Peak Cortisol Research Articles

Occupational exposure to pesticides deregulates systemic cortisol levels in women with breast cancer and correlates with poor prognosis features.

Pesticides have been pointed out as hormone disruptors and may significantly affect the prognosis of hormone-dependent diseases such as breast cancer (BC). Here, we investigated the impact of occupational pesticide exposure on systemic cortisol levels in female rural workers diagnosed with BC. Occupational exposure was assessed by interviews with a standardized questionnaire. Plasma samples (112 from pesticide-exposed women and 77 from unexposed women) were collected in the afternoon, outside the physiological cortisol peak, and analyzed by a chemiluminescent paramagnetic immunoassay for the quantitative determination of cortisol levels in serum and plasma. The results from both groups were categorized according to patients' clinicopathological and exposure data. BC pesticide-exposed women presented higher levels of cortisol than the unexposed. Higher cortisol levels were also detected in the exposed group with more aggressive disease (triple-negative BC), with tumors over 2 cm, with lymph node metastases, and with high risk of disease recurrence and death. These findings demonstrated that there is an association between pesticide exposure and BC that affected cortisol levels and correlated to poor disease prognosis.

Maltreatment type differences in cortisol stress response trajectories across adolescence.

This study examined cortisol stress response trajectories across adolescence in 454 maltreated and comparison youth recruited from Los Angeles County between 2002 and 2005 (66.7% maltreated; 46.7% girls; 39.0% Latino; 37.7% Black; 12.3% Mixed or Biracial; 11.0% White; Mage = 10.9 years, SD = 1.2). Adolescents' peak activation and cortisol reactivity and recovery slopes following the Trier Social Stress Test for Children were calculated at four waves, then used to model peak activation and cortisol reactivity and recovery trajectories arrayed by age. Maltreated youth had blunted cortisol reactivity at age 9 relative to comparison youth (b = -.19, p = .02). Sexually and physically abused youth showed blunted cortisol reactivity and recovery trajectories relative to emotionally abused and neglected youth.

Early childhood multiple or persistent regulatory problems and diurnal salivary cortisol in young adulthood

BackgroundEarly childhood multiple or persistent regulatory problems (RPs; crying, sleeping, or feeding problems) have been associated with a risk of behavioural problems in young adulthood. It has been suggested that this may be due to the possible influence of early RPs on the functioning of the hypothalamic-pituitary-adrenal (HPA) axis. However, associations between early RPs and HPA-axis activity in young adulthood remain unexplored. Thus, the aim of the current study was to investigate whether early childhood multiple or persistent RPs are associated with diurnal salivary cortisol in young adulthood. MethodsAt the ages of 5, 20 and 56 months, RPs of 308 children from the Arvo Ylppö Longitudinal Study were assessed via standardized parental interviews and neurological assessments. Multiple RPs were defined as two or three RPs at the age of 5 months and persistent RPs as at least one RP at 5, 20 and 56 months. At the mean age of 25.4 years (SD= 0.6), the participants donated saliva samples for cortisol at awakening, 15 and 30 min thereafter, 10:30 am, at noon, 5:30 pm, and at bedtime during one day. We used mixed model regressions, and generalized linear models for testing the associations, controlling for important covariates. ResultsOf the 308 children, 61 (19.8%) had multiple or persistent RPs in early childhood: 38 had multiple, and 27 had persistent RPs. Persistent RPs were associated with significantly higher cortisol peak and output in the waking period, and cortisol awakening response. On the other hand, multiple RPs were not associated with salivary cortisol. ConclusionChildren displaying persistent RPs throughout early childhood show, over two decades later, increased HPA axis activity in response to awakening stress. This may be one physiological mechanism linking early childhood RPs to adulthood behavioural outcomes.

Academic stress and practical performance of freshmen in human anatomy

Objective: to evaluate salivary Cortisol and Alpha-amylase levels, relating them to the level of stress and academic performance of calories in the Human Anatomy discipline. Methods: Saliva collection procedures were performed before and after the application of the practical assessment of Human Anatomy. Saliva Cortisol and alpha-amylase concentrations were evaluated by ELISA method. The short version of the Stress Assessment Questionnaire for Nursing Students (ASNS) was used. Results: There was an increase in the students' stress level, with a significant increase of 46.8% in the levels of Cortisol and 46.1% of Alpha-amylase, (p <0.0009 and p <0.0001, respectively) after performing the proof. Initial averages were evaluated, before the start of the evaluation, of 0.440 ± 0.047 µg/dL for Cortisol and 111.19 ± 11.86 U/mL for salivary Alpha-amylase, and final average, after the evaluation was carried out, of Cortisol and final Alpha-amylase of 0.646 ± 0.178 µg/dL and 162.45 ± 44.69, respectively. The level of stress detected by the questionnaire presented significantly and positively (Cortisol: r²= 0.4353; p=0.0272/Alpha-amylase: r²= 0.4413; p=0.0258), with peak Cortisol (0, 21±0.15 μg/dL) and alpha-amylase (162.5 ± 44.7 U/ml). There was a significant and negative glow of academic performance with the peak of Cortisol (r²= 0.4169; p=0.0319) and Alpha-amylase (r²=0.4178; p=0.0316). Conclusion: The increase in declared stress is multifactorial, in which the university routine and emotional instability intensify the increase in anxiety and self-demand, which has repercussions on the performance of academics.

