Hydrocortisone Replacement Therapy Research Articles

Postpartum pituitary necrosis and hypopituitarism, a sequela of severe falciparum malaria in pregnancy – a case report

A 37 year old woman presented with a history of weakness and lethargy for many years. She had been amenorrhoeic for 5 years after a still birth at 37 weeks gestation, due to severe falciparum malaria. On examination, she appeared pale and lethargic, with a blood pressure of 100/70 mm Hg. Her systemic examination was unremarkable. Laboratory tests revealed low 9.00 am serum ACTH and cortisol levels, along with low free T4, FSH and LH levels. A short synacthen test showed an inadequate cortisol response at 30 minutes. MRI of the Pituitary gland displayed an empty sella. She was diagnosed with hypopituitarism due to postpartum pituitary necrosis, and was treated with hydrocortisone, thyroxine and sex hormone replacement therapy. The patient showed an excellent response to treatment. Keywords: Postpartum, hypopituitarism, falciparum malaria.

Hyponatremia in Neurosurgical Patients

Hyponatremia refers to a common and potentially dangerous electrolyte imbalance observed in neurosurgical patients, particularly following traumatic brain injuries, subarachnoid hemorrhages, brain tumors, and pituitary surgeries. The paper discusses primary causes and pathophysiology of hyponatremia, including the syndrome of inappropriate secretion of antidiuretic hormone, central adrenal insufficiency, and cerebral salt wasting syndrome. The paper presents differential diagnostic approaches for accurately identifying the underlying causes of hyponatremia, as well as therapeutic strategies that include hypertonic sodium solution infusions, hydrocortisone replacement therapy, and the use of vasopressin receptor antagonists. The study delineates the potential complications associated with overly rapid correction of sodium levels, such as osmotic demyelination syndrome. It emphasizes the importance of accurate diagnosis and timely treatment to enhance patient outcomes and minimize the risk of complications.

8673 Exploring A Case Study On Navigating Complexities In Endocrine Health And Reproductive Challenges

Abstract Disclosure: S.Y. Rizvi: None. E. Villanueva: None. Introduction: Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting many reproductive-age women, characterized by irregular menstrual cycles, hirsutism, and challenges with fertility. In this case study, we delve into the medical history of a 24-year-old female presenting with PCOS-related symptoms, hirsutism, and infertility, unraveling the multifaceted aspects of her healthcare journey. Case Description: This patient's diagnostic path began when she received an initial diagnosis of PCOS in her home country due to irregular menstrual periods and clinical signs of hirsutism. Her treatment included metformin, but it was interrupted when she relocated to the United States. Upon her arrival in the U.S., her medical course took an unexpected turn as further evaluations revealed elevated salivary cortisol (++), and a 24-hour urine free cortisol recorded 94.2 mcg (normal 4-50 mcg), indicating hypercortisolism. DHEAS: 730 mcg/dl (normal 18-390 mcg/dl), 17-hydroxyprogesterone: 508 (pre-midluteal: 431), free testosterone: 13 pg/ml (normal 0.1-6.4 pg/ml), with normal CBC, TSH, prolactin, and TPO. CT scan showed large 4.8 cm left adrenal mass. These findings indicated adrenal Cushing's syndrome, leading to referral to a tertiary care hospital's endocrine surgeon. Two months post-adrenalectomy, successful removal of the adrenal mass left the patient with relative adrenal insufficiency. Hydrocortisone replacement therapy was initiated, addressing Cushing's syndrome and revealing a potential factor contributing to infertility. Postoperatively, the patient entered the first trimester unexpectedly, complicating her case. Ensuring proper hydrocortisone levels became crucial for her well-being and the fetus, prompting a collaborative approach with obstetricians and maternal-fetal medicine specialists for optimal pregnancy care. Despite ongoing PCOS effects, including hirsutism, treatment options were limited by pregnancy constraints, deferring Aldactone due to its contraindication during pregnancy. Continuous monitoring included hormonal assessments, metabolic panels, and thyroid tests, aiming to balance adrenal insufficiency, PCOS symptoms, and a healthy pregnancy. Conclusion: This case emphasizes challenges in differentiating PCOS from adrenal Cushing's due to overlapping symptoms. Despite classic symptoms, the initial PCOS misdiagnosis highlights the need for vigilance and comprehensive diagnostics. Complex cases underscore the importance of individualized management and interdisciplinary collaboration. Positive outcomes in complex endocrine disorders and pregnancy are attainable through accurate diagnoses and tailored treatments. The case underscores the critical importance of meticulous evaluation for successful outcomes in challenging medical scenarios. Presentation: 6/3/2024

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) 0.5–10 mg hydrocortisone as granules, (ii) 20 mg 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.Graphical

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.

