Cushing's Syndrome after Hemodialysis for 21 Years

Koki Mise, Yoshifumi Ubara, Keiichi Sumida, Rikako Hiramatsu, Eiko Hasegawa, Masayuki Yamanouchi, Noriko Hayami, Tatsuya Suwabe, Junichi Hoshino, Naoki Sawa, Masaji Hashimoto, Takeshi Fujii, Hironobu Sasano and Kenmei Takaichi

- Author Affiliations

Nephrology Center (K.M., Y.U., K.S., R.H., E.H., M.Y., N.H., T.S., J.H., N.S., K.T.), Surgical Gastroenterology (M.H.), Pathology (T.F.), and Okinaka Memorial Institute for Medical Research (Y.U., K.T.), Toranomon Hospital, 1058470 Tokyo, Japan; and Department of Pathology (H.S.), Tohoku University Graduate School of Medicine, 9800872 Sendai, Japan

Address all correspondence and requests for reprints to: Koki Mise, M.D., Nephrology Center, Toranomon Hospital Kajigaya, 1-3-1, Kajigaya, Takatu-ku, Kawasaki-shi, Kanagawa-ken, 213-0015, Japan. E-mail: kokimise@yahoo.co.jp.

Abstract

Context: Hyperkalemia and weight loss are critical clinical problems for hemodialysis patients. There have been no documented reports of adrenal Cushing's syndrome with central obesity and hypokalemia in a hemodialysis patient.

Objective: The aim of the study was to report a patient with Cushing's syndrome after chronic hemodialysis, review the published literature, and discuss the significance of hypokalemia and obesity in anuric hemodialysis patients from the perspective of cortisol metabolism.

Patient: A 61-yr-old woman who had been on hemodialysis for 21 yr presented with persistent hypokalemia and central obesity. In 2002, her dry weight was 48.1 kg, but thereafter she gained weight to 60 kg.

Results: Adrenal Cushing's syndrome was diagnosed from endocrinological findings such as increased cortisol secretion without a circadian rhythm and suppression of plasma ACTH. Spironolactone was administered (25 to 50 mg/d), and her serum potassium became normal. Then, left adrenalectomy was performed by laparoscopic surgery. The resected specimen contained a well-circumscribed adrenal adenoma expressing P450c17. After surgery, hypokalemia improved gradually without medication, and her weight gain stopped.

Conclusions: This is the first documented case of adrenal Cushing's syndrome in a patient on long-term hemodialysis, although several authors have reported a relation between hypokalemia and primary hyperaldosteronism in hemodialysis patients.

From The Journal of Clinical Endocrinology and Metabolism

Use of ketoconazole in the treatment of Cushing's syndrome

An older, but still useful, abstract:

J Clin Endocrinol Metab. 1986 Dec;63(6):1365-71.

 

Loli P, Berselli ME, Tagliaferri M.

Abstract

The therapeutic value of ketoconazole for long term treatment of patients with Cushing's syndrome was studied. Seven patients with Cushing's disease and one with an adrenal adenoma received 600-800 mg/day ketoconazole for 3-13 months. Plasma ACTH, cortisol, and dehydroepiandrosterone sulfate levels and urinary cortisol, 17-ketosteroid, and tetrahydro-11-deoxycortisol excretion were determined periodically during the treatment period.

Plasma ACTH and cortisol responses to CRH stimulation were determined before and during treatment. Rapid and subsequently persistent clinical improvement occurred in each patient; plasma dehydroepiandrosterone sulfate and urinary 17-ketosteroid and cortisol excretion decreased soon after the initiation of treatment, subsequently remaining normal or nearly so throughout the treatment period. Urinary tetrahydro-11-deoxycortisol excretion increased significantly. Plasma cortisol levels decreased. Plasma ACTH levels did not change, and individual plasma ACTH and cortisol increments in response to CRH were comparable before and during treatment. The cortisol response to insulin-induced hypoglycemia improved in one patient and was restored to normal in another.

The seven patients tested recovered normal adrenal suppressibility in response to a low dose of dexamethasone during ketoconazole treatment. Ketoconazole is effective for long term control of hypercortisolism of either pituitary or adrenal origin. Its effect appears to be mediated by inhibition of adrenal 11 beta-hydroxylase and 17,20-lyase, and it, in some unknown way, prevents the expected rise in ACTH secretion in patients with Cushing's disease.

From http://www.ncbi.nlm.nih.gov/pubmed/3023421

 

Adrenal cavernous hemangioma with subclinical Cushing’s syndrome: report of a case

Masaharu Oishi, Shugo Ueda, Sachiko Honjo, Hiroyuki Koshiyama, Yoshiaki Yuba and Arimichi Takabayashi

 

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Cavernous hemangioma of the adrenal gland is a rare tumor, which does not usually have endocrinological function. We report to our knowledge, the third documented case of a functioning adrenal hemangioma.

Interestingly, this tumor indicated glucocorticoid hypersecretion, whereas the two previous cases showed mineralocorticoid hypersecretion. The tumor was 5 cm in diameter with typical computed tomography and magnetic resonance imaging findings.

Subclinical Cushing’s syndrome was diagnosed preoperatively, as there was insufficient suppression of cortisol by low-dose dexamethasone, a low adrenocorticotropic hormone (ACTH) concentration, and diminished ACTH and cortisol circadian rhythms without the typical clinical manifestation and symptoms of hypercortisolism.

Intraoperative hypotension occurred immediately after tumor removal and following postoperative adrenal insufficiency, which support that the tumor was hyperfunctioning. The postoperative adrenal insufficiency had recovered completely by 12 months after the operation.

Read more at http://www.springerlink.com/content/5mv23480j870462m/

 

Pregnancy-induced Cushing’s Syndrome: A Case Report

 

Cushing’s syndrome(CS) during pregnancy is a rare condition with fewer than 150 cases reported in the literature. Adrenal adenomas were found to be the commonest cause.The other causes include tumors in hypothalamus and pituitary. Ectopic ACTH secretion has been reported to cause CS.

There is a very rare condition. Cushing’s syndrome develops in pregnancy and resolving after delivery. The mechanisms underlying these conditions are poorly understood.

There are non-significant differences in the clinical features of pregnant and non-pregnant women with CS.The gestation dramatically affects the maternal hypothalamic-pituitary-adrenal axis, The normal gestational changes in the HPA axis alter these parameters and complicate the screening process for CS.

Comparing with non-pregnant women with CS, the treatment is different in Cushing’s syndrome during pregnancy.

We described here the case of a 25-year-old woman with CS during her forth [sic] pregnancy. Hypertension, diabetes, hypopotassaemia, purple striae and acne are present. Cushing’s syndrome in the patient resolved within four weeks of artificial termination. Eight months after artificial termination, the patient became pregnant again and rapidly developed Cushing’s syndrome with typical clinical symptoms and signs and laboratory results.

