Hypothalamic-pituitary-adrenal Research Articles

7990 Reduced Alpha-1 Antitrypsin Activity Is Associated with Higher Plasma Free Cortisol and Increased Tissue Glucocorticoid Exposure in Humans in vivo

Abstract Disclosure: L.D. Boyle: None. M. Nixon: None. C.M. Underhill: None. L.A. Hill: None. N.Z. Homer: None. M. Magennis: None. R. Andrew: None. G.L. Hammond: None. J.G. Lewis: None. R.H. Stimson: None. B.R. Walker: None. Background: Corticosteroid Binding Globulin (CBG) binds >85% of plasma cortisol, modulating its biological activity. Proteolytic cleavage by neutrophil elastase (NE) reduces CBG binding capacity, proposed to increase free cortisol availability to inflamed tissues. Genetic variation at the locus spanning SERPINA1 (encoding alpha-1 antitrypsin, AAT, the endogenous inhibitor of NE) and SERPINA6 (CBG) altered morning total plasma cortisol. We hypothesised that AAT deficiency increased CBG cleavage and hence free plasma cortisol, resulting in amplified tissue cortisol delivery and increased HPA axis negative feedback. We tested this in recall-by-genotype studies of people who are heterozygous for inactivating mutations in SERPINA1. Methods: 16 asymptomatic carriers of deleterious SERPINA1 single nucleotide polymorphisms (rs17580 & rs28929474) and 16 age-, gender- and BMI-matched controls were recruited from the Generation Scotland Biobank. To quantify in vivo whole body glucocorticoid appearance and clearance rates, and estimate tissue cortisol uptake, we performed arterio-venous plasma sampling across abdominal adipose and skeletal muscle during steady-state 9,11,12,12-[2H]4-cortisol tracer infusion. To assess endogenous negative feedback, participants underwent combined receptor antagonist stimulation of the HPA axis (‘CRASH’) testing using RU486 and spironolactone, or placebo in a double blind randomised crossover design. Total cortisol (LC-MS/MS), free cortisol (isotopic dilution & ultrafiltration), CBG binding capacity (radioligand displacement), CBG concentration and AAT (ELISA) were measured in plasma. Tissue cortisol (LC-MS/MS) and glucocorticoid-dependent transcripts (qPCR) were measured in adipose biopsy samples collected at end of study. Results: AAT was ∼30% lower in AAT+/- (p=0.0002 vs control). Plasma CBG concentration, binding capacity and total cortisol were similar between groups. However, plasma free cortisol fraction was higher in AAT+/- subjects (16.1 +/- 0.2 vs 13.9 +/- 0.04 %, p<0.0001). Adipose tissue from AAT+/- subjects displayed increased cortisol levels and increased glucocorticoid-responsive transcripts PER1 and LPL compared to controls. Consistent with release from CBG, total and free cortisol release across skeletal muscle was increased in AAT+/- subjects vs controls. The rate of appearance of 9,12,12-[2H]3-cortisol was reduced in AAT+/- (p=0.03 vs control), consistent with decreased whole body 11β-HSD1 activity. CRASH testing did not reveal additional differences between groups. Discussion: Subclinical AAT deficiency is associated with a higher free cortisol fraction and increased tissue glucocorticoid exposure. Although consistent with the hypothesis of local tissue-mediated control of glucocorticoid exposure via the NE/AAT/CBG axis, these findings were not accompanied by measurable changes in CBG. Presentation: 6/3/2024

9225 Reduced Alpha-1 Antitrypsin Activity Is Associated with Higher Plasma Free Cortisol and Increased Tissue Glucocorticoid Exposure in Humans in vivo

Abstract Disclosure: L.D. Boyle: None. M. Nixon: None. C.M. Underhill: None. L.A. Hill: None. N.Z. Homer: None. M. Magennis: None. R. Andrew: None. G.L. Hammond: None. J.G. Lewis: None. R.H. Stimson: None. B.R. Walker: None. Background Corticosteroid Binding Globulin (CBG) binds >85% of plasma cortisol, modulating its biological activity. Proteolytic cleavage by neutrophil elastase (NE) reduces CBG binding capacity, proposed to increase free cortisol availability to inflamed tissues. Genetic variation at the locus spanning SERPINA1 (encoding alpha-1 antitrypsin, AAT, the endogenous inhibitor of NE) and SERPINA6 (CBG) altered morning total plasma cortisol. We hypothesised that AAT deficiency increased CBG cleavage and hence free plasma cortisol, resulting in amplified tissue cortisol delivery and increased HPA axis negative feedback. We tested this in recall-by-genotype studies of people who are heterozygous for inactivating mutations in SERPINA1. Methods 16 asymptomatic carriers of deleterious SERPINA1 single nucleotide polymorphisms (rs17580 & rs28929474) and 16 age-, gender- and BMI-matched controls were recruited from the Generation Scotland Biobank. To quantify in vivo whole body glucocorticoid appearance and clearance rates, and estimate tissue cortisol uptake, we performed arterio-venous plasma sampling across abdominal adipose and skeletal muscle during steady-state 9,11,12,12-[2H]4-cortisol tracer infusion. To assess endogenous negative feedback, participants underwent combined receptor antagonist stimulation of the HPA axis (‘CRASH’) testing using RU486 and spironolactone, or placebo in a double blind randomised crossover design. Total cortisol (LC-MS/MS), free cortisol (isotopic dilution & ultrafiltration), CBG binding capacity (radioligand displacement), CBG concentration and AAT (ELISA) were measured in plasma. Tissue cortisol (LC-MS/MS) and glucocorticoid-dependent transcripts (qPCR) were measured in adipose biopsy samples collected at end of study. Results AAT was ∼30% lower in AAT+/- (p=0.0002 vs control). Plasma CBG concentration, binding capacity and total cortisol were similar between groups. However, plasma free cortisol fraction was higher in AAT+/- subjects (16.1 +/- 0.2 vs 13.9 +/- 0.04 %, p<0.0001). Adipose tissue from AAT+/- subjects displayed increased cortisol levels and increased glucocorticoid-responsive transcripts PER1 and LPL compared to controls. Consistent with release from CBG, total and free cortisol release across skeletal muscle was increased in AAT+/- subjects vs controls. The rate of appearance of 9,12,12-[2H]3-cortisol was reduced in AAT+/- (p=0.03 vs control), consistent with decreased whole body 11β-HSD1 activity. CRASH testing did not reveal additional differences between groups. Discussion Subclinical AAT deficiency is associated with a higher free cortisol fraction and increased tissue glucocorticoid exposure. Although consistent with the hypothesis of local tissue-mediated control of glucocorticoid exposure via the NE/AAT/CBG axis, these findings were not accompanied by measurable changes in CBG. Presentation: 6/3/2024

