151
0 1992
Original Articles
The Japanese Society of Pathology
Inhibitory Influence of a New Steroidal Anti-androgen, TZP-4238, on Prostatic Hyperplasia in the Beagle Dog
Masanori Murakoshi', Rie Inadal, Masashi Tagawa', Masao Makino', Minoru Suzuki', Mamoru Mieda2, Seijiroh Honma2, Yutaka Takezawa3, and Hidetoshi Yamanaka3
The effect of a synthetic steroidal anti-androgen, TZP4238, on spontaneous benign prostatic hyperplasia (BPH) in dogs was investigated. Old male beagle dogs (5-9 years old) were divided into three experimental groups. Group 1 consisted of BPH controls. Groups 2 and 3 received TZP4238 0.1 mg/kg/day and chlormadinone acetate (CMA) 0.3 mg/kg/day P.o., respectively, for 5 months. In group 1, glandular hyperplasia of the prostate was clearly detected. In contrast, TZP-4238 (Group2) or CMA (Group3) produced marked atrophy of the glandular epithelium. In addition, a histopathological study showed that TZP-4238 or CMA medication for 5 months exerted no effect on the testes and the pituitary luteinizing hormone (LH) cells. Therefore, it is suggested that TZP-4238 (0.1 mg/kg) or CMA (0.3 mg/kg) causes regression of spontaneous canine BPH without any histopathological effects on the testes and pituitary LH cells. However, slightly decreased serum testosterone levels were found in TZP-4238-treated animals, due apparently to a direct and/or indirect effect on the testes. Thus, it is suggested that a marginal antigonadotrophic effect cannot be excluded. It is concluded that TZP--4238 is a potent anti-androgen for the treatment of spontaneous canine BPH, without any negative influence on the function of the testes and the pituitary LH cells. Acta Pathol Jpn 42: 151-157, 1992. Key words : Anti-androgen, TZP-4238, Chlormadinone acetate, Canine prostatic hyperplasia, Luteinizing hormone cells
Received August 23, 1991. Accepted for publication November 20, 1991. Departments of 'Safety Research and 2Pharmacological Research, Teikoku Hormone Mfg. Co. Ltd., Kawasaki. 3Department of Urology, Gunma University, School of Medicine, Maeba s hi. Mailing address: Masanori Murakoshi, Ph.D., Safety Research Department, Teikoku Hormone Mfg. Co. Ltd., 1604 S himosakunobe, Taka tsu- ku, Kawasaki 2 13, Japan.
Benign prostatic hyperplasia (BPH) is a major disease in both the aging dog and man(1-9). Therefore, the dog is the best available model for studying BPH, since the disease occurs spontaneously or experimentally upon treatment with steroid hormones (1-10). Furthermore, it is known that canine BPH can be completely cured by either anti-androgen therapy or castration. Previous studies using castrated steroid-treated dogs have indicated that TZP-4238 (Fig. la), a new type of steroidal anti-androgen, inhibits the experimental induction of BPH (11). Furthermore, we have found that the dose of TZP-4238 required to inhibit the development of glandular hyperplasia is lower than that of chlormadinone acetate (CMA) (Fig. 1b) (11). Therefore, we postulated that TZP-4238 was more potent than CMA in preventing steroid-induced canine prostatic hyperplasia (11). In addition, TZP-4238 exerts its anti-androgenic activity by competing with androgen at the receptor site
(1 2). On the other hand, it is well known that steroidal antiandrogens such as cyproterone acetate inhibit gonadotropin (LH) secretion and testosterone biosynthesis, unlike non-steroidal anti-androgens, which produce increases in luteinizing hormone (LH) and testosterone, when given alone(l3). The purpose of the present study was to further examine the effect of TZP-4238 on spontaneous canine prostatic hyperplasia. In addition, the effects of TZP-4238 on testicular morphology, pituitary LH cells and serum androgen concentrations were also investigated.
