ARMC5 Mutations in Macronodular Adrenal Hyperplasia with Cushing's Syndrome

Guillaume Assié, M.D., Ph.D., Rossella Libé, M.D., Stéphanie Espiard, M.D., Marthe Rizk-Rabin, Ph.D., Anne Guimier, M.D., Windy Luscap, M.Sc., Olivia Barreau, M.D., Lucile Lefèvre, M.Sc., Mathilde Sibony, M.D., Laurence Guignat, M.D., Stéphanie Rodriguez, M.Sc., Karine Perlemoine, B.S., Fernande René-Corail, B.S., Franck Letourneur, Ph.D., Bilal Trabulsi, M.D., Alix Poussier, M.D., Nathalie Chabbert-Buffet, M.D., Ph.D., Françoise Borson-Chazot, M.D., Ph.D., Lionel Groussin, M.D., Ph.D., Xavier Bertagna, M.D., Constantine A. Stratakis, M.D., Ph.D., Bruno Ragazzon, Ph.D., and Jérôme Bertherat, M.D., Ph.D.

N Engl J Med 2013; 369:2105-2114 November 28, 2013 DOI: 10.1056/NEJMoa1304603

BACKGROUND

Corticotropin-independent macronodular adrenal hyperplasia may be an incidental finding or it may be identified during evaluation for Cushing’s syndrome. Reports of familial cases and the involvement of both adrenal glands suggest a genetic origin of this condition.

METHODS

We genotyped blood and tumor DNA obtained from 33 patients with corticotropin-independent macronodular adrenal hyperplasia (12 men and 21 women who were 30 to 73 years of age), using single-nucleotide polymorphism arrays, microsatellite markers, and whole-genome and Sanger sequencing. The effects of armadillo repeat containing 5 (ARMC5) inactivation and overexpression were tested in cell-culture models.

RESULTS

The most frequent somatic chromosome alteration was loss of heterozygosity at 16p (in 8 of 33 patients for whom data were available [24%]). The most frequent mutation identified by means of whole-genome sequencing was in ARMC5, located at 16p11.2. ARMC5 mutations were detected in tumors obtained from 18 of 33 patients (55%). In all cases, both alleles of ARMC5 carried mutations: one germline and the other somatic. In 4 patients with a germline ARMC5 mutation, different nodules from the affected adrenals harbored different secondary ARMC5 alterations. Transcriptome-based classification of corticotropin-independent macronodular adrenal hyperplasia indicated that ARMC5 mutations influenced gene expression, since all cases with mutations clustered together. ARMC5 inactivation decreased steroidogenesis in vitro, and its overexpression altered cell survival.

CONCLUSIONS

Some cases of corticotropin-independent macronodular adrenal hyperplasia appear to be genetic, most often with inactivating mutations of ARMC5, a putative tumor-suppressor gene. Genetic testing for this condition, which often has a long and insidious prediagnostic course, might result in earlier identification and better management. (Funded by Agence Nationale de la Recherche and others.)

Supported in part by grants from Agence Nationale de la Recherche (ANR-10-Blan-1136), Corticomedullosurrénale Tumeur Endocrine Network (Programme Hospitalier de Recherche Clinique grant AOM95201), Assistance Publique–Hôpitaux de Paris (Clinical Research Center Grant Genhyper P061006), Institut National du Cancer (Recherche Translationelle 2009-RT-02), the Seventh Framework Program of the European Commission (F2-2010-259735), INSERM (Contrat d’Interface, to Dr. Assié), the Conny-Maeva Charitable Foundation, and the intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Drs. Assié, Libé, Espiard, Rizk-Rabin, Ragazzon, and Bertherat contributed equally to this article.