7741 Artri King As A Cause Of Adrenal Insufficiency

Abstract Disclosure: Q. Aziz: None. S. Fatima: None. A.L. Champion: None. K.E. Izuora: None. IntroductionDietary supplements are highly unregulated and may have substance that can be harmful. Due to its easy availability, more patients may have access to these supplements which can cause detrimental health outcomes, such as adrenal insufficiency. Clinical Case Patient is a 46 year old female with past medical history of hypertension and obesity presents to the hospital for worsening left hip pain, which started 2 weeks ago. She heard a crack in her left hip and denied any trauma or injury prior. She was found to have subtrochanteric fracture. Nine months ago, she had right hip pain and was unable to bear weight. Physical exam was notable for alopecia in frontal and temporal region, dorsocervical fat pad, multiple bruises, round facies, and multiple purple straie. She also reported a 50 pound weight gain in the last year. She stated that she took an over the counter “pain medication”, but denied any supplements. Due to the non-traumatic fracture and physical features, AM cortisol was ordered for suspicion of Cushing’s Syndrome by primary team and was low at 2.4. Endocrinology team was consulted. Cosyntropin stimulation test showed baseline AM cortisol level 1.4 and 1 hour after cosyntropin, cortisol was 8.3. ACTH 3.4, testosterone undetectable, androstendione undetectable, Aldosterone 42.2, DHEA undetectable. It was found later that patient was taking an over the counter supplement called Artri King, up to 4 tablets a day. Artri King has been advertised as a supplement for joint and muscle pain and contains unknown amount of dexamethasone and diclofenac. She was soon placed on hydrocortisone for adrenal insufficiency and was titrated down. The hypothalamic-pituitary-adrenal (HPA) axis can be suppressed with as low as 5 mg prednisone equivalent a day. This can lead to inadequate adrenal response to stress. If a patient has prolonged exposure to exogenous steroids, insufficient ACTH secretion can lead to atrophy of the zona fasciculata and reticularis, resulting in reduced ability to secrete cortisol. Therefore, it is important to help withdraw patient from glucocorticoids. When initiating glucocorticoid withdrawal, hydrocortisone may be helpful due to short half life, allowing HPA axis more opportunity to recover. Adrenal atrophy may be slowly reversible, but 4 years after diagnosis of glucocorticoid induced adrenal insufficiency, recovery of adrenal function is unlikely to occur. ConclusionsIt is important to obtain a thorough history, especially for supplements. Many supplements are not regulated and can pose harm to our patients. Adrenal insufficiency due to glucocorticoids may not only occur from steroid injections, long course of prescription glucocorticoids, but can include supplements if it is hidden from the ingredient list. Presentation: 6/3/2024

12417 Atypical Patterns Of Hypoglycemia Post-bariatric Surgery Due To Pancreatic Insulinoma

Abstract Disclosure: K.A. Chopra: None. Accurately diagnosing an insulinoma in patients who have had bariatric surgery can be challenging because the autonomic symptoms of palpitations, tremors, anxiety and neuroglycopenic hypoglycemia symptoms of confusion and loss of consciousness may overlap with dumping syndrome or be attributed to non-insulinoma pancreatogenous hypoglycemia. When evaluating hypoglycemia, it is crucial to obtain a detailed history of the pattern and timing of hypoglycemia episodes and collect a critical sample of insulin, proinsulin, c-peptide levels during an episode of low glucose to prevent misdiagnosis. 58-year-old woman with hypertension, obesity, and history of laparoscopic sleeve gastrectomy presented for evaluation of hypoglycemia. The patient lost 100 pounds after her sleeve gastrectomy. Within the past year, the patient had two hospitalizations for severe symptomatic hypoglycemia with associated loss of consciousness. Imaging showed atrophic pancreas and she was discharged with a prescription for daily prednisone without critical sample testing for insulin or c-peptide levels. She sought a second opinion for her hypoglycemia at UCM. Since she was taking prednisone for 10 months prior to initial evaluation at UCM, evaluation for adrenal insufficiency could not be completed initially. She started continuous glucose monitoring which showed multiple daily episodes of hypoglycemia, fasting and at other various timepoints. Fasting labs showed low glucose of 20 mg/dL (RR 60-99 mg/dL), elevated proinsulin 120 pmol/L (RR 3.6- 22 pmol/L), inappropriately normal insulin 16.4 uIU/mL (RR <28.5 uIU/mL), and inappropriately normal c-peptide 0.82 pmol/mL (RR 0.30-2.35 pmol/mL), consistent with insulinoma. CT abdomen showed 1.4 cm arterially enhancing round lesion in the pancreatic body. Endoscopic ultrasound showed 13 mm mass in the pancreatic body with fine needle aspiration with pathology showing a well-differentiated neuroendocrine tumor. She received stress dose hydrocortisone preceding surgery and underwent successful enucleation of 1.6 cm pancreatic neuroendocrine tumor. A few weeks after her surgery, her HPA axis was re-evaluated, and steroids were discontinued. She has had no episodes of hypoglycemia since. Although hypoglycemia can be associated post-bariatric surgery, most patients develop postprandial hypoglycemia due to surgical alterations in alimentary flow leading to increased incretin and insulin secretion (Mulla et al 2016). Therefore, it is important to consider insulinoma in the differential diagnosis of post-bariatric surgery patients presenting without typical postprandial patterns of hypoglycemia. Reference: Mulla CM, Storino A, Yee EU, Lautz D, Sawnhey MS, Moser AJ, Patti ME, Insulinoma After Bariatric Surgery: Diagnostic Dilemma and Therapeutic Approaches. Obes Surg. 2016 Apr;26(4):874-81. Presentation: 6/1/2024

