Plasma Adrenocorticotropic Hormone Levels Research Articles

Higher levels of plasma Adrenocorticotropic hormone (ACTH) are associated with lower suicidal ideation in depressed patients compared to controls and suicide attempters, independently from depression severity

IntroductionSuicidal ideation, an important risk factor for suicide attempts, has an unclear neurobiological basis and is potentially linked to the dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and immune-inflammatory systems. While inflammatory markers have been associated with suicide attempts and, to a lower extent suicidal ideation, the data on the role of a stress-response system is less robust, with most studies carried out with cortisol showing inconsistent results. The present study extends on the previous studies implicating stress-response and immune-inflammatory systems in suicidal thoughts and behaviours, focusing on the associations of several stress-response (adrenocorticotropic hormone (ACTH), cortisol, and dehydroepiandrosterone (DHEA)) and immune-inflammatory (C-reactive protein (CRP),interle ukin-6 (IL-6), and tumour necrosis factor-alpha (TNF-alpha)) with suicidal ideation severity in recent suicide attempters, patients with major depressive disorder, and non-psychiatric controls. MethodsThis observational study included 156 adults from three Vilnius hospitals, recruited into one of the three groups in equal parts: recent suicide attempters, patients with major depressive disorder in current depressive episode, and non-psychiatric controls. Measures included the Hamilton Depression Rating Scale (HDRS-17) and the Beck Scale for Suicide Ideation/Suicide Severity Index (BSS/SSI), alongside sociodemographic data, alcohol, tobacco use, and morning blood samples, measuring plasma ACTH, cortisol, DHEA, CRP, and IL-6. Data were analysed with non-parametric tests, Kendall's tau correlation, and multivariate linear regression adjusted for confounders. ResultsWe found a negative correlation between the plasma ACTH levels and suicidal ideation severity (tau = −0.130, p = 0.033), which was driven by the patients with major depressive disorder (tau = −0.237, p = 0.031). Suicidal ideation severity was also negatively correlated with TNF-alpha (tau = −0.231; p < 0.001), positively correlated with IL-6 (tau = 0.154, p = 0.015), and CRP levels (tau = 0.153, p = 0.015), but no differences were observed in group-stratified analyses. The association between plasma ACTH levels and suicidal ideation severity in patients with major depressive disorder remained robust to adjustment for major confounders (adjusted for age, sex, education years, body mass index, smoking status, plasma CRP and PEth concentration (measuring chronic alcohol exposure), and antidepressant use) in the linear regression model (t = −2.71, p = 0.011), as well as additionally adjusting for depression severity (t = −2.99, p = 0.006). DiscussionThe present study shows an association between plasma ACTH levels and suicidal ideation severity in patients with major depressive disorder, robust to adjustment for antidepressant use and depression severity. This finding highlights the potential role of ACTH, in elucidating the effects of stress and mental health disorders. Our findings underscore the importance of the HPA axis in the diagnosis and treatment of suicidal ideation in major depressive disorder and invite further research on interventions targeting this pathway.

Glucagon does not directly stimulate pituitary secretion of ACTH, GH or copeptin

Glucagon is best known for its contribution to glucose regulation through activation of the glucagon receptor (GCGR), primarily located in the liver. However, glucagon’s impact on other organs may also contribute to its potent effects in health and disease. Given that glucagon-based medicine is entering the arena of anti-obesity drugs, elucidating extrahepatic actions of glucagon are of increased importance. It has been reported that glucagon may stimulate secretion of arginine-vasopressin (AVP)/copeptin, growth hormone (GH) and adrenocorticotrophic hormone (ACTH) from the pituitary gland. Nevertheless, the mechanisms and whether GCGR is present in human pituitary are unknown. In this study we found that intravenous administration of 0.2 mg glucagon to 14 healthy subjects was not associated with increases in plasma concentrations of copeptin, GH, ACTH or cortisol over a 120-min period. GCGR immunoreactivity was present in the anterior pituitary but not in cells containing GH or ACTH. Collectively, glucagon may not directly stimulate secretion of GH, ACTH or AVP/copeptin in humans but may instead be involved in yet unidentified pituitary functions.

