Cushing’s Syndrome: A Tale of Frequent Misdiagnosis


What is it?

Cushing’s syndrome is a condition you probably have never heard of, but for those who have it, the symptoms can be quite scary.  Worse still, getting it diagnosed can take a while.  Cushing’s syndrome occurs when the tissues of the body are exposed to high levels of cortisol for an extended amount of time. Cortisol is the hormone the body produces to help you in times of stress. It is good to have cortisol at normal levels, but when those levels get too high it causes health problems.  Although cortisol is related to stress, there is no evidence that Cushing’s syndrome is directly or indirectly caused by stress.

Cushing’s syndrome is considered rare, but that may be because it is under-reported. As a result, we don’t have good estimates for how many people have it, which is why the estimates for the actual number of cases vary so much–from 5 to 28 million people.[1] The most common age group that Cushing’s affects are those 20 to 50 years old.  It is thought that obesity, type 2 diabetes, and high blood pressure may increase your risk of developing this syndrome.[2]

What causes Cushing’s Syndrome?

Cushing’s syndrome is caused by high cortisol levels. Cushing’s disease is a specific form of Cushing’s syndrome. People with Cushing’s disease have high levels of cortisol because they have a non-cancerous (benign) tumor in the pituitary gland.  The tumor releases adrenocorticotropin hormone (ACTH), which causes the adrenal glands to produce excessive cortisol.

Cushing’s syndrome that is not Cushing’s disease can be also caused by high cortisol levels that result from tumors in other parts of the body.  One of the causes is “ectopic ACTH syndrome.” This means that the hormone-releasing tumor is growing in an abnormal place, such as the lungs or elsewhere.  The tumors can be benign, but most frequently they are cancerous. Other causes of Cushing’s syndrome are benign tumors on the adrenal gland (adrenal adenomas) and less commonly, cancerous adrenal tumors (adrenocortical carcinomas). Both secrete cortisol, causing cortisol levels to get too high.

In some cases, a person can develop Cushing’s syndrome from taking steroid medications, such as prednisone. These drugs, known as corticosteroids, mimic the cortisol produced by the body. People who have Cushing’s syndrome from steroid medications do not develop a tumor.[3]

What are the signs and symptoms of Cushing’s Syndrome?

The appearance of people with Cushing’s syndrome starts to change as cortisol levels build up. Regardless of what kind of tumor they have or where the tumor is located, people tend to put on weight in the upper body and abdomen, with their arms and legs remaining thin; their face grows rounder (“moon face”); they develop fat around the neck; and purple or pink stretch marks appear on the abdomen, thighs, buttocks or arms. Individuals with the syndrome usually experience one or more of the following symptoms: fatigue, muscle weakness, high glucose levels, anxiety, depression, and high blood pressure. Women are more likely than men to develop Cushing’s syndrome, and when they do they may have excess hair growth, irregular or absent periods, and decreased fertility.[4]

Why is Cushing’s Syndrome so frequently misdiagnosed?

These symptoms seem distinctive, yet it is often difficult for those with Cushing’s syndrome to get an accurate diagnosis.  Why?  While Cushing’s is relatively rare, the signs and symptoms are common to many other diseases. For instance, females with excess hair growth, irregular or absent periods, decreased fertility, and high glucose levels could have polycystic ovarian syndrome, a disease that affects many more women than Cushing’s.   Also, people with metabolism problems (metabolic syndrome), who are at higher than average risk for diabetes and heart disease, also tend to have abdominal fat, high glucose levels and high blood pressure.[5]

Problems in testing for Cushing’s

When Cushing’s syndrome is suspected, a test is given to measure cortisol in the urine. This test measures the amount of free or unbound cortisol filtered by the kidneys and then released over a 24 hour period through the urine. Since the amount of urinary free cortisol (UFC) can vary a lot from one test to another—even in people who don’t have Cushing’s—experts recommend that the test be repeated 3 times. A diagnosis of Cushing’s is given when a person’s UFC level is 4 times the upper limit of normal.  One study found this test to be highly accurate, with a sensitivity of 95% (meaning that 95% of people who have the disease will be correctly diagnosed by this test) and a specificity of 98% (meaning that 98% of  people who do not have the disease will have a test score confirming that).[6] However, a more recent study estimated the sensitivity as only between 45%-71%, but with 100% specificity.[7]  This means that the test is very accurate at telling people who don’t have Cushing’s that they don’t have it, but not so good at identifying the people who really do have Cushing’s.  The authors that have analyzed these studies advise that patients use the UFC test together with other tests to confirm the diagnosis, but not as the initial screening test.[8]  

