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At least 721 records · Page 40Linked to original sources
PubMed1987

Pharmacokinetic properties of the antiglucocorticoid and antiprogesterone steroid RU 486 in man.

RU 486 (17 beta-hydroxy-11 beta-[4-dimethylamino phenyl]-17 alpha-[1-propynyl]estra-4,9-dien-3-one) is a clinically useful glucocorticoid and progesterone antagonist. The authors studied the pharmacokinetic properties of this drug in normal volunteers and patients with Cushing's syndrome using a rat progesterone radioreceptor assay. This assay gave values similar to those obtained with a rat glucocorticoid radioreceptor assay. After a single oral dose of 25 mg/kg (n = 11) or 10 mg/kg (n = 11) to normal volunteers, plasma concentrations of progesterone receptor-reactive material reached maximal levels of 754 +/- 288 (mean +/- S.D.) and 517 +/- 183 micrograms/dl. This occurred at 3.1 +/- 1.9 and 2.5 +/- 1.0 h, respectively. The respective apparent plasma half-lives were 19.2 +/- 7.0 and 20.6 +/- 7.7 h. Four patients with Cushing's syndrome treated chronically (10-20 mg/kg/day) had relatively constant plasma levels of receptor reactivity ranging from 506 to 1184 micrograms/dl. Chromatographic characterization of circulating receptor reactivity showed that the active fraction corresponded to RU 486 and its hydrophilic N-mono- and N-didemethylated metabolites. Less than 0.5% of the daily dose was excreted in the urine of two of these patients as receptor reactivity. The drug bound extensively to circulating albumin, which competed with the glucocorticoid receptor of intact human mononuclear leukocytes for [3H]RU 486 in a concentration-dependent manner.

Adult↗
PubMed1987

Fatty acid synthetase and its mRNA are induced by progestins in breast cancer cells.

The growth of hormone-dependent breast cancer cell lines (MCF7 and T47D) is inhibited in vitro by progestins which also induce several proteins. We have cloned cDNA sequences corresponding to one of them, a 250-kDa protein, and have shown that the corresponding mRNA is also rapidly induced by progestins (Chalbos D., Westley B., May F.E.B., Alibert C., and Rochefort H. (1986) Nucleic Acids Res. 14, 965-982). We show here that the 250-kDa protein is very similar, if not identical, to fatty acid synthetase: fatty acid synthetase is regulated to the same extent by progestins, the 250-kDa protein is specifically immunoprecipitated by antibodies to fatty acid synthetase, and fatty acid synthetase covalently labeled by [14C]pantothenate is immunoprecipitated by antibodies to the 250-kDa protein. The induction of fatty acid synthetase by progestin in cancer cells thus provides another model for studying the mechanism regulating steroid transcription in human cells. Since fatty acid synthetase regulation by progestins appears to be the opposite in cancer and normal mammary cells, this observation may also be a clue for understanding the role of progestins in mammary carcinogenesis.

Antibodies↗
PubMed1987

Regional sex differences in progestin receptor induction in the rat hypothalamus: effects of various doses of estradiol benzoate.

In the rat, sex differences in behavioral responsiveness to progesterone have been correlated with a sex difference in estrogen-induced progestin receptor induction in the ventromedial nucleus (VMN). It has recently been suggested that this sex difference in progestin receptor induction may only be present after treatment with large doses of estrogen. We have evaluated the sex difference in hypothalamic cytosol progestin receptor induction in gonadectomized/adrenalectomized rats treated with moderate doses of estradiol benzoate (EB; 20 micrograms/kg body weight). No sex differences were detected in cytosol progestin binding in mediobasal hypothalamus or preoptic area of animals treated with this dose 48 hr before they were killed. However, a higher level of progestin binding in the VMN of females than of males was found when these brain regions were examined using a microdissection technique. Saturation binding analysis of progestin binding in the VMN indicated that this sex difference in binding reflects a difference in the number of progestin binding sites, and not a difference in binding affinity. A dose-response study of progestin receptor induction in the medial preoptic nucleus (mPON), arcuate-median eminence region (ARC-ME), and VMN of male and female rats indicated a sex difference in cytosol progestin binding in the VMN at all EB doses tested (2, 8, 40, or 200 micrograms/kg body weight). No sex differences in cytosol progestin binding in the mPON or ARC-ME were observed at any of the tested doses. These results support the idea that the differences in behavioral sensitivity to progesterone may result in part from sex differences in the estrogen induction of progestin receptors in the VMN.

