Effects of the Progesterone Antagonist RU486 on Ovarian Activity in the Rat*

Schoot, P. van der; Bakker, G.H.; Klijn, Jan G.M.

doi:10.1210/endo-121-4-1375

Cited by 68 publications

(31 citation statements)

References 14 publications

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“…The failure of luteolysis is usually associated with increased appearance of follicular cysts and an increase in ovarian weight. These findings on the increased ovarian activity induced by the progesterone antagonists in tumorbearing mice and rats are in line with the results reported by van der Schoot and co-workers [16] as well as by Bakker and co-workers [5] on the effects of RU 486 in the rat. The increase in ovarian weights is known to be accompanied by elevated blood concentrations of LH, prolactin, progesterone, and estradiol after treatment with RU 486 according to these authors.…”

Section: Discussionsupporting

confidence: 92%

Antitumor activity of the antiprogestins ZK 98.299 and RU 38.486 in hormone dependent rat and mouse mammary tumors: Mechanistic studies

Michna¹,

Schneider²,

Nishino³

et al. 1989

Breast Cancer Res Tr

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In the transplantable MXT mammary tumor model of the mouse and in the DMBA- and MNU-induced mammary tumor models of the rat, the progesterone antagonists ZK 98.299 and RU 38.468 were shown to have potent antitumor activity. The weight and/or morphology of the ovaries, uterus, and vagina, as well as the effects on serum hormone levels, indicate that the antitumor activity of both antiprogesterones in these models does not depend on a blockade of the ovarian and pituitary functions and does not depend on a non receptor-mediated cytotoxic effect. On the other hand, the morphology of the MXT and the DMBA-induced mammary tumors after treatment with the progesterone antagonists is completely different from that observed after ovariectomy. Treatment with the antiprogesterones seems to trigger differentiation of the mitotically active polygonal tumor cells towards glandular structures and acini with a massive sequestering of secretory products, as well as towards spindle-shaped necrobiotic subpopulations. By contrast, the induction of tumor cell degeneration and cytolysis is the predominant feature of the mammary tumors after ovariectomy. In conclusion, our results indicate that the main mechanism of the antitumor action of antiprogesterones in these models is a direct progesterone receptor-mediated antiproliferation effect at the level of the mammary tumor cells, most probably via the induction of terminal differentiation associated with terminal cell death. This antiproliferative effect seems to be dissociated from the antihormone (antiprogestational) activity of these progesterone antagonists.

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Section: Discussionsupporting

confidence: 92%

Antitumor activity of the antiprogestins ZK 98.299 and RU 38.486 in hormone dependent rat and mouse mammary tumors: Mechanistic studies

Michna¹,

Schneider²,

Nishino³

et al. 1989

Breast Cancer Res Tr

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show abstract

“…In the adrenals, bilateral cortical hypertrophy characterized by increased size of the zona fasciculata and zona reticularis corresponding to the increased adrenal weights, was observed. These changes probably indicate an increase in pituitary adrenocorticotropic hormone (ACTH) secretion caused by feedback mechanisms due to a corticosteroid antagonistic effect of mifepristone (van der Schoot et al, 1987). In a previous study, it was hormone (TSH) and a decrease in triiodothyronine (T3) and thyroxine (T4) with histopathological changes in the thyroid were induced by mifepristone treatment in rats (O'Connor et al, 2000).…”

Section: Discussionmentioning

confidence: 97%

“…Due to its antiprogesterone activity, it was proposed that mifepristone be used for the termination of early human pregnancy (Sitruk-Ware, 2006). In animal experiments in rats, it has been reported that mifepristone treatment induced ovulatory failure, morphological changes in the reproductive and endoits progesterone-and corticosteroid antagonistic properties (van der Schoot et al, 1987;Sánchez-Criado et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that mifepristone, selected as a test article, induced ovulatory failure and fertility impairment in rats due to its progesterone antagonistic property (van der Schoot et al, 1987;Sánchez-Criado et al, 1996;Telleria et al, 1997). The present study was designed to determine whether a 2-or 4-week administration period repeated-dose toxicity study to compare potential ovarian toxicity with female reproductive function in a fertility study.…”

Section: Introductionmentioning

confidence: 94%

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Collaborative work on evaluation of ovarian toxicity 2) Two- or four-week repeated dose studies and fertility study of mifepristone in female rats

et al. 2009

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-In order to assess ovarian pathological changes and their relationship to changes in female fertility parameters, mifepristone, a progesterone receptor antagonist, was selected as the test article and was administered orally to female rats at dose levels of 0, 0.8, 4, 20 and 100 mg/kg for 2 or 4 weeks in repeated dose-toxicity studies and in a female fertility study at dose levels of 0, 0.8, 4 and 20 mg/kg from > 2 weeks before copulation to postcoital day 7. In the repeated dose toxicity studies, persistent estrus was seen in the vaginal smears, and multiple cysts in the ovaries at necropsy, increases in luteinized cysts and hypertrophy of previously formed corpora lutea were observed in the histopathological examination of ovaries in rats receiving 20 mg/kg or more for 2 or 4 weeks. In female fertility studies, persistent vaginal the animals were completely infertile when dosed with 20 mg/kg during the post-coital period. An increase in pre-implantation losses was observed in the animals treated with 20 mg/kg during the pre-coital phase, while treatment with 4 mg/kg mifepristone during the post-coital phase induced an increase in post-implan-

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“…The progesterone receptor (PR) is a member of the nuclear receptor transcription factor superfamily (4). PR signaling is required for progesterone-mediated effects on ovulation, because the PR antagonist RU486 blocks ovulation in rats (5) and mice (6), and because the anti-progestogen Org-31710 blocks ovulation of in vitro cultured mouse follicles (7). In the rat ovary, PR mRNA is induced rapidly and only briefly by the surge of luteinizing hormone (LH); this induction occurs selectively in granulosa cells of preovulatory follicles destined to ovulate (8).…”

mentioning

confidence: 99%

Progesterone-regulated genes in the ovulation process: ADAMTS-1 and cathepsin L proteases

Robker

Russell

Espey

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

482

369

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Ovulation is a precisely timed process by which a mature oocyte is released from an ovarian follicle. This process is initiated by the pituitary surge of luteinizing hormone (LH), is temporally associated with transcriptional regulation of numerous genes, and is presumed to involve the synthesis and͞or activation of specific proteases that degrade the follicle wall. The progesterone receptor (PR), a nuclear receptor transcription factor, is induced in granulosa cells of preovulatory follicles in response to the LH surge and has been shown to be essential for ovulation, because mice lacking PR fail to ovulate and are infertile. Using these mice as a model in which to elucidate PR-regulated genes in the ovulation process, we show that the matrix metalloproteinases MMP-2 and MMP-9 are not targets of PR during ovulation. In contrast, two other proteases, ADAMTS-1 (A disintegrin and metalloproteinase with thrombospondin-like motifs) and cathepsin L (a lysosomal cysteine protease), are transcriptional targets of PR action. ADAMTS-1 is induced after LH stimulation in granulosa cells of preovulatory follicles and depends on PR. Cathepsin L is induced in granulosa cells of growing follicles by follicle-stimulating hormone, but the highest levels of cathepsin L mRNA occur in preovulatory follicles in response to LH in a PR-dependent manner. The identification of two regulated proteases in the ovary, together with their abnormal expression in anovulatory PR knockout mice, suggests that each plays a critical role in follicular rupture and represents a major advance in our understanding of the proteolytic events that control ovulation.

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Effects of the Progesterone Antagonist RU486 on Ovarian Activity in the Rat*

Cited by 68 publications

References 14 publications

Antitumor activity of the antiprogestins ZK 98.299 and RU 38.486 in hormone dependent rat and mouse mammary tumors: Mechanistic studies

Antitumor activity of the antiprogestins ZK 98.299 and RU 38.486 in hormone dependent rat and mouse mammary tumors: Mechanistic studies

Collaborative work on evaluation of ovarian toxicity 2) Two- or four-week repeated dose studies and fertility study of mifepristone in female rats

Progesterone-regulated genes in the ovulation process: ADAMTS-1 and cathepsin L proteases

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