Demonstration of a direct carcinogenic effect of estradiol on Leydig cells of the mouse.

When testes of 1-day-old BALB/c mice were transplanted to the spleen of castrated isologous recipients and a pellet composed of 20% 17 beta-estradiol-80% cholesterol was placed next to these explants, typical Leydig cell tumors developed in 14 of 24 grafts that were in close apposition to the estrogen source. No tumors developed in such intrasplenic grafts in eight animals in which the pellet was at a distance from the graft. Also, neither tumors nor areas of Leydig cell hyperplasia developed in the 32 testicular grafts placed in the fourth mammary gland of the same animals. Grafting of 1-day-old testes to the spleen of castrated untreated males did not result in the development of tumors during a 1-year period of observation, and implantation of a 17 beta-estradiol pellet into the spleen of 6-week-old animals resulted in no morphological changes in the Leydig cells unless adhesions between the spleen and the abdominal wall had occurred that resulted in a significant systemic circulation of unmetabolized 17 beta-estradiol. A 5-MG 20% 17 beta-estradiol pellet implanted in the s.c. tissues was an effective means of producing Leydig cell tumors both in testes in situ and in testes that had been grafted either to the spleen or to the fourth mammary gland. The results of these experiments indicate that the carcinogenic effect of 17 beta-estradiol results from an action of this estrogen directly upon the Leydig cells rather than by either the action of some systemic metabolite or the alteration of the general endocrine status of the animals.