Animals↗
PubMed1987

Effects of 17 beta-estradiol and R5020 on glucose-6-phosphate dehydrogenase activity in MCF-7 human breast cancer cells: a cytochemical assay.

Although increasing levels of glucose-6-phosphate dehydrogenase (G6PD) have been widely reported in human breast tumor tissue, the effects of 17 beta-estradiol and progesterone on this key enzyme of cellular growth processes have not been well documented. Cellular heterogeneity of breast tumor tissue, coupled with the low sensitivity of classical biochemical assays of G6PD, are the main sources of difficulties in these studies. In the present report, the effects of estradiol and a progesterone analogue (R5020) on G6PD activity were studied using the MCF-7 cell line and a cytochemical assay of G6PD activity. Our results show that: (a) this assay can be used to perform quantitative measurements of G6PD on individual cells using small number of cells (20-30); and (b) both estradiol (10(-8)-10(-5) M) and R5020 (10(-9)-10(-5) M) stimulate the G6PD activity in dividing MCF-7 cells. Maximal stimulation (20-30%) was obtained after 24 h of treatment. This combination of MCF-7 cells and cytochemical assay is suitable for further studies on the effects of estradiol and R5020 stimulation of G6PD activity in breast tumors.

Breast Neoplasms↗
PubMed1986

Sex steroid receptors in transformed human cervical tissue.

Investigation of the binding affinity, the concentration and the DNA binding ability of the sex steroid receptors in transformed human cervical tissue has shown considerable changes in comparison to normal specimens. Lower level of hormone receptors and higher dissociation constants are the essential characteristics of the majority of analysed transformed tissue specimens. The DNA binding of steroid-receptor complexes is in agreement with mentionated data. These preliminary results are just one more evidence on the existence of relationship between modified properties of sex steroid receptors and different histological alterations of their target tissues. Further investigations are necessary to make some conclusion about the possible involvement of estrogen and progesterone receptors in pathological transformation of the portio vaginalis uteri.

Adenocarcinoma↗
PubMed1986

Progesterone receptor synthesis and degradation in MCF-7 human breast cancer cells as studied by dense amino acid incorporation. Evidence for a non-hormone binding receptor precursor.

We have used the technique of density labeling of proteins by biosynthetic incorporation of 2H, 13C, 15N (dense) amino acids to study the synthesis and degradation rates of the progesterone receptor in MCF-7 human breast cancer cells. In cells grown in the absence of progestin, sucrose gradient shift analyses reveal that it takes 17 h for the normal density progesterone receptor levels to be reduced to half the initial value, whereas in the presence of 10 nM of the synthetic progestin [3H]R5020, the receptor turns over more rapidly, such that the normal density R5020-occupied progesterone receptor complexes are reduced to half in 12 h. The accelerated progesterone receptor turnover in the presence of [3H]R5020 reflects increased turnover rates of both the A (Mr-85,000) and B (Mr-115,000) subunits, as determined by sodium dodecyl sulfate gel analyses of dense and light receptors photoaffinity labeled with [3H]R5020. In both control and progestin-exposed cells, the time course of progesterone receptor turnover shows a lag of approximately 6 h after dense (15N, 13C, 2H) amino acid exposure, before dense hormone binding receptor species are seen and before normal density progestin binding activity starts decreasing. Since our evaluations of progesterone receptor depend upon its binding of radiolabeled ligand ([3H]R5020), this lag in the density shift kinetics would be consistent with the presence of a non-hormone binding biosynthetic precursor, from which the hormone-binding form of progesterone receptor is derived. A kinetic model is used to analyze the lag-decay profiles and to determine the rate constants for progesterone receptor synthesis, activation to the hormone-binding form, and degradation.

Amino Acids↗
PubMed1987

Growth inhibition by progestins in a human endometrial cancer cell line with estrogen-independent progesterone receptors.

