Predictors Of Biochemical Remission And Recurrence After Surgical And Radiation Treatments Of Cushing Disease: A Systematic Review And Meta-Analysis

Objective: We conducted a systematic review and meta-analysis to synthesize the evidence about predictors that may affect biochemical remission and recurrence after transsphenoidal surgery (TSS), radiosurgery (RS), and radiotherapy (RT) in Cushing disease.Methods: We searched multiple databases through December 2014 including original controlled and uncontrolled studies that enrolled patients with Cushing disease who received TSS (first-line), RS, or RT. We extracted data independently, in duplicates. Outcomes of interest were biochemical remission and recurrence. A meta-analysis was conducted using the random-effects model to estimate event rates with 95% confidence intervals (CIs).Results: First-line TSS was associated with high remission (76% [95% CI, 72 to 79%]) and low recurrence rates (10% [95% CI, 6 to 16%]). Remission after TSS was higher in patients with microadenomas or positive–adrenocorticotropic hormone tumor histology. RT was associated with a high remission rate (RS, 68% [95% CI, 61 to 77%]; RT, 66% [95% CI, 58 to 75%]) but also with a high recurrence rate (RS, 32% [95% CI, 16 to 60%]; RT, 26% [95% CI, 14 to 48%]). Remission after RS was higher at short-term follow-up (≤2 years) and with high-dose radiation, while recurrence was higher in women and with lower-dose radiation. Remission was after RT in adults who received TSS prior to RT, and with lower radiation doses. There was heterogeneity (nonstandardization) in the criteria and cutoff points used to define biochemical remission and recurrence.Conclusion: First-line TSS is associated with high remission and low recurrence, while RS and RT are associated with reasonable remission rates but important recurrence rates. The current evidence warrants low confidence due to the noncomparative nature of the studies, high heterogeneity, and imprecision.Abbreviations:ACTH = adrenocorticotropic hormoneMRI = magnetic resonance imagingRS = radiosurgeryRT = radiotherapySC = serum cortisolTSS = transsphenoidal surgeryUFC = urinary free cortisol     

Clinical Presentation and Long-Term Outcome of Patients With Ectopic Acth Syndrome Due to Bronchial Carcinoid Tumors: A One-Center Experience

Objective: To describe the diagnostic features and long-term outcome of patients with bronchial carcinoid tumors with ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS), treated in our department.Methods: We studied 10 cases with EAS and histologically confirmed bronchial carcinoid tumors, diagnosed from 1992 until 2006. Diagnosis was based upon blood, urine, radiologic, and interventional tests. Disease status at the time of the last follow-up was the primary outcome measure.Results: Clinical manifestations included Cushingoid features (100%), psychiatric symptoms (90%), hypertension (70%), diabetes/impaired glucose tolerance (40%), osteoporosis (10%), and hypokalemia (10%). The average time from the onset of symptoms until diagnosis was 14.2 ± 17.0 months. None of the patients exhibited a positive cortisol or ACTH response to corticotropin-releasing hormone (CRH) test, and none showed a positive gradient on bilateral inferior petrosal sinus sampling (BIPSS). All tumors were identified by computed tomography and by octreotide scintigraphy in 8 patients. All patients underwent surgical resection of the tumor, and 2 patients had adjuvant radiation therapy. The mean follow-up was 126.6 ± 63.3 months. At latest follow-up, 8 patients were in remission and 2 had recurrence of the EAS; both had a multifocal tumor. The 2 patients submitted to adjuvant radiation therapy were in remission at their latest follow-up, despite local invasion and lymph node metastases.Conclusion: CRH test and BIPSS are the most useful methods in diagnosing EAS. For localization, repeated imaging studies are necessary. Surgical treatment is effective in most cases. Adjunctive radiotherapy may be useful in patients with lymph node metastases. Patients with multifocal disease should be monitored for potential recurrence.Abbreviations: ACTH = adrenocotricotropic hormone BC = bronchial carcinoid BIPSS = bilateral inferior petrosal sinus sampling CD = Cushing disease CRH = corticotropin-releasing hormone CS = Cushing syndrome CT = computed tomography EAS = ectopic ACTH syndrome HDDST = high-dose dexamethasone suppression test HPA = hypothalamic-pituitary-adrenal IPS:P = inferior petrosal sinus to periphery ratio MRI = magnetic resonance imaging     

Asymmetric Dimethylarginine Levels and Atherosclerosis Markers in Cushing Syndrome

