Investigation of possible underlying mechanisms behind water-induced glucose reduction in adults with high copeptin

Elevated copeptin, a surrogate marker of vasopressin, is linked to low water intake and increased diabetes risk. Water supplementation in habitual low-drinkers with high copeptin significantly lowers both fasting plasma (fp) copeptin and glucose. This study aims at investigating possible underlying mechanisms. Thirty-one healthy adults with high copeptin (> 10.7 pmol·L−1 (men), > 6.1 pmol−1 (women)) and 24-h urine volume of < 1.5L and osmolality of > 600 mOsm·kg−1 were included. The intervention consisted of addition of 1.5 L water daily for 6 weeks. Fp-adrenocorticotropic hormone (ACTH), fp-cortisol, 24-h urine cortisol, fasting and 2 h (post oral glucose) insulin and glucagon were not significantly affected by the water intervention. However, decreased (Δ baseline-6 weeks) fp-copeptin was significantly associated with Δfp-ACTH (r = 0.76, p < 0.001) and Δfp-glucagon (r = 0.39, p = 0.03), respectively. When dividing our participants according to baseline copeptin, median fp-ACTH was reduced from 13.0 (interquartile range 9.2–34.5) to 7.7 (5.3–9.9) pmol L−1, p = 0.007 in the top tertile of copeptin, while no reduction was observed in the other tertiles. The glucose lowering effect from water may partly be attributable to decreased activity in the hypothalamic–pituitary–adrenal axis.ClinicalTrials.gov: NCT03574688.

Validation study of canine urine cortisol measurement with the Immulite 2000 Xpi cortisol immunoassay

We report here validation of the Immulite 2000 Xpi cortisol immunoassay (Siemens; with kit lot numbers <550) for measurement of urine cortisol in dogs, with characterization of the precision (CV), accuracy (spiking-recovery [SR] bias), and observed total error (TEo = bias + 2CV) across the reportable range. Linearity assessed by simple linear regression was excellent. Imprecision, SR bias, and TEo increased markedly with decreasing urine cortisol concentration. Interlaboratory comparison studies determined range-based (RB) bias and average bias (AB). The 3 biases (SR, RB, and AB) and resulting TEo differed markedly. At 38.6 and 552 nmol/L (1.4 and 20 μg/dL), between-run CVs were 10% and 4.5%, respectively, and TEoRB were ~30% and 20%, respectively, similar to observations in serum in another validation study. These analytical performance parameters should be considered for urine cortisol:creatinine ratio (UCCR) result interpretation, given that, for any hypothetical errorless urine creatinine measurement, the error % on UCCR mirrors the error % on urine cortisol. Importantly, there is no commonly used interpretation threshold for UCCR, given that UCCR varies greatly depending on measurement methods and threshold computation. To date, there is no manufacturer-provided quality control material (QCM) with target values for urine cortisol with an Immulite; for Liquicheck QCM (Bio-Rad), between-run imprecision was ~5% for both QCM levels. Acceptable QC rules are heavily dependent on the desired total allowable error (TEa) for the QCM system, itself limited by the desired clinical TEa.

Ectopic Cushing’s From Metastatic Prostate Cancer

Objective: Ectopic ACTH production from malignancy is a rare etiology of Cushing’s syndrome. The most common tumors associated with this syndrome include small cell lung cancer, pancreatic neuroendocrine tumors, pheochromoctoma, thymic carcinoma, and bronchial carcinoma. Metastatic prostate cancer does not commonly produce ACTH. Here, we present a rare case of Cushing’s syndrome due to metastatic prostate cancer. Case Report: Patient is a 64 year old man with a 2 year history of castrate-resistant prostate cancer who was admitted for the 2nd time in 1 month for profound weakness and new onset hypokalemia. Initial analysis revealed hypertension with systolic blood pressure in the 150s, potassium in the mid 2s, an ACTH level of &gt;1000pg/mL, and a 24-hr urine cortisol of almost 10,000mcg/24hrs. This was confirmed on repeat analysis. Metyrapone was initiated for treatment of hypercortisolemia and systemic chemotherapy with Cisplatin/Irinotecan was started to treat metastatic prostate cancer. ACTH and 24-hr urine cortisol levels returned to normal within a few weeks of therapy. The patient was able to discontinue Metyrapone following systemic chemotherapy treatment. Subsequent labs following discontinuation of metyrapone confirmed ongoing resolution of hypercortisolemia. Conclusion: This case represents an extremely rare cause of Cushing’s syndrome. Metastatic prostate cancer can rarely produce ACTH and cause clinical Cushing’s syndrome. Ectopic Cushing’s syndrome is often due to very aggressive tumors and is associated with a poor prognosis. Rapid recognition and treatment of this condition can be lifesaving.

