Treatment Of Cushing's Syndrome Research Articles

Cushing's syndrome in the elderly.

Management of Cushing's syndrome (CS) can be particularly challenging in older patients, due to the lack of several clinical features associated with cortisol excess along with a greater burden of comorbidities in them, as compared with the younger. Moreover, interpretation of diagnostic tests could be influenced by age-related physiological changes of cortisol secretion. While mortality is higher and quality of life is more impaired in the elderly with CS as compared with the younger, there is currently no agreement on the most effective therapeutic options in aged individuals, and safety data concerning medical treatment are scanty. In this review, we summarize the current knowledge about age-related differences in etiology, clinical presentation, treatment and outcomes of CS, and describe the potential underlying mechanisms.

Emergence of De Novo Conditions Following Remission of Cushing Syndrome: A Case Report and Scoping Review.

Onset and exacerbation of autoimmune, inflammatory or steroid-responsive conditions have been reported following the remission of Cushing syndrome, leading to challenges in distinguishing a new condition versus expected symptomatology following remission. We describe a case of a 42-year-old man presenting with new-onset sarcoidosis diagnosed 12 months following the surgical cure of Cushing syndrome and synthesise existing literature reporting on de novo conditions presenting after Cushing syndrome remission. A scoping review was conducted in Medline, Epub, Ovid and PubMed. Case reports and case series detailing adult patients presenting with new-onset conditions following Cushing syndrome remission were included. In total, 1641 articles were screened, 138 full-text studies were assessed for eligibility, and 43 studies were included, of which 84 cases (including our case) were identified. Most patients were female (85.7%), and the median reported age was 39.5 years old (IQR = 13). Thyroid diseases were the most commonly reported conditions (48.8%), followed by sarcoidosis (15.5%). Psoriasis, lymphocytic hypophysitis, idiopathic intracranial hypertension, multiple sclerosis, rheumatoid arthritis, lupus and seronegative arthritis were reported in more than one case. The median duration between Cushing remission and de novo condition diagnosis was 4.1 months (IQR = 3.75). Of those patients, 59.5% were receiving corticosteroid therapy at the time of onset. Our scoping review identified several cases of de novo conditions emerging following the remission of Cushing syndrome. They occurred mostly in women and within the year following remission. Clinicians should remain aware that new symptoms, particularly in the first year following the treatment of Cushing syndrome, may be manifestations of a wide range of conditions aside from adrenal insufficiency or glucocorticoid withdrawal syndrome.

P-03 A report of recurring pregnancy-induced Cushing's Syndrome

Abstract Introduction The incidence of pregnancy-induced Cushing's syndrome (CS) is very low. However, the diagnosis of CS in pregnant patients is very difficult because of an overlapping signs and symptoms. Clinical Case A 20-year-old woman with polycystic ovarian syndrome (PCOS) was successfully treated with clomiphene for infertility and pregnant in September of 2016 for the first time. She experienced out of proportion abdominal obesity, excessive striosis, exacerbation of hirsutism and myasthenia during the first trimester of her pregnancy. Initial diagnosis of ovarian hyperstimulation syndrome (OHSS) was made and due to concomitant intrauterine growth retardation (IUGR), the pregnancy was electively terminated at the 8th week. All associated symptoms spontaneously regressed within 2-3 months after the abortion. The second pregnancy was induced with a pulse treatment of letrozole 5 mg, followed by 3 every other day injections of 100 units recombinant follicle-stimulating hormone. Within the first 4 weeks into the second pregnancy, the patient developed recurrence of OHSS symptoms. In addition to the prior symptoms and progressive proximal myasthenia, the patient developed hypertension, round moon-like face, back hump, and suprasternal fat pad consistent with the typical features of CS. In week 14 of pregnancy, the patient complained from acute-onset bilateral blindness and hypertension (blood pressure of 180/120 mmHg), which soon progressed into loss of consciousness and grand-mal seizure. She was admitted to the intensive care unit (ICU). Admission laboratory testing included those to assess the function of the pituitary-adrenal axis (HPA) due to the presence of symptoms related to CS. Based on available clinical information a diagnosis of hemolysis, elevated liver enzymes, and a low platelet count (HELLP) syndrome was made and emergency termination of pregnancy was carried out at the gestational age of 14 weeks. The patient`s clinical signs such as hypertension and acute blindness were totally subsided soon after the therapeutic abortion. Diagnosis of ACTH independent CS was made based on elevated 8 a.m. serum cortisol level unresponsive to low-dose dexamethasone (45-41 µg/ dL). Conclusion Diagnosis of CS in pregnancy is challenging as the physiological changes during pregnancy may mimic those of CS. Long-term treatment of gestational CS has not been as successful. However, in the case of adrenal hyperplasia, bilateral adrenalectomy offers a certain cure. Our patient had a therapeutic abortion due to severe maternal complications and development of CS during the early gestational age. The patient was reeducated on the subject of contraception and the possibility of adrenalectomy for future pregnancies. Due to the temporal relation between the occurrence of CS after each pregnancy the diagnosis of gestational hypercortisolism was made, and for further pregnancies bilateral adrenalectomy was recommended.

