Endocrinology, Vol 137, 4210-4216, Copyright © 1996 by Endocrine Society

ARTICLES

Gonadotropins are essential modifier factors for gonadal tumor development in inhibin-deficient mice

TR Kumar, Y Wang and MM Matzuk
Department of Pathology, Baylor College of Medicine, Houston, Texas 77030, USA.

We previously demonstrated that mice deficient in inhibin develop gonadal sex cord-stromal tumors with nearly 100% penetrance. These ovarian and testicular tumors develop as early as 4 weeks of age and eventually cause cachexia-like symptoms and death in the inhibin- deficient mice. Gonadectomized inhibin-deficient mice initially do not develop this wasting syndrome, but eventually will develop adrenal cortical tumors with similar penetrance. These studies have demonstrated that inhibin is a secreted type of tumor suppressor in the gonads and adrenal glands. Gonadotropins are implicated to influence gonadal tumor development in humans as well as experimental animals, and in inhibin-deficient mice, serum FSH levels are elevated. To determine whether gonadotropins influence the development and/or progression of the tumors in the inhibin-deficient mice, we took advantage of a naturally occurring mutant mouse, hypogonadal (hpg); hpg/hpg mice lack a functional GnRH gene and, therefore, have suppressed FSH and LH levels. Heterozygous hpg/+mice were crossed to heterozygous inhibin mutant mice to generate compound homozygous mutant mice that lack both inhibin and GnRH. These compound homozygous mutant mice do not develop a wasting syndrome, do not exhibit gonadal or adrenal tumors, and can survive for more than 1 yr. These results demonstrate that gonadotropins are essential modifier factors for tumor development in inhibin-deficient mice.

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