[Progesterone therapy of endometrial cancer].
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Endometrial Neoplasms↗
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Results for “Progesterone Congeners”
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Regression of subcutaneous lymphoma following removal of an ovarian granulosatheca cell tumor in a horse.
A 9-year-old Arabian mare was admitted for evaluation of multiple subcutaneous nodules and infertility. Fine-needle aspiration of one of the subcutaneous nodules resulted in a cytologic diagnosis of histiolymphocytic lymphoma. Palpation per rectum and transrectal ultrasonography revealed a mass associated with the left ovary. Excision of the ovarian tumor was performed, and a histopathologic diagnosis of granulosa-theca cell tumor was made. After removal of the granulosa-theca cell tumor, subcutaneous nodules regressed. The referring veterinarian reported that the nodules had also disappeared and then recurred after administration of a synthetic progestin. To further characterize the lymphoma and investigate this possible hormonal relationship, immunophenotyping and estrogen and progesterone receptor assays were performed. The subcutaneous lymphoma was classified as a T-cell rich B-cell lymphoma, results of estrogen receptor assays were negative, and results of progesterone receptor assays were positive. Clinical observations of subcutaneous lymphoma in horses indicate that the waxing and waning nature of these tumors may be associated with the estrous cycle, pregnancy, foaling, and lactation. Clinical observations and identification of progesterone receptors suggest that a relationship between serum steroid hormone concentrations, such as estrogen and progesterone, and subcutaneous lymphoma may exists.
Animals↗
Estrogen and estrogen plus progestin act directly on the mammary gland to increase proliferation in a postmenopausal mouse model.
Hormone replacement therapy (HRT) with ovarian hormones is an important therapeutic modality for postmenopausal women. However, a negative side effect of HRT is an increased risk of breast cancer. Surgical induction of menopause by ovariectomy (OVX) in mice is an experimental model that may provide insights into the effects of hormone replacement therapy on the human breast. We have developed a mouse model of early and late postmenopausal states to investigate the effects of HRT on the normal mammary gland. The purpose of this study was to determine if HRT-induced proliferation was due to the direct action of the hormones on the mammary gland, or mediated systemically by hormones or growth factors produced elsewhere in the body. Estrogen (E) or E plus the synthetic progestin, R5020, were implanted directly into the mammary glands of early (1 week post OVX) and late (5 week post OVX) postmenopausal mice instead of administration by injection. We report that responses of early and late postmenopausal mice to implanted hormones were the same as those observed previously with systemically administered hormones. Implanted E conferred an enhanced proliferative response in the late postmenopausal gland characterized morphologically by enlarged duct ends. E+R5020 implants induced similar degrees of cell proliferation in both postmenopausal states but the morphological responses differed. Ductal sidebranching was observed in early postmenopausal mice, whereas duct end enlargement was observed in late postmenopausal mice. The differences in morphological response to E+R5020 in 5 week post OVX were associated with an inability of E to induce progesterone receptors (PR) in the late postmenopausal gland. The responses of the late postmenopausal glands to E and E+P were very similar to that observed previously in immature pubertal glands in ovary-intact mice. In pubertal mice, PR cannot be induced by E unless the mammary gland is pre-treated with EGF-containing implants. Similarly, herein pre-treatment of the late postmenopausal mammary gland with EGF-containing implants restored PR induction by E. Thus, EGF may determine the sensitivity of the mammary gland to E and E+P in late postmenopause and at puberty.
Animals↗
Progestin binding by brain and pituitary cell nuclei and female rat sexual behavior.
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Animals↗
Effects of oral contraceptive steroids on pituitary prolactin secretion.
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Adult↗
STS 557, a new orally active progestin with antiprogestational and contragestational properties in rabbits.
STS 557 (17 alpha-cyanomethyl-17 beta-hydroxy-estra-4.9(10)-diene-3-one) is a potent progestin. This compound was 10 times as potent as the standard levonorgestrel as judged by the classic Clauberg-McPhail Assay. The antiprogestational response is significant when STS 557 treatment starts 2 days before progesterone administration. It does not disturb the priming activity of estradiol. This compound alone is adequate for endometrial priming. Early pregnancy is maintained in ovariectomized does. Administration on day 1 of pregnancy reduces the number of implantations. In comparison with chlormadinone acetate and d-norgestrel, only STS 557 treatment causes complete inhibition of egg fertilization.
Animals↗
Steroid-binding specificity of the progesterone receptor from rat placenta.