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

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

7684 Resistance to Thyroid Hormone Beta Mistaken as Primary Hypothyroidism: Variable Phenotypes and Diagnostic Dilemmas

Abstract Disclosure: H.F. Belal: None. A.N. Mukhtar: None. J.M. Chehade: None. Background: The differential diagnosis of hyperthyroxinemia and nonsupressed TSH includes assay interference, resistance to thyroid hormone beta (RTHb) and TSHoma. Correlation of laboratory findings with clinical presentation is crucial to avoid misdiagnosis. Clinical Case: A 50 year old female presented with palpitations, tremors, headaches, diarrhea, heat intolerance, chronic attention difficulty, pre-syncope and fatigue over several years. She had regular menses with no birth control use. There was no amiodarone, lithium or biotin use. Exam: vitals stable, no thyromegaly, no hand tremors, no exophthalmos. At 26 years old she was started on Levothyroxine (LEVO) 50 mcg for elevated TSH; FT4 was not measured. Over the past 10 years her labs demonstrated elevated FT4, elevated FT3, elevated FT4 by direct dialysis, normal TBG and inappropriately normal/elevated TSH while on LEVO 75 - 175 mcg. On LEVO 75 mcg: elevated TSH 5.94 uIU/mL (0.27-4.2), elevated FT4 2.2 ng/dL (0.8-1.7), elevated FT3 6.0 pg/mL (2.0-4.4), elevated FT4 direct dialysis 2.9 ng/dL (0.8-1.7), normal pituitary panel (including alpha subunit), low alpha subunit/TSH molar ratio (0.71). During an ED visit for chest pain, EKG revealed poor R wave progression, non-specific T wave abnormality. She was also found to have hepatic steatosis. RTHb was diagnosed and her LEVO was gradually tapered. Conclusion: TSH receptor beta is expressed in hypothalamus, pituitary, cochlea, retina, liver and kidney. TSH receptor alpha is expressed in skeletal muscle, heart, brain and bone. RTHb occurs at a frequency of 1 in 19,000 to 40,000 leading to resistance to thyroid hormone action at the HPA axis and liver. This produces higher FT4 and FT3 that act on normal TSH alpha receptors. Clinical phenotypes vary from euthyroid to hyperthyroid. Mistreating RTHb as hypothyroidism can worsen the thyrotoxic state. Testing for RTHb genetic mutation is available, yet 15% of RTHb patients do not have an identifiable pathogenic variant[1]. Treatment of RTHb ranges from observation, beta blockade, antithyroid drugs or TRIAC, a thyroid hormone analog which act at the HPA axis to inhibit TSH secretion.[1] Life threatening cases may require total thyroidectomy or radioiodine ablation; often avoided due to difficulty managing thyroid hormone replacement afterwards. Cases of goiter and ADHD in RTHb have been successfully treated with supraphysiologic every-other-day liothyronine.2 Management should be patient tailored and symptom specific.

7180 Adrenal Histoplasmosis And Tuberculosis: Clinical Presentations And Prevalence Of Adrenal Insufficiency

Abstract Disclosure: T. Vorasayun: None. P. Pengkhum: None. T. Porntharukchareon: None. R. Plongla: None. K. Sasiprang: None. T. Snabboon: None. W.W. Parksook: None. T. Wannachalee: None. S. Sunthornyothin: None. Background: Adrenal infection is an important cause of adrenal insufficiency (AI). Commonly reported pathogens are Histoplasma capsulatum and Mycobacterium tuberculosis (TB). These two pathogens can cause similar clinical presentations, yet patients require different specific treatments. Methods: We performed a retrospective study of patients with adrenal histoplasmosis and TB at two referral centers in Bangkok, Thailand. Adrenal infection was diagnosed by proven microbiologic evidence of infection and morphologic adrenal abnormalities on cross-sectional imaging. We evaluated clinical characteristics, prevalence of AI, and treatment. Results: Of the 47 patients, 33 (70%) had adrenal histoplasmosis, 13 (28%) had adrenal TB, and 1 (2%) had coinfection with both pathogens. The majority were HIV-negative (91%) and males (whole cohort; 81%, histoplasmosis; 94%, TB; 54%, coinfection; 100%). The mean age at the diagnosis was 64 years in patients with adrenal histoplasmosis and 49 in adrenal TB. One patient with coinfection was 84 years. Extra-adrenal manifestations were 55%, 77%, and 100% in patients with adrenal histoplasmosis, TB, and coinfection, respectively. At presentation, all patients with adrenal histoplasmosis had anorexia/weight loss, while this symptom was present in 54% of patients with adrenal TB. The most common presentation in adrenal TB was hyperpigmentation (77%), while it was documented in less than half of adrenal histoplasmosis (45%). On cross-sectional imaging, the majority (83%) had bilateral adrenal abnormalities, of which 81% were mass-like. The median diameter of the adrenal lesions with histoplasmosis infection was 5.6 and 5.4 cm on the right and left adrenal glands, respectively, while the median diameter of the adrenal lesions with TB infection was 3.2 cm on both sides. The prevalence of AI was 88% in the whole cohort (83% in adrenal histoplasmosis, 100% in adrenal TB and coinfection). In patients with AI, the median 8 AM cortisol levels were 4 ug/dl (histoplasmosis; 8.0 ug/dl and TB; 2.3 ug/dl), and the median ACTH levels were 431 pg/ml (histoplasmosis; 189 pg/ml and TB; 1377 pg/ml). During a median follow-up time of 22 months, 100% received antituberculosis/antifungal agents, while only 21% underwent adrenalectomy, in which most patients were those with adrenal histoplasmosis. All patients with AI received steroid replacement, yet 11% had an adrenal crisis. There was no HPA axis recovery in any AI patients. Conclusion: There were high rates of AI in patients with adrenal histoplasmosis and/or TB. No recovery of the HPA axis was observed, even after antifungal/TB agents and without bilateral adrenalectomy. Most patients were non-HIV males and had bilateral mass-like adrenal lesions. There was a slightly higher prevalence of extra-adrenal manifestations and AI in TB, and it affected more women than histoplasmosis. Presentation: 6/3/2024