Title: Pregnancy-induced Cushing’s Syndrome: A Case Report

Category: Tumor Biology

Filename: Pregnancy-induced Cushing’s Syndrome: A Case Report.pdf

Pages: 101

Price: US$48.00

Buy this pater at http://www.tumorres.com/tumor-biology/25201.htm

 

Treatment Options in Cushing’s Disease

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Authors: Ahmed Rizk, Juergen Honegger, Monika Milian and Tsambika Psaras

Publication Date: 11 Jan 2012

Journal: Clinical Medicine Insights: Oncology

Citation: Clinical Medicine Insights: Oncology 2012:6 75-84

doi: 10.4137/CMO.S6198

 

Abstract

Endogenous Cushing’s syndrome is a grave disease that requires a multidisciplinary and individualized treatment approach for each patient. Approximately 80% of all patients harbour a corticotroph pituitary adenoma (Cushing’s disease) with excessive secretion of adrenocorticotropin-hormone (ACTH) and, consecutively, cortisol.

The goals of treatment include normalization of hormone excess, long-term disease control and the reversal of comorbidities caused by the underlying pathology. The treatment of choice is neurosurgical tumour removal of the pituitary adenoma. Second-line treatments include medical therapy, bilateral adrenalectomy and radiation therapy.

Drug treatment modalities target at the hypothalamic/pituitary level, the adrenal gland and at the glucocorticoid receptor level and are commonly used in patients in whom surgery has failed.

Bilateral adrenalectomy is the second-line treatment for persistent hypercortisolism that offers immediate control of hypercortisolism. However, this treatment option requires a careful individualized evaluation, since it has the disadvantage of permanent hypoadrenalism which requires lifelong glucocorticoid and mineralocorticoid replacement therapy and bears the risk of developing Nelson’s syndrome.

Although there are some very promising medical therapy options it clearly remains a second-line treatment option. However, there are numerous circumstances where medical management of CD is indicated.

Medical therapy is frequently used in cases with severe hypercortisolism before surgery in order to control the metabolic effects and help reduce the anestesiological risk. Additionally, it can help to bridge the time gap until radiotherapy takes effect.

The aim of this review is to analyze and present current treatment options in Cushing’s disease.

From http://www.la-press.com/treatment-options-in-cushings-disease-article-a2985

 

Subclinical Cushings syndrome: definition and management

Subclinical Cushing's syndrome is an ill-defined endocrine disorder that may be observed in patients bearing an incidentally found adrenal adenoma. The concept of subclinical Cushing's syndrome stands on the presence of ACTH-independent cortisol secretion by an adrenal adenoma, that is not fully restrained by pituitary feed-back. A hypercortisolemic state of usually minimal intensity may ensue and eventually cause harm to the patients in terms of metabolic and vascular diseases, and bone fractures.

However, the natural history of subclinical Cushing's syndrome remains largely unknown. The present review illustrates the currently used methods to ascertain the presence of subclinical Cushing's syndrome and the surrounding controversy. The management of subclinical Cushing's syndrome, that remains a highly debated issue, is also addressed and discussed.

Most of the recommendations made in this chapter reflects the view and the clinical experience of the Authors and are not based on solid evidence.

Document Type: Research article

DOI: http://dx.doi.org/10.1111/j.1365-2265.2011.04253.x

Affiliations: 1: Internal Medicine I, San Luigi Gonzaga Hospital, University of Turin, Orbassano, Italy

Buy the article at http://www.ingentaconnect.com/content/bsc/cend/2012/00000076/00000001/art00003

Cushing’s Syndrome Clinical Analysis of 77 Cases

OBJECTIVE To analyze the cause of Cushing’s syndrome classification, the major clinical manifestations and laboratory features of frequency of occurrence, and the efficiency of various diagnostic methods to evaluate the clinical doctors to improve diagnosis and treatment of disease, improve patient prognosis.

METHODS from 2004 to 2009 in our hospital by clinical or pathological diagnosis of Cushing’s syndrome in patients with clinical data, of which 57 cases of females, 20 males. For the 77 cases of clinical manifestations, laboratory examination, imaging studies, clinical diagnostic tests, pathological characteristics and with the results of literature analysis and summary of them were analyzed retrospectively.

RESULTS 1. From 2004 to 2009 were diagnosed 77 cases of Cushing’s syndrome, of which 20 males, female 57 cases, male: female = 2:2.85, adrenal adenoma 80% of female patients of childbearing age women.

2. In Cushing’s disease causes the most common (35 cases), followed by adrenal cortical adenoma (30 cases, the left side of 21 cases), there is a growing trend in the latter. Cushing’s disease course and age of onset of adrenal adenomas were higher than those, the difference was statistically significant (P <0.05), the shortest duration of adrenal carcinoma.

3. Clinical performance, the performance of the diversity of its starter, Hypertension and central obesity were the most frequently occur in 75%, and 79.22% suffering from hypertension, Hypertension 1 11.48%, Hypertension 2 62.30%, Hypertension 3 grade 26.23%, and the incidence of abnormal glucose metabolism and hyperlipidemia, respectively 41% and 68%, of which the proportion of diabetes by 30%, 65% of patients had hypokalemia, mostly mild to moderate, adrenal cortex carcinoma 100% of patients with a low potassium, and is of moderate to severe hypokalemia. Cushing’s disease and adrenal adenoma in serum potassium, blood pressure and gender showed no significant difference.

4. In the diagnosis of Cushing’s syndrome test, blood cortisol circadian rhythm disappeared (98.65%), elevated midnight serum cortisol (98.55%), 4Pm serum cortisol increased (97.14%), low-dose dexamethasone suppression test (94.59%), 24hUFC increased (91.22%), morning serum cortisol increased (71.62%). Low-dose dexamethasone suppression of serum cortisol in the morning the next day the basis of 8:00 of serum cortisol of 50% and 275,200,138,50 nmol/Lthe sensitivity of the cut-off point were 94.6%, 95.9%, 97.3% , 97.3% and 100%.

5. Patients with Cushing’s syndrome in the differential diagnosis, 80% of Cushing’s patients can be high-dose dexamethasone suppression, while more than 95% of patients with adrenal cortical adenoma can not be high-dose dexamethasone suppression. Cushing’s patients compared with blood cortisol and ACTH levels were significantly higher in patients with adrenal tumors, while the latter’s rhythmic performance is worse, the differences were statistically significant (P<0.05). Both urinary free cortisol showed no significant difference.6. imaging examination, pituitary MRI can detect 88% of Cushing’s disease there is pituitary adenoma, while the adrenal CT 100% can find out the adrenal tumors, adrenal CT of adrenal tumors and hyperplasia pathology consistent rate of 97.5%.

