Hypercortisolism Is Associated With Increased Coronary Arterial Atherosclerosis

Posted on May 21, 2013 by MaryO

Hypercortisolism Is Associated With Increased Coronary Arterial Atherosclerosis: Analysis of Noninvasive Coronary Angiography Using Multidetector Computerized Tomography

Journal of Clinical Endocrinology and Metabolism, 05/21/2013  Clinical Article

  1. Nicola M. Neary*,
  2. O. Julian Booker*,
  3. Brent S. Abel,
  4. Jatin R. Matta,
  5. Nancy Muldoon,
  6. Ninet Sinaii,
  7. Roderic I. Pettigrew,
  8. Lynnette K. Nieman and
  9. Ahmed M. Gharib

–Author Affiliations


  1. Program in Reproductive and Adult Endocrinology (N.M.N., L.K.N., B.S.A.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; Laboratory of Cardiac Energetics (O.J.B.), National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892; Integrative Cardiovascular Imaging Laboratory (J.R.M., R.I.P., A.M.G.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892; Critical Care Medicine (N.M.), Clinical Center, National Institutes of Health, Bethesda, Maryland 20892; and Biostatistics and Clinical Epidemiology Service (N.S.), Clinical Center, National Institutes of Health, Bethesda, Maryland 20892
  1. Address all correspondence and requests for reprints to: Ahmed M. Gharib, MB, ChB, National Institutes of Health, Building 10, Room 3-5340, Mail Stop Code 1263, 10 Center Drive, Bethesda, MD 20892. E-mail: agharib@mail.nih.gov.

  1. ↵* N.M.N. and O.J.B. contributed equally to this work.

Abstract

Background: Observational studies show that glucocorticoid therapy and the endogenous hypercortisolism of Cushing’s syndrome (CS) are associated with increased rates of cardiovascular morbidity and mortality. However, the causes of these findings remain largely unknown.

Objective: To determine whether CS patients have increased coronary atherosclerosis.

Design: A prospective case-control study was performed.

Setting: Subjects were evaulated in a clinical research center.

Subjects: Fifteen consecutive patients with ACTH-dependent CS, 14 due to an ectopic source and 1 due to pituitary Cushing’s disease were recruited. Eleven patients were studied when hypercortisolemic; 4 patients were eucortisolemic due to medication (3) or cyclic hypercortisolism (1). Fifteen control subjects with at least one risk factor for cardiac disease were matched 1:1 for age, sex, and body mass index.

Primary outcome variables: Agatston score a measure of calcified plaque and non-calcified coronary plaque volume were quantified using a multidetector CT (MDCT) coronary angiogram scan. Additional variables included fasting lipids, blood pressure, history of hypertension or diabetes, and 24-hour urine free cortisol excretion.

Results: CS patients had significantly greater noncalcified plaque volume and Agatston score (noncalcified plaque volume [mm3] median [interquartile ranges]: CS 49.5 [31.4, 102.5], controls 17.9 [2.6, 25.3], P < .001; Agatston score: CS 70.6 [0, 253.1], controls 0 [0, 7.6]; P < .05). CS patients had higher systolic and diastolic blood pressures than controls (systolic: CS 143 mm Hg [135, 173]; controls, 134 [123, 136], P < .02; diastolic CS: 86 [80, 99], controls, 76 [72, 84], P < .05).

Conclusions: Increased coronary calcifications and noncalcified coronary plaque volumes are present in patients with active or previous hypercortisolism. Increased atherosclerosis may contribute to the increased rates of cardiovascular morbidity and mortality in patients with glucocorticoid excess.

  • Received October 29, 2012.
  • Accepted March 7, 2013.

From JCEM

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Hyperthyroidism due to thyroid stimulating hormone secretion after surgery for Cushing’s syndrome: A novel cause of the syndrome of inappropriate secretion of thyroid stimulating hormone

Posted on May 14, 2013 by MaryO
Overview of the thyroid system (See Wikipedia:...

