Podcast Summary: AACE Podcasts – Episode 72

Recognizing Non-Neoplastic Hypercortisolism

Date: December 5, 2025
Host: Dr. Bahar Force
Guests: Dr. James Findling & Dr. Ty Carroll

Episode Overview

This episode centers on the increasingly recognized and nuanced clinical challenge of non-neoplastic hypercortisolism. Host Dr. Bahar Force is joined by Dr. James Findling and Dr. Ty Carroll, two internationally respected endocrinologists with expertise in pituitary and adrenal disorders, especially Cushing's syndrome. Together, they discuss definitions, clinical features, diagnostic challenges, new laboratory tools, pitfalls, and future directions for research and management in this field.

Key Discussion Points & Insights

1. Defining Non-Neoplastic Hypercortisolism

(02:32) Dr. Ty Carroll:

• Non-neoplastic hypercortisolism refers to cortisol elevations not caused by a tumor (adrenal, pituitary, or ectopic source).
• The term replaces older, less accurate terms like “pseudo-Cushing’s.”
• Common causes: Alcohol use disorder, untreated sleep apnea, advanced chronic kidney disease, and untreated depression.
• On prevalence: “Non-neoplastic hypercortisolism is probably quite common because these conditions and others are very common... but we don't have good studies to give us an idea of the exact prevalence...” (03:23)

2. Clinical Recognition & Overlap with Cushing’s Syndrome

(04:24) Dr. James Findling:

• Increased screening for hypercortisolism (due to guideline changes, adrenal nodule evaluation) leads to more abnormal test results, often in patients without true neoplastic disease.
• Key clinical features: “They may have truncal obesity, hypertension, diabetes, metabolic bone disease, or adrenal nodule disease...” (05:08)
• Alcohol use disorder is commonly under-reported and a frequent cause in his practice: “Patients often under report or underestimate the amount of alcohol they consume.” (05:35)
• Other contributors: poorly controlled diabetes, severe sleep apnea, major mental health disorders.

3. Interpretation of Biochemical Tests

(06:38) Dr. Ty Carroll:

• The main screening tests (dexamethasone suppression, urinary free cortisol, late-night salivary cortisol) do not differentiate neoplastic vs. non-neoplastic causes.
• Discordant results (some normal, some abnormal tests) should prompt clinicians to consider common non-neoplastic causes more seriously.
• “It's very unusual for a patient to have both [salivary cortisol and dexamethasone suppression] be normal and have true neoplastic hypercortisolism.” (07:22)
• ACTH levels: High cortisol from neoplastic sources is usually associated with very high levels; however, ACTH alone is not definitive—“patients with non-neoplastic hypercortisolism may have elevated ACTH levels occasionally.” (08:44)
• Magnitude matters: “Urine cortisol, late night [salivary] cortisol greater than five times the upper limit of normal and overt clinical features...are much higher risk to have neoplastic hypercortisolism.” (08:27)

4. The Role of the Desmopressin Stimulation Test

(09:48) Dr. James Findling:

• With CRH no longer available in many countries, the desmopressin stimulation test is becoming a standard for distinguishing neoplastic from non-neoplastic hypercortisolism.
• Mechanism: Desmopressin stimulates ACTH via the V3 (and possibly V2) receptors, particularly in pituitary (and sometimes ectopic) ACTH-secreting tumors.
• Interpretation: “In patients with pituitary Cushing's, the ACTH response...is very dramatic...within 5 to 20 minutes. Really not equivocal.” (12:00)
• Precautions: Test should be done before 9 a.m.; hyponatremia is a risk, so screen electrolytes and restrict fluids post-test.
• Adoption: Common in Europe; expected to become more widely used in the U.S.

5. Application in Cyclic or Intermittent Hypercortisolism

(14:16) Dr. Ty Carroll & (15:34) Dr. James Findling:

• Usefulness in biochemical nadir is unclear—some data and anecdotal cases suggest it can still be positive in cyclical disease but robust studies are lacking.
• Dr. Carroll cites an NIH case where the test was helpful even during a biochemical nadir; Dr. Findling has seen similar anecdotal reports.
• Caveat: Retesting and further evaluation are often warranted, especially given patient-driven awareness from social media.

6. Unanswered Questions & Future Directions

(17:17) Dr. James Findling:

• The Catalyst Study shows that a large proportion of patients with poorly controlled diabetes have abnormal dexamethasone suppression tests; interventions targeting cortisol receptors (antagonists) improved diabetic outcomes.
• Raises possibility of pharmacologic therapy for non-neoplastic hypercortisolism, particularly in comorbid conditions like diabetes.
• Criticism: These studies haven’t always clearly differentiated neoplastic from non-neoplastic causes.
• “This opens the door to a further evaluation of patients with known non-neoplastic hypercortisolism for pharmacotherapy...” (18:20)
• Dr. Carroll emphasizes that ongoing research may show treating hypercortisolism (regardless of etiology) benefits metabolic health.

Notable Quotes & Memorable Moments

• On Terminology
  “We used to use terms such as pseudo Cushing’s and others, but those have really fallen out of favor and they’re not as accurate as the term non neoplastic hypercortisolism.”
  —Dr. Ty Carroll (03:07)

• On Hidden Alcohol Use
  “Patients often under report or underestimate the amount of alcohol they consume. So I think that's the most common thing I see in my practice.”
  —Dr. James Findling (05:35)

• On Magnitude of Abnormal Results
  “Urine cortisol, late night [salivary] cortisol greater than five times the upper limit of normal and overt clinical features...are much higher risk to have neoplastic hypercortisolism.”
  —Dr. James Findling (08:27)

• On the Desmopressin Test
  “This test helps to distinguish neoplastic from non neoplastic hypercortisolism because patients typically with non neoplastic hypercortisolism do not have any ACTH response.”
  —Dr. James Findling (10:52)

• Future Research Outlook
  “Maybe treating hypercortisolism, no matter what the etiology, will be beneficial. We just don't know that yet and I think we need further investigation…”
  —Dr. Ty Carroll (19:31)

Timestamps for Important Segments

• Definition and Prevalence: 02:32 – 04:00
• Clinical Features and Comorbidities: 04:24 – 06:09
• Biochemical Testing Nuances: 06:38 – 09:11
• Desmopressin Stimulation Test Overview: 09:48 – 13:36
• Cyclical/Intermittent Hypercortisolism Discussion: 14:16 – 16:36
• Emerging Research and Future Directions: 17:17 – 19:58

Summary Table: Biochemical Testing Insights

| Test | Neoplastic (Cushing’s) Pattern | Non-Neoplastic Pattern | Key Notes | |----------------------------------|--------------------------------------------|---------------------------------------|-----------------------------------------------| | Late Night Salivary Cortisol | High (>5x ULN) | Mildly elevated; often discordant | Both high: suspect neoplastic | | Dexamethasone Suppression | Abnormal | Often normal or mildly abnormal | Discordance: consider non-neoplastic causes | | ACTH | High (esp. pituitary-dependent) | Variable, sometimes high | ACTH alone not reliable | | Desmopressin Stimulation Test | Robust, rapid ACTH & cortisol response | Little/no response | Useful, but not perfect |

Closing Thoughts

• Non-neoplastic hypercortisolism is common but can closely mimic Cushing’s syndrome both clinically and biochemically.
• A thorough evaluation—including clinical context, biochemical test patterns, and newer diagnostic tools like the desmopressin stimulation test—can help differentiate the two.
• Ongoing research may soon broaden therapeutic strategies for patients with metabolic disease and cortisol excess, regardless of etiology.