A Reserch for Regulation of the Human Epididymal 5 alpha-Reductase Intended in Development of Male Cotraceptives.

1991 Fiscal Year Final Research Report Summary

• Project/Area Number: 01570900
• Research Category: Grant-in-Aid for General Scientific Research (C)
• Allocation Type: Single-year Grants
• Research Field: Urology
• Research Institution: Yokohama City University
• Principal Investigator: KINOSHITA Yuzo Yokohama City University School of Medicine. Department of Urology, Assocciate Professor, 医学部, 助教授 (00186298)
• Co-Investigator(Kenkyū-buntansha): HOSAKA Masahiko Yokohama City University School of Medicine. Department of Urology, Professor, 医学部, 教授 (30106330)
• Project Period (FY): 1989 – 1991
• Keywords: testosterone 5 alpha -reductase / epididymis / estrogens / antiandrogens / down-regulation

Research Abstract

The inhibitory effects of various antiandrogens on testosterone 5 alpha -reductase in the human epididymis were studied. In the current study, it was ellucidated that the inhibitory effcts could be obviously devided into two categories : (1) direct inhibitory effect and (2) indirect in hibitory effect. Finasteride and ONO-3805 were potent direct 5 alpha -reductase inhibitor, the former was competitive and the latter noncompetitive. The Ki value in the human epididimal microsomes were 1.3 x 10^<-9>M and 2.5 x 10^<-8>M,respectively. Allylestrenol shows a direct inhibition only in the concentration more than 10^<-4>M and 3-ketoallylestrenol inhibited 5 alpha -reductase in 10^<-8> - 10^<-7>M.Ethynylestradiol, estradiol-17 beta, estriol, estrone were very weak inhibitor and the mode was primarily noncompetitive. The potency of the inhibitory effect by clormadinone acetate and 3 beta -hydroxychlormadinone acetate were also very weak but their inhibition mode was clearly competitive. In spite of the weak potency for the direct inhibition, ethnylestradiol and chlormadinone acetete inhibit human epididymal 5 alpha -reductase very potently. The suppressed 5 alpha -reductase had a significantly decreased Vmax value whereas the Km value was unchanged. The mechanism of inhibition is an indirect type, most probably the downregulation of the 5 alpha -reductase expression through the suppressed hypophyseal-testicular axis.