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: kennedl4@ccf.org.

Disclosures: The authors report no relevant financial disclosures.

From https://www.healio.com/endocrinology/adrenal/news/in-the-journals/%7Bf9721377-6a2a-401c-a16d-2d4624233b63%7D/late-night-salivary-cortisol-often-fluctuates-widely-in-cushings-disease

Hair Test for Cushing Syndrome?

Cortisol levels in hair correlated strongly with standard tests

by Jeff Minerd
Contributing Writer, MedPage Today

Analyzing the levels of cortisol in hair may aid in the diagnosis of Cushing syndrome, perhaps one day replacing invasive blood tests, scientists said.

Cortisol levels in the proximal ends of hair samples taken from patients with the syndrome correlated strongly with blood tests (R=0.4; P=0.03) and urine tests (R=0.5; P=0.005) for cortisol, reported Mihail Zilbermint, MD, of the National Institute of Child Health and Human Development in Bethesda, Md., and colleagues.

“The diagnosis of Cushing syndrome is often challenging and inconclusive, despite numerous tests used for the detection of hypercortisolemia and its origin, and is associated with high morbidity and high risk for mortality, if undiagnosed and untreated,” Zilbermint and colleagues wrote online in Endocrine: International Journal of Basic and Clinical Endocrinology.

“As a potential solution to the limitations of these tests, hair cortisol has been increasingly studied as an additional means to diagnose patients with Cushing Syndrome. Much like hemoglobin A1C is a longitudinal marker of blood glucose levels, hair cortisol can be a measure of the body’s glucocorticoid levels over the previous several weeks to months.”

“Our results are encouraging,” Zilbermint said in a statement. “We are hopeful that hair analysis may ultimately prove useful as a less-invasive screening test for Cushing syndrome or in helping to confirm the diagnosis.”

The study included 30 patients with Cushing syndrome and six control individuals without the disease. The participants’ average age was 26, and 75% were female and 75% were Caucasian.

The investigators took 3 cm-long hair samples from all patients, analyzed the proximal, medial, and distal segments of the samples for cortisol, and compared the results with results of standard blood and urine tests. Cortisol levels were highest in the proximal segments and correlated best with the standard tests, the investigators reported.

“We found that proximal hair cortisol directly correlates with late night serum cortisol and UFC [urinary free cortisol] in patients with and without Cushing syndrome. The most proximal 1 cm of hair was the best section of hair for stratifying the two groups of patients in our cohort.

“These findings support further research on the use of this modality in the workup for Cushing syndrome.”

Regarding the study’s limitations, the team pointed to the small control group of only six patients. Another limitation is that more than half of the participants (58%) were younger than age 18, and pubertal status on cortisol metabolism may be a factor in hair cortisol measurement.

“However, our study’s strengths are that it is the largest sample so far to analyze segmental hair cortisol in Cushing syndrome, and that it is the largest study to compare hair cortisol to any biochemical test for hypercortisolemia in patients with Cushing syndrome,” Zilbermint and colleagues said. “Our study also included a large cohort of Cushing Disease patients, which has been under-represented in prior studies on hair cortisol.”

The study was funded by the National Institutes of Health. Zilbermint and colleagues reported having no relevant financial relationships with industry.

Cushing’s disease best treated by endocrinologist

Dear Dr. Roach: I was told that I have Cushing’s disease, which has caused diabetes, high blood pressure, hunger, weight gain and muscle loss. I was never sick before this, and I did not have any of those things. I am told I have a tumor on my right adrenal gland. I have been to numerous doctors, but most have not been too helpful. They seem to try to treat the diabetes or blood pressure, but nothing else. They seem not to be familiar with Cushing’s. I tell them which medication works, but they still give me new medication. I have an endocrinologist and am scheduled to meet a urologist.

I have managed to go to physical therapy, exercise every day and lose over 50 pounds. I am not happy with the advice I’m getting. I was told that surgery to remove the tumor will fix everything, but that I would need to take steroids for either a short term or for life. My body is already making too much cortisol. I have 50 more pounds to lose. I work hard to keep the weight down. I feel like a science experiment. Within a week, I have had three different medications. I could not tell which was causing the side effects and making me dehydrated. I am not sure surgery is right for me, because they said it can be done laparoscopically, but if they can’t do it that way, they will have to cut me all the way across, which may take a long time to heal and may get infected.

