Midnight Cortisol Levels Research Articles

An aggressive Cushing's syndrome originating from a rare thymic neuroendocrine tumor, controlled successfully with fluconazole and octreotide therapy before surgery.

Cushing's syndromes (CSs) due to the thymic neuroendocrine tumors are rarely seen. Here, a case of ectopic CS originating from an atypical neuroendocrine tumor has been presented. A 49-year-old woman was hospitalized with symptoms of fatigue, chest pressure, dyspnea, muscle weakness, and resistant hypertension. There was marked hyperpigmentation in the whole-body surface suggestive of adrenocorticotropic hormone (ACTH) excess and there were physical features of CS. There was deep hypokalemia. Basal hormone profile, dexamethasone suppression tests, midnight cortisol, and 24-hour urine cortisol levels were suggestive of ectopic CS. The pituitary magnetic resonance imaging revealed a 5 mm cystic lesion and the patient refused inferior petrosal sinus sampling. Thorax computerized tomography showed an anterior mediastinal mass. A fluorodeoxyglucose-positron emission tomography showed the same mediastinal lesion (suvmax: 11.4), and no other tumor focus was detected. There was an aggressive cortisol excess causing acute respiratory distress syndrome, making it difficult to perform the surgery. We immediately started fluconazole and octreotide therapy and were successful in lowering the cortisol level. Then a complete resection of the tumor had been able to be surgically performed and tumor cells showed strong cytoplasmic immunopositivity with ACTH. A definitive diagnosis of "ACTH secreting atypical thymic carcinoid tumor" was rendered based on the histopathological and immunohistochemical features. There was only surrounding vessel invasion, and no lymphoid or other organ metastases were detected. As there were surrounding vessel invasions, a two-cycle regimen cisplatin-etoposide chemotherapy and radiotherapy were employed. After surgical and medical therapy, the cortisol and ACTH levels turned to normal. The patient is in biochemical and clinical remission and has no tumor recurrence yet. Ectopic ACTH-producing thymic carcinoids are rare but life-threatening tumors because of the underlying malignancy and severe hypercortisolemia. It is important to consider this disease and perform appropriate treatment at the right time. Today, surgery is the standard therapeutic modality if it is possible to perform, but there is not a clear and constant recommendation for nonsurgical therapeutic modalities. Further studies are needed for the optimal treatment strategies.

Association of Midnight Cortisol Level with Bone Mineral Density in Chinese Patients with Type 2 Diabetes Mellitus: A Cross-Sectional Study.

To investigate the association of the midnight cortisol level with bone mineral density (BMD) in patients with type 2 diabetes mellitus (T2DM). This study included 249 T2DM patients (148 males with an average age of 53.8 years and 101 postmenopausal females with an average age of 63.6 years) admitted to Xiamen Hospital of Zhongshan Hospital Affiliated to Fudan University from January 2018 to April 2020. Baseline data were compared between patients with normal BMD and those with osteoporosis/osteopenia. The patients also were divided into groups according to the tertiles of midnight cortisol levels. Among all T2DM, 178 had osteoporosis/osteopenia, including 98 men and 80 women. The baseline data analysis showed that patients with osteoporosis/osteopenia were more likely to be older, female, and thin, and to have high cortisol. Additionally, elevated estradiol levels had a protective effect on bone; once osteoporosis/osteopenia occurred, the probability of severe osteoporotic fracture was significantly increased. The BMD of the femoral neck, hip joint and lumbar spine decreased with increasing midnight cortisol level in men, postmenopausal women, and all T2DM patients (P<0.05). Multivariate logistic regression analysis identified body mass index, estradiol level, and midnight cortisol level as independent risk factors for osteoporosis/osteopenia in T2DM patients. Higher midnight cortisol levels are significantly associated with increased risk of osteoporosis/osteopenia in T2DM patients. Thus, the midnight cortisol level represents a valuable marker for assessing osteoporosis/osteopenia risk in these patients.

Predictor of Steroid Replacement Duration after Removal of Cortisol-producing Adenoma.

