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

Filed under: adrenal, Cushing, Cushing's, Helpful Doctors, pituitary | Tagged: , , , , , , , , , , , , , , , , , , , , , | Leave a comment »

Identification Of Potential Markers For Cushing’s Disease

Posted on January 27, 2026 by MaryO

Endocr Pract. 2016 Jan 20. [Epub ahead of print]

Broder MS1, Chang E1, Cherepanov D1, Neary MP2, Ludlam WH2.

Author information

Abstract

OBJECTIVE:

Cushing’s disease (CD) causes a wide variety of nonspecific symptoms, which may result in delayed diagnosis. It may be possible to uncover unusual combinations of otherwise common symptoms using ICD-9-CM codes. Our aim was to identify and evaluate dyads of clinical symptoms or conditions associated with CD.

METHODS:

We conducted a matched case-control study using a commercial healthcare insurance claims database, designed to compare the relative risk (RR) of individual conditions and dyad combinations of conditions among patients with CD versus matched non-CD controls.

RESULTS:

With expert endocrinologist input, we isolated 10 key conditions (localized adiposity, hirsutism, facial plethora, polycystic ovary syndrome, abnormal weight gain, hypokalemia, deep venous thrombosis, muscle weakness, female balding, osteoporosis) with RR varying from 5.1 for osteoporosis to 27.8 for hirsutism. The RR of dyads of these conditions ranged from 4.1 for psychiatric disorders/serious infections to 128.0 for hirsutism/fatigue in patients with vs. without CD. Construction of uncommon dyads resulted in further increases in RR beyond single condition analyses, such as osteoporosis alone had RR of 5.3, which increased to 8.3 with serious infections and to 52.0 with obesity.

CONCLUSION:

This study demonstrated that RR of any one of 10 key conditions selected by expert opinion was ≥5 times greater in CD compared to non-CD, and nearly all dyads had RR≥5. An uncommon dyad of osteoporosis and obesity had an RR of 52.0. If clinicians consider the diagnosis of CD when the highest-risk conditions are seen, identification of this rare disease may improve.

KEYWORDS:

Cushing’s disease; delay in diagnosis; disease markers; insurance claims; relative risk

PMID:
26789346
[PubMed – as supplied by publisher]

From http://www.ncbi.nlm.nih.gov/pubmed/26789346

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Iatrogenic Cushing’s Syndrome and the Hidden Ingredient of Artri King

Posted on January 8, 2026 by MaryO

Abstract

Cushing’s syndrome is a rare disorder caused by prolonged exposure to glucocorticoids, either from endogenous overproduction or exogenous sources, with exogenous steroid use being the most common etiology. Clinical manifestations may include moon facies, abdominal striae, easy bruising, muscle weakness, and complications such as osteoporosis and fragility fractures. Many remedies and supplements marketed for inflammatory conditions are sold online or over the counter, and some may contain hidden or undisclosed steroids that can lead to hypercortisolism. We present a case of a 52-year-old man with osteoporosis who sustained fragility fractures and became wheelchair-bound due to progressive lower extremity weakness. Evaluation demonstrated suppression of the hypothalamic-pituitary-adrenal axis, with undetectable salivary and urinary cortisol levels. Further investigation revealed long-term use of Artri King, a supplement for musculoskeletal pain that contains undisclosed glucocorticoids. This case highlights the risk of unregulated supplements causing iatrogenic Cushing’s syndrome and its associated complications.

Introduction

Cushing’s syndrome represents a constellation of signs and symptoms resulting from prolonged exposure to glucocorticoids [1]. Common manifestations may include moon facies, facial plethora, abdominal striae, easy bruising, and proximal muscle weakness [1]. Etiologies may be adrenocorticotropic hormone (ACTH)-dependent, originating from pituitary or ectopic sources, or ACTH-independent, such as adrenal pathology. In everyday clinical practice, however, exogenous glucocorticoid exposure remains the most common cause [2,3].

Exogenous steroids are available in multiple formulations, including oral, parenteral, inhaled, and topical preparations, and may be prescribed by healthcare providers or found in commercial products sold online or over the counter [4]. Prolonged exposure can result in hypercortisolism and its associated complications [5]. Therefore, careful assessment for exogenous steroid use is essential when evaluating patients with suspected Cushing’s syndrome. We report a case of iatrogenic Cushing’s syndrome secondary to the use of Artri King, a “herbal” supplement containing undisclosed glucocorticoids.

Case Presentation

A 52-year-old male with a history of prediabetes presented with osteoporosis and fragility fractures. Osteoporosis was diagnosed during imaging performed for the evaluation of back pain, which revealed thoracic spine compression fractures as well as a healed rib fracture. As a result, he became wheelchair-bound due to progressive lower extremity weakness. The patient denied prior trauma and had no family history of osteoporosis or pathologic fractures. He denied the use of steroids, proton pump inhibitors, anticoagulants, or antiseizure medications. He did not smoke and reported no alcohol use. There was no history of hypogonadism, bone disease, or fractures during childhood. Biochemical evaluation revealed a normal complete blood count, with pertinent laboratory results summarized in Table 1.

Laboratory test Value Units Reference range
Total testosterone 415 ng/dL 264–916
Intact parathyroid hormone 9.4 pg/mL 8.7–77.1
Corrected serum calcium 9.6 mg/dL 8.6–10.3
24-hour urine calcium 144 mg/24 hours 100–300*
Plasma adrenocorticotropic hormone Undetectable pg/mL 7–63*
Late-night salivary cortisol Undetectable µg/dL ≤0.09*
24-hour urine free cortisol Undetectable µg/24 hours 10–50*
Table 1: Biochemical laboratory results.

*: Reference intervals may vary by assay method and laboratory.

Given the presence of fragility fractures and physical examination findings consistent with Cushing’s syndrome, including moon facies, dorsocervical and supraclavicular fat fullness, and purplish striae (Figure 1), further evaluation was pursued. Laboratory testing demonstrated an undetectable serum ACTH level, and both late-night salivary cortisol and 24-hour urinary free cortisol levels were undetectable, raising concern for exogenous glucocorticoid exposure (Table 1). Dual-energy X-ray absorptiometry demonstrated a spinal bone mineral density of 0.686 g/cm² with a T-score of −3.7.

Purplish-(violaceous)-abdominal-striae-over-the-abdomen.
Figure 1: Purplish (violaceous) abdominal striae over the abdomen.

On further questioning, the patient reported taking Artri King for two years, obtained from Mexico, for joint pain and arthritis. A review of U.S. Food and Drug Administration (FDA) reports confirmed that Artri King contains hidden ingredients, including dexamethasone, not listed on its label. The supplement was discontinued, and the patient was started on a gradual steroid taper to minimize glucocorticoid withdrawal symptoms and allow for the recovery of hypothalamic-pituitary-adrenal (HPA) axis function.

Discussion

Cushing’s syndrome is a rare disorder characterized by a constellation of signs and symptoms affecting multiple organ systems as a result of prolonged exposure to excess cortisol. Hypercortisolism may result from endogenous overproduction of cortisol or from exposure to exogenous glucocorticoids [1]. Regardless of etiology, clinical manifestations commonly include moon facies, abdominal striae, truncal obesity, and easy bruising [1]. Patients with Cushing’s syndrome may also develop complications such as hyperglycemia, uncontrolled hypertension, proximal muscle weakness, and reduced BMD, which can lead to fragility fractures [2]. These complications significantly impair quality of life and may be fatal if the condition is not diagnosed and treated promptly [3].

Endogenous hypercortisolism is less common, with an estimated incidence of 2-3 cases per million per year [4]. However, recent studies suggest a higher prevalence among individuals with diabetes mellitus, osteoporosis, particularly those with fragility fractures, and hypertension [5]. Cushing’s syndrome can be classified as ACTH-dependent, in which ACTH originates from the pituitary gland or an ectopic source, or ACTH-independent, typically due to adrenal adenoma, adrenal hyperplasia, or adrenal carcinoma [5]. Although exogenous glucocorticoid exposure is the most common cause of Cushing’s syndrome, the true incidence of iatrogenic Cushing’s syndrome remains unknown [6]. Rarely, Cushing’s syndrome may result from concurrent exogenous steroid use and endogenous cortisol overproduction, which presents diagnostic challenges [6].

Glucocorticoid-containing medications are widely used in the management of inflammatory diseases, malignancies, and post-transplant care [7,8]. All forms of exogenous glucocorticoids, including oral, inhaled, injectable, and topical preparations, can cause features of hypercortisolism when used at high doses or for prolonged periods [9-12]. Extended exposure, particularly at higher doses, may also result in secondary adrenal insufficiency, even with topical formulations [13]. In addition to conventional glucocorticoids, other medications may induce iatrogenic hypercortisolism; for example, high-dose megestrol exhibits glucocorticoid-like activity and can produce Cushing’s syndrome-like features [14]. Furthermore, drugs that inhibit cytochrome P450 metabolism, such as itraconazole, can impair steroid clearance and increase systemic glucocorticoid exposure [15].

Of increasing concern is the availability of steroid-containing supplements sold over the counter or online without prescription [16]. These products are commonly marketed for conditions such as arthritis and other inflammatory disorders [16]. Prolonged use may cause Cushing’s syndrome with complications such as skin atrophy, obesity, myopathy, and fractures. The U.S. FDA has issued multiple warnings regarding dietary supplements and conventional foods found to contain undisclosed pharmaceutical ingredients [17]. A 2016 study evaluating 12 over-the-counter “adrenal support” supplements in the United States found that most contained at least one steroid hormone [18]. Another analysis of FDA warnings on unapproved pharmaceutical ingredients reported that 37.5% of products marketed for inflammatory conditions, including joint and muscle pain, contained dexamethasone [19]. Among these products, Artri King, marketed for joint pain and arthritis, has been associated with multiple FDA reports of adverse events due to undisclosed dexamethasone and methylprednisolone. These supplements remain widely available online, in select retail stores, and internationally [20].

Conclusions

This case highlights the importance of considering unregulated supplements as a potential source of exogenous glucocorticoids in patients presenting with osteoporosis and unexplained fragility fractures. Although the patient initially denied steroid use, detailed history revealed prolonged exposure to Artri King, resulting in iatrogenic Cushing’s syndrome with HPA axis suppression. Before discontinuation of steroid-containing supplements, evaluation for adrenal insufficiency is essential. Gradual tapering of glucocorticoids remains the standard approach to prevent withdrawal symptoms and support recovery of adrenal function.

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  11. Hughes JM, Hichens M, Booze GW, Thorner MO: Cushing’s syndrome from the therapeutic use of intramuscular dexamethasone acetate. Arch Intern Med. 1986, 146:1848-9.
  12. Weber SL: Cushing’S syndrome attributable to topical use of lotrisone. Endocr Pract. 1997, 3:140-4. 10.4158/EP.3.3.140
  13. Pektas SD, Dogan G, Cinar N: Iatrogenic Cushing’s syndrome with subsequent adrenal insufficiency in a patient with psoriasis vulgaris using topical steroids. Case Rep Endocrinol. 2017, 2017:8320254. 10.1155/2017/8320254
  14. Steer KA, Kurtz AB, Honour JW: Megestrol-induced Cushing’s syndrome. Clin Endocrinol (Oxf). 1995, 42:91-3. 10.1111/j.1365-2265.1995.tb02603.x
  15. Bolland MJ, Bagg W, Thomas MG, Lucas JA, Ticehurst R, Black PN: Cushing’s syndrome due to interaction between inhaled corticosteroids and itraconazole. Ann Pharmacother. 2004, 38:46-9. 10.1345/aph.1D222
  16. Saad-Omer SM, Kinaan M, Matos M, Yau H: Exogenous Cushing syndrome and hip fracture due to over-the-counter supplement (Artri King). Cureus. 2023, 15:e41278. 10.7759/cureus.41278
  17. Patel R, Sherf S, Lai NB, Yu R: Exogenous Cushing syndrome caused by a “herbal” supplement. AACE Clin Case Rep. 2022, 8:239-42. 10.1016/j.aace.2022.08.001
  18. Akturk HK, Chindris AM, Hines JM, Singh RJ, Bernet VJ: Over-the-counter “adrenal support” supplements contain thyroid and steroid-based adrenal hormones. Mayo Clin Proc. 2018, 93:284-90. 10.1016/j.mayocp.2017.10.019
  19. Tucker J, Fischer T, Upjohn L, Mazzera D, Kumar M: Unapproved pharmaceutical ingredients included in dietary supplements associated with US Food and Drug Administration warnings. JAMA Netw Open. 2018, 1:e183337. 10.1001/jamanetworkopen.2018.3337
  20. U.S. Food and Drug Administration. Public Notification: Artri King contains hidden drug ingredients. (2022). Accessed: December 18, 2025: https://www.fda.gov/drugs/medication-health-fraud/public-notification-artri-king-contains-hidden-drug-ingredients.