Peak Serum Cortisol Cutoffs to Diagnose Adrenal Insufficiency Across Different Cortisol Assays in Children

Current peak serum cortisol cutoffs for the diagnosis of adrenal insufficiency (AI) after Cosyntropin stimulation have been established using polyclonal antibody (pAb) immunoassays. However, new and highly specific cortisol monoclonal antibody (mAb) immunoassays are being used more widely, which can potentially yield higher false positive rates. Thus, this study aimed to redefine the biochemical diagnostic cutoff points for AI in children when using a highly specific cortisol mAb immunoassay and liquid chromatography tandem mass spectrometry (LC/MS) to avoid unnecessary steroid use. Cortisol levels from 36 children undergoing 1 mcg Cosyntropin stimulation tests to rule out AI were measured using pAb immunoassay (Roche Elecsys Cortisol I), mAB immunoassay (Roche Elecsys Cortisol II), and LC/MS. Logistic regression was used to predict AI using the pAB as the reference standard. A receiver operator characteristic curve, area under the curve (AUC), sensitivity, specificity, and kappa agreement were also calculated. Using a peak serum cortisol cutoff value of 12.5 μg/dL for the mAb immunoassay provided 99% sensitivity and 94% specificity for diagnosing AI, when compared to the historical pAb immunoassay cutoff of 18 μg/dL (AUC=0.997). Likewise, a cutoff of value of 14 μg/dL using the LC/MS, provided 99% sensitivity and 88% specificity when compared to the pAb immunoassay (AUC=0.995). To prevent overdiagnosis of AI in children undergoing 1 mcg Cosyntropin stimulation test, our data support using a new peak serum cortisol cutoff of 12.5 μg/dL and 14 μg/dL to diagnose AI when using mAb immunoassays and LC/MS in children, respectively.

Effect of Adrenocorticotropic Hormone Stimulation on Ischemiamodified Albumin Levels in vivo

Ischemia-modified albumin (IMA) formation is associated with increased reactive oxygen species (ROS) production, while increased cortisol leads to decreased ROS levels. We aimed to evaluate the effect of adrenocorticotropic hormone (ACTH) stimulation on IMA levels and whether the effect was dose-dependent or not. A total of 99 subjects with normal ACTH test results were included in the study. Of these, 80 had standard-dose ACTH test while 19 had low-dose ACTH test. Blood samples were collected to determine cortisol and IMA levels; at minutes 0, 30, and 60 following the standard-dose ACTH test and at minutes 0 and 30 following the low-dose ACTH test. IMA levels decreased significantly within 30 minutes and the decrease continued up to the sixtieth minute (p=0.002) after standard-dose ACTH stimulation. After ACTH stimulation, a weak negative correlation was found between peak cortisol and IMA levels at the thirtieth minute (r=0.233, p=0.02). There was no significant difference in IMA levels after low-dose ACTH stimulation, despite an increase in cortisol (p=0.161). IMA levels decreased rapidly after standard-dose ACTH stimulation, while a decrease in IMA levels was not observed after low-dose ACTH stimulation. The lack of decrease in IMA levels after low-dose ACTH stimulation suggests a possible dose-dependent relationship between ACTH and IMA. The moderate increase in cortisol with no reduction in IMA levels after low-dose ACTH stimulation and the weak correlation between peak cortisol and 30-minute IMA levels after standard-dose ACTH stimulation suggest that ACTH may have a direct effect on IMA.

Performance of synacthen test in chronic hemodialysis patients

BackgroundAdrenal function tests (Synacthen test) in chronic hemodialysis (HD) patients are currently performed off dialysis. The study aimed to demonstrate equivalence of serum cortisol concentrations pre- and during HD, each for standard-dose (250 µg) and low-dose (1 µg) Synacthen test.MethodsIn a single-center cross-over diagnostic equivalence study, Synacthen tests were performed in four settings, in standard- and low-dose as well as pre- and during HD. Serum cortisol concentration was measured at 30 and 60 min after Synacthen administration, and additionally at 20 min in low dose test. Based on a multivariable linear mixed model the means of cortisol concentration on log-scale were estimated in each dose and test time combination. Differences in means were calculated and the TOST approach was applied to test for equivalence. Equivalence was proven if the 90% confidence interval of the difference of two cortisol means was entirely between − 0.22 and 0.22.ResultsIn 28 chronic HD patients, serum cortisol concentrations at 30 and 60 min after Synacthen administration in both standard- and low-dose were shown to be equivalent pre- and during HD. In 10 of 56 low-dose tests, the cortisol peak was already reached after 20 min. However, cortisol concentrations at 20 and 30 min after low-dose Synacthen test pre- and during HD showed no significant difference.ConclusionThese results suggest that the adrenal function test may be carried out during an ongoing HD session, leading to a more patient-friendly performance of the test, less organizational effort and potentially earlier diagnosis of adrenal insufficiency.