Objective Cortisol-producing adenoma (CPA) is a major subtype of functional adrenal tumors. CPAs are generally treated with adrenalectomy; however, it is difficult to predict the ideal duration of glucocorticoid replacement after resection. This study explored pre-operative factors predictive of glucocorticoid replacement therapy duration after CPA resection. Mehtods This multicenter retrospective observational study was conducted as part of the Advancing Care and Pathogenesis of Intractable Adrenal Diseases in Japan (ACPA-J) from January 2006 to December 2015. Patients This study was conducted at 10 referral centers and included 124 patients who received hydrocortisone replacement therapy after adrenalectomy for CPA. Results The median duration of replacement therapy was 12 (interquartile range, 5-24) months. In the single regression analysis, the sex (P=0.04), morning ACTH level (P=0.02), morning serum cortisol level (P=0.003), midnight serum cortisol level (P<0.001), serum cortisol level after a 1-mg dexamethasone suppression test (P<0.001), presence of lumbar compression fracture (P=0.015), and Cushingoid appearance (P<0.001) were all significantly associated with the replacement therapy duration. In multiple regression analyses, the midnight serum cortisol level and presence of lumbar compression fracture were significantly correlated with the replacement therapy duration after adjusting for other parameters. Conclusion Our results suggest that high midnight serum cortisol levels, which cause persistent suppression of the HPA axis, contribute to a delay in HPA axis recovery. Lumbar compression fracture is an important symptom that reflects the severity and persistence of cortisol secretion.

Subcentimeter Corticotroph Adenoma: an Evaluation of Diagnostic Elements

Cushing’s disease (CD) is an uncommon yet serious disorder, linked to increased morbidity and mortality. Diagnosis of these patients are complex, and emphasis should be placed on early detection for better management of these patients. The objective of this case report is to evaluate the diagnostic elements in the identification of a subcentimeter adrenocorticotrophic hormone (ACTH)-dependent pituitary adenoma. We report a case of a 26-year-old man who presented with extensive superficial fungal infection of the skin, unintentional weight gain, hypertension, dyslipidaemia as well as cushingoid appearance suspicious of hypercortisolism. Raised midnight plasma cortisol and 24-hour urinary cortisol levels warranted further investigation. Overnight and 48-hour low-dose dexamethasone suppression test (LDDST) were non-suppressed. Subsequent bilateral inferior petrosal sinus sampling (BIPSS) was not only efficient in differentiating pituitary from ectopic Cushing’s syndrome (CS) but was shown to be superior to magnetic resonance imaging (MRI) in lateralisation of the pituitary adenoma.

The effects of hypercortisolism on the frequency and magnitude of sleep EEG waves in patients with Cushing syndrome: A spectral analysis study

ObjectivesOur aim was to investigate the effects of endogenous chronic hypercortisolism on sleep electroencephalogram (EEG) and differences between the adrenocorticotropic hormone (ACTH)-dependent and independent Cushing Syndrome (CS) patients through a sleep spectral analysis program. MethodsA total of 32 patients diagnosed as having endogenous CS (12 ACTH-dependent and 20 ACTH-independent) and a control group comprising 16 healthy individuals were included in the study. Polysomnographic analysis was performed. Blood samples were collected at 08:00 AM for analysis of ACTH and basal cortisol, and at 00:00 AM for midnight cortisol levels. The frequency and power of the slow wave activity (SWA), theta, alpha, and beta waves of the first and last non-rapid eye movement (NREM) cycles were measured with a spectral analysis program. ResultsThe CS patient group had higher SWA power, especially in the first NREM cycle. In the ACTH-dependent group, SWA maximum and mean power values were higher in the frontal channels in the first NREM, compared to the last NREM sleep stage (p<0.05). ConclusionCortisol has been found to be associated with SWA waves, making these waves higher in power, especially in the first NREM phase. This difference was much less pronounced in the final NREM sleep stage. The difference between the first and last NREM sleep stages with respect to the power of SWA in the frontal channel in the ACTH-dependent group suggests that not only cortisol but also high levels of ACTH affect the power of slow waves during sleep.

Diurnal Cortisol Features and Type 2 Diabetes Risk in Patients With Hypertension and Obstructive Sleep Apnea: A Cohort Study.

The hypothalamic-pituitary-adrenal (HPA) axis may be associated with type 2 diabetes (T2D); however, whether HPA axis dysfunction is associated with incident T2D remains unclear in patients with hypertension and obstructive sleep apnea (OSA). To investigate the relationship between the diurnal cortisol features and the risk of incident T2D in patients with hypertension and OSA. Participants with cortisol rhythm test at baseline in the Urumqi Research on Sleep Apnea and Hypertension cohort were enrolled. The Cox regression model was used to evaluate the relationship between ln-transformed diurnal cortisol features and T2D risk. Stratified and sensitivity analyses were also performed. A total of 1478 patients with hypertension and OSA were enrolled in this study. During a median follow-up of 7.0 years, 196 participants developed T2D. Overall, a steep diurnal cortisol slope (DCS) was significantly associated with decreased T2D risk (per SD increase, HR 0.88, 95% CI 0.79-0.97, P = .014). Midnight cortisol was positively associated with increased T2D risk (per SD increase, HR 1.25, 95% CI 1.08-1.45, P = .003). Sensitivity analyses showed similar results. Neither DCS nor midnight cortisol was associated with incident T2D in the women's subgroup or participants with mild OSA. Steeper DCS and higher midnight cortisol levels are associated with lower and higher T2D risks in patients with hypertension and OSA, respectively, at least in men or participants with moderate to severe OSA. Diurnal cortisol features may represent an early prevention target for diabetes in this population.

