Hypercortisolism Is Associated With Increased Coronary Arterial Atherosclerosis

Hypercortisolism Is Associated With Increased Coronary Arterial Atherosclerosis: Analysis of Noninvasive Coronary Angiography Using Multidetector Computerized Tomography
Journal of Clinical Endocrinology and Metabolism, 05/21/2013  Clinical Article

1. Nicola M. Neary*, 
2. O. Julian Booker*, 
3. Brent S. Abel, 
4. Jatin R. Matta,
5. Nancy Muldoon, 
6. Ninet Sinaii, 
7. Roderic I. Pettigrew, 
8. Lynnette K. Nieman and
9. Ahmed M. Gharib

-Author Affiliations

1. Program in Reproductive and Adult Endocrinology (N.M.N., L.K.N., B.S.A.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; Laboratory of Cardiac Energetics (O.J.B.), National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892; Integrative Cardiovascular Imaging Laboratory (J.R.M., R.I.P., A.M.G.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892; Critical Care Medicine (N.M.), Clinical Center, National Institutes of Health, Bethesda, Maryland 20892; and Biostatistics and Clinical Epidemiology Service (N.S.), Clinical Center, National Institutes of Health, Bethesda, Maryland 20892

1. Address all correspondence and requests for reprints to: Ahmed M. Gharib, MB, ChB, National Institutes of Health, Building 10, Room 3-5340, Mail Stop Code 1263, 10 Center Drive, Bethesda, MD 20892. E-mail: agharib@mail.nih.gov.

1. ↵* N.M.N. and O.J.B. contributed equally to this work.

Abstract

Background: Observational studies show that glucocorticoid therapy and the endogenous hypercortisolism of Cushing's syndrome (CS) are associated with increased rates of cardiovascular morbidity and mortality. However, the causes of these findings remain largely unknown.

Objective: To determine whether CS patients have increased coronary atherosclerosis.

Design: A prospective case-control study was performed.

Setting: Subjects were evaulated in a clinical research center.

Subjects: Fifteen consecutive patients with ACTH-dependent CS, 14 due to an ectopic source and 1 due to pituitary Cushing's disease were recruited. Eleven patients were studied when hypercortisolemic; 4 patients were eucortisolemic due to medication (3) or cyclic hypercortisolism (1). Fifteen control subjects with at least one risk factor for cardiac disease were matched 1:1 for age, sex, and body mass index.

Primary outcome variables: Agatston score a measure of calcified plaque and non-calcified coronary plaque volume were quantified using a multidetector CT (MDCT) coronary angiogram scan. Additional variables included fasting lipids, blood pressure, history of hypertension or diabetes, and 24-hour urine free cortisol excretion.

Results: CS patients had significantly greater noncalcified plaque volume and Agatston score (noncalcified plaque volume [mm³] median [interquartile ranges]: CS 49.5 [31.4, 102.5], controls 17.9 [2.6, 25.3], P < .001; Agatston score: CS 70.6 [0, 253.1], controls 0 [0, 7.6]; P < .05). CS patients had higher systolic and diastolic blood pressures than controls (systolic: CS 143 mm Hg [135, 173]; controls, 134 [123, 136], P < .02; diastolic CS: 86 [80, 99], controls, 76 [72, 84], P < .05).

Conclusions: Increased coronary calcifications and noncalcified coronary plaque volumes are present in patients with active or previous hypercortisolism. Increased atherosclerosis may contribute to the increased rates of cardiovascular morbidity and mortality in patients with glucocorticoid excess.

• Received October 29, 2012.
• Accepted March 7, 2013.

• Copyright © 2013 by The Endocrine Society

From JCEM

Ectopic Cushing's Syndrome Secondary to Pulmonary Carcinoid Tumor

Shahriar Hashemzadeh, MD, Atabak Asvadi Kermani, MD, Akbar Ali-Asgharzadeh, MD, Moneireh Halimi, MD, Mina Soleimani, MD, Amirhosein Ladan, MD

The Annals of Thoracic Surgery, Volume 95, Issue 5, May 2013, Pages 1797-1799 

http://dx.doi.org/10.1016/j.athoracsur.2012.09.039

Adrenocorticotropic hormone (ACTH) overproduction within the pituitary gland or ectopically leads to hypercortisolism.

In this study a case of Cushing's syndrome caused by an ectopic ACTH-secreting carcinoid tumor in lung is discussed, as are the available diagnostic procedures.

The patient was a 28-year-old woman with clinical features starting about 6 months previously. The results of her biochemical tests suggested ectopic Cushing's syndrome.

Full-body computed tomography revealed a single nodule in the inferior lobe of the right lung.

After removal of the nodule, the patient's symptoms subsided clinically, and laboratory tests confirmed remission of the hypercortisolism.

View Full Text

Cushing's syndrome

Betul A. Hatipoglu MD*

Article first published online: 27 JUN 2012

DOI: 10.1002/jso.23197

Keywords:

Cushing's syndrome; adrenal carcinoma; virilization; hypercortisolism

Abstract

Cushing's syndrome (CS) results from prolonged exposure to elevated endogenous cortisol. Majority of cases are caused by ACTH, pituitary, or ectopic origin. Primary adrenal hypersecretion is 15–20% caused by adenomas, carcinomas (ACC), and rarely by nodular adrenocortical disease. CS presents with all typical features.

Commonly recommended initial testing are urinary free cortisol, late-night salivary cortisol, and 1-mg overnight dexamethasone suppression test (DST). Imaging is the key to diagnosis. CS continues to pose diagnostic and therapeutic challenges; life-long follow-up is mandatory.

J. Surg. Oncol © 2012 Wiley Periodicals, Inc.

Read this article at Wiley Online Publications

Cortendo Receives Positive Orphan Drug Opinion from EMA for NormoCort for Cushing’s Disease

Cortendo AB with support from their preclinical development partner, PharmaDirections, Inc. received a positive opinion from the European Medicines Agency for NormoCort.

Radnor, PA (PRWEB) June 26, 2012

Cortendo AB [ticker: CORT on the Norwegian NOTC-A], a biopharmaceutical Corporation focused on the development of new therapies in the field of Metabolic Diseases, obtained a positive opinion by the European Medicines Agency's Committee for Orphan Medicinal Products, on its application for orphan drug designation for NormoCort (COR-003) for the treatment of hypercortisolism (Cushing’s Syndrome). The positive opinion of the COMP for NormoCort has now been forwarded to the EU commission for final approval and publication in the EU community register. With orphan drug designation granted in the US by the FDA in March and now with this positive opinion from the EU’s COMP, Cortendo is well positioned to move NormoCort into pivotal global clinical trials in Cushing’s Syndrome.

Cortendo is a biopharmaceutical company that relies in part on quality consultants and CRO’s to support the research and development of its pipeline. For the past year, Cortendo has contracted with PharmaDirections for a number of key services ranging from CMC to US and European Regulatory support. PharmaDirections’ regulatory services have ranged from the successful preparation and support to orphan drug designation applications in both the US and Europe to support with both IND and CTA preparation. “Cortendo has appreciated the high quality of support particularly in the areas of regulatory, CMC, and project management services offered by PharmaDirections”, said Dr. Ted Koziol, COO of Cortendo.

