Hypercortisolism Is Associated With Increased Coronary Arterial Atherosclerosis

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.

• Copyright © 2013 by The Endocrine Society

From JCEM

Classifying hypertension

HYPERTENSION is classified into two categories according to its cause: essential and secondary.

The vast majority of patients have essential or primary hypertension, while only about 5-10% of patients have secondary hypertension, which are mainly caused by kidney and hormonal conditions like renal artery stenosis, hyperthyroidism, Cushing’s syndrome, and even pregnancy, among others.

The exact cause of essential hypertension is still unknown, although it is certainly the result of a combination of factors, including increasing age, having relatives with high blood pressure (ie family history), a sedentary lifestyle, a poor diet with too much salt, drinking too much alcohol, smoking and too much stress.

Says Malaysian Society of Hypertension president and Universiti Malaya Department of Primary Care Medicine senior consultant Prof Datin Dr Chia Yook Chin: “Each factor increases blood pressure by just a little, but when you add them all together little by little, it raises it by quite a lot.”

Despite not knowing the root cause of hypertension, it has been established that there is overstimulation of the sympathetic nerves in people with this condition.

This in turn increases the secretion of certain hormones involved in the regulation of sodium and fluids in the body, called renin, angiotensin, and aldosterone.

The amount of salt and water in our body affects our blood pressure – the more salt and water present, the higher our blood pressure.

These two elements are regulated by our kidneys through the three hormones mentioned above, which are produced by the adrenal glands located on top of the kidneys.

The overstimulation of the sympathetic nerves also results in increased vascular tone, which causes our arteries to become constricted, thus, also raising blood pressure.

From The Star

The Deadline is Friday for Helping Grow the Rare Disease Congressional Caucus

Friday, May 17 at 8PM eastern is the deadline for this.  

We want to have Caucus Members from all 50 States. 

We have 28 to go: AL, AK, AZ, CO, CT, DE, HI, ID, KS, KY, LA, ME, MD, MS, MO, MT, NV, NH, NM, ND, OK, RI, SC, SD, UT, VT, WI, & WY If you live in one of these states or know someone who does - Please take ACTION today! 

http://bit.ly/RareAlert

Original post:

Help us strengthen the rare disease community's voice on Capitol Hill!  Please take 3 minutes to ask your Member of Congress to join the Rare Disease Caucus at http://bit.ly/RareAlert.

 

It's easy - the Action Center has a draft letter that will automatically be sent to your Member of Congress - just put in your name and address & click send.  We also encourage you to personalize the letter to share information about your specific disease.  If your Congress Member is already on the Caucus, the letter will automatically populate as a thank you letter instead - these are just as important to send!

 

It can take up to 10 letters from constituents for a Member to respond so please share this Action Alert with your friends, family & colleagues.  Join our Facebook event & invite your friends:   http://on.fb.me/17Mlpjg 

 

The Rare Disease Congressional Caucus will help bring public and Congressional awareness to the unique needs of the rare disease community – patients, physicians, scientists, and industry, and create opportunities to address roadblocks in access to and development of crucial treatments.  The Caucus will give a permanent voice to the rare disease community on Capitol Hill.  Working together, we can find solutions that turn hope into treatments.

Related articles

• In the US? Ask your Member of Congress to join the Rare Disease Congressional Caucus (cushieblog.com)
• Help Grow the Rare Disease Congressional Caucus (maryomedical.com)
• Cushing's Awareness Challenge, Day 1: Rare Disease Congressional Caucus Briefing (cushieblog.com)
• Cushing's on Capitol Hill: Cushing's Awareness Challenge (cushieblog.com)

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

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.

• Copyright © 2013 by The Endocrine Society

Ask your Member of Congress to join the Rare Disease Congressional Caucus

Help us strengthen the rare disease community's voice on Capitol Hill!  Please take 3 minutes to ask your Member of Congress to join the Rare Disease Caucus at http://bit.ly/RareAlert.

It's easy - the Action Center has a draft letter that will automatically be sent to your Member of Congress - just put in your name and address & click send.  We also encourage you to personalize the letter to share information about your specific disease.  If your Congress Member is already on the Caucus, the letter will automatically populate as a thank you letter instead - these are just as important to send!

It can take up to 10 letters from constituents for a Member to respond so please share this Action Alert with your friends, family & colleagues.  Join our Facebook event & invite your friends:   http://on.fb.me/17Mlpjg 

The Rare Disease Congressional Caucus will help bring public and Congressional awareness to the unique needs of the rare disease community – patients, physicians, scientists, and industry, and create opportunities to address roadblocks in access to and development of crucial treatments.  The Caucus will give a permanent voice to the rare disease community on Capitol Hill.  Working together, we can find solutions that turn hope into treatments.