Adrenal Suppression in Children During the Treatment for Acute Lymphoblastic Leukemia Beyond Induction.

Adrenal suppression (AS) is an iatrogenic, life-threatening condition that can occur after glucocorticoid exposure. Despite recognition that AS occurs after induction phase treatment in children with acute lymphoblastic leukemia (ALL), the risk of AS in phases beyond induction is unknown. We conducted a pilot study in pediatric patients with ALL to ascertain whether the risk of AS persists in post-induction phases of treatment. Patients diagnosed between 12 months to younger than 18 years with B or T-ALL and starting any new phase of treatment were eligible for the study. Relapsed or infant ALL were excluded. Low dose ACTH stimulation testing (LDST), measurement of albumin and cortisol binding globulin were performed in all patients. Screening for symptoms of AS was done. Twenty-four patients enrolled in the study. One was diagnosed with clear AS. Five others had a borderline cortisol peak, representing possible mild AS. Symptoms were nonspecific and did not help distinguish patients with normal LDST from those with borderline or abnormal results. Patients on treatment for ALL continue to be at risk of AS beyond induction treatment. Although this risk appears small, physicians must be vigilant as patients may be asymptomatic but could develop adrenal crisis during treatment.

THU214 Exploratory Study Of The Association Of Genetic Factors With Recovery Of Hypothalamic-Pituitary-Adrenal Axis In Cushing Disease

Abstract Disclosure: M.H. Nguyen: None. W. Zhang: None. N. Pankratz: None. J. Lane: None. P. Chittiboina: None. F.R. Faucz: None. A. Liu: None. J.L. Mills: None. C.A. Stratakis: None. C. Tatsi: None. Successful treatment of endogenous Cushing syndrome (CS) is often followed by a period of adrenal insufficiency of variable duration. Recovery of the hypothalamic-pituitary-adrenal (HPA) axis may range from 6 months to more than 2 years. Previous studies have investigated potential clinical and biochemical factors involved in this process with variable results. We performed an exploratory study on genetic factors potentially involved in HPA axis recovery in patients with Cushing disease (CD). Ninety (90) patients with CD, who were treated with transsphenoidal surgery (TSS), had initial remission, and a follow up of at least 3 months postoperatively, were included in the study. Recovery of the HPA axis was defined as morning cortisol level or peak cortisol during a standard dose (250 mcg) IV corticotropin stimulation test of >18mcg/dL. Genetic data was obtained by whole exome sequencing (WES). Variants 1) in genes potentially involved in the HPA axis, 2) rare in the general population and 3) predicted as possibly or probably damaging in silico, were selected from WES. Statistical analysis was performed for each variant or for each gene (calculating all variants present in the same gene) using a Cox proportional hazard model. Correction for multiple comparisons was assessed with the false discovery rate (FDR) method.We identified 97 variants in 47 genes of interest that met the above criteria. Although five variants showed a trend toward association with shorter duration of postsurgical adrenal insufficiency (AI), no significant association was noted after correction for multiple comparisons. Furthermore, each variant was present in only one patient. At the gene-level, the BAG1 gene showed significant correlation with shorter postsurgical duration of AI (Hazard ratio: 28.7, 95% Confidence Interval: 5.4-151.1, FDR q-value=0.004), but both patients with a BAG1 variant later experienced recurrent disease, which could suggest an independent predictor of shorter recovery time. When we excluded patients with recurrence, no significant association was reported on the gene-level. In this exploratory study, we did not identify a significant genetic modifier of HPA recovery time. Other factors, clinical or surgical, may play a more important role in the recovery process or larger cohort studies may be required. Presentation: Thursday, June 15, 2023

THU023 Sparse Granulation In Growth Hormone Secreting Adenomas: Clinical Implications Of A Rare Histological Finding

