It has been suggested that a proportion of the adenomas and the nodular hyperplasia of cells in the pituitary gland in cases of Cushing's disease are derived from cells of the pars intermedia rather than the pars anterior. The evidence can be summarized as follows: the posterior site of adenoma or nodular hyperplasia in the pituitary, the innervation of cells and the suppressive response to the dopamine agonist bromocriptine in vivo or to dopamine in vitro. All these observations infer analogy with cells of the pars intermedia of other species, which are controlled by direct neural tonic dopaminergic inhibition. The adult human pituitary gland, however, does not possess a morphologically distinct pars intermedia, due to regression of the rudimentary fetal pars intermedia after birth, with mixing of cells into the pars anterior and pars nervosa. Since cells of the pars intermedia characteristically synthesize alpha-MSH, we have studied this peptide in order to assess the occurrence and distribution of intermedia-derived cells in the adult human pituitary. Sections from 100 pituitaries, removed at autopsy, were stained by an indirect immunoperoxidase technique using non-cross-reacting antisera specific for alpha-MSH and ACTH. Immunoreactive alpha-MSH (IR-alpha-MSH) cells were found in a total of 97 specimens. Of these, only ten cases showed a marked concentration of IR-alpha-MSH cells in the zona intermedia. In the majority of pituitaries, IR-alpha-MSH cells were more commonly seen in the pars anterior than in the zona intermedia; in 41 cases, IR-alpha-MSH cells were completely absent from the zona intermedia.(ABSTRACT TRUNCATED AT 250 WORDS)