Effect of AA560 (a nonsteroidal antiandrogen) implantation in the hypothalamus on gonadotropin secretion in male rats.

AA 560, one of potent nonsteroidal antiandrogens, was implanted in the arcuate nucleus of the hypothalamus of intact male rats through a stainless double cannula. The prostate weight and serum LH level significantly increased on the 5th day after the implantation of AA 560 when compared with those in the sham-operated animals. There existed a definite correlation between the weight of the ventral prostate and the serum LH level in AA 560 implanted animals. Many reports have indicated that the presence of a 5α-dihydro-testosterone receptor in the cytosol prepared from male rat brain (Kato and Onouchi, 1973a; Kato and Onouchi, 1973b; Naess et al., 1975; Mercier et al., 1976; Lieberburg et al., 1977). A novel nonsteroidal antiandrogen, [N-(2-chloromethyl-2-hydroxypropionyl)-3, 4, 5-trichloroaniline] (AA560) is a derivative of anilide (Fig. 1) and a comparative study on castrated and intact male rats revealed that the inhibitory effect of AA560 on rat prostate weight was stronger than that of SCHI3521 (Shida, 1980). Shida et al. (1980) have shown that the oral administration of AA560 to intact male rats cause a decrease in prostate weight and a rise in the serum LH and FSH levels. We have also indicated that AA560 prevents the binding of 5α-dihydrotestosterone at the receptor in the brain as well as in the prostate (Yamanaka et al., 1979). The present study was aimed at finding whether the intrahypothalamic implantaion of AA560 in male rats might exert any effect on gonadotropin secretion and consequently on prostate weight. Fig. 1. Chemical slructure of AA 560 Received July 9, 1981. 820 YAMANAKA et al. Endocrinol. Japon. December 1981 Materials and Methods Chemicals AA 560 [N-(2-cholromethyl-2-hydroxypropionyl)3, 4, 5-tricholoroaniline] was obtained from Teikoku Hormone Mfg. Co., Kawasaki, Japan. Animals Male Wister strain rats (200-220g.) were maintaintained on laboratory chow from Japan Clea Co. and water ad libitum. The animals were housed in metabolic cages in a temperature controlled room under a 12h light l2h dark lighting schedule. AA 560 implantation was performed through a double cannule. The stainless 0.7mm outside diameter tube was stereotaxically implanted into the arcuate nucleus of the hypothalamus as the outer cannula under ether anesthesia according to the atlas by Sherwood and Timiras (1970). On the 10th day after the outer cannula implantation, the 0.35 mm outer diameter inner cannula bearing crystalline AA 560 was iuserted into the outer cannula and extended approximately 0.5mm beyond the tip of the outer cannula. The animals were autopsied on the 5th day affer insertion of the inner cannula. At autopsy, the prostate was weighed and brain was fixed in formalin, sectioned, and stained for verification of implant locations. All blood samples were taken from the vena cava and sera were stored at-80°C until assayed. Serum LH, FSH measurement Serum LH or FSH was measured as described previously (Wakabayashi, 1977) by radioimmunoassay employing RIA kits supplied by Dr. A. F. Parlow of Rat Pituitary Hormone Program, NIAMDD, NIH. The results were expressed as the equivalent of NIH-LH-SI for LH and NIH-FSH-SI for FSH. Results Table 1 shows the changes in ventral prostate weight, serum LH and FSH concentration 5days after AA560 implantation into the arcuate nucleus of the hypothalamus of mature male rats. The ventral prostate weight was significantly higher in AA560 implanted animals than in shamoperated controls. It is also apparent from Table 1 that AA560 in the arcuate nucleus significantly raised the serum LH level. On the other hand, serum FSH titers were not significantly altered by AA560 implant in the arcuate nucleus. There existed a definite correlation between the weight of the ventral prostate and the serum LH level in AA560 implanted animals (r: +0.8621), but not in sham-operated animals (r: -0.0206). There was a significant difference between AA560 imp1anted and sham-operated animals in the r value (p<0.05). Table 1. Effect of AA 560 implantation in the arcuate nucleus of the hypothalamus of male rats. Legend to Table 1. Data are shown as mean±standard error. *: Significant difference from the mean for the sham-operated group . (p<0.05) **: Significant difference from the mean for the sham -operated group. (p<0.02) Vol.28, No.6 HYPOTHALAMIC AA560 IMPLANTATION IN MALES 821 Fig. 2. The relationship between the serum LH level and the ventral prostate weight. The rs represent the coefficient correlation.