We have attempted to delineate some salient features of the progesterone binding site of the cytosol progesterone receptor (Rp) in rat placenta by studying the binding profile of various chemical modifications of the progesterone molecule (P). The relative competition ratio (RCR) was used to calculate the relative affinity of P and the modified ligand for receptor (Kaprog/Kainh). Cortisol exhibited no appreciable binding. Other corticoids (corticosterone, deoxycorticosterone, 11 beta-hydroxyprogesterone) had relative affinities 10-30-fold lower than P. Alterations in the structure of P which caused extensive declines in relative binding affinity (i.e. greater than or equal to 100-fold) include: reduction of A-ring to the 5 alpha-stereoisomere (A/B trans), introduction of a 17 alpha-hydroxyl group greater than removal of C17 side chain greater than reduction of C20 carbonyl. The binding profile of the rat placental Rp was similar to that described for uterine Rp from other species indicating a high degree of conservation of molecular structure for the progesterone receptor binding site from species to species.
Adrenal Cortex Hormones↗
Progesterone receptor in the rat anterior pituitary: effect of estrogen priming and adrenalectomy.
The present study was done to determine if a progesterone receptor is present in rat pituitary. Cytosol was labeled with 3H-progesterone (3HP) or 3H-R5020 (3HR) and subjected to sucrose-glycerol density-gradient centrifugation. Serum progesterone was measured for correlation with progesterone receptor levels. Two 3HP-binding peaks (4S + 6S) were evident in uterine and pituitary cytosols. The 4S peak was eliminated by competition with unlabeled cortisol leaving a single 6S peak (progesterone receptor). Estradiol (E) priming of the male or female rat increased progesterone receptor levels in pituitary cytosol as demonstrated using 3HP and 3HR, and pituitary progesterone receptor bound 3HR with a higher affinity than 3HP. Following adrenalectomy of gonadectomized rats, progesterone receptor levels were increased in pituitary and uterine cytosol of both E-primed and unprimed groups. An inverse relationship was established between serum progesterone and progesterone receptor levels in the uterus and pituitary suggesting that stress-induced adrenal progesterone secretion significantly influences progesterone receptor levels in the rat. These results demonstrate an estrogen-inducible progesterone receptor in the rat pituitary with properties similar to those of the uterine progesterone receptor.
Adrenalectomy↗
Interaction of [3H]nomegestrol acetate with cytosolic progesterone receptors from the rat uterus.
The binding characteristics of the progestin 17 alpha-acetoxy-6-methyl-19-[3H]norpregna-4,6-diene-3,20-dione, nomegestrol acetate ([3H]NOM-Ac) to progesterone receptors (PgRs) of uterus were determined in the rat. Scatchard plot analysis of the equilibrium binding data showed that [3H]NOM-Ac binds to uterine PgR with a Kd of 5.44 +/- 1.27 nM and a Bmax of 1.51 +/- 0.11 pmol/mg protein. Analysis of dissociation kinetics showed that [3H]NOM-Ac dissociates slowly from the PgR, k - 1 = 4.9 +/- 0.5 10(-5) s-1. Competition experiments against [3H]NOM-Ac showed the specificity of the binding with a sequence in relative affinity as follows: ORG 2058 greater than P greater than NOM-Ac greater than medroxyprogesterone acetate greater than megestrol acetate greater than cyproterone acetone greater than NOM.
Animals↗
Differences in the association of the progesterone receptor ligated by antiprogestin RU38486 or progestin ORG 2058 to chromatin components.
We assessed the hypothesis that due to variations in the conformation of the progesterone receptor induced by the antiprogestin RU38486 compared to the progestin ORG 2058, differences may result in the association of the receptor with some of the chromatin components. The physical properties of the receptor-bound chromatin fragments released by micrococcal nuclease digestion were characterized by sucrose gradient sedimentation and by gel filtration on Agarose A-1.5m or Agarose A-5m columns. The nuclear fraction was isolated from T47D cells previously exposed to 0.1 microM [3H]RU38486 or 0.1 microM [3H]ORG 2058. Micrococcal nuclease digestion solubilized two receptor forms sedimenting at 4.4 S and 6.3 S for the antiprogestin bound receptor and only one receptor at 4.4 S for the progestin ligated receptor. High-salt buffer dissociated either the antiprogestin or the progestin-bound receptor to smaller receptor forms sedimenting at 3.5 S. Chemical cross-linking with the cross-linker 2-iminothiolane of the micrococcal nuclease solubilized receptor forms resulted in 6.7-S and 4.4-S forms sedimenting on 0.4 M KCl gradients for the antiprogestin and progestin ligated receptors, respectively. Stokes radii of 7.3 nm and 6.4 nm were determined by gel filtration in 0.4 M KCl for the 6.7-S and the 4.4-S receptor forms, respectively. Using the sedimentation coefficient and the Stokes radius, molecular weights of 202,000 and 116,000 were calculated for the antiprogestin and progestin ligated receptors. We conclude that the micrococcal nuclease solubilized antiprogestin ligated receptor is associated with additional or different chromatin components compared to the progestin bound receptor.
