Adrenal Function Research Articles

ODP323 Increased Serum High-Sensitivity C-Reactive Protein Levels in Adult Growth Hormone Deficient Patients with Non-Functioning Pituitary Tumors

Abstract Background Growth hormone (GH) deficiency, a common endocrine deficit in non-functioning pituitary tumors, causes visceral obesity and fatty liver and increases cardiovascular event risks. High-sensitivity C-reactive protein (hs-CRP) has been used as a useful marker to estimate cardiovascular event risks. Because GH supplementation therapy was reported to decrease serum hs-CRP levels in GH deficient patients, inflammatory processes might be activated in GH deficient state, however, the underlying mechanism has been still unknown. Patients and Methods We retrospectively reviewed charts of 134 patients with non-functioning pituitary adenoma and Rathke's cysts who underwent preoperative GH-releasing peptide-2 (GHRP-2) tests and investigated the association between serum hs-CRP levels and background characteristics. Patients who had a history of pituitary surgery, severe renal insufficiency or active inflammatory diseases or received GH supplementation therapy were excluded. GH secretion was determined by GHRP-2 tests. Results Among 134 patients (94 NFPA and 40 Rathke's cysts), 46 (34%) presented severe GH deficiency, as diagnosed using GHRP-2 tests. Serum hs-CRP levels were significantly higher in the patients with severe GH deficiency than in those without severe GH deficiency (723 [299-1285] vs 278 [124-561] ng/mL, P < 0. 001). Serum hs-CRP levels were significantly higher in men (P = 0. 003) and in patients with diabetes mellitus (P = 0. 040) and were significantly correlated with age (r s = 0.19, P = 0. 039), body mass index (r s = 0.37, P < 0. 001), serum levels ofgamma-glutamyl transpeptidase(r s = 0.28, P = 0. 001), creatinine (r s = 0.30, P < 0. 001), low-density lipoprotein cholesterol (r s = 0.21, P = 0. 013), triglyceride (r s = 0.38, P < 0. 001) and free thyroxine (r s = -0.30, P= 0. 001), blood hemoglobin A1c levels (r s = 0.20, P = 0. 018), peak GH response to GHRP-2 (r s = -0.47, P < 0. 001) and IGF-1 SD score (r s = -0.18, P = 0. 040). In the multiple regression analysis, peak GH response to GHRP-2 was a significant variable for determining serum hs-CRP levels (β = -0.340, P = 0. 003) after adjustment with age, sex, BMI, smoking, alcohol consumption, hypertension, diabetes mellitus, serum levels ofgamma-glutamyl transpeptidase, creatinine,triglyceride and free thyroxine and adrenal function. Conclusion We observed a significant association between GH deficiency and increased serum hs-CRP levels independent to BMI and liver dysfunction. GH deficient state might cause inflammation independent to development of visceral obesity and fatty liver. Presentation: No date and time listed

PSUN24 Adrenal Metastases Treated with Radiotherapy: Development of Adrenal Insufficiency

Abstract Introduction Adrenal metastases are the second most common neoplasms of the adrenal cortex. Adrenal insufficiency (AI) develops when more than 90% of the cortex is destroyed. In patients with adrenal metastases requiring local treatment, stereotactic ablative radiation therapy (SAbR) has been shown to be well tolerated. Yet, data on the development of AI following adrenal SAbR are scarce. Therefore, we aimed to assess the incidence, timing, and factors associated with the development of AI in patients undergoing SAbR for the treatment of adrenal metastases. Utilizing an IRB approved registry protocol, we conducted a retrospective longitudinal follow-up study to characterize 66 patients (73% men; median age 61 years) with adrenal metastases who underwent SabR, followed for median 3.8 years from the initial cancer diagnosis and 11.5 months from SAbR. The diagnosis of primary AI was based on low morning serum cortisol levels (<5 μg/dL) with >2-fold elevated plasma ACTH, or peak cortisol <18 μg/dL post cosyntropin. Primary carcinomas included renal cell (41%), lung (38%), colorectal (9%), melanoma (5%), and others (7%). Twenty-four (38%) patients had bilateral adrenal metastases. At the time of SAbR, 41 (62.1%) patients had uninvolved contralateral adrenal glands, 16 (24.2%) had bilateral adrenal metastases, and 9 (13.6%) had contralateral adrenalectomy prior to SAbR. Nine patients had bilateral SAbR and 9 had SAbR to one adrenal gland in the setting of contralateral adrenalectomy. Most patients (66.7%) underwent 5 SAbR fractions, with a median dose of 800 cGy/fraction. In our cohort, 39/66 (59%) patients underwent comprehensive assessment of adrenal function. Overall, 7 (10.6%) patients developed post-SAbR AI at median time of 4.3 months (range, 0.7-20.2). The incidence of post-SAbR AI was 22.2% (2/9) in patients with prior contralateral adrenalectomy, 18.8% (3/16) with bilateral adrenal metastases, and 0% (0/41) with normal contralateral adrenal gland. A 6-month-AI-free survival rate was 72.7% (95% CI, 37.0-90.3) in patients with bilateral metastases and 64.8% (1.6-73.7) in patients with contralateral adrenalectomy. Post-SAbR median progression-free survival (local disease) was 3.0 years, with 6-month and 1-year survival rates of 82.4% and 75.0%, respectively. Conclusions Our study shows thatpatients with a normal contralateral adrenal gland are unlikely to develop post-SAbR AI. In contrast, AI occurred in ∼ 20% of patients with prior contralateral adrenalectomy or bilateral adrenal metastases. In this high-risk cohort, only 60% of patients underwent assessment of adrenal function. It is crucial to monitor adrenal function in patients undergoing SAbR for adrenal metastasis, especially in those with affected or surgically absent contralateral gland. This study reinforces the importance of a team-based approach to the management of patients with adrenal metastasis to improve patient outcomes. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

