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).

  1. Download: Download high-res image (566KB)
  2. Download: Download full-size image

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.

  1. Download: Download high-res image (1MB)
  2. Download: Download full-size image

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 »

Graphic Era Hospital’s Milestone Treatment of Two Complex Cases

Posted on August 26, 2025 by MaryO
DEHRADUN, 23 August: Graphic Era Hospital has achieved a remarkable mileston by successfully treating two complex cases of the rare hormonal disorder Cushing’s Disease in Dehradun. The hospital’s experts used advanced technology and surgical skills to give the patients a new lease on life, marking this significant achievement.
In the first case, a 27-year-old woman was brought to the Endocrinology Department at Graphic Era Hospital after long-term weight gain, facial puffiness, irregular menstrual cycles, high blood pressure, and kidney stones. Tests and lab reports confirmed that the patient was suffering from ACTH-dependent Cushing’s Syndrome – Pituitary Microadenoma. A 3-Tesla Dynamic Pituitary MRI revealed a 6 mm tumor, while other organs were normal.
The specialists performed surgery using endoscopic trans-nasal neuro-navigation technology, completing it successfully without opening the brain. After the operation, the patient experienced significant weight loss, normalized blood pressure, regular menstrual cycles, and all hormone levels returned to normal.
In the second case, a 24-year-old woman came to Graphic Era Hospital with extremely high blood pressure (200/100), headache, weight gain, and irregular menstrual cycles. MRI revealed a 7–9 mm tumor in an unusual location in the pituitary gland, which was also affecting the pituitary fossa bone. Despite multiple medications, her blood pressure remained uncontrolled, and CT scans showed an impact on her heart.
The multi-specialty team performed surgery using endoscopic trans-nasal neuro-navigation technology, again without opening the brain. After surgery, her blood pressure normalized and her menstrual cycles became regular.
In both cases, pituitary microadenomas were diagnosed. The surgeries were done through the nasal route using microscopes and endoscopes, with neuro-navigation helping to accurately locate the tumors while protecting the pituitary gland. The multi-specialty team included Head of Neurosciences and HOD Neurosurgery Partha P Bishnu, Senior Consultant Neurosurgery Ankur Kapoor, Senior Neurosurgeon and Neurointervention Specialist Payoz Pandey, Senior Consultant ENT Parvendra Singh, Director Endocrinology, Obesity and Diabetes Sunil Kumar Mishra, and the Neuro-Anesthesia Team.
With the latest technology and expert doctors at Graphic Era Institute of Medical Sciences, new milestones continue to be achieved. Previously, the hospital’s expert doctors had successfully implanted pacemakers in the brain, placed a third pacemaker in complex pediatric cases, replaced two heart valves without open-heart surgery, unblocked the esophagus without surgery, and performed open-heart surgery through a small 2.5-inch facial incision without cutting bones. Director of Graphic Era Hospital, Puneet Tyagi,  Mefical Superintendent, Gurdeep Singh Jheetay, Dean SL Jethani and COO Atul Bahl were present at the press conference.

Filed under: Cushing's, pituitary, symptoms, Treatments | Tagged: , , , , , , , , , | Leave a comment »

Cushing’s Syndrome in a Young Woman Due to Prolonged Betamethasone Nasal Drop Use

Posted on August 11, 2025 by MaryO

Abstract

Background

Cushing’s syndrome is an uncommon but serious condition caused by long-term exposure to elevated cortisol levels, which is usually iatrogenic in origin. Although systemic corticosteroids are the most frequent agents, the association of intranasal corticosteroids with this condition is remarkably rare.

Case presentation

This report is about a 21-year-old Iranian woman using betamethasone nasal drops for nasal obstruction. The patient presented with weight gain, Amenorrhea, mood disturbances, red purplish striae, and mild hirsutism. Hormonal assessments revealed suppression of the hypothalamic–pituitary–adrenal axis.

Conclusion

This case demonstrates the underappreciated systemic effects of intranasal betamethasone to induce Cushing’s syndrome. It serves as a pivotal reminder of the need for vigilance in prescribing practices and reinforces the importance of early diagnosis to ensure favorable patient outcomes.

