Diagnosis and Differential Diagnosis of Cushing’s Syndrome

Posted on April 8, 2026 by MaryO

D. Lynn Loriaux, M.D., Ph.D.

N Engl J Med 2017; 376:1451-1459April 13, 2017DOI: 10.1056/NEJMra1505550

More than a century ago, Harvey Cushing introduced the term “pluriglandular syndrome” to describe a disorder characterized by rapid development of central obesity, arterial hypertension, proximal muscle weakness, diabetes mellitus, oligomenorrhea, hirsutism, thin skin, and ecchymoses.1 Cushing knew that this syndrome was associated with adrenal cancer,2 and he suspected that some cases might have a pituitary component.

On September 6, 1911, he performed a craniotomy on one of his patients (referred to as Case XLV) but found no pituitary tumor.3 In his description of the case, he goes on to say that “we may perchance be on the way toward the recognition of the consequences of hyperadrenalism.”2 With time, it became clear that the disorder could be caused by small basophilic adenomas of the pituitary gland,4 and the pluriglandular syndrome became known as Cushing’s syndrome.

Fuller Albright provided the next conceptual advance in an extraordinary report, published in the first volume of the Laurentian Hormone Conference, “The Effects of Hormones on Osteogenesis in Man”5:

It has been our concept that protoplasm in general, like the protoplasmic matrix of bone, is constantly being anabolized and catabolized at one and the same time; a factor which increases catabolism would lead to very much the same net result as a factor which inhibits anabolism, but there would be some differences; it is my belief that the “S” hormone [cortisol] is anti-anabolic rather than catabolic. . . . The anti-anabolism . . . is contrasted with the increased anabolism due to an excess of the “N” hormone [testosterone] in the adreno-genital syndrome. This anti-anabolism of protoplasm in Cushing’s syndrome accounts for not only the osteoporosis, but the muscular weakness, the thin skin, probably the easy bruisability, and possibly the atrophy of the lymphoid tissues and thymus.

Nonetheless, in the intervening years, the physical examination of patients suspected to have glucocorticoid excess focused on the anabolic changes, essentially to the exclusion of the antianabolic changes. With the rapid increase in the rate of obesity in the general population, Cushing’s syndrome can no longer be reliably separated from the metabolic syndrome of simple obesity on the basis of anabolic signs alone. However, the antianabolic changes in Cushing’s syndrome are very effective in making this distinction. This review focuses on the problems introduced into the diagnosis and differential diagnosis of Cushing’s syndrome by the obesity epidemic and on ways to alter the traditional approach, using the antianabolic changes of excess cortisol to separate patients with Cushing’s syndrome from obese patients with the insulin-resistant metabolic syndrome.

PHYSICAL EXAMINATION

Andreas Vesalius (1514–1564) published his transformational work on human anatomy, De Humani Corporis Fabrica Libri Septem, in 1543. It is the book that corrected many of Galen’s anatomical errors. The book was met with considerable hostility. As an example, Jacobus Sylvius (Jacques Dubois, 1478–1555), the world’s leading anatomist at the time and Vesalius’s former mentor, on being asked his opinion of the work, replied, “Galen is not wrong. It is man that has changed, and not for the better.”6 This was not true then, but it is true now.

Approximately one third of the U.S. population is obese. The worldwide prevalence of the metabolic syndrome among obese persons is conservatively estimated at 10%; that is, approximately 12 million people have the obesity-related metabolic syndrome.7,8 The clinical picture of this syndrome is almost the same as that of Cushing’s syndrome.9,10 The prevalence of undiagnosed Cushing’s syndrome is about 75 cases per 1 million population, or 24,000 affected persons. On the basis of these prevalence estimates, the chance that a person with obesity, hypertension, hirsutism, type 2 diabetes, and dyslipidemia has Cushing’s syndrome is about 1 in 500. In Harvey Cushing’s era, when obesity was rare, making the diagnosis of Cushing’s syndrome was the most certain aspect of the management of this disorder. Today, making the diagnosis is the least certain aspect in the care of patients with Cushing’s syndrome.

The metabolic syndrome caused by glucocorticoid hypersecretion can be differentiated from the obesity-associated metabolic syndrome with the use of a careful assessment of Albright’s antianabolic effects of cortisol. These effects — osteopenia, thin skin, and ecchymoses — are present in patients with Cushing’s syndrome but not in patients with simple obesity.

Patients in whom osteoporosis is diagnosed radiographically are more likely to have Cushing’s syndrome than those who do not have osteoporosis, with a positive likelihood ratio of 11.11-13 Today, a z score of −2 at the lumbar spine supports this criterion. Skinfold thickness is conveniently measured with an electrocardiographic caliper that has the points dulled with a sharpening stone and the screws tightened so that the gap is maintained when the caliper is removed from the skinfold. The skin over the proximal phalanx of the middle finger of the nondominant hand is commonly used for this measurement

 

(Figure 1 FIGURE 1Measurement of Skinfold Thickness.). A thickness of less than 2 mm is considered to be thin skin. Patients who have thin skin are more likely to have Cushing’s syndrome, with a positive likelihood ratio of 116

 

(Figure 2 FIGURE 2 Comparison of Skinfold Thickness in Patients with Cushing’s Syndrome and Those with Other Conditions Related to Insulin Resistance.).13-15 Finally, patients who have three or more ecchymoses that are larger than 1 cm in diameter and not associated with trauma such as venipuncture are more likely to have Cushing’s syndrome than are patients without such findings, with a positive likelihood ratio of 4.13,16

If we know the prevalence of undiagnosed Cushing’s syndrome in the population of persons with the obesity-related metabolic syndrome, we can begin to calculate the probability that a person has Cushing’s syndrome, using the likelihood ratios for the antianabolic features observed on physical examination. Likelihood ratios can be converted into probabilities with the use of Bayes’ theorem. This conversion is markedly facilitated by the Fagan nomogram for this purpose.17

The prevalence of undiagnosed Cushing’s syndrome is not known, but it can be estimated. Two persons per 1 million population die from adrenal cancer every year.18 The current life span for patients with adrenocortical carcinoma, after diagnosis, is between 2 and 4 years.19,20 Allowing 3 years to make the diagnosis, the prevalence of undiagnosed Cushing’s syndrome is 6 cases per million. In most case series of Cushing’s syndrome, an average of 8% of patients have adrenal carcinoma.21 If 6 per million is 8% of the group, the total Cushing’s syndrome group is 75 persons per million, or 24,000 persons. If all 24,000 patients are included in the metabolic syndrome group, comprising 12 million people, the prevalence of Cushing’s syndrome is 0.002, or 0.2%. With a probability of 0.2% and a likelihood ratio of 116 for thin skin, 18 for osteopenia, and 4 for ecchymoses, the probability that a patient with these three findings has Cushing’s syndrome is 95%.

