Estrogenic effects of the antiprogestin onapristone (ZK98.299) in the rodent uterus

Robert Bigsby, Peter C M Young

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

OBJECTIVE: Our purpose was to assess the estrogenc action of onapristone (ZK299). STUDY DESIGN: Three rodent models of estrogen action in the uterus were used. Deoxyribonucleic acid synthesis in the uterine epithelium of neonatal mice was determined by thymidine sutoradiography. In adult ovariectomzled mice uterine wet weight and progesterone receptor and estrogen receptor concentrations were determined. In immature rats uterine deoxyribonucleic acid synthetic activity was determined by thymidine autoradiography, epithelial hypertrophy and stromal edema were assessed histomorphometricaliy, and complement C3 protein synthesis was assessed by metabolic labeling in vitro. The effects of ZK299 were challenged with the antiestrogens ICI 164,384 and tamoxifen. The ability of ZK299 to displace tritiated-estradiol from the estrogen receptor was assessed in cytosolic preparations from mouse uterus. RESULTS: In the neonatal mouse ZK299 stimulated epithelial deoxyribonucleic acid synthesis; two other antiprogestins, RU486 and ZK98.734, had no effect. Three daily injections of ZK299 at 10 μg/gm body weight to 6-week-old ovariectomized mice increased uterine progesterone receptor 42%; this effect was blocked by ICl164,384. In another experiment three daily doses of ZK299 (20 μg/gm) to 10-week-old ovariectomized mice increased progesterone receptor concentration by 63% and uterine wet weight by 42%. In 21-day-old rats a single injection of ZK299 increased uterine epithelial deoxyribonucleic acid synthesis; this effect was blocked by tamoxifen. Both ZK299 and tamoxifen increased epithelial cell height and thymidine labeling in the stroma. ZK98.734 had no effect on epithelium or stroma. ZK299 also stimulated synthesis of complement C3 by uteri of immature rats. In competitive binding assays ZK299 exhibited weak relative binding affinity (0.05%) for mouse uterine estrogen receptor. CONCLUSIONS: ZK299 can act as a weak estrogen in the rodent uterus, most likely through a direct, low-affinity interaction with the estrogen receptor. Because estrogens may increase the risk for endometrial, breast, and liver cancer, caution is warranted in long-term administration of this drug to women.

Original languageEnglish
Pages (from-to)188-194
Number of pages7
JournalAmerican Journal of Obstetrics and Gynecology
Volume171
Issue number1
DOIs
StatePublished - 1994

Fingerprint

Uterus
Rodentia
Estrogens
Estrogen Receptors
Progesterone Receptors
Tamoxifen
Thymidine
Complement C3
DNA
Epithelium
Estradiol Receptors
Weights and Measures
Injections
Competitive Binding
Estrogen Receptor Modulators
Liver Neoplasms
Endometrial Neoplasms
onapristone
Autoradiography
Hypertrophy

Keywords

  • antiprogestins
  • estrogen
  • Onapristone
  • rodent uterus

ASJC Scopus subject areas

  • Medicine(all)
  • Obstetrics and Gynecology

Cite this

Estrogenic effects of the antiprogestin onapristone (ZK98.299) in the rodent uterus. / Bigsby, Robert; Young, Peter C M.

In: American Journal of Obstetrics and Gynecology, Vol. 171, No. 1, 1994, p. 188-194.

Research output: Contribution to journalArticle

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abstract = "OBJECTIVE: Our purpose was to assess the estrogenc action of onapristone (ZK299). STUDY DESIGN: Three rodent models of estrogen action in the uterus were used. Deoxyribonucleic acid synthesis in the uterine epithelium of neonatal mice was determined by thymidine sutoradiography. In adult ovariectomzled mice uterine wet weight and progesterone receptor and estrogen receptor concentrations were determined. In immature rats uterine deoxyribonucleic acid synthetic activity was determined by thymidine autoradiography, epithelial hypertrophy and stromal edema were assessed histomorphometricaliy, and complement C3 protein synthesis was assessed by metabolic labeling in vitro. The effects of ZK299 were challenged with the antiestrogens ICI 164,384 and tamoxifen. The ability of ZK299 to displace tritiated-estradiol from the estrogen receptor was assessed in cytosolic preparations from mouse uterus. RESULTS: In the neonatal mouse ZK299 stimulated epithelial deoxyribonucleic acid synthesis; two other antiprogestins, RU486 and ZK98.734, had no effect. Three daily injections of ZK299 at 10 μg/gm body weight to 6-week-old ovariectomized mice increased uterine progesterone receptor 42{\%}; this effect was blocked by ICl164,384. In another experiment three daily doses of ZK299 (20 μg/gm) to 10-week-old ovariectomized mice increased progesterone receptor concentration by 63{\%} and uterine wet weight by 42{\%}. In 21-day-old rats a single injection of ZK299 increased uterine epithelial deoxyribonucleic acid synthesis; this effect was blocked by tamoxifen. Both ZK299 and tamoxifen increased epithelial cell height and thymidine labeling in the stroma. ZK98.734 had no effect on epithelium or stroma. ZK299 also stimulated synthesis of complement C3 by uteri of immature rats. In competitive binding assays ZK299 exhibited weak relative binding affinity (0.05{\%}) for mouse uterine estrogen receptor. CONCLUSIONS: ZK299 can act as a weak estrogen in the rodent uterus, most likely through a direct, low-affinity interaction with the estrogen receptor. Because estrogens may increase the risk for endometrial, breast, and liver cancer, caution is warranted in long-term administration of this drug to women.",
keywords = "antiprogestins, estrogen, Onapristone, rodent uterus",
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AU - Young, Peter C M