RF02 | PMON309 Two Siblings with p.Arg92Trp Variant in NR5A1 Presenting with Testicular Disorder of Sexual Differentiation

Abstract Introduction Disorders of sexual differentiation (DSD) are conditions of abnormal chromosomal development leading to atypical gonadal and anatomic sexual characteristics. We present the case of two siblings with 46, XX testicular DSD due to a mutation in the nuclear receptor subfamily 5 group A member 1 gene (NR5A1). While there is extensive literature about pathogenic variants of this gene, this is the first variant that has been shown to cause DSD in XX individuals, rather than XY. Case presentation This is the case of a sibling pair with male phenotype and history of hypospadias and hypogonadism in the setting of 46, XX karyotype. Sibling A presented with hypospadias at birth and hypergonadotropic hypogonadism in childhood, initially managed with testosterone. Testicular biopsy revealed bilateral germ cell aplasia with degeneration of seminiferous tubules. Sibling B presented at age 8 with precocious puberty. He had a history of hypospadias and cryptorchidism at birth. Gonadotropins and testosterone levels were prepubertal. Testicular biopsy showed only Sertoli cells. Their adrenal gland and thyroid function was normal, their bone age was advanced. FISH was negative for the SRY gene in both cases, no ovaries or mullerian structures found in pelvic imaging. DSD genetic panels were sent, resulting positive for the R92W variant in NR5A1. Neither of them have intellectual disability; however, sibling B has attention deficit and hyperactivity disorder (ADHD) and obsessive compulsive disorder (OCD). Family history is remarkable for two uncles that have been unable to conceive. Their mother had oligomenorrhea and difficulty conceiving, typical presentation of a female carrier of this mutation. Discussion and conclusions The majority of DSD in individuals with a 46, XX karyotype are due to congenital adrenal hyperplasia (CAH) secondary to 21-hydroxylase deficiency, however, mutations in NR5A1 have been among the most frequently identified genetic causes of gonadal development disorders and are associated with a wide phenotypic spectrum. NR5A1 is an essential transcription factor that regulates target genes crucial for normal reproductive physiology and endocrine function, controlling several steps of adrenal and gonadal development. While there is extensive literature about the phenotype caused by variants of NR5A1 in XY individuals, the recurrent heterozygous p.Arg92Trp NR5A1 variant R92W that our patients have, is the only one that has been shown to cause DSD in XX individuals, with variable degrees of testis development. It has previously been described, however, in women with primary ovarian insufficiency (POI). Morevariants of this gene will continue to arise, playing a pivotal role in reproductive endocrinology. Presentation: Saturday, June 11, 2022 1:00 p.m. - 1:05 p.m., Saturday, June 11, 2022 1:00 p.m. - 1:05 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

PMON318 Nephrogenic syndrome of inappropriate antidiuresis in a 19 months old child with gross developmental delay

Abstract Case report 19 months old African American boy with nonsignificant past medical history presented with inability to walk, hypotonia chewing difficulties and speech delay. Initial laboratory evaluations demonstrated serum hyponatremia of 120-129 mEq/dl, low serum osmolality 261 mosm/kg (normal serum osmolality 275-295 mosm/kg) with inappropriately high urine osmolality 445 mosm/kg) (normal urine osmolality 300-1000 mosm/kg). Blood work for thyroid, adrenal, and pituitary function was unremarkable. Vasopressin level of 2.4 pg/ml (normal 0.0 - 4.7 pg/mL) did not support the diagnosis of Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH). Fludrocortisone challenge test ruled out aldosterone deficiency with insufficient decrease in urine sodium and no response in serum sodium. Renal ultrasound and brain MRI were normal. Genetic testing revealed AVPR2 X-linked mutation c.409C>T p.R137C, consistent with nephrogenic syndrome of inappropriate antidiuresis (NSIAD). The patient was discharged on sodium chloride tablets 2g every 8 hours and remained stable, asymptomatic. One month after discharge patient showed significant neurological improvement. Discussion Sodium is known to play a significant role in growth and maturation of the whole body, especially of the nervous system. Moderate (120-129 mEq/L) to severe (<120 mEq/L) hyponatremia can present with nausea, malaise, headache, lethargy, motor and speech delay, seizures and even death due to brain herniation. Normal fluid and electrolyte balance is achieved by the thirst mechanism and free water excretion in kidneys. This is mediated by Vasopressin, which acts through V2R receptor in distal renal collecting duct. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the most common cause of hyponatremia. Reset osmostat syndrome with a congenitally low serum osmolality threshold is one of the rare disorders on the differential. Hereditary nephrogenic syndrome of inappropriate antidiuresis is very rare mutation in vasopressin receptor, which clinically resembles SIADH except for normal/low vasopressin levels in set of hyponatremia. It causes gain of function and inappropriately high water retention. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