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Ectopic Adrenocorticotropic Hormone (ACTH)-Dependent Cushing Syndrome Secondary to Olfactory Neuroblastoma

Posted on September 15, 2025 by MaryO

Abstract

Background/Objective

Ectopic adrenocorticotropic hormone (ACTH)-dependent Cushing syndrome is a rare paraneoplastic disorder caused by excessive cortisol production from nonpituitary tumors. Olfactory neuroblastoma (ONB), a rare neuroendocrine malignancy of the sinonasal cavity, is an exceedingly uncommon source of ectopic ACTH production, with fewer than 25 cases reported worldwide. This report presents a case of ACTH-dependent Cushing syndrome due to ONB, emphasizing the diagnostic complexity, multidisciplinary management, and favorable clinical outcomes.

Case Presentation

A 70-year-old male presented with progressive muscle weakness, facial rounding, weight gain, hypertension, hypokalemia, and recurrent epistaxis. Laboratory evaluation revealed marked hypercortisolism and elevated plasma ACTH. Imaging demonstrated an expansile ethmoid sinus mass. Inferior petrosal sinus sampling excluded a pituitary source of ACTH. Endoscopic biopsy confirmed Hyams grade 2 ONB with positive immunohistochemical staining for neuroendocrine markers and ACTH. The patient received preoperative cortisol-lowering therapy and underwent complete endoscopic tumor resection followed by adjuvant radiotherapy. Postoperative assessment showed biochemical remission, resolution of Cushingoid features, and eventual recovery of the hypothalamic–pituitary–adrenal axis.

Discussion

This case highlights the importance of a systematic diagnostic approach that includes biochemical testing, imaging, inferior petrosal sinus sampling, and histopathology to identify ectopic ACTH sources. It demonstrates the necessity of collaboration among endocrinology, otolaryngology, neurosurgery, radiology, and oncology teams in managing rare ACTH-secreting tumors.

Conclusion

Timely diagnosis and definitive surgical resection of ACTH-producing ONB, along with endocrine stabilization and adjuvant radiotherapy, can lead to endocrine remission and improved long-term outcomes.

Key words

cushing syndrome
ectopic ACTH syndrome
neuroendocrine tumor
olfactory neuroblastoma
paraneoplastic syndrome

Abbreviations

ACTH

adrenocorticotropic hormone

AM

morning (ante meridiem)

DDAVP

desmopressin acetate

DHEA-S

dehydroepiandrosterone sulfate

EAS

ectopic ACTH syndrome

ENT

otolaryngology

IPSS

inferior petrosal sinus sampling

ONB

olfactory neuroblastoma

UFC

urinary free cortisol

Highlights

  • •
    Rare case of ectopic adrenocorticotropic hormone syndrome secondary to olfactory neuroblastoma
  • •
    Diagnostic challenges highlighted, including nondiagnostic inferior petrosal sinus sampling results
  • •
    Multidisciplinary approach enabled complete tumor resection and hormonal remission
  • •
    Preoperative ketoconazole minimized perioperative cortisol-related morbidity
  • •
    Adjuvant radiotherapy optimized local control in intermediate-risk olfactory neuroblastoma

Clinical Relevance

This case emphasizes the importance of recognizing olfactory neuroblastoma as a rare source of ectopic adrenocorticotropic hormone production. It demonstrates the value of integrated biochemical, radiologic, surgical, and histopathologic strategies to achieve endocrine remission and prevent recurrence.

Introduction

Ectopic ACTH syndrome (EAS) is a rare paraneoplastic disorder resulting in ACTH-dependent hypercortisolism, which manifests clinically as Cushing syndrome. Although it accounts for approximately 10% to 15% of ACTH-dependent cases, EAS is most frequently caused by bronchial carcinoids, small cell lung carcinoma, and pancreatic neuroendocrine tumors.1,2 In contrast, olfactory neuroblastoma (ONB), also known as esthesioneuroblastoma—a neuroendocrine malignancy of the upper nasal cavity—is a highly uncommon cause, with fewer than 1% of ONB cases associated with EAS.2,3
ONB arises from the olfactory epithelium and represents 2% to 3% of all sinonasal cancers.4,5 Its nonspecific presentation—ranging from nasal obstruction to epistaxis or anosmia—can delay diagnosis, and advanced tumors may invade adjacent structures such as the orbit or anterior cranial fossa.4,5 Histological overlap with other small round blue cell tumors necessitates immunohistochemical markers such as synaptophysin, chromogranin A, and S-100 for accurate identification.4,6 Factors such as age may influence tumor behavior, treatment selection, and prognosis.7
When ONB presents with ectopic ACTH secretion, the resulting hypercortisolism can lead to profound metabolic and cardiovascular complications.8,9 Due to its extreme rarity, this combination may not be initially suspected, delaying targeted therapy. This report presents a rare case of ACTH-dependent Cushing syndrome caused by ONB, highlighting the diagnostic complexity and need for multidisciplinary management.3,10

Case Presentation

A 70-year-old male presented with 6 weeks of progressively worsening generalized, proximal muscle weakness, intermittent headaches, recurrent nosebleeds, abdominal fullness, leg swelling, and an unexplained 20-pound (9.1 kg) weight gain.
His medical history includes asthma, benign prostatic hyperplasia, hyperlipidemia, and retained shrapnel in the neck from military service in Vietnam. He has no history of hypertension, diabetes, or smoking. His family history includes a father who suffered a myocardial infarction at 51 years old, a mother with rheumatoid arthritis and osteoporosis, and a maternal uncle with lupus. His current medications include rosuvastatin 5 mg daily, tamsulosin 0.4 mg daily, and an albuterol inhaler as needed.
On examination, his vital signs were notable for an elevated blood pressure of 171/84 mmHg (normal: <120/<80 mmHg), a temperature of 37.2 C (99 F) (normal: 36.1–37.2°C [97–99 F]), a heart rate of 91 bpm (normal: 60–100 bpm), a respiratory rate of 16 breaths per minute (normal: 12–20 breaths per minute), an oxygen saturation of 92% on room air (normal: ≥95%), and a weight of 78.9 kg (174 lb). Physical examination revealed a round plethoric face (“moon facies,”) a prominent dorsocervical fat pad (“buffalo hump,”) supraclavicular fullness, mild abdominal tenderness, violaceous striae across the abdomen, diffuse soft tissue swelling, and bilateral 2+ pitting edema in the lower extremities.

Diagnostic Assessment

Laboratory evaluation demonstrated severe hypokalemia (1.6 mEq/L [1.6 mmol/L]; normal: 3.5–5.0 mEq/L [3.5–5.0 mmol/L]) and marked fasting hyperglycemia (244.0 mg/dL [13.5 mmol/L]; normal: 70–99 mg/dL [3.9–5.5 mmol/L]), in addition to leukocytosis, hypochloremia, acute kidney injury, hypoproteinemia, and hypoalbuminemia.
Hormonal evaluation (Table 1) was consistent with ACTH-dependent hypercortisolism, characterized by elevated serum cortisol and ACTH concentrations, lack of suppression with dexamethasone, and suppressed dehydroepiandrosterone sulfate (DHEA-S). Aldosterone and plasma renin activity were within normal limits, effectively excluding primary hyperaldosteronism. Plasma free metanephrines and normetanephrines were also within reference ranges, ruling out pheochromocytoma. Repeat morning cortisol remained markedly elevated, and late-night salivary cortisol levels on 2 occasions were significantly above the reference range. Twenty-four-hour urinary free cortisol (UFC) was profoundly elevated on both collections. Following a 1 mg overnight dexamethasone suppression test, serum cortisol, ACTH, and dexamethasone levels confirmed a lack of cortisol suppression despite adequate dexamethasone absorption (Table 1). These results were consistent with ACTH-dependent Cushing syndrome.

Table 1. Hormone Panel Results

Test Value Normal Range
AM cortisol 29 μg/dL (800.11 nmol/L) (high) 3.7–19.4 μg/dL (102–535 nmol/L)
Repeated AM cortisol 26 μg/dL (717.34 nmol/L) (high) 3.7–19.4 μg/dL (102–535 nmol/L)
ACTH 250 pg/mL (30.03 pmol/L) (high) 10–60 pg/mL (2.2–13.2 pmol/L)
Plasma renin activity 1.2 ng/mL/h (1.2 μg/L/h) (normal) 0.2–4.0 ng/mL/h (0.2–4.0 μg/L/h)
DHEA-S 50 μg/dL (1.25 μmol/L) (low) 65–380 μg/dL (1.75–10.26 μmol/L)
Aldosterone, blood 4. 9 ng/dL (0.14 nmol/L) (normal) 4.0–31.0 ng/dL (110–860 pmol/L)
Plasma free metanephrines 0.34 nmol/L (0.034 μg/L) (normal) <0.50 nmol/L (<0.09 μg/L)
Plasma free normetanephrines 0.75 nmol/L (0.075 μg/L) (normal) <0.90 nmol/L (<0.16 μg/L)
Late-night salivary cortisol (1st) 0.27 μg/dL (7.45 nmol/L) (high) ≤0.09 μg/dL (≤2.5 nmol/L) (10 PM–1 AM)
Late-night salivary cortisol (2nd) 0.36 μg/dL (9.93 nmol/L) (high) ≤0.09 μg/dL (≤2.5 nmol/L) (10 PM–1 AM)
24-h urinary free cortisol (1st) 5880.0 μg/d (16 223 nmol/d) (high) ≤60.0 μg/d (≤165 nmol/d)
24-h urinary free cortisol (2nd) 4920.0 μg/d (13 576 nmol/d) (high) ≤60.0 μg/d (≤165 nmol/d)
AM cortisol level (after 1 mg dexamethasone) 12.3 μg/dL (339 nmol/L) (high) <1.8 μg/dL (<50 nmol/L) adequate suppression
Dexamethasone level(after 1 mg dexamethasone) 336 ng/dL (8.64 nmol/L) (normal) >200 ng/dL (>5.2 nmol/L) adequate absorption
ACTH level (after 1 mg dexamethasone) 242 pg/mL (53.27 pmol/L) (not suppressed) 10–60 pg/mL (2.2–13.2 pmol/L)
Abbreviations: μg/d = micrograms per day; μg/dL = Micrograms per deciliter; μg/L = micrograms per liter; μmol/L = micromoles per liter; AM = morning (Ante Meridiem); nmol/L = nanomoles per Liter; ng/mL/h = nanograms per milliliter per hour; pmol/L = picomoles per liter; pg/mL = picograms per milliliter; μg/L/h = micrograms per liter per hour; ng/dL = nanograms per deciliter; nmol/d = nanomoles per day.
Inferior petrosal sinus sampling (IPSS) was performed using contrast-enhanced fluoroscopy to confirm accurate catheter placement in both inferior petrosal sinuses. Absolute ACTH values obtained during IPSS are shown in (Table 2). The central-to-peripheral ACTH gradient at baseline was 1.1, which is below the diagnostic threshold of 2.0 typically required to support a pituitary source of ACTH. Following desmopressin acetate (DDAVP) stimulation, peak left: peripheral and right: peripheral ACTH ratios reached 1.7 and 1.5, respectively—well below the accepted post-stimulation cut-off of 3.0. In addition, the left: right petrosal ACTH ratios remained between 1.03 and 1.15 throughout the sampling period, indicating no significant lateralization of ACTH secretion. These findings are not consistent with Cushing’s disease and instead support a diagnosis of ectopic ACTH syndrome.