Peer Review reports

Background

Iatrogenic Cushing’s syndrome (CS) is an endocrine disease caused by long-term or high-dose glucocorticoid use [1]. Although iatrogenic cases are commonly associated with oral or injectable glucocorticoids [2], few reports described CS after the use of intranasal steroid sprays (INS) such as betamethasone in adults [3,4,5,6,7]. Currently, INS is widely used for managing conditions such as allergic rhinitis, nasal polyposis, and other upper airway disorders owing to their localized effects and limited systemic absorption [8, 9]. However, prolonged use, high doses, or using potent formulations can lead to significant systemic absorption, resulting in Hypothalamic–pituitary–adrenal (HPA) axis suppression, and frank CS [10]. Betamethasone nasal spray, a cornerstone in the treatment of nasal congestion, has the potential for systemic absorption by the nasal mucosa, particularly with prolonged or excessive use [11].

This report presents the case of a young woman who developed CS following the overuse of betamethasone nasal drops. It also highlights the importance of detailed patient histories when diagnosing CS and highlights the critical need to educate patients on the proper use and potential risks of steroid therapies to prevent complications. This case report adheres to the case report (CARE) guidelines [12].

Case presentation

This is the case of a 21-year-old Iranian female who presented with a history of rapid weight gain (30 kg in 8 months), irregular menstrual cycles, and significant mood changes. Her body mass index (BMI) was calculated at 40.07 kg/m2, classifying her as obese, and her blood pressure was recorded at 115/75 mmHg. In addition, she exhibited red–purple striae on her abdomen and limbs and mild hirsutism (modified Ferriman–Gallwey Score (FGS) score = 10), prompting admission for further evaluation after multiple outpatient visits yielded no definitive diagnosis.

Figure 1 is a clinical photograph (with patient consent) or an illustration of the red–purple striae.

Fig. 1

figure 1

Clinical photograph showcasing the red–purplish striae on the patient’s abdomen, arms, and lower limbs

Upon admission, the patient’s history revealed prolonged use of betamethasone 0.1% 1 mg/mL nasal drops, administered at a daily dosage of 5 cc, in combination with oxymetazoline (a sympathomimetic nasal preparation) at a daily dosage of 1 cc, over approximately 12 months, to address nasal obstruction. Her symptoms began 6 months after starting the nasal drops. Further medication history revealed no other corticosteroid use. Notably, the patient had a past diagnosis of polycystic ovary (PCO) syndrome made on the basis of Rotterdam 2003 criteria (oligomenorrhea since menarche and clinically androgen excess) but did not undergo treatment or maintain laboratory records.

A detailed hormonal evaluation was undertaken. Morning plasma cortisol less than 0.05 µg/dL and adrenocorticotropic hormone (ACTH) less than 5 (10–56 pg/mL) measurements were abnormally low. Her 24-hour urine-free cortisol concentrations of 1.04 µg/24 h were significantly reduced, indicating suppression of the HPA axis secondary to prolonged exogenous corticosteroid exposure. All tests were repeated several times by endocrinologists during the time course of disease manifestations.

Table 1 summarizes the hormonal test results to clearly display the abnormalities.

Table 1 Hormonal and biochemical test results with reference values

Imaging studies before admission included a computed tomography (CT) scan of the adrenal glands, which showed that both adrenal glands were of normal size. However, a dynamic pituitary magnetic resonance imaging (MRI) revealed an 11 mm pituitary gland, despite there being no rationale for imaging studies in this scenario.

The patient was counseled extensively about the condition, and betamethasone nasal drops were discontinued immediately. Ear, nose, and throat (ENT) consultation revealed normal findings and the psychiatric team diagnosed her with major depressive disorder (MDD). She was discharged on 15 mg prednisolone with a structured tapering plan to allow for gradual recovery of adrenal function and to prevent acute adrenal insufficiency. Follow-up appointments were scheduled to monitor her clinical progress and re-evaluate her HPA axis recovery.

Discussion

This case highlights the rare but significant occurrence of iatrogenic CS secondary to prolonged use of intranasal betamethasone. Although oral corticosteroids are well-known to cause HPA axis suppression, INS is generally considered safer owing to their localized effects and lowering systemic absorption side effects. However, the associated potential of systemic absorption in INS remains a concern [13]. As demonstrated in this case, prolonged use of potent formulations such as betamethasone can lead to significant systemic effects, particularly when administered inappropriately or at high doses.

