Molecular Endocrinology, Vol 9, 1337-1345, Copyright © 1995 by Endocrine Society

ARTICLES

Synergistic effects of inhibins and mullerian-inhibiting substance on testicular tumorigenesis

MM Matzuk, MJ Finegold, Y Mishina, A Bradley and RR Behringer
Department of Pathology, Baylor College of Medicine, Houston, Texas 77030, USA.

Members of the transforming growth factor-beta (TGF-beta) superfamily regulate diverse physiological processes in multiple tissues. In particular, important roles for the inhibins and mullerian-inhibiting substance (MIS) have been demonstrated in the regulation of cell growth control both in vitro and in vivo. Inhibin-deficient male and female mice develop mixed granulosa/Sertoli cell tumors with nearly 100% penetrance. MIS-deficient male mice develop as pseudohermaphrodites with oviducts and uteri. In addition, MIS-deficient males have Leydig cell hyperplasia 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 deficient for both inhibins and MIS were generated. Adult inhibin/MIS-deficient male mice developed testicular tumors and large fluid-filled uteri. The accumulation of uterine fluid was due in part to an increase in estradiol secretion from the tumors and was blocked by a pure estrogen antagonist, ICI 182,780. The testes of the inhibin/MIS-deficient males developed granulosa/Sertoli cell tumors and Leydig cell neoplasia earlier, grew faster, were less hemorrhagic, and produced less estradiol than the testes of inhibin-deficient controls. These results demonstrate that inhibin and MIS synergize to influence testicular tumor development.

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