ENDO 2021 Roundup: COVID-19 Risk With Adrenal Insufficiency, Cushing’s Death Risk, Jatenzo Liver Data, and More

Some of the latest research advancements in the field of endocrinology presented at the Endocrine Society’s virtual ENDO 2021 meeting included quantifying diabetic ketoacidosis readmission rateshyperglycemia as a severe COVID-19 predictor, and semaglutide as a weight loss therapy. Below are a few more research highlights:

More Safety Data on Jatenzo

In a study of 81 men with hypogonadism — defined as a serum testosterone level below 300 ng/dL — oral testosterone replacement therapy (Jatenzo) was both safe and effective in a manufacturer-sponsored study.

After 24 months of oral therapy, testosterone concentration increased from an average baseline of 208.3 ng/dL to 470.1 ng/dL, with 84% of patients achieving a number in the eugonadal range.

And importantly, the treatment also demonstrated liver safety, as there were no significant changes in liver function tests throughout the 2-year study — including alanine aminotransferase (28.0 ± 12.3 to 26.6 ± 12.8 U/L), aspartate transaminase (21.8 ± 6.8 to 22.0 ± 8.2 U/L), and bilirubin levels (0.58 ± 0.22 to 0.52 ± 0.19 mg/dL).

Throughout the trial, only one participant had elevation of liver function tests.

“Our study finds testosterone undecanoate is an effective oral therapy for men with low testosterone levels and has a safety profile consistent with other approved testosterone products, without the drawbacks of non-oral modes of administration,” said lead study author Ronald Swerdloff, MD, of the Lundquist Research Institute in Torrance, California, in a statement.

In addition, for many men with hypogonadism, “an oral option is preferred to avoid issues associated with other modes of administration, such as injection site pain or transference to partners and children,” he said. “Before [testosterone undecanoate] was approved, the only orally approved testosterone supplemental therapy in the United States was methyltestosterone, which was known to be associated with significant chemical-driven liver damage.”

Oral testosterone undecanoate received FDA approval in March 2019 following a rocky review history.

COVID-19 Risk With Adrenal Insufficiency

Alarming new data suggested that children with adrenal insufficiency were more than 23 times more likely to die from COVID-19 than kids without this condition (relative risk 23.68, P<0.0001). This equated to 11 deaths out of 1,328 children with adrenal insufficiency compared with 215 deaths out of 609,788 children without this condition (0.828% vs 0.035%).

These young patients with adrenal insufficiency also saw a much higher rate of sepsis (RR 21.68, P<0.0001) and endotracheal intubation with COVID-19 infection (RR 25.45, P<0.00001).

Data for the analysis were drawn from the international TriNetX database, which included patient records of children ages 18 and younger diagnosed with COVID-19 from 60 healthcare organizations in 31 different countries.

“It’s really important that you take your hydrocortisone medications and start stress dosing as soon as you’re sick,” study author Manish Raisingani, MD, of the University of Arkansas for Medical Sciences and Arkansas Children’s in Little Rock, explained during a press conference. “This will help prevent significant complications due to COVID-19 or any other infections. A lot of the complications that we see in kids with adrenal insufficiency are due to inadequate stress dosing of steroids.”

And with kids starting to return back to in-person schooling, “parents should also be reeducated about using the emergency injections of hydrocortisone,” Raisingani added. He noted that the COVID-19 complication rates were likely so high in this patient population because many had secondary adrenal insufficiency due to being on long-term, chronic steroids. Many also had comorbid respiratory illnesses, as well.

Cushing’s Death Risk

In a systematic review and meta-analysis of 87 studies — including data on 17,276 patients with endogenous Cushing’s syndrome — researchers found that these patients face a much higher death rate than those without this condition.

Overall, patients with endogenous Cushing’s syndrome faced a nearly three times higher mortality ratio (standardized mortality ratio 2.91, 95% CI 2.41-3.68, I2=40.3%), with those with Cushing’s disease found to have an even higher mortality risk (SMR 3.27, 95% CI 2.33-4.21, I2=55.6%).

And those with adrenal Cushing’s syndrome also saw an elevated death risk, although not as high as patients with the disease (SMR 1.62, 95% CI 0.08-3.16, I2=0.0%).

The most common causes of mortality among these patients included cardiac conditions (25%), infection (14%), and cerebrovascular disease (9%).

“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,” said lead study author Padiporn Limumpornpetch, MD, of the University of Leeds in England, in a statement.

From https://www.medpagetoday.com/meetingcoverage/endo/91808

Mortality rate in Cushing’s syndrome ‘unacceptably high’

A large study of mortality in Cushing’s syndrome calculated a threefold higher mortality rate for these patients, with cerebrovascular and atherosclerotic vascular diseases and infection accounting for 50% of deaths, researchers reported.

