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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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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Pituitary adenoma growth rate influenced by multiple factors

Posted on January 9, 2026 by MaryO

Monsalves E. J. Clin Endocrinol Metab. 2013; doi: 10. 1210/jc.2013-3054.

The etiology of pituitary adenoma growth rate is multifactorial and may be influenced by patient age and gender, as well as adenoma subtype, hormonal activity, immunohistological profile and the direction of growth relative to the pituitary fossa, according to results of a retrospective study.

Researchers evaluated pre- and postoperative pituitary adenoma (PA) traits in relation to patient demographics, MRI specifications and histopathological factors. They examined 153 patients who underwent surgery for removal of a histologically-proven PA at Toronto Western Hospital between 1999 and 2011.

All patients had at least two preoperative and two postoperative MRIs to measure tumor volume doubling time. Both scans were completed a minimum of 3 months apart.

Patients all underwent a sella/pituitary imaging protocol, and volume was determined using partitioning and target volume software. Each patient was also reviewed by two endocrine pathologists, and standardized diagnostic synoptic pathology reports provided information on MIB-1 labeling index, p27 and N-terminally truncated fibroblast growth factor receptor 4 (FGFR4). Growth direction patterns were classified as superior, anterior, posterior and lateral in relation to the sellar fossa.

The researchers found a relationship between preoperative growth rate and age (P=.0001), as well as suprasellar growth (P=.003), existence of a cyst or hemorrhage (P= .004), the MIB-1 (P=.005), FGFR4 positivity (P=.047) and p27 negativity (P=.007).

Postoperatively, 34.6% of patients demonstrated residual volumes, while the remaining 100 patients did not. Residual volume was found to be associated with older patient age (57 vs. 51, P=.038), as well as growth patterns, including anterior, posterior, suprasellar and cavernous sinus extension (P=.001). There was a correlation between pre-and postoperative growth rates (r=0.497, P=.026). The rates of postoperative growth were linked with age (P=.015) and gender (P= .017).

“Due to the heterogeneity of PA, no single predictor of PA growth behavior can be taken in isolation as a means to predict its outcome,” the researchers wrote.  “These predictors must be combined in order to formulate the most accurate estimation of PA growth, which in turn will inform sound clinical management.”

Disclosures: The researchers report no relevant financial disclosures.

From http://www.healio.com/endocrinology/neuroendocrinology/news/online/%7B7cb2ec5d-eaa6-42a3-b279-2c2436d0fbd0%7D/pituitary-adenoma-growth-rate-influenced-by-multiple-factors

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Genetic mutation lowers obesity in Cushing’s syndrome

Posted on January 5, 2026 by MaryO

London E. J Clin Endocrinol Metab. 2013; doi:10.1210/jc.2013-1956.

Among adult patients with Cushing’s syndrome, those with mutations in PRKAR1A, the gene that controls cAMP-dependent protein kinase, are less obese than their counterparts without these mutations, according to a recent study.

The retrospective study evaluated adrenalectomy samples from 51 patients with Cushing’s syndrome, 13 with PRKAR1A mutations and 32 without. Of the 51 patients, 40 were female and 11 were male, and patients ranged in age from 4 to 74 years.

A non-Cushing’s syndrome comparison group consisting of 6 adrenalectomy patients with aldosterone producing adenomas (APAs) was included. Additional comparison groups comprising clinical data from 89 patients with Cushing’s disease and 26 with hyperaldosteronism were also studied.

Researchers recorded the weight, height and BMI of all patients, and measured abdominal subcutaneous adipose tissue (ScAT) and periadrenal adipose tissue (PAT) using computed tomography. PAT was collected and frozen for evaluation; the extracts were assessed for levels of cAMP and protein kinase (PKA) activity, as well as for protein and mRNA expression of subunits of PKA. Diurnal cortisol levels and urine-free cortisol were also measured preoperatively.

The study found that in adults with Cushing’s syndrome, the mean BMI of those with PRKAR1A mutations was lower than that of patients with noPRKAR1A mutations (P<.05), and was not inconsistent with the hyperaldosteronism comparison group.

In pediatric patients with adrenal Cushing’s syndrome, the presence of PRKAR1A mutation did not have an impact on mean BMI z-scores. However, in comparison with pediatric patients with pituitary Cushing’s disease, the BMI z-scores were significantly lower in pediatric Cushing’s disease patients with PRKAR1Amutations (P<.05). Patients with Cushing’s syndrome without PRKAR1A mutations had significantly more PAT and ScAT than non-Cushing’s syndrome patients. Additionally, the ratio of basal-to-total (cAMP-triggered) PKA activity was significantly lower in patients with PRKAR1A mutations, suggesting greater proportions of active PKA (P<.005).