Table 2. Bilateral Petrosal Sinus and Peripheral Adrenocorticotropin Levels Before and After Intravenous Injection of Desmopressin Acetate (DDAVP) 10 mcg

Time post DDAVP, min Left petrosal ACTH Left: peripheral ACTH Right petrosal ACTH Right: peripheral ACTH Peripheral ACTH Left: right petrosal ACTH
0 165 pg/mL (36.3 pmol/L) 1.1 160 pg/mL (35.2 pmol/L) 1.1 150 pg/mL (33.0 pmol/L) 1.03
3 270 pg/mL (59.4 pmol/L) 1.6 245 pg/mL (53.9 pmol/L) 1.4 170 pg/mL (37.4 pmol/L) 1.10
5 320 pg/mL (70.4 pmol/L) 1.7 285 pg/mL (62.7 pmol/L) 1.5 185 pg/mL (40.7 pmol/L) 1.12
10 350 pg/mL (77.0 pmol/L) 1.4 305 pg/mL (67.2 pmol/L) 1.2 250 pg/mL (55.0 pmol/L) 1.15
Abbreviations: ACTH = adrenocorticotropin; DDAVP = desmopressin acetate; pg/mL = picograms per milliliter; pmol/L = picomoles per liter.
Magnetic resonance imaging of the head could not be performed due to a history of retained shrapnel in the neck from combat in Vietnam. Noncontrast computed tomography (CT) images of the head and paranasal sinuses revealed no evidence of a pituitary tumor but demonstrated an expansile mass measuring approximately 2.4 × 4.3 × 3.3 cm, centered within the bilateral ethmoid sinuses with extension into both the anterior and posterior ethmoidal air cells (Fig. 1A, B). A contrast-enhanced CT scan of the abdomen, performed following improvement in renal function, demonstrated marked bilateral adrenal gland enlargement (Fig. 1C).

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Fig. 1. (A) Axial and (B) coronal noncontrast computed tomography (CT) images of the head demonstrate a heterogeneous soft tissue mass at the anterior skull base extending toward the cribriform plate and into the right nasal cavity, involving the ethmoid sinus and eroding the lamina papyracea, resulting in medial displacement of the right orbital contents (blue arrows). (C) Axial contrast-enhanced CT of the abdomen reveals bilateral adrenal gland enlargement. (D) Whole-body single-photon emission computed tomography/computed tomography (SPECT/CT) using indium-111 pentetreotide demonstrates intense radiotracer uptake localized to the biopsy-confirmed esthesioneuroblastoma in the ethmoid sinuses, with no evidence of metastatic octreotide-avid lesions. (G) Coronal contrast-enhanced CT scan of the abdomen, performed after surgery, shows normalization in the size of both adrenal glands. (E) Coronal and (F) axial noncontrast CT images of the paranasal sinuses obtained postoperatively demonstrate complete surgical resection of the tumor.

The otolaryngology (ENT) team was consulted and recommended an endoscopic biopsy of the nasal mass. Histopathologic examination revealed a Hyams Grade 2 olfactory neuroblastoma (Fig. 2A, B), characterized by well-circumscribed lobules of small round blue cells with scant cytoplasm, a neurofibrillary background matrix, and low mitotic activity, without necrosis or rosette formation—findings typical of a moderately differentiated tumor in the Hyams grading system.

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Fig. 2. (A) Low-power H&E (4×) shows well-circumscribed lobules of small round blue cells with fibrovascular stroma and a neurofibrillary matrix; no necrosis or rosettes are seen. (B) High-power H&E (40×) reveals neoplastic cells with high nuclear-to-cytoplasmic ratio, hyperchromatic nuclei, and granular chromatin, consistent with Hyams Grade 2 ONB. (C) Chromogranin A shows granular cytoplasmic positivity in tumor nests, confirming neuroendocrine differentiation. (D) Synaptophysin shows diffuse granular cytoplasmic staining in tumor clusters, with negative stromal background. (E) S-100 highlights sustentacular cells in a peripheral pattern around tumor nests. (F) ACTH staining shows patchy to diffuse cytoplasmic positivity in tumor cells, confirming ectopic ACTH production in ONB. A nuclear medicine octreotide scan (111 Indium-pentetreotide scintigraphy) with single-photon emission computed tomography/computed tomography (SPECT/CT) demonstrated intense radiotracer uptake in the biopsy-proven esthesioneuroblastoma centered within the ethmoid sinuses, confirming the tumor’s expression of somatostatin receptors. There was no evidence of locoregional or distant metastatic disease demonstrating octreotide avidity (Fig. 1D).

Immunohistochemical staining supported the diagnosis: tumor cells were positive for chromogranin A (Fig. 2C), synaptophysin (Fig. 2D), and S-100 (Fig. 2E). Chromogranin A and synaptophysin are markers of neuroendocrine differentiation, confirming the tumor’s neuroendocrine origin. S-100 positivity in the sustentacular cells surrounding tumor nests is a classic feature of olfactory neuroblastoma. Staining was negative for neurofilament protein, AE1/AE3, and epithelial membrane antigen, helping exclude other small round blue cell tumors, such as neuroendocrine carcinoma or sinonasal undifferentiated carcinoma. Importantly, the tumor cells showed positive cytoplasmic staining for ACTH (Fig. 2F), confirming ectopic ACTH production by the tumor itself. This finding definitively links the olfactory neuroblastoma as the source of paraneoplastic ACTH secretion, consistent with the patient’s clinical picture of ectopic Cushing’s syndrome.

Treatment

Hypokalemia was corrected, and oral ketoconazole 200 mg twice daily was initiated preoperatively to mitigate the metabolic complications of hypercortisolism. Ketoconazole was discontinued on the day of surgery. The tumor was resected via an endoscopic endonasal approach. A blood sample was obtained immediately following tumor removal for measurement of ACTH and cortisol levels. Intravenous hydrocortisone (100 mg every 6 h) was initiated promptly thereafter. Postoperative cortisol and ACTH levels were undetectable: cortisol <5 μg/dL [<138 nmol/L] (normal: 5–25 μg/dL [138–690 nmol/L]); ACTH <5 pg/mL [<1.1 pmol/L] (normal: 10–60 pg/mL [2.2–13.3 pmol/L]). These findings confirmed successful surgical resection of the ACTH-secreting tumor. These issues extended the hospital stay and required treatment with antiseizure medications, antibiotics, and additional surgeries by ENT and Neurosurgery teams.

Outcome and Follow-Up

The patient demonstrated significant normalization of blood pressure (124/78 mmHg), fasting blood glucose (95 mg/dL [5.3 mmol/L]), and potassium (4.3 mEq/L [4.3 mmol/L]) within 2 weeks postoperatively. ACTH levels decreased from preoperative values of 220–250 pg/mL (48.4–55.2 pmol/L) to 29 pg/mL (5.5 pmol/L), and morning (AM) cortisol levels decreased from preoperative values of 29 μg/dL (800 nmol/L) to 12 μg/dL (331 nmol/L). These values were obtained at 2 weeks postoperatively. While early normalization of ACTH and cortisol levels could raise concern for residual disease, the patient’s subsequent sustained biochemical remission, clinical recovery, and a robust response to cosyntropin stimulation at 3 months post-op were reassuring. Adjuvant radiotherapy was also administered to mitigate any potential risk of recurrence.
He was subsequently transferred to an inpatient rehabilitation facility while receiving oral hydrocortisone replacement therapy, during which his functional status progressively improved. The patient was later discharged home on oral hydrocortisone replacement therapy with plans for continued outpatient physical therapy. Hydrocortisone was gradually tapered and discontinued 3 months after surgery, at which point blood pressure (122/76 mmHg), fasting glucose (90 mg/dL [5.0 mmol/L]), potassium (4.2 mEq/L [4.2 mmol/L]), ACTH (25 pg/mL [4.9 pmol/L]), and AM cortisol (15 μg/dL [414 nmol/L]) demonstrated sustained normalization. Following administration of 250 mcg intramuscular cosyntropin, serum cortisol peaked at 21 μg/dL (580 nmol/L), confirming an adequate adrenal reserve and complete recovery of the hypothalamic–pituitary–adrenal axis. Additionally, late-night salivary cortisol was remeasured on 2 occasions after hydrocortisone discontinuation and found to be 0.04 μg/dL (1.10 nmol/L) and 0.03 μg/dL (0.83 nmol/L), both within normal reference limits (≤0.09 μg/dL [≤2.5 nmol/L]). A 24-hour UFC collected at the same time measured 38 μg/d (105 nmol/d), confirming biochemical resolution of hypercortisolism. Cushing’s stigmata, including muscle weakness and skin changes, showed marked improvement by 3 months postoperatively (Table 3).

Table 3. Timeline of Clinical and Biochemical Recovery Following Resection of Ectopic ACTH-Secreting Olfactory Neuroblastoma

Parameter Preoperative value 24–48 h Postop 2 wks postop 3 mo postop Normal range
Blood pressure 171/84 mmHg 140/80 mmHg 124/78 mmHg 122/76 mmHg <130/80 mmHg
Fasting glucose 244 mg/dL (13.5 mmol/L) 160 mg/dL (8.9 mmol/L) 95 mg/dL (5.3 mmol/L) 90 mg/dL (5.0 mmol/L) 70–99 mg/dL (3.9–5.5 mmol/L)
Potassium 1.6 mEq/L (1.6 mmol/L) 3.8 mEq/L (3.8 mmol/L) 4.3 mEq/L (4.3 mmol/L) 4.2 mEq/L (4.2 mmol/L) 3.5–5.0 mEq/L (3.5–5.0 mmol/L)
ACTH 220–250 pg/mL (48.4–55.2 pmol/L) <10 pg/mL (<2.2 pmol/L) 29 pg/mL (5.5 pmol/L) 25 pg/mL (4.9 pmol/L) 10–60 pg/mL (2.2–13.3 pmol/L)
AM cortisol 29 μg/dL (800 nmol/L) <5 μg/dL (<138 nmol/L) 12 μg/dL (331 nmol/L) 15 μg/dL (414 nmol/L); Cosyntropin peak: 21 μg/dL (580 nmol/L) 5–25 μg/dL (138–690 nmol/L); adequate response >18 μg/dL (500–550 nmol/L)
LNSC 0.27/0.36 μg/dL (7.45/9.93 nmol/L) — — 0.04/0.03 μg/dL (1.10/0.83 nmol/L) ≤0.09 μg/dL (≤2.5 nmol/L) (10 PM–1 AM)
UFC (24-h) 5880/4920 μg/d (16 223/13 576 nmol/d) — — 38 μg/d (105 nmol/d) ≤60 μg/d (≤165 nmol/d)
Cushing’s Stigmata Moon facies, dorsocervical fat pad, violaceous striae, severe muscle weakness No change Partial improvement: BP/glucose control; decreased edema Marked improvement; muscle strength restored; striae fading Not applicable
Abbreviations: ACTH = adrenocorticotropin; mmHg = illimeters of mercury; mEq/L = milliequivalents per liter; mg/dL = milligrams per deciliter; mmol/L = millimoles per liter; μg/dL = micrograms per deciliter; AM = morning (Ante Meridiem); pg/mL = picograms per milliliter; pmol/L = picomoles per liter; nmol/L = nanomoles per liter.
dfA follow-up CT scan of the adrenals with contrast, performed following improvement in renal function, confirmed normalization in the size of the previously enlarged adrenal glands (Fig. 1E). A follow-up CT of sinuses without contrast confirmed complete resection of the tumor (Fig. 1F, G).
Adjuvant radiotherapy was recommended in view of the patient’s Kadish stage B tumor, Hyams grade 2 histology, and the elevated risk of local recurrence inherent to olfactory neuroblastoma. Despite complete surgical excision, radiotherapy was pursued to mitigate recurrence risk, particularly considering the tumor’s ectopic ACTH secretion, which suggested biologically aggressive behavior, as well as the patient’s satisfactory functional status and anticipated favorable treatment tolerance. A total of 30 fractions of 2 Gy were administered using volumetric modulated arc therapy.