O-03 Adrenalectomy for Cushing's syndrome during pregnancy

Abstract Introduction Cushing's syndrome (CS) is rare in pregnancy because CS itself is a cause of anovulatory infertility due to excess cortisol secretion. Moreover it is also difficult to diagnose CS in pregnancy because placental production of corticotropin releasing and adrenocorticotropic hormone (ACTH), increased maternal production of estrogen induced corticosteroid binding globulin leads to physiological hypercortisolism during pregnancy. So physicians face a clinical overlap in many features of CS such as weight gain, fatigue, edema, hypertension, hyperglycemia, stretch marks, mood changes that can also be attributed to pregnancy. Thus their coexistence represents a diagnostic challenge. Herein we report a case of CS that was diagnosed and successfully treated during pregnancy. Clinical Case A 43-year-old gravida 3 female was consulted at the 21st week of gestation with persistent high blood pressure and hyperglycemia for a month. She had an obstetric history of 2 spontaneous first term abortion, 2 healthy labor 18 years ago and she was healthy after. She was in such a depressive mood that she was consulted with psychiatry many times. On physical examination edema, proximal weakness of lower extremities and hirsutism (modified Ferriman–Gallwey score of 9) was detected. Initial laboratory tests were all within normal range except potassium level (2.7 mmol/L), the results were not consistent with preeclampsia and there was a suspicious adrenal mass detected on ultrasound. She was currently receiving high dose antihypertensive treatment with methyldopa, calcium channel blockers, rapid acting and detemir insulin for diabetes and i.v. potassium replacement. We ruled out conns syndrome with normal plasma aldosterone renin ratio and found catecholamine levels normal. Hormonal analyses revealed with high plasma cortisol levels, increased nocturnal cortisolemia, a suppressed plasma ACTH and dehydroepiandrosterone sulfate level and distinctly elevated 24-hour urinary cortisol greater than 3-fold the upper normal reference range. Non contrast magnetic resonance imaging demonstrated a 47×32 mm left adrenal mass. Laparoscopic adrenalectomy was performed in the 26th week of gestation and the following histopathology revealed an adrenocortical adenoma. Antihypertensive medication was progressively reduced, glycemic control and hypokalemia reversal were achieved. She was followed up with appropriate glucocorticoid replacement. At 34 weeks of gestation, after sudden labor pain and regular uterine contractions a 2586 g male infant with Apgar scores of 8 was born by cesarean section. They were discharged in good health. Conclusion CS should be kept in mind especially in the case of hypertension and diabetes that started before the 20th gestational age. Analysis of the urinary free cortisol level and circadian rhythm of cortisol is necessary to diagnose. Despite the diagnostic challenge we can achieve better maternal and fetal outcomes with proper management.Figure 1.Non-contrast magnetic resonance imaging of the patient Table 1.Patient's laboratuary test results Table 2.Patient's laboratory test results

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.

Inhibitory action of B-type natriuretic peptide on adrenocorticotropic hormone in patients with acute coronary syndrome.

In addition to the classical actions of hemodynamic regulation, natriuretic peptides (NPs) interact with various neurohumoral factors that are deeply involved in the pathophysiology of cardiovascular diseases. However, their effects on the hypothalamic-pituitary-adrenal (HPA) axis, which is activated under acute high-stress conditions in acute coronary syndrome (ACS), remain largely unknown. We investigated the impact of plasma B-type NP (BNP) on plasma adrenocorticotropic hormone (ACTH)-cortisol levels during the acute phase of ACS ischemic attacks. The study population included 436 consecutive patients with ACS for whom data were collected during emergency cardiac catheterization. Among them, biochemical data after acute-phase treatment were available in 320 cases, defined as the ACS-remission phase (ACS-rem). Multiple regression analyses revealed that plasma BNP levels were significantly negatively associated with plasma ACTH levels only during ACS attacks (P < 0.001), but not in ACS-rem, whereas plasma BNP levels were not significantly associated with plasma cortisol levels at any point. Accordingly, covariance structure analyses were performed to clarify the direct contribution of BNP to ACTH by excluding other confounding factors, confirming that BNP level was negatively correlated with ACTH level only during ACS attacks (β = -0.152, P = 0.002), whereas BNP did not significantly affect ACTH in ACS-rem. In conclusion, despite the lack of a significant direct association with cortisol levels, BNP negatively regulated ACTH levels during the acute phase of an ACS attack in which the HPA axis ought to be activated. NP may alleviate the acute stress response induced by severe ischemic attacks in patients with ACS.NEW & NOTEWORTHY BNP negatively regulates ACTH during a severe ischemic attack of ACS in which hypothalamic-pituitary-adrenal axis ought to be activated, indicating an important role of natriuretic peptides as a mechanism of adaptation to acute critical stress conditions in humans.