“Our Cortendo relationship is a great example of a virtual company using outsourced resources to their maximum advantage” said Dr. Richard Soltero, President of PharmaDirections.

About Cortendo:

Cortendo is a pioneer in the field of cortisol inhibition. The development of the lead drug candidate NormoCort (COR-003), the 2S,4R-enantiomer of ketoconazole, has been directed to Cushing’s Syndrome. The company’s strategy is to focus its resources to opportunities where the path to commercialization or partnership is clear and relatively near-term. Strategically, Cortendo’s business model is to commercialize relevant opportunities in the United States while partnering its assets ex-US. Backed by a highly experienced leadership team Cortendo has plans to continue to implement its pipeline expansion efforts in osteoarthritis and diabetes, as well as other near term revenue opportunities.

About PharmaDirections:

PharmaDirections, Inc. provides pharmaceutical consulting and project management services with a focus on preclinical development, formulation development and CMC, and regulatory affairs. The company was founded in 2003 and is based in Cary, North Carolina.

From PRWeb

Corcept Therapeutics Incorporated Announces FDA Approval of Korlym™ (mifepristone) 300 mg Tablets: First and Only Approved Medication for Cushing’s Syndrome Patients

MENLO PARK, Calif. - February 17, 2012

Corcept Therapeutics (NASDAQ:CORT) announced today that the U.S. Food and Drug Administration (FDA) has approved Korlym™ (mifepristone) 300 mg Tablets as a once-daily oral medicine to control hyperglycemia secondary to hypercortisolism in adult patients with endogenous Cushing's syndrome who have diabetes mellitus type 2 or glucose intolerance and have failed surgery or are not candidates for surgery.

"We appreciate the FDA's diligent attention to our NDA and its grant of approval on the PDUFA date," said Joseph K. Belanoff, M.D., the company's Chief Executive Officer. "We plan to make Korlym available to patients by May 1 through a distribution system designed to support both patients and prescribers."

Corcept will be the sole marketer of Korlym. "A relatively small number of endocrinologists regularly treat patients with Cushing's syndrome," added Dr. Belanoff. "These doctors can be reached without a large sales and marketing infrastructure." The company has begun hiring Medical Science Liaisons to inform practitioners about the drug, which will be dispensed by the leading specialty pharmacy company CuraScript SP, a subsidiary of Express Scripts.

"Korlym is a significant advance in the treatment of patients suffering from the debilitating symptoms of Cushing's syndrome," said Robert L. Roe, M.D., Corcept's President. "For the first time, these patients have access to an approved therapy when surgery has failed or is not an option."

Korlym clinical trial investigator Amir Hamrahian, M.D., Department of Endocrinology, Diabetes and Metabolism at the Cleveland Clinic said, "There are not many effective treatment options for patients with Cushing's syndrome. Although surgery is standard first line treatment for the disease, it is not always successful and not all patients are candidates. As part of the clinical trial, I have used Korlym successfully and my patients continue to do well on the medicine. I'm excited to be able to continue using Korlym in these patients and others who need it. This medicine's approval gives me a much needed tool to better treat patients."

Dr. Hamrahian's comments were seconded by Maureen V., a patient in Corcept's Phase 3 clinical trial: "I had pituitary surgery to treat my Cushing's syndrome. Unfortunately, my surgery wasn't successful. I was lucky to get into the study and get Korlym treatment. I have been taking the medicine successfully for over a year, and I am extremely happy that it was approved by the FDA. Now I know I'll be able to keep taking it. It has made a big difference in my life."

Clinical Trial Results Supporting FDA Approval 
The clinical data supporting the FDA approval of Korlym resulted from an uncontrolled, open-label, multi-center, 24-week phase III study of 50 patients who had endogenous Cushing's syndrome and were either not eligible for or had relapsed from surgery and were either glucose intolerant (29 patients) or had hypertension (21 patients). Within the glucose intolerant group, 60 percent of patients had a greater than 25 percent reduction from baseline in the area under the curve in the oral glucose tolerance test. In this group, mean hemoglobin A1C (HbA1C) was reduced from 7.4 percent to 6.3 percent. All 14 patients with above-normal HbA1C levels at baseline experienced reductions. Eight of these 14 normalized their HbA1C. Antidiabetic medications were reduced in seven of the 15 patients with diabetes mellitus type 2 and remained constant in the others.

Patients who responded to therapy were allowed enrollment in an extension trial. Eighty-eight percent of the patients who completed the trial chose to do so.

A peer-reviewed analysis of the study results will soon be published in a leading journal.

Patients in the study started Korlym treatment on a dose of 300 mg administered once daily. Their dose was then titrated to maximum clinical effect. As indicated in the medicine's label, physicians prescribing Korlym may determine the appropriate dose for each patient by assessing tolerability and degree of improvement in Cushing's syndrome manifestations. In the first six weeks, these manifestations may include changes in glucose control, anti-diabetic medication requirements, insulin levels and psychiatric symptoms. After two months, assessment may also be based on improvements in cushingoid appearance, acne, hirsutism, striae, decreased body weight, along with further changes in glucose control.

About Korlym™ (mifepristone) 300 mg Tablets
Korlym is a once-daily oral medication that blocks the glucocorticoid receptor type II (GR-II) to which cortisol normally binds. By blocking this receptor, Korlym inhibits the effects of excess cortisol in Cushing's syndrome patients.

The FDA has designated Korlym as an Orphan Drug for treatment of the clinical manifestations of endogenous Cushing's syndrome. Orphan Drug designation is a special status designed to encourage the development of medicines for rare diseases and conditions. Because Korlym is an Orphan Drug, Corcept will have marketing exclusivity consistent with the FDA's designation until February 2019.

About Cushing's Syndrome 
Endogenous Cushing's syndrome is a rare and life-threatening endocrine disorder that results from long-term exposure to excess levels of the hormone cortisol. This excess is caused by tumors that usually occur in the pituitary or adrenal glands that over-produce, or prompt the over-production of, cortisol.

Although cortisol at normal levels is essential to health, in excess it causes a variety of problems, including hyperglycemia, upper body obesity, a rounded face, stretch marks on the skin, an accumulation of fat on the back, thin and easily bruised skin, muscle weakness, bone weakness, persistent infections, high blood pressure, fatigue, irritability, anxiety, psychosis and depression. Women may have menstrual irregularities and facial hair growth, while men may have decreased fertility or erectile dysfunction. More than 70 percent of Cushing's syndrome patients suffer from glucose intolerance or diabetes.

The treatment of an endogenous Cushing's syndrome patient depends on the cause. The first-line approach is surgery to remove the tumor.  If surgery is not successful or is not an option, radiation may be used, but that therapy can take up to ten years to achieve full effect.  Surgery and radiation are successful in only approximately one-half of all cases.

If left untreated, Cushing's syndrome has a five-year mortality rate of 50 percent.

An orphan disease, Cushing's syndrome occurs in about 20,000 people in the United States, mostly women between the ages of 20 and 50.

Conference Call Information 
Corcept will hold a conference call on Tuesday, February 21, 2012 at 9:00 a.m. Eastern Time (6:00 a.m. Pacific Time) to discuss this announcement. To participate in the live call please dial 1-800-264-7882 from the United States or +1-847-413-3708 internationally. The pass code is 31838602. Please dial in approximately 10 minutes before the start of the call.