Abstract Disclosure: A. Merrill: None. R. Varughese: None. G. Campbell: None. L. Belalcazar: None. Introduction: Acromegaly is an uncommon disease. Endocrinologists may be unfamiliar with the clinical implications of granularity findings on the histology of growth hormone (GH)-secreting adenomas. We present the case of a patient with acromegaly in whom a sparsely granulated (SG) histological subtype was identified post-operatively. We discuss the clinical presentation and therapeutic implications of this finding. Case Presentation: A 36-year-old man was admitted to the hospital with rectal bleeding and incidentally found to have features consistent with acromegaly. Patient reported that over 1 year he had noticed changes in his facial features, enlargement of his hands and had developed hand and knee arthralgias. During the 6 months prior to admission, he experienced worsening fatigue, but denied severe headaches or vision changes. Past medical history was significant for osteosarcoma as a young child treated with an above the knee amputation. Family history was negative for pituitary tumors or colon cancer. Physical exam revealed a blood pressure of 104/53 mmHg and an amputation-adjusted body mass index of 27.4 _kg/ m2 . He had mild frontal bossing, enlarged nose, macroglossia, swollen hands and foot. Rectal examination revealed hemorrhoids but no masses. Gross visual field deficits were identified at bedside. Laboratory findings were significant for an elevated IGF-1 at 975 ng/mL (83-240 ng/mL) and GH 45.2 ng/mL (0.3-9 ng/mL). Patient was also found to have panhypopituitarism: TSH 1.54 mIU/L (0.45-4.70 mIU/L), Free T4 0.62 ng/dl (0.78 - 2.20 ng/dL); ACTH 13.3 pg/ml (7.2 - 63.3 pg/mL), cortisol AM 3.6 ug/dL (4.5-23.0 ug/dL), peak cortisol after ACTH stimulation 16.0 ug/dL; testosterone 31.6 ng/dl (132-813 ng/dL), LH 1.75 mIU/ml (1.2-8.6 mIU/mL). His hemoglobin A1c was 5.7%. MRI of the brain revealed a large enhancing lobulated sellar/suprasellar lesion of 5.0 x 2.4 x 2.8 cm, with extension to the third ventricle and mass effect on the optic chiasm. Patient underwent partial surgical resection of the large tumor. Pathology identified a SG somatotroph tumor with most cells being negative or weakly positive for GH on immunohistochemical staining. TSH, prolactin, and ACTH stains were negative. There was evidence of residual tumor, which was located superiorly, not accessible through the transsphenoidal route.A colonoscopy and formal visual field testing are pending currently. Patient is waiting for a second surgery via craniotomy and, given the SG finding on histology, pasireotide therapy will be offered. Discussion: The sparsely granulated (SG) subtype is an uncommon variant of GH-producing. Our patient illustrates the aggressive nature of SG GH-producing adenomas. These tumors express more invasive growth and resistance to standard somatostatin analogue therapy. There is a growing recognition that adenoma granulation is an important consideration in the management of acromegaly. Presentation: Thursday, June 15, 2023

FRI252 Novel Mutation Presenting With Hypoaldosteronism In X-Linked Adrenal Hypoplasia Congenita

Abstract Disclosure: E. Ismail: None. L. Jacobsen: None. Background: X-linked adrenal hypoplasia congenita (AHC) is a rare disorder due to a mutation in DAX-1/NR0B1, a nuclear factor that is important for the development and function of the adrenals and reproductive system. It usually presents with adrenal insufficiency in infancy and later hypogonadotropic hypogonadism. Here we describe a patient who presented with a salt wasting crisis due to hypoaldosteronism and genetic testing revealed a novel frameshift mutation in NR0B1/DAX-1 resulting in premature protein termination. Clinical Case: A 4 week old male presented with poor feeding, failure to thrive, hyponatremia, hyperkalemia, and acidosis. No hypoglycemia present. He also had an undetectable aldosterone level, high renin, normal cortisol, high ACTH, and normal 17OHP. Adrenal ultrasound (US) failed to show the right adrenal gland. With suspicion for primary hypoaldosteronism, he was started on salt supplementation and fludrocortisone with improved growth, electrolytes, and renin. His genitalia were that of a typical male infant without cutaneous hyperpigmentation. ACTH level continued to trend up despite appropriate baseline cortisol. Stimulation test with 250 mcg of Cosyntropin was done which revealed suboptimal peak cortisol of 11.5 mcg/dL (normal >18 mcg/dL), so he was started on stress dose precautions of hydrocortisone without physiologic replacement. Repeat US 2 months later did not visualize his adrenals. With suspicion for AHC, genetic testing was obtained which revealed a novel frame shift variant in NR0B1 (c.1069del, p.Gln357Argfs*15, hemizygous), resulting in premature protein termination. He was then started on daily hydrocortisone replacement. As this is an X-linked mutation, genetic testing for mother and older brother is pending. To the best of our knowledge this variant has not been reported in the literature. Conclusion: DAX-1 mutations should be considered in male infants presenting with primary hypoaldosteronism. ACTH stimulation testing is necessary to assess glucocorticoid function, especially if ACTH is elevated, which can precede cortisol deficiency. There is a wide heterogeneity in the presentation of this rare disorder, so genetic diagnosis is important to guide management, later monitoring for hypogonadism and fertility, and family testing. Presentation: Friday, June 16, 2023

SAT300 Use of Overnight Metyrapone Test In Suspected Adrenal Insufficiency: A Retrospective Single Center-Study