ODP387 Hemihypertrophy: A Rare Clinical Presentation of Cushing's disease

Abstract Background Hemihypertrophy is a rare clinical presentation of Cushing's disease. It has been described in three newborns with massive enlargement of adrenal glands in presence of other congenital abnormalities and in a 17-year-old female with pituitary adenoma with a genetic diagnosis of Beckwith Weidman syndrome. We describe a case of Cushing's disease with lower extremity hemihypertrophy in the absence of features suggestive of an underlying syndrome. 1,2 Clinical Case: A 12-year-old male with no significant past medical history presented with poor growth and rapid weight gain. In addition, he had hemihypertrophy of left lower extremity interfering with his physical activity. Physical exam showed Tanner Stage 1 for pubic hair and testicular volume of 4 ml bilaterally, with no signs of hirsutism, bruising or purplish striae. Initial work up showed normal thyroid hormone and growth factor levels. Midnight salivary cortisol levels were 238 ng/dl and 51 ng/dl respectively (range &amp;lt;100 ng/dl). One mg dexamethasone suppression test showed suppressed cortisol level of 1 mcg/dl. At the subsequent visit seven months later, he had gained 13.8 kg and grown 0.9 cm in height. Physical exam showed facial plethora and buffalo hump, which had not been present at the initial visit. Left and right leg circumference above the knee were 22 inches and 20 inches respectively. Repeat midnight cortisol levels on two separate occasions were 251 ng/dl and 441 ng/dl respectively. Repeat 1 mg dexamethasone suppression test showed suppressed cortisol levels of 1.2 mcg/dl. Because of clinical picture consistent with Cushing syndrome and elevated salivary cortisol levels, 24-hour urine cortisol levels were ordered that were 145 mcg and 276 mcg/24h respectively (range 1-45 mcg/24hours). ACTH was elevated at 65 pg/ml. CT scan of abdomen and pelvis was normal. Left leg ultrasound was normal. MRI of brain showed a 4 mm hypoenhancing lesion in the pituitary gland to the left of midline. A peripheral DDAVP stimulation test showed elevated ACTH and cortisol levels suggestive of pituitary origin. MRI of legs showed asymmetric fat deposition causing hemihypertrophy. Patient underwent transsphenoidal resection of pituitary adenoma with postoperative remission (postop cortisol nadir &amp;lt;1 mcg/dl). At follow up visit after surgery, patient had lost 0.2 kg, buffalo hump had disappeared, and left leg circumference had slightly improved. Genetic testing ispending. Conclusion This case demonstrates that hemihypertrophy can be a presenting symptom of Cushing's disease.

ODP058 Topiramate causing elevation of urinary cortisol assay

Abstract 69-year-old female with pituitary adenoma status-post transsphenoidal resection 6 years prior and isolated growth hormone deficiency [on somatropin 0.2 mg daily], migraines [on topiramate 25 mg daily], left lipid-rich adrenal incidentaloma, primary hypothyroidism [on levothyroxine 75 mcg daily], and secondary hyperparathyroidism from vitamin-D deficiency [on ergocalciferol 50000 IU weekly] and hydrochlorothiazide 25 mg daily presented for follow-up. Physical exam: afebrile, blood pressure hypertensive at 163/71 mmHg, heart rate 91 beats per minute, respiratory rate 18 breaths per minute, saturating 100% on room air and patient weighed 105 kg. Patient appeared obese but did not exhibit cervicodorsal fat pads, abdominal striae, or other cushingoid features. Neck was supple and did not demonstrate palpable nodules or lymphadenopathy. Labs ordered at clinic visit demonstrated normal TSH 1.28 with normal free T4 1.21, elevated PTH 232 with corrected calcium 9.7 (on hydrochlorothiazide) and normal vitamin-D, 25 level 43, normal ACTH 21, and normal IGF-1 level 75. Given adrenal incidentaloma and prior pituitary adenoma, the integrity of the hypothalamus-pituitary-adrenal axis was also tested. A subsequent 8: 00 a. m. cortisol was insufficiently suppressed at 5.2 after 1 mg dexamethasone suppression test which raised concern for hypercortisolism from pituitary adenoma or adrenal adenoma. Accordingly, ACTH as well as DHEA-S and 24 hour urine cortisol as well as midnight salivary cortisol level was ordered to assess pituitary versus adrenal origin, respectively. Interestingly, while midnight salivary cortisol was found to be normal at less than 50, the 24 hour urine cortisol measurement was elevated at 878 despite otherwise normal cortisol findings. ACTH and DHEA-S levels are still pending. Plan was made to check two additional midnight cortisol levels and await ACTH and DHEA-S levels. In an effort to explain the urinary cortisol elevation, the patient's medications were reviewed and subsequent literature search revealed that topiramate may interfere with urinary cortisol measurement by causing a dose-dependent increase in the measured urinary cortisol, presumably due to its action on the kidney during renal excretion. Patient had been on topiramate for approximately 6 months prior to this assay. Presentation: No date and time listed

