Largest-ever analysis of its kind finds Cushing’s syndrome triples risk of death

WASHINGTON–Endogenous Cushing’s syndrome, a rare hormonal disorder, is associated with a threefold increase in death, primarily due to cardiovascular disease and infection, according to a study whose results will be presented at ENDO 2021, the Endocrine Society’s annual meeting.

The research, according to the study authors, is the largest systematic review and meta-analysis to date of studies of endogenous (meaning “inside your body”) Cushing’s syndrome. Whereas Cushing’s syndrome most often results from external factors–taking cortisol-like medications such as prednisone–the endogenous type occurs when the body overproduces the hormone cortisol, affecting multiple bodily systems.

Accurate data on the mortality and specific causes of death in people with endogenous Cushing’s syndrome are lacking, said the study’s lead author, Padiporn Limumpornpetch, M.D., an endocrinologist from Prince of Songkla University, Thailand and Ph.D. student at the University of Leeds in Leeds, U.K. The study analyzed death data from more than 19,000 patients in 92 studies published through January 2021.

“Our results found that death rates have fallen since 2000 but are still unacceptably high,” Limumpornpetch said.

Cushing’s syndrome affects many parts of the body because cortisol responds to stress, maintains blood pressure and cardiovascular function, regulates blood sugar and keeps the immune system in check. The most common cause of endogenous Cushing’s syndrome is a tumor of the pituitary gland called Cushing’s disease, but another cause is a usually benign tumor of the adrenal glands called adrenal Cushing’s syndrome. All patients in this study had noncancerous tumors, according to Limumpornpetch.

Overall, the proportion of death from all study cohorts was 5 percent, the researchers reported. The standardized mortality ratio–the ratio of observed deaths in the study group to expected deaths in the general population matched by age and sex–was 3:1, indicating a threefold increase in deaths, she stated.

This mortality ratio was reportedly higher in patients with adrenal Cushing’s syndrome versus Cushing’s disease and in patients who had active disease versus those in remission. The standardized mortality ratio also was worse in patients with Cushing’s disease with larger tumors versus very small tumors (macroadenomas versus microadenomas).

On the positive side, mortality rates were lower after 2000 versus before then, which Limumpornpetch attributed to advances in diagnosis, operative techniques and medico-surgical care.

More than half of observed deaths were due to heart disease (24.7 percent), infections (14.4 percent), cerebrovascular diseases such as stroke or aneurysm (9.4 percent) or blood clots in a vein, known as thromboembolism (4.2 percent).

“The causes of death highlight the need for aggressive management of cardiovascular risk, prevention of thromboembolism and good infection control and emphasize the need to achieve disease remission, normalizing cortisol levels,” she said.

Surgery is the mainstay of initial treatment of Cushing’s syndrome. If an operation to remove the tumor fails to put the disease in remission, other treatments are available, such as medications.

Study co-author Victoria Nyaga, Ph.D., of the Belgian Cancer Centre in Brussels, Belgium, developed the Metapreg statistical analysis program used in this study.

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Endocrinologists are at the core of solving the most pressing health problems of our time, from diabetes and obesity to infertility, bone health, and hormone-related cancers. The Endocrine Society is the world’s oldest and largest organization of scientists devoted to hormone research and physicians who care for people with hormone-related conditions.

The Society has more than 18,000 members, including scientists, physicians, educators, nurses and students in 122 countries. To learn more about the Society and the field of endocrinology, visit our site at http://www.endocrine.org. Follow us on Twitter at @TheEndoSociety and @EndoMedia.

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From https://www.eurekalert.org/pub_releases/2021-03/tes-lao031621.php

New study identifies the main genetic causes of autoimmune Addison’s disease

Novel genetic associations could pave the way for early interventions and personalized treatment of an incurable condition.

Scientists from the University of Bergen (Norway) and Karolinska Institutet (Sweden) have discovered the genes involved in autoimmune Addison’s disease, a condition where the body’s immune systems destroys the adrenal cortex leading to a life-threatening hormonal deficiency of cortisol and aldosterone.

Groundbreaking study

The rarity of Addison’s disease has until now made scanning of the whole genome for clues to the disease’s genetic origins difficult, as this method normally requires many thousands of study participants. However, by combining the world’s two largest Addison’s disease registries, Prof. Eystein Husebye and his team at the University of Bergen and collaborators at Karolinska Institutet in Sweden (prof. Kämpe) were able to identify strong genetic signals associated with the disease. Most of them are directly involved in the development and functioning of the human immune system including specific molecular types in the so-called HLA-region (this is what makes matching donors and recipients in organ transplants necessary) and two different types of a gene called AIRE (which stands for AutoImmune REgulator).

AIRE is a key factor in shaping the immune system by removing self-reacting immune cells. Variants of AIRE, such as the ones identified in this study, could compromise this elimination of self-reacting cells, which could lead to an autoimmune attack later in life.

Knowing what predisposes people to develop Addison’s disease opens up the possibilities of determining the molecular repercussions of the predisposing genetic variation (currently ongoing in Prof. Husebye’s lab). The fact that it is now feasible to map the genetic risk profile of an individual also means that personalised treatment aimed at stopping and even reversing the autoimmune adrenal destruction can become a feasible option in the future.

