transsphenoidal Resection Complicated by Panhypopituitarism Requiring Glucocorticoid Replacement

7412 A Case of Exogenous Cushing Syndrome in a Patient with History of Acromegaly Status Post Transsphenoidal Resection Complicated by Panhypopituitarism Requiring Glucocorticoid Replacement

Glucocorticoid replacement therapy in congenital adrenal hyperplasia and its associations with growth outcomes - real world data analysis from an international cohort of 1500 patients

Glucocorticoid replacement therapy in congenital adrenal hyperplasia and its associations with growth outcomes - real world data analysis from an international cohort of 1500 patients

SARS-CoV-2 infection and vaccination in patients with pituitary diseases: the experience of a Brazilian reference center.

To evaluate the prevalence and characteristics of SARS-CoV-2 infection, and the prevalence, efficacy, and safety of anti-SARS-CoV-2 vaccination in patients with pituitary diseases. Observational, cross-sectional study of adult patients with pituitary diseases followed in a reference center. Clinical data were collected and a questionnaire about SARS-CoV-2 infection, vaccination and its possible adverse effects was applied. COVID-19 disease severity was defined as mild, moderate, and severe according to the WHO classification. 145 patients were studied (79 women; age 50 ± 15.8 years; duration of pituitary disease 16.8 ± 11.5 years), the cause of pituitary disease was tumoral in 74.5%, and 45.9% were on glucocorticoid replacement due to ACTH deficiency. SARS-CoV-2 infection was confirmed in 51 patients (35.2%; 32 women; age 53.8 ± 14.8 years, 22 before vaccination), with 28 (54.9%), 17 (33.3%) and 6 (11.8%) cases of mild, moderate, and severe disease, respectively, and hospitalization was indicated in 7 (14%) cases. One mild case presented pituitary apoplexy after SARS-CoV-2 infection. Advanced age was a risk factor for COVID-19. Patients with moderate and severe forms of COVID-19 had higher prevalence of dyslipidemia and duration of pituitary disease. All but one of the participants were vaccinated against COVID-19, and 60.4% had adverse events, the most common local pain (54.0%), fever (33.3%), and headache (18.4%), with one case of alopecia and two of persistent fatigue. The prevalence of SARS-CoV-2 infection in our cohort was 35.2%, including 14% of moderate and severe cases requiring hospitalization. The vaccination was universal and safe.

Cardiovascular risk and glucocorticoids: a Dutch National Registry of growth hormone treatment in adults with growth hormone deficiency analysis

PurposePatients with hypopituitarism are at increased cardiovascular risk, in part because of growth hormone deficiency (GHD), but probably also because of the overuse of glucocorticosteroids in concomitant adrenal insufficiency (AI). We hypothesized that patients with hypopituitarism that were on glucocorticosteroid replacement therapy for concomitant AI would have worse cardiovascular outcomes than those without.MethodsRetrospective nationwide cohort study. GHD patients from the Dutch National Registry of Growth Hormone Treatment in adults were grouped by the presence (AI; N = 1836) or absence (non-AI; N = 750) of concomitant AI, and differences between groups were analyzed for baseline characteristics and cardiovascular risk, at baseline and during GHRT.ResultsAt baseline, AI patients had higher levels of total and LDL cholesterol (both p < 0.01). During GHRT, AI patients were more likely to use cardiovascular drugs (p ≤ 0.01), but we did not find worse outcomes for blood pressure, body composition, lipid and glucose metabolism. The risk of developing peripheral arterial disease (HR 2.22 [1.06–4.65]) and non-fatal cerebrovascular events (HR 3.47 [1.60–7.52]) was higher in AI patients, but these differences disappeared in the models adjusted for baseline differences.ConclusionWe found no clear evidence to support our hypothesis that patients with hypopituitarism and concomitant AI have worse cardiovascular outcomes than non-AI patients. This suggests that glucocorticoid replacement therapy in AI may be safer than previously thought. However, cardiovascular burden, events and medication use at baseline and during GHRT (in unadjusted models) were higher in AI; so the lack of power, the important role of (adjusting for) other risk factors, and the inability to distinguish between glucocorticoid treatment regimens may have influenced the outcomes.