Body composition and cardiovascular risk markers after remission of Cushing's disease: a prospective study using whole-body MRII

Geer EB, Shen W, Strohmayer E, Post KD, Freda PU.

J Clin Endocrinol Metab. 2012 May; 97(5):1702-11

John Newell-Price and Miguel Debono, University of Sheffield, UK. F1000 Diabetes & Endocrinology

26 Jun 2012 | Confirmation, Good for Teaching

Excess endogenous glucocorticoids cause central obesity with an increased visceral to total fat ratio and this is associated with the metabolic syndrome and insulin resistance, increasing the cardiovascular risk. This is a prospective study in 14 subjects where whole-body magnetic resonance imaging (MRI) has been used for the first...

Read this article at http://f1000.com/717297977

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

Genetic variant is linked to obesity and insulin resistance

A large study in people at risk of diabetes has found a direct association between the presence of a small genetic alteration in a hormone receptor and increased body fat and insulin resistance. The results, to be presented Tuesday at The Endocrine Society's 94th Annual Meeting in Houston, suggest an adverse role for a previously described genetic variant, the BclI polymorphism.

"Our findings support the idea that even small variations in hormone receptor sensitivity can have metabolic implications, such as obesity or diabetes," said co-author Bastiaan Havekes, MD, PhD, of Maastricht University Medical Center, Maastricht, the Netherlands.

"Endocrinologists should not just focus on hormone levels themselves. Taking into account hormone receptor sensitivity could help in better understanding hormone-mediated effects on metabolism," he said.

The inherited BclI polymorphism occurs in the gene encoding for the glucocorticoid receptor, which controls the actions of glucocorticoids, steroid hormones that affect every system in the body. This small variant makes the receptor more sensitive to glucocorticoids, resulting in greater effects with similar hormone levels, Havekes said.

The effects of this change appear to be similar to, although much smaller than, the excessive glucocorticoid exposure that can occur from certain medications or diseases, Havekes said. Such excess exposure can result in weight gain, especially around the abdomen, as well as in disturbed blood sugar metabolism. This exposure most often occurs from long-term use of prednisone or other glucocorticoid medications, which are widely used to treat inflammatory diseases or to suppress the immune system. It also can result from endocrine diseases such as Cushing's syndrome. Cushing's causes overproduction in the body of the glucocorticoid cortisol, often called the "stress hormone."

Patients in this study, however, did not have known excess exposure to glucocorticoids, according to Havekes. He and his co-investigators studied 1,228 adults who participated in one of two Dutch studies focusing on diabetes in the general population. More than half of the study participants had either prediabetes (23 percent) or Type 2 diabetes (33 percent). All subjects underwent genetic testing for the BclI polymorphism.

The researchers found that 519 subjects did not carry the alternative form of the gene, or G-allele, for the BclI polymorphism on either chromosome. Another 540 subjects were heterozygous carriers, meaning the G-allele was present on one of the two chromosomes. The remaining 169 subjects were homozygous carriers and therefore carried the G-allele on both chromosomes.

Those who had the BclI polymorphism on each chromosome had a significantly higher body mass index and larger waist and hip circumferences than did noncarriers or heterozygous carriers, the authors reported. This was reflected by greater insulin resistance, meaning that insulin is less effective at lowering blood glucose (blood sugar).

"Determining an individual's genetic risk profile for metabolic disease is of paramount importance to prevent development of cardiovascular diseases," he said. "Future studies concerning cardiovascular risk profiling should perhaps consider the BclI polymorphism."

Provided by The Endocrine Society and posted by MedicalXPress.com

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

Dr. Cargill Alleyne - Augusta, GA 2012 Best Doctors

Dr. Cargill Alleyne

Neurosurgeon

You’re going to work hard whatever you do, so work hard doing something you love,” says Dr. Cargill Alleyne, director of the neurosurgery residency program at Georgia Health Sciences University, among other professional appointments. Research, instruction, publishing, inventing and clinical practice stimulate, invigorate and energize him. “When you’re in the operating room, you’re dedicating all your energies, all your senses, to one specific problem and time flies,” he says. That experience of flow along with the element of human interaction drew him to medicine and specifically to neurosurgery.

His unique ability to be in the moment, tending to each patient one-on-one and, at the same time, to consider the bigger picture and how he can contribute to it distinguishes his approach to medicine. The model for his own career and his message to the neurosurgeons he teaches is this: Perform one surgery and change a single life. Teach another person to perform that surgery, change several lives. Conduct research and publish results and broaden the scope of impact by reaching practitioners around the world. Improve a current procedure or implement a new treatment paradigm and influence the healing of future generations of patients. Every element of this model supports a philosophy of providing the best care possible at the personal level and ensuring that every person receives the best care possible.

