Protection of the germinal epithelium in the rat from the cytotoxic effects of chemotherapy by a luteinizing hormone-releasing hormone agonist and antiandrogen therapy

Abstract

The protection of spermatogenesis during chemotherapy using an antiandrogen and a luteinizing hormone-releasing hormone (LHRH) agonist was examined in the rat. Previous studies using LHRH agonists alone have been inconclusive, as both protective and deleterious effects on the germinal epithelium have been reported. Flutamide has not previously been used in this manner but theoretically should protect the germinal epithelium, since flutamide rapidly blocks testosterone at the cellular level and also minimizes the testosterone "flare" when LHRH agonist therapy is initiated. Mature Sprague-Dawley rats were pretreated with flutamide, sustained-release goserelin acetate (Zoladex), or a combination of flutamide and sustained-release goserelin acetate for 14 days before 4 weekly doses of procarbazine were initiated. The seminiferous tubules were evaluated histologically after a 90-day regeneration period using the stem cell assay test. After treatment with procarbazine alone, only 43% of the seminiferous tubules were active; however, 80% were active if protected with flutamide, 91% if protected with sustained-release goserelin acetate, and 95% if protected with both flutamide and goserelin acetate. Flutamide, sustained-release goserelin acetate, and a combination of these agents were effective in protecting the germinal epithelium of the rat during chemotherapy. A combination of flutamide and goserelin acetate provided the best protection. This study demonstrates for the first time the protective effect of flutamide and flutamide with goserelin acetate on the germinal epithelium during chemotherapy.