We thank Drs. J. Chelly and M. Delpech of the cell bank of Cochin Hospital and Dr. B. Terris of the tumor bank of Cochin Hospital for their help in sample collection; Dr. E. Clauser of the oncogenetic unit of Cochin Hospital for help in microsatellite analysis; Drs. J. Guibourdenche and E. Clauser of the hormone biology unit of Cochin Hospital for cortisol assays; Drs. F. Tissier and Pierre Colin for pathological analysis; Anne Audebourg for technical assistance; J. Metral and A. de Reynies of the Cartes d’Identité des Tumeurs program of Ligue Nationale contre le Cancer for help in genomics studies and fruitful discussions; Dr. P. Nietschke of the bioinformatics platforms of Paris Descartes University for helpful discussions; all the members of the Genomics and Signaling of Endocrine Tumors team and of the genomic platform of Cochin Institute for their help in these studies; and the patients and their families, as well as the physicians and staff involved in patient care, for their active participation.

SOURCE INFORMATION

From INSERM Unité 1016, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Institut Cochin (G.A., R.L., S.E., M.R.-R., A.G., W.L., O.B., L.L., S.R., K.P., F.R.-C., F.L., L. Groussin, X.B., B.R., J.B.), Faculté de Médecine Paris Descartes, Université Paris Descartes, Sorbonne Paris Cité (G.A., S.E., A.G., O.B., L.L., M.S., K.P., F.R.-C., L. Groussin, X.B., J.B.), Department of Endocrinology, Referral Center for Rare Adrenal Diseases (G.A., R.L., O.B., L. Guignat, L. Groussin, X.B., J.B.), and Department of Pathology (M.S.), Assistance Publique–Hôpitaux de Paris, Hôpital Cochin, and Unit of Endocrinology, Department of Obstetrics and Gynecology, Hôpital Tenon (N.C.-B.) — all in Paris; Unit of Endocrinology, Centre Hospitalier du Centre Bretagne, Site de Kério, Noyal-Pontivy (B.T.), Unit of Endocrinology, Hôtel Dieu du Creusot, Le Creusot (A.P.), and Department of Endocrinology Lyon-Est, Groupement Hospitalier Est, Bron (F.B.-C.) — all in France; and the Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics and the Pediatric Endocrinology Inter-Institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD (C.A.S.).

Address reprint requests to Dr. Bertherat at Service des Maladies Endocriniennes et Métaboliques, Centre de Référence des Maladies Rares de la Surrénale, Hôpital Cochin, 27 rue du Faubourg St. Jacques, 75014 Paris, France, or at jerome.bertherat@cch.aphp.fr.

Access this article: Subscribe to NEJM | Purchase this article

Related articles

• Are you carrying adrenal Cushing’s syndrome without knowing it?(cushieblog.com)
• ARMC5 mutation identified in patients with macronodular adrenal hyperplasia(2minutemedicine.com)

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Cushing Syndrome Overview

Cushing’s syndrome (pronounced KOOSH-ingz SIN-drohm) is a condition that occurs when a person’s body tissues are exposed over time to too much of the hormone cortisol (pronouncedKAWR-tuh-sawl). The syndrome can be caused by taking certain medicines or, less commonly, it can be caused by noncancerous or cancerous tumors. Cushing’s syndrome includes a range of symptoms, but they can be treated and, in most cases, the syndrome can be cured. The NICHD is one of the many federal agencies that support and conduct research on the causes of Cushing’s syndrome, detection of its symptoms as soon as possible, and development of improved treatments.

For more information about this topic, select the Condition Information, Research Information, Clinical Trials, or Resources and Publications link in the menu on the left.