Betamethasone nasal drops, although effective for treating nasal congestion and inflammation [14, 15], carry a potential risk of systemic absorption through the nasal mucosa. Factors, such as prolonged use [6, 16, 17], and high potency [18], can significantly increase systemic bioavailability. R. J. Perry et al. [19] in study of seven children highlights that even patients receiving doses within conventional safety ranges may exhibit varying sensitivity to glucocorticoids, leading to symptomatic adrenal suppression or glucocorticoid excess. Unlike newer corticosteroid compounds, such as fluticasone or mometasone, which undergo extensive first-pass metabolism in the liver, betamethasone exhibits minimal hepatic metabolism, contributing to its prolonged systemic activity [20, 21]. This pharmacokinetic profile underscores the need for careful regulation and monitoring of its use, even in ostensibly localized therapies.

The clinical manifestations in this patient, including central obesity, striae, hirsutism, and mood changes, were classic features of CS and guided the diagnostic process [22]. Scutelnicu et al. [23] reported a case of a patient in the second trimester of pregnancy who, owing to chronic sinusitis, underwent intranasal betamethasone spray therapy. The patient manifested extensive striae on the lower limbs, as well as edema in the legs, arms, and face, accompanied by a weight gain of 22 kg over 3 months. After switching the patient’s treatment to an alpha-1 adrenergic agonist spray, the condition was managed uneventfully without any symptoms of adrenal insufficiency.

Requesting imaging assessments, including a CT scan and MRI, as a first step further complicated the diagnostic process. This highlights a common diagnostic pitfall: the use of imaging as an initial approach can lead to the discovery of incidentalomas, which may misdirect clinical attention. Such findings risk overshadowing the primary etiology of the condition, potentially resulting in misdiagnosis or delayed treatment. This emphasizes the importance of prioritizing functional assessments over imaging in the early diagnostic workup to avoid unwarranted diagnostic confusion and ensure accurate identification of the underlying pathology.

Management involved the immediate cessation of betamethasone nasal drops and initiation of a structured tapering regimen with prednisolone to support adrenal recovery. The importance of stress-dose precautions during intercurrent illnesses was emphasized, alongside comprehensive patient education to prevent future misuse of corticosteroids. The gradual improvement in adrenal function during follow-up highlights the reversibility of glucocorticoid-induced adrenal suppression with appropriate intervention.

Conclusion

This case underscores several critical lessons. First, it emphasizes the importance of heightened awareness among healthcare providers regarding the potential systemic effects of topical corticosteroids, particularly potent formulations such as betamethasone. Second, it highlights the need for thorough history-taking and detailed patient education to prevent corticosteroid misuse. This report contributes to the limited body of literature on iatrogenic CS from intranasal corticosteroids, particularly in adults. Documenting the clinical presentation, diagnostic challenges, and successful management of this case, provides valuable insights into preventing, recognizing, and treating similar cases. It serves as a reminder of the delicate balance between therapeutic benefit and potential harm in corticosteroid therapy and advocates for ongoing research to establish safer prescribing practices.

Data availability

The data analyzed and generated in this study can be accessed through the corresponding author upon reasonable request.

Abbreviations

CS:
Cushing’s syndrome
INS:
Intranasal corticosteroids
HPA axis:
Hypothalamic–pituitary–adrenal axis
BMI:
Body mass index
FGS:
Ferriman–Gallwey Score
PCO:
Polycystic ovary
ACTH:
Adrenocorticotropic hormone
CT:
Computed tomography
MRI:
Magnetic resonance imaging
ENT:
Ear, nose, and throat
MDD:
Major depressive disorder

References

  1. Cristante J, Chabre O. Factitious, or iatrogenic but unexpected Cushing’s syndrome. Ann Endocrinol (Paris). 2023;84(3):370–2.

    PubMed Google Scholar

  2. Lacroix A, Feelders RA, Stratakis CA, Nieman LK. Cushing’s syndrome. Lancet. 2015;386(9996):913–27.

    CAS PubMed Google Scholar

  3. Scutelnicu A, Panaitescu AM, Ciobanu AM, Gica N, Botezatu R, Peltecu G, et al. Iatrogenic cushing’s syndrome as a consequence of nasal use of betamethasone spray during pregnancy. Acta Endocrinol. 2020;16(4):511–7.