Abstract Disclosure: J. Saini: None. R. Gregg Garcia: None. J. Herndon: None. D.Z. Erickson: None. L. Gruber: None. I. Bancos: None. Context: Overnight metyrapone test (OMT) is a dynamic test used to diagnose secondary adrenal insufficiency (SAI). However, it is uncommonly used and the data on the OMT indications and performance are scarce. We aimed to characterize the indications, performance, and safety of outpatient OMT. Methods: Single center retrospective study in adults with OMT between April 1st, 2018 -July 31st, 2022. We evaluated three post-OMT cutoffs diagnostic of SAI: 1) 11-deoxycortisol ≤7 mcg/dL (11D≤7); 2) 11-deoxycortisol ≤10 mcg/dL (11D≤10), or 3) sum of cortisol and 11-deoxycortisol ≤15 mcg/dL (sum≤15), in comparison to pre-test probability and reference standard, defined as clinician-made diagnosis of SAI. When available, OMT-based SAI diagnosis was compared to results from the cosyntropin stimulation test (CST). Results: OMT was performed in 109 patients (76, 70% women) at a median age of 48 (IQR, 37-59) years. Pre-test probability for SAI was high in 13 (12%), moderate in 46 (43%), and low in 49 (45%) patients. Indications for OMT included evaluation of symptoms without clear SAI risk factors (38, 35%), suspected SAI due to chronic opioid use (25, 23%), pituitary pathology/therapies (25, 23%), exogenous glucocorticoid use (8, 7%), other (13, 12%). Overnight metyrapone was administered at a median dose of 2500 (IQR, 2125-3000). Adverse events were reported by 9 (8%) patients and were mild (nausea, fatigue) except for 1 patient who had to be hospitalized. The final diagnosis of SAI was made in 25 (48%) patients: 92%, 52%, and 12% of patients with high, moderate, and low pre-test probability. When compared to the clinician-made SAI diagnosis, OMT-based diagnosis of SAI was made in 60% of patients using the 11D≤7 cutoff, and in 81% of patients using the other cutoffs (11D≤10 or sum≤15). In 50 patients with concomitant CST, the final diagnosis of SAI was made in 23 (46%) patients, despite the normal CST results (post-cosyntropin peak cortisol ≥18 mcg/dL) in 12/23 patients. In patients with post-cosyntropin peak cortisol ≥18 mcg/dL, OMT was abnormal in 14% of patients (using post-OMT cutoff 11D≤7), 29% of patients (based on cutoff 11D≤10), and in 30% of patients (based on sum≤15). Conclusions: Outpatient OMT is well tolerated and was mostly used in patients with low/moderate pre-test probability for SAI. In patients with normal CST, OMT may diagnose SAI in additional 30% of patients, especially if the pre-test probability is high. Post-OMT sum of 11-deoxycortisol and cortisol <15 mcg/dL performs well in diagnosing SAI while allowing confirmation of adequate cortisol suppression. Presentation: Saturday, June 17, 2023

SAT343 Nicotinamide Nucleotide Transhydrogenase (NNT)-related Familial Glucocorticoid Deficiency: More Than Adrenal Insufficiency

Abstract Disclosure: A. Shanker: None. H.L. Calero: None. K. DeCarlo: None. Background: Familial glucocorticoid deficiency (FGD) is a rare cause of primary adrenal insufficiency, with an estimated prevalence of fewer than 5,000 cases in the United States. Patients often present as infants with signs including hypoglycemia, failure to thrive, seizures, and recurrent infections. Clinical Case: A 25-year-old woman with a history of intellectual disability was admitted with MIS-A due to COVID-19. Her presenting symptoms were lethargy and fever for several days. Her vitals were significant for a heart rate of 122 with atrial flutter and blood pressure of 90/50. Her initial labs showed elevated TSH (24.07 mcIU/mL [0.35-4.00]), normal free T4 (0.7 ng/dL [0.6-1.7]), hyponatremia (133 mmol/L [135-145]), and low alkaline phosphatase (25 U/L [40-125). Her physical exam was notable for hyperpigmentation, macrognathia, and oral mucositis. Her parents report she has limited daily activities and recalls recurrent illnesses as a child. She has been amenorrheic for the past 5 years; menarche was at age 12. Further chart review revealed that ketotic hypoglycemic seizure was diagnosed during hospitalization at 11 months of age. . Pediatric Endocrinology diagnosed Addison’s disease, which was treated until age 12 when she was lost to follow-up. On this admission, ACTH was elevated (756.5 pg/mL [7.2 - 63.3]), 8 AM cortisol was 1.2 ug/dL, and peak cortisol obtained after high dose co-syntropin stimulation was abnormal at 1.1 ug/dL upon high dose. Primary adrenal insufficiency was confirmed, and stress-dose steroids were initiated; her clinical condition improved. She was discharged with prednisone and fludrocortisone maintenance therapy. As an outpatient, TSH was persistently elevated (17.9 mcIU/mL [0.35-4.00]) and weight-based levothyroxine was initiated. Secondary amenorrhea testing demonstrated normal FSH, LH, and estradiol levels and discussions began regarding progesterone withdrawal testing (pending given patient again lost to follow up). The nutritional screening revealed deficiencies in vitamins A, C, and D, and supplementation was initiated. A unifying diagnosis was reached with microarray and whole exome sequencing showing nicotinamide nucleotide transhydrogenase (NNT) -related FGD. Conclusions: In FGD, several causative genes have been identified. One of these, NNT is expressed in most tissues, including cardiac, renal, thyroid, gastrointestinal, and gonadal tissue. This may predispose patients to organ dysfunction outside of the prominent effect on the adrenal glands. Since NNT is widely expressed, routine screening can include nutritional, renal, and hepatic labs and patients should receive reproductive counseling due to the risk of gonadal dysfunction. Therefore, patients with NNT-related glucocorticoid FGD require significant care coordination to ensure that patients receive uninterrupted therapy and appropriate multispecialty follow-up. Presentation: Saturday, June 17, 2023