Overview of the thyroid system (See Wikipedia:Thyroid). To discuss image, please see Talk:Human body diagrams (Photo credit: Wikipedia)

  1. Daisuke Tamada, MD1,
  2. Toshiharu Onodera, MD1,
  3. Tetsuhiro Kitamura, MD, PhD1,
  4. Yuichi Yamamoto, MD1,
  5. Yoshitaka Hayashi, MD, PhD2,
  6. Yoshiharu Murata, MD, PhD2,
  7. Michio Otsuki, MD, PhD1 and
  8. Iichiro Shimomura, MD, PhD1

Author Affiliations


  1. 1Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Osaka, Japan

  2. 2Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
  1. Address all correspondence and requests for reprints to: Michio Otsuki, MD, PhD, Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2–2 Yamada-oka, Suita, Osaka 565-0871, Japan, Telephone: +81-6-6879-3732. Fax: +81-6-6879-3739, E-mail: otsuki@endmet.med.osaka-u.ac.jp.

Abstract

Context: Hyperthyroidism with the syndrome of inappropriate secretion of thyroid stimulating hormone (TSH) (SITSH) occurred by a decrease in hydrocortisone dose after surgery for Cushing’s syndrome. This is a novel cause of SITSH.

Objective: The aim of this study was to describe and discuss the two cases of SITSH patients who were found after surgery for Cushing’s syndrome. We also checked whether SITSH occurred in the consecutive 7 patients with Cushing’s syndrome after surgery.

Patients and Methods: A 45-year-old Japanese woman with adrenocorticotropin (ACTH)-independent Cushing’s syndrome and a 37-year-old Japanese man with ACTH-dependent Cushing’s syndrome presented SITSH caused by insufficient replacement of hydrocortisone for postoperative adrenal insufficiency. When the dose of hydrocortisone was reduced to less than 20 mg/day within 18 days after operation, SITSH occurred in both cases. We examined whether the change of the hydrocortisone dose induced the secretion of TSH. Free T3 and TSH were normalized by the hydrocortisone dose increase of 30 mg/day and these were elevated by the dose decrease of 10 mg/day. We also checked TSH and thyroid hormone the consecutive 7 patients with Cushing’s syndrome after surgery. Six (66.6 %) of nine patients showed SITSH.

Conclusions: This is the first report that insufficient replacement of hydrocortisone after the surgery of Cushing’s syndrome caused SITSH. Hyperthyroidism by SITSH as well as adrenal insufficiency can contribute to withdrawal symptoms of hydrocortisone replacement. So we need to consider the possibility of SITSH for the pathological evaluation of withdrawal syndrome of hydrocortisone replacement.

  • Received May 4, 2013.
  • Accepted May 8, 2013.

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Salk scientists find potential therapeutic target for Cushing’s disease

Posted on May 7, 2013 by MaryO

LA JOLLA, CA—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 early online edition of Proceedings of the National Academy of Sciences.

“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.”

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Predictors of Mortality, CVD Risk in Cushing’s Disease ID’d

Posted on February 28, 2013 by MaryO

(HealthDay News) – A number of factors, including the duration of glucocorticoid exposure, older age at diagnosis, and preoperative adrenocorticotropic hormone (ACTH) concentration, are associated with a higher risk of mortality in patients treated for Cushing’s disease (CD), according to research published online Feb. 7 in the Journal of Clinical Endocrinology & Metabolism.

In an effort to identify predictors of mortality, cardiovascular disease, and recurrence with long-term follow-up, Jessica K. Lambert, MD, of the Mount Sinai Medical Center in New York City, and colleagues performed a retrospective chart review of 346 patients with CD who underwent transsphenoidal adenectomy.

The researchers found that the average length of exposure to glucocorticoids was 40 months. The risk of death was higher for those patients who had a longer duration of glucocorticoid exposure, older age at diagnosis, and higher preoperative ACTH concentration. For patients who achieved remission, depressed patients had a higher risk of death. The risk of cardiovascular disease was highest for men, older people, and those with diabetes or depression.

“Our study has identified several predictors of mortality in patients with treated CD, including duration of exposure to excess glucocorticoids, preoperative ACTH concentration, and older age at diagnosis. Depression and male gender predicted mortality among patients who achieved remission,” the authors write. “These data illustrate the importance of early recognition and treatment of CD. Long-term follow-up, with management of persistent comorbidities by an experienced endocrinologist, is needed even after successful treatment of CD.”

