Detailed MRI Analysis Provides Correlations with Clinical Features and Response to Treatment in Cushing’s Disease

Posted on April 1, 2018 by MaryO

Detailed imaging analysis of patients with Cushing’s disease (CD) and other disorders caused by pituitary adenomas (tumors that arise from the pituitary, a small gland in the brain) provides correlation with clinical characteristics and treatment response, a new Turkish study reports.

The research, “Clinicopathological significance of baseline T2-weighted signal intensity in functional pituitary adenomas,” appeared in the journal Pituitary.

Diagnosis of pituitary adenomas is often done with magnetic resonance imaging (MRI), which provides data on the tumor’s localization, its invasiveness, as well as cell death and other changes. However, MRI does not enable precise evaluation of the tumor’s hormone production and behavior.

Studies on T2-weighted signal intensity (T2-WSI) — one of the basic parameters in MRI scans that highlights fat and water in the body — shows that it correlates with collagen content, degree of fibrosis (scarring), amyloid protein accumulation, and granulation pattern of somatotroph adenomas, which produce excessive levels of growth hormone, causing acromegaly (a hormonal disorder that results from too much growth hormone in the body).

Evaluation of granulation patterns is key in predicting response to somatostatin analogues (SSAs) treatment, the researchers observed. SSAs are intended to stop excess hormone production.

In contrast, analysis of T2-WSI in corticotroph adenomas — benign tumors typical in Cushing’s disease patients that release elevated levels of adrenocorticotropin (ACTH) – is still lacking.

The research team assessed the correlation of T2-WSI with clinical features, granulation patterns, and response to treatment in patients with functional pituitary adenomas (FPAs), which are collectively characterized by excessive production of one or more hormones.

Specifically, scientists focused on 29 patients with Cushing’s disease, 87 with acromegaly, and 78 with prolactinoma, a type of benign pituitary tumor that produces elevated amounts of prolactin.

Results showed that while most somatotroph adenomas (53%) were hypointense, which means a darker image on MRI, the majority of prolactinomas (55%) and corticotroph adenomas (45%) were at least generally hyperintense, meaning lighter on image.

Data also revealed that hyperintense somatotroph adenomas were larger, sparsely granulated, and exhibited reduced shrinkage after treatment with SSAs.

In contrast, hypointense tumors were associated with higher levels of baseline insulin-like growth factor (IGF)-1% ULN, a predictor of insulin sensitivity, and a better response to SSAs.

In women with prolactinomas, hyperintensity correlated with smaller tumor diameter. In turn, hypointense prolactinomas were linked with younger age at diagnosis, higher baseline prolactin levels, and resistance to treatment with a dopamine agonist.

Scientists also found that hyperintense corticotroph adenomas correlated with larger tumor size and a sparsely granulated pattern. No difference was found between hyper and hypointense adenomas on cortisol and ACTH levels.

Investigators also reported that T2-WSI was not correlated with better surgical outcomes or with recurrent Cushing’s disease. Analysis of tumor shrinkage in these patients was not possible, the researchers noted.

“Although in present there is no immediate clinical application, we believe that if medical shrinkage of corticotrophs ever became a part of clinical practice, similar analyses could be performed in the future,” the researchers wrote.

“Further studies with larger series are required in order to make stronger suggestions,” they added.

From https://cushingsdiseasenews.com/2018/03/23/detailed-mri-analysis-correlates-with-cushings-disease-clinical-features/

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Late-night Salivary Cortisol a Poor Approach for Detecting Cushing’s in Obese Patients

Posted on March 30, 2018 by MaryO

Assessment of late-night salivary cortisol (LNSC) levels is a poor diagnostic tool for detecting Cushing’s disease in obese patients, a new study from Germany shows.

The test demonstrated a particularly poor sensitivity in obese people, meaning it will often suggest a patient has Cushing’s disease when that is not the case — called a false-positive.

The study, “Specificity of late‑night salivary cortisol measured by automated electrochemiluminescence immunoassay for Cushing’s disease in an obese population,” appeared in the Journal of Endocrinological Investigation.

Although excessive weight gain is a common symptom of Cushing’s disease, existing indications advise clinicians to test for Cushing’s in obese people only if the disease is clinically suspected.

The utility of measuring LNSC for Cushing’s disease screening is well established. However, differences in assays, sample collection methods, and controls have led to a great variability in the proposed reference ranges and cut-off values. Also, according to the Endocrine Society, the influence of gender, age, and co-existing medical conditions on LNSC concentrations is still unclear.

Regarding obesity, data on the specificity of assessing late-night salivary cortisol levels is contradictory, as some studies found no differences while others reported lower specificity compared to healthy individuals.

An additional factor complicating LNSC measures in obese people is the prevalence of type 2 diabetes mellitus (T2DM), which may also lead to elevated cortisol levels.

Research showed a high rate of false-positive LNSC measurements in obese patients with poorly controlled type 2 diabetes. Also, in patients with recently diagnosed diabetes, investigators found that LNSC had very low specificity — the proportion of patients with Cushing’s who test positive — and a poor predictive value.