ODP618 The profile of patients with ACTH-secreting pituitary adenomas and subclinical pituitary apoplexy

Abstract Background Subclinical hemorrhage or necrosis of pituitary adenomas (PAs), often defined as subclinical pituitary apoplexy (SPA), presents in up to 20% of all PAs and is more common in large prolactinomas. SPA in corticotropinomas in patients with Cushing disease (CD) is not common and the clinical and biochemical characteristics of patients with CD and SPA are not known. Subjects and methods: Pediatric patients with confirmed CD diagnosed between 2005-2021 with available MRI images before any surgical intervention were included in the study (n= 171). SPA diagnosis was based on MRI findings. Although MRI sequences and machines were not same for all patients and varied over time, the results were based on possible signs of hemorrhage on the available images, but smaller areas of bleeding or necrosis may have been missed. Statistical analyses were performed with Wilcoxon signed-rank test, chi-square or Fisher's exact test, and Cox proportional hazard as appropriate. Results are shown as median [Q1, Q3], count (percentage) and odds ratio (OR) (95% confidence intervals, 95%CI). Results Out of 171 patients, 12 patients (7%) were found to have imaging characteristics of possible hemorrhage or intratumor infarct. Patients with and without SPA were similar in age (median age: 12.5 years [10.6, 15.6] in SPA group vs 13.1 years [10.6, 15.4] in non-SPA group, p= 0.95) and gender distribution (n of female= 5 (41.7%) in SPA group vs 89 (56%) in non-SPA group, p= 0.51). Patients with SPA had shorter duration of disease as noted by changes in their growth chart parameters (median duration: 1. 0 year [1. 0, 2. 0] in SPA group vs 2.5 years [1.5, 3. 0] in non-SPA group, p= 0. 014). Morning and midnight cortisol and 24hour urinary cortisol levels were similar in both groups, but patients with SPA had higher levels of morning ACTH (60.8 pg/mL [43.5, 80.3]) compared to patients without SPA (39.8 pg/mL [28.5, 53.4], p=0. 017). Change of cortisol and ACTH levels during CRH stimulation test were similar between the two groups, but patients with SPA had lower suppression of cortisol after overnight high dose (8mg or weight-based equivalent) dexamethasone suppression test (58. 0% [-85.4, -49.7]) compared to patients without SPA (85.8 [-90.5, -76.8], p= 0. 035). Specifically, patients with SPA had lower chance of passing the threshold of 69% that it suggestive of pituitary source of hypercortisolemia compared to patients without SPA (OR: 0.18, 95%CI: 0. 03-0.95). The odds of remission after surgery and the risk of recurrence after initial remission did not differ based on the presence of SPA. Conclusion Patients with CD and sings of hemorrhage or necrosis in their tumor may present with different characteristics on their biochemical evaluation which should be considered during their diagnostic workup, especially in the setting of a discordant dexamethasone suppression test. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

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.

Diurnal cortisol features with cardiovascular disease in hypertensive patients: a cohort study.

The hypothalamic-pituitary-adrenal (HPA) axis may be associated with cardiovascular disease (CVD) and the effects of diurnal cortisol features on future CVD remain unclear among patients with hypertension. This study aimed to evaluate the association between diurnal cortisol features and CVD in patients with hypertension. Participants with cortisol rhythm test at baseline in Urumqi Research on Sleep Apnea and Hypertension (UROSAH) in 2011-2013 were enrolled and followed up till 2021. Incident events included coronary heart disease, stroke, and heart failure. Cox proportional hazards model was used to evaluate the relationship between diurnal cortisol features and incident CVD. Sex-specific and sensitivity analyses were also performed. In total, 2305 hypertensive participants comprised the current analytical sample. During a median follow-up of 7.2 years and 16374.9 person-years, there were 242 incident CVD cases. Multivariable Cox regression showed that steep diurnal cortisol slope (DCS) was significantly associated with decreased CVD risk (per s.d., hazard ratio (HR) = 0.86, 95% CI: 0.77-0.96, P = 0.011). Midnight cortisol was positively associated with an increased CVD risk (per s.d., HR = 1.24, 95% CI: 1.08-1.42, P = 0.002). Comparable results were observed in the sensitivity analyses. Neither midnight cortisol nor DCS was associated with incident CVD in the female subgroup. Flatter DCS and higher midnight cortisol levels are associated with an increased risk of CVD in patients with hypertension, especially in men. The detection of diurnal cortisol rhythm may help identify patients with hypertension at high risk of CVD.