Objective: As a consequence of hypercortisolism, Cushing syndrome (CS) is frequently observed with other diseases that are associated with atherosclerosis, including diabetes mellitus, dyslipidemia, hypertension, and obesity. Cardiovascular disease (CVD) is the primary cause of mortality and morbidity in CS. We investigate CVD risk markers such as asymmetric dimethylarginine (ADMA), lipoprotein-associated phospholipase A2 (Lp-PLA2), highsensitive C-reactive protein (hsCRP), homocysteine, lipid levels, ankle-brachial index (ABI), and carotid intimamedia thickness (CIMT) in CS.Methods: Our study included 27 patients with CS and 27 age-, sex-, body mass index (BMI)-, and comorbid disease–matched control subjects.Results: Plasma ADMA levels were significantly lower in the CS group than the control group (P = .013). Total cholesterol, low-density lipoprotein, triglycerides, high-density lipoprotein, and apolipoprotein A1 and apolipoprotein B levels were higher in patients with CS than the control group (P<.05). We did not find any statistically significant differences in levels of hsCRP, Lp-PLA2, or homocysteine or CIMT and ABI measurements between the CS group and comorbidity-matched control group (P>.05).Conclusion: We found that ADMA levels were lower in CS, the finding that should be further investigated. Levels of hsCRP, Lp-PLA2, and homocysteine levels and CIMT and ABI measurements were similar between the CS group and comorbidity-matched control group. None of these markers was prominent to show an increased risk of CVD in CS, independent of the comorbidities of CS.Abbreviations:ABI = ankle-brachial indexApo = apolipoproteinADMA = asymmetric dimethylarginineBMI = body mass indexCVD = cardiovascular diseaseCIMT = carotid intima-media thicknessCS = Cushing syndromeDM = diabetes mellitusDDAH = dimethylarginine dimethylaminohydrolaseELISA = enzyme-linked immunosorbent assayHDL = high-density lipoproteinhsCRP = high-sensitive C-reactive proteinHOMA-IR = homeostatic model assessment of insulin resistanceHT = hypertensionLDL = low-density lipoproteinLp-PLA2 = lipoprotein-associated phospholipase A2Lp-a = lipoprotein aNO = nitric oxide     

Postsurgical Recurrent Cushing Disease: Clinical Benefit of Early Intervention in Patients with Normal Urinary Free Cortisol

Objective: To assess the performance of biochemical markers in the detection of recurrent Cushing disease (CD), as well as the potential benefit of early intervention in recurrent CD patients with elevated late-night salivary cortisol (LNSC) and normal urinary free cortisol (UFC).Methods: The design was a single-center, retrospective chart review. Patients treated by the authors from 2008–2013 were included. Recurrence was defined by postsurgical remission of CD with subsequent abnormal LNSC, UFC, or dexamethasone suppression test (DST).Results: We identified 15 patients with postsurgical recurrent CD after initial remission; all but one underwent testing with LNSC, DST, and UFC. Although 12 of 15 patients had normal UFC at time of recurrence, DST was abnormal in 11 of 15, and all 14 patients with LNSC results had ≥1 elevated measurement. Nine patients (7 with normal UFC) showed radiologic evidence of a pituitary tumor at time of recurrence. Among the 14 patients with available follow-up data, 12 have demonstrated significant improvement since receiving treatment. Five patients underwent repeat pituitary surgery and 4 achieved clinical and biochemical remission. Eight patients received mifepristone or cabergoline, and 6 showed clinical and/or biochemical improvement. Three patients (2 with prior mifepristone) underwent bilateral adrenalectomy and 2 demonstrated significant clinical improvements.Conclusion: LNSC is more sensitive than UFC or DST for detection of CD recurrence. Prompt intervention when LNSC is elevated, despite normal UFC, may yield significant clinical benefit for many patients with CD. Early treatment for patients with recurrent CD should be prospectively evaluated, utilizing LNSC elevation as an early biochemical marker.Abbreviations:ACTH = adrenocorticotropic hormoneCD = Cushing diseaseCS = Cushing syndromeCV = coefficient of variationDST = dexamethasone suppression testIPSS = inferior petrosal sinus samplingLNSC = late-night salivary cortisolQoL = quality of lifeTSS = transsphenoidal adenoma resectionUFC = urinary free cortisol     

Conditioning Factors for High Cardiovascular Risk in Patients with Cushing Syndrome

