Cushing's Syndrome Patients Research Articles

MON-182 Increased Risk of Bleeding and Excessive Anticoagulation Using Standard Dose Low Molecular Weight Heparin (LMWH) in Cushing’s Syndrome

Background: Cushing’s Syndrome (CS) is a hypercoagulable state with increased risk of venous thrombosis events (VTE) including pulmonary embolism (PE) and deep venous thrombosis (DVT). In the absence of clear recommendations (1), a standard dose of low molecular weight heparin (LMWH) is given: 1 mg/kg q12h (with dose reduction for CrCl < 30ml/min and low BMI). Here we report an excessive level of anticoagulation (based on standard LMWH anti-Xa levels) using standard dosing requirements in 8 of 11 patients with CS complicated by VTE who received treatment with Enoxaparin. Methods: We retrospectively studied 6 women and 5 men with active hypercortisolism and VTE (6 PE and 5 DVT) treated with Enoxaparin given at doses below every 12 hours. Self-declared race/ethnicity were 7 white (one Hispanic), 2 unknown, 1 Asian, and 1 African. Anticoagulation therapy was monitored 4 hours after administration with measurement of LMWH anti-Xa (therapeutic range: 0.5-1.2 IU/mL). Results: The (subsequent) etiology of CS was ectopic ACTH secretion in 6 patients (3 pulmonary NET, 3 occult) and Cushing’s disease in 5. Median age was 53 years (range 24 - 74); median BMI 34.7 kg/M2 (range 24.9 - 52.9). Median urine cortisol was 659 mcg/24h (range 122 - 32,444; nl reference range 3.5 - 45). All had CrCl > 60 ml/min. 6 patients were taking a CYP3A4 inhibitor (Ketoconazole: n=5 or Mifepristone: n=1). 6/7 patients who received an initial dose of 1 mg/kg had supratherapeutic anti-Xa levels, from 1.4 - 2 IU/ml; five were on a CYP3A4 inhibitor. One died from a massive retroperitoneal bleed leading to organ failure. The other five required dose reduction; the median dose at which anti-Xa levels were at goal was 0.56 mg/kg (range 0.36 - 0.87 mg/kg). The sixth patient had an initial anti-Xa level of 0.2 IU/ml, which normalized on a dose of 1.1 mg/kg.One patient started at 1.3 mg/kg exhibited an anti-Xa level of 1.7 IU/ml, with appropriate anti-Xa levels at a dose of 0.6 mg/kg. 3 patients started at reduced treatment doses (0.68, 0.78 and 0.87 mg/kg) exhibited therapeutic anti-Xa levels. In summary, therapeutic anti-Xa levels were achieved at a dose of approximately 1 mg/kg in only three patients (0.87, 0.96, 1.12 mg/kg); others required reduction of the usual recommended dose to between 0.36 and 0.78 mg/kg. CYP3A4 inhibitors were used in 5/8 patients with elevated anti-Xa levels. Conclusions: Patients with Cushing’s syndrome appear to require lower than standard dose of enoxaparin; which may be only partly explained by concomitant CYP3A4 inhibitors. We suggest that anti-Xa levels be more closely monitored in CS patients to avoid morbidity and mortality caused by PE or bleeding. Further studies are needed to determine if this risk is present in patients receiving supraphysiologic doses of exogenous glucocorticoids.1. Wagner J et al. Front Endocrinol (Lausanne). 9: 805, 2018

High likelihood for atrial fibrillation in Cushing's syndrome.

This review analyzes the prevalence of the most important comorbidities associated with atrial fibrillation (AF) in the growing population of patients with Cushing's syndrome (CS). The review is arranged in a way to list important risk factors for AF and the references, which suggest the significant prevalence of these particular risk factors in CS. The search is conducted on PubMed, Science Direct, Springer, Wiley, SAGE, Oxford Press, and Google Scholar. PubMed search for "Cushing's syndrome atrial fibrillation" on 8/7/2019 revealed 4 papers only. None of them either analyzed or implicated high risk for AF in CS. Arterial hypertension (AHT) can be found in approximately 80% of adult individuals with endogenous CS and in 20% of patients with exogenous CS. The reported prevalence of diabetes mellitus (DM) is from 13% to 47% in CS patients and the risk for de novo DM is approximately two-fold higher in individuals treated with glucocorticoids. High risk for myocardial infarction (MI) with hazard ratio (HR) 3.7 (95% confidence intervals, CI 2.4-5) in patients with endogenous CS was found. In CS patients the obesity can be detected in up to 41% and overweight in 21-48%. Left ventricular hypertrophy (LVH), pulmonary thromboembolism (PTE), infections, and hypokalemia are also more prevalent in CS as compared to healthy population. All cited comorbidities have been associated with AF. Therefore, clustering of the important factors associated with AF is confirmed repeatedly in CS. The prevalence of AF in CS should be studied more precisely, both in a scientific way and at the individual patient's level.

