Mineralocorticoid Replacement Research Articles

Adrenal insufficiency and the use of mineralocorticoid treatment in male patients with adrenoleukodystrophy; a retrospective analysis of an institutional database

IntroductionAdrenoleukodystrophy (ALD) patients exhibit three primary clinical phenotypes: primary adrenal insufficiency, adrenomyeloneuropathy, and cerebral demyelination due to the accumulation of saturated very long-chain fatty acids in the adrenal cortex and central nervous system white matter and axons. We investigated the diagnosis of adrenal insufficiency (AI) and the use of mineralocorticoid treatment in male ALD patients.MethodsA retrospective chart review of electronic medical records was conducted for all ALD patients at a single institution between January 1, 2011, and December 6, 2021.ResultsAmong the 437 ALD patients, 82% were male and 18% were female. Of the male ALD patients, 60% (213 out of 358) had a diagnosis of AI, and 39% (84 out of 213) of those with AI were prescribed mineralocorticoid replacement therapy.ConclusionAI is highly prevalent among ALD patients, with approximately 40% of those with a diagnosis of AI undergoing mineralocorticoid replacement therapy. Further research is warranted to delineate the characteristics of patients predisposed to developing mineralocorticoid deficiency within the context of ALD and AI.

Tratamiento de la insuficiencia suprarrenal

Adrenal insufficiency is an endocrine disorder with a low prevalence, though it can potentially be severe if not treated. Hemodynamic collapse and refractory hypotension characterize an acute adrenal crisis. Treatment must never be delayed while awaiting biochemical results in these cases. Hydrocortisone, the pharmacological name for cortisol, is the drug of choice, as it has greater mineralocorticoid activity than other synthetic glucocorticoids. During an acute crisis, clearly supraphysiological doses should be used together with aggressive fluid replacement until hemodynamic stabilization is achieved. In patients with chronic manifestations, the maintenance dose is 15 to 25mg, accompanied by mineralocorticoid replacement if the origin of the AI is primary. Clinical response is the best indicator of treatment response. Patient education is fundamental and should be aimed at recognizing an acute crisis and how to act in stressful situations in order to prevent them.

Severe adrenal insufficiency in six neonates with normal newborn screening for CAH.

Newborn screening (NBS) reduces the risk of mortality in congenital adrenal hyperplasia (CAH), mainly due to the salt-wasting form of 21-hydroxylase deficiency. There is limited knowledge regarding the results of NBS in non-CAH primary adrenal insufficiency (non-CAH PAI). Clinical and NBS for CAH data of neonates who were diagnosed with non-CAH PAI between January and December 2022 were examined. Patients (n = 6, 4 females) were presented with severe hyperpigmentation (n = 6), hypoglycemia (n = 4), hyponatremia (n = 3), hyperkalemia (n = 1), respiratory distress syndrome (n = 1) between 3rd hour to 2 months of life. All had normal NBS results. The median first-tier 17-hydroxyprogesterone (17OHP) concentration in NBS for CAH was 0.14 ng/mL (range; 0.05-0.85). Molecular studies revealed biallelic mutations in the MC2R (n = 4; 3 homozygous, 1 compound heterozygous), MRAP (n = 1) and STAR (n = 1) genes. Glucocorticoid with or without mineralocorticoid replacement was initiated once the diagnosis ofnon-CAH PAI was established. Neonates with non-CAH PAI have always normal NBS due to persistently low 17OHP, even when these newborn infants are severely symptomatic for adrenal insufficiency. Clinicians should be alert for signs of adrenal insufficiency in neonates, even if the patient has a 'normal' screening for CAH, so as not to delay diagnosis and treatment. This fact should be kept in mind particularly in countries where these conditions are more common than elsewhere.

Performance of renin assays in selecting fludrocortisone dose in children with adrenal disorders.

