Cortisol Hypersecretion Research Articles

MILD CORTISOL HYPERPRODUCTION IS ASSOCIATED WITH IMPAIRED GLUCOSE HOMEOSTASIS AND INSULIN-RESISTANCE IN NON-DIABETIC ESSENTIAL HYPERTENSIVE PATIENTS

Objective: Patients with Cushing syndrome (CS) and subclinical Cushing syndrome (SCS) have higher risk of cardiovascular events than the general population. Excess cortisol secretion might reduce insulin secretion, insulin sensitivity, glucose uptake, and increase gluconeogenesis. Data on cortisol secretion in patients with essential hypertension and on its relationships with glucose homeostasis are scanty. The aim of the study was to evaluate cortisol secretion and its relationship with glucose homeostasis and insulin-sensitivity in essential hypertensive (EH) patients. Design and method: In 155 EH patients (age 43 ± 13 years, 81 men) we measured fasting glucose and insulin, HOMA index, plasma cortisol levels at 8 AM, 5 PM and 11 PM, and after an overnight suppression test (DST) with 1 mg of dexamethasone, 24-h free urinary cortisol, and ACTH, and performed a standard oral glucose tolerance test (OGTT), calculating the area under the curve for glucose (G-AUC) and insulin (I-AUC). Results: Fasting glucose was positively related to 11 PM cortisol level (r = 0.221, P = 0.019) and post-DST cortisol levels (r = 0.244, P = 0.002). Post-DST cortisol level was positively related with fasting insulin (r = 0.264, P = 0.001), HOMA (r = 0.273, P = 0.001) and I-AUC (r = 0.185, P = 0.023). G-AUC was positively related to 11 PM cortisol (r = 0.246, P = 0.008) and post-DST cortisol levels (r = 0.216, P = 0.007). These associations were independent of age, body mass index, alcohol intake, physical activity, plasma potassium and ACTH levels. Conclusions: In non-diabetic patients with EH, relative cortisol hypersecretion is independently associated with impaired glucose homeostasis and insulin resistance.

The Importance of Dietary Fiber on Stress Hormone in Pregnancy: A Literature Review

Antepartum depression is a mental health issue that is frequently ignored and often leads to suicidal behaviours. The harmful effects of antepartum depression are not only experienced by mothers, but also by children in the future. Depression due to pregnancy is usually attributed to several causes, including the biological component. Biological shifts that arise during gestation interrupt the maternal stress protection mechanism, one of which is the dysregulation of the hypothalamus-pituitary-adrenal axis (HPA-axis) resulting in hypersecretion of cortisol. Excessive release of cortisol as a stress hormone has been correlated with depressive symptoms, particularly throughout pregnancy. Recently, dietary factors, in particular dietary fiber, have become of concern as component that is recognized to attenuate stress hormones. The dietary fiber that is ingested will be digested by intestinal bacteria and will produce short-chain fatty acids as the essential metabolites. These metabolites are known to play a role in various brain functions, including HPA-axis through various means. The objective of this research is aimed at determining the function of dietary fiber within cortisol as a biomarker of the central stress response system, particularly throughout pregnancy.

Application of stereotactic radiosurgery and radiotherapy in the treatment of Itsenko — Cushing’s disease

Cushing’s disease is caused by a pituitary tumor which causes increased production of adrenocorticotropic hormone, leading to chronic hypersecretion of cortisol by the adrenal cortices. Endoscopic transnasal adenomectomy is the initial treatment of choice with the greatest efficiency for the treatment of the disease. However in the absence of remission or relapse of hypercortisolism after neurosurgical surgery, as well as in cases when surgical intervention cannot be carried due to medical contraindications to surgical intervention, radiation treatment is used as an alternative or adjoining therapy. In this literature review the efficiency of different radiation techniques (the conventional and the modern techniques), as well as possible complications of modern methods of radiosurgery and radiotherapy have been looked for.