    CAS Google Scholar

  4. Sakamoto M, Morita K, Okamura E, Uchino T, Okamoto K, Ozawa Y, et al. A case of iatrogenic cushing syndrome due to overuse of nasal steriod and concurrent administration of clarithromycin. Teikyo Med J. 2018;41(4):161–8.

    Google Scholar

  5. Nutting CM, Page SR. Iatrogenic Cushing’s syndrome due to nasal betamethasone: a problem not to be sniffed at! Postgrad Med J. 1995;71(834):231–2.

    CAS PubMed PubMed Central Google Scholar

  6. Stevens DJ. Cushing’s syndrome due to the abuse of betamethasone nasal drops. J Laryngol Otol. 1988;102(3):219–21.

    CAS PubMed Google Scholar

  7. Dow A, Yu R, Carmichael J. Too little or too much corticosteroid? Coexisting adrenal insufficiency and Cushing’s syndrome from chronic, intermittent use of intranasal betamethasone. Endocrinol Diabetes Metab Case Rep. 2013;2013:13–0036.

    Google Scholar

  8. Bachert C, Desrosiers MY, Hellings PW, Laidlaw TM. The role of biologics in chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol Pract. 2021;9(3):1099–106.

    CAS PubMed Google Scholar

  9. Bachert C, Han JK, Wagenmann M, Hosemann W, Lee SE, Backer V, et al. EUFOREA expert board meeting on uncontrolled severe chronic rhinosinusitis with nasal polyps (CRSwNP) and biologics: definitions and management. J Allergy Clin Immunol. 2021;147(1):29–36.

    CAS PubMed Google Scholar

  10. Quddusi S, Browne P, Toivola B, Hirsch IB. Cushing syndrome due to surreptitious glucocorticoid administration. Arch Intern Med. 1998;158(3):294–6.

    CAS PubMed Google Scholar

  11. Grayson JW, Harvey RJ. Topical corticosteroid irrigations in chronic rhinosinusitis. Int Forum Allergy Rhinol. 2019;9(S1):S9–15.

    PubMed Google Scholar

  12. Gagnier JJ, Kienle G, Altman DG, Moher D, Sox H, Riley D. The CARE guidelines: consensus-based clinical case reporting guideline development. Global Adv Health Med. 2013;2(5):38–43.

    Google Scholar

  13. McDonnell J, Weller K, Pien LC. Safety of intranasal steroids: an updated perspective. Curr Allergy Asthma Rep. 2020;20(11):69.

    PubMed Google Scholar

  14. Scadding GK. Other anti-inflammatory uses of intranasal corticosteroids in upper respiratory inflammatory diseases. Allergy. 2000;55(s62):19–23.

    PubMed Google Scholar

  15. Chong LY, Head K, Hopkins C, Philpott C, Burton MJ, Schilder AG. Different types of intranasal steroids for chronic rhinosinusitis. Cochrane Database Syst Rev. 2016;4(4):Cd011993.

    PubMed Google Scholar

  16. Findlay CA, Macdonald JF, Wallace AM, Geddes N, Donaldson MD. Childhood Cushing’s syndrome induced by betamethasone nose drops, and repeat prescriptions. BMJ. 1998;317(7160):739–40.

    CAS PubMed PubMed Central Google Scholar

  17. Reynolds C, Agrawal P, McCann A, O’Sullivan T, Chroinin MN, O’Riordan SMP. Cushing syndrome and adrenal insufficiency induced by high dose prolonged intranasal betamethasone. Arch Dis Child. 2019;104:A275.

    Google Scholar

  18. Oluwayemi IO, Oduwole AO, Oyenusi E, Onyiriuka AN, Abdullahi M, Fakeye-Udeogu OB, et al. Iatrogenic Cushing’s syndrome in children following nasal steroid. Pan Afr Med J. 2014;17:237.

    PubMed PubMed Central Google Scholar

  19. Perry RJ, Findlay CA, Donaldson MDC. Cushing’s syndrome, growth impairment, and occult adrenal suppression associated with intranasal steroids. Arch Dis Child. 2002;87(1):45–8.