Adrenal Hemorrhaging in a Patient with Severe Obstructive Sleep Apnea Syndrome with Elevated Plasma ACTH Levels.

Adrenal hemorrhaging (AH) is a rare condition characterized by bleeding into the suprarenal glands. A 62-year-old man with untreated obstructive sleep apnea syndrome (OSAS) was admitted to our hospital complaining of abdominal stiffness. He was diagnosed with left-sided AH and underwent adrenalectomy. Pre- and post-surgery, elevated plasma adrenocorticotropic hormone (ACTH) levels were observed. However, Cushing's syndrome and adrenal insufficiency were negative, and nasal continuous positive airway pressure (CPAP) normalized the plasma ACTH levels. Elevated ACTH levels are reportedly present in patients with OSAS. ACTH may be associated with the development of AH through the change in blood supply and other mechanisms.

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.

Intact GR dimerization is critical for restraining plasma ACTH levels during chronic psychosocial stress

Male C57BL/6N mice exposed to the chronic subordinate colony housing (CSC; 19 days) paradigm, a preclinically validated model of chronic psychosocial stress, are characterized by unaffected basal morning plasma corticosterone (CORT) concentrations despite adrenal and pituitary hyperplasia and increased adrenocorticotropic hormone (ACTH) plasma concentrations, compared with single-housed control (SHC) mice. However, as CSC mice are still able to show an increased CORT secretion towards novel heterotypic stressors, these effects might reflect an adaptation rather than a functional breakdown of general hypothalamus-pituitary-adrenal (HPA) axis functionality. In the present study we used male mice of a genetically modified mouse line, to investigate whether genetically-driven ACTH overexpression compromises adaptational processes occurring at the level of the adrenals during CSC exposure. Experimental mice carried a point mutation in the DNA binding domain of the glucocorticoid (GC) receptor (GR), attenuating dimerization of GR (GRdim), resulting in a congenially compromised negative feedback inhibition at the level of the pituitary.In line with previous studies, CSC mice in both the wild type (WT; GR+/+) and GRdim group developed adrenal enlargement. Moreover, compared with respective SHC and WT mice, CSC GRdim mice show increased basal morning plasma ACTH and CORT concentrations. Quantitative polymerase chain reaction (qPCR) analysis revealed neither a genotype effect, nor a CSC effect on pituitary mRNA expression of the ACTH precursor proopiomelanocortin (POMC). Finally, CSC increased anxiety-related behavior, active coping and splenocyte in vitro (re)activity in both WT and GRdim mice, while a CSC-induced increase in adrenal lipid vesicles and splenic GC resistance was detectable only in WT mice. Of note, lipopolysaccharide (LPS)-stimulated splenocytes of GRdim mice were resistant to the inhibitory effects of CORT.Together our findings support the hypothesis that pituitary ACTH protein concentration is negatively controlled by GR dimerization under conditions of chronic psychosocial stress, while POMC gene transcription is not dependent on intact GR dimerization under both basal and chronic stress conditions. Finally, our data suggest that adrenal adaptations during chronic psychosocial stress (i.e., ACTH desensitization), aiming at the prevention of prolonged hypercorticism, are protective only to a certain threshold of plasma ACTH levels.

Endocrine characteristics and risk factors of type 2 diabetes complicated with gastrointestinal autonomic neuropathy: A single-center retrospective study.