SUN-158 Testosterone and Cortisol Secreting Large Adreno- Cortical Adenoma

Background: Functional adrenal adenomas most commonly secrete cortisol or aldosterone. Secretion of multiple hormones is commonly seen in adrenocortical carcinomas and is rare in benign adrenal adenomas. We present a case of a patient with a 6 cm benign adrenal adenoma that was secreting both cortisol and testosterone.Clinical case: A 44-year-old Caucasian female with past medical history of Grave’s disease, hypertension, prediabetes and hyperlipidemia presented with hirsutism and weight gain. Physical exam was suggestive of cushing’s disease with elevated blood pressure, hirsutism, supraclavicular fullness, moon facies, facial plethora, dorsocervical fat pad and abdominal striae. Further workup revealed elevated testosterone level of 152ng/dL (9-55ng/dl) and elevated androstenedione level of 2.520ng/ml (0.130–0.820 ng/ml). DHEA 0.741 ng/ml (0.630–4.7ng/ml) and DHEAS 65ug/dl (32-240ug/dl) were both within reference range. The 24-hour urine free cortisol was also elevated at 107.1ug/gram of creatinine (< 24 ug/gram of creatinine) with an undetectable ACTH level of < 5 pg/ml indicating adrenal source of Cushing’s syndrome. CT abdomen and pelvis with and without contrast revealed a 6.3 x 5.2 x 5.6 cm left adrenal mass which measured 22 Hounsfield units (HU) on non-contrast imaging, 85 HU on 70 second imaging and 48 HU on 15 min delayed phase. Calculated percent relative washout was 43.5 % and absolute washout was 59.4 %. There was another 1.1 cm low density nodule on left adrenal genu. The right adrenal gland also had a 1.2 cm low density nodule with 0 HU on all phases compatible with a lipid rich adenoma. Patient then underwent left open adrenalectomy. Pathology revealed a 6 cm adrenocortical adenoma. There was no tumor invasion into adjacent sites, no vascular invasion or tumor necrosis noted. MIB1 index was <1 %. Patient had resolution of hypertension and prediabetes after the surgery. Her cortisol and androgen levels also normalized. Biochemical follow up 6 months post-surgery has not demonstrated any increase in cortisol or androgen levels.Conclusion: Both androgen and cortisol hypersecretion can cause severe hyperandrogenism and virilization but these hormones are commonly secreted in isolation in functional adrenal adenomas. Adrenal masses co-secreting androgen and cortisol are usually indicative of adrenocortical cancer. In this rare case report, both of these hormones were secreted by a unilateral adrenal adenoma, with resolution of symptoms and normalizing of androgen and cortisol levels post left adrenalectomy.

SAT-197 Unilateral Adrenalectomy Can Induce Control in ARMC5 Mutations Patients

Primary macronodular hyperplasia (PMAH) is a rare cause of endogenous Cushing’s syndrome characterized by functioning adrenal macronodules and variable cortisol secretion. ARMC5 is the most frequent gene responsible for PMAH. Genetic mutations including inactivating germline mutations in armadillo repeat-containing 5 (ARMC5) gene have been identified. The occurrence of several other non adrenal tumors (meningioma, breast, colon, thyroid and parathyroid) has also been associated with PBMAH, suggesting a possible role of ARMC5 for the development of other neoplasias. The best treatment to this condition is not established. Clinical case: 64-year-old man, referred due to bilateral adrenal incidentalomas on a CT scan with characteristics of adenoma/hyperplasia. He had type-2 diabetes, hypertension and dyslipidemia for about 4 years. He was being treated with 4 different anti-hypertensive medications, gliclazide and simvastatin. Physical examination revealed thin and dry skin, obesity with centripetal fat distribution, multiple ecchymosis and facial erythrosis. He had a son and a daughter. No known familial relevant diseases. His laboratory workup revealed ACTH-independent hypercortisolism: failure to suppress on the overnight dexametasone suppression test - cortisol 27.6ug/dL- and on the low-dose dexamethasone test- cortisol 24ug/dL- associated to morning ACTH <1ng/L. He underwent stimulation tests with tetracosactide, LHRH, TRH, vasopressin, metoclopramide, glucagon anddeambulation test, which were overall negative. It was decided to proceed to bilateral adrenalectomy. Due to surgical complications, only right adenalectomy was performed. Histology revealed adrenal nodular hyperplasia. Molecular study in DNA extracted from peripheral blood leucocyte and in the adrenal gland revealed the presence in heterozygosity of the pathogenic mutation c.1379T>C in the ARMC5 gene. The patient underwent a cerebral CT scan which showed a meningioma in the posterior left temporal convexity. Genetic testing was also performed on the daughter and son of the patient, which revealed the same mutation. They were also tested for hypercortisolism and underwent adrenal and cerebral CT scan, which showed no abnormality. The adrenal CT scan of the daughter showed enlargement of the left adrenal gland, with aspects suggestive of nodular hyperplasia. Her blood tests revealed no sign of hypercortisolism - overnight dexametasone test- cortisol 1.0 ug/dL, morning ACTH 19.1 ng/L. The patient is currently with cortisol hypersecretion controlled. Conclusion: All patients with PMAH should be tested for ARMC5 mutations and if they are found, family screening is mandatory in this autosomal dominant disorder. Unilateral adrenalectomy could control the cortisol hypersecretion, however some of these patients can have subclinical Cushing Syndrome.