Fast Facts

Common Name

• Cushing's syndrome

Scientific Name

• Hyperadrenocorticism (pronounced HAHY-per-uh-dree-noh-KAWR-ti-siz-uhm)
• Hypercortisolism (pronounced HAHY-per-KAWR-ti-sol-iz-uhm)

Causes

The most common cause of Cushing’s syndrome is taking medication that contains the hormone cortisol. This leaves the body with more cortisol than it would normally contain from the natural production of cortisol.¹ Less commonly, a cancerous or noncancerous tumor in the body can cause too much cortisol production.²

Number of People Affected

Among 1 million people, two or three will develop endogenous (non-medicine-related) Cushing’s syndrome each year in the United States.³ Women are three times more likely than men to have the condition.⁴

Common Symptoms

The symptoms of Cushing’s syndrome vary, especially in mild cases, but patients may have some or most of the following¹:

• Upper-body obesity, with thin arms and legs
• A round, red face
• Skin problems, such as acne, reddish-blue streaks, or easy bruising
• Muscle and bone weakness, including backache
• Fat that collects between the shoulders
• Poor growth in children⁵

Common Treatments

In most cases Cushing’s syndrome can be cured. The treatment depends on what is causing the excess cortisol in the body.^6,7

Cushing’s syndrome can be treated by the following:

• Medication. If medication is to blame, a health care provider can reduce the dose or change the type of drug.
• Overproduction. If the body is making too much cortisol because of a tumor, treatments may include oral medication, surgery, radiation, or a combination of these approaches.

 

---

1. Stewart P. M., & Krone, N. P. (2011). The adrenal cortex. In Kronenberg, H. M., Shlomo, M., Polonsky, K. S., & Larsen, P. R. (Eds.). Williams textbook of endocrinology (12th ed.) (chap. 15). Philadelphia, PA: Saunders Elsevier. [top]
2. Nieman, L. K., & Ilias, I. (2005) Evaluation and treatment of Cushing’s syndrome. Journal of American Medicine, 118(12), 1340-1346. PMID 16378774. [top]
3. Lindholm, J., Juul, S., Jørgensen, J. O. L, Astrup, J., Bjerre, P., Feldt-Rasmussen, U., et al. (2001). Incidence and late prognosis of Cushing’s syndrome: A population-based study. Journal of Clinical Endocrinology and Metabolism, 86(1), 117-123. PMID 11231987. [top]
4. Steffensen, C., Bak, A. M., Rubeck, K. Z., & Jørgensen, J. O. (2010). Epidemiology of Cushing’s syndrome. Neuroendocrinology, 92(Suppl 1), 1-5. PMID 20829610. [top]
5. Batista, D. L., Riar, J., Keil, M., & Stratakis, C.A. (2007). Diagnostic tests for children who are referred for the investigation of Cushing syndrome. Pediatrics, 120(3), e575-e586. [top]
6. Nieman, L. K., Biller, B. M. K., Findling, J. W., Newell-Price, J., Savage, M. O., et al. (2008). The diagnosis of Cushing’s syndrome: An Endocrine Society clinical practice guideline. Retrieved April 8, 2012, fromhttp://www.endo-society.org/guidelines/final/upload/Cushings_Guideline.pdf (PDF - 510 KB). [top]
7. Boscaro, M., & Arnaldi, G. (2009). Approach to the patient with possible Cushing’s syndrome. Journal of Clinical Endocrinology and Metabolism, 94(9), 3121. [top]

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Last Updated Date: 11/30/2012
Last Reviewed Date: 11/30/2012

From https://www.nichd.nih.gov/health/topics/cushing/Pages/default.aspx

Magic Foundation Cushing's Conference, 2013

Dates:

Friday, April 19, 2013 - Registration and exhibits-4 PM to 9 PM

Saturday, April 20, 2013 - Educational segments

Sunday, April 21, 2013 – Educational Segments

Monday, April 22, 2013 – Departure or visiting sites of Las Vegas

 

Registration: $155 for members $190 for non-members (includes 1 yr membership)

Registration fee includes: Thursday exhibits and refreshments, Friday continental breakfast, and lunch and Saturday continental breakfast and lunch. An optional dinner will be held on Friday night for $25.00 per person.

