Can You Have Cushing Disease With a Normal Brain MRI?

Yes, a person can have Cushing disease even if their brain or pituitary MRI is normal. Specialist reviews indicate that a substantial minority of patients with confirmed Cushing disease—up to 40% in some specialized centers—have no visible tumor on a standard clinical MRI ^[1].

Getting a “normal” scan when you are experiencing severe symptoms can be stressful and may lead to feelings of imposter syndrome. However, in the diagnosis of Cushing disease, a negative MRI is a known possibility, not a definitive rule-out ^[2].

Why Might the Tumor Be Invisible on an MRI?

Cushing disease is caused by a benign (non-cancerous) tumor in the pituitary gland that secretes excess ACTH (adrenocorticotropic hormone), which is a hormone that signals your adrenal glands to produce too much cortisol ^[3]. Although these tumors are benign, the excess cortisol they cause seriously affects blood pressure, blood sugar, mood, and muscle strength.

The vast majority of these tumors are microadenomas, meaning they are very small ^[4]. In Cushing disease, they can sometimes be just 1 to 2 millimeters in size ^[5].

Because of their tiny size, these tumors may not appear on standard imaging ^[1]. A routine brain MRI is typically not optimized to find a corticotroph microadenoma. Even with a dedicated dynamic contrast pituitary MRI on a high-resolution 3-Tesla (3T) scanner, the smallest tumors can blend in with healthy tissue and remain undetected ^[6].

The Diagnostic Pathway: Testing Hormones First

Because imaging cannot always find these small tumors, endocrinologists rely on a careful biochemical process to confirm the diagnosis before deciding on next steps:

1. Confirming excess cortisol (hypercortisolism): Doctors use tests like 24-hour urinary free cortisol, late-night salivary cortisol, and dexamethasone suppression testing to verify that your body is producing an abnormal, excess amount of cortisol ^[7].
2. Establishing ACTH-dependence: Next, doctors measure your blood ACTH levels. If your ACTH is high or unsuppressed (meaning the hormone level does not drop as it normally should), it indicates your condition is ACTH-dependent—meaning a tumor is actively driving the excess cortisol ^[3].
3. Evaluating the source: An ACTH-dependent result does not automatically mean the tumor is in the pituitary gland. It could also come from an ectopic source (a tumor located elsewhere in the body, such as the lungs) ^[8].

Locating the Source: What is IPSS?

If your tests confirm ACTH-dependent hypercortisolism but your pituitary MRI is normal (or shows an uncertain spot smaller than 6 millimeters), an endocrinologist at a specialized center may recommend Inferior Petrosal Sinus Sampling (IPSS) ^[8].

IPSS is a highly accurate, specialized procedure used to help distinguish a pituitary source from an ectopic source ^[9].

During IPSS, an interventional radiologist carefully guides small catheters through a vein in the groin up to the inferior petrosal sinuses, which are the veins that drain blood directly from the pituitary gland ^[9]. The doctor measures the ACTH levels in the blood draining from the pituitary and compares them to the ACTH levels in your general bloodstream.

Samples are usually taken before and after administering a stimulating hormone, like CRH or desmopressin ^[8]. A central-to-peripheral ACTH ratio (comparing the pituitary-draining blood to the general circulating blood) of at least 2 before stimulation, or at least 3 after stimulation, strongly supports a pituitary source ^{[8] [10]}.

Important considerations regarding IPSS:

• It is not definitive proof of a tumor’s exact location: While IPSS strongly supports a pituitary diagnosis, it is not infallible. Also, while it compares the left and right sides of the pituitary, this side-to-side lateralization is imperfect and should not independently determine which part of the gland a surgeon targets ^[11].
• It requires specialized expertise: IPSS is an invasive procedure that carries uncommon but serious risks, such as bleeding, infection, clotting, contrast-related reactions, and very rarely, neurological complications ^[12]. It should only be performed at a highly experienced center ^[13].

What This Means For Your Treatment

A negative MRI does not exclude you from having Cushing disease, nor does it automatically rule out transsphenoidal pituitary surgery ^[2].

If your biochemical tests and IPSS indicate the pituitary is the source, an expert pituitary surgeon may perform surgery even if the MRI is negative ^[14]. The surgeon will use the biochemical data, IPSS results, and direct inspection of the gland during the operation to search for and remove the abnormal tissue.

While patients with MRI-negative disease can achieve remission through surgery, finding the tiny tumor is challenging. Remission is not guaranteed, and the lesion may not always be found ^[14]. If surgery does not lead to remission, or if the tumor cannot be located, your care team will discuss alternative options. These can include medical therapies to control cortisol levels, repeat surgery, radiation, or treatments directed at the adrenal glands.