MATERIALS AND METHODS A nima Is Male beagle dogs were obtained from Laboratory
152
Effect of TZP-4238 on Prostatic Hyperplasia (Murakoshi et a/.) Table 1. Effect of TZP-4238 o r CMA on Prostatic Weight, Testicuiar Weight, Pituitary Weight, Pituitary LH Group
n Final age (years) 3 3 2
1 2 3
6-7 9 7-9
Body weight (kg)
Treatment
11.851.25 11.7i1.81 10.7 +O. 14
~
TZP-4238 CMA
Prostatic weight
Testicular weight--
(g)
(g) Absolute Relative 15.6 i1.32 1.33 -t 0.1 1 1 8 . l t 1 . 4 6 a 1.58k0.31 19.0+4.a2 1.77to.42
Absolute 16.36 ? 4.15 8.73+3.20a 9.92ii.46
Relative 1 . 3 8 i0.32 0.76t0.28a 0.931-0.15
CMA, Chlormadinone acetate Values are means+S D a P
0 1992
Original Articles
The Japanese Society of Pathology
Inhibitory Influence of a New Steroidal Anti-androgen, TZP-4238, on Prostatic Hyperplasia in the Beagle Dog
Masanori Murakoshi', Rie Inadal, Masashi Tagawa', Masao Makino', Minoru Suzuki', Mamoru Mieda2, Seijiroh Honma2, Yutaka Takezawa3, and Hidetoshi Yamanaka3
The effect of a synthetic steroidal anti-androgen, TZP4238, on spontaneous benign prostatic hyperplasia (BPH) in dogs was investigated. Old male beagle dogs (5-9 years old) were divided into three experimental groups. Group 1 consisted of BPH controls. Groups 2 and 3 received TZP4238 0.1 mg/kg/day and chlormadinone acetate (CMA) 0.3 mg/kg/day P.o., respectively, for 5 months. In group 1, glandular hyperplasia of the prostate was clearly detected. In contrast, TZP-4238 (Group2) or CMA (Group3) produced marked atrophy of the glandular epithelium. In addition, a histopathological study showed that TZP-4238 or CMA medication for 5 months exerted no effect on the testes and the pituitary luteinizing hormone (LH) cells. Therefore, it is suggested that TZP-4238 (0.1 mg/kg) or CMA (0.3 mg/kg) causes regression of spontaneous canine BPH without any histopathological effects on the testes and pituitary LH cells. However, slightly decreased serum testosterone levels were found in TZP-4238-treated animals, due apparently to a direct and/or indirect effect on the testes. Thus, it is suggested that a marginal antigonadotrophic effect cannot be excluded. It is concluded that TZP--4238 is a potent anti-androgen for the treatment of spontaneous canine BPH, without any negative influence on the function of the testes and the pituitary LH cells. Acta Pathol Jpn 42: 151-157, 1992. Key words : Anti-androgen, TZP-4238, Chlormadinone acetate, Canine prostatic hyperplasia, Luteinizing hormone cells
Received August 23, 1991. Accepted for publication November 20, 1991. Departments of 'Safety Research and 2Pharmacological Research, Teikoku Hormone Mfg. Co. Ltd., Kawasaki. 3Department of Urology, Gunma University, School of Medicine, Maeba s hi. Mailing address: Masanori Murakoshi, Ph.D., Safety Research Department, Teikoku Hormone Mfg. Co. Ltd., 1604 S himosakunobe, Taka tsu- ku, Kawasaki 2 13, Japan.
Benign prostatic hyperplasia (BPH) is a major disease in both the aging dog and man(1-9). Therefore, the dog is the best available model for studying BPH, since the disease occurs spontaneously or experimentally upon treatment with steroid hormones (1-10). Furthermore, it is known that canine BPH can be completely cured by either anti-androgen therapy or castration. Previous studies using castrated steroid-treated dogs have indicated that TZP-4238 (Fig. la), a new type of steroidal anti-androgen, inhibits the experimental induction of BPH (11). Furthermore, we have found that the dose of TZP-4238 required to inhibit the development of glandular hyperplasia is lower than that of chlormadinone acetate (CMA) (Fig. 1b) (11). Therefore, we postulated that TZP-4238 was more potent than CMA in preventing steroid-induced canine prostatic hyperplasia (11). In addition, TZP-4238 exerts its anti-androgenic activity by competing with androgen at the receptor site
(1 2). On the other hand, it is well known that steroidal antiandrogens such as cyproterone acetate inhibit gonadotropin (LH) secretion and testosterone biosynthesis, unlike non-steroidal anti-androgens, which produce increases in luteinizing hormone (LH) and testosterone, when given alone(l3). The purpose of the present study was to further examine the effect of TZP-4238 on spontaneous canine prostatic hyperplasia. In addition, the effects of TZP-4238 on testicular morphology, pituitary LH cells and serum androgen concentrations were also investigated.
MATERIALS AND METHODS A nima Is Male beagle dogs were obtained from Laboratory
152
Effect of TZP-4238 on Prostatic Hyperplasia (Murakoshi et a/.) Table 1. Effect of TZP-4238 o r CMA on Prostatic Weight, Testicuiar Weight, Pituitary Weight, Pituitary LH Group
n Final age (years) 3 3 2
1 2 3
6-7 9 7-9
Body weight (kg)
Treatment
11.851.25 11.7i1.81 10.7 +O. 14
~
TZP-4238 CMA
Prostatic weight
Testicular weight--
(g)
(g) Absolute Relative 15.6 i1.32 1.33 -t 0.1 1 1 8 . l t 1 . 4 6 a 1.58k0.31 19.0+4.a2 1.77to.42
Absolute 16.36 ? 4.15 8.73+3.20a 9.92ii.46
Relative 1 . 3 8 i0.32 0.76t0.28a 0.931-0.15
CMA, Chlormadinone acetate Values are means+S D a P