THU577 Acth Dependent Cushing Syndrome Identification And Management Challenges

Abstract Disclosure: B.C. Barreto: None. S. Patrick: None. H. Oktaei: None. H.O. Steinberg: None. Endogenous Cushing Syndrome(CS) is rare with an incidence of 0.2-5.0 per million people per year. 70 to 80% of CS is ACTH dependent and subclassified into Cushing Disease, Ectopic ACTH Syndrome and Ectopic CRH Syndrome. Ectopic ACTH secretion(EAS) has a variable clinical presentation. Atypical features like refractory hypokalemia in a patient with a tumoral lesion should raise suspicion. When imaging is inconclusive, differentiating between pituitary or ectopic disease includes invasive and noninvasive methods. We report a case of EAS. Case: A 57-year-old male with history of metastatic small-cell lung-cancer on palliative chemotherapy was admitted for acute coronary syndrome. Endocrinology evaluated the patient’s uncontrolled hypertension, hyperglycemia, and hypokalemia (1.5 mmol/L). He had no suppression with low dose dexamethasone (cortisol>75mcg/dL, ACTH 926pg/mL). Examination was pertinent for an elevated BMI 36.1kg/m2, hyperpigmented anterior thorax but no other stigmata of hypercortisolism. Laboratory analysis showed baseline cortisol 146.1mcg/dL(8.7-22), ACTH 590pg/ml(6-50), 24hr Urine Free Cortisol 736mcg/24h(5-50), which were not suppressed by high dose dexamethasone suppression test(HDDST). Aldosterone and PRA were undetectable. Brain MRI showed an enlarged pituitary gland, but no focal mass. CT abdomen pelvis showed bilateral adrenal hyperplasia, multiple hepatic masses, and bone lesions. Since the patient was a poor surgical candidate, medical therapy was initiated with ketoconazole 200mg TID, aldactone 50mg BID and potassium chloride 40mEq TID. After twelve days cortisol levels decrease to 65.2 mcg/dL, potassium 3.8 mmol/L and glucose 146 mg/dL. Hospitalization was complicated by a small bowel ileus. Medications were held due to poor gastrointestinal absorption and parenteral octreotide 200mcg TID was initiated. Once the ileus resolved, ketoconazole 200mg TID, eplerenone 50mg daily, and dexamethasone 0.5mg daily was started. Despite medical care, the patient eventually expired. Discussion: The HDDST can help distinguish pituitary from an ectopic ACTH overproduction. HDDST with >50% suppression, has been described with sensitivity-specificity of 60 to 100% for pituitary ACTH source. Symptomatic treatment of CS requires rapid normalization of hypercortisolism action. Surgery is the first line approach. When surgery is not an option, medical therapy should be considered. Adrenal steroidogenesis inhibitors, such as ketoconazole, are the first line due to rapid onset of action. Agents such as glucocorticoid receptor antagonists have limited availability in the inpatient setting. Somatostatin analogs and etomidate that inhibit 11-ßhydroxylase are potential options but require close monitoring. Severe hypercortisolism in the critically ill prompts the use of noninvasive evaluation tools and alternative medical approaches. Presentation Date: Thursday, June 15, 2023

THU035 Impact Of Surgery Or Medical Treatment With The Selective Glucocorticoid Receptor Modulator Relacorilant On Hypercoagulopathy In Patients With Cushing Syndrome

Abstract Disclosure: C. Simeoli: None. N. Di Paola: None. A. Stigliano: None. P. Lardo: None. T. Kearney: Other; Self; Corcept Therapeutics. E. Mezosi: Grant Recipient; Self; Corcept Therapeutics. E. Ghigo: None. R. Giordano: None. C.N. Mariash: Grant Recipient; Self; Corcept Therapeutics. D. Donegan: Advisory Board Member; Self; Corcept Therapeutics. Other; Self; Corcept Therapeutics. R.A. Feelders: Consulting Fee; Self; Recordati. Grant Recipient; Self; Corcept Therapeutics. Speaker; Self; Recordati, HRA Pharma. A.L. Hand: Employee; Self; Corcept Therapeutics. A.G. Moraitis: Employee; Self; Corcept Therapeutics. R. Pivonello: Consulting Fee; Self; Corcept Therapeutics. Grant Recipient; Self; Corcept Therapeutics. In patients with Cushing syndrome (CS), hypercoagulability represents a significant concern, leading to an elevated risk for thrombotic events. Hypercoagulability persists for several months (mos) after curative surgery, and current CS treatment guidelines recommend anticoagulation therapy for up to 3 mos after surgery. In patients with Cushing disease, hemostatic parameters may even worsen after surgery, independent of surgical outcome, with improvements beginning about 3 mos after successful surgery (Casonato et al. Blood Coagul Fibrinolysis 1999). This transient worsening may be due to increased inflammation as cortisol levels, and hence cortisol’s anti-inflammatory effects, are reduced after successful surgery, leading to increased activity in the coagulation cascade, which normalizes over time. Here, we evaluate the impact of surgery or treatment with the selective glucocorticoid receptor modulator relacorilant (RELA) on the coagulation state in patients with CS, reporting findings from a retrospective, longitudinal, monocentric, surgical cohort study and an open-label phase 2 study of RELA (NCT02804750). In the surgical study, coagulation markers were assessed in 30 patients before curative surgery and in remission. In the RELA study, patients received either RELA 100-200 mg for 12 weeks or RELA 250-400 mg for 16 weeks; coagulation markers were assessed in 34 patients throughout the study. In the surgical study, baseline (BL) mean 24-h urinary free cortisol (UFC) was 615.6 mcg/day (by immunoassay; 2.1x upper limit of normal [ULN]); mean and median time to hemostasis assessment after remission were 6.2 and 6 mos, respectively. Significant mean changes from BL were observed in activated partial thromboplastin time (aPTT; +2.0 sec, P=0.031), factor VIII (fVIII; -24.2%, P=0.044), and von Willebrand factor (vWF; -20.6%, P=0.018), whereas platelet count was unchanged. In the RELA study, BL mean UFC was 211.9 mcg/day (by tandem mass spectrometry; 4.2x ULN). Similar to the surgical study, significant mean changes from BL to last observed visit were reported in aPTT (+1.5 sec, P=0.046), fVIII (-18.9%, P=0.022), and platelet count (-68.8*109/L, P<0.0001), while vWF was unchanged. Significant improvements in other coagulation factors, eg, fIX and fX, were seen in patients with abnormal values at BL. These studies showed that coagulation markers in patients with CS improve 6 mos after curative surgery, and that treatment with RELA may have similar effects after 3-4 mos. The previously observed transient increase in fVIII immediately after surgery was absent with RELA, where negative mean changes from BL were seen throughout the study. This is presumably due to the less abrupt reduction of cortisol activity with RELA compared to surgery. RELA’s effects on hypercoagulopathy support further investigation of preoperative use and in patients with CS who are not eligible for surgery. Presentation: Thursday, June 15, 2023

