Massive Macronodular Adrenal Disease (MMAD)

MMAD, also known as ACTH-independent macronodular adrenal hyperplasia (AIMAH), is a very rare form of bilateral adrenal disease, in which the adrenal glands are replaced by large hyperfunctioning nodules that work independently of the regulation of the adrenal gland.

The disease affects both adrenal glands equally, to the point where the glands may grown 50-100 times larger than normal glands. The nodules are heterogenous and bilateral, so treatment typically involves the removal of both adrenal glands. By and large, these glands are rather inefficient producers of adrenal gland hormones, so that the clinical manifestations only appear when the glands have reached quite large sizes.

In terms of clinical syndromes associated with MMAD, adrenal glands affected by this condition can secrete any adrenal hormone, including cortisol, androgens or estrogens. Typically, MMAD glands secrete cortisol, leading to the clinical Cushing syndrome. However, case reports also indicate that MMAD can cause feminization of males, or virilization of females.

At the molecular level, there is accumulating evidence that MMAD may be caused by ectopic expression of receptors in the adrenal gland. These receptors, which accept signals from hormones that do not normally regulate adrenal function, lead to the production of hormones in an inappropriate fashion, usually meaning hormone excess. To date, reports have been made of adrenal glands expressing the GIP (gastric inhibitory polypeptide) receptor, the vasopressin receptor, and the beta-adrenergic receptor.

In our own experience, we have had a number of cases which do not appear to contain these defects, so that it is difficult to make generalizations about the cause of MMAD.

In general, this disease does not appear to be genetic in nature, although there are two reports suggesting familial patterns.

Clearly, much more work needs to be done on this interesting disease in order to understand it.