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, < 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

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.

FRI202 A Curious Case Of Psychosis

Abstract Disclosure: F. Waqar: None. A. Arif: None. A. Muazzam: None. R. Wadood: None. A.S. Khakwani: None. U.A. Khan: None. Ascertaining the cause of mental and behavioral changes can be challenging in patients with complex medical histories. We are sharing a thought-provoking case of psychosis. A 51-year-old woman with past medical history of ESRD, stroke, diabetes, depression, and endometrial cancer was brought to the hospital for lethargy and confusion. It was preceded by some nausea, vomiting, and abdominal pain. Upon admission, she was noted to be hypotensive and minimally responsive. She was given fluids (with subsequent improvement in blood pressure) and started on antibiotics empirically for concerns of sepsis. During her hospital course, her mental status fluctuated from being completely normal to having episodes of becoming still, with total lack of response to any stimulus. During these episodes, she would be awake, breathing spontaneously and vitally stable, but unresponsive, mimicking catatonia however lacked muscle stiffness/ rigidity. Each episode resolved spontaneously after a few hours. Multiple CT scans and a CT Angiogram of the Head &amp; Neck were negative for acute findings. Continuous EEG revealed no epileptic activity. Infectious work-up was unrevealing. Labs were within the expected range of the intra-dialytic period. Two of her medications, gabapentin and mirtazapine were thought to be the contributors and were stopped upon admission, however with little improvement. Her symptoms were ultimately deemed to be psychogenic in origin, and she was started on an anti-psychotic regimen. Fortunately, as part of her workup, a morning cortisol level was checked, which resulted to be quite low at 1.6 mcg/dL, consistent with adrenal insufficiency. Co-syntropin stimulation test confirmed adrenal insufficiency, the actual cause of her presentation. This explained her intermittent hypotension along with mental and behavioral changes. Interestingly, she was found to be on megestrol acetate which is notorious for causing secondary adrenal insufficiency. She was ultimately started on hydrocortisone replacement therapy, with subsequent improvement and stabilization of her mental status, mood, and behavior; and was discharged with outpatient Endocrinology follow-up. This case highlights the importance of the broad differentials to consider for mental and behavioral changes. We want to alert physicians to include adrenal insufficiency in the differentials of acute psychosis as symptoms and electrolyte abnormalities may be atypical and masked in dialysis patients. The exact mechanism of neuropsychiatric symptoms (which may precede metabolic abnormalities) is unknown but is hypothesized to involve elevated levels of endorphins and electrophysiological disturbances as glucocorticoid receptors are widely distributed in the brain, specifically in the hippocampus. Megestrol is an established cause of secondary adrenal insufficiency, and monitoring is essential with long-term use. Presentation: Friday, June 16, 2023

THU243 Fitting Together The Pieces Of The Puzzle Between Isolated ACTH Deficiency And Immunodeficiency: DAVID Syndrome