Unexpected exacerbation of cryptococcal meningitis after unilateral adrenalectomy in a PMAH patient: a case report and literature review

BackgroundPrimary bilateral macronodular adrenal hyperplasia (PMAH) combined with infection by an opportunistic pathogen is complicated. Clinical evidence on managing PMAH patients with infections by opportunistic pathogens is insufficient.Case presentationA 66-year-old male was admitted with bilateral adrenal masses and was diagnosed with PMAH. Fever and disturbance of consciousness appeared after laparoscopic left adrenalectomy. Cryptococcal meningitis was confirmed by cerebrospinal fluid (CSF) culture. The exacerbation of his medical condition was suspected to result from immune reconstitution inflammatory syndrome (IRIS), and he had been treated with antifungal therapy and glucocorticoid replacement, but he responded poorly and eventually died of multiorgan failure. We summarized the clinical observations of 12 Cushing's syndrome (CS) patients infected by Cryptococcus. Seven out of nine patients who were treated for cryptococcus infection before receiving CS survived, while three patients treated for cryptococcus infection after CS treatment developed signs of IRIS and eventually died.ConclusionCushing's syndrome, complicated with cryptococcal infection, has a high mortality rate, mainly when IRIS emerges. Carefully identifying the presence of the suspected infection, and controlling cryptococcal infection before removing the culprit adrenals could be the rational choice.

Pregnancy complicated with adrenal adenoma causing ACTH-independent Cushing's syndrome, accompanied by obstetric antiphospholipid syndrome and severe pre-eclampsia: case report and literature review.

This case report shares the management experience of a patient with pregnancy combined with adrenal adenoma causing ACTH-independent Cushing's syndrome (CS), accompanied by obstetric antiphospholipid syndrome (OAPS) and severe pre-eclampsia. The case was a 26-year-old that presented with typical clinical symptoms and signs of CS. The patient had a history of 4 spontaneous abortions in the last 4 years. The 24-hour urinary free cortisol was significantly increased, an abnormal cortisol circadian rhythm was demonstrated by a high late-night salivary cortisol, blood ACTH was suppressed (< 1ng/dL), anticardiolipin antibody was positive, and imaging examination showed an adrenal tumor. The patient underwent laparoscopic adrenal tumor resection under general anesthesia at 23 weeks of gestation. The tumor was pathologically confirmed to be an adrenocortical adenoma. The patient underwent a cesarean section at 39 weeks of gestation to give birth to a healthy baby girl with an Apgar score of 10. Pregnancy complicated by CS is clinically rare, easily masked by normal physiological changes of pregnancy, and is difficult to diagnose. The determination of 24-hour urinary free cortisol, the circadian rhythm of serum cortisol, ultrasound, and MRI can be helpful in the diagnosis of CS during pregnancy. Surgery is the first choice for the treatment of CS during pregnancy. As a subtype of antiphospholipid syndrome, patients with OAPS are prone to thrombotic events and recurrent miscarriages if not treated accordingly. To our knowledge no cases of CS with OAPS and severe pre-eclampsia have been reported. We summarize the experience of the treatment of this patient and review the literature to improve clinicians' awareness of this disease.