Children with salt-wasting adrenal insufficiency are managed with glucocorticoid and mineralocorticoid replacement. Measurement of renin activity or concentration alongside blood electrolyte levels is used to monitor the adequacy of mineralocorticoid replacement. Our unit changed from using renin activity to renin concentration and carried out a service review to assess whether this influenced decision-making for fludrocortisone dosing. In total, 50 measurements of plasma renin activity and 50 of renin concentration were analysed on separate cohorts before and after the assay change, with values standardised to multiples of the upper limit of normal (MoU) to allow comparison between assays. We were more likely to increase the fludrocortisone dose for a raised renin concentration than a raised renin activity. The renin concentration MoU was more strongly related to plasma sodium (negatively) and 17α-hydroxyprogesterone (17α-OHP) (positively) than the renin activity MoU. Using a MoU cut-off of 1.5, a decision to increase the dose of fludrocortisone was more likely to be made when using the renin concentration assay compared with the activity assay. Using a cut-off of 40 nmol/L for 17α-OHP, a decision not to change the fludrocortisone dose when 17α-OHP was <40 was more likely when using the renin concentration assay. For both assays, a plasma sodium <140 mmol/L was more likely to lead to a fludrocortisone dose increase, and most likely for the renin concentration assay. Overall, the decision to adjust fludrocortisone dose in this cohort of children with adrenal insufficiency was better supported by the biochemical parameters when based on renin concentration results and clinical status.

Current Update on the Management and Treatment of Congenital Adrenal Hyperplasia

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

Fertility and pregnancy in adrenal insufficiency.

Despite the availability of adrenal hormone replacement therapy, patients with adrenal insufficiency can be affected by reduced fertility and parity. Patients with well-managed adrenal insufficiency are expected to have uneventful pregnancies and favourable outcomes, but an increased risk of maternal and neonatal complications has been reported in some cases. Many physiological changes occur to the hypothalamic-pituitary-adrenal (HPA) axis during pregnancy, often making a new diagnosis and management of adrenal insufficiency challenging. The management of adrenal insufficiency also needs to reflect the physiologic changes of pregnancy, often requiring increased doses of glucocorticoid as pregnancy progresses and in some circumstances mineralocorticoid replacement (in primary adrenal insufficiency patients only), especially in the third trimester. To date, there are no prospective data guiding management of adrenal insufficiency in pregnancy. In this review, we focus on the impact of adrenal insufficiency on fertility and parity based on the aetiology of adrenal insufficiency and provide a practical approach to the management of patients with adrenal insufficiency before and during pregnancy.

SAT286 Effect of Tildacerfont On Gonadotropins And Testicular Steroidogenesis In Men With Classic 21-hydroxylase Deficiency

Abstract Disclosure: R. Charlton: Employee; Self; Spruce Biosciences, Inc. A. Khattab: Consulting Fee; Self; Antares Pharma, Inc. R.J. Auchus: Grant Recipient; Self; Spruce Biosciences, Inc. Research Investigator; Self; Spruce Biosciences, Inc. Impaired testicular function is a common comorbidity of classic 21-hydroxylase deficiency (21OHD). Testicular adrenal rest tumors (TART) can disrupt testicular architecture and cause primary hypogonadism. Both supraphysiologic glucocorticoid doses and adrenal-derived androgens and estrogens can suppress gonadotropins and cause secondary hypogonadism. We conducted a post-hoc analysis of gonadal axis function in men with 21OHD participating in SPR001-201 and SPR001-202, two phase 2 studies of tildacerfont, a once-daily oral corticotrophin-releasing factor receptor 1 (CRFR1) antagonist, designed to reduce ACTH and adrenal steroid production, including androstenedione (A4). Study 201 included 3 cohorts: Cohort A, 5 men who received tildacerfont in a 6-week dose escalation - 2 weeks at 200 mg QD, 2 weeks at 600 mg QD, and 2 weeks at 1000 mg QD without washout between doses; Cohort B, 1 man who received tildacerfont for 2 weeks at 200 mg BID; and Cohort C, 4 men who received tildacerfont for 2 weeks at 100 mg BID. Study 202 included 4 men who received tildacerfont 400 mg QD for 12 weeks. Participants continued their previously prescribed glucocorticoid ± mineralocorticoid replacement without dose adjustments. Geometric means were used to describe hormone levels due to the small participant numbers. Mean and median ages were 46/32y in Study 201 and 32/35y in Study 202 (range 18-54 in both studies). All participants reported race as white except one who identified as white and Asian. Four reported ethnicity as Hispanic or Latino. At baseline, testosterone (T) levels were normal except for four 201 participants that had T &amp;lt;300 ng/dL. At baseline, 6/11 (55%) had suppressed LH (including the four with low T), and 11/14 (79%) had A4/T ratios &amp;gt;1, indicating a predominantly adrenal origin of T. In Study 201, mean T levels increased in Study 201 from 375.5 ng/dL to 390.5 ng/dL at week 2 (n=9), 485.4 ng/dL at week 4 (n=4) and 420.7 ng/dL at week 6 (n=4). In Study 202, mean T levels were 448.4 ng/dL at baseline and 412.0 ng/dL at week 12. Mean LH levels increased in Study 201 from 0.68 IU/L to 1.59 IU/L at week 2 (n=10), 1.62 IU/L at week 4 (n=5) and 0.85 IU/L at week 6 (n=4) (normal 1.8-8.6IU/L). In Study 202, mean LH levels increased from 0.44 IU/L at baseline to 0.87 IU/L at week 12. Of the four men who had low T and suppressed LH (hypogonadotropic hypogonadism), LH rose in all 4 and normalized in 3/4 (75%). Mean A4/T ratios decreased across both studies. In Study 201, the mean declined from a baseline of 1.28 to 0.59 at week 2 (n=9), 0.87 at week 4 (n=4), and 1.03 at week 6 (n=4). In Study 202, the A4/T ratio decreased from baseline of 2.44 to 0.68 at week 12. All the hypogonadal men experienced reductions in A4/T ratios, and 3/4 (75%) achieved A4/T &amp;lt;1. This post-hoc analysis highlights that gonadal axis disruption is common in men with 21OHD and suggests that modulation of adrenal androgen production via CRFR1 antagonism may improve testicular function. Presentation: Saturday, June 17, 2023