URINARY FREE CORTISOL

The diagnosis of all endocrine diseases requires a clinical presentation that is compatible with the disease, as well as identification of the pathophysiological cause. An assessment for excess glucocorticoid effects can be made by measuring the 24-hour urinary free cortisol level.22 There are two kinds of free cortisol: plasma protein-unbound cortisol and cortisol unconjugated to sulfuric or hyaluronic acid. Protein-unbound cortisol is filtered in the glomerulus and then reabsorbed in the collecting system. About 3% of filtered cortisol ends up in the urine. This free cortisol in the urine is unconjugated. Thus, the urinary free cortisol level is a direct reflection of the free, bioactive cortisol level in plasma. The free cortisol level is quantified in a 24-hour urine sample by averaging the increased secretion of cortisol in the morning and the decreased secretion in the afternoon and at night. Urinary creatinine is also measured to determine whether the collection is complete. Creatinine levels of less than 1.5 g per day for men and less than 1 g per day for women indicate incomplete collection, and the test should be repeated in patients with these levels.

Unconjugated cortisol can be extracted directly from urine with a nonpolar lipid solvent. After extraction, the cortisol is purified by means of high-pressure liquid chromatography and then quantified with a binding assay, usually radioimmunoassay. Free cortisol also can be quantitated directly by means of mass spectroscopy. The urinary free cortisol assay of choice uses high-pressure liquid chromatographic separation followed by mass spectrometric quantitation.23 With the use of this assay, the urinary free cortisol level in healthy adults ranges from 8 to 51 μg per 24 hours (mean [±SD], 23±8). Clinical depression increases urinary free cortisol excretion, and most studies show that the level of urinary free cortisol ranges from 10 to 60 μg per day in patients with typical clinical signs and symptoms of depression. If we use 60 μg per day as the cutoff between normal values (<60 μg per day) and elevated values (≥60 μg per day), urinary free cortisol excretion of 62 μg per day or more has a positive likelihood ratio of 11.24 Thus, in a patient presenting with obesity, hypertension, type 2 diabetes, and hirsutism who has thin skin, osteopenia, ecchymoses, and an elevated urinary free cortisol level, the probability of Cushing’s syndrome is 1 (100%). For such patients, the clinician should move directly to a differential diagnostic evaluation.

DEXAMETHASONE-SUPPRESSION TEST

The dexamethasone-suppression test is commonly used in the diagnosis of Cushing’s syndrome. This test was developed by Grant Liddle in the early 1960s as a differential diagnostic test to separate corticotropin-dependent from corticotropin-independent Cushing’s syndrome. This is now done by measuring the plasma corticotropin level. Unfortunately, dexamethasone suppression has continued to be used as a screening test for Cushing’s syndrome.

The control group for this test comprises patients with obesity and depression in whom cortisol secretion is not suppressed in response to an oral dose of 1 mg of dexamethasone at midnight. Of the current U.S. population of 360 million people, approximately one third (120 million people) are obese. Of those who are obese, 10% (12 million people) have depression. In half these patients (6 million people), the plasma cortisol level will not be suppressed in response to a dexamethasone challenge. On the basis of my estimate of the current prevalence of undiagnosed Cushing’s syndrome (24,000 cases) and the estimate of the at-risk population (6 million persons), the positive predictive value of the dexamethasone-suppression test is only 0.4%. Thus, this test should not influence what the physician does next and should no longer be used for this purpose.

OUTLIERS

For patients with convincing evidence of Cushing’s syndrome on physical examination and an elevated 24-hour urinary free cortisol level, the differential diagnostic process outlined below should be initiated. However, a small group of patients will not meet these criteria.

Some patients have a strongly positive physical examination but low or zero urinary free cortisol excretion. Plasma corticotropin levels are suppressed in these patients. These patients are receiving exogenous glucocorticoids. The glucocorticoid must be identified, and a plan must be made for its discontinuation. Sometimes the glucocorticoid is being given by proxy (e.g., by a parent to a child), and no history of glucocorticoid administration can be found. Nevertheless, the glucocorticoid must be identified and discontinued.

Other patients have few or no clinical signs of Cushing’s syndrome but do have elevated urinary free cortisol excretion. Plasma corticotropin is measurable in these patients. They are usually identified during an evaluation for arterial hypertension. All such patients should undergo inferior petrosal sinus sampling to determine the source of corticotropin secretion. Ectopic sources are almost always neoplastic and are usually in the chest.25 Patients with eutopic secretion usually have the syndrome of generalized glucocorticoid resistance.26

Finally, a few patients have convincing findings on physical examination coupled with a normal urinary free cortisol level. In such cases, the clinician should make sure that urinary free cortisol is being measured with high-performance liquid chromatography and mass spectrometry, that renal function is normal, and that the collections are complete. “Periodic” Cushing’s syndrome must be ruled out by measuring urinary free cortisol frequently over the course of a month.27 If these efforts fail, the patient should be followed for a year, with urinary free cortisol measurements performed frequently. No additional tests should be performed until the situation is sorted out. More tests would be likely to lead to an unnecessary surgical procedure.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of Cushing’s syndrome is shown in Figure 3

FIGURE 3Differential Diagnosis of Cushing’s Syndrome.. If plasma corticotropin is measurable, the disease process is corticotropin-dependent. If corticotropin is not measurable, the process is corticotropin-independent.