A replay of the conference call will be available through March 6, 2012 at 1-888-843-7419 from the United States and +1-630-652-3042 internationally. The pass code is 31838602.

IMPORTANT SAFETY INFORMATION

WARNING: TERMINATION OF PREGNANCY

See full prescribing information for complete boxed warning.

has potent antiprogestational effects and will result in the termination of pregnancy. Pregnancy must therefore be excluded before the initiation of treatment with Korlym, or if treatment is interrupted for more than 14 days in females of reproductive potential.

Contraindications

• Pregnancy
• Use of simvastatin or lovastatin and CYP 3A substrates with narrow therapeutic range
• Concurrent long-term corticosteroid use
• Women with history of unexplained vaginal bleeding
• Women with endometrial hyperplasia with atypia or endometrial carcinoma

Warnings and Precautions

• Adrenal insufficiency: Patients should be closely monitored for signs and symptoms of adrenal insufficiency.
• Hypokalemia: Hypokalemia should be corrected prior to treatment and monitored for during treatment.
• Vaginal bleeding and endometrial changes: Women may experience endometrial thickening or unexpected vaginal bleeding. Use with caution if patient also has a hemorrhagic disorder or is on anti-coagulant therapy.
• QT interval prolongation: Avoid use with QT interval-prolonging drugs, or in patients with potassium channel variants resulting in a long QT interval.
• Use of Strong CYP3A Inhibitors: Concomitant use can increase plasma levels significantly. Use only when necessary and limit dose to 300 mg.

Adverse Reactions

Most common adverse reactions in Cushing's syndrome (≥ 20%): nausea, fatigue, headache, decreased blood potassium, arthralgia, vomiting, peripheral edema, hypertension, dizziness, decreased appetite, endometrial hypertrophy.

To report suspected adverse reactions, contact Corcept Therapeutics at 1-855-844-3270 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Drug Interactions

• Drugs metabolized by CYP3A: Administer drugs that are metabolized by CYP3A at the lowest dose when used with Korlym
• CYP3A inhibitors: Caution should be used when Korlym is used with strong CYP3A inhibitors. Limit mifepristone dose to 300 mg per day when used with strong CYP3A inhibitors.
• CYP3A inducers: Do not use Korlym with CYP3A inducers.
• Drugs metabolized by CYP2C8/2C9: Use the lowest dose of CYP2C8/2C9 substrates when used with Korlym.
• Drugs metabolized by CYP2B6: Use of Korlym should be done with caution with bupropion and efavirenz.
• Hormonal contraceptives: Do not use with Korlym.

Use in Specific Populations

• Nursing mothers: Discontinue drug or discontinue nursing.

Please see the accompanying full Prescribing Information including boxed warning atwww.corcept.com/prescribinginfo.pdf

Please see the accompanying Medication Guide at www.corcept.com/medicationguide.pdf

About Corcept Therapeutics Incorporated
Corcept is a pharmaceutical company engaged in the discovery, development and commercialization of drugs for the treatment of severe metabolic and psychiatric disorders. Korlym, a first generation GR-II antagonist, is the company's first FDA-approved medication. The company has a portfolio of new selective GR-II antagonists that block the effects of cortisol but not progesterone. Corcept also owns an extensive intellectual property portfolio covering the use of GR-II antagonists, including mifepristone, in the treatment of a wide variety of psychiatric and metabolic disorders. The company also holds composition of matter patents for its selective GR-II antagonists.

Statements made in this news release, other than statements of historical fact, are forward-looking statements. Forward-looking statements are subject to a number of known and unknown risks and uncertainties that might cause actual results to differ materially from those expressed or implied by such statements. For example, there can be no assurances that clinical results will be predictive of real-world use, or regarding the pace of Korlym's acceptance by physicians and patients, the reimbursement decisions of government or private insurance payers, the effects of rapid technological change and competition, the protections afforded by Korlym's Orphan Drug Designation or by Corcept's other intellectual property rights, and the cost, pace and success of Corcept's other product development efforts. These and other risks are set forth in the Company's SEC filings, all of which are available from our website (www.corcept.com) or from the SEC's website (www.sec.gov). We disclaim any intention or duty to update any forward-looking statement made in this news release.

CONTACTS:

Invvestor Contact
Charles Robb
Chief Financial Officer 
Corcept Therapeutics
650-688-8783 

Media Contact
Alissa Maupin
Communications Strategies, Inc.
973-635-6669

From http://www.corcept.com/news_events/pr_1329524335

Clinical relevance of cardiac structure and function abnormalities in patients with Cushing's syndrome before and after cure

Authors: Toja, Paola M.1; Branzi, Giovanna2; Ciambellotti, Francesca2; Radaelli, Piero3; De Martin, Martina1; Lonati, Laura Maria2; Scacchi, Massimo; Parati, Gianfranco; Cavagnini, Francesco1; Giraldi, Francesca Pecori

Source: Clinical Endocrinology, Volume 76, Number 3, 1 March 2012 , pp. 332-338(7)

Publisher: Wiley-Blackwell

 

Abstract:

Objectives  Sustained hypercortisolism impacts cardiac function, and, indeed, cardiac disease is one of the major determinants of mortality in patients with Cushing's syndrome. The aim of this study was to assess the clinical relevance of cardiac structure and function alterations by echocardiography in patients with active Cushing's syndrome and after disease remission.

Study design  Seventy-one patients (61 women, 10 men) with Cushing's syndrome and 70 age-, sex- and blood pressure-matched controls were enrolled. Echocardiography was performed in 49 patients with active disease and at several time points after remission in 44 patients (median follow-up 46·4 months), and prevalence of abnormal left ventricular mass measurements and systolic and diastolic functions indices was compared between patients with active disease, after remission and controls. Twenty-two patients were evaluated both before and after remission.

Results  Up to 70% of patients with active Cushing's syndrome presented abnormal left ventricular mass parameters; 42% presented concentric hypertrophy and 23% concentric remodelling. Major indices of systolic and diastolic functions, i.e. ejection fraction and E/A ratio, respectively, were normal. Upon remission of hypercortisolism, left ventricular mass parameters ameliorated considerably, although abnormal values were still more frequent than in controls. Both cortisol excess and hypertension contribute to cardiac mass alterations and increase the prevalence of target organ damage.

Conclusions  Cushing's syndrome is associated with an increased risk for abnormalities of cardiac mass, which ameliorates, but does not fully disappear after remission. Systolic and diastolic functions are largely within the normal range in these patients.