MON-LB035 Adrenal Venous Sampling in the Lateralization of Acth-Independent Cushing Syndrome With Bilateral Adrenal Masses: A Case With a 5-Year Follow-Up

Background Nearly 25% of adrenal Cushing syndrome (CS) patients with bilateral adrenal masses have unilateral hypercortisolism, making localization crucial for surgical planning. Since there is no standardized protocol for adrenal venous sampling (AVS) in lateralizing adrenal hypercortisolism, we share our experience with a case of CS with bilateral adrenal masses in which lateralization via AVS permitted unilateral adrenalectomy. Clinical Case A 59-year-old woman with hypertension, hyperlipidemia, and prediabetes was hospitalized for worsening back pain and hypertension. Her BMI was 26.5 kg/m2, BP 173/93 mmHg, HR 73/min, she was anxious, diaphoretic, and hirsute. Glucose was 118 mg/dL and HbA1c 6.6%. Abdominal computed tomography revealed a type B aortic dissection with both right (6.1 x 3.1cm and 3.6 x 2.4cm), and left (largest 1.7 cm) sided adrenal masses. Plasma and 24 hour-urine metanephrine, normetanephrine and catecholamines, as well as plasma renin and aldosterone levels, were normal. AM cortisol on three different occasions was 21.30, 20.70, and 21.30 mcg/dL. Midnight cortisol was 17.8 mcg/dL, and 24-hour urine free cortisol on two occasions was 163 mcg (urine volume 3.4L with creatinine 1.14) and 99.2 mcg (urine volume 1.15L). After 1mg dexamethasone her AM ACTH and cortisol were <5 and 18.70 mcg/dL, respectively. Preoperative AVS was performed and 8mg of dexamethasone was administered the night prior to ensure ACTH suppression during the procedure, and epinephrine was measured to ascertain adequate adrenal vein cannulation. Cortisol levels (in mcg/dL) from the common iliac, right and left adrenal veins were 14.7, 61.5, and 23.5 at 0 minute and 15.2, 61.0, and 22.7 at 2 minutes, respectively. Epinephrine levels (in pg/dL) from the common iliac, right and left adrenal veins were 42, 577, and 3225 at 0 minutes, and 46, 718, and 2989 at 2 minutes. Despite higher epinephrine levels from the left adrenal, the cortisol ratio of the right adrenal vein to peripheral vein was 4.18 with the right-to-left ratio of 2.59 and 2.68 at 0 and 2 minutes, suggesting hypersecretion of cortisol from the right adrenal gland. Unilateral right adrenalectomy revealed a 5.6 cm adrenal adenoma arising in a background of adrenal cortical hyperplasia. Morning postoperative cortisol was 2.2 mcg/dL. She was placed on hydrocortisone and tapered over a 10-month period with remission maintained for more than 3.5 years post-operatively. Conclusion This case demonstrates the safety, usefulness, and necessity, of AVS in localizing cortisol production when bilateral adrenal masses are present. In addition, this case suggests that the use of high dose dexamethasone and measurement of catecholamines may be helpful for more accurate interpretation. More data on AVS in CS patients with bilateral adrenal masses is needed so a well-validated and standardized CS-specific ACS protocol can be developed.

SAT-310 Analysis of the Influence of Glucocorticoid Receptor Gene Polymorphism BCL-1 on Clinical and Psychiatric Manifestations in Brazilian Patients with Cushing’s Disease

In Cushing’s disease (CD), the spectrum of clinical manifestations is considerably wide, and the intensity of symptoms does not correlate with the magnitude of cortisol hypersecretion or with pituitary tumor size. Polymorphisms in the gene that encodes the glucocorticoid receptor (GR), an essential regulator of the hypothalamic-pituitary-adrenal axis, have been linked to some psychiatric disorders. Considering that psychiatric manifestations are present in nearly all patients with hypercortisolism, we hypothesized a possible correlation of polymorphisms in the GR gene and clinical and psychiatric manifestations, in CD. To investigate the frequency and clinical implications of the GR gene polymorphism Bcl-1 in patients with CD, we conducted a cross-sectional, case-controlled study. Fifty-three Brazilian patients with CD aged between 12 and 75 years and one hundred healthy controls aged between 42 and 67 years, of both genders, who provided written informed consent, were enrolled. Blood samples were collected from patients for DNA extraction and sequencing for analysis of the GR gene polymorphism Bcl-1. Clinical data (obesity, skin lesions, muscle weakness, hypertension, diabetes, hypokalemia, and sex-related disorders) were obtained through retrospective analysis of medical records, appointment with endocrinologist and with psychiatrist. Mini International Neuropsychiatric Interview, scales self-applicable of anxiety and depression were used to address psychiatric conditions. From the 53 patients studied, 48 were women (90,56%), and 16 patients had macroadenoma (2 of them had tumors larger than 4 cm). Overall frequencies of the Minor Allele for Bcl-1 polymorphism, which corresponds to the risk allele for psychiatric illness in the normal population, did not significantly differ between CD patients (67.92%) and controls (74.00%). Similarly, differences in Minor Allele Frequencies among subgroups of patients presenting with psychiatric and clinical manifestations of CD were not statistically significant. Although data from the literature strongly suggests a correlation between Bcl-1 polymorphism with psychiatric disorders (especially depression) in the normal population, this association was not observed in our cohort of patients with CD. More studies are needed to better clarify a possible role for GR gene polymorphisms as modifiers of the spectrum of psychiatric and clinical manifestations of CD.