7029 Changes In Adrenal Gland Size Seen By Linear Assessment On Routine Abdominal CT During Critical Illness

Abstract Disclosure: D.R. Vangipuram: None. N. Bhagat: None. R. Borkar: None. N.T. Mazengia: None. S. Williams, MD: None. S.K. Majumdar: None. Introduction: During acute stress, the hypothalamus-pituitary-adrenal (HPA) axis is activated, ultimately releasing adrenocorticotropic hormone (ACTH) from the pituitary gland, which stimulates cortisol synthesis and release from the adrenal gland. During this process, ACTH also increases adrenal blood flow which may result in noticeable changes in adrenal gland size on imaging. A previous study compared adrenal gland volume in patients with and without sepsis and concluded that adrenal gland volume was found to be nearly double in sepsis compared with patients without sepsis(1). Another study that evaluated adrenal gland size on MDCT, to provide normal values for volumetry and linear dimensions, found a concordance between volumetric and linear assessment (by cumulative width), though volumetry was more reproducible(2). Method: This is a retrospective study that included 50 adult patients (age 18 and over) who underwent a non-contrast or contrast CT scan of the abdomen within 5 years prior to admission to the Intensive Care Unit (ICU) with any critical illness, and then had another CT of the abdomen during the admission to the ICU. We measured the maximum width of the body (corpus) and that of the medial and lateral limbs of both the adrenal glands, perpendicular to the long axis, as seen on CT. The total (cumulative) width was calculated by adding the width of the corpus and both the limbs of each adrenal gland. The measurements were made by two different radiologists, who were blinded both to the before/after ICU admission CTs, and to each other’s measurements. Results: There was concordance in the measurements made by both the radiologists. We used the averages of both their measurements for analysis. The mean cumulative width of each adrenal gland, i.e., corpus+medial limb+lateral limb (in mm), was: Right adrenal before ICU admission 13.52 (± 3.20); during ICU admission 13.24 (± 3.13); p 0.444. Left adrenal before ICU admission 16.03 (± 3.18); during ICU admission 15.12 (± 3.47); p 0.021. Conclusion: There was a statistically significant decrease in the size of the left adrenal gland during critical illness, but no significant change in the right. Our findings do not suggest an increase in adrenal gland size during ICU admission.

6903 The Treatment May Be Worse Than The Disease: The Real-World Clinical Burden Of Disease And Treatment In Congenital Adrenal Hyperplasia

Abstract Disclosure: W. Huang: Consulting Fee; Self; Spruce Biosciences. Research Investigator; Self; Spruce Biosciences. R. Charlton: Employee; Self; Spruce Biosciences. S. Sile: Employee; Self; Spruce Biosciences. C. Dieyi: Employee; Self; STATinMED. S. Adams: Employee; Self; STATinMED. J. Maynard: Employee; Self; STATinMED. C.N. Barnes: Employee; Self; Spruce Biosciences. A.H. Hamrahian: Consulting Fee; Self; Spruce Biosciences. Research Investigator; Self; Spruce Biosciences. Background and Aims: Classic congenital adrenal hyperplasia (CAH) is a group of autosomal recessive conditions that affects the production of adrenal hormones, leading to deficiencies in cortisol and aldosterone, and excess in adrenal androgens. Current treatment includes mineralocorticoids and oral glucocorticoids (GCs) for physiologic cortisol replacement and hypothalamic-pituitary-adrenal (HPA) axis suppression to control androgen levels. The health impacts of hyperandrogenemia include accelerated skeletal maturation leading to adult short stature, precocious puberty, acne, hirsutism, male pattern baldness, adrenal rest tumors, and infertility. There are also serious adverse events due to the long-term use of supraphysiologic doses of GCs. The aim of this study was to explore the risks associated with CAH diagnosis and treatment. Methods: This cross-sectional study used medical administrative claims data within 2014-2021 from RWD Insights®, an all-payer claims database in the US. Adult patients were required to have a diagnosis of CAH (ICD-9/10-CM: 255.9, E25.0, E25.9) and continuous use of oral GCs (defined as a proportion of days covered of 75% or more in any given calendar year). Patients were further required to receive an average daily GC dose of ≥10mg/day hydrocortisone equivalent and be free of pituitary disorders. Non-CAH controls were also selected if they did not have a CAH diagnosis or any GC use. Demographic characteristics and comorbidity rates were compared between patients with and without CAH during the study period. For comorbidity rate comparisons, rate ratios (RR) and 95% confidence intervals (CI) were computed. Results: A total of 1,532,141 (CAH: 2,033; Non-CAH: 1,530,108) were eligible for the study. A lower proportion of the CAH cohort was elderly (i.e., 65+ years; 11% vs. 26%), and there were more females (67% vs. 57%), as compared to the non-CAH cohort. After propensity score matching (PSM) on demographic characteristics, there were 2,019 and 8,076 patients in the CAH and non-CAH cohort, respectively, and patient characteristics were balanced. There were higher rates of comorbidities in the CAH cohort. Some notable differences, RR (95%CI), include GC related comorbidities such as osteoporosis/necrosis, 3.48 (3.36, 3.60) and fractures, 2.14 (1.90, 2.39); metabolic disorders, 2.20 (2.08, 2.33), obesity, 1.35 (1.26-1.44), type 2 diabetes, 1.27 (1.18,1.36), and cardiovascular disorders, 1.24 (1.16, 1.33); and CAH related comorbidities, hirsutism, 11.70 (11.34, 12.06) and testicular hypofunction, 5.48 (5.24, 5.71). Conclusions: This study suggests the association of several comorbidities with CAH, highlighting the burden of both the disease and treatment. Novel, non-steroidal treatments that improve hormonal balance in CAH could ameliorate the systemic risks associated with hyperandrogenemia and chronic overexposure to GCs. Presentation: 6/1/2024

