Pasireotide and Mifepristone: New Options in the Medical Management of Cushing's Disease

ObjectiveTo review and evaluate medical therapies for Cushing’s disease (CD), with an emphasis on recent clinical trial experience with pasireotide and mifepristone, and to discuss the therapeutic potential and appropriate selection of these compounds in this patient population.MethodsRecently published Phase III trial data for each compound are reviewed and assessed, and relative benefits and risks are examined and compared where possible.ResultsMifepristone and pasireotide are both potentially beneficial for CD patients but have greatly dissimilar mechanisms of action and adverse event (AE) profiles. Pasireotide acts at the level of the pituitary adenoma, reducing cortisol levels through inhibition of adrenocorticotropic hormone (ACTH) release. However, pasireotide reduces insulin secretion and incretin hormone response and is associated with significant risk for new or worsening hyperglycemia. Mifepristone ameliorates the signs and symptoms of hypercortisolemia via glucocorticoid receptor (GR2) blockade, but this approach raises serum cortisol levels and increases risk for adrenal insufficiency (AI), hypokalemia, and endometrial thickening. While response to pasireotide can be monitored via measurements of serum, urine, or late-night salivary cortisol, evaluation of response to mifepristone is solely based on changes in clinical parameters (e.g., hyperglycemia, hypertension, body weight/composition).ConclusionManagement of persistent CD is challenging, and the decision to initiate medical treatment hinges on many factors. Pasireotide may be a more attractive option for most patients due to its action at the underlying tumor and the ability to monitor biochemical responses. However, mifepristone may be more appropriate when it is necessary to avoid or minimize risk for hyperglycemiarelated complications. (Endocr Pract. 2014;20:84-93)     

Clinical Aspects of Hyperthyroidism,Hypothyroidism, and Thyroid Screening in Pregnancy

ObjectiveTo evaluate the peer-reviewed literature on hypothyroidism, hyperthyroidism, and thyroid autoimmunity in pregnancy.MethodsWe review published studies on thyroid autoimmunity and dysfunction in pregnancy, the impact of thyroid disease on pregnancy, and discuss implications for screening.ResultsOvert hyperthyroidism and hypothyroidism are responsible for adverse obstetric and neonatal events. Several studies of association suggest that either subclinical hypothyroidism or thyroid autoimmunity increase the risk of complications. One randomized controlled trial showed that pregnant women with subclinical hypothyroidism benefit from treatment in terms of obstetric and neonatal complications, whereas another study demonstrated no benefit in the intelligence quotient of babies born to women with subclinical hypothyroidism. Thyroid autoimmunity has been associated with increased rate of pregnancy loss, recurrent miscarriage, and preterm delivery.ConclusionCurrent guidelines agree that overt hyperthyroidism and hypothyroidism need to be promptly treated and that as potential benefits outweigh potential harm, subclinical hypothyroidism also requires substitutive treatment. The chance that women with thyroid autoimmunity may benefit from levothyroxine treatment to improve obstetric outcome is intriguing, but adequately powered randomized controlled trials are needed. The issue of universal thyroid screening at the beginning of pregnancy is still a matter of debate, and aggressive case-finding is supported. (Endocr Pract. 2014;20:597-607)     