CONCLUSION 1. The present study in Cushing’s disease and adrenal cortical adenoma is still the most common cause of this group a high proportion of cases of adrenal adenoma, left more common. Cushing’s syndrome more common in women of childbearing age women, more common adrenal adenoma, Hypertension is the most common symptoms, mostly moderate to severe hypertension, diabetes, low potassium, high incidence of dyslipidemia.

2. Diagnostic tests in the CS, the morning cortisol increase the sensitivity of the worst, and serum cortisol circadian rhythm disappeared, midnight serum cortisol increased, 4PM cortisol rise, low-dose dexamethasone suppression test, 24hUFC elevated. There was no significant difference。

3. Patients with Cushing’s disease course, age of onset, blood cortisol and ACTH levels were higher than the adrenal adenoma, the latter comparison rhythm of blood cortisol rhythm performance is worse. The serum potassium, blood pressure and no significant difference in gender.

4. High-dose dexamethasone suppression test is to identify Cushing’s disease and adrenal cortical adenoma of the most appropriate method, CT of the adrenal lesion positive rate and help confirm the diagnosis and localization, B super-positive rate was significantly lower than CT, head MRI in Cushing’s disease positive rate.

From http://www.tumorres.com/tumor-metastasis/15968.htm

Adrenal glands: The reserve tank for stress?

Have you ever noticed that when you are "stressed" you can feel either emotionally/physically depleted or energized? When our body is under stress the brain responds by producing epheniphrine (aka adrenaline), sending signals to our adrenal glands, increasing the rate at which our heart beats while releasing oxygen to our muscles. The long term response to this process produces cortisol (aka the stress hormone) facilitating the release of energy throughout our body. However, when our body isn't properly balanced these hormones can wreak havoc on our wellness possibly resulting in one of three conditions: Cushing's syndrome, Cushing's disease or Addison's disease.

The actual Adrenal glands sit physically atop both kidneys, taking on a triangular shape and a roundish rectangular type shape. These glands are responsible for our sex hormones and cortisol, helping us respond to stress amongst other functions. When our body is under stress, physically and/or nutritionally, it responds one of two ways: Produces too much or too little of the cortisol hormone. Our Adrenal glands also contribute to regulating our blood sugar, blood pressure, salt and water.

Adrenal disorders can cause our body to make too much or not enough of these hormones, bringing about adrenal gland related syndromes and disease. Cushing's syndrome results from our body making too much versus Addison's disease produces too little.

Cushing's syndrome vs Cushing's disease

Glucocorticoids (naturally produced in our body or received through medicine) are groups of corticosteroids (cortisol or dexamethasone) involved in metabolizing our carbohydrates and proteins. When taken synthetically (i.e. treatment of allergies, skin problems, and respiratory problems) or over-produced naturally, the side effects can result in "Cushing's syndrome".

Cushing's syndrome can occur one of two ways: Endogenous or Exogenous. Endogenous is caused by the body (usually through tumors). Exogenous is caused by medication. In both cases, the body produces too much cortisol.

Symptoms: Severe fatigue/muscle weakness, high blood sugar and high blood pressure, upper body obesity, thin arms/legs, bruising easily.

Treatment: The cure and treatment for Cushing's Syndrome and disease can come through medicine, surgery, or by lowering the dosage of your current synthetic hormone treatment and can likely be cured.

Cushing's disease is the most common form of endogenous Cushing's syndrome and is likely treatable. Caused by a tumor in the pituitary gland secreting too much Adrenocorticotropic hormone (ACTH), this type of tumor does not spread and can be removed through surgery.

Nutrition: See a nutritionist or dietician for your condition. Mostly, avoid excess sodium. High blood sugar (hyperglycemia) and high blood pressure can easily occur with this condition. Bone loss density is common with this condition, so be extra aware of your calcium (800 – 1200 mg per day, based upon age) and Vitamin D intake (5mcg from age 0-50, increasing up to 10 mcg 50-71, and 15 mcg after 71). Eating healthy, balanced and whole food (versus processed) is extremely important. (Resource: http://www.aboutcushings.com/understanding-cushings-disease/causes-and-differences.jsp)

Addison's disease Opposite from Cushing's syndrome, Addison's disease doesn't make “enough” of the sex hormones and cortisol. The result of this disease causes our immune system to attack our tissue, damaging our adrenal glands.

Symptoms: Weight loss, muscle weakness, increasingly worse fatigue, low blood pressure and patchy or dark skin.

Treatment: If left untreated, the condition can be fatal. Lifetime hormone treatment is usually required. Addison disease patients should always carry medical/emergency ID on them, listing their medication, dosage and disease

Lab tests can confirm that you have Addison's disease. If you don't treat it, it can be fatal. Very likely, you will need to take hormone pills for the rest of your life. If you have Addison's disease, you should carry an emergency ID. It should say that you have the disease, list your medicines and say how much you need in an emergency.

(Ref: http://www.nlm.nih.gov/medlineplus/cushingssyndrome.html, NIH: National Institute of Neurological Disorders and Stroke)

If all of this sounds a little overwhelming there is hope. Learning how to balance our stress-filled lives is extremely important to our overall health. Healthy nutrition always contributes benefits to our overall wellness. We can overwhelm our endocrine system by simply not eating nutritionally. Understanding that “Food is a drug” is vitally important to how we help our body naturally heal itself. The above conditions are the result of our body not handling the stress we are putting it through, causing our body to producing too much or too little of the sex hormones and cortisol.

Unless we first address what we can do naturally through nutrition, the medicine we consume will only do so much in helping our body heal completely. You simply cannot continue doing the same thing over and over again, expecting the medicine to do all the work. Some diseases are brought upon us through our environment (emotionally as well as physically) as well as our diet/nutrition. Reviewing our entire wellness is always wisdom whenever we're diagnosed with anything.

Certainly listen to your doctor and their advice. But also ask your doctor to refer you to a nutritionist or clinical/registered dietician for a complete evaluation that includes a review of your nutritional diet/wellness. Too often we reach for a pill or a procedure to “fix” our health problems, ignoring what we should be doing on our own to help our body heal. Medical intervention is "sometimes" the result of providing our body with what it cannot produce on its own. Nutrition should always be the “natural” medicine we take, as well as what we might need through prescribed medication.

Quick Tips for Wellness: Living “well” requires living nutritionally balanced.

Adapted From http://hamptonroads.com/2011/12/adrenal-glands-reserve-tank-stress

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

Corlux: Corcept Therapeutics Announces Third Quarter Results and Corporate and Development Update

MENLO PARK, CA, Nov 07, 2011 (MARKETWIRE via COMTEX) -- Corcept Therapeutics IncorporatedCORT -1.58% , a pharmaceutical company engaged in the discovery, development and commercialization of drugs for the treatment of severe metabolic and psychiatric disorders, today reported financial results for the quarter ended September 30, 2011, and updated its corporate progress.

