OR17-Novel Aspects of Adrenal Tumors and the HPA Axis

Posted on March 6, 2015 by MaryO

ENDO_2015

 

March 06, 2015

OR17-Novel Aspects of Adrenal Tumors and the HPA Axis

Epigenetic modulation of DNA Is associated with fatigue, depression and anxiety in patients with Cushing’s syndrome in remission: A genome-wide methylation study

CAM Glad, JC Andersson-Assarsson, P Berglund, R Bergthorsdottir, O Ragnarsson, G Johannsson

Summary: Researchers conducted this study to determine whether patients with Cushing’s syndrome (CS) that is in remission have specific epigenetic alterations that are associated with persistent cognitive impairments, anxiety, fatigue, and depression. Patients with CS in remission were shows to have specific DNA methylation that differed from that of healthy controls and was strongly correlated with clinical traits of anxiety, depression and fatigue, they concluded, adding that their results may suggest that an interaction between the glucocorticoid and the retinoic acid receptor is implicated in the long-term outcome of patients with CS in remission. The persistent cognitive impairment observed in patients with CS in remission, therefore, may be due to epigenetic modulation of DNA, they concluded.

Methods:

  • For this cross-sectional, case-controlled, single center study, researchers included 48 women with CS in remission (mean age±SD: 52.9±14 years) and 16 controls (mean age±SD: 53.6±16 years) matched for age, gender and educational level.
  • The mean age at diagnosis of CS was 37±14 years and the median (interquartile range) duration of remission was 13 (5-19) years.
  • In all, 37 patients had Cushing’s disease (CD) and 11 had a cortisol producing adrenal adenoma.
  • Researchers used the fatigue impact scale (FIS) to evaluate fatigue, and the comprehensive psychopathological rating scale to evaluate depression and anxiety; they assessed cognitive function by standardized neuropsychological tests.
  • DNA was isolated from whole blood, and DNA methylation was analyzed on the Illumina Infinium HumanMethylation450K BeadChip, which simultaneously interrogates >465,000 methylation sites per sample.
  • Researchers performed data quality control and analysis using the ChAMP methylation analysis package in R, and used Spearmen’s rho to perform correlation analyses.

Results:

  • Researchers found that patients had higher median score for FIS, depression and anxiety.
  • Methylation analysis identified 3,903 probes (in 340 genes) in regions that were differently methylated between CS patients and controls, and they found that 28% of these were significantly correlated to at least one of the clinical traits.
  • Fatigue, depression and anxiety were the most commonly correlated traits, and two of the most highly correlated genes were RXRB and COL11A2.
  • Gene ontology analysis revealed that these belong to the same GO-terms and are involved in retinoic acid receptor activity.
  • Finally, researchers found that both genes were specifically hypomethylated in cases as compared to controls.

 

This project has received financial support from the Swedish federal government under the LUA/ALF agreement, The Health & Medical Care Committee of the Regional Executive Board, Region Västra Götaland, The Swedish Society of Medicine and The Swedish Society of Endocrinology.

From http://www.mdlinx.com/endocrinology/conference-abstract.cfm/ZZ5BA369FDE9DE4CED82CB6A7CD5BFD1BE/42321/?utm_source=confcoveragenl&utm_medium=newsletter&utm_content=abstract-list&utm_campaign=abstract-ENDO2015&nonus=0

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Cortisol Dysregulation and Alcoholism: Consequence, Correlation or Causality?

Posted on March 6, 2015 by MaryO

What

The National Institute on Alcohol Abuse and Alcoholism (NIAAA), part of the National Institutes of Health, announces that Gary S. Wand, M.D., will deliver the 7th Annual Jack Mendelson Honorary Lecture. Dr. Wand is an internationally recognized neuroendocrinologist and the inaugural Rivière Professor in Endocrinology and Metabolism at The Johns Hopkins University School of Medicine. The title of his presentation is “Cortisol Dysregulation and Alcoholism: Consequence, Correlation or Causality?”