For additional attendees in your family there will be no registration fee but a $75 charge for inclusion of the segments and meals. (optional dinner on Friday night not included in the $75 fee)

 

Accommodations:

Tuscany Suites & Casino (Just off the Las Vegas Strip)

255 East Flamingo Rd

Las Vegas, NV

Guest room costs: 

Friday and Saturday $105 per guestroom, single or double occupancy ($117.60 w/tax)

Sunday thru Thursday $65 per guestroom, single or double occupancy ($72.80 w/tax)

Reservations made after March 20, 2013 at noon will be charged the prevailing room rate if accommodations are available. To book your room you must call Tuscany Room Reservations, 877-887-2261 and ask for MAGIC Foundation group rates. You will be required to provide a major credit card for the first night’s room and tax deposit, which will be charged in order to guarantee accommodations.

Evaluation of depression, quality of life and body image in patients with Cushing’s disease

Nilufer Alcalar, Sedat Ozkan, Pinar Kadioglu, Ozlem Celik, Penbe Cagatay, Baris Kucukyuruk and Nurperi Gazioglu

 

• Download PDF (220.3 KB)
• View HTML

Abstract

The aim of this study was to evaluate patients with Cushing’s disease (CD) who had undergone transsphenoidal surgery in terms of depression, quality of life (QoL), and perception of body image in comparison to healthy controls.

Forty patients with CD and 40 healthy controls matched for demographic characteristics were included in the study. The subjects were evaluated with the Beck depression inventory (BDI), the health survey-short form (SF-36) and the multidimensional body-self relations questionnaire (MBSRQ). Subgroups of the patients with CD were formed on the basis of remission status and BDI scores. In this study, QoL in the general health category and body image were lower in the patients with CD than in the healthy subjects. However, no differences in depression scores were found between the two groups.

When the CD group was evaluated according to remission rate, the mean BDI score was significantly higher in the CD patients without remission than in both the CD patients with remission and the healthy subjects (p = 0.04). However, the physical functioning, bodily pain and general health scores of the CD patients without remission on the SF-36 questionnaire were lower than in the CD patients in remission and the healthy subjects (p = 0.002, p = 0.04, p = 0.002, respectively). Fitness evaluation, health evaluation and body areas satisfaction scores of the MBSRQ were significantly different in the three groups (p = 0.003, p = 0.009 and p = 0.001, respectively). In this study, patients with CD were found to have lower QoL, lower body image perception and higher levels of depression compared to healthy controls, particularly if the disease is persistant despite surgery.

Keywords  Cushing’s disease – Pituitary surgery – Depression – Quality of life – Body image

Fulltext Preview

 

 

Share Your Cushing's Story on TV

A new series on Lifetime TV's daily morning talk show, The Balancing Act is featuring Cushings Syndrome.

Producers are looking for patients to share their stories in the comments of their landing page for Unveiling the Mystery: Rare and Genetic Diseases!

http://www.thebalancingact.com/rare/

Surgical Versus Medical Treatment for Cushing Disease, the New and the Old

Surgical Versus Medical Treatment for Cushing Disease the New and the Old

Interview with Dr. Amir H. Hamrahian

Amir H. Hamrahian, MD, is a Staff member in the Department of Endocrinology, Diabetes and Metabolism at Cleveland Clinic's main campus, having accepted that appointment in 2005. Prior to that appointment, he was also a clinical associate there for nearly five years. 

His clinical interests include pituitary and adrenal disorders.

Dr. Hamrahian received his medical degree from Hacettepe University in Ankara, Turkey, and upon graduation was a general practitioner in the provinces of Hamadan and Tehran, Iran. He completed an internal medicine residency at the University of North Dakota, Fargo, and an endocrinology fellowship at Case Western Reserve University and University Hospitals, Cleveland.

In 2003, he received the Teacher of the Year award from Cleveland Clinic's Department of Endocrinology, Diabetes and Metabolism. Dr. Hamrahian speaks three languages -- English, Turkish and Farsi -- and is board-certified in internal medicine as well as endocrinology, diabetes and metabolism. He is a member of the Endocrine Society, Pituitary Society and the American Association of Clinical Endocrinologists.