Corticotropin-dependent causes of Cushing’s syndrome are divided into those in which the corticotropin comes from the pituitary (eutopic causes) and those in which the corticotropin comes from elsewhere (ectopic causes). This differentiation is made with the measurement of corticotropin in inferior petrosal sinus plasma and the simultaneous measurement of corticotropin in peripheral (antecubital) plasma immediately after corticotropin-releasing hormone stimulation of pituitary corticotropin secretion. In samples obtained 4, 6, and 15 minutes after stimulation with corticotropin-releasing hormone, eutopic corticotropin secretion is associated with a ratio of the central-plasma corticotropin level to the peripheral-plasma corticotropin level of 3 or more. Ectopic corticotropin secretion is associated with a central-to-peripheral corticotropin ratio of less than 3. The positive predictive value of this test is 1 (Figure 4

FIGURE 4Maximal Ratio of Corticotropin in Inferior Petrosal Sinus Plasma to Corticotropin in Peripheral Plasma in Patients with Cushing’s Syndrome, Ectopic Corticotropin Secretion, or Adrenal Disease.).28

Although some authorities suggest that inferior petrosal sinus sampling can safely be bypassed in patients with corticotropin-dependent Cushing’s syndrome and a well-defined pituitary adenoma, I disagree. The incidence of nonfunctioning pituitary microadenomas is between 15% and 40%.29 This means that up to 40% of patients with ectopic secretion of corticotropin have an incidental pituitary abnormality. If it is assumed that the pituitary abnormality is responsible for corticotropin secretion, 15 to 40% of patients with ectopic secretion of corticotropin will be misdiagnosed and submitted to a transsphenoidal exploration of the sella turcica and pituitary gland. The prevalence of ectopic corticotropin secretion in the population of patients with undiagnosed Cushing’s syndrome is about 10%, accounting for 2400 patients. Up to 40% of these patients, or 960, have an incidental pituitary tumor. The mortality associated with transsphenoidal microadenomectomy is 1%.30 If all 360 to 960 patients undergo this procedure, there will be up to 10 deaths from an operation that can have no benefit. For this reason alone, all patients with corticotropin-dependent Cushing’s syndrome should undergo inferior petrosal sinus sampling to confirm the source of corticotropin secretion before any surgical intervention is contemplated.

Patients with eutopic corticotropin secretion are almost certain to have a corticotropin-secreting pituitary microadenoma. An occasional patient will have alcohol-induced pseudo–Cushing’s syndrome. The slightest suggestion of alcoholism should lead to a 3-week abstinence period before any surgery is considered.31

Patients with ectopic corticotropin secretion are first evaluated with computed tomography (CT) or magnetic resonance imaging (MRI) of the chest. In two thirds of these patients, a tumor will be found.25 If nothing is found in the chest, MRI of the abdominal and pelvic organs is performed. If these additional imaging studies are also negative, there are two options: bilateral adrenalectomy or blockade of cortisol synthesis. If blockade is chosen, the patient should undergo repeat scanning at 6-month intervals.32 If no source is found by the end of the second year, it is unlikely that the source will ever be found, and bilateral adrenalectomy should be performed for definitive treatment (Doppman JL: personal communication).

Corticotropin-independent Cushing’s syndrome is usually caused by an adrenal neoplasm. Benign tumors tend to be small (<5 cm in diameter) and secrete a single hormone, cortisol. The contralateral adrenal gland is suppressed by the cortisol secreted from the tumorous gland. If the value for Hounsfield units is less than 10 and the washout of contrast material is greater than 60% at 15 minutes, the tumor is almost certainly benign.33 Such tumors can be treated successfully with laparoscopic adrenalectomy.

The syndromes of micronodular and macronodular adrenal dysplasia usually affect both adrenal glands. The nodules secrete cortisol. Corticotropin is suppressed, as is the internodular tissue of the adrenal glands. Percutaneous bilateral adrenalectomy, followed by glucocorticoid and mineralocorticoid treatment, is curative.

Adrenal tumors secreting more than one hormone (i.e., cortisol and androgen or estrogen) are almost always malignant. Surgical removal of all detectable disease is indicated, as is a careful search for metastases. If metastases are found, they should be removed. This usually requires an open adrenalectomy. It goes without saying that adrenal tumors, nodules, and metastases should be treated by the most experienced endocrine cancer surgeon available.

If the plasma cortisol level on the morning after a transsphenoidal microadenomectomy is 0, the operation was a success. The patient should be treated with oral hydrocortisone, at a dose of 12 mg per square meter of body-surface area once a day in the morning, and a tetracosactide (Cortrosyn) stimulation test should be performed at 3-month intervals. When the tetracosactide-stimulated plasma cortisol level is higher than 20 μg per deciliter (551 μmol per liter), cortisol administration can be stopped. The same rule applies in the case of a unilateral adrenalectomy. If the adrenalectomy is bilateral, cortisol, at a dose of 12 to 15 mg per square meter per day, and fludrocortisone (Florinef), at a dose of 100 μg per day, should be prescribed as lifelong therapy.

SUMMARY

The obesity epidemic has led to necessary changes in the evaluation and treatment of patients with Cushing’s syndrome. The most dramatic change is the emphasis on the antianabolic alterations in Cushing’s syndrome, which can provide a strong basis for separating patients with Cushing’s syndrome from the more numerous patients with obesity and the metabolic syndrome. More can be done along these lines. Likelihood ratios are known for proximal muscle weakness and can be known for brain atrophy and growth failure in children.

