Magic Conference: Treating Cushing’s Disease with Surgery: Ways of Achieving a Cure

MEETING NOTES : Dr. McCutcheon

Meeting Created: July 21, 2012 9:15 AM

Treating Cushing’s Disease with Surgery: Ways of Achieving a Cure

Dr. McCutcheon will discuss the ways of treating Cushing’s disease from the surgical
perspective, including the different ways of getting to the pituitary, the chances of
success, and the potential complications. In addition, special nuances and pitfalls of
surgery in Cushing’s (as opposed to other types of pituitary tumor) will be addressed. 

First, there was a special presentation to Phil.  (image in next post)

Medical and Surgical

Dr. Cushing

Adrenal-pituitary axes in various conditions leading to CS

No one wants to operate on wrong place

CS is too much cortisol, CD is pituitary

Ectopic

Focus on pituitary

Raise cortisol: depression, anorexia, stress, alcoholism, drugs (BCP)

Signs/Symptoms, usual stuff

Pictures of Cushies

Also:

• Body builder who lost weight
• Thin, vigorous woman with small weight gain (10-15 lbs). Looks fine
• Cyclical or mild symptoms.  Many patients.  Symptoms come and go
• Steroids
• Have to be smarter than disease
• Cushing called it polyglandular syndrome
• Cushing depended on autopsy for diagnosis
• Dogs, horses, cats

Most Cushings is pituitary

Measure cortisol

• Am/pm cortisol.  Better at midnight?
• UFC
• Salivary
• Dex (not sex) suppression.  Low dose confirms CS, high dose addresses etiology of cortisol excess
• CRH stimulation
• Petrosal sinus sampling

Circadian rhythm

ACTH

• Half-life is 17 minutes in plasma
• Must cool specimen, add protease inhibitors
• Adrenal:  ACTH down
• Ectopic:ACTH very high
• Pituitary tumor: ACTH nl or up

ACTH-secreting tumors are usually small but visible on MRI

Less than 10% of tumors are large.

Occult tumor

• BiochemicalnCushing's but tumor doesn't show up
• 10% show no tumor during surgery
• Plan for this!
• Tumors of less than a millimeter can cause CD

When tumor is not shown

• Current MRI allows about 95% of tumors to be detected
• Small dark path may be only clue
• Scan is truly normal, surgery may show tumor, hyperplasia or no abnormality

3T is strongest MRI available to public.  9T is available to research

• No evidence that increasing the strength of MRI increases diagnosis in small pituitary tumors
• 3T won't help if tumor didn't show on 1.5T.  Not worse, either
• Dynamic MRI makes scan more sensitive
• Sella protocol
• For dynamic, get contrast while sliding into machine

Petrosal sinus sampling

• Controversial
• 50-70% correct in predicting tumor side.  Same as flipping a coin
• Midline tumors and crossover venous drainage can occur
• Best for actively producing ACTH
• Time of day matter?  Lab has to get samples fast.  Best done in middle of day for staffing
• CRH is now absent in the US so they have to use DDVAP.  Wait until they make CRH again if possible

Aims in management

• Suppression of hormones
• Reduce tumor mass with correction of visual and neurological deficits
• Preserve pituitary function
• Quality of life

Surgery first line unless too risky, or radiation better option

Different ways to get to tumor

• Transnasal, preferred now
• Endonasal
• Sublabial, wider, better angle, more working room, tooth numbness, better for suprasella
• Trans-ethmoidal, on side of eye, angle to target, not many done
• Trans-palate, very big tumor, not standard
• Craniotomy
• Cut side of nose.  Really large tumors

Turbinates (flexible bones) move out of the way usually

Mesh, fat plug

No way to prevent a new tumor that anyone knows

Dr. Hardy, trained Dr IMMC. First to remove microadenoma in 1964. Before that, only large tumors were removed

30-day (yes, DAY) mortality improving since Cushing's day thanks to improvements on many levels

