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B12. ANtiprogestogens: Perspectives from a Global Research Program
Pages 253-277

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From page 253...
... VON HERTZEN, M.D., D.D.S. Special Programme of Research, Development and Research Training in Human Reprocluction World Health Organization, Geneva ABSTRACT Because of their unique ability to block the action of progesterone at the cellular level through binding to the progesterone receptor, antiprogestogens are proving to be one of the most significant developments in endocrinology in recent years.
From page 254...
... Progesterone receptors are found primarily, albeit not exclusively, in the organs of the female reproductive tract and in the pituitary and hypothalamus, in keeping with the hormone's central role in female reproductive physiology. Other normal Tim in which r~=tnrc h=`rm ~ A I_ ~ ~ ~ ~4 i_7 ~ &~ ~ Ha_ been demonstrated include, inter alla, the cerebral cortex, thymus, and muscle cells of uterine arteries (Savouret et al., 1990)
From page 255...
... Since then, the research of the Special Programme has been focused on examining various combination regimens of mifepristone and different prostaglandin analogues, and on determining the lowest effective doses. Concomitantly, studies have been initiated on other possible uses of mifepristone in fertility regulation, including ripening of the cervix, induction of missed menses, prevention of implantation, and post-coital contraception.
From page 256...
... 256 6~ Atom DO ^ C7 ~ '< .
From page 257...
... Greater detail about antiprogestogens in general and about the Special Programme's research with these compounds in particular can be found in our earlier reviews (Van Look and Bygdeman, 1989; Puri and Van Look, 1991; Van Look and van Hertzen, 1992a,b, 1993~. COMPOUNDS Compounds with antiprogesterone activity can be grouped into two main categories: (1)
From page 258...
... Epostane is the more potent of these two compounds; hence virtually all of the studies in primates, including the human, have been done with this inhibitor. A detailed review of these studies has been published (Van Look and Bygdeman, 1989~.
From page 259...
... Mifepristone (RU 38486, later shortened to RU 486) was produced a few months later, in April 1980 and, when tested for in vitro binding to the five classes of steroid receptors, was found to possess high affinity not only for the glucocorticoid receptor but also for the progesterone receptor, and low affinity for the androgen receptor (Philibert, 1984~.
From page 260...
... In the case of lilopristone, the more favorable antiprogestationaVantiglucocorticoid potency ratio found in animal studies did not make the compound more potent in the termination of early pregnancy in the human compared to mifepristone (Swahn et al., 1993~. The results obtained to date with mifepristone leave little doubt that antiprogestogens will make a significant impact on fertility regulation in obstetrics and gynecology and, possibly also, in other branches of medicine.
From page 261...
... 261 sages of having pure, and preferably also more potent, antiglucocorticoids.and antiprogestogens are manifold. Availability of selective glucocorticoid- and progesterone-receptor blockers will provide basic researchers with powerful tools to study the effects of selective receptor blockage at the cellular level and thus provide further insights into the mechanism of action of these compounds.
From page 262...
... and from computer modeling studies of the stereochemical complementarily of steroid hormones and cavities between base pairs in DNA (Hendry and Mahesh, 1992~. ANIMAL MODELS Identification of potential antiprogestogens generally involves, in the first instance, determination of the in vitro binding affinities of the newly synthesized compounds for the progesterone receptor and receptors of other steroid hormones.
From page 263...
... In general, the animal models used have been fairly reliable in predicting the effects of mifepristone in the human in spite of some major differences between humans and even their closest relatives, the nonhuman primates, in important areas such as the pharmacokinetics of the compound and the type of placentation. Receptor Binding Antiprogestogens have been demonstrated to bind to progesteronereceptor preparations from a variety of species including rat, rabbit, calf, marmoset, bonnet monkey, and human (for review see Van Look and Bygdeman, 1989~.
From page 264...
... Orosomucoid becomes saturated at mifepristone concentrations exceeding 2.5 ,uM (Heikinheimo et al., 1987~; drug in excess of this concentration is probably bound with low affinity to albumin, and hence is available for metabolism and extravasation into tissues (Lahteenmaki et al., 1987~. The presence of a plasma carrier protein in the human is the likely explanation for the divergent pharmacokinetic behavior of mifepristone between the human and other mammalian species (Deraedt et al., 1985~.
From page 265...
... led to the development of the sequential treatment regimen of mifepristone followed by prostaglandin, now used clinically in France, Great Britain, and Sweden as a nonsurgical method for early pregnancy termination (for review see, for example, Van Look and van Hertzen, 1992a)
From page 266...
... Work supported by the Special Programme has been concentrated primarily on the changes induced by antiprogestogens in three areas, namely, prostaglandin metabolism, myometrial gap junctions, and progesterone- and estrogen-receptor concentrations in decidua and trophoblast (for review see Van Look and van Hertzen, 1993~. Prostaglandin Metabolism Initial studies established that mifepristone administration resulted in an increase in the sensitivity of the uterus to exogenous prostaglandins followed by the onset of spontaneous uterine contractility, which reached a maximum level about 36~8 hours after the start of therapy (Bygdeman and Swahn, 1985; Swahn and Bygdeman, 1988~.
From page 267...
... It is of interest to note in this context that a marked leukocyte infiltration has been reported in an electron microscopy study of guinea pig cervical tissue after administration of onapristone (Hegele-Hartung et al., 1989~. The results described above on the effects of antiprogestogens on prostaglandin metabolism suggest that compounds capable of inhibiting prostaglandin catabolism such as inhibitors of the dehydrogenase enzyme could have abortifacient activity similar to antiprogestogens.
From page 268...
... Thus, compounds that affect the formation and/or function of gap junctions may prove useful to replace or complement antiprogestogens for induction of abortion and labor, and research aimed at finding such agents may prove rewarding. Estrogen and Progesterone Receptors The Special Programme has supported research on the distribution and characteristics of estrogen and progesterone receptors in decidua and trophoblast following mifepristone treatment in early pregnancy.
From page 269...
... that prolactin production and morphological decidualization in this part of the decidua are not affected by mifepristone treatment, in contrast to the decidua parietalis. Steroid binding assays on villous cytosol failed to demonstrate the presence of a specific progesterone-binding component, and immunostaining for progesterone receptor was weak in both villous and extravillous trophoblasts (Shi et al., 1993b)
From page 270...
... ) · Ectopic pregnancya · Premenstrual tensiona ObstetTics · Therapeutic pregnancy termination in second or third trimester (therapeutic abortion, intrauterine fetal death, compromised pregnancies)
From page 271...
... Potential uses of antiprogestogens in fertility regulation (Figure B12.5) are multiple and have been detailed in other papers in this report and earlier reviews (e.g., Van Look and van Hertzen, 1992a)
From page 272...
... 272 _ o~ _ _ o _ z on_ LLl ~ _ Z _ 3 ~ ~ ~ 3 ~ .
From page 273...
... Benhamou, B., Garcia, T., Lerouge, T., et al. A single amino acid that determines the sensitivity of progesterone receptors to RU 486.
From page 274...
... Studies on interactions of antiprogestins with prostaglandins and sex hormone-related agents at the myometrial level in pregnant guinea pigs. In Hormone Antagonists for Fertility Regulation.
From page 275...
... Complete amino acid sequence of the human progesterone receptor deduced from cloned cDNA. Biochemical and Biophysical Research Communications 143:740-748, 1987.
From page 276...
... Puri, C.P., and Van Look, P.F.A. Newly developed competitive progesterone antagonists for fertility control.
From page 277...
... Van Look, P.F., and von Hertzen, H Antiprogestins in fertility regulation.


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