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PubMed1985

[Studies of progestin specific binding protein in the human prostate. [III]; Sodium molybdate effect on SDG analysis].

The effect of sodium molybdate on the specific binding protein (SBP) of synthetic progestin 17 alpha-methyl-[3H]-promegestone (R5020) in the cytosol of the human prostate was studied. In a sucrose density gradient analysis, two R5020 SBP components at 4S and 7-8S were observed. It was apparent that the 4S component was reduced and the 7-8S component increased with the addition of 10mM sodium molybdate into the cytosol. Therefore, the molybdate enhancement degree on total SBP amount (4S plus 7-8S) was decided by the relationship between the decreasing rate at 4S and the increasing one at 7-8S. It was shown that the molybdate effect was time-dependent and was not related to the SBP state, whether it was bounded with steroid or not. Moreover, it was estimated that the molybdate effect was not related to phosphatase inhibition since R5020 SBP in SDG was not enhanced by the addition of sodium fluoride which was a phosphatase inhibitor. In this report, the possibility of the existence of the 7-8S forming factor in the human prostate and the relationship between it and sodium molybdate was also discussed through an experiment on a Sephadex G-25.

Carrier Proteins↗
PubMed1987

[Effects of estrogen and endocrine therapeutic agents on the estrogen receptor, progesterone receptor and DNA synthesis in MCF-7 human breast cancer cells using the whole cell uptake method].

In order to investigate the mechanisms of the endocrine therapeutic agents and the applicability of combined endocrine therapies for breast cancers, we studied the effects of estrogen and the endocrine therapeutic agents on estrogen receptor (ER), progesterone receptor (PgR), and DNA synthesis in MCF-7 human breast cancer cells, which is known to be sensitive to estrogen. ER and PgR of MCF-7 cells were determined by whole cell uptake method. In brief, intact MCF-7 cells cultured in the multi-well plates were incubated with various concentrations of tritiated estradiol (E2) or promegestone (R5020) at 37 degrees C for 1 hour. The characteristics of the hormone binding were analyzed by Scatchard plots. MCF-7 cells had single class of ER (Kd: 2.1 +/- 0.2 X 10(-10) M, MBC: 9.0 +/- 1.5 X 10(3) sites/cell) and PgR (Kd: 7.2 +/- 1.1 X 10(-10) M, MBC: 3.1 +/- 0.5 X 10(4) sites/cell). When cultured in the presence of 10(-8) M or 10(-6) M of E2, tamoxifen (TAM), R5020 or medroxyprogesterone acetate (MPA) for 48 hrs, the numbers of binding sites of ER and PgR altered, but the affinities of either of them did not change. E2(10(-8) or 10(-6) M) increased about twice the number of PgR. Although treatment of 10(-8) M TAM, a non-steroidal antiestrogen, slightly increased the number of PgR, 10(-6) M TAM significantly decreased the number of PgR. Both of R5020 (10(-8) or 10(-6) M) and MPA (10(-8) or 10(-6) M), synthetic progestins, decreased the number of ER dose-dependently. On the other hand, E2 (10(-8) and 10(-6) M) and R5020 (10(-8) M) enhanced DNA synthesis, but 10(-6) M TAM or MPA inhibited DNA synthesis. The effects of single, sequential and coincidental treatment of these agents were compared. The sequential treatment of 10(-8) M E2 for 36 hrs and followed 10(-6) M MPA for 36 hrs ("10(-8) M E2----10(-6) M MPA") and "10(-6) M TAM----10(-6) M MPA" inhibited DNA synthesis of MCF-7 cells more efficiently than 10(-6) M TAM alone or 10(-6) M MPA alone for 72 hrs. However, "10(-6) M MPA----10(-6) M TAM" inhibited DNA synthesis less than "10(-6) M TAM----10(-6) M MPA".(ABSTRACT TRUNCATED AT 400 WORDS)

Breast Neoplasms↗
PubMed1997

Ligand specificity of uterine oestrogen and progesterone receptors in the subadult African elephant, Loxodonta africana.