The Rationale for Prandial Glycemic Control in Diabetes Mellitus

Background:Diabetes mellitus (DM) is of epidemic proportions worldwide, and its microvascular and macrovascular complications have been well described. Achieving glycemic control has been demonstrated to reduce patients' risk of developing these complications.Objective:The objective of this article was to examine how prandial hyperglycemia-especially postprandial hyperglycemia (PPHG)-affects overall glycemic control and the complications of DM and to discuss the pharmacologic agents available to reduce PPHG.Methods:Materials used for this article were identified through a MEDLINE search of the literature (1975–2006). English-language randomized, controlled, prospective, cohort, and observational studies were chosen using the search terms postprandial hyperglycemia, oxidative stress, cardiovascular disease, macrovascular disease, microvascular disease, lipidemia, and coagulation.Results:Data show that controlling prandial hyperglycemia reduces the risk of cardiovascular disease (CVD) andmicrovascular complications, lowers glycosylated hemoglobin levels, causes less oxidative stress, and leads to a more favorable coagulation and postprandial lipidemia profile. Guidelines for targeting PPHG are becoming standard, and various pharmacologic agents (eg, a-glucosidase inhibitors, amylin analogues, incretin mimetics, rapid-acting insulins and insulin analogues, meglitinide analogues) that target PPHG may also improve overall glycemic control and reduce CVD risk.Conclusions:Although the level of hyperglycemia that leads to microvascular and macrovascular complications inpatients with DM remains to be elucidated, it appears prudent to address prandial hyperglycemia, especially PPHG, rather than focus solely on fasting glucose levels. Clinicians should consider incorporating agents that lower PPHG in their treatment of patients with DM.     

Results of repeated transsphenoidal surgery in Cushing's disease. Long-term follow-up

ObjectiveTranssphenoidal surgery (TSS) is the treatment of choice for Cushing's disease (CD). However, the best treatment option when hypercortisolism persists or recurs remains unknown. The aim of this study was to analyze the short and long-term outcome of repeat TSS in this situation and to search for response predictors.Patients and methodsData from 26 patients with persistent (n = 11) or recurrent (n = 15) hypercortisolism who underwent repeat surgery by a single neurosurgeon between 1982 and 2009 were retrospectively analyzed. Remission was defined as normalization of urinary free cortisol (UFC) levels, and recurrence as presence of elevated UFC levels after having achieved remission. The following potential outcome predictors were analyzed: adrenal status (persistence or recurrence) after initial TSS, tumor identification in imaging tests, degree of hypercortisolism before repeat TSS, same/different surgeon in both TSS, and time to repeat surgery.ResultsImmediate postoperative remission was achieved in 12 patients (46.2%). Five of the 10 patients with available follow-up data relapsed after surgery (median time to recurrence, 13 months). New hormone deficiencies were seen in seven patients (37%), and two patients had cerebrospinal fluid leakage. No other major complications occurred. None of the preoperative factors analyzed was predictive of surgical outcome.ConclusionsWhen compared to initial surgery, repeat TSS for CD is associated to a lower remission rate and a higher risk of recurrence and complications. Further studies are needed to define outcome predictors.     

Neurologic Complications of Paget Disease of Bone

ObjectiveTo review the epidemiology, evaluation, and management of the neurologic complications associated with Paget disease of bone (PDB).MethodsWe reviewed the English-language medical literature using MEDLINE data sources from 1950 to August 2008 and manually searched cross-references from original articles and reviews. Search terms included “Paget* disease of bone” and “neurologic* complications,” “cranial nerve,” “spinal cord,” or “peripheral nerve.”ResultsSeveral neurologic problems in the central and peripheral nervous systems may complicate PDB. Up to 76% of patients may have some form of neurologic involvement. Neurologic complications can occur in patients with a long history of PDB as well as in patients with previously unrecognized disease. The primary mechanisms of nerve damage in PDB involving the spine are ischemic myelitis and compression due to bone hypertrophy. Evaluation includes determining the serum alkaline phosphatase level and imaging by radiography, bone scintigraphy, computed tomographic scanning, and, for lesions of the central nervous system, magnetic resonance imaging. If a soft-tissue mass is found, biopsy should be considered to exclude the presence of sarcoma. Treatment strategies include calcium, vitamin D, bisphosphonates, and possibly surgical intervention for refractory cases.ConclusionNeurologic sequelae of PDB may be underappreciated. Despite the paucity of data guiding treatment, zoledronic acid is a reasonable first-line therapy. Lack of response to treatment or relapse should prompt diagnostic reevaluation with a heightened suspicion for tumor. (Endocr Pract. 2009;15:158-166)     