Selective LC-MRM/SIM-MS based profiling of adrenal steroids reveals metabolic signatures of 17α-hydroxylase deficiency

Adrenal steroids are generated in the adrenal cortex and metabolized by various enzymes such as hydroxylases, dehydrogenases, and reductases. Determining the comprehensive metabolic signatures of adrenal steroids can provide insight into their metabolic functions and roles in the pathophysiology of adrenal diseases, including Cushing’s syndrome (CS) and congenital adrenal hyperplasia (CAH). To this end, we developed an advanced quantitative profiling method of serum adrenal steroids with liquid chromatography-mass spectrometry (LC–MS) under molecular-specific scan modes. Twenty-seven steroids were separated on a 1.9-μm particle C18 column (50 × 2.1 mm) at a flow rate of 250 μL/min and quantified via triple-quadrupole MS with electrospray ionization. During validation, linearities ( r2) were higher than 0.940 with a limit of quantification of 0.1–5.0 ng/mL, and precision (coefficient of variation) and accuracy (%bias) of 3.7–14.3 % and 96.3–113.1 %, respectively. In contrast with the significantly increased serum levels of mineralocorticoids (P < 0.001), the present LC–MS assay revealed remarkably decreased levels of all glucocorticoids and androgens in a patient diagnosed with 17α-hydroxylase deficiency CAH (P < 0.001) compared to those of age- and sex-matched healthy and CS subjects. In the CAH patient, the metabolic ratios for 17α-hydroxylase were significantly decreased, whereas there was no reduction in the metabolic ratio of 17-hydroxyprogesterone to androstenedione, indicating 17,20-lyase activity. In particular, both pregnenolone and dehydroepiandrosterone sulfates, and their metabolic ratio, were identified as potential biomarkers for 17α-hydroxylase deficiency (all P < 0.001), which were also distinct from those of CS patients. The devised LC–MS assay clearly revealed the metabolic signatures of 17α-hydroxylase deficiency, as a rare phenotype of CAH, compared to both healthy and CS subjects, indicating its utility for screening adrenal diseases.

Thigh Muscle Fat Infiltration Is Associated With Impaired Physical Performance Despite Remission in Cushing's Syndrome.

Muscle weakness is common in patients with Cushing's syndrome (CS) and may persist after the resolution of hypercortisolism. Intramuscular fatty infiltration has been associated with the deterioration of muscle performance in several conditions. To quantify the degree of fatty infiltration in the thigh muscles of "cured" CS patients and evaluate the relationship between intramuscular fatty infiltration and physical performance. This was a cross-sectional study. Tertiary referral center. Thirty-six women with CS in remission, and 36 controls matched for age, BMI, menopausal status, and level of physical activity. We analyzed the percentage fat fraction (FF) of the thigh muscles in the anterior, posterior, and combined anterior and posterior compartments using MRI and 2-point Dixon sequence. We assessed muscle function and strength using the following tests: gait speed (GS), timed up and go (TUG), 30-second chair stand, and hand grip strength. Fat fraction in all the compartments analyzed was increased in patients as compared with controls. The performance on TUG, 30-second chair stand, and GS was more impaired in CS patients versus controls. In patients, greater FF was negatively associated with performance on functional tests. Fat fraction in the combined anterior and posterior compartments predicted performance on TUG (ß 0.626, P < 0.000) and GS (ß -0.461, P = 0.007), after adjusting for age, BMI, menopausal status, and muscle mass. Thigh muscle fatty infiltration is increased in "cured" CS patients and is associated with poorer muscle performance. Future studies are needed to establish therapeutic strategies to improve muscle weakness in these patients.

Neurocognitive Functions and Brain Volume in Patients with Endogenous Cushing's Syndrome Before and After Curative Surgery.

