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At least 19 recordsLinked to original sources
PubMed1992

Double-blind trial of promegestone (R 5020) and lynestrenol in the treatment of benign breast disease.

One hundred thirty-two women between the ages of 19 and 50, with various forms of benign breast diseases received 1 mg promegestone, or 0.5 mg promegestone, or 10 mg lynestrenol daily (double-blind), for 15 days per cycle, during three cycles. The groups were identical before treatment, with the exception of a longer history of mastodynia and mastopathies in the 1 mg promegestone group than in the lynestrenol group (P = 0.04) and a greater proportion of mastosis zones in the lynestrenol group as compared to the 0.500 mg promegestone group (P = 0.05). The effectiveness of lynestrenol both in terms of symptomatology (evaluated as good or excellent in 66.6% of the cases) and of clinical observations (evaluated as good or excellent in 59% of the cases) is not significantly different statistically from that of promegestone at 1 mg, whose effectiveness on symptomatology was good or excellent in 65.9% and 57.1% of the cases, respectively, or from that of promegestone at 0.5 mg/day (with 65% and 51.3% effectiveness, respectively). Clinical tolerance was rated good or excellent for 73.9% of the women on 1 mg promegestone and for 59.5% of the women on 0.500 mg promegestone, compared to 66.7% of the women on lynestrenol. No statistically significant difference was observed, neither between lynestrenol and promegestone 1 mg nor between lynestrenol and promegestone 0.5 mg. This study shows a clear improvement in functional and physical signs in patients treated with promegestone. Promegestone's efficacy is close to that of lynestrenol, a nonsteroidal progestin.2+ off

Adult↗
PubMed1992

Progesterone and promegestone stimulate human bone cell proliferation and insulin-like growth factor-2 production.

Recent clinical studies suggest that progesterone may be involved in the regulation of bone turnover and could promote bone formation. This study was undertaken to evaluate whether progesterone and promegestone (a 19 nor-PG derivative) may have a direct effect on human bone cells and, if so, whether growth factor production could be involved in promoting this effect. The osteosarcoma cell line TE85 and untransformed normal human osteoblastic cells derived from iliac crest were used as in vitro model systems. Progesterone and promegestone were found to significantly increase [3H]thymidine incorporation in TE85 cells in a dose-dependent manner at concentrations ranging from 10(-12) to 10(-8) mol/l after four days of cultivation (p less than 0.01, ANOVA). Consistent with this response in the TE85 cells, progesterone and promegestone increased cell number in human osteoblastic cells after six days of treatment (p less than 0.05, ANOVA). To determine whether this effect on cell proliferation was mediated by the insulin-like growth factor (IGF) regulatory system, the levels of IGF-1, IGF-2 and IGF binding protein (IGFBP) were measured in the conditioned media of both TE85 and human osteoblast cells. While no significant changes in IGF-1 levels were found in the conditioned media of progesterone and promegestone treated cultures, progesterone and promegestone at the concentration of 5 nmol/l significantly increased IGF-2 levels 2.4 and 1.5-fold respectively, at 48 h in the conditioned medium of TE85 cells as compared to control. Similarly, a 4.1 and 1.9-fold increase in IGF-2 levels was found upon treatment with progesterone and promegestone in human osteoblastic cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Bone and Bones↗
PubMed1982

Saturable binding of [3H]-promegestone in sheep liver cytosol is not to receptors for progesterone or glucocorticoids.

Saturable, high affinity binding of [3H]-promegestone has been observed in sheep liver cytosol. In two tissues specimens the Kd values were 5.9 and 6.3 nmol/l, and the concentrations of binding sites were 84.5 and 66.2 pmol/g wet tissue respectively. The synthetic steroids methyltrienolone and ORG 2058 were capable of some degree of competition. Progesterone was a weak competitor; cortisol, dexamethasone and testosterone were ineffective. Bound promegestone in liver cytosol was taken up by liver nuclei, but not by sheep uterine nuclei. These promegestone-binding sites are neither progesterone or glucocorticoid receptors.