AACE/ACE Disease State Clinical Review: Medical Management of Cushing Disease

ObjectiveTo review available medical therapies for patients with Cushing disease and to provide a roadmap for their use in clinical practice.MethodsPubMed searches were performed to identify all of the available published data on medical management of Cushing disease.ResultsMedical therapy is usually not the firstline treatment for patients with Cushing disease but may be used to improve clinical manifestations of Cushing disease in patients who are not suitable candidates for surgery, following unsuccessful surgery or recurrence, or as a “bridge therapy” in those who have undergone radiotherapy. Medical therapy may also be used in preoperative preparation of patients with severe disease. Current available medical options for patients with Cushing disease include centrally acting agents, steroidogenesis inhibitors, and a glucocorticoid receptor antagonists. At present, there are no head-to-head studies comparing the efficacy, tolerability, and safety of different U.S. Food and Drug Administration (FDA)- and non-FDA-approved drugs in patients with Cushing disease. With the initiation of new studies and the completion of ongoing clinical trials, the number of FDA-approved drugs for medical treatment of Cushing disease is expected to increase.ConclusionMedical therapy has an important adjunctive role in the management of patients with Cushing disease. The decision to initiate medical treatment depends on many factors, including patient characteristics and preference. Long-term studies are needed to better define the clinical efficacy, safety, and tolerability of medical treatment of Cushing disease, including the role of combination therapies. (Endocr Pract. 2014;20:746-757)     

Osilodrostat: A Review of Recent Clinical Studies and Practical Recommendations for its Use in the Treatment of Cushing Disease

ObjectiveCushing disease (CD) is characterized by chronic hypercortisolism caused by an adrenocorticotropic hormone-secreting pituitary adenoma. Surgery remains the first-line treatment option; however, medical therapy is essential if surgery is contraindicated or fails to achieve remission or when recurrence occurs after surgical remission. Osilodrostat (Isturisa), a novel steroidogenic inhibitor, is now approved for the treatment of CD in the United States and Cushing syndrome in Europe. Herein, we review pharmacology and data on the efficacy, safety, and clinical use of osilodrostat and provide guidance on its use in treating patients with CD.MethodsWe reviewed the literature and published clinical trial data of osilodrostat use in patients with Cushing syndrome. Detailed information related to the clinical assessment of osilodrostat use, potential drug-to-drug interactions, drug initiation, dose titration, and the monitoring of drug tolerability were discussed.ResultsClinical trial data demonstrated that osilodrostat, by virtue of inhibiting 11-β hydroxylase, potently and rapidly decreased the 24-hour urinary free cortisol levels and sustained these reductions, with improved glycemia, blood pressure, body weight, and quality of life as well as lessened depression. Osilodrostat may interact with certain drugs, resulting in QT prolongation, which requires careful assessment of concomitant medications and periodic monitoring using electrocardiogram, respectively. The common adverse effects include adrenal insufficiency, hypokalemia, edema, and hyperandrogenic symptoms, which can be minimized using a slower up-titration dosing regimen.ConclusionOsilodrostat is an effective, new treatment option for CD, with positive effects on cardiovascular and quality of life parameters as well as tolerable adverse effects. This article provides a review of the pharmacology of osilodrostat and offers practical recommendations on the use of osilodrostat to treat CD.     

Mebendazole Monotherapy and Long-Term Disease Control in Metastatic Adrenocortical Carcinoma

ObjectiveTo describe successful long-term tumor control in metastatic adrenocortical carcinoma, a relatively rare tumor with limited treatment options outside of surgery.MethodsWe present the clinical, radiologic, and pathologic findings in a patient with failure of or intolerance to conventional treatments for metastatic adrenocortical carcinoma.ResultsA 48-year-old man with adrenocortical carcinoma had disease progression with systemic therapies including mitotane, 5-fluorouracil, streptozotocin, bevacizumab, and external beam radiation therapy. Treatment with all chemotherapeutic drugs was ceased, and he was prescribed mebendazole, 100 mg twice daily, as a single agent. His metastases initially regressed and subsequently remained stable. While receiving mebendazole as a sole treatment for 19 months, his disease remained stable. He did not experience any clinically significant adverse effects, and his quality of life was satisfactory. His disease subsequently progressed after 24 months of mebendazole monotherapy.ConclusionMebendazole may achieve long-term disease control of metastatic adrenocortical carcinoma. It is well tolerated and the associated adverse effects are minor. (Endocr Pract. 2011;17:e59-e62)     

