Dihydrotestosterone (DHT) is the primary androgen acting in the epididymis, the site of sperm maturation. Previously, we showed that the treatment of male rats with PNU157706, an inhibitor that acts on both isoforms of 5α-reductase to prevent DHT formation, has effects on the expression of genes implicated in processes that create the optimal luminal microenvironment required for sperm maturation, and on sperm maturation itself. However, signaling pathways involved in regulating or mediating DHT actions in the epididymis remain largely unknown. The goals of this study were to determine the expression profiles of potential signaling systems in the epididymis and assess their DHT-dependence using two different dual 5α-reductase inhibitors. Rats were untreated or gavaged with vehicle, 10 mg/kg per day PNU157706 or 32 mg/kg per day FK143 for 28 days and epididymal gene expression was analyzed. Gene array analysis revealed analogous effects of FK143 on overall epididymal gene expression when compared with previous PNU157706 studies. Quantitative RT-PCR analysis of the expression of the 5α-reductase isozymes, androgen receptor, and members of the IGF, FGF, TGF, and VEGF families revealed novel region-specific expression profiles in the epididymis that were differentially affected by 5α-reductase inhibition; the two inhibitors had parallel effects. Specifically, in proximal regions, 5α-reductase 1, androgen receptor, and TGF-β1 expression increased after treatment, while in distal regions expression of IGF-I, IGFBP-5, IGFBP-6, and FGF-10 decreased. These results provide insight into epididymal signaling mechanisms and indicate potential candidates acting either upstream or downstream of DHT to regulate and/or mediate its actions in the epididymis.

01 May 2006·Molecular and Cellular EndocrinologyQ2 · MEDICINE

Actions of 5α-reductase inhibitors on the epididymis

Q2 · MEDICINE

Review

Author: Bernard Robaire ; Natali A. Henderson

Testosterone is converted to the more biologically active androgen, dihydrotestosterone (DHT), by steroid 5alpha-reductase. Two isozymes of 5alpha-reductase, types 1 and 2, are abundantly expressed in the epididymis. DHT is the androgen found in the nuclei of epididymal cells and is essential for the maturation of spermatozoa. Thus, one approach to block androgen action in the epididymis is to inhibit DHT formation. Several compounds have been reported to inhibit either one or both forms of 5alpha-reductase in many tissues. The first commercially available inhibitor of 5alpha-reductase, finasteride, has a predominant effect on the type 2 isozyme, while more recently developed agents, such as dutasteride, PNU157706 and FK143, act as dual inhibitors. We found that the treatment of adult rats with such agents results in pronounced effects on the expression of genes essential to the formation of the optimal luminal microenvironment that is required for proper sperm maturation. Furthermore, drug treatment caused a significant decrease in the percentage of progressively motile and morphologically normal spermatozoa in the cauda epididymides. Mating females to treated males resulted in fewer successful pregnancies and a higher rate of pre-implantation loss. Thus, there may be a role for dual 5alpha-reductase inhibitors as potential components of a male contraceptive.

01 Jul 2001·Clinical cancer research : an official journal of the American Association for Cancer Research

Preventive effect of FK143, a 5alpha-reductase inhibitor, on chemical hepatocarcinogenesis in rats.

Article

Author: El-Assal, O N ; Yamanoi, A ; Nagasue, N ; Dhar, D K ; Satoh, K ; Okita, K ; Maruyama, S

The incidence of hepatocellular carcinoma (HCC) is more prevalent in males than in females. 5alpha-Dihydrotestosterone is the most potent form of androgen and is converted from testosterone by 5alpha-reductase. The antitumor effect of a 5alpha-reductase inhibitor (FK143) was evaluated in a rat chemical hepatocarcinogenesis model (Solt-Farber). Male Fischer 344 rats were used in three groups: (a) control group; (b) low-dose FK143 (FKL) group (20 ppm FK143); and (c) high-dose FK143 (FKH) group (200 ppm FK143). The numbers of both glutathione S-transferase placental form-positive foci (P < 0.05) and hyperplastic nodules (HNs; P < 0.01) in the liver were significantly lower in the FKL group than in the control group. The numbers (P < 0.05) and tumor volume (P < 0.01) of HCCs per liver were significantly lower in the FKL group when compared with the control group. All HCCs were well differentiated in the FKL group, whereas 38% and 36% of HCCs were moderate to poorly differentiated in the control group and the FKH group, respectively. The proliferating cell nuclear antigen labeling index:apoptotic index ratios of enzyme-altered foci, HNs, and HCCs were significantly lower in the FKL group than in the control group. Serum 5alpha-dihydrotestosterone was significantly lower in both the FKL and FKH groups. However, a high dose of FK143 (200 ppm) provided no protection against hepatocarcinogenesis, and the level of serum testosterone was elevated in this group when compared with that in the control group. The low dose of FK143 significantly suppressed the formation of enzyme-altered foci, HNs, and HCCs in rat hepatocarcinogenesis. This may indicate that 5alpha-dihydrotestosterone enhances hepatocarcinogenesis. We conclude that an optimal dose of FK143 may have a suppressive effect on hepatocarcinogenesis.

100 Deals associated with FK-143

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Indication	Highest Phase	Country/Location	Organization	Date
Liver Cancer	Phase 2	JP	Fujisawa Pharmaceutical Co., Ltd.	-
Prostatic Hyperplasia	Phase 2	-	Astellas Pharma, Inc.	-
Prostatic Hyperplasia	Phase 2	JP	Fujisawa Pharmaceutical Co., Ltd.	-

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