Post-Operative Cushing Syndrome Care

Posted on January 22, 2022 by MaryO

Justine Herndon, PA-C, and Irina Bancos, MD, on Post-Operative Cushing Syndrome Care

– Curative procedures led to widespread resolution or improvement of hyperglycemia

by Scott Harris , Contributing Writer, MedPage Today January 18, 2022

In a recent study, two-thirds of people with Cushing syndrome (CS) saw resolved or improved hyperglycemia after a curative procedure, with close post-operative monitoring an important component of the process.

Among 174 patients with CS included in the longitudinal cohort study (pituitary in 106, ectopic in 25, adrenal in 43), median baseline HbA1c was 6.9%. Of these, 41 patients were not on any therapy for hyperglycemia, 93 (52%) took oral medications, and 64 (37%) were on insulin.

At the end of the period following CS remission (median 10.5 months), 37 (21%) patients had resolution of hyperglycemia, 82 (47%) demonstrated improvement, and 55 (32%) had no change or worsened hyperglycemia. Also at the end of follow-up, HbA1c had fallen 0.84% (P<0.0001), with daily insulin dose decreasing by a mean of 30 units (P<0.0001).

Justine Herndon, PA-C, and Irina Bancos, MD, both endocrinology researchers with Mayo Clinic in Minnesota, served as co-authors of the report, which was published in the Journal of the Endocrine Society. Here they discuss the study and its findings with MedPage Today. The exchange has been edited for length and clarity.

What was the study’s main objective?

Herndon: As both a hospital diabetes provider and clinic pituitary/gonadal/adrenal provider, I often hear questions from colleagues about how to manage a patient’s diabetes post-operatively after cure from CS. While clinical experience has been helpful in guiding these discussions, the literature offered a paucity of data on diabetes/hyperglycemia specifically after surgery. There was also a lack of data on specific subgroups of CS, whether by sub-type or severity.

Therefore, we felt it was important to see what our past patient experiences showed in terms of changes in laboratory data, medications, and which patients were more likely to see improvement in their diabetes/hyperglycemia. The overall goal was to help clinicians provide appropriate patient education and care following a curative procedure.

In addition to its primary findings, the study also identified several factors associated with resolution or improvement of hyperglycemia. What were these factors?

Bancos: Both clinical and biochemical severity of CS, as well as Cushing subtype, were associated with improvement. We calculated severity based on symptoms and presence of comorbidities, and we calculated biochemical severity based on hormonal measurements. As clinical and biochemical scores were strongly correlated, we chose only one (biochemical) for multivariable analysis.

In the multivariable analysis of biochemical severity of Cushing, subtype of Cushing, and subtype of hyperglycemia, we found that patients with a severe biochemical severity score were 2.4 fold more likely to see improved hyperglycemia than people with a moderate or mild severity score (OR 2.4 (95% CI 1.1-4.9). We also found that patients with the nonadrenal CS subtype were 2.9 fold more likely to see improved hyperglycemia when compared to people with adrenal CS (OR of 2.9 (95% CI 1.3-6.4).

The type of hyperglycemia (diabetes versus prediabetes) was not found to be significant.

Did anything surprise you about the study results?

Herndon: I was surprised to see improvement in hyperglycemia in patients who were still on steroids, as you would expect the steroids to still have an impact. This shows how much a CS curative procedure truly leads to changes in the comorbidities that were a result of the underlying disease.

Also, I was surprised that the type of hyperglycemia was not a predictor of improvement after cure, although it was quite close. We also had a few patients whose hyperglycemia worsened, and we could not find a specific factor that predicted which patients did not improve.

What are the study’s implications for clinicians who treat people with CS?

Bancos: We think our study shows the clear need for closer follow-up — more frequently than the typical three-to-six months for diabetes. This can be accomplished through review of more than just HbA1c, such as reviewing blood glucose logbooks, asking about hypoglycemia symptoms, and so forth.

Patients with severe CS who are being treated with insulin or hypoglycemic medications are especially likely to decrease their medications to avoid hypoglycemia during postoperative period.

Read the study here.

Bancos reported advisory board participation and/or consulting with Strongbridge, Sparrow Pharmaceutics, Adrenas Therapeutics, and HRA Pharma outside the submitted work. Herndon did not disclose any relevant financial relationships with industry.

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Curative Treatment on Hyperglycemia in Cushing Syndrome

Posted on December 28, 2021 by MaryO

A retrospective analysis of data from more than 170 patients with Cushing syndrome and hyperglycemia provides insight into the effects of curative treatment on hyperglycemia among these patients.

An analysis of retrospective data from a 20-year period details the impact of curative treatment on hyperglycemia among patients with Cushing syndrome.