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     

Multiple Endocrinopathies Associated with Lithium Therapy

ObjectiveTo illustrate a case of lithium-associated primary hyperparathyroidism, thyrotoxicosis, and nephrogenic diabetes insipidus and to discuss the potential mechanisms for these complications.MethodsWe describe the clinical and laboratory findings in our current patient and review the related medical literature.ResultsA 65-year-old Chinese woman with bipolar affective disorder, who had received maintenance lithium therapy for 10 years, was seen in an acute care hospital because of fever and confusion. Investigations showed that she had primary hyperparathyroidism and hyperthyroidism. She underwent a parathyroidectomy, which revealed a parathyroid adenoma. Her initial subclinical hyperthyroidism evolved into overt hyperthyroidism after use of lithium was discontinued. Therapy was initiated with carbimazole, which was up-titrated briefly; the patient was subsequently weaned off this medication. Her postoperative course was complicated by persistent polyuria in conjunction with a negative fluid balance, consistent with nephrogenic diabetes insipidus. Thus, amiloride therapy was instituted. The results of an objective causality assessment suggested that the primary hyperparathyroidism, hyperthyroidism, and nephrogenic diabetes insipidus were possibly or probably related to the lithium therapy.ConclusionLithium remains an intriguing drug with numerous potential endocrinologic complications. It is important that clinicians prescribing lithium are aware of its side effects and have a strategy for their detection and management. (Endocr Pract. 2007;13:758-763)     

Celiac Disease Manifesting as Isolated Hypocalcemia

ObjectiveTo describe a patient who presented with hypocalcemia and hypocalciuria as the initial manifestations of celiac disease, despite a normal vitamin D status.MethodsWe review the diagnostic evaluation, treatment, and biochemical and bone mineral density responses of a patient with asymptomatic celiac disease, which was initially suggested because of a low serum calcium level that became attributable to isolated malabsorption of calcium.ResultsA 36-year-old woman presented with hypocalcemia in the presence of normal serum 25- hydroxyvitamin D and high serum 1,25-dihydroxyvitamin D levels. She had hypocalciuria and secondary hyperparathyroidism that were refractory to pharmacologic calcium and cholecalciferol supplementation. Fecal calcium excretion indicated malabsorption of calcium, and biopsy of the small intestine demonstrated pathologic changes characteristic of celiac disease. Bone mineral density, determined by dual-energy x-ray absorptiometry, was in the osteopenic range at the femoral neck. The initiation of a gluten-free diet resulted in correction of all biochemical abnormalities and a substantial increase in bone mineral density.ConclusionPrimary intestinal malabsorption of calcium without concomitant vitamin D deficiency is possible in celiac disease because of the preferential involvement of the proximal small intestine early in the disease process. Our patient had hypocalcemia caused by celiac disease and values for serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D that were normal and elevated, respectively. Correction was demonstrated after dietary gluten withdrawal. (Endocr Pract. 2004;10:203-207)     

Increased Risk of Radioiodine Treatment Failure Associated with Graves Disease Refractory to Methimazole

Objective: Iodine 131 (I-131) radioactive iodine (RAI) therapy has been the preferred treatment for Graves disease in the United States; however, trends show a shift toward antithyroid drug (ATD) therapy as first-line therapy. Consequently, this would favor RAI as second-line therapy, presumably for ATD refractory disease. Outcomes of RAI treatment after first-line ATD therapy are unclear. The purpose of this study was to investigate treatment failure rates and potential risk factors for treatment failure, including ATD use prior to RAI treatment.Methods: A retrospective case control study of Graves disease patients (n = 200) after I-131 RAI therapy was conducted. Treatment failure was defined as recurrence or persistence of hyperthyroidism in the follow-up time after therapy (mean 2.3 years). Multivariable regression models were used to evaluate potential risk factors associated with treatment failure.Results: RAI treatment failure rate was 16.5%. A majority of patients (70.5%) used ATD prior to RAI therapy, predominantly methimazole (MMI) (91.9%), and approximately two-thirds of patients used MMI for >3 months prior to RAI therapy. Use of ATD prior to RAI therapy (P = .003) and higher 6-hour I-123 thyroid uptake prior to I-131 RAI therapy (P<.001) were associated with treatment failure. MMI use >3 months was also associated with treatment failure (P = .002).Conclusion: More patients may be presenting for RAI therapy after failing first-line ATD therapy. MMI use >3 months was associated with RAI treatment failure. Further studies are needed to investigate the association between long-term first-line ATD use and RAI treatment failure.     