Abstract Disclosure: K.V. Buchanan: None. A.C. Hurst: None. A.P. Ashraf: None. Objectives: DAVID syndrome is a rare genetic disorder with common variable immunodeficiency (CVID) and anterior pituitary hormonal deficiencies due to a pathogenic variant in NFKB2. We aim to describe asymptomatic ACTH deficiency identified after the diagnosis of CVID in a patient with DAVID syndrome. Methods: A retrospective chart review of a patient with DAVID syndrome was performed. Results: The patient is a 15 year and 9-month-old female with weight in the 71st percentile and height in the 64th percentile, who was diagnosed with DAVID syndrome at 10 years through a Primary Immunodeficiency panel which identified a pathogenic variant in NFKB2 c.2557C&amp;gt;T,p.Arg853* and a variant of unknown significance in STAT2 c.1301C&amp;gt;T (p.Thr434Met). The panel was performed due to the patient’s history of recurrent sinus infections, hypogammaglobulinemia, and alopecia totalis. The patient did not have symptoms of ACTH deficiency including hypoglycemia and hypotension. After the genetic diagnosis was made, an anterior pituitary hormone evaluation was performed which showed an ACTH &amp;lt;5 pg/ml, AM cortisol &amp;lt;0.2 mcg/dL, TSH 3.48 uIU/ml, FT4 0.82 ng/dL, thyroid peroxidase antibody 29 IU/mL (normal &amp;lt;9), somatomedin-c 44 ng/mL (reference range 152-593), LH 5.36 mIU/mL, and FSH 14.25 mIU/mL. Adrenal insufficiency was diagnosed since the patient did not show incremental cortisol response (serum cortisol &amp;lt;0.2 mcg/dL at 30 and 60 minutes) post Cosyntropin stimulation test. The patient had normal electrolytes. Hydrocortisone replacement therapy was initiated. A growth hormone stimulation test was not performed since the patient had normal height and interval height velocity. The thyroid function remained stable, and the patient attained menarche at age 14. Conclusions: This patient is unique in having asymptomatic, acquired, isolated ACTH deficiency diagnosed in later childhood, despite having frequent sinopulmonary infections since infancy as part of DAVID syndrome. Further research needs to be done to elucidate how NFKB2 variants contribute to acquired, isolated, central ACTH deficiency or autoimmune pituitary disease. Presentation: Thursday, June 15, 2023

SAT317 Adrenal Insufficiency Diagnosed During Pregnancy

Abstract Disclosure: A. Rosado-Burgos: None. L.N. Madera Marin: None. M.A. Ortiz-Rivera: None. L. El Musa Penna: None. W. Medina-Torres: None. L.R. Sepulveda-Garcia: None. M. Alvarado: None. L.A. Gonzalez-Rodriguez: None. M. Ramirez: None. Introduction: Primary adrenal insufficiency (AI) that is a potentially life-threatening condition and commonly associated to destruction of adrenal cortex by autoantibodies. AI predominantly affects women of reproductive age and can affect the outcome and course of pregnancy, causing reduced parity, risk of preterm birth, and low birth weight. Symptoms of AI are nonspecific and can result in a challenging diagnosis. Clinical case: 25 year-old pregnant female G1P0A0 at 12 weeks gestational age (WGA) with long standing history of Type 1 Diabetes Mellitus (DMT1) and Hypothyroidism. She was evaluated while hospitalized for metabolic control during pregnancy. The patient had been previously admitted at 7 WGA with hyperglycemic episodes requiring insulin dosing adjustments. Now, 5 weeks later, was found with numerous hypoglycemic episodes even after omitting pre-prandial insulins. Additionally, she had persistent fatigue, general malaise, nausea, vomits, anorexia, and difficulty concentrating. Laboratory workup showed a TSH of 22.96 uIU/mL (nl 0.4-4.0), FreeT4 0.91 (nl 0.89-1.74), that had been within normal limits 6 weeks prior. She reported taking pre-natal vitamins only one hour after LT4, therefore malabsorption was suspected. Insulin requirements were decreased by 50%. Vitals signs without evidence of hemodynamic instability and laboratory workup without electrolyte nor acid base disturbances. However, due to clinical presentation and history of other autoimmune diseases, AI was suspected. Severe hypothyroidism, AI and hyperemesis gravidarum can mimic several features of each other’s clinical presentation. Midmorning cortisol level was found at 7.8 ug/dl (nl for pregnancy &amp;gt;19) but no ACTH levels taken prior to replacement. Considering acuteness and severity of symptoms it was decided to administer IV LT4 equivalent dose which can increase cortisol metabolism precipitating adrenal crisis. For this reason, stress dose hydrocortisone (HC) was empirically administered. Rapid clinical improvement was observed after LT4 and corticosteroid replacement therapy with resolution of nausea, vomits, anorexia as well as hypoglycemic episodes and was discharge home with her usual LT4 PO dose and corticosteroid replacement therapy. Twenty-one-alpha hydroxylase antibodies were positive, making the diagnosis of primary adrenal insufficiency highly suspected. Conclusion: Presentation was consistent with Polyglandular Autoimmune Syndrome Type 2. Diagnosis of AI during pregnancy is rare as it is considered a hypercortisolemic state. Changes in cortisol levels during pregnancy make the diagnosis of AI even more challenging. Dynamic testing can be considered, however, most of these studies have not been validated in pregnancy. In this case patient continues with HC replacement therapy while in her 3rd trimester of pregnancy without any maternal of fetal complications. Presentation: Saturday, June 17, 2023

FRI255 Polyglandular Autoimmune Syndrome Type 2 Presenting With Severe Hyponatremia

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

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

Tissue Glucocorticoid Metabolism in Adrenal Insufficiency: A Prospective Study of Dual-release Hydrocortisone Therapy.