Problems

• Hole in septum
• Loss of sense of smell
• Carotid artery
• Opening too small
• Hurt optic nerve
• Hurt pituitary

find a surgeon who has done 500, if possible

Post op

Endonasal fewer complaints?  Depends on reporting surgeon

Change

• Endoscopic
• Image-guided
• En bloc removal

Advantages of endoscopy

• Smaller opening
• See around tumor
• Reduce nasal complications 

Disadvantages

• Need equipment
• One hand skill
• Hard to learn
• Blood gets in way
• Lack of 3D

Computer-assisted surgery

Trajectory is very important

image guidance as extra scan, use for wandering carotids

Intraoperative MRI

Cushings surgery problems

• Electrolyte
• Hypertension
• Cardiomyopathy
• Obesity makes hard to position
• IV problems
• Bleed more
• Bleeding
• CSF leak

Failure

• Don't find tumor
• Invasion of other areas

Occult tumor

• Cushings but no tumor on MRI
• Small or hyperplasia.
• He moved on too fast to get all this 

Dual-producing tumor or 2 tumors, producing different hormones

Hyperplasia, less well-defined. Hard to get all edges.  Remove more than you think, removing normal gland or remove less and see how patient does

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…

The Trip So Far...

MEETING NOTES : The Trip So Far...

Meeting Created: July 20, 2012 11:56 PM

Lombard

Thursday morning I got up about 5 am to head to the airport.  I hadn't slept much the night before because I always get nervous flying.  My first flight was at 9 and left onetime, no problems at all.

I got to Boston for the layover. The first thing I needed to do was get cash for the rest of the trip.  Unfortunately, the ATM didn't play nice and no cash came out.  I called the number on the machine and got the old "push 1 for...". I finally figured out what was the right number and I got a recording telling me to call my bank.

So, I had to make another call.  I am not a phone person at all so this was not a great way to spend my free time.  I finally got through that phone tree and got to a real person.  I told him I had a receipt.  When I actually looked it, I saw that the machine had never intended to give me any money - I had chosen savings instead of checking account. DUH

This time when I tried, I actually got my cash.

The next plane was over an hour late, waiting for a plane to arrive from DC. Huh?  Why did I have to take an earlier flight if there was this later one?

Many babies and toddlers on this flight. The row ahead of me had 2 babies and right across the aisle was a toddler.  So much for a nap.

When we got to Chicago, my bag was the third on the carrousel.  Unheard of.

I called the shuttle company and the person hung up on me.  Called again and the person said I had to wait until 5. I was 3:30.  So I wandered around O'Hare a bit and finally went out.  The shuttle was about 20 minutes late.

Got to the hotel and Terry came over to greet me.  I checked in, took my stuff to my room and back down to the exhibit hall.  I saw Sarah (again) and met several new folks, including 2 Corcept nurses.  Picked up some cool stuff.  

Several of us went to dinner at the hotel then unpacking and bedtime for me.

Friday:

I'm still on eastern time so I woke up earlier than I'd have liked.  I couldn't get back to sleep so I checked email, did some web work.

The first lecture was Dr Frohman. I got a fruit plate and 2 cups of coffee so I wouldn't have to go get more during his talk.  I got to sit next to Denise, who I haven't seen for several years.

Dr. Frohman's and all the lectures are available on http://www.cushingshelp.blogspot.com 

So far, I've been able to get them available within 5 minutes of the end of the lecture-a first for me.

After the break, I found that they'd taken the coffee away.  Aacckk!  Will have to hoard more tomorrow so I don't get a headache.  Karen had a brilliant idea and she ordered a pot from room service, which we split.

Dr. Salvatori was next, then lunch followed by Dr. Salvatori again (see lecture notes!). Then Dr. Heaney and a bit of a break before dinner.  I bought a blue short sleeved golf shirt, the same as Denise.

Back to the room to brush my teeth and off to dinner.  It was nice, conference-y food:  chicken in a sauce, roast potatoes, beans, carrot, asparagus, salad and a rich apple caramel dessert.

After dinner, the obligatory pictures.  

Then off to the mall.  I got a sweater.  It's cold in the meeting room!  

A few of us went in the pool but there were lots of kids.  Maybe tomorrow, when they're at the zoo...