A Stepwise Approach to the Evaluation and Treatment of Subclinicalhyperthyroidism

ObjectivesTo review a stepwise approach to the evaluation and treatment of subclinical hyperthyroidism.MethodsEnglish-language articles regarding clinical management of subclinical hyperthyroidism published between 2007 and 2012 were reviewed.ResultsSubclinical hyperthyroidism is encountered on a daily basis in clinical practice. When evaluating patients with a suppressed serum thyrotropin value, it is important to exclude other potential etiologies such as overt triiodothyronine toxicosis, drug effect, nonthyroidal illness, and central hypothyroidism. In younger patients with mild thyrotropin suppression, it is acceptable to perform testing again in 3 to 6 months to assess for persistence before performing further diagnostic testing. In older patients or patients with thyrotropin values less than 0.1 mIU/L, diagnostic testing should proceed without delay. Persistence of thyrotropin suppression is more typical of nodular thyroid autonomy, whereas thyroiditis and mild Graves disease frequently resolve spontaneously. The clinical consequences of subclinical hyperthyroidism, such as atrial dysrhythmia, accelerated bone loss, increased fracture rate, and higher rates of cardiovascular mortality, are dependent on age and severity. The decision to treat subclinical hyperthyroidism is directly tied to an assessment of the potential for clinical consequences in untreated disease. Definitive therapy is generally selected for patients with nodular autonomous function, whereas antithyroid drug therapy is more appropriate for mild, persistent Graves disease.ConclusionThe presented stepwise approach to the care of patients presenting with an isolated suppression of serum thyrotropin focuses on the differential diagnosis, a prediction of the likelihood of persistence, an assessment of potential risks posed to the patient, and, finally, a personalized choice of therapy. (Endocr Pract. 2012;18: 772-780)     

Management of Patients With Low-Risk Papillary Thyroid Carcinoma

ObjectiveTo define a rational, cost-effective, simple approach to managing most patients with papillary thyroid cancer (PTC) who are at low-risk of either cause-specific mortality or tumor recurrence.MethodsTaking advantage of the collective experience of a cohort of 2512 patients with PTC who had initial definitive treatment at the Mayo Clinic in Rochester, Minnesota, between 1940 and 2000, a 5-step approach to the management of low-risk PTC has been devised. This program is based on appropriate preoperative ultrasound localization of neck disease and potentially curative surgery consisting of near-total or total thyroidectomy, with appropriate neck nodal exploration and resection.ResultsThe emphasis of the present program is on the extent of initial surgery, where optimal care is ascribed to a near-total thyroidectomy with curative intent and appropriate neck nodal resection as predicated by appropriate preoperative ultrasonography evaluation of regional lymph nodes. Radioiodine remnant ablation (RRA) is not applicable to patients with PTC who are defined on the day of definitive initial surgery to be at low risk as defined by a metastasis, age, completeness of resection, invasion, and size (MACIS) score of less than 6.ConclusionThe outlook for patients with low-risk PTC is very optimistic, with rates at 30 postoperative years of only 1% for cause-specific mortality and less than 15% for tumor recurrence at any site. The long-term results obtained by potentially curative bilateral resection, appropriate regional lymph nodal excision, and selective use of RRA are excellent. Realistically improving these acceptably low rates for cause-specific mortality and tumor recurrence may be difficult. (Endocr Pract. 2007;13:521-533)     

