Morning Plasma Research Articles

8319 Pituitary Apoplexy Leads to the Spontaneous Resolution of Hypercortisolism Secondary to Cushing Disease: A Clinical Case

Abstract Disclosure: N. Sweis: None. J. Sanchez Perez: None. M. Fariduddin: None. R.M. Sargis: None. D.J. Toft: None. S. Reutrakul: None. Background: Pituitary apoplexy is a potentially fatal condition involving the infarction or hemorrhage of the pituitary gland. Rarely, it can occur in the setting of an ACTH-secreting pituitary adenoma. Clinical Case: A 27-year-old female with a past medical history of obesity, spontaneous miscarriages, and amenorrhea presented to the ER with an acute onset frontal headache of throbbing quality, associated with nausea and vomiting. The headache began two days prior, rapidly intensified, and did not improve with oral acetaminophen. CT of the head revealed an enlarged pituitary gland, while neurovascular imaging showed no abnormalities. Her neurologic examination was normal. She denied visual changes, photophobia, neck rigidity, fevers, chills, or recent infections. Furthermore, she endorsed a weight gain of about 40 pounds over the past year despite no change in dietary habits. This was accompanied by amenorrhea, hair thinning, itchy comedonal acne, hirsutism, and a loss of libido. Her physical examination was remarkable for the presence of cushingoid features including violaceous abdominal striae, facial acne, moon facies, a dorsal fat pad, and acanthosis nigricans around the neck and axillae. Pituitary MRI with and without contrast showed an enlarged sellar and suprasellar macroadenoma measuring approximately 2.1x1.4x1.2 cm abutting the optic chiasm. The visualized lesion contained hemorrhagic products, suggesting pituitary apoplexy. Biochemical testing on admission included a low morning plasma cortisol of 6.5 ug/dL (ref. range: 6.7-22.6 ug/dL), a 24-hour urine free cortisol of 12.0 (<=45.0 ug/24 hour), and an elevated ACTH of 145.0 pg/mL (7.2 - 63.3 pg/mL). A1c was 5.8% (<5.7%). Serum levels of prolactin, IGF1, GH, LH, FSH, TSH, Free T4, estradiol, total and bioavailable testosterone were within normal limits. She was evaluated with an ACTH stimulation test, which showed a morning cortisol level of 1.2 ug/dL at baseline, lower from prior. Cortisol levels were adequately increased at 19.6 ug/dL and 22.6 ug/dL, 30 and 60 minutes after the administration of Cosyntropin 250 mcg, respectively (>=18 ug/dL after 30-60 mins). The level of ACTH at the time was also decreased to 76.6 pg/mL. The patient was therefore started on steroid replacement therapy with hydrocortisone and later underwent transsphenoidal resection of the pituitary mass without complications. Histopathological examination of the resected mass showed pituitary adenoma cells with diffuse weak to moderate ACTH staining, most consistent with a sparsely granulated corticotroph pituitary adenoma. Conclusion: We report an interesting case of Cushing disease that spontaneously resolved after pituitary apoplexy. Our case underlines the importance of close monitoring of such patients who may rapidly undergo a period of adrenal insufficiency after hypercortisolism. Presentation: 6/3/2024

Sex differences in binge drinking-related higher morning cortisol levels and in prospective association with future alcohol intake.

Peripheral cortisol represents one biological measure of the hypothalamic-pituitary-adrenal (HPA) axis, a significant component of the stress system, which is altered by chronic alcohol consumption. However, whether heavy alcohol use affects the HPA axis differentially between the sexes and whether basal cortisol levels are a biomarker of prospective alcohol intake is unknown. We recruited light moderate (LM) and binge-heavy (BH) drinkers of alcohol (n = 118). Repeated fasting morning cortisol levels were studied over a 2-hour period to assess basal levels while participants underwent a neuroimaging scan. Significantly higher average cortisol levels in BH compared to LM groups across four timepoints were observed (P < .018). Overall sex differences were observed with women showing higher initial cortisol levels at the first timepoint with a blunted decrease over the morning relative to men (P<.003). Average morning cortisol differentially predicted prospective future 30-day daily reports of alcohol consumption by sex and group, such that LM males had a positive significant relationship and BH males had a negative non-significant relationship between cortisol and drinking. Findings indicate that morning plasma cortisol is upregulated in the BH vs. LM group. Although females had higher initial morning cortisol levels, BH males showed a dysregulated negative relationship between stress and binge drinking in contrast to the LM group. Future work should further investigate the role of cortisol and other stress hormones as biomarkers of problematic drinking behaviors in men and women.

Serum phosphate levels at diagnosis predict long-term risk for hypopituitarism in patients with acromegaly.