Other common tests that may be used to diagnose Cushing’s syndrome are: 1) the midnight plasma cortisol and late-night salivary cortisol measurements, and 2) the low-dose dexamethasone suppression test (LDDST).  The first test measures the amount of cortisol levels in the blood and saliva at night.  For most people, their cortisol levels drop at night, but people with Cushing’s syndrome have cortisol levels that remain high all night. In the LDDST, dexamethasone is given to stop the production of ACTH.  Since ACTH produces cortisol, people who don’t have Cushing’s syndrome will get lower cortisol levels in the blood and urine. If after giving dexamethasone, the person’s cortisol levels remain high, then they are diagnosed with Cushing’s.[9]

Even when these tests, alone or in combination, are used to diagnose Cushing’s, they don’t explain the cause. They also don’t distinguish between Cushing’s syndrome, and something called pseudo-Cushing state.

Pseudo-Cushing state

Some people have an abnormal amount of cortisol that is caused by something unrelated to Cushing’s syndrome such as polycystic ovarian syndrome, depression, pregnancy, and obesity. This is called pseudo-Cushing state.  Their high levels of cortisol and resulting Cushing-like symptoms can be reversed by treating whatever disease is causing the abnormal cortisol levels. In their study, Dr. Giacomo Tirabassi and colleagues recommend using the desmopressin (DDAVP) test to differentiate between pseudo-Cushing state and Cushing’s.  The DDAVP test is especially helpful in people who, after being given dexamethasone to stop cortisol production, continue to have moderate levels of urinary free cortisol (UFC) and midnight serum cortisol.[10]

An additional test that is often used to determine if one has pseudo-Cushing state or Cushing’s syndrome is the dexamethasone-corticotropin-releasing hormone (CRH) test. Patients are injected with a hormone that causes cortisol to be produced while also being given another hormone to stop cortisol from being produced. This combination of hormones should make the patient have low cortisol levels, and this is what happens in people with pseudo-Cushing state.  People with Cushing’s syndrome, however, will still have high levels of cortisol after being given this combination of hormones.[11]

How can Cushing’s be treated?

Perhaps because Cushing’s is rare or under-diagnosed, few treatments are available. There are several medications that are typically the first line of treatment.  None of the medications can cure  Cushing’s, so they are usually taken until other treatments are given to cure Cushing’s, and only after that if the other treatment fails.

The most common treatment for Cushing’s disease is transsphenoidal surgery, which requires the surgeon to reach the pituitary gland through the nostril or upper lip and remove the tumor.  Radiation may also be used instead of surgery to shrink the tumor.  In patients whose Cushing’s is caused by ectopic ACTH syndrome, all cancerous cells need to be wiped out through surgery, chemotherapy, radiation or a variety of other methods, depending on the location of the tumor. Surgery is also recommended for adrenal tumors.  If Cushing’s syndrome is being caused by corticosteroid (steroid medications) usage, the treatment is to stop or lower your dosage.[12]

Medications to control Cushing’s (before treatment or if treatment fails)

According to a 2014 study in the Journal of Clinical Endocrinology and Metabolism, almost no new treatment options have been introduced in the last decade. Researchers and doctors have focused most of their efforts on improving existing treatments aimed at curing Cushing’s. Unfortunately, medications used to control Cushing’s prior to treatment and when treatment fails are not very effective.

Many of the medications approved by the FDA for Cushing’s syndrome and Cushing’s disease, such as pasireotide, metyrapone, and mitotane, have not been extensively studied.  The research presented to the FDA by the makers of these three drugs did not even make clear what an optimal dose was.[13] In another 2014 study, published in Clinical Epidemiology, researchers examined these three same drugs, along with ten others, and found that only pasireotide had moderate evidence to support its approval.  The other drugs, many of which are not FDA approved for Cushing’s patients, had little or no available evidence to show that they work.[14] They can be sold, however, because the FDA has approved them for other diseases.  Unfortunately, that means that neither the FDA nor anyone else has proven the drugs are safe or effective for Cushing patients.