 

Document Type: Research article

DOI: http://dx.doi.org/10.1111/j.1365-2265.2011.04206.x

Affiliations: 1: Ospedale San Luca, Neuroendocrinology Research Lab, Istituto Auxologico Italiano IRCCS 2: Department of Cardiology, Ospedale San Luca, Istituto Auxologico Italiano IRCCS 3: Department of Medical Sciences, University of Milan

Buy this article here: http://www.ingentaconnect.com/content/bsc/cend/2012/00000076/00000003/art00004

Synchronous bilateral adrenalectomy by midline incision: A reliable method for treatment of hypercortisolism

Sayyed Abbas Tabatabaee, Sayyed Mozaffar Hashemi, Mohamadreza Fazel Najafabadi, Amirhossein Davarpanah Jazi

Abstract

• Cushing syndrome is one of the diseases associated with adrenals secreting too much cortisol. The syndrome was first described by Harvey Cushing in 1932.¹ It can be caused either by a tumor originating from the corticotroph cells located in pituitary glands, called corticotroph adenoma, or primary adrenal hyperplasia. It can be also the consequence of some other rare conditions such as ectopic corticotropin-releasing hormone (CRH) causing increased adrenocorticotropic (ACTH) secretion and macronodular adrenal hyperplasia (a primary pigmented nodular adrenal disease).^2,3 To manage the situation, previous articles demonstrated some strategies including two main groups of surgical treatments and non-surgical procedures.

  Surgical interventions are very important to completely cure this condition. Pituitary surgery, referred to as transsphenoidal operation, is the treatment of choice for patients with secondary disease.² However, in some situations, e.g. in patients with recurrent or persistent Cushing syndrome and those not responding to medical therapies after the surgery, the effectiveness of pituitary surgery is under question. Such patients are the best candidates for bilateral adrenalectomy. Some previous articles outlined this method.⁴ Laparoscopy is one of the methods recently used for adrenalectomy. During the surgery, some complications may occur which deteriorates patient's condition with noticeable rates of 9.5 to 12%. These complications are bleeding, organ damages, pain and deep vein thrombosis.^7,8
  
  Although in recent years the experts have achieved great improvements in management and treatment of the patients suffering from Cushing syndrome, some controversies still exist. In this manuscript, we explained a new method to accomplish a reliable bilateral adrenalectomy to manage the disease and cure the condition completely.

  After opening the abdomen, left adrenal gland is determined and adjacent vessels are ligated. Then, the enlarged adrenal gland would be entirely removed. However, adrenalectomy at the right side is not as simple as the left side. Renal vein detachment from the inferior vena cava can be a serious complication of right adrenalectomy if it is performed without enough exposure and experience. Massive bleeding in such clinical setting may significantly compromise patient's outcome. To avoid this complication during the procedure we can perform a new method explained below.
  Access to the right gland cannot be obtained by conventional retraction of the liver and it is necessary to mobilize the right hepatic lobe by fully incising the falciform ligament, the right triangular ligament, and rotating the right lobe medially. In this procedure, the bare area of the liver is dissected from the diaphragm. Care must be taken to avoid twisting and occluding the vena cava during this maneuver. After medial rotation of the liver in the proper position, the right adrenal and inferior vena cava can be directly visualized. This excellent exposure makes adrenalectomy very simple and minimizes the risk for renal vein detachment as a significant complication.

  This method was conducted on 6 cases admitted due to Cushing syndrome in Alzahra Hospital, Isfahan, Iran. While no major complications were observed, favorable outcomes were found in the 6-month follow-up period.

  Based on our experience, bilateral adrenalectomy via a midline incision is a promising and acceptable technique for patients with Cushing syndrome. However, due to excess adipose tissue and lack of enough exposure, adrenalectomy by lumbotomy in such patients has prominent limitations. Therefore, midline incision provides feasible exposure for direct visualization of both adrenals.

Full Text: PDF
This work is licensed under a Creative Commons Attribution 3.0 License

---

This work is licensed under a Creative Commons Attribution 3.0 Unported License.

 

Do patients with Type 2 Diabetes Mellitus have an increased prevalence of Cushing's Syndrome?

Therese Krarup,  Thure Krarup,  Claus Hagen

Copyright © 2011 John Wiley & Sons, Ltd.

Keywords: Type 2 diabetes; Cushing's syndrome; hypercortisolism

Abstract

Many clinical features are common for patients with Type 2 Diabetes Mellitus (T2DM) and Cushing's Syndrome (CS) such as central obesity, hypertension and dyslipidaemia. Patients with CS often have T2DM. Since T2DM is much more frequent than CS it is possible that some patients with T2DM have increased production of cortisol and thus represent patients with CS.

The aim of this review is to evaluate the prevalence of CS in patients with T2DM.

A search was performed in Pubmed and Medline. We found 7 prospective studies, 2 case control studies and 2 cross sectional studies.

The difficulties in diagnosing subclinical Cushing's Syndrome is discussed.

The most frequent tests for diagnosing CS, late night salivary cortisol, 1 mg dexamethasone suppression test, and urinary free cortisol are discussed and put in relation to the results of the literature found.

The observed prevalence of CS in patients with T2DM varies widely between the different studies, ranging from 0% - 9,4%. This may be due to patient selection, differences in test methodology, including choice of test, cut off values and different cortisol assays. The true prevalence of CS in T2DM has not been determined. We need more studies investigating the prevalences of CS in T2DM patients. There is a need for developing more specific tests for diagnosing CS in patients with only slightly elevated cortisol secretion and subclinical CS.

We suggest that examination for hypercortisolism should only be performed in T2DM patients with a cushingoid appearance and hypertension or truncal obesity or dyslipidaemia. Copyright © 2011 John Wiley & Sons, Ltd.

Get PDF (555K)

From http://onlinelibrary.wiley.com/doi/10.1002/dmrr.2262/abstract;
jsessionid=BFC6D112B014B14DF8973B1EF380E381.d03t01

 

ACTH-secreting pituitary adenomas: size does not correlate with hormonal activity

Nestoras Mathioudakis, Courtney Pendleton, Alfredo Quinones-Hinojosa, Gary S. Wand and Roberto Salvatori

• Download PDF (243.3 KB)
• View HTML

Abstract

ACTH-secreting pituitary adenomas (Cushing’s disease, CD) are the most frequent cause of Cushing’s syndrome. To test whether the size of ACTH-secreting adenomas correlates with the degree of biochemical and clinical features of hypercortisolism, we retrospectively reviewed all newly diagnosed CD patients seen at our institution by two neuro-endocrinologists over a 10-year time period. We documented the number of clinical manifestations and baseline hormonal measurements.

There were 37 microadenomas (μAs) and 16 macroadenomas (MAs). We sought to characterize the relationship between tumor size (μA vs. MA) and number of signs and symptoms of hypercortisolism and biochemical assessment of hypercortisolemia. There were no significant differences in mean age, BMI, or prevalence of hypertension and type 2 diabetes between the μA and MA groups. However, the MAs had fewer clinical manifestations of hypercortisolism (29.4% vs. 36.1%, P = 0.02) compared to μAs.

There was a higher prevalence of easy bruisability and proximal muscle weakness in the μAs, but otherwise the prevalence of signs and symptoms were similar between groups. The MAs had a lower random serum cortisol (18.2 ± 2.4 vs. 25.9 ± 1.8 mcg/dl, P = 0.018), lower cortisol:ACTH ratio (0.25 ± 0.03 vs. 0.42 ± 0.05, P < 0.048), and lower cortisol:tumor diameter ratio (14.1 ± 2.2 vs. 56.8 ± 7.2, P < 0.0001) than the μAs.

We conclude that tumor size does not directly correlate with the extent of hormonal activity in ACTH-secreting adenomas. Biochemical activity and clinical manifestations may be mild even in larger tumors, and therefore a high index of suspicion may be necessary to recognize hypercortisolism in pituitary MAs.