Animals↗
PubMed1986

Interactions of oestradiol benzoate and promegestone upon basal and TRH-induced prolactin secretion in postmenopausal women.

The interactions of ovarian steroids with PRL secretion in women are still controversial. Ten healthy postmenopausal women, on no medication, received during the first period of 2 months later in a cross-over design study, i.m. injections of 0.625 mg of oestradiol benzoate (EB) alone for 10 d or in combination with 750 micrograms/d of a pure progestin promegestone for 10 d. A TRH (200 micrograms i.v.) stimulation test was performed before the start and at the completion of each treatment period. Basal plasma gonadotrophins, PRL and oestradiol were measured every day by radioimmunoassay. The EB-induced rise in oestradiol levels was similar during the two periods. In response to EB treatment serum PRL levels increased from 6.1 +/- 0.9 ng/ml to 22.9 +/- 3.4 ng/ml. With the addition of promegestone, the increase in PRL, from 6.7 +/- 1.3 ng/ml to 13.8 +/- 2.5 ng/ml, was significantly diminished (P less than 0.001). The PRL release induced by TRH was significantly greater with EB treatment than was the response with the combined treatment (P less than 0.05, Wilcoxon test to compare the areas under the curves). These data suggest that in postmenopausal women oestrogens act as stimulators of PRL release and promegestone is able to partially counteract the stimulatory effect of oestradiol benzoate upon basal and TRH-stimulated PRL secretion.

Drug Interactions↗
PubMed1986

Effect of 16 beta-ethyl-17 beta-hydroxy-4-estren-3-one (TSAA-291) on the binding of promegestone (R5020) and methyltrienolone (R1881) to hyperplastic and neoplastic human prostate.

The effect of a synthetic steroidal compound TSAA-291 (16 beta-ethyl-17 beta-hydroxy-4-estren-3-one) on the binding of methyltrienolone (R1881) and promegestone (R5020) to hyperplastic and neoplastic human prostate was investigated. TSAA-291 inhibits both androgen and progestogen binding to hyperplastic and neoplastic human prostate. Glycerol density gradient analysis revealed that the inhibition of promegestone (R5020) binding by TSAA-291 was significantly greater than that of methyltrienolone (R1881) in both hyperplastic and neoplastic human prostate. The nature of the inhibition was competitive as determined by Scatchard analysis and double reciprocal plots. Comparison of the Ki values for the inhibition by TSAA-291 of R1881 binding (3.2 X 10(-7) M) and of R5020 binding (2.0 X 10(-8) M) suggests that TSAA-291 binds to progesterone receptor with a greater affinity than to androgen receptor. Our results suggest that the effectiveness of the drug in the treatment of benign hyperplasia might be due not only to its anti-androgenic properties but also due to its ability to inhibit progesterone receptor.

Binding, Competitive↗
PubMed1988

Effects of progesterone, promegestone and RU 486 on glucocorticoid receptor levels in primary cultures of mouse mammary epithelial cells.

Mammary epithelial cells isolated from midpregnant mice and cultured on collagen gels contain glucocorticoid receptors whose levels are modulated by a variety of steroids. In the absence of any added steroid to the cell culture medium, the levels of glucocorticoid receptors in the cells decline during culture, which is counteracted by the addition of a variety of glucocorticoid agonists. The effectiveness of the glucocorticoid in preventing the loss of glucocorticoid receptors is in turn counteracted by the addition of the synthetic progestin promegestone and the synthetic antiglucocorticoid RU 486. Of the two, RU 486 is the most potent in antagonizing the effect of cortisol on the GR levels. Promegestone antagonizes the effect of cortisol, too, although higher concentrations are necessary. Progesterone was without a clear effect either as a glucocorticoid agonist or an antagonist. Progesterone, however, was extensively metabolized by mammary epithelial cells in culture. Based on these observations we conclude that in mammary epithelial cells glucocorticoids positively regulate the metabolism of their own receptors and that antiglucocorticoids, such as RU 486 and progestins, can antagonize that effect.