“These findings have obvious implications in the establishment of the diagnosis of CS in patients with PRKAR1A mutations: These patients may be leaner than other patients with [Cushing’s syndrome],” the study authors wrote. “Perhaps more importantly, our findings point to the importance of cAMP and or PKA signaling in the regulation of adiposity.”

Disclosures: The researchers report no relevant financial disclosures.

From http://www.healio.com/endocrinology/adrenal/news/online/%7B693f94cd-359d-4c52-8e0d-bfd0e4a51d03%7D/genetic-mutation-lowers-obesity-in-cushings-syndrome

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Enhanced Radiological Detection of a Corticotroph Adenoma Following Treatment With Osilodrostat

Posted on October 28, 2025 by MaryO

Abstract

In approximately 30% of patients with Cushing disease, pituitary magnetic resonance imaging (MRI) does not reliably identify a corticotroph adenoma. Importantly, surgical remission rates are >2.5 fold higher for microadenomas that are radiologically visible on preoperative imaging when compared with “MRI-negative” cases. We describe a 42-year-old woman with Cushing disease, in whom MRI findings at presentation were equivocal with no clear adenoma visualized. She was initially treated with metyrapone, which resulted in partial biochemical control of hypercortisolism. After switching to osilodrostat, there was a marked improvement in her symptoms and rapid normalization of cortisol levels. Following 3 months of eucortisolemia, [11C]methionine positron emission tomography (MET-PET) coregistered with volumetric MRI (MET-PET/MRCR) localized the site of the corticotroph tumor and the patient underwent successful transsphenoidal resection. She remains in full clinical and biochemical remission at >2 years postsurgery. This case suggests that a period of eucortisolemia induced by osilodrostat may facilitate localization of corticotroph microadenomas using functional (PET) imaging.

Cushing disease, osilodrostat, [11C]methionine PET, corticotroph adenoma
Issue Section:

Case Report

Introduction

Cushing disease, caused by an ACTH-secreting pituitary adenoma, accounts for approximately 80% of endogenous Cushing syndrome [1]. Although transsphenoidal surgery remains the preferred treatment for the majority of patients, even in expert centers recurrence rates as high as 27% have been reported [2, 3]. Surgery is preferred over medical therapy because it offers the potential for definitive cure by directly removing the pituitary adenoma. In contrast, medical therapy is typically reserved for patients in whom surgery is contraindicated, incomplete, or has failed to achieve remission. Linked to this, magnetic resonance imaging (MRI) fails to detect an adenoma in approximately one third of cases [4]. In a recent systematic review, postsurgical remission rates were 2.63-fold higher (95% CI, 2.06-3.35) for MRI-detected corticotroph adenomas when compared with “MRI-negative” cases [5]. Several alternative magnetic resonance sequences have therefore been proposed to aid tumor localization (including dynamic and volumetric [eg, gradient recalled echo MRI]), but these still fail to detect a significant proportion of microcorticotropinomas [6, 7]. Accordingly, molecular (functional) imaging with positron emission tomography (PET) radiotracers that target key properties of corticotroph adenomas (eg, [11C]methionine [MET-PET], [18F]fluoroethyltyrosine, or [68Ga]DOTA-corticotropin-releasing hormone PET) has been proposed as an additional tool for localizing corticotroph tumors that evade detection on conventional MRI [6-10].

Medical therapy is often required for patients in whom surgery is not an immediate option or when there is persistent hypercortisolism postoperatively [11]. Cortisol-lowering treatment may also be considered before surgery to reduce morbidity and perioperative complications [11]. An important recent addition to the armory of medications used to treat Cushing syndrome is osilodrostat, a potent oral inhibitor of the key adrenal steroidogenic enzyme 11β-hydroxylase [12, 13].

Here, we describe how preoperative medical therapy with osilodrostat yielded dual benefits in a patient with inconclusive primary imaging: (1) rapid and effective control of hypercortisolism and (2) facilitation of the localization of a previously occult microcorticotroph adenoma using MET-PET coregistered with volumetric MRI (MET-PET/MRCR).