Objective: To characterize the alterations in carbohydrate and lipoprotein metabolism, to evaluate markers of lipoprotein functionality, and to identify the presence of novel atherogenic risk factors in patients with Cushing syndrome (CS) in comparison with sex- and age-matched controls.Methods: In an open, cross-sectional study, 32 nontreated patients with active CS were consecutively recruited from the Endocrinology Service at “José de San Martín” Clinical Hospital, University of Buenos Aires, Argentina, between April 11, 2010 and December 11, 2012. The patients were compared with sex- and age-matched controls.Results: Versus controls, patients with CS presented with excess weight, central obesity, and hypercortisolism. They also exhibited an insulin-resistant state, with high resistin levels (median [interquartile range], 16 [10 to 22] ng/mL versus 6 [5 to 9] ng/mL; P<.0001), a more atherogenic lipoprotein profile, high oxidized low-density lipoprotein levels (oxLDL; mean ± SD, 100 ± 31 U/L versus 75 ± 32 U/L; P<.05) and high sensitive C-reactive protein levels (median [interquartile range], 1.2 [0.6 to 3.1] mg/L versus 0.6 [0.3 to 1.1] mg/L; P<.05), and increased leukocyte count (mean ± SD, 9.5 ± 2.6 × 10³ cells/μL versus 6.5 ± 1.4 × 10³ cells/μL; P<.0001). Multivariate analyses showed that the increase in waist circumference was associated with both the diagnosis of CS and the degree of insulin resistance. Resistin concentration was related to a greater extent to the diagnosis of CS than to homeostasis model assessment–insulin resistance. Triglyceride and oxLDL levels were only significantly associated with the diagnosis of CS.Conclusion: Hypercortisolism is related to the increase observed in triglycerides and oxLDL levels, and, in combination with insulin resistance, acts to increase waist circumference and amplify the inflammatory process, key factors for the development of cardiovascular disease.Abbreviations: apo = apolipoprotein ARE = arylesterase CETP = cholesteryl ester transfer protein CRP = C-reactive protein CS = Cushing syndrome CV = coefficient of variation HDL = high-density lipoprotein HDL-C = high-density-lipoprotein cholesterol HOMA = homeostasis model assessment LDL = low-density lipoprotein LDL-C = low-density-lipoprotein cholesterol Lp-PLA₂ = lipoprotein-associated phospholipase A₂ oxLDL = oxidized LDL PON = paraoxonase TG = triglyceride     

Association Between Mifepristone Dose,Efficacy, and Tolerability in Patients With Cushing Syndrome

Objective: To examine the relationship between dose, clinical response (based on independent evaluation of metabolic, physical, neurologic, and social assessments), and safety of mifepristone treatment in patients with endogenous Cushing syndrome (CS).Methods: This post hoc analysis included 40 clinical responders and 50 participants who received a dose of mifepristone (safety population) in the 24-week phase 3 SEISMIC (Study of the Efficacy and Safety of Mifepristone in the Treatment of Endogenous Cushing Syndrome) trial. The dose of mifepristone at the initial clinical response was analyzed, and the rate of serious adverse events (SAEs) and AEs reported in ≥20% of patients were compared to average mifepristone doses over time.Results: Among the clinical responders, 85% and 35% had their initial clinical responses at mifepristone doses ≥600 and ≥900 mg/day, respectively. The SAE rate did not increase with a higher dose over time. The AE rates for fatigue, headache, nausea, and peripheral edema declined significantly at weeks 16 to 24 (all P<.05 vs. weeks 1–2) as the study progressed and mifepristone doses were increased. Other AEs such as hypokalemia, vomiting, and decreased appetite did not significantly increase from weeks 1 to 2 as mifepristone doses were increased.Conclusions: The majority of clinical responders in the SEISMIC trial received mifepristone doses ≥600 mg/day suggesting that higher doses were required to achieve optimal clinical benefit in patients with endogenous CS. Notably, mifepristone dose escalations did not result in any significant or concordant increase in the rates of SAEs and common AEs.Abbreviations:ACTH = adrenocorticotropic hormoneAE = adverse eventCD = Cushing diseaseCS = Cushing syndromeSAE = serious adverse event     

Utility of a Single Late-Night Plasma Cortisol and Acth for the Diagnosis of Cushing Syndrome