The presence of estrogen-independent progesterone receptors (PgR) was demonstrated in a subline of a human endometrial cancer cell line, Ishikawa cells, although the original Ishikawa cells contained estrogen-inducible PgR. Scatchard plot analysis of cytoplasmic binding data in our subline (IK-90) revealed a high affinity binding site for R5020 (Kd, 1.0 nM) with maximum binding sites of 158 fmol/mg protein. Competition experiments showed a binding specificity similar to that of typical PgR. By low-salt sucrose gradient centrifugation, radioactive 8S and 4S peaks were found. The addition of 1 microM progesterone in culture medium resulted in a rapid nuclear translocation of cytoplasmic PgR. In contrast to the original cells, estrogen receptors could not be detected in IK-90 cells, and an addition of 17 beta-estradiol (10 nM) to culture medium failed to increase PgR. Accumulation of glycogen in cytoplasm of IK-90 cells in response to R5020 (0.1-1 microM) was observed by periodic acid-Schiff staining. The addition of R5020 to culture medium (0.1-1 microM) also caused a marked decrease in the growth of IK-90 cells, whereas the other steroids including 17 beta-estradiol, tamoxifen, testosterone, and cortisol had no significant effects. These results demonstrate for the first time the presence of a progestin-responsive human endometrial cancer cell line that contains estrogen-independent functional PgR. IK-90 cells appear to be an ideal model for studying the mechanism of the antiproliferative effect of progestin on endometrial cancer cells.

Cell Division↗
PubMed1985

Progestin receptors in adult rat ovary during estrous cycle.

Using a synthetic progestin (P)(i.e. R5020), characteristics of P receptors were determined in the ovarian tissue cytosols from adult estradiol benzoate-treated or 4-day cycling rats. In the estradiol benzoate-treated rats a specific 3H-R5020 binding in the cytosol was found with a number of binding sites, V max = 110 fmol/mg protein and the equilibrium dissociation constant, Kd = 14 nM. In the 4-day cycling rats, specific binding was found in the 6-7 S region with the Vmax which fluctuated during the estrous cycle: the sequence of Vmax (fmol/mg protein) was 395 (proestrus) greater than 122 (diestrus) greater than 96 (late estrus) greater than 62 (metestrus) greater than 40 (early estrus). The Kd value varied during the cycle, the highest (22 nM) in proestrus and the lowest (5 nM) in early estrus. In addition, 3H-R5020 binders were thermolabile and of protein in nature. These results suggest that the rat ovary contains P receptors in its cytoplasm with high affinity and low capacity of P binding, the level of which fluctuates during the estrous cycle.

Animals↗
PubMed1985

Growth inhibition and increase of insulin receptors in antiestrogen-resistant T47DCO human breast cancer cells by progestins: implications for endocrine therapies.

There is renewed interest in the use of progestins to treat advanced breast cancer because results with these agents are comparable to those obtained with antiestrogens. However, it is not known whether progestins inhibit the growth of breast tumor cells directly and independently of estradiol. To study this, we have used T47DCO human breast cancer cells. The progesterone receptors in these cells do not require estrogen induction, and this permits study of pure progestin effects without interference by estradiol. We report here that, in the absence of estradiol, physiological concentrations of progestins directly inhibit proliferation of these cells. At the same time, progestins increase the levels of the receptors for insulin, a common cell mitogen. Ten days of treatment with 1 or 10 nM of the synthetic progestin R5020 suppresses cell growth approximately 50 to 60%. This is consistent with the concentrations that either partially (approximately 10%) or more extensively (greater than 60%) translocate cytoplasmic progesterone receptors. Even a brief 1-hr pulse of R5020 has long-term growth-inhibitory effects. Progesterone is also antiproliferative, but its effects are attenuated because, unlike R5020, it is rapidly metabolized in the medium. Other synthetic progestins also inhibit cell growth, but unrelated steroids (estradiol, androgens, glucocorticoids, 1,25-dihydroxyvitamin D3) are ineffective. While growth is suppressed by R5020, insulin receptors increase rapidly and then fall to a new, elevated steady state as the cells slowly begin to proliferate. Only progestins have this effect on insulin receptors. We conclude that the hormonal regulation of breast tumor cell growth is complex and includes progestins among the regulating factors. Furthermore, since T47Dco cells are antiestrogen-resistant and estrogen receptor-negative, the antiproliferative effects of progestins must be mediated through mechanisms that differ from the cytotoxic effects of antiestrogens. We propose that, clinically, antiestrogens and progestins may have complementary uses in breast cancer treatment, and we outline two therapeutic strategies.