Pasireotide, the one medication with moderate evidence supporting its approval, caused hyperglycemia (high blood sugar) in 75% of patients who participated in the main study for the medication’s approval for Cushing’s.  As a result of developing hyperglycemia, almost half (46%) of the participants had to go on blood-sugar lowering medications. The drug was approved by the FDA for Cushing’s anyway because of the lack of other effective treatments.

Other treatments used for Cushing’s have other risks.  Ketoconazole, believed to be the most commonly prescribed medications for Cushing’s syndrome, has a black box warning due to its effect on the liver that can lead to a liver transplant or death.  Other side effects include: headache, nausea, irregular periods, impotence, and decreased libido. Metyrapone can cause acne, hirsutism, and hypertension. Mitotane can cause neurological and gastrointestinal symptoms such as dizziness, nausea, and diarrhea and can cause an abortion in pregnant women.[15]

So, what should you do if you suspect you have Cushing’s Syndrome?

Cushing’s syndrome is a serious disease that needs to be treated, but there are treatment options available for you if you are diagnosed with the disease. If the symptoms in this article sound familiar, it’s time for you to go see your doctor. Make an appointment with your general practitioner, and explain your symptoms to him or her.  You will most likely be referred to an endocrinologist, who will be able to better understand your symptoms and recommend an appropriate course of action.

 

All articles are reviewed and approved by Dr. Diana Zuckerman and other senior staff.

  1. Nieman, Lynette K. Epidemiology and clinical manifestations of Cushing’s syndrome, 2014. UpToDate: Wolters Kluwer Health
  2. Cushing’s syndrome/ disease, 2013. American Association of Neurological Surgeons. http://www.aans.org/Patient%20Information/Conditions%20and%20Treatments/Cushings%20Disease.aspx
  3. Cushing’s syndrome, 2012. National Endocrine and Metabolic Diseases: National Institutes of Health. http://endocrine.niddk.nih.gov/pubs/cushings/cushings.aspx#treatment
  4. Cushing’s syndrome, 2012. National Endocrine and Metabolic Diseases: National Institutes of Health. http://endocrine.niddk.nih.gov/pubs/cushings/cushings.aspx#treatment
  5. Cushing’s syndrome, 2012. National Endocrine and Metabolic Diseases: National Institutes of Health. http://endocrine.niddk.nih.gov/pubs/cushings/cushings.aspx#treatment
  6. Newell-Price, John, Peter Trainer, Michael Besser and Ashley Grossman. The diagnosis and differential diagnosis of Cushing’s syndrome and pseudo-Cushing’s states, 1998. Endocrine Reviews: Endocrine Society
  7. Carroll, TB and JW Findling. The diagnosis of Cushing’s syndrome, 2010. Reviews in Endocrinology and Metabolic Disorders: Springer
  8. Ifedayo, AO and AF Olufemi. Urinary free cortisol in the diagnosis of Cushing’s syndrome: How useful?, 2013. Nigerian Journal of Clinical Practice: Medknow.
  9. Cushing’s syndrome, 2012. National Endocrine and Metabolic Diseases: National Institutes of Health. http://endocrine.niddk.nih.gov/pubs/cushings/cushings.aspx#treatment
  10. Tirabassi, Giacomo, Emanuela Faloia, Roberta Papa, Giorgio Furlani, Marco Boscaro, and Giorgio Arnaldi. Use of the Desmopressin test in the differential diagnosis of pseudo-Cushing state from Cushing’s disease, 2013. The Journal of Clinical Endocrinology & Metabolism: Endocrine Society.
  11. Cushing’s syndrome, 2012. National Endocrine and Metabolic Diseases: National Institutes of Health. http://endocrine.niddk.nih.gov/pubs/cushings/cushings.aspx#treatment
  12. Cushing’s syndrome, 2012. National Endocrine and Metabolic Diseases: National Institutes of Health. http://endocrine.niddk.nih.gov/pubs/cushings/cushings.aspx#treatment
  13. Tirabassi, Giacomo, Emanuela Faloia, Roberta Papa, Giorgio Furlani, Marco Boscaro, and Giorgio Arnaldi. Use of the Desmopressin test in the differential diagnosis of pseudo-Cushing state from Cushing’s disease, 2013. The Journal of Clinical Endocrinology & Metabolism: Endocrine Society.
  14. Galdelha, Monica R. and Leonardo Vieira Neto. Efficacy of medical treatment in Cushing’s disease: a systematic review, 2014. Clinical Endocrinology: John Wiley & Sons.
  15. Adler, Gail. Cushing syndrome treatment & management, 2014. MedScape: WebMD.