The ligand specificity of progesterone and oestrogen receptors in the uteri of four nonpregnant, nonlactating African elephants, killed during routine culling in the Kruger National Park, were determined. The mean (+/-SEM) Kd values of the oestrogen (0.18 +/- 0.019 x 10(-9) mol l-1, n = 12) and progesterone (0.22 +/- 0.025 x 10(-9) mol l-1, n = 12) receptors were essentially similar when [3H]promegestone was used as radioligand in the progesterone receptor assays. However, when [3H]progesterone was used as radioligand, the progesterone receptor exhibited a significantly higher Kd value (1.03 +/- 0.132 x 10(-9) mol l-1, n = 12) than that of the oestrogen receptor. The use of the different radioligands did not significantly affect the quantitative values obtained for the progesterone receptor. Both the oestrogen and the progesterone receptors displayed a high ligand specificity. The 5 alpha-reduced metabolites of progesterone exhibited a high relative binding affinity for the progesterone receptor (5 alpha-pregnane-3,20-dione: relative binding affinity = 43%; 5 alpha-pregnane-3 alpha-ol-20-one: relative binding affinity = 20%) but the synthetic antiprogestin RU 486 did not compete successfully with progesterone in competitive binding studies. However, norethindrone (relative binding affinity = 293%) competed successfully for binding to the progesterone receptor, and may have some potential in the future development of a technique to control reproductive output in the African elephant.

Animals↗
PubMed1980

Hormones modulate the concentration of cytoplasmic progestin receptors in the brain of male ring doves (Streptopelia risoria).

A cytoplasmic progestin receptor has been characterized in the brain of castrated ring doves using an in-vitro assay that measures the binding of a synthetic progestin, [3H]17 alpha,21-dimethyl-19-nor-pregna-4,9-diene-3,20-dione(promegestone; R5020). The affinity of the receptor was similar in both the hyperstriatum and the hypothalamus (Kd approximately equal to 4 X 10(-10) mol/l). Its concentration was higher in the anterior hypothalamus-preoptic area (63 +/- 4 fmol/mg (S.E.M.) protein) than in other brain regions (posterior hypothalamus, 33 +/- 5; hyperstriatum, 28 +/- 3; midbrain, 17 +/- 4 fmol/mg protein; n = 7). Progesterone and R5020 competed well for binding but oestradiol and 5 beta-dihydrotestosterone did not. Corticosterone and, to a lesser extent, testosterone and 5 alpha-dihydrotestosterone completed for binding but much higher concentrations were required than for progestins. Injections of testosterone (200 micrograms testosterone propionate daily for 7 days) significantly increased the concentration of progestin receptors in the anterior and posterior hypothalamus without having any significant effect on other brain areas. Shorter treatment, lasting for 2 days, with testosterone propionate (200 micrograms daily), 5 alpha-dihydrotestosterone (200 micrograms daily) or oestradiol benzoate (50 micrograms daily) did not always cause this increase but seven injections of oestradiol benzoate (50 micrograms daily for 7 days) were even more effective than seven injections of testosterone propionate (200 micrograms daily for 7 days). These data suggested that the sensitivity to progesterone of the brain of the bird changes as a consequence of increases in the level of testosterone in the circulation.

Animals↗
PubMed1981

Estrogen and progestogen binding in the myometrium of the ewe. I. During the estrous cycle.

Estradiol, progesterone, estradiol binding, and promegestone (R5020, a progestogen) binding were measured in the cytoplasmic an nuclear fractions of sheep myometrium on days O (estrus), 3, 6, 9, 12 and 15 of an estrous cycle. Estradiol and the numbers of unfilled estrogen binding sites were greatest at estrus in both the cytoplasm (.33 and 7.5 pmole/mg of DNA, respectively) and nuclei (.58 and 3.9 pmoles/mg DNA) and declined to low values by days 12 and 15 of the estrous cycle. The number of R5020 binding sites was greatest in both the cytoplasm (13.5 pmoles/mg of DNA) and nuclei (4.2 pmoles/mg of DNA) on days 0 and 3 of the estrous cycle). Progesterone in the tissues peaked on day 9 in the cytoplasm (2.0 pmoles/mg of DNA) and on day 6 in nuclei (1.2 pmoles/mg of DNA). High levels of estrogen binding and estradiol in the myometrium at estrus suggest that the marked stimulation or contractions at estrus by ovarian estrogens is mediated via myometrial binding of estrogen. High levels of progesterone were found when contractile activity was known to be relatively quiescent. High levels of progestogen binding found at estrus might play a role in progesterone-induced uterine quiescence during the luteal phase of the estrous cycle.