Objective: To evaluate the diagnostic efficacy of various screening tests for the diagnosis of Cushing syndrome (CS).Methods: Thirty-five patients with CS and 16 patients of pseudo-CS were enrolled. Assessment of 24-h urinary free cortisol (UFC), late-night salivary cortisol (LNSC), overnight dexamethasone suppression test (ONDST), late-night plasma cortisol (LNPC), and adrenocorticotropic hormone (ACTH) on outpatient basis, and during sleep as well as in awake state after 48 hours of hospital admission.Results: We found that 24-h UFC performed the best among the screening tests with sensitivity, specificity and areas under the curve (AUCs) of 96.0%, 99%, and 0.988, respectively, at a cut-off of 144.6 μg/24 h. A cut-off of 10.5 nmol/L for LNSC had sensitivity 85.7%, specificity 88.2%, and an AUC of 0.897. A cut-off of 412.4 nmol/L for LNPC on outpatient basis had sensitivity 88.2%, specificity 91.2%, and an AUC of 0.957. Cut-offs of 215 and 243.3 nmol/L for LNPC during sleep and awake states after acclimatization had sensitivity, specificity, and an AUC of 94.1%, 88.2%, and 0.958, respectively. An ONDST cut-off of 94.6 nmol/L provided sensitivity, specificity, and an AUC of 96.0%, 99.03% and 0.995, respectively. A cut-off of 30.3 pg/mL for late-night ACTH on outpatient basis had sensitivity 67.6%, specificity 99.9%, and an AUC 0.796.A cut-off of 22.6 pg/mL for ACTH during sleep state after acclimatization had sensitivity, specificity, and an AUC of 73.5%, 99.2%, and 0.827, respectively.Conclusion: UFC is the best screening test for CS. Furthermore, single measurements of LNPC and ACTH help to establish the diagnosis and ACTH dependency of CS in the majority of patients with CS.Abbreviations:ACTH = adrenocorticotropic hormoneAUC = area under the curveCRH = corticotropin-releasing hormoneCS = Cushing syndromeECLIA = electrochemiluminescence immuno-assayLDDST = low-dose dexamethasone suppression testLNPC = late-night plasma cortisolLNSC = late-night salivary cortisolONDST = overnight dexamethasone suppression testRIA = radio-immuno assayUFC = urinary free cortisol     

Pathogenesis of Cushing Disease: An Update on the Genetics of Corticotropinomas

Objective: Cushing disease is a rare severe condition caused by pituitary tumors that secrete adrenocorticotropic hormone (ACTH), leading to excessive endogenous glucocorticoid production. Tumors causing Cushing disease, also called corticotropinomas, are typically monoclonal neoplasms that mainly occur sporadically.Methods: Literature review.Results: Cushing disease is very rarely encountered in genetic familial syndromes. Oncogenes and tumor suppressor genes commonly associated with other tumor types are only rarely mutated in this tumor type. The advent of next-generation sequencing led to the identification of a single mutational hotspot in the ubiquitin-specific protease 8 (USP8) gene in almost half of Cushing disease tumors.Conclusion: The new discoveries showcase a novel mechanism responsible for corticotroph tumorigenesis and ACTH hypersecretion and highlight USP8 and its downstream signaling pathways as potential promising pharmacologic targets for the management of Cushing disease.Abbreviations: ACTH = adrenocorticotropic hormone; BRG1 = Brahma-related gene 1; CABLES1 = CDK5 and ABL1 enzyme substrate 1; CD = Cushing disease; CNC = Carney complex; DICER1 = cytoplasmic endoribonuclease III; EGFR = epidermal growth factor receptor; GR = glucocorticoid receptor; IL = interleukin; MEN = multiple endocrine neoplasia; miRNA = microRNA; POMC = proopiomelanocortin; SSTR = somatostatin receptor; USP8 = ubiquitin-specific protease 8     

Pituitary Mri Findings in Patients With Pituitary and Ectopic Acth-Dependent Cushing Syndrome: Does A 6-Mm Pituitary Tumor Size Cut-Off Value Exclude Ectopic Acth Syndrome?

Objective: Expert opinion and a consensus statement on Cushing syndrome (CS) indicate that in a patient with a clinical presentation and biochemical studies consistent with a pituitary etiology, the presence of a pituitary tumor ≥6 mm is highly suggestive of Cushing disease (CD). The purpose of the present study was to determine the optimal pituitary tumor size that can differentiate between patients with CD and ectopic adrenocorticotrophic hormone (ACTH) secretion (EAS) and obviate the need for inferior petrosal sinus sampling (IPSS).Methods: We performed a retrospective study of 130 patients seen between 2000 and 2012 including 104 patients with CD and 26 patients with EAS.Results: A pituitary lesion was reported in 6/26 (23%) patients with EAS and 71/104 (68.3%) patients with CD, with median (range) sizes of 5 mm (3–14) and 8 mm (2–31), respectively. All tumors in the EAS group measured ≤6 mm except for 1 that measured 14 mm. The presence of a pituitary tumor >6 mm in size had 40% sensitivity and 96% specificity for the diagnosis of CD. ACTH levels >209 pg/mL and serum potassium <2.7 mmol/L were found in patients with EAS. All patients with EAS had a 24-hour urine free cortisol (UFC) >3.4 times the upper limit of normal (×ULN)Conclusion: Pituitary incidentalomas as large as 14 mm in size can be seen in patients with EAS. However, the 6-mm tumor size cut-off value provided 96% specificity and may be a reasonable threshold to proceed with surgery without the need for IPSS when the biochemical data support a pituitary etiology.Abbreviations: ACTH = adrenocorticotropic hormone CD = Cushing disease CRH = corticotropin-releasing hormone CS = Cushing syndrome EAS = ectopic ACTH secretion IPSS = inferior petrosal sinus sampling HDDST = high-dose dexamethasone suppression test LDDST = low-dose dexamethasone suppression test MRI = magnetic resonance imaging UFC = urine free cortisol ULN = upper limit of normal     