Recent reports showed a high diagnostic accuracy using automated electrochemiluminescent assays (ECLIA) in patients with Cushing’s disease. These methods use special labels conjugated to antibodies that produce light when they bind to a specific target.

The research team used an ECLIA assay to test the specificity of LNSC in obese patients both with and without diabetes. The investigators also intended to establish a reference range and cut-off value for this diagnostic approach.

Adults who requested weight loss treatment were included in the study, including 34 patients with a confirmed diagnosis of Cushing’s and 83 obese people, defined as having a body mass index (BMI) of at least 35 kg/m2. Forty healthy individuals were also analyzed.

Eight out of the 34 Cushing’s patients had a BMI within the obese range, which correlates with an overlap in patients awaiting bariatric surgery for weight loss, the investigators observed.

All subjects underwent LNSC assessment at 11 p.m. Results revealed significant differences in mean LNSC values — 19.9 nmol/L in Cushing’s disease patients, 10.9 nmol/L in obese subjects, and 4.7 nmol/L in those of normal weight.

Compared to healthy and obese participants, measuring LNSC in Cushing’s disease patients had a maximum sensitivity of 67.6% and a specificity of 85.4%. This was lower than prior data from obese patients with two features of Cushing’s disease.

The cut-off value for detecting Cushing’s was 12.3 nmol/L, which is in line with other studies “and underlines the importance of an evaluation with an obese cohort vs. [Cushing’s disease],” the investigators wrote.

Results did not show an association between BMI, type 2 diabetes, and LNSC for all groups.

“In our obese cohort, we found that LNSC assayed by ECLIA had a low specificity in the diagnosis of [Cushing’s disease],” the researchers wrote. “However, the clear advantage of LNSC over other tests is the simple and stress-free sampling method.”

From https://cushingsdiseasenews.com/2018/03/29/nighttime-salivary-cortisol-poor-approach-detect-cushings-disease-obese-patients/

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USC’s 7 Tesla MRI scanner first to identify Cushing’s disease in US patient

Posted on March 24, 2018 by MaryO

A noninvasive 7 Tesla MRI scanner at University of Southern California is the first 7T scanner to be used on a patient with Cushing’s disease in the U.S., according to a USC news release.

When a brain tumor was found to be “MRI-negative” in a 28-year-old female patient, physicians at the USC’s Pituitary Center were unsatisfied with the results. After deciding to use the Neuroimaging and Informatics Institute’s (INI) new ultrahigh field 7 Tesla MRI scanner to localize the tumor, the patient was officially diagnosed with Cushing’s disease and researchers were finally able to [be] see the tumor that would’ve otherwise appeared hidden in a standard MRI.

Cushing’s disease is caused by a pituitary microadenoma, or very small tumor, which results in chronically elevated cortisol. Symptoms include weight gain, skin bruising and hair loss and if left untreated, the condition can be fatal.  Because of this case, USC researchers believe the 7T scanner will be able to replace the standard, and invasive, method of clinical diagnosis, according to the news release.

“It’s clear that this is the beginning of a new frontier for ultrahigh field MR technologies,” said Arthur Toga, PhD, director of the INI, in a prepared statement. “The enhanced image quality opens many doors for neuroscientists in both research and clinical settings.”

From http://www.healthimaging.com/topics/neuroimaging/uscs-7-tesla-mri-scanner-first-identify-cushings-disease-us-patient

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Repeat Checks of Cortisol Levels in Saliva May Improve Use of Metopirone as Cushing’s Treatment

Posted on February 16, 2018 by MaryO

Measuring cortisol levels in saliva multiple times a day is a convenient and useful way to determine the best course of treatment for patients with Cushing’s syndrome, a preliminary study shows.

The research, “Multiple Salivary Cortisol Measurements Are a Useful Tool to Optimize Metyrapone Treatment in Patients with Cushing’s Syndromes Treatment: Case Presentations,” appeared in the journal Frontiers of Endocrinology.

Prompt and effective treatment for hypercortisolism — the excessive amount of cortisol in the blood — is essential to lowering the risk of Cushing’s-associated conditions, including infections, cardiovascular disease, and stroke.

Steroid hormone inhibitors, such as HRA Pharma’s Metopirone (metyrapone), have been used significantly in Cushing’s syndrome patients.

These therapies not only suppress cortisol levels, but also avoid adrenal insufficiency (where not enough cortisol is produced) and restore the circadian rhythm, which is disrupted in Cushing’s patients. However, effective medical treatment requires monitoring cortisol activity throughout the day.

Salivary measurements of cortisol are a well-known method for diagnosing and predicting the risk of recurrence of Cushing’s syndrome. The method is convenient for patients and can be done in outpatient clinics. However, the medical field lacks data on whether measuring cortisol in saliva works for regulating treatment.

Researchers analyzed the effectiveness of salivary cortisol measurements for determining the best dosage and treatment timing of Cushing’s patients with Metopirone.