    CAS PubMed PubMed Central Google Scholar

  20. Matera MG, Rinaldi B, Calzetta L, Rogliani P, Cazzola M. Pharmacokinetics and pharmacodynamics of inhaled corticosteroids for asthma treatment. Pulm Pharmacol Ther. 2019;58: 101828.

    CAS PubMed Google Scholar

  21. Krzyzanski W, Milad MA, Jobe AH, Peppard T, Bies RR, Jusko WJ. Population pharmacokinetic modeling of intramuscular and oral dexamethasone and betamethasone in Indian women. J Pharmacokinet Pharmacodyn. 2021;48(2):261–72.

    CAS PubMed PubMed Central Google Scholar

  22. Savas M, Mehta S, Agrawal N, van Rossum EFC, Feelders RA. Approach to the patient: diagnosis of Cushing syndrome. J Clin Endocrinol Metab. 2022;107(11):3162–74.

    PubMed PubMed Central Google Scholar

  23. Scutelnicu A, Panaitescu AM, Ciobanu AM, Gica N, Botezatu R, Peltecu G, et al. Iatrogenic Cushing’s syndrome as a consequence of nasal use of betamethasone spray during pregnancy. Acta Endocrinol (Buchar). 2020;16(4):511–7.

    CAS PubMed Google Scholar

Download references

Acknowledgements

Not applicable.

Funding

Not Applicable.

Author information

Authors and Affiliations

  1. Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran

    Mohammadsadra Shamohammadi

  2. M.D., Endocrinologist Assistant Professor of Internal Medicine Assistant Professor of Internal Medicine, Iran University of Medical Sciences at Rasool Akram General Hospital, Tehran, Iran

    Delaram Eskandari

  3. Professor of Endocrinology Department of Endocrinology, Rasool Akram Medical Complex, School of Medicine, Iran University of Medical Sciences, Tehran, Iran

    Amir Ziaee

  4. Assistant Professor of Endocrinology & Metabolism Department of Internal Medicine, School of Medicine Hazrat-e Rasool General Hospital Iran University of Medical Sciences Medical Doctor at Iran University of Medical Sciences, Tehran, Iran

    Seyed Hossein Samadanifard

  5. Assistant Professor of Endocrinology & Metabolism Department of Internal Medicine, School of Medicine, Iran University of Medical Sciences, Tehran, Iran

    Haleh Chehrehgosha

  6. M.D., Endocrinologist Assistant Professor of Internal Medicine Assistant Professor of Internal Medicine, Iran University of Medical Sciences at Rasool Akram General Hospital, Tehran, Iran

    Amir Hossein Ghanooni

Contributions

MS and DE wrote the original draft; AZ and SHS collected the data. DE and HC were the patient’s doctors; MS and AHG reviewed, edited, and supervised the manuscript. All authors have read and approved the final version of the manuscript.

Corresponding author

Correspondence to Delaram Eskandari.

Ethics declarations

Ethics approval and consent to participate

This study was conducted in accordance with ethical guidelines and was approved by the Research Ethics Committee of Iran University of Medical Sciences under approval number IR.IUMS.REC.1404.208.

Consent for publication

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Filed under: adrenal crisis, 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