Excess growth hormone (GH) secretion in acromegaly has a major impact on mineral balance and serum phosphate levels. However, the clinical utilization of serum phosphate levels as a marker for long-term disease outcomes in acromegaly has not been evaluated. This is a retrospective study of patients with acromegaly who were followed in a tertiary center. Data were retrieved on patient characteristics, endocrine and biochemical evaluation, and tumor parameters. Comparisons were performed by measuring baseline phosphate levels and conductingcorrelation analysis and multivariable logistic regression. Sixty-one patients were followed for 4.5years (range 1-21). Patients with hyperphosphatemia (> 4.5mg/dl) at baseline had larger adenomas (15.0mm [8.0, 47.0] vs. 10.0mm [3.0, 24.0], p = 0.001), a rate chance of invasive adenoma (16 [80.0%] vs. 14 [46.7%], p = 0.02), and lower serum cortisol levels (226.0nmol/l [27.6, 516.0] vs. 294.0nmol/l [32.0, 610.0], p = 0.02). Baseline serum phosphate levels positively correlated with IGF-1 levels (r = 0.43, p = 0.003) and negatively correlated with morning plasma cortisol levels (r = -0.46, p = 0.002). Regarding long-term impact, baseline phosphate levels correlated with the number of pituitary axes involved 6months after diagnosis (r-0.34, p = 0.01). In multivariable analysis, baseline plasma phosphate levels were independently associated with risk for disease progression/recurrence (odds ratio [OR] 9.66, 95% confidence interval [CI] 1.5, 105.9, p = 0.03) and for invasive adenoma (OR 6.21, 95% CI 1.6, 28.7, p = 0.01). Elevated pretreatment serum phosphate levels are associated with a greater risk of disease persistence and recurrence and with altered pituitary function in patients with acromegaly.

Cortisol, Stress, and Disease-Bidirectional Associations; Role for Corticosteroid-Binding Globulin?

Selye described stress as a unified neurohormonal mechanism maintaining homeostasis. Acute stress system activation is adaptive through neurocognitive, catecholaminergic, and immunomodulation mechanisms, followed by a reset via cortisol. Stress system components, the sympathoadrenomedullary system, hypothalamic-pituitary-adrenal axis, and limbic structures are implicated in many chronic diseases by establishing an altered homeostatic state, allostasis. Consequent "primary stress system disorders" were popularly accepted, with phenotypes based on conditions such as Cushing syndrome, pheochromocytoma, and adrenal insufficiency. Cardiometabolic and major depressive disorders are candidates for hypercortisolemic etiology, contrasting the "hypocortisolemic symptom triad" of stress sensitivity, chronic fatigue, and pain. However, acceptance of chronic stress etiology requires cause-and-effect associations, and practical utility such as therapeutics altering stress system function. Inherent predispositions to stress system perturbations may be relevant. Glucocorticoid receptor (GR) variants have been associated with metabolic/neuropsychological states. The SERPINA6 gene encoding corticosteroid-binding globulin (CBG), was the sole genetic factor in a single-nucleotide variation-genome-wide association study linkage study of morning plasma cortisol, a risk factor for cardiovascular disease, with alterations in tissue-specific GR-related gene expression. Studies showed genetically predicted high cortisol concentrations are associated with hypertension and anxiety, and low CBG concentrations/binding affinity, with the hypocortisolemic triad. Acquired CBG deficiency in septic shock results in 3-fold higher mortality when hydrocortisone administration produces equivocal results, consistent with CBG's role in spatiotemporal cortisol delivery. We propose some stress system disorders result from constitutional stress system variants rather than stressors themselves. Altered CBG:cortisol buffering may influence interstitial cortisol ultradian surges leading to pathological tissue effects, an example of stress system variants contributing to stress-related disorders.

The Severity of Bone Loss in Cushing’s Diseases

&amp;lt;i&amp;gt;Introduction: &amp;lt;/i&amp;gt;Endogenous Cushing&amp;apos;s syndrome (CS) is a known cause of secondary osteoporosis, characterized by a loss of bone mass and density. Cushing&amp;apos;s osteopathy is one of it’s most severe complications. Abnormal bone turnover, decreased bone mineral density (BMD), and increased fracture risk are common effects of glucocorticoid excess. &amp;lt;i&amp;gt;Objectives:&amp;lt;/i&amp;gt; The aim of our work is to determine the bone densitometric profile of patients followed for Cushing&amp;apos;s disease, to define the characteristics of osteoporosis and osteopenia in these patients, and to analyze the factors influencing BMD. &amp;lt;i&amp;gt;Materials and methods: &amp;lt;/i&amp;gt;This is a retrospective descriptive study involving patients followed for Cushing&amp;apos;s disease in the endocrinology-diabetology department of the public hospital establishment (EPH) of Bologhine-Algiers, during a period of 10 years, going from the January 2013 to January 2023. &amp;lt;i&amp;gt;Results: &amp;lt;/i&amp;gt;58 patients were followed during this period with an average age was 34 years, with a clear female predominance and a sex ratio of ≈ 4. Average Z score was (-1.6) at the vertebral level and (-1.09) at the femoral level. Osteoporosis was found in 44.8% (n = 26) patients and osteopenia in 37.9% (n = 22), while normal BMD was found in 17.24% (n = 10). Note that Z-score values were significantly lower at the lumbar spine than at the femoral neck. No significant difference in BMD was found between eumenorrheic and hypo-/amenorrheic females with Cushing&amp;apos;s disease. Our study demonstrated a significant negative correlation between morning plasma cortisol and BMD. While there is a significant positive correlation between BMD and ACTH concentration in CD patients, BMD at the lumbar spine and femoral neck also had a significant positive correlation with weight and BMI. &amp;lt;i&amp;gt;Conclusion:&amp;lt;/i&amp;gt; Early detection and management of CS are essential to reduce bone complications. BMD examinations should be performed to enable rapid recognition and intervention for osteoporosis. Lumbar bone loss occurs earlier and more extensively.