Discussion

Diagnostic Considerations

EAS poses a significant diagnostic challenge due to its variable presentation and the urgency of identifying the source of ACTH excess. ONB, although rare, should be considered in patients with ACTH-dependent Cushing syndrome who present with sinonasal masses. ONB accounts for only 2% to 3% of all malignant sinonasal tumors,4,6 with fewer than 25 cases documented as sources of ectopic ACTH production.3,11,12
While ectopic ACTH syndrome remains the most well-recognized endocrine manifestation of ONB, a broader spectrum of paraneoplastic syndromes has also been described. These include syndrome of inappropriate antidiuretic hormone secretion, paraneoplastic hypercalcemia—often mediated by parathyroid hormone–related protein—and catecholamine excess mimicking pheochromocytoma.11 These atypical presentations underscore the neuroendocrine complexity of ONB and the diagnostic challenges they pose.
Diagnosis involves biochemical confirmation of hypercortisolism using low-dose dexamethasone suppression, 24-hour UFC, late-night salivary cortisol, and plasma ACTH levels. Interestingly, despite markedly elevated ACTH levels, our patient exhibited a low DHEA-S concentration and a normal aldosterone level. This biochemical pattern supports previous observations that EAS may present with a dissociation in adrenal steroidogenesis. Chronic hypercortisolemia may suppress the zona reticularis,13 while ectopic ACTH-producing tumors may secrete aberrant precursors that preferentially stimulate glucocorticoid rather than androgen synthesis.14 Cortisol excess can also downregulate key enzymes such as 17,20-lyase and SULT2A1, thereby impairing DHEA-S production.15 Moreover, the rapid onset and severity of ectopic ACTH production may preclude the compensatory DHEA-S rise typically observed in pituitary-driven Cushing disease. Although cortisol excess is known to suppress the renin-angiotensin-aldosterone system, aldosterone levels may remain detectable in certain EAS cases, particularly in early-stage or physiologically variable presentations.16
Once ACTH-dependence is established, localization of the tumor becomes essential. IPSS, although considered the gold standard for distinguishing pituitary from ectopic ACTH sources, may yield inconclusive results in cases of ONB due to altered venous drainage pathways.3 Functional imaging with 111In-octreotide single-photon emission computed tomography/computed tomography or 68Ga-DOTATATE positron emission tomography/computed tomography facilitates localization of neuroendocrine tumors that express somatostatin receptors. Histopathologic confirmation using ACTH immunostaining and neuroendocrine markers such as chromogranin A, synaptophysin, and S-100 is essential to confirm diagnosis.

Therapeutic Approach and Challenges

Surgical resection remains the cornerstone of management for ACTH-producing ONB.9 Endoscopic endonasal approaches are preferred when anatomically feasible due to their minimally invasive nature and favorable access to the anterior skull base. Preoperative pharmacologic inhibition of cortisol biosynthesis (utilizing ketoconazole, which was specifically selected for our patient, metyrapone, or etomidate) represents a critical intervention to attenuate hypercortisolism-related metabolic complications and minimize perioperative morbidity.3,8 Intraoperative glucocorticoid replacement should be administered following tumor resection to prevent adrenal insufficiency. Postoperative complications—such as cerebrospinal fluid leak or infection—require prompt multidisciplinary intervention.
Adjuvant radiotherapy is generally recommended for intermediate-to high-grade ONBs, even after gross total resection, given their aggressive behavior and high risk of recurrence. Volumetric modulated arc therapy delivers precise radiation doses while minimizing toxicity to adjacent structures.5,9 Platinum-based chemotherapy remains a therapeutic option in patients with unresectable or metastatic disease.9
Emerging therapeutic strategies include somatostatin receptor–directed theranostics. Zhi et al (2025) recently demonstrated the dual diagnostic and therapeutic potential of 68Ga-DOTATATE positron emission tomography/computed tomography imaging and 177Lu-DOTATATE peptide receptor radionuclide therapy in ONB, offering promising future directions for patients with advanced or somatostatin receptor–positive disease.17

Prognosis and Future Directions

The prognosis of ONB is influenced by Kadish staging, Hyams histologic grading, and treatment strategy. Recurrence rates are reported to range from 30% to 60%,9,18 and 5-year survival rates vary from 45% to 80% depending on tumor grade, stage, and completeness of resection.6,19 Early detection, complete surgical resection, and multimodal therapy, including radiotherapy, are associated with improved outcomes. Lifelong follow-up with serial imaging and endocrine evaluation is essential to monitor for recurrence and late-onset adrenal insufficiency.10,19
Continued advancements in molecular imaging and targeted therapies, particularly those leveraging somatostatin receptor biology, may expand the therapeutic landscape for patients with recurrent or progressive ONB.

Conclusion

This case highlights the importance of timely diagnosis, comprehensive biochemical and radiologic assessment, and coordinated multidisciplinary management in ACTH-producing ONB. In addition to surgery and preoperative endocrine stabilization, adjuvant radiotherapy and long-term surveillance are critical components of care. As somatostatin receptor–based imaging and theranostic therapies evolve, they offer exciting opportunities to individualize treatment in this rare but challenging neuroendocrine malignancy.

Statement of Patient Consent

Written informed consent was obtained from the patient for publication of this case report and any accompanying images.

Disclosure

The author has no conflict of interest to disclose.

References

Filed under: Cushing's, Rare Diseases | Tagged: , , , , , , , , , , , | Leave a comment »

Therapeutic Options for the Prevention of Thromboses in Cushing’s Syndrome

Posted on June 24, 2025 by MaryO

Abstract

Introduction

Cushing’s syndrome, or hypercortisolism, occurs after prolonged exposure to excess cortisol, and can be characterized by moon facies, central fat redistribution, proximal limb muscle weakness and wasting, and abdominal striae. Medical literature points to a relationship between hypercortisolism and hypercoagulability, with higher rates of venous thromboembolism noted. Current guidelines recommend prophylaxis with low-molecular weight heparin (LMWH), but there is little evidence to support LMWH over other forms of anticoagulation.

Methods

We utilized TriNetX US Collaborative Network (TriNetX, LLC, Cambridge, Massachusetts, United States) to investigate the efficacy of different forms of anticoagulation in patients with hypercortisolism, defined by International Classification of Diseases, Tenth Revision (ICD-10) codes. Adult patients with hypercortisolism and prescribed enoxaparin, a form of LMWH, were compared to patients with hypercortisolism prescribed unfractionated heparin, warfarin, apixaban, and aspirin at 81 mg. Groups were propensity-matched according to age at index event, sex, race, ethnicity, and comorbid conditions. The outcomes studied included pulmonary embolism (PE), upper extremity deep vein thrombosis (UE DVT), lower extremity deep venous thrombosis (LE DVT), superficial venous thrombosis (superficial VT), bleeding, transfusion, and all-cause mortality.

Results

No significant differences in outcomes were noted between enoxaparin and heparin, warfarin, or apixaban in patients with hypercortisolism of any cause. Uniquely, the enoxaparin cohort had significantly higher risk of PE, LE DVT, and all-cause mortality compared to the aspirin 81 mg cohort (PE: hazard ratio (HR) 1.697, 95%CI 1.444-1.994, p=0.0345; LE DVT: HR 1.492, 95%CI 1.28-1.738, p=0.0017; mortality: HR 1.272, 95%CI 1.167-1.386, p=0.0002). With further sub-analysis of pituitary-dependent (Cushing’s Disease), enoxaparin continued to demonstrate a higher risk for LE DVT (HR 1.677, 95%CI 1.353-2.079, p=0.0081), and all-cause mortality (HR 1.597, 95%CI 1.422-1.794, p=0.0005).

Conclusion

Although LMWH is currently recommended as the gold standard for anticoagulation in patients with hypercortisolism, our evidence suggests that low-dose antiplatelets such as aspirin 81 mg could outperform it. Further research is warranted to confirm and replicate our findings.

Introduction

Cortisol is produced within the zona fasciculata of the adrenal cortex and is typically released under stress [1]. Cushing’s Syndrome, first defined in 1912 by American neurosurgeon Harvey Cushing, is a state of prolonged hypercortisolism, presenting with classic phenotypic manifestations, including moon facies, central fat deposition, proximal limb muscle weakness and muscle wasting, and abdominal striae [2]. Cushing’s syndrome can be exogenous (medication-induced/iatrogenic) or endogenous (ectopic adrenocorticotrophic hormone (ACTH), pituitary-dependent, or adrenal adenoma/carcinoma) [3]. Pituitary adenomas causing ACTH-dependent cortisol excess account for 80% of endogenous cases of Cushing’s Syndrome and are more specifically termed Cushing’s Disease [4]. Overall, however, the most common cause of Cushing’s Syndrome is iatrogenic, from exogenous corticosteroid administration [5].

Hypercortisolism has also been demonstrated to affect coagulation, though the mechanism is unclear [6]. Both venous thromboemboli and pulmonary emboli rates are increased among these patients [7]. The Endocrine Society Guidelines for Treatment of Cushing Syndrome describe altered coagulation profiles that take up to one year to normalize [8]. As a result, limited guidelines recommend prophylactic anticoagulation in Cushing syndrome; while low-molecular-weight heparin (LMWH) is the gold standard, there is little evidence behind this recommendation [9]. Furthermore, few studies assessed individual Cushing’s Syndrome subtypes and associated clotting risks or anticoagulation impact. It is currently unknown whether the antagonistic effects of cortisol will be augmented or hindered by anticoagulation other than LMWH.

This retrospective multicenter study aimed to address this paucity in data by analyzing differences among various forms of anticoagulation. Patients with Cushing syndrome who were on one of three common anticoagulants, or aspirin, were compared to patients with Cushing’s Syndrome on enoxaparin, an LMWH considered the gold standard for prophylaxis in this population. Primary objectives included end-points concerning thromboses (such as pulmonary embolism (PE), upper and lower extremity deep vein thromboses (DVTs), and superficial venous thrombosis (VT)). Secondary objectives included analyzing safety profiles (bleeding, transfusion requirements, and all-cause mortality).

Materials & Methods

Eligibility criteria

TriNetX Global Collaborative network (TriNetX, LLC, Cambridge, Massachusetts, United States), a nationwide database of de-identified health data across multiple large healthcare organizations (HCOs), was utilized to compile patients according to International Classification of Diseases, Tenth Revision (ICD-10) codes (Figure 1).