SAT281 Screening For Adrenocortical Insufficiency In Patients With X-linked Adrenoleukodystrophy

Abstract Disclosure: J. Berquist: None. R.N. Kiani: None. M.P. Wahl: None. Background: A 41-year-old male initially presented to neurology clinic for complaints of poor balance, lower extremity weakness, and numbness. He previously had exam findings of lower extremity spasticity and hyperreflexia, distal vibratory loss, positive Romberg, and difficulty with Tandem gait. His symptoms had been progressive following an ankle sprain 8 years earlier and he was treated with physical therapy and baclofen. He is highly active otherwise and enjoys rock climbing, which was difficult to do given his symptoms. Clinical Case: Genetic screening was performed to evaluate for hereditary spastic paraparesis, which resulted positive for a mutation in the ABCD1 gene with a p.Lys336Glu mutation of uncertain significance. Interestingly, this ABDC1 variant was not detected in submitted maternal sample, hence patient’s mutation likely occurred de novo. This variant is not established in population databases (gnomAD no frequency) but has been observed in at least one individual with clinical features of adrenomyeloneuropathy. X-linked adrenoleukodystrophy causes impairment of beta oxidation that leads to accumulation of saturated very long chain fatty acids (VFLA) in multiple tissues. There are many clinical phenotypes, but they are hallmarked by neurologic signs and symptoms. Although neurologic symptoms can often develop in childhood, they can be delayed and present in adulthood, as can adrenal insufficiency (AI). However, males are overwhelmingly likely to develop adrenocortical insufficiency compared to females. Our patient presented with a BMI of 22.94, HR 50 bpm, and blood pressure 120/76; reflecting his active lifestyle. Recent electrolytes were within normal limits, AM cortisol was 13.0, and ACTH 544.0 Given the elevated ACTH and known cause of adrenal insufficiency, we proceeded with ACTH stimulation test. Peak cortisol resulted at 13.1 (at 60 minutes) and he was started on replacement glucocorticoid therapy per body-surface area. Upon further literature review, patients can also develop loss of mineralocorticoid production. Renin and aldosterone were ordered and were both within normal limits. Conclusion: Males with adrenoleukodystrophy are at a much higher risk of developing adrenal insufficiency (AI) compared to females. Additionally, AI will often develop later in life, so a low threshold for screening should be present for the endocrinologist. Mineralocorticoid deficiency can also develop, although not as commonly. Loss of adrenal function can lead to patient demise, and therefore adrenal function needs to be closely evaluated in people with leukodystrophy. Presentation: Saturday, June 17, 2023

FRI245 Non-classic CAH Presenting As Bilateral Adrenal Incidentalomas

Abstract Disclosure: Y.A. Chin: None. T. Puar: None. T. King: None. Introduction: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is an autosomal recessive disorder. Non-classic CAH usually presents in late childhood or asymptomatic may remain undiagnosed. Adrenal incidentalomas have been reported as a presentation of CAH. Clinical Case: A 56-year-old man presented with a 4-day history of epigastric pain associated with chest discomfort and diaphoresis. There was no postural giddiness, vomiting, paroxysm or constitutional symptoms. He was a smoker, his parents were non-consanguineous and he had fathered 2 children. He was tachycardic at 114 bpm, but normotensive (129/89 mmHg) with no postural hypotension and no abnormal pigmentation. He had evidence of heart failure with bibasal crepitations and pedal oedema. Secondary sexual characteristics were normal and testicular volume was 15 mls bilaterally with no palpable mass. CT abdomen showed grossly enlarged bilateral adrenal glands with heterogenous nodular appearance with several focal hypodense cystic components, with absolute washout <60%. Biochemistry was consistent with primary adrenal insufficiency (PAI); 8am serum cortisol 188 nmol/L, with peak cortisol post 250mcg synacthen of 195 nmol/L. Serum ACTH was elevated at 254.6 ng/L, aldosterone and renin were normal and 24hr urinary normetanephrine was mildly elevated at 1982 nmol/d (NR 600-1900 nmol/d). Echocardiography revealed severe global hypokinesia (EF 20%) but myocardial perfusion imaging was negative for ischemia. In view of suspicion for tuberculosis, malignancy or infiltrative disease, CT guided adrenal biopsy was performed. Histology showed hyperplastic adrenal cortex with lipofuscin pigments, focal lymphohistiocytic infiltrates. No lymphoplasmacytic infiltrate with IgG 4 plasma cells, granuloma, malignant cells or amyloid deposits were seen. Serum 17-OHP level later came back elevated at 39.7 nmol/L (NR 1.8-10.4 nmol/L). DNA sequencing of CYP21 revealed compound heterozygous mutations in c.292+1G>A and c.518T>A, both of which have been reported to be causative of CAH. He was transitioned from stress dose to physiological glucocorticoid replacement and ACTH normalised on subsequent outpatient visits. Follow up imaging after 6 months and 2 1/2 years revealed no change in size or morphology of the adrenal glands. Follow up echocardiography showed no improvement in ejection fraction despite intensive heart failure treatment. Conclusion: Nodular adrenal hyperplasia is well described among CAH individuals, especially in those with inadequate glucocorticoid replacement and chronically elevated ACTH levels. There was no change in size of the adrenal lesions despite adequate glucocorticoid replacement. Improvement of cardiac function with glucocorticoid replacement has been reported in paediatric patients with CAH, but our case did not show any improvement on serial echocardiography. Presentation: Friday, June 16, 2023