"Following the acceptance by the U.S. Food and Drug Administration (FDA) of our New Drug Application (NDA) for the use of our lead product candidate, Korlym(TM), in Cushing's Syndrome," said Joseph Belanoff, M.D., Chief Executive Officer of Corcept, "we continue to focus our efforts on building our commercial capabilities to support the launch of Korlym, if Korlym is approved by the FDA, in order to allow us to provide an important treatment option to patients suffering from Cushing's Syndrome."

Corporate and Development Highlights

--  Received notification in October 2011 that the FDA had accepted our proposed brand name, Korlym (formerly referred to as CORLUX(R)), for our lead product candidate in the treatment of endogenous Cushing's Syndrome.   --  Advanced our commercial launch preparations related to Korlym for the treatment of Cushing's Syndrome, including developing our internal infrastructure and engaging third-party vendors to provide market analytics and to support distribution and other logistical needs in the event Korlym is approved by the FDA.   --  Received notification in October 2011 that the European Commission had granted Korlym Orphan Designation for the treatment of endogenous Cushing's Syndrome (hypercortisolism) in the European Union (EU). Benefits of Orphan Drug Designation in the EU are similar to those in the U.S., but include ten years of marketing exclusivity in all 27 member states, free scientific advice during drug development, access to a centralized review process and a reduction or complete waiver of fees levied by the European Medicines Agency.   --  Enrolled additional patients in our double-blind placebo controlled Phase 3 trial of Korlym for the treatment of the psychotic features of psychotic depression.   --  Continued the clinical portion of our Phase 1b/2a multi-dose safety and proof of concept studies of CORT 108297, one of our selective GR-II antagonists.   --  Identified additional compounds from among our proprietary series of selective GR-II antagonists to advance toward an Investigational New Drug submission.

Third Quarter Financial Results

For the third quarter of 2011, Corcept reported a net loss of $6.4 million, or $0.08 per share, compared to a net loss of $7.1 million, or $0.10 per share, for the third quarter of 2010.

In the third quarter of 2011, research and development expenses decreased to $3.2 million from $5.2 million in the third quarter of 2010. This decrease in research and development expenses was due primarily to decreases in clinical trial costs related to drug-drug interaction and other NDA-supportive studies with Korlym, which were substantially completed in late 2010, and decreases in the clinical trial costs related to the Phase 1b/2a studies with CORT 108297. These decreases were partially offset by increased costs associated with the prosecution of our NDA for Korlym for the treatment of Cushing's Syndrome. General and administrative expenses increased to $3.2 million for the third quarter of 2011 from $1.9 million for the same period in 2010 due primarily to additional expenditures on commercialization activities for the potential launch of Korlym for Cushing's Syndrome.

Our cash balance as of September 30, 2011 was $45.9 million, up from $24.6 million at December 31, 2010. "We anticipate that our current cash balance is sufficient to fund the company through the end of 2012," said Charles Robb, the company's Chief Financial Officer.

Anticipated Activities for the Remainder of 2011

We continue to concentrate our efforts on advancing Korlym toward approval and commercialization for the treatment of Cushing's Syndrome. We also continue our efforts to be prepared to respond in a timely fashion to any questions posed by the FDA during the course of their review of our NDA.

"We are focused intently on developing the commercial and logistical capabilities we will need to make Korlym available to patients suffering from Cushing's Syndrome, should the FDA approve our drug for this indication," added Dr. Belanoff. "Korlym is the first step in unlocking the value of our scientific platform. The regulation of cortisol is a critical biological function; its dysregulation is equally critical in many important disease states. Our own research and research from increasing numbers of academic investigators point to the potential importance of cortisol antagonism in a wide variety of diseases. We believe our expanding library of selective cortisol antagonists may help address these unmet medical needs."

About Cushing's Syndrome

Endogenous Cushing's Syndrome is caused by prolonged exposure of the body's tissues to high levels of the hormone cortisol and is generated by tumors that produce cortisol or ACTH. Cushing's Syndrome is an orphan indication which most commonly affects adults aged 20 to 50. An estimated 10 to 15 of every one million people are newly diagnosed with this syndrome each year, resulting in over 3,000 new patients in the United States. An estimated 20,000 patients in the United States have Cushing's Syndrome. Symptoms vary, but most people have one or more of the following manifestations: high blood sugar, diabetes, high blood pressure, upper body obesity, rounded face, increased fat around the neck, thinning arms and legs, severe fatigue and weak muscles. Irritability, anxiety, cognitive disturbances and depression are also common. Cushing's Syndrome can affect every organ system in the body and can be lethal if not treated effectively.

About Psychotic Depression

Psychotic depression is a serious psychiatric disorder that affects approximately three million people annually in the United States. It is more prevalent than either schizophrenia or bipolar I disorder. The disorder is characterized by severe depression accompanied by delusions, hallucinations or both. People with psychotic depression are approximately 70 times more likely to commit suicide than the general population and often require lengthy and expensive hospital stays. There is no FDA-approved treatment for psychotic depression.

About Weight Gain Caused by Antipsychotic Medications

The group of medications known as second-generation antipsychotics, including olanzapine (Zyprexa), risperidone (Risperdal), quetiapine (Seroquel) and clozapine (Clozaril), are widely used to treat schizophrenia and bipolar disorder. All medications in this group are associated with treatment emergent weight gain of varying degrees and also carry warning labels relating to treatment emergent hyperglycemia and diabetes mellitus. There is no FDA-approved treatment for the weight gain associated with the use of antipsychotic medications.

About Korlym

Corcept's first-generation compound, Korlym, also known as mifepristone, directly blocks the cortisol (GR-II) receptor and the progesterone (PR) receptor. Intellectual property protection is in place to protect important methods of use for Korlym. Corcept retains worldwide rights to its intellectual property related to Korlym.

About CORT 108297

CORT 108297 is a potent, selective antagonist of the cortisol (GR-II) receptor that we have discovered and for which Corcept owns worldwide intellectual property rights. In in vitro binding affinity and functional assays this compound has no affinity for the progesterone (PR), estrogen (ER), androgen (AR) or mineralocorticoid (GR-I) receptors.

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. The company has completed its Phase 3 study of Korlym for the treatment of Cushing's Syndrome, and has an ongoing Phase 3 study of Korlym for the treatment of the psychotic features of psychotic depression. Corcept also has a Phase 2 program for CORT 108297, a selective GR-II antagonist that blocks the effects of cortisol but not progesterone. Corcept has developed an extensive intellectual property portfolio that covers the use of GR-II antagonists in the treatment of a wide variety of psychiatric and metabolic disorders, including the prevention of weight gain caused by the use of antipsychotic medication, as well as composition of matter patents for our selective GR-II antagonists.