Atypical Adrenocortical Incidentaloma Causing Autonomous Cortisol Secretion and Cardiovascular Complications

Introduction: Autonomous cortisol secretion (ACS) is found in approximately 10% of patients with an adrenocortical incidentaloma (AI). The majority of these cases are due to non-ACTH-dependent ACS. 2% of patients with AI have adrenocortical cancer. ACS is associated with cardiovascular morbidity, includes arterial stiffness, hypertension, coronary heart disease, and fatal or nonfatal myocardial infarction. Case presentation: A 62-year-old Caucasian male with a history of hypertension (HTN), hyperlipidemia (HLD) and poorly controlled type-2 diabetes mellitus (T2DM) and a recent myocardial infarction (MI) status post (s/p) coronary artery bypass graft (CABG) who presented to the endocrine clinic for evaluation of left adrenal mass. Family history was significant for adrenal carcinoma of his brother at the age of 60. The patient denied any facial flushing, palpitations, tremors, heat or cold intolerance, abnormal sweating, diarrhea, constipation, abdominal pain, recent weight change. Physical examination was unremarkable except midline sternal scar s/p CABG. Vital signs were remarkable for a blood pressure of 142/90. Labs were unremarkable. CT adrenal revealed a left adrenal mass 4.9 x 3.5 x 2.3 cm with HU -3 to 28 heterogeneous. HbA 1C was 8.2 %. Adrenal incidentaloma workup revealed a normal 24-hour urine cortisol level of 29 mcg, abnormal mid-night salivary cortisol of 0.13 mcg/dL and 0.31 mcg/dL, elevated cortisol after 1 mg dexamethasone suppression test (DST) of 343 mcg/dL, elevated cortisol after 8 mg DST of 90 mcg/dL, normal metanephrines of 10 pg/mL and normal normetanephrine of 49 pg/mL, normal aldosterone of 6.1 ng/dL, normal renin activity of 0.36 ng/ml/hr (Aldo/ PRA ratio 16). ACTH was 4.5 pg/ml. The endocrine surgeon was consulted for left adrenalectomy. The pathology showed atypical adrenal cortical neoplasm which does not clearly fulfill the criteria for adrenal cortical carcinoma confirmed by two pathologists. Upon six months follow-up, a 24-hour urine cortisol level was normal, 1mg overnight DST was normal, and no evidence of left adrenal on adrenal CT. Discussion: Adrenal incidentaloma (AI) is a common endocrine diagnosis affecting ~2% of the general population. Up to 10% of patients with AI have autonomous secretion of adrenal hormones. Pheochromocytoma and autonomous cortisol secretion should be excluded in every case and aldosteronism in patients with underlying hypertension and/or hypokalemia. ACS in patients AI has been associated with hypertension, insulin resistance, type 2 diabetes mellitus, obesity, metabolic syndrome, coronary artery disease, and increased mortality. Adrenalectomy is recommended for patients with a functional unilateral adenoma, with clinically significant hormone excess. Metabolic improvement after adrenalectomy, including weight loss, blood pressure lowering, glucose tolerance, lower lipids have been reported.

The Diagnosis and Management of a Rare ACTH-Producing Neuroendocrine Tumor Causing Cushing’s Syndrome