Keywords  Pituitary adenoma – Cushing – ACTH – Symptoms

Fulltext Preview

• From http://www.springerlink.com/content/m624211x08224761/

Endoscopic bilateral adrenalectomy (BLA) in patients with ectopic Cushing's syndrome

Alberda WJ, van Eijck CH, Feelders RA, Kazemier G, de Herder WW, Burger JW; Surgical Endoscopy (Nov 2011)

BACKGROUND: Bilateral adrenalectomy (BLA) is a treatment option to alleviate symptoms in patients with ectopic Cushing's syndrome (ECS) for whom surgical treatment of the responsible nonpituitary tumor is not possible. ECS patients have an increased risk for complications, because of high cortisol levels, poor clinical condition, and metabolic disturbances. This study aims to evaluate the safety and long-term efficacy of endoscopic BLA for ECS.

METHODS: From 1990 to present, 38 patients were diagnosed and treated for ECS in the Erasmus University Medical Center, a tertiary referral center. Twenty-four patients were treated with BLA (21 endoscopic, 3 open), 9 patients were treated medically, and 5 patients could be cured by complete resection of the adrenocorticotropic hormone (ACTH)-producing tumor. The medical records were retrospectively reviewed and entered into a database. For evaluation of the efficacy of BLA, preoperative biochemical and physical symptoms were assessed and compared with postoperative data.

RESULTS: Endoscopic BLA was successfully completed in 20 of the 21 patients; one required conversion to open BLA. Intraoperative complications occurred in two (10%) patients, and postoperative complications occurred in three (14%) patients. Median hospitalization was 9 (2-95) days, and median operating time was 246 (205-347) min. Hypercortisolism was resolved in all patients. Improvements of hypertension, body weight, Cushingoid appearance, impaired muscle strength, and ankle edema were achieved in 87, 90, 65, 61, and 78% of the patients, respectively. Resolution of diabetes, hypokalemia, and metabolic alkalosis was achieved in 33, 89, and 80%, respectively.

CONCLUSION: Endoscopic BLA is a safe and effective treatment for patients with ectopic Cushing's syndrome.

From http://www.docguide.com/endoscopic-bilateral-adrenalectomy-patients-ectopic-cushings-syndrome?tsid=5

Investigational drug improves symptoms of Cushing’s disease

BOSTON — Phase 3 data from the PASPORT-CUSHINGS trial show significantly reduced cortisol levels and improved quality of life in patients with Cushing’s disease who were assigned to pasireotide.

The investigational somatostatin analogue (SOM230, Novartis) targets cortisol production in Cushing’s disease. Currently, there is no approved medical treatment for the disease; most patients undergo surgery or radiation therapy. Now, researchers said these latest data support the potential use of pasireotide “as the first specific pituitary-targeted treatment in this disorder.”

The randomized, double blind PASPORT CUSHINGS trial enrolled 162 patients with Cushing’s disease from 18 countries. The majority of patients (n=135) had persistent or recurrent Cushing’s disease after prior treatment; 27 had new-onset disease but were not eligible for surgery. Researchers randomly assigned patients to twice-daily pasireotide injections of 600 mcg or 900 mcg. The blinding treatment was lifted at 6 months or at 3 months if patients did not respond to therapy. Months 6 to 12 were open-label, and nonresponders received a higher dose, if needed. The primary endpoint was urinary free cortisol levels at 6 months without dose titration. Lack of response was demonstrated by increased levels of urinary free cortisol or a urinary free cortisol level more than two times the upper limit of normal. Annamaria Colao, MD, from University of Naples, presented data on 103 patients during an oral session.

Of the patients assigned to the 900-mcg dose, 26.3% achieved normal urinary free cortisol levels at 6 months and 25% maintained normal levels at 12 months. Nearly 15% of patients assigned to the 600-mcg dose met the primary endpoint at 6 months and 13.4% at 12 months. Most patients with uncontrolled disease could be identified within 2 months, based on urinary free cortisol levels, the researchers said. Reductions in serum and salivary cortisol levels and plasma ACTH were also observed.

As urinary free cortisol levels decreased, symptoms of Cushing’s disease improved, including significant reductions in body weight, blood pressure and LDL cholesterol. The researchers also noted improvements in quality of life.

“The safety profile of pasireotide is similar to that of other somatostatin analogues,” Colao and colleagues said. Adverse events included transient gastrointestinal comfort and hyperglycemic events (reported in 70%). Elevations in fasting blood glucose and HbA1c levels were seen soon after pasireotide initiation. Thirteen (8%) of patients had an adverse event of hypercortisolism that the researchers said was responsive to dose reduction.

Endocrine Today previously reported phase 2 data from the PASPORT CUSHINGS trial.

Disclosure: The research was supported by Novartis. Dr. Colao reports no relevant financial disclosures. Other researchers report relevant ties to Novartis, Ipsen, Otsuka, Pfizer and Corcept Pharmaceuticals.

For more information:

• Colao A. OR09-6. Presented at: The Endocrine Society 93rd Annual Meeting & Expo; June 4-7, 2011; Boston.

From http://www.endocrinetoday.com/view.aspx?rid=84332

Cushing's syndrome - Clinical trials

Information provided by WHO International Clinical Trials Registry The clinical trials below are relevant to Cushing's syndrome.

Title	Recruitment status	Location
Prospective, Open-Label, Multicenter, International Study of Mifepristone for Symptomatic Treatment of Cushing's Syndrome Caused by Ectopic Adrenal Corticotrophin Hormone (ACTH) Secretion	Recruiting	United Kingdom
Glucocorticoid Receptor Antagonism in Subclinical Cushings	Not recruiting	United Kingdom
Adrenal Tumors - Pathogenesis and Therapy	Recruiting	Germany
Protein turnover and energy expenditure in normal subjects, growth hormone deficiency, acromegaly and Cushing's syndrome	Recruiting	Australia
Insulin Sensitivity and Substrate Metabolism in Patients With Cushing's Syndrome	Recruiting	Denmark
Study of Depression, Peptides, and Steroids in Cushing's Syndrome	Recruiting	United States
Stepwise medical treatment of Cushing's disease	Recruiting	The Netherlands
Prospective, Open-Label, Multicenter, International Study of Mifepristone for Symptomatic Treatment of Cushing's Syndrome Caused by Ectopic Adrenal Corticotrophin Hormone (ACTH) Secretion	Recruiting	France
Prospective, Open-Label, Multicenter, International Study of Mifepristone for Symptomatic Treatment of Cushing's Syndrome Caused by Ectopic Adrenal Corticotrophin Hormone (ACTH) Secretion	Recruiting	Germany
Prospective, Open-Label, Multicenter, International Study of Mifepristone for Symptomatic Treatment of Cushing's Syndrome Caused by Ectopic Adrenal Corticotrophin Hormone (ACTH) Secretion	Recruiting	Italy