The dexamethasone-suppression test, although still very popular, no longer has a role in the evaluation and treatment of patients with Cushing’s syndrome. Only three biochemical tests are needed: urinary free cortisol, plasma corticotropin, and plasma cortisol measurements. Urinary free cortisol excretion is the test that confirms the clinical diagnosis of Cushing’s syndrome. To be trustworthy, it must be performed in the most stringent way, with the use of high-pressure liquid chromatography followed by mass spectrometric quantitation of cortisol. Measurement of plasma corticotropin is used to separate corticotropin-dependent from corticotropin-independent causes of Cushing’s syndrome and to separate eutopic from ectopic secretion of corticotropin. Inferior petrosal sinus sampling should be performed in all patients with corticotropin-dependent Cushing’s syndrome because of the high prevalence of nonfunctioning incidental pituitary adenomas among such patients. Measurement of plasma cortisol has only one use: determining the success or failure of transsphenoidal microadenomectomy or adrenalectomy. If the plasma cortisol level is not measurable on the morning after the operation (<5 μg per deciliter [138 μmol per liter]), the procedure was a success; if it is measurable, the operation failed. The surgeon must not administer intraoperative or postoperative synthetic glucocorticoids until the plasma cortisol level has been measured.

Successful evaluation of a patient who is suspected of having Cushing’s syndrome requires an endocrinologist who is skilled in physical diagnosis. Also required is a laboratory that measures urinary free cortisol using high-performance liquid chromatography and mass spectrometry and that can measure plasma cortisol and plasma corticotropin by means of radioimmunoassay.

Inferior petrosal sinus sampling is performed by an interventional radiologist. The treatment for all causes of Cushing’s syndrome, other than exogenous glucocorticoids, is surgical, and neurosurgeons, endocrine surgeons, and cancer surgeons are needed. This level of multidisciplinary medical expertise is usually found only at academic medical centers. Thus, most, if not all, patients with Cushing’s syndrome should be referred to such a center for treatment.

Disclosure forms provided by the author are available with the full text of this article at NEJM.org.

No potential conflict of interest relevant to this article was reported.

SOURCE INFORMATION

From the Division of Endocrinology, Diabetes, and Clinical Nutrition, Oregon Health and Science University, Portland.

Address reprint requests to Dr. Loriaux at the Division of Endocrinology, Diabetes, and Clinical Nutrition, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd., L607, Portland, OR 97239-3098, or at .

From http://www.nejm.org/doi/full/10.1056/NEJMra1505550

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Transsphenoidal Surgery Leads to Remission in Children with Cushing’s Disease

Posted on January 19, 2026 by MaryO

Transsphenoidal surgery — a minimally invasive surgery for removing pituitary tumors in Cushing’s disease patients — is also effective in children and adolescents with the condition, leading to remission with a low rate of complications, a study reports.

The research, “Neurosurgical treatment of Cushing disease in pediatric patients: case series and review of literature,” was published in the journal Child’s Nervous System.

Transsphenoidal (through the nose) pituitary surgery is the main treatment option for children with Cushing’s disease. It allows the removal of pituitary adenomas without requiring long-term replacement therapy, but negative effects on growth and puberty have been reported.

In the study, a team from Turkey shared its findings on 10 children and adolescents (7 females) with the condition, who underwent microsurgery (TSMS) or endoscopic surgery (ETSS, which is less invasive) — the two types of transsphenoidal surgery.

At the time of surgery, the patients’ mean age was 14.8 years, and they had been experiencing symptoms for a mean average of 24.2 months. All but one had gained weight, with a mean body mass index of 29.97.

Their symptoms included excessive body hair, high blood pressure, stretch marks, headaches, acne, “moon face,” and the absence of menstruation.

The patients were diagnosed with Cushing’s after their plasma cortisol levels were measured, and there was a lack of cortical level suppression after they took a low-dose suppression treatment. Measurements of their adrenocorticotropic (ACTH) hormone levels then revealed the cause of their disease was likely pituitary tumors.

Magnetic resonance imaging (MRI) scans, however, only enabled tumor localization in seven patients: three with a microadenoma (a tumor smaller than 10 millimeters), and four showed a macroadenoma.

CD diagnosis was confirmed by surgery and the presence of characteristic pituitary changes. The three patients with no sign of adenoma on their MRIs showed evidence of ACTH-containing adenomas on tissue evaluation.

Eight patients underwent TSMS, and 2 patients had ETSS, with no surgical complications. The patients were considered in remission if they showed clinical adrenal insufficiency and serum cortisol levels under 2.5 μg/dl 48 hours after surgery, or a cortisol level lower than 1.8 μg/dl with a low-dose dexamethasone suppression test at three months post-surgery. Restoration of normal plasma cortisol variation, eased symptoms, and no sign of adenoma in MRI were also requirements for remission.

Eight patients (80%) achieved remission, 4 of them after TSMS. Two patients underwent additional TSMS for remission. Also, 1 patient had ETSS twice after TSMS to gain remission, while another met the criteria after the first endoscopic surgery.

The data further showed that clinical recovery and normalized biochemical parameters were achieved after the initial operation in 5 patients (50%). Three patients (30%) were considered cured after additional operations.

The mean cortisol level decreased to 8.71 μg/dl post-surgery from 23.435 μg/dl pre-surgery. All patients were regularly evaluated in an outpatient clinic, with a mean follow-up period of 11 years.

Two patients showed pituitary insufficiency. Also, 2 had persistent hypocortisolism — too little cortisol — one of whom also had diabetes insipidus, a disorder that causes an imbalance of water in the body. Radiotherapy was not considered in any case.

“Transsphenoidal surgery remains the mainstay therapy for CD [Cushing’s disease] in pediatric patients as well as adults,” the scientists wrote. “It is an effective treatment option with low rate of complications.”

 

From https://cushingsdiseasenews.com/2019/01/15/transsphenoidal-surgery-enables-cushings-disease-remission-pediatric-patients-study/

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CV risk elevated in patients with adrenal incidentalomas, mild hypercortisolism

Posted on January 17, 2026 by MaryO

Patients with adrenal incidentalomas and mild hypercortisolism have an increased risk for cardiovascular events and mortality. This risk was evident even when clinical signs of overt hypercortisolism were not present, according to data published in The Lancet Diabetes & Endocrinology.