THU186 A Case Of 3beta-hydroxysteroid Dehydrogenase Type2 Deficiency Diagnosed By Whole Genome Sequencing In A Patient With Congenital Adrenal Hyperplasia

Abstract Disclosure: S. Chang: None. C. Kim: None. 3β-hydroxysteroid dehydrogenase type 2 deficiency (3βHSD2D) is a very rare type of congenital adrenal hyperplasia (CAH) caused by HSD3B2 gene mutations. The estimated prevalence is less than 0.5% of all CAH and less than 1/1,000,000 at birth. It is a disorder of impaired steroidogenesis and sex steroid deficiency characterized by variable degrees of salt wasting, hypoglycemia, male incomplete masculinization and female virilization. Some newborns with 3βHSD2D have increased level of 17-hydroxyprogesterone (17OHP) that clinicians misdiagnose them as having classic 21-hydroxylase deficiency. A male newborn was referred to our hospital for generalized hyperpigmentation. Laboratory test showed hyponatremia, hyperkalemia and hypoglycemia. Hormonal study showed high level of adrenocorticotropic hormone, 17OHP, progesterone, renin activity, dehydroepiandrosterone (DHEA), androstenedione and low level of aldosterone. Clinically diagnosing with CAH, we administered glucocorticoid and mineralocorticoid replacement. We performed PCR sequencing for CYP21A2 gene mutation to confirm 21 hydroxylase deficiency but revealed normal result. After follow-up for 17 years with replacement treatment, he happened to have the opportunity to perform whole genome sequencing. Whole genome sequencing allowed to detect two pathogenic mutations in the HSD3B2 gene, described in compound heterozygosity (p.Arg249Ter and c.-149_143-1766del). One mutation (c.-149_143-1766del) is inherited from his father and the mother was not done for gene study. While there have been less than 100 cases of 3βHSD2D reported worldwide, in our best knowledge, this is the first case of genetically confirmed 3βHSD2D in Korea. Presentation: Thursday, June 15, 2023

SAT322 Case report: Impact Of Combined Treatment To Prolong Overall Survival In Advanced Adrenocortical Pediatric Cancer Associated With Li-Fraumeni Syndrome