To analyze endocrine characteristics and risk factors of type 2 diabetes mellitus (T2DM) gastrointestinal autonomic neuropathy. A total of 202 patients with T2DM with obesity who were hospitalized at our institute between January 2019 and June 2021 were selected. Based on adrenocorticotropic hormone (ACTH) levels, 102 patients were placed in the ACTH abnormal group and 100 patients were placed in the non-ACTH abnormal group. Ninety-five healthy adults without diabetes, hyperlipidemia, osteoporosis, or endocrine system abnormalities who were examined at our hospital during the same period were selected as the control group. Fasting plasma glucose (FPG), fasting insulin (FINS), triglycerides (TG), total cholesterol (TC), homeostasis model assessment of insulin resistance (HOMA-IR), ACTH level, body mass index (BMI), and bone mineral density (BMD) were measured to evaluate endocrine characteristics and risk factors. BMI, FPG, FINS, HOMA-IR, TG, TC, and ACTH levels in the abnormal ACTH group were significantly higher than those in the other 2 groups, while BMD was significantly lower than that in the other 2 groups (all P < .05). BMI, FPG, FINS, HOMA-IR, TG, TC, and ACTH in the non-ACTH abnormal group were significantly higher than those in the control group, whereas BMD was significantly lower than that in the control group (all P < .05). The plasma ACTH level in patients with abnormal ACTH levels was significantly positively correlated with BMI, FPG, FINS, HOMA-IR, TG, and TC and negatively correlated with BMD (all P < .05). Multivariate regression analysis showed that BMI, advanced age, FINS, TG, and FPG were risk factors for ACTH abnormalities in patients with diabetes (odds ratio > 1, all P < .05). BMI, advanced age, FINS, TG and FPG are the risk factors of abnormal ACTH in T2DM patients with gastrointestinal autonomic neuropathy.

The expression of glucocorticoid and mineralocorticoid receptors in pituitary tumors causing Cushing's disease and silent corticotroph tumors.

Pituitary neuroendocrine corticotroph tumors commonly cause Cushing's disease (CD) that results from increased adrenocorticotropic hormone (ACTH) secretion by the pituitary tumor and consequent increase of cortisol levels in blood. However, in some patients, corticotroph tumors remain clinically non-functioning. Cortisol secretion is regulated by the hypothalamic-pituitary-adrenal axis and includes a negative feedback between cortisol and ACTH secretion. Glucocorticoids reduce ACTH level both by hypothalamic regulation and acting on corticotrophs via glucocorticoid (GR) and mineralocorticoid (MR) receptors. The aim of the study was to determine the role of GR and MR expression at mRNA and protein levels in both functioning and silent corticotroph tumors. Ninety-five patients were enrolled, including 70 with CD and 25 with silent corticotroph tumors. Gene expression levels of NR3C1 and NR3C2 coding for GR and MR, respectively, were determined with qRT-PCR in the two tumor types. GR and MR protein abundance was assessed with immunohistochemistry. Both GR and MR were expressed in corticotroph tumors. Correlation between NR3C1 and NR3C2 expression levels was observed. NR3C1 expression was higher in silent than in functioning tumors. In CD patients NR3C1 and NR3C2 levels were negatively correlated with morning plasma ACTH levels and tumor size. Higher NR3C2 was confirmed in patients with remission after surgery and in densely granulated tumors. Expression of both genes and GR protein was higher in USP8-mutated tumors. Similar relationship between USP8 mutations and expression levels were observed in analysis of silent tumors that also revealed a negative correlation between GR and tumor size and higher NR3C1 expression in densely granulated tumors. Although the associations between gene/protein expression and patients clinical features are not strong, they consistently show an evident trend in which higher receptor expression corresponds to more favorable clinical characteristics.

Three cases of immune-related hypopituitarism after atezolizumab-bevacizumab treatment for hepatocellular carcinoma.

We herein report three cases of immune-related hypopituitarism after atezolizumab-bevacizumab treatment for hepatocellular carcinoma (HCC). Case 1 was a man in his 60s with hepatitis C-related liver cirrhosis. He had been diagnosed with HCC and undergone surgical resection. However, HCC recurred 17months after surgery. After 13 cycles of atezolizumab-bevacizumab therapy, general fatigue, appetite loss, and muscle weakness appeared. The plasma levels of adrenocorticotropic hormone (ACTH) and cortisol were decreased. He was diagnosed with central adrenal insufficiency associated with hypopituitarism. Glucocorticoid therapy rapidly improved his symptoms. Case 2 was a man in his 70s with HCC associated with non-alcoholic steatohepatitis (NASH). After eight cycles of atezolizumab-bevacizumab therapy, general fatigue, appetite loss, and muscle weakness appeared. Hyponatremia and eosinophilia were observed. He was also diagnosed with hypopituitarism, and glucocorticoid therapy rapidly improved his symptoms. Case 3 was a man in his 60s with HCC associated with alcoholic liver cirrhosis. After 10 cycles of atezolizumab-bevacizumab therapy, hypopituitarism developed. In these cases, the presence of hyponatremia and/or eosinophilia was useful for making a diagnosis. Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) antibody is reported to be likely to induce hypophysitis two to three months after its administration. In contrast, anti-programmed cell death 1 (PD-1) antibody is likely to induce hypopituitarism six to seven months after its administration. These three patients treated with anti-programmed death ligand 1 (PD-L1) antibody developed hypopituitarism six to nine months later, close to the condition with anti-PD-1 antibody administration. Although immune-related hypopituitarism after atezolizumab-bevacizumab treatment is rare, we should be alert for hypopituitarism developing during atezolizumab-bevacizumab treatment.