Night!

Magic Conference: Cushing’s Disease, Are We Closer to Medical Therapies?

MEETING NOTES : Dr. Heaney

Meeting Created: July 20, 2012 3:18 PM

Lombard

Cushing’s Disease, Are We Closer to Medical Therapies?

A significant proportion of patients with Cushing's Disease are not cured by primary surgical
treatment, the disease is prone to relapse and significantly damages quality of life. Adjuvant
radiotherapy is an increasingly unattractive option for clinicians who wish to spare their
patients hypopituitarism and other potential complications. Some pharmacological options are
currently available but tend to have dose-limiting side effects. New agents recently approved or
under investigation will be discussed and strategies to select the optimal drug or drug
combination for individual patients reviewed. 

Dr Anthony Heaney

Cushings

• Iatrogenic 1% taking oral steroids
• Creams, inhaled, parental, rectal, articular

Endogenous, 2-3/million a year

• Pituitary-dependent (75%), ACTH secretion

Ectopic ACTH, CRH secretion 

At risk populations for Cushing's?

• Adrenal incedentaloma. 9.2% have Cushing's

Why treat?

• Increased mortality, survival 4.6 years untreated
• Quality of life
• Improve blood pressured and bone density

Clival chordoma?  (look this up later) Clivus bone behind pituitary. http://en.wikipedia.org/wiki/Clivus_(anatomy)

Surgery is first-line therapy

• Experienced surgeon
• 65-90% remission
• Large tumors is less than 65%
• Success rate for repeat surgery is lower
• Reoperation has greater risk for pituitary damage
• Microadenoma 5-10% risk of remission at 5 years
• 30% don't get remission

Radiation

• Control, in 50-60 %
• Relapse possible
• Nelson's
• Can take a long time to control symptoms

Medical therapy

• Ketoconazole: antifungal, lowers testosterone and cortisol.  Several side effects, no impact on pit tumor, adjust dose over time
• Metyrapone: side effects.  Can be used in pregnancy, clinical trials coming soon, no impact on pituitary tumor, dose adjusted over time
• Mitotane
• Pasireotide, control within 1-2 months or not at all, decrease in BP and UFC.  Hyperglycemia.  Some patients discontinued due to that
• Korlym, trying to find correct dose, not an accurate assessment of adrenal insufficiency.  May need sprolactone for hypokalemia?  Blocks all cortisol, need to monitor.  Korlym reps say it's only blocking number 2 receptor.  Could become hyper adrenal/adrenal crisis.  It's a challenge.  Blocks progesterone receptor-termination of pregnancy, pregnancy tests, unopposed estrogen can cause hypertrophy of uterus and unexplained vaginal bleeding
• Combination therapy. Start with pasireotide, then add Cabergoline, then Keto.  Possible AI but can measure cortisol with these drugs
• LCI 699 originally for high BP. Normalized UFC in 11 of 12 Cushies.  US study

Advantages

• No/less surgery
• Gradual reduction of cortisol. Is that better?
• Life-long therapy

Somatostatin action in Cushing's

Normalizing UFC

Orphan disease has major pharmacy attention-we are getting closer?

Magic Conference: Managing Medications and Aftercare of Treatments

MEETING NOTES : Dr. Salvatori, 2

Meeting Created: July 20, 2012 1:33 PM

Lombard

Managing Medications and Aftercare of Treatments

It is crucial to monitor your treatments and aftercare of treatments when living with a pituitary
disorder. Dr. Salvatori will discuss the importance of these issues so you will be aware of how
to manage your pituitary disorder. A simple diagnosis does not mean that medications may be
altered or changed in the future. This segment will assist you with information on how to
manage your future. 

Usually prolactinoma easier to treat

Therapy

• Larger the tumor, less likely surgery will work
• Medications, dopaminergic drugs
• Shrinkage on meds

Bromocriptine, cabergoline.  Cabergoline: take less often, works better, fewer side effects.  Heart valve abnormalities in Parkinson's patients but they take 20-40 times as much, also Pergolide.

Acromegaly...

