Inhibition of the pituitary-gonadal axis in nude male mice by continuous administration of LHRH agonists and antagonists

Analogues of LHRH can be used for the treatment of sex hormone-dependent tumours. The nude mouse is a valuable model for the investigation of transplanted human cancers, but there is a body of literature reporting that the function of the pituitary-gonadal axis in normal (immunocompetent) and nude (immunocompromized) mice, unlike that of other species, cannot be suppressed by the administration of LHRH agonists and antagonists. To explore this view further, long-term experiments were carried out in nude male mice, in which sustained-release formulations of the agonist [D-Trp⁶]-LHRH and of two new potent antagonists were used which permitted a continuous release of the peptides into the circulation. Nude male mice were treated for 28-30 days with 50 μg of antagonists [Ac-D-Nal(2)¹,D-Phe(4Cl)²,D-Trp³,D-Cit⁶,D-Ala¹⁰]-LHRH (SB-30) or [Ac-D-Nal(2)¹,D-Phe(4Cl)²,D-Pal(3)³,D-Cit⁶,D-Ala¹⁰]-LHRH (SB-75)/day delivered by osmotic minipumps. Some mice were injected twice a day with 25 μg SB-75. Other groups received microcapsule preparations of the agonist [D-Trp⁶]-LHRH, releasing 25 or 12.5 μg/day for 30 days. At autopsy, in mice which received 50 μg SB-30 or SB-75/day by minipumps, there was a significant decrease in weights of testes, ventral prostate and seminal vesicles compared with controls. [D-Trp⁶]-LHRH microcapsules at either dose also reduced weights of testes and accessory sex organs. Serum LH and testosterone were significantly reduced in all groups treated with analogues. There was a greater decrease in testicular weights and serum testosterone in nude mice which received SB-75 in a continuous fashion from minipumps than in animals injected twice a day. These results clearly demonstrate, contrary to the existing data, that the pituitary-gonadal axis of nude mice can be inhibited by LHRH agonists or antagonists if they are administered by continuous release systems. This study indicates that when the sustained-release formulations are used, nude mice can be valuable for studying the effects of analogues of LHRH on tumour biology