Case Presentation

A 42-year-old woman presented with a 7-year history of progressive central weight gain, facial plethora, acne, worsening hypertension, depression, and proximal myopathy. Her symptoms had become more pronounced during the COVID-19 pandemic, leading to profound emotional distress and functional decline. She described feeling persistently tearful and fatigued, with markedly reduced energy levels that rendered her unable to work or care for her young child, and severely affecting her quality of life. She had no significant medical history and was taking amlodipine and the progesterone-only pill. On examination, her body mass index was 29.6 kg/m² and blood pressure was markedly elevated at 197/111 mm Hg. Clinical features consistent with hypercortisolism included easy bruising, centripetal adiposity, and proximal muscle wasting. Initial laboratory evaluation was unremarkable; however, her hemoglobin A1c was at the upper end of normal (41 mmol/mol or 5.9%).

Diagnostic Assessment

Biochemical testing confirmed ACTH-dependent Cushing syndrome (Table 1). Cortisol levels following overnight and 48-hour dexamethasone suppression were elevated at 8 µg/dL (SI: 219 nmol/L) and 16 µg/dL (SI: 434 nmol/L), respectively (reference range: < 1.8 µg/dL [SI: < 50 nmol/L]). Plasma ACTH concentrations ranged from 36 to 55 ng/L (SI: 7.9-12.1 pmol/L) (reference range: 10-30 ng/L [SI: 2.2-6.6 pmol/L]), consistent with an ACTH-driven process. Urinary free cortisol (UFC) was markedly elevated at 690.95 µg/24 hours (SI: 1907 nmol/24 hours) (reference range: 18-98 µg/24 hours [SI: 50-270 nmol/24 hours]). Late-night salivary cortisol and cortisone levels were also elevated at 0.95 µg/dL (SI: 26.2 nmol/L) (reference range: < 0.09 µg/dL [SI: < 2.6 nmol/L]) and 2.7 µg/dL (SI: 74.5 nmol/L) (reference range: < 0.7 µg/dL [SI: < 18 nmol/L]) respectively. Inferior petrosal sinus sampling excluded an ectopic source of ACTH production (central-to-peripheral ACTH ratio: baseline 18.60, 0 minutes 18.4, peak at 2 minutes 94.9, 5 minutes 42.4, 10 minutes 22.3) (Table 2). However, pituitary MRI findings were inconclusive, with no definite adenoma identified. In addition, the left intracavernous carotid artery encroached medially, creating a narrow intercarotid window with distortion of normal pituitary anatomy (Fig. 1). Given these findings, the decision was made to initiate cortisol-lowering therapy and to reassess imaging appearances after a period of biochemical normalization.

Pituitary MRI at initial presentation. No discrete adenoma is visible on T1-weighted coronal precontrast (A) and postcontrast (B), T2-weighted coronal (C), and T1-weighted sagittal postcontrast (D) sequences. The sellar anatomy appears asymmetric, consistent with a medially positioned left internal carotid artery.

Figure 1.

Pituitary MRI at initial presentation. No discrete adenoma is visible on T1-weighted coronal precontrast (A) and postcontrast (B), T2-weighted coronal (C), and T1-weighted sagittal postcontrast (D) sequences. The sellar anatomy appears asymmetric, consistent with a medially positioned left internal carotid artery.

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Table 1.

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Biochemical investigations at diagnosis confirming ACTH-dependent Cushing syndrome

Tests Results Reference Range
Overnight dexamethasone suppression test (ONDST) Cortisol: 8 µg/dL (SI: 219 nmol/L) <1.8 µg/dL (SI: < 50 nmol/L)
48-hour dexamethasone suppression test (DST) Cortisol: 16 µg/dL (SI: 434 nmol/L) <1.8 µg/dL (SI: < 50 nmol/L)
ACTH 36-55 ng/L (SI: 7.9-12.1 pmol/L) 10-30 ng/L (SI: 2.2-6.6 pmol/L)
24-hour urinary free cortisol (UFC) 690.95 μg/24 h (SI: 1907 nmol/24 h) 18-98 µg/24 h (SI: 50-270 nmol/24 hours)
Late-night salivary cortisol
late-night salivary cortisone		 0.95 µg/dL (SI: 26.2 nmol/L)
2.7 µg/dL (SI: 74.5 nmol/L)		 <0.09 µg/dL (SI: <2.6 nmol/L) <0.7 µg/dL (SI: <18 nmol/L)

Results are reported in both conventional and SI units with reference ranges shown in parentheses.