Led by a team of investigators from the Mayo Clinic in Rochester, MN, the study examined a cohort of 174 adult patients with Cushing Syndrome and determined 2-in-3 patients with hyperglycemia experienced resolution or improvement of hyperglycemia after a curative procedure.

“This is the first study to analyze the quantitative changes based on the time from the curative surgery, to assess the changes in the intensity of hyperglycemia therapy and identify predictors for hyperglycemia improvement,” wrote investigators.

A team led by Irina Bancos, MD, endocrinologist at the Mayo Clinic Rochester, designed the current study with an interest in examining the impact of curative procedures on hyperglycemia and its management in patients with Cushing syndrome from electronic medical record data of patients treated at a referral center from 2000-2019. The primary purpose of the study was to assess the impact of curative procedures on extent of hyperglycemia and the secondary aim was to investigators how baseline factors might influence improvement of hyperglycemia at follow-up.

For inclusion in the analysis, patients needed to be at least 18 years of age, diagnosed with Cushing syndrome, and have hyperglycemia treated with a curative procedure from January 1, 2000-November 1, 2019. For the purpose of analysis, Cushing syndrome was diagnosed based on clinical evaluation by an endocrinologist and diagnosed according to the most recent guidelines. Hyperglycemia was defined according to American Diabetes Association guidelines.

The primary outcome of interest for the study was the resolution of hyperglycemia following resolution of Cushing syndrome. For the purpose of analysis, resolution was defined as absence of hyperglycemia without the need for antihyperglycemic therapy. Secondary outcomes of interest included changes in HbA1c, and the intensity of hyperglycemia management.

Overall, 174 patients were identified for inclusion in the study. This cohort had a median age of diagnosis of 51 (range, 16-82) years and 73% (n=127) were women. When assessing subtype of Cushing syndrome, the most common form was pituitary Cushing syndrome (60.9%), followed by ectopic (14.4%), and adrenal (24.7%). The median baseline HbA1c was 6.9% (range, 4.9-13.1), 24% of patients were not on any therapy for hyperglycemia, 52% were on oral medications, and 37% were on insulin (mean daily units, 58; range, 10-360).

When assessing differences between subtypes, results indicated those with pituitary Cushing syndrome were younger at the time of surgery (P=.0009), and included more women (P=.0023), and reported a longer duration of symptoms prior to diagnosis. Investigators noted patients with pituitary Cushing syndrome also had the highest clinical severity score (P <.0001), but patients with ectopic Cushing syndrome had the highest biochemical severity score (P <.0001).

Following Cushing syndrome remission and at the end of follow-up, which occurred at a median of 10.5 months, 21% of patients demonstrated resolution of hyperglycemia, 47% demonstrated improvement, and 32% had no change or worsening hyperglycemia. When assessing secondary end points, results indicate HbA1c decreased by 0.84% (P <.0001) and daily insulin dose decreased by a mean of 30 units (P <.0001). Further analysis indicated hypercortisolism severity score (severe vs moderate/mild: OR, 2.4; 95% CI, 1.1-4.9) and Cushing syndrome subtype (nonadrenal vs adrenal: OR, 2.9; 95% CI, 1.3-6.4) were associated with hyperglycemia improvement, but not type of hyperglycemia (diabetes vs prediabetes: OR, 2,1; 95% CI, 0.9-4.9) at the end of follow-up.

“We demonstrated that almost 70% of patients with CS demonstrate either resolution or improvement in hyperglycemia following CS remission. As a group, patients demonstrate a decrease in HbA1c, and can be treated with less insulin and fewer non-insulin agents. Patients with more severe hyperglycemia, ACTH-dependent CS, and more severe CS are more likely to improve after surgery,” added investigators.

This study, “The impact of curative treatment on hyperglycemia in patients with Cushing syndrome,” was published in The Journal of the Endocrine Society.

From https://www.endocrinologynetwork.com/view/obesity-overweight-responsible-for-1-in-5-future-thyroid-cancers-in-australia

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What Causes Blood Sugar to Rise in Non-Diabetics?

Posted on May 26, 2021 by MaryO

High blood sugar or glucose, also called hyperglycemia, occurs when there is too much sugar in the blood. High blood sugar is the primary symptom that underlies diabetes, but it can also occur in people who don’t have type 1 or type 2 diabetes, either because of stress or trauma, or gradually as a result of certain chronic conditions.

It is important to manage high blood sugar, even if you don’t have diabetes, because elevated blood glucose can delay your ability to heal, increase your risk of infections, and cause irreversible damage to your nerves, blood vessels, and organs, such as your eyes and kidneys. Blood vessel damage from high blood sugar also increases your risk of heart attack and stroke.

