Metabolomic Biomarkers in Urine of Cushing’s Syndrome Patients

Posted on January 29, 2026 by MaryO
Int. J. Mol. Sci. 2017, 18(2), 294; doi:10.3390/ijms18020294 (registering DOI)

Alicja Kotłowska 1,* , Tomasz Puzyn 2, Krzysztof Sworczak 3, Piotr Stepnowski 4 and Piotr Szefer 1

1 Department of Food Sciences, Faculty of Pharmacy, Medical University of Gdańsk, Al. Gen. J. Hallera 107, 80-416 Gdańsk, Poland
2 Laboratory of Environmental Chemometrics, Faculty of Chemistry, University of Gdańsk, ul. Wita Stwosza 63, 80-308 Gdańsk, Poland
3 Department of Endocrinology and Internal Medicine, Medical University of Gdańsk, ul. Dębinki 7, 80-211 Gdańsk, Poland
4 Department ofEnvironmental Analytics, Institute for Environmental and Human Health Protection, Faculty of Chemistry, University of Gdańsk, ul. Wita Stwosza 63, 80-308 Gdańsk, Poland
* Author to whom correspondence should be addressed.
Academic Editor: Ting-Li (Morgan) Han
Received: 5 December 2016 / Revised: 9 January 2017 / Accepted: 19 January 2017 / Published: 29 January 2017
(This article belongs to the Section Molecular Diagnostics)
Download PDF [1853 KB, uploaded 29 January 2017]

Abstract

Cushing’s syndrome (CS) is a disease which results from excessive levels of cortisol in the human body. The disorder is associated with various signs and symptoms which are also common for the general population not suffering from compound hypersecretion. Thus, more sensitive and selective methods are required for the diagnosis of CS.

This follow-up study was conducted to determine which steroid metabolites could serve as potential indicators of CS and possible subclinical hypercortisolism in patients diagnosed with so called non-functioning adrenal incidentalomas (AIs).

Urine samples from negative controls (n = 37), patients with CS characterized by hypercortisolism and excluding iatrogenic CS (n = 16), and patients with non-functioning AIs with possible subclinical Cushing’s syndrome (n = 25) were analyzed using gas chromatography-mass spectrometry (GC/MS) and gas chromatograph equipped with flame ionization detector (GC/FID). Statistical and multivariate methods were applied to investigate the profile differences between examined individuals. The analyses revealed hormonal differences between patients with CS and the rest of examined individuals.

The concentrations of selected metabolites of cortisol, androgens, and pregnenetriol were elevated whereas the levels of tetrahydrocortisone were decreased for CS when opposed to the rest of the study population. Moreover, after analysis of potential confounding factors, it was also possible to distinguish six steroid hormones which discriminated CS patients from other study subjects.

The obtained discriminant functions enabled classification of CS patients and AI group characterized by mild hypersecretion of cortisol metabolites. It can be concluded that steroid hormones selected by applying urinary profiling may serve the role of potential biomarkers of CS and can aid in its early diagnosis.

 

Keywords: Cushing’s syndrome; metabolomics; multivariate analysis; biomarkers; steroid hormones; urinary profiling; gas chromatography; linear discriminant analysis
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

Supplementary material

From http://www.mdpi.com/1422-0067/18/2/294

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Cushing’s Syndrome Subtype Affects Postoperative Time to Adrenal Recovery

Posted on January 25, 2026 by MaryO

Berr CM. J Clin Endocrinol Metab. 2014;doi:10.1210/jc.2014-3632.

January 16, 2015

In patients undergoing curative surgical tumor resection for Cushing’s syndrome, the time to recovery of adrenal function is contingent upon the underlying etiology of the disease, according to recent findings.

In the retrospective study, researchers reviewed case records of 230 patients with Cushing’s syndrome. All patients were seen at a tertiary care center in Munich between 1983 and 2014, whose cases were documented in the German Cushing’s Registry. Patients were divided into three subgroups of Cushing’s syndrome: Cushing’s disease, adrenal Cushing’s syndrome and ectopic Cushing’s syndrome.

After applying various exclusion criteria, the researchers identified 91 patients of the three subgroups who were undergoing curative surgery at the hospital. The patients were followed for a median of 6 years. The researchers defined adrenal insufficiency as the need for hydrocortisone replacement therapy, and collected this information from patient records and laboratory results.

The duration of adrenal insufficiency was calculated as the interval between successful surgery and the completion of hydrocortisone replacement therapy. Cushing’s syndrome recurrence was defined as biochemical and clinical signs of hypercortisolism.