A 57-year-old woman presented with a three-month history of worsening lethargy, weight gain, central adiposity, proximal muscle weakness, and hypokalemic hypertension. Initial investigations were consistent with ACTH-dependent Cushing’s Syndrome. 24-hour urine cortisol: 711nmol/day (normal&lt;275), cortisol after 1 mg dexamethasone suppression test 960nmol/L (normal&lt;50)), 2-day dexamethasone suppression cortisol: 575 and ACTH: 19 pmol/L. MRI sella was normal. She required several hospital admissions for worsening proximal muscle weakness and falls. She was started on ketoconazole and spironolactone. Basal insulin was started for dysglycemia. Petrosal vein sampling indicated ectopic ACTH production. CT scan of chest/abdomen/pelvis showed no intrathoracic or intra-abdominal abnormality. Thyroid ultrasound and whole-body octreotide scan showed no abnormalities. A Gallium 68-dotatate PET scan showed focal tracer uptake in the pancreatic tail suspicious for a well-differentiated neuroendocrine tumor (NET). MRI pancreas showed a slightly truncated pancreatic tail with no discrete lesion. We proceeded with Endoscopic Ultrasound (EUS) which revealed an irregular hypoechoic mass in the pancreatic tail. EUS–guided fine-needle biopsy (EUS-FNB) using a 22G SharkCore needle, revealed a neuroendocrine neoplasm staining positively for ACTH. She underwent distal pancreatectomy with pathology showing a 1.4cm well-differentiated NET, staining positive for ACTH with a Ki67 index of 10%. Postoperatively, her ketoconazole, spironolactone, and insulin were discontinued. Her dysglycemia, hypertension and other clinical symptoms gradually improved. Immediately post-operatively, her AM cortisol was 403 and her 24-hour urine cortisol was elevated 959nmol/day. Repeat AM cortisol and 24-hour urine cortisol one-month post-surgery were 392 nmol/L and 72 nmol/day respectively, confirming biochemical remission. Discussion: ACTH-producing pancreatic NETs are rare, accounting for less than 15% of reported cases of EAS. They are often aggressive, with 78.7% of reported cases having distant metastasis at diagnosis (1). They are associated with significant morbidity and mortality. Diagnosis and management can be difficult and require multiple investigations and multidisciplinary team involvement. In our case, we utilized endoscopic ultrasound to ensure a correct preoperative localization. We discuss the systematic approach for diagnosis and the management of an ACTH-producing pancreatic NET. References: 1. Maragliano R, Vanoli A, Albarello L, Milione M, Basturk O, et al. ACTH-secreting pancreatic neoplasms associated with Cushing syndrome: clinicopathologic study of 11 cases and review of the literature. Am J Surg Pathol. 2015 Mar;39(3):374-82. doi: 10.1097/PAS.0000000000000340. PMID: 25353285.

SEVERE HYPERANDROGENISM IN A PREMENOPAUSAL WOMAN WITH AN IMAGING-NEGATIVE LEYDIG CELL TUMOR

Objective: Hirsutism and hyperandrogenism in premenopausal women are most often associated with polycystic ovarian syndrome. We present a case of progressive, severe hyperandrogenism with negative imaging identified on surgical histopathology as being due to a Leydig cell tumor (LCT), thus illustrating localization challenges associated with these small tumors. Methods: Laboratory investigations included testosterone, dehydroepiandrosterone sulfate, 17-hydroxyprogesterone, luteinizing hormone, follicle-stimulating hormone, thyroid-stimulating hormone, 24-hour urine cortisol, and prolactin. Imaging included pelvic ultrasound, adrenal magnetic resonance imaging, and computed tomography. Ovarian vein sampling was not available. Results: A 42-year-old woman presented with frontal alopecia, voice deepening, coarse facial hair, and amenorrhea on a background of lifelong oligomenorrhea. Peak testosterone was 30.2 nmol/L (female normal range is <2.0 nmol/L) with normal dehydroepiandrosterone sulfate, 17-hydroxyprogesterone, prolactin, 24-hour urine cortisol, and thyroid-stimulating hormone. Transvaginal ultrasound, adrenal magnetic resonance imaging, and computed tomography of the thorax and abdomen revealed no androgen source. Testosterone failed to suppress with gonadotropin-releasing hormone agonist. Although no abnormality was seen during oophorectomy, surgical pathology documented a 1.8-cm, well-circumscribed hilar LCT. Postoperative testosterone was <0.5 nmol/L. Conclusion: Although this patient had testosterone levels well into the masculine range, multiple imaging results were negative with a LCT found only after oophorectomy. LCTs are rare ovarian stromal tumors and while 50 to 70% of these tumors produce androgen, size and clinical severity may not be well correlated. This case report illustrates that despite an association with substantially elevated androgen levels, the small size of LCTs can result in localization challenges.