Flow-chart-for-inclusion-and-exclusion-criteria-for-the-study
Figure 1: Flow chart for inclusion and exclusion criteria for the study

PE: pulmonary embolism; VT: venous thrombosis; DVT: deep vein thrombosis; UE: upper extremity; LE: lower extremity

ICD-10 codes included those related to Cushing’s Syndrome and one of five studied medications: enoxaparin, heparin, apixaban, warfarin, and aspirin, included in Tables 1 and 2, respectively. ICD-10 codes also included those related to outcomes, including PE, upper extremity (UE) DVT, lower extremity (LE) DVT, superficial VT, bleeding, transfusion, and all-cause mortality (Table 3). Measures of association involved calculating risk differences and relative risks (RRs) with 95% confidence intervals (CIs) to compare the proportion of patients experiencing each outcome across cohorts.

Cushing’s Syndrome Type ICD-10 Code
Cushing Syndrome (unspecified) Drug-Induced Cushing Syndrome (UMLS:ICD10CM:E24.2)
Other Cushing Syndrome (UMLS:ICD10CM:E24.8)
Cushing Syndrome, Unspecified (UMLS:ICD10CM:E24.9)
Pituitary-Dependent Cushing Disease (UMLS:ICD10CM:E24.0)
Cushing Syndrome (UMLS:ICD10CM:E24)
Ectopic ACTH Syndrome (UMLS:ICD10CM:E24.3)
Cushing Syndrome (pituitary) Pituitary-Dependent Cushing Disease (UMLS:ICD10CM:E24.0  )
Table 1: International Classification of Disease (ICD)-10 codes utilized to identify patients with Cushing Syndrome in the TriNetX database
Medication ICD-10 Code
Enoxaparin NLM:RXNORM:67108
Warfarin NLM:RXNORM:11289
Heparin NLM:RXNORM:5224
Apixaban NLM:RXNORM:1364430
Aspirin NLM:RXNORM:1191
Table 2: International Classification of Disease (ICD)-10 codes utilized to identify anticoagulants and antiplatelets studied in the TriNetX database
Outcome ICD-10 Codes
Pulmonary Embolism Pulmonary Embolism UMLS:ICD10CM:I26
Upper Extremity DVT Acute embolism and thrombosis of deep veins of unspecified upper extremity UMLS:ICD10CM:I82.629
Chronic embolism and thrombosis of deep veins of unspecified upper extremity UMLS:ICD10CM:I82.729
Acute embolism and thrombosis of deep veins of right upper extremity UMLS:ICD10CM:I82.621
Acute embolism and thrombosis of deep veins of left upper extremity UMLS:ICD10CM:I82.622
Acute embolism and thrombosis of deep veins of upper extremity, bilateral UMLS:ICD10CM:I82.623
Chronic embolism and thrombosis of deep veins of right upper extremity UMLS:ICD10CM:I82.721
Chronic embolism and thrombosis of deep veins of left upper extremity UMLS:ICD10CM:I82.722
Chronic embolism and thrombosis of deep veins of upper extremity, bilateral UMLS:ICD10CM:I82.723
Lower Extremity DVT Acute embolism and thrombosis of unspecified deep veins of unspecified lower extremity UMLS:ICD10CM:I82.409
Chronic embolism and thrombosis of unspecified deep veins of unspecified lower extremity UMLS:ICD10CM:I82.509
Chronic embolism and thrombosis of unspecified deep veins of lower extremity UMLS:ICD10CM:I82.50
Chronic embolism and thrombosis of unspecified deep veins of lower extremity, bilateral UMLS:ICD10CM:I82.503
Acute embolism and thrombosis of unspecified deep veins of lower extremity UMLS:ICD10CM:I82.40
Acute embolism and thrombosis of unspecified deep veins of left lower extremity UMLS:ICD10CM:I82.402
Acute embolism and thrombosis of unspecified deep veins of right lower extremity UMLS:ICD10CM:I82.401
Chronic embolism and thrombosis of unspecified deep veins of left lower extremity UMLS:ICD10CM:I82.502
Chronic embolism and thrombosis of unspecified deep veins of right lower extremity UMLS:ICD10CM:I82.501
Chronic embolism and thrombosis of left femoral vein UMLS:ICD10CM:I82.512
Chronic embolism and thrombosis of right femoral vein UMLS:ICD10CM:I82.511
Acute embolism and thrombosis of right iliac vein UMLS:ICD10CM:I82.421
Chronic embolism and thrombosis of femoral vein, bilateral UMLS:ICD10CM:I82.513
Chronic embolism and thrombosis of unspecified deep veins of unspecified distal lower extremity UMLS:ICD10CM:I82.5Z9
Chronic embolism and thrombosis of unspecified tibial vein UMLS:ICD10CM:I82.549
Acute embolism and thrombosis of deep veins of lower extremity UMLS:ICD10CM:I82.4
Chronic embolism and thrombosis of deep veins of lower extremity UMLS:ICD10CM:I82.5
Chronic embolism and thrombosis of other specified deep vein of unspecified lower extremity UMLS:ICD10CM:I82.599
Acute embolism and thrombosis of unspecified deep veins of unspecified proximal lower extremity UMLS:ICD10CM:I82.4Y9
Superficial VT Embolism and thrombosis of superficial veins of unspecified lower extremity UMLS:ICD10CM:I82.819
Acute embolism and thrombosis of superficial veins of unspecified upper extremity UMLS:ICD10CM:I82.619
Chronic embolism and thrombosis of superficial veins of unspecified upper extremity UMLS:ICD10CM:I82.719
Bleeding Hematemesis UMLS:ICD10CM:K92.0
Hemoptysis UMLS:ICD10CM:R04.2
Hemorrhage from respiratory passages UMLS:ICD10CM:R04
Hemorrhage from other sites in respiratory passages UMLS:ICD10CM:R04.8
Hemorrhage from other sites in respiratory passages UMLS:ICD10CM:R04.89
Melena UMLS:ICD10CM:K92.1
Hemorrhage of anus and rectum UMLS:ICD10CM:K62.5
Epistaxis UMLS:ICD10CM:R04.0
Transfusion Transfusion of Nonautologous Whole Blood into Peripheral Vein, Percutaneous Approach UMLS:ICD10PCS:30233H1
Transfusion of Nonautologous Whole Blood into Central Vein, Percutaneous Approach UMLS:ICD10PCS:30243H1
Transfusion of Nonautologous Red Blood Cells into Peripheral Vein, Percutaneous Approach UMLS:ICD10PCS:30233N1
Transfusion, blood or blood components UMLS:CPT:36430
Transfusion of Nonautologous Red Blood Cells into Central Vein, Percutaneous Approach UMLS:ICD10PCS:30243N1
Transfusion of Nonautologous Frozen Red Cells into Peripheral Vein, Percutaneous Approach UMLS:ICD10PCS:30233P1
Transfusion of Nonautologous Red Blood Cells into Peripheral Artery, Percutaneous Approach (deprecated 2020) UMLS:ICD10PCS:30253N1
Transfusion of Nonautologous Frozen Red Cells into Central Vein, Percutaneous Approach UMLS:ICD10PCS:30243P1
Transfusion of Nonautologous Red Blood Cells into Central Artery, Percutaneous Approach (deprecated 2020) UMLS:ICD10PCS:30263N1
Transfusion of Nonautologous Frozen Red Cells into Peripheral Artery, Percutaneous Approach (deprecated 2020) UMLS:ICD10PCS:30253P1
Transfusion of Nonautologous Frozen Red Cells into Central Artery, Percutaneous Approach (deprecated 2020) UMLS:ICD10PCS:30263P1
Transfusion of blood product UMLS:SNOMED:116859006
Transfusion of red blood cells UMLS:SNOMED:116863004
Mortality Deceased Deceased (demographic)
Table 3: International Classification of Disease (ICD)-10 codes utilized to identify outcomes followed in the TriNetX database

DVT: Deep Venous Thrombosis; VT: Venous Thrombosis

Cohort definitions

For each medication listed, two cohorts were compared: (i) a cohort of patients with hypercortisolism on enoxaparin and (ii) a cohort of patients with hypercortisolism on heparin, warfarin, apixaban, or aspirin at 81 mg (Table 4). The cohorts strictly assessed only adult patients (defined as at least 18 years of age); pediatric patients were not analyzed.

Cohort Run
Enoxaparin 146 HCOs with 99 providers responding with 12,885 patients
Heparin 145 HCOs with 97 providers responding with 16,376 patients
Warfarin 145 HCOs with 82 providers responding with 3,230 patients
Apixaban 146 HCOs with 91 providers responding with 3,982 patients
Aspirin (81 mg) 144 HCOs with 51 providers responding with 8,200 patients
Table 4: Outputs of healthcare organization queries as defined in corresponding tables

HCO: Healthcare Organization

Statistical analysis

Index events and time windows were defined to analyze patient outcomes. The index event was defined as the first date a patient met the inclusion criteria for a cohort. The time window was defined as the five years after the index event during which a pre-defined outcome could occur. Outcomes of interest were identified using ICD-10 codes as outlined in Table 1, and included PE, UE DVT, LE DVT, superficial VT, bleeding, transfusion, and all-cause mortality. Cohorts were propensity score-matched 1:1 according to age at index event, sex, race and ethnicity, and comorbid conditions, including endocrine, cardiac, pulmonary, gastrointestinal, and genitourinary conditions (Table 5). Propensity score-matching was performed using TriNetX, with a greedy (nearest) neighbor matching algorithm (caliper of 0.1 pooled standard deviations).

Variable ICD-10 Code
Demographics Age at Index (AI)
Female (F)
Black/African American (2054-5)
Male (M)
White (2106-3)
American Indian/Alaskan Native (1002-5)
Unknown Race (UNK)
Native Hawaiian/Other Pacific Islander (2076-8)
Unknown Gender (UN)
Not Hispanic/Latino (2186-5)
Hispanic/Latino (2135-2)
Other Race (2131-1)
Asian (2028-9)
Diagnosis Endocrine, nutritional and metabolic diseases (E00-E89)
Factors influencing health status and contact with health services (Z00-Z99)
Diseases of the musculoskeletal system and connective tissue (M00-M99)
Diseases of the circulatory system (I00-I99)
Diseases of the digestive system (K00-K95)
Diseases of the nervous system (G00-G99)
Diseases of the respiratory system (J00-J99)
Diseases of the genitourinary system (N00-N99)
Diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism (D50-D89)
Neoplasms (C00-D49)
Diseases of the skin and subcutaneous tissue (L00-L99)
Table 5: International Classification of Disease (ICD)-10 codes utilized to propensity match cohorts in the TriNetX database

Three analytical approaches were performed for this study, including measures of association, survival analysis, and frequency analysis. The measure of association analysis involved calculating RRs (and risk differences) with 95%CIs, comparing the proportion of patients across each cohort experiencing an outcome. Survival analysis was performed with Kaplan-Meier estimators (evaluating time-to-event outcomes), with Log-Rank testing incorporated to compare the survival curves. Furthermore, Cox proportional hazard models were incorporated to provide an estimate of the hazard ratios (HR) and 95%CIs. Patients who exited a cohort before the end of the time window were excluded from the survival analysis. The frequency analysis was performed by calculating the proportion of patients in each cohort who experienced an outcome during the defined period of five years.

For statistically significant associations, an E-value was calculated to assess the potential impact of unmeasured confounders, quantifying the minimum strength of association that would be required by an unmeasured confounder to explain the observed effect (beyond our measured covariates); an E-value of above 2.0 was considered modestly robust, and above 3 was considered strongly robust. Additionally, a limited sensitivity analysis assessing Pituitary Cushing’s (the most common cause of endogenous Cushing’s Syndrome) was performed. All analyses were conducted through TriNetX, with statistical significance defined as a p-value < 0.05.