Animals↗
PubMed1981

Estrogen and progestogen binding in the myometrium of the ewe. II. Regulation by estradiol and progesterone.

Two experiments were conducted to study the role of estradiol and progesterone in regulating steroid binding sites in sheep uterine myometrium. Exogenous estradiol increased the concentration of estradiol binding sites in nuclei and subsequently increased the total cell content of estradiol binding sites. Estradiol increased the number of progestogen binding sites (promegestone binding) and may have enhanced the translocation of progestogen binding sites to nuclei. Progesterone decreased the number of progestogen binding sites and blocked estradiol-induced increase in cytoplasmic estradiol binding sites. Progesterone did not block the estradiol-induced increase in estradiol binding sites in nuclei. Estradiol increases myometrial RNA to DNA ratios with in 24 hr of a single injection, whereas progesterone did not. Progesterone blocked the estradiol-induced increase in RNA:DNA. Estradiol apparently promotes the synthesis of both types of binding site. Progesterone, on the other hand, appears to inhibit estrogen-induced synthesis of steroid binding sites by blocking estradiol action at the nucleus. Progesterone may also decrease the number of progestogen binding site through a mechanism other than its "anti-estrogenic" action.

Animals↗
PubMed1990

Sex steroid hormone modulation of NADPH pathways in MCF-7 cells.

Hormonal modulation of glucose-6-phosphate dehydrogenase (G6PD) and of utilization pathways of NADPH generated by G6PD was studied in the MCF-7 human breast cancer cell line, using a quantitative cytochemical method. Our results show that G6PD is increased by 17 beta-estradiol (estradiol) and synthetic progestin (promegestone R5020). The synthetic antiestrogen tamoxifen has no effect on G6PD activity. When it is present in the medium with estradiol, tamoxifen can oppose the stimulatory effect of estradiol on G6PD activity. Mifepristone (RU 38486) has no effect on G6PD activity, but it inhibits the R5020 stimulation of G6PD activity. After MCF-7 pretreatment with estradiol, there is a much stronger stimulation of G6PD activity by R5020. When we studied the effect of the steroid on the two utilization pathways of NADPH generated by G6PD activity, we observed that, in the cells treated with estradiol, there is an increase in reducing equivalents generated by G6PD activity which only affects the NADPH2 pathway, and that there is cell growth stimulation. When tamoxifen is present in the medium, we found no effect on the NADPH utilization pathways, nor on cell growth. In the presence of R5020, the NADPH2 pathway activity is increased but, under our experimental conditions, there was no effect on cell growth. On the other hand, even though RU 38486 is without effect on total G6PD activity, it does cause a modification in the distribution of reducing equivalents: the NADPH2 pathway activity is decreased, while the NADPH1 pathway is stimulated.

Breast Neoplasms↗
PubMed1989

[Antiestrogens and normal human breast cell proliferation].

Steroidal (progestins) and non steroidal antiestrogens (tamoxifen and derivatives) are strong antiproliferative molecules when added to normal human breast cells in culture. The antiproliferative action of tamoxifen and 4-hydroxytamoxifen isomers is comparable to that observed in cultured breast cell lines. The progestin promegestone (R 5020) is a strong antiproliferative agent in the presence as well as in the absence of estradiol. Identically, at higher concentration the antiprogestin RU 486 slows down cell proliferation probably due to its progesterone agonist activity. Both progestins and antiprogestins stimulate 17 beta-hydroxysteroid dehydrogenase activity, a marker of progesterone receptor but only in estradiol primed cells.

17-Hydroxysteroid Dehydrogenases↗
PubMed1988

Estrogen-sensitive proliferation pattern of cloned Syrian hamster kidney tumor cells.