Abstract Disclosure: I.P. de Magalhães: None. N.C. de Sousa: None. H.L. Charchar: None. A.W. Kuhn: None. M.Y. Nishi: None. F.L. Ledesma: None. R.I. Lopes: None. F.T. Dénes: None. P. Herman: None. M.R. Menezes: None. A. Latronico: None. B.B. Mendonca: None. M.Q. Almeida: None. M.B. Fragoso: None. Background: Adrenocortical cancer (ACC) in pediatric patients (&amp;lt;15 years of age) are even rarer compared to the general population it is a classic presentation of Li-Fraumeni syndrome (LFS). ACC incidence in this subgroup is limited to 0.3 cases per million per year with a high incidence in Sothwest of Brazil. Furthermore, the overall five-year survival of pediatric ACC cases is better than in adult with a rate of approximately 50%, considering a complete resection required for cure. However, prognosis of childhood ACC is highly variable and difficult to predict in clinical practice. Clinical Case: We present the case of a 3-year-old girl who was diagnosed with metastatic adrenocortical carcinoma with classical signs of virilization and Cushing's syndrome. The patient underwent transperitoneal right adrenalectomy in May 2011. During surgery, there was rupture of the tumor capsule and the inferior vena cava. She was referred to our service after 8 months due to the presence of locoregional recurrence and maintained hormonal secretion. Histological data confirmed ACC and the tumor was classified as Weiss score 5, Wieneke: 4, Ki67 40%. Genetic analysis identified germline confirmed p-R337H on TP53, XAF1-E134. Imaging exams documented suspected liver metastasis and peritoneal implants. She underwent palliative treatment with mitotane (M) and systemic chemotherapy EDP+M with partial response. A new surgical approach to the residual lesions was proposed. The patient underwent right partial hepatectomy and peritoneal implant removed in September 2012. After metastasectomy, the patient presented persistence of the disease. The patient was exposed to a new cycle of EDP+M, but the disease progressed. She underwent radiofrequency ablation of abdominal lesions in July 2013 without success. A new surgical approach was indicated in July 2013. The histological analysis confirmed metastases of ACC. She underwent a new chemotherapy regimen with gemcitabine, docetaxel and fluorouracil + M. She presented a complete response confirmed by radiological exams and hormonal data. Mitotane was discontinued in 2016 due to bladder bleeding. She presented an excellent response with combined treatment, without recurrence up to now with 10 years of recurrence free survival and 12 years of overall survival. She developed normal puberty and reached the target height and maintains primary adrenal insufficiency with glico and mineralocorticoid replacement. Although the tumor spillage, histological and molecular data predicted a dismal outcome this patient surprisingly is presenting an excellent evolution under continuous surveillance. Clinical Lesson: This report described a challenging pediatric advanced ACC which the combined treatment strategy provided successful outcome Presentation: Saturday, June 17, 2023

FRI241 Late Diagnosis Of Non-classical CAH In An Elderly Male Previously Diagnosed With Estrogen Producing Adrenal Tumor

Abstract Disclosure: R. Kaval: None. J. Subauste: None. In 2013 a 66-year-old Caucasian male presented to the VA outpatient endocrinology clinic to establish care; the patient carried a diagnosis of estrogen producing left adrenal tumor in 1989 at the age of 42 at an outside facility. On review of records the patient was initially worked up for hypogonadism and was noted to have an elevated estrogen level and a “left adrenal tumor”. He subsequently underwent an unilateral left adrenalectomy for treatment and pathology reported with benign tumor findings. Following surgery, the patient was started on steroid and mineralocorticoid replacement for primary adrenal insufficiency (PAI) and topical testosterone gel for hypogonadism. The question was raised as to why this patient had PAI as he had an intact right adrenal gland on CT scan. On laboratory work-up in 2006 the patient had baseline cortisol of 3.4 ug/dl, ACTH was elevated at 99 pg/ml [7.2- 63.3], and adrenal antibodies (21-OH antibody] were negative. Renin was 2.35 ng/ml/hr [0.167-5.380], Estradiol was 41.8 pg/ml [7.6 - 42.6], LH was low at 0.20 mIU/ml [1.2-8.6] and total testosterone was low at 2.2 ng/ml [1.8-7.8]. Repeat testing yielded ACTH that was elevated at 686.7 pg/ml [7.2- 63.3], electrolytes including sodium and potassium were normal. On physical examination the patient had hyperpigmented skin, normal height, weight and otherwise unremarkable. On CT scan of the abdomen the right adrenal gland was mildly diffusely enlarged. In 2019, 30 years after his initial diagnosis the team questioned whether the adrenal tumor was truly an estrogen producing tumor. As a result, 17-OH progesterone was obtained, and the unstimulated value resulted as 3522 ng/dl [27-199]. With the elevated 17 OH &amp;gt;1000 ng/dL this was diagnostic for Non-classical CAH. The unilateral adrenalectomy likely unmasked the underlying impairment of cortisol production leading to primary AI that is seen with Non-classical CAH patients. The patient was lost to follow up during the pandemic, hence we were not able to perform and further testing. Presentation: Friday, June 16, 2023

FRI259 Antiphospholipid Syndrome And Adrenal Insufficiency: An Underrated Association

