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An In Vivo Estrogen Deficiency Mouse Model for Screening Exogenous Estrogen Treatments of Cardiovascular Dysfunction After Menopause
Published on: August 13, 2019
Mouse bioassay for in vivo screening of oestrogen and progesterone antagonists
1Institute of Animal Physiology and Genetics, Academy of Sciences of the Czech Republic, Vídenská 1083, 142 20 Prague 4, Czech Republic.
Abstract:
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.
Insights
This study evaluated anti-oestrogens and anti-progestins in mouse models, revealing mixed agonist/antagonist activities for EM-800 and demonstrating the utility of mouse models for detecting steroid hormone activities.
Area of Science:
- Endocrinology
- Pharmacology
- Reproductive Biology
Background:
- Steroid hormone antagonists are crucial for understanding reproductive health and developing therapies.
- Evaluating the complex agonist and antagonist activities of these compounds requires robust in vivo models.
Purpose of the Study:
- To compare the anti-proliferative and proliferative effects of specific anti-oestrogens and anti-progestins.
- To assess these effects across four distinct mouse model systems (intact and ovariectomized females, intact and castrated males).
- To validate the utility of these mouse models for detecting steroid hormone agonist and antagonist activities.
Main Methods:
- Tested two anti-oestrogens (ICI 182,780 and EM-800) and three anti-progestins (onapristone, RU 46556, RU 38486).
- Utilized four mouse models: young intact females, adult ovariectomized (OV-X) females, young intact males, and adult castrated males.
- Administered endogenous and exogenous hormones (progesterone, 17beta-oestradiol) to assess drug effects on mammary, uterine, and seminal vesicle growth.
Main Results:
- ICI 182,780 consistently reduced hormone-stimulated growth in females; EM-800 showed mixed agonist/antagonist activity, stimulating growth alone or with progesterone but antagonizing oestrogen effects.
- In males, both ICI 182,780 and EM-800 reduced hormone-stimulated mammary growth, with varied effects on seminal vesicle growth depending on the compound and hormonal status.
- Anti-progestins significantly reduced norethindrone acetate-stimulated mammary growth in both sexes and affected uterine and seminal vesicle weights differently across models.
Conclusions:
- The mouse models effectively detected diverse steroid hormone agonist and antagonist activities of tested compounds.
- EM-800 exhibits complex, context-dependent mixed agonist and antagonist properties in reproductive tissues.
- These validated mouse models serve as valuable in vivo tools for screening chemical compounds for endocrine-disrupting potential.