PSAT012 Endogenous Hypercortisolism Concealing an Autoimmune Disease

Abstract Background Endogenous hypercortisolism may mask symptoms of autoimmune diseases by suppressing immune responses. These conditions can flare upon resolution of hypercortisolism. We report a case of a patient with adrenal Cushing's syndrome (CS) who was diagnosed with seropositive rheumatoid arthritis (RA) after resolution of hypercortisolism post adrenalectomy. Clinical Case A 38-year-old woman presented with a two-year history of a 30-pound weight gain, purple striae, acne, easy bruising, and worsening anxiety. Evaluation was consistent with an ACTH-independent CS: cortisol 33 ug/dL (3-17), ACTH &amp;lt;1 pg/mL (7.2-63.3), DHEA-S 53 ug/dL (45-270), elevated 24-hour urine free cortisol 354.1 ug/day (&amp;lt;45), and an abnormal 1mg dexamethasone suppression with cortisol 23 ug/dL and dexamethasone level 215.1 ng/dL (140-295). CT abdomen revealed bilateral adrenal nodules: right 2.3cm×2.9cm with HU of 19 and left 2.1cm×2.3cm with HU of -16 consistent with bilateral macronodular hyperplasia. A laparoscopic right adrenalectomy and a left cortical-sparing adrenalectomy was performed with the goal of preventing adrenal insufficiency by preserving sufficient adrenal cortex tissue. She was discharged on a hydrocortisone taper following perioperative stress doses. While on hydrocortisone 15mg in the morning and 5mg in the afternoon, no evidence of hypothalamus-pituitary-adrenal (HPA) axis recovery was seen: cortisol &amp;lt;1 ug/DL with ACTH 2.5 pg/mL. Electrolytes and plasma renin activity remained normal. However, once glucocorticoids were tapered to a physiologic dose, she experienced fatigue, diffuse muscle aches, polyarticular joint pain, swelling, and stiffness concerning for an underlying inflammatory disorder. Rheumatology evaluation was consistent with seropositive RA: cyclic citrullinated peptide &amp;gt;200 units (&amp;lt;200) and rheumatoid factor 34 IU/mL (0-14) in the setting of tenosynovitis of her wrists and fingers. Her symptoms rapidly improved on methotrexate 15mg weekly and prednisone 20mg daily. Prednisone was then tapered by 5mg every 2 weeks to physiologic, 5mg daily, without issues while continuing methotrexate. Repeat assessment of her HPA axis is pending. Conclusion Untreated CS with hypercortisolism may mask autoimmune diseases by suppressing inflammation until the hypercortisolism is reversed, and patients no longer have endogenous glucocorticoid excess. The incidence of new onset autoimmune diseases after treatment of CS is not well described in the literature. One single center retrospective analysis of 147 CS patients found 9 cases of patients developing autoimmune diseases such as thyroiditis and vasculitis after treatment of their CS. Here we add to these described cases with the uncovering of RA after normalization of cortisol levels. It is important for clinicians to distinguish activation of autoimmune disorders after CS is treated from manifestations of glucocorticoid withdrawal postoperatively. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Challenges in Diagnosis and Treatment of Cushing Syndrome in Bilateral Macronodular Adrenal Hyperplasia

Background. Bilateral adrenal cortical hyperplasia (ACH) is one of the rare causes of adrenocorticotropic hormone (ACTH)-independent Cushing’s syndrome (CS), where lateralization of cortisol secretion and choice of treatment techniques are challenging. Percutaneous radiofrequency ablation (RFA) is a safe and effective minimally invasive treatment for benign and malignant tumors, but it is not commonly used to treat CS in bilateral ACH. Case description. A 79-year-old patient developed ACTH-independent CS with bilateral ACH. Adrenal venous sampling (AVS) showed right sided cortisol hypersecretion. Due to serious comorbidities it was decided to perform percutaneus RFA. The procedure was successful and without any complications. Hydrocortisone replacement therapy was given to ma­nage adrenal insufficiency after the procedure. Conclusions. Percutaneous RFA is an effective minimally invasive procedure for the treatment of cortisol producing adrenal tumors. Reduction of symptoms caused by the disease has been observed after the procedure. It is also expected that hormone deficiency developed after the procedure will be transient.

Cushing Syndrome is Associated with Increased Stage N2 Sleep and Decreased SWS Partially Reversible After Treatment.

The aim of the present study was to evaluate the sleep parameters of patients with Cushing syndrome (CS) at the time of diagnosis and 12-months after treatment. Thirty four newly diagnosed patients with endogenous CS (17 with ACTH-secreting pituitary adenoma, 17 with adrenal CS) and 23 controls with similar age were included in the study. Two polysomnography (PSG) recordings were performed; one at the time of diagnosis and the other 12 months after resolution of hypercortisolemia. Control group had only baseline PSG. Based on the PSG findings, stage N2 sleep was found to be prolonged, stage N3 and REM sleep were shortened in patients with CS. Average heart rate and mean Apnea Hypopnea Index (AHI) score were higher in patients with CS than the control subjects. Sixteen (47.1%) patients with CS and 4 (17.4%) controls had obstructive sleep apnea (OSA; AHI ≥5). There were no significant differences in sleep parameters of patients according to the etiology of CS (adrenal vs. pituitary) patients. Following 12-months of treatment, a significant decrease in stage N2 sleep and a significant increase in stage N3 sleep were detected, but there was no change in terms of AHI. In conclusion, Cushing syndrome has disturbing effects on sleep structure and these effects are at least partially reversible after treatment. However, the increased risk of OSA was not reversed a year after treatment indicating the importance of early diagnosis and treatment of CS.