Animals↗
PubMed1983

[Promegestone, a new progestin].

The biological activities of promegestone (R 5020), used world-wide as a radioligand for the progestin receptor, are described. Promegestone is a potent progestin devoid of androgenic side-effects and has marked anti-estrogenic activity. Its therapeutical effectiveness (0.125 mg or 0.250 mg) in luteal insufficiency has been established in a double-blind clinical trial versus dydrogesterone (10 or 20 mg) which revealed its significantly superior potency (p less than 0.001). On the basis of the pharmacological data described, its use in cancer therapy according to a sequential protocol for the treatment of hormone-dependent breast cancer and in psychiatry to palliate the psychological disorders of the premenstrual syndrome and the perimenopause seems promising.

Animals↗
PubMedDate not supplied

Effect of promegestone, tamoxifen, 4-hydroxytamoxifen and ICI 164,384 on the oestrone sulphatase activity of human breast cancer cells.

In the present study, we explored the effects on sulphatase activity by Promegestone (R-5020), Tamoxifen (TAM), 4-hydroxytamoxifen (4-OH-TAM) and ICI 164,384 in the T-47D hormone-dependent and MDA-MB-231 hormone-independent mammary cancer cell lines. Using homogenates of these cells it was observed that Promegestone has a significant effect on the inhibition of oestrone (E1) sulphatase activity. As this effect is competitive, it is suggested that there is a direct action of this compound on the enzyme. Tamoxifen has very little or no effect, 4-hydroxytamoxifen has an intermediate effect and ICI 164,384 is active in the enzyme inhibition, particularly with MDA-MB-231 cells. The present data could open new possibilities for human breast cancer treatment, as sulphatase is very active in the first step of the conversion of oestrone sulphate (E1S) to oestradiol (E2), and oestradiol is one of the principal carcinogenic factors in human hormone-dependent breast cancer.

Binding, Competitive↗
PubMed1995

Transformation of estrone and estradiol in hormone-dependent and hormone-independent human breast cancer cells. Effects of the antiestrogen ICI 164,384, danazol, and promegestone (R-5020).

Using different hormone-dependent (MCF-7, T-47D) and hormone-independent (MDA-MB-231, Hs-578S, MDA-MB-436) human breast cancer cells, the interconversion estrone (E1)<-->estradiol (E2) was explored. The data show very clearly that in the hormone-dependent cells the tendency is to form E2 after incubation with E1, whereas after incubation with E2 most of this estrogen remains unchanged. In the hormone-independent cells, in contrast most of E1 remains E1, while E2 is converted into E1. The tendency of the reductive<-->oxidative direction is supported by the analysis of estrogens in the culture medium. To explore the possible action of different drugs on the 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) activity, it was observed that the potent antiestrogen ICI 164,384 inhibits the conversion of E1 to E2, while a lesser effect is observed with Danazol and only weak inhibition is obtained with the progestagen Promegestone (R-5020). It is concluded that the orientation of 17 beta-HSD activity for the interconversion E1<-->E2 in hormone-dependent and -independent cells is related to the hormonal status of the cells.

17-Hydroxysteroid Dehydrogenases↗
PubMed1992

Effect of the progestagen R5020 (promegestone) and of progesterone on the uptake and on the transformation of estrone sulfate in the MCF-7 and T-47d human mammary cancer cells: correlation with progesterone receptor levels.