17-alpha-Hydroxyprogesterone↗
PubMed1986

Characterization of estrogen and progesterone receptors and the dissociated regulation of growth and progesterone receptor stimulation by estrogen in MDA-MB-134 human breast cancer cells.

We have examined the properties of the estrogen receptor and progesterone receptor in MDA-MB-134 human breast cells and have evaluated the effects of estrogen on cell proliferation and progesterone receptor levels in these cells as indices of hormonal sensitivity. These cells contain high levels of estrogen receptor (approximately 1.5 pmol/mg DNA) and low levels of progesterone receptor (0.15 pmol/mg DNA). More than 80% of the estrogen receptor is found in the nuclear fraction in the absence of estrogen, and the Kd of the receptor for estradiol is approximately 1.5 X 10(-10) M. Upon exposure to estradiol, the receptors become occupied, but there is no processing or apparent decrease in either nuclear or total cellular estrogen receptor content, as can be seen in MCF-7 human breast cancer cells. The nuclear estrogen receptor sediments as a 4.6 S species on high salt sucrose gradients, and it can be detected on sodium dodecyl sulfate-polyacrylamide gel immunoblot analysis as a species of molecular weight 65,000, identical to that of the MCF-7 estrogen receptor, using the monoclonal antibodies D75P3 gamma and H222Sp gamma prepared against the MCF-7 estrogen receptor. The estrogen receptor shows binding selectivity for estrogens and antiestrogens, and its affinity for ligands follows the order diethylstilbestrol (190%) greater than estradiol (100%) greater than estriol (13%) greater than tamoxifen (3%), as expected for estrogen receptor. Hence the receptor appears normal in many of its physicochemical properties and in terms of its binding affinity and specificity for estrogens and antiestrogens. Control cells contain low levels of progesterone receptor that display high affinity (Kd = 6 X 10(-9) M) for the synthetic progestin R5020, but exposure to estradiol (10(-11)-10(-7)M) fails to increase cellular progesterone receptor levels. In contrast, estradiol markedly stimulates the rate of cell proliferation, while tamoxifen suppresses the growth of control and of estradiol treated cells. Hence, our data show that these cells, which contain substantial levels of estrogen receptor, respond to estrogen with enhanced cell proliferation but fail to have their progesterone receptor level modulated by estradiol. These cells represent an interesting and unusual situation in which estrogenic regulation of proliferation and the stimulation of progesterone receptor are dissociated. These cells should prove useful in further evaluation of estrogenic regulation of cell proliferation and specific protein synthesis in human breast cancer.

Antibodies, Monoclonal↗
PubMed1984

Hormone load tests in the first half of pregnancy--a diagnostic and therapeutic approach.

In view of still unsolved problems concerning disturbances in early pregnancy, the efficacy of various substances with regard to endocrine systems in the first trimester of pregnancy has been investigated. Seventy-five women, who had been referred to our hospital for an authorized termination of pregnancy during weeks 7-9 of gestation, and 6 women between weeks 10 and 16 of gestation volunteered to take part in the study. After single administration of the test substances, blood was drawn from an indwelling catheter with one group of patients at hourly intervals over an 8-hour period, while with all other patients this was done at 3-hourly intervals over a 24-hour period. In all samples beta-HCG, progesterone (P), estradiol-17 beta (E2), and 17 alpha-hydroxyprogesterone (17-OHP) were determined. The following substances were studied in detail: HCG, allylestrenol, 17-hydroxyprogesterone caproate, tamoxifene, R 5020, betamethasone, and dehydroepiandrosterone sulfate (DHAS). Two hundred and seventy-one women with imminent abortion were either treated with allylestrenol (n = 130) or simple clinotherapy and no medication (n = 141). One hundred and two women had a miscarriage, while 168 carried to term. The serum concentrations of beta-HCG, P, E2 and estriol (E3) were determined serially. Twelve women with a history of repeated miscarriages were treated with vaginal progesterone suppositories. Five of them experienced another miscarriage. The serum concentrations of beta-HCG and P were determined serially. It could be shown that diagnostics in early pregnancy have been complemented by assessment of the E2-increase after DHAS loading. Maternal serum concentrations were not affected by administration of HCG and various progestational agents including allylestrenol. Only in the case of parenteral or vaginal application of progesterone could increased serum concentrations of this hormone be demonstrated. Progesterone substitution in early pregnancy may, therefore, be chosen under special conditions as possible therapeutic procedure.