THU131 Functional Hypogonadotropic Hypogonadism And Failure To Thrive In A Poorly Controlled Type 1 Diabetes Patient

Abstract Disclosure: P. Rakhra: None. V. Wright: None. I. Athanassaki: None. Background: Multiple reports exist of obese males with type 2 diabetes linked to hypogonadotropic hypogonadism. We report a rare case of poorly controlled type 1 diabetes leading to functional hypogonadotropic hypogonadism as well as failure to thrive. Clinical Case: A 16-year-old Caucasian male with type 1 diabetes, antibody positive, diagnosed at 3 years of age presented in severe diabetic ketoacidosis. Patient had been lost to follow-up and had not had a clinic visit in over three years. He had reportedly been using a family member’s Tresiba and over the counter Humulin in the interim. Upon presentation, his hemoglobin A1c was found to be 11.8%. It was last documented at greater than 14%. He was also at less than the first percentile for height and weight, with a BMI of 16 kg/m2. His mid-parental height was 68.5 inches (25 – 50th percentile). His physical exam was remarkable for Tanner III pubic hair with 12 cc testicular volume bilaterally. Biochemical analysis revealed LH was in pubertal range of 0.5 mIU/mL (0.2 – 2.3 mIU/mL), low FSH <0.7 mIU/mL (0.7 – 6.2 mIU/mL), and low testosterone 7.7 ng/dL (200 – 1036 ng/dL). IGF-1 was low at 49 ng/mL (230 – 769 ng/mL) and low IGF-BP3 at 2.6 mg/L (3.1 – 8.9 mg/L). Bone age per the standards of Greulich and Pyle was delayed at 14 years with a predicted adult height of 68 inches. Associated conditions known to cause failure to thrive in patients with diabetes, such as adrenal insufficiency, hyperthyroidism, and celiac disease were ruled out. ACTH stimulation test revealed cortisol peak of 24.6 ug/dL (>18.0 ug/dL). TSH was normal 2.474 mIU/mL (0.5 – 3.4 mIU/mL) and normal Free T4 0.8 ng/dL (0.8 – 2 ng/dL). Mauriac syndrome was considered however, patient lacked any Cushingoid features, did not have hepatomegaly on exam, and had normal liver function tests. A brain/pituitary MRI was performed prior to discharge and was found to be normal, ruling out concerns for a central lesion causing delayed puberty. Patient was able to gain weight during the admission with intensive insulin management. However, he remains less than the first percentile for height and weight. A growth hormone stimulation test (with clonidine and arginine) was performed outpatient. Patient was primed with estrace prior to the test and results revealed a peak of 15.0 ng/mL (>10 ng/mL) ruling out concerns for growth hormone deficiency. Conclusion: We report this case to highlight that although uncommon in the developed world, delayed puberty and growth failure are known but rare complications of poorly controlled type 1 diabetes. Presentation: Thursday, June 15, 2023

The Reliability of Salivary Cortisol Compared to Serum Cortisol for Diagnosing Adrenal Insufficiency with the Gold Standard ACTH Stimulation Test in Children.

The ACTH (adrenocorticotropic hormone) stimulation test is the gold standard for the diagnosis of adrenal insufficiency (AI), performed with ACTH high dose (HDT) or low dose (LDT). As salivary cortisol has been proposed as an alternative to serum cortisol, our aim was to evaluate the reliability of salivary cortisol compared to serum cortisol for diagnosing AI in children. Data were collected retrospectively. Salivary and serum cortisol values derived by 80 ACTH stimulation tests were obtained (39 F, 36 M; median age 11.5 years, IQR 6.9). Sampling was performed at baseline and after 30 and 60 min from ACTH administration during the HDT, and at baseline and 10, 20, 30, 40 and 60 min after the stimulation for the LDT. A serum cortisol level > 420 nmol/L ruled out AI. The correlation coefficients between serum and salivary cortisol for the HDT (n = 24) were 0.80 at t0, 0.48 at t30 and 0.75 at t60. All patients were adrenal sufficient. In 41% of the LDT, peak serum cortisol indicated insufficient adrenal function. The correlation coefficients between serum and salivary cortisol were 0.59 at t0 and 0.33 at the peak. For a cut-off of salivary cortisol < 15 nmol/L, sensitivity was 73.9% and specificity 69.6%. Our data do not support salivary cortisol as a valid alternative to serum cortisol during LDT. Regarding the HDT, results are more encouraging, however, further studies are needed.