Cell Line↗
Regulation of cytosol and nuclear progesterone receptors in rabbit uterus by estrogen, antiestrogen and progesterone administration.
A synthetic progestin, 16 alpha-ethyl-21-hydroxy-19-nor-4-pregnene-3,20-dione (ORG 2058), was utilized to measure progesterone receptors from the rabbit uterus. This steroid has a high affinity for both cytosol and nuclear receptors, with KD values of 1.2 nM (at 0--4 degrees C) and 2.3 nM (at 15 degrees C), respectively. Administration of estradiol-17 beta or a non-steroidal antiestrogen, tamoxifen, for 5 days to estrous rabbits led to a progressive rise in the cytosol receptor levels: from 34,000 to 120,000 (estradiol-17 beta) and 80,000 (tamoxifen) receptors/cell, without any major influence on the nuclear receptor content. A single intravenous injection of progesterone (5 mg/kg) elicited a 3-fold increase in the mean nuclear receptor content at 30 min after injection (from 18,000 to 48,000 receptors/nucleus). Nuclear receptor accumulation was short-lived and returned to control levels within 4 h after treatment. A second dose of progesterone given 24 h later doubled the nuclear receptor level (from 18,000 to 35,000 receptors/nucleus). The concomitant decline in the cytosol receptor content was twice that accounted for by the nuclear receptor accumulation (70,000 vs. 30,000, and 40,000 vs. 17,000 receptors/cell, after the first and second progesterone injection, respectively). Following progesterone administration, the cytosol receptor level reached a nadir by 30 min, exhibited minimal replenishment within the ensuing 24 h, and remained at approx. 50% of the pretreatment values. After a single dose or two consecutive doses of progesterone, total uterine progesterone receptor content declined to about 60% of the level prior to each dose, a nadir being reached at 2 h after treatment.
Animals↗
Inhibition by nomegestrol acetate and other synthetic progestins on proliferation and progesterone receptor content of T47-D human breast cancer cells.
Progesterone receptors (PgR) of human breast cancer T47-D cells grown in an estrogenic environment (presence of phenol red, natural estrogens of foetal calf serum and insulin) were found to be present in considerable amounts (1-3 pmol/mg protein and 20 pmol/mg DNA), and to specifically bind progestins with a high affinity characterized by a Kd around 3 nM for ORG2058, and 4 nM for nomegestrol acetate (NOM; 17 alpha-acetoxy-6-methyl-19-nor-pregna-4,6-diene-3, 20-dione), when measured under equilibrium conditions. Both compounds formed an highly stable ligand-receptor complex with a dissociation constant (k-1) around 1 x 10(-5) s-1. At high pharmacological concentrations, NOM, ORG2058 and other synthetic progestins including promegestone (R5020), medroxy-progesterone acetate and norethindrone acetate (NOR), induced a dose-dependent inhibition of cell proliferation as measured by [3H]thymidine incorporation. Dexamethasone, which did not bind to PgR, did not reproduce this inhibitory effect. NOM, R5020 and NOR treatments of T47-D cells at concentrations around Kd resulted in an 80% decrease in PgR content. Our data on NOM as compared to other progestins are consistent with their antiproliferative effects on human breast cancer cells grown in estrogenic conditions.
Breast Neoplasms↗
Reptilian (Chrysemys picta) hepatic progesterone receptors: relationship to plasma steroids and the vitellogenic cycle.
In non-mammals, estrogen-induced yolk precursors produced by the adult female liver are the main nutritional source for development. Evidence exists that progesterone exerts counter-regulatory effects on estrogen-induced vitellogenesis, and we have used the turtle model (Chrysemys picta) to study changes in hepatic progesterone receptor during the vitellogenic cycle. Using radioligand methods, we show that high and lower affinity binding sites are present in the cytosolic but not nuclear extracts. The lower affinity site is detectable at all times of the year; the high affinity site is mainly observed during non-vitellogenic periods and does not correlate with plasma estrogen. DNA-cellulose chromatography shows that PR-A is present in spring, summer, and winter, and that PR-B is down-regulated except in animals which recently laid eggs. Western blots confirm the presence of PR in all months, but PR-A (88 kDa) is the dominant isoform. PR-B (125 kDa) is well correlated with the luteal phase, winter and fall. Immunocytochemical studies show that PR is nuclear in location, and nuclear heat shock protein 90 (hsp90) is present. Competitive binding studies of both sites reveal that progesterone is the most effective ligand for both, followed by pregnenolone, deoxycorticosterone, and R5020. RU 486 does not bind to the high affinity site but binds moderately well to the lower affinity site. This study suggests that progesterone receptor isoforms are differentially expressed and may be involved as transcriptional regulators of hepatic function outside the periods of active vitellogenesis in the turtle.
Animals↗
Sex steroid receptor expression in the oviduct and uterus of sheep with estrus synchronized with progestagen or prostaglandin analogues.