Non-Diabetic Hyperglycemia and Prediabetes

You are considered to have impaired glucose tolerance or prediabetes if you have a fasting glucose level between 100–125 mg/dL, and hyperglycemia if your fasting blood glucose level is greater than 125 mg/dL, or greater than 180 mg/dL one to two hours after eating.

The body obtains glucose mainly through carbohydrate consumption, but also through the breakdown of glycogen to glucose—a process called glycogenolysis—or conversion of non-carbohydrate sources to glucose—called gluconeogenesis—that primarily occurs in the liver.

While 50% to 80% of glucose is used by the brain, kidneys, and red blood cells for energy, the remaining supply of glucose is used to produce energy. It is stored as glycogen in the liver and muscles, and can be tapped into at a later time for energy or converted into fat tissue.

In healthy people, blood glucose levels are regulated by the hormone insulin to stay at a steady level of 80–100 mg/dL. Insulin maintains steady blood sugar by increasing the uptake and storage of glucose and decreasing inflammatory proteins that raise blood sugar when there is an excess of glucose in the blood.

Certain conditions can increase your blood glucose levels by impairing the ability of insulin to transport glucose out of the bloodstream. When this occurs, you develop hyperglycemia, which puts you at an increased risk of prediabetes, diabetes, and related complications.

Common Causes

Cushing’s Syndrome

Cushing’s syndrome results from excess secretion of the adrenocorticotropic hormone, a hormone produced in the anterior portion of the pituitary gland that causes excess cortisol to be produced and released from the adrenal glands. Pituitary adenomas, or tumors of the pituitary gland, are the cause of Cushing’s syndrome in more than 70% of cases, while prolonged use of corticosteroid medication can also significantly increase the risk.

People with Cushing’s syndrome are at an increased risk of developing impaired glucose tolerance and hyperglycemia as a result of increased levels of cortisol throughout the body. Cortisol is a hormone that counteracts the effects of insulin by blocking the uptake of glucose from the bloodstream, thereby increasing insulin resistance and maintaining high blood sugar levels. Elevated cortisol levels also partially decrease the release of insulin from where it is produced in the pancreas.

Approximately 10% to 30% of people with Cushing’s syndrome will develop impaired glucose tolerance, while 40% to 45% will develop diabetes.

Corticosteroid medication is often prescribed to decrease inflammation throughout the body, but can lead to the development of Cushing’s syndrome and hyperglycemia because it activates specific enzymes that increase the conversion of non-carbohydrate molecules into glucose (gluconeogenesis). Corticosteroids also disrupt pancreatic cell function by inhibiting cell signaling pathways involved in the release of insulin from the pancreas.

Read other causes at https://www.verywellhealth.com/causes-blood-sugar-rise-in-non-diabetics-5120349

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Long-acting Signifor Has Similar Safety Profiles as Twice-daily Treatment in Cushing’s Patients, Trial Showed

Posted on November 11, 2017 by MaryO

A long-acting, once-a-month treatment of Signifor (pasireotide) normalized cortisol levels in 40% of patients with Cushing’s disease whose disease had recurred after surgery, or who were not candidates for surgery, according to new data from a Phase 3 trial.

The safety profiles of the once-monthly regimen proved to be similar to standard twice-daily Signifor treatments, researchers found.

The study, “Efficacy and safety of once-monthly pasireotide in Cushing’s disease: a 12 month clinical trial,” was published in the journal The Lancet Diabetes & Endocrinology.

Novartis‘ Signifor in its twice-daily injection formulation has already been approved for treating Cushing’s in the U.S. and elsewhere.

The 12-month, Phase 3 trial (NCT01374906) was conducted at 57 sites in 19 countries. The study included 150 patients with Cushing’s whose cortisol levels had risen or not dropped at all after surgery, or who were unable to undergo surgery.

Between Dec. 28, 2011, and Dec. 9, 2014, participants were randomized to receive either 10 mg or 30 mg of Signifor every four weeks, via an injection to the muscle. If, after four months of therapy, cortisol urinary levels (mUFC) were 50% greater than the upper normal limit, the dose could be increased from 10 mg to 30 mg, or from 30 mg to 40 mg. It could also be increased after seven, nine, or 12 months if the mUFC concentration was greater than normal.

The goal was to normalize average concentrations of free cortisol in the urine to less than or equal to the upper normal limit at month seven. It was met by 31 of the 74 patients in the 10 mg group (41.9%) and 31 of the 76 patients in the 30 mg group (40.8%).

The most common adverse events were hyperglycemia (high concentration of blood sugar), diarrhea, cholelithiasis (gall stones), diabetes, and nausea.

The researchers consider this treatment to be a good option for patients whose disease has returned after surgery, or who cannot undergo surgery. The long-lasting treatment schedule of one injection per month is more convenient for patients than the twice-daily subcutaneous injection, making it more likely that they would not discontinue treatment.