Adapted from https://www.center4research.org/cushings-syndrome-frequent-misdiagnosis/

Cortisol: Chronic Stress Increases the Risk of Early Puberty

Scientists are trying to understand how childhood adversity affects puberty, but linking the two is difficult. Hair cortisol concentration (HCC) is a potentially useful biological marker of chronic stress. However, previous studies were unable to link childhood adversity to puberty in boys.

Research published in JAMA Pediatrics by Ying Sun and colleagues examined HCC and pubertal development in 1263 elementary school-aged children (age range 6.4 – 9.9 years) in China. Cortisol was extracted from hair samples and measured using a commercially available cortisol test kit.

For girls, breast development was assessed by the same pediatric endocrinologist using Breast Tanner stages, a scale of physical development. For boys, a Prader orchidometer was used to estimate testicular volume. The study found no difference in cortisol levels between boys and girls. Early breast development was significantly higher for girls with the HCC levels in the third and fourth quartile compared to those with lower HCC levels. Overall, the investigators found a 2.5-fold increase in the risk of early breast development in girls in the highest quartile of HCC compared to those in the lowest quartile.

Similarly, testicular volume in boys was significantly correlated (p< .001) with HCC, those with higher levels of HCC had larger mean testicular volumes. A 0.12-milliliter increase in testicular volume was observed with each quartile increase in HCC in boys.

This is the first study to measure the cortisol level in hair of children in relation to puberty. Scientists hope that additional studies will help us better understand the timing of puberty and how chronic stress increases the risk of early puberty.

Written By: Cindi A. Hoover, Ph.D.

From https://www.medicalnewsbulletin.com/chronic-stress-increases-risk-early-puberty/

Cushing’s Testing at NIH

Rank Status Study
1 Recruiting Study to Evaluate CORT125134 in Patients With Cushing’s Syndrome

Condition: Cushing’s Syndrome
Intervention: Drug: CORT125134
2 Recruiting Cushing’s Disease Complications

Condition: Cushing’s Disease
Intervention: Other: Exams and questionnaires
3 Recruiting The Accuracy of Late Night Urinary Free Cortisol/Creatinine and Hair Cortisol in Cushing’s Syndrome Diagnosis

Condition: Cushing Syndrome
Intervention:
4 Recruiting Treatment for Endogenous Cushing’s Syndrome

Condition: Endogenous Cushing’s Syndrome
Intervention: Drug: COR-003
5 Recruiting Saliva Cortisol Measurement as a Screening Test for Suspicious Cushings Syndrome in Children.

Condition: Cushings Syndrome
Intervention: Other: Children refered to the obesity clinic
6 Recruiting Safety and Efficacy of LCI699 for the Treatment of Patients With Cushing’s Disease

Condition: Cushing’s Disease
Intervention: Drug: LCI699
7 Recruiting Treatment of Cushing’s Disease With R-roscovitine

Condition: Cushings Disease
Intervention: Drug: R-roscovitine
8 Recruiting A Study of ATR-101 for the Treatment of Endogenous Cushing’s Syndrome

Condition: Cushing Syndrome
Interventions: Drug: ATR-101;   Drug: Placebos
9 Recruiting Evaluation of 68Ga-DOTATATE PET/CT, Octreotide and F-DOPA PET Imaging in Patients With Ectopic Cushing Syndrome

Condition: Cushing Syndrome
Interventions: Drug: F-DOPA PET Scan;   Drug: Mifepristone;   Drug: Ga-DOTATATE;   Drug: Octreoscan;   Other: CT, MRI
10 Not yet recruiting Endocrine Cardiomyopathy in Cushing Syndrome: Response to Cyclic GMP PDE5 inhibitOrs

Condition: Cushing’s Syndrome Cardiomyopathy
Intervention: Drug: Tadalafil
11 Recruiting Long-term Beneficial Metabolic Effects of Adrenalectomy in Subclinical Cushing’s Syndrome of Adrenal Incidentaloma