Introduction:Cushing's syndrome (CS) leads to various neuropsychiatric manifestations due to structural and functional changes of the brain and contributes significantly in the impairment of health-related quality of life.Aim and Objective:This study is conducted with aims to evaluate neurocognitive functions and brain volume in patients with endogenous Cushing's syndrome before and after curative surgery.Methods:The diagnosis of CS was made by clinical features, abnormal cortisol dynamics, ACTH levels, and imaging studies. Neuropsychiatric tests (Beck depression Index, Spatial span test, PGI memory scale, Color trail test, Verbal fluency test), and Brain volume (Bi-caudate and third ventricular diameter) were done before and after curative surgery.Results:Fifteen patients of CS were included for the study; all patients underwent curative surgery, neuropsychiatric assessment, and brain volume measurements. Nine patients were followed successfully till remission and repeat evaluation of these patients was done. Depression was the most common neuropsychiatric illness. Severity of depression positively correlated with 0800 h plasma cortisol and ACTH. Patients with higher severity of depression had maximum improvement after curative surgery. Significant decrease in the third ventricular, as well as bicaudate diameter, was observed after curative surgery (P < 0.01).Conclusion:Neuropsychiatric functions and structural brain changes reverse after curative surgery in patients with endogenous CS, however, long term follow-up is required to know whether these changes reverse completely or not.

Hypercoagulability in Cushing Syndrome, Prevalence of Thrombotic Events: A Large, Single-Center, Retrospective Study.

BackgroundThe risk of Cushing syndrome (CS) patients experiencing a thrombotic event (TE) is significantly higher (odds ratio; OR 18%) than that of the general population. However, there are currently no anticoagulation guidelines.MethodsA retrospective, single-center, longitudinal study of patients undergoing all types of treatment—surgical (pituitary, unilateral, and bilateral adrenalectomy) and medical treatment—was undertaken. TEs were recorded at any point up until last patient follow-up; myocardial infarction (MI), deep venous thrombosis (DVT), and pulmonary embolism (PE) or stroke. Patients’ doses and complications of anticoagulation were recorded.ResultsIncluded were 208 patients; a total of 165 (79.3%) were women, and mean age at presentation was 44 ± 14.7 years. Thirty-nine (18.2%) patients had a TE; extremity DVT (38%), cerebrovascular accident (27%), MI (21%), and PE (14%). Of 56 TEs, 27 (48%) were arterial and 29 (52%) were venous. Patients who underwent bilateral adrenalectomy (BLA) had an odds ratio of 3.74 (95% CI 1.69-8.27) of developing a TE. Of patients with TEs, 40.5% experienced the event within the first 60 days after surgery. Baseline 24-hour urinary free cortisol levels did not differ in patients with or without TE after BLA. Of 197 patients who underwent surgery, 50 (25.38%) received anticoagulation after surgery, with 2% having bleeding complications.ConclusionsThe risk of TEs in patients with CS was approximately 20%. Many patients had more than 1 event, with higher risk 30 to 60 days postoperatively. The optimal prophylactic anticoagulation duration is unknown, but most likely needs to continue up to 60 days postoperatively, particularly after BLA.

Remission of hypertension after surgical cure of Cushing's syndrome.

Hypertension associated with Cushing's syndrome (CS) increases cardiovascular risk. The time-course of improvement after cure is unclear. To describe the time-course and predictors of blood pressure (BP) normalization during one year after surgical cure of CS. Retrospective chart review of 75 hypertensive adults cured of CS (72 with ACTH-dependent CS; 3 with adrenal adenoma). Hypertension was defined as current use of antihypertensives, a systolic BP >130mmHg, or diastolic BP >80mmHg. Remission of hypertension: BP ≤130/80mmHg and no antihypertensive medications. Improvement in hypertension: BP >130/80mmHg and decreased number or dose of medications, or blood pressure ≤130/80 with continued use of medications at constant dose. At postoperative discharge, 17 (23%, P<.001), 51 (68%, P<.001) and 7 (9%) patients had remission, improvement in hypertension or no change. Twenty-nine had no follow-up. Others achieved remission at 3 (n=5), 6 (n=6), or 12-months (n=5). At the last evaluation, 33/75 (44%) had remission, 36/75 (48%) had improved hypertension and 6 were unchanged. Patients with improvement discontinued a median of one medication (P<.001). At 12-months, 27/42 (64%) patients had normal BP (P<.002). Longer estimated duration of CS (P=.0106), younger age (P=.0022), and lower baseline body mass index (P=.0413) predicted hypertension remission. About 80% of CS patients experienced BP normalization or improvement within 10days of cure, but about half failed to normalize BP by one year. BP should be monitored after cure, and antihypertensive medications adjusted to avoid unwanted cardiovascular effects.