Results

Cushing’s syndrome, unspecified

Enoxaparin and Heparin

After propensity-score matching, 8,658 patients were identified in each cohort. The average age at index event for the enoxaparin cohort was 54.5 + 16.5 years, compared to 53.1 + 17.3 years for the heparin cohort. The enoxaparin cohort had 6,216 females (71.8%), compared to 6,000 (69.3%) in the heparin cohort. Within the enoxaparin cohort, 6035 (69.7%) were Caucasian patients, followed by 987 (11.4%) African American patients, 753 (8.7%) Hispanic/Latino patients, and 216 (2.5%) Asian patients. The heparin cohort was similar in ethnicity, with 5,800 (67.0%) Caucasian patients, 1,099 (12.7%) African American patients, 753 (8.7%) Hispanic/Latino patients, and 268 (3.1%) Asian patients. The enoxaparin and heparin cohorts demonstrated no significant differences in PE (HR 1.171, 95%CI 1.017-1.348, p=0.1797), UE DVT (HR 1.067, 95%CI 0.837-1.362, p=0.8051), LE DVT (HR 1.066, 95%CI 0.931-1.222, p=0.1922), superficial VT (HR 0.974, 95%CI 0.672-1.41, p=0.4576), bleeding (HR 0.948, 95%CI 0.855-1.05, p=0.3547), transfusion (HR 0.873, 95%CI 0.786-0.969, p=0.1767), or all-cause mortality (HR 1.036, 95%CI 0.966-1.11, p=0.9954). A comprehensive summary of the results is demonstrated in Table 6.

p-value Medication 1 Medication 2 PE UE DVT LE DVT S VT Bleeding Transfusion Mortality
enoxaparin heparin 0.1797 0.8051 0.1922 0.4576 0.3547 0.1767 0.9954
enoxaparin warfarin 0.3828 0.6 0.1963 0.0995 0.7768 0.5715 0.15
enoxaparin apixaban 0.6491 0.6275 0.723 0.4198 0.4356 0.4299 0.2628
enoxaparin aspirin 81 mg 0.0345 0.587 0.0017 0.4218 0.246 0.2057 0.0002
– – – – – – – – – –
HR Medication 1 Medication 2 PE UE DVT LE DVT S VT Bleeding Transfusion Mortality
enoxaparin heparin 1.171 1.067 1.066 0.974 0.948 0.873 1.036
enoxaparin warfarin 0.936 0.969 0.708 0.655 0.961 1.127 1.042
enoxaparin apixaban 0.798 0.666 0.684 4.059 0.933 1.089 1.041
enoxaparin aspirin 81 mg 1.697 1.398 1.492 1.718 1.107 1.347 1.272
– – – – – – – – – –
95% CIs Medication 1 Medication 2 PE UE DVT LE DVT Superficial VT Bleeding Transfusion Mortality
enoxaparin heparin 1.017-1.348 0.837-1.362 0.931-1.222 0.672-1.41 0.855-1.05 0.786-0.969 0.966-1.11
enoxaparin warfarin 0.755-1.161 0.692-1.356 0.583-0.859 0.376-1.142 0.812-1.137 0.95-1.336 0.93-1.167
enoxaparin apixaban 0.608-1.047 0.431-1.03 0.593-0.788 1.156-14.258 0.771-1.129 0.892-1.33 0.912-1.189
enoxaparin aspirin 81 mg 1.444-1.994 1.06-1.845 1.28-1.738 1.011-2.92 0.986-1.243 1.185-1.532 1.167-1.386
Table 6: Hazard Ratio, 95% Confidence Intervals and p-values for anticoagulation and antiplatelet comparisons in all causes of Cushing’s Syndrome

HR: hazard ratio; CI: confidence interval; PE: pulmonary embolism; VT: venous thrombosis; DVT: deep vein thrombosis; UE: upper extremity; LE: lower extremity

Enoxaparin and Warfarin

After propensity-score matching, 2,786 patients were identified in each cohort. The average age at index event for the enoxaparin cohort was 54.8 + 16.4 years, compared to 58.9 + 15.9 years for the warfarin cohort. The enoxaparin cohort had 2,020 female patients (72.5%) compared to 1,861 (66.8%) in the warfarin cohort. Within the enoxaparin cohort, 2,000 (71.8%) were Caucasian patients, followed by 334 (12.0%) African American patients, 220 (7.98%) Hispanic/Latino patients, and 64 (2.3%) Asian patients. The warfarin cohort was similar, with 2,056 (73.8%) Caucasian patients, 312 (11.2%) African American patients, 170 (6.1%) Hispanic/Latino patients, and 92 (3.3%) Asian patients. The enoxaparin and warfarin cohorts demonstrated no significant differences in PE (HR 0.936, 95%CI 0.755-1.161, p=0.3828), UE DVT (HR 0.969, 95%CI 0.692-1.356, p=0.6), LE DVT (HR 0.708, 95%CI 0.583-0.859, p=0.1963), superficial VT (HR 0.655, 95%CI 0.376-1.142, p=0.0995), bleeding (HR 0.961, 95%CI 0.812-1.137, p=0.7768), transfusion (HR 1.127, 95%CI 0.95-1.336, p=0.5715), or all-cause mortality (HR 1.042, 95%CI 0.93-1.167, p=0.15) (Table 6).

Enoxaparin and Apixaban

After propensity-score matching, 2,429 patients were identified in each cohort. The average age at index event for the enoxaparin cohort was 54.6 + 16.4 years, compared to 61.2 + 15.2 years for the apixaban cohort. The enoxaparin cohort had 1,746 female patients (71.9%) compared to 1,571 (64.7%) in the apixaban cohort. Within the enoxaparin cohort, 1632 (67.2%) were Caucasian patients, 318 (13.1%) African American patients, 219 (9.0%) Hispanic/Latino patients, and 68 (2.8%) Asian patients. A similar composition was noted in the apixaban cohort, with 1,683 (69.3%) Caucasian patients, 321 (13.2%) African American patients, 141 (5.8%) Hispanic/Latino patients, and 53 (2.2%) Asian patients. The enoxaparin and apixaban cohorts demonstrated no significant differences in PE (HR 0.798, 95%CI 0.608-1.047, p=0.6491), UE DVT (HR 0.666, 95%CI 0.431-1.03, p=0.6275), LE DVT (HR 0.684, 95%CI 0.593-0.788, p=0.723), superficial VT (HR 4.059, 95%CI 1.156-14.258, p=0.4198), bleeding (HR 0.933, 95%CI 0.771-1.129, p=0.4356), transfusion (HR 1.089, 95%CI 0.892-1.33, p=0.4299), or all-cause mortality (HR 1.041, 95%CI 0.912-1.189, p=0.2628) (Table 6).

Enoxaparin and Aspirin 81 mg

After propensity-score matching, 6,433 patients were identified in each cohort. The average age at index event for the enoxaparin cohort was 54.5 + 16.6 years, compared to the aspirin 81 mg cohort at 58.8 + 14.9 years. The enoxaparin cohort had 4664 female patients (72.5%) compared to 4,445 (69.1%) in the aspirin 81 mg cohort. Within the enoxaparin cohort, 4,522 (70.3%) were Caucasian patients, followed by 766 (11.9%) African American patients, 521 (8.1%) Hispanic/Latino patients, and 193 (3.0%) Asian patients. Similar demographics were noted within the Aspirin 81 mg cohort, with 4,670 (72.6%) Caucasian patients, 817 (12.7%) African American patients, 425 (6.6%) Hispanic/Latino patients, and 167 (2.6%) Asian patients. The enoxaparin cohort demonstrated a significantly higher risk of PE (HR 1.697, 95%CI 1.444-1.994, p=0.0345), LE DVT (HR 1.492, 95%CI 1.28-1.738, p=0.0017), and all-cause mortality (HR 1.272, 95%CI 1.167-1.386, p=0.0002) compared to the aspirin 81 mg cohort (Figure 2). There was no significant difference in rates of UE DVT (HR 1.398, 95%CI 1.06-1.845, p=0.587), superficial VT (HR 1.718, 95%CI 1.011-2.92, p=0.4268), bleeding (HR 1.107, 95%CI 0.986-1.243, p=0.246), or transfusion (HR 1.347, 95%CI 1.185-1.532, p=0.2057) (Table 6). Due to a significant difference between enoxaparin and Aspirin 81 mg, an E-value was calculated for PE (E-value = 2.783), LE DVT (E-value = 2.348), and all-cause mortality (E-value = 1.860).

Kaplan-Meier-survival-curve-for-pituitary-Cushing's-subtype-(mortality,-LE-DVT,-and-PE)
Figure 2: Kaplan-Meier survival curve for pituitary Cushing’s subtype (mortality, LE DVT, and PE)

(A) Mortality of enoxaparin compared to aspirin 81mg (HR 1.272, 95% CI 1.167-1.386, p=0.0002); (B) LE DVT risk with enoxaparin compared to aspirin 81 mg (HR 1.492, 95%CI 1.28-1.738, p=0.0017); (C) PE risk with enoxaparin compared to aspirin 81 mg (HR: 1.697, 95%CI 1.444-1.994, p=0.0345)

DVT: deep vein thrombosis; LE: lower extremity; PE: pulmonary embolism

Pituitary hypercortisolism (Cushing’s disease)

Enoxaparin and Heparin

Propensity-score matching identified 5,602 patients per cohort. The average age at index for the enoxaparin cohort was 53.9 + 16.7 years, compared to 53.7 + 16.9 years in the heparin cohort. The enoxaparin cohort had 4,088 female patients (72.97%) compared to 4,066 (72.58%) in the heparin cohort. The enoxaparin cohort was predominantly Caucasian patients (n=3,948; 70.47%), followed by 641 (11.45%) African American patients, 424 (7.57%) Hispanic/Latino patients, and 139 (2.48%) Asian patients. The heparin cohort was also predominantly Caucasian (n=3,947; 70.46%), followed by 669 (11.94%) African American patients, 401 (7.16%) Hispanic/Latino patients, and 148 (2.64%) Asian patients. There were no significant differences in rates of PE (HR 1.208, 95%CI 1.007 – 1.451, p=0.5803), UE DVT (HR 1.156, 95%CI 0.841 – 1.59, p=0.6863), LE DVT (HR 1.246, 95%CI 1.063 – 1.46, p=0.8996), superficial VT (HR 1.347, 95%CI 0.874 – 2.075, p=0.3731), bleeding (HR 0.916, 95%CI 0.809 – 1.037, p=0.1578), transfusion (HR 0.912, 95%CI 0.798 – 1.042, p=2119), or all-cause mortality (HR 1.02, 95%CI 0.935 – 1.112, p=0.8734). A comprehensive summary of the results is demonstrated in Table 7.

p-value Medication 1 Medication 2 PE UE DVT LE DVT Superficial VT Bleeding Transfusion Mortality
enoxaparin heparin 0.5189 0.2468 0.7586 0.7708 0.5894 0.6273 0.8433
enoxaparin warfarin 0.4842 0.7763 0.9651 0.682 0.1996 0.5309 0.399
enoxaparin apixaban 0.1047 0.0423 0.647 0.4824 0.2698 0.1122 0.1044
enoxaparin aspirin 81 mg 0.9651 0.6358 0.8448 0.9765 0.1167 0.4854 0.5001
– – – – – – – – – –
HR Medication 1 Medication 2 PE UE DVT LE DVT Superficial VT Bleeding Transfusion Mortality
enoxaparin heparin 1.186 1.332 1.232 1.183 0.876 0.963 1.016
enoxaparin warfarin 0.804 0.76 0.688 0.815 1.008 1.009 0.976
enoxaparin apixaban 0.875 0.761 0.954 3.068 1.084 1.359 1.115
enoxaparin aspirin 81 mg 1.173 1.157 1.226 1.165 0.908 0.915 1.028
– – – – – – – – – –
95% CIs Medication 1 Medication 2 PE UE DVT LE DVT Superficial VT Bleeding Transfusion Mortality
enoxaparin heparin 0.983-1.433 0.941-1.885 1.032-1.47 0.776-1.803 0.769-0.998 0.808-1.147 0.929-1.112
enoxaparin warfarin 0.612-1.055 0.467-1.235 0.539-0.877 0.447-1.489 0.816-1.246 0.76-1.34 0.843-1.13
enoxaparin apixaban 0.659-1.162 0.456-1.271 0.736-1.236 0.843-11.166 0.845-1.381 0.962-1.921 0.944-1.317
enoxaparin aspirin 81mg 0.969-1.419 0.827-1.619 1.03-1.46 0.763-1.78 0.797-1.035 0.772-1.085 0.938-1.127
Table 7: Hazard ratio, 95% confidence intervals, and p-values for anticoagulation and antiplatelet comparisons in pituitary Cushing’s syndrome