Who

Dr. Wand’s research has advanced our understanding of the genetic and environmental determinants of the stress response and has elucidated how excessive stress hormone production may contribute to neurobiological conditions such as alcohol or drug disorders.

Some of Dr. Wand’s seminal discoveries include identifying unique pharmacological responses to naloxone in individuals at increased risk for alcohol use disorders, identifying specific hormonal responses in subjects with alcohol use disorders, and characterizing human brain neurochemical changes using imaging in subjects with substance use disorders.

Dr. Wand is studying the epigenetic modulation of stress and cortisol exposure in rodent and human models, based on the hypothesis that specific epigenetic events affect how much cortisol an individual produces, which in turn influences dopamine transmission.

Dr. Wand received his medical degree and subsequent training in internal medicine from the George Washington University. Following post-doctoral training in Endocrinology and Metabolism at The Johns Hopkins University School of Medicine, he was a fellow in the peptide laboratories of Richard Mains, Ph.D. and Betty Eipper, Ph.D. in JHU’s Department of Neuroscience. Dr. Wand then joined the faculty of the Johns Hopkins University School of Medicine.

In 2000, NIAAA and the NIH honored Dr. Wand with a 10-year Merit Award to continue his research on the role of the HPA axis in alcoholism. He has also received numerous local and national “Best Doctor” awards. Dr. Wand is the author of more than 175 articles and chapters and is on the editorial board of several journals.

When

Thursday, March 19th at 1:30 p.m. EDT

Where

Masur Auditorium, NIH Building 10, Bethesda, Maryland

Background

NIAAA established the Jack Mendelson Honorary Lecture Series as a tribute to Dr. Jack Mendelson, who made remarkable scientific contributions to the field of clinical alcohol research. The purpose of this honorary lecture series is to highlight clinical/human research in the alcohol field by an outstanding investigator who has made significant and long-term contributions to our understanding of alcoholism susceptibility, alcohol’s effects on the brain and other organs, and the prevention and treatment of alcohol use disorders. NIAAA is pleased to present this series of scientific lectures to acknowledge the advances researchers are making in a wide range of alcohol-related areas of clinical research, and to honor the memory of an individual whose exciting and pioneering research with human alcoholics remains relevant today.

For additional information about the lecture see: http://www.niaaa.nih.gov/about-niaaa/our-work/research-portfolio/projects-initiatives/keller-and-mendelson-honorary-lecture

The Mendelson Honorary Lecture is free and open to the public. Sign language interpreters will be provided. For other reasonable accommodations or further information call Joanna Mayo, 301-443-3860, or visit www.niaaa.nih.gov. For TTY callers, please call the above number through the Federal Relay Service at 1-800-877-8339.

The National Institute on Alcohol Abuse and Alcoholism, part of the National Institutes of Health, is the primary U.S. agency for conducting and supporting research on the causes, consequences, prevention, and treatment of alcohol abuse, alcoholism, and alcohol problems. NIAAA also disseminates research findings to general, professional, and academic audiences. Additional alcohol research information and publications are available at http://www.niaaa.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

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After massive weight gain, Cushing’s disease diagnosis saves man’s life – Health – TODAY.com

Posted on March 4, 2015 by MaryO

Donelle Trotman was only in his 30s when his health suddenly took a strange and frightening turn.

He was rapidly gaining weight — more than 100 pounds in one year. His upper torso was getting bigger, but not his legs. And he felt overwhelmingly tired.

“My body just started changing,” the Staten Island, New York, native told TODAY as part of a three-day series, “Medical Mysteries,” looking at people who have recovered from rare diseases.

It was especially puzzling because Trotman had never had weight issues before.

In school, Trotman was never a skinny kid, but he wasn’t overweight. He loved sports, playing both basketball and baseball.

So as he entered adulthood, he was active and in good shape. Then, three years ago, he suddenly began to gain weight.

“It was just specific places: My stomach, under my arms, my back of my neck, my face, the bottom of my back,” Trotman said. “My legs stayed the same for a long time.”