New insights to the potential mechanisms driving coronary flow reserve impairment in Cushing's syndrome: A pilot noninvasive study by transthoracic Doppler echocardiography

BackgroundThe contribution of functional and/or structural remodeling to reduced coronary flow velocity reserve (CFVR), reflecting impaired coronary microcirculation in Cushing's syndrome (CS), has not been clearly elucidated. We aimed to identify the potential mechanisms of coronary microvascular impairment in CS. MethodsWe studied 15 CS patients (11 female, age 50 ± 9 years) without clinical evidence of cardiovascular disease. Coronary flow velocity in the left anterior descending coronary artery was measured by transthoracic Doppler echocardiography, at rest, and during adenosine infusion. Average peak flow velocities, CFVR, and microvascular resistance in baseline (BMR) and hyperemic conditions (HMR) were assessed. CFVR ≤2.5 was considered a marker of microvascular disease (CMD). Diastolic function (E/e′), global longitudinal strain (GLS) and fractional pulse pressure (fPP), an index of arterial stiffness, were also assessed. ResultsCMD was present in 5 patients (33.3%). CMD was primarily driven by increased baseline peak flow velocity (29 ± 12 versus 19.6 ± 4.2 cm/s, p = .03) in the presence of decreased BMR (3.62 ± 0.6 versus 5.46 ± 1.4 mm Hg·s/cm, p = .03). Moreover, urinary cortisol and E/e′ were higher (p = .001 and p = .001, respectively) and GLS was lower (p = .009) in patients with CMD. fPP was higher in patients with CMD (p = .01). Urinary cortisol correlated to CFVR (p = .008), E/e′ (p < .0001) and GLS (p < .0001). fPP directly correlated to average peak flow velocities at rest (p = .01) and inversely to BMR (p = .03). ConclusionsFunctional microvascular regulatory impairment seems to be the potential mechanism of CMD in CS. CMD seems to be related to decreased myocardial contractility and diastolic dysfunction associated with cortisol excess.

Glucocorticoid Receptor Polymorphisms Influence Muscle Strength in Cushing's Syndrome.

An important clinical feature of Cushing's syndrome (CS) is proximal muscle myopathy caused by glucocorticoid induced protein metabolism. However, interindividual differences cannot be explained solely by the pure extent of hypercortisolemia. To evaluate the effects of glucocorticoid receptor (GR) polymorphisms (BclI, N363S, ER22/23EK and A3669G), which influence peripheral glucocorticoid sensitivity on muscular function in endogenous CS. 205 patients with proven endogenous CS (128 central, 77 adrenal) from 3 centers of the German Cushing's Registry and 125 subjects, in whom CS was ruled out, were included. All subjects were assessed for grip strength (via hand grip dynamometer) and performed a chair-rising test (CRT). DNA samples were obtained from peripheral blood leukocytes for GR genotyping. In patients with active CS, normalized handgrip strength of the dominant and nondominant hand was higher in A3669G minor allele than in wildtype carriers (P = .006 and P = .021, respectively). CS patients in remission and ruled-out CS showed no differences in handgrip strength regarding A3669G minor allele and wildtype carriers. Male CS patients harboring the ER22/23EK wildtype presented lower hand grip strength than minor allele carriers (P = .049 dominant hand; P = .027 nondominant hand). The other polymorphisms did not influence handgrip strength. CRT showed no differences regarding GR polymorphisms carrier status. Handgrip strength seems to be more susceptible to hypercortisolism in A3669G wildtype than in A3669G minor allele carriers. This might partially explain the inter-individual differences of glucocorticoid-induced myopathy in patients with endogenous CS. ER22/23EK polymorphism seems to exert sex-specific differences.

