leuprolide and Urinary-Bladder-Neoplasms

It has been reported that blocking of testosterone production inhibits bladder carcinogenesis in various animal models. We investigated how testosterone acts on rat bladder carcinogenesis using an antiandrogen, flutamide, and a 5 alpha-reductase inhibitor, finasteride.. Experiment 1: we administered 0.05% BBN [N-butyl-N-(4-hydroxybutyl)nitrosamine] orally to 117 Wistar rats for 10 weeks, divided them into seven groups-control, surgical castration, finasteride (2 mg/kg), luteinizing hormone releasing hormone (LH-RH) agonist (1 mg/kg) flutamide (50 mg/kg), LH-RH agonist plus finasteride, and LH-RH agonist plus flutamide-, and then cystectomized them to investigate the incidence of bladder cancer on week 21; experiment 2: we administered 0.05% BBN to 154 Wistar rats for 7 weeks, divided them into seven groups-control, finasteride 2, 4, and 8 mg/kg, and flutamide 50, 100, and 200 mg/kg-, and then we cystectomized them to investigate the dose-dependent influence on bladder carcinogenesis of these drugs on week 20, and experiment 3: we investigated the presence of androgen receptors in rat and mouse normal bladder mucosa using a monoclonal antibody.. Experiment 1: Surgical castration and LH-RH agonist treatment significantly reduced the occurrence of carcinomas. There was no significant additive effect of coadministered finasteride or flutamide with LH-RH agonist. Finasteride or flutamide monotherapy showed no statistically significant effects on the results of experiment 1 at the doses used. Experiment 2: Flutamide showed a dose-dependent effect on reducing the number of rats with bladder cancer, and at a dosis of 200 mg/kg twice a week, the difference was statistically significant when compared with the control group, whereas finasteride had no statistically significant suppressing effect at any dose. Experiment 3: Mouse and rat bladder urothelium expressed the androgen receptor. Our results indicate that testosterone itself might have a more potent action on bladder carcinogenesis rather than its converting form, 5 alpha-dihydrotestosterone.

Topics: Administration, Oral; Androgen Antagonists; Animals; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Butylhydroxybutylnitrosamine; Carcinogens; Carcinoma; Cholestenone 5 alpha-Reductase; Disease Models, Animal; Enzyme Inhibitors; Finasteride; Flutamide; Gonadotropin-Releasing Hormone; Immunohistochemistry; Leuprolide; Male; Mice; Mice, Inbred C3H; Oxidoreductases; Rats; Rats, Wistar; Urinary Bladder Neoplasms

In several previous reports, it has been suggested that the androgen system is related to bladder carcinogenesis. In this study, to understand the mechanism underlying this relationship, we administered a LH-RH agonist depot (Leuprolide depot), a pure-antiandrogen (flutamide) or a 5 alpha-reductase inhibitor (finasteride) to the mice in the promotion state of bladder carcinogenesis by N-butul-N-(4-hydroxybutyl) nitrosamine (BBN).. 177 C3H/He male mice were divided into 7 groups. All mice were treated with 0.05% BBN for 10 weeks and were maintained over the subsequent 12 weeks with the following treatments. Group 1 was a control group; in group 2, castration was performed at the 11th week; in group 3, finasteride was administered starting the 11th week; in group 4, a LH-RH agonist depot was administered starting the 11th week; in group 5, flutamide was administered starting the 11th week; in group 6, both finasteride and a LH-RH agonist depot were administered simultaneously starting the 11th week; and in group 7, both flutamide and a LH-RH agonist depot were administered simultaneously starting the 11th week.. (1) We confirmed that castration significantly suppressed bladder carcinogenesis. (2) Finasteride or flutamide administration as monotherapy had no effect on the results; however, the dosages of these drugs may have been too low, so we are planning a study with higher doses. (3) Conversely, the LH-RH agonist depot significantly promoted bladder carcinogenesis, we believe that the high levels of testosterone immediately after the administration were responsible for this promotion. (4) Simultaneous administration of flutamide suppressed this LH-RH induced promotion of carcinogenesis.