PMON312 A De Novo Heterozygous Nonsense Variant In The SEC31A Gene Associated With Pituitary Hormone Deficiency And Disorders Of Sex Development.

Abstract Introduction XYdisorders of sex development (DSD) result from variants in many different human genes but frequently have no detectable molecular cause. In approximately 25% of cases of XY DSD, the index case may have associated malformations. Genetic disorders of endoplasmic reticulum (ER) function are increasingly being recognised but have not been associated with DSD or pituitary disorders. Clinical case Three siblings (with unaffected non-consanguineous parents) were reviewed at the tertiary endocrine clinic. Child I was noted at birth to have cliteromegaly. Imaging and examination under anaesthetic revealed a normal vagina and uterus but gonads of indeterminate origin. She was 46,XY and basal endocrine investigations at the age of 4 years showed a low AMH for male but otherwise normal gonadal and thyroid function and normal IGF-1. She had a laparoscopic bilateral gonadectomy aged 5 years. Pathology demonstrated bilateral testicular tissue, with substantial fibrotic atrophic change and occasional placental alkaline phosphatase (PLAP) positive cells, suggestive of germ cell tumours. Aged 8 years she developed obesity and later hypertension. Child II was reviewed due to short stature and diagnosed with GH deficiency aged 2 years. She has normal adrenal and thyroid function and gonadotrophins. MRI demonstrated an ectopic posterior pituitary. Child III presented with perineal hypospadias, a small phallus, bilateral undescended testes and craniofacial abnormalities. Endocrine investigations revealed hypogonadotrophic hypogonadism, with no testosterone response to hCG stimulation, a low normal AMH and no response of LH or FSH on LHRH stimulation. He has panhypopituitarism with an ectopic posterior pituitary gland on MRI and is currently on treatment with GH, hydrocortisone and levothyroxine. His BP is on the 98th centile for age and height. Child I and Child III have mild developmental delay but are in mainstream school with additional educational support. High-throughput DNA sequencing revealed, in all three siblings, a heterozygous truncating variant in the SEC31A gene that encodes a component of the COPII-complex that coats the vesicles mediating ER to Golgi transport. CRISPR-Cas9 targeted knockout of the corresponding Sec31a region resulted in embryonic lethality in homozygous mice. mRNA phenotyping of ER-related genes demonstrated increased mRNA expression of ATF4 and CHOP in the affected children, genes encoding key ER stress-related proteins, associated with defective protein transport. Conclusions Dysregulation ofanterograde and retrograde COPII-coated-vesicle ER-Golgi transport is increasingly recognised to underlie human developmental disorders, including Craniolenticulosutural dysplasia (OMIM 607812) and Saul-Wilson syndrome (OMIM 618150). The de novo SEC31A nonsense variant in all three affected siblings, the ER stress response, plus reported developmental syndromes with dysfunction of this transport mechanism and evidence from the preclinical mouse model suggest that SEC31A might underlie a previously unrecognised clinical syndrome comprising DSD, endocrine abnormalities, dysmorphic features and developmental delay. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

GABA System in Depression: Impact on Pathophysiology and Psychopharmacology.

The pathophysiology of major depressive disorder (MDD), one of the major causes of worldwide disability, is still largely unclear, despite the increasing data reporting evidence of multiple alterations of different systems. Recently, there was a renewed interest in the signalling of gamma aminobutyric acid (GABA) - the main inhibitory neurotransmitter. The aim of this study was to review and comment on the available literature about the involvement of GABA in MDD, as well as on novel GABAergic compounds possibly useful as antidepressants. We carried out a narrative review through Pubmed, Google Scholar and Scopus, by using specific keywords. The results, derived from various research tools, strongly support the presence of a deficiency of the GABA system in MDD, which appears to be restored by common antidepressant treatments. More recent publications would indicate the complex interactions between GABA and all the other processes involved in MDD, such as monoamine neurotransmission, hypothalamus-pituitary adrenal axis functioning, neurotrophism, and immune response. Taken together, all these findings seem to further support the complexity of the pathophysiology of MDD, possibly reflecting the heterogeneity of the clinical pictures. Although further data are necessary to support the specificity of GABA deficiency in MDD, the available findings would suggest that novel GABAergic compounds might constitute innovative therapeutic strategies in MDD.