“Our findings are important because they add to the previously scant information about adrenal incidentalomas, which will be of use to doctors who are seeing an increasing number of patients with these masses,” Renato Pasquali, MD, of the S. Orsola-Malpighi Hospital in Bologna, Italy, said in a press release.

The retrospective study by Pasquali and colleagues assessed the adrenal incidentalomas of 198 outpatients treated every 18 to 30 months, with a mean follow-up of 7.5 years. At the time of follow-up, 114 patients demonstrated stable non-secreting adrenal incidentalomas (<50 nmol/L), 61 had either a stable intermediate phenotype (50 nmol/L-138 nmol/L) or subclinical Cushing’s syndrome (>138 nmol/L), and 23 patients had worsening pattern of secretion.

The incidence of CV events appeared higher in patients with a stable intermediate phenotype or subclinical Cushing’s syndrome (6.7% vs. 16.7%; P=.04) and in those with worsened secreting patterns (6.7% vs. 28.4%; P=.02) compared with patients with stable non-secreting adrenal incidentalomas, according to data.

In addition, CV events were independently related to changes in cortisol concentrations after the 1-mg dexamethasone suppression test (DST; HR=1.13; 95% CI, 1.05-1.21) from baseline to follow-up.

Patients with stable intermediate phenotype adrenal incidentalomas (57%) or subclinical Cushing’s syndrome (91.2%) tended to have lower survival rates for all-cause mortality (P=.005), researchers wrote. The main risk factors for all-cause mortality were age (HR=1.06; 95% CI, 1.01-1.12) and mean concentrations of cortisol after DST (HR=1.1; 95% CI, 1.01-1.19).

The unadjusted survival for CV-related mortality was lower in patients with either a stable intermediate phenotype (97.5%) or subclinical Cushing’s syndrome (78.4%; P=.02) vs. those with stable non-secreting adrenal incidentalomas (97.5%), and patients with worsened secreting patterns (60%; P=.01).

In an accompanying comment, Rosario Pivonello, MD, PhD, Maria Cristina De Martino, PhD, and Annamaria Colao, MD, PhD, of the Federico II University of Naples, Italy, wrote that the study supports the importance of long-term hormonal follow-up for clinical management of patients with adrenal incidentalomas.

“Furthermore, clinical monitoring of cardiometabolic risks seems to be important in these patients, particularly in those with subclinical Cushing’s syndrome and intermediate phenotype adrenal incidentalomas, for whom medical or surgical intervention could be needed,” they wrote.

They suggest long-term prospective studies to determine the frequency of new CV events and mortality in this patient population.

For more information:

Di Dalmazi G. Lancet Diabetes Endocrinol. 2014;doi:10.1016/S2213-8587(13)70211-0.

Pivonello R. Lancet Diabetes Endocrinol. 2014;doi:10.1016/S2213-8587(13)70190-6.

Disclosure: The researchers report no relevant financial disclosures.

This article is from http://www.healio.com/endocrinology/adrenal/news/online/%7B85f94352-9529-4cb7-9532-9c4518f77d80%7D/cv-risk-elevated-in-patients-with-adrenal-incidentalomas-mild-hypercortisolism

 

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Think Like a Doctor: Red Herrings Solved!

Posted on January 11, 2026 by MaryO

By LISA SANDERS, M.D.

On Thursday we challenged Well readers to take the case of a 29-year-old woman with an injured groin, a swollen foot and other abnormalities. Many of you found it as challenging as the doctors who saw her. I asked for the right test as well as the right diagnosis. More than 200 answers were posted.

The right test was…

The dexamethasone suppression test,though I counted those of you who suggested measuring the cortisol in the urine.

The right diagnosis was…

Cushing’s disease

More than a dozen of you got the right answer or the right test, but Dr. Davin Quinn, a consultant psychiatrist at the University of New Mexico Hospital, was the first to be right on both counts. As soon as he saw that the patient’s cortisol level was increased, he thought of Cushing’s. And he had treated a young patient like this one some years ago as a second year resident.

The Diagnosis:

Cushing’s disease is caused by having too much of the stress hormone cortisol in the body. Cortisol is made in the adrenal glands, little pyramid shaped organs that sit atop the kidneys. It is normally a very tightly regulated hormone that helps the body respond to physical stress.

Sometimes the excess comes from a tumor in the adrenal gland itself that causes the little organ to go into overdrive, making too much cortisol. More often the excess occurs when a tumor in the pituitary gland in the brain results in too much ACTH, the hormone that controls the adrenal gland.

In the body, cortisol’s most fundamental job is to make sure we have enough glucose around to get the body’s work done. To that end, the hormone drives appetite, so that enough fuel is taken in through the food we eat. When needed, it can break muscle down into glucose. This essential function accounts for the most common symptoms of cortisol excess: hyperglycemia, weight gain and muscle wasting. However, cortisol has many functions in the body, and so an excess of the hormone can manifest itself in many different ways.

Cushing’s was first described by Dr. Harvey Cushing, a surgeon often considered the father of modern neurosurgery. In a case report in 1912, he described a 23-year-old woman with sudden weight gain, mostly in the abdomen; stretch marks from skin too thin and delicate to accommodate the excess girth; easy bruising; high blood pressure and diabetes.

Dr. Cushing’s case was, it turns out, a classic presentation of the illness. It wasn’t until 20 years later that he recognized that the disease had two forms. When it is a primary problem of an adrenal gland gone wild and producing too much cortisol on its own, the disease is known as Cushing’s syndrome. When the problem results from an overgrown part of the pituitary making too much ACTH and causing the completely normal adrenal glands to overproduce the hormone, the illness is called Cushing’s disease.

It was an important distinction, since the treatment often requires a surgical resection of the body part where the problem originates. Cushing’s syndrome can also be caused by steroid-containing medications, which are frequently used to treat certain pulmonary and autoimmune diseases.

How the Diagnosis Was Made:

After the young woman got her lab results from Dr. Becky Miller, the hematologist she had been referred to after seeing several other specialists, the patient started reading up on the abnormalities that had been found. And based on what she found on the Internet, she had an idea of what was going on with her body.