Cushing's:

Don't switch labs! Stay with the same lab for all testing, if possible

Minnie G., pitituitary apoplexy? Carney Complex?

Hypopituitary

• Take glucocorticoids
• THS is not useful blood test to diagnose
• Testosterone or estrogen
• Growth Hormone

Circadian rhythm

• Cortisol dosage
• Most patients are over treated
• No test tells right dose
• Use the lowest dose that keeps you going
• Always increase for illness
• Always get a flu shot at the beginning of the season

Growth Hormone Deficiency

OTC growth hormone no good

GH deficiency:

• Cholesterol
• Osteoporosis
• Diminished quality of life

Tips:

• No long term studies
• Not for cancer patients
• Maybe need for more cortisol, thyroid hormone
• Serum IGF-1 monitored bi-annually

Secondary hypothyroidism

• Several weeks for improvement
• Twice a year testing
• Do not rely on TSH
• Wide range of normal
• He sees no advantage to "natural" preparations, variable by batch (armour)
• "Wilson syndrome" does not exist
• Because someone wrote a book doesn't make it true...

Diabetes Insipidus (DI)

DDVAP, nasal spray lasts longer

All should have a period during the 24 hours when DDVAP has worn off. 

Brain can only expand 8%

Q&A

Correlation cortisol and blood pressure

ERs not giving steroids even with medic alert bracelet and letters from doctor.

Solu-cortef, troubles getting it in the ER

Take 5-20 mg pills if you can keep it down.

Shouldn't need an emergency kit unless far from hospital

Doctor meeting patient at ER, or calls attending

Rectal version for steroids?

Magic Conference: Testing and Diagnosis Process for Pituitary Disorders

MEETING NOTES : Dr. Salvatori

Meeting Created: July 20, 2012 11:00 AM

Lombard

Testing and Diagnosis Process for Pituitary Disorders 

Pituitary disorders can be difficult to diagnose in many cases. Dr. Salvatori will discuss the

different testing and diagnostic procedures to determine the pituitary disorder. MAGIC
receives many calls asking about diagnostic procedures. This segment will be helpful in under-
standing what procedures are used today to provide the best treatment available. 

Dr. Cushing picture

Dr. S only sees diagnosed patients

Dr C 1932 description from Johns Hopkins, pre-MRI

Causes do CS

• Prescriptions, iatrogenic
• ACTH independent adrenal 20%
• ATCH dependent, 80%, 85%of those Cushings

Signs best to discriminate

• Bruisings
• Facial plethora, redness
• Weakness
• Striae

Symptoms

• Fat pads
• Moon face
• Thin skin
• Acne
• Depression
• Fatigue
• Weight gain
• Menstrual
• Decreased libido
• Irritability

diagnosis

• UFC
• Overnight sex
• Salivary
• Dex-CRF

Why bedtime cortisol?

Diurnal rhythm, changing time zones, what helps you wake up

Is CS ACTH-dependent?

Where is the ACTH coming from?

• Up to 30% not visible on MRI
• Up to 10% of normal people suggest pituitary incidentaloma
• MRI is not good test to diagnose

First do no harm, be sure before surgery

IPSS, not to diagnose Cushings, just to find where ACTH is coming from 

Lose more blood testing for Cushings than during surgery

Prolactinoma vs. pseudo-prolactinoma

• Pregnant
• Psychoactive drugs

Acromegaly: IGF-1 not whole story

Hugo brothers

Hypopituitarism

• Many undiagnosed
• 45/100,000 from Spanish study
• 94/100,000 from Belgian

Secondary, TSH isn't a good test

Testicle size

Adrenal insufficiency

AM cortisol less then 3 ug/dl

Random cortisol above 15 ug/dl rules it out

Tests

• ITT
• ACTH stimulation

Adrenals shrink

Pituitary apoplexy=acute adrenal insufficiency

GH deficiency

IGF-1 not good test

Glucagon used now at Hopkins.  Cutoff is 3

Heavier you are, lower GH on stimulation test

Pan-hypopituitary don't need stimulation testing

Causes of hypopituitary

Traumatic brain injury, mostly young men

Cancer, radiation to brain

Hypopituitary

• Undiagnosed
• Gradual symptoms
• Steroid replacement before thyroid replacement