To lose the extra pounds, Trotman began running, working out and lifting weights. Nothing worked.

In the span of one year, Trotman gained more than 120 pounds, topping the scale at 366 pounds, twice the amount he weighed at 18.

“I doubled, like, I got a whole person on me,” he said.

There were other alarming changes. Trotman became so easily tired that he’d get out of breath just by chewing food. When he woke up seeing double three months ago, he knew it was time to go to the hospital.

Doctors ran a flurry of tests, but the results offered few clues, leaving everyone puzzled. Then one day, an intern noticed stretch marks all over Trotman’s body, a telltale sign that solved the mystery. Trotman had Cushing’s disease, a rare condition that affects fewer than 50,000 people in the U.S. every year.

Trotman’s weight gain was being caused by a tiny tumor at the base of his brain, prompting his body to produce too much of the hormone cortisol. He had some of the classic symptoms: major weight gain in his upper body, skin problems and acne, plus fatigue.

Dr. John Boockvar and Dr. Peter Costantino at New York’s Lenox Hill Hospital discovered Trotman had steroid levels ten times higher than normal.

“In Cushing’s disease, the pituitary gland has a small growth that releases a single hormone that causes the body to live with very high levels of steroids. The skin becomes very thin. You get increased acne. You can grow hair. You start sweating. You gain a lot of fat,” Boockvar said.

There was no time to lose: Untreated, Cushing’s is a fatal disease. Trotman was getting close to the point where doctors would not be able to reverse the changes, Costantino noted. He underwent surgery two weeks ago and had the growth successfully removed.

“The tumor was no bigger than the size of the tip of my pen,” Boockvar said. “And that something so small can cause a man to grow to 350 pounds and absolutely destroy his life is rather remarkable.”

These days, Trotman is feeling much better. His main focus now is to lose the weight he gained and regain an active lifestyle. He hopes to play basketball with his son soon.

“It’s wonderful. Every day it’s just like I feel a little stronger,” he said.

Doctors say Trotman will continue to lose weight and can shoot hoops with his son in about three months. There is an 8-10 percent chance the disease could come back, but Trotman said he knows what to look for now.

One of the reasons Trotman wanted to share his story is so others might recognize the symptoms of Cushing’s, although doctors stress it is a very rare illness.

 

Watch the video here: After massive weight gain, Cushing’s disease diagnosis saves man’s life – Health – TODAY.com.

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Scientists Find Potential Therapeutic Target for Cushing’s Disease

Posted on March 2, 2015 by MaryO

Scientists at the Salk Institute for Biological Studies have identified a protein that drives the formation of pituitary tumors in Cushing’s disease, a development that may give clinicians a therapeutic target to treat this potentially life-threatening disorder.

The protein, called TR4 (testicular orphan nuclear receptor 4), is one of the human body’s 48 nuclear receptors, a class of proteins found in cells that are responsible for sensing hormones and, in response, regulating the expression of specific genes. Using a genome scan, the Salk team discovered that TR4 regulates a gene that produces adrenocorticotropic hormone (ACTH), which is overproduced by pituitary tumors in Cushing’s disease (CD). The findings were published in the May 6, 2013 early online edition of Proceedings of the National Academy of Sciences.

The diagram shows how adrenocorticotropin hormone is secreted in Cushing's disease.

“We were surprised by the scan, as TR4 and ACTH were not known to be functionally linked,” says senior author Ronald M. Evans, a professor in Salk’s Gene Expression Laboratory and a lead researcher in the Institute’s Helmsley Center for Genomic Medicine. “TR4 is driving the growth and overexpression of ACTH. Targeting this pathway could therapeutically benefit treatment of CD.”

In their study, Evans and his colleagues discovered that forced overexpression of TR4 in both human and mouse cells increased production of ACTH, cellular proliferation and tumor invasion rates. All of these events were reversed when TR4 expression was reduced.