“I think I have Cushing’s disease,” the patient told her endocrinologist when she saw him again a few weeks later.

The patient laid out her argument. In Cushing’s, the body puts out too much cortisol, one of the fight-or-flight stress hormones. That would explain her high blood pressure. Just about everyone with Cushing’s disease has high blood pressure.

She had other symptoms of Cushing’s, too. She bruised easily. And she’d been waking up crazy early in the morning for the past year or so – around 4:30 – and couldn’t get back to sleep. She’d heard that too much cortisol could cause that as well. She was losing muscle mass – she used to have well-defined muscles in her thighs and calves. Not any more. Her belly – it wasn’t huge, but it was a lot bigger than it had been. Cushing’s seemed the obvious diagnosis.

The doctor was skeptical. He had seen Cushing’s before, and this patient didn’t match the typical pattern. She was the right age for Cushing’s and she had high blood pressure, but nothing else seemed to fit. She wasn’t obese. Indeed, she was tall (5- foot-10) and slim (150 pounds) and athletic looking. She didn’t have stretch marks; she didn’t have diabetes. She said she bruised easily, but the endocrinologist saw no bruises on exam. Her ankle was still swollen, and Cushing’s can do that, but so can lots of other diseases.

The blood tests that Dr. Miller ordered measuring the patient’s ACTH and cortisol levels were suggestive of the disease, but many common problems — depression, alcohol use, eating disorders — can cause the same result. Still, it was worth taking the next step: a dexamethasone suppression test.

Testing, Then Treatment:

The dexamethasone suppression test depends on a natural negative feedback loop whereby high levels of cortisol suppress further secretion of the hormone. Dexamethasone is an artificial form of cortisol. Given in high doses, it will cause the level of naturally-occurring cortisol to drop dramatically.

The patient was told to take the dexamethasone pills the night before having her blood tested. The doctor called her the next day.

“Are you sure you took the pills I gave you last night?” the endocrinologist asked her over the phone. The doctor’s voice sounded a little sharp to the young woman, tinged with a hint of accusation.

“Of course I took them,” she responded, trying to keep her voice clear of any irritation.

“Well, the results are crazy,” he told her and proposed she take another test: a 24-hour urine test.

Because cortisol is eliminated through the kidneys, collecting a full day’s urine would show how much cortisol her body was making. So the patient carefully collected a day’s worth of urine.

A few days later, the endocrinologist called again: her cortisol level was shockingly high. She was right, the doctor conceded, she really did have Cushing’s.

An M.R.I. scan revealed a tiny tumor on her pituitary. A couple of months later, she had surgery to remove the affected part of the gland.

After recovering from the surgery, the patient’s blood pressure returned to normal, as did her red blood cell count and her persistently swollen ankle. And she was able to once again sleep through the night.

Red Herrings Everywhere:

As many readers noted, there were lots of findings that didn’t really add up in this case. Was this woman’s groin sprain part of the Cushing’s? What about the lower extremity swelling, and the excess red blood cell count?

In the medical literature, there is a single case report of high red blood cell counts as the presenting symptom in a patient with Cushing’s. And with this patient, the problem resolved after her surgery – so maybe they were linked.

And what about the weird bone marrow biopsy? The gastritis? The enlarged spleen? It’s hard to say for certain if any of these problems was a result of the excess cortisol or if she just happened to have other medical problems.

Why the patient didn’t have the typical symptoms of Cushing’s is easier to explain. She was very early in the course of the disease when she got her diagnosis. Most patients are diagnosed once symptoms have become more prominent

By the time this patient had her surgery, a couple of months later, the round face and belly characteristic of cortisol excess were present. Now, two years after her surgery, none of the symptoms remain.

From http://well.blogs.nytimes.com/2014/01/17/think-like-a-doctor-red-herrings-solved/?_php=true&_type=blogs&_r=0

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Co-Occurrence of Endogenous and Exogenous Cushing’s Syndromes: Does “Double Cushing Syndrome” Really Exist? A Case Report

Posted on December 1, 2025 by MaryO

ABSTRACT

Double Cushing syndrome exists: exogenous steroid use can mask concurrent adrenal hypercortisolism. When symptoms persist and cortisol remains high after tapering or stopping prescribed glucocorticoids, an endogenous source is likely. Early recognition with ACTH testing, dexamethasone suppression, and adrenal imaging reduces misdiagnosis, favors timely surgery, and supports safe tapering.

1 Introduction

Cushing syndrome (CS) is a non-physiological increase in plasma glucocorticoids [1]. In most cases, the source of increased plasma glucocorticoids is caused by exogenous steroid administration, which is quite common, and about 1% of the world population is on long-term (more than 3 months) oral glucocorticoids [1, 2]. On the contrary, endogenous overproduction of glucocorticoids is rare, and annually, only two to eight per million people are diagnosed with endogenous CS [3]. The simultaneous occurrence of endogenous and exogenous CS is an exceptionally uncommon phenomenon. This dual manifestation has been reported in a few case reports, highlighting its rarity and the complex diagnostic and therapeutic challenges it poses [4, 5]. Therefore, in this study, we discuss a patient who presented with cushingoid features and was simultaneously diagnosed with both endogenous and exogenous CS or, as it is called, double CS.

2 Case Presentation

The patient was a 46-year-old male with a history of new-onset hypertension and recurrent deep vein thrombosis (DVT) who was referred to our endocrinology clinic with a chief complaint of hip pain and weakness of the lower limbs. In the past 3 years, the patient had been receiving 50 mg/day of oral prednisolone and inhalation powder of Umeclidinium and Vilanterol (62.5/25 μg/dose) because of respiratory complications that started after Coronavirus Disease 2019 (COVID-19) vaccination. After 3 months of corticosteroid treatment, he experienced DVT for the first time when he was started on rivaroxaban. However, while he was on treatment, the second DVT occurred 1 month before his referral, and therefore, rivaroxaban was changed to warfarin 5 mg/day.