Effects of electroacupuncture on perioperative anxiety and stress response in patients undergoing surgery for gastric or colorectal cancer: Study protocol for a randomized controlled trial.

Perioperative anxiety is one of the main psychological stresses experienced by patients who undergo cancer surgery. The surgery itself inevitably causes a stress response characterized by activation of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis. Both the perioperative anxiety and surgical stress response lead to increased levels of catecholamines and prostaglandins, which may be related to perioperative suppression of antimetastatic immunity and tumor-promoting alterations in the microenvironment. Hence, we designed this clinical trial to investigate the effect of electroacupuncture in reducing perioperative anxiety and surgical stress response. This is a randomized, single-center, parallel, and controlled clinical trial. Seventy-eight participants between the ages of 35 and 85 with gastric or colorectal cancer who plan to undergo tumorectomy will be randomly divided into an electroacupuncture group and a control group. The primary outcome will be the six-item short form of the State-Trait Anxiety Inventory score. The secondary outcomes will be the Amsterdam Preoperative Anxiety and Information Scale score; levels of plasma cortisol, adrenocorticotropic hormone, interleukin-6, and tumor necrosis factor-α; first exhaust time after surgery; postoperative quality of the recovery-15 score, numeric rating scale for pain score; and dosage of postoperative analgesics. Cumulative studies revealed the efficacy of various types of acupuncture therapy with regard to reducing the anxiety and stress response caused by surgery. We expect that the results of this trial will provide high-quality clinical evidence for the choice of perioperative acupuncture for patients undergoing cancer surgery. https://www.chictr.org.cn, identifier ChiCTR200003 7127.

Intermittent Hypoxia and Weight Loss: Insights into the Etiology of the Sleep Apnea Phenotype.

Sleep apnea (SA) is a major respiratory disorder with increased risk for hypertension and obesity; however, our understanding of the origins of this complex disorder remains limited. Because apneas lead to recurrent drops in O2 during sleep, intermittent hypoxia (IH) is the main animal model to explore the pathophysiology of SA. Here, we assessed the impacts of IH on metabolic function and related signals. Adult male rats were exposed to 1week of moderate IH (FiO2=0.10-30s, ten cycles/hour, 8h/day). Using whole-body plethysmography, we measured respiratory variability and apnea index during sleep. Blood pressure and heart rate were measured by the tail-cuff method; blood samples were taken for multiplex assay. At rest, IH augmented arterial blood pressure, respiratory instability, but not apnea index. IH induced weight, fat, and fluid loss. IH also reduced food intake and plasma leptin, adrenocorticotropic hormone (ACTH), and testosterone levels but increased inflammatory cytokines. We conclude that IH does not replicate the metabolic clinical features of SA patient, thus raising our awareness of the limitations of the IH model. The fact that the risk for hypertension occurs before the appearance of apneas provides new insights into the progression of the disease.

Intraoperative Predictor of Remission in Cushing Disease.

Cushing disease represents a challenge for neurosurgeons, with high recurrence rates reported. Characteristics associated with remission are incompletely understood; thus, an intraoperative predictor for outcome would be valuable for assessing resection of adrenocorticotropic hormone (ACTH) secreting tissue. To evaluate whether intraoperative ACTH measurement could predict outcome after surgery for Cushing disease. Retrospective cohort study of 55 consecutive encounters with Cushing disease who had peripheral plasma ACTH levels measured intraoperatively before, during, and after tumor resection. The primary outcome measure was remission, defined by either 2 negative 24-hour urine free cortisol or 2 negative midnight salivary cortisol measurements. A logistic regression machine learning model was generated using recursive feature elimination. Fifty-five operative encounters, comprising 49 unique patients, had a mean follow-up of 2.73 years (±2.11 years) and a median follow-up of 2.07 years. Remission was achieved in 69.1% (n = 38) of all operations and in 78.0% (n = 32) of those without cavernous sinus invasion. The final ACTH level measured intraoperatively correctly predicted outcome (area under the curve = 0.766; P value = .002). The odds ratio of remission in patients with the lowest quartile vs highest quartile final intraoperative ACTH was 23.4 ( P value = .002). Logistic regression machine learning model resulted in incorporating postoperative day 1 morning cortisol, final intraoperative ACTH that predicted outcome with an average area under the curve of 0.80 ( P = .0027). Intraoperative ACTH may predict outcome after surgery in Cushing disease; furthermore, investigation is warranted.