HR: hazard ratio; CI: confidence interval; PE: pulmonary embolism; VT: venous thrombosis; DVT: deep vein thrombosis; UE: upper extremity; LE: lower extremity

Enoxaparin and Warfarin

Propensity-score matching was performed with 1,694 patients per cohort identified. The average age at index for the enoxaparin cohort was 58.1 + 15.8 years, compared to 58.1 + 15.9 years in the warfarin cohort. The enoxaparin cohort had 1,142 female patients (67.41%) compared to 1,143 (67.47%) in the warfarin cohort. Within the enoxaparin cohort, 1,224 (72.2%) were Caucasian patients, followed by 194 (11.45%) African American patients, 97 (5.73%) Hispanic/Latino patients, and 57 (3.37%) Asian patients. The warfarin cohort had similar demographics, with 1,223 (72.2%) Caucasian patients, followed by 194 (11.45%) African American patients, 102 (6.02%) Hispanic/Latino patients, and 65 (3.84%) Asian patients. There were no significant differences in rates of PE (HR 0.907, 95%CI 0.694 – 1.186, p=0.8117), UE DVT (HR 0.988, 95%CI 0.628 – 1.555, p=0.9848), LE DVT (HR 0.739, 95%CI 0.589 – 0.929, p=0.4445), superficial VT (HR 0.815, 95%CI 0.44 – 1.511, p=0.8098), bleeding (HR 1.001, 95%CI 0.814 – 1.231, p=0.0987), transfusion (HR 1.106, 95%CI 0.889 – 1.376, p=0.4904), or all-cause mortality (HR 0.951, 95%CI 0.83 – 1.089, p=0.1656) (Table 7).

Enoxaparin and Apixaban

Propensity-score matching identified 1,489 patients per cohort. The enoxaparin cohort was 61.1 + 15.1 years old at the index event, versus the apixaban cohort at 61.4 + 14.9 years. The enoxaparin cohort had 1,054 (70.79%) female patients compared with 1,029 (69.11%) in the apixaban cohort. The enoxaparin cohort was primarily Caucasian patients (n=1,105; 74.21%), followed by 179 (12.02%) African American patients, 74 (4.97%) Hispanic/Latino patients, and 27 (1.81%) Asian patients. The apixaban cohort demonstrated similar demographics with 1,080 (72.53%) Caucasian patients, followed by 180 (12.09%) African American patients, 76 (5.1%) Hispanic/Latino patients, and 27 (1.81%) Asian patients. There were no significant differences in rates of PE (HR 0.949, 95%CI 0.673 – 1.339, p=0.4372), UE DVT (HR 0.832, 95%CI 0.472 – 1.466, p=0.1538), LE DVT (HR 1.166, 95%CI 0.869 – 1.566, p=0.8595), superficial VT (HR 5.323, 95%CI 1.19 – 23.815, p=0.493), bleeding (HR 1.218, 95%CI 0.948 – 1.565, p=0.4021), transfusion (HR 1.319, 95%CI 0.993 – 1.753, p=0.1663), or all-cause mortality (HR 1.131, 95%CI 0.966 – 1.325, p=0.0839) (Table 7).

Enoxaparin and Aspirin 81 mg

Propensity-score matching revealed 3,475 patients per cohort. The enoxaparin cohort was 58.8 + 15.3 years at index event, compared to the aspirin cohort at 58.2 + 14.3 years. The enoxaparin cohort had 2,438 (70.16%) female patients compared to the aspirin cohort with 2,445 (70.36%). Within the enoxaparin cohort, 2,539 (73.06%) were Caucasian patients, followed by 378 (10.88%) African American patients, 182 (5.24%) Hispanic/Latino patients, and 74 (2.13%) Asian patients. The aspirin cohort demonstrated similar demographics with 2,554 (73.5%) Caucasian patients, followed by 363 (10.45%) African American patients, 196 (5.64%) Hispanic/Latino patients, and 68 (1.96%) Asian patients. The enoxaparin cohort demonstrated significantly increased risk of LE DVT (HR 1.677, 95%CI 1.353 – 2.079, p=0.0081) and all-cause mortality (HR 1.597, 95%CI 1.422 – 1.794, p=0.0005) (Figure 3). There were no significant differences in rates of PE (HR 1.74, 95%CI 1.354 – 2.236, p=0.2408), UE DVT (HR 1.773, 95%CI 1.108 – 2.837, p=0.8625), superficial VT (HR 4.273, 95%CI 1.969 – 9.273, p=0.5196), bleeding (HR 1.093, 95%CI 0.937 – 1.275, p=0.8554), or transfusion (HR 1.896, 95%CI 1.556 – 2.311, p=0.2609) (Table 7). Due to a significant difference between enoxaparin and Aspirin 81 mg, an E-value was calculated for LE DVT (E-value = 2.744) and all-cause mortality (E-value = 2.574).

Kaplan-Meier-survival-curve-for-pituitary-Cushing's-subtype-(mortality-and-LE-DVT)
Figure 3: Kaplan-Meier survival curve for pituitary Cushing’s subtype (mortality and LE DVT)

(A) Mortality of enoxaparin compared to aspirin 81 mg (HR 1.597, 95%CI 1.422-1.794, p=0.0005); (B) LE DVT of enoxaparin compared to aspirin 81 mg (HR 1.677, 95%CI: 1.353-2.079, p=0.0081)

HR: hazard ration; DVT: deep vein thrombosis; LE: lower extremity

Discussion

The concept of hypercoagulability in the setting of hypercortisolemia has been documented since the 1970s [10]. Estimates suggest an 18-fold risk of venous thromboembolism in patients with Cushing’s syndrome compared to the general population [11]. Furthermore, venous thromboembolism accounts for up to 11% of all deaths in Cushing’s syndrome [12]. Patients are often noted to have a “coagulation paradox” in Cushing’s syndrome, whereby there is a heightened risk for thrombosis, with concurrent bruising of the skin; thromboembolism is due to an imbalance between pro- and anti-coagulant pathways, whereas bruising is due to atrophy of the skin and capillary fragility [11]. As noted by Feelders and Nieman, two prominent phases for the development of thromboembolic events include the untreated (active) hypercortisolemia and the postoperative phases [11]. Population-based studies have demonstrated a heightened risk for venous thromboembolism prior to diagnosis (in some studies as early as three years before diagnosis) [9].

Despite this heightened risk for venous thromboembolic events, there appears to be a lack of awareness amongst institutions (and individual practitioners), along with improper management. Fleseriu and colleagues, however, do note that in 2020, the awareness of hypercoagulability in Cushing’s syndrome increased around fourfold in two years, with routine prophylaxis increasing to 75% (from 50%) perioperatively (however, most patients only received prophylaxis for up to two weeks postoperatively) [13]. Another survey was performed by the European Reference Network on Rare Endocrine Conditions, noting concerns of heterogeneity with timing, type, and duration of prophylaxis, noting most centers do not have a thromboprophylaxis protocol (identifying only one reference center had a standardized thromboprophylaxis protocol for Cushing’s syndrome) [14]. From the European survey, it was noted that prophylaxis was initiated at diagnosis in 48% of patients, with 17% preoperatively, 26% on the day before (or of) surgery, 13% postoperatively, and 9% “depending on the presentation”. With regards to discontinuation of thromboprophylaxis, in centers with a standardized protocol (35% of reference centers), 38% of centers stopped at one month post-operatively, 25% between two and four weeks, and 37% between one week before and two weeks after surgery, between four and six days postoperatively, and at three months postoperatively. When cessation was individualized (in the remaining 65% of reference centers), 60% discontinued thromboprophylaxis once the patient was mobile, 40% with achievement of remission, 27% regarding patient status, and 7% dependent upon hemostatic parameters [14].

There is limited guidance concerning thromboprophylaxis recommendations in Cushing’s syndrome. For example, the Endocrine Society merely recommends assessing the risk of thrombosis in Cushing’s syndrome and administering perioperative prophylaxis if undergoing surgery, but provides no further recommendations [8]. The Pituitary Society highlights the absence of standardized practice for both pre- and postoperative thromboprophylaxis in patients with Cushing’s syndrome [15]. There appears to only be one set of guidelines for thromboprophylaxis in Cushing’s syndrome, known as the “Delphi Panel Consensus”, which forms the basis for the guidelines from the European Society for Endocrinology [9]. The Delphi Panel Consensus recommends considering anticoagulation for all patients with Cushing’s syndrome (in the absence of contraindications), regardless of the underlying etiology, and is recommended in the presence of risk factors [9]. Moreover, thromboprophylaxis is advised to begin at the time of diagnosis [9]. Currently, there is not enough evidence to provide a recommendation for thromboprophylaxis in mild autonomous cortisol secretion [9]. As with any medical patient, thromboprophylaxis should be initiated in all patients with active Cushing’s syndrome who are hospitalized (without contraindications) [9, 15]. Apart from chemical prophylaxis, anti-embolic stockings are not recommended due to the risk of skin fragility and friability [9]. The Delphi Consensus Panel furthermore advises to continue prophylactic anticoagulation for at least three months after biochemical remission (eucortisolemia) has occurred, and note those without additional risk factors (such as obesity, immobility, prior history of venous thromboembolism, or cardiac risk factors) can be considered candidates to stop the medication; one caveat, however, is for patients medically managed with mitotane (which can alter liver function and coagulation factor metabolism), there is an increased risk of bleeding, for which careful monitoring of renal function and bleeding risk is advised [9]. The Pituitary Society provides additional recommendations, such as discontinuing estrogen therapy in women (if used for contraception) [15]. While the Delphi Consensus Panel does not comment upon pediatric patients, the Pituitary Society advises against the use of thromboprophylaxis in the pediatric population due to bleeding risks [15].

The Delphi Consensus Panel furthermore recommend considering thromboprophylaxis at the time of inferior petrosal sinus sampling (if not started before this), due to the risk of thrombosis associated with this intervention; for those who are receiving prophylaxis, it is recommended to continue throughout the procedure, however, if has not been started, it is advised to initiate 12 hours post procedure. Similarly, if thromboprophylaxis was not considered earlier in a patient’s course, it should be reconsidered in the perioperative period, with the last dose of LMWH administered 24 hours prior to surgery and reinitiated 24 hours postoperatively [9]. Isand et al. recommend continuing thromboprophylaxis for three months after cortisol levels normalize (< 5 μg/dL) and when patients can mobilize [9]. In patients for whom a venous thromboembolism develops, patients are advised to receive a therapeutic dose of anticoagulation (preferably LMWH) for three to six months, followed by prophylaxis for three months after resolution of Cushing’s syndrome [9]. The Delphi Consensus Panel provides a summary of their recommendations, shown in Figure 4.