Statements made in this news release, other than statements of historical fact, are forward-looking statements, including, for example, statements relating to the potential benefit of Korlym for patients diagnosed with Cushing's Syndrome, Corcept's clinical development and research programs, the outcome of the FDA's review of our NDA filing, our estimates for our capital requirements and needs for additional financing, the introduction of Korlym and future product candidates, including CORT 108297, the ability to create value from Korlym or other future product candidates or our scientific platform and our commercialization plans. 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 with respect to the cost, rate of spending, completion or success of clinical trials; financial projections may not be accurate; there can be no assurances that Corcept will pursue further activities with respect to the development of Korlym, CORT 108297, or any of its other selective GR-II antagonists. These and other risk factors 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.

CORCEPT THERAPEUTICS INCORPORATED CONDENSED BALANCE SHEETS (in thousands)  September 30,  December 31, 2011           2010 -------------- -------------- (Unaudited)      (Note) ASSETS: Current assets: Cash and cash equivalents                    $       45,909 $       24,578 Other current assets                                    427            418 -------------- -------------- Total current assets                               46,336         24,996  Other assets                                               43            108 -------------- -------------- Total assets                               $       46,379 $       25,104 ============== ==============  LIABILITIES AND STOCKHOLDERS' EQUITY: Current liabilities: Accounts payable                             $        1,066 $          817 Other current liabilities                             1,647          3,043 -------------- -------------- Total current liabilities                           2,713          3,860  Total stockholders' equity                             43,666         21,244 -------------- --------------  Total liabilities and stockholders' equity $       46,379 $       25,104 ============== ==============  Note: Derived from audited financial statements at that date.  CORCEPT THERAPEUTICS INCORPORATED CONDENSED STATEMENTS OF OPERATIONS (in thousands, except per share amounts)  (Unaudited)  For the Three Months Ended   For the Nine Months Ended September 30,               September 30, --------------------------  -------------------------- 2011          2010          2011          2010 ------------  ------------  ------------  ------------  Operating expenses: Research and development*      $      3,228  $      5,224  $     14,355  $     14,286 General and administrative*          3,209         1,881         8,049         5,327 ------------  ------------  ------------  ------------ Total operating expenses               6,437         7,105        22,404        19,613 ------------  ------------  ------------  ------------  Loss from operations       (6,437)       (7,105)      (22,404)      (19,613)  Interest and other income, net                    3             4             3           758 Other expense                  (1)           (3)          (17)          (18) ------------  ------------  ------------  ------------ Net loss         $     (6,435) $     (7,104) $    (22,418) $    (18,873) ============  ============  ============  ============   Basic and diluted net loss per share  $      (0.08) $      (0.10) $      (0.27) $      (0.28) ============  ============  ============  ============ Shares used in computing basic and diluted net loss per share                 84,188        72,045        83,000        66,982 ============  ============  ============  ============  *Includes non-cash stock-based compensation of the following: Research and development     $        110  $         45  $        432  $        170 General and administrative           844           500         1,971         1,361 ------------  ------------  ------------  ------------ Total non-cash stock-based compensation  $        954  $        545  $      2,403  $      1,531 ============  ============  ============  ============

CONTACT: Charles Robb Chief Financial Officer Corcept Therapeutics 650-688-8783 Email Contact  www.corcept.com

SOURCE: Corcept Therapeutics

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What Is the Best Approach for the Evaluation and Management of Endocrine Incidentalomas?

Key points include:  Advances and more frequent use of diagnostic radiology have led to the increased prevalence of endocrine incidentalomas;  Pituitary, thyroid, and adrenal incidentalomas must be assessed for dysfunctional hormone secretion and malignant potential; Inpatient management of endocrine incidentalomas should include consultation of endocrine or surgical teams in cases of dysfunctional or malignant lesions; Post-discharge instructions shouldclearly delineate timelines for repeat imaging, laboratory testing, and subspecialist follow-up.

by Darlene Tad-y, MD, Section of Hospital Medicine, University of Colorado Denver

Benign adrenal gland tumors.

Case

A 54-year-old man with a history of hypertension treated with hydrocholorothiazide and Type 2 diabetes mellitus is admitted with abdominal pain and found to have an incidental 2.1-cm left adrenal mass on CT scan of the abdomen. He denies symptoms of headache, palpitations, weight gain, or muscle weakness. His exam is significant for mildly elevated blood pressure. What is the best approach for evaluation and management of this incidental finding?

Overview

Incidentalomas are mass lesions that are inadvertently discovered during radiolographic diagnostic testing or treatment for other clinical conditions that are unrelated to the incidental mass. In recent decades, improvements in radiographic diagnostic techniques and sensitivity have led to increasing discovery of incidental lesions that are often in the absence of clinical signs or symptoms.¹ Three commonly discovered lesions by hospitalists are pituitary, thyroid, and adrenal incidentalomas.² The concerns associated with these findings relate to the potential for dysfunctional hormone secretion or malignancy.

Patients found with pituitary incidentalomas can be susceptible to several types of adverse outcomes: hormonal hypersecretion, hypopituitarism, neurologic morbidity due to tumor size, and malignancy in rare cases. Thyroid incidentalomas are impalpable nodules discovered in the setting of ultrasound or cross-sectional neck scans, such as positron emission tomography (PET) scans. Discovery of a thyroid incidentaloma raises concern for thyroid malignancy.³ The increased use of abdominal ultrasound, CT scans, and MRI has fueled the growing incidence of adrenal incidentalomas (AIs).

The discovery of an endocrine incidentaloma in the inpatient setting warrants a systematic approach that includes both diagnostic and potentially therapeutic management. A hospitalist should consider an approach that includes (see Table 1):

click for large version

Table 1. General inpatient approach to endocrine incidentalomas

1. Characterization of the incidentaloma, including clinical signs and symptoms, size, hormonal function, and malignant potential;
2. Immediate management, including medical versus surgical treatment; and
3. Post-discharge management, including monitoring.

Review of the Data

Pituitary incidentalomas. The prevalence of pituitary incidentalomas found by CT ranges from 3.7% to 20%, while the prevalence found by MRI approximates 10%. Autopsy studies have revealed a prevalence ranging from 1.5% to 26.7% for adenomas less than 10 mm, considered to be microadenomas. Broad categories of etiologies should be considered: pituitary adenoma, nonpituitary tumors, vascular lesions, infiltrative disorders, and others (see Table 2). The majority of pituitary adenomas secrete prolactin (30% to 40%) or are nonsecreting (30% to 40%). Adenomas secreting adrenocorticotropin hormone (ACTH, 2% to 10%), growth hormone (GH, 2% to 10%), thyroid-stimulating hormone (TSH, <1%), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) are much less common.2 Significant morbidity and premature mortality are associated with hyperprolactinemia, acromegaly (growth hormone excess), Cushing’s syndrome, and hyperthyroidism. Additionally, up to 41% of patients with macroadenomas were found to have varying degrees of hypopituitarism due to compression of the hypothalamus, the hypothalamic-pituitary stalk, or the pituitary itself.⁴

TABLE 2. DIFFERENTIAL DIAGNOSIS FOR PITUITARY INCIDENTALOMAS^2,4,14

Pituitary adenoma:

• Secreting: prolactin, growth hormone, ACTH, glycopeptides (LH, FSH, TSH, a-subunit)
• Nonsecreting

Non-pituitary tumors:

• Germ cell tumors
• Craniopharyngioma
• Meningioma
• Metastatic disease

Vascular lesions:

• Aneurysms
• Hamartomas
• Infarctions

Infiltrative:

• Sarcoidosis
• Histiocytosis
• Lymphocytic hypophysitis
• Eosinophilic granulomas

Other:

• Rathke’s cleft cyst
• Anatomic abnormalities

ACTH=adrenocorticotropin hormone, GH=growth hormone, TSH=thyroid-stimulating hormone (thyrotropin), LH=luteinizing hormone, FSH=follicle-stimulating hormone

Recently, the Endocrine Society released consensus recommendations to guide the evaluation and treatment of pituitary incidentalomas, which are included in the approach outlined below.⁵ A detailed history and physical examination should be obtained with specific inquiry as to signs and symptoms of hormonal excess and mass effect from the tumor. Examples of symptoms of hormone excess can include:

• Prolactin: menstrual irregularity, anovulation, infertility, decreased libido, impotence, osteoporosis;
• Growth hormone: high frequency of colonic polyps and colon cancer (chronic excess);
• TSH: thyrotoxicosis, atrial fibrillation; and
• ACTH: hypertension, osteoporosis, accelerated vascular disease.

Symptoms related to the mass effect of the tumor include visual field defects and hypopituitarism related to the deficient hormone, including:

• FSH/LH: oligomenorrhea, decreased libido, infertility;
• TSH: hypothyroidism (weight gain, constipation, cold intolerance);
• ACTH: adrenal insufficiency (hypotension, hypoglycemia, weight loss); and
• ADH: polyuria, polydypsia.

The size and location of the pituitary lesion must be assessed. Lesions greater than 10 mm are considered macroademonas, and their size will affect their management. If the lesion was initially identified by CT scan, an MRI is recommended to better evaluate it.⁵ If the MRI locates the incidentaloma abutting the optic nerve or chiasm, then the patient should undergo a formal visual field examination.

Indications for an inpatient surgical referral for treatment include: a lesion larger than 2 cm, evidence of mass effect such as visual field defects, neurologic compromise, opthalmoplegia, hypopituitarism, a tumor abutting the optic nerve or chiasm, pituitary apoplexy, and hypersecretion of hormones other than prolactin. Patients with prolactinomas warrant an inpatient endo-crinology consult and may need medical management with a dopamine agonist. Hormone replacement therapy can also be provided for patients with hypopituitarism.^2,5

For patients who do not meet the criteria for inpatient surgical therapy, follow-up management must be arranged at the time of discharge. Clinical, laboratory assessment, and an MRI should be scheduled six months after the initial finding of the incidentaloma with the patient’s PCP or with an endocrinologist.⁵

Thyroid incidentalomas. The prevalence of thyroid nodules based on ultrasound studies ranges from 19% to 46%, with autopsy studies estimating an incidence of approximately 50%.^2,6 Incidence of thyroid nodules also increases with age, as almost 60% of people over the age of 60 harbor a thyroid incidentaloma. The rate of malignancy in the general population has ranged between 8% and 24%; however, in the last decade, the rates have increased by 2.4 times as more sophisticated ultrasound techniques and liberal use of fine-needle aspiration (FNA) biopsies have detected subclinical disease.^7,8

Etiologies for incidental thyroid nodules can be divided into benign and malignant causes. Benign etiologies include thyroid cyst (simple or complex), multinodular goiter, and Hashimoto’s thryoiditis, while malignant causes include papillary, medullary, follicular, Hurthle cell, and anaplastic carcinomas, thyroid lymphomas, and rare instances of metastatic cancers.^2,3

Targeted history and physical examination helps to characterize the thyroid incidentaloma. Historical features, such as palpitations, weight loss, anxiety, new onset atrial fibrillation, or menstrual irregularities, coupled with tachycardia, tremors, proximal muscle weakness, and a palpable nodule aid in the diagnosis of hyperthyroidism. Findings such as a family history of thyroid cancer, symptoms of hoarseness or dysphagia, rapid growth of the nodule, environmental or history of head or neck irradiation along with physical findings of a hard, fixed nodule, or cervical lymphadenopathy increase the suspicion for malignancy.^2,7

The functionality of the nodule can be assessed by checking TSH, free T3, and free T4 levels. Suppression of TSH (< 0.1 mU/L) with elevated levels of free T3 and T4 indicates nodule production of excess thyroid hormone and warrants thyroid scintography. Thyroid scintography will identify the nodule as “hot” (hyperfunctioning) or “cold” (nonfunctioning).²

Regardless of the radiographic modality that initially identified the thyroid incidentaloma, a dedicated thyroid high-resolution ultrasound should be ordered to assess the size, multiplicity (single or multinodular), location, and character (solid, cystic, or mixed).⁷

Recommendations for proceeding to FNA to evaluate for malignancy differ among subspecialty societies. Generally, nodules larger than 1 cm or nodules smaller than 1 cm with risk factors for malignancy should be referred for FNA.^2,7

If diagnostic workup identifies a patient with hyperthyroidism due to an autonomously functional nodule or a nodule that may be at high risk for malignancy, it is appropriate to involve an endocrinologist and possibly a surgical subspecialist prior to discharge. Management of hyperthyroidism can include starting antithyroid agents (methimazole or propylthiouracil), radioactive iodine ablation, or referral for surgery.

Preparation for discharge of the patient whose incidentaloma is nonfunctional or does not appear to be malignant should include appointments to recheck thyroid hormone levels, including TSH as well as a thyroid ultrasound within one year of the initial discovery.

Adrenal incidentaloma. The prevalence of AIs found by CT of the abdomen ranges from 0.4% to 4%, while autopsy studies have found a prevalence of 1.4% to 9% with increasing prevalence with age.^2,9,10 The majority of AIs are benign and nonfunctioning adenomas, in the absence of known malignancy. Other differential diagnoses include Cushing’s syndrome, pheochromocytoma, adrenocortical adenoma, aldosteronoma, and metastatic lesions.