Limitations of Current Approaches For The Treatment of Acromegaly

Objective: Acromegaly is a rare disease characterized by hypersecretion of growth hormone (GH), typically from a benign pituitary somatotroph adenoma, that leads to subsequent hypersecretion of insulin-like growth factor 1 (IGF-1). Patients with acromegaly have an increased risk of mortality and progressive worsening of comorbidities. Surgery, medical therapy, and radiotherapy are currently available treatment approaches for patients with acromegaly, with overall therapeutic goals of lowering GH levels and achieving normal IGF-1 levels, reducing tumor size, improving comorbidities, and minimizing mortality risk. Although surgery can lead to biochemical remission in some patients with acromegaly, many patients will continue to have uncontrolled disease and require additional treatment.Methods: We reviewed recently published reports and present a summary of the safety and efficacy of current treatment modalities for patients with acromegaly.Results: A substantial proportion of patients who receive medical therapy or radiotherapy will have persistently elevated GH and/or IGF-1. Because of the serious health consequences of continued elevation of GH and IGF-1, there is a need to improve therapeutic approaches to optimize biochemical control, particularly in high-need patient populations for whom current treatment options provide limited benefit.Conclusion: This review discusses current treatment options for patients with acromegaly, limitations associated with each treatment approach, and areas within the current treatment algorithm, as well as patient populations for which improved therapeutic options are needed. Novel agents in development were also highlighted, which have the potential to improve management of patients with uncontrolled or persistent acromegaly.Abbreviations:AACE = American Association of Clinical EndocrinologistsAE = adverse eventATG = AutogelCFRT = conventional fractionated radiotherapyDA = dopamine agonistENDO = Endocrine SocietyGH = growth hormoneGHRA = growth hormone receptor antagonistIGF-1 = insulin-like growth factor 1LAR = long-acting releaseLFT = liver function testSC = subcutaneousSRS = stereotactic radiosurgerySSA = somatostatin analoguesst = somatostatin receptorsst₂ = somatostatin receptor subtype 2sst₅ = somatostatin receptor subtype 5TSS = transsphenoidal surgery     

Successful Long-Term Treatment of Cushing Disease with Mifepristone (RU486)

ObjectiveWe describe a girl with Cushing disease for whom surgery and radiation treatments failed and the sub- sequent clinical course with mifepristone therapy.MethodsWe present the patient’s clinical, biochemi- cal, and imaging findings.ResultsA 16-year-old girl presented with classic Cushing disease. After transsphenoidal surgery, Cyberknife radiosurgery, ketoconazole, and metyrapone did not control her disease, and she was prescribed mifepristone, which was titrated to a maximal dosage of 1200 mg daily with subsequent symptom improvement. Mifepristone (RU486) is a high-affinity, nonselective antagonist of the glucocor- ticoid receptor. There is limited literature on its use as an off-label medication to treat refractory Cushing disease. Over her 8-year treatment with mifepristone, her therapy was complicated by hypertension and hypokalemia requir- ing spironolactone and potassium chloride. She received a 2-month drug holiday every 4 to 6 months to allow for withdrawal menstrual bleeding with medroxyprogester- one acetate. Urinary cortisol, serum cortisol, and cortico- tropin levels remained elevated during mifepristone drug holidays. While on mifepristone, her signs and symptoms of Cushing disease resolved. Repeated magnetic resonance imaging demonstrated stable appearance of the residual pituitary mass. Bilateral adrenalectomy was performed, and mifepristone was discontinued after 95 months of medical therapy.ConclusionsWe describe the longest duration of mifepristone therapy thus reported for the treatment of refractory Cushing disease. Mifepristone effectively controlled all signs and symptoms of hypercortisolism. Menstruating women who take the drug on a long-term basis should receive periodic drug holidays to allow for menses. The lack of reliable serum biomarkers to monitor the success of mifepristone therapy requires careful clini- cal judgment and may make its use difficult in Cushing disease. (Endocr Pract. 2012;18:e114-e120)     

Outcomes of Transsphenoidal Surgery in Cushing Disease Patients with Negative Pituitary Magnetic Resonance Imaging Findings: A Single-Center Experience