Estrogen-sensitive hamster kidney tumor cells H301 and their clonal derivatives were inhibited from proliferating in culture by charcoal-dextran (CD) stripped serum in a dose-dependent manner. Homologous serum was more potent an inhibitor than heterologous (human, bovine, equine) sera. Natural and synthetic estrogens failed to increase the proliferation rate of cells maintained in 2% CD Syrian hamster serum (SHS). At CDSHS concentrations above 2%, cell proliferation was significantly inhibited and estrogens completely reversed this inhibitory effect. Nonestrogenic steroids failed to overcome the serum inhibition. Two synthetic estrogens, moxestrol and 11 beta-chloromethylestradiol, were 10-fold more potent than estradiol in increasing cell proliferation yields; they were however, less potent than estradiol in inhibiting [3H]estradiol binding to intracellular estrophilins. d-Equilenin, a poor inducer of kidney tumors, was a weak estrogen in the "in culture" proliferation assay. Ethynylestradiol was highly estrogenic in culture while reports suggest that it is poor tumor inducer in the animal. Progestagens inhibit the growth of estrogen-induced kidney tumors; only promegestone partially blocked the proliferative effect of estradiol in cultures supplemented with 10% CDSHS. Charcoal-dextran stripped serum from animals bearing a diethylstillbestrol implant was as effective as the serum of untreated male hamsters in inhibiting the proliferation of B3H301 cells. These results are compatible with the following interpretations: (a) hamster serum contains a potent specific inhibitor of the proliferation of estrogen-sensitive cells (estrocolyone); (b) estrogens induce cell proliferation by neutralizing the effect of this serum-borne inhibitor; (c) the poor correlation between estrophilin binding and proliferative potency suggests no direct estrophilin involvement in the proliferative effect of estrogens on these cells; (d) the results obtained in this "in culture" model using estrogen (except ethynylestradiol) and other steroids are compatible with the results obtained in the animal; and (e) the tumorigenic process in Syrian hamster kidneys triggered by estrogens probably involves their direct interaction within these cells (shut-off effect) in addition to the neutralization of the estrocolyone.

Animals↗
PubMed1988

[Interaction of pregna-D'-pentaranes--pentacyclic derivatives of progesterone--with gestagen-binding sites of uterine cytosol].

The interaction of promegestone (R-5020), progesterone (P) and its derivatives having and additional carbocyclic D' (pregna-D'-pentrans) with progestin-binding cytosol system of the uterus was studied in different species (rabbits, rats, guinea-pigs and men). A comparative analysis of the competitive binding data for the mentioned compounds has shown interspecies differences in ligand specificity. Two types of binding sites for 3H-D'-pentran (in contrast to R-5020 and P) have been detected in rabbit uterus cytosol, both in intact and estrogenized animals. However, in rabbits, estrogenization altered the values of the apparent equilibrium constants and binding capacities. At the same time, the interaction of pentran with progestin-binding sites in guinea-pig and human uterus cytosol is nonspecific. It is suggested that the features of the interaction of 3H-D'-pentran with its binding sites in rabbit uterus cytosol may be determined by an increase in hydrophobic bond.

Animals↗
PubMed1987

[Observations on the new progestational agents].

The purpose of this article will be to present informations regarding two new progestational++ medications: nomegestrol acetate (Lutenyl), and promegestone (Surgestone) in order to make use of them in our prescription habits. We will situate them in relation to various groups of progestative medications and present their specific properties and their tolerance. Finally, we will demonstrate their role in contraception and their effectiveness in the main indications of progestative medications.

Contraceptive Agents, Female↗
PubMed1985

Photoaffinity labeling of the progesterone receptor from human endometrial carcinoma.

A nude mouse model for the growth of human endometrial carcinoma and hormonal modulation of the progesterone receptor (PR) was established previously. This study describes the effect of 17 beta-estradiol and tamoxifen (TAM) on growth rate and PR concentration in a hormonally responsive human endometrial tumor (EnCa 101) grown in this experimental system and presents the first characterization of human endometrial carcinoma PR. EnCa 101 was transplanted subcutaneously into ovariectomized, BALB/c, nu/nu athymic mice and grown under 17 beta-estradiol-stimulated, TAM-stimulated, and control conditions. Both 17 beta-estradiol and TAM increased the growth rate of EnCa 101 in nude mice, and a parallel increase in the cytosol PR concentration was observed, from 130 +/- 55 (SD) fmol/mg protein to 1,311 +/- 598 fmol/mg protein and 710 +/- 310 fmol/mg protein, respectively. PR was partially purified by phosphocellulose and DEAE cellulose chromatography, and the DEAE eluate was analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and photoaffinity labeling with [17 alpha-methyl-3H]promegestone ([3H]R5020). Two PR-negative tumors (EnCa K and EnCa V) were also examined in parallel. Coomassie blue staining of gels revealed that the protein patterns of all of the partially purified preparations from EnCa 101, EnCa K, and EnCa V were essentially identical. In contrast, photolabeling and sodium dodecyl sulfate-polyacrylamide gel electrophoresis of EnCa 101 grown in the presence of 17 beta-estradiol or TAM revealed incorporation of [3H]R5020 into proteins of molecular weight approximately 116,000 and 85,000. Labeled proteins of molecular weight 66,000, 45,000, and 35,000 were also observed. In each case, the labeling was competable with excess non-radioactive R5020. No incorporation of [3H]R5020 was observed in EnCa 101 grown in the absence of estrogen, nor was any observed in EnCa K or EnCa V.