Title	Recruitment status	Location
Prospective, Open-Label, Multicenter, International Study of Mifepristone for Symptomatic Treatment of Cushing's Syndrome Caused by Ectopic Adrenal Corticotrophin Hormone (ACTH) Secretion	Recruiting	Netherlands
Prospective, Open-Label, Multicenter, International Study of Mifepristone for Symptomatic Treatment of Cushing's Syndrome Caused by Ectopic Adrenal Corticotrophin Hormone (ACTH) Secretion	Recruiting	United States
Defining the Genetic Basis for the Development of Primary Pigmented Nodular Adrenocortical Disease (PPNAD) and the Carney Complex	Recruiting	United States
An Investigation of Pituitary Tumors and Related Hypothalmic Disorders	Recruiting	United States
New Imaging Techniques in the Evaluation of Patients With Ectopic Cushing Syndrome	Recruiting	United States
A Study to Assess SOM230 in Patients With Pituitary Cushing's Disease	Not recruiting	United States
Long Term Post Operative Follow-Up of Cushing Syndrome	Not recruiting	United States
A Study to Confirm Recurrent or Persistent Cushing's Syndrome in Patients With Signs or Symptoms of Hypercortisolemia	Not recruiting	United States
Adrenalectomy Versus Follow-up in Patients With Subclinical Cushings Syndrome	Not recruiting	Sweden
Hippocampal Complex Volume and Memory Dysfunction in Cushing's Syndrome	Not recruiting	United States

Title	Recruitment status	Location
Study of Hypercortisolism in Cushing's Syndrome and Stress-Induced Pseudo-Cushing's Syndrome	Not recruiting	United States
Study of Cushing's Syndrome Not Related to ACTH Production	Not recruiting	United States
Management of subclinical Cushing's syndrome in adrenal incidentalomas	Not recruiting	Italy
An Extension Study of CORLUX in the Treatment of Endogenous Cushing's Syndrome	Not recruiting	United States
Diagnostic Performance of Screening Tests for Cushing's Syndrome	Not recruiting	United States
Cognition, Steroids, and Imaging in Cushings Disease	Not recruiting	United States
A Study of the Efficacy and Safety of CORLUX in the Treatment of Endogenous Cushing's Syndrome	Not recruiting	United States
Preclinical Study Towards an Immunotherapy in Adrenocortical Carcinoma	Not recruiting	Germany
Dose Response Relationship for Single Doses of Corticotropin Releasing Hormone (CRH) in Normal Volunteers and in Patients With Adrenal Insufficiency	Not recruiting	United States
Jugular Vein Sampling for Hormone Levels for the Diagnosis of Cushing Syndrome	Not recruiting	United States

Updated NIH Clinical Trials of interest to Cushing's patients

• A Study to Confirm Recurrent or Persistent Cushing's Syndrome in Patients With Signs or Symptoms of Hypercortisolemia
• Extension Study to Assess the Safety and Efficacy of Pasireotide in Patients With Cushing's Disease
• Prospective, Open-Label, Multicenter, International Study of Mifepristone for Symptomatic Treatment of Cushing's Syndrome Caused by Ectopic Adrenal Corticotrophin Hormone (ACTH) Secretion
• A Study of the Efficacy and Safety of CORLUX in the Treatment of Endogenous Cushing's Syndrome
• Diagnostic Performance of Screening Tests for Cushing's Syndrome
• Long-term Cardiovascular Risk in Cured Cushing's Patients
• Long Term Post Operative Follow-Up of Cushing Syndrome
• Jugular Vein Sampling for Hormone Levels for the Diagnosis of Cushing Syndrome
• New Imaging Techniques in the Evaluation of Patients With Ectopic Cushing Syndrome
• An Extension Study of CORLUX in the Treatment of Endogenous Cushing's Syndrome
• Study of Hypercortisolism in Cushing's Syndrome and Stress-Induced Pseudo-Cushing's Syndrome
• Preoperative Bexarotene Treatment for Cushing's Disease
• Glucocorticoid Receptor Antagonism in Subclinical Cushings
• Safety and Efficacy of Different Dose Levels of Pasireotide in Patients With de Novo, Persistent or Recurrent Cushing's Disease
• Adrenalectomy Versus Follow-up in Patients With Subclinical Cushings Syndrome
• Insulin Sensitivity and Substrate Metabolism in Patients With Cushing's Syndrome
• A Study to Assess SOM230 in Patients With Pituitary Cushing's Disease
• Study of Cushing's Syndrome Not Related to ACTH Production
• Study of Depression, Peptides, and Steroids in Cushing's Syndrome
• Hippocampal Complex Volume and Memory Dysfunction in Cushing's Syndrome

Back Ache And Hypercortisolism

Hypercortisolism is an extended medical time period that defines Cushing’s syndrome. Cushing’s syndrome is a hyperactive disorder that affects the adrenal cortex and leads to extreme secretion of cortisol, which is handed from Glucocorticoids. Cushing’s syndrome can increase sex hormones and mineralocorticoids.

The pituitary glands are stimulated by hypothalamic. The pituitary glands are additionally affected by carcinoma and/or adenoma. As nicely, the adrenal glands are affected by hyperplasia when Cushing’s syndrome is present. When Cushing’s syndrome is current, exogenous secretes into the ACTH through the neoplasm, which is malignant. It continues onto the gallbladder and lungs. You will need to read the anatomy of the skeleton system to see the way it affects the spinal column, which in turn causes back pain.

The dysfunction prolongs or submits excessive administration of ACTH and/or Glucocorticoids into the system, which transmits to the cortex. Since ACTH is secreted excessively into the system, it causes joint ache, edema, fragile pores and skin, weight achieve, hypertension, ecchymosis, fatigue, weak spot, hirsutism, temper swings, and so on. The signs carry onto create acne, stomach striae, slow healing, moon face, muscle waste, recurrent infections, buffalo humps, gynecomastia, truncal weight problems, and so on. We see that weight problems, joint pain, weight acquire, edema, and other components of the dysfunction causes back ache as well.

The signs are thought of earlier than diagnostics is conducted. Medical doctors will use a wide range of assessments to find Hypercortisolism or Cushing’s syndrome. In brief, Cushing’s syndrome is a condition set up by weak muscles and obesity, or irregular situations of the physique’s functions. The exams performed to show Cushing’s syndrome include blood chemistry, dexamethasone suppression, X-rays, GTT, CT scans, angiography, ultrasonography, and so on. Throughout testing docs will search for decreases in “17-OHCS,” osteoporosis, tumors, particularly in the pituitary glands and adrenal glands, decreases in potassium, will increase in cortisol, sodium, Aldosterone, ACTH, etc. Doctors will also search for decreases in eosinophilis, pink blood cells, and white blood cells.

When the situation is noted, docs suggest management. Diets are instructed, which include low-calorie, sodium, carbohydrates, etc. The patient is ordered to take excessive-protein and potassium regimens as well. Activity is ordered, but solely as tolerated by the patient.

Once management begins, the doctor will monitor the patient. During monitoring your physician will perform extra checks, which include UO, I/O, VS, glucose, ketones, and so on. Radiation remedy is prescribed within the worst conditions.

Cushing’s syndrome can lead to additional problems, together with nephrosclerosis, inadequate adrenal, fractures, arteriosclerosis, infections, diabetes mellitus, hypertension, CHF, arrhythmias, psychosis, and so on.

If you are diagnosed with Cushing’s syndrome, it is important to maintain your weight loss plan, steadiness fluids, relaxation, and restrict intake of water. Your physician will arrange a routine and/or management scheme, which you need to comply with accordingly to avoid additional complications. Since this dysfunction affects the whole body and puts you liable to fractures, peptic ulcers, and many others, you will need to observe precise orders.