7487 Iatrogenic Cushing’s Syndrome In A Patient On Prezcobix And Fluticasone

Abstract Disclosure: A.N. Davis: None. M. Nicholson: None. Introduction: The HIV medication Prezcobix contains darunavir, a protease inhibitor which is known to inhibit the hepatic enzyme CYP3A4. This may lead to accumulation of some medications in the blood, including fluticasone. We present a patient with iatrogenic Cushing’s syndrome while on Prezcobix and fluticasone. Case: Patient is a 55-year-old man who presented to clinic 3/13/23 for evaluation for cushingoid appearance at the request of his infectious disease (ID) physician. The patient has history of HIV, asthma, and seasonal allergies and had been taking Prezcobix, inhaled fluticasone, and intranasal fluticasone for over 3 years. Patient noted easy bruising and difficulty with weight loss. Vital signs were remarkable for elevated blood pressure at 165/86 despite taking amlodipine, HCTZ, and carvedilol. He was overweight with BMI 27.2. Physical exam revealed a somewhat rounded face, mild central obesity, no dorsocervical or supraclavicular fat pads, and no purple striae. Labs on 3/8/23 were remarkable for cortisol level <0.40mcg/dL at 4:10PM. Labs on 3/13/23 were remarkable for cortisol <0.40mcg/dL, ACTH level <5.0pg/mL, and urine fluticasone 17-beta carboxylic acid elevated at 540pg/mL (<10pg/mL) at 3:57PM. His ID physician planned to transition the patient off of Prezcobix and onto Tivicay, so patient was started on hydrocortisone 15mg PO daily at 8AM and 5mg daily at 2PM on the day he switched to Tivicay. He was gradually tapered off of hydrocortisone over a 2-3 month period without any symptoms concerning for adrenal insufficiency. His Cortisol level on 7/10/23 off hydrocortisone was 4.98mcg/dL at 7:56AM. Discussion: Prezcobix contains darunavir which is known to inhibit CYP3A4. With most patients, use of inhaled and intranasal fluticasone does not result in physiologically meaningful systemic levels of fluticasone. However, metabolism of fluticasone is dependent on CYP3A4, so systemic levels may increase with use of inhaled fluticasone with Prezcobix resulting in excess of corticosteroids and suppression of the native hypothalamic-pituitary-adrenal (HPA) axis. Fluticasone 17-beta carboxylic acid is a metabolite of fluticasone which is detectable in the urine. Sudden cessation of Prezcobix after prolonged use may result in secondary adrenal insufficiency from prolonged HPA axis suppression. Our case demonstrates how the use of Prezcobix with fluticasone may result in iatrogenic Cushing’s syndrome. Additionally, our case demonstrates that anticipation of secondary adrenal insufficiency after stopping Prezcobix allows for implementation of a safe transition plan. Presentation: 6/1/2024

7988 A Case of Spontaneous Pituitary Hemorrhage in Late Pregnancy

Abstract Disclosure: D. Poudyal: None. G.L. Prince: None. Background: Pituitary apoplexy (PA), caused by hemorrhage into the pituitary gland, is rare. The prevalence in pregnancy is also quite rare, with PA complicating 1 in 10,000 pregnancies. PA usually occurs in patients with pre-existing pituitary adenomas. Spontaneous pituitary hemorrhage (PH) causing PA in the absence of a known adenoma or other precipitating factors is less frequently described. Presenting symptoms of PA are non-specific and can pose diagnostic challenges, yet PA must be managed urgently and decisively due to the risk of life-threatening hormonal deficiencies that can ensue. Physiologic changes in pregnancy pose additional challenges in evaluating and managing patients with possible PA. Here we present a case of spontaneous PH during the third trimester of pregnancy in the absence of pre-existing pituitary pathology or known precipitants. Case presentation: A 31-year-old female, G2P1, with an uncomplicated first pregnancy, presented with acute-onset headache and vision loss at 36 weeks gestation. Her symptoms resolved spontaneously in 45 minutes. MRI brain without contrast showed hemorrhage within the left aspect of the pituitary gland, a mildly displaced infundibulum, but no mass effect on the optic chiasm. MRI brain obtained 1 year prior for headache was unremarkable. Lab work showed an 8AM cortisol of 19 ug/dL (Ref range 3.7 - 19.4 ug/dL), and a total T4 of 11.3 ug/dL (Ref 4.9 - 11.7 ug/dL). Ultimately, interpretation of her cortisol testing was limited by: elevated cortisol-binding globulin in the high-estrogen state of pregnancy, elevated cortisol production by an intact hypothalamic-pituitary-adrenal (HPA) axis during the latter portion of pregnancy, and the lack of validated cutoff values for 8AM serum cortisol levels during pregnancy. In light of these factors and the risk of undiagnosed adrenal insufficiency (AI), she was treated empirically with oral hydrocortisone. Subsequently, she had an uneventful vaginal delivery, supported by stress dosing of her steroids. Postpartum, she had a normal 8AM cortisol level of 14 ug/dL, and she was noted to quickly begin breastfeeding without incident. Conclusion: PA remains a critical diagnosis that cannot be missed in patients presenting with concerning symptoms and signs, in order to identify and treat life-threatening hormonal deficiencies. Pregnancy poses unique challenges in diagnosing hormonal deficiencies such as AI due to normal physiologic changes affecting the HPA axis as well as other pituitary axes. Therefore, the benefit of empiric hydrocortisone treatment likely outweighs any associated treatment risk in cases with consistent symptomatology and radiographic findings. Presentation: 6/2/2024

6579 Neuroendocrine Signatures of Social-Defeated Stress Expressed by Adrenal Hormones in Mice

Abstract Disclosure: J. Noh: None. J. Choi: None. S. Myung: None. M. Kim: None. M. Choi: None. While psychological stress is one of the prevalent contributors to depression, the precise role of metabolic phenotypes in the development of depression remains elusive. Abnormality in hypothalamus-pituitary-adrenal (HPA) axis is a classical feature of depression. Here, an animal model of social defeat stress (SDS) was established with five-week-old C57BL/6J mice to repeated episodes of social defeat for a period of 10 days, facilitated by an aggressive CD-1 mouse. Liquid chromatography-mass spectrometry-based profiling of 29 adrenocortical steroids and 6 medullary amines was employed for serum samples collected at 3, 5, 7, and 10 days during the modeling from both control (n = 28) and SDS (n = 32) group. In response to initial stress, corticosterone (B) and its two precursors were significantly increased (p < 0.03 for all) during 3 days, while 18-hydroxyB was remarkably elevated (p < 0.003 for 3 days and p < 0.005) in SDS mice. In contrast, dopamine (p < 0.03) and metanephrine (p < 0.008) were significantly increased during 5 days in SDS mice, while remarkably higher levels of norepinephrine were also observed during 7 days (p < 0.01). The SDS mice showed the increased levels of normetanephrine for all days of repeated stress exposure (p < 0.002 for all, except 10 days of p < 0.02). In this study, the HPA regulated negative feedback in short period, whereas sympathetic nervous system was continuously stimulated during repeated stress exposure. The present study may provide insight into the neuroendocrine effects of social stress on allostatic overload. Presentation: 6/2/2024