Abstract Disclosure: S. Khalid: None. M. Arumugam: None. P. Passarella: None. Introduction: Catastrophic Antiphospholipid Syndrome (CAPS) is a rare and life-threatening subtype of Antiphospholipid Syndrome (APS) that causes widespread vascular thrombi. Endocrine complications of APS are very rare, however the most common is Adrenal Insufficiency (AI). Overt AI is only found in 0.4% of patients with APS while only 0.5% of patients with AI are diagnosed with APS. Either thrombosis leading to infarction or hemorrhage can cause AI in patients with APS. Sometimes, adrenal insufficiency or crisis can be the primary presentation of APS. Here, we present a case of AI in the setting of CAPS. Case Presentation: A 17-year-old woman with past medical history of chronic immune thrombocytopenia was admitted to the intensive care unit due to cardiogenic and distributive shock. One week prior to her presentation she had developed a sore throat followed by progressive lethargy that eventually evolved into a state of unconsciousness and she was brought to the emergency department. Her presenting vital signs included temperature of 40.7 C and blood pressure of 89/36 mmHg. On physical exam, she appeared somnolent and pale, and had cool extremities. Labs on admission (11 pm) revealed cortisol level of 3.6 UG/DL (reference range 3.8-19.4 UG/DL), TSH 4.61 UIU/ml (reference range 0.45-4.5 UIU/ml), free T4 1.3 ng/dl (reference range 0.6-1.3 ng/dl), aldosterone 11.3 ng/dl (reference range supine &amp;lt; 3-39.2 ng/dl), sodium 135 MEQ/L (reference range 135-145 MEQ/L), and potassium 4.7 MEQ/L (reference range 3.5-5.2 MEQ/L). Echocardiogram was remarkable for new onset reduced ejection fraction of 25-30% and left ventricular thrombi. Additionally, brain MRI showed acute infarcts. Due to concern for an underlying rheumatological disease, extensive autoimmune work up was initiated, and she was started empirically on methylprednisolone 30 mg intravenous twice daily. To further evaluate thrombi, CT scan of the abdomen and pelvis was performed, revealing bilaterally enlarged and hypoenhancing adrenal glands likely related to ischemia or infarction along with left renal vein thrombosis. Laboratory work-up returned positive for anti-cardiolipin IgM and IgG antibodies. In the setting of multiple vascular thrombi and positive antibodies, she was diagnosed with CAPS. The diagnosis of AI was made due to a low cortisol level in a state of shock and was deemed secondary to CAPS. For the treatment of CAPS she was continued on methylprednisolone with a plan for a slow taper. To ensure mineralocorticoid replacement was adequate fludrocortisone was also added at a dose of 0.1 mg with close monitoring of electrolytes and vital signs. Conclusion: Our case illustrates a rare though potentially fatal endocrine complication of CAPS and highlights the importance of its awareness. Undiagnosed and untreated adrenal insufficiency can lead to extremely poor outcomes, including death. Presentation: Friday, June 16, 2023

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

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

Mineralocorticoid replacement therapy in salt-wasting congenital adrenal hyperplasia.

Patients with salt-wasting congenital adrenal hyperplasia (SW-CAH) usually show pronounced impairment of aldosterone secretion and, therefore, also require mineralocorticoid replacement. While a lot of research and discussion focusses on the glucocorticoid therapy in SW-CAH to replace the missing cortisol and to control adrenal androgen excess, very little research is dealing with mineralocorticoid replacement. However, recent data demonstrated an increased cardiovascular risk in adult CAH patients urging to reflect also on the current mineralocorticoid replacement therapy. In this review, we explain the role and function of the mineralocorticoid receptor, its ligands and inhibitors and its relevance for the therapy of patients with SW-CAH. We performed an extensive literature search and present data on mineralocorticoid therapy in SW-CAH patients as well as clinical advice how to monitor and optimise mineralocorticoid replacement therapy.

Assessing treatment adherence is crucial to determine adequacy of mineralocorticoid therapy.