  1. Ulrich-Lai YM, Figueiredo HF, Ostrander MM, Choi DC, Engeland WC, Herman JP: Chronic stress induces adrenal hyperplasia and hypertrophy in a subregion-specific manner. Am J Physiol Endocrinol Metab. 2006, 291:E965-73. 10.1152/ajpendo.00070.2006
  2. Lindholm J: Cushing’s syndrome: historical aspects. Pituitary. 2000, 3:97-104. 10.1023/a:1009905808033
  3. Raff H, Carroll T: Cushing’s syndrome: from physiological principles to diagnosis and clinical care. J Physiol. 2015, 593:493-506. 10.1113/jphysiol.2014.282871
  4. Newell-Price J, Bertagna X, Grossman AB, Nieman LK: Cushing’s syndrome. Lancet. 2006, 367:1605-17. 10.1016/S0140-6736(06)68699-6
  5. Savas M, Mehta S, Agrawal N, van Rossum EF, Feelders RA: Approach to the patient: diagnosis of Cushing syndrome. J Clin Endocrinol Metab. 2022, 107:3162-74. 10.1210/clinem/dgac492
  6. Suarez MG, Stack M, Hinojosa-Amaya JM, et al.: Hypercoagulability in Cushing syndrome, prevalence of thrombotic events: a large, single-center, retrospective study. J Endocr Soc. 2020, 4:bvz033. 10.1210/jendso/bvz033
  7. St-Jean M, Lim DS, Langlois F: Hypercoagulability in Cushing’s syndrome: from arterial to venous disease. Best Pract Res Clin Endocrinol Metab. 2021, 35:101496. 10.1016/j.beem.2021.101496
  8. Nieman LK, Biller BM, Findling JW, Murad MH, Newell-Price J, Savage MO, Tabarin A: Treatment of Cushing’s syndrome: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2015, 100:2807-31. 10.1210/jc.2015-1818
  9. Isand K, Arima H, Bertherat J, et al.: Delphi panel consensus on recommendations for thromboprophylaxis of venous thromboembolism in endogenous Cushing’s syndrome: a position statement. Eur J Endocrinol. 2025, 192:R17-27. 10.1093/ejendo/lvaf017
  10. McCormick JP, Sun M, Shafqat I, Heaney AP, Bergsneider M, Wang MB: Venous thromboembolic (VTE) prophylaxis in Cushing Disease patients undergoing transsphenoidal surgery. Interdiscip Neurosurg. 2022, 27:10.1016/j.inat.2021.101371
  11. Feelders RA, Nieman LK: Hypercoagulability in Cushing’s syndrome: incidence, pathogenesis and need for thromboprophylaxis protocols. Pituitary. 2022, 25:746-9. 10.1007/s11102-022-01261-9
  12. Varlamov EV, Langlois F, Vila G, Fleseriu M: Management of endocrine disease: cardiovascular risk assessment, thromboembolism, and infection prevention in Cushing’s syndrome: a practical approach. Eur J Endocrinol. 2021, 184:R207-24. 10.1530/EJE-20-1309
  13. Fleseriu M, Biller BM, Grossman A, Swearingen B, Melmed S: Hypercoagulability in Cushing’s disease: a risk awareness and prophylaxis survey on behalf of the Pituitary Society. 15th International Pituitary Congress: Program and Abstracts. The Pituitary Society, Orlando, FL; 2017. 35.
  14. van Haalen FM, Kaya M, Pelsma IC, et al.: Current clinical practice for thromboprophylaxis management in patients with Cushing’s syndrome across reference centers of the European Reference Network on Rare Endocrine Conditions (Endo-ERN). Orphanet J Rare Dis. 2022, 17:178. 10.1186/s13023-022-02320-x
  15. Fleseriu M, Auchus R, Bancos I, et al.: Consensus on diagnosis and management of Cushing’s disease: a guideline update. Lancet Diabetes Endocrinol. 2021, 9:847-75. 10.1016/S2213-8587(21)00235-7
  16. Lopes V, Marques O, De Sousa Lages A: Preventive strategies for hypercoagulation in Cushing’s syndrome: when and how. Thromb J. 2023, 21:72. 10.1186/s12959-023-00515-1
  17. Barbot M, Daidone V, Zilio M, et al.: Perioperative thromboprophylaxis in Cushing’s disease: what we did and what we are doing?. Pituitary. 2015, 18:487-93. 10.1007/s11102-014-0600-y
  18. Isand K, Feelders R, Brue T, et al.: High prevalence of venous thrombotic events in Cushing’s syndrome: data from ERCUSYN and details in relation to surgery. Eur J Endocrinol. 2024, 190:75-85. 10.1093/ejendo/lvad176
  19. Zilio M, Mazzai L, Sartori MT, et al.: A venous thromboembolism risk assessment model for patients with Cushing’s syndrome. Endocrine. 2016, 52:322-32. 10.1007/s12020-015-0665-z
  20. Zaorsky NG, Buyyounouski MK, Li T, Horwitz EM: Aspirin and statin nonuse associated with early biochemical failure after prostate radiation therapy. Int J Radiat Oncol Biol Phys. 2012, 84:e13-7. 10.1016/j.ijrobp.2012.02.050
  21. Semple PL, Laws ER Jr: Complications in a contemporary series of patients who underwent transsphenoidal surgery for Cushing’s disease. J Neurosurg. 1999, 91:175-9. 10.3171/jns.1999.91.2.0175
  22. Smith TR, Hulou MM, Huang KT, Nery B, de Moura SM, Cote DJ, Laws ER: Complications after transsphenoidal surgery for patients with Cushing’s disease and silent corticotroph adenomas. Neurosurg Focus. 2015, 38:E12. 10.3171/2014.10.FOCUS14705
  23. Diep R, Garcia D: Does aspirin prevent venous thromboembolism?. Hematology Am Soc Hematol Educ Program. 2020, 2020:634-41. 10.1182/hematology.2020000150
  24. Maddukuri RK, Chava H, Kondaveeti ST, Mutthineni MV, Vegesana BP: Aspirin for prophylaxis of VTE in patients with hip/ knee replacement: systematic review and meta-analysis of non-randomized studies. Indian J Pharmacol. 2024, 56:420-9. 10.4103/ijp.ijp_732_21
  25. Spoladore R, Milani M, Spreafico LP, Agnelli G, Savonitto S: Prevention of thromboembolism after a fracture: is aspirin enough?. Eur Heart J Suppl. 2024, 26:i102-7. 10.1093/eurheartjsupp/suae025
  26. Undas A, Brummel-Ziedins KE, Mann KG: Antithrombotic properties of aspirin and resistance to aspirin: beyond strictly antiplatelet actions. Blood. 2007, 109:2285-92. 10.1182/blood-2006-01-010645

