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/

The Effect Of Biochemical Remission on Bone Metabolism in Cushing’s Syndrome

Braun LT, Fazel J, Zopp S
Journal of Bone and Mineral Research

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May 22, 2020

This study was attempted to assess bone mineral density and fracture rates in 89 patients with confirmed Cushing’s syndrome at the time of diagnosis and 2 years after successful tumor resection.

Researchers ascertained five bone turnover markers at the time of diagnosis, 1 and 2 years postoperatively. Via chemiluminescent immunoassays, they assessed bone turnover markers osteocalcin, intact procollagen‐IN‐propeptide, alkaline bone phosphatase, CrossLaps, and TrAcP 5b in plasma or serum. For comparison, they studied 71 gender‐, age‐, and BMI‐matched patients in whom Cushing’s syndrome had been excluded.

The outcomes of this research exhibit that the phase immediately after surgical remission from endogenous CS is defined by a high rate of bone turnover resulting in a striking net increase in bone mineral density in the majority of patients.

Read the full article on Journal of Bone and Mineral Research.

Long-Term Obesity Persists Despite Pituitary Adenoma Treatment In Childhood

Sethi A, et al. Clin Endocrinol. 2019;doi:10.1111/CEN.14146.

January 5, 2020

Obesity is common at diagnosis of pituitary adenoma in childhood and may persist despite successful treatment, according to findings published in Clinical Endocrinology.

“The importance of childhood and adolescent obesity on noncommunicable disease in adult life is well recognized, and in this new cohort of patients, we report that obesity is common at presentation of pituitary adenoma in childhood and that successful treatment is not necessarily associated with weight loss,” Aashish Sethi, MD, MBBS, a pediatric endocrinologist in the department of endocrinology at Alder Hey Children’s Hospital in Liverpool, United Kingdom, and colleagues wrote. “We have reported obesity, and obesity-related morbidity in a mixed cohort of children and young adults previously, but [to] our knowledge, this is the first time this observation has been reported in a purely pediatric cohort.”

In a retrospective study, Sethi and colleagues analyzed clinical and radiological data from 24 white children from Alder Hey Children’s Hospital followed for a median of 3.3 years between 2000 and 2019 (17 girls; mean age at diagnosis, 15 years). Researchers assessed treatment modality (medical, surgical or radiation therapy), pituitary hormone deficiencies and BMI, as well as results of any genetic testing.

Within the cohort, 13 girls had prolactinomas (mean age, 15 years), including 10 macroadenomas between 11 mm and 35 mm in size. Children presented with menstrual disorders (91%), headache (46%), galactorrhea (46%) and obesity (38%). Nine children were treated with cabergoline alone, three also required surgery, and two were treated with the dopamine agonist cabergoline, surgery and radiotherapy.

Five children had Cushing’s disease (mean age, 14 years; two girls), including one macroadenoma. Those with Cushing’s disease presented with obesity (100%), short stature (60%) and headache (40%). Transsphenoidal resection resulted in biochemical cure; however, two patients experienced relapse 3 and 6 years after surgery, respectively, requiring radiotherapy. One patient also required bilateral adrenalectomy.

Six children had a nonfunctioning pituitary adenoma (mean age, 16 years; two girls), including two macroadenomas. These children presented with obesity (67%), visual field defects (50%) and headache (50%). Four required surgical resections, with two experiencing disease recurrence after surgery and requiring radiotherapy.

During the most recent follow-up exam, 13 children (54.1%) had obesity, including 11 who had obesity at diagnosis.

“The persistence of obesity following successful treatment, in patients with normal pituitary function, suggests that mechanisms other than pituitary hormone excess or deficiency may be important,” the researchers wrote. “It further signifies that obesity should be a part of active management in cases of pituitary adenoma from diagnosis.” – by Regina Schaffer

Disclosures: The authors report no relevant financial disclosures.