First described more than 80 years ago, Cushing’s disease is a rare disorder that is caused by pituitary tumors or excess growth of the pituitary gland located at the base of the brain. People with CD have too much ACTH, which stimulates the production and release of cortisol, a hormone that is normally produced during stressful situations.

While these pituitary tumors are almost always benign, they result in excess ACTH and cortisol secretion, which can result in various disabling symptoms, including diabetes, hypertension, osteoporosis, obesity and psychological disturbances. Surgical removal of the tumors is the first-line therapy, with remission rates of approximately 80 percent; however, the disease recurs in up to 25 percent of cases.

Drugs such as cabergoline, which is used to treat certain pituitary tumors, alone or in combination with ketoconazole, a drug normally used to treat fungal infections, have been shown to be effective in some patients with Cushing’s disease. More recently, mefipristone-best known as the abortion pill RU-486-was approved by the FDA to treat CD. Despite these advances in medical therapy, the Salk scientists say additional therapeutic approaches are needed for CD.

“Pituitary tumors are extremely difficult to control,” says Michael Downes, a senior staff scientist in the Gene Expression Laboratory and a co-author of the study. “To control them, you have to kill cells in the pituitary gland that are proliferating, which could prevent the production of a vital hormone.”

Previous studies have found that, by itself, TR4 is a natural target for other signaling molecules in the pituitary. Small-molecule inhibitors that have been developed for other cancers could be potentially applied to disrupt this signaling cascade. “Our discovery,” says Evans, a Howard Hughes Medical Institute investigator and holder of the March of Dimes Chair in Molecular and Developmental Biology, “might lead clinicians to an existing drug that could be used to treat Cushing’s disease.

Notes about this neurogenetics and Cushing’s disease research

Other researchers on the study were Li Du, Marvin Bergsneider, Leili Mirsadraei, Stephen H. Young, William H. Yong and Anthony P. Heaney of the David A. Geffen School of Medicine at the University of California, Los Angeles, and Johan W. Jonker of the University of Groningen.

The study was supported by the National Institutes of Health, the Leona M. and Harry B. Helmsley Charitable Trust, the Samuel Waxman Cancer Research Foundation, the Jonsson Comprehensive Cancer Center at UCLA, and Ipsen/Biomeasure.

Contact: Andy Hoang – Salk Institute
Source: Salk Institute press release
Image Source: The ACTH Cushing’s disease diagram is credited to NIDDK/NIH and is available in the public domain.
Original Research: Abstract for “Evidence for orphan nuclear receptor TR4 in the etiology of Cushing disease” by Li Du, Marvin Bergsneider, Leili Mirsadraei, Steven H. Young, Johan W. Jonker, Michael Downes, William H. Yong, Ronald M. Evans, and Anthony P. Heaney in Proceedings of the National Academy of Sciences. Published May 6 2013 doi: 10.1073/pnas.1306182110

From http://neurosciencenews.com/tr4-cushings-disease-acth-neurogenetics-120/

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Myth: Even Though You Are Chronically Ill, You Should Have The Same Amount Of Energy Every Day,,,

Posted on February 17, 2015 by MaryO

myth-busted

 

Myth: Even though you are chronically ill, you should have the same amount of energy every day. “You look SO good and you went to that party last month! Why can’t you come to MY party?!” When you say you are not well enough to do something, you are just making excuses. You could do it, just like you did that other thing; you are just choosing not to!

 

Fact: You may have heard me talk about “The Spoon Theory”. It was created by someone named Christine Miserandino, to explain the experience of someone with chronic illness in terms of using energy to live and to complete tasks every day. Though the myth assumes that one should have the same amount of energy all the time; the fact is that energy levels fluctuate and people who are chronically ill must make conscious decisions about what they can spend their energy on.

Christine Miserandino (2010) uses the spoon theory to answer the question, “What does it feel like to be sick?” The spoons serve as a symbol for resources available and energy spent to get through every moment of every day. Miserandino states that “The difference in being sick and being healthy is having to make choices or to consciously think about things when the rest of the world doesn’t have to”. Most people who get sick feel a loss of a life they once knew. When you are healthy, you expect to have a never ending supply of spoons. But, when you are not well, you need to count your spoons to keep track and you can never forget about it or take it for granted. Each task costs a spoon and each spoon is not to be taken for granted. Miserandino (2010) asks, “Do you know how many spoons people waste every day?”