7372 Anti-Corticotropin-Releasing Hormone (CRH) Monoclonal Antibody HBM9013 For The Treatment Of Congenital Adrenal Hyperplasia (CAH) And Polycystic Ovarian Syndrome (PCOS)

Abstract Disclosure: H. Pan: None. L.L. Liu: None. Q. Lv: None. F.G. Grosveld: None. D. Drabek: None. R.V. Haperen: None. X. Wang: None. Y. He: None. Y. Wang: None. J. Huang: None. J. Lee: None. G. Zhang: None. J.J. Rong: None. H.V. Chen: None. J.A. Majzoub: Advisory Board Member; Self; Chair of SAB of Harbour BioMed Alpha Therapeutics, which owns the rights of HBM9013.. Stock Owner; Self; Equity Owner of Harbour BioMed Alpha Therapeutics, which owns the rights of HBM9013.. J.J. Zhao: None. Anti-Corticotropin-Releasing Hormone (CRH) Monoclonal Antibody HBM9013 for the Treatment of Congenital Adrenal Hyperplasia (CAH) and Polycystic Ovarian Syndrome (PCOS). Abstract Congenital Adrenal Hyperplasia (CAH) is a rare autosomal recessive genetic disease due to mutation of CYP21A2 which leads to deficiency of 21-Hydroxylase enzymatic activity. Classical CAH patients are born with life-threatening deficiency of glucocorticoid (GC) and mineralocorticoid. Due to this enzymatic block and the lack of negative feedback on the hypothalamic-pituitary-adrenal (HPA) axis by GC, the adrenal gland produces excessive amounts of androgen which result in masculinized genitalia and virilization. The current standard care is supraphysiological doses of GC, which are difficult to balance between excess GC exposure and excess androgen secretion. Too little GC does not suppress production of androgen sufficiently and too much GC leads to Cushing Syndrome (CS). Previous work found that corticotropin-releasing hormone (CRH) is absolutely required for activation of the HPA axis during loss of GC negative feedback, via adrenocorticotropic hormone (ACTH) (1), which is necessary for production of adrenal androgens (2). We report here the development of Anti-CRH humanized monoclonal antibody HBM9013 (PR302334-24) for the treatment of CAH. HBM9013 binds to CRH with high affinity and neutralizes its signaling through both CRH Receptor 1 (CRHR1) and CRH Receptor 2 (CRHR2) in vitro. HBM9013 shows in vivo activities in two preclinical models. It blocks restraint stress-induced increases in plasma ACTH and corticosterone in mouse and rat. Mouse ACTH and Corticosterone were reduced from 210 ± 63 pg/ml to 27 ± 8 pg/ml (Mean ± SD, p = 5.2*10-6; IgG1 Control Group = 6 mice; HBM9013 Group = 8 mice) and from 303 ± 28 ng/ml to 57 ± 15 ng/ml (Mean ± SD, p = 6.2*10-[1][1]; IgG1 Control Group = 6 mice; HBM9013 Group = 8 mice), respectively. It also markedly reduces the constitutive, extremely elevated plasma ACTH levels in Mrap-knockout mice from 3847 ± 240 pg/mL to 1080 ± 302 pg/mL (Mean ± SD, n = 5 independent experiments, p = 2.3*10-7). HBM9013 has excellent CMC characteristics with ∼5 g/L titer and ∼80% yield. HBM9013 also has an excellent safety profile with no-observed-adverse-effect-level (NOAEL) of 150 mg/kg in weekly dosing for five doses in both rat and cynomolgus dose-ranging-finding (DRF) toxicology studies. HBM9013 is formulated up to 150 mg/ml as a weekly to monthly subcutaneous injection for ease of administration and compliance for CAH patient. HBM9013 could be a next generation therapy for CAH, in combination with a low physiological dose of GC that would avoid CS. Since ∼50% of Polycystic Ovarian Syndrome (PCOS) androgens may be of adrenal origin, we believe that HBM9013 could also be indicated for PCOS. References(1)Muglia LJ et al. J Clin Invest. 2000. 105:1269-77.(2)Weber A et al. Clin Endocrinol. 1997. 46:431-7. Presentation: 6/1/2024

8644 Dynamic Insights into Glucocorticoid Receptor Dysfunction: Novel patient-derived T437I Mutation and Its Impact on Glucocorticoid Receptor Function

Abstract Disclosure: T. Tettey: None. S. Kim: None. K. Wagh: None. Q. Lao: None. L.R. Schiltz: None. D.A. Stavreva: None. D.M. Presman: None. D.P. Merke: None. G.L. Hager: None. The glucocorticoid receptor (GR) is a hormone regulated transcription factor which binds chromatin to regulate many genes, including stress-response and inflammatory genes. Dexamethasone, a GR agonist, is widely used in the treatment of severe inflammation, including COVID-19. GR is vital for life and several GR mutations have been linked to severe pathophysiological conditions. Here we report a novel mutation in the DNA binding domain (DBD) of GR (T437I) in a patient with partial glucocorticoid resistance, a rare genetic disorder characterized by generalized insensitivity to glucocorticoids and a consequent hyperactivation of the hypothalamic pituitary adrenal axis. While the clinical manifestations of this hT437I GR mutation are apparent, its molecular mechanisms remain unexplored. Employing a comprehensive approach that integrates biophysical methods, molecular biology, and genomics, we investigate the molecular underpinnings of this genetic anomaly. Using CRISPR/Cas9 gene editing, we introduce GFP or Halo-tagged hT437I GR mutant into GR null mouse cells. Our findings indicate that the T437I GR variant exhibits normal hormone binding and nuclear translocation. Live-cell imaging using number and brightness analysis reveals that the mutant receptor maintains a wildtype-like oligomeric state but adopts a heterodimeric conformation in the presence of endogenous GR. Global transcriptomics analyses of the mouse hT437I mutant show that most dexamethasone-regulated genes are unresponsive following hormone treatment. We hypothesize that this mutation within the DBD compromises the binding of GR to regulatory sites of target genes. Leveraging fluorescence high-resolution microscopy, we employ single molecule tracking to study the dynamic behavior of Halo-tagged hT437I GR in mouse cells. Our results indicate that the GR mutant has a higher dwell-time on chromatin compared to the wild-type receptor. This suggests that the hT437I mutation impairs the receptor's binding to genomic sites, potentially leading to a failure in regulating GR target genes. This ongoing exploration of the molecular intricacies aims to deepen our understanding of the clinical phenotype observed in the patient. Presentation: 6/2/2024