Condition: Cushing Syndrome
Intervention: Procedure: surgery
12 Recruiting Long Term Safety and Efficacy of Pasireotide s.c. in Patients With Cushing’s Disease

Condition: Cushings Disease
Intervention: Drug: SOM230
13 Recruiting New Imaging Techniques in the Evaluation of Patients With Ectopic Cushing Syndrome

Condition: Cushing Syndrome
Interventions: Drug: Pentetreotide;   Drug: 18-F-fluorodeoxyglucose;   Drug: (18F)-L-3,4-dihydroxyophenylalanine (18F-DOPA)
14 Not yet recruiting Targeting Iatrogenic Cushing’s Syndrome With 11β-hydroxysteroid Dehydrogenase Type 1 Inhibition

Condition: Iatrogenic Cushing’s Disease
Interventions: Drug: AZD4017 and prednisolone;   Drug: Placebo Oral Tablet and prednisolone
15 Not yet recruiting Assessment of Persistent Cognitive Impairment After Cure of Cushing’s Disease

Condition: Cushing’s Disease
Intervention: Device: Virtual radial task in 3D
16 Recruiting Biomarker Expression in Patients With ACTH-Dependent Cushing’s Syndrome Before and After Surgery

Condition: Cushing’s Syndrome
Intervention:
17 Recruiting Efficacy and Safety Evaluation of Osilodrostat in Cushing’s Disease

Condition: Cushing’s Disease
Interventions: Drug: osilodrostat;   Drug: osilodrostat Placebo
18 Recruiting Effects of Metyrapone in Patients With Endogenous Cushing’s Syndrome

Condition: Cushing’s Syndrome
Intervention: Drug: metyrapone
19 Recruiting Adrenal Venous Sampling in Patients With Overt or Subclinical Cushings Syndrome, and Bilateral Adrenal Tumors

Condition: Cushing Syndrome
Intervention: Radiation: Adrenal venous sampling
20 Recruiting Glycemic Fluctuations in Newly Diagnosed Growth Hormone-Secreting Pituitary Adenoma and Cushing Syndrome Subjects

Condition: Pituitary Adenoma
Intervention: Device: continuous glucose monitoring
Rank Status Study
21 Recruiting Targeted Therapy With Gefitinib in Patients With USP8-mutated Cushing’s Disease

Conditions: Cushing’s Disease;   Corticotrophin Adenoma
Intervention: Drug: Gefitinib
22 Recruiting Cardiac Steatosis in Cushing’s Syndrome

Conditions: Endocrine System Disease;   Cardiovascular Imaging
Intervention: Other: 1H magnetic resonance spectroscopy and CMRI
23 Recruiting Study of Management of Pasireotide-induced Hyperglycemia in Adult Patients With Cushing’s Disease or Acromegaly

Conditions: Cushing’s Disease;   Acromegaly
Interventions: Drug: Pasireotide s.c.;   Drug: Sitagliptin;   Drug: Liraglutide;   Drug: Insulin;   Drug: Pasireotide LAR;   Drug: Metformin
24 Recruiting Study of Efficacy and Safety of Osilodrostat in Cushing’s Syndrome

Conditions: Cushing’s Syndrome;   Ectopic Corticotropin Syndrome;   Adrenal Adenoma;   Adrenal Carcinoma;   AIMAH;   PPNAD
Intervention: Drug: Osilodrostat
25 Recruiting Effects of Hormone Stimulation on Brain Scans for Cushing s Disease

Condition: Pituitary Neoplasm
Intervention: Drug: Acthrel
26 Recruiting Does Serum-DXM Increase Diagnostic Accuracy of the Overnight DXM Suppression Test in the Work-up of Cushing’s Syndrome?