Some of the questions answered in this interview October 1, 2012 include (not in this order):

 

• Can you tell me a little about you endocrine practice and your experience with Cushing’s as part of your practice?
• What are some of biggest challenges you have in treating Cushing’s?
• How do you test cyclical/episodic Cushing's?
• Can someone with cyclical/episodic Cushing's take Korlym?
• I know that Cushing's patients (those that currently have it and/or are cured/in remission can have healthy pregnancies with the right care. How do doctors support this process? Through an endocrinologist and a high-risk ob/gyn? And what sort of treatment is given throughout the pregnancy to prevent hypercortisolism.
• While many patients have a successful long term result from surgery, there are just as many that don’t. Do you find that there are any particular challenges treating patients with Cushing’s disease when pituitary surgery has already failed?
• As I understand, you were an investigator in the clinical trial for Korlym, and I think you treated 4 patients. Did these patients all have a previous surgery that had failed?
• Many Cushing’s patients are trying to understand if they might be candidates for Korlym treatment, can you tell me a little history about the types of patients you treated with Korlym?  I hear that not all patients can take Korlym. Which type of patient should not take it?
• Every past treatment for Cushing’s has always had the goal of lowering cortisol levels, but Korlym doesn’t lower cortisol levels, can you explain how it works?
• So, how do you judge success for a Cushing’s patient on Korlym?
• I lost copious amounts of hair while on Korlym, is this a known side effect?
• Are there any long term reproductive implications due to use of Korlym?

Listen to this interview at http://www.blogtalkradio.com/cushingshelp/2012/10/01/dr-amir-hamrahian-answers-our-questions or to the podcast by searching for Cushings in the iTunes podcast area or click here: http://itunes.apple.com/podcast/cushingshelp-cushie-chats/id350591438

 

 

Dr. Amir Hamrahian Answers Our Questions About Cushing's and Korlym

October 1, 2012 at 6:30 PM eastern, Dr. Amir Hamrahian will answer our questions about Cushing's, pituitary or adrenal issues and Korlym (mifepristone) in BlogTalkRadio at http://www.blogtalkradio.com/cushingshelp/2012/10/01/dr-amir-hamrahian-answers-our-questions

 

You may listen live at the link above.  The episode will be added to the Cushing's Help podcast after the show is over.  Listen to the podcasts by searching for Cushings in the iTunes podcast area or click here: http://itunes.apple.com/podcast/cushingshelp-cushie-chats/id350591438

 

Dr. Hamrahian has had patients on Korlym for about 4 years.

 

Please submit your questions below or email them to CushingsHelp@gmail.com before Sunday, September 30.

 

From Dr. Hamrahian's bio at http://my.clevelandclinic.org/staff_directory/staff_display.aspx?doctorid=3676

 

 

Amir Hamrahian, M.D. 

(216) 444-6568

Appointed: 2000

Request an Appointment

Department:Endocrinology, Diabetes and Metabolism

Location:Cleveland Clinic Main Campus
Mail Code F20 
9500 Euclid Avenue
Cleveland, OH 44195

Appointment:(216) 444-6568

Desk:(216) 445-8538

Fax:(216) 445-1656

Department:Brain Tumor and Neuro-Oncology Center

Location:Cleveland Clinic Main Campus
Mail Code R20 
9500 Euclid Avenue
Cleveland, OH 44195

Appointment:(216) 444-6568

Desk:(216) 445-8538

Fax:(216) 445-1656

Surgeon:

No

Treats:

Adults Only

Research & Publications †

( † Disclaimer: This search is powered by PubMed, a service of the U.S. National Library of Medicine. PubMed is a third-party website with no affiliation with Cleveland Clinic.)

Biographical Sketch

Amir H. Hamrahian, MD, is a Staff member in the Department of Endocrinology, Diabetes and Metabolism at Cleveland Clinic's main campus, having accepted that appointment in 2005. Prior to that appointment, he was also a clinical associate there for nearly five years. 

His clinical interests include pituitary and adrenal disorders.