Differences in Regulation of Cortisol Secretion Contribute to Left Ventricular Abnormalities in Patients With Essential Hypertension.

Left ventricular (LV) abnormalities were reported in patients with overt and subclinical Cushing syndrome. The aim of this study was to investigate the relationships of daily plasma cortisol profile and cortisol response to an overnight suppression test with cardiac changes in patients with hypertension. In a cross-sectional study, we included 136 nondiabetic, patients with essential hypertension who were free of cardiovascular and renal complications. Plasma cortisol was measured at 8 am, 3 pm, and 12 am and at 8 am after overnight suppression with 1 mg dexamethasone (dexamethasone suppression test [DST]). Echocardiography was performed with standard B-mode and tissue-Doppler imaging. LV hypertrophy was present in 30% and LV diastolic dysfunction in 51% of patients who were older and had significantly higher body mass index, systolic blood pressure, duration of hypertension, and 12 am and DST cortisol. LV mass index and relative wall thickness increased progressively across tertiles of DST cortisol, together with progressive worsening of diastolic function. LV mass index was directly related to age, systolic blood pressure, duration of hypertension, and 12 am and DST cortisol, and inversely to creatinine clearance. Multivariate regression analysis showed independent correlation of LV mass index with body mass index, systolic blood pressure, and 12 am and DST cortisol. Logistic regression showed that DST cortisol independently predicted LV hypertrophy. Midnight and DST plasma cortisol levels are independent determinants of LV mass and geometry in patients with essential hypertension suggesting that even minor changes in regulation of cortisol secretion could contribute to cardiac abnormalities in these patients.

Performance of DHEAS as a Screening Test for Autonomous Cortisol Secretion in Adrenal Incidentalomas: A Prospective Study.

Autonomous cortisol secretion (ACS) affects up to 30% of patients with adrenal incidentalomas (AIs). The current guidelines for ACS diagnosis are not decisive. A lower dehydroepiandrosterone sulfate (DHEAS) level is a potential biomarker, but the evidence is conflicting. This prospective study aimed to evaluate and validate the ACS screening and diagnostic accuracy of DHEAS. Recruited patients with AI were screened for adrenal medullary and cortisol hypersecretion. The diagnosis of ACS was based on a serum cortisol level ≥ 50 nmol/L following a 1-mg dexamethasone suppression test (DST) and a low-dose DST. Age- and sex-specific DHEAS ratios were also calculated. In the development cohort (45 ACS and 242 non-ACS patients), the areas under the receiver operator characteristic curves (AUCs) of DHEAS and the DHEAS ratio were 0.869 (95% CI 0.824-0.906) and 0.799 (95% CI 0.748-0.844), respectively. The optimal DHEAS cutoff for diagnosing ACS was 60 μg/dL, with a sensitivity of 75.6% (95% CI 60.5-87.1) and a specificity of 81.4% (95% CI 76.4-86.5). The midnight serum cortisol level had moderate diagnostic accuracy [AUC 0.875 (95% CI 0.831-0.911)]. Suppressed adrenocorticotropic hormone (≤2.2 pmol/L) had a lower sensitivity (55.6%), and the 24-hour urinary free cortisol lacked sensitivity and specificity [AUC 0.633 (95% CI 0.603-0.721)]. In the validation cohort (14 ACS and 45 non-ACS patients), the sensitivity and specificity of the optimized DHEAS cutoff were 71.4% (95% CI 41.9-91.6) and 82.2% (95% CI 68.0-92.0), respectively. A single basal measurement of DHEAS is valuable for identifying ACS. Because of its stability and ease of use, the DHEAS level could be used as an ACS screening test.

Association between Neutrophilic Granulocyte Percentage and Diabetes Mellitus in Cushing's Syndrome Patients: A Cross-Sectional Study.