From https://www.healio.com/endocrinology/adrenal/news/online/%7Bde3fd83b-e8e0-4bea-a6c2-99eb896356ab%7D/long-term-obesity-persists-despite-pituitary-adenoma-treatment-in-childhood

BIPSS Diagnostic Method May Cause False Positive in Some Cases of Cyclic Cushing’s Syndrome

A diagnostic technique called bilateral inferior petrosal sinus sampling (BIPSS), which measures the levels of the adrenocorticotropic hormone (ACTH) produced by the pituitary gland, should only be used to diagnose cyclic Cushing’s syndrome patients during periods of cortisol excess, a case report shows.

When it is used during a spontaneous remission period of cycling Cushing’s syndrome, this kind of sampling can lead to false results, the researchers found.

The study, “A pitfall of bilateral inferior petrosal sinus sampling in cyclic Cushing’s syndrome,” was published in BMC Endocrine Disorders.

Cushing’s syndrome is caused by abnormally high levels of the hormone cortisol. This is most often the result of a tumor on the pituitary gland that produces too much ACTH, which tells the adrenal glands to increase cortisol secretion.

However, the disease may also occur due to adrenal tumors or tumors elsewhere in the body that also produce excess ACTH — referred to as ectopic Cushing’s syndrome.

Because treatment strategies differ, doctors need to determine the root cause of the condition before deciding which treatment to choose.

BIPSS can be useful in this regard. It is considered a gold standard diagnostic tool to determine whether ACTH is being produced and released by the pituitary gland or by an ectopic tumor.

However, in people with cycling Cushing’s syndrome, this technique might not be foolproof.

Researchers reported the case of a 43-year-old woman who had rapidly cycling Cushing’s syndrome, meaning she had periods of excess cortisol with Cushing’s syndrome symptoms — low potassium, high blood pressure, and weight gain — followed by normal cortisol levels where symptoms resolved spontaneously.

In general, the length of each period can vary anywhere from a few hours to several months; in the case of this woman, they alternated relatively rapidly — over the course of weeks.

After conducting a series of blood tests and physical exams, researchers suspected of Cushing’s syndrome caused by an ACTH-producing tumor.

The patient eventually was diagnosed with ectopic Cushing’s disease, but a BIPSS sampling performed during a spontaneous remission period led to an initial false diagnosis of pituitary Cushing’s. As a result, the woman underwent an unnecessary exploratory pituitary surgery that revealed no tumor on the pituitary.

Additional imaging studies then identified a few metastatic lesions, some of which were removed surgically, as the likely source of ACTH. However, the primary tumor still hasn’t been definitively identified. At the time of publication, the patient was still being treated for Cushing’s-related symptoms and receiving chemotherapy.

There is still a question of why the initial BIPSS result was a false positive. The researchers think that the likely explanation is that BIPSS was performed during an “off phase,” when cortisol levels were comparatively low. In fact, a later BIPSS performed during a period of high cortisol levels showed no evidence of ACTH excess in the pituitary.

This case “demonstrates the importance of performing diagnostic tests only during the phases of active cortisol secretion, as soon as first symptoms appear,” the researchers concluded.

From https://cushingsdiseasenews.com/2020/01/02/cushings-syndrome-case-study-shows-drawback-in-bipss-method/

Cushing’s Disease—Monthly Injection Is Good Alternative to Surgery

Written by Kathleen Doheny with Maria Fleseriu, MD, FACE, and Vivien Herman-Bonert, MD

Cushing’s disease, an uncommon but hard to treat endocrine disorder, occurs when a tumor on the pituitary gland, called an adenoma—that is almost always benign—leads to an overproduction of ACTH (adrenocorticotropic hormone), which is responsible for stimulating the release of cortisol, also known as the stress hormone.

Until now, surgery to remove the non-cancerous but problematic tumor has been the only effective treatment. Still, many patients will require medication to help control their serum cortisol levels, and others cannot have surgery or would prefer to avoid it.

Finally, a drug proves effective as added on or alternative to surgery in managing Cushing’s disease. Photo; 123rf

New Drug Offers Alternative to Surgery for Cushing’s Disease

Now, there is good news about long-term positive results achieved with pasireotide (Signifor)—the first medication to demonstrate effectiveness in both normalizing serum cortisol levels and either shrinking or slowing growth of tumors over the long term.1,2  These findings appear in the journal, Clinical Endocrinology, showing that patients followed for 36 months as part of an ongoing study had improved patient outcomes for Cushing’s disease.2

“What we knew before this extension study was—the drug will work in approximately half of the patients with mild Cushing’s disease,” says study author Maria Fleseriu, MD, FACE, director of the Northwest Pituitary Center and professor of neurological surgery and medicine in the division of endocrinology, diabetes and clinical nutrition at the Oregon Health and Sciences University School of Medicine.