Comparison of Cortisol level by Shift Cycle in Korean Firefighters

(1) Study Objectives: By investigating the change of cortisol levels during shift cycles among professional firefighters in Korea, this study aims to evaluate the difference between individuals’ stress response and the recovery of their circadian rhythm after working night shifts. (2) Methods: A total of 325 shift firefighters, who were working in 3, 6, 9, or 21 day cycles, participated in the study. Their urinary and serum cortisol levels were measured during the day (09–18), during the night (18–09), and every 24 h (09–09) per shift cycle, and adjustments were made for confounding factors. (3) Results: Serum cortisol levels were significantly increased after working during the night or for 24 h compared with that of working throughout the day. However, whether working night or 24 h shifts, the serum cortisol levels were undoubtedly different based on the 3, 6, 9, or 21 day cycles. In all shift cycles, the urinary cortisol level decreased during the night or throughout the 24 h shifts compared with sleeping during this time, but this was considered to be significantly applicable only to those working in 21 day cycles. Additionally, in serial measurements, the recovery of urinary cortisol secretion after a night or 24 h shift was successful for individuals working in 9 day cycles, but the recovery was delayed for those working in 6 or 21 day cycles. (4) Conclusions: After analyzing the urine cortisol levels, the study indicates that only subjects working in 9 day cycles fully recovered their circadian rhythm while those working in 6 day or 21 day cycles did not completely recover. Therefore, it is important to recognize how stressful night shifts can be, and it is crucial to enhance firefighters’ current shift cycles in order to allow sufficient recovery of their circadian rhythm as well as the prevention of disrupting their circadian rhythm after working at night. Further research is necessary to take into account the amount of work load, the challenges of being sleep deprived, and the individual’s capacity to overcome sleepiness.

A New Perioperative Glucocorticosteroid Replacement Therapy for Cushing's Syndrome

Background: To evaluate the safety and effects of a new perioperative glucocorticosteroid replacement therapy for Cushing,s syndrome.Methods: A simple method of glucocorticosteroid replacement therapy as follow was adopted for 83 cases of Cushing's syndrome patient which were diagnosed before the operation: No glucocorticosteroid was used before operation, but during adrenal adenoma resection 100 mg hydrocortisone was given by intravenous injection，and another 200 mg hydrocortisone was given on the day of surgery. On day 1 and day 2 postoperative, 100 mg/12h and 100 mg/24h hydrocortisone were given by intravenous injection respectively. Prednisone(10mg/8h) was given from the day 2 postoperative by oral administration, then 5mg was reduced once a week until a maintenance dosage (5mg) was reached. Clinical symptoms were observed, plasma cortisol and 24h urine cortisol levels were intermittently measured post-operation to evaluate the safety and the curative effect of this new glucocorticosteroid replacement therapy.Results: Adrenal insufficiency and steroid withdrawal syndrome did not occur with all patients. Compared with the concentration of urine cortisol preoperation, it was significantly decreased on the day 7 postoperative. Plasma cortisol concentration was significantly decreased on day 6 postoperative compared with preoperative. All the patients were followed up to 6 months, plasma cortisol and 24h urine cortisol levels were all normal.Conclusions: This new glucocorticosteroid replacement therapy was safe, simple, and effective.

Hair Cortisol Concentrations as a Biological Marker of Maternal Prenatal Stress: A Systematic Review

Recently, biological markers of maternal prenatal stress, hair cortisol, along with saliva, blood, and urine cortisol, have received attention. However, it is necessary to validate measuring hair cortisol concentrations (HCC) as a biomarker of perceived stress among healthy and high-risk pregnant women. This study aimed to confirm the correlation between HCC and the perceived stress of pregnant women over 18 years of age. In this systematic review, we used various search engines to extract relevant articles using specific keywords related to pregnancy, hair cortisol, and psychological stress. Four out of 3639 studies met the inclusion criteria. We conducted a quality assessment with the help of three independent reviewers using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement. The correlation between HCC and perceived stress was confirmed in one study. There was only one study on hair washing, shampoo, conditioner, and hair structure that could affect hair samples. In four studies, hair samples differed in length, methods of storage, and laboratory analysis. The review was limited to confirming the relationship between HCC and perceived stress in pregnant women based on the current evidence. Studies on hair cortisol need regulated and standardized methods for collection, storage, and analysis of hair samples.