Background Glucose metabolism is frequently impaired in patients with Cushing's syndrome (CS) due to chronic exposure to excess glucocorticoids. Inflammation plays an essential role in the pathophysiology of diabetes mellitus (DM). The present study aimed to investigate the potential associations of inflammatory blood cell parameters, including white blood cell (WBC) count, neutrophil count, neutrophilic granulocyte percentage (NEUT%), lymphocyte count (LYM), and lymphocyte proportion (LYM%), with diabetes mellitus in Cushing's syndrome patients. Materials and Methods The cross-sectional study was conducted in Zhongshan Hospital of Fudan University, China. A total of 150 patients with Cushing's syndrome were retrospectively screened from 2017 to 2019. The demographic data, clinical data, and blood samples (lipids, adrenal, glucose, and inflammatory blood cell parameters) were recorded. Statistical analyses were carried out by using the SPSS software package, version 13.0. Results In this study, the prevalence of diabetes mellitus was 38.7% in patients with Cushing's syndrome. Patients with DM had higher WBC, neutrophil, NEUT% levels than patients without DM (p < 0.05). As the NEUT% increased, a stepwise increase in glucose and glycated hemoglobin (HbA1c) level was observed. In addition, in the multivariate logistic regression, NEUT% was a significant independent risk factor for DM, regardless of gender, age, body mass index (BMI), and triglyceride and 12 midnight cortisol (12 MN cortisol) level (OR = 2.542, 95% CI 1.337–4.835, p < 0.001). Conclusions In conclusion, elevated NEUT% level was linked to diabetes in patients with Cushing's syndrome. The neutrophilic granulocyte percentage may be referred to as a new predictor for diabetes in Cushing's syndrome patients.

The association of glucocorticoid receptor polymorphism with metabolic outcomes in menopausal women with adrenal incidentalomas

ObjectivesTo investigate whether BclI polymorphism in the glucocorticoid receptor gene influences hypothalamic-pituitary-adrenal (HPA) axis regulation, body composition and metabolic parameters in women with adrenal incidentalomas (AIs). Study designA cross-sectional study. Main outcome measuresWe analyzed 106 women with AIs. Insulin resistance was assessed using a homeostasis model while HPA activity was assessed using dexamethasone suppression tests (DST), basal ACTH, urinary free cortisol, and midnight serum cortisol level. Body composition was analyzed using dual-energy X-ray absorptiometry. DNA was obtained from peripheral blood leucocytes and BclI polymorphism was detected using PCR, RFLP and DNA sequencing. ResultsBclI carriers in comparison with those with wild-type BclI had less suppressed cortisol after DST-0.5 mg (126.4 ± 111.4 vs 80.9 ± 75.7 nmol/l, p = 0.026) and had a lower prevalence of impaired glucose tolerance and of type 2 diabetes mellitus (T2DM). BclI carriers had a higher percentage of leg fat mass (FM), lower left-sided limb muscle mass and a decline in total lean body mass. Duration of menopause remained a strong predictor of appendicular lean mass index (ALMI) (β=-0.125, p = 0.034). BclI polymorphism was significantly associated with sum of legs FM percentage (β=0.327, p = 0.048). T2DM was negatively associated with BclI polymorphism, after adjusting for age, truncal FM, ALMI, and sum of legs FM (OR=0.158, 95%CI 0.031–0.806, p = 0.027). ConclusionsBclI polymorphism is associated with tissue-specific glucocorticoid sensitivity, relative glucocorticoid resistance of the HPA axis and peripheral adipose tissue, and glucocorticoid hypersensitivity at the muscle level. By modulating glucocorticoid and insulin sensitivity, BclI polymorphism appears to reduce the risk of T2DM in women with AIs.

Depression: another cortisol-related comorbidity in patients with adrenal incidentalomas and (possible) autonomous cortisol secretion.

Hypercortisolism is associated with a high prevalence of depression and impaired health-related quality of life (QoL). According to the available literature, studies examining the depression risk in patients with adrenal incidentalomas (AI), nonfunctioning and the ones with (possible) autonomous cortisol secretion ((P)ACS) are scarce. The aim of this observational, case-control study was to screen patients with nonfunctioning adrenal incidentalomas (NAI) and the ones with (P)ACS for depression and to assess their QoL. The total studied group consisted of 92 subjects-26 with NAI, 34 with (P)ACS and 32 age-matched healthy controls (HC). To screen for depression, we used the Beck Depression Inventory-II (BDI-II) and to assess the QoL, we used the Short-Form 36 Health Survey (SF-36). Patients with (P)ACS had significantly higher BDI-II scores and substantially lower QoL than patients with NAI or HC. Midnight cortisol level was the most significant predictor of BDI-II and SF-36 score. The receiver operating characteristic curve analysis demonstrated that a midnight cortisol value of 86.95nmol/l had a high sensitivity (82.8%) and high specificity (80%) for detection of mild depression in patients with (P)ACS. Screening for depression and QoL assessment should become an integral part of clinical evaluation in patients with (P)ACS.

