Question: I had surgery 3 weeks ago, and am experiencing a slow drop in cortisol, rather than an immediate drop. How often does this happen, how long does it take to drop, and does this influence the chances that I might recur?

Answer: This is an important question. Most patients do have a rapid drop in cortisol if they have successful surgery. Blood (serum), 24 hour urine and salivary cortisols are often very low or even undetectable within a few days of complete removal of a tumor. However, in a small number of patients (5.6% of patients with Cushing’s disease), it may take many weeks or even months.

Why do cortisol levels usually fall very rapidly after successful surgery? When a patient has Cushing’s syndrome, meaning levels of cortisol are higher than normal, the system responsible for production of cortisol senses that there is too much, and the normal parts of the system shut down. For example, if someone has the most common cause of Cushing’s — a benign tumor in the pituitary gland overproducing adrenocorticotropic hormone (ACTH, the hormone that signals the adrenal gland to make cortisol), the rest of the pituitary gland stops making ACTH completely. Because ACTH is being produced by the tumor, cortisol levels continue to be high. However, once the tumor is removed, there is no signal to the adrenal glands, because only the normal pituitary gland is left, and it has not produced ACTH for a long time. Eventually, ACTH production will resume in most patients, but this can take 6-18 months. During this time, patients need to take cortisol replacement pills every day, until the ACTH production gradually recovers, and signals the adrenals to make cortisol again. This is the situation in most patients, that is, they go from having cortisol levels that are too high before surgery to having levels that are very low within a few days of surgery.

However, you have asked about the exception to this usual pattern — the situation where there is not a rapid drop in cortisol. If cortisol levels are completely unchanged on repeated measurements using different tests after surgery for several weeks, then it is quite likely that the surgery was not successful, and further treatment is advised. But in some cases, the levels do fall, but more slowly than usual. How often does this happen? A large study of 620 patients with pituitary Cushing’s at three major pituitary centers (Massachusetts General Hospital in Boston in the US and University of Milan and University Vita-Salute in Milan, Italy) evaluated the timing of the fall in cortisol after pituitary surgery. In most patients (70.5%) the decline to below or within the normal range was considered “Immediate”, meaning within the first 3 days after surgery. Another 23.9% never experienced a fall in cortisol no matter how long they were followed (called “No Control”); this is the group that would receive additional treatment. That leaves a total of 35 patients in the study (5.6%) who eventually did achieve a low or normal cortisol. This group was called “Delayed Control”, and it took an average of just over a month (38 days), but there was a wide range in the timing. In some patients the levels had fallen within a week and in other patients it took as long as 180 days to reach controlled levels.

The reasons for the delayed decline are not yet known. A key finding was that most patients with the delayed decline did have a progressive decrease from one measurement to the next. This means that if the levels are falling, but are not yet normal or low, more tests over time are usually indicated, to see if they continue to fall before recommending further treatment. In contrast, if levels stay consistently high over a long period of time, a later sudden drop is not likely. An important point is that the rate of Cushing’s recurrence at a later time was higher in the patients whose control was delayed after surgery (14% in the Immediate Control group compared with 43% in the Delayed Control group), so these patients should be carefully followed. However, remember that every patient in remission from Cushing’s disease should be monitored for the small chance of recurrence, because it never falls completely to zero. In summary, if your cortisol levels after surgery are falling, but are not yet low or normal, ask your endocrinologist if you might be among the 5.6% of patients with Delayed Control.

Reference

Valassi E et al. “Delayed Remission after Transsphenoidal Surgery in Patients with Cushing’s Disease”. J Clin Endocrinol Metab 95: 601-10, 2010

By Beverly MK Biller MD (Spring, 2011)