SUN-169 A Rare Case of Adrenocortical Carcinoma Presenting as Hyperaldosteronism Combined with Cushing’s Syndrome

Introduction: Adrenocortical carcinoma (ACC) is a rare malignancy with poor prognosis. Most ACC cases are hormonally functional. Commonly produced hormones are cortisol, followed by adrenal androgens. Aldosterone secretion is quite rare (< 2%) (1). Co-secretion of multiple hormones is further rare. Case Presentation: A 59 year old female presented with progressive worsening hypertension. Initial biochemical evaluation confirmed primary hyperaldosteronism. Her potassium was low at 2.9 mEq/L (N: 3.5-5.3 meq/L). Aldosterone level was elevated at 23 ng/dL (N: < or = 28 ng/mL), renin value was 0.90 ng/mL/h (N: 0.25-5.82 ng/mL/h). Aldosterone Renin Ratio was 25. CT abdomen with and without contrast showed 2 lesions within the right adrenal gland. The larger nodule was 3.7 x 2.7 x 4.9 cm with an absolute washout of 61%. A smaller nodule was 2.3x1.8 cm with an absolute washout of approximately 64%. Left adrenal gland was unremarkable.Further biochemical workup showed plasma catecholamines and metanephrines were normal. A random cortisol value was 22.8 mcg/dL (N: 3.0-16.0 mcg/dL) with a low ACTH level of 3.3 pg/mL (N: 7.2 - 63.3 pg/mL). Given suspicion for adrenal Cushing’s syndrome, we further obtained a 24 hour free urinary cortisol which was elevated at 84.1 mcg/24 h (N: 4-50 mcg/24 h). 8 am Cortisol after an overnight 1 mg Dexamethasone failed to suppress at 17.5 mcg/dL (n<1.8 mcg/dL). DHEAS level was low at 14.1 ug/dL (N: 29.4-220.5 ug/dL). The patient eventually underwent a right adrenalectomy. Post-operatively, her cortisol was suppressed at 1.9 mcg/dL (8 am ref range: 4-22 mcg/dL), and Hydrocortisone replacement dose was initiated. Surgical pathology report was consistent with adrenocortical carcinoma. The patient continues to follow-up with the endocrinology and oncology department for treatment. Conclusion: This case is particularly interesting given the co-secretion of both aldosterone and cortisol by an adrenocortical carcinoma which has been reported in only a few cases in literature. The case highlights the importance of completing a comprehensive biochemical workup pre-operatively in patients with suspicious adrenal mass. There should especially be a low threshold for initiating workup for cortisol hypersecretion as early intervention can help avoid an adrenal crisis in the post-operative period for such patients. A low DHEAS level should raise suspicion for cortisol hypersecretion in a patient with adrenal lesions. As ACTH is the primary stimulant of DHEA, the suppression of ACTH secretion in the setting of adrenal Cushing’s syndrome can contribute to a low DHEAS level. Reference 1.Else, T et al. Adrenocortical Carcinoma. Endocr Rev. 2014; 35(2):282-326.

Estrogen receptor α plays an important role in Cushing’s syndrome during pregnancy

Cushing’s syndrome (CS) during pregnancy is very rare with a few cases reported in the literature. Of great interest, some cases of CS during pregnancy spontaneously resolve after delivery. Most studies suggest that aberrant luteinizing hormone (LH)/human chorionic gonadotropin (hCG) receptor (LHCGR) seems to play a critical role in the pathogenesis of CS during pregnancy. However, not all women during pregnancy are observed cortisol hypersecretion. Moreover, some cases of adrenal tumors or macronodular hyperplasia with LHCGR expressed, have no response to hCG or LH. Therefore, alternative pathogenic mechanisms are indicated. It has been recently reported that estrogen binding to estrogen receptor α (ERα) could enhance the adrenocortical adenocarcinoma (ACC) cell proliferation. Herein, we hypothesize that ERα is probably involved in CS development during pregnancy. Better understanding of the possible mechanism of ERα on cortisol production and adrenocortical tumorigenesis will contribute to the diagnosis and treatment of CS during pregnancy.