Correlation of lower 2\u2009h C-peptide and elevated evening cortisol with high levels of depression in type 2 diabetes mellitus

BackgroundA number of studies have explored the association between depression and ghrelin, leptin, and cortisol; further, postprandial C-peptide levels have a therapeutic effect on type 2 diabetes mellitus (T2DM). However, the relationship between C-peptide and depression in patients with diabetes, remains unclear. The aim of this study was to explore the association between depression and ghrelin, leptin, cortisol, and C-peptide in patients with diabetes.MethodsWe enrolled 50 adults without T2DM, 77 non-depressed adults with T2DM (free of Axis-I psychiatric disorders as assessed using the Mental Illness Needs Index (MINI), Patient Health Questionnaire (PHQ-9 score ≤ 4)) and 59 patients with T2DM and depression (PHQ-9 ≥ 7 and positive by the Structured Clinical Interview for DSM-5). The age range of the participants was 45–59 years of age. We compared the above three groups and explored the association between ghrelin, leptin, cortisol, C-peptide, and depression in patients with diabetes. A post-hoc power-analysis was finished.ResultsCompared with the non-depression T2DM group, the depression T2DM group had significantly higher blood glucose fluctuations. Further, compared with the non-depression T2DM and non-diabetic groups, the depression T2DM group had significantly lower levels of post-meal 2-h C-peptide and elevated evening cortisol (p < 0.01). Regression analysis revealed a significant negative correlation between depression severity and 2-h postprandial C-peptide in patients with diabetes (p < 0.01) and a significant positive correlation with midnight cortisol levels (p < 0.01). A post hoc power analysis showed that we had an adequate sample size and met the minimum requirement to attain 80% power. A post hoc power calculation also demonstrated that this study basically achieved power of 80% at 5% alpha level.ConclusionsOur findings indicate a correlation of low fasting levels of 2-h C-peptide as well as higher midnight cortisol levels with higher depression severity in middle-aged patients with T2DM.

Clinical features and outcomes of surgical versus conservative management in patients with subclinical Cushing's syndrome

Objective: To examine the clinical characteristics and metabolic features of subclinical Cushing's syndrome (SCS), and determine the effects of surgical or conservative approaches on the hormone levels and metabolic comorbidities in patients with SCS, thereby providing the evidence for decision-making in SCS management. Methods: A total of 56 consecutive SCS patients were selected in Drum Tower Hospital Affiliated to Nanjing University Medical School between 2010 and 2018, with 41 patients undergoing surgical treatment and 15 patients receiving conservative therapy. Meanwhile, 56 and 68 cases of sex-and age-matched patients diagnosed as nonfunctional adrenal adenoma (NFA) and adrenal Cushing's syndrome (CS) were included respectively. Clinical characteristics of patients in different groups were compared. Hormone levels and metabolic comorbidities were also observed during follow-up. Results: There were 56 SCS patients, including 15 males and 41 females, with an age of (52.0±12.6) years. The circadian rhythms of adrenocorticotropic hormone (ACTH) and cortisol disappeared in CS and SCS groups. Compared to NFA group, patients with SCS were characterized by suppressed plasma ACTH level [2.40 (1.11, 4.33) pmol/L vs 4.23 (2.74, 6.26) pmol/L], elevated midnight cortisol level [(240±121) nmol/L vs (59±8) nmol/L] and increased cortisol level after 1 mg overnight dexamethasone suppression test [(241±130) nmol/L vs (34±12) nmol/L] (all P<0.01). The derangement of ACTH-cortisol axis was more obvious in CS patients compared to SCS patients. The prevalence of hypertension, glucose intolerance, dyslipidemia and osteopenia/osteoporosis were higher in SCS patients compared to NFA patients (75.0% vs 41.1%, 33.9% vs 12.5%, 62.5% vs 28.6%, 35.7% vs 8.9%, all P<0.05). The 24-hour urine free cortisol correlated positively with systolic blood pressure, glycated hemoglobin A1c (HbA1c) and fasting blood glucose in SCS patients (r=0.335, 0.562 and 0.463, respectively, all P<0.05). In the surgical group, body weight, body mass index (BMI) and blood pressure decreased significantly after surgery (all P<0.05). Glucose intolerance/diabetes mellitus improved in 6 of 9 patients, BMI of 4 of 11 overweight/obesity patients normalized, and hypertension in 54.5% of patients (12/22) showed improvement after surgery. However, no alterations of hormone levels and metabolic parameters were observed in conservatively-managed patients. Conclusions: Patients with SCS are characterized by mild autonomous cortisol secretion and increased risk of metabolic comorbidities. Compared with conservative management, hormone abnormalities were corrected and metabolic abnormalities were improved in some SCS patients after surgery.