There is no consensus strategy for mineralocorticoid (MC) therapy titration in patients with primary adrenal insufficiency (PAI). We aim to measure serum fludrocortisone (sFC) and urine fludrocortisone (uFC) levels and to determine their utility, alongside clinical/biochemical variables and treatment adherence to guide MC replacement dose titration. Multi-centre, observational, cross-sectional study on 41 patients with PAI on MC replacement therapy. sFC and uFC levels (measured by liquid chromatography-tandem mass spectrometry), plasma renin concentration (PRC), electrolytes (Na+, K+), mean arterial blood pressure (MAP), total daily glucocorticoid (dGC) and MC (dMC) dose, and assessment of treatment adherence were incorporated into statistical models. We observed a close relationship between sFC and uFC (r = 0.434, P = 0.005) and between sFC and the time from the last fludrocortisone dose (r = -0.355, P = 0.023). Total dMC dose was related to dGC dose (r = 0.556, P < 0.001), K+ (r = -0.388, P = 0.013) as well as sFC (r = 0.356, P = 0.022) and uFC (r = 0.531, P < 0.001). PRC was related to Na+ (r = 0.517, P < 0.001) and MAP (r = -0.427, P = 0.006), but not to MC dose, sFC or uFC. Regression analyses did not support a role for sFC, uFC or PRC measurements and confirmed K+ (B = -44.593, P = 0.005) as the most important variable to guide dMC titration. Of the patients, 32% were non-adherent with replacement therapy. When adherence was inserted into the regression model, it was the only factor affecting dMC. sFC and uFC levels are not helpful in guiding dMC titration. Treatment adherence impacts on clinical variables used to assess MC replacement and should be included as part of routine care in patients with PAI.

Differentiation of human adipose tissue–derived mesenchymal stromal cells into steroidogenic cells by adenovirus-mediated overexpression of NR5A1 and implantation into adrenal insufficient mice

Background aimsCell therapy for adrenal insufficiency is a potential method for physiological glucocorticoid and mineralocorticoid replacement. We have previously shown that mouse mesenchymal stromal cells (MSCs) differentiated into steroidogenic cells by the viral vector–mediated overexpression of nuclear receptor subfamily 5 group A member 1 (NR5A1), an essential regulator of steroidogenesis, and their implantation extended the survival of bilateral adrenalectomized (bADX) mice. MethodsIn this study, we examined the capability of NR5A1-induced steroidogenic cells prepared from human adipose tissue-derived MSCs (MSC [AT]) and the therapeutic effect of the implantation of human NR5A1-induced steroidogenic cells into immunodeficient bADX mice. ResultsHuman NR5A1-induced steroidogenic cells secreted adrenal and gonadal steroids and exhibited responsiveness to adrenocorticotropic hormone and angiotensin II in vitro. In vivo, the survival time of bADX mice implanted with NR5A1-induced steroidogenic cells was significantly prolonged compared with that of bADX mice implanted with control MSC (AT). Serum cortisol levels, which indicate hormone secretion from the graft, were detected in bADX mice implanted with steroidogenic cells. ConclusionsThis is the first report to demonstrate steroid replacement by the implantation of steroid-producing cells derived from human MSC (AT). These results indicate the potential of human MSC (AT) to be a source of steroid hormone-producing cells.

Modified-release hydrocortisone is associated with lower plasma renin activity in patients with salt-wasting congenital adrenal hyperplasia.

Poorly controlled salt-wasting (SW) congenital adrenal hyperplasia (CAH) patients often require high 9α-fluorocortisol doses as they show high levels of 17-hydroxyprogesterone (17OHP), which is a mineralocorticoid (MC)-receptor antagonist. We investigated the renin-angiotensin-aldosterone system in patients with SW-CAH receiving twice daily modified-release hydrocortisone (MR-HC, Efmody) compared with standard glucocorticoid (GC) therapy. Data were analyzed from the 6-month, phase 3 study of MR-HC (n = 42) versus standard GC therapy (n = 41). MC replacement therapy remained unchanged throughout the study. Blood pressure, serum potassium, serum sodium, plasma renin activity (PRA), and serum 17OHP and androstenedione concentrations were analyzed at baseline, 4, 12, and 24 weeks. The median serum 17OHP in the morning was significantly lower on MR-HC compared with standard GC at 24 weeks (2.5 nmol L-1 (IQR 8.3) versus 10.5 nmol L-1 (IQR 55.2), P = .001). PRA decreased significantly from baseline to 24 weeks in patients on MR-HC (0.83 ng L-1 s-1 (IQR 1.0) to 0.48 ng L-1 s-1 (IQR 0.61), P = .012) but not in patients on standard GC (0.53 ng L-1 s-1 (IQR 0.66) to 0.52 ng L-1 s-1 (IQR 0.78), P = .613). Serum sodium concentrations increased from baseline to 24 weeks in patients on MR-HC (138.8 ± 1.9 mmol L-1 to 139.3 ± 1.8 mmol L-1, P = .047), but remained unchanged on standard GC (139.8 ± 1.6 mmol L-1 to 139.3 ± 1.9 mmol L-1, P = .135). No significant changes were seen in systolic and diastolic blood pressure and serum potassium levels. 6 months of MR-HC therapy decreased PRA and increased sodium levels indicating a greater agonist action of the 9α-fluorocortisol dose, which may be due to the decreased levels of the MC-receptor antagonist 17OHP.