Patients use the metaphor of a banking system. In this system, patients must make a withdrawal of a spoon every time they complete a task. Cushing’s and Adrenal Insufficiency patients talk about the “Cortisol Bank” metaphor. The concept is the same and the idea is that certain stressors and/or tasks cause one’s body to make a cortisol withdrawal from the body. Bad things happen when there is a cortisol deficit, meaning that there is not enough cortisol in the body for one to live everyday because of the amount of cortisol that has already been used up. If a person continues to draw from the bank on an account that is already negative, the situation can become worse and worse as each day passes.

Something needs to happen in order to start making appropriate deposits. This can include, taking more medication (stress dosing or an emergency shot), resting, getting adequate physical and emotional support and help, and saying “NO!”. Even when in a deficit, many patients have a difficult time saying “no” to an invitation to an event, completing a task, or engaging someone in a way that will use up more energy because of their fear of their loved one’s reactions. Much of the time, this fear is warranted because of the actual reactions they have received. Ever heard, “But you volunteered for the bake sale last week! You must be better! Why can’t you come to church this week?!”. You may have heard something similar.

It is important for loved ones to understand the amount of “spoons” it takes for a chronically ill person just to get through every single day. EVERYTHING costs spoons! The amount of spoons paid by each person varies from person to person. It all depends on that individual’s situation, body, level of illness, etc. What is common for all, though, is that spoons must be used and eventually those spoons run out. In order to avoid becoming sick or to recuperate from getting sick, the chronically ill patient must evaluate how he/she will use spoons and what tasks can be feasibly completed that day or week. Please understand that when the chronically ill patient says, “YES” to you; he/she is making a conscious choice to use up spoons to meet your need, request, or demand. Talking on the phone, going out to lunch, making dinner, coming to your event all required a sacrifice of another task that day or week. Your friend may have come to lunch with you but that required that she skipped washing the dishes that day or washing her hair, or is even giving up doing something important the next day. Instead of being angry at your friend, please consider why the request is denied at times.

spoons-mythsRefer to the attached picture. This is not an exact science but gives some idea of the spoon bank. If you have time, try doing this exercise: Lay out 8-12 physical spoons. As you complete certain tasks throughout the day, use this chart to subtract spoons from your pile.

Each and every thing requires a spoon. Taking a shower, washing your hair, cooking, cleaning, watching a movie, going out to lunch, working, writing this post (Ha)! When you are done with your day, notice how many spoons you have left. Observe your feelings after this exercise. You can even do it for a week. Lay out a certain amount of spoons for every day for seven days. If you go into a deficit, borrow spoons from the following day. However, if you do borrow spoons; you must take away a task that you WERE planning to originally do that day. Notice what happens and notice how you feel at the end of the week.

You can view “The Spoon Theory” in its entirety at: http://www.butyoudontlooksick.com/articles/written-by-christine/the-spoon-theory/

Can you think of any other tasks that are not on this chart? Help our friends who are doing the activity. List those tasks and assign how many spoons each task will require.
Spoon Bank
Get out of bed- 1 Spoon
Shower- 2 Spoons
Attend Special Event- 5 Spoons
Go out for Coffee- 4 Spoons
Drive- 4 Spoons
Make a Phone Call- 3 Spoons
Work- 5 spoons
Play Games-3 Spoons
Clean the House- 5 Spoons
Have a Meal- 2 Spoons
Walk the Dog- 4 Spoons
Study- 5 Spoons
Watch TV- 3 Spoons
Ironing- 5 Spoons
Exercise- 4 Spoons
Shopping- 4 Spoons
Read- 2 Spoons
Catch Public Transport- 4 Spoons
Cook- 4 Spoons

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