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Contact information:

Professor at the University of Bergen, Eystein Husebye – Eystein.Husebye@uib.no – cell phone +47 99 40 47 88

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

From https://www.eurekalert.org/pub_releases/2021-02/tuob-nsi021221.php

Thyroid cancer: Cushing syndrome is a lesser-known warning sign – what is it?

Thyroid cancer survival rates are 84 percent for 10 years or more if diagnosed early. Early diagnosis is crucial therefore and spotting the unusual signs could be a matter of life and death. A sign your thyroid cancer has advanced includes Cushing syndrome.

What is it?

What is Cushing syndrome?

 

Cushing syndrome occurs when your body is exposed to high levels of the hormone cortisol for a long time, said the Mayo Clinic.

The health site continued: “Cushing syndrome, sometimes called hypercortisolism, may be caused by the use of oral corticosteroid medication.

“The condition can also occur when your body makes too much cortisol on its own.

“Too much cortisol can produce some of the hallmark signs of Cushing syndrome — a fatty hump between your shoulders, a rounded face, and pink or purple stretch marks on your skin.”

In a study published in the US National Library of Medicine National Institutes of Health, thyroid carcinoma and Cushing’s syndrome was further investigated.

The study noted: “Two cases of thyroid carcinoma and Cushing’s syndrome are reported.

“Both of our own cases were medullary carcinomas of the thyroid, and on reviewing the histology of five of the other cases all proved to be medullary carcinoma with identifiable amyloid in the stroma.

“A consideration of the temporal relationships of the development of the carcinoma and of Cushing’s syndrome suggested that in the two cases with papillary carcinoma these conditions could have been unrelated, but that in eight of the nine cases with medullary carcinoma there was evidence that thyroid carcinoma was present at the time of diagnosis of Cushing’s syndrome.

“Medullary carcinoma of the thyroid is also probably related to this group of tumours. It is suggested that the great majority of the tumours associated with Cushing’s syndrome are derived from cells of foregut origin which are endocrine in nature.”

In rare cases, adrenal tumours can cause Cushing syndrome a condition arising when a tumour secretes hormones the thyroid wouldn’t normally create.

Cushing syndrome associated with medullary thyroid cancer is uncommon.

The syndrome is more commonly caused by the pituitary gland overproducing adrenocorticotropic hormone (ACTH), or by taking oral corticosteroid medication.

See a GP if you have symptoms of thyroid cancer, warns the NHS.

The national health body added: “The symptoms may be caused by less serious conditions, such as an enlarged thyroid, so it’s important to get them checked.

“A GP will examine your neck and can organise a blood test to check how well your thyroid is working.

“If they think you could have cancer or they’re not sure what’s causing your symptoms, you’ll be referred to a hospital specialist for more tests.”

 

Adapted from https://www.express.co.uk/life-style/health/1351753/thyroid-cancer-signs-symptoms-cushing-syndrome

Earwax may reveal how stressed you are

How stressed are you? Your earwax could hold the answer.

A new method of collecting and analyzing earwax for levels of the stress hormone cortisol may be a simple and cheap way to track the mental health of people with depression and anxiety.

Cortisol is a crucial hormone that spikes when a person is stressed and declines when they’re relaxed. In the short-term, the hormone is responsible for the “fight or flight” response, so it’s important for survival. But cortisol is often consistently elevated in people with depression and anxiety, and persistent high levels of cortisol can have negative effects on the immune system, blood pressure and other bodily functions.

There are other disorders which involve abnormal cortisol, including Cushing’s disease (caused by the overproduction of cortisol) and Addison’s disease (caused by the underproduction of cortisol). People with Cushing’s disease have abnormal fat deposits, weakened immune systems and brittle bones. People with Addison’s disease have dangerously low blood pressure.

There are a lot of ways to measure cortisol: in saliva, in blood, even in hair. But saliva and blood samples capture only a moment in time, and cortisol fluctuates significantly throughout the day. Even the experience of getting a needle stick to draw blood can increase stress, and thus cortisol levels. Hair samples can provide a snapshot of cortisol over several months instead of several minutes, but hair can be expensive to analyze — and some people don’t have much of it.

Andrés Herane-Vives, a lecturer at University College London’s Institute of Cognitive Neuroscience and Institute of Psychiatry, and his colleagues instead turned to the ear. Earwax is stable and resistant to bacterial contamination, so it can be shipped to a laboratory easily for analysis. It also can hold a record of cortisol levels stretching over weeks.

But previous methods of harvesting earwax involved sticking a syringe into the ear and flushing it out with water, which can be slightly painful and stressful. So Herane-Vives and his colleagues developed a swab that, when used, would be no more stressful than a Q-tip. The swab has a shield around the handle, so that people can’t stick it too far into their ear and damage their eardrum, and a sponge at the end to collect the wax.