Health Care Resource Use and Costs Among Patients with Cushing Disease

ObjectiveTo assess health care costs associated with Cushing disease and to determine changes in overall and comorbidity-related costs after surgical treatment.MethodsIn this retrospective cohort study, patients with Cushing disease were identified from insurance claims databases by International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes for Cushing syndrome (255.0) and either benign pituitary adenomas (227.3) or hypophysectomy (07.6x) between 2004 and 2008. Each patient with Cushing disease was age- and sex-matched with 4 patients with nonfunctioning pituitary adenomas and 10 population control subjects. Comorbid conditions and annual direct health care costs were assessed within each calendar year. Postoperative changes in health care costs and comorbidity-related costs were compared between patients presumed to be in remission and those with presumed persistent disease.ResultsOf 877 identified patients with Cushing disease, 79% were female and the average age was 43.4 years. Hypertension, diabetes mellitus, and hyperlipidemia were more common among patients with Cushing disease than in patients with nonfunctioning pituitary adenomas or in control patients (P < .01). For every calendar year studied, patients with Cushing disease had significantly higher total health care costs (2008: $26440 [Cushing disease] vs $13 708 [nonfunctioning pituitary adenomas] vs $5954 [population control], P < .01). Annual outpatient costs decreased significantly for patients in remission after surgery, and there was a trend towards improvement in overall disease-related costs with remission. A significant increase in postoperative health care costs was observed in those patients not in remission.ConclusionsPatients with Cushing disease had more comorbidities than patients with nonfunctioning pituitary adenomas or control patients and incurred significantly higher annual health care costs; these costs decreased after successful surgery and increased after unsuccessful surgery. (Endocr Pract. 2011;17:681-690)     

Important Management Considerations In Patients With Pituitary Disorders During The Time Of The Covid-19 Pandemic

Objective: In December 2019, a novel coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused an outbreak of coronavirus disease 2019 (COVID-19) that resulted in a global pandemic with substantial morbidity and mortality. Currently, there is no specific treatment or approved vaccine against COVID-19. The underlying associated comorbidity and diminished immune function of some pituitary patients (whether caused by the disease and its sequelae or treatment with excess glucocorticoids) increases their risk of contracting and developing complications from COVID-19 infection.Methods: A review of studies in PubMed and Google Scholar published between January 2020 to the time of writing (May 1, 2020) was conducted using the search terms ‘pituitary,’ ‘coronavirus,’ ‘COVID-19’, ‘2019-nCoV’, ‘diabetes mellitus’, ‘obesity’, ‘adrenal,’ and ‘endocrine.’Results: Older age and pre-existing obesity, hypertension, cardiovascular disease, and diabetes mellitus increase the risk of hospitalization and death in COVID-19 patients. Men tend to be more severely affected than women; fortunately, most men, particularly of younger age, survive the infection. In addition to general comorbidities that may apply to many pituitary patients, they are also susceptible due to the following pituitary disorder–specific features: hypercortisolemia and adrenal suppression with Cushing disease, adrenal insufficiency and diabetes insipidus with hypopituitarism, and sleep-apnea syndrome and chest wall deformity with acromegaly.Conclusion: This review aims to focus on the impact of COVID-19 in patients with pituitary disorders. As most countries are implementing mobility restrictions, we also discuss how this pandemic has affected patient attitudes and impacted our decision-making on management recommendations for these patients.Abbreviations: ACE = angiotensin-converting enzyme; AI = adrenal insufficiency; ARB = angiotensin receptor blocker; ARDS = acute respiratory disease syndrome; COVID-19 = coronavirus disease 2019; CPAP = continuous positive airway pressure; DI = diabetes insipidus; DM = diabetes mellitus; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2     