Assessing the Role of Cortisol in Anxiety, Major Depression, and Neuroticism: A Mendelian Randomization Study Using SERPINA6/SERPINA1 Variants

BackgroundPrevious evidence informed by the toxic stress model suggests that higher cortisol causes anxiety and major depression, but clinical success is lacking. To clarify the role of cortisol, we used Mendelian randomization to estimate its associations with anxiety, major depression, and neuroticism, leveraging the largest available genome-wide association studies including from the Psychiatric Genomics Consortium, the UK Biobank, and FinnGen. MethodsAfter meta-analyzing 2 genome-wide association studies on morning plasma cortisol (n = 32,981), we selected single nucleotide polymorphisms (SNPs) at p < 5 × 10−8 and r2 < 0.3 in the SERPINA6/SERPINA1 gene region encoding proteins that influence cortisol bioavailability. We applied these SNPs to summary genetic associations with the outcomes considered (n = 17,310–449,484), and systolic blood pressure as a positive outcome, using inverse-variance weighted meta-analysis accounting for correlation. Sensitivity analyses addressing SNP correlation and confounding by childhood maltreatment and follow-up analyses using only SNPs that colocalized with SERPINA6 expression were conducted. ResultsCortisol was associated with anxiety (pooled odds ratio [OR] 1.16 per cortisol z score; 95% CI, 1.04 to 1.31), but not major depression (pooled OR 1.02, 95% CI, 0.95 to 1.10) or neuroticism (β −0.025; 95% CI, −0.071 to 0.022). Sensitivity analyses yielded similar estimates. Cortisol was positively associated with systolic blood pressure, as expected. Using rs9989237 and rs2736898, selected using colocalization, cortisol was associated with anxiety in the UK Biobank (OR 1.32; 95% CI, 1.01 to 1.74) but not with major depression in FinnGen (OR 1.14; 95% CI, 0.95 to 1.37). ConclusionsCortisol was associated with anxiety and may be a potential target for prevention. Other targets may be more relevant to major depression and neuroticism.

Links between the genetic determinants of morning plasma cortisol and body shape: a two-sample Mendelian randomisation study

High cortisol production in Cushing’s syndrome leads to fat centralisation. The influence of modest cortisol variations on body shape, however, is less clear. We examined potentially causal associations between morning plasma cortisol and body shape and obesity with inverse-variance weighted random-effects models in a two-sample Mendelian randomisation analysis. We used publicly available summary statistics from the CORtisol NETwork (CORNET) consortium, UK Biobank, and the Genetic Investigation of Anthropometric Traits (GIANT) consortium. Only in women, morning plasma cortisol (proxied by ten genetic polymorphisms) was associated positively with waist size reflected in waist-to-hip index (WHI, 0.035 standard deviation (SD) units change per one SD cortisol increase; 95% confidence interval (0.002–0.067); p = 0.036) and “a body shape index” (ABSI; 0.039 (0.006–0.071); p = 0.021). There was no evidence for associations with hip index (HI) or body mass index (BMI). Among individual polymorphisms, rs7450600 stood out (chromosome 6; Long Intergenic Non-Protein-Coding RNA 473 gene, LINC00473). Morning plasma cortisol proxied by rs7450600 was associated positively with WHI and inversely with HI and BMI in women and men. Our findings support a causal association of higher morning plasma cortisol with larger waist size in women and highlight LINC00473 as a genetic link between morning plasma cortisol and body shape.

Basal cortisol in relation to metyrapone confirmation in predicting adrenal insufficiency after pituitary surgery

PurposePituitary surgery can lead to post-surgical adrenal insufficiency with the need for glucocorticoid replacement and significant disease related burden. In patients who do not receive hydrocortisone replacement before surgery, at our center, an early morning plasma cortisol concentration using a cut-off value of 450 nmol/L 3 days after surgery (POD3) is used to guide the need for hydrocortisone replacement until dynamic confirmatory testing using metyrapone. The aim of this study was to critically assess the currently used diagnostic and treatment algorithm in patients undergoing pituitary surgery in our pituitary reference center.MethodsRetrospective analysis of all patients with a POD3 plasma cortisol concentration < 450 nmol/L who received hydrocortisone replacement and a metyrapone test after 3 months. Plasma cortisol concentration was measured using an electrochemiluminescence immunoassay (Roche). All patients who underwent postoperative testing using metyrapone at Amsterdam UMC between January 2018 and February 2022 were included. Patients with Cushing’s disease or those with hydrocortisone replacement prior to surgery were excluded.ResultsNinety-five patients were included in the analysis. The postoperative cortisol concentration above which no patient had adrenal insufficiency (i.e. 11-deoxycortisol > 200 nmol/L) was 357 nmol/L (Sensitivity 100%, Specificity 31%, PPV:32%, NPV:100%). This translates into a 28% reduction in the need for hydrocortisone replacement compared with the presently used cortisol cut-off value of 450 nmol/L.ConclusionEarly morning plasma cortisol cut-off values lower than 450 nmol/L can safely be used to guide the need for hydrocortisone replacement after pituitary surgery.