In the present study we have explored the actions of the progestagen R5020 (Promegestone: 17 alpha, 21-dimethyl-19-nor-pregna-4, 9-diene-3,20-dione) and progesterone on the uptake of [3H]estrone sulfate ([3H]E1S) and its conversion to estradiol (E2) by two hormone-dependent mammary cancer cell lines: MCF-7 and T-47D. R5020 or progesterone significantly decreased the uptake of [3H]E1 and its conversion to (E2). In the cells of the two lines, R5020 or progesterone (5 x 10(-6) M) decreased the E2 concentrations by 2-3 times in relation to the levels in untreated cells. E1S (1 x 10(-7) M) also increased expression of the progesterone receptor (PR) and both R5020 (5 x 10(-6) M) and progesterone (5 x 10(-6) M) blocked this stimulatory action of E1S in cells of both cell lines. As E2 is one of the main factors of cancerization in the breast and estrone sulfate is quantitatively the most important precursor of E2 in this tissue, the decrease of E2 by these progestagens could open new possibilities for the control of E2 in the breast cancer tissue.

Biotransformation↗
PubMed1986

Effects of estradiol and promegestone on human breast cell cultures. An ultrastructural study.

Effects of estradiol (E2) and promegestone (R 5020) were tested on primary cultures of epithelial human breast cells prepared from surgical specimens of reduction mammoplasty. Comparative morphological studies were performed by means of transmission and scanning electron microscopy in cells without any hormonal adjunction and in those previously treated with E2 or E2 + R 5020. The results were as follows: In basal medium used as control the majority of epithelial cells, although well-differentiated, remained flat with few microvilli, well-developed Golgi apparatus and rough endoplasmic reticulum, was obvious. R 5020 added with E2 increased differentiation of epithelial cells covered with scarce long and branched microvilli, but reduced the turn-over of young cells. E2 seemed to generate more active proliferation of cells. R 5020 inhibited this effect and induced a higher differentiation of mammary epithelial cells.

Breast↗
PubMed1990

Radiosequence analysis of the human progestin receptor charged with [3H]promegestone. A comparison with the glucocorticoid receptor.

Partially purified preparations of the human progestin receptor and the human and rat glucocorticoid receptor proteins were covalently charged with the synthetic progestin, [3H]promegestone, by photoaffinity labeling. After labeling, the denaturated protein was cleaved and the mixture of peptides subjected to radiosequence analysis as previously described for the rat glucocorticoid receptor protein (Carlstedt-Duke, J., Strömstedt, P.-E., Persson, B., Cederlund, E., Gustafsson, J.-A., and Jörnvall, H. (1988) J. Biol. Chem. 263, 6842-6846). The radioactivity labels identified, corresponded to Met-759 and Met-909 after photoaffinity labeling of the human progestin receptor, and Met-622 and Cys-754 after labeling of the rat glucocorticoid receptor. The residues labeled in the glucocorticoid receptor are the same as those previously reported to bind triamcinolone actonide. The corresponding residues were also labeled in the human glucocorticoid receptor. Met-759 of the progestin receptor and Met-622 of the rat glucocorticoid receptor are positioned within a segment with an overall high degree of sequence similarity and are equivalent. However, Met-909 (progestin receptor) and Cys-754 (glucocorticoid receptor) do not occur within equivalent segments of the two proteins. Thus, although the two classes of steroid hormone share a common structure within the A-ring, there are subtle differences in their interaction with the two separate receptor proteins.

Affinity Labels↗
PubMedDate not supplied

Effect of the progestagen Promegestone (R-5020) on mRNA of the oestrone sulphatase in the MCF-7 human mammary cancer cells.

Using reverse transcriptase polymerase chain reaction amplification it was possible to detect the presence of oestrogen sulphatase mRNA in different hormone-dependent (MCF-7, T-47D) and hormone-independent (MDA-MB-231, MDA-MB-468) mammary cancer cell lines. The expression of this mRNA is significantly higher in T-47D and MDA-MB-231 than in the other cell lines, and a correlation of this expression with the enzymatic activities was observed. The progestagen Promegestone (R-5020) can significantly decrease the mRNA of the sulphatase in MCF-7 cells. As this progestagen can also inhibit the enzyme itself in the same mammary cancer cell line, it is suggested that for the decrease in the sulphatase activity not only the effect on the enzyme, but also the effect on transcriptional factor(s) which express this enzyme are involved. The present data not only contribute to the knowledge of the mechanism of the sulphatase activity, but also can open new possibilities in breast cancer treatment.

