Clinical Applications of Mifepristone (RU486) and Other Antiprogestins Assessing the Science and Recommending a Research Agenda (1993) / Chapter Skim
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B11. Primate Models for the Study of Antiprogestins in Reproductive Medicine
B11. Primate Models for the Study of Antiprogestins in Reproductive Medicine
Pages 243-252
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From page 243... ...
President, The Jones institute for Reproductive Medicine Department of Obstetrics and Gynecology, Eastern Virginia Meclical School PART I: ACTIVITY EXPRESSIONS OF ANTIPROGESTINS Progesterone Antagonists The new class of hormonal compounds called antiprogestins are so named because, whether they are steroids or nonsteroids, they bind to the progesterone receptor, thereby competitively inhibiting the binding of progesterone itself (Figure Bll.l)
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From page 244... ...
. However, since such antiproliferative actions do not arise through competitive binding of antiprogestins to the estrogen receptor (apparently postreceptor binding mechanisms intervene)
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From page 245... ...
For example, although more than 400 chemical structures of antiprogestins have been devised, and many patented as unique chemical entities, the biological data base from which the above remarks derive largely reflects research on only two antiprogestins. Of the almost 1000 scientific manuscripts and abstracts worldwide, perhaps as much as two-thirds of these reports are on the Roussel-Uclaf (Paris)
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From page 246... ...
3 Values ~ SD ~tid B~d E~d ~d lepbm J~pl~ bit net rid' no ll,ullOL Pn~e 221l1dOL RW86 KIWI RU 486 ~ 4Bod'~ 4~ 4~ Total Bum Nucleu Payroll FIGURE B11.5 Endometrial estradiol-receptor concentrations measured after different treatment regimens (estradiol implants versus estradiol implants plus 11 ,u~M progesterone, orestradiol implants plus 2.2 ,uM or 11 ,uM mifepristone)
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From page 247... ...
Initial Evidence of Noncompetitive Antiestrogenic Activity of Mifepristone In previous studies, mifepristone administration arrested spontaneous folliculogenesis (van Uem et al., 1989~. To investigate the central versus peripheral effects of mifepristone on the ovarian menstrual cycle, including endometrial proliferation, mifepristone was administered daily [10 mg/lcg per day, intramuscular (IM)
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From page 248... ...
Whereas endometrial biopsies performed on cycle day 25 in control monkeys revealed an in-phase mature secretory endometrium, histologic sections from mifepristone plus hMG/hCGtreated females uniformly demonstrated atrophic to weakly proliferative endometrium on cycle day 25. This was despite serum estradiol levels of >300 pa/ml during hMG/hCG treatment (Figure B11.6~.
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From page 249... ...
It elicited a persistent retardation of early proliferative endometrium when administered daily beginning in early or midfollicular phase. The normal mitogenic effects of elevated ovarian estrogen secretion on endometrial tissue were quelled, which uniformly resulted in amenorrhea (Figure B11.3~.
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From page 251... ...
E2 per gram of protein; the nuclear binding portion was about 17 percent. Scatchard plot analysis indicated that the Kit app of the estrogen receptor (1.04 x 1O-9 M)
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From page 252... ...
Uterine estrogen receptors are increased by RU 486 in late pregnant rhesus macaques but not after spontaneous labor. Journal of Clinical Endocrinology and Metabolism 70:181-186, 1990.
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