Q & A

Magic Conference: Understanding your Pituitary Gland in Health and Disease

MEETING NOTES : Dr. Frohman

Meeting Created: July 20, 2012 9:00 AM

Chicago

Understanding your Pituitary Gland in Health and Disease

Dr. Frohman will present an overview of the pituitary gland. He will cover general aspects of
pituitary function and testing and also review the types of pituitary disease that occur,
including pituitary tumors and Sheehan’s Syndrome. Many people ask and wonder if Growth
Hormone Deficiency can be inherited. Dr. Frohman will also briefly address that concern. 

Pituitary

Sheep studies, pulses pulsatile

GH secretion at night, varies with age.  Most in teens then downhill, follows diurnal rhythm

High igf= cancer?

Hypothalamus

Chris

Anterior pituitary

ACTH

Cortisol

Then back to hypothalamus

Inhibin to inhibit ovary and testes

Types of tumors

Alpha subunit no signs or symptoms 

Microadenoma, macroadenoma

Mass effects

Headache, visual disturbance, neurological damage

Impaired pit function...hypopituitarism

Hypersecretion 

Acromegaly

Hands, feet, facial swelling, sleep apnea, snoring, tall, oily skin, increased soft tissue, Goliath, carpal tunnel

TMJ, osteoarthritis

Metabolic changes

Organ enlargement, hypertension

Cushing's

ACTH, cortisol

Acne, hirsuitism, striae, other usual symptoms

Therapy

Surgery

Drugs keto, mifepristone, pasireotide

Radiation stereotactic, gamma knife can cause hypopituitarism

Hypopituitarism

• Primary, Sheehan's syndrome uncommon today
• Genetic

Secondary

• Trauma
• Tumor
• Iatrogenic
• Traumatic brain injury
• Anorexia
• Tumors
• Steroids

Clinical features

• Acute
• Slow

Hypo clinical features

Diagnosis, testing

Q&A

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

Pasireotide in Cushing's Disease

N Engl J Med 2012; 366:2134-2135 May 31, 2012

 

To the Editor:

In their study, Colao et al. (March 8 issue)1 examined the clinical efficacy and safety of two different doses of subcutaneous pasireotide in patients with newly diagnosed, persistent, or recurrent Cushing's disease. Since alternative therapies (including bilateral adrenalectomy) are available for patients with persistent or recurrent Cushing's disease, it would be important to consider all options before embarking on what might turn out to be many years of medication.

Giovanni Targher, M.D.
University of Verona, Verona, Italy 
giovanni.targher@univr.it

No potential conflict of interest relevant to this letter was reported.

1 References

To the Editor:

The phase 3 trial by Colao et al. showed the efficacy of 12 months of treatment with subcutaneous pasireotide (600 or 900 μg twice daily) in patients with Cushing's disease. We now report results after 7 years of treatment with pasireotide administered as part of a phase 2 study.1 In July 2004, a 43-year-old woman with Cushing's disease, whose 24-hour urinary free cortisol level was 9.2 times the upper limit of normal, began 15 days of treatment with subcutaneous pasireotide (600 μg twice daily) that resulted in normalization of these levels (Figure 1AFIGURE 1Effects of Pasireotide Treatment on 24-Hour Urinary Free Cortisol Levels and on Adrenocorticotropin Hormone Levels during Desmopressin-Stimulation Testing.). When treatment was halted for 35 days, urinary free cortisol levels increased. In September 2004, she resumed treatment with pasireotide (600 μg twice daily), which led to clinical improvement (i.e., a weight loss of 13 kg, regular menstrual cycles, and reduced hirsutism). Hyperglycemia ensued (glycated hemoglobin, 5.7 to 7.7%), and weakness necessitated a temporary reduction in the dose to 450 μg twice daily (November 2004 to October 2005). Since November 2005, when the patient resumed taking the 600-μg dose twice daily, urinary free cortisol levels have remained in the normal range at most monthly assessments. Basal and desmopressin-stimulated adrenocorticotropin levels also decreased as a result of treatment with pasireotide (Figure 1B). To date, she has not had any serious adverse events. This case illustrates the long-term efficacy of pasireotide without the development of resistance to the drug's effects.