“Surgical resection of the causative pituitary adenoma is the first-line treatment of choice for most patients with Cushing’s disease, which leads to remission in greater than 75% of patients if done by an expert pituitary surgeon,” wrote Dr. Andre Lacroix, MD, a professor in the Department of Medicine at the University of Montreal teaching hospital, and colleagues.

“However, surgery is not always successful, and disease recurrence can occur several years after initial remission, while some patients refuse or are not candidates for surgery. As a result, many patients require additional treatment options.”

“Long-acting pasireotide normalized mUFC concentration in about 40% of patients with Cushing’s disease at month 7 and had a similar safety profile to that of twice-daily subcutaneous pasireotide,” the team wrote in the study.

“Long-acting pasireotide is an efficacious treatment option for some patients with Cushing’s disease who have persistent or recurrent disease after initial surgery or are not surgical candidates, and provides a convenient monthly administration schedule,” researchers concluded.

From https://cushingsdiseasenews.com/2017/10/31/long-acting-signifor-for-cushings-disease-has-similar-efficacy-and-safety-as-twice-daily-treatment/

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Silibinin from milk thistle seeds as novel, non-invasive treatment strategy for Cushing Disease

Posted on June 4, 2015 by MaryO
Silibinin has an outstanding safety profile in humans and is currently used for the treatment of liver disease and poisoning. Scientists at the Max Planck Institute of Psychiatry in Munich discovered in collaboration with scientists from the Helmholtz Zentrum München in cell cultures, animal models and human tumor tissue that silibinin can be applied to treat Cushing Disease, a rare hormone condition caused by a tumor in the pituitary gland in the brain. The researchers have filed a patent and now plan clinical trials using silibinin as a non-invasive treatment strategy. Thus, in future, patients might not have to undergo brain surgery anymore.
Treatment with silibinin, a constituent of milk thistle seeds, alleviated symptoms of Cushing Disease in cell cultures, animal models and human tumor tissue. In future, patients might not have to undergo brain surgery anymore.

Cushing Disease, not to be confused with Cushing’s Syndrome, is caused by a tumor in the pituitary gland in the brain. The tumor secrets increased amounts of the stress hormone adrenocorticotropin (ACTH) followed by cortisol release from the adrenal glands leading to rapid weight gain, elevated blood pressure and muscular weakness. Patients are prone to osteoporosis and infections and may show cognitive dysfunction or even depression. In 80 to 85 % of the patients, the tumor can be removed by uncomfortable brain surgery. For inoperable cases, there is currently only one targeted therapy approved, which unfortunately causes intense side effects such as hyperglycemia in more than 20 % of the patients.

Scientists around Günter Stalla, endocrinologist at the Max Planck Institute of Psychiatry in Munich, have now discovered in cell cultures, animal models and human tumor tissue that a harmless plant extract can be applied to treat Cushing Disease. “Silibinin is the major active constituent of milk thistle seeds. It has an outstanding safety profile in humans and is already used for the treatment of liver disease and poisoning,” explains Marcelo Paez-Pereda, leading scientist of the current study published in the renowned scientific journal Nature Medicine. After silibinin treatment, tumor cells resumed normal ACTH production, tumor growth slowed down and symptoms of Cushing Disease disappeared in mice.

In 2013, the Max Planck scientists filed a patent on a broad family of chemical and natural compounds, including silibinin, to treat pituitary tumors. Compared to humans, where only 5.5 in 100,000 people worldwide develop Cushing Disease, this condition is very common in several pets. For example, 4 % of dogs and even 7 % of horses suffer from Cushing Disease. Thus, the researchers now plan to test special formulations with a very pure substance and slow release of the active component silibinin in clinical trials.

Silibinin: Mode of action

“We knew that Cushing Disease is caused by the release of too much ACTH. So we asked ourselves what causes this over production and how to stop it,” says Paez-Pereda. In their first experiments, the researchers found tremendously high amounts of the heat shock protein 90 (HSP90) in tumor tissue from patients with Cushing Disease. In normal amounts, HSP90 helps to correctly fold another protein, the glucocorticoid receptor, which in turn inhibits the production of ACTH. “As there are too many HSP90 molecules in the tumor tissue, they stick to the glucocorticoid receptor,” explains Paez-Pereda. “We found that silibinin binds to HSP90 thus allowing glucocorticoid receptor molecules to dissolve from HSP90. With silibinin, we might have discovered a non-invasive treatment strategy not only for the rare Cushing Disease but also for other conditions with the involvement of glucocorticoid receptors, such as lung tumors, acute lymphoblastic leukemia or multiple myeloma,” concludes Paez-Pereda.

From http://www.psych.mpg.de/2034377/PM1507

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