Fractures can result in critical back pain. Fractures are outlined in medical terms as permanence breaks of the bones. Cushing’s syndrome places you susceptible to fractures, which may embody greenstick, avulsions, pathologic, melancholy, indirect, spiral, compound, compressed, etc. In addition to fractures, weight problems will cause back pain. If attainable, attempt to scale back your weight. You may ask your medical doctors about exercises suited for your condition, which you can act on to reduce weight. Your physician might counsel some steps you may take to scale back weight as well.

Cushing’s syndrome can cause back pain, but numerous other illnesses could cause pain to the again as well, together with cholecystitis. Learn extra concerning the inflammatory illness to see the way it causes again pain.

 

From http://www.relievechronicbackpains.com/474

ENEA 2010: Potential new options for the treatment of Cushing's disease: the dawn of a new era?

24/09/2010
Posted by Jo Armstrong, ecancer

Beverly Biller, Massachusetts General Hospital, USA

The goal of treatment of Cushing's disease is to normalise cortisol levels. However, current treatment options are limited and are associated with a variety of drug related adverse events and relapse. There are no approved medical therapies for Cushing's disease, and the efficacy of medical treatments that are used is limited, highlighting the unmet need in these patients.

Of great benefit would be a pituitary-directed medical treatment which targets the underlying cause of ACTH hypersecretion. There are a number of agents under investigation for the treatment of Cushing's disease, including pituitary targeted drugs and drugs targeting blockade of the glucocorticoid receptor.

Pasireotide, a new investigational drug with multi-serotonin subtype receptor affinity, is a pituitary targeted medical therapy that has been associated with rapid normalisation of UFC levels in a small number of patients in a Phase II study of patients with Cushing's disease. This has led to a Phase III, randomised, double-blind, multicentre study, the initial results of which were presented at ENEA 2010. This ongoing clinical trial is the largest study to evaluate a medical therapy in this patient population. After 6 months of treatment with pasireotide 600 or 900 µg sc bid, 14.6% and 26.3% of patients with moderate to severe hypercortisolism achieved UFC ≤ULN. At 12 months, 13.4% and 25.0% patients achieved UFC ≤ULN. Overall, there was a rapid and sustained improvement in clinical signs and symptoms from baseline, as well as improvements in patient health related quality of life. Around 50% of patients at ≥1.5 to <2 ULN achieved UFC ≤ULN with 900 at 6 months. In addition, systolic and diastolic blood pressure and weight improved in line with the decline in cortisol levels. Non-responding patients, based on UFC levels, were identified early after treatment initiation, which may be clinically useful for identifying patients inappropriate for this therapy.

With the exception of hyperglycaemia, the safety profile of pasireotide was similar to that of other somatostatin analogues. As expected with an active agent in Cushing's disease, some patients experienced symptoms of hypocortisolism, which was adequately managed in patients by decreasing the dose of pasireotide.

 

From http://www.ecancermedicalscience.com/blog.asp?postId=113

The diagnosis of Cushing’s syndrome

Reviews in Endocrine & Metabolic Disorders

DOI: 10.1007/s11154-010-9143-3

Ty B. Carroll and James W. Findling

Download PDF (172.4 KB)

View HTML

 

Abstract

Spontaneous Cushing’s syndrome is well known but unusual clinical disorder. Many of the clinical features (central weight gain, glucose intolerance, hypertension, muscle weakness) are seen in other common conditions. Recognition of patients with multiple features, features unusual for their age (i.e. early onset osteoporosis or hypertension), patients with features more specific to Cushing’s syndrome (i.e. easy bruising, facial plethora, and violaceous striae), and patients with incidental adrenal mass or polycystic ovary syndrome should prompt an evaluation for cortisol excess. Late-night salivary cortisol, 1 mg overnight dexamethasone suppression testing, or 24 h urine free cortisol determination have excellent diagnostic characteristics and should be obtain in patients with suspected Cushing’ syndrome. If this initial testing is abnormal, further evaluation should be directed by an endocrinologist experienced in the diagnosis and differential diagnosis of Cushing’ syndrome.

Keywords  Cushing’s syndrome - Cushing’s disease - Diagnosis - Hypercortisolism

Fulltext Preview

 

From http://www.springerlink.com/content/k25125412307h623/

High Prevalence of Normal Tests Assessing Hypercortisolism in Subjects with Mild and Episodic Cushing's Syndrome...

High Prevalence of Normal Tests Assessing Hypercortisolism in Subjects with Mild and Episodic Cushing's Syndrome Suggests that the Paradigm for Diagnosis and Exclusion of Cushing's Syndrome Requires Multiple Testing

T. C. Friedman1, D. E. Ghods1, H. K. Shahinian2, L. Zachery1, N. Shayesteh1, S. Seasholtz1, E. Zuckerbraun1, M. L. Lee1, I. E. McCutcheon3

1 Division of Endocrinology, Metabolism, and Molecular Medicine, Charles Drew University of Medicine and Science, Los Angeles, CA, USA
2 Skull Base Institute, Los Angeles, CA, USA
3 Department of Neurosurgery, MD Anderson Medical Center, Houston TX, USA
Abstract

Many Endocrinologists believe that a single determination of eucortisolism or a single demonstration of appropriate suppression to dexamethasone excluded Cushing's syndrome, except in what was previously thought to be the rare patient with episodic or periodic Cushing's syndrome. We hypothesize that episodic Cushing's syndrome is relatively common and a single test assessing hypercortisolism may not be sufficient to accurately rule out or diagnose Cushing's syndrome and retrospectively examined the number of normal and abnormal tests assessing hypercortisolism performed on multiple occasions in 66 patients found to have mild and/or episodic Cushing's syndrome compared to a similar group of 54 patients evaluated for, but determined not to have Cushing's syndrome. We found that 65 of the 66 patients with Cushing's syndrome had at least one normal test of cortisol status and most patients had several normal tests. The probability of having Cushing's syndrome when one test was negative was 92% for 23:00 h salivary cortisol, 88% for 24-h UFC, 86% for 24-h 17OHS, and 54% for nighttime plasma cortisol. These results demonstrated that episodic hypercortisolism is highly prevalent in subjects with mild Cushing's syndrome and no single test was effective in conclusively diagnosing or excluding the condition. Rather, the paradigm for the diagnosis should be a careful history and physical examination and in those patients in whom mild Cushing's syndrome/disease is strongly suspected, multiple tests assessing hypercortisolism should be performed on subsequent occasions, especially when the patient is experiencing signs and symptoms of short-term hypercortisolism.

Key words

Cushing's syndrome - episodic - periodic - urinary free cortisol - salivary cortisol - cortisol-binding globulin - 17-hydroxycorticosteroids

From https://www.thieme-connect.de/ejournals/abstract/hmr/doi/10.1055/s-0030-1263128

Recurrence of Cushing’s Disease Preceded by the Reappearance of ACTH and Cortisol Responses to Desmopressin Test

Chiara Dall’Asta, Laura Barbetta, Luigi Bonavina, Paolo Beck-Peccoz and Bruno Ambrosi

 

Download PDF (2.2 MB)

View HTML

 

At present no single test is considered of absolute value in identifying patients successfully operated for Cushing's disease who are at risk for recurrence. The present report describes the first two patients in whom ACTH/cortisol abnormal responses to desmopressin disappeared after cure and then clearly reappeared during long-term follow-up several months before the clinical and hormonal features of hypercortisolism became manifest.