Do you know what tests will confirm the diagnosis? Would surgery fix all these problems? I had the 24-hour urine test, the saliva test and blood tests. I want to know if it may be something else instead of Cushing’s. I’m not on anything for the high cortisol levels.

– A.L.

A: It sounds very much like you have Cushing’s syndrome, which is caused by excess cortisone, a hormone that has many effects. It is called Cushing’s disease when the underlying cause is a pituitary tumor that causes the adrenal gland to make excess cortisone. (Cortisone and cortisol are different names for the same chemical, also called a glucocorticoid.) Cushing’s syndrome also may be caused by an adenoma (benign tumor) of the adrenal gland, which sounds like the case in you.

The high amounts of cortisone produced by the adrenal tumor cause high blood pressure, glucose intolerance or frank diabetes, increased hunger, obesity (especially of the abdomen – large bellies and skinny limbs are classic), dark-colored striae (stretch marks), easy bruising, a reddish face and often weakness of arm and leg muscles. When full-blown, the syndrome is easy to spot, but many people don’t have all the characteristics, especially early in the course of the disease.

Your endocrinologist is the expert in diagnosis and management, and has done most of the tests. I am somewhat surprised that you haven’t yet seen a surgeon to have the tumor removed. Once it is removed, the body quickly starts to return to normal, although losing the weight can be a problem for many.

I have seen cases in my training where, despite many tests, the diagnosis was still uncertain. The endocrinologist orders a test where the blood is sampled from both adrenal veins (which contain the blood that leaves the adrenal glands on top of the kidneys). If the adrenal vein on the side of the tumor has much more cortisone than the opposite side, the diagnosis is certain.

By DR. KEITH ROACH For the Herald & Review at http://herald-review.com/news/opinion/editorial/columnists/roach/dr-roach-cushing-s-disease-best-treated-by-endocrinologist/article_38e71835-464d-5946-aa9c-4cb1366bcee3.html

Midnight Salivary Cortisol Versus Urinary Free and Midnight Serum Cortisol as Screening Tests for Cushing’s Syndrome

From PubMed

Gafni RI, Papanicolaou DA, Nieman LK.
Developmental Endocrinology Branch, National Institute of Child Health and Human Development, Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, MD 20892-1862, USA.

OBJECTIVE: There is currently no optimal test to screen for endogenous Cushing’s syndrome (CS) in children. Traditional 24-hour urine or midnight serum cortisol values may be difficult to obtain or elevated by venipuncture stress. We hypothesized that salivary cortisol measurement is a reliable way to screen for CS in children.

STUDY DESIGN: Sixty-seven children (5-17 years) were studied: 24 obese volunteers, 29 non-obese volunteers, and 14 children with CS. Saliva was obtained at 7:30 AM, bedtime, and midnight for measurement of free cortisol by radioimmunoassay.

RESULTS: Salivary cortisol was detectable in all morning and evening samples from patients with CS but was frequently undetectable in healthy children at bedtime (66%) and at midnight (90%). With cut points that excluded healthy children, a midnight salivary cortisol value of 7.5 nmol/L (0.27 microg/dL) identified 13 of 14 patients with CS, whereas a bedtime value >27.6 nmol/L (1 microg/dL) detected CS in 5 of 6 patients. The diagnostic accuracies of midnight salivary cortisol and urinary free cortisol per square meter were the same (93%).

CONCLUSION: Salivary cortisol measurement at bedtime or midnight rules out CS in nearly all cases. Nighttime salivary cortisol sampling is thus a simple, accurate way to screen for hypercortisolism in children. PMID: 10891818 [PubMed – indexed for MEDLINE]


THE PRINCIPLE RESEARCHER FOR SALIVARY CORTISOLS IS HERSHEL RAFF AT THE UNIVERSITY OF WISCONSIN. HE IS A RESEARCH SCIENTIST, NOT A DOCTOR. YOU CAN CONTACT HIM DIRECTLY FOR ORDERING INFO.