Base Sequence↗
PubMed1983

Distribution of specific binding of [3H]promegestone in benign prostatic hypertrophy in regard to age, race and histological differences.

Progesterone receptors were measured in BPH tissues obtained via open prostatectomy on over thirty [30] patients. Specific receptor concentration was determined by computation of the suppressible binding from the 8S region of the glycerol density gradient (centrifuged in a vertical rotor) as described by McGuire and his colleagues. Measurable progesterone receptor concentrations were obtained from all thirty specimens. These patients were subsequently categorized on the basis of several parameters including age, race, and histology of the hyperplasia. Age and race groupings demonstrated no specific distribution pattern, however, there was a marked difference in mean receptor concentration between the histological classifications.

Aged↗
PubMed1988

Progesterone receptor quantification with radiolabeled promegestone (R 5020) in frozen sections of endometrium and breast cancer tissue.

A technique for the determination of the progesterone receptor content at sections was developed. Series of coverglass-mounted unfixed frozen sections were incubated with [3H]R5020 only, to determine total binding, or with excess unlabeled R5020, to determine non-specific binding. Ligand binding in the tissue sections was measured by liquid scintillation counting after repeated washing of the coverslips. Elution of ligand binding proteins into the incubation buffer was quantitated with the dextran-coated charcoal method. Specific ligand binding was related to the total tissue protein content which was determined on parallel, unmounted sections. Scatchard analysis showed specific saturable and high affinity (Kd = 0.01-2 nM) section-bound and soluble binding sites in cryostat sections of calf uterus, human endometrium and breast cancer samples. Ligand specificity was studied by competition of [3H]R5020 with a 100-fold excess of various steroid receptor ligands. The competition was excellent for R5020 and progesterone, negligible for estrogens and slight for androgens and corticosteroids. These binding characteristics provide evidence that with this assay progesterone receptors are determined. Exchange experiments showed that with this method total, free as well as occupied, progesterone receptors can be measured. A highly significant linear correlation, and agreement in PR status classification between assay on cytosol and sections was obtained for a series of 21 breast cancer samples. Finally, progesterone receptor analysis using cryostat sections results in the recovery of 2-3 times more PR from the same amount of tissue as compared to the use of cytosol. These results indicate that progesterone receptors can be reliably assayed with Scatchard analysis using cryostat sections, which requires less tissue than the cytosol assay. This method, which is simple and easy to perform could be of practical importance, particularly when only small tissue samples (which also have to be analyzed morphologically or histochemically) are available and when quantitative radiochemical progesterone receptor data are required for direct comparison with (immuno-) histochemical information.

Animals↗
PubMed1984

Binding of progesterone with the oviduct cytosol fraction of estrogen-primed quail (Coturnix coturnix japonica).

Progesterone-specific binding components were detected in the cytosol fraction of enlarged oviducts from estrogen (diethylstilbestrol)-primed immature Japanese quail (Coturnix coturnix japonica) females by several techniques using [3H]promegestone. The oviduct as a target tissue of progesterone is the most efficient in [3H]promegestone binding, and muscle and intestine as nontarget tissues and plasma are less efficient as expected. By using [3H]promegestone for binding, the possibility of blood contamination of the oviduct may have been eliminated with the detection of a specific binding site. The participation of protein in the steroid-binding site was inferred from the destruction of the binding component by protease, but not by RNase or DNase. The interaction with [3H]promegestone in low salt conditions has a high affinity (Kd 0.69 nM) and low capacity (the number of binding sites per milligram of protein is about 1.3 pmol). Six unlabeled steroids were tested as competitors for binding to [3H]promegestone in vitro. Progesterone-like steroids competed specifically with [3H]promegestone: progesterone congruent to promegestone greater than deoxycorticosterone greater than testosterone much greater than estradiol-17 beta greater than cortisol. These chemical properties show that the progesterone binding protein present in the oviduct of estrogen-primed quail is essentially similar to that obtained from chick oviduct. In addition, heterogeneity of the [3H]promegestone binding components was shown. The binding component was eluted as an aggregate on gel (Bio-Gel A-0.5m) column chromatography in low salt conditions which reverted to two major peaks, tentatively named I (molecular weight, about 110,000) and II (about 41,000), in the presence of high salt (0.3 M KCl). The relative amounts of the two peaks differed. It was interesting that peak II of the small component was not found in the estrogen-primed chick and was a distinctive one in quail. On the other hand, both peaks were recovered with 0.3 M KCl elution on DEAE-cellulose column chromatography. These studies suggest that this binding component may function as a biological receptor for progesterone in the estrogen-enlarged oviduct, and the problems to be solved are under examination.