Persistent improvement of bone mineral density up to 20 years after treatment of Cushing's syndrome.

Cushing's syndrome (CS) is associated with osteoporosis and high fracture risk. Besides male sex, it is unknown which variables influence bone mineral density (BMD) at diagnosis and it is unclear to what extent BMD normalizes during long-term follow-up after treatment of CS. The aim of this study was to determine factors associated with BMD at diagnosis of CS and to determine the long-term course of BMD and fracture rate after successful treatment of CS. Retrospective cross-sectional and longitudinal cohort study. Data were collected from 231 patients with CS who were treated at the Radboud University Medical Centre between 1968 and 2020. At diagnosis, male sex was associated with lower Z-scores at the lumbar spine (LS) compared with female sex: -0.97s.d. (-1.45 to -0.49) after correction for possible confounders. Shorter duration of symptoms and younger age were also associated with lower Z-scores at diagnosis, while etiology of CS, urinary cortisol excretion and gonadal status were not associated with Z-scores at diagnosis. Z-scores improved up to 20 years after treatment. Fifteen years after treatment, men showed larger improvements of Z-scores than women; +2.56 (1.82-3.30) increase in LS Z-score vs +1.48 (0.96-2.00) respectively. Fracture incidence was highest during the 2 years before diagnosis and decreased after treatment. Male sex, younger age and shorter duration of symptoms are associated with lower BMD at diagnosis of CS. BMD continues to improve up to 20 years after treatment of CS. Fracture rate decreases after treatment of CS.

1177-P: The Reduction in Hepatic Steatosis after Cushing’s Syndrome Treatment Is a Marker of Improving Glycemia

Cushing Syndrome (CS) is characterized by cortisol excess that leads to impaired glucose tolerance and obesity. CT imaging shows 20% of CS patients have nonalcoholic steatohepatitis (NASH). While the gold standard diagnostic test for NASH is liver biopsy, it has too much risk for CS patients. This study evaluated the ability of noninvasive, magnetic resonance spectroscopy (MRS) to measure liver fat percentage in CS patients and followed temporal changes in metabolic parameters before and after successful treatment. The primary outcome was protein density fat fraction (PDFF) by MRS at 3 timepoints: baseline, 6 months, and 12 months after treatment, which consisted of surgery as indicated based on ACTH source. The diagnosis was confirmed if there was histology consistent with corticotrope adenoma, adrenal tumor, or an ectopic source. We prospectively studied 41 consecutive patients: 85% female; 44±1.8 y; 32.6±1.5 kg/m²; urine cortisol excretion 2242.7±1806.3 [nl 3.5-45.0 mcg/24h]). Each underwent MRS at 3T where NASH was defined as &amp;gt;5% PDFF. A1c and BMI were measured. Changes over time were evaluated using Wilcoxon signed-rank test, and correlation among variables was done with Spearman’s rank test. At baseline, mean PDFF was 10.4±1.7 and correlated positively with BMI (r=0.57, P&amp;lt;0.001). NASH was present in 32% of patients. PDFF reductions were similar after 6 and 12 months of treatment (-52%, P=0.001 and -50%, P=0.02); rates of NASH declined to 13% and 11%; BMI decreased (-9%; P=0.002 and -12%, P&amp;lt;0.001). A1c was lower at 12 months (6.2±1.1 to 5.6±0.5, P&amp;lt;0.001). The reduction in liver fat correlated with changes in visceral fat mass (r=0.70, P&amp;lt;0.001). In summary, MRS-PDFF was effective at diagnosing NASH in CS. Physiologically, definitive treatment of CS reduced liver fat by 6 months after normalization of cortisol and also preceded the improvement in A1c. These results suggest that liver insulin resistance due to fat accumulation has an important role in diabetes pathophysiology in CS. Disclosure A. Pierce: None. Z. A. Sater: None. A. M. Cypess: None.

Avascular femoral necrosis as part of Cushing syndrome presentation: a\xa0case report

BackgroundThe clinical characteristics and complications of Cushing syndrome (CS) are well known and described in the literature. Nevertheless, rare, atypical presentations may go unnoticed. Osteonecrosis is a well-documented complication of glucocorticoid therapy. However, endogenous hypercortisolism is a rare, but relevant, cause of bone avascular necrosis. We describe the case of a woman with CS undiagnosed for 2 years after presenting with femoral avascular necrosis.Case presentationA 38-year-old Caucasian woman was referred for evaluation of secondary amenorrhea, associated with oral contraception withdrawal in the context of deep venous thrombosis (DVT). She had a previous right hip arthroplasty for treatment of avascular necrosis of the femoral head, diagnosed after 3 years of progressive right hip pain and limited mobility. She also had high blood pressure (HBP) of 5 years’ duration, and reported weight gain (4 kg in 2 years). There was no history of infertility (gravida 2, para 2). Physical examination revealed buffalo hump, truncal obesity, facial plethora, muscular atrophy and proximal myopathy, and easy bruising (under anticoagulant treatment for DVT). Workup showed abnormal overnight dexamethasone suppression test (DST) (serum cortisol 21.5 µg/dL; normal < 1.8 µg/dL), elevated 24-hour urinary free cortisol (UFC) (728.9 µg/day; reference range 36.0–137.0 µg/day), and suppressed plasma adrenocorticotropic hormone (ACTH) (< 1.0 pg/mL), findings consistent with ACTH-independent CS. Urinary metanephrines and catecholamines were normal, and the remaining analytical study showed no major changes, apart from glycated hemoglobin (HbA1c) of 6.8%. Adrenal computed tomography (CT) scan showed a 25 mm lesion in the left adrenal gland, with density non-suggestive of adenoma. The patient underwent unilateral adrenalectomy and started steroid replacement. Histology revealed an adrenal cortex adenoma. Three months after surgery the patient presented with resolution of HBP and hypercortisolism (UFC 37.4 µg/day; reference range 36.0–137.0 µg/day).ConclusionIn some cases, CS signs may go unnoticed and the diagnosis postponed. Avascular necrosis is a rare presenting feature of endogenous hypercortisolism, and, if left untreated, complete collapse of the femoral head may ensue, rendering the need for hip replacement in up to 70% of patients. Suspicion and recognition of atypical features is therefore important in avoiding complications and delay in treatment of CS.