Identification of Potential Markers for Cushing Disease

Objective: Cushing disease (CD) causes a wide variety of nonspecific symptoms, which may result in delayed diagnosis. It may be possible to uncover unusual combinations of otherwise common symptoms using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes. Our aim was to identify and evaluate dyads of clinical symptoms or conditions associated with CD.Methods: We conducted a matched case-control study using a commercial healthcare insurance claims database designed to compare the relative risk (RR) of individual conditions and dyad combinations of conditions among patients with CD versus matched non-CD controls.Results: With expert endocrinologist input, we isolated 10 key conditions (localized adiposity, hirsutism, facial plethora, polycystic ovary syndrome, abnormal weight gain, hypokalemia, deep venous thrombosis, muscle weakness, female balding, osteoporosis) with RRs varying from 5.3 for osteoporosis to 61.0 for hirsutism (and infinite RR for localized adiposity). The RRs of dyads of these conditions ranged from 4.1 for psychiatric disorders/serious infections to 128.0 for hirsutism/fatigue in patients with versus without CD. Construction of uncommon dyads resulted in further increases in RRs beyond single condition analyses; for example, osteoporosis alone had an RR of 5.3, which increased to 8.3 with serious infections and to 52.0 with obesity.Conclusion: This study demonstrated that RR of any one of 10 key conditions selected by expert opinion was ≥5 times greater in CD compared to non-CD, and nearly all dyads had RR≥5. An uncommon dyad of osteoporosis and obesity had an RR of 52.0. If clinicians consider the diagnosis of CD when the highest-risk conditions are seen, identification of this rare disease may improve.Abbreviations:CD = Cushing diseaseCPT = Current Procedural TerminologyCS = Cushing syndromeEMR = electronic medical recordICD-9-CM = International Classification of Diseases, Ninth Revision, Clinical ModificationID = identificationRR = relative risk     

Disease Presentation and Remission Rate in Graves Disease Treated With Antithyroid Drugs: is Gender Really A Factor?

Objective: Male gender is considered an adverse prognostic factor for remission of Graves disease treatment with antithyroid drugs (ATDs), although published data are conflicting. This often results in early consideration of radioiodine treatment and surgery for men. Our objective was to compare disease presentation and outcome in men versus women treated with ATDs.Methods: Retrospective study of 235 patients (64 men, 171 women) with Graves disease who were evaluated for features at presentation and outcome at the end of follow-up between 2010 and 2015.Results: Disease presentation was similar in men and women for age at diagnosis (41.4 ± 14 years vs. 40 ± 15 years), duration of follow-up (6.6 ± 7 years vs. 7.7 ± 6 years), rates of comorbid autoimmune diseases, and rate of Graves ophthalmopathy. Smoking was more prevalent in males (31% vs. 15%; P = .009). Free thyroxine and triiodothyronine levels were comparable. ATDs were first-line treatment in all males and in 168 of 171 females, for a median duration of 24 and 20 months, respectively (P = .55). Remission rates were 47% in men and 58% in women (P = .14). Males had fewer adverse events (9% vs. 18%) and treatment discontinuation (5% vs. 16%). Disease recurrence was comparable (14% vs. 20%; P = .32), as was requirement for second-line treatment, either radioiodine therapy or thyroidectomy.Conclusion: Graves disease presentation is similar in men and women. Men treated with ATDs have high remission rates and similar recurrence rates compared to women, with fewer adverse events and less discontinuation of treatment. ATDs are an attractive first-line treatment for both genders.Abbreviations: ATA = American Thyroid Association; ATD = antithyroid drug; GO = Graves ophthalmopathy; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone     

Necessity of Multimodal Treatment of Acromegaly and Outcomes

Objective: Uncontrolled acromegaly is associated with increased morbidity and mortality. Despite multimodal therapeutic options, adequate control can be challenging and lead to prolonged exposure to growth hormone excess. The aim of this study was to assess treatment patterns and outcomes in patients with acromegaly following surgery at a single institution.Methods: A retrospective analysis of response to treatment modalities for patients with a new diagnosis of acromegaly at the Mayo Clinic in Rochester, Minnesota, from 1995–2015.Results: A total of 245 patients with newly diagnosed acromegaly (mean age at diagnosis, 47 ± 14 years; mean follow-up, 5.5 ± 5 years) were evaluated. Primary surgical intervention was performed in 236 patients; 117 (54%) did not achieve remission. Among those with ≥3 months follow-up, 76/217 (35%) patients required three or more forms of treatment. Mean tumor size at diagnosis was 1.6 ± 0.8 cm (80% macroadenomas), and 35% (75/217) had cavernous sinus invasion on pre-operative imaging. The most common second-line treatment was radiation treatment (RT) (50%, 59/117). Among those with persistent disease following surgery, a normal insulin-like growth factor 1 (IGF-1) was achieved in 52% (61/117), with a median time to acromegaly control of 4.5 years. The rate of IGF-1 normalization was 2.1-fold higher in those who received RT compared to those who did not.Conclusion: In patients with persistent acromegaly following surgery, multiple treatment modalities, including RT, may be required to achieve remission. Treatment outcome uncertainty and the need for multiple interventions add to the disease burden associated with persistent acromegaly.Abbreviations: CI = confidence interval; GH = growth hormone; IGF-1 = insulin like growth factor-1; KM = Kaplan-Meier; RT = radiation treatment     

Venous Sampling for Cushing Disease: Comparison of Internal Jugular Vein and Inferior Petrosal Sinus Sampling