High bone marrow fat in patients with Cushing’s syndrome and vertebral fractures

The evaluation of skeletal fragility in Cushing's syndrome (CS) is a clinical challenge, since dual-energy X-ray absorptiometry (DXA) does not capture abnormalities in bone microstructure induced by glucocorticoid excess. Hypercortisolism was shown to increase bone marrow adiposity, but it is still unknown whether high bone marrow fat (BMF) as measured by vertebral magnetic resonance spectroscopy may predict fracture risk in this clinical setting. In this cross-sectional study, we evaluated the association between BMF and vertebral fractures (VFs) in patients with CS. Twenty patients (5 M, age 44 ± 13 years) with active CS were evaluated for morphometric VFs, lumbar spine BMF, and bone mineral density (BMD). Fifteen healthy volunteers (4 M, age 43 ± 12 years) acted as control group for BMF evaluation. BMF was significantly higher in CS patients vs. controls (52.0% vs. 27.0%, p < 0.01), and was directly correlated with patients' age (p = 0.03), 24-hours urine-free cortisol (p = 0.03), midnight serum cortisol (p = 0.02), and serum CTX (p = 0.01). Patients with VFs (13 cases) showed significantly higher BMF vs. patients without VFs (65.0% vs. 24.0%, p = 0.03). Fractured patients with either normal BMD or osteopenia showed comparable BMF to fractured patients with either osteoporosis or low BMD for age (p = 0.71). When the analysis was restricted to patients with normal BMD or osteopenia, VFs were still significantly associated with higher BMF (p = 0.05). This study provides a first evidence that vertebral adiposity may be a marker of hypercortisolism-induced skeletal fragility and measurement of spine BMF could have a role in the diagnostic work-up for the assessment of fracture risk in CS.

A study of thyroid functions in patients with Cushing's syndrome: a single-center experience.

ObjectiveThe aim of this study was to evaluate thyroid functions in Cushing’s syndrome (CS), the dynamic changes of thyroid hormones and antithyroid antibodies in Cushing’s disease (CD) pre- and postoperatively.Design and methodsThis is a retrospective study enrolling 118 patients with CS (102 CD, 10 adrenal CS and 6 ectopic adrenocorticotropic syndrome (EAS)). Thyroid functions (thyroid-stimulation hormone (TSH), T3, free T3 (FT3), T4 and free T4 (FT4)) were measured in all CS at the time of diagnosis and in all CD 3 months after transsphenoidal pituitary tumor resection. Postoperative hormone monitoring within 3 months was conducted in 9 CD patients completing remission. Twenty-eight remitted CD patients experienced hormone and antithyroid antibody evaluation preoperatively and on the 3rd, 6th and 12th month after surgery.ResultsTSH, T3 and FT3 were below the reference range in 31%, 69% and 44% of the 118 CS patients. Remitted CD patients (81/102) had significantly higher TSH (P = 0.000), T3 (P = 0.000) and FT3 (P = 0.000) than those in the non-remission group (21/102). After remission of CD, TSH, T3 and FT3 showed a significant increase, with a few cases above the reference range. By 12 months, most CD patients’ thyroid functions returned to normal. Thyroid hormones (including TSH, T3 and FT3) were negatively associated with serum cortisol levels both before and after surgery. No significant changes of antithyroid autoantibodies were observed.ConclusionsTSH, T3 and FT3 are suppressed in endogenous hypercortisolemia. After remission of CD, TSH, T3 and FT3 increased significantly, even above the reference range, but returned to normal 1 year after surgery in most cases. Antithyroid antibodies did not change significantly after remission of CD.

The Pathophysiology and Treatment of Hypertension in Patients With Cushing's Syndrome.

When hypertension, a pathology that is frequently found in the general population, presents in a young patient, secondary causes such as Cushing's syndrome (CS), a rare disease characterized by long-term elevated cortisol levels, should be considered. Present in ~80% of CS patients independently of their age and sex, hypertension is one of the pathology's most prevalent, alarming features. Its severity is principally associated with the duration and intensity of elevated cortisol levels. Prompt diagnosis and rapid initiation of treatment are important for reducing/delaying the consequences of hypercortisolism. Glucocorticoid excess leads to hypertension via a variety of mechanisms including mineralocorticoid mimetic activity, alterations in peripheral and renovascular resistance, and vascular remodeling. As hypertension in CS patients is caused by cortisol excess, treating the underlying pathology generally contributes to reducing blood pressure (BP) levels, although hypertension tends to persist in approximately 30% of cured patients. Surgical removal of the pituitary tumor remains the first-line treatment for both adrenocorticotropin hormone (ACTH) dependent and independent forms of the syndrome. In light of the fact that surgery is not always successful in curing the underlying disease, it is essential that other treatments be considered and prescribed as needed. This article discusses the mechanisms involved in the pathogenesis of CS and the pros and the cons of the various antihypertensive agents that are presently available to treat these patients.