Patients with adrenal insufficiency (AI) require life-long glucocorticoid (GC) replacement therapy. Within tissues, cortisol (F) availability is under the control of the isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD). We hypothesize that corticosteroid metabolism is altered in patients with AI because of the nonphysiological pattern of current immediate release hydrocortisone (IR-HC) replacement therapy. The use of a once-daily dual-release hydrocortisone (DR-HC) preparation, (Plenadren®), offers a more physiological cortisol profile and may alter corticosteroid metabolism in vivo. Prospective crossover study assessing the impact of 12 weeks of DR-HC on systemic GC metabolism (urinary steroid metabolome profiling), cortisol activation in the liver (cortisone acetate challenge test), and subcutaneous adipose tissue (microdialysis, biopsy for gene expression analysis) in 51 patients with AI (primary and secondary) in comparison to IR-HC treatment and age- and BMI-matched controls. Patients with AI receiving IR-HC had a higher median 24-hour urinary excretion of cortisol compared with healthy controls (72.1 µg/24 hours [IQR 43.6-124.2] vs 51.9 µg/24 hours [35.5-72.3], P = .02), with lower global activity of 11β-HSD2 and higher 5-alpha reductase activity. Following the switch from IR-HC to DR-HC therapy, there was a significant reduction in urinary cortisol and total GC metabolite excretion, which was most significant in the evening. There was an increase in 11β-HSD2 activity. Hepatic 11β-HSD1 activity was not significantly altered after switching to DR-HC, but there was a significant reduction in the expression and activity of 11β-HSD1 in subcutaneous adipose tissue. Using comprehensive in vivo techniques, we have demonstrated abnormalities in corticosteroid metabolism in patients with primary and secondary AI receiving IR-HC. This dysregulation of pre-receptor glucocorticoid metabolism results in enhanced glucocorticoid activation in adipose tissue, which was ameliorated by treatment with DR-HC.

Immune-related adrenal insufficiency: A single center retrospective analysis.

2659 Background: Immune checkpoint inhibitors (ICI) became widely used for treatment of various malignancies. They may cause different immune-related adverse events (irAEs), including adrenal insufficiency (irAI). IrAI was reported to be comparatively uncommon but potentially life threatening. We conducted a retrospective single center study to identify and describe the incidence and characteristics of AI associated with ICI. Methods: We reviewed the medical records of patients treated at an oncological department at Loginov Moscow Clinical Scientific Center between Sep’2019 and Jan’2023 with immunotherapy under direct cortisol monitoring every 6-8 weeks. The main criteria for AI was low serum cortisol in the absence of glucocorticoid intake. Results: A total 101 patients (pts) treated by ICI or ICI in combination with chemotherapy or targeted therapy for various malignancies were included in our retrospective analysis. 16 patients (15.8%) were diagnosed with AI: 7 pts with renal cell carcinoma (RCC), 6 pts with melanoma (2 in adjuvant setting), 1 with non-small-cell lung cancer (NSCLC), 1 with small-cell lung cancer (SCLC), 1 with MSI-high colorectal cancer (CRC). Median age was 65 (range 46-79), the majority (10 pts, 62.5%) were male. The median time of irAI onset from ICI start was 5 months (range 2-15). Assessment of serum cortisol was performed every 6-8 weeks routinely and off-schedule in patients who had new onset AI-like symptoms. The most frequent symptoms were unspecific and included fatigue and weakness (100%), loss of appetite/anorexia (69%), hypotension (50%), weight loss (44%), insomnia (38%), chills (31%), nausea/vomiting (31%), muscle pain or cramps (31% and 25% respectively), dizziness (25%), dry mouth (25%), headache (13%), fever (6%). Remarkably, laboratory detected serum cortisol decline preceded any AI symptoms in 7 patients (43.7%). Other 7 patients (43.7%) had concurrent secondary hypothyroidism which suggested panhypopituitarism. Hydrocortisone replacement led to rapid symptoms recovery in 15/16 patients. Additional treatment with fludrocortisone was required for only one patient who had primary/mixed AI due to bilateral metastases of RCC in adrenal glands. All patients resumed immunotherapy after symptoms resolved. Only 1 patient needed treatment modification (ipilimumab cessation). By 12th February 2023 median follow-up from irAI onset is 7 months (range 0.5-37), 12 patients are alive, they all remain on permanent hydrocortisone replacement therapy. Conclusions: Routine cortisol assessment during immunotherapy allowed us to detect irAI in 15.8% of patents that is higher than usually reported. Detection of irAI before clinical presentation let us prevent severe consequences including life threating. We consider that routine cortisol assessment during immunotherapy should be implemented in clinical practice.