“Pasireotide also offers good clinical benefits,” says Dr. Fleseriu who is also the president of the Pituitary Society, “which includes improvements in blood pressure, other signs and symptoms of Cushing’s symptom], and quality of life.”2

What Symptoms Are Helped by Drug for Cushing’s Disease?  

Among the signs and symptoms of Cushing’s disease that are lessened with treatment are:3

  • Changes in physical appearance such as wide, purple stretch marks on the skin (eg, chest, armpits, abdomen, thighs)
  • Rapid and unexplained weight gain
  • A more full, rounder face
  • Protruding abdomen from fat deposits
  • Increased fat deposits around the neck area

The accumulation of adipose tissue raises the risk of heart disease, which adds to the urgency of effective treatment. In addition, many individuals who have Cushing’s disease also complain of quality of life issues such as fatigue, depression, mood and behavioral problems, as well as poor memory.2

As good as the results appear following the longer term use of pasireotide,2 Dr. Fleseriu admits that in any extension study in which patients are asked to continue on, there are some built-in limitations, which may influence the findings. For example, patients who agree to stay on do so because they are good responders, meaning they feel better, so they’re happy to stick with the study.

“Fortunately, for the patients who have responded to pasireotide initially, this is a drug that can be  continued as there are no new safety signals with longer use,” Dr. Fleseriu tells EndocrineWeb, “and when the response at the start is good, very few patients will lose control of their urinary free cortisol over time. That’s a frequent marker used to monitor patient’s status. For those patients with large tumors, almost half of them had a significant shrinkage, and all the others had a stable tumor size.”

What Are the Reasons to Consider Drug Treatment to Manage Cushing’s Symptoms

The extension study ”was important because we didn’t have any long-term data regarding patient response to this once-a-month treatment to manage Cushing’s disease,” she says.

While selective surgical removal of the tumor is the preferred treatment choice, the success rate in patients varies, and Cushing’s symptoms persist in up to 35% of patients after surgery. In addition, recurrent rates (ie, return of disease) range from 13% to 66% after individuals experience different durations remaining in remission.1

Therefore, the availability of an effective, long-lasting drug will change the course of therapy for many patients with Cushing’s disease going forward. Not only will pasireotide benefit patients who have persistent and recurrent disease after undergoing surgery, but also this medication will be beneficial for those who are not candidates for surgery or just wish to avoid having this procedure, he said.

Examining the Safety and Tolerability of Pasireotide  

This long-acting therapy, pasireotide, which is given by injection, was approved in the US after reviewing results of a 12-month Phase 3 trial.1  In the initial study, participants had a confirmed pituitary cause of the Cushing’s disease. After that, the researchers added the optional 12-month open-label, extension study, and now patients can continue on in a separate long-term safety study.

Those eligible for the 12-month extension had to have mean urinary free cortisol not exceeding the upper limit of normal (166.5 nanomoles per 24 hour) and/or be considered by the investigator to be getting substantial clinical benefit from treatment with long-action pasireotide, and to demonstrate tolerability of pasireotide during the core study.1

Of the 150 in the initial trial, 81 participants, or 54% of the patients, entered the extension study. Of those, 39 completed the next phase, and most also enrolled in another long-term safety study—these results not yet available).2

During the core study, 1 participants were randomly assigned to 10 or 30 mg of the drug every 28 days, with doses based on effectiveness and tolerability. When they entered the extension, patients were given the same dose they received at month.1,2

Study Outcomes Offer Advantages in Cushing’s Disease

Of those who received 36 months of treatment with pasireotide, nearly three in four (72.2%) had controlled levels of urinary free cortisol at this time point.2 Equally good news for this drug was that tumors either shrank or did not grow. Of those individuals who started the trial with a measurable tumor (adenoma) as well as those with an adenoma at the two year mark (35 people), 85.7% of them experienced a reduction of 20% or more or less than a 20% change in tumor volume. No  macroadenomas present at the start of the study showed a change of more than 20% at either month 24 or 36.2