Results from the phase 3 multicenter SONICS study of levoketoconazole: subgroup analysis of Cushing's syndrome patients with diabetes mellitus

Results from the phase 3 multicenter SONICS study of levoketoconazole: subgroup analysis of Cushing's syndrome patients with diabetes mellitus

MON-LB074 Ultrasonography May Reliably Assess Muscle Architecture in Patients with Cushing's Syndrome in Remission: Comparison with Gold-Standard Muscle MRI

Myopathy is a frequent feature in patients with Cushing’s syndrome (CS), long-term after eucortisolism is achieved. Muscle magnetic resonance imaging (MRI) is the gold standard technique to assess muscle architecture but cannot be performed in daily clinical practice. Ultrasonography (US) may be a useful and cost-effective tool to evaluate muscle impairment in the clinical setting. Utility of US to evaluate the impairment of muscle structure in “cured” CS patients is not established. The aim of our study was to assess the correlation between US- and MRI-measured parameters of muscle architecture. We included 21 female patients [mean (±SD) age, 50±12 years; mean (±SD) BMI, 26.7±3.8] and 21 age- and BMI-matched healthy women. Mean (±SD) duration of remission was 132±87 months. We obtained transverse ultrasound images of the rectus femoris and assessed muscle intensity at both the midpoint (QmitR) and the distal third (QtercR), between the anterior inferior iliac spine and the proximal end of the patella. We scored muscle intensity using the Heckmatt’s rating scale and classified our findings as follows: 1-normal, 2-mildy increased muscle echoes with normal bone reflection, 3-moderately increased muscle echoes with reduced bone, 4-severely increased muscle echoes with absent bone reflection. We found that mean US intensity score of the rectus femoris at midpoint (QmitR) was increased in patients vs. the control group (p<0.001), suggesting more impaired architecture in the former, likely due to fibrosis/fatty infiltration. We also measured the degree of fatty infiltration of the thigh muscles using magnetic resonance imaging (MRI) and ultrashort multiecho T2-weighted and 3-point Dixon sequences in the anterior, posterior, and anterior+posterior muscle compartments. T2 signal intensity was classified as “high” (corresponding to fat), “medium” (muscle) or “low” (macromolecules-muscle). Of note, mean muscle fat fraction (%) in the posterior compartment, as determined by 3-point Dixon, was increased in patients vs. the control group (20±6% vs. 17±3%; p=0.018), indicating greater muscle fatty infiltration in the former. When US and MRI findings were compared, higher QtercR was associated with greater mean muscle fat fraction in the anterior (ρ=0.697, p=0.003), in posterior (ρ=0.600, p=0.014), and anterior+posterior compartment (ρ=0.702, p=0.002) in patients. QmitR was associated with greater mean muscle fat fraction in the anterior (ρ=0.510, p=0.043) and anterior+posterior compartment (ρ=0.500, p=0.049). No correlations were found between muscle US and MRI in controls. We conclude that US parameters of muscle architecture are correlated with muscle MRI measurements in “cured” CS patients. US may be a useful technique to identify, in a clinical setting, those CS patients showing residual myopathy. This work was supported by ISCIII FIS PI14/0194 and PI17/00749 and FEDER funds. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

SAT-459 Hypothalamic-Pituitary-Gonadal (HPG) and Hypothalamic-Pituitary-Thyroid (HPT) Axes in Cushing Syndrome (CS): A Retrospective Cohort Study