Dr. Hamrahian received his medical degree from Hacettepe University in Ankara, Turkey, and upon graduation was a general practitioner in the provinces of Hamadan and Tehran, Iran. He completed an internal medicine residency at the University of North Dakota, Fargo, and an endocrinology fellowship at Case Western Reserve University and University Hospitals, Cleveland.

In 2003, he received the Teacher of the Year award from Cleveland Clinic's Department of Endocrinology, Diabetes and Metabolism. Dr. Hamrahian speaks three languages -- English, Turkish and Farsi -- and is board-certified in internal medicine as well as endocrinology, diabetes and metabolism. He is a member of the Endocrine Society, Pituitary Society and the American Association of Clinical Endocrinologists.

Education & Fellowships

Fellowship - University Hospitals of Cleveland

Endocrinology
Cleveland, OH USA
2000

Residency - University of North Dakota Hospital

Internal Medicine
Fargo, ND USA
1997

Medical School - Hacettepe University School of Medicine

Ankara Turkey
1991

Certifications

• Internal Medicine
• Internal Medicine- Endocrinology, Diabetes & Metabolism

Specialty Interests

Cushing syndrome, acromegaly, pheochromocytoma, prolactinoma, primary aldosteronism, pituitary disorders, adrenal tumor, adrenocortical carcinoma, MEN syndromes, adrenal disorders

Awards & Honors

• Best Doctors in America, 2007-2008 

Memberships

• Pituitary Society
• Endocrine Society
• American Association of Clinical Endocrinologists
• American Medical Association

Treatment & Services

• Radioactive Iodine Treatment
• Thyroid Aspiration
• Thyroid Ultrasound

Specialty in Diseases and Conditions

• Acromegaly
• Addison’s Disease
• Adrenal disorders
• Adrenal insufficiency
• Adrenal Insufficiency and Addison’s Disease
• Adrenal Tumors
• Adrenocortical Carcinoma
• Adrenoleukodystrophy (ALD)
• Amenorrhea
• Androgen Deficiency (Low Testosterone)
• Androgen Excess
• Calcium Disorders
• Carcinoid Syndrome
• Conn's Syndrome
• Cushing's Syndrome
• Empty sella
• Erectile Dysfunction
• Familial Multiple Endocrine Neoplasia
• Fasting hypoglycemia
• Flushing Syndromes
• Galactorrhea
• Goiter
• Growth hormone deficiency
• Growth hormone excess
• Gynecomastia
• Hirsutism
• Hyperaldosteronism
• Hyperandrogenism
• Hyperprolactinemia
• Hypertension - High Blood Pressure
• Hyperthyroidism
• Hypocalcemia
• Hypoglycemia
• Hypogonadism
• Hypoparathyroidism
• Hypophysitis
• Hypopituitarism
• Hypothyroidism
• Mastocytosis
• Menopause, Male
• Menstrual Disorders
• Paget's Disease
• Panhypopituitarism
• Parathyroid Cancer
• Parathyroid Disease and Calcium Disorders
• Pheochromocytoma
• Pituitary Cysts
• Pituitary Disorders
• Pituitary stalk lesions
• Pituitary Tumors
• Premenstrual Syndrome (PMS)
• Primary Hyperaldosteronism
• Primary Hyperparathyroidism
• Prolactin Excess States
• Prolactinoma
• Thyroid and pregnancy
• Thyroid Cancer
• Thyroid Disease
• Thyroid Nodule

Today, We're Twelve!

 

Twelve  years ago yesterday  I was talking with my dear friend Alice, who runs a wonderful menopause site, Power Surge, wondering why there weren't many support groups online (OR off!) for Cushing's and I wondered if I could start one myself.  We decided that I could.

This website (http://www.cushings-help.com) first went "live" July 21, 2000 and the message boards September 30, 2000. Hopefully, with this site, I’ve made  some helpful differences in someone else's life.

Who could have known how this site – now sites – could have grown and grown.

