Endocrinology · Cushing Syndrome

Biology & The Search for the Source: Disease vs. Syndrome

At a Glance

Cushing's syndrome is a general term for having too much cortisol in the body, while Cushing's disease is a specific type caused by a pituitary tumor. Doctors diagnose the exact cause by testing ACTH levels to determine if the problem originates in the pituitary gland, adrenal glands, or elsewhere.

Understanding the biology of your diagnosis requires looking at a delicate communication loop in your body called the HPA Axis (the Hypothalamic-Pituitary-Adrenal axis). In a healthy body, this loop acts like a thermostat for your stress hormones. In your case, that thermostat has been broken, leading to a state of hypercortisolism—too much cortisol in the blood ^[1].

The Difference: Syndrome vs. Disease

The terms “Cushing Syndrome” and “Cushing Disease” are not the same, though they are often confused.

Cushing Syndrome is an “umbrella term.” It refers to any clinical condition caused by having too much cortisol in the body, regardless of the cause ^[2].
Cushing Disease is a specific type of Cushing Syndrome. It is caused by a small tumor in the pituitary gland (a PitNET) that pumps out too much ACTH (Adrenocorticotropic Hormone) ^[3].

In short: All Cushing Disease is Cushing Syndrome, but not all Cushing Syndrome is Cushing Disease.

How the Broken Loop Works

To find the cause, doctors look at where the “signal” to make cortisol is coming from. They categorize the condition into two main types based on the level of ACTH in your blood:

1. ACTH-Dependent (The Problem is the “Signal”)

In this version, your adrenal glands are healthy, but they are being “bullied” into overproducing cortisol by too much ACTH ^[3].

Cushing Disease (Pituitary): This is the most common cause (about 70% of cases). A tumor in the pituitary gland (PitNET) ignores the body’s signals to stop and continuously pours out ACTH ^[4].
Ectopic ACTH Syndrome: A tumor located elsewhere in the body (often in the lungs or pancreas) begins producing ACTH on its own ^[5]. This acts just like Cushing Disease but the source is not the pituitary ^[6].

2. ACTH-Independent (The Problem is the “Factory”)

In this version, your ACTH levels are very low or “suppressed.” This is because your body is trying to shut off the signal, but the adrenal glands (the cortisol “factories”) are producing cortisol anyway ^[2].

Adrenal Tumors: A growth on the adrenal gland itself produces cortisol autonomously, ignoring all signals from the brain ^[7].
Exogenous Steroids: This is the most common cause of Cushing Syndrome overall. It happens when someone takes steroid medications (like prednisone) for a long time to treat other conditions like asthma or lupus ^[8].

How Doctors Solve the Puzzle

Distinguishing between these causes is a step-by-step process of elimination:

Diagnostic Step	What it Tells the Doctor
ACTH Blood Test	If ACTH is low (<5 pg/mL), the problem is likely in the adrenal glands. If it is high (>20 pg/mL), the source is either the pituitary or an ectopic tumor ^[9].
Pituitary MRI	Looks for a tumor (PitNET) in the brain. However, these tumors are often so small they don’t show up on a standard scan ^[3].
BIPSS (Sampling)	If the MRI is unclear, doctors may use Bilateral Inferior Petrosal Sinus Sampling. This involves taking blood directly from the veins near the pituitary to see if that is where the high ACTH is coming from ^[9]^[10].
Dexamethasone Test	You take a synthetic steroid (dexamethasone) to see if your body responds by lowering its cortisol production. Pituitary tumors sometimes respond slightly, while ectopic or adrenal tumors usually do not ^[11].

By determining exactly where the loop is broken, your care team can ensure they are treating the source of the problem—whether that means surgery on the pituitary gland, the adrenal gland, or managing medication ^[12].

Common questions in this guide

What is the difference between Cushing syndrome and Cushing disease?

Cushing syndrome is an umbrella term for any condition caused by having too much cortisol in your body. Cushing disease is a specific type of Cushing syndrome caused by a small tumor in the pituitary gland that overproduces the hormone ACTH.

What does it mean if my Cushing syndrome is ACTH-dependent?

ACTH-dependent means your adrenal glands are healthy, but they are producing too much cortisol because they are receiving excessive ACTH signals. This is usually caused by a tumor in the pituitary gland or, less commonly, a tumor elsewhere in the body.

What happens if my ACTH levels are low but my cortisol is high?

If your ACTH is low or suppressed, your condition is considered ACTH-independent. This indicates that the excess cortisol is likely coming directly from a tumor on your adrenal glands or from taking steroid medications, rather than from a pituitary signal.

How do doctors determine where my high cortisol is coming from?

Doctors use a step-by-step process of elimination to find the source. This typically starts with an ACTH blood test, followed by a pituitary MRI, a dexamethasone test, or specialized blood sampling (BIPSS) if the MRI does not show a clear tumor.