“[We have seen] improvement in outcome since 2000, but mortality is still unacceptably high,” Padiporn Limumpornpetch, MD, an endocrinologist at Prince of Songkla University in Thailand and PhD student at the University of Leeds, U.K., told Healio during the ENDO annual meeting. “The mortality outcome has shown an unacceptable standardized mortality rate of 3:1, with poorer outcomes in patients with adrenal Cushing’s [and] active and larger tumors in Cushing’s disease.”

Atherosclerotic vascular disease was the top cause of death in Cushing’s disease, with infection coming in as the second-highest cause of death. Data were derived from Limumpornpetch P. OR04-4. Presented at: ENDO annual meeting; March 20-23, 2021 (virtual meeting).

For a meta-analysis and meta-regression analysis of cause of death among patients with benign endogenous Cushing’s syndrome, Limumpornpetch and colleagues reviewed data published from 1952 to January 2021 from 92 study cohorts with 19,181 patients that reported mortality rates, including 66 studies that reported causes of death.

The researchers calculated the standardized mortality rate (SMR) for Cushing’s syndrome at 3 (95% CI, 2.3-3.9). For patients with adrenal Cushing’s syndrome, SMR was 3.3 (95% CI, 0.5-6.6) — higher than for those with Cushing’s disease, with an SMR of 2.8 (95% CI, 2.1-3.7). Rates were similar by sex and by type of adrenal tumor.

Deaths occurring within 30 days of surgery for Cushing’s syndrome fell to 3% after 2000 from 10% before that date (P < .005). During the entire study period, atherosclerotic vascular disease accounted for 27.4% of deaths in Cushing’s syndrome, and 12.7% were attributable to infection, 11.7% to cerebrovascular diseases, 10.6% to malignancy, 4.4% to thromboembolism, 2.9% to active disease, 3% to adrenal insufficiency and 2.2% to suicide.

“We look forward to the day when our interdisciplinary approach to managing these challenging patients can deliver outcomes similar to the background population,” Limumpornpetch said.

From https://www.healio.com/news/endocrinology/20210322/mortality-rate-in-cushings-syndrome-unacceptably-high

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

Health Alert: Adrenal Crisis Causes Death in Some People Who Were Treated with hGH

Doctors conducting the follow-up study of individuals treated with hGH looked at causes of death among recipients and found some disturbing news. Many more people have died from a treatable condition called adrenal crisis than from CJD (MaryO’Note: Creutzfeldt-Jakob Disease). This risk does not affect every recipient. It can affect those who lack other hormones in addition to growth hormone. Please read on to find out if this risk applies to you. Death from adrenal crisis can be prevented.

Adrenal crisis is a serious condition that can cause death in people who lack the pituitary hormone ACTH. ACTH is responsible for regulating the adrenal gland. Often, people are unaware that they lack this hormone and therefore do not know about their risk of adrenal crisis.

Most people who were treated with hGH did not make enough of their own growth hormone. Some of them lacked growth hormone because they had birth defects, tumors or other diseases that cause the pituitary gland to malfunction or shut down. People with those problems frequently lack other key hormones made by the pituitary gland, such as ACTH, which directs the adrenal gland to make cortisol, a hormone necessary for life. Having too little cortisol can be fatal if not properly treated.

Treatment with hGH does not cause adrenal crisis, but because a number of people lacking growth hormone also lack ACTH, adrenal crisis has occurred in some people who were treated with hGH. In earlier updates we have talked about how adrenal crisis can be prevented, but people continue to die from adrenal crisis, which is brought on by lack of cortisol. These deaths can be prevented. Please talk to your doctor about whether you are at risk for adrenal crisis.

  • Why should people treated with hGH know about adrenal crisis? Among the people who received hGH, those who had birth defects, tumors, and other diseases affecting the brain lacked hGH and often, other hormones made by the pituitary gland. A shortage of the hormones that regulate the adrenal glands can cause many health problems. It can also lead to death from adrenal crisis. This tragedy can be prevented.
  • What are adrenal hormones? The pituitary gland makes many hormones, including growth hormone and ACTH, a hormone which signals the adrenal glands to make cortisol, a hormone needed for life. If the adrenal gland doesn’t make enough cortisol, replacement medications must be taken. The most common medicines used for cortisol replacement are:
    • Hydrocortisone
    • Prednisone
    • Dexamethasone
  • What is adrenal crisis? Adrenal hormones are needed for life. The system that pumps blood through the body cannot work during times of physical stress, such as illness or injury, if there is a severe lack of cortisol (or its replacement). People who lack cortisol must take their cortisol replacement medication on a regular basis, and when they are sick or injured, they must take extra cortisol replacement to prevent adrenal crisis. When there is not enough cortisol, adrenal crisis can occur and may rapidly lead to death.
  • What are the symptoms of lack of adrenal hormones? If you don’t have enough cortisol or its replacement, you may have some of these problems:
    • feeling weak
    • feeling tired all the time
    • feeling sick to your stomach
    • vomiting
    • no appetite
    • weight loss

    When someone with adrenal gland problems has weakness, nausea, or vomiting, that person needs immediate emergency treatment to prevent adrenal crisis and possible death.

