Remission Doesn’t Fully Reverse Changes to Brain Caused by Excessive Cortisol, Study Reports

Pituitary surgery that restores healthy cortisol levels in people with Cushing’s disease only partly reverses changes in the brain that were caused by excessive levels, a study from China reports.

Specifically, the surgery partly normalizes gray matter volume, where most nerve and other cells are found, but alterations to the brain’s white matter — largely nerve fibers or axons — persist after remission, the researchers found.

Their study, “Reversible and the irreversible structural alterations on brain after resolution of hypercortisolism in Cushing’s disease,” appeared in the journal Steroids.

The damaging effects of excessive cortisol levels on the brain in Cushing’s disease patients have been addressed in studies, and are known to include psychiatric symptoms similar to those seen in people with stress-related disorders.

Despite reports of normalized volumes of gray matter and cerebrospinal fluid (CSF; the liquid surrounding the brain and spinal cord) following the normalization of cortisol, however, whether brain damage due to high cortisol levels is reversed remains unclear.

Researchers addressed this gap by analyzing CSF, gray matter, and white matter changes in 61 patients with active Cushing’s disease, 28 in remission over less than six months, 35 with longer-term remission, and 74 healthy controls.

While gray matter is made of cell bodies, their projections, and the sites where neurons communicate (called synapses), white matter contains nerve fibers and makes up about half of the human brain.

The study was conducted in patients at Rui-Jin Hospital in Shanghai between July 2013 and July 2019. All were treated with transsphenoidal surgery (TSS) without radiotherapy or bilateral adrenalectomy — the removal of both adrenal glands. Remission was confirmed by normal urinary-free cortisol (UFC) levels; remission duration was calculated from the date of the surgery.

Patients with active disease had a higher body mass index, body weight, blood pressure, as well as higher levels of 24-hour UFC, serum cortisol, glucose, and adrenocorticotropin hormone (ACTH).  People in remission for a shorter period and 21 of those with longer-lasting remission remained glucocorticoid-dependent after surgery, and were treated with hydrocortisone.

Active disease patients were seen on magnetic resonance imaging (MRI) scans to have the smallest volume of gray matter. Healthy controls had the largest gray and white matter volumes of the four groups.

CSF volume was larger in patients with active disease and those with shorter remission times, than in those with longer-term remission or who served as controls.

Researchers also found that the larger the gray matter volume, the longer was the remission duration, but only in patients with shorter-term remission. An opposite correlation was found in CSF volumes, as they were lower in people with longer remissions. Larger white matter volumes correlated with younger age in patients with longer-term remission.

A subsequent analysis confirmed that, after the excess cortisol was resolved, gray matter volume increased but CSF volume dropped. No such changes were found in white matter and total intracranial volumes.

Overall, “the altered GM [gray matter] volumes in Cushing’s disease were partially recovered shortly after resolution of hypercortisolism, but the alterations of WM [white matter] seem to be independent of concomitant hypercortisolism, persisting after remission,” the researchers wrote. As such, this work “enhances our understanding of the reversible and the irreversible structural alterations in the human brain due to hypercortisolism.”

It may also aid in developing “longitude studies with comprehensive neuropsychological tests on the influence of hypercortisolism,” they added.