An investigation into the anti-androgenic properties of the non-steroidal compound, sch 13521 (4′-nitro-3′-trifluoromethylisobutyrylanilide)

Mainwaring, W.I.P.; Mangan, F. R.; Feherty, Patricia; Freifeld, Martin

doi:10.1016/0303-7207(74)90004-5

Cited by 50 publications

(10 citation statements)

References 18 publications

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“…Mainwaring et al(1974) have reported similar results, namely, antiandrogens such as SCHI3521or BOMT increased the uptake of 3H-androgens in the homogenates and decreased the3H-uptake in the nuclear fraction. They gave the most plausible explanation about these phenomena that the compounds under evaluation affected the rate of entry of3H-testosterone into only androgen dependent cells such as those in the prostate.…”

Section: Effect Of Aa560onsupporting

confidence: 52%

Action of a novel nonsteroidal antiandrogen, AA560.

et al. 1980

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SynopsisThe antiandrogenic properties of a new nonsteroidal antiandrogens, AA560 (N-(2-chloromethyl-2-hydroxypropionyl)-3, 4, 5-trichloroaniline) were investigated. The ventral prostate, dorselateral prostate and coagulating gland weights in rats given AA560 at1-9mg/head were significantly less than those in the intact rats. The seminal vesicle weights in rats given3-9mg/head were significantly less than those of the intact group.In intact animals given daily3or9mg of AA560there were significantly increases of serum FSH, LH and testosterone concentrations.In the in vivo experiment, the pretreatment with AA560decreased the uptake of 3H-androgens in the nuclear fraction of the ventral prostate.On the other hand, a significant increase in the uptake of3H-radioactivity in the cytosol fraction was observed.It was proved by the in vitro displacement study that AA560inhibited the binding of5a-dihydrotestosterone with a receptor protein in the prostatic cytosol.

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Section: Effect Of Aa560onsupporting

confidence: 52%

Action of a novel nonsteroidal antiandrogen, AA560.

et al. 1980

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“…Furthermore our decrease in fertility cannot be related to a decrease in sexual behaviour since Södersten et al (1975) and Gray (1977) have demonstrated that flutamide does not impair the sexual behaviour of the male rat. Nor is this partial loss of fertility likely to be a conse¬ quence of a lower production of sperm, as elonga¬ ted spermatids were not affected, but related to a dysfunction of accessory sex organs, specially epi¬ didymis (Dhar & Setty 1976) and ventral prostate (Mainwaring et al 1974). In this case, a 15 day treatment with flutamide could reveal this tempo¬ rary decrease in fertility, while after a prolonged administration, spermatogenesis and the normal activity of accessory sex organs could be restored by the high level of testosterone induced by the treatment.…”

Section: Discussionmentioning

confidence: 94%

“…This involution of accessory organs of the genital tract is a direct consequence of the ability of flutamide to bind androgen receptors (Liao et al 1974; Mainwaring et al 1974). However, the decrease in accessory sex organs weight is more marked if rats are treated before puberty (Viguier-Martinez et al 1983), as growing sex organs are more sensitive to the anabolizing action of testosterone.…”

Section: Discussionmentioning

confidence: 98%

Endocrinological and histological changes induced by flutamide treatment on the hypothalamo-hypophyseal testicular axis of the adult male rat and their incidences on fertility

Viguier-Martinez

Reviers

Barenton³

et al. 1983

Acta Endocrinologica

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Adult male Wistar rats were treated with flutamide from 90 to 105 days of age. In a first experiment, testis and accessory sex organs were weighed. In the same animals, hypothalamic LRH content, pituitary gonadotrophin concentrations, plasma LH, FSH, prolactin and testosterone levels, and testicular gonadotrophin receptors were evaluated. In a second experiment, fertility was tested at the end of the treatment, and histology of the testis was performed. All the results were compared to those obtained in control animals of the same age. Accessory glands of genital tract were significantly lower in flutamide-treated animals (P < 0.01). Hypothalamic LRH, pituitary and plasma FSH, and prolactin concentrations were unchanged, while pituitary and plasma LH level and especially plasma testosterone concentration were increased (P < 0.001).Flutamide therefore exerted a strong inhibition on testosterone-dependent organs, and blocked the negative feedback of testosterone on the hypothalamo-pituitary axis, increasing the LH levels. Testis weight, intertubular tissue volume, total number and total volume of Leydig cells/testis, as well as total length and diameter of seminiferous tubules were unchanged in flutamide treated rats. However number of LH receptors/Leydig cell, nuclear area of Sertoli cells, number of FSH receptors/Sertoli cell, number of leptotene spermatocytes and of round spermatids per cross section, and yield of spermatogonial divisions were decreased after treatment. Flutamide treatment also decreased fertility by 48% (P < 0.05). This lowered fertility is likely the result of impaired spermatogenesis and/or a dysfunction of accessory sex organs.Flutamide (4'-nitro-3'-trifIuoro-methylisobutyranilide, Sch 13521), is a potent, non-steroidal antiandrogen with neither progestational nor oestrogenic effects Neumann et al. 1977). As shown previously (Viguier-Martinezetal. 1983), flutamide induces important changes in growing male rats on the hypothalamo-pituitary axis as well as on testicular physiology. The present work was designed to study the effects of flutamide treatment on the hypothalamo-pituitary testicular axis in the adult and to compare to those already obtained in the prepubertal rat. This experiment performed in adult rats could moreover allow to test the incidence of flutamide on the fertility, at the end of a short-term treatment. Such a model could be used to investigate the possible differences in the feedback control of LH and FSH, as well as to estimate the direct or indirect actions of a pure anti-androgen on the testicular physiology of the adult rat.Materials and Methods a. Animah Two groups of 15 male Wistar rats each received a daily sc injection from 90 to 105 days of age. In the control group, rats received solvent (0.2 ml arachis oil/benzyl alcohol 9:1 v/v); in the flutamide group, rats received 10 mg/kg/day of flutamide (Schering Corp. Bloomfield,

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“…Some receptor accumulation over the control levels also occurred when 5a-dihydrotestosterone was given. The notion that androgens indeed translocate progestin receptors to the nuclei is strongly supported by findings that Flutamide, a non-steroidal antiandrogen known to prevent nuclear retention of androgen receptors (Liao et al 1974;Mainwaring et al 1974), did not influence the action of progesterone or 7n. 17a-dimethyl-19-nortestosterone.…”

Section: Accumulation O F Progestin Receptors Within Rabbit Uterine Nmentioning

confidence: 94%

Progestational Activity of Natural and Synthetic Androgens

et al. 1978

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Uteroglobin, a progesterone‐regulated secretory protein in rabbit uterus, was used as a marker protein for studies on progestational activity of various natural and synthetic androgens. All the androgens investigated were able to induce uteroglobin synthesis in rabbit uterus; some of the synthetic androgens were even better inducers than progesterone itself. Our results suggest that androgens elicit their regulatory action on uteroglobin synthesis by way of progestin receptor mechanism, since: (i) There was an intimate correlation between the in vitro binding affinity to progestin receptor and the in vivo potency of the androgens to induce uteroglobin synthesis; (ii) Androgens were able to translocate cytosol progestin receptors to uterine nuclei; (iii) Dose‐response curves for uteroglobin induction were parallel for androgens and progestins, and (iv) Flutamide, a non‐steroidal antiandrogen, did not abolish androgen‐induced synthesis of uteroglobin or androgen‐promoted nuclear translocation of cytosol progestin receptors. Both progesterone and androgens seem to control uteroglobin synthesis through mechanisms involving formation of new mRNA species, since in each case there was an increase in the uterine preuteroglobin‐mRNA activity, as evaluated by a cell‐free in vitro translation assay, which correlated with the amount of uteroglobin secreted into the uterine fluid. Some of the androgens studied (7α, 17α‐dimethyl‐19‐nortestosterone, 17α‐ethyl‐19‐nortestosterone and 11‐methylene‐17α‐methyl‐19‐nortestosterone) enhanced uteroglobin synthesis to the same or greater extent than progesterone. Interestingly, these steroids are also known to be very potent androgens. The progestational actions of androgens may be applicable to human tissues, too, since all the androgens investigated were bound by the human uterine progestin receptor in a fashion identical with the rabbit receptor.

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An investigation into the anti-androgenic properties of the non-steroidal compound, sch 13521 (4′-nitro-3′-trifluoromethylisobutyrylanilide)

Cited by 50 publications

References 18 publications

Action of a novel nonsteroidal antiandrogen, AA560.

Action of a novel nonsteroidal antiandrogen, AA560.

Endocrinological and histological changes induced by flutamide treatment on the hypothalamo-hypophyseal testicular axis of the adult male rat and their incidences on fertility

Progestational Activity of Natural and Synthetic Androgens

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