Objective: Because magnetic resonance imaging (MRI) fails to detect many adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas, inferior petrosal sinus sampling (IPSS) is considered the gold standard to differentiate Cushing disease (CD) from ectopic ACTH secretion syndrome (EAS). Some authors have suggested internal jugular vein sampling (IJVS) as an alternative to IPSS.Methods: We simultaneously compared IJVS to IPSS in 30 consecutive patients referred for ACTH-dependent Cushing syndrome and equivocal MRI exams. Five sites were simultaneously sampled in each patient (right and left IPS, right and left IJV, and femoral vein) before and after the administration of corticotrophin-releasing hormone or desmopressin. The test was considered consistent with CD when the IPS to peripheral ratio was >2 at baseline or >3 after stimulus and the IJV to peripheral ratio was >1.7 at baseline or >2 after stimulus.Results: In 27 of 30 patients, IPSS results were consistent with a central source of ACTH. Two of the other 3 patients had EAS (one lung carcinoid and one occult), and 1 patient had pathology-proven CD. The sensitivity of IPSS was 96.4%. Only 64.2% of these patients had results meeting criteria for a central source of ACTH by IJVS criteria. Twenty patients with centralizing IPPS have undergone pituitary surgery. Of these, the central origin of excessive ACTH was confirmed with certainty in 16 patients. Among these 16 patients, the IPSS sensitivity was 93.8%, whereas 5 patients had false-negative IJVS (68.7% sensitivity).Conclusion: These results do not support the routine use of IJVS in establishing if the pituitary is the source of excessive ACTH.Abbreviations:ACTH = adrenocorticotropic hormoneCD = Cushing diseaseCRH = corticotrophin-releasing hormoneCS = Cushing syndromeDDAVP = desmopressinEAS = ectopic ACTH secretionIJVS = internal jugular vein samplingIPSS = inferior petrosal sinus samplingJVS = jugular venous samplingMRI = magnetic resonance imaging     

Study Of The Prevalence Of Autoimmune Thyroid Disease In Women With Breast Cancer

Objective: The aim of this study was to analyze the prevalence of thyroid disorders in patients with a positive biopsy for breast cancer prior to specific antitumor treatment.Methods: The frequency and pattern of thyroid disorders were evaluated in 112 patients with breast cancer (G1) and 125 control patients (G2) by analyzing serum thyroid-stimulating hormone (TSH), anti–thyroid peroxidase antibodies, and anti-thyroglobulin antibodies. In addition, the expression of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2 (HER2) was assessed in the breast biopsies by immunohistochemistry.Results: The frequency of thyroid disorders, such as changes in TSH levels and/or the presence of thyroid antibodies, was not different between the 2 groups examined (30.4% in G1 versus 28.0% in G2) (P = .69). However, a family history of thyroid disease was more frequent in patients with breast cancer (50.5% in G1 versus 28.2% in G2) (P = .001). Regarding the clinical stage of breast cancer, there was no difference between women with autoimmune thyroiditis and those without thyroid dysfunction (P = .316). Similarly, there were no differences in hormone receptor (estrogen or progesterone) and HER2 expression between patients who tested positive and those who tested negative for anti-thyroid antibodies (P = .052 and P = .549, respectively).Conclusion: The data obtained in this study did not reveal a higher frequency of autoimmune thyroid disease in patients with breast cancer compared to controls. A family history of thyroid disease was more common in those with breast cancer.Abbreviations:anti-Tg = anti-thyroglobulinanti-TPO = anti–thyroid peroxidaseBIRADS = Breast Imaging-Reporting and Data SystemER = estrogen receptorFT₄ = free thyroxineG1 = study groupG2 = final control groupHER2 = human epidermal growth factor receptor 2PR = progesterone receptorTSH = thyroid-stimulating hormone     