The case histories of 2 young women are reported. The diagnosis of Cushing's disease was made on the basis of clinical features and standard hormonal criteria. Both patients, showing abnormal ACTH/cortisol rises after desmopressin test, underwent pituitary adenomectomy by transsphenoidal surgery and after operation plasma ACTH and serum cortisol levels were 0.2 and 0.4 pmol/l and 56 and 32 nmol/l, respectively. During the follow-up both patients underwent desmopressin (10 U g iv), ovine CRH (1 U g/kg iv) and 1 mg dexamethasone tests at 1, 6, 12, 24 months after surgery.

In these two cases the ACTH/cortisol response to desmopressin normalized following pituitary adenomectomy, concomitantly with the normalization of all the other clinical and hormonal parameters. Subsequently abnormal rises after the synthetic AVP analogue administration appeared: paradoxical ACTH/cortisol increments after desmopressin occurred 24 and 6 months before any other hormonal or clinical sign of recurrence of hypercortisolism.

As desmopressin may be able to stimulate ACTH/cortisol release in Cushing's disease, but not in normal subjects, we suggest that it can have a role in early identifying successfully operated Cushing's patients at risk for recurrence.

Key Words  desmopressin - hypercortisolism - ACTH - cushing's disease - recurrence

Fulltext Preview

From http://www.springerlink.com/content/g5555t0654m22q41/

Role of adrenalectomy in recurrent Cushing’s disease

DING Xue-fei, LI Han-zhong, YAN Wei-gang, GAO Ying, LI Xiao-qiang

Free Full Text [ HTML | PDF(100K) ] Abstract download [TXT | XML]

Keywords: adrenal gland·Cushing’s disease·adrenalectomy·laparoscopy

Abstract:

Background  Cushing’s disease is a pituitary-dependent type of Cushing’s syndrome. Treatment consists of pituitary surgery or radiotherapy, but the recurrence rate at 10 years is as high as 40%. Adrenalectomy is considered an effective treatment to refractory Cushing’s disease. The objective of this study was to examine the efficacy of laparoscopic adrenalectomy and open adrenalectomy in Cushing’s disease, focusing on reversing the sequelae of hypercortisolism and improving patients’ quality of life.

Methods Forty-three patients (29 women, 14 men) with recurrent Cushing’s disease after transsphenoidal operation underwent laparoscopic (n=32) or open (n=11) adrenalectomy from 2000 to 2008. Surgical results were evaluated for all the 43 patients. Patients completed a follow-up survey, including the short-form 36-item (SF-36) health survey.

Results All the 43 patients achieved clinical reversal of hypercortisolism after adrenalectomy. Time to symptom resolution varied from a few weeks to up to 3 years. Most physical changes had resolved by a mean of 8 months after surgery. These conditions were not significantly different between the laparoscopy and open groups. Median length of hospital stay was shorter in the laparoscopy group (4 vs. 9 days; P <0.001).

Median follow-up was 48.5 months. Of the 34 (79%) patients available for follow-up, 22 (65%) had adrenocorticotropic hormone levels >200 ng/ml and 6 (27%) had clinical Nelson syndrome. Four patients died by 75 months after surgery. Using SF-36, 30 (88%) patients reported they felt their health status was good to excellent compared with 1 year before adrenalectomy; however, they showed significantly lower scores in all the 8 SF-36 parameters compared with the general population. No significant difference emerged in SF-36 scores between the laparoscopy and open groups.

Conclusions Adrenalectomy showed high survival and clinical benefits in recurrent Cushing’s disease patients. Despite patient-reported improvement in health after adrenalectomy, patients continue to experience poor health status compared with the general population.

Chinese Medical Journal 2010;123(13):1658-1662

Free Full Text [ HTML | PDF(100K) ] Abstract download [TXT | XML]

DING Xue-fei Department of Urology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing 100730, China; LI Han-zhong Department of Urology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing 100730, China; YAN Wei-gang Department of Urology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing 100730, China; GAO Ying Department of Obstetrics and Gynecology, Affiliated Hospital of North China Coal Medical College, Tangshan, Hebei 063000, China; LI Xiao-qiang Department of Urology, Affiliated Hospital of North China Coal Medical College, Tangshan, Hebei 063000, China
Correspondence to: LI Han-zhong  Department of Urology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing 100730, China  (Tel:86-10-65296073 Fax:86-10-65296073 Email:lihanzhong@163.com )

From http://www.cmj.org/Periodical/AbstractList.asp?titleid=LW201072399187207308

The 4-mg intravenous dexamethasone suppression test in the diagnosis of Cushing's syndrome

Authors: Jung, Caroline; Alford, Frank P.; Topliss, Duncan J.; Burgess, John R.¹; Long, Fiona²; Gome, James J.; Stockigt, Jim R.; Inder, Warrick J.

Source: Clinical Endocrinology, Volume 73, Number 1, July 2010 , pp. 78-84(7)

Publisher: Blackwell Publishing

Abstract:

Summary

Objective Optimal diagnostic criteria for the 4-mg intravenous dexamethasone suppression test (IVDST) in patients with Cushing's syndrome (CS), compared with normal subjects, have not been established. We evaluated the performance of the 4-mg IVDST for differentiating CS from normal subjects and to define the responses in CS of various aetiologies.

Design, subjects, measurements Thirty-two control subjects [normal and overweight/obese participants with or without type 2 diabetes) were prospectively studied, and data from 66 patients with Cushing's disease (CD), three with ectopic ACTH syndrome (EAS), 14 with adrenal Cushing's (AC)] and 15 with low probability of CS (LPC) from three tertiary hospitals were retrospectively evaluated. Dexamethasone was infused at 1 mg/h for 4 h. Plasma cortisol and ACTH were measured at −60 min (baseline), −5 min, +3 h, +4 h, +5 h and at +23 and +23·5 h on Day 2.

Results Control subjects (including those with type 2 diabetes) exhibited a marked suppression of cortisol which was maintained until Day 2. Two of 15 patients with LPC had Day 2 cortisol results that overlapped with CS. Patients with CD demonstrated partial suppression, with rebound hypercortisolism on Day 2. Patients with AC and EAS did not suppress cortisol levels. Day 2 cortisol level of >130 nmol/l (or >20% of the baseline) diagnosed CS with 100% sensitivity and 96% specificity.

Conclusion While the IVDST allowed complete discrimination between control subjects and CS, 13% of LPC overlapped with CS. Given the small number of EAS, no conclusion can be drawn regarding the utility of this test in the differential diagnosis of CS.

Document Type: Research article

DOI: 10.1111/j.1365-2265.2009.03756.x

Affiliations: 1: Department of Endocrinology and Diabetes, Royal Hobart Hospital and Menzies Research Institute, Tas. 2: Department of Endocrinology and Diabetes, The Alfred Hospital, Vic.

From http://www.mdlinx.com/EndoLinx/newsl-article.cfm/3199167/ZZ4747461521296427210947/?news_id=561&newsdt=062910