The researchers found a significant difference between Cushing’s syndrome subtypes in the likelihood of regaining adrenal function within 5 years of follow-up: The probability was 82% in ectopic Cushing’s syndrome, 58% in Cushing’s disease and 38% in adrenal Cushing’s syndrome (P=.001). Among the 52 participants who recovered adrenal function, the median type to recovery also differed between subtypes and was 0.6 years in ectopic Cushing’s syndrome, 1.4 years in Cushing’s disease and 2.5 years in adrenal Cushing’s syndrome (P=.002).

An association also was found between younger age and adrenal recovery in the Cushing’s disease participants (P=.012).

This association was independent of sex, BMI, symptom duration, basal adrenocorticotropic hormone and cortisol levels. No association was seen between adrenal recovery and length of hypercortisolism or postoperative glucocorticoid replacement dosage.

“It is the main finding of this series that the median duration of tertiary adrenal insufficiency was dependent on the etiology of [Cushing’s syndrome]: It was shortest in the ectopic [Cushing’s syndrome], intermediate in [Cushing’s disease] and longest in adrenal [Cushing’s syndrome] caused by unilateral cortisol producing adenoma,” the researchers wrote. “The significant difference to [Cushing’s disease] is an unexpected finding since by biochemical means cortisol excess is generally less severe in adrenal [Cushing’s syndrome]. If confirmed by others, our data have clinical impact for the follow-up of patients after curative surgery: Patients should be informed that adrenocortical function may remain impaired in benign conditions such as cortisol-producing adenoma.”

Disclosure: The study was funded in part by the Else Kröner-Fresenius Stiftung.

The original article is here: Healio

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Myth: “Each Person Requires the Same Dose of Steroid in Order to Survive…

Posted on January 19, 2026 by MaryO

Myth: “Each person requires the same dose of steroid in order to survive with Secondary or Primary Adrenal Insufficiency”

myth-busted

Fact: In simple terms, Adrenal Insufficiency occurs when the body does not have enough cortisol in it. You see, cortisol is life sustaining and we actually do need cortisol to survive. You have probably seen the commercials about “getting rid of extra belly fat” by lowering your cortisol. These advertisements make it hard for people to actually understand the importance of the function of cortisol.

After a Cushing’s patient has surgery, he/she goes from having very high levels of cortisol to no cortisol at all. For pituitary patients, the pituitary, in theory, should start working eventually again and cause the adrenal glands to produce enough cortisol. However, in many cases; the pituitary gland does not resume normal functioning and leaves a person adrenally insufficient. The first year after pit surgery is spent trying to get that hormone to regulate on its own normally again. For a patient who has had a Bilateral Adrenalectomy (BLA), where both adrenal glands are removed as a last resort to “cure” Cushing’s; his/her body will not produce cortisol at all for his/her life. This causes Primary Adrenal Insufficiency.

All Cushing’s patients spend time after surgery adjusting medications and weaning slowly from steroid (cortisol) to get the body to a maintenance dose, which is the dose that a “normal” body produces. This process can be a very long one. Once on maintenance, a patient’s job is not over. He/She has to learn what situations require even more cortisol. You see, cortisol is the stress hormone and also known as the Fight or Flight hormone. Its function is to help a person respond effectively to stress and cortisol helps the body compensate for both physical and emotional stress. So, when faced with a stressor, the body will produce 10X the baseline levels in order to compensate. When a person can not produce adequate amounts of cortisol to compensate, we call that Adrenal Insufficiency. If it gets to the point of an “Adrenal Crisis”, this means that the body can no longer deal and will go into shock unless introduced to extremely high levels of cortisol, usually administered through an emergency shot of steroid.

There are ways to help prevent a crisis, by taking more steroid than the maintenance dose during times of stress. This can be anything from going to a family function (good stress counts too) to fighting an infection or illness. Acute stressors such as getting into a car accident or sometimes even having a really bad fight require more cortisol as well.

It was once believed that everyone responded to every stressor in the exact same way. So, there are general guidelines about how much more cortisol to introduce to the body during certain stressors. For instance, during infection, a patient should take 2-3X the maintenance dose of steroid (cortisol). Also, even the maintenance dose was considered the same for everyone. Now a days, most doctors will say that 20 mg of Hydrocortisone (Steroid/Cortisol) is the appropriate maintenance dose for EVERYONE. Now, we know that neither is necessarily true. Although the required maintenance dose is about the same for everyone; some patients require less and some require more. I have friends who will go into an adrenal crisis if they take LESS than 30 mg of daily steroid. On the other hand, 30 mg may be way too much for some and those folks may even require LESS daily steroid, like 15 mg. Also, I want to stress (no pun intended) that different stressors affect different people differently. For some, for instance, an acute scare may not affect them. However, for others, receiving bad news or being in shock WILL put their bodies into crisis. That person must then figure out how much additional steroid is needed.