The brain is the last frontier, rife with the potential for specialties and sub-specialties. Despite technological advances made since Dr. Harvey Cushing (1869-1939), the undisputed Father of Neurosurgery, pioneered effective operations, the organ of the brain still holds many mysteries. Young residents, believes Dr. Alleyne, have the advantage of flexible thinking and, thus, possess the power to not just practice neurosurgery competently, but to improve it.

Interestingly, Dr. Alleyne has combined his love of Hollywood productions, his interest in medical history and his professional training in neurosurgery to write a screenplay, Hands of Gold, Feet of Clay–The Harvey Cushing Story, which won 13th place at the 2006 FilmMakers International Screenwriting Awards. Though he very humbly says, “It was something to do,” the project required extensive reading and research and took a year to complete. A collection of coincidences suggests that perhaps it was more than something to do; it was something he was meant to do. For example, Cushing, incidentally, had a brother named Alleyne. Cushing and Dr. Alleyne both attended Yale. And the Cushing Tumor Registry, a collection of glass jars containing brain tissues from Cushing’s many surgeries, was stored in the basement of the building in which Dr. Alleyne lived during medical school at Yale.

Neurosurgeons dedicate six to seven years beyond medical school to honing their craft. They perfect technically precise procedures. Many lose themselves in their careers. Cushing performed more than 2,000 brain surgeries and recorded volumes of detailed notes and illustrations, advancing successful treatment methods but spending little time with his wife and five children. Dr. Alleyne shares Cushing’s commitment. Yet, he also values building a strong family with his wife Audrey and their children, Nicole, 10, and Nathan, 12. Working hard at what he loves energizes him for the ones he loves.

Read more at Augusta Magazine

Clinicopathological Correlations in Pituitary Adenomas

Ozgur Mete, Sylvia L. Asa

Article first published online: 14 JUN 2012

DOI: 10.1111/j.1750-3639.2012.00599.x

Keywords:

corticotroph adenoma;gonadotroph adenoma;immunohistochemistry;lactotroph adenoma;pituitary adenoma;somatotroph adenoma;thyrotroph adenoma;transcription factors

Abstract

Pituitary adenomas are common neuroendocrine neoplasms arising from adenohypophysial cells. Recent progress in our understanding of pituitary tumorigenesis as well as pathways involved in molecular cytodifferentiation of the adenohypophysis has impacted on the classification of pituitary adenomas.

The detailed comprehensive classification of pituitary adenomas is now well recognized to reflect specific clinical features and genetic changes that predict targeted treatments, as well as prognostic information for patients with pituitary adenomas.

Therefore, the clinical responsibility of pathologists is not only limited to the distinction of pituitary adenomas from other sellar lesions, but also to provide a comprehensive subtype classification using appropriate ancillary tools. In this article, we highlight an approach to clinical diagnosis and pitfalls in the classification of these common neoplasms.

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Medical management of Cushing's disease: what is the future?

Fleseriu M, Petersenn S.

Source

Departments of Medicine and Neurological Surgery, Northwest Pituitary Center, Oregon Health & Science University, Portland, OR, USA.

Abstract

Cushing's disease (CD) is caused by a corticotroph, adrenocorticotropic-hormone (ACTH)-secreting pituitary adenoma resulting in significant morbidity and mortality. Transsphenoidal surgery is the initial treatment of choice in almost all cases.

Remission rates for microadenomas are good at 65-90 % (with an experienced neurosurgeon) but remission rates are much lower for macroadenomas. However, even after postoperative remission, recurrence rates are high and can be seen up to decades after an initial diagnosis. Repeat surgery or radiation can be useful in these cases, although both have clear limitations with respect to efficacy and/or side effects.

Hence, there is a clear unmet need for an effective medical treatment. Currently, most drugs act by inhibiting steroidogenesis in the adrenal glands. Most is known about the effects of ketoconazole and metyrapone. While effective, access to ketoconazole and metyrapone is limited in many countries, experience with long-term use is limited, and side effects can be significant. Recent studies have suggested a role for a pituitary-directed therapy with new multireceptor ligand somatostatin analogs (e.g., pasireotide, recently approved in Europe for treatment of CD), second-generation dopamine agonists, or a combination of both.

Mifepristone (a glucocorticoid receptor antagonist) is another promising drug, recently approved by the FDA for treatment of hyperglycemia associated with Cushing's syndrome. We review available medical treatments for CD with a focus on the two most recent compounds referenced above.

Our aim is to expand awareness of current research, and the possibilities afforded by available medical treatments for this mesmerizing, but often frightful disease.

PMID: 22674211 [PubMed - as supplied by publisher]

From http://www.ncbi.nlm.nih.gov/pubmed/22674211