SYNERGISTIC EFFECTS OF INHIBINS AND MULLERIAN-INHIBITING SUBSTANCE ONTESTICULAR TUMORIGENESIS

Members of the transforming growth factor-beta (TGF-beta) superfamily regulate diverse physiological processes in multiple tissues. In parti cular, important roles for the inhibins and Mullerian-inhibiting subst ance (MIS) have been demonstrated in the regulation of cell growth con trol both in vitro and in vivo. Inhibin-deficient male and female mice develop mixed granulosa/Sertoli cell tumors with nearly 100% penetran ce. MIS-deficient male mice develop as pseudohermaphrodites with ovidu cts and uteri. In addition, MIS-deficient males have Leydig cell hyper plasia and, in one case, a Leydig cell tumor. To determine whether MIS could modify the development of the granulosa/Sertoli cell tumors in inhibin-deficient mice or whether inhibin could alter the development of the Leydig cell hyperplasia of MIS-deficient mice, animals deficien t for both inhibins and MIS were generated. Adult inhibin/MIS-deficien t male mice developed testicular tumors and large fluid-filled uteri. The accumulation of uterine fluid was due in part to an increase in es tradiol secretion from the tumors and was blocked by a pure estrogen a ntagonist, ICI 182,780. The testes of the inhibin/MIS-deficient males developed granulosa/Sertoli cell tumors and Leydig cell neoplasia earl ier, grew faster, were less hemorrhagic, and produced less estradiol t han the testes of inhibin-deficient controls. These results demonstrat e that inhibins and MIS synergize to influence testicular tumor develo pment.