Hypothalamic-Pituitary Adrenal Axis Status 3 Months After Recovery From COVID-19 Infection

ABSTRACT Context Coronavirus disease 2019 (COVID-19) predominantly involves the lungs, albeit many other organ systems, including the hypothalamic-pituitary-adrenal (HPA) axis, can be affected due to the expression of the angiotensin-converting enzyme 2 (ACE2) binding receptor. Few studies have reported the involvement of adrenal gland and the HPA axis during the acute phase of COVID-19; however, the data on the long-term effect of COVID-19 on the HPA axis after acute infection is scarce. Objective To assess and compare the changes in HPA axis in mild, moderate and severe COVID-19 categories at ≥ 3 months after acute infection. Methods A prospective, observational study was conducted to assess the HPA axis status among COVID-19 subjects at least 3 months after recovery from acute infection. The study was conducted from June 2021 to May 2022. Subjects visited the hospital in the fasting state (8.00–9.00am), serum cortisol levels were measured at baseline, 30 and 60 minutes after a 1-μg short Synacthen test (SST). Results A total of 66 subjects ≥ 18 years of age were included in the study. The mean age (SD) was 49.13 ± 11.9 years, 45(68.18%) were male and 21 (31.81%) were female subjects. The mean BMI in the study was 25.91 ± 4.26 kg/m2. Seventeen (25.8%) subjects had mild, twelve (18.2%) had moderate and thirty-seven (56.1%) subjects had severe COVID-19 infection. Out of the sixty-six subjects with COVID-19, nine subjects (9/66, 13.63%) had peak serum cortisol < 496.62 nmol/L suggestive of adrenal insufficiency (AI). SST peak serum cortisol levels did not differ significantly across the disease severity [Mild, (628.50 ± 214.65 nmol/L) vs moderate, [603.39 ± 161.95 nmol/L) vs severe, (597.59 ± 163.05 nmol/L), P = 0.617]. Six subjects with AI came for follow-up at 12 months, and all had normal HPA axis. Conclusion HPA axis is affected in 13.63% (9/66) of subjects at least 3 months after recovery from COVID-19 infection. AI in COVID-19 might be transient and would recover spontaneously. These findings have important implications for the clinical care and long-term follow-up of subjects after COVID-19 infection.

Resilience as a predictor of habituation

Habituation refers to the physiological adaptation to recurrent stressors, which can be measured by cortisol levels, and is considered a central mechanism in reducing allostatic load. Resilience, a potential factor influencing stress reduction, is the focus of this study. Specifically, the study aims to investigate the impact of resilience, as assessed by the Brief Resilience Scale (BRS), on habituation. The Trier Social Stress Test (TSST) was used as the recurrent stressor, and it was administered to each of the 56 subjects at 4 consecutive measurements. To assess habituation, various physiological parameters including the area under the curve with respect to the ground (AUCg) and with respect to the increase (AUCi), cortisol peak, slope from baseline to peak, and recovery were calculated. Mixed linear models were employed to examine the differences in the influence of resilience on habituation across the different time points. The findings indicate that the influence of resilience significantly varies from the first to the fourth measurement time point for AUCg (p = .048), while no significant differences were observed for the other cortisol parameters. The effects plot suggests that individuals with higher levels of resilience exhibit lower AUCg values throughout the measurements. These findings provide initial evidence supporting resilience as a predictor of cortisol habituation. However, future studies should also consider dynamic resilience models, utilizing longitudinally assessed resilience as a predictor for habituation, to explore whether resilience acts as a determinant of habituation or if habituation itself constitutes a resilience mechanism.

Pulsatile Subcutaneous Hydrocortisone Replacement in Primary Adrenal Insufficiency.

Pulsatile endogenous cortisol secretion is critical for physiological glucocorticoid gene signaling. Conventional glucocorticoid replacement therapy does not mimic endogenous cortisol pulsing in primary adrenal insufficiency. In an open-labeled, two-week, nonrandomized cross-over study of five patients with adrenal insufficiency (Addison's disease in two, bilateral adrenalectomy in one, and congenital adrenal hyperplasia in two patients) we compared pulsatile and continuous cortisol pump treatment and conventional oral glucocorticoid therapy with respect to 24-h serum corticosteroid levels and plasma adrenocorticotropic hormone (ACTH). Pulsed pump restored ultradian rhythmicity as demonstrated by five peaks of serum (all patients) and subcutaneous tissue cortisol (four patients). Morning subcutaneous cortisol and cortisone were higher in continuous and pulsed pump treatment than in oral therapy despite nearly similar serum cortisol levels in all treatment arms. ACTH was within the physiological range during pulsed pump treatment in all patients except for slightly elevated levels in the morning hours 04:00-08:00 h. During oral therapy, ACTH was very high in patients with Addison's disease and suppressed in patients with congenital adrenal hyperplasia. In conclusions, mimicking endogenous cortisol rhythmicity by ultradian subcutaneous infusion of cortisol is feasible. It was superior to both continuous pump and oral therapy in maintaining normal ACTH levels throughout the 24-h cycle. Our results demonstrate a low free cortisol bioavailability on thrice daily oral replacement therapy compared to both types of subcutaneous infusion.