Can steroid medications cause Cushing syndrome?

Yes. Taking steroid-based medications like prednisone, asthma inhalers, skin creams, or joint injections for a long period is the most common cause of Cushing syndrome overall. This is known as exogenous Cushing syndrome.

Curated prompts to bring to your next appointment.

1.What was my blood ACTH level, and does it indicate an 'ACTH-dependent' or 'ACTH-independent' cause?
2.If my ACTH is high but my pituitary MRI is clear, what are the next steps to look for an 'ectopic' source?
3.Do my lab results suggest my cortisol production is coming from my adrenal glands directly or from a signal elsewhere?
4.How do we rule out 'Exogenous Cushing' from the medications or supplements I’ve taken in the past?
5.Is it possible I have 'Pseudo-Cushing' caused by other health factors like stress or alcohol?

Tap a prompt to share your answer — we'll use it plus this page's context to start a tailored conversation.

References (12)

1
Prospective Evaluation of Late-Night Salivary Cortisol and Cortisone by EIA and LC-MS/MS in Suspected Cushing Syndrome.
Kannankeril J, Carroll T, Findling JW, et al.
Journal of the Endocrine Society 2020; (4(10)):bvaa107 doi:10.1210/jendso/bvaa107.
PMID: 32935666
2
Cushing syndrome: Old and new genes.
Tatsi C, Flippo C, Stratakis CA
Best practice & research. Clinical endocrinology & metabolism 2020; (34(2)):101418 doi:10.1016/j.beem.2020.101418.
PMID: 32414619
3
Cushing Disease: Medical and Surgical Considerations.
Bray DP, Rindler RS, Dawoud RA, et al.
Otolaryngologic clinics of North America 2022; (55(2)):315-329 doi:10.1016/j.otc.2021.12.006.
PMID: 35256173
4
PATHOGENESIS OF CUSHING DISEASE: AN UPDATE ON THE GENETICS OF CORTICOTROPINOMAS.
Albani A, Perez-Rivas LG, Reincke M, Theodoropoulou M
Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists 2018; (24(10)):907-914 doi:10.4158/EP-2018-0111.
PMID: 30084690
5
Clinical profile and treatment outcomes of patients with ectopic ACTH syndrome compared to Cushing disease: a single-center experience.
Attri B, Goyal A, Kalaivani M, et al.
Endocrine 2023; (80(2)):408-418 doi:10.1007/s12020-022-03298-z.
PMID: 36609908
6
Cushing Disease Mimicking Ectopic Adrenocorticotropic Hormone-Secreting Disease.
Fisher DL, Fraenkel M, Baraf L
AACE endocrinology and diabetes 2025; (12(3)):174-177 doi:10.1016/j.aed.2025.06.001.
PMID: 41048684
7
Adrenocorticotropic hormone (ACTH) independent Cushing's syndrome due to unilateral adrenocortical hyperplasia: two case reports.
Aouinati Y, Mjabber A, Haraj NE, et al.
The Pan African medical journal 2021; (38()):367 doi:10.11604/pamj.2021.38.367.26040.
PMID: 34367446
8
Iatrogenic Cushing's Syndrome and the Hidden Ingredient of Artri King.
Ataallah B, Al Tameemi M
Cureus 2026; (18(1)):e100843 doi:10.7759/cureus.100843.
PMID: 41646561
9
A comparison of bilateral internal jugular vein sampling with bilateral inferior petrosal sinus sampling at Mayo Clinic for the subtype evaluation of corticotropin-dependent cushing syndrome.
O'Keeffe DT, Maraka S, Kotwal A, et al.
Pituitary 2025; (28(6)):118 doi:10.1007/s11102-025-01595-0.
PMID: 41125990
10
Enhancing Cushing's disease diagnosis: exploring the impact of desmopressin on ACTH gradient during BIPSS.
de Almeida TS, Rodrigues TDC, Costenaro F, et al.
Frontiers in endocrinology 2023; (14()):1224001 doi:10.3389/fendo.2023.1224001.
PMID: 37600715
11
Ectopic Adrenocorticotropic Hormone (ACTH)-Dependent Cushing Syndrome Secondary to Olfactory Neuroblastoma: A Rare Entity.
Eisa N
AACE endocrinology and diabetes 2025; (12(4)):249-254 doi:10.1016/j.aed.2025.08.004.
PMID: 41467146
12
The diagnosis and management of Cushing's syndrome in pregnancy.
Hamblin R, Coulden A, Fountas A, Karavitaki N
Journal of neuroendocrinology 2022; (34(8)):e13118 doi:10.1111/jne.13118.
PMID: 35491087

This page explains the biology and diagnosis of Cushing disease and syndrome for educational purposes only. Always consult your endocrinologist or care team to interpret your specific ACTH and cortisol test results.

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