Answer: Pituitary, or corticotroph, hyperplasia has for many years been mentioned as a possible basis of Cushing’s disease (pituitary Cushing’s). The term hyperplasia means an increase in the number of cells, for example corticotroph cells that make ACTH. CRH, the hypothalamic hormone that stimulates the pituitary corticotroph to make and release ACTH, was isolated and sequenced by Dr. Wylie Vale in the early 1980s. That permitted the development of antibodies to CRH and permitted CRH levels to be measured. Within a few years, several patients who had an ectopic tumor that secreted CRH and who had hyperplasia of the pituitary corticotrophs were described. Continuous exposure to elevated CRH levels causes the number of ACTH secreting cells to increase, thus those patients have pituitary hyperplasia causing Cushing’s disease. However, patients with ectopic CRH production are extremely rare and only a few handfuls of patients are known to have this in all the published literature.
A more common circumstance is that of a patient who has surgery for a diagnosis of Cushing’s disease and no tumor is found, but the normal gland that is biopsied has corticotroph cells that stain positive for ACTH. Since patients with Cushing’s disease do not produce their own ACTH-cortisol for weeks to months after selective removal of an ACTH-producing tumor, it is assumed by many physicians that the normal corticotrophs will not stain for ACTH if the normal gland is sampled during pituitary surgery for Cushing’s disease. Thus, in the presence of this ACTH staining of the normal corticotrophs, the patient may be advised that they have pituitary hyperplasia. However, this is an erroneous diagnosis, as the normal corticotrophs always (that is, ALWAYS) stain positive for ACTH in patients with Cushing’s disease. Thus, if no tumor can be found during surgical exploration of the pituitary in a patient with a diagnosis of Cushing’s disease and a portion of the normal gland is removed, the corticotrophs of the normal gland will stain for ACTH and the patient may be misdiagnosed as having pituitary hyperplasia if their doctors do not know that the normal corticotrophs always show ACTH staining in patients with Cushing’s disease. In an experience of 1300-1400 patients with surgery for Cushing’s disease I have not seen, or known about, a convincing case of pituitary hyperplasia that was not one of these rare instances of ectopic CRH production.
Thus, the only generally accepted basis of corticotroph hyperplasia as the cause of Cushing’s disease today is ectopic CRH production. Today the peripheral blood can be assayed for CRH to test for the presence of this very rare syndrome.
By Dr. Eward Oldfield, Summer 2014