PSAT045 Spontaneous Adrenal Hemorrhage with Partial Adrenal Insufficiency in a Patient Anticoagulated with Apixaban for Antiphospholipid Syndrome

Abstract Background Addison's disease secondary to adrenal hemorrhage is a rare complication of antiphospholipid syndrome (APLS). Anticoagulation with a direct oral anticoagulant (DOAC) might increase the risk of adrenal hemorrhage. We report a patient who developed bilateral adrenal hemorrhage after starting apixaban for deep venous thrombosis (DVT) and pulmonary embolism (PE) in the setting of latent APLS. Clinical Case A 45-year-old man without significant past medical history presented with a left lower extremity DVT and PE. He had no personal or family history of previous trauma, bleeding or clotting events. He was discharged on apixaban. Three days later he was readmitted with bilateral flank pain. Computerized tomography (CT) imaging showed bilateral adrenal gland edema. He was hemodynamically stable. Due to persistent right flank pain and concern for ileus, CT was repeated and revealed findings concerning for adrenal hemorrhage. He subsequently complained of asthenia. Further testing revealed a reduced morning cortisol of 1.4 ug/dL (reference: 6.0 - 18.4 ug/dL) and an elevated morning ACTH of 149 pg/mL (7.2-63.3 pg/mL). Plasma dehydroepiandrosterone sulphate (DHEA-S) was reduced at 39 mcg/dL (70 - 495 mcg/dL), and epinephrine and norepinephrine were undetectable. Morning plasma aldosterone was undetectable and renin activity was 0.76 ng/mL/h (0.25 - 5.82 ng/mL/h). He was started on stress dose steroids and discharged on maintenance hydrocortisone without reinitiating anticoagulation. Two weeks later, he re-presented with a right lower extremity DVT. An APLS panel revealed elevated anti-beta2 glycoprotein 1 IgG and anti-cardiolipin IgG. Laboratory work-up for other causes of thrombosis, including inherited and acquired thrombophilias, anatomical vascular obstruction, paroxysmal nocturnal hemoglobinuria (PNH), heparin-induced thrombocytopenia (HIT), and myeloproliferative neoplasms (MPN), was unrevealing. Warfarin was started with an international normalized ratio (INR) target range of 2-3. Hydrocortisone was continued at a total daily dose of 30mg. Since discharge, his morning cortisol levels have been low at 4.4-4.9 ug/dL and ACTH has remained high at 92-137 pg/mL, but aldosterone has been variable at <1 to 9 ng/dL, and renin has been normal at 0.35 ng/mL/h. This suggests what transpired had been microthrombi-associated intra-adrenal hemorrhage involving the zona fasciculata with sparing of the glomerulosa. Conclusion This case highlights DOAC-associated adrenal hemorrhage in a patient with underlying APLS, an under-appreciated complication. The extent to which the various layers of the adrenal gland are affected may vary. Since guidelines on the management of patients with partial adrenal insufficiency are lacking, further reporting is needed on long term outcomes and adrenal function of these patients. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

RF09 | PSAT83 Diagnosis of Adrenal Insufficiency Based on Peak Stimulated Cortisol Levels Between 14 and 18 mcg/dL on High Dose Cosyntropin Stimulation Testing

Abstract Background Traditionally, stimulated serum cortisol < 18 mcg/dL at 30 or 60 minutes has been used as the cutoff for diagnosis of adrenal insufficiency (AI) during high dose cosyntropin stimulation testing (CST). Recent studies suggest that a cutoff of 14-15 mcg/dL is more accurate when using more specific monoclonal immunoassays (IAs). In February 2017, our institution switched from a polyclonal IA to a monoclonal IA. Despite this change, providers were diagnosing AI based on the 18 mcg/dL cutoff. Long term glucocorticoid use has several unwanted pleiotropic effects such as impaired glucose tolerance or diabetes mellitus (DM), hypertension (HTN), and increased risk of infection. Our study aims to evaluate patients with peak stimulated cortisol levels between 14-18 mcg/dL diagnosed with AI and placed on steroids. Methods We retrospectively reviewed charts of patients with peak cortisol levels 14-18 mcg/dL at 30 or 60 minutes on high dose CST with 250 mcg cosyntropin between February 2017 and August 2021. Cortisol levels were assessed using the monoclonal IA Roche Elecsys Cortisol II. Data regarding type and etiology of AI as well as patient demographics, comorbidities, steroid regimen, and follow up cortisol testing was collected. Worsening HTN and DM were defined as increase in blood pressure and HgbA1c respectively and/or intensification of medications between baseline at time of CST and last follow up while on steroids. Results 41 patients met inclusion criteria. 29 (71%) patients were female and mean age at CST was 52 years (range 21-86). Most patients were diagnosed with secondary (71%) or partial secondary (19%) AI by provider. Most common etiologies were pituitary disease (45%), chronic steroid use (24%), and unilateral adrenalectomy (19%). Mean follow up was 23 months (range 0.5-57). 33 (80%) patients were started or continued on glucocorticoid replacement. Remaining patients who were never started on steroids had a peak cortisol ≥ 15.6 mcg/dL. 21/33 (64%) of patients started on steroids had repeat adrenal function testing a mean of 18 months (range 2-42) after the initial CST. Based on testing or clinical judgement, 19/33 (58%) were taken off steroids. In patients treated with steroids, 64% developed weight gain, 42% worsening HTN, and 6% worsening DM. Additionally, 48% developed an infection, 24% insomnia, and 15% psychiatric illness. Conclusions The majority of patients with peak stimulated cortisol between 14-18 mcg/dL on high dose CST had secondary AI. Over 50% of patients started on steroids were later able to stop. Steroid-related complications were observed, but this may not differ significantly from the general population. This study underscores the importance of interpreting CST results in the context of the cortisol assay used and evaluating patients with secondary AI for recovery of the hypothalamic-pituitary-adrenal axis. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Saturday, June 11, 2022 1:06 p.m. - 1:11 p.m.