Conditions: Cushing’s Syndrome;   Adrenal Incidentalomas;   Alcoholism;   Obesity
Intervention:
27 Recruiting Adrenalectomy Versus Follow-up in Patients With Subclinical Cushings Syndrome

Condition: Adrenal Tumour With Mild Hypercortisolism
Intervention: Procedure: Adrenalectomy
28 Recruiting Study of Adrenalectomy Versus Observation for Subclinical Hypercortisolism

Conditions: Hypercortisolism;   Cushing Syndrome
Interventions: Procedure: Adrenalectomy;   Other: Observation
29 Not yet recruiting Dynamic Hormone Diagnostics in Endocrine Disease

Conditions: Adrenal Insufficiency;   Congenital Adrenal Hyperplasia;   Cushing Syndrome;   Growth Hormone Deficiency;   Acromegaly;   Primary Hyperaldosteronism
Intervention: Other: 27 hour subcutaneous fluid sampling
30 Recruiting An Investigation of Pituitary Tumors and Related Hypothalmic Disorders

Conditions: Abnormalities;   Craniopharyngioma;   Cushing’s Syndrome;   Endocrine Disease;   Pituitary Neoplasm
Intervention:
31 Recruiting Ga-68-DOTATOC -PET in the Management of Pituitary Tumours

Condition: Pituitary Tumours
Intervention: Procedure: Gallium-68 DOTATOC PET
32 Recruiting Efficacy of Mifepristone in Males With Type 2 Diabetes Mellitus

Conditions: Type 2 Diabetes Mellitus;   Insulin Resistance
Interventions: Drug: Mifepristone 600 mg daily;   Drug: Placebo
33 Recruiting Targeted Therapy With Lapatinib in Patients With Recurrent Pituitary Tumors Resistant to Standard Therapy

Conditions: Pituitary Adenomas;   Prolactinomas
Intervention: Drug: Lapatinib
34 Recruiting Mutations of Glucocorticoid Receptor in Bilateral Adrenal Hyperplasia

Condition: General Glucocorticoid Resistance
Intervention: Genetic: blood collection for mutation characterization
35 Recruiting Defining the Genetic Basis for the Development of Primary Pigmented Nodular Adrenocortical Disease (PPNAD) and the Carney Complex

Conditions: Cushing’s Syndrome;   Hereditary Neoplastic Syndrome;   Lentigo;   Neoplasm;   Testicular Neoplasm
Intervention:
36 Not yet recruiting Reduction by Pasireotide of the Effluent Volume in High-output Enterostomy in Patients Refractory to Usual Medical Treatment

Condition: Enterostomy
Interventions: Drug: Pasireotide;   Drug: Placebo
37 Recruiting Mifepristone for Breast Cancer Patients With Higher Levels of Progesterone Receptor Isoform A Than Isoform B.

Condition: Breast Cancer
Intervention: Drug: Mifepristone
38 Recruiting SOM230 Ectopic ACTH-producing Tumors

Condition: Ectopic ACTH Syndrome
Intervention: Drug: Pasireotide
39 Recruiting Decreasing Rates of Intraurethral Catheterization Postoperatively in Spine Surgery

Condition: Post-operative Urinary Retention
Interventions: Drug: Tamsulosin;   Drug: Placebo
40 Recruiting Adrenal Tumors – Pathogenesis and Therapy

Conditions: Adrenal Tumors;   Adrenocortical Carcinoma;   Cushing Syndrome;   Conn Syndrome;   Pheochromocytoma
Intervention:

Basal Cortisol Elevated in Patients with ACTH-Staining Pituitary Macroadenoma

Preoperative identification of patients with silent adrenocorticotrophic hormone-secreting tumors could potentially change the approach to management. A new study aimed to determine whether a preoperative adrenocorticotrophic hormone stimulation test for evaluation of nonfunctional pituitary macroadenoma could aid in identifying adrenocorticotrophic hormone-staining pathology yielded large variability and did not allow clinical utility.

Thus, researchers concluded that larger, multicenter research is needed to determine whether this test can be useful.

“As ACTH stimulation tests are performed routinely when evaluating macroadenoma when there is no suspicion for a state of endogenous hypercortisolism, we sought to determine if the test could reliably identify these pathologies during the preoperative evaluation. We hypothesized that patients with subclinical Cushing’s disease or silent ACTH-secreting tumors would have a higher delta cortisol on the ACTH stimulation tests vs. other types of macroadenoma pathologies,” Kevin Pantalone, DO, ECNU, FACE, staff endocrinologist and director of clinical research in the department of endocrinology at Cleveland Clinic, told Endocrine Today.

Pantalone and colleagues performed a retrospective chart review of 148 patients with pituitary macroadenoma who underwent preoperative ACTH stimulation tests, with the goal of determining whether the test can aid in the identification of ACTH-staining pathology.