Model-Informed Target Morning 17α-Hydroxyprogesterone Concentrations in Dried Blood Spots for Pediatric Congenital Adrenal Hyperplasia Patients

Monitoring cortisol replacement therapy in congenital adrenal hyperplasia (CAH) patients is vital to avoid serious adverse events such as adrenal crises due to cortisol underexposure or metabolic consequences due to cortisol overexposure. The less invasive dried blood spot (DBS) sampling is an advantageous alternative to traditional plasma sampling, especially in pediatric patients. However, target concentrations for important disease biomarkers such as 17α-hydroxyprogesterone (17-OHP) are unknown using DBS. Therefore, a modeling and simulation framework, including a pharmacokinetic/pharmacodynamic model linking plasma cortisol concentrations to DBS 17-OHP concentrations, was used to derive a target morning DBS 17-OHP concentration range of 2-8 nmol/L in pediatric CAH patients. Since either capillary or venous DBS sampling is becoming more common in the clinics, the clinical applicability of this work was shown by demonstrating the comparability of capillary and venous cortisol and 17-OHP concentrations collected by DBS sampling, using a Bland-Altman and Passing-Bablok analysis. The derived target morning DBS 17-OHP concentration range is a first step towards providing improved therapy monitoring using DBS sampling and adjusting hydrocortisone (synthetic cortisol) dosing in children with CAH. In the future, this framework can be used to assess further research questions, e.g., target replacement ranges for the entire day.

Intraoperative hypovolemia as a possible precipitating factor for pituitary apoplexy: a case report

BackgroundPituitary apoplexy is acute infarction with or without hemorrhage of the pituitary gland. It is a rare but potentially life-threatening emergency that most commonly occurs in the setting of pituitary adenoma. The mechanisms underlying pituitary apoplexy are not well understood, but are proposed to include factors of both hemodynamic supply and adenoma demand. In the case of patients with known pituitary macroadenomas undergoing major surgery for other indications, there is a theoretically increased risk of apoplexy in the setting of “surgical stress.” However, risk stratification of patients with nonfunctioning pituitary adenomas prior to major surgery is challenging because the precipitating factors for pituitary apoplexy are not completely understood. Here we present a case in which intraoperative hypovolemia is a possible mechanistic precipitating factor for pituitary apoplexy.Case presentationA 76-year-old patient with a known hypofunctioning pituitary macroadenoma underwent nephrectomy for renal cell carcinoma, during which there was significant intraoperative blood loss. He became symptomatic with ophthalmoplegia on the second postoperative day, and was diagnosed with pituitary apoplexy. He was managed conservatively with cortisol replacement therapy, and underwent therapeutic anticoagulation 2 months after pituitary apoplexy for deep vein thrombosis. His ophthalmoplegia slowly resolved over months of follow-up. Pituitary apoplexy did not recur with therapeutic anticoagulation.ConclusionsWhen considering the risk of surgery in patients with a known pituitary macroadenoma, an operation with possible high-volume intraoperative blood loss may have increased risk of pituitary apoplexy because intraoperative hypovolemia may precipitate ischemia, infarction, and subsequent hemorrhage. This may be particularly relevant in the cases of elective surgery. Additionally, we found that we were able to therapeutically anticoagulate a patient 2 months after pituitary apoplexy for the management of deep vein thrombosis without recurrence of pituitary apoplexy.

