Long-term testosterone treatment prevents gonadal and adrenal tumorigenesis of mice transgenic for the mouse inhibin-alpha subunit promoter/simian virus 40 T-antigen fusion gene

We have developed a transgenic (TG) mouse model for tumorigenesis of gonada l somatic cells using a 6 kb fragment of the mouse inhibin-alpha subunit pr omoter (Inh-alpha) fused with the simian virus 40 T-antigen (Tag) coding se quence. Gonadal tumors, of Leydig or granulosa cell origin, develop in the TG mice with 100% penetrance by the age of 5-8 months. Conspicuously, if th e mice are gonadectomized, they develop adrenal tumors. Gonadal and adrenal tumorigenesis in these mice seem to be gonadotropin dependent. On the othe r hand, testosterone stimulates the proliferation of a cell line (C alpha 1 ) established from one of the adrenal tumors. The purpose of the present st udy was therefore to investigate further whether testosterone affects the g rowth of these gonadal and adrenal tumors in vivo. Two experimental models were used: (1) Tag TG/hypogonadotropic (hpg) double mutant mice and (2) castrated Tag TG mice. Both were treated between 1-2 a nd 7-8 months of age with Silastic rods (length 2 cm) containing testostero ne. None of the control or testosterone-treated Tag/hpg mice developed gona dal or adrenal tumors. The castrated Tag TG mice displayed, upon microscopi cal examination, early stages of adrenal tumors, whereas those receiving te stosterone did not show such changes. Testosterone increased the weights of gonads in the Tag/hpg mice, and those of uteri and seminal vesicles in bot h groups. In contrast, the adrenal weights were significantly reduced in bo th groups by testosterone treatment. Gonadal histology of the testosterone- treated mice showed hyperplasia of testicular Leydig cells and ovarian stro ma. Spermatogenesis was induced by testosterone in the Tag/hpg mice. Adrena l histology of the testosterone-treated animals demonstrated the disappeara nce of the X-zone. Serum levels of FSH in testosterone-treated Tag/hpg mice were significantly increased, while those of serum LH were decreased. In conclusion, the present result indicate that the suppression of gonadotr opins by testosterone implants in castrated Inh-alpha/Tag TG mice prevents the tumorigenesis of their adrenals. In intact Tag/hpg mice, testosterone i mplants were not able to induce gonadal or adrenal tumorigenesis. Although testosterone treatment was able to induce interstitial cell hyperplasia in gonads of the Inh-alpha/Tag mice, direct gonadotropin action is responsible for gonadal and adrenal tumorigenesis.