In a small pilot study, researchers collected blood, hair and earwax from 37 participants at two different time points. At each collection point, they sampled earwax using a syringe from one ear, and using the new self-swab method from the other. The researchers then compared the reliability of the cortisol measurements from the self-swab earwax with that of the other methods.

They found that cortisol was more concentrated in earwax than in hair, making for easier analysis. Analyzing the self-swabbed earwax was also faster and more efficient than analyzing the earwax from the syringe, which had to be dried out before using. Finally, the earwax showed more consistency in cortisol levels compared with the other methods, which were more sensitive to fluctuations caused by things like recent alcohol consumption. Participants also said that self-swabbing was more comfortable than the syringe method.

The researchers reported their findings Nov. 2 in the journal Heliyon. Herane-Vives is also starting a company called Trears to market the new method. In the future, he hopes that earwax could also be used to monitor other hormones. The researchers also need to follow up with studies of Asian individuals, who were left out of this pilot study because a significant number only produce dry, flaky earwax as opposed to wet, waxy earwax.

“After this successful pilot study, if our device holds up to further scrutiny in larger trials, we hope to transform diagnostics and care for millions of people with depression or cortisol-related conditions such as Addison’s disease and Cushing syndrome, and potentially numerous other conditions,” he said in a statement.

Originally published in Live Science.

Muscle Weakness Persists in Cushing’s Syndrome Despite Remission

People with Cushing’s syndrome experience muscle weakness that persists even when the disorder is in remission, a new study shows.

The study, “Persisting muscle dysfunction in Cushing’s syndrome despite biochemical remission,” was published in The Journal of Clinical Endocrinology and Metabolism.

Cushing’s syndrome is characterized by abnormally high levels of the hormone cortisol. This can result in a variety of symptoms, including muscle weakness. However, it’s unclear the extent to which treatment of the underlying syndrome affects muscle weakness in the long term.

In the new study, researchers analyzed data for 88 people with endogenous Cushing’s syndrome diagnosed between 2012 and 2018 who had undergone regular muscle function tests. The data were collected as part of the German Cushing’s Registry, and the assessed group was mostly female (78%), with an average age of 49.

Of note, not all individuals had data available for every time point assessed — for example, at four years of follow-up, data were available for only 22 of the people analyzed.

Of the 88 individuals assessed, 49 had Cushing’s disease (a form of Cushing’s syndrome driven by a tumor on the pituitary gland). All 88 underwent curative surgery. The median time between diagnosis and remission was two months.

The researchers measured muscle strength in two ways: by grip strength and the chair rising test.

On average, and after statistical adjustments for age and sex, grip strength at diagnosis was 83% (with 100% reflecting the average for people without Cushing’s syndrome). Six months after surgery, average grip strength had decreased to 71%. A year after surgery, average grip strength was 77%. At all time points measured, up to four years after surgery, grip strength was significantly lowered in people with Cushing’s syndrome.

The chair rising test (CRT) involves measuring how quickly a person can rise from a seated position. Generally, being able to do so more quickly indicates greater muscle strength. People with Cushing’s syndrome showed improvement in the CRT six months after treatment (median 7 seconds), compared to the beginning of the study (8 seconds).

However, no further improvement was observed at subsequent time points up to four years, and compared to controls, CRT remained abnormal over time (7 seconds in Cushing patients at three years of follow-up vs 5 seconds in controls).

“The main finding of our study is that muscle strength remains impaired even after years in remission,” the researchers wrote.

“Another interesting finding is that at 6 months follow-up grip strength and CRT performance show opposite effects. Whereas grip strength has worsened, CRT performance has improved,” they added.

The investigators speculated that this difference is probably due to changes in body weight. Cushing’s syndrome commonly results in weight gain, and treatment resulted in significant decreases in body mass index in the analyzed group. As such, it may have been easier for individuals to stand up because there was less mass for their muscles to move, not necessarily because their muscles were stronger.

“Why patients with CS in remission showed a temporary worsening in grip strength 6 months after surgery remains unclear in terms of pathophysiology,” the researchers wrote.

They speculated that this could be due to treatment with glucocorticoids, which may affect muscle strength, but added that, “Whether the necessity of a long-term glucocorticoid replacement influences muscle strength or myopathy [muscle disease] outcome remains controversial.”

The researchers also conducted statistical analyses to determine what patient factors were associated with poorer muscle function outcomes. They found statistically significant associations between poor muscle function and older age, higher waist-to-hip-ratio, and higher levels of HbA1c (a marker of metabolic disease like diabetes).

“Influencing factors for myopathy outcome are age, waist-to-hip-ratio and HbA1c, suggesting that a consistent and strict treatment of diabetic metabolic state during hypercortisolism [high cortisol levels] is mandatory,” the investigators wrote.

The study was limited by its small sample size, the researchers noted, particularly at longer follow-up times, and by the fact that only a few measurements of muscle strength were used. Additionally, since all the data were collected at one of three centers in Germany, the analyzed population may not be representative of the worldwide population of people with Cushing’s syndrome.

Adapted from https://cushingsdiseasenews.com/2020/09/30/muscle-weakness-persists-in-cushings-syndrome-despite-remission-study-finds/

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