PSAT066 Adrenal Insufficiency Associated with Amyloidosis and Sickle Cell Disease

Abstract Background Amyloidosis causes chronic inflammation by the deposition of amyloid protein fragments in multiple organs, such as kidneys, adrenal, and pituitary glands. It is a challenge to access adrenocortical function in renal amyloidosis patients due to heavy proteinuria induced hypoproteinemia and low corticosteroid-binding globulin (CBG) which may cause false positive adrenocorticotropin (ACTH) test and the reduced cortisol level uncorrelated with free cortisol. On the other hand, adrenal insufficiency also frequently occurs in Sickle Cell Disease (SCD) patients. The hypothalamic-pituitary-adrenal (HPA) axis can be affected by tissue hypoxia during recurrent small vessel occlusion, chronic anemia, and iron-overload related oxidative stress. We report a SCD patient with nephrotic syndrome due to amyloidosis, who has adrenal insufficiency. Case Presentation A 41 years old female with Nephrotic syndrome secondary to Amyloid A (AA) amyloidosis, Adrenal insufficiency, Sickle cell disease (HbSC), Graves’ Hyperthyroidism, CVA, and bilateral femoral head avascular necrosis, presented with sickle cell pain crisis and anasarca with hypotension. She was on Hydrocortisone for 12 years but was not compliant for 2 months. She was on Methimazole for several years before it was discontinued one year ago. She has amenorrhea, severe edema with anasarca from the lower extremities to the abdomen. Labs showed morning cortisol 5.46 ug/dL, low albumin 2.4 g/dL, high TSH 5.43 uIU/mL, normal FT4 1.60 ng/dL, high urine protein 996.2 mg/dL, and eGFR 21.2. CT revealed pericardial effusion, free pelvic fluid, splenomegaly, edema, and thyroid goiter. Previous labs showed persistent low cortisol 0.9 to 3.5 ug/dL, high ferritin 1007 ng/mL, and pituitary workup was normal for Prolactin 4.6 ug/L, LH 5.02 mIU/mL, FSH 9.9 mIU/mL, IGF1 216 ng/mL, and ACTH 13.1 pg/mL. NM thyroid uptake elevated 51.7% and positive TPO 79.7 IU/mL. CT head was unremarkable. The patient was managed with Lasix and Albumin infusion for anasarca, Cyclosporine for amyloidosis, and Midodrine 10 mg TID for hypotension. Hydrocortisone stress dose was given followed by Prednisone 30 mg BID. Her symptoms improved. Discussion In Amyloidosis patients with heavy proteinuria, the low serum CBG levels affect total cortisol level. Therefore, the proper assessment for the adrenal function should be used with albumin-calculated free cortisol or cortisol/CBG ratio in addition to the ACTH stimulation tests. It is essential to differentiate between adrenal insufficiency and amyloidosis-related symptoms to prevent adrenal crisis and refrain from glucocorticoid side effects by unnecessary steroid use. On the other hand, endocrine manifestations of SCD may include hypogonadism, thyroid, adrenal, and pituitary dysfunction due to vaso-occlusive episodes induced multi-organ ischemic damage. This patient has amenorrhea, adrenal insufficiency, and normalized thyroid function test in Graves’ disease. It is crucial to avoid iron-overload induced oxidative stress which would worsen endocrine dysfunctions as well. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