Cushing Syndrome in the Setting of Chronic Dilated Cardiomyopathy: Can Treatment Improve Chronic Dilated Cardiomyopathy?

Background: Cushing syndrome (CS) is well known to be associated with metabolic syndrome, venous thromboembolism, hypertension, left ventricular hypertrophy, and rarely dilated cardiomyopathy. The pathophysiological effects of hypercortisolism on the myocardium results in cardiomyocyte hypertrophy, myofibrillolysis, myocardial fibrosis, global longitudinal and circumferential strain. Our patient presents an example of CS in the setting of chronic heart failure with reduced ejection fraction, multiple thromboembolic events, and diabetes mellitus in a young adult.Clinical Case: A 34-year male with a past medical history of dilated cardiomyopathy with biventricular failure and left ventricle ejection fraction of 10%, pulmonary embolism, diabetes mellitus, and gout presented with shortness of breath. On physical exam he presented with symptoms of CS: moon facies, supraclavicular fat pads, dorsal fat pads, purple striae of abdominal skin, truncal obesity, ecchymosis, and skin atrophy. Labs showed elevated morning cortisol after overnight 1 mg dexamethasone suppression test (cortisol 8.6 mcg/dl, n< 5 mcg/dl), repeat morning cortisol after overnight 1 mg dexamethasone suppression test (cortisol 5.7 mcg/dl, n< 5 mcg/dl), and ACTH-concentrations <5 pg/ml. CT-scan was insignificant for adrenal hyperplasia. He was admitted and treated for acute congestive heart failure exacerbation with plans for definitive treatment of CS outpatient with further imaging studies.Conclusion: The occurrence of CS induced heart failure results in increased mortality. There have been numerous accounts of resolution of cardiomyopathy after surgical treatment for CS secondary to adrenal adenoma. Our patient had a 10-year history of chronic dilated cardiomyopathy prior to cushingoid symptoms and confirmatory endocrinological data. The definitive treatment for CS syndrome in our patient would eventually be surgery targeting the source of hypercortisolism, however his cardiovascular risk factors would make him a poor surgical candidate. Severely reduced ejection fraction is a contraindication for generalized anesthesia needed for surgery. When surgery is contraindicated in CS medical management is recommended according to guidelines that target pituitary-directed medical treatments for Cushing’s disease and targeted therapies to treat ectopic ACTH syndrome. To our knowledge there have been few studies that demonstrate the effects of CS treatment on chronic conditions such as dilated cardiomyopathy. Studies have shown that surgical treatment for CS have reversed cardiomyopathy caused by CS but it still remains to be answered whether this same effect is achieved to some degree in chronic dilated cardiomyopathy.

ACTH Producing Mediastinal Tumor - Multidisciplinary Approach

Abstract Introduction: Ectopic ACTH syndrome is rare but is frequently a severe condition because of the intensity of the hypercortisolism. Patient management is complex and demands both strategies: the diagnosis and treatment of Cushing syndrome, and the specific management of neuroendocrine tumors. Therefore, management should be performed ideally by experienced endocrinology teams in collaboration with surgeons, oncologists, nuclear medicine, specialized hormonal laboratory and modern imaging platforms. Clinical Case: Female patient, born in 2000, at the age of 15 was diagnosed with Cushing’s syndrome secondary to ACTH secretion by mediastinal tumor. At diagnosis, ACTH 1152pg/ml was found (reference value &amp;lt;46pg/ml). Turkish seat resonance was normal, and chest tomography described a 4.5x3.6x3.8cm mediastinal lesion. Underwent a mediastinal surgical approach in 2015, with clinical and laboratory remission of hypercortisolism. The analysis of the lesion revealed a well-differentiated neuroendocrine carcinoma, with Ki67 5%. Progression of the mediastinal lesion was observed, without an exuberant clinic or laboratory, and a new surgery was performed in 2017, with a remaining macroscopic tumor, due to technical difficulties in resection due to contact with vascular structures. The immunohistochemistry of the resected lesion in this approach showed Ki67 30%, which reflects loss of differentiation. Octreoscan was performed, with no uptake. She evolved without exuberant Cushing’s syndrome until May 2019, when the clinical condition decompensated due to hypercortisolism, and was submitted to a new hospitalization. She was assisted by the thoracic surgery and oncology teams. From this moment a follow-up with endocrinology team started. Ketoconazole was introduced and PET-DOTATOC was requested. She underwent chemotherapy with Oxaliplatin and Capecitabine. In March 2020, DOTATOC uptake was checked and a somatostatin analogue was started. She showed considerable clinical and laboratory improvement. The patient remains clinically stable, with control of hypercortisolism using Ketoconazole 600mg daily and Octreotide 30mg every 28 days. The patient remains under clinical and laboratory surveillance. Awaiting PET-FDG. Mediastinal radiotherapy, lutetium, new mediastinal surgical approach, and bilateral adrenalectomy are also considered as possible therapeutic alternatives. Clinical Lesson: The reported case shows a rare location of an ACTH-producing tumor, emphasizing the severity of the presentation, the evolution of tumor de-differentiation, the different results identified in octreoscan and PET-DOTATOC, and the importance of multidisciplinary management.