Because functioning adrenal incidentalomas may be clinically silent, any patient found with an AI must undergo biochemical workup as part of their evaluation to assess for pheochromocytoma, Cushing’s syndrome, and if he or she has a history of hypertension or hyperaldosteronism (Conn’s syndrome). Table 3 outlines the approach for characterizing adrenal incidentalomas.^2,11,12 An important point is that imaging studies are not useful in distinguishing a functioning versus nonfunctioning tumor but rather can help to discriminate malignant lesions.¹¹

click for large version

Table 3. Characterization of the adrenal incidentaloma^2,11

Inpatient surgical consult for resection is indicated if the patient is found to have pheochromocytoma, clinically apparent functioning adrenocortical adenoma, or a tumor size greater than 4 cm. Consultation with an endocrinologist is also recommended if biochemical tests are positive. If the diagnostic workup leads to suspicion for infection or metastatic disease, the patient should be referred for FNA.^2,12

For patients whose lesions do not require surgical resection, repeat CT scan of the abdomen is recommended six months from the initial finding. Hospitalists should also arrange for the patient to repeat biochemical testing, including an overnight dexamethasone test.^12,13

Back to the Case

The patient underwent biochemical testing and was found to have normal levels of plasma-free metanephrines, a plasma aldosterone, plasma renin activity ratio less than 20, and a serum cortisol level of 7 mg/dL after his overnight dexamethasone suppression test. The 24-hour urine collection for free cortisol revealed elevated levels of cortisol in the urine, and the ACTH level was low.

Endocrinology and endocrine surgery teams were consulted, and recommended surgical resection. After surgical resection of his tumor, the patient was started on glucocorticoid replacement and was discharged with a follow-up appointment with endocrinology.

Bottom Line

An inpatient approach to endocrine incidentalomas should include characterization of the clinical signs and symptoms, size, function, and malignant potential of the lesion. Based on this, inpatient surgical or medical management can be determined. Post-discharge management should include arrangements for surveillance testing and follow-up with appropriate subspecialists.

Dr. Tad-y is assistant professor of medicine and a hospitalist at the University of Colorado Denver.

KEY POINTS

• Advances and more frequent use of diagnostic radiology have led to the increased prevalence of endocrine incidentalomas.
• Pituitary, thyroid, and adrenal incidentalomas must be assessed for dysfunctional hormone secretion and malignant potential.
• Inpatient management of endocrine incidentalomas should include consultation of endocrine or surgical teams in cases of dysfunctional or malignant lesions.
• Post-discharge instructions should clearly delineate timelines for repeat imaging, laboratory testing, and subspecialist follow-up.

ADDITIONAL READING

• Shirodkar M, Jabbour SA. Endocrine incidentalomas. Int J Clin Pract. 2008; 62:1423-1431.
• Freda PU, Beckers AM, Katznelson L, et al. Pituitary incidentaloma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2011;96:894-904.
• Iyer NG, Shaha AR, Silver CE, et al. Thyroid incidentalomas: to treat or not to treat. Eur Arch Otorhinolaryngol. 2010;267:1019-1026.
• Zeiger MA, Siegelman SS, Hamrahian AH. Medical and surgical evaluation and treatment of adrenal incidentalomas. J Clin Endocrinol Metab. 2011;96:2004-2015.

References

1. Aron DC, Howlett TA. Pituitary incidentalomas. Endocrinol Metab Clin North Am. 2000;29:205-221.
2. Shirodkar M, Jabbour SA. Endocrine incidentalomas. Int J Clin Pract. 2008;62:1423-1431.
3. Burguera B, Gharib H. Thyroid incidentalomas. Prevalence, diagnosis, significance, and management.Endocrinol Metab Clin North Am. 2000;29:187-203.
4. Molitch ME. Nonfunctioning pituitary tumors and pituitary incidentalomas. Endocrinol Metab Clin North Am. 2008;37:151-171, xi.
5. Freda PU, Beckers AM, Katznelson L, et al. Pituitary incidentaloma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2011;96:894-904.
6. Gough J, Scott-Coombes D, Fausto Palazzo F. Thyroid incidentaloma: an evidence-based assessment of management strategy. World J Surg. 2008;32:1264-1268.
7. Iyer NG, Shaha AR, Silver CE, et al. Thyroid incidentalomas: to treat or not to treat. Eur Arch Otorhinolaryngol. 2010;267:1019-1026.
8. Jin J, Wilhelm SM, McHenry CR. Incidental thyroid nodule: patterns of diagnosis and rate of malignancy. Am J Surg. 2009;197:320-324.
9. Davenport C, Liew L, Doherty B, et al. The prevalence of adrenal incidentaloma in routine clinical practice.Endocrine. 2011;40:80-83.
10. Zeiger MA, Siegelman SS, Hamrahian AH. Medical and surgical evaluation and treatment of adrenal incidentalomas. J Clin Endocrinol Metab. 2011;96: 2004-2015.
11. Zeiger MA, Thompson GB, Duh QY, et al. American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons Medical Guidelines for the Management of Adrenal Incidentalomas: executive summary of recommendations. Endocr Pract. 2009;15:450-453.
12. NIH state-of-the-science statement on management of the clinically inapparent adrenal mass (“incidentaloma”).NIH Consens State Sci Statements. 2002;19:1-25.
13. Young WF. Clinical practice. The incidentally discovered adrenal mass. N Engl J Med. 2007;356:601-610.
14. Chidiac RM, Aron DC. Incidentalomas. A disease of modern technology. Endocrinol Metab Clin North Am. 1997;26:233-253.

 

From http://www.the-hospitalist.org/details/article/1380161/What_Is_the_Best_Approach_for_the_Evaluation_and_Management_of_Endocrine_Inciden.html

Effects of Hormone Stimulation on Brain Scans for Cushing's Disease

This study is currently recruiting participants.

Verified on August 2011 by National Institutes of Health Clinical Center (CC)

First Received on October 21, 2011.   No Changes Posted

Sponsor:	National Institute of Neurological Disorders and Stroke (NINDS)
Information provided by:	National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:	NCT01459237

  Purpose

Background:

• Cushing's disease can be caused by a tumor of the pituitary gland, a small gland about the size of a pea located at the base of the brain. These tumors produce high levels of hormones, which cause obesity, diabetes, and growth problems. The cure for this type of Cushing's disease is to have surgery that removes the tumor but leaves the pituitary gland alone. Currently, magnetic resonance imaging scans are the best way to find these tumors. However, many of these tumors do not show up on the scan.
• Positron emission tomography (PET) scans use radioactive chemicals to light up parts of the body that are more active, such as tumors. Researchers want to try to make the small Cushing's disease tumors more active to help them show up on the scans. A special hormone will be given before the scan to make the tumors more active.

Objectives:

- To test the use of hormone stimulation to improve brain scans for Cushing's disease tumors.

Eligibility:

- Individuals at least 8 years of age who will be having surgery to remove Cushing's disease tumors.

Design:

• Participants will be screened with a medical history, physical exam, blood and urine tests, and imaging studies.
• They will have three brain scans before surgery. The first scan is a magnetic resonance imaging scan to show a full picture of the brain. The second and third scans are PET scans.
• The first PET scan will be given without the special hormone. The second PET scan will be done more than 24 hours but less than 14 days after the first PET scan. The second PET scan will be given with the special hormone.
• Participants will have tumor removal surgery through another study protocol....