Maternal plasma cortisol’s effect on offspring birth weight: a Mendelian Randomisation study

BackgroundObservational studies and randomized controlled trials have found evidence that higher maternal circulating cortisol levels in pregnancy are associated with lower offspring birth weight. However, it is possible that the observational associations are due to residual confounding.MethodsWe performed two-sample Mendelian Randomisation (MR) using a single genetic variant (rs9989237) associated with morning plasma cortisol (GWAS; sample 1; N = 25,314). The association between this maternal genetic variant and offspring birth weight, adjusted for fetal genotype, was obtained from the published EGG Consortium and UK Biobank meta-analysis (GWAS; sample 2; N = up to 406,063) and a Wald ratio was used to estimate the causal effect. We also performed an alternative analysis using all GWAS reported cortisol variants that takes account of linkage disequilibrium. We also tested the genetic variant’s effect on pregnancy cortisol and performed PheWas to search for potential pleiotropic effects.ResultsThe estimated effect of maternal circulating cortisol on birth weight was a 50 gram (95% CI, -109 to 10) lower birth weight per 1 SD higher log-transformed maternal circulating cortisol levels, using a single variant. The alternative analysis gave similar results (-33 grams (95% CI, -77 to 11)). The effect of the cortisol variant on pregnancy cortisol was 2-fold weaker than in the original GWAS, and evidence was found of pleiotropy.ConclusionsOur findings provide some evidence that higher maternal morning plasma cortisol causes lower birth weight. Identification of more independent genetic instruments for morning plasma cortisol are necessary to explore the potential bias identified.

O-02 Inactivation of KDM1A with the concurrent presence of MGUS in a patient with GIP-dependent Cushing's syndrome and the vanishing effect of octreotide therapy

Abstract Introduction Glucose-dependent insulinotropic peptide (GIP)-dependent primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of Cushing's syndrome. It has germline genetic predisposition and requires for personalized approaches to investigation and therapy. We aimed to present the rare case of a GIP-dependent PBMAH patient with unusually severe cortisol secretion and a KDM1A inactivation with an accompanying haematological co-morbidity related to that mutation. Clinical Case A 41-year-old woman presented with a 5-kg weight gain in last 6 months, irritability and fatique. Physical examination revealed elevated blood pressure, increased supraclavicular fat pads, and abdominal obesity. The cortisol level was 25.9 (6.7-22.6) µg/dL in the morning, 16.9 µg/dL in the late night, and 6.5 µg/dL in the morning after an overnight 1 mg of dexamethasone. Urinary free cortisol (UFC) level was also elevated to 2150 (58-403) µg/24-h. The early morning plasma ACTH level was 1.5 (7-63) pg/mL. Abdominal imaging revealed 29×23 mm adenomas on the right and 46×35 mm on the left with high fat content. Cortisol was stimulated by the administration of mixed meals (+537%) but not by TRH, GnRH, metoclopramide or upright posture. The response to mixed meals was blunted by pretreatment with subcutaneous 100 mg octreotide. Following the patient's diagnosis of GIP-dependent PBMAH, octreotide LAR therapy was initiated. Although inducing a significant acute suppression of UFC and improvement in symptoms during the first 3 months, the UFC began to rise due to the resistance in the following period (Figure 1). After 9 months of octreotide LAR treatment, left adrenalectomy was performed according to the adrenal volumetric assessment. Histopathology was reported as diffuse macronodular adrenal hyperplasia without internodular atrophy. Even though the patient had a unilateral adrenalectomy, adrenal insufficiency occurred in the postoperative period. Subsequently, the patient has been closely monitored and followed up with a physiological, divided-dose hydrocortisone replacement regimen for 7 months. A germline heterozygous variant in the KDM1A gene in the patient's blood sample and a recurrent deletion in the short p arm of chromosome 1 harboring the KDM1A locus in the adrenal sample were identified. When screened for diseases associated with the KDM1A mutation, monoclonal gammopathy of undetermined significance (MGUS) was detected in the patient with mild anemia, and genetic counseling was also provided. Conclusion The management of GIP-dependent PBMAH remains controversial, and further therapeutic options are under investigation. Due to the very limited number of case reports and the heterogeneous nature of the disease, special features of our case, which are severe cortisol excess, accompanying MGUS, the vanishing effect of octreotide, and adrenal insufficiency after unilateral adrenalectomy, might contribute to the existing literature.Figure 1.Urinary free cortisol levels following octreotide therapyUFC: Urinary free cortisol, ULN: Upper limit normal, LAR: Long acting release

Influence of the Antimycotic Drug Itraconazole on Plasma Cortisol Levels and Blood Pressure in a Patient with Burnout Syndrome