Affinity Labels↗
PubMed1984

Estradiol and progesterone nuclear and cytosol receptors of hydrosalpinx.

Hydrosalpinx is usually associated with a low intrauterine pregnancy rate following restoration of tubal patency by microsurgery. The biochemical evaluation of pathologic tubes from 11 infertile patients showed the presence of estradiol (E2) and progesterone (P) receptors at the cytosol and nuclear levels. The binding constants (Kd) for these specific proteins for E2 and Promegestone (R5020) were of the same magnitude as observed in normal tissue. Mean levels of E2 cytosolic and nuclear receptors and cytosolic P receptors of hydrosalpinx were significantly lower than those of a normal fallopian tube (P less than 0.05). No correlation between the severity of the histologic appearance of the tissue and the subcellular distribution of receptors was observed. We conclude that the decrease in the steroid receptor population of these damaged tubes could be counted as another factor to be considered in the poor intrauterine rate of the salpingoneostomy.

Adult↗
PubMed1984

Autoradiographic study on localization of progestin target cells in the chicken testes.

Using an autoradiographic technique, the localization and concentration of progestin (P) in cell constituents of testes from the immature 25-to-70-day-old and mature 120-day-old chickens were investigated. After incubation of the frozen tissue sections with 3H-Promegestone (R5020), a synthetic P, specific radioactivity, was found in the seminiferous epithelium and interstitium in all the animals in the presence or in the absence of various non-radioactive steroids, and the intensity of radioactivity differed with age: high in 25-, 70-and 120-day-old chickens, and low in 50-day-old chickens. Estrogen treatment enhanced the intensity of radioactivity in the cells at all ages. The concentration of radioactivity was higher in the seminiferous epithelium than in the interstitial cells. In the frozen tissue sections, it was not possible to identify the kind of cell taking up the high amount of radioactivity. These results indicate that the testes from chicken during their growing stages contain cell constituents that specifically bind P.

Age Factors↗
PubMed1993

[High-dose progestational contraception: advantages].

In spite of the nearly total effectiveness of classic estrogen-progestogen oral contraception and its good overall tolerance, in a not inconsiderable number of situations yet, it is not possible to resort to it. These situations are the following: high blood pressure, hyperlipemia, diabetes, minor mastopathy, premenstrual tension either spontaneous or under estroprogestogen therapy. Macroprogestational contraception using either pregnanes (chlormadinone acetate) or nor-pregnanes, promegestone, nomegestrol acetate, can be then the right solution. Clinical and metabolic tolerance is excellent. In the occurrence of hypoestrogeny symptoms, a combination of nomegestrol acetate-estradiol 17 beta, transdermally administered, has given top results in a preliminary study.

Administration, Cutaneous↗
PubMed1990

Autoradiographic localization of progestin-concentrating cells in the brain of the zebra finch.

The production of song in passerine birds is under the control of steroid hormones, and brain regions involved in song production have been shown to contain androgen and/or estrogen receptors. Studies to date, however, have not considered the possible role of progestins in this behavior. As one approach to this question, the autoradiographic method was used to investigate the distribution of progestin-concentrating cells in the brain of the adult male zebra finch (Poephila guttata) after injection of the radiolabeled synthetic progestin [17 alpha-methyl-3H]-promegestone. In the telencephalon, identifiable groups of progestin-accumulating cells were found in the hyperstriatum dorsale, at the medial edge of the lobus parolfactorius, and in the medial septum. In the diencephalon, labeled groups of cells were found in the preoptic area, through much of the medial hypothalamus--including nucleus periventricularis magnocellularis, nucleus medialis hypothalami posterialis, and area infundibularis--and in the medial spiriform nucleus and dorsomedial thalamus. In the myelencephalon, labeled cells are described at the dorsal edge of the medulla and scattered lateral to nXII. These findings offer no support for the hypothesis that progestin acts on any of the known song regions, but do suggest areas of progestin action in the avian central nervous system outside of the known song system. Not surprisingly, these include many areas of the medial hypothalamus and other midline structures.