Each situation is different and each time may be different. Depending on the stressor, a person may need just a little more cortisol or a lot. Every person must, therefore, learn their own bodies when dealing with Adrenal Insufficiency. This is VERY important! I learned this the hard way. As a Clinical Psychologist; I assumed that my “coping skills” would be enough to prevent a stressor from putting me into crisis. That was FAR from the truth! I have learned that I can not necessarily prevent my body’s physiological response to stress. People often ask me, “BUT you are a psychologist! Shouldn’t you be able to deal with stress?!!!!” What they don’t realize is that my BODY is the one that has to do the job of compensating. Since my body can not produce cortisol at all, my job is to pay close attention to it so that I can take enough steroid to respond to any given situation. We all have to do that. We all have to learn our own bodies. This is vitally important and will save our lives!

To those we have lost in our community to Adrenal Insufficiency after treatment of Cushing’s, Rest in Peace my friends! Your legacies live on forever!

~ By Karen Ternier Thames

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

Posted on January 18, 2026 by MaryO

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

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Study Supports Midnight Salivary Cortisol Test to Diagnose Cushing’s in Chinese Population

Posted on January 11, 2026 by MaryO

A simple test that measures free cortisol levels in saliva at midnight — called a midnight salivary cortisol test — showed good diagnostic performance for Cushing’s syndrome among a Chinese population, according to a recent study.

The test was better than the standard urine free cortisol levels and may be an alternative for people with end-stage kidney disease, in whom measuring cortisol in urine is challenging.

The study, “Midnight salivary cortisol for the diagnosis of Cushing’s syndrome in a Chinese population,” was published in Singapore Medical Journal.

Cushing’s syndrome, defined by excess cortisol levels, is normally diagnosed by measuring the amount of cortisol in bodily fluids.

Traditionally, urine free cortisol has been the test of choice, but this method is subject to complications ranging from improper collection to metabolic differences, and its use is limited in people with poor kidney function.

Midnight salivary cortisol is a test that takes into account the normal fluctuation of cortisol levels in bodily fluids. Cortisol peaks in the morning and declines throughout the day, reaching its lowest levels at midnight. In Cushing’s patients, however, this variation ceases to exist and cortisol remains elevated throughout the day.

Midnight salivary cortisol was first proposed in the 1980s as a noninvasive way to measure cortisol levels, but its efficacy and cutoff value for Cushing’s disease in the Chinese population remained unclear.

Researchers examined midnight salivary cortisol, urine free cortisol, and midnight serum cortisol in Chinese patients suspected of having Cushing’s syndrome and in healthy volunteers. These measurements were then combined with imaging studies to make a diagnosis.

Overall, the study included 29 patients with Cushing’s disease, and 19 patients with Cushing’s syndrome — 15 caused by an adrenal mass and four caused by an ACTH-producing tumor outside the pituitary. Also, 13 patients excluded from the suspected Cushing’s group were used as controls and 21 healthy volunteers were considered the “normal” group.

The team found that the mean midnight salivary cortisol was significantly higher in the Cushing’s group compared to both control and normal subjects. Urine free cortisol and midnight serum cortisol were also significantly higher than those found in the control group, but not the normal group.

The optimal cutoff value of midnight salivary cortisol for diagnosing Cushing’s was 1.7 ng/mL, which had a sensitivity of 98% — only 2% are false negatives — and a specificity of 100% — no false positives.

While midnight salivary cortisol levels correlated with urine free cortisol and midnight serum cortisol — suggesting that all of them can be useful diagnostic markers for Cushing’s — the accuracy of midnight salivary cortisol was better than the other two measures.

Notably, in one patient with a benign adrenal mass and impaired kidney function, urine free cortisol failed to reach the necessary threshold for a Cushing’s diagnosis, but midnight salivary and serum cortisol levels both confirmed the diagnosis, highlighting how midnight salivary cortisol could be a preferable diagnostic method over urine free cortisol.

“MSC is a simple and non-invasive tool that does not require hospitalization. Our results confirmed the accuracy and reliability of [midnight salivary cortisol] as a diagnostic test for [Cushing’s syndrome] for the Chinese population,” the investigators said.

The team also noted that its study is limited: the sample size was quite small, and Cushing’s patients tended to be older than controls, which may have skewed the results. Larger studies will be needed to validate these results in the future.

From https://cushingsdiseasenews.com/2019/01/10/midnight-salivary-cortisol-test-helps-diagnose-cushings-chinese-study-shows/

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