PSAT049 A Case of Hypercalcemia as the First Presentation of Addison's Disease

Abstract Introduction Hypercalcemia is stratified into mild, moderate, and severe. This stratification is determined by serum ionized calcium and total calcium. For example, mild hypercalcemia is defined as a serum ionized calcium of 5.6 - 8. 0 mg/dL [1.4 - 2 mmol/L] or a total calcium of 10 - 12 mg/dL [2.5 - 3 mmol/L]. Hypercalcemia is commonly caused by primary hyperparathyroidism and malignancy. Other causes include vitamin D excess or immobilization. An uncommon cause that is pertinent to the patient is primary adrenal insufficiency. A patient with hypercalcemia can either be asymptomatic or have a wide array of symptoms, such as musculoskeletal pain, nausea/vomiting or constipation, and altered mental status. Case Presentation The patient is a 36 year old female who came to the ED due to sharp upper quadrant abdominal pain that waxed and waned for about 8 weeks in duration. During her visit in the ED, the patient was hypotensive and tachycardic, which improved with IVF. The patient was also experiencing loss of appetite, nausea/vomiting, diarrhea. She also reported to have lost 38 lbs unintentionally dating back to 07/2021. The patient had undergone an EGD and colonoscopy, however the results were unremarkable. She also required further evaluation of her hypercalcemia of 12.7. She reported to take an unknown amount of vitamin D on a daily basis. She stopped taking her calcium supplementation a few weeks prior to her visit. The patient was afebrile, moderately tachycardic, tachypneic, and hypotensive. The physical exam was remarkable for tenderness to palpation in the epigastric region and skin hyperpigmentation. CT chest, abdomen, pelvis with contrast revealed intralobular septal thickening, diffuse mild colitis, some reactive mesenteric and retroperitoneal lymph nodes. Bone survey, CT head without contrast, gastric emptying study and hepatobiliary scan were unremarkable. Labs revealed: Ca 12.7, Na 132, K 4.4. PTH 6.3, ACTH 2,400, Cortisol base <1. 0, Serum Aldosterone <3. 0, Positive 21-Hydroxylase Autoantibody, DHEA 0. 099, DHEA sulfate 8. 0. Total 25-Hydroxyvitamin D 34. 0, 1,25-Dihydroxyvitamin D 5.6. After hydrocortisone and florinef administration, the patient's hypercalcemia normalized. As a result, the patient's hypercalcemia was secondary to primary adrenal insufficiency. Discussion Primary adrenal insufficiency is an uncommon cause of hypercalcemia. This can be attributed to a hypovolemic state that arises from a reduction in mineralocorticoids. As a result, there is a reduction in the GFR, which reduces glomerular filtration of calcium and increases reabsorption of calcium in the proximal tubule. Another proposed mechanism is the increase in 1-alpha-hydroxylase due to a reduction in glucocorticoids. Consequently, an increase in 1-alpha-hydroxylase will increase calcitriol production, which subsequently increases intestinal calcium absorption. These proposed mechanisms highlight the importance of adrenal function on calcium regulation and homeostasis. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

PSUN21 Adrenal Incidentaloma: Is Interval Scanning Warranted?

Abstract Background Adrenal incidentaloma (AI) is an increasingly recognised finding, with pressure on healthcare systems. Earlier guidelines recommended interval scanning and testing to ensure stability. However, the recent European guidelines do not recommend the need for repeat scanning if initial assessment is reassuring. Aim To explore the utility of this guidance on need for interval scanning of benign AI. Methods A retrospective unselected review of AI cases seen in our unit before the launch of the European guidelines was conducted. At that time, a local protocol was in use to characterise scan and test adrenal functions at baseline, and at two years, the scan and endocrine tests were repeated. We compared the baseline scan results with those at two-years. Results We collected data on 54 patients initially identified between 2011 and 2016. Of these, 31 had left-sided lesions, 15 had right-sided lesions and 8 bilateral. Of the left-sided lesions, 16 increased in size over the 2.2-year follow-up period, 4 decreased in size and 17 remained the same. Of the right-sided lesions, 3 increased in size over the follow-up period, 6 decreased in size and 13 remained the same. Of those that increased (left- or right-sided), the largest increase was 5mm. Taking 2 mm as the cut-off for a significant change: on the left, 32/37 (86%) had a change ≤2mm (P<0. 001 for no increase). On the right, 21/22 (95%) had a change ≤2mm (P<0. 001). Using a ≤5% increase as cut-off: 28/37 on the left (P=0. 028) and 20/22 on the right (p<. 001) showed ≤5% increase. There was no statistical difference in change in lesion size in terms of laterality, being indeterminate on initial scanning, gender, age or initial size on presentation. Conclusion We found that there was no significant change in size after two years. Therefore, our data support the European guidelines that repeat scanning is unnecessary. This should be reassuring to patients and provide a more cost-effective service. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Epitope-tagged and phosphomimetic mouse models for investigating natriuretic peptide-stimulated receptor guanylyl cyclases.

