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

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.


Late-night salivary cortisol often fluctuates widely in Cushing’s disease

Among patients with new, persistent or recurrent Cushing’s disease, researchers observed cortisol levels that fluctuated widely over 6 months, with measurements falling into the normal range more than 50% of the time for a few patients, according to findings from a prospective study.

“Cortisol levels, as represented by late-night salivary cortisol, in Cushing’s disease patients without variable symptoms fluctuate much more widely than many endocrinologists may realize,” Laurence Kennedy, MD, FRCP, chairman of the department of endocrinology, diabetes and metabolism at the Cleveland Clinic, told Endocrine Today. “In patients with recurrent or persistent Cushing’s disease, the late-night salivary cortisol can be normal much more frequently than has been appreciated.”

Kennedy and colleagues analyzed late-night salivary samples (between 11 p.m. and midnight) from 16 patients with confirmed Cushing’s disease for up to 42 consecutive nights between January and June 2014 (age range, 27-62 years). Researchers defined normal late-night salivary cortisol as between 29 ng/dL and 101 ng/dL.

Within the cohort, eight patients had a new diagnosis of Cushing’s disease and underwent transsphenoidal surgery; eight patients had recurrent or persistent Cushing’s disease.

Researchers observed at least three peaks and two troughs in 12 of the 16 patients, and late-night salivary cortisol levels were in the normal range on at least one occasion in 14 patients (all patients with recurrent/persistent disease and six of eight patients with new disease). Only two of the 16 patients exhibited fluctuations that were deemed cyclical, according to researchers, with the interval between peaks approximately 4 days, they noted.

In five of the eight patients with recurrent or persistent disease, the lowest late-night salivary cortisol measurement was at or below the limit of detection on the assay and approximately 1 in 3 measurements were in the normal range, researchers found. Four patients had normal measurements more than 50% of the time.

Additionally, six of the patients with recurrent or persistent disease had measurements in the normal range on two consecutive nights on at least one occasion, two patients had six such measurements in a row, and one had 31 consecutive normal levels, according to researchers.

In six patients with newly diagnosed Cushing’s disease with at least one normal late-night salivary cortisol measurement, the maximum levels ranged from 1.55 to 15.5 times the upper limit of normal.

“First, widely fluctuant cortisol levels in patients with Cushing disease do not appear to be associated with fluctuating symptoms, at least in our patient population,” Kennedy said. “Second, you need to be careful drawing conclusions on the efficacy of potential medical treatments for Cushing’s disease based on only one or two late-night salivary cortisol levels, given the extreme variation that occurs in the untreated patient. Third, diagnosing recurrent or persistent Cushing’s disease can be challenging at the best of times, and, though it is felt that late-night salivary cortisol may be the best test for early diagnosis, it may require more than the suggested two, three or four tests on successive nights to make the diagnosis.”

Kennedy said better tests for diagnosing Cushing’s disease are needed, adding that investigating the potential utility of salivary cortisone could be useful. – by Regina Schaffer

For more information:

Lawrence Kennedy, MD, can be reached at Cleveland Clinic, Department of Endocrinology, Diabetes and Metabolism, 9500 Euclid Ave., Cleveland, OH 44195; email:

Disclosures: The authors report no relevant financial disclosures.


Cushing Patients Could Be Diagnosed, Subtyped Using Plasma Steroid Levels

Patients with different subtypes of Cushing’s syndrome (CS) have distinct plasma steroid profiles. This could be used as a test for diagnosis and classification, a German study says.

The study, “Plasma Steroid Metabolome for Diagnosis and Subtyping Patients with Cushing Syndrome,” appeared in the journal Clinical Chemistry.

A quick diagnosis of CS is crucial so that doctors can promptly give therapy. However, diagnosing CS is often complicated by the multiple tests necessary not just to diagnose the disease but also to determine its particular subtype.

Cortisol, which leads to CS when produced at high levels, is a steroid hormone. But while earlier studies were conducted to determine whether patients with different subtypes of CS had distinct steroid profiles, the methods researchers used were cumbersome and have been discontinued for routine use.

Recently, a technique called LC-MS/MS has emerged for multi-steroid profiling in patients with adrenocortical dysfunction such as congenital adrenal hyperplasia, adrenal insufficiency and primary aldosteronism.

Researchers at Germany’s Technische Universität in Dresden used that method to determine whether patients with the three main subtypes of CS (pituitary, ectopic and adrenal) showed differences in plasma steroid profiles. They measured levels of 15 steroids produced by the adrenal glands in single plasma samples collected from 84 patients with confirmed CS and 227 age-matched controls.

They found that CS patients saw huge increases in the plasma steroid levels of 11-deoxycortisol (289%), 21-deoxycortisol (150%), 11-deoxycorticosterone (133%), corticosterone (124%) and cortisol (122%), compared to patients without the disease.