17 alpha-Hydroxyprogesterone Caproate↗
PubMed1981

[Identification and characteristics of steroid hormone receptor binding properties in the nuclear fraction of human prostatic adenoma].

Steroid receptors in adenoma nuclear fraction of the human prostate were studied. Androgen and progestin receptors were revealed in 0.4 KCl nuclear extracts. The measured association constant values were 6.05 +/- 1.45 X 10(9) M-1 and 2.08 +/- 0.37 X 10(9) M-1 for 5 alpha-dihydrotestosterone and progesterone, respectively. Only 5 alpha-dihydrotestosterone and testosterone competed markedly with 3H-5 alpha-dihydrotestosterone, hormonal specificity of 3H-progesterone binding affinity being less pronounced. Specific estradiol binding being found in several adenomas was very low. Glucocorticoid receptors were not detected.

Cell Nucleus↗
PubMed1984

Dual effects of the progestin R5020 on proteins released by the T47D human breast cancer cells.

R5020, a synthetic progestin, regulates the production of [35S]methionine-labeled proteins released into the medium by T47D human breast cancer cells in culture, as measured by trichloroacetic acid precipitation and dodecyl hydrogen sulfate sodium salt-polyacrylamide gel electrophoresis. Two contrasting responses were observed: (a) a rapid and specific accumulation in the medium of a newly synthesized protein of molecular weight 48,000 and (b) a subsequent general inhibition of the release of proteins within the first 6 days of treatment while the cell number was not altered. These responses were triggered by physiologically active concentrations of progestins (progesterone, R5020, medroxyprogesterone acetate) but not by other classes of steroids, and were not observed in a progesterone receptor negative cell line (BT20), indicating that they were mediated by the progesterone receptor. A progestin antagonist, RU38,486, inhibited the production of the 48-kilodalton released protein. The production of androgen-regulated proteins (43 kilodaltons, 18 kilodaltons) was also increased by dihydrotestosterone and higher concentrations of R5020. These results show that progestins specifically regulate the production of proteins in cell culture. Subsequently, R5020 also inhibit the growth of T47D cells in the presence of estradiol (Vignon, F., Bardon, S., Chalbos, D., and Rochefort, H. (1983) J. Clin. Endocrinol. Metab. 56, 1124-1130), suggesting that the proteins released into the medium may be related to the control of cell proliferation.

Breast Neoplasms↗
PubMedDate not supplied

Steroid receptor pattern of human colorectal neoplasms.

Twenty-four colorectal carcinomas were assayed for estrogen and progestin receptors by sucrose gradient centrifugation. Most biopsies were either completely estrogen receptor negative or displayed low titers of specific estrogen binding. Only three tumors demonstrated moderate estrogen binding activity (10-18 fmol/mg cytosol protein). In four tumors specific progestin binding exceeded 20 fmol/mg protein. Only a minor subset of the binders sedimented at 8S. Twenty-one colorectal tumors examined for the presence of glucocorticoid receptors were found to be receptor positive, without exception. Biopsies from normal colorectal mucosa displayed minute quantities of specific 8S estrogen and progestin binding, but significant titers of specific glucocorticoid binding. Our findings support the hypothesis that estrogens and progestins are unlikely to play a major role in endocrine control of colorectal neoplasms. The role of glucocorticoids in growth control of colorