Microheterogeneity of pituitary FSH in male rats: differential effects of chronic androgen deprivation induced by castration or androgen blockade.

Testicular androgens are known to influence not only the secretion but also the bioactivity and molecular composition of pituitary FSH. In the present study, we investigated the effects of chronic androgen blockade and castration on the molecular heterogeneity of the gonadotrophin. Groups of male adult rats (five animals per group) received one of the following treatments: vehicle, the non-steroidal anti-androgens casodex (20 mg/kg per day) or flutamide (20 mg/kg per day), or castration. After 8 weeks, the animals were killed and individual pituitary homogenates fractionated by isoelectric focusing (IEF) on sucrose density gradients in the pH range 2·5–8. FSH was measured by radioimmunoassay (RIA) in the individual fractions and by in-vitro bioassay (Sertoli cell aromatase bioassay) in pools of fractions which were combined according to pH intervals of 0·5 units. Bioactive and immunoreactive FSH were also measured in sera and unfractionated pituitary extracts. Testosterone and inhibin were assayed in sera by RIA.A significant increase in serum immunoreactive and bioactive FSH was demonstrated in flutamide-treated and castrated animals, whereas the pituitary content of bioactive FSH remained unchanged in the four groups. Serum testosterone and inhibin were undetectable in castrated animals and significantly increased in those treated with flutamide. By RIA, the IEF profiles of the flutamide-treated and castrated rats showed a significant reduction of the FSH isoforms with 3·54 only in the castrated group. By bioassay, there was a significant decrease in the isoforms with 3·5<pI<4 in both casodex- and flutamide-treated animals, with no significant differences between the two groups. Castration caused a further significant shift in the relative distribution of FSH isoforms towards the less acidic components, with a significant increase in the isoforms with 5<pI<5·5 not attained by androgen blockade alone.These results suggest that the effects of long-lasting castration on pituitary FSH heterogeneity cannot be entirely reproduced by the androgen blockade. Since inhibin, eliminated by castration but not by androgen blockade, is a major regulator of FSH in the male rat, we speculate that it might not only influence FSH secretion but also modulate its qualitative properties

Comparative effects of chronic administration of the non-steroidal antiandrogens flutamide and casodex on the reproductive system of the adult male rat.

The effects of chronic blockade of androgen action by the antiandrogens flutamide and Casodex on serum and pituitary concentrations of LH and FSH, serum and testicular androgen levels, reproductive organ weights, and on spermatogenesis were compared in the adult rat. Animals were treated for 3 and 8 weeks with vehicle, Casodex (20 mg.kg-1.(day)-1, flutamide (20 mg.kg-1.(day)-1) and GnRH antagonist (150 micrograms/day, Detirelix). Treatment with GnRH antagonist suppressed gonadotropin and testosterone production, reduced the weights of testes, epididymides and seminal vesicles, and inhibited germ cell development. Flutamide administration markedly elevated serum and pituitary levels of gonadotropins as well as serum and testicular androgen concentrations. Casodex-induced elevation of gonadotropin concentrations was less pronounced and serum and testicular levels of androgens did not change significantly. The reduction of seminal vesicle weights was similar after Casodex and GnRH antagonist treatment, whereas flutamide was less effective. Testicular weight and spermatogenesis (assessed by light microscopical and flow-cytometric analysis) remained unaffected by Casodex and flutamide. It is concluded, that 1. Casodex, in contrast to flutamide, is a peripherally selective antiandrogen, and 2. Casodex influences release of gonadotropins into circulation less than flutamide. Therefore this antiandrogen might be useful clinically for selectively blocking androgen actions in the accessory sex glands

Antiproliferative activity of casodex (ICI 176.334) in hormone-dependent tumours

The nonsteroidal antiandrogen casodex has been described as a peripherally selective drug for the treatment of prostatic cancer. In this study we determined its activity in various models of hormone-dependent malignancies including those of the prostate and the breast. Analysis of endocrine effects in rats after 15 days of treatment revealed a strong reduction of the weights of prostates and seminal vesicles and a significant rise of testosterone serum levels as a result of the interference with central feedback mechanisms. The growth of androgen-sensitive human LNCaP/FGC prostate cancer cells was strongly inhibited by casodex. Unlike hydroxyflutamide, casodex was also active in hormone-depleted medium. The inhibitory effect was overcome by addition of testosterone propionate, which indicates an androgen-receptor-mediated mode of action. In rats bearing Dunning R3327-G prostate carcinomas casodex exerted a strong antitumour effect at the beginning of therapy. However, after 4 weeks of treatment tumours resumed growth whereas diethylstilboestrol-treated tumours remained static. In MXT-M3.2 mouse mammary tumours with significant quantities of androgen receptors casodex was also effective in inhibiting tumour growth. After 6 weeks of treatment, tumour weights were reduced by 69% whereas uterine weights were significantly increased, possibly because of a progestin-like activity of the drug. Csodex is very active in various models of hormone-dependent carcinomas. However, the limited duration of action in prostatic tumours and the incomplete growth inhibition in mammary tumours suggest that it should be used only combination with other endocrine therapies