The natriuretic peptide receptors NPR1 and NPR2, also known as guanylyl cyclase A and guanylyl cyclase B, have critical functions in many signaling pathways, but much remains unknown about their localization and function in vivo. To facilitate studies of these proteins, we developed genetically modified mouse lines in which endogenous NPR1 and NPR2 were tagged with the HA epitope. To investigate the role of phosphorylation in regulating NPR1 and NPR2 guanylyl cyclase activity, we developed mouse lines in which regulatory serines and threonines were substituted with glutamates, to mimic the negative charge of the phosphorylated forms (NPR1-8E and NPR2-7E). Here we describe the generation and applications of these mice. We show that the HA-NPR1 and HA-NPR2 mice can be used to characterize the relative expression levels of these proteins in different tissues. We describe studies using the NPR2-7E mice that indicate that dephosphorylation of NPR2 transduces signaling pathways in ovary and bone, and studies using the NPR1-8E mice that indicate that the phosphorylation state of NPR1 is a regulator of heart, testis, and adrenal function.

Delayed effects of neonatal immune activation on brain neurochemistry and hypothalamic-pituitary-adrenal axis functioning.

During the postnatal period, the brain is highly sensitive to stress and inflammation, which are hazardous to normal growth and development. There is increasing evidence that inflammatory processes in the early postnatal period increase the risk of psychopathologies and cognitive impairment later in life. On the other hand, there are few studies on the ability of infectious agents to cause long-term neuroinflammation, leading to changes in the hypothalamic-pituitary-adrenal axis functioning and an imbalance in the neurotransmitter system. In this review, we examine short- and long-term effects of neonatal-induced inflammation in rodents on glutamatergic, GABAergic and monoaminergic systems and on hypothalamic-pituitary-adrenal axis activity.

Multimodality Imaging Findings in Waterhouse-Friderichsen Syndrome: A Case Report and a Short Literature Review

Waterhouse-Friderichsen syndrome is a rare disease characterized by bleeding into the adrenal glands, and its symptoms may vary from non-specific abdominal pain to multi-organ failure. Commonly related to a variety of infectious diseases among which sepsis from Neisseria meningitidis is the most frequent, many other etiologies have been described, and in some rare cases, even no apparent cause can be identified. We report a rare case of an idiopathic bilateral adrenal hemorrhage in a 70-year-old male who presented to our emergency department with non-specific abdominal pain. Ultrasonography Scan (US) and Computed Tomography (CT) findings were crucial for making an early diagnosis, which resulted in a short hospitalization time and, eventually, a complete recovery of the adrenal function. After discharge, Magnetic Resonance Imaging (MRI) was also performed, providing a more complete ensemble of multimodality imaging findings that can be associated with this rare syndrome.

Recording of Chromaffin Cell Electrical Activity In Situ in Acute Adrenal Slices.

Because catecholamines secretion mainly relies on the excitable nature of adrenal chromaffin cells, monitoring their electrical activity is an essential step in assessing the adrenal medullary tissue function. The difficult access to the gland in vivo allows only population activity to be recorded in this condition. In vitro preparations allow recordings of spontaneous or evoked activity from single or multiple cells, depending on the biological samples used (dissociated chromaffin cells versus adrenal tissue preparations). In this chapter, I provide a detailed description of the techniques used for electrophysiological recordings in rodent chromaffin cells in acute adrenal slices, using the patch-clamp technique. This methodology allows preservation of the tissue integrity and detection of action potentials, synaptic activity, and secretory events; it is thus suitable for the study of adrenomedullary activity-secretion coupling.

Association between carbon monoxide poisoning and adrenal insufficiency: a nationwide cohort study

Carbon monoxide poisoning may damage the brain and adrenal glands, but it is unclear whether it is associated with adrenal insufficiency. We identified all COP patients diagnosed between 1999 and 2012 in Taiwan using the Nationwide Poisoning Database and selected a reference cohort (participants without COP) from the same database by exact matching of age and index date at a 1:2 ratio. Participants with a history of adrenal insufficiency or steroid use of more than 14 days were excluded. We followed up participants until 2013 and compared the risk of developing adrenal insufficiency between the two cohorts. The 21,842 COP patients had a higher risk for adrenal insufficiency than the 43,684 reference participants (adjusted hazard ratio [AHR] = 2.5; 95% confidence interval [CI]: 1.8–3.5) after adjustment for sex and underlying comorbidities (liver disease, thyroid disease, mental disorder). The risk continued to elevate even after 1 year (AHR = 2.1; 95% CI: 1.4–3.4). The COP patients who had acute respiratory failure had an even higher risk for adrenal insufficiency than those without acute respiratory failure, which may indicate a dose–response relationship. Stratified analyses showed that female patients had an elevated risk (AHR = 3.5; 95% CI: 2.1–6.0), but not male patients. Younger patients (< 50 years) had higher risks, and the AHR reached statistical significance in the age groups 20–34 (AHR = 5.5; 95% CI: 1.5–20.6) and 35–49 (AHR = 4.9; 95% CI: 2.3–10.6) years old. The risk for developing adrenal insufficiency elevated after COP, especially in female and younger patients. Carbon monoxide is the most common gaseous agent causing acute intoxication worldwide. Results of the current study call for monitoring adrenal function of patients with COP.