Objective: Transsphenoidal surgery (TSS) is a first-line treatment for Cushing disease (CD). However, a subset of patients with CD have no visible adenoma on magnetic resonance imaging (MRI), and whether MRI results affect surgical outcomes is controversial. The aim of this study was to compare the surgical outcomes of CD patients with negative MRI findings to those of patients with positive MRI findings.Methods: The clinical features and outcomes of CD patients who underwent TSS between January 2000 and July 2019 at Peking Union Medical College Hospital were collected from medical records. The clinical, endocrinologic, histopathologic, surgical outcomes, and a minimum 12-month follow-up of 125 consecutive CD patients with negative MRI findings were compared with those of 1,031 consecutive CD patients with MRI-visible adenomas.Results: The total remission rate was 73.3% after TSS, and 11.8% of patients experienced recurrence. Of 1,031 patients with MRI-visible adenomas, postoperative remission was achieved in 762 patients (73.9%), and the recurrence of CD was observed in 94 (12.3%) patients. Of the 125 patients with negative MRI findings, postoperative remission was achieved in 85 (68%) patients, and recurrence was observed in 6 (7.1%) patients. The remission rate and recurrence rate were not significantly different between patients with negative MRI findings and those with positive MRI findings (all P>.05). The remission rate was not significantly different between patients who did or did not undergo bilateral inferior petrosal sinus sampling (BIPSS) in patients with negative MRI findings (P>.05). In the patients with negative MRI findings who underwent BIPSS, the remission rate of patients with positive BIPSS results was not different from that in patients with negative BIPSS results (P>.05). The lack of prior TSS, the detection of a tumor during operation, and pathologic confirmation of adenoma were associated with a higher surgical remission rate in patients with negative MRI findings (all P<.05). Similar results were observed in the patients with positive MRI findings (all P<.05). In addition, the major perioperative complications, including intraoperative cerebrospinal fluid leakage, hypopituitarism, and transient diabetes insipidus, were not related to the MRI results (all P>.05).Conclusion: The remission rate and recurrence rate were not different between patients with negative MRI findings and those with positive MRI findings. If CD is clearly diagnosed according to biochemical tests, radiologic examinations, and BIPSS, we recommend TSS as the first-line treatment for patients, even if the MRI results are negative.     

Effects of Metabolic Syndrome with or without Obesity on Outcomes after Coronary Artery Bypass Graft. A Cohort and 5-Year Study

BackgroundMetabolic syndrome (MetS) and obesity are risk factors for cardiovascular disease, however, it remains unclear about effects of MetS with or without obesity on perioperative and long-term morbidity and mortality after coronary artery bypass graft (CABG).MethodsAn observational cohort study was performed on 4,916 consecutive patients receiving isolated primary CABG in Fuwai hospital. Of all patients, 1238 patients met the inclusion criteria and were divided into three groups: control, MetS with obesity and MetS without obesity (n = 868, 76 and 294 respectively). The patient’s 5-year survival and major adverse cerebral and cardiovascular events (MACCE) were studied.ResultsAmong all three groups, there were no significant differences in in-hospital postoperative complications, epinephrine use, stroke, ICU stay, ventilation time, atrial fibrillation, renal failure, coma, myocardial infarction, repeated revascularization, and long-term stroke. The patients in MetS without obesity group were not associated with increased perioperative or long-term morbidities and mortality. In contrast, the patients in MetS with obesity group were associated with significant increased perioperative complications including MACCE (30.26% vs. 20.75%, 16.7%, p = 0.0074) and mortality (11.84% vs. 3.74%, 3.11%, p = 0.0007) respectively. Patients in MetS with obesity group was associated with significantly increased long-term of MACCE (adjusted OR:2.040; 95%CI:1.196–3.481; P＜0.05) and 5-years of mortality (adjusted HR:4.659; 95%CI:1.966–11.042; P＜0.05).ConclusionsPatients with metabolic syndrome and obesity are associated with significant increased perioperative and long-term complications and mortality, while metabolic syndrome without obesity do not worsen outcomes after CABG.