Overall, 9.5% of patients showed diffuse staining, 50.6% showed other-staining (diffuse staining for anterior pituitary hormones other than ACTH) and 39.9% showed no staining (no staining for any anterior pituitary hormones).

The researchers calculated delta total cortisol at 30 and 60 minutes from baseline and reviewed preoperative ACTH stimulation tests. Additionally, Pantalone and colleagues compared the basal and maximal delta cortisol between the ACTH-staining pituitary macroadenoma and the non-ACTH staining (n = 134), other staining (n = 75) and non-staining (n = 59) tumors.

According to data reported at the American Association of Clinical Endocrinologists Annual Scientific and Clinical Congress, the ACTH-staining group had higher mean basal cortisol levels compared with the non-ACTH-staining (P = .012), other staining (P = .018) and the non-staining (P = .012) tumors. The researchers found no significant differences in maximal delta cortisol between the groups.

“While we found basal cortisol levels were higher in patients with ACTH-staining pituitary microadenoma vs. non-ACTH-staining macroadenoma, the large variability in cortisol values did not allow for clinical utility,” Pantalone told Endocrine Today.

“Unfortunately, in the end, our study was limited by the number of cases with ACTH-staining pathology. Thus, we were unable to determine if the ACTH stimulation test could reliably assist clinicians in potentially identifying ACTH-staining pathology in the preoperative setting,” he said. “A multicenter study, affording a large number of ACTH-staining tumors, is needed. This may allow for us to determine if the ACTH-stimulation test can really be clinically useful in preoperatively identifying ACTH-staining pathology.” – by Amber Cox

Comparison of MRI techniques for detecting microadenomas in Cushing’s disease

1Department of Neurological Surgery and 2Department of Radiology, University of Virginia Health Science Center, University of Virginia, Charlottesville, Virginia
ABBREVIATIONS ACTH = adrenocorticotropic hormone; CMRI = conventional MRI; DMRI = dynamic contrast-enhanced MRI; FSH = follicle-stimulating hormone; IPSS = inferior petrosal sinus sampling; SE = spin echo; SGE = spoiled-gradient echo 3D T1 sequence; SPGR = spoiled gradient–recalled acquisition; VIBE = volumetric interpolated breath-hold examination.

INCLUDE WHEN CITING Published online April 28, 2017; DOI: 10.3171/2017.3.JNS163122.

Correspondence Edward H. Oldfield, Department of Neurological Surgery, University of Virginia, Box 800212, Charlottesville, VA 22908. email: .
OBJECTIVE

Many centers use conventional and dynamic contrast-enhanced MRI (DMRI) sequences in patients with Cushing’s disease. The authors assessed the utility of the 3D volumetric interpolated breath-hold examination, a spoiled-gradient echo 3D T1 sequence (SGE) characterized by superior soft tissue contrast and improved resolution, compared with DMRI and conventional MRI (CMRI) for detecting microadenomas in patients with Cushing’s disease.

METHODS

This study was a blinded assessment of pituitary MRI in patients with proven Cushing’s disease. Fifty-seven patients who had undergone surgery for Cushing’s disease (10 male, 47 female; age range 13–69 years), whose surgical findings were considered to represent a microadenoma, and who had been examined with all 3 imaging techniques were included. Thus, selection emphasized patients with prior negative or equivocal MRI on referral. The MRI annotations were anonymized and 4 separate imaging sets were independently read by 3 blinded, experienced clinicians: a neuroradiologist and 2 pituitary surgeons.

RESULTS

Forty-eight surgical specimens contained an adenoma (46 ACTH-staining adenomas, 1 prolactinoma, and 1 nonfunctioning microadenoma). DMRI detected 5 adenomas that were not evident on CMRI, SGE detected 8 adenomas not evident on CMRI, including 3 that were not evident on DMRI. One adenoma was detected on DMRI that was not detected on SGE. McNemar’s test for efficacy between the different MRI sets for tumor detection showed that the addition of SGE to CMRI increased the number of tumors detected from 18 to 26 (p = 0.02) based on agreement of at least 2 of 3 readers.

CONCLUSIONS

SGE shows higher sensitivity than DMRI for detecting and localizing pituitary microadenomas, although rarely an adenoma is detected exclusively by DMRI. SGE should be part of the standard MRI protocol for patients with Cushing’s disease.

Full text at http://thejns.org/doi/full/10.3171/2017.3.JNS163122

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