Table 2.

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Results of inferior petrosal sinus sampling (IPSS)

Time Plasma ACTH
(min) Left petrosal sinus Right petrosal sinus Peripheral vein
−5 1159 ng/L (255 pmol/L) 144 ng/L (32 pmol/L) 62.3 ng/L (14 pmol/L)
0 1147 ng/L (253 pmol/L) 222 ng/L (49 pmol/L) 62.3 ng/L (14 pmol/L)
2 5257 ng/L (1157 pmol/L) 2159 ng/L (475 pmol/L) 55.4 ng/L (12.2 pmol/L)
5 3677 ng/L (810 pmol/L) 2976 ng/L (655 pmol/L) 86.8 ng/L (19 pmol/L)
10 2251 ng/L (496 pmol/L) 545 ng/L (120 pmol/L) 101 ng/L (22 pmol/L)

Time Plasma cortisol
(min) Left petrosal sinus Right petrosal sinus Peripheral vein
−5 24.94 μg/dL (668 nmol/L) 25.30 μg/dL (698 nmol/L) 23.56 μg/dL (650 nmol/L)
0 25.08 μg/dL (692 nmol/L) 24.07 μg/dL (664 nmol/L) 23.34 μg/dL (644 nmol/L)
2 23.31 μg/dL (643 nmol/L) 24.32 μg/dL (671 nmol/L) 23.78 μg/dL (656 nmol/L)
5 21.97 μg/dL (606 nmol/L) 23.67 μg/dL (653 nmol/L) 23.23 μg/dL (641 nmol/L)
10 27.62 μg/dL (762 nmol/L) 26.17 μg/dL (722 nmol/L) 25.26 μg/dL (697 nmol/L)

Time Plasma prolactin
(min) Left petrosal sinus Right petrosal sinus Peripheral vein
−5 1835 mU/L (86 μg/L) 356 mU/L (17 μg/L) 251 mU/L (11 μg/L)
0 1725 mU/L (81 μg/L) 498 mU/L (23 μg/L) 248 mU/L (12 μg/L)
2 2151 mU/L (101 μg/L) 409 mU/L (19 μg/L) 240 mU/L (11 μg/L)
5 2239 mU/L (105 μg/L) 711 mU/L (33 μg/L) 246 mU/L (12 μg/L)
10 1883 mU/L (89 μg/L) 410 mU/L (19 μg/L) 244 mU/L (11 μg/L)

Central-to-peripheral ACTH gradients before and after corticotropin-releasing hormone (CRH) stimulation support a pituitary source of ACTH secretion. Reference cutoffs: basal ACTH gradient ≥2 and/or CRH-stimulated ACTH gradient ≥3 indicate central ACTH secretion.

Treatment

The patient was started on metyrapone, but despite dose escalation up to 4000 mg daily, which was associated with significant nausea and malaise, she did not achieve eucortisolemia (Fig. 2C). She was therefore transitioned to osilodrostat, which rapidly normalized cortisol levels within 5 weeks at a maintenance dose of 6 mg twice daily (Fig. 2B and 2C). In contrast to metyrapone, osilodrostat was well-tolerated with no reported side effects. Serum cortisol and clinical status were closely monitored throughout, with no biochemical or clinical evidence of adrenal insufficiency.

Bar charts illustrating changes in urinary, salivary, and serum cortisol, as well as serum ACTH, during medical treatment. (A) A 24-hour UFC (black bars, left y-axis) normalized during osilodrostat treatment, whereas serum ACTH (gray bars, right y-axis) increased. Dotted lines represent the upper limit of normal: 59.4 µg/24 hours (SI: 164 nmol/24 hours) for UFC and 30 ng/L (SI: 6.6 pmol/L) for ACTH. X-axis labels indicate treatment week and total daily osilodrostat dose. (B) Salivary free cortisol levels, collected alongside serum cortisol during a cortisol day curve (at 09:00, 12:00, 15:00, and 18:00), fully normalized with osilodrostat therapy. Bar shading from black to light gray denotes sampling time. The dotted line indicates upper limit of normal: 9.4 ng/dL (SI: 2.6 nmol/L). (C) Serum free cortisol levels during day curves showed inadequate control on escalating doses of metyrapone, with normalization achieved following initiation of osilodrostat.

Figure 2.