Burnout is a syndrome that is increasingly common nowadays. It is associated with reduced work efficiency and chronic exhaustion. The main cause of burnout is continuous stress at work and not enough rest. The main system involved in the pathogenesis of burnout is the hypothalamic–pituitary–adrenocortical axis with the final substrate of the glucocorticoid hormone cortisol. Therefore, in patients with burnout syndrome, the morning plasma cortisol levels are elevated, but there is no significant change in its evening values. This correlates with an increase in blood pressure, weight gain, muscle weakness, low immunity, etc. The following case report is about the unusual effect of the antifungal drug itraconazole on the circadian rhythm of the plasma cortisol levels, as well as on the blood pressure in patient with burnout syndrome. One month of peroral application of 100 mg itraconazole every day reduces the morning plasma cortisol levels to the greatest extent (by approximately 37%) rather than the evening cortisol levels (by circa 17.5%). The decrease in the mean ambulatory systolic and diastolic blood pressure is also not uniform (it is stronger in diastolic – 27% than in systolic – 17%).

Higher circulating cortisol is associated with amyloidogenesis in post‐menopausal women: The Framingham Heart Study

AbstractBackgroundReports of a correlation between higher baseline cortisol and faster progression of Alzheimer’s disease (AD) in longitudinal cohorts and more advanced AD pathology in cross sectional studies raise the possibility that cortisol dysregulation contributes to AD pathogenesis. The current data, however, is less strong with regards to possible mechanisms underlying this relationship or the direction of influence between higher cortisol and AD severity. The goal of this study was to examine the associations between cortisol levels and incident cerebral amyloid and tau PET deposition.MethodsWe present a prospective cohort study of cognitively normal individuals derived from Framingham Heart Study (generation 3‐mean age 39.6±8.1 years, 48.5% women) who had measures of fasting morning plasma cortisol at baseline and PET measures of brain amyloid and tau 15±1.6 years later. Fasting cortisol levels were examined as tertitles (Cortisol level (min,max)‐ T1:3.92‐11.12; T2:11.13‐15.50; T3:15.76‐50.07). Linear regression was used to evaluate associations baseline plasma cortisol (in tertiles) with amyloid and tau deposition, adjusted for age, sex, and the duration between cortisol and PET imaging assessments. We assessed interactions by ApoE4 positivity, sex and menopausal status (women only).ResultsWe found no association between serum cortisol and amyloid/tau burden, and no significant interaction with age or ApoE4 status. However, the association between cortisol and amyloid retention interacted significantly with sex in our primary regions of interest (posterior cingulate cortex [PCC] β:0.059±0.027, p = 0.031; precuneus [PC] 0.071±0.025, 0.005, and whole brain [represented by FLR] 0.039±0.014, 0.006). Comparing the highest relative to the middle cortisol (the referent) tertiles among women, amyloid deposition was higher in PCC (β±SE: 0.059±0.027, p = 0.031), PC (0.071±0.025, 0.005), and FLR ROIs (0.039±0.014, p = 0.006). The same relationships did not hold in men or in relations to tau. Furthermore, the effect was only present in postmenopausal women, with the higher amyloid deposition in PC (β:0.103±0.040, p = 0.012) and FLR ROIs (0.071±0.020, 0.001) as well as superior temporal sulcus (secondary outcome). We did not observe any statistically significant association comparing bottom to the middle cortisol tertile.ConclusionAlthough future research is needed, the results suggest that serum cortisol may contribute to Alzheimer’s pathogenesis by driving amyloidogenesis in postmenopausal women.

Multi-Omics Analysis of Circulating Exosomes in Adherent Long-Term Treated OSA Patients.

Obstructive sleep apnea (OSA) is a highly prevalent chronic disease affecting nearly a billion people globally and increasing the risk of multi-organ morbidity and overall mortality. However, the mechanisms underlying such adverse outcomes remain incompletely delineated. Extracellular vesicles (exosomes) are secreted by most cells, are involved in both proximal and long-distance intercellular communication, and contribute toward homeostasis under physiological conditions. A multi-omics integrative assessment of plasma-derived exosomes from adult OSA patients prior to and after 1-year adherent CPAP treatment is lacking. We conducted multi-omic integrative assessments of plasma-derived exosomes from adult OSA patients prior to and following 1-year adherent CPAP treatment to identify potential specific disease candidates. Fasting morning plasma exosomes isolated from 12 adult patients with polysomnographically-diagnosed OSA were analyzed before and after 12 months of adherent CPAP therapy (mean ≥ 6 h/night) (OSAT). Exosomes were characterized by flow cytometry, transmission electron microscopy, and nanoparticle tracking analysis. Endothelial cell barrier integrity, wound healing, and tube formation were also performed. Multi-omics analysis for exosome cargos was integrated. Exosomes derived from OSAT improved endothelial permeability and dysfunction as well as significant improvement in tube formation compared with OSA. Multi-omic approaches for OSA circulating exosomes included lipidomic, proteomic, and small RNA (miRNAs) assessments. We found 30 differentially expressed proteins (DEPs), 72 lipids (DELs), and 13 miRNAs (DEMs). We found that the cholesterol metabolism (has04979) pathway is associated with lipid classes in OSA patients. Among the 12 subjects of OSA and OSAT, seven subjects had complete comprehensive exosome cargo information including lipids, proteins, and miRNAs. Multi-omic approaches identify potential signature biomarkers in plasma exosomes that are responsive to adherent OSA treatment. These differentially expressed molecules may also play a mechanistic role in OSA-induced morbidities and their reversibility. Our data suggest that a multi-omic integrative approach might be useful in understanding how exosomes function, their origin, and their potential clinical relevance, all of which merit future exploration in the context of relevant phenotypic variance. Developing an integrated molecular classification should lead to improved diagnostic classification, risk stratification, and patient management of OSA by assigning molecular disease-specific therapies.