Precocious puberty and other endocrine disorders during mitotane treatment for paediatric adrenocortical carcinoma - case series and literature review.

Adrenocortical carcinoma (ACC) is rare and an aggressive tumour. Mitotane is the mainstay adjuvant drug in treating ACC. The study aimed to describe patients diagnosed with precocious puberty (PP) and other endocrinological complications during mitotane therapy. This retrospective study enrolled 4 patients with ACC treated with mitotane therapy complicated by PP. We analysed clinical manifestations, radiological, histopathological findings, and hormonal results. The median age at the diagnosis of ACC was 1.5 years. All patients were treated with surgery and mitotane, accompanied by chemotherapy regimens in 2 cases. The median time from surgery to the initiation of mitotane therapy was 26 days. During mitotane treatment, PP was confirmed based on symptoms, and hormonal and imaging tests. In one patient, incomplete peripheral PP was followed by central PP. The median time from the therapy initiation to the first manifestations of PP was 4 months. Additionally, due to mitotane-induced adrenal insufficiency, patients requiredasupraphysiological dose of hydrocortisone (HC), and in one patient, mineralocorticoid (MC) replacement with fludrocortisone was necessary. In 2 patients, hypothyroidism was diagnosed. All patients presented neurological symptoms of varying expression, which were more severe in younger children. The side effects of using mitotane should be recognized quickly and adequately treated. In prepubertal children, PP could beacomplication of therapy. The need to use supraphysiological doses of HC, sometimes with MC, should be highlighted. Some patients require levothyroxine replacement therapy. The neurotoxicity of mitotane isasignificant clinical problem.

Bilateral Adrenal Masses with Different Aetiologies Presenting as Addisonian Crisis with Acute Kidney Injury: A Case Series

An Addisonian Crisis (AC) is an endocrinological emergency associated with high mortality, resulting from an acute deficit of hormones from the adrenal glands. It can occur either in a patient with known Adrenal Insufficiency (AI) or as the initial presentation of the disease. Primary Adrenal Insufficiency (PAI), which can be caused by autoimmune adrenalitis or tubercular adrenalitis, is the most common cause worldwide and particularly prevalent in developing countries like India. Other causes of PAI include infiltrative pathology, drugs, haemorrhage, or, rarely, malignancy. Secondary Adrenal Insufficiency (SAI) often occurs due to abrupt steroid withdrawal or defects at the level of the pituitary or hypothalamus. The present case series highlights three cases (three male patients) in which patients presented with adrenal crisis despite no prior history of AI. Subsequently, they were diagnosed with bilateral adrenal masses of different aetiologies, including primary adrenal malignancy and granulomatous infiltration of the adrenals due to Tuberculosis (TB). One case involved bilateral primary adrenal malignancy with left perirenal and pararenal space infiltration, while the other two patients were diagnosed with disseminated TB with adrenal gland infiltration. The presentation of all three cases was characterised by non specific symptoms. Initial management for all three patients involved mineralocorticoid and glucocorticoid replacement, and they were discharged with corticosteroid supplements. However, the patient with bilateral adrenal malignancy was referred to the surgery and oncology department for further evaluation and management, whereas the remaining two patients were started on Antitubercular (ATT) drugs for definite treatment.

LBODP013 Hypophysitis And Adrenalitis Associated With The Use Of Immunotherapy "clinical Case Report"

Abstract Background we present a case of hypophysitis with gonadotropic and somatotropic axis compromise and adrenalitis secondary to the use of nivolumab and ipilimumab. Clinical Case A 74-year-old woman with a history of metastatic renal cell carcinoma treated with ipilimumab and nivolumab for 10 months, suspended treatment due to pneumonitis. Three months later, she consulted the emergency department due to limitations in daily activities, asthenia, and drowsiness. physical examination was unremarkable except for hypotension. Laboratory studies showed profound hyponatremia (106 mEq/l, n: 135 a 145 mEq/l), low serum osmolality (236 mmol/kg n: 275 - 295 mmol/kg) and a basal cortisol (5 μg/dL n: 3.7 - 19.4 μg/dL). Hypophysitis was suspected and a pituitary profile revealed low somatomedin C (25 ng/ml n: 54 204 ng/ml), FSH (20.6 UI/L n: 26.7 -133.4 UI/L), and strikingly elevated ACTH (91.9 pg/mL n: 4.7 - 48.5 pg/mL). Pituitary MRI had no structural anomaly. A diagnosis of hypophysitis and primary adrenal insufficiency secondary to adrenalitis due to the use of immunotherapy was made. The compromise of the gonadotropic and somatotropic axis with a normal image can occur in up to 23% of patients with this clinical entity. The patient had significant clinical improvement with glucocorticoid and mineralocorticoid replacement. Conclusions To our knowledge this is the first reported case of hypophysitis and adrenalitis secondary to immunotherapy. Hypophysitis has a prevalence up to 8% with the combination of ipilimumab plus nivolumab. It should be considered despite a normal pituitary MRI. However, adrenalitis associated with the use of these drugs has only been reported in 2.6% and the coexistence of both entities is even rarer Presentation: No date and time listed