Machine Learning Models for Classification of Cushing's Syndrome Using Retrospective Data.

Accurate classification of Cushing's Syndrome (CS) plays a critical role in providing the early and correct diagnosis of CS that may facilitate treatment and improve patient outcomes. Diagnosis of CS is a complex process, which requires careful and concurrent interpretation of signs and symptoms, multiple biochemical test results, and findings of medical imaging by physicians with a high degree of specialty and knowledge to make correct judgments. In this article, we explore the state of the art machine learning algorithms to demonstrate their potential as a clinical decision support system to analyze and classify CS to facilitate the diagnosis, prognosis, and treatment of CS. Prominent algorithms are compared using nested cross-validation and various class comparison strategies including multiclass, one vs. all, and one vs. one binary classification. Our findings show that Random Forest (RF) algorithm is most suitable for the classification of CS. We demonstrate that the proposed approach can classify CS with an average accuracy of 92% and an average F1 score of 91.5%, depending on the class comparison strategy and selected features. RF-based one vs. all binary classification model achieves sensitivity of 97.6%, precision of 91.1%, and specificity of 87.1% to discriminate CS from non-CS on the test dataset. RF-based multiclass classification model achieves average per class sensitivity of 91.8%, average per class specificity of 97.1%, and average per class precision of 92.1% to classify different subtypes of CS on the test dataset. Clinical performance evaluation suggests that the developed models can help improve physicians' judgment in diagnosing CS.

Cushing Syndrome

Cushing syndrome is a condition with protean manifestations that are caused by chronic exposure to excess glucocorticoids. Treatment with supraphysiologic doses of glucocorticoids is the most common cause. Pathologic hypercortisolism may result from autonomous adrenal production or as a result of the action of excessive adrenocorticotropic hormone (ACTH) production by a tumor, which stimulates adrenal cortisol production. Primary adrenal forms include unilateral adenoma or carcinoma or, rarely, bilateral hyperplasia and/or nodules. This chapter covers the epidemiology, etiology, pathophysiology, and diagnosis of Cushing syndrome. Clinical manifestations, physical examination findings, and laboratory tests, including tests of the blood and other body fluids, imaging studies, and biopsy, are discussed. The differential diagnosis, treatment options, complications, and prognosis are described. Tables outline clinical features and causes of Cushing syndrome, abnormalities associated with primary adrenal causes of Cushing syndrome, diagnostic accuracy of screening tests, endogenous hypercortisolism without Cushing syndrome, and medical therapy for Cushing syndrome. Figures illustrate the causes of Cushing syndrome and a comparison of the hypothalamic-pituitary-adrenal axis in patients with ACTH-dependent Cushing syndrome and those with pseudo–Cushing syndrome. Algorithms show the evaluation of possible Cushing syndrome and evaluation of the causes of Cushing syndrome. Second-line treatments for Cushing syndrome when surgery fails or is not possible are also detailed. This chapter contains 5 figures, 7 tables, 50 references.

Cushing Syndrome

Cushing syndrome is a condition with protean manifestations that are caused by chronic exposure to excess glucocorticoids. Treatment with supraphysiologic doses of glucocorticoids is the most common cause. Pathologic hypercortisolism may result from autonomous adrenal production or as a result of the action of excessive adrenocorticotropic hormone (ACTH) production by a tumor, which stimulates adrenal cortisol production. Primary adrenal forms include unilateral adenoma or carcinoma or, rarely, bilateral hyperplasia and/or nodules. This chapter covers the epidemiology, etiology, pathophysiology, and diagnosis of Cushing syndrome. Clinical manifestations, physical examination findings, and laboratory tests, including tests of the blood and other body fluids, imaging studies, and biopsy, are discussed. The differential diagnosis, treatment options, complications, and prognosis are described. Tables outline clinical features and causes of Cushing syndrome, abnormalities associated with primary adrenal causes of Cushing syndrome, diagnostic accuracy of screening tests, endogenous hypercortisolism without Cushing syndrome, and medical therapy for Cushing syndrome. Figures illustrate the causes of Cushing syndrome and a comparison of the hypothalamic-pituitary-adrenal axis in patients with ACTH-dependent Cushing syndrome and those with pseudo–Cushing syndrome. Algorithms show the evaluation of possible Cushing syndrome and evaluation of the causes of Cushing syndrome. Second-line treatments for Cushing syndrome when surgery fails or is not possible are also detailed. This chapter contains 5 figures, 7 tables, 50 references.