Improvements in blood pressure, body mass index (BMI) and waist circumference continued throughout the extension study.1  Those factors influence CVD risk, the leading cause of death in those with Cushing’s.4

As for adverse events, most of the study participants, 91.4%, did report one or more complaint during the extension study—most commonly, it was high blood sugar, which was reported by nearly 40% of participants.2. This is not surprising when you consider that most (81.5%) of the individuals participating in the extension trial entered with a diagnosis of diabetes or use of antidiabetic medication, and even more of them (88.9%) had diabetes at the last evaluation.1  

This complication indicates the need for people with Cushing’s disease to check their blood glucose, as appropriate.

Do You Have Cushing’s Disese [sic]? Here’s What You Need to Know 

Women typically develop Cushing’s disease more often than men.

What else should you be aware of if you and your doctor decide this medication will help you? Monitoring is crucial, says Dr. Fleseriu, as you will need to have your cortisol levels checked, and you should be on alert for any diabetes signals, which will require close monitoring and regular follow-up for disease management.

Another understanding gained from the results of this drug study: “This medication works on the tumor level,” she says. “If the patient has a macroadenoma (large tumor), this would be the preferred treatment.” However, it should be used with caution in those with diabetes given the increased risk of experiencing high blood sugar.

The researchers conclude that “the long-term safety profile of pasireotide was very favorable and consistent with that reported during the first 12 months of treatment. These data support the use of long-acting pasireotide as an effective long-term treatment option for some patients with Cushing’s Disease.”1

Understanding Benefits of New Drug to Treat Cushing’s Diseease [sic]

Vivien S. Herman-Bonert, MD, an endocrinologist and clinical director of the Pituitary Center at Cedars-Sinai Medical Center in Los Angeles, agreed to discuss the study findings, after agreeing to review the research for EndocrineWeb.

As to who might benefit most from monthly pasireotide injections? Dr. Herman-Bonert says, “any patient with Cushing’s disease that requires long-term medical therapy, which includes patients with persistent or recurrent disease after surgery.” Certainly, anyone who has had poor response to any other medical therapies for Cushing’s disease either because they didn’t work well enough or because the side effects were too much, will likely benefit a well, she adds.

Among the pluses that came out of the study, she says, is that nearly half of the patients had controlled average urinary free cortisol levels after two full years, and 72% of the participants who continued on with the drug for 36 months were able to remain in good urinary cortisol control .1

As the authors stated, tumor shrinkage was another clear benefit of taking long-term pasireotide. That makes the drug a potentially good choice for those even with large tumors or with progressive tumor growth, she says. It’s always good for anyone with Cushing’s disease to have an alterative [sic] to surgery, or a back-up option when surgery isn’t quite enough, says Dr. Herman-Bonert.

The best news for patients is that quality of life scores improved,she adds.

Dr Herman-Bonert did add a note of caution: Although the treatment in this study is described as ”long-term, patients will need to be on this for far longer than 2 to 3 years,” she says. So, the data reported in this study may or may not persist, and we don’t yet know what the impact will be 10 or 25 years out.

Also, the issue of hyperglycemia-related adverse events raises a concern, given the vast majority (81%) of patients who have both Cushing’s disease and diabetes. Most of those taking this drug had a dual diagnosis—having diabetes, a history of diabetes, or taking antidiabetic medicine.

If you are under care for diabetes and you require treatment for Cushing’s disease, you must be ver mindful that taking pasireotide will likely lead to high blood sugar spikes, so you should plan to address this with your healthcare provider.

 

Dr. Fleseriu reports research support paid to Oregon Health & Science University from Novartis and other 0companies and consultancy fees from Novartis and Strongbridge Biopharma. Dr. Herman-Bonert has no relevant disclosures.

The study was underwritten by Novartis Pharma AG, the drug maker. 

From https://www.endocrineweb.com/news/pituitary-disorders/62449-cushings-disease-monthly-injection-good-alternative-surgery

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