12376 Comparison Of 1 Mg Versus 2 Mg Dexamethasone Suppression In Obesity

Abstract Disclosure: H. Babu: None. A. Nawaz: None. A.J. Spiro: None. T.D. Hoang: None. M.K. Shakir: None. The overnight 1 mg dexamethasone suppression test (DST) is widely used to screen for Cushing’s Syndrome (CS), especially due to its low incidence of false negative results. Serum cortisol concentrations <1.8 µg/dL suggests adequate HPA axis suppression and usually excludes CS. Concentrations >1.8 µg/dL should be verified with a second test. However, the lack of suppression on DST has been documented previously in 1.46% to 15% of obese patients without CS. Previous studies have suggested simultaneous measurements of serum cortisol, ACTH, and dexamethasone levels after DST to ensure adequate suppression. In this retrospective analysis, we compared the plasma levels of ACTH, dexamethasone, and cortisol levels after 1 mg and 2 mg DST in healthy obese (class III) subjects. The study involved 6 subjects (2 males, 4 females, age 37.5 ± 8.79 years, BMI 43.65 ± 3.12 (kg/m2) who were referred for evaluation of abnormal weight gain. Exclusion criteria for these subjects included diabetes mellitus, pregnancy, history of CS, psychiatric disorders, chronic liver disease, chronic renal failure, malabsorption disorders and nephrotic syndrome. The exclusion of CS was done by history and physical examination showing the lack of specific clinical features of CS. Additionally, none of the subjects were taking drugs that interfered with CYP3A4 or oral contraceptives within 3 months preceding the study. None of the participants reported alcohol consumption of more than 30 g per day. Screening tests for CS involved 1 mg, 2 mg DST, LNSC and 24-hour urine cortisol levels. Results: Following 1 mg DST in 5 subjects, the mean serum cortisol levels were 1.35 ± 0.13 mcg/dL and the mean serum dexamethasone levels, and ACTH levels were 282 ± 44 ng/dL and 5.92 ± 1.56 pg/mL, respectively. However, in one subject (BMI 43.5) the post-DST cortisol level was 2.96 mcg/dL with corresponding dexamethasone level of 138 ng/dL and ACTH level of 21 pg/mL. However, following 2 mg DST in all 6 subjects the serum cortisol levels were less than 1.8 mcg/dL (1.21± 0.22 mcg/dL) with ACTH levels (3.87 ± 0.70 pg/mL) and dexamethasone levels of 482 ± 80 ng/dL. The LNSC levels were normal in 4 subjects (0.010 ± 0.005 mcg/dL), whereas in 2 subjects these were minimally elevated. 24-hour urine cortisol levels were normal in 5 subjects (29.4 ± 3.74 mcg) and in one subject this was mildly elevated (67 mcg). Long term follow-up of all subjects confirmed normal cortisol status. Previous studies have demonstrated that routine CS screening of patients affected by severe obesity is not indicated. However, other investigations have shown CS may occur in a small percentage of severe obese patients. In conclusion, 2 mg DST is a preferred test in obese patients suspected to have CS although 1 mg DST generally can be used as an initial screening test. Additionally, serum dexamethasone and ACTH measurements may still be useful in patients who are suspected to have a false-positive DST. Presentation: 6/1/2024

12271 Differential Impacts Of Body Composition Indices On Cortisol Response And Hpa Axis Activity

Abstract Disclosure: S.G. Gonsalves: None. A. Ross: None. M.E. Steele: None. L.N. Saligan: None. Aim: The continued interest in the influence of muscle mass and fat distribution on stress stems from its implications on preventative healthcare. Fat mass index (FMI) and fat-free mass index (FFMI) were proposed as valuable indicators of body composition beyond body mass index (BMI). This study investigated correlations of FMI and FFMI with inflammatory stress markers, hypothesizing that these body composition indices identify inflammatory stress markers more distinctly than BMI. Methods: Skeletal muscle mass was assessed by Dual-Energy X-ray Absorptiometry, HPA axis response through an adrenocorticotropic hormone (ACTH) stimulation test, and markers of inflammation and stress response (e.g., dehydroepiandrosterone, DHEA) from peripheral blood of 104 healthy individuals aged 18-71 years, 52% female, with a mean BMI of 26.3 (+4.83). Perceived stress and fatigue were captured using patient-reported outcome questionnaires before the HPA procedure. Results: ACTH correlated with FFMI at baseline (ρ=0.299, p=0.009) and 60 minutes (ρ=0.254, p=0.041). Cortisol correlated with FFMI at 15 (ρ=–0.248, p≤0.025), 30 (ρ=–0.284, p≤0.010), and 60 minutes (ρ=–0.364, p≤0.001), and with BMI at 15 (ρ=–0.228, p=0.041). FMI and BMI did not correlate with ACTH and FMI with cortisol at any timepoint. With repeated measures ANOVA, FFMI at 50th percentile had large effect on cortisol (p=0.005, partial eta=0.094) at each timepoint, higher for the under lean than those with higher FFMI, compared to BMI at the same percentile (p=0.037, partial eta=0.054). None of the indices reached significance with ACTH. FMI correlated with Erythrocyte Sedimentation Rate (ESR) (ρ=0.521), C-reactive protein (CRP, ρ=0.493, both at p≤0.001), DHEA (ρ=0.252, p=0.030), and epinephrine (ρ=–0.246, p=0.045). FFMI was not correlated with ESR and CRP. BMI correlated only with albumin (ρ = –0.412, p ≤ 0.001 and CRP (ρ=0.342, p≤0.003). Discussion: The higher correlations of inflammatory stress markers with FMI and FFMI, as compared to BMI, supports our study hypothesis. These results hint that these body composition indices may detect subtle stress-related inflammatory changes than BMI. Future research should clarify underlying mechanisms driving these associations and explore the impact of targeted interventions on these indices and subsequent changes to inflammation and stress. Presentation: 6/1/2024

