Endometrial and Pituitary Responses to the Steroidal Antiprogestin RU 486in Postmenopausal Women

Gravanis, Achille; Schaison, G; George, Mercy; Brux, J. De; Satyaswaroop, P.G.; Baulieu, Étienne Émile; Röbel, P

doi:10.1210/jcem-60-1-156

Cited by 190 publications

(38 citation statements)

References 18 publications

(16 reference statements)

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“…In our system, we found that Mifepristone has weak agonist activity, mediating PSA gene up-regulation at concentrations .10-8 M. This agonist activity was not observed by Philibert et al (1985), further suggesting that their biological tests are not as sensitive as our tissue culture system in detecting such an effect. In support of our data are reports by others showing weak agonist activity of RU486 in various systems (Gravanis et al, 1985;Gronemeyer et al, 1991;Wehle et al, 1995). It remains to be seen if the weak agonist activity of mifepristone is mediated by the androgen, glucocorticoid or the progesterone receptor.…”

Section: Discussionsupporting

confidence: 92%

Steroid hormone regulation of prostate-specific antigen gene expression in breast cancer

Zarghami

Grass²,

Diamandis³

1997

Br J Cancer

113

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Summary We have recently reported that about 30-40% of female breast tumours produce prostate-specific antigen (PSA) and that PSA production is associated with the presence of oestrogen (ER) and progesterone (PR) receptors. We have now developed a tissue culture system to study the regulation of the PSA gene in breast cancer. The breast carcinoma cell line T-47D produces PSA when stimulated by androgens, progestins and glucocorticoids/mineralocorticoids but not oestrogens. PSA mRNA appears approximately 2 h after stimulation; PSA protein appears after 4-8 h. Among 38 compounds tested, only androgens and progestins were able to stimulate PSA production at concentrations below 10-9 M. Evidence that the progesterone and androgen receptors can regulate the PSA gene independently was provided as follows: (a) the progestin norgestimate, which does not bind to the androgen receptor, up-regulates the PSA gene at concentrations as low as 10-10 M; (b) triamicinolone acetonide, which does not bind to the androgen receptor (AR) but binds to the PR, acts similarly to norgestimate; (c) the antiandrogen cyproterone acetate, which blocks the androgen receptor but has progestational activity, up-regulates the PSA gene at concentrations as low as 10-10 M; (d) the antiprogestin mifepristone completely blocks the stimulation of the specific progestin norgestimate. Our tissue culture system identified androgen -progestin agonist activities of 17a-ethinyloestradiol, the antioestrogen RU56, 187 and the antiprogestin mifepristone. Our data suggest that the expression of the PSA gene in the female breast is under the control of androgens and progestins. Our tissue culture system is a highly sensitive in vitro method for evaluating the biological activity of candidate compounds having agonist and antagonist steroid hormone activity.

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Section: Discussionsupporting

confidence: 92%

Steroid hormone regulation of prostate-specific antigen gene expression in breast cancer

Zarghami

Grass²,

Diamandis³

1997

Br J Cancer

113

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“…Such an effect could not be demonstrated in the monkey (Healy et al, 1983;Asch and Rojas, 1985). On the other hand, RU486 administered to normal women, in the mid-luteal phase of the menstrual cycle (Schaison et al, 1985) and to postmenopausal women (Gravanis et al, 1985), resulted in a decrease in mean LH levels and the disappearance of pulsatile release. It is noteworthy, however, that in women with anovulatory cycles no effect on LH could be observed (Schaison et al, 1985).…”

Section: Discussionmentioning

confidence: 99%

The effect of RU486 administered during the proliferative and secretory phase of the cycle on the bleeding pattern, hormonal parameters and the endometrium

Swahn¹,

Johannisson²,

Daniore³

et al. 1988

Human Reproduction

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Seventeen healthy women aged 24-45 years with regular menstrual periods, proven fertility and not using steroidal contraceptives or IUD were recruited for the study. The volunteers were followed during one control, one treatment and one follow-up cycle. Daily morning urine samples were obtained during the control and the treatment cycle. The samples were analysed with regard to pregnanediol glucuronide (P2-G), oestrone glucuronide (Ej-G), oestradiol (E2), progesterone (P4), LH and creatinine. During the entire 3-month study the subjects kept a record of uterine bleeding and side effects. The subjects received 50 mg RU486 daily either on cycle days 7-10 (n = 7) or on cycle days 20-23 (n = 10). An endometrial biopsy was taken on cycle day 10 in the first group and on cycle days 21-28 in the second group of patients. Treatment during the proliferative phase caused significant prolongation of the cycle length due to a delay of the oestrogen and LH surge. However, once the oestrogen concentration started to increase, the remaining part of the cycle was normal. The length of the follow-up cycle was similar to that of the control cycle. The morphology of the endometrium did not differ from control samples taken from untreated women at the same time of the cycle. All ovulating women (n = 9) treated in the mid-luteal phase started to bleed on the 3rd to 4th day of the treatment. In four of these women the bleeding was scanty and followed by a menstrual-like bleeding at expected time, while in the remaining five volunteers the treatment bleeding was heavier and not followed by a new bleeding until a month later. The duration of the secretory phase was 16.5 ±1.3 days in women with two bleeding episodes and 11.8 ± 1.9 days in women with one bleeding episode (P < 0.05). The hormonal parameters were similar in both groups up to the start of the treatment. In the patients with one bleeding episode, the treatment was associated with a reduction in progesterone concentration, while in the patients with two bleeding episodes the progesterone concentration remained elevated until the second bleeding episode. Light microscopic examination of the endometrium revealed unique changes in the endometrial morphology. The results indicate that RU486 acts mainly on the endometrium but a direct or indirect effect on the corpus luteum cannot be excluded. The age of the corpus luteum may be of importance for its susceptibility to RU486 treatment.

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“…There has been increasing interest in the development of antiprogestins for both anti-neoplastic and obstetrical applications (Cadepond et al, 1997;Gravanis et al, 1985;Rocereto et al, 2000). However, some of the progesterone antagonists can have undesired agonist-like effects that are associated with cell, tissue and species specificity.…”

mentioning

confidence: 99%

“…However, some of the progesterone antagonists can have undesired agonist-like effects that are associated with cell, tissue and species specificity. For example, RU486 has been reported to have agonist-like activities in postmenopausal women, as well as in numerous in vitro studies, under conditions in which inhibition would be expected (Gravanis et al, 1985;Meyer et al, 1990;Nordeen et al, 1993). The clinical consequences of the inappropriate agonist-effect of an antagonist can be grave.…”

mentioning

confidence: 99%

Demonstration of mixed properties of RU486 in progesterone receptor (PR)-transfected MDA-MB-231 cells: a model for studying the functions of progesterone analogues

Lin

et al. 2001

Br J Cancer

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Summary Progesterone antagonist RU486 (mifepristone) has been implicated for many anti-neoplastic and obstetrical applications. But the compound has demonstrated undesired agonist-like effect depending on cell, tissue and species studied. Using PR-transfected breast cancer cells MDA-MB-231, this report describes the similarities and differences between progesterone-and RU486-mediated effects on cell growth, cell differentiation and, at the molecular level, on the activation of p44/p42 MAP kinases (MAPK). Like progesterone, RU486 inhibited cells growth by arresting the cells in G0/G1 phase of the cell cycle. In contrast to progesterone that induced cell spreading, RU486 induced a multipolar, stellate morphology. RU486-treated cells showed no increase of stress fibers, nor was there any increase of focal adhesions as progesterone-treated cells did. Furthermore, despite of the fact that both compounds inhibited cell growth, RU486 significantly stimulated the activation of p44/p42 MAP kinases whereas progesterone markedly inhibited the activation. Nonetheless, the effects of RU486 were PR-mediated and RU486 was able to antagonize the effect of progesterone on cell growth and focal adhesion. In conclusion, RU486 can act not only as a progesterone antagonist, a progesterone agonist but also induced morphological and molecular changes that were distinct from progesterone-mediated effects in PR-transfected MDA-MB-231 cells. The non-progesterone-like effect of RU486 may be mediated through a pathway that is different from the progesterone-mediated pathway, or it is the result of a blockade of certain critical step(s) in the progesterone-mediated pathway. MATERIALS AND METHODS ChemicalsProgesterone was obtained from Sigma Chemical Co (St. Louis, MO USA). RU486 (mifepristone) and ZK98299 (onapristone) were from Siniwest Holdings, Inc. All tissue culture plastics and reagents were obtained from GIBCO BRL, Life Technologies, Inc. Cell cultureMDA-MB-231 cells were obtained from American Tissue Culture Collection (ATCC) in 1995 at passage 28. MDA-MB-231 cells were cloned using 96-well plates by plating 0.5 cell/well. Clone 2 (known as MDA-MB-231-CL2) was selected for transfection studies. All cells were routinely maintained in phenol-red containing Dulbecco's Modified Eagle Medium (DMEM) supplemented with 7.5% fetal calf serum (FCS), 2 mM glutamine and 40 mg/l gentamycin. TransfectionMDA-MB-231-CL2 cells were transfected with PR expression vectors hPR1 and hPR2 coding for PR isoform B and isoform A, respectively, in pSG5 plasmid (Kastner et al, 1990). Vector pBK-CMV (Stratagene) containing the neomycin-resistant gene was cotransfected with hPR1 and hPR2. Details of transfection were described previously (Lin et al, 1999). Cell growthCells (2 × 10 4 ) in their late exponential growth phase were seeded onto the 6-well plates in phenol red-free DMEM supplemented with 2 mM L-glutamine, 40 mg/l gentamycin and 5% dextran-coated charcoal (DCC)-treated FCS (Test Medium). Treatment of FCS with dextran-coated charcoal was to remove fro...

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Endometrial and Pituitary Responses to the Steroidal Antiprogestin RU 486in Postmenopausal Women

Cited by 190 publications

References 18 publications

Steroid hormone regulation of prostate-specific antigen gene expression in breast cancer

Steroid hormone regulation of prostate-specific antigen gene expression in breast cancer

The effect of RU486 administered during the proliferative and secretory phase of the cycle on the bleeding pattern, hormonal parameters and the endometrium

Demonstration of mixed properties of RU486 in progesterone receptor (PR)-transfected MDA-MB-231 cells: a model for studying the functions of progesterone analogues

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