Clinical characteristics of patients with unexplainable hypothalamic disorder diagnosed by the corticotropin-releasing hormone challenge test: a retrospective study

The corticotropin-releasing hormone (CRH) challenge test can distinguish the disorders of the hypothalamus from those of the pituitary. However, the pathophysiology of hypothalamic disorder (HD) has not been fully understood. This study aimed to elucidate the clinical characteristics of patients with unexplainable HD, diagnosed by the CRH challenge test. We retrospectively reviewed patients who underwent the CRH challenge test. Patients were categorized into four groups as follows: patients with peak serum cortisol ≥18 μg/dL were assigned to the normal response (NR) group (n = 18), among patients with peak serum cortisol < 18 μg/dL and peak adrenocorticotropic hormone (ACTH) increase ≥two-fold, patients without obvious background pathology were assigned to the unexplainable-HD group (n = 18), whereas patients with obvious background pathology were assigned to the explainable-HD group (n = 38), and patients with peak serum cortisol < 18 μg/dL and peak ACTH increase <two-fold were assigned to the pituitary disorder (PD) group (n = 15). Inter-group comparisons were performed based on clinical characteristics. In the CRH challenge test, the peak plasma ACTH levels were significantly lower in the unexplainable-HD group than in the NR group, despite more than two-fold increase compared to basal levels. The increase in serum cortisol was significantly higher in the unexplainable-HD group than in the explainable-HD and PD groups. Although patients in the unexplainable-HD group showed a clear ACTH response in the insulin tolerance test, some patients had peak serum cortisol levels of < 18 μg/dL. Furthermore, attenuated diurnal variations and low normal levels of urinary free cortisol were observed. Most patients in the unexplainable-HD group were young women with chronic fatigue. However, supplementation with oral hydrocortisone at physiological doses reduced fatigue only in some patients. Patients with unexplainable HD diagnosed by the CRH challenge test had hypothalamic-pituitary-adrenal (HPA) axis dysfunction and some patients had mild central adrenal insufficiency. Hydrocortisone supplementation reduced fatigue only in some patients, suggesting that HPA axis dysfunction may be a physiological adaptation. Further investigation of these patients may help elucidate the pathophysiology of myalgic encephalitis/chronic fatigue syndrome.

ODP639 The Occurrence and Predictors of Postoperative Adrenal Insufficiency for Patients With Subclinical Cushing's Syndrome

Abstract Objective To identify the occurrence and predictive factors of postoperative adrenal insufficiency in patients with subclinical Cushing's syndrome (SCS), and try to provide evidence for decision-making in SCS management. Methods The present retrospective analysis included 77 patients who underwent unilateral laparoscopic adrenalectomy for SCS between December 2011 and April 2021. Among them, 59 patients with complete follow-up data were included. We compared clinical characteristics of patients with and without postoperative adrenal insufficiency. The logistic regression model was used to find the potential risk factors in predicting the occurrence of postoperative adrenal insufficiency. The receiver operating characteristic (ROC) curve was used to evaluate the predictive values. Results We included 59 patients, of whom the incidence of postoperative adrenal insufficiency is 42.37%. The circadian rhythms of adrenocorticotropic hormone (ACTH) and cortisol disappeared in both two groups. Compared patients without postoperative adrenal insufficiency, patients with postoperative adrenal insufficiency were characterized by suppressed plasma ACTH level [1.11(1.11, 1.83) pmol/L vs 2.56(1.16, 4.63) pmol/L], elevated midnight cortisol level [268. 00(164. 00, 347.50) nmol/L vs 181.50(156.32, 227. 00) nmol/L] and increased cortisol level after 1 mg overnight dexamethasone suppression test (DST) [281. 00(241. 00, 396.64) nmol/L vs 172.50(144. 05, 215.25) nmol/L] (all P &amp;lt; 0. 05). Multivariate logistic regression analysis showed that the serum cortisol after a 1 mg-DST was the only independent predictive factor for the occurrence of postoperative adrenal insufficiency. The ROC curve showed that the best cut-off value of the serum cortisol after a 1 mg-DST was 233 nmol/L, with a sensitivity of 80. 00% and a specificity of 82.35%. The combination of the serum cortisol after a 1 mg-DST, plasma ACTH and midnight cortisol had the highest predictive accuracy (83. 05%). Conclusion Patients who underwent unilateral laparoscopic adrenalectomy for SCS had a risk of postoperative adrenal insufficiency. The pre-surgical assessment of the serum cortisol after a 1 mg-DST plus elevated midnight cortisol and suppressed plasma ACTH had predictive value for the occurrence of postoperative adrenal insufficiency. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Monday, June 13, 2022 1:00 p.m. - 1:05 p.m.