12361 An Unusual Case of Myxedema Coma

Abstract Disclosure: N. Hasan: None. D. Yang: None. T. Othman: None. J. Dai-Ju: None. Background: Most cases of Myxedema Coma are associated with primary hypothyroidism with significantly elevated TSH levels. However the presence severe illness can contribute to decreased TSH release even in the absence of central lesions. Case: 60 year old female was found down covered in feces. She was hypothermic to 89°F, with a pulse of 62. Physical exam revealed hair loss, thick tongue, non-pitting edema, and delayed relaxation of brachial reflexes. Labs showed Sodium of 123, blood glucose of 80. Thyroid function testing revealed only a mildy elevated TSH of 13 with free T4 <0.025. Anti-TPO antibodies were elevated at 157. MRI of the Sella was negative any lesions. Thyroid ultrasound showed atrophic bilateral thyroid lobes. Assessment for hypopituitarism did not show any significant deficiencies with Cortisol 45, ACTH 11, LH 0.5, FSH 8.5, IGF-33, and Total Testosterone 10. She was found to have septic shock secondary to perforated sigmoid colon requiring colectomy. She was initially loaded with Dexamethasone 4mg followed by IV Levothyroxine 100mcg, with steroids being discontinued after AI was ruled out. After treating her sepsis she was transitioned to 150mcg of oral Synthroid with improvement of her thyroid function tests to TSH of 2.7 and free T4 of 1.56. Discussion: The majority of Myxedema Coma is associated with primary hypothyroidism. In these cases, TSH levels are markedly elevated, often greater than 100. When the TSH is not as elevated as we would expect, many factors must be considered, the greatest being central hypothyroidism where TSH secretion may be impaired from pituitary tumors, surgery, radiation, and other causes. Our patient however did not have any central lesions on imaging and was found to have anti TPO antibodies with atrophic thyroid lobes on ultrasound suggestive of primary hypothyroidism. This brings us to the effect of acute illness on the balance of thyroid hormones. Conditions such as sepsis stimulates elevations in inflammatory cytokines which disrupt the physiologic response to release TSH. Previous studies involving sepsis revealed the main cytokines implicated are TNF alpha, Interferon gamma, IL-1, and IL-6. The degree of inadequate TSH secretion is often times proportional to the severity of illness and improves after recovery from the illness. Conclusion: Our body's response to critical illness involves complex hormonal changes which affect the HPA axis and can decrease TSH secretion, even in myxedema coma without central lesions. Presentation: 6/1/2024

The Interrelationship between Stress, Sugar Consumption and Depression.

Depression is a leading cause of disability in the United States. Previous research has shown that added sugar consumption and stress are both risk factors for depression. Despite evidence that stress predicts added sugar consumption, and both affect the HPA axis, no research has explored how stress, added sugar consumption and depression are related. In this study, we investigated the possible effects of total added sugar and sugar-sweetened beverage consumption on depression, as well as their potential interactions with chronic stress. Measures of sugar consumption, chronic stress and depression were taken in an adult community sample at two time points. We hypothesized that high sugar consumption would predict more depression even after stress was statistically adjusted for, but that stress would moderate the relationship between added sugar consumption and depressive symptoms, amplifying the effect. We found that both total sugar consumption and sugar-sweetened beverage consumption at baseline predicted depressive symptoms one month later. However, only sugar-sweetened beverage consumption was a significant predictor of depression after controlling for stress, possibly because stress is related to diet quality. Stress did not moderate the relationship between added sugar consumption and depressive symptoms. These results suggest that stress should be included in future research on sugar and depression.

Do stress hormones influence choice? A systematic review of pharmacological interventions on the HPA axis and/or SAM system.

The hypothalamus-pituitary-adrenal axis (HPA axis) and the sympathetic-adrenal-medullary system (SAM system), two neuroendocrine systems associated with the stress response, have often been implicated to modulate decision-making in various domains. This systematic review summarizes the scientific evidence on the effects of pharmacological HPA axis and SAM system modulation on decision-making. We found 6375 references, of which 17 studies fulfilled our inclusion criteria. We quantified the risk of bias in our results with respect to missing outcome data, measurements, and selection of the reported results. The included studies administered hydrocortisone, fludrocortisone (HPA axis stimulants), yohimbine, reboxetine (SAM system stimulants), and/or propranolol (SAM system inhibitor). Integrating the evidence, we found that SAM system stimulation had no impact on risk aversion, loss aversion or intertemporal choice, while SAM system inhibition showed a tentative reduction in sensitivity to losses. HPA axis stimulation had no effect on loss aversion or reward anticipation but likely a time-dependent effect on decision under risk. Lastly, combined stimulation of both systems exhibited inconsistent results that could be explained by dose differences (loss aversion) and sex differences (risk aversion). Future research should address time-, dose-, and sex-dependencies of pharmacological effects on decision-making.

Examining hypothalamic-pituitary-adrenal axis genetic variation on cortisol and alpha-amylase reactivity during an explicit negative-evaluative stress induction.

Prior work consistently links additive genetic variation in the hypothalamic-pituitary-adrenal (HPA) axis-a multilocus genetic profile score (MGPS)-to depression risk in the context of stress exposure. However, despite that HPA MGPS variants were selected based on evidence that they elevate cortisol reactivity, there are surprisingly few tests of whether an HPA MGPS elevates cortisol reactivity to lab-based stress. Similarly, despite neurobiological connections and coordination between the HPA axis and the sympathetic nervous system (e.g., in the paraventricular nucleus and locus coeruleus), no work has tested whether an HPA MGPS influences sympathetic nervous system reactivity to stress. We investigated whether an HPA MGPS moderates the relation between lab-based stress and: (1) HPA activity indexed by cortisol, and/or (2) sympathetic activity indexed by salivary alpha-amylase, sAA. Emerging adults (N=152; mean age=19.5, largest subsample 44.4% Black/African American) were randomly assigned to one of two Trier Social Stress Test variations, a non-evaluative control, or an explicitly negative-evaluative condition. Participants provided DNA and repeated saliva samples for sAA and cortisol. The HPA MGPS did not significantly moderate the relationship between stress condition and cortisol or sAA reactivity, respectively; moreover, post-hoc tests highlight that individual polymorphisms showed non-significant effects in opposite directions from each other, cancelling out in aggregate. Findings suggest that the HPA MGPS's associations with cortisol reactivity are not as straightforward as initially believed. We speculate that the relationships of some HPA variants to biomarker reactivity may vary between modest lab-based stressors and the explicit negative-evaluative induction used here.