We had previously shown that homoeostatic thymus hormone (HTH), an H2A-H2B histone dimer, possesses an age-dependent adrenostimulatory activity in vivo. It was therefore of interest to investigate the adrenocorticotropin (ACTH)-releasing activity of histones and other related preparations on perifused pituitary cells from young (2-4 months) and mature (16-18 months) rats. Histones and protamines gave a positive interference with the immunoradiometric assays (IRMA) for ACTH and corticotropin releasing hormone (CRH) whereas the histone fragment MB35, as well as nucleohistone and nucleoprotamine complexes did not. The latter three substances induced a significant ACTH response in pituitary cells from young and, to a lesser extent, mature rats. Our results suggest that nucleoprotein complexes released into the extracellular milieu may act as hypophysiotropic signals. On the other hand, the responsiveness of pituitary cells to these signals seems to decrease with the age of the donor.