Abstract
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Day Eleven, Cushing’s Awareness Challenge

Posted on April 11, 2012 by MaryO

In March of 1987, after the endo finally  confirmed that I had Cushing’s, I saw sent to a local hospital where they repeated all those same tests for another week and decided that it was not my adrenal gland (Cushing’s Syndrome) creating the problem. The doctors and nurses had no idea what to do with me, so they put me on the brain cancer ward.

When I left this hospital after a week, we didn’t know any more than we had before.

As luck would have it, NIH (National Institutes of Health, Bethesda, Maryland) was doing a clinical trial of Cushing’s. I live in the same area as NIH so it was not too inconvenient but very scary at first to think of being tested there. At that time I only had a choice of NIH, Mayo Clinic and a place in Quebec to do this then-rare pituitary surgery called a Transsphenoidal Resection.

My husband asked my endo if it were his wife, if he would recommend this surgery.  The endo responded that he was divorcing his wife – he didn’t care what happened to her.  Oh, my!

I chose NIH – closest and free. After I was interviewed by the Doctors there, I got a letter that I had been accepted into the clinical trial.

The night before I was admitted, I signed my will.  I was sure I was going to die there.  If not during testing, as a result of surgery.

The first time I was there was for 6 weeks as an inpatient. More of the same tests.

There were about 12 of us there and it was nice not to be alone with this mystery disease. Many of these Cushies (mostly women) were getting bald, couldn’t walk, having strokes, had diabetes. One was blind, one had a heart attack while I was there. Several were from Greece.

Towards the end of my testing period, I was looking forward to the surgery just to get this whole mess over with – either a cure or dying. While I was at NIH, I was gaining about a pound a day!

During the time I was home the weekend  before surgery, a college classmate of mine (I didn’t know her) DID die at NIH of a Cushing’s-related problem. I’m so glad I didn’t find out until reading the alumnae magazine a couple months later!  She was the same class, same major, same home-town, same disease…

We have a Scottish doctor named James Lind to thank for the clinical trial.  He  conducted the first ever clinical trial in 1747 and developed the theory that citrus fruits cured scurvy.  Lind  compared the effects of various different acidic substances, ranging from vinegar to cider, on groups of afflicted sailors, and found that the group who were given oranges and lemons had largely recovered from scurvy after 6 days.

I’d like to think that I advanced the knowledge of Cushing’s at least a little bit by being a guinea  pig in 1987-1989.

From the NIH: http://endocrine.niddk.nih.gov/pubs/cushings/cushings.aspx

Hope through Research

Several components of the National Institutes of Health (NIH) conduct and support research on Cushing’s syndrome and other disorders of the endocrine system, including the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Child Health and Human Development (NICHD), the National Institute of Neurological Disorders and Stroke, the National Cancer Institute, and the National Center for Research Resources.

NIH-supported scientists are conducting intensive research into the normal and abnormal function of the major endocrine glands and the many hormones of the endocrine system. Researchers continue to study the effects of excess cortisol, including its effect on brain structure and function. To refine the diagnostic process, studies are under way to assess the accuracy of existing screening tests and the effectiveness of new imaging techniques to evaluate patients with ectopic ACTH syndrome. Researchers are also investigating jugular vein sampling as a less invasive alternative to petrosal sinus sampling. Research into treatment options includes study of a new drug to treat the symptoms of Cushing’s syndrome caused by ectopic ACTH secretion.

Studies are under way to understand the causes of benign endocrine tumor formation, such as those that cause most cases of Cushing’s syndrome. In a few pituitary adenomas, specific gene defects have been identified and may provide important clues to understanding tumor formation. Endocrine factors may also play a role. Increasing evidence suggests that tumor formation is a multistep process. Understanding the basis of Cushing’s syndrome will yield new approaches to therapy.

The NIH supports research related to Cushing’s syndrome at medical centers throughout the United States. Scientists are also treating patients with Cushing’s syndrome at the NIH Clinical Center in Bethesda, MD. Physicians who are interested in referring an adult patient may contact Lynnette Nieman, M.D., at NICHD, 10 Center Drive, Room 1-3140, Bethesda, MD 20892-1109, or by phone at 301-496-8935. Physicians interested in referring a child or adolescent may contact Constantine Stratakis, M.D., D.Sc., at NICHD, 10 Center Drive, Room 1-3330, Bethesda, MD 20892-1103, or by phone at 301-402-1998.

 

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