Modern Methods of Stereotactic Radiosurgery and Radiotherapy for the Treatment of Cushing Disease.

Cushing's disease is caused by a pituitary tumor causing increased production of adrenocorticotropic hormone, which leads to chronic hypersecretion of cortisol through adrenal cortices. Endoscopic trans-sphenoidal adenomectomy is the first choice of treatment with greatest efficiency for the treatment of the disease. However, in the absence of remission or recurrence of hypercortisolism after neurosurgical resection (adenomectomy), as well as in cases when surgical intervention cannot be carried due to medical contraindications to surgical intervention, radiation treatment is used as an alternative or adjoining therapy. In this literature review the efficiency of different radiation techniques (the conventional and the modern techniques), as well as possible complications of modern methods of radiosurgery and radiotherapy have been looked for.

Obesity and stress: endocrine and social aspects of the problem in the modern Russian society

The purpose of the article is to consider stress as one of the etiological factors of obesity and metabolic syndrome. The review discusses both endocrine and social aspects of stress as a syndrome of adaptation to the current situation in Russian society. It is emphasized that lifestyle factors contributing to the growth of overweight are gaining popularity in the society, and the high incidence of obesity is directly related to the level, quality and lifestyle of a modern man. Constant nervous tension, negative emotions, fear in conditions of abundance of food directly contributes to obesity, which is associated with a large number of other serious diseases. Chronic hyperactivation of the hypothalamic-pituitary-adrenal axis and chronic hypersecretion of cortisol, if persistence is not a purely physiological condition. Endocrine mechanisms mediating the development of metabolic disorders on the background of chronic stress include activation of the hypothalamic-pituitary-adrenal system, changes in eating behavior, hyper-production of glucagon and triglyceride accumulation in visceral fat depots. Processes and social changes occurring in modern society contribute to the construction of everyday socio-cultural environment characterized by increased stress. Chronic stress in combination with physical inactivity, the result of improper lifestyle of modern people, becomes an effective factor contributing to the spread among the population of Russia not only overweight, but also various forms of obesity. It is emphasized that at the state level there is an urgent need to adopt and implement effective programs and mechanisms to ensure the population meets modern requirements and environmental standards of healthy food, rationalization of food distribution among the population, the formation of a culture of food consumption, improving the quality of life of the population and the culture of a healthy lifestyle, teaching the population the correct stress-coping behavior.

Cortisol, Amyloid-β, and Reserve Predicts Alzheimer's Disease Progression for Cognitively Normal Older Adults.

Elevated cortisol as a measure of hypothalamic-pituitary-adrenal-axis hyperactivity has emerged as a predictor of clinical progression of Alzheimer's disease (AD), in conjunction with amyloid-β (Aβ) abnormalities. Yet factors exist which have the propensity to delay AD symptomatic expression in the face of an AD-type biomarker-based pathological profile. This study sought to determine whether abnormal cerebrospinal fluid (CSF) Aβ and elevated cortisol levels are associated with clinical transition to mild cognitive impairment (MCI) and AD in cognitively normal (CN) individuals, and if this association is modified by reserve proxies. Data from 91 CN individuals participating in the Alzheimer's Disease Neuroimaging Initiative (ADNI) with available morning CSF cortisol and Aβ42 were evaluated. Reserve was modelled as a latent composite score of standardized intracranial volume and lifetime experience proxies. Cox regressions were used to test associations between baseline CSF cortisol/Aβ42, reserve score and AD progression; adjusting for age, sex, apolipoprotein E genotype, and depressive symptoms. Individuals with elevated cortisol + abnormal Aβ42 levels at baseline showed highest risk of clinical progression. After a median of 84 months follow-up, significant cortisol/Aβ/ reserve interaction for clinical progression was noted (adjusted HR = 0.15, p < 0.001), suggesting a moderating effect of reserve on the association between cortisol/Aβ+ and clinical progression. Our findings indicate that cortisol hypersecretion accelerates clinical progression in CN individuals presenting with pathological Aβ42. High reserve reduces the associated AD progression risk in these high-risk individuals.

ARMC5 Alterations in Primary Macronodular Adrenal Hyperplasia (PMAH) and the Clinical State of Variant Carriers.