Management Of Catecholamine-Secreting Tumors In Pregnancy: A Review

Objective: Catecholamine-secreting tumors (pheochromocytomas and paragangliomas) presenting during pregnancy are extremely rare, but they can be fatal to both mother and fetus. Recent discoveries in the genetic background of these tumors are expected to address an increasing number of at-risk women to prenatal diagnosis.Methods: The literature was reviewed in order to provide clinicians with a practical and updated guide on how to manage this life-threatening condition.Results: The clinical presentation of catecholamine-secreting tumors can be deceptive and mimic common disorders of pregnancy. Silent catecholamine-secreting tumors can become evident during pregnancy, and hypertension cannot be considered a hallmark for this condition: some women may be normotensive or develop orthostatic hypotension. Biochemical screening includes measurement of plasma free metanephrines or urinary fractioned metanephrines. Measurement of catecholamines, dopamine, and methoxytyramine can provide further information on tumor biology, location, and prognosis. Diagnostic imaging is limited, and medical treatment requires a cautious balance between hemodynamic control and effects on the fetoplacental unit. Several genes have been associated with syndromes including catecholamine-secreting tumors, and positive genetic testing can correlate with tumor behavior. Timing and modalities for tumor removal and delivery, including anesthetic management, depend on gestational age, maternal and fetal wellbeing, control of catecholamine excess, suspicion of multiple or malignant disease, and surgical accessibility to the tumor.Conclusion: A timely diagnosis and a multidisciplinary approach are the keys to improve pregnancy outcomes in patients with a catecholamine-secreting tumor; each case should be managed in a tertiary referral center.Abbreviations:CCB = calcium channel blockerCST = catecholamine-secreting tumorMRI = magnetic resonance imagingPG = paragangliomaPHEO = pheochromocytoma     

Clinical Heterogeneity of Ectopic ACTH Syndrome: A Long-Term Follow-Up Study

Objective: Ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) is a heterogeneous condition caused by neuroendocrine neoplasms (NENs) located in the lungs, thymus, or pancreas. Our purpose was to evaluate the long-term outcome of these patients.Methods: Retrospective study at a referral center. The charts of 164 patients with Cushing syndrome, followed at our center from 1993 to 2019, were analyzed.Results: EAS was found in 16 patients (9.75%, 9 women, mean age 36.01 years) who had been followed for a median of 72 months. The source of EAS was a NEN in 10 patients (8 bronchial and 2 thymic carcinoid tumors) and a mixed corticomedullary tumor, consisting of a pheochromocytoma and an adrenocortical carcinoma in 1 patient. In 2 of the 6 patients initially considered to have occult EAS, the source of the ACTH excess became apparent after adrenalectomy, whereas in the remaining 4 (25%) patients, it has remained occult. Of the 11 patients in whom resection of the NEN was attempted, 10 patients achieved an early remission (91%), but 4 (25%) of these patients had a recurrence during follow-up (biochemically and clinically silent in 2 patients). Three patients died (18.75%): the young woman with the mixed corticomedullary tumor, a man with a thymic NEN that evolved into a neuroendocrine (NE) carcinoma after 11 years of follow-up, and a woman with a bronchial NEN.Conclusion:The course of EAS varies according to tumor type and grade. Some patients have a protracted course, whereas others may evolve into neuroendocrine carcinomas.Abbreviations: ACTH = adrenocorticotropic hormone; CS = Cushing syndrome; CT = computed tomography; CV = coefficient of variation; EAS = ectopic ACTH syndrome; IQR = interquartile range; NEN = neuroendocrine neoplasm; SCCL = small cell carcinoma of the lung; TSS = transsphenoidal surgery; UFC = urinary free cortisol     

Cushing Disease Revealed by Bilateral Atypical Central Serous Chorioretinopathy: Case Report

ObjectiveWe report the case of a patient with Cushing disease revealed by bilateral central serous chorioretinopathy (CSCR).MethodsWe present the clinical history, physical findings, laboratory results, and imaging studies of a 53-year- old Chinese woman with a Cushing disease revealed by bilateral CSCR. The association with CSCR and the pertinent literature are reviewed.MethodsWe present the clinical history, physical findings, laboratory results, and imaging studies of a 53-year- old Chinese woman with a Cushing disease revealed by bilateral CSCR. The association with CSCR and the pertinent literature are reviewed.ResultsA 53-year-old patient initially presented to the Department of Ophthalmology with a 4-week history of decreased vision in the left eye. Standard ophthalmologic examination and fluorescein angiography established the diagnosis of bilateral CSCR. Systemic clinical signs and biochemical analysis indicated hypercortisolism. Magnetic resonance imaging (MRI) of the pituitary gland showed a left-side lesion compatible with a microadenoma. The diagnosis of Adrenocorticotropic hormone (ACTH)-dependent Cushing syndrome secondary to a pituitary microadenoma was selected. Endoscopic endonasal transsphenoidal surgery was performed and the pituitary adenoma was successfully removed. The histology confirmed the presence of ACTH-immunopositive pituitary adenoma. Early postoperative morning cortisol levels indicated early remission. At 6 weeks postoperatively, the patient’s morning cortisol remains undetectable, and serous retinal detachments had regressed.ConclusionCSCR is an uncommon manifestation of endogenous Cushing syndrome. It can be the first presentation of hypercortisolism caused by Cushing disease. CSCR should be considered when assessing patients with Cushing syndrome complaining of visual disorders. On the other hand, it is useful in patients with an atypical form of CSCR to exclude Cushing’s syndrome. (Endoer. Praet. 2013;19:el29-el33)