Mouse bioassay for in vivo screening of oestrogen and progesterone antagonists.

This study tested and compared the anti-proliferative and proliferative activities of two anti-oestrogens and three anti-progestins on four separate mouse model systems: young intact and adult ovariectomized (OV-X) females, and young intact and adult castrated males. Pure steroidal anti-oestrogen ICI 182,780 (ICI) decreased mammary and uterine growth stimulated by endogenous hormones in young intact females and by exogenous hormones [progesterone (Prog), 17beta-oestradiol (E) or E plus Prog] in both young intact and adult ovariectomized (OV-X) females. Non-steroidal anti-oestrogen EM-800 (EM), on the other hand, had no effect on mammary and uterine growth stimulated by endogenous hormones in young intact females and in adult OV-X females. Uterine growth was even stimulated by EM alone, and a combination of EM plus Prog not only stimulated uterine growth but also mammary growth (an oestrogenic agonistic activity). However, EM showed anti-oestrogenic activities in both mammary and uterine tissues in females treated with E or E plus Prog. In males, ICI and EM decreased mammary growth stimulated by exogenous hormones (E or E plus Prog) in both young intact and adult castrated animals. In young intact, but not in adult castrated males, ICI increased seminal vesicle growth affected by both endogenous and exogenous (Prog, E or E plus Prog) hormones. EM, on the other hand, decreased seminal vesicle weights in E or E plus Prog and increased its weights in Prog-treated young intact males. Thus, under certain conditions EM possess mixed agonist and antagonist activity in the mammary gland, uterus and seminal vesicles. Norethindrone acetate (NA)-stimulated mammary growth was decreased by anti-progestins onapristone (ON), RU 46556 (RU), and RU 38486 (MI) by 34-59% in females and by 35-93% in males. Uterine weights of NA-treated females were decreased by ON and RU by 29-55% but not by MI. In NA-treated young intact males, seminal vesicle weights were stimulated by RU (by 63%) and not affected by ON and MI. In NA-treated adult castrated males, seminal vesicle weights were decreased by ON, increased by RU and not affected by MI. The results obtained in these and our earlier studies show clearly that mouse four-model systems could serve as in vivo tool for the detection of steroid hormone agonist and antagonist activities of natural and man-made chemicals.

Mouse bioassay to assess oestrogenic and anti-oestrogenic compounds: hydroxytamoxifen, diethylstilbestrol and genistein.

Young intact and adult gonadectomized C3H male and female mice were utilized as bioassay models to detect endocrine disruption chemicals. Animals treated with oestradiol (E) or progesterone (Prog) or E plus Prog were used to assess steroid hormone agonist and antagonist activities of 4-OH-tamoxifen (TAM), diethylstilbestrol (DES) and genistein (GEN) by bioassay. The stimulation or inhibition of mammary growth by TAM depended on sex, the state of animal (intact or gonadectomized), hormonal treatment (Prog, E, E plus Prog) and dose of TAM. TAM stimulated mammary growth in untreated ovariectomized (OV-X) females and in Prog-treated intact males and OV-X females. In intact males, mammary growth was increased by TAM at dose 0.1-1 microg day(-1) and decreased at dose 10 microg day(-1). Mammary growth was inhibited by TAM in Prog-treated intact females and in E or E plus Prog-treated intact and gonadectomized males and females. Uterine weights were increased by TAM in both untreated and treated (E, Prog, E plus Prog) intact and OV-X females; however, seminal vesicle weights were decreased by TAM in both untreated and treated (E, Prog, E plus Prog) intact males. DES alone affected mammary growth (an inverted-U-shaped dose-response curve) both in male and female mice. DES increased uterine weights; however, seminal vesicle weights were decreased. GEN increased mammary and uterine growth in OV-X females, GEN plus Prog stimulated mammary growth in intact males. The results obtained in these studies show clearly that only a bioassay consisting of several endpoints reflective to the mechanism of oestrogen and anti-oestrogen action has the ability to evaluate activities of a molecule.