Increased Hippocampal Glucocorticoid Receptor Expression and Reduced Anxiety-Like Behavior Following Tuina in a Rat Model With Allergic Airway Inflammation

ObjectiveThis study aimed to explore the influence mechanism of Tuina on anxiety-like behavior in immature rats with allergic airway inflammation (AAI). MethodsA total of 27 Sprague-Dawley male rats (aged ∼5 weeks) were divided randomly into control, AAI, and AAI with Tuina groups (9 rats per group). The anxiety-like behavior was assessed by an open field test and elevated plus-maze test. Allergic airway inflammation was assessed based on the pathological score of the lung, plasma ovalbumin-specific immunoglobulin E, interleukin 4, interleukin 5, and tumor necrosis factor-alpha levels. Glucocorticoid receptor (GR) messenger RNA and protein expression in the hippocampus and lung were detected by polymerase chain reaction and immunohistochemistry, respectively. Meanwhile, corticotropin-releasing hormone (CRH) messenger RNA in the hypothalamus, the plasma levels of adrenocorticotropic hormone and corticosterone were also determined respectively by polymerase chain reaction and enzyme-linked immunosorbent assay for hypothalamic-pituitary-adrenal axis (HPA) function. ResultsThe AAI group had obvious anxiety-like behavior and hyperactive HPA axis, along with decreased GR expression in the hippocampus and lung. Following Tuina, AAI and the anxiety-like behavior were efficiently reduced, and the hyperactivity of HPA axis was efficiently inhibited, along with enhanced GR expression in the hippocampus and lung. ConclusionGlucocorticoid receptor expression in the hippocampus and lung was enhanced, and anxiety-like behavior was reduced following Tuina in rats with AAI.

Analysis of Adrenocorticotropic Hormone and Cortisol Levels in Acute Respiratory Distress Syndrome COVID-19 Patients.

Objective SARS-CoV-2 infection may cause multiple organ failure. However, scarce information can be found on the impact on the endocrine system. This study was conducted to determine plasma Adrenocorticotropic hormone (ACTH) and plasma cortisol levels in a cohort of COVID-19 patients with Acute Respiratory Distress Syndrome (ARDS). Methods A prospective cohort study was conducted on COVID-19 patients who manifested ARDS and were admitted to the ICU of Dr. Soetomo Tertiary Hospital, Surabaya, Indonesia. Morning plasma ACTH and plasma total cortisol were measured on 45 recruited patients. The outcome of the patient was justified based on the survivance on days 7th and 30th during the follow-up with groupings of surviving for survived patients and nonsurvive for deceased patients. Results The ACTH and cortisol median were 1.06 (0.5–64.57) pg/mL and 17.61 (0.78–75) μg/dL, respectively. Both parameters were assembled to allow the allocation of the 45 subjects into the survive and nonsurvive groups. There was a moderate correlation between ACTH and cortisol levels in all groups (r = 0.46, p < 0.002) and particularly ACTH and cortisol levels in COVID-19 patients who survived on the 7th-day and 30th-day follow-up (r = 0.518 and r = 0.568, respectively, with p < 0.05). It is important to note that there was no correlation for an individual parameter, either ACTH only or cortisol only, compared to the outcome among patients with various comorbid. Conclusion ACTH or cortisol alone has no correlation to the outcome of these patients. Therefore, further study of the potential use of corticosteroid treatments guided by ACTH and cortisol levels in reducing the risk of ARDS warrants further investigation.