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

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

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

Posted on May 26, 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

  1. Ulrich-Lai YM, Figueiredo HF, Ostrander MM, Choi DC, Engeland WC, Herman JP: Chronic stress induces adrenal hyperplasia and hypertrophy in a subregion-specific manner. Am J Physiol Endocrinol Metab. 2006, 291:E965-73. 10.1152/ajpendo.00070.2006
  2. Lindholm J: Cushing’s syndrome: historical aspects. Pituitary. 2000, 3:97-104. 10.1023/a:1009905808033
  3. Raff H, Carroll T: Cushing’s syndrome: from physiological principles to diagnosis and clinical care. J Physiol. 2015, 593:493-506. 10.1113/jphysiol.2014.282871
  4. Newell-Price J, Bertagna X, Grossman AB, Nieman LK: Cushing’s syndrome. Lancet. 2006, 367:1605-17. 10.1016/S0140-6736(06)68699-6
  5. Savas M, Mehta S, Agrawal N, van Rossum EF, Feelders RA: Approach to the patient: diagnosis of Cushing syndrome. J Clin Endocrinol Metab. 2022, 107:3162-74. 10.1210/clinem/dgac492
  6. Suarez MG, Stack M, Hinojosa-Amaya JM, et al.: Hypercoagulability in Cushing syndrome, prevalence of thrombotic events: a large, single-center, retrospective study. J Endocr Soc. 2020, 4:bvz033. 10.1210/jendso/bvz033
  7. St-Jean M, Lim DS, Langlois F: Hypercoagulability in Cushing’s syndrome: from arterial to venous disease. Best Pract Res Clin Endocrinol Metab. 2021, 35:101496. 10.1016/j.beem.2021.101496
  8. Nieman LK, Biller BM, Findling JW, Murad MH, Newell-Price J, Savage MO, Tabarin A: Treatment of Cushing’s syndrome: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2015, 100:2807-31. 10.1210/jc.2015-1818
  9. Isand K, Arima H, Bertherat J, et al.: Delphi panel consensus on recommendations for thromboprophylaxis of venous thromboembolism in endogenous Cushing’s syndrome: a position statement. Eur J Endocrinol. 2025, 192:R17-27. 10.1093/ejendo/lvaf017
  10. McCormick JP, Sun M, Shafqat I, Heaney AP, Bergsneider M, Wang MB: Venous thromboembolic (VTE) prophylaxis in Cushing Disease patients undergoing transsphenoidal surgery. Interdiscip Neurosurg. 2022, 27:10.1016/j.inat.2021.101371
  11. Feelders RA, Nieman LK: Hypercoagulability in Cushing’s syndrome: incidence, pathogenesis and need for thromboprophylaxis protocols. Pituitary. 2022, 25:746-9. 10.1007/s11102-022-01261-9
  12. Varlamov EV, Langlois F, Vila G, Fleseriu M: Management of endocrine disease: cardiovascular risk assessment, thromboembolism, and infection prevention in Cushing’s syndrome: a practical approach. Eur J Endocrinol. 2021, 184:R207-24. 10.1530/EJE-20-1309
  13. Fleseriu M, Biller BM, Grossman A, Swearingen B, Melmed S: Hypercoagulability in Cushing’s disease: a risk awareness and prophylaxis survey on behalf of the Pituitary Society. 15th International Pituitary Congress: Program and Abstracts. The Pituitary Society, Orlando, FL; 2017. 35.