Development and internal validation of a predictive score for the diagnosis of central adrenal insufficiency when morning cortisol is in the grey zone

BackgroundWhen evaluating a patient for central adrenal insufficiency (CAI), there is a wide range of morning cortisol values for which no definite conclusion on hypothalamus–pituitary–adrenal (HPA) axis function can be drawn; in these cases, a stimulation test is required. Aim of this study was to develop an integrated model for CAI prediction when morning cortisol is in the grey zone, here defined as 40.0–160.0 μg/L.MethodsOverall, 119 patients with history of sellar tumour which underwent insulin tolerance test (ITT) for the evaluation of HPA axis were enrolled. Supervised regression techniques were used for model development.ResultsAn integrated predictive model was developed and internally validated, and showed a significantly better diagnostic performance than morning cortisol alone (AUC 0.811 vs 0.699, p = 0.003). A novel predictive score (CAI-score) was retrieved, on a 5.5-point scale, by considering morning cortisol (0 points if 130.1–160.0 μg/L, 1 point if 100.1–130.0 μg/L, 1.5 points if 70.1–100.0 μg/L, 2.5 points if 40.0–70.0 μg/L), other pituitary deficits (2 points if ≥ 3 deficits), and sex (1 point if male). A diagnostic algorithm integrating CAI-score and ITT was finally proposed, with an overall accuracy of 99%, and the possibility to avoid the execution of stimulation tests in 25% of patients.ConclusionsThis was the first study that proposed an integrated score for the prediction of CAI when morning cortisol is in the grey zone. This score might be helpful to reduce the number of patients who need a stimulation test for the assessment of HPA axis function.

Theory of mind and hair cortisol in healthy young adults: the moderating effects of childhood trauma

ABSTRACT Background: Experiences of negative social interactions and childhood trauma (CT) can lead to aberrant hypothalamic–pituitary–adrenal functions. Poor theory of mind (ToM) ability is related to increased social stress levels; however, studies on the relationship between ToM and cortisol remain scarce. Objective: This study aimed to evaluate the relationship between ToM and the hair cortisol concentration (HCC) in healthy young adults considering the moderating role of CT. Method: A total of 206 healthy young adults were divided into two groups based on an experience of moderate-to-severe childhood trauma (CT+ and CT–). To determine whether CT moderated the relationship between ToM and HCC, moderation analysis was conducted controlling for age, sex, years of education, and scores of perceived stress, depression, and anxiety. Results: CT+ individuals reported higher subjective stress perception and depressive symptoms than CT– individuals, whereas anxiety-related symptoms, ToM, and HCC were not different between the groups. The experience of CT significantly moderated the relationship between ToM and HCC. The association between poorer ToM ability and higher HCC was significant only in CT+ group. Conclusion: CT is a moderator of the association between ToM and HCC, indicating the importance of CT in social cognition and the stress response.

Prevalence and Characteristics of Adrenal Tumors in an Unselected Screening Population : A Cross-Sectional Study.

With the widespread use of advanced imaging technology, adrenal tumors are increasingly being identified. To investigate the prevalence and characteristics of adrenal tumors in an unselected screening population in China. Cross-sectional study. (ClinicalTrials.gov: NCT04682938). A health examination center in China. Adults having an annual checkup were invited to be screened for adrenal tumors by adrenal computed tomography. The participants with adrenal tumors had further evaluation for malignancy risk and adrenal function. A total of 25356 participants were screened, 351 of whom were found to have adrenal tumors, for a prevalence of 1.4%. The prevalence increased with age, from 0.2% in participants aged 18 to 25 years to 3.2% in those older than 65 years. Among 351 participants with adrenal tumors, 337 were diagnosed with an adrenocortical adenoma, 14 with another benign nodule, and none with a malignant mass. In 212 participants with an adenoma who completed endocrine testing, 69.3% were diagnosed with a nonfunctioning adenoma, 18.9% with cortisol autonomy, 11.8% with primary aldosteronism, and none with pheochromocytoma. Proportions of nonfunctioning adenomas were similarly high in various age groups (72.2%, 67.8%, and 72.2% in those aged <46, 46 to 65, and ≥66 years, respectively). Only 212 of 337 participants with an adrenocortical adenoma had endocrine testing. The prevalence of adrenal tumors in the general adult screening population is 1.4%, and most of these tumors are nonfunctioning regardless of patient age. Cortisol and aldosterone secretion are the main causes of functional adenomas. National Key Research and Development Program of China and National Natural Science Foundation of China.

Congenital hypothyroidism and hyperthyroidism alters adrenal gene expression, development, and function

Congenital hypothyroidism and hyperthyroidism alters adrenal gene expression, development, and function