ContextPrimary macronodular adrenal hyperplasia (PMAH) is a rare type of Cushing or subclinical Cushing syndrome and is associated with bilateral multinodular formation. ARMC5 is one of the responsible genes for PMAH.ObjectivesThis study was performed to identify the genotype-phenotype correlation of ARMC5 in a cohort of Japanese patients.Patients and MethodsFourteen patients with clinically diagnosed PMAH and family members of selected patients were studied for ARMC5 gene alteration and clinical phenotype. The associated nonadrenal tumor tissues were also studied.ResultsOf fourteen patients with PMAH, 10 had pathogenic or likely pathogenic variants of ARMC5. We found two variants. Five unrelated patients had identical variants (p.R619*). In two patients, the variant was found in offspring with the asymptomatic or presymptomatic state. Six of ten patients who tested positive for the ARMC5 pathogenic or likely pathogenic variant carried nonadrenal tumors; however, no loss of heterozygosity (LOH) or second hit of the ARMC5 gene was evident. The ARMC5 variant–positive group showed a significantly higher basal cortisol level. Furthermore, age-dependent cortisol hypersecretion was seen in the ARMC5 variant–positive group.Conclusions ARMC5 pathogenic variants are common (71%) in Japanese patients with PMAH. p.R619* might be a hot spot in Japanese patients with PMAH. Asymptomatic or presymptomatic pathogenic variant carriers were found among the family members of the patients. Although 50% of ARMC5 variant carriers had nonadrenal neoplastic lesions, no LOH or second hit of ARMC5 in the tumor tissues was evident. The ARMC5 variant–positive mutant group showed a higher basal cortisol level than the negative group.

Improvement in cognitive impairment following the successful treatment of endogenous Cushing\u2019s syndrome-a case report and literature review

BackgroundEndogenous Cushing’s syndrome, a rare endocrine disorder, characterised by chronic cortisol hypersecretion, results in neuropsychiatric disturbances and in cognitive deficits, which are only partially reversible after the biochemical remission of the disease.Case presentationWe report a case of a woman with a profound cognitive deficit and a gradual functional decline caused by Cushing’s disease of at least 10 years duration. The neurosurgical resection of her 2 mm adrenocorticotropic hormone (ACTH) secreting pituitary microadenoma resulted in a successful resolution of the patient’s hypercortisolism and a significant recovery of her neurocognitive function. The patient’s progress was evaluated using serial clinical observations, functional assessments, Mini-Mental Status exams and through the formal neuropsychological report. Furthermore, the patient’s recovery of her neurocognitive function was reflected by a sustained improvement in the patient’s specific structural brain abnormalities on radiological imaging.ConclusionsThis report illustrates the importance of early detection and treatment of Cushing’s syndrome in order to prevent neurocognitive impairment and neuropsychiatric disorders which are associated with an endogenous cortisol hypersecretion. The long term adverse effects of severe hypercortisolaemia on brain function and the pathophysiological mechanisms responsible for the structural and functional changes in brain anatomy due to glucocorticoid excess are reviewed.

Hypercortisolism and primary aldosteronism caused by bilateral adrenocortical adenomas: a case report

BackgroundCo-existing Cushing’s syndrome and primary aldosteronism caused by bilateral adrenocortical adenomas, secreting cortisol and aldosterone, respectively, have rarely been reported. Precise diagnosis and management of this disorder constitute a challenge to clinicians due to its atypical clinical manifestations and laboratory findings.Case presentationWe here report a Chinese male patient with co-existing Cushing’s syndrome and primary aldosteronism caused by bilateral adrenocortical adenomas, who complained of intermittent muscle weakness for over 3 years. Computed tomography scans revealed bilateral adrenal masses. Undetectable ACTH and unsuppressed cortisol levels by dexamethasone suggested ACTH-independent Cushing’s syndrome. Elevated aldosterone to renin ratio and unsuppressed plasma aldosterone concentration after saline infusion test suggested primary aldosteronism. Adrenal venous sampling adjusted by plasma epinephrine revealed hypersecretion of cortisol from the left adrenal mass and of aldosterone from the right one. A sequential bilateral laparoscopic adrenalectomy was performed. The cortisol level was normalized after partial left adrenalectomy and the aldosterone level was normalized after subsequent partial right adrenalectomy. Histopathological evaluation of the resected surgical specimens, including immunohistochemical staining for steroidogenic enzymes, revealed a left cortisol-producing adenoma and a right aldosterone-producing adenoma. The patient’s symptoms and laboratory findings resolved after sequential adrenalectomy without any pharmacological treatment.ConclusionsAdrenal venous sampling is essential in diagnosing bilateral functional adrenocortical adenomas prior to surgery. Proper interpretation of the laboratory findings is particularly important in these patients. Immunohistochemistry may be a valuable tool to identify aldosterone/cortisol-producing lesions and to validate the clinical diagnosis.