The objective of this study was to investigate differences in the expression of estrogen receptor-alpha (ERalpha), progesterone receptor (PR) and the proliferative indexes (Ki-67), in the uterus and oviduct of sheep with estrus synchronized either by prostaglandin analogues (Group PA, n=27) or by treatment with progestagens (Group P, n=29) on days 4 and 7 (day 0=estrus), when the embryos were collected. Immunohistochemical methods were used to quantify ERalpha, PR and Ki-67 in six superficial and deep compartments in the uterus and oviduct. The expression of ERalpha was significantly (P<0.01) lower in progestagen treated ewes than in prostaglandin analogues treated group in the luminal epithelium, superficial glands and superficial stroma in the uterus on day 4. The expression of PR was significantly lower in progesterone treated ewes than in the PA Group in the superficial gland (P<0.05) in both days studied. The lowest expression of PR was observed in the luminal caruncular epithelium and superficial glands in both treatments, obtaining the lowest levels on day 4 (P<0.05). There were significant differences between days 4 and 7 in the Ki-67 immunostaining in the luminal epithelium (P<0.01) and superficial glands (P<0.05). A higher cell proliferation was observed in the uterine epithelium (P<0.05) on day 4 in the animals treated with progestagens. Results indicate that sheep with synchronization of estrus with progestagens showed a reduction of ERalpha and PR protein expression in most of oviductal and uterine cells.
Animals↗
Calcyclin gene expression modulation by medroxyprogesterone acetate.
Calcyclin is a cell-cycle-related gene corresponding to a calcium-binding protein whose expression is mainly controlled by platelet-derived growth factor. This paper illustrates medroxyprogesterone acetate (MPA) inhibition of endogenous calcyclin RNA expression of both estrogen-dependent human mammary carcinoma cells and estrogen-independent hamster fibroblasts. Transfection of fragments of the calcyclin promoter driving the chloramphenicol-acetyl-transferase (CAT) gene into hamster fibroblasts was used to evaluate the hormone sensitivity of different promoter regions by considering calcyclin expression at both the RNA and protein level, as evaluated by the CAT assay. A 164 bp promoter fragment showed a good activity that was inhibited by MPA, thereby confirming the results of the observation of endogenous calcyclin gene: smaller fragments, however, required cotransfection of progestin receptor to show full activity, with MPA displaying a stimulatory effect. These findings show that progestin modulation of calcyclin gene expression may be independent of progestin receptors, and that MPA has opposite effects on different promoter regions.
Animals↗
Oestrogen-replacement therapy.
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Carcinogens↗
o,p'-DDT and its metabolites inhibit progesterone-dependent responses in yeast and human cells.
Using a combination of in vitro assays we have evaluated whether DDT metabolites can interact with the progesterone receptor pathway in yeast expressing human progesterone receptor (hPR) and in T47D human breast cancer cells which express endogenous hPR. In transactivation assays using both yeast and T47D cells, o,p'-DDT and the metabolites p,p'-DDT, o,p'-DDD, p,p'-DDD, o,p'-DDE, p,p'-DDE, p,p'-DDA, and DDOH inhibited progesterone-induced reporter gene activity in a dose-dependent manner. None of the DDT metabolites functioned as hPR agonists. Whole cell competition binding assays using T47D cells indicated that the inhibitory effects of DDT metabolites on progesterone-dependent activites may occur through both hPR-dependent and hPR-independent pathways. Our results and previous reports of DDT metabolites interacting with estrogen and androgen receptors suggests that this class of environmental chemicals may interact with numerous hormone receptor signaling pathways.
Binding, Competitive↗
Characterization of ligand binding, DNA binding and phosphorylation of progesterone receptor by two novel progesterone receptor antagonist ligands.
In order to gain a better understanding of the distinctive mechanisms of the various types of antiprogestins, we have characterized in vitro ligand binding, specific DNA binding and phosphorylation of progesterone receptor (PR) from T47D cells after treatment of cells with progestins (progesterone, R5020) and antiprogestins (RU486, ZK98299, Org 31806 and Org 31710). Treatment of the cells with R5020 or PR antagonists, with the exception of ZK98299, resulted in a quantitative upshift of PR-A and PR-B indicative of ligand/DNA-induced phosphorylation of PR. Treatment of cells with RU486, Org 31710 or Org 31806, but not R5020 or ZK98299 resulted in detectable PR-progesterone response element complexes (PR-PREc) as assessed by gel mobility shift assay. Although treatment of cells with ZK98299, a type I PR antagonist, did not induce phosphorylation, the antiprogestins, Org 31806 and Org 31710, in a manner identical to RU486, did. Our data suggest that Org 31806 and Org 31710 affect properties of PR from T47D cells that are similar to RU486.
Binding, Competitive↗