Bolus Injection of Liraglutide Raises Plasma Glucose in Normal Rats by Activating Glucagon-like Peptide 1 Receptor in the Brain.

Diabetes is commonly treated with glucagon-like peptide-1 receptor (GLP-1R) agonists including liraglutide and others. However, liraglutide was found to raise plasma glucose levels in normal rats. The current study aims to determine how liraglutide causes this contentious condition in rats, both normal and diabetic. An adrenalectomy was performed to investigate the relationship between steroid hormone and liraglutide. To investigate the effect of central liraglutide infusion on blood glucose in rats, rats were intracerebroventricularly administrated with liraglutide with or without HPA axis inhibitors such as berberine and dexamethasone. The results showed that a single injection of liraglutide caused a temporary increase in blood glucose in healthy rats. Another GLP-1R agonist, Exendin-4 (Ex-4), increased blood sugar in a manner similar to that of liraglutide. The effects of liraglutide were also blocked by guanethidine pretreatment and vanished in normal rats with adrenalectomy. Additionally, central infusion of liraglutide via intracerebroventricular (icv) injection into normal rats also causes a temporary increase in blood glucose that was blocked by GLP-1R antagonists or the inhibitors such as berberine and dexamethasone. Similarly, central liraglutide treatment causes temporary increases in plasma glucose, adrenocorticotropic hormone (ACTH), and cortisol levels, which were reversed by inhibitors for the hypothalamic-pituitary-adrenal (HPA) axis. In normal rats, the temporary glucose-increasing effect of liraglutide was gradually eliminated during consecutive daily treatments, indicating tolerance formation. Additionally, liraglutide and Ex-4 cross-tolerance was also discovered in normal rats. Liraglutide was more effective in diabetic rats than in normal rats in activating GLP-1R gene expression in the isolated adrenal gland. Interestingly, the effect of liraglutide on glycemic control varied depending on whether the rats were diabetic or not. In normal rats, bolus injection of liraglutide, such as Ex-4, may stimulate the HPA axis, resulting in hyperglycemia. The cross-tolerance of liraglutide and Ex-4 provided a novel perspective on GLP-1R activation.

Isolated ACTH deficiency following immunization with the BNT162b2 SARS-CoV-2 vaccine: a case report

BackgroundThe global COVID-19 pandemic requires urgent development of new vaccines. Endocrinological adverse effects following the new mRNA vaccine against COVID-19 have been reported in several cases. Specific to the involvement of pituitary function; however, only a single case with hypophysis has been reported. This is the first case of isolated adrenocorticotropic hormone (ACTH) deficiency (IAD) following mRNA vaccination against COVID-19.Case presentationA healthy 31-year-old man received the BNT162b2 SARS-CoV-2 mRNA vaccine. The first injection was uneventful. One day after the second injection, he noticed general fatigue and fever. In the following several days, he additionally developed headaches, nausea, and diarrhea. Four days after the vaccine injection, he visited a hospital with worsening of these symptoms. Physical examination revealed slight disorientation but no other deficits. Laboratory tests revealed hyponatremia, hypoglycemia, and extremely low plasma ACTH and serum cortisol levels (ACTH < 1.5 pg/ml, cortisol 1.6 μg/dl). He was diagnosed with adrenal crisis and was emergently treated with hydrocortisone. The symptoms responded well and he recovered within a few days. Magnetic resonance images after the replacement with hydrocortisone revealed an atrophic pituitary gland. The patient was referred to our tertiary hospital for further endocrinological examination. Pituitary endocrine load tests revealed isolated adrenocortical response deficiency. After other clinical assessments, he was diagnosed as having isolated ACTH deficiency. After initiation of hydrocortisone replacement, there has been no recurrence of symptoms related to adrenocortical insufficiency nor involvement of other pituitary functions.ConclusionThis is the first reported case of IAD potentially associated with COVID-19 immunization. Recent reports have emphasized the importance of adjuvants in the mRNA vaccine that induce the endocrinological adverse effects through disturbance of the autoimmune system, but details are still unclear. Given the broad and rapid spread of vaccinations against COVID-19, it is clinically important to consider that there could be cases with a rare but emergent adrenal crisis even among those who present common symptoms of adverse effects following inactive SARS-CoV-2 mRNA vaccination.