  14. van Haalen FM, Kaya M, Pelsma IC, et al.: Current clinical practice for thromboprophylaxis management in patients with Cushing’s syndrome across reference centers of the European Reference Network on Rare Endocrine Conditions (Endo-ERN). Orphanet J Rare Dis. 2022, 17:178. 10.1186/s13023-022-02320-x
  15. Fleseriu M, Auchus R, Bancos I, et al.: Consensus on diagnosis and management of Cushing’s disease: a guideline update. Lancet Diabetes Endocrinol. 2021, 9:847-75. 10.1016/S2213-8587(21)00235-7
  16. Lopes V, Marques O, De Sousa Lages A: Preventive strategies for hypercoagulation in Cushing’s syndrome: when and how. Thromb J. 2023, 21:72. 10.1186/s12959-023-00515-1
  17. Barbot M, Daidone V, Zilio M, et al.: Perioperative thromboprophylaxis in Cushing’s disease: what we did and what we are doing?. Pituitary. 2015, 18:487-93. 10.1007/s11102-014-0600-y
  18. Isand K, Feelders R, Brue T, et al.: High prevalence of venous thrombotic events in Cushing’s syndrome: data from ERCUSYN and details in relation to surgery. Eur J Endocrinol. 2024, 190:75-85. 10.1093/ejendo/lvad176
  19. Zilio M, Mazzai L, Sartori MT, et al.: A venous thromboembolism risk assessment model for patients with Cushing’s syndrome. Endocrine. 2016, 52:322-32. 10.1007/s12020-015-0665-z
  20. Zaorsky NG, Buyyounouski MK, Li T, Horwitz EM: Aspirin and statin nonuse associated with early biochemical failure after prostate radiation therapy. Int J Radiat Oncol Biol Phys. 2012, 84:e13-7. 10.1016/j.ijrobp.2012.02.050
  21. Semple PL, Laws ER Jr: Complications in a contemporary series of patients who underwent transsphenoidal surgery for Cushing’s disease. J Neurosurg. 1999, 91:175-9. 10.3171/jns.1999.91.2.0175
  22. Smith TR, Hulou MM, Huang KT, Nery B, de Moura SM, Cote DJ, Laws ER: Complications after transsphenoidal surgery for patients with Cushing’s disease and silent corticotroph adenomas. Neurosurg Focus. 2015, 38:E12. 10.3171/2014.10.FOCUS14705
  23. Diep R, Garcia 😧 Does aspirin prevent venous thromboembolism?. Hematology Am Soc Hematol Educ Program. 2020, 2020:634-41. 10.1182/hematology.2020000150
  24. Maddukuri RK, Chava H, Kondaveeti ST, Mutthineni MV, Vegesana BP: Aspirin for prophylaxis of VTE in patients with hip/ knee replacement: systematic review and meta-analysis of non-randomized studies. Indian J Pharmacol. 2024, 56:420-9. 10.4103/ijp.ijp_732_21
  25. Spoladore R, Milani M, Spreafico LP, Agnelli G, Savonitto S: Prevention of thromboembolism after a fracture: is aspirin enough?. Eur Heart J Suppl. 2024, 26:i102-7. 10.1093/eurheartjsupp/suae025
  26. Undas A, Brummel-Ziedins KE, Mann KG: Antithrombotic properties of aspirin and resistance to aspirin: beyond strictly antiplatelet actions. Blood. 2007, 109:2285-92. 10.1182/blood-2006-01-010645

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

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

« Previous Page — Next Page »