Algorithm-for-thromboprophylaxis-in-Cushing's-syndrome
Figure 4: Algorithm for thromboprophylaxis in Cushing’s syndrome

IPSS: inferior petrosal sinus sampling; VTE: venous thromboembolism; LMWH: low-molecular-weight heparin; DOAC: direct oral anticoagulant

Source: Isand et al., 2025 [9]; Published with permission.

Although intuitively, one may expect the procoagulant profile of Cushing’s syndrome to resolve upon attainment of eucortisolemia with medical management, studies have failed to demonstrate a reduction in venous thromboembolism with medical therapy [16]. Additionally, while one may expect resolution of hypercoagulability with surgical intervention (transsphenoidal sinus surgery or adrenalectomy), the risk maintains in the postoperative period, comparable to that of orthopedic surgery, at times up to one year and beyond to normalize [17]; data from European Register on Cushing’s Syndrome (ERCUSYN) database suggest the risk is greatest six months postoperatively [18]. The estimated risk for postoperative venous thromboembolism in pituitary-dependent Cushing’s is around 4.3% (compared to 0% with a non-functional pituitary adenoma); regarding adrenal surgery, the risk is estimated at around 2.6% [11]. Although the underlying mechanism for the persistent risk for venous thromboembolism remains unknown, it is hypothesized that a sudden drop in cortisol can lead to an inflammatory response (itself activating the coagulation cascade) [16]. Lopes and colleagues note an increase in the number of lymphocytes (because of loss of Th1 cell suppression), with increases in cytokines (such as interferon-gamma, interleukin-2, and transforming growth factor-beta) [16]. Comorbidities such as osteoporosis and myopathy (from hypercortisolemia) may be associated with decreased mobility in the postoperative period, influencing the risk for thrombosis [16].

Whilst all subtypes of Cushing’s syndrome can be associated with a heightened risk for venous thromboembolism (pituitary adenoma, adrenal adenoma, medication-induced, ectopic ACTH, and adrenal carcinoma), the latter two are often associated with malignant disease, which itself poses a risk for hypercoagulability from the underlying neoplasm [11]. Patients with Cushing’s syndrome have been found to demonstrate a reduction in activated partial thromboplastin time (aPTT), alongside increases in clot lysis time, procoagulant factors (such as factor VIII, von-Willebrand factor and fibrinogen) and fibrinolysis inhibitors (including plasminogen activator-inhibitor-1, thrombin activatable fibrinolysis inhibitor, and alpha-2 antiplasmin) [11,12,17]. Varlamov et al. have also noted an increase in thrombin, thromboxane A2, and platelets. Other studies have additionally demonstrated elevated proteins C and S as well as antithrombin III, which are hypothesized to be increased as a compensatory mechanism from the state of hypercoagulability [12]. Barbot et al. demonstrate elevation in factor VIII and von-Willebrand factor within the first few months after transsphenoidal sinus surgery, along with abnormally large von-Willebrand multimers (which are typically found in the cellular components), which can induce spontaneous platelet aggregation [17].

Lopes et al. note that altered von-Willebrand factor levels are not a constant feature reported in Cushing’s syndrome, and state it depends upon the polymorphism of the gene promoter, providing an example of haplotype 1 of the gene promoter conferring the greatest risk for elevated von-Willebrand factor levels by cortisol [16]. Barbot and colleagues furthermore note ABO blood groupings as an additional influencer of the procoagulant state; as an example, blood group-O patients have a near one-quarter reduction in levels of von-Willebrand factor [17]. Feelders and Nieman note heterogeneity in coagulation profiles based on individual characteristics and differing assay techniques [11]. van Haalen and colleagues note an absence of a correlation between severity of hypercortisolism and hemostatic abnormalities [14]; this is echoed by Varlamov et al., stating there is no linear relationship between coagulation parameters and venous thromboembolic events, nor with urinary free cortisol elevation [12]. Varlamov and colleagues further note that a subset of patients may have unaltered coagulation parameters, for which they advise against stratifying patients’ risk based on coagulation parameters [12].

In 2016, Zilio and colleagues posed a scoring system to stratify patients with active Cushing’s syndrome, including both clinical and biochemical parameters, including age (> 69 = 2 points), reduction in mobility (2 points), acute severe infection (1 point), prior cardiovascular event(s) (1 point), midnight plasma cortisol (> 3.15 times upper limit of normal = 1 point), and shortened aPTT (1 point) [19]. Lopes et al. describe the stratification as follows: 2 points (low risk), 3 points (moderate risk), 4 points (high risk), and > 5 points (very high risk) [16]. It should be noted, however, that Zilio et al.’s study was performed on only 176 patients and has not been validated in other studies [19]. Further drawbacks include the failure to account for postoperative events (a major source of venous thromboembolism in Cushing’s syndrome), and despite the stratification categories, no recommendations for treatment are provided.

LMWH is the first-line medication, consistent across differing societies. Despite being the gold standard, there are limited studies demonstrating a beneficial reduction in venous thromboembolic events in such cohorts; similarly, studies are lacking in analysis of the other classes of anticoagulants in head-to-head comparisons against LMWH for thromboprophylaxis in hypercortisolism. Another limitation is the fact that certain studies solely address thromboprophylaxis in the postoperative period. As an example, McCormick et al. performed one of the only trials comparing unfractionated heparin and LMWH (enoxaparin), noting no differences in hemorrhagic complications or thromboses; however, this was analyzed in patients undergoing transsphenoidal sinus surgery [10].

The current study retrospectively analyzed the various anticoagulant agents for the prevention of venous thromboembolism in Cushing’s syndrome (of any subtype), compared to the gold standard, LMWH (in this study, enoxaparin). When analyzing Cushing’s syndrome, our study demonstrated no significant differences in outcomes between enoxaparin and warfarin, apixaban, or unfractionated heparin; however, aspirin 81 mg demonstrated a lower risk of all-cause mortality, PE, and LE DVT. With subanalysis of Cushing’s disease (pituitary-related), there was no significant difference between enoxaparin and warfarin, apixaban or unfractionated heparin; aspirin 81 mg again noted a reduced all-cause mortality and LE DVT (but did not lower the risk of PE, compared with Cushing’s syndrome of all types combined). With E-value sensitivity analysis, the association remained moderately robust with PE (all Cushing’s types combined), LE DVT (all Cushing’s types and pituitary Cushing’s), and mortality (solely pituitary Cushing’s), however, mortality was weak-to-moderate with Cushing’s syndrome of all types (Table 8).

Outcome Hazard Ratio E-value Interpretation
PE (All Cushing’s Types) 1.697 2.783 Moderate
LE DVT (All Cushing’s Types) 1.492 2.348 Moderate
LE DVT (Pituitary) 1.677 2.744 Moderate
Mortality (All Cushing’s Types) 1.272 1.860 Weak
Mortality (Pituitary) 1.597 2.574 Moderate
Table 8: E-value sensitivity analyses for significant findings

DVT: deep vein thrombosis; LE: lower extremity; PE: pulmonary embolism

Aspirin, a non-steroidal anti-inflammatory drug, was first identified to irreversibly inhibit platelet function in the 1950s by Dr. Lawrence Craven [20]. Data is scarce in terms of aspirin’s role in thromboprophylaxis in hypercortisolemia. In 1999, Semple and Laws Jr. initially reported the use of aspirin postoperatively for six weeks (starting postoperative day one) in patients with Cushing’s disease who underwent transsphenoidal sinus surgery; while the authors mentioned a reduction in rates of venous thromboemboli, no factual data was provided (including dose of aspirin, complications experienced, and number of venous thromboemboli before and after) [21]. In 2015, Smith et al. performed an additional study with 81 mg of aspirin again administered starting postoperative day one (alongside sequential compression devices and mobilization), reporting that none of the 82 patients developed DVTs (with only two cases of epistaxis) [22]. It was not until 1994, however, in the Antiplatelet Trialists’ Collaborations’ meta-analysis, that aspirin demonstrated a reduced risk for venous thromboembolism, with similar findings replicated in the Pulmonary Embolism Prevention trial in 2000 and the WARFASA (Warfarin and Aspirin) and ASPIRE (Aspirin to prevent recurrent venous thromboembolism) trials in 2012 [23]. In 2012, the American College of Chest Physicians [24,25] were the first to recommend aspirin as thromboprophylaxis following total hip or knee replacement, followed by the National Institute for Health and Care Excellence in 2018 (advising LMWP followed by aspirin) and the American Society of Hematology in 2019 (advising either aspirin or oral anticoagulation after total hip or knee replacement) [25]. Despite recognition of the reduction in venous thromboembolism by aspirin (and its incorporation into guidelines), its role in thromboprophylaxis is largely limited to orthopedic surgery. The mechanisms of aspirin and its reduction in venous thromboembolism is not entirely understood, but believed to occur via differing mechanisms, including inhibition of cyclooxygenase-1 (which reduces thromboxane A2, a promoter of platelet aggregation), prevention of thrombin formation and thrombin-mediated coagulant reactions, acetylation of proteins involved in coagulation (such as fibrinogen), and enhancing fibrinolysis [23,26].

Strengths and limitations

To the best of our knowledge, a study specifically comparing the impact of aspirin with that of LMWP in Cushing’s syndrome has not been performed; as a result, our study adds to the paucity of literature pertaining to this topic. Notable strengths in the study include a large sample size (allowing robust comparisons amongst treatment arms), incorporation of propensity-score matching (allowing for internal validity through balancing baseline comparison groups), and comprehensive measurable outcomes.

Limitations to our study are multifold, and include retrospective design, for which intrinsic biases are inherent and can affect causal inference (despite matching techniques). Furthermore, data collection (via TriNetX) relied on correct ICD-10 coding, which could be a source of potential error if conditions and medications are coded improperly, or if our queries missed ICD-10 codes that could also correspond with outcomes. Similarly, TriNetX also relies on queries of healthcare organizations, many of which may not have responded with data, which could inaccurately skew the results. Although TriNetX uses global data, the majority of patient data was derived from the United States population, which could result in less generalizable data to the global public. These findings should be interpreted within the correct context and with caution to prevent misrepresentation. Compliance was a variable that could not be controlled for. Moreover, those who had taken the medication before the index event were excluded from analysis. While aspirin 81 mg demonstrated a reduction in LE DVT and mortality in Cushing’s disease along with PE with Cushing’s syndrome, we only performed a subgroup analysis concerning pituitary-related causes of Cushing’s syndrome (Cushing’s disease); it remains unclear why the risk of PE was not reduced in the latter subgroup. Due to limitations in ICD-10 coding, further subgroup analyses were not performed (such as adrenal adenoma, adrenal adenocarcinoma, or ectopic ACTH syndrome), for which the implications of treating with aspirin 81 mg cannot be inferred from our data. Similarly, further subgroup analyses, such as gender and race, were not performed. Our study assessed adult patients with Cushing’s syndrome, and not pediatric patients, which limits the applicability of our findings to such a cohort. Further studies are required to confirm and replicate our findings in a prospective fashion, stratifying subtypes of Cushing’s Syndrome.

Conclusions

Cushing’s syndrome is associated with a heightened risk for venous thromboembolism, regardless of the underlying etiology. Currently, LMWHs such as enoxaparin remain the gold standard for both thromboprophylaxis and treatment in such patients. There is limited data to support superiority over alternative agents. Our study analyzed enoxaparin against warfarin, unfractionated heparin, and apixaban, for which there was no significant risk difference. When compared to aspirin, enoxaparin demonstrated a greater risk for the development of PE, LE DVT, and all-cause mortality. Further prospective trials are required to replicate our findings and confirm the superiority of aspirin over LMWH.

References

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From https://www.cureus.com/articles/371036-therapeutic-options-for-the-prevention-of-thromboses-in-cushings-syndrome-a-propensity-matched-retrospective-cohort-analysis#!/

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