Animals↗
PubMed1991

Enzyme kinetic and inhibition analyses of cytochrome P450XVII, a protein with a bifunctional catalytic site. Quantification of effective substrate concentrations at the active site and their significance for intrinsic control of the hydroxylase/lyase reaction sequence.

An enzyme kinetic analysis of the cytochrome P450XVII-dependent testicular steroid-17 alpha-hydroxylase/17,20-lyase system was performed which catalyzes simultaneously, at one active site, the formation of androstenedione from progesterone (productive pathway, coordinated performance of both hydroxylase and lyase activities) and the formation of 17 alpha-hydroxyprogesterone as the intermediate (abortive pathway, isolated performance of hydroxylase activity only). Progesterone was used as the substrate and promegestone (17 alpha, 21-dimethyl-4,9(10)-pregnadiene-3,20-dione) or estradiol as competitive inhibitors, and description of the data was based on the discrimination of those alternative routes of progesterone metabolism. The overall catalytic activity of P450XVII obeyed Michaelis-Menten kinetics (control incubations: V = 440 nM/min with 80 nM P450XVII, Km = 140 nM), and KI values amounted to 6.8 microM for promegestone and to 23.5 microM for estradiol. In contrast, analysis of the rates of both abortive and productive events yielded curvilinear Eadie-Hofstee plots. The former presented an apparent negative cooperative behavior with nh = 0.78 in the region of Kh, while the latter presented an apparent substrate inhibition behavior with the maximal rate occurring at that progesterone concentration where nh for the abortive path reached its minimum. Consequently, the ratio of productive versus abortive catalytic events decreased with increasing substrate supply, but did not reach zero. Effective substrate concentrations [S]eff with respect to either the productive or the abortive pathway were derived from Hill plots. Linearization of Eadie-Hofstee plots and parallel calculation methods using these [S]eff instead of [S] yielded V = 236 nM/min and [S]eff(0.5) = 131 nM for the abortive events and V = 217 nM/min and [S]eff(0.5) = 38 nM for the productive events. Both promegestone and estradiol were identified as competitive inhibitors of either reaction after consideration of effective progesterone concentrations. With the inhibitors, ratios of productive versus abortive events were constantly higher at a given substrate concentration than in control incubations, although neither promegestone nor estradiol affected progesterone or 17 alpha-hydroxyprogesterone accumulation in the endoplasmic reticulum membrane compartment. Rather, a linear correlation between ratios of productive versus abortive events and the overall catalytic rate as a measure of E.S complex concentration was obtained irrespective of the absence or presence of inhibitor. It was therefore concluded that promegestone and estradiol inhibit access or binding of progesterone to P450XVII, whereas the relative efficiency of androgen formation is solely dictated by the local substrate concentration being effective with respect to E.S formation. A model of P450XVII function is presented which proposes that excess substrate at the active site of the P450XVII enzyme protein hinders a certain fraction of a putative transient intermediate from being retained at the bifunctional catalytic site with the consequence that it cannot be further processed to androgen.

Animals↗