MR Brain Spectroscopy Detects Damage In The Hippocampus Of Patients Exposed To Excess Cortisol

New research shows that patients who are "biochemically cured" of Cushing's syndrome have levels of brain metabolites which are associated with neural damage. This will have implications for treatment of Cushing's patients, but might also suggest that patients using high levels of glucocorticoid drugs may suffer similar long-term problems. The work was presented yesterday at the European Congress of Endocrinology in Copenhagen.

Cushing's syndrome is an endocrine disease causing an overproduction of the stress hormone cortisol. Surgery and medical treatment can normalise cortisol levels, however recently it has been shown that "biochemically cured" patients continue to have memory problems. Now for the first time a group of researchers from the Sant Pau Hospital in Barcelona has scanned the brains of patients who had suffered from Cushing's syndrome and found that they exhibit changed levels of brain metabolites, which are associated with memory and cognitive impairments. This finding may also have clinical implications for otherwise healthy patients who take high levels of glucocorticoid drugs for inflammatory, rheumatoid diseases, allergies and probably everyday chronic stress.

Cortisol (a glucocorticoid hormone), is naturally produced by the adrenal glands in response to stress. Long term exposure to high levels of cortisol is known to be associated with a range of cognitive impairments - this is true for Cushing's syndrome patients, and probably would be also for those who take glucocorticoid drugs.

Eugenia Resmini and colleagues, working at the Centre for Biomedical Research on Rare Diseases (CIBERER), Sant Pau hospital in Barcelona, used proton magnetic resonance spectroscopy to measure a series of metabolites in the hippocampus of the brains of 18 patients who had been treated for Cushing's syndrome, and compared these results to 18 healthy control subjects. They found that levels of the metabolite NAA (NAcetyl-aspartate) were significantly lower in the Cushing's patients, indicating neural dysfunction, whereas Glx (Glutamate +Glutamine) levels were higher, suggesting that glial cells were proliferating as a repair mechanism.

According to Dr Resmini MD, PhD, Endocrinologist at the Centre for Biomedical Research on Rare Diseases (CIBERER), Hospital de Sant Pau, Barcelona, Spain:

"Patients with Cushing's syndrome are exposed to abnormally high levels of glucocorticoids, which is associated with a wide range of cognitive impairments, as well as loss of brain volume. We studied the hippocampus, which is a critical area for learning and memory and, as it is rich in glucocorticoid receptors, is especially vulnerable to glucocorticoid overexposure. Cushing's syndrome patients with severe memory impairment are known to have a smaller hippocampus. We have now found abnormal levels of metabolites in the hippocampi of Cushing's patients with normal hippocampal volumes, indicating that these are early markers of glucocorticoid neurotoxicity, which would precede hippocampal volume reduction.

"Identifying these metabolites as a marker would be a way of allowing earlier diagnosis and treatment of cognitive impairments. This may also allow us to monitor patients taking glucocorticoid drugs, which have potentially damaging side effects. On the other hand, the fact that these markers are still present in Cushing's patients after being "biochemically cured", may show that once cognition has been damaged in Cushing's syndrome, it may not be fully reversible. For this reason an earlier diagnosis of the disease and a rapid normalization of hypercortisolism would avoid the progression of hippocampal damage and of memory problems".

From Medical News Today

Salk scientists find potential therapeutic target for Cushing's disease

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."

Source: Salk Institute

Abnormal Metabolites Found in Cured Cushing’s Patients

Patients with Cushing's syndrome have abnormal brain metabolites suggestive of neuronal dysfunction even after they appeared to have been cured, according to a study presented at the annual European Congress of Endocrinology, held from April 27 to May 1 in Copenhagen.

(HealthDay News) -- Patients with Cushing's syndrome have abnormal brain metabolites suggestive of neuronal dysfunction even after they appeared to have been cured, according to a study presented at the annual European Congress of Endocrinology, held from April 27 to May 1 in Copenhagen.

Using proton magnetic resonance spectroscopy, Eugenia Resmini, M.D., Ph.D., from Hospital Sant Pau in Barcelona, Spain, and colleagues measured metabolites in the hippocampi of 18 adults with Cushing's syndrome who had been biochemically cured and 18 age- and education-matched healthy adults.