It started as a one-page bit of information about Cushing’s  In people, not dogs, horses, ferrets…

Then, it started growing and growing, taking on a life of its own.  To truly emulate Alice, I added message boards in September.  They were really low-quality, a type put together by an old HTML editor but we had members and actually had discussions.

Not too long after, a real board was opened up and things really started happening.  Then we outgrew that board and ended up in our current home.

The message boards are still very active and we have weekly online text chats, live interviews, local meetings, email newsletters, a clothing exchange, a Cushing's Awareness Day Forum, podcasts, phone support and much more.

Whenever one of the members of the boards gets into NIH, I try to go to visit them there. Other board members participate in the "Cushie Helper" program where they support others with one-on-one support, doctor/hospital visits, transportation issues and more.

Things have changed over the years, though.  The original Cushings-Help site is still updated with new bios, new Helpful Doctor listings, meetings and more but all new articles have moved to a new site - http://www.cushie.info/ – which is much easier to maintain than the older strictly-HTML site.

Also new are a CushieWiki, a site for the Cushing’s Help Organization, several blogs (of which this is one), three Facebook entities (Cushing's Help Cause; Cushing's Help and Support Group; and the Cushings Help Organization, Inc.); a Twitter stream and much more.

New recently:

NEW! Daily News Summary at Cushing's Daily News

NEW! cushie.info is now optimized for viewing on PDAs and mobile phones

NEW!  Medical Centers. These are centers which specialize in Cushing's, pituitary or adrenal patients.  If you, as a patient, have one that you'd like to have added, please send any info you may have to Mary O'Connor (MaryO).  Thank you!

Occasional Newsletters are Back: Members of cushie.info will automatically receive these occasional newsletters. Of course, you may opt-out at any time. Thank you for your interest.  Non-members may subscribe through the Newsletter Subscription module on the left side of this page.

Cushie Toolbar: Be the first to know! The Cushie Toolbar features a Google search box, the 911 Adrenal Crisis! page, the Cushie Reads book recommendations page, Cushie Calendar, all the bios, arranged by diagnosis type or date, add (or update) your bio, our locations around the world, the message boards and chatroom, Helpful Doctors list, add (or update) your Helpful Doctor, support page, scrolling message area for Cushing’s news, Cushing’s blogs, NIH Clinical trials for Cushing’s, pituitary and adrenal, the Cushings Help Organization cause on Facebook, Staticnrg and Cushings on Twitter, new CushieWiki and listen to the Cushing’s podcasts right from this toolbar.

CushieWiki: Please feel free to contribute! The CushieWiki is an ever-changing, ever-growing body of Cushing's knowledge provided by *YOU* and other patients.

Members of the cushie.info site have additional features:

• Your Profile
• Contact Us
• Member List
• How To Add Friends
• Local Liaisons
• Pen Pals
• Add an Article!
• Access the Archives.  News items and abstracts are archived after one month
• Calendar: Add Events
• Calendar: Add a Meeting Venue
• Photos and Images
• Upload Images
• Submit a Link
• Track Health & Fitness Achieve your goals, print charts for your doctors. Add anything else that you would like to track. These are private graphs, available only to you.
• A special menu along the bottom of each page where you can take notes, make changes to your profile, subscribe to RSS feeds and much more.
• Add your Twitter user name and the last 10 "tweets" will show up in your profile for other members to see
• Members can submit links (URLs), send each other PMs, email each other directly, add avatars, add Helpful Doctors and rate current ones or add reviews.  They can also add articles, events and meeting venues. Some articles are available to members only.

We’ve grown out of control from that simple one-page info sheet to way more than I could have ever imagined in that phone conversation with my friend.  I would never have thought that I could do any of this, provide these services and touch the lives of so many others.

I also never thought that I would spend hours a day updating, adding, improving, helping, emailing, phoning, paperwork, writing…

But it’s all worth it if the lives of other Cushies are made better.

-->

Here’s to another 12 years…

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