Patients with the ectopic subtype had the biggest jumps in levels of these steroids. However, plasma 18-oxocortisol levels were particularly low in ectopic disease. Other steroids demonstrated considerable variation.

Patients with the adrenal subtype had the lowest concentration of dehydroepiandrosterone (DHEA) and DHEA-SO4, which are androgens. Patients with the ectopic and pituitary subtype had the lowest concentration of aldosterone.

Through the use of 10 selected steroids, patients with different subtypes of CS could be identified almost as closely as with other tests, including the salivary and urinary free cortisol test, the dexamethasone-suppressed cortisol test, and plasma adrenocorticotropin levels. The misclassification rate using steroid levels was 9.5 percent, compared to 5.8 percent in other tests.

“This study using simultaneous LC-MS/MS measurements of 15 adrenal steroids in plasma establishes distinct steroid metabolome profiles that might be useful as a test for CS,” the team concluded, adding that using LC-MS/MS is advantageous, as specimen preparation is simple and the entire panel takes 12 minutes to run. This means it could be offered as a single test for both identification and subtype classification.


Oral Test for Adult Growth Hormone Deficiency Approved in US

The US Food and Drug Administration (FDA) has approved an orally available ghrelin agonistmacimorelin (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.


Desmopressin is Promising Alternative in Diagnosing Cushing’s Disease

Bilateral inferior petrosal sinus sampling (IPSS) — a procedure that uses desmopressin to determine levels of ACTH hormone from veins that drain from the pituitary gland, is a sensitive way to diagnose patients with Cushing’s disease and find tumors, a Chinese study shows.

The study, “Tumour Lateralization in Cushing’s disease by Inferior Petrosal Sinus Sampling with desmopressin,” appeared in the journal Clinical Endocrinology.

Cushing’s disease is characterized by excessive production of the adrenocorticotropin hormone (ACTH) caused by a tumor in the pituitary gland. ACTH is the hormone that causes the adrenal glands to produce cortisol.

Currently, pituitary imaging is insufficient to confirm a Cushing’s diagnosis. This is because 70 percent of pituitary adenomas in Cushing’s are microadenomas, which are physically very small. As a result, 40 percent of Cushing’s patients are reported as being healthy.

This means that a Cushing’s diagnosis requires a combination of techniques including clinical symptoms, imaging methods and endocrinological assays that include measures of serum cortisol and ACTH levels.

IPSS determines ACTH levels from veins that drain from the pituitary gland. ACTH levels are then compared to ACTH levels in blood. Higher levels in the pituitary gland indicate a pituitary tumor.

IPSS can also be used to determine tumor lateralization, which refers to which side of the pituitary gland the tumor is located on. The test is 69 percent accurate.

Doctors administer IPSS along with corticotropin-releasing hormone (CRH) stimulation. IPSS with CRH is considered the gold standard for preoperative diagnosis of Cushing’s, with a diagnostic sensitivity (or true positive rate) of 95 percent and specificity (or true negative rate) of 90 to 95 percent. Unfortunately, the high cost and limited availability of CRH make it impractical for many patients.

Desmopressin has been used to replace CRH to stimulate ACTH secretion for IPSS, and prior studies have shown that desmopressin’s sensitivity is comparable to that of CRH.

Researchers at Peking Union Medical College in Beijing conducted a retrospective analysis of their experience using desmopressin-stimulated IPSS to determine its diagnostic value for Cushing’s and its predictive value for tumor lateralization.

Researchers analyzed 91 Cushing’s patients who either had negative findings on the MRI imaging of the pituitary or negative high-dose dexamethasone suppression tests, which is another method of evaluation. All patients underwent IPSS with desmopressin, followed by pituitary surgery to extract the tumor.

Of the 91 patients tested, 90 patients had confirmed Cushing’s. And of these, 89 had positive IPSS findings, which led to a sensitivity of 98.9 percent for this test. One patient out of 91 who did not have Cushing’s also underwent this test, which led to a negative IPSS result and a specificity of 100 percent.

Researchers also determined tumor lateralization in patients who were ultimately diagnosed with Cushing’s and underwent surgery. Results of the IPSS showed a 72.5 percent concordance between the results from the IPSS and the surgery.

Therefore, IPSS with desmopressin is a comparable approach to IPSS with CRH for the diagnosis of Cushing’s. It also demonstrates moderate accuracy in determining the location of tumors.

“Like many medical centers in China, we currently have no supply of CRH, while desmopressin is readily available,” researchers concluded. “Moreover, desmopressin is cheaper than CRH. As our data and other studies indicate, IPSS with desmopressin yielded comparable outcomes to IPSS with CRH. Therefore, desmopressin-stimulated IPSS might serve as a possible alternative to CRH-stimulated IPSS.”


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