Condition
Pituitary Neoplasm

Study Type:	Observational
Official Title:	Prospective Evaluation of the Effect of Corticotropin-Releasing Hormone Stimulation on 18F-Fludeoxyglucose High-Resolution Positron-Emission Tomography in Cushing's Disease

Resource links provided by NLM:

MedlinePlus related topics: Cancer Cushing's Syndrome Nuclear Scans Pituitary Tumors

Drug Information available for: Corticotropin Corticotropin-releasing hormone

U.S. FDA Resources 

Further study details as provided by National Institutes of Health Clinical Center (CC):

Estimated Enrollment:	30
Study Start Date:	October 2011

Detailed Description:

Objective

Preoperative imaging identification and localization of adrenocorticotropin hormone (ACTH)-secreting pituitary adenomas is critical for the accurate diagnosis and the successful surgical treatment of Cushing's disease (CD). Unfortunately, over 40 percent of CD patients do not have a visible pituitary adenoma on magnetic resonance (MR)-imaging (the most sensitive imaging modality for ACTH-positive adenoma detection and localization). Lack of MR-imaging for diagnosis and to guide surgical resection results in significantly higher rates of surgical failure compared to cases associated with adenomas visible on MR-imaging. Because ACTH-adenomas are metabolically active compared to the surrounding pituitary gland, (18)F-fludeoxyglucose ((18)F-FDG) positron emission tomography (PET)-imaging in CD patients could be used to detect adenomas not detectable on MR-imaging. Moreover, corticotropin-releasing hormone (CRH) can be given to selectively increase the metabolic activity of ACTH-secreting pituitary adenomas to increase the likelihood of their detection and localization by (18)F -FDG PET-imaging. To determine the effect of CRH stimulation on (18)F-FDG uptake using PET-imaging in CD, we will perform (18)F-FDG high-resolution PET-imaging (with and without CRH stimulation) in CD patients.

Study Population

Thirty male and female CD patients 8 years and older will participate in this study.

Study Design

This is a single center trial to determine the effect of CRH stimulation on (18)F-FDG uptake in high-resolution PET-imaging of ACTH-adenomas in CD patients. CD patients will undergo (18)F-FDG high-resolution PET-imaging without CRH stimulation and (18)F-FDG high-resolution PET-imaging with intravenous CRH stimulation. The order of the PET scans will be randomized and the second PET scan will occur greater than 24 hours but less than 14 days after initial PET-imaging. For (18)F-FDG PET-imaging with CRH stimulation, intravenous (18)F-FDG will be given just before CRH administration. The PET images will be read by radiologists who are blinded to the administration of CRH. Within 12 weeks after completion of the last (18)F-FDG high-resolution PET-imaging scan, patients will undergo surgical resection of the pituitary adenoma. Surgical and histological confirmation of adenoma location will be used to assess the diagnostic and localization accuracy of PET-imaging and to compare to preoperative MR-imaging results in CD patients. Inferior petrosal sinus sampling (IPSS) results will be compared with imaging results and with surgical and histological findings.

Outcome Measures

The primary objective of this study is to determine the effect of CRH stimulation on (18)F-FDG uptake in high-resolution PET-imaging for CD. To assess and compare (18)F-FDG uptake without and with CRH stimulation, we will compare (18)F-FDG standardized uptake values (SUVs) in the region of interest (pituitary gland and pituitary adenoma). Secondary objectives include determining if CRH stimulation enhances detection of ACTH-adenomas as demonstrated on (18)F-FDG high-resolution PET-imaging and assessing the accuracy and sensitivity of (18)F-FDG high-resolution PET-imaging detection of ACTH-adenomas compared to MR-imaging. Measures to assess for these secondary objectives include comparing (18)F-FDG high-resolution PET-imaging (with and without CRH stimulation) detection to (1) MR-imaging detection of adenomas, (2) IPSS results, and (3) actual tumor location confirmed by histological findings to location predicted by PET- and MR-imaging within patients.

  Eligibility

Ages Eligible for Study:	8 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

• INCLUSION CRITERIA:

To be eligible for entry into the study, patients must meet all the following criteria:

1. Be 8 years of age or older and able to undergo PET-imaging without needing general anesthesia.
2. Able to provide informed consent (or guardian is able to provide consent in case of minor).
3. Clinical diagnosis of CD based on medical records.
4. Medically able to undergo resection of pituitary adenoma and planning to undergo surgical resection of adenoma within 12 weeks of PET-imaging.
5. Normal liver enzymes: tests should be completed within 14 days before injection of the radiopharmaceutical; SGOT, SGPT less than or equal to 5 times ULN; bilirubin less than or equal to 2 times ULN.

EXCLUSION CRITERIA:

Candidates will be excluded if they meet any of the following criteria:

1. Pregnant or nursing women.
2. Contraindication to MR-scanning, including pacemakers or other implanted electrical devices, brain stimulators, some types of dental implants, aneurysm clips (metal clips on the wall of a large artery), metallic prostheses (including metal pins and rods, heart valves, and cochlear implants), permanent eyeliner, implanted delivery pump, or shrapnel fragments
3. Severe chronic renal insufficiency (glomerular filtration rate < 30 mL/min/1.73 m(2)), hepatorenal syndrome or post-liver transplantation.
4. Elevated blood glucose level above 200 mg/dL on the day of the scan prior to (18)F-FDG administration.

  Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01459237

Contacts

Contact: Patient Recruitment and Public Liaison Office	(800) 411-1222	prpl@mail.cc.nih.gov
Contact: TTY	1-866-411-1010

Locations

United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike	Recruiting
Bethesda, Maryland, United States, 20892

Sponsors and Collaborators

National Institute of Neurological Disorders and Stroke (NINDS)

  More Information

Additional Information:

NIH Clinical Center Detailed Web Page  

Publications:

Alzahrani AS, Farhat R, Al-Arifi A, Al-Kahtani N, Kanaan I, Abouzied M. The diagnostic value of fused positron emission tomography/computed tomography in the localization of adrenocorticotropin-secreting pituitary adenoma in Cushing's disease. Pituitary. 2009;12(4):309-14. Epub 2009 Apr 22.

Arnaldi G, Angeli A, Atkinson AB, Bertagna X, Cavagnini F, Chrousos GP, Fava GA, Findling JW, Gaillard RC, Grossman AB, Kola B, Lacroix A, Mancini T, Mantero F, Newell-Price J, Nieman LK, Sonino N, Vance ML, Giustina A, Boscaro M. Diagnosis and complications of Cushing's syndrome: a consensus statement. J Clin Endocrinol Metab. 2003 Dec;88(12):5593-602. Review.

Batista D, Gennari M, Riar J, Chang R, Keil MF, Oldfield EH, Stratakis CA. An assessment of petrosal sinus sampling for localization of pituitary microadenomas in children with Cushing disease. J Clin Endocrinol Metab. 2006 Jan;91(1):221-4. Epub 2005 Oct 11.