Rossella Libé, M.D.
INSERM Unité 1016, Paris, France

Lionel Groussin, M.D., Ph.D.
Université Paris Descartes, Paris, France

Jérôme Bertherat, M.D., Ph.D.
Hôpital Cochin, Paris, France 
jerome.bertherat@cch.aphp.fr

Drs. Libé and Bertherat report being investigators for studies of pasireotide in Cushing's disease funded by Novartis. No other potential conflict of interest relevant to this letter was reported.

1 References

Author/Editor Response

We concur with Targher's implication that the advantages and disadvantages of all management options should be considered for each patient before a specific treatment is advised.

Libé and colleagues present a very interesting case of a patient with Cushing's disease in the extension of a phase 2 study of pasireotide. This patient was treated with pasireotide for a much longer duration than the 1 year reported in the phase 3 study.

Annamaria Colao, M.D., Ph.D.
University of Naples Federico II, Naples, Italy

Mario Maldonado, M.D.
Novartis Pharma, Basel, Switzerland

Since publication of their article, the authors report no further potential conflict of interest.

 

From http://www.nejm.org/doi/full/10.1056/NEJMc1204078

Correlation Between Histological Subtypes and MRI Findings in Clinically Nonfunctioning Pituitary Adenomas

Hiroshi Nishioka, Naoko Inoshita, Toshiaki Sano, Noriaki Fukuhara and Shozo Yamada

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Clinically nonfunctioning pituitary adenomas (CNFPAs) consist of several histological subtypes, including null cell adenoma (NCA), silent gonadotroph cell adenoma (SGA), silent corticotroph adenoma (SCA), and other silent adenomas (OSA) (i.e., GH, TSH, and prolactin adenomas).

To detect possible correlations between MRI findings and the subtypes, we retrospectively studied 390 consecutive patients with CNFPA who underwent surgery between 2008 and 2010. They were classified into three groups: NCA/SGA (313 cases), SCA (39 cases), and OSA (36 cases); in addition there were two unusual cases of plurihormonal adenoma.

Three MRI findings were less common in NCA/SGA than in the other groups (P < 0.0001): giant adenoma (>40 mm), marked cavernous sinus invasion (Knosp grade 4), and lobulated configuration of the suprasellar tumor. When these MRI findings were negative in patients older than 40 years old, 91.0 % (212/233) were NCA/SGA.

These MRI findings were frequently noted despite a low MIB-1 index in SCA. OSA showed a high MIB-1 index and a preponderance in younger patients. In conclusion, although SCA and OSA consisted of only 20 % of CNFPAs, their frequency significantly increased when the tumor was large, invasive, and lobulated, and the patient was younger than 40 years old.

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• From http://www.springerlink.com/content/4r466139264616q2/

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/

 

Course of pregnancies in women with Cushing’s disease treated by gamma-knife

(doi:10.3109/09513590.2012.683057)

Francesco Ferraù1, Marco Losa2, Oana Ruxandra Cotta1, Maria Luisa Torre1, Marta Ragonese1, Francesco Trimarchi1, Salvatore Cannavò1

1Department of Medicine and Pharmacology, Section of Endocrinology, University of Messina, Messina, Italy

2Department of Neurosurgery, Istituto Scientifico San Raffaele, Milan, Italy

Correspondence: Francesco Ferraù, MD, Department of Medicine and Pharmacology, Section of Endocrinology, University of Messina, AOU Policlinico “G. Martino” (Pad. H, floor 4), Via Consolare Valeria 1, 98125 Messina, Italy. Tel: +39 090 2213507. Fax: +39 090 2213945. E-mail: ferrau1@interfree.it

 

Data concerning pregnancy in women with Cushing’s disease treated by gamma-knife (GK) are scanty. We present and discuss the course and outcome of five pregnancies in two women with Cushing’s disease (CD), the first of whom was treated only by GK, and the second one treated by surgery, GK and ketoconazole.