Animals↗
PubMed2007

Regulation of expression of the retinoic acid metabolizing enzyme CYP26A1 in uteri of ovariectomized mice after treatment with ovarian steroid hormones.

The retinoic acid (RA) synthesizing enzymes, retinaldehyde dehydrogenases (RALDH), are expressed in specific spatial and temporal patterns in uterine tissues during estrous cycle and early pregnancy in mice. Expression of RALDH1 and 2 has been shown to be induced by estrogen treatment within the uterus. In this study, we determined the influence of progesterone and 17-ss-estradiol on the uterine expression of the RA-metabolizing enzyme CYP26A1 after specific time intervals (1, 4, 24, and 48 hr after treatment of ovariectomized mice). In a following experiment, we investigated the influence of gestagen (promegestone 0.3 mg/kg body weight), estrogen (estradiol 3 microg/kg), their combination, as well as the antagonizing anti-progesterone hormone (RU 486 10 mg/kg) on the uterine expression of CYP26A1. Expression of CYP26A1 was localized using in situ hybridization and quantified using RT-PCR. CYP26A1 mRNA expression was strongly--although transiently--induced in uterine endometrial epithelial and glandular cells after administration of gestagen or the combination of gestagen + estrogen, but not by estrogen alone. These observations were confirmed by semi-quantitative RT-PCR experiments on whole uteri. Thus, we show that the expression of CYP26A1 in endometrial epithelial cells is regulated by progesterone and not significantly influenced by co-administration of estrogen. These data indicate an additional level of hormonal control of endogenous RA levels in the mouse uterus, where its synthesis would rely on estrogen-dependent expression of RALDH enzymes, whereas its active metabolism would be triggered by progesterone-induced CYP26A1 expression.

Animals↗
PubMed1992

ZK98299--a new antiprogesterone: biochemical characterization of steroid binding parameters in the calf uterine cytosol.

We have examined steroid binding characteristics of a newly synthesized antisteroid, ZK98299 [onapristone, 11 beta-(4-dimethylaminophenyl)-17 alpha-hydroxy-17 beta-(3-hydroxypropyl)- 13 alpha-methyl-4,9-gonadien-3-one], in the calf uterus cytosol and compared the nature of this interaction with the binding of progesterone receptor (PR) agonist R5020 [promegestone, 17,21-dimethylpregna-4,9-diene-3,20-dione]. In the freshly prepared cytosol, [3H]ZK98299 interacted specifically with a macromolecule: the binding was abolished in the presence of excess progestins (R5020 and progesterone) and the antiprogesterone ZK98299. The high affinity (Kd = 2.5 nM) interaction between [3H]ZK98299 and PR was temperature- and time-dependent, reaching an optimum by 2-3 h at 0 degrees C, and was facilitated by 20 mM Na2MoO4. Under nontransforming conditions, [3H]ZK98299-receptor complexes sedimented as 8 S species in 8-30% linear glycerol gradients. Upon salt or thermal transformation, there was a loss of the 8 S form, with only a small fraction of total complexes (5-7%) binding to DNA-cellulose. In contrast, transformed [3H]R5020-receptor complexes exhibited a greater extent of binding (25-55%) to DNA-cellulose. [3H]ZK98299-receptor complexes could be resolved into two ionic species over DEAE-Sephacel following incubation of the complexes at 0 or 23 degrees C. [3H]ZK98299 binding was sensitive to sulfhydryl group modification as beta-mercaptoethanol increased the extent of steroid binding. Although treatment with iodoacetamide (IA) abolished [3H]R5020 binding, there was a significant (nearly twofold) increase in the [3H]ZK98299 binding. The results of this study point to similarities and differences between the steroid binding properties of the uterine PR occupied by R5020 and ZK98299: both steroids appear to bind the same 8 S receptor but exhibit differential DNA binding and sensitivity to IA. The reported antagonist properties of ZK98299 may, therefore, be explained on the basis of a distinct receptor conformation induced by the antisteroid.

Animals↗