Background: It is well known that persistent hypercortisolemia suppresses thyroid and gonadal function. However, there are few data on the degree and type of derangement or the course of recovery of these axes after cure. To investigate this, we studied the pre- and post-surgical characteristics of the gonadal and thyroid axis hormones in CS patients (pts). Methods: We retrospectively reviewed records of 23 adult CS pts admitted to our protocols from 2010 - 2018 who received curative surgery with follow-up for 6 - 12 months (6M-12M). We recorded morning serum free T4 (fT4) and TSH, and morning LH, FSH, estradiol (E, premenopausal only) or testosterone (T, in men only) values before (0M), and 6M and 12M after definitive surgery. The rate of abnormal values was calculated at each timepoint. Data were analyzed using SPSS 23 software and are shown as percentage, mean ± SD or median(Interquartile Range). Results: Pt age was 45.6 ± 10.8 years; 21 (91%) were female. Before surgery fT4 (Nl: 0.9 - 1.7ng/dL) and TSH (Nl: 0.27 - 4.2mcIU/mL) were low normal. Subnormal values were seen for LH (13%), FSH (9.5%), E (14.2%, Nl: 15 - 350 pg/mL) and T (100%, n=2, Nl: 181-758ng/dL). fT4 increased from 0.96 ± 0.2 at 0M to 1.12 ± 0.13 at 12M (p=0.016), remaining in the lower half of the normal range. TSH increased significantly from 0M (0.98 ± 0.57) to 6M (2.8 ± 1.4) and 12M (2.9 ± 0.13) (p<0.0005 for both). In premenopausal women (n=14), there was a statistically significant (SS) change from 0M to 12M in both serum E (38.9 pg/mL (21.4 - 51) to 132.3 pg/mL (84.2 - 388), p=0.028) and LH levels (2.9 U/L (3.3 - 5.9) to 7.5 (3.6 - 13.6), nl(follicular phase): 1-12 U/L, p=0.019); the change in E, LH and FSH at 6M and in FSH at 12M was not SS. Menses were documented only in 8; resumption of normal cycles occurred 2 - 11 months after surgery. In postmenopausal females(n=7) there were no SS changes in LH or FSH from OM (LH: 21.4+11.1, nl: 11-40 U/L; FSH 54.3+30.5, nl: 22-153 U/L) to 6M or 12M. One man was taking T at 0M and one had a low T level at 0M (88.2 ng/dL) that normalized (357 ng/dL, nl: 181 - 758ng/dL ) at 6M.Conclusions: HPT and HPG axes improved after cure. While the HPT axis may start recovery at 6M, reflected by SS rise in TSH at 6M, HPG axis recovery was more homogeneous. Larger studies are needed to uncover the effects of hypercortisolemia on Hypothalamic-Pituitary-End organ axes and timelines of their recovery after treatment.

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.

SAT-357 Cotton Swab-Based Metabolic Signatures of Salivary Cortisol Measured by Liquid Chromatography-Mass Spectrometry

The comprehensive screening assay of salivary cortisol and its metabolic analogs is necessary to evaluate their pathophysiological functions in various adrenal diseases, such as Cushing’s Syndrome (CS). In contrast to the conventional method with Salivette®, the cotton swab may provides a point-of-care sampling for clinical screening as well as emergency management, and it also takes an advantage of sample preparation protocol. Sample preparation of salivary cortisol and its metabolic analogs was achieved by purification with solid-phase extraction after enzymatic hydrolysis with β-glucuronidase, and the sample was quantitatively measured by liquid chromatography-mass spectrometry (LC-MS) with selective MS scan modes and polarity swithcing. Due to uncertain sample volume in the cotton swab, the metabolic ratio of cortisol to cortisone, corresponding for 11β-HSD activity, may be an alternative marker in addition to individual salivary concentrations of cortisol and its analogs. The metabolic ratios of cortisol to cortisone in control group was higher than those of CS patients (1.93±4.09 vs. 0.66±1.08), while the increased ratios from 0.63±0.99 to 1.26±1.24 were obtained after surgery. The present swab-based LC-MS method may be appropriate for collecting saliva and the metabolic ratios of cortisol to its analogs could be the good screening tool for adrenal diseases.

MON-LB073 The Serum Creatinine to Serum Cystatin C Ratio Is a Reliable Surrogate Marker of Sarcopenia in Patients with Cushing's Syndrome in Remission

Sarcopenia, the loss of skeletal muscle mass and function, is a frequent finding in patients chronically exposed to glucocorticoids. Patients with active Cushing’s syndrome (CS) show reduced muscle mass and weakness. Decreased MRI-measured lean mass has been found in CS after 20 months since successful therapy vs. pre-treatment. Persistence and worsening of muscle strength has been described in CS despite long-term remission, suggesting that previous exposure to excessive cortisol may have induced irreversible alterations of muscle structure and function. Low muscle mass can be detected using several techniques, including dual-energy X-ray absorptiometry (DXA), ultrasonography (US), magnetic resonance imaging (MRI) and computed tomography (CT), while low muscle strength and performance can be diagnosed through functional testing. The Sarcopenia Index (SI),-(serum creatinine value [mg/dl]/serum cystatin C value[mg/L]) × 100, has been proposed as a potential, reliable surrogate marker of low muscle mass and function. Clinical usefulness of this parameter in CS is currently unknown. The aim of our study was to establish the correlation between SI and the techniques commonly used to evaluate muscle mass, including DXA, US, MRI, as well as tests of muscle function including gait speed velocity (GS), timed up and go (TUG), 30-second chair stand and hand grip strength (HGS). We studied 30 CS women [mean(±SD) age, 50±12 years; mean(±SD) BMI, 26.7±3.8] and 30 age- and BMI-matched healthy women. We studied whole-body composition by DXA, and calculated the Skeletal Muscle Index (SMI), defined as the ratio of the DXA-measured appendicular skeletal muscle mass (ASM) [Kg] and the height squared [m2]. We evaluated US muscle thickness using transverse images of rectus femoris and vastus intermedious at the midpoint and at the distal third. We measured the volume of lean mass (DxLean; ml) of the thigh muscles using MRI, 3-point Dixon sequences. SI was associated with both US-measured section of the distal third of the right rectus femoris (ρ=0.47, p=0.008), and the DxLean (ρ=-0.46, p=0.011) in patients. We found no correlations between SI and either SMI or DXA-measured lean mass (gr) (p=n.s.). SI was negatively associated with both total body fat mass (gr) (ρ=-0.45, p=0.010) and trunk fat mass (gr) (ρ=0.065 p<0.001). SI was related to GS (ρ=0.416, p=0.022), TUG (ρ=-0.544, p=0.002), 30-sec chair stand (ρ=-0.518, p=0.003) and right HGS (ρ=0.387, p=0.035) in patients. When SI, DxLean, US-measured section of the distal third of the right rectus femoris, age and BMI were entered in a multiple regression model, SI was an independent predictor of right HGS (ß 0.27, p=0.033. SI may be a helpful surrogate marker to identify those CS patients who are more likely to show low muscle mass and strenght after remission. This work was supported by ISCIII (FIS PI14/0194 and PI17/00749), FEDER funds Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Performance of LC–MS/MS and immunoassay based 24-h urine free cortisol in the diagnosis of Cushing's syndrome

24-h urine free cortisol (UFC) is an indicator of integrated cortisol secretion and established screening tool for Cushing’s syndrome (CS). Doubts have been raised regarding specificity of immunoassays, and mass spectrometric techniques have been proposed as an alternative. In the present study we compared diagnostic accuracy of UFC measured with LC–MS/MS vs. immunoassay in patient with CS and patients where CS has been excluded. We examined 24-h urine samples from patients with surgically confirmed CS (n = 77; Cushing’s disease (n = 44), ectopic CS (n = 5), adrenal CS (n = 28)) and patients in whom Cushing’s syndrome was excluded (n = 97) by long-term follow up. UFC was first measured by automated chemiluminescence immunoassays (ADVIA Centaur, Siemens; LIAISON, DiaSorin). Aliquots of all samples were also analyzed by liquid chromatography-tandem mass spectrometry (LC–MS/MS). Statistics: Passing-Bablok Regression, Receiver operating characteristic (ROC) analysis with Youden’s index calculation. UFC of CS patients were higher with both immunoassays compared to LC–MS/MS (913 +/- 235 vs. 303 +/- 155 μg/24 h (ADVIA) and 898 +/-216 vs. 399 +/- 196 μg/24 h (LIAISON)). Similarly, UFC were higher with immunoassays than with LC–MS/MS in the control group (223 +/- 10 vs. 23 +/- 2 μg/24 h (ADVIA) and 105 +/- 6 vs. 27 +/- 4 ug/24 h for (LIAISON)). Passing-Bablok regression showed good correlation between LC–MS/MS and ADVIA as well as between LCMS/MS and LIAISON (r = 0.96 and r = 0.99, p < 000.1) but less correlation in controls (r = 0.83 and r = 0.74, respectively, p < 000.1). ROC calculation revealed the highest ROC AUC (0.89) for the LIAISON immunoassay, followed by LC–MS/MS (0.82) and the ADVIA (0.80). In direct comparison, AUCs from LC–MS/MS and immunoassays in the same patient were not statistically different (p < 0,001). Best cut-off concentration to identify patients with CS was 234 μg/24 h (LIAISON), 51 μg/24 h for LC–MS/MS and 330 μg/24 h (ADVIA Centaur).In summary, UFC values were measured substantially higher by both immunoassays compared to LC–MS/MS. This is most likely due to cross-reactivity from interfering glucocorticoid metabolites. Nevertheless, all three methods correlated well. ROC analysis revealed the highest AUC for one of the immunoassays, although differences between the three methods were not significant. Direct comparison with LC–MS/MS indicates that high diagnostic accuracy can be obtained with suitable immunoassays.

Screening subclinical Cushing syndrome in patients with obesity and glucose metabolism impairment

Screening subclinical Cushing syndrome in patients with obesity and glucose metabolism impairment