Comparison of the response of rat testis and accessory sex organs to treatment with testosterone and the synthetic androgen methyltrienolone (R1881).

Abstract

We have studied the ability of the synthetic androgen methyltrienolone (R1881) to maintain testis and accessory organ weights, as compared to the effect of testosterone propionate (TP). In contrast to TP, R1881 is not metabolized and does not significantly bind to androgen-binding protein (ABP). Thirty-six rats were treated with ethane dimethane sulphonate (EDS) and GnRH antagonist (Org30267) to abolish all testicular androgen production, and recombinant human FSH (rec-hFSH, Org32489) was administered to ensure adequate FSH levels. Of these rats, five groups of four rats were treated daily with 0-, 50-, 100-, 200-, and 400-microgram TP, s.c., and four groups of four rats were treated daily with 150-, 300-, 600-, and 1200-microgram R1881, s.c. One control group of four rats received vehicle injections only. EDS treatment, followed by GnRH antagonist and rec-hFSH treatment for 17 days, significantly reduced testis, prostate, and seminal vesicle weights (P < 0.001, P < 0.01, P < 0.001, respectively). Simultaneous treatment with androgens prevented this organ weight decrease, in a dose-dependent manner. In all TP-treated animals, relative weights (% of control) of the acces, sory sex organs were significantly higher than the relative testis weights (P < 0.001). However, there was no difference in relative weights between testis and accessory sex organs in the R1881-treated animals. In another series of experiments, we investigated the effect of treatment with Finasteride, a 5 alpha-reductase inhibitor, on testis and accessory sex organ weights in rats treated with EDS and TP. Treatment with EDS, TP (300 micrograms/day) and Finasteride (40 mg/kg/day) did not alter testis weight as compared to the effect of treatment with EDS and TP alone. Prostate and seminal vesicle weights were, however, markedly reduced (significantly different from rats treated with EDS and TP alone; P < 0.01 and P < 0.05, respectively). Immunohistochemical analysis of androgen-receptor (AR) expression in the testis revealed that testicular AR immunoexpression is androgen dependent and that FSH alone is not able to maintain AR immunoexpression. Furthermore, the stage-dependent pattern of AR immunoexpression in Sertoli-cell nuclei, during the spermatogenic cycle, is identical in all TP- and R1881-treated rats. It is concluded that testes, prostate, and seminal vesicles are equally stimulated when the androgen receptor in these tissues is exposed to the same intracellular concentration of free androgen and that the low 5 alpha-reductase activity in the testis plays a critical role in the differential response of the testis and the accessory sex organs to T. Furthermore, stage-dependent AR immunoexpression in Sertoli cells does occur in the absence of testicular androgen production and is not due to androgen metabolism or local differences in androgen concentration.