A case of pituitary gland abscess associated with granulomatous hypophysitis

BackgroundGranulomatous hypophysitis is a rare disease that presents with chronic inflammation of the pituitary gland. In this study, we reported a case of granulomatous hypophysitis associated with a pituitary abscess.Case presentationA 39-year-old woman presented with a 2-year history of infertility. For the past six months, she has suffered from amenorrhea, decreased libido, headaches, and vertigo. She was referred to our hospital with a suspected diagnosis of nonfunctioning pituitary adenoma based on her presentation and brain MRI findings. She underwent trans-sphenoidal surgery (TSS). Direct observation during surgery revealed drainage of malodor pus and pituitary gland abscess. The histopathological evaluation also showed granulomatous hypophysitis and neutrophilic microabscess formation.The patient was initially treated with high doses of ceftriaxone (2 g twice daily) and metronidazole (500 mg (mg) four times per day). Also, the patient received cortisol replacement therapy after the operation. After obtaining the antibiogram and culture results, the treatment regimen was continued for 4 weeks postoperatively, followed by amoxicillin-clavulanate (500/125 mg three times daily) for a total duration of 12 weeks.ConclusionThe patient recovered uneventfully and the postoperative MRI was normal without any remnant lesions.

Insights in the maturational processes influencing hydrocortisone pharmacokinetics in congenital adrenal hyperplasia patients using a middle-out approach.

Introduction: Hydrocortisone is the standard of care in cortisol replacement therapy for congenital adrenal hyperplasia patients. Challenges in mimicking cortisol circadian rhythm and dosing individualization can be overcome by the support of mathematical modelling. Previously, a non-linear mixed-effects (NLME) model was developed based on clinical hydrocortisone pharmacokinetic (PK) pediatric and adult data. Additionally, a physiologically-based pharmacokinetic (PBPK) model was developed for adults and a pediatric model was obtained using maturation functions for relevant processes. In this work, a middle-out approach was applied. The aim was to investigate whether PBPK-derived maturation functions could provide a better description of hydrocortisone PK inter-individual variability when implemented in the NLME framework, with the goal of providing better individual predictions towards precision dosing at the patient level. Methods: Hydrocortisone PK data from 24 adrenal insufficiency pediatric patients and 30 adult healthy volunteers were used for NLME model development, while the PBPK model and maturation functions of clearance and cortisol binding globulin (CBG) were developed based on previous studies published in the literature. Results: Clearance (CL) estimates from both approaches were similar for children older than 1 year (CL/F increasing from around 150 L/h to 500 L/h), while CBG concentrations differed across the whole age range (CBGNLME stable around 0.5 μM vs. steady increase from 0.35 to 0.8 μM for CBG PBPK). PBPK-derived maturation functions were subsequently included in the NLME model. After inclusion of the maturation functions, none, a part of, or all parameters were re-estimated. However, the inclusion of CL and/or CBG maturation functions in the NLME model did not result in improved model performance for the CL maturation function (ΔOFV > -15.36) and the re-estimation of parameters using the CBG maturation function most often led to unstable models or individual CL prediction bias. Discussion: Three explanations for the observed discrepancies could be postulated, i) non-considered maturation of processes such as absorption or first-pass effect, ii) lack of patients between 1 and 12 months, iii) lack of correction of PBPK CL maturation functions derived from urinary concentration ratio data for the renal function relative to adults. These should be investigated in the future to determine how NLME and PBPK methods can work towards deriving insights into pediatric hydrocortisone PK.

LAPAROSCOPIC ADRENAL-SPARING SURGERY CASE SERIES: PARTIAL ADRENALECTOMY AND CYST RESECTION.

The aim is to present our case series documenting indications, laparoscopic technique, surgical and endocrinologic outcomes of laparoscopic partial adrenalectomy. In the period from April 2011 until October 2021, we performed 39 procedures. The patients were divided into three groups: unilateral adrenal gland tumor with a normal contralateral gland (group 1), tumor of the solitary adrenal gland (group 2), and adrenal cysts (group 3). There were 20 patients in group 1, 6 patients in group 2, and 13 patients in group 3. The most common histology in group 1 was adenoma (40%), all tumors in group 2 were renal cell carcinoma metastases, and all cysts in group 3 were benign. There were no major complications (Clavien Dindo grade ≥2) in the whole cohort. All patients in groups 1 and 3 had favorable endocrinologic outcomes, and 50% of group 2 patients required lifelong hydrocortisone replacement therapy. The procedure is safe and feasible with favorable outcomes in the hands of a high volume adrenal surgeon.