Salivary Cortisol: A Screening Technique

By: Dr. Hershel Raff

Cushing’s syndrome – endogenous hypercortisolism – is characterized by a loss of circadian rhythmicity. In normal patients, cortisol levels peak in the early morning hours and decrease to substantially lower levels at night. Rather than the normal decrease in late evening cortisol, patients with Cushing’s syndrome of any cause fail to decrease cortisol secretion in the late evening. Therefore, the measurement of elevated late evening cortisol is helpful in the diagnosis of Cushing’s syndrome. Obtaining a late night, unstressed plasma cortisol is virtually impossible in most clinical practices. Salivary cortisol is in equilibrium with the free, biologically active portion of cortisol in the plasma. Therefore, if one obtains a saliva sample in patients at bedtime in their homes under unstressed conditions, one can make the diagnosis of endogenous hypercortisolism.

A simple way to sample saliva is by using a Salivette made by the Sarstedt Company (Newton, NC). This device consists of a cotton tube and plastic tubes. The patient only has to chew the cotton tube for 2-3 minutes and place it in the plastic tube. The tube is then transported to our lab for analysis.

Late-evening salivary cortisol is not intended to replace the current standard screening test – measurement of a 24 hr urine free cortisol. However, the salivary cortisol test can be extremely useful for patients suspected of having intermittent Cushing’s syndrome. Due to the convenience of sample collection, the patient can sample saliva several evenings in a row. In fact, our clinical endocrinologists routinely order 2-3 consecutive late-evening salivary cortisol samples.


Our research (Raff H, Raff JL, Findling JW. 1998 LATE-NIGHT SALIVARY CORTISOL AS A SCREENING TEST FOR CUSHING’S SYNDROME. J Clin Endocrinol Metab. 83:2681-2686) has shown that the combination of late-evening salivary cortisol and urine free cortisol is very accurate in diagnosing Cushing’s syndrome in most patients. Doctors can obtain a kit by contacting ACL Client Services at 1-800-877-7016.

Editor’s Note: DR. HERSHEL RAFF, PH.D. IS A PROFESSOR OF MEDICINE AND PHYSIOLOGY AT THE MEDICAL COLLEGE OF WISCONSIN’S ENDOCRINE RESEARCH LABORATORY AT ST. LUKE’S MEDICAL CENTER IN MILWAUKEE, WISCONSIN.

A Single-Center 10-Year Experience with Pasireotide in Cushing’s Disease: Patients’ Characteristics and Outcome

Pasireotide is the first pituitary-directed drug approved for treating patients with Cushing’s disease (CD). Our 10-year experience with pasireotide in CD is reported here.

Twenty patients with de novo, persistent, or recurrent CD after pituitary surgery were treated with pasireotide from December 2003 to December 2014. Twelve patients were treated with pasireotide in randomized trials and 8 patients with pasireotide sc (Signifor®; Novartis AG, Basel, Switzerland) in clinical practice. The mean treatment duration was 20.5 months (median 9 months; range, 3-72 months).

Urinary free cortisol (UFC) levels mean percentage change (± SD) at last follow-up was-40.4% (± 35.1; range, 2-92%; median reduction 33.3%) with a normalization rate of 50% (10/20). Ten patients achieved sustained normalized late night salivary cortisol (LNSC) levels during treatment. LNSC normalization was associated with UFC normalization in 7/10 patients. Serum cortisol and plasma ACTH significantly decreased from baseline to last follow-up. Body weight decrease and blood pressure improvement during pasireotide treatment were independent from UFC response. Glucose profile worsening was observed in all patients except one. The frequency of diabetes mellitus increased from 40% (8/20) at baseline to 85% (17/20) at last follow-up requiring initiation of medical treatment only in 44% of patients.

Pasireotide treatment was associated with sustained biochemical and clinical benefit in about 60% of CD patients. Glucose profile alteration is a frequent complication of pasireotide treatment; however, it seems to be easy to manage with diet and lifestyle intervention in almost half of the patients.

From http://www.ncbi.nlm.nih.gov/pubmed/27127913

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