In the first patient, pregnancy was uneventful and full-term. During gestation, plasma ACTH, serum cortisol and 24-h urinary free cortisol (UFC) levels were steady, and always in the normal range for healthy non-pregnant individuals. The newborn was healthy and normal-weight.

In the second woman, two pregnancies, occurring 3 years after GK and few months after ketoconazole withdrawal, were interrupted by spontaneous abortion or placental disruption despite normal cortisol levels. This patient became again pregnant 3 years later and delivered vaginally a healthy full-term infant.

Seven months after the delivery, the patient became pregnant again and at the 39th week of gestation delivered vaginally a healthy male. Hypoprolactinemia and/or central hypothyroidism occurred in both cases. In women with CD treated by GK, pregnancy can occur. However, pregnancy is at risk even when ACTH and cortisol levels are normalized by treatment. After GK, evaluation of pituitary function is mandatory due to the risk of hypopituitarism.

Read More: http://informahealthcare.com/doi/abs/10.3109/09513590.2012.683057

Have You Learned About Cushing's At a Health Fair?

I cannot imagine this myself, since Cushing's is so hard to diagnose but an article at yourdailyjournal.com claims: 

The blood profiles provide a comprehensive look at several physiological systems in the body at a cost that is very reasonable for the patients, all in one panel,” Laboratory Manager Rhonda Outlaw said. “The cost savings would amount to anywhere from $185 to $1,100, depending on the tests done and whether they were drawn at a physician’s office or on an outpatient basis.

 

“The panel itself will give indication of possible problems with kidney functions, hematological functions, like anemia, platelet function and infection; cardiovascular disease, thyroid functions, diabetes detection, liver functions and electrolyte function, like Cushings Syndrome, potassium regulation and dehydration detection.”

What do you think about this?

 

 

A New Blogging Challenge

If any other Cushie bloggers are interested in this challenge, let me know and I'll promote your blog on http://www.cushie-blogger.blogspot.com/

Attention bloggers! WEGO Health has found another writing challenge in honor of National Women's Health Week, The Fitness & Health Bloggers Conference (the same one that one of our Health Activists will be attending!) is hosting a week long blogger challenge in honor of National Women's Health Week. The theme for National Women's Health Week is "It's Your Time" National Women’s Health Week empowers women to make their health a top priority. It also encourages women to take the following steps to improve their physical and mental health and lower their risks of certain diseases

Psychological Manifestations of Pituitary Disease

From the May 2012 PNA Newsletter:

 

Psychological Manifestations of Pituitary Disease

Editor’s note: This is an introduction to a lecture given by Dr. Michael Weitzner. It makes many of the points that the PNA strives to promote.

The objectives of this lecture are to provide an overview of the psychological and neuropsychiatric problems faced by patients with pituitary disease, the impact on family, and the options for treatment.

Cushing, himself, believed that there was a need to differentiate the psychological effects that resulted from the pituitary tumor from those that resulted from the stress of illness. It is now recognized that the hypothalamic-pituitary axis is not only an integral element in the expression of behavior, but also an essential part of the limbic system which controls our emotions.

Many patients with pituitary tumors develop an apathy syndrome which is the result of this interplay between the limbic system and the hypothalamic-pituitary axis. An important task is the differentiation of this apathy syndrome from other psychiatric disturbances which are also seen in patients with pituitary disease. It is well recognized that depression and anxiety are present in many patients with hyperprolactinemia and Cushing’s disease. Personality change and anxiety are commonly seen in patients with acromegaly and hypopituitarism. There are several options for treatment, both pharmacological and psychological. One element that is unfortunately ignored in this illness is the effect on the family. Effective treatment of the patient with pituitary disease included treatment of the family.

Michael A. Weitzner, M.D., Department of Psychiatry,University of South Florida, Tampa, Florida

From www.pituitary.org

Questions about Korlym?

Corcept is providing a nurse to help with insurance and other topics.