SAT-370 Clinical Characteristics and Metabolic Features of Patients with Subclinical Cushing's Syndrome and Its Correlation with Cortisol Level

Objective The aim of this study was to examine the clinical characteristics and metabolic features of subclinical Cushing’s syndrome (SCS), and to investigate the association of the cortisol level with the metabolic features in patients with SCS. Methods 52 patients with non-functioning adenoma (NFA), 45 patients diagnosed with SCS and 61 patients with overt adrenal Cushing’s syndrome (CS) participated in this study. Clinical data and endocrine function of the patients as well as histological findings were all reviewed. Results 1) The average age of patients with SCS was 52.56±13.25 years, 68.9% patients were female. No difference was detected in age, gender and BMI between patients with SCS and NFA (P > 0.05). Compared to patients with SCS, CS was more common in younger and female patients (43.90±13.83, 83.6%). The prevalence of diabetes mellitus, hypertension, and osteopenia/osteoporosis were significantly higher in patients with SCS compared to those with nonfunctioning tumors (57.8% vs 32.7%, 73.3% vs 53.8%, 41.2% vs 19.2%; P < 0.05). No difference was detected between SCS and CS patients in the prevalence of metabolic disease. 2) Compared to patients with NFA, plasma ACTH level is lower in patients with SCS (P < 0.05). Whereas, the midnight cortisol level and cortisol level after 1mg overnight dexamethasone suppression is higher in SCS than NFA (P < 0.05). No difference was detected between SCS and NFA in 24h urinary free cortisol and early-morning cortisol level (P > 0.05). Compared to SCS, the derangement of ACTH-cortisol axis is more prominent in CS patients demonstrated as suppressed plasma ACTH level and elevated plasma and 24h urine cortisol level. 3) In SCS cohort, SBP, FBG and HbA1c correlated positively with 24h urinary free cortisol (r =0.394, P =0.021; r =0.426, P =0.011, r =0.398, P =0.015; respectively). When controlling for age and gender, the correlation was also significant (P < 0.05). No correlations were found between BMI, TG, HDL and 24h urinary free cortisol. Conclusion Patients with SCS showed slight derangement of the circadian rhythm of cortisol and cortisol excess, and increased prevalence of metabolic disease. Furthermore, the cortisol level was related closely to blood glucose and blood pressure. Our findings might suggestive in therapeutic decision making (conservative vs surgery approach) in patients with SCS.

SUN-369 Challenges in Diagnosing and Managing PPNAD in a Patient with Carney Complex

Background Carney complex (CNC) is a rare disorder associated with endocrine, cardiac, cutaneous and neural tumors. Primary pigmented nodular adrenocortical disease (PPNAD) is the most frequent endocrine manifestation in patients with CNC and can be challenging to diagnose and manage. Case A 35 yo female with CNC diagnosed at the age of 3 yrs presented with a 20 lb. weight gain over last 1 year associated with easy bruising, anxiety, dorsocervical and supraclavicular fat pad. She had no other comorbidities and had normal bone density. Her morning cortisol after 8 mg dexamethasone was not suppressed (cortisol 14.9 mcg/dl, dexamethasone 1920 ng/dl); however, urine cortisol values were high normal to only mildly elevated (42.7, 48.4; n-3.5-45 mcg/24hr). Loss of circadian rhythm was noted on comparing midnight and morning cortisol level (8.4, 8.3 mcg/dl respectively), ACTH was suppressed (<5 pg/ml) and DHEAS was low (0.26; n-0.35-4.30 mcg/ml). Her Liddle’s test was not consistent with PPNAD. Adrenal CT was suggestive of possible focal enlargement of medial limb of left adrenal. She was offered bilateral adrenalectomy, but has deferred it at this time. Discussion CNC was first described by Dr. Carney in 1985 as ‘the complex of myxomas, spotting pigmentation and endocrine over-reactivity’. It is a rare disorder with 750 known cases. It has autosomal dominant inheritance with almost 100% penetrance. PPNAD is seen clinically in 25-60% of patients with CNC, however, it has been found in almost every individual with CNC who underwent autopsy, suggesting significant variability in presentation. Symptoms may evolve over a span of many years, making it difficult to determine the appropriate timing of treatment. Diagnosing PPNAD can be challenging as cortisol production can be cyclical, periodic or subclinical. The paradoxical rise in glucocorticoids in response to dexamethasone (Liddle’s test) is reported in 69% of patients but is not pathognomonic. Radiological diagnosis is also challenging as most nodules are less than 4 mm in size, so the adrenals may appear normal on CT scan. Recommended treatment for PPNAD is bilateral adrenalectomy, but this introduces a lifelong burden of steroid replacement and risk of adrenal crisis. Recently, Xu et al performed unilateral adrenalectomy in patients with PPNAD with remission of disease in 12/13 patients with mean follow-up of 3.9 yrs. Longer follow up is needed to determine if unilateral adrenalectomy is an acceptable treatment in PPNAD. Conclusion Diagnosing PPNAD and deciding appropriate time of surgery can be challenging. Unilateral adrenalectomy as a treatment modality needs to be further studied. References Correa et al. Carney Complex: An Update. Eur J Endocrinol 2015. Xu et al. The Role of Unilateral Adrenalectomy in Corticotropin-Independent Bilateral Adrenocortical Hyperplasias. World J Surg 2013.