The researchers found that the two groups had similar left and right total hippocampal volumes. Patients with Cushing's syndrome had significantly lower NAcetyl-aspartate in the left and right hippocampus as well as significantly lower NAcetyl-aspartate plus N-Acetyl-aspartyl-glutamate in the right hippocampus. In addition, patients with Cushing's syndrome had significantly higher glutamate plus glutamine in both hippocampi. The alterations are suggestive of neuronal dysfunction, according to the authors.

"Persistently abnormal metabolites are evidenced in the hippocampi of Cushing's syndrome patients despite endocrine cure," Resmini and colleagues conclude. "These functional alterations could be early markers of glucocorticoids neurotoxicity and would precede hippocampal volume reduction."

Abstract
More Information

From HealthDay

Diagnostic performance of salivary cortisol in the diagnosis of Cushing's syndrome, adrenal incidentaloma and adrenal insufficiency

Ceccato F, Barbot M, Zilio M, Ferasin S, Occhi G, Daniele A, Mazzocut S, Iacobone M, Betterle C, Mantero F, Scaroni C.

Source

F Ceccato, Department of Medicine - DIMED, University of Padova, Endocrinology Unit, Padova, Italy.

Abstract

OBJECTIVE:

Salivary cortisol has been recently suggested for studies on the hypothalamic-pituitary-adrenal (HPA) axis: lack of circadian rhythm is a marker of Cushing's syndrome (CS), and some authors report that low salivary cortisol levels may be a marker of adrenal insufficiency. The aim of our study was to define the role of salivary cortisol in specific diagnostic setting of HPA axis disease.

SUBJECTS AND METHODS:

We analyzed morning salivary cortisol (MSC) and late night salivary cortisol (LNSC) in 406 subjects: 52 Cushing's disease (CD), 13 ectopic-CS, 17 adrenal-CS, 27 CD in remission (mean follow-up of 66 ± 39 months), 45 adrenal incidentalomas, 73 patients assessed of CS and then ruled out for endogenous hypercortisolism, 75 patients with adrenal insufficiency and 104 healthy subjects.

RESULTS:

A LNSC value above 5.24 ng/mL differentiated CS from controls with high sensitivity (96.3%) and specificity (97.1%), we found higher LNSC in ectopic-CS than in CD. We found no difference in MSC and LNSC levels between CD in remission and healthy subjects. Both MSC and LNSC were higher in adrenal incidentaloma than in healthy controls. MSC below 2.65 ng/mL distinguished patients with adrenal insufficiency from controls with high sensitivity (97.1%) and specificity (93.3%).

CONCLUSIONS:

salivary cortisol is a useful tool to assess endogenous cortisol excess or adrenal insufficiency and to evaluate stable CD in remission.

PMID:

 

23610124

 

[PubMed - as supplied by publisher]

From PubMed

Know Your Number

English: "Dr. Harvey Cushing," oil on canvas, by the American artist Edmund Tarbell. Courtesy of the Dittrick Medical History Center. (Photo credit: Wikipedia)

From my email:

As an advocate for patients with Cushing’s disease and their supporters, you certainly understand the importance of continually monitoring cortisol.
April 8th marks Cushing’s Awareness Day and the birthday of Dr. Harvey Cushing, who first described the disease in 1912. We want to use the month of April to bring attention to this disease. In honor of this day, Novartis Pharmaceuticals Corporation is kicking off “Know Your Number,” an important new program emphasizing the importance of cortisol regulation.

Being an advocate for those with Cushing’s disease and for those who care for them, you know that even after a successful pituitary surgery, where cortisol levels return to normal, there is still up to a 35% risk the pituitary tumor could begin to grow again, thus causing hypercortisolism. This potential rise in cortisol is also true for patients who are currently taking medication to control their Cushing’s disease. Over time, this control may begin to diminish. These important facts make it essential that your members are aware of the need to monitor their cortisol level.

Novartis Pharmaceuticals Corporation is initiating an important new program, and we would like to partner with Cushing’s Help and Support to bring this information to your membership and to all patients with Cushing’s disease. “Know Your Number” reminds both endocrinologists and patients that hypercortisolism can have devastating consequences on a patient’s body and emotions. “Know Your Number” promotes follow-up cortisol testing to help identify those patients whose cortisol levels have increased.

Please reach out to your membership with this message during the month of April as we celebrate Dr. Harvey Cushing’s birthday.

To learn more about this program and Cushing’s disease, and to download a discussion guide, please visit www.CushingsDisease.com

Know Your Number.