The study included six patients, three with cortisol-secreting masses in the adrenal glands and and three with ACTH (or adrenocorticotropin)-secreting adenomas in the pituitary glands, taking Metopirone. Investigators collected samples before and during treatment to assess morning serum cortisol and urinary free cortisol (UFC). Patients also had salivary cortisol assessments five times throughout the day.

Saliva samples were collected at 6 a.m. (wake-up time), 8 a.m. (before breakfast), noon (before lunch), 6 p.m. (before dinner), and 10 p.m. (before sleep).

Other studies have used UFC assessments to monitor treatment. However, the inability of this parameter to reflect changes in diurnal cortisol requires alternative approaches.

Results showed that although UFC was normalized in five out of six patients, multiple salivary cortisol measurements showed an impaired diurnal cortisol rhythm in these patients.

Whereas patients with cortisol-secreting adrenocortical adenoma showed elevated cortisol levels throughout the day, those with ACTH-secreting pituitary adenoma revealed increased levels mainly in the morning. This finding indicates that “the significance of elevated morning cortisol levels is different depending on the disease etiology,” the researchers wrote.

In a prospective case study to better assess the effectiveness of performing multiple salivary cortisol assessments, the research team analyzed one of the participants who had excessive cortisol production that was not controlled with four daily doses of Metoripone (a daily total of 2,250 mg).

Results revealed that cortisol levels increased before each dosage. After the patient’s treatment regimen was changed to a 2,500 mg dose divided into five daily administrations, researchers observed a significant improvement in the diurnal cortisol pattern, as well as in UFC levels.

Subsequent analysis revealed that performing multiple salivary cortisol measurements helps with a more precise assessment of excess cortisol than analyzing UFC levels, or performing a unique midnight salivary cortisol collection, the researchers said.

Although more studies are required, the results “suggest that multiple salivary cortisol measurements can be a useful tool to visualize the diurnal cortisol rhythm and to determine the dose and timing of metyrapone [Metopirone] during the treatment in patients with [Cushing’s syndrome],” the researchers wrote.

Future studies should include a larger sample size, evaluate changes over a longer term, use a standardized protocol for treatment dosing and timing, and evaluate changes in a patient’s quality of life, the investigators said.

From https://cushingsdiseasenews.com/2018/02/15/multiple-saliva-cortisol-checks-cushings-metyrapone-study/

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Oral Test for Adult Growth Hormone Deficiency Approved in US

Posted on December 22, 2017 by MaryO

The US Food and Drug Administration (FDA) has approved an orally available ghrelin agonist, macimorelin (Macrilen, Aeterna Zentaris), to be used in the diagnosis of patients with adult growth-hormone deficiency (AGHD).

Macimorelin stimulates the secretion of growth hormone from the pituitary gland into the circulatory system. Stimulated growth-hormone levels are measured in four blood samples over 90 minutes after oral administration of the agent for the assessment of growth-hormone deficiency.

Prior to the approval of macimorelin, the historical gold standard for evaluation of adult growth-hormone deficiency was the insulin tolerance test (ITT), an intravenous test requiring many blood draws over several hours.

The ITT procedure is inconvenient for patients and medical practitioners and is contraindicated in some patients, such as those with coronary heart disease or seizure disorder, because it requires the patient to experience hypoglycemia to obtain an accurate result.

Adult growth-hormone deficiency is a rare disorder characterized by the inadequate secretion of growth hormone from the pituitary gland. It can be hereditary; acquired as a result of trauma, infection, radiation therapy, or brain tumor growth; or can even emerge without a diagnosable cause. Currently, it is treated with once-daily injections of subcutaneous growth hormone.

“Clinical studies have demonstrated that growth-hormone stimulation testing for adult growth-hormone deficiency with oral…macimorelin is reliable, well-tolerated, reproducible, and safe and a much simpler test to conduct than currently available options,” said Kevin Yuen, MD, clinical investigator and neuroendocrinologist, Barrow Neurological Institute, and medical director of the Barrow Neuroendocrinology Clinic, Phoenix, Arizona, in a press release issued by Aeterna Zentaris.

“The availability of…macimorelin will greatly relieve the burden of endocrinologists in reliably and accurately diagnosing adult growth-hormone deficiency,” he added.

Aeterna Zentaris estimates that approximately 60,000 tests for suspected adult growth-hormone deficiency are conducted each year across the United States, Canada, and Europe.

“In the absence of an FDA-approved diagnostic test for adult growth-hormone deficiency, Macrilen fills an important gap and addresses a medical need for a convenient test that will better serve patients and health providers,” said Michael V Ward, chief executive officer, Aeterna Zentaris.

Macrilen is expected to be launched in the United States during the first quarter of 2018.

It is also awaiting approval in the European Union.

Follow Lisa Nainggolan on Twitter: @lisanainggolan1. For more diabetes and endocrinology news, follow us on Twitter and on Facebook.

From https://www.medscape.com/viewarticle/890457

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