If you want a person to talk with her contact info is:

Kate Tully, R.N., B.S.N.
(650) 688-2804
ktully@corcept.com

Cushing’s Patient Advocate
Corcept Therapeutics
149 Commonwealth Drive
Menlo Park, CA 94025

More information about Korlym at http://www.korlym.com

MEN1 and pituitary adenomas

Abstract

MEN1 gene mutations predispose carriers to pituitary tumors. Molecular pathways involved in the development of these tumors seem different to what is known in sporadic tumors. Clinical studies showed that all types of adenomas can be found with a predominance of prolactinoma and macroadenoma compared to a control population.

These MEN1 tumors seem more aggressive, invasive and resistant to treatment requiring a very careful long-life follow-up. Occurrence of these tumors can be described in the pediatric population and it can be the first and only manifestation of MEN1 for some years asking the question of the systematic screening for MEN1 gene mutation in pediatric population with pituitary adenoma.

More at http://www.sciencedirect.com/science/article/pii/S0003426612000625

Cushing’s Disease and Idiopathic Intracranial Hypertension

Gabriel Zada, Amir Tirosh, Ursula B. Kaiser, Edward R. Laws and Whitney W. Woodmansee

Department of Neurosurgery (G.Z., E.R.L.) and Division of Endocrinology, Diabetes, and Hypertension (A.T., U.B.K., W.W.W.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115

Address all correspondence and requests for reprints to: Gabriel Zada, M.D., 15 Francis Street, PBB3, Boston, Massachusetts 02115. E-mail: gzada@usc.edu.

Abstract

Case Illustration: A 33-yr-old woman with Cushing’s disease underwent successful surgical resection of a pituitary adenoma and developed IIH 11 months later after inadvertent withdrawal of oral glucocorticoids.

Methods: A review of the literature was conducted to identify previous studies pertaining to IIH in association with neuroendocrine disease, focusing on reports related to HPA axis dysfunction.

Results: A number of patients developing IIH due to a relative deficiency in glucocorticoids, after surgical or medical management for Cushing’s disease, withdrawal from glucocorticoid replacement, or as an initial presentation of Addison’s disease, have been reported. Hypotheses regarding the underlying pathophysiology of IIH in this context and, in particular, the role of cortisol and its relationship to other neuroendocrine and inflammatory mediators that may regulate the homeostasis of cerebrospinal fluid production and absorption are reviewed.

Conclusion: In a subset of patients, dysfunction of the HPA axis appears to play a role in the development of IIH. Hormonal control of cerebrospinal fluid production and absorption may be regulated by inflammatory mediators and the enzyme 11ß-hydroxysteroid dehydrogenase type 1. Further study of neuroendocrine markers in the serum and cerebrospinal fluid may be an avenue for further research in IIH.

Read the entire article at http://jcem.endojournals.org/content/95/11/4850.full

Pituitary Hormone Deficiency in Women

The pituitary gland secretes a number of hormones that are used to regulate the function of the ovaries. For this reason a loss or a deficiency in one of the pituitary hormones can impact greatly impact women.

Treatments

A deficiency in some of the pituitary hormones can be replaced with medications. Thyroid hormone can be replaced in thyroid hormone deficiencies, adrenal deficiencies can be treated with hydrocortisone, or cortisol replacements. And if a women loses reproductive function those can be replaced with estrogen/progesterone combinations. If fertility is an issue a neuroendocrinologist may work in conjunction with reproductive endocrinologists and OB/GYN to help fertility induction.

Oral Contraceptive Use

Oral contraceptives are often used in women who are not having normal cycles as a result of their neuroendocrine disease. These women are often also estrogen deficient, which is not good for their bones or women’s health in general. Oral contraceptives or other forms of estrogen and progesterone are often used to replace these hormones and help regulate the cycle if a women is of pre-menopausal age. These hormones are usually replaced until the age in which a woman would normally go through menopause when the medications would be stopped.

From http://www.brighamandwomens.org/Departments_and_Services/
neurology/services/WomensNeurology/WomensNeuroendocrine/hormonedeficienciesinwomen.aspx