  • Why are adrenal hormones so important? Cortisol (or its replacement) helps the body respond to stress from infection, injury, or surgery. The normal adrenal gland responds to serious illness by making up to 10 times more cortisol than it usually makes. It automatically makes as much as the body needs. If you are taking a cortisol replacement drug because your body cannot make these hormones, you must increase the cortisol replacement drugs during times of illness, injury, or surgery. Some people make enough cortisol for times when they feel well, but not enough to meet greater needs when they are ill or injured. Those people might not need cortisol replacement every day but may need to take cortisol replacement medication when their body is under stress. Adrenal crisis is extremely serious and can cause death if not treated promptly. Discuss this problem with your doctor to help decide whether you need more medication or other treatment to protect your health.
  • How is adrenal crisis treated? People with adrenal crisis need immediate treatment. Any delay can cause death. When people with adrenal crisis are vomiting or unconscious and cannot take medicine, the hormones can be given as an injection. Getting an injection of adrenal hormones can save your life if you are in adrenal crisis. If you lack the ability to make cortisol naturally, you should carry a medical ID card and wear a Medic-Alert bracelet to tell emergency workers that you lack adrenal hormones and need treatment. This precaution can save your life if you are sick or injured.
  • How can I prevent adrenal crisis?
    • If you are always tired, feel weak, and have lost weight, ask your doctor if you might have a shortage of adrenal hormones.
    • If you take hydrocortisone, prednisone, or dexamethasone, learn how to increase the dose when you become ill.
    • If you are very ill, especially if you are vomiting and cannot take pills, seek emergency medical care immediately. Make sure you have a hydrocortisone injection with you at all times, and make sure that you and those around you (in case you’re not conscious) know how and when to administer the injection.
    • Carry a medical ID card and wear a bracelet telling emergency workers that you have adrenal insufficiency and need cortisol. This way, they can treat you right away if you are injured.

Remember: Some people who lacked growth hormone may also lack cortisol, a hormone necessary for life. Lack of cortisol can cause adrenal crisis, a preventable condition that can cause death if treated improperly. Deaths from adrenal crisis can be prevented if patients and their families recognize the condition and are careful to treat it right away. Adrenal crisis is a medical emergency. Know the symptoms and how to adjust your medication when you are ill. Taking these precautions can save your life.

From https://www.niddk.nih.gov/health-information/endocrine-diseases/national-hormone-pituitary-program/health-alert-adrenal-crisis-causes-death-people-treated-hgh

Rare Malignant Tumor of Adrenal Gland Led to Cushing’s, Girl’s Death

While adrenocortical carcinoma — a malignant tumor of the adrenal gland — appears only rarely in children, the tumor may cause secondary Cushing’s syndrome in these patients, a new case report shows.

Early diagnosis of the causes of Cushing’s syndrome could improve the prognosis of these children, researchers say.

The study, “Cushing Syndrome Revealing an Adrenocortical Carcinoma,” was published in the Open Journal of Pediatrics.

Adrenocortical carcinoma is a malignant tumor that develops in the cortex of the adrenal gland. It usually is identified by increased amounts of hormones that are produced by the adrenal glands, like cortisol.

This tumor type is very rare in children, representing fewer than two in every 1,000 pediatric tumors.

Researchers at the University Hospital Center Souro Sanou, in Burquina Faso (West Africa), described the case of a 10-year-old girl who developed this rare cancer.

The patient’s first symptoms were loss of consciousness and recurrent seizures without fever. The patient also had experienced excessive weight gain in the preceding months. At admission she was in a light state of coma and showed obesity in the face and trunk.

An initial analysis of blood, urine, and cerebrospinal fluid failed to detect any alterations, with no diabetes, kidney damage, or infection identified. And, even though no lesions or alteration were seen in the pituitary gland region, brain swelling was detected.

While in the hospital, the patient’s condition continued to deteriorate. She developed fever and difficulty speaking, while showing persistent seizures.

In the absence of a diagnosis, physicians focused on the safeguard of major vital function, control of seizures, and administration of large-spectrum antibiotics. Her condition improved slightly, regaining consciousness and control of seizures.

One month later, however, the patient developed symptoms that are commonly associated with increased levels of cortisol and male sex hormones, including obesity and early development of pubic hair.

After confirming high cortisol levels, physicians examined the patient’s abdominal region,  which revealed a tumor in the left adrenal gland.

The patient received a ketoconazole treatment and a surgery to remove the tumor was planned. But her condition worsened, with development of malignant hypertension and convulsive illness, which led to her death before the tumor was removed.

“The delay in the diagnosis and the insufficiency of the therapeutic means darken the prognosis in our context,” the researchers wrote.

“[Adrenocortical carcinoma] diagnosis should be considered in presence of virilization and early signs of puberty,” the researchers suggested. “Early diagnosis and multidisciplinary management of adrenocortical carcinoma could improve the prognosis in children.”

From https://cushingsdiseasenews.com/2018/05/04/rare-malignant-tumor-adrenal-gland-caused-cushings-case-report/

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