Abstract 17143: Lorundrostat for Treatment of Obesity-Related, Aldosterone-Dependent Hypertension - An Endotype-Specific, Targeted Approach to the Treatment of Uncontrolled Hypertension

Hyperaldosteronism manifests as low renin hypertension (HTN) with endothelial dysfunction and vascular fibrosis. In the aging vasculature, these pathological changes may be exacerbated by non-genomic aldosterone signaling via GPER (GPR30), which is not inhibited by mineralocorticoid receptor antagonists (MRA). In trials with healthy subjects and patients with uncontrolled HTN, the novel, highly selective aldosterone synthase inhibitor, lorundrostat, reduced median morning plasma aldosterone concentration (PAC) by approximately 70%. PAC reduction was dose-dependent and associated with a mean placebo-adjusted reduction in systolic blood pressure (BP) of -16.7 mmHg (N=15, p&lt;0.01, 90% CI: -25.5 to -7.9 mmHg) and -12.3 mmHg (N=12, p&lt;0.03, 90% CI: -21.6 to -3.1 mmHg) in subjects with body mass index (BMI) &gt; 30 kg/m 2 receiving 50mg or 100mg QD of lorundrostat, respectively. In contrast, in non-obese individuals, BP reductions were modest and not statistically significant. Salutary BP effects of 100mg QD lorundrostat at week 8 were observed in individuals with normal to high renin (N=30, -11.4 ± 2.5 mmHg) and low renin (N=25, -11.9 ± 2.8 mmHg). Linkage between obesity, HTN and increased aldosterone has been suggested by studies in a mouse model of obesity, hyperleptinemia and HTN. In this model, both leptin receptor blockade and lorundrostat restored normal BP. As anticipated, in the Phase 2 trial, mean serum leptin was elevated at baseline in obese (N=103, 37.8 ± 2.4 ng/mL) v. non-obese (N=88, 21.6 ± 1.9 ng/mL, p&lt;0.001) individuals with uncontrolled HTN and could be a useful biomarker to identify lorundrostat-responsive HTN. MRAs are recommended as fourth-line therapy for resistant HTN. However, MRAs can be associated with hormonal side-effects and stimulate excess aldosterone production that may increase non-genomic signaling, endothelial dysfunction and vessel wall remodeling. Lorundrostat has neither of these liabilities and may be an important new antihypertensive. Renin-independent, leptin- and aldosterone-dependent HTN defines a unique endotype in obese hypertensive individuals. Endotype-targeted therapy may allow early identification, intervention and improved BP control in obese individuals.

THU091 Hypopituitarism And The Finding Of Hyperprolactinemia Following Mild Traumatic Brain Injury In Female Athletes

Abstract Disclosure: L.Ó. Eggertsdóttir Claessen: None. H. Kristjánsdóttir: None. M.K. Jónsdóttir: None. S.H. Lund: Employee; Self; Amgen Inc. I.S. Kristensen: None. H.Á. Sigurjónsdóttir: None. Background Hypopituitarism (HP) following mild traumatic brain injury (mTBI) in sports can have serious consequences making prompt diagnosis and treatment essential. Studies have focused on male populations despite female athletes being more susceptible to mTBI. To the best of our knowledge, this study is the first all-female study reporting the prevalence of HP following mTBI. Subjects The study included 508 female athletes aged 18 to 45 years currently active in or retired from soccer, team handball, basketball, ice hockey, and martial arts who answered an online questionnaire regarding mTBI history. Women who reported one or more concussions (n = 308) were invited to participate in a medical interview and a physical examination with 151 accepting. Consequently, 133 women attended pituitary hormone screening blood tests (SBT). Methods SBT were taken at 8 a.m. and included S-IGF1, S-cortisol, S-prolactin, S-TSH, S-fT4, S-FSH, S-oestrogen, and S-progesterone measurements. When SBT were repeatedly outside reference value (O-RV), participants were referred to an endocrinologist for a medical interview and physical examination. Detailed endocrinological tests for possible HP were performed as indicated. When serum levels of TSH or fT4 were O-RV, anti-TPO antibodies were measured and when negative, an MRI was performed. If S-prolactin was repeatedly above reference value (RV) an MRI was performed. When S-cortisol was below 350 mmol/L, morning plasma ACTH was added and morning Synacthen test performed. When S-IGF1 was below median RV and clinical symptoms of GHD were present, a GHRH-arginine test was performed. An ITT was performed in one woman due to practical reasons and strong clinical symptoms indicating GHD. Results etailed endocrinological evaluation for possible HP was indicated in 86 women. Pituitary dysfunction (PD) was diagnosed in 16 women (12.0%). Six (4.5%) women had HP. One woman had GH measurements below RV in a GHRH-arginine test (peak GH levels ≤11.0 µg/L for BMI &amp;lt;25 kg/m2) and one had GH below &amp;lt;3µg/L in an ITT. Four women had low or normal TSH levels (reference range 0.270 - 4.20 mIU/L), low fT4 (reference range 12 - 22 pmol/L) and a negative anti-TPO measurement. Ten women (7.5%) had hyperprolactinemia (HPRL) (reference range 4.79 - 23.3 μg/L). Four of the 10 women with HPRL were diagnosed with a prolactinoma following an MRI. Medical treatment was initiated for 13 (9.8%) women as one woman had a prolactinoma but no clinical symptoms of HPRL. Conclusions PD is an important consideration in post-concussion care as 12.0% had PD following mTBI with 9.8% requiring medical treatment. Six women (4.5%) had HP following mTBI (GHD = 2 and central hypothyroidism n = 4). This is lower than previously reported and may be due to HP recovering with time. As six women had HPRL without a prolactinoma, HRPL may represent pituitary or hypothalamic injury following mTBI. Presentation: Thursday, June 15, 2023

Complete recovery after glucocorticoid replacement therapy in a case of primary adrenal insufficiency caused by adrenal tuberculosis infection.

Symptoms of primary adrenal insufficiency (PAI) are commonly nonspecific, causing the disease to be misdiagnosed or often delayed, and patients may present to the hospital with a life-threatening crisis. Previous case reports have documented that patients in this condition often require lifelong glucocorticoid replacement therapy. This study aimed to present a noteworthy outcome of PAI caused by adrenal tuberculosis infection, demonstrating complete recovery after six months of glucocorticoid replacement therapy. A 38-year-old Indonesian man presented to the endocrinology clinic in a tertiary hospital with a chief complaint of epigastric pain. The patient experienced nausea, vomiting, loss of consciousness, weight loss, excessive sweat, decreased appetite, weakness, and dizziness in the past 2 weeks. Laboratory examinations revealed hyponatremia, elevated adrenocorticotropic hormone, and suppressed morning plasma cortisol level. A non-contrast-enhanced abdominal MRI showed unilateral right-side adrenal enlargement and calcification. The patient's Mantoux test was positive. Corticosteroids and anti-tuberculosis therapy were administered. After 6 months, hydrocortisone was discontinued due to the patient's good clinical condition and normal morning plasma cortisol levels. After a 1-year follow-up, the patient remained asymptomatic with normal cortisol levels. We hypothesized several reasons for this unique outcome: (i) the patient was relatively young compared to previous cases, suggesting an adequate immune system may play a role; (ii) despite a 1-month delay in diagnosis and treatment, the absence of skin hyperpigmentation suggested an acute presentation, potentially contributing to the favorable outcome; and (iii) the absence of comorbidities potentially positively impacted the patient's outcome. Symptoms of adrenal insufficiency are often nonspecific and may only become apparent once significant damage has occurred to the adrenal gland. Clinical adjustments and a comprehensive understanding of epidemiological knowledge are necessary for diagnosing patients with endocrine diseases in limited-resource settings. Complete recovery in primary adrenal insufficiency caused by tuberculosis infection might be due to younger age, acute presentation, and absence of comorbidities.

Hippocampal Dynamic Functional Connectivity, HPA Axis Activity, and Personality Trait in Bipolar Disorder with Suicidal Attempt

Introduction: Suicide in bipolar disorder (BD) is a multifaceted behavior, involving specific neuroendocrine and psychological mechanisms. According to previous studies, we hypothesized that suicidal BD patients may exhibit impaired dynamic functional connectivity (dFC) variability of hippocampal subregions and hypothalamic-pituitary-adrenal (HPA) axis activity, which may be associated with suicide-related personality traits. The objective of our study was to clarify this. Methods: Resting-state functional magnetic resonance imaging data were obtained from 79 patients with BD, 39 with suicidal attempt (SA), and 40 without SA, and 35 healthy controls (HCs). The activity of the HPA axis was assessed by measuring morning plasma adrenocorticotropic hormone (ACTH) and cortisol (CORT) levels. All participants underwent personality assessment using Minnesota Multiphasic Personality Inventory-2 (MMPI-2). Results: BD patients with SA exhibited increased dFC variability between the right caudal hippocampus and the left superior temporal gyrus (STG) when compared with non-SA BD patients and HCs. BD with SA also showed significantly lower ACTH levels in comparison with HCs, which was positively correlated with increased dFC variability between the right caudal hippocampus and the left STG. BD with SA had significantly higher scores of Hypochondriasis, Depression, and Schizophrenia than non-SA BD. Additionally, multivariable regression analysis revealed the interaction of ACTH × dFC variability between the right caudal hippocampus and the left STG independently predicted MMPI-2 score (depression evaluation) in suicidal BD patients. Conclusion: These results suggested that suicidal BD exhibited increased dFC variability of hippocampal-temporal cortex and less HPA axis hyperactivity, which may affect their personality traits.