Topics: 5-alpha Reductase Inhibitors; Androgen Antagonists; Animals; Butylhydroxybutylnitrosamine; Finasteride; Flutamide; Gonadotropin-Releasing Hormone; Leuprolide; Male; Mice; Mice, Inbred C3H; Orchiectomy; Urinary Bladder Neoplasms

In previous studies, it has been suggested that the suppression of testicular androgen had inhibits bladder carcinogenesis. In this study we investigated which phase of bladder carcinogenesis is inhibited by the hormonal change of the hypothalamus-pituitary-testicular axis induced by the depot form of the LH-RH agonist. All rats were treated with 0.05% BBN in tap water for 8 weeks and were observed for the following 16 weeks. They were divided into five groups. Group 1 (Control group); The LH-RH agonist was not administered. Group 2 (Initiation group); The LH-RH agonist (depot form) was administered subcutaneously two weeks before and after the initiation of the experiment. Group 3 (Promotion group); The LH-RH agonist (depot form) was subcutaneously administered at intervals of 4 weeks starting 6 weeks after the initiation of the experiment. Group 4 (Full term group); The LH-RH agonist (depot form) was administered subcutaneously at intervals of 4 weeks starting from 2 weeks before the initiation of the experiment. Group 5 (Castration group); Bilateral orchiectomy was performed one week before the beginning of the experiment. From our results, the followings were suggested, (1) more intensive inhibition of bladder carcinogenesis was observed in the group which received the LH-RH agonist (depot form), compared with the Castration group, (2) the bladder carcinogenesis was more intensively inhibited when the LH-RH analogue (depot from) was given in the promotion phase and (3) not only testosterone but also the regulatory system of the hypothalamus-pituitary-testicular axis is related to the bladder carcinogenesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Butylhydroxybutylnitrosamine; Hypothalamus; Injections, Subcutaneous; Leuprolide; Male; Orchiectomy; Pituitary Gland; Rats; Rats, Wistar; Testis; Testosterone; Urinary Bladder Neoplasms

As a first step of investigating male predominance of bladder cancer incidence, we have studied relationships between rat bladder carcinogenesis, induced by BBN, and changes of pituitary-testicular axis, induced by a LH-RH analogue. The rats were divided into the following five groups. The first group (Age matched control group) was given normal drinking water for 30 weeks. The 2nd group (BBN group) was given a drinking water containing 0.05% BBN for 6 weeks. The 3rd group (LH-RH group) was given subcutaneous injections of a LH-RH analogue depot every four weeks. The 4th group (LH-RH + BBN group) was given subcutaneous injections of the LH-RH analogue depot every four weeks and a drinking water containing 0.05% BBN for 6 weeks. The 5th group (castration group) was castrated and given normal drinking water. The results were summarized as follows. 1) Serum LH, FSH and testosterone levels reached their peaks one day after the LH-RH analogue injection and decreased afterwards. Testosterone marked a castration level one week after the LH-RH analogue injection. 2) There was no significant difference between the BBN and non BBN groups in serum LH, FSH and testosterone levels. Thus, BBN did not influence the pituitary-testicular axis and the action of the LH-RH analogues. 3) Incidence of cancer was higher in the group of BBN + LH-RH than in the group of BBN 8 weeks after the start of the experiment. Then, the incidence was reversed between 20 weeks and 26 weeks; finally it became almost the same at 30 weeks. This phenomenon may be explained by the experimented schedule we applied; that is, BBN and LH-RH analogue were administered simultaneously. 4) Thus, changes of the pituitary-testicular axis induced by the LH-RH analogue seemed to have influence on bladder carcinogen.

Topics: Animals; Butylhydroxybutylnitrosamine; Gonadotropin-Releasing Hormone; Leuprolide; Male; Pituitary Gland; Rats; Rats, Inbred Strains; Testis; Urinary Bladder Neoplasms