The patient also mentioned weight gain with his body mass index (BMI) rising from 26 to 31 kg/m2, progressive weakness of proximal muscles, easy bruising, decreased libido, mood changes with mostly euphoric mood, and irritability during the last 2 years. Moreover, multiple osteoporotic fractures of ribs, clavicle, sternum, and lumbar vertebrae were added to his symptoms in the past 5 months. At that time, he underwent bone densitometry, which revealed osteopenia of the left hip with a Z-score of −1.3 and severe osteoporosis of total lumbar spine with a T-score of −3.9. He started taking calcium and vitamin D3 supplements and received a single injection of 750 μg/3 mL teriparatide 30 days before his referral to our center.

Two months ago, the patient gradually reduced the dosage of prednisolone by tapering the dose to 12.5 mg/day. However, a month later, the hip pain and muscle weakness worsened to such an extent that the patient was unable to walk. Due to his signs and symptoms, the patient was referred to our center for further evaluation of CS. The patient also mentioned a history of nephrolithiasis, new-onset hypertension, and lower limb edema, for which he was started on eplerenone 25 mg and furosemide 20 mg tablets once daily. In his family history, the patient’s mother had type 2 diabetes mellitus, and his two sisters had a history of nephrolithiasis. The patient did not mention any history of allergies to medications or foods. He was addicted to opium and had 15 pack-years of smoking, but he did not mention alcohol consumption.

Upon admission, the patient presented with a blood pressure of 150/83 mmHg, heart rate of 74 bpm, respiratory rate of 20/min, temperature of 36.5°C, oxygen saturation of 93%, and BMI of 31 kg/m2. He was sitting in a wheelchair due to weakness and severe pain in the hip. On physical examination, the patient showed the features of CS, including moon face, buffalo hump, central obesity, facial plethora, thin and brittle skin, acne, and purple stretch marks (striae) on the flanks (Figure 1). Proximal muscle weakness in the lower limbs with a muscle force grade of 4/5 and 3+ edema was also observed. Laboratory investigations are shown in Table 1.

Details are in the caption following the image

De-identified clinical photographs illustrating the Cushingoid phenotype. (A) Overall habitus with marked central (truncal) adiposity. (B) Rounded plethoric face (“moon facies”). (C) Relatively slender distal extremities compared with truncal obesity. (D) Dorsocervical fat pad (“buffalo hump”). (E) Upper thoracic/supraclavicular fat accumulation. (F) Protuberant abdomen with wide violaceous striae.
TABLE 1. Laboratory findings of case report.
Laboratory test Patient value (in-hospital) Patient value (follow-up) Reference range
On admission
Hemoglobin (g/dL) 16.6 13.6 13.5–17.5
Hematocrit (%) 49.5 42.1 42–52
WBC (white blood cells; 103/μL) 11.8 7.1 4.0–11.0
PLT (platelet count; 103/μL) 286 294 150–450
BUN (blood urea nitrogen; mg/dL) 10 11 7–18
Cr (creatinine; mg/dL) 0.9 0.9 0.7–1.3
ALP (alkaline phosphatase; IU/L) 1016 129 44–147
AST (aspartate aminotransferase; IU/L) 48 30 < 31
ALT (alanine transaminase; IU/L) 88 21 < 31
CRP (C-reactive protein; mg/dL) 31 3 < 5
ESR (erythrocyte sedimentation rate; mm/h) 63 24 < 15
Sodium (mEq/L) 148 141 136–145
Potassium (mEq/L) 4.8 4.3 3.5–5
FBS (fasting blood glucose; mg/dL) 97 89 80–100
TC (total cholesterol; mg/dL) 267 182 < 200
TG (triglyceride; mg/dL) 148 104 < 200
LDL (low-density lipoprotein; mg/dL) 138 98 < 130
HDL (high-density lipoprotein; mg/dL) 64 55 30–70
In hospital
Cortisol 8 a.m. fasting (μg/dL) 20.2 14.1 4.3–24.9
ACTH (adrenocorticotropic hormone; pg/mL) < 1 — 7.2–63.3
1 mg Overnight dexamethasone suppression test (μg/dL) 16.5 — < 1.8

3 Methods (Differential Diagnosis, Investigations, and Treatment)

Initially suspected of having exogenous-induced CS, the patient’s prednisolone was on hold for 3 days. Cortisol 8 a.m. fasting level, measured with Electrochemiluminescence (ECL) and adrenocorticotropic hormone (ACTH) test, was 20.2 μg/dL (585.4 nmol/L) and < 1 pg/mL, respectively. Due to the lack of suppression of serum cortisol despite not using oral glucocorticoids, the absence of adrenal insufficiency symptoms, and the fact that the patient’s symptoms remained unchanged during this period, co-occurrence of endogenous CS was suspected.

A 1 mg overnight dexamethasone suppression test was performed to confirm endogenous CS diagnosis, and the results were reported as 16.5 μg/dL (normal range < 1.8 μg/dL). Considering the possibility of an ACTH-independent CS, the patient underwent an abdominopelvic multidetector computed tomography (MDCT) of abdominopelvic with adrenal protocol, which revealed a well-defined lesion with an approximate size of 32.8 × 38.6 mm in the left adrenal gland with a radiodensity of 90 Hounsfield units and a normal right adrenal gland (Figure 2). Moreover, evidence of previous old fractures as multiple callus formation was seen involving the clavicles, sternum, bilateral ribs, ischium, and pelvic bones. Multilevel old stable compression fractures of thoracic and lumbar vertebral bodies were also present. The differential diagnoses were glucocorticoid secretory adrenal tumors, including adrenal cell carcinoma and lipid-poor adenoma. In order to rule out pheochromocytoma, 24-h urine catecholamines were measured, and the results were negative.

Details are in the caption following the image

Abdominopelvic multidetector computed tomography (MDCT) with adrenal protocol showing a well-defined lesion with an approximate size of 32.8 × 38.6 mm in the left adrenal gland; radiodensity 90 HU. (A) Transverse plane. (B) Coronal plane. (C) Sagittal plane.

Finally, the patient underwent left adrenalectomy and corticosteroid replacement therapy due to the suppression of the other adrenal gland. According to the post-operative pathological investigations, immunohistochemistry markers reported as negative chromogranin, positive melan-A and inhibin, less than 3% Ki-67 marker, and lipid-poor adrenal cortical adenoma without invasions were diagnosed (Figure 3).

Details are in the caption following the image

Immunohistochemistry of the adrenal lesion (all panels acquired with a 100× oil-immersion objective; 10× eyepiece; original magnification ×1000). (A) Positive inhibin, (B) Positive Melan-A, (C) Less than 3% Ki-67 marker, and (D) Negative chromogranin.

4 Results (Outcome and Follow-Up)

Within 3 months after the operation, the patient’s corticosteroid was tapered and then discontinued due to the normalization of the cortisone serum test (14.1 μg/dL). Proximal limb weakness and hip pain, which had deprived the patient of the ability to move, gradually improved so that he could walk easily and perform daily activities. The signs and symptoms related to CS, including the patient’s mood, skin signs, and general appearance, returned to normal. The patient has been followed up for 6 months after the surgery. The patient’s BMI decreased to 24 kg/m2, and he stopped his anti-hypertensive medications with a blood pressure of 100/60 mmHg without previously prescribed drugs. So far, the laboratory tests have been within the normal range, and he has no complaints (Table 1).

5 Discussion

The described case was diagnosed with a cortisol-producing adrenocortical adenoma accompanied by exogenous CS. CS is an uncommon clinical condition caused by prolonged exposure to increased cortisol levels, which can be due to endogenous or exogenous factors [6]. Endogenous CS is infrequent and is classified as ACTH-dependent (80% of cases) or ACTH-independent (20% of cases) [7]. In the ACTH-independent category, adrenal adenoma accounts for 60% of cases and only 12% of cases of endogenous CS [7, 8]. Exogenous CS mainly occurs due to prolonged administration of glucocorticoids, which are used to manage a broad spectrum of diseases such as inflammatory, autoimmune, or neoplastic disorders and are the most common cause of CS worldwide [9]. Multiple factors, including formulation, duration of administration, pharmacokinetics, affinity, and potency of exogenous glucocorticoids, affect the probability of exogenous CS, but all forms of glucocorticoids can induce CS [10].

In the setting of cushingoid clinical features with chronic administration of high-dose glucocorticoids, especially oral prednisolone, the probability of exogenous CS is remarkably high; therefore, CS diagnostic approaches suggest that the first step after confirmation of cortisol excess is ruling out exogenous glucocorticoid administration [7, 8, 10]. Therefore, the possibility of co-occurrence of endogenous CS with iatrogenic CS is extremely low, and the diagnosis requires high clinical suspicion [4].

Differentiating endogenous and exogenous CS based on clinical features can be challenging and far-fetched. However, a few points can help physicians distinguish between these two. First, exogenous CS symptoms tend to be more striking, while endogenous CS appears more gradually. Second, hypertension, hypokalemia, and features of androgen excess, such as acne and hirsutism, are more common in endogenous CS [4, 10]. In addition, endogenous CS should be suspected if the patient’s symptoms continue after corticosteroid discontinuation or if the serum cortisol level is high despite corticosteroid cessation. In our case, the patient had a high cortisol level despite stopping prednisolone for 3 days, and he did not have any symptoms of adrenal insufficiency despite stopping prednisolone suddenly. Consequently, it was suspected that glucocorticoids might come from an endogenous source. Because ACTH was suppressed concurrently with elevated cortisol, non-ACTH-dependent CS was suspected, and MDCT of abdominopelvic confirmed it.

So far, few similar cases of simultaneous endogenous and exogenous CS have been reported. The first case was a 23-year-old woman with juvenile idiopathic arthritis who was administered high doses of triamcinolone for 16 years [4]. The development of cushingoid features that favored endogenous CS, such as hirsutism and acne, strengthened the suspicion of endogenous CS, and a CT scan revealed hypercortisolism with a bulky and nodular left adrenal gland, and a double CS was confirmed [4]. The second case was a 66-year-old woman diagnosed with exogenous CS after consumption of Traditional Chinese medicine (TCM) for a year [5]. The cessation of TCM did not significantly improve her cushingoid features, and she developed additional CS complications, including hypertension, diabetes mellitus, and osteoporotic fractures over the next 8 years. CS workup revealed a right-sided adrenal adenoma, and after the adrenalectomy, her clinical cushingoid features markedly improved [5]. These cases suggest that exogenous and endogenous CS can exist simultaneously in the same person. Although it is very rare, it should be considered in a person who still complains of CS symptoms after corticosteroid cessation. We suggest clinicians evaluate the patients for the disappearance of exogenous CS symptoms after tapering and stopping glucocorticoids. If the symptoms remain, they should be evaluated for endogenous CS.

6 Conclusion

The co-occurrence of an endogenous CS in the setting of an exogenous CS is curious. The diagnosis is based on a high clinical suspicion. Clinicians should evaluate patients for symptom resolution after tapering and discontinuing corticosteroids. Clinical cushingoid features that do not resolve after discontinuing exogenous glucocorticoids and high cortisol levels despite discontinuing corticosteroids should raise clinicians’ suspicion of the co-occurrence of exogenous and endogenous CS.

Author Contributions

Reza Amani-Beni: investigation, methodology, writing – original draft, writing – review and editing. Atiyeh Karimi Shervedani: methodology, writing – original draft. Bahar Darouei: conceptualization, validation, writing – review and editing. Matin Noroozi: methodology, writing – original draft. Maryam Heidarpour: conceptualization, supervision, validation, writing – review and editing.

Acknowledgments

The authors have nothing to report.

Consent

Written informed consent was obtained from the patient to publish this report, including de-identified clinical photographs, in accordance with the journal’s patient consent policy.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that supports the findings of this study are available on request of the corresponding author. The data are not publicly available due to privacy restrictions.

https://onlinelibrary.wiley.com/doi/10.1002/ccr3.71419

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