PSAT040 Bilateral Adrenal Infarcts: Initial Presentation in Concurrent Myelodysplastic Syndrome and Anti-Phospholipid Syndrome

Abstract Introduction Bilateral adrenal hemorrhage (BAH) has been noted in several conditions. Bilateral adrenal infarcts (BAI) are rarer but have been seen in anti-phospholipid syndrome (APS). Adrenal insults are not commonly associated with myelodysplastic syndrome (MDS). We present a patient who developed BAI as initial presentation of APS in the setting of MDS and discuss management considerations. Case A 58-year-old female with MDS diagnosed one month prior presented with abdominal pain, present for one year but acutely worse in the past week. CT A/P showed nodularity of bilateral adrenal glands. She was treated conservatively but continued to experience nausea, vomiting, and abdominal pain – repeat CT A/P one month later was suspicious for bilateral peri-adrenal hemorrhages. MRI with adrenal protocol demonstrated bilateral non-hemorrhagic adrenal infarcts. VS were negative for hypothermia or hypotension. Labs showed Na 136 (135-145 mmol/L), K 3.5 (3.4-5.1 mmol/L), BG 108 (mg/dL), DHEA-S 9.3 (8.0-391 mcg/dL), renin 6.7 (0.5-4.0 ng/mL/hr), aldosterone 6.2 (&amp;lt;31.0 ng/dL), 60-minute cortisol after ACTH stimulation test 34.3 (5.2-22.5 mcg/dL), plasma metanephrines &amp;lt;0.10 (0.00-0.49 nmol/L), plasma normetanephrines 0.34 (0.00-0.89 nmol/L), Hgb 11.8 (12.0-15.5 g/dL), and plts 129K (140-450 K/mcL). No history of anticoagulant use, trauma, or VTE. COVID-19 PCR was negative on two separate tests. Hypercoagulability testing noted positive lupus anticoagulant. Anticoagulation was deferred due to underlying bone marrow abnormalities and thrombocytopenia; aspirin was recommended instead by hematology. Outpatient testing revealed 12pm cortisol of 12.6 (5.2-22.5 mcg/dL), ACTH 108.3 (7.2-63.0 pg/mL), and DHEA-S 6.2 (8.0-391 mcg/dL). Patient was empirically started on hydrocortisone for glucocorticoid replacement therapy. Conclusion BAI is not typically associated with MDS but can occur in the setting of a concurrent hypercoagulable process such as APS. The adrenal glands are the most commonly involved glands in APS. Patients often present in adrenal crisis but can present in stable condition as in this case. The adrenal glands are particularly vulnerable due to the "vascular dam" near the zona reticularis. Imaging and laboratory investigation can clarify the nature of the adrenal insult and guide management. Treatment strategy may include anticoagulation to prevent further VTE events, but bleeding risk must be considered. Both glucocorticoid and mineralocorticoid replacement should be considered until residual adrenal reserve can be fully elucidated, which may take several months from initial diagnosis. References Rao RH. Bilateral massive adrenal hemorrhage. Med Clin North Am 1995; 79(1): 107-29. Aron DC, Findling JW, Tyrrell JB. Glucocorticoids and adrenal androgens. In: Greenspan's Basic and Clinical Endocrinology. Gardner DG, Shoback D (eds). Mc Graw Hill 2007; pp 367-378. Caron P, Chabannier MH, Cambus JP, Fortenfant F, Otal P, Suc JM. Definitive adrenal insufficiency due to bilateral adrenal hemorrhage and primary antiphospholipid syndrome. J Clin Endocrinol Metab 1998; 83(5): 1437-9. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.