Bar charts illustrating changes in urinary, salivary, and serum cortisol, as well as serum ACTH, during medical treatment. (A) A 24-hour UFC (black bars, left y-axis) normalized during osilodrostat treatment, whereas serum ACTH (gray bars, right y-axis) increased. Dotted lines represent the upper limit of normal: 59.4 µg/24 hours (SI: 164 nmol/24 hours) for UFC and 30 ng/L (SI: 6.6 pmol/L) for ACTH. X-axis labels indicate treatment week and total daily osilodrostat dose. (B) Salivary free cortisol levels, collected alongside serum cortisol during a cortisol day curve (at 09:00, 12:00, 15:00, and 18:00), fully normalized with osilodrostat therapy. Bar shading from black to light gray denotes sampling time. The dotted line indicates upper limit of normal: 9.4 ng/dL (SI: 2.6 nmol/L). (C) Serum free cortisol levels during day curves showed inadequate control on escalating doses of metyrapone, with normalization achieved following initiation of osilodrostat.

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ACTH levels progressively increased as the dose of osilodrostat was escalated (Fig. 2A). After 3 months of biochemical eucortisolism, she underwent Met-PET/MRCR, which revealed a distinct methionine-avid lesion in the right posterolateral aspect of the sella (Fig. 3). Imaging was performed as previously reported [7, 8, 14]. Conventional MRI findings remained stable, with no new abnormalities. As she remained clinically and biochemically eucortisolemic on osilodrostat, glucocorticoid supplementation was not required pre- or perioperatively.

11C-Methionine PET/CT coregistered with volumetric MRI (MET-PET/MRCR) following treatment with osilodrostat. A subtle area of reduced gadolinium enhancement can now be appreciated on the right posterosuperior aspect of the gland (A-C). MET-PET/MRCR confirms focal tracer uptake at this site (yellow arrows) and also within normal gland anteriorly (white arrow) (D-F). Three-dimensional reconstruction using CT, MRI, and PET datasets demonstrating the location of the corticotroph microadenoma which was confirmed at subsequent surgery (G-H).

Figure 3.

11C-Methionine PET/CT coregistered with volumetric MRI (MET-PET/MRCR) following treatment with osilodrostat. A subtle area of reduced gadolinium enhancement can now be appreciated on the right posterosuperior aspect of the gland (A-C). MET-PET/MRCR confirms focal tracer uptake at this site (yellow arrows) and also within normal gland anteriorly (white arrow) (D-F). Three-dimensional reconstruction using CT, MRI, and PET datasets demonstrating the location of the corticotroph microadenoma which was confirmed at subsequent surgery (G-H).

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Outcome and Follow-up

At transsphenoidal surgery, abnormal tissue was resected from the site identified on MET-PET/MRCR. Histological examination revealed normal anterior pituitary tissue (adenohypophysis) with no evidence of a pituitary adenoma. Occasional cells showed possible Crooke’s hyaline change. The Ki-67 proliferation index was very low (<1%). Despite the absence of histological confirmation of a corticotroph adenoma, the patient entered complete biochemical and clinical remission. Early postoperative cortisol was 3 µg/dL (SI: 82.8 nmol/L), prompting initiation of glucocorticoid replacement with prednisolone. Prednisolone was chosen for its longer half-life, enabling convenient once-daily dosing. We routinely monitor prednisolone levels to guide adjustment of replacement dosing. Prednisolone was successfully tapered over a period of 6 months, with biochemical confirmation of adrenal recovery. At 2 years postsurgery, the patient had no clinical features of hypercortisolism with sustained weight loss of >20 kg. Morning 09:00 cortisol and ACTH were consistent with ongoing eucortisolism. Serial late-night salivary cortisol and cortisone levels were normal, and cortisol was undetectable following a 1-mg overnight dexamethasone suppression test, confirming durable remission of Cushing disease.