Fluconazole treatment in severe ectopic Cushing syndrome

SummarySevere Cushing syndrome (SCS) is considered an emergency that requires immediate treatment to lower serum cortisol levels. Fluconazole may be considered an alternative treatment in Cushing syndrome when ketoconazole is not tolerated or unavailable. We report a 39-year-old woman with a history of partial pancreaticoduodenectomy due to a periampullary neuroendocrine tumor with locoregional extension. Three years after surgery, she developed liver metastases and was started on 120 mg of lanreotide/month, despite which, liver metastases progressed in the following 6 months. The patient showed extreme fatigue, muscle weakness, delirium, moon face, hirsutism and severe proximal weakness. Laboratory tests showed anemia, hyperglycemia and severe hypokalemia. 24-h urinary free cortisol: 2152 nmol/day (reference range (RR): <276), morning serum cortisol 4883.4 nmol/L (RR: 138–690), ACTH 127.3 pmol/L (RR: 2.2–10). She was diagnosed with ectopic ACTH syndrome (EAS). On admission, she presented with acute upper gastrointestinal tract bleeding and hemodynamic instability. Intravenous fluconazole 400 mg/day was started. After 48 h, her mental state improved and morning cortisol decreased by 25%. The dose was titrated to 600 mg/day which resulted in a 55% decrease in cortisol levels in 1 week, but then had to be decreased to 400 mg/day because transaminase levels increased over 3 times the upper normal level. After 18 days of treatment, hemodynamic stability, lower cortisol levels and better overall clinical status enabled successful bilateral adrenalectomy. This case report shows that intravenous fluconazole effectively decreased cortisol levels in SCS due to EAS.Learning points:Severe Cushing syndrome can be effectively treated with fluconazole to achieve a significant improvement of hypercortisolism prior to bilateral adrenalectomy.Intravenous fluconazole is an alternative treatment when ketoconazole is not tolerated and etomidate is not available.Fluconazole is well tolerated with mild side effects. Hepatotoxicity is usually mild and resolves after drug discontinuation.

SUN-451 A Randomized-Withdrawal, Placebo-Controlled, Phase 3 Study to Assess the Efficacy and Safety of Selective Glucocorticoid Receptor Antagonist, Relacorilant, in Patients with Cushing Syndrome (GRACE Study)

Relacorilant is a highly selective glucocorticoid receptor antagonist (GRA) that modulates the effects of excess cortisol while showing no affinity for progesterone, mineralocorticoid, androgen, or estrogen receptors. In a phase 2 study, treatment with relacorilant showed improvement in glycemic and hypertension endpoints as well as other manifestations of cortisol excess in patients with endogenous Cushing syndrome (CS). Relacorilant was well tolerated, with no instances of drug-related hypokalemia or antiprogesterone effects. A multicenter phase 3 clinical trial of relacorilant is underway (GRACE Study: NCT03697109) that uses a randomized withdrawal (RW) design to evaluate efficacy and safety. Based on the mechanism of action of GRAs, clinical efficacy endpoints are being used. The study includes a 6-week (6wk) screening phase, followed by a 22wk open-label (OL) treatment phase, where eligible patients 18-80 years old with a confirmed biochemical diagnosis of endogenous CS, clinical signs and symptoms of CS, and either diabetes mellitus/impaired glucose tolerance (DM/IGT) or hypertension will receive relacorilant (100 mg/day, titrated to 400 mg/day, as tolerated). Those patients who complete the OL phase and meet clinical response criteria (assessed at OL wk22) are eligible to enter the blinded RW phase, where they will receive either placebo or relacorilant at the same dose they received at the end of the OL phase. During the RW phase, increases in antidiabetic and/or antihypertensive agents are allowed if there is a loss of response compared to OL wk22. Criteria for RW entry in the DM/IGT group include one of the following: ≥0.5% decrease in HbA1c from baseline, normalization or ≥50 mg/dL decrease in 2-hour OGTT glucose from baseline, or decrease in daily insulin or sulfonylurea dose and HbA1c unchanged or decreased. Criteria for RW entry in the hypertension group include one of the following: ≥5 mmHg decrease in mean systolic and/or diastolic blood pressure (SBP/DBP) without worsening of either, or a reduction in the number/dose of antihypertensives and no worsening of SBP/DBP. The primary efficacy endpoint in the DM/IGT group is the mean change from OL wk22 to RW wk12 in 2-hour OGTT glucose as compared between treatment groups. In the hypertension group, the primary endpoint is the proportion of patients with a loss of response with respect to hypertension from OL wk22 to RW wk12 as compared between treatment groups. Loss of response is defined as an increase in SBP or DBP ≥5 mmHg or any increase in dose or number of antihypertensive medications. Secondary efficacy endpoints include the proportion of patients meeting any DM/IGT and/or hypertension RW entry criteria at the end of the OL phase. Cushing Quality-of-Life and Global Clinical Response scores are also assessed. In conclusion, GRACE is enrolling participants in the first RW trial to assess relacorilant in the treatment of CS.