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N2 - OBJECTIVE: Our purpose was to assess the estrogenc action of onapristone (ZK299). STUDY DESIGN: Three rodent models of estrogen action in the uterus were used. Deoxyribonucleic acid synthesis in the uterine epithelium of neonatal mice was determined by thymidine sutoradiography. In adult ovariectomzled mice uterine wet weight and progesterone receptor and estrogen receptor concentrations were determined. In immature rats uterine deoxyribonucleic acid synthetic activity was determined by thymidine autoradiography, epithelial hypertrophy and stromal edema were assessed histomorphometricaliy, and complement C3 protein synthesis was assessed by metabolic labeling in vitro. The effects of ZK299 were challenged with the antiestrogens ICI 164,384 and tamoxifen. The ability of ZK299 to displace tritiated-estradiol from the estrogen receptor was assessed in cytosolic preparations from mouse uterus. RESULTS: In the neonatal mouse ZK299 stimulated epithelial deoxyribonucleic acid synthesis; two other antiprogestins, RU486 and ZK98.734, had no effect. Three daily injections of ZK299 at 10 μg/gm body weight to 6-week-old ovariectomized mice increased uterine progesterone receptor 42%; this effect was blocked by ICl164,384. In another experiment three daily doses of ZK299 (20 μg/gm) to 10-week-old ovariectomized mice increased progesterone receptor concentration by 63% and uterine wet weight by 42%. In 21-day-old rats a single injection of ZK299 increased uterine epithelial deoxyribonucleic acid synthesis; this effect was blocked by tamoxifen. Both ZK299 and tamoxifen increased epithelial cell height and thymidine labeling in the stroma. ZK98.734 had no effect on epithelium or stroma. ZK299 also stimulated synthesis of complement C3 by uteri of immature rats. In competitive binding assays ZK299 exhibited weak relative binding affinity (0.05%) for mouse uterine estrogen receptor. CONCLUSIONS: ZK299 can act as a weak estrogen in the rodent uterus, most likely through a direct, low-affinity interaction with the estrogen receptor. Because estrogens may increase the risk for endometrial, breast, and liver cancer, caution is warranted in long-term administration of this drug to women.

AB - OBJECTIVE: Our purpose was to assess the estrogenc action of onapristone (ZK299). STUDY DESIGN: Three rodent models of estrogen action in the uterus were used. Deoxyribonucleic acid synthesis in the uterine epithelium of neonatal mice was determined by thymidine sutoradiography. In adult ovariectomzled mice uterine wet weight and progesterone receptor and estrogen receptor concentrations were determined. In immature rats uterine deoxyribonucleic acid synthetic activity was determined by thymidine autoradiography, epithelial hypertrophy and stromal edema were assessed histomorphometricaliy, and complement C3 protein synthesis was assessed by metabolic labeling in vitro. The effects of ZK299 were challenged with the antiestrogens ICI 164,384 and tamoxifen. The ability of ZK299 to displace tritiated-estradiol from the estrogen receptor was assessed in cytosolic preparations from mouse uterus. RESULTS: In the neonatal mouse ZK299 stimulated epithelial deoxyribonucleic acid synthesis; two other antiprogestins, RU486 and ZK98.734, had no effect. Three daily injections of ZK299 at 10 μg/gm body weight to 6-week-old ovariectomized mice increased uterine progesterone receptor 42%; this effect was blocked by ICl164,384. In another experiment three daily doses of ZK299 (20 μg/gm) to 10-week-old ovariectomized mice increased progesterone receptor concentration by 63% and uterine wet weight by 42%. In 21-day-old rats a single injection of ZK299 increased uterine epithelial deoxyribonucleic acid synthesis; this effect was blocked by tamoxifen. Both ZK299 and tamoxifen increased epithelial cell height and thymidine labeling in the stroma. ZK98.734 had no effect on epithelium or stroma. ZK299 also stimulated synthesis of complement C3 by uteri of immature rats. In competitive binding assays ZK299 exhibited weak relative binding affinity (0.05%) for mouse uterine estrogen receptor. CONCLUSIONS: ZK299 can act as a weak estrogen in the rodent uterus, most likely through a direct, low-affinity interaction with the estrogen receptor. Because estrogens may increase the risk for endometrial, breast, and liver cancer, caution is warranted in long-term administration of this drug to women.

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