SUN-LB065 A Rare Case of Adrenal Corticomedullary Adenoma: Coexistence of Cushing's Syndrome and Elevated Catecholamines in a Patient With an Incidental Adrenal Mass

Background:Most primary neoplasms of the adrenal gland arise from either adrenal cortical cells or the chromaffin cells of the adrenal medulla. Here we describe a case in which a patient was found to have an incidental adrenal mass with both cortical and medullary components on histology. Clinical Case:A 51-year-old female with DM2 and HTN, presented with an incidental left (L) adrenal mass. She had a 30-pound weight gain over 6 months with complaints of fatigue and easy bruising. CT of her adrenals demonstrated a 3.1 cm L adrenal mass with pre-contrast HU of 31 and washout >50%, suggesting a lipid poor adenoma with a normal contralateral adrenal gland. Her blood pressure was 165/88 mm Hg and BMI was 34. Dorsocervical fat pad enlargement and supraclavicular fullness were noted. A 1 mg dexamethasone suppression test (DST) was abnormal with a dexamethasone (DEX) level- 209 ng/dL (180-550) and cortisol- 8.2 mcg/dL. A late-night salivary test was normal with a cortisol- 0.05 mcg/dl (0.04-0.56). Basal am ACTH and cortisol levels were 24 pg/mL (6-50) and 20.5 mcg/dL (4-22) respectively. Plasma metanephrine- 114 pg/mL (<57), normetanephrine- 300 pg/mL (<148), and total metanephrine- 414 pg/mL (<205) were elevated. DHEA-S, plasma renin and aldosterone were all within normal range. These results suggested that both pheochromocytoma (Pheo) and Cushing’s syndrome (CS) were present. The differential diagnosis included ACTH- secreting Pheo, pituitary CS coexisting with a Pheo, or corticomedullary adenoma. After L adrenalectomy, histological examination showed positive immunohistochemical staining with chromogranin and intermingled adrenocortical components within the same mass, consistent with a corticomedullary adenoma. ACTH immunostaining was positive in a small subpopulation of cells. Post-operatively, the metanephrine levels normalized. The 1 mg DST improved but remained abnormal (DEX level- 245 ng/dL, cortisol- 3.4 mcg/dl). The basal 8 am ACTH and cortisol were 28 pg/mL and 12.7 mcg/dL respectively. She did not require hydrocortisone replacement. Her HTN improved and insulin was discontinued. There were no mutations found in a hereditary Pheo panel (Invitae- 14 genes). Conclusion:Corticomedullary adenomas associated with hypersecretion of cortisol and catecholamines have rarely been reported. All 5 of the previously reported cases have been unilateral with a predilection for females in the third to sixth decades of life1. In this case, the histologic diagnosis and clinical improvement after adrenalectomy supports a diagnosis of corticomedullary adenoma as the source of hypersecretion of both cortisol and catecholamines. This case demonstrates the importance of screening for CS and Pheo in all patients when evaluating an incidental adrenal mass. Reference:1.Lau, S., Annals of Diagnostic Pathology, 15:185, 2011 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.

SUN-372 A Case of Adrenal Adenoma Co-Secreting Aldosterone and Cortisol: Limits of Adrenal Vein Sampling

Background: AVS Adrenal vein sampling (AVS) is the gold standard for localizing the lesion in primary hyperaldosteronism. This case illustrates the limitations of AVS in cortisol co-secreting adenomas and highlights features of co-secreting adrenal adenomas. CASE: A 65 yr old man with hypertension and hypokalemia was diagnosed with primary hyperaldosteronism in the setting of low renin (0.41 ng/ml/h (0.25-5.82), elevated aldosterone level (39 ng/dl) and an elevated aldosterone-renin ratio (ARR) of 95. CT abdomen showed a 4.4 cm left adrenal mass with pre-contrast attenuation of negative 5 houndsfield units and 60 % post contrast washout. The patient also had elevated 24- hour urine free cortisol levels of 72.5 mcg/24hr (4.0-50.0) and an elevated morning cortisol of 10 ug/dl(<1.8) after 1mg dexamethasone. Although he had no clinical evidence of Cushings syndrome on examination, his laboratory results were consistent with cortisol hypersecretion. An initial adrenocorticotrophic hormone (ACTH) stimulated AVS was done while on spironolactone, with potassium of 3.6 mEq/L. The selectivity index was > 3.0 indicating appropriate catheter placement, however results failed to demonstrate a unilateral process (lateralization index ___ at 15 minutes). AVS was repeated off of spironolactone and the lateralization index was ___ at 15 minutes post ACTH. the pt underwent left adrenalectomy for growth of the adenoma and mild hypercortisolism. Pathology confirmed an adrenocortical adenoma. Despite 2 AVS that suggested a bilateral process, post-operatively potassium and blood pressure normalized and aldosterone level reduced to <1ng/dl with renin levels of 2.35 ng/ml/h (ARR- 0.42). This case highlights the pitfalls of using AVS in co-secreting adenoma. The lateralization index is calculated by aldosterone/cortisol ratio of dominant to non- dominant side. The higher levels of cortisol on the side of the adenoma can falsely reduce the ratio of the affected side, falsely lowering the lateralization index. Conclusion: AVS can be misleading in an adenoma that is co-secreting aldosterone and cortisol and results in false negative results.

Pharmacological and analytical interference in hormone assays for diagnosis of adrenal incidentaloma

Adrenal incidentaloma refers to an asymptomatic adrenal mass detected through an imaging procedure performed for reasons unrelated to adrenal dysfunction or suspected dysfunction. In general, adrenal incidentalomas are non-functioning adrenal adenomas, but in some cases, may require therapeutic intervention: eg., adrenocortical carcinoma, pheochromocytoma, primary aldosteronism, cortisol hypersecretion, or adrenal insufficiency. Hormone assessment is crucial to characterize adrenal incidentaloma. Nowadays, various hormone assay methods are available, such as immunoassay and mass spectrometry. However, there are several pitfalls that should be considered: e.g., circadian rhythm, gender/age dependency, preanalytical and analytical issues, and drug interactions. Pharmacological or analytical interference can lead to false serum concentrations and may result in misinterpretation of results and thus inappropriate treatment. The purpose of this review was to study the main interferences that may be observed in the different tumor types of adrenal incidentalomas in order to help physicians in their clinical decision-making and for the overall benefit of patients.

Morbidity and mortality of bone metastases in advanced adrenocortical carcinoma: a multicenter retrospective study

Introduction Adrenocortical carcinoma (ACC) is a rare cancer that commonly spreads to the liver, lungs and lymph nodes. Bone metastases are infrequent. Objective The aim of this report was to describe the clinical characteristics, survival perspective, prognostic factors and frequency of adverse skeletal-related events (SREs) in patients with ACC who developed bone metastasis. Methods This is a retrospective, observational, multicenter, multinational study of patients diagnosed with bone metastases from ACC who were treated and followed up in three European countries (France, Italy and The Netherlands) and one center in the United States. Results Data of 156 patients were captured. The median overall survival was 11 months. SREs occurred in 47% of patients: 17% bone fractures, 17% spinal cord compression, 1% hypercalcemia, 12% developed more than one SRE. In multivariate analysis, cortisol hypersecretion was the only prognostic factor significantly associated with a higher mortality risk (hazard ratio (HR) 2.24, 95% confidence interval (CI): 1.19-4.23, P = 0.013) and with the development of a SREs (of border line significance). The administration of antiresorptive therapies (bisphosphonates and denosumab) was associated with a lower risk of death, even if not significant, and their survival benefit appeared confined in patients attaining serum mitotane levels within the therapeutic range. Conclusion Bone metastases in ACC patients are associated with poor prognosis and high risk of SREs. Cortisol hypersecretion was the only prognostic factor suggesting a potential benefit from antisecretory medications. The therapeutic role of bisphosphonates and denosumab to improve patient outcome deserves to be tested in a prospective clinical trial.

Exercise Reduces Salivary Morning Cortisol Levels in Patients with Depression

Purpose of the Study: Cortisol hypersecretion plays a role in depression pathophysiology. Internet-based cognitive behavioural therapy (ICBT) and physical exercise (PE) are new treatment alternatives for depression, and their long-lasting effect on cortisol is unknown. We investigated cortisol level changes after 12 weeks of ICBT, PE or treatment as usual (TAU). Procedures: The present pre-post repeated measure study analysed data derived from a randomised controlled trial evaluating the effects of 12 weeks’ interventions of ICBT, PE and TAU in depressed primary care patients (Sweden 2011–2013) and aimed at prospectively evaluating the within-group effects of ICBT, PE and TAU on diurnal salivary cortisol levels in a small representative subsample (n = 56, 38 and 27, respectively). Results: We found a marked flattening of the diurnal cortisol slope (p = 0.004) and a reduced cortisol level at awakening (p = 0.017) after 12 weeks of PE treatment. No apparent effects of ICBT or TAU interventions were seen on diurnal cortisol levels. Conclusions and Message: PE reduced the rate of cortisol level decline across the day in depressed adults. ICBT and TAU treatments had no detectable effects on diurnal cortisol levels. Larger samples are required for the detection and comparison of smaller effects of PE, ICBT and TAU on diurnal cortisol levels.