Plasma Metanephrines Yield Fewer False-Positive Results Than Urine Metanephrines in Patients With Obstructive Sleep Apnea.

Obstructive sleep apnea (OSA) is associated with increased nocturnal sympathetic activity. In OSA patients, elevations in metanephrines may lead to false-positive tests when evaluating for pheochromocytoma or paraganglioma (PPGL). To evaluate whether morning plasma metanephrines would lead to fewer false-positive results than 24-hour urinary metanephrines in OSA patients. Patients undergoing polysomnography for suspected OSA were recruited. Plasma free and 24-hour urinary metanephrines were measured by HPLC-MS/MS. Patients with elevated levels had repeat measurements, abdominal imaging, and follow-up to diagnose or exclude a PPGL. Seventy-six patients completed polysomnography and biochemical testing; 68 (89.5%) patients had OSA, of whom 19 (27.9%) had elevated plasma and/or urinary metanephrines. On follow-up, one patient had a bladder paraganglioma, while PPGL was excluded in the remaining patients. OSA patients had more false-positive urinary metanephrines (17 of 67, 25.4%) than plasma metanephrines (2 of 67, 3.0%), P < .01, and this was more common in severe OSA (13 of 34, 38.2%), compared to moderate/mild OSA (4 of 33, 12.1%), P < .01. Both plasma and urinary metanephrines decreased after treatment with continuous positive airway pressure. On multivariable analysis, severe OSA, obesity, and family history of hypertension were positive predictors for false-positive urinary metanephrines in patients with suspected OSA. In OSA patients, plasma metanephrines are less likely to yield false-positive results for the diagnosis of PPGL than 24-hour urinary metanephrines. In patients with suspected OSA, obesity, or a family history of hypertension, plasma metanephrines may be the preferred first-line test to avoid unnecessary anxiety or follow-up.

Plasma cortisol-linked gene networks in hepatic and adipose tissues implicate corticosteroid-binding globulin in modulating tissue glucocorticoid action and cardiovascular risk.

Genome-wide association meta-analysis (GWAMA) by the Cortisol Network (CORNET) consortium identified genetic variants spanning the SERPINA6/SERPINA1 locus on chromosome 14 associated with morning plasma cortisol, cardiovascular disease (CVD), and SERPINA6 mRNA expression encoding corticosteroid-binding globulin (CBG) in the liver. These and other findings indicate that higher plasma cortisol levels are causally associated with CVD; however, the mechanisms by which variations in CBG lead to CVD are undetermined. Using genomic and transcriptomic data from The Stockholm Tartu Atherosclerosis Reverse Networks Engineering Task (STARNET) study, we identified plasma cortisol-linked single-nucleotide polymorphisms (SNPs) that are trans-associated with genes from seven different vascular and metabolic tissues, finding the highest representation of trans-genes in the liver, subcutaneous fat, and visceral abdominal fat, [false discovery rate (FDR) = 15%]. We identified a subset of cortisol-associated trans-genes that are putatively regulated by the glucocorticoid receptor (GR), the primary transcription factor activated by cortisol. Using causal inference, we identified GR-regulated trans-genes that are responsible for the regulation of tissue-specific gene networks. Cis-expression Quantitative Trait Loci (eQTLs) were used as genetic instruments for identification of pairwise causal relationships from which gene networks could be reconstructed. Gene networks were identified in the liver, subcutaneous fat, and visceral abdominal fat, including a high confidence gene network specific to subcutaneous adipose (FDR = 10%) under the regulation of the interferon regulatory transcription factor, IRF2. These data identify a plausible pathway through which variation in the liver CBG production perturbs cortisol-regulated gene networks in peripheral tissues and thereby promote CVD.

Factitious cushing's syndrome with unusual presentation: a case report and literature review.

A 40-year-old female patient who worked as a registered nurse presented with clinical features of CS but denied any exogenous corticosteroid use. The endocrine workup revealed that the patient had a high 24h urinary-free cortisol collection before admission. Subsequent evaluations showed low levels of morning cortisol and plasma adrenocorticotropic hormone along with a suppressed overnight low-dose dexamethasone suppression test, leading to an investigation of hypercortisolism. Unexpectedly, subsequent testing showed a normal 24h urinary-free cortisol level. Additionally, the patient was diagnosed with panhypopituitarism, the radiological investigations showed normal pituitary and adrenal glands. Despite consistently denying the use of corticosteroids, it was finally discovered that the patient had been surreptitiously taking prednisone and receiving multiple dexamethasone injections over the past few months. The patient received treatment through a gradual prednisone tapering regimen, accompanied by comprehensive psychiatric evaluation and management. This case underscores the exceptional rarity of factitious CS and emphasizes the importance of considering it as a potential differential diagnosis in hypercortisolism cases, particularly when the patient's medical history contradicts investigative findings. Furthermore, it highlights the criticality of adopting a multidisciplinary approach to investigate patients whose clinical presentation aligns with factitious CS.