Discussion

Early transsphenoidal surgery remains the treatment of choice for most patients with Cushing disease, with the highest chance of cure achieved following a successful first operation [11]. However, even in expert centers, persistent or recurrent disease is diagnosed during follow-up, and is more likely when initial MRI has failed to identify a clear surgical target [5]. Reoperation carries increased technical difficulty and a higher risk of iatrogenic hypopituitarism, underscoring the importance of accurate preoperative localization of corticotroph adenomas. Our case illustrates a potential novel added benefit of a trial of primary medical therapy in a patient with Cushing disease and equivocal or negative MRI findings at initial presentation. Specifically, we have shown how osilodrostat, a potent inhibitor of 11β-hydroxylase, can achieve rapid normalization of cortisol levels, consistent with the findings of the LINC (LCI699 [osilodrostat] in Cushing disease) series of studies [15-17], and at the same time help reveal the location of the occult microcorticotropinoma. An important consequence of achieving effective adrenal blockade in our patient was the more than threefold accompanying rise in plasma ACTH levels (Fig. 2). We hypothesized that such an increase in tumoral activity might facilitate its detection using molecular (functional) imaging. MET-PET has been shown in several studies to facilitate localization of de novo and recurrent corticotroph adenomas [8, 18, 19] in a significant proportion of patients with equivocal or negative MRI findings. We have now shown that such an approach could potentially be enhanced by pretreatment with the potent 11β-hydroxylase inhibitor osilodrostat.

We also considered whether the rise in ACTH during osilodrostat therapy reflected increased tumor activity alone or was associated with a change in tumor size. In our case, ACTH rose significantly, likely reflecting enhanced secretory activity, whereas repeat conventional MRI remained stable, with no new abnormalities or interval changes. In the LINC 4 study, tumor volume data were available for 35 patients at both baseline and week 48. Among these, 40.0% had a ≥20% increase, 28.6% had a ≥20% decrease, and 31.4% had <20% change in tumor volume. These outcomes were observed in both microadenomas and macroadenomas, with no clear correlation to treatment duration or osilodrostat dose [20]. This variability suggests that osilodrostat does not exert a consistent effect on tumor volume.

Interestingly, although histopathological analysis did not confirm a corticotroph adenoma, this is a well-recognized finding and has been reported in a significant proportion of patients undergoing surgery for Cushing disease [21, 22]. Nonetheless, we consider the diagnosis of pituitary-dependent Cushing syndrome was clearly established by the clinical features, results of initial laboratory testing and findings at inferior petrosal sinus sampling (which demonstrated a clear central-to-peripheral ACTH gradient). In addition, abnormal tissue was identified intraoperatively at the site visualized on MET-PET and fully resected, and no other abnormal foci of tissue were seen. The patient has subsequently achieved complete and sustained clinical and biochemical remission, consistent with successful removal of an ACTH-secreting adenoma.

Recent case reports have raised concerns about prolonged adrenal insufficiency following extended osilodrostat use—an unexpected finding given the drug’s short half-life [23-25]. Although adrenal insufficiency requiring temporary glucocorticoid replacement had been reported in clinical trials (most commonly in patients undergoing rapid dose escalation [12, 15, 16]), prolonged hypothalamopituitary-adrenal axis suppression resulting from supraphysiologic glucocorticoid replacement could also be contributory. For now, the exact mechanism of this observed phenomenon remains unclear. Our patient managed to wean glucocorticoid replacement postoperatively and did not demonstrate prolonged adrenal suppression; at the same time, clinical and biochemical testing confirmed full remission from Cushing disease.

This case supports the hypothesis that preoperative cortisol suppression may enhance the diagnostic accuracy of molecular (functional) imaging in Cushing disease, particularly in cases with inconclusive MRI findings. If validated in prospective studies, this approach could refine surgical planning and potentially lead to better surgical success and durable clinical outcomes.

Learning Points

  • Approximately 30% of corticotroph adenomas causing Cushing disease are not readily localized on conventional pituitary MRI.

  • Functional imaging modalities such as MET-PET/MRCR can improve detection of previously occult pituitary adenomas in Cushing disease.

  • A period of medical pretreatment with osilodrostat, with consequent reduction in negative feedback by glucocorticoid at the hypothalamic-pituitary level, may augment tumor localization by molecular imaging.

Acknowledgments

The authors acknowledge Debbie Papadopoulou and Niamh Martin for their contributions to clinical management. Nigel Mendoza performed the transsphenoidal surgery.

Contributors

All authors made individual contributions to authorship. Z.H., L.Y., J.M., M.G., and F.W. were involved in the diagnosis and management of this patient and manuscript submission. J.M., D.G., and M.G. performed and analyzed the patient’s functional imaging. All authors reviewed and approved the final draft.

Funding

No public or commercial funding

Disclosures

None declared.

Informed Patient Consent for Publication

Signed informed consent obtained directly from the patient.

Data Availability Statement

Original data generated and analyzed during this study are included in this published article.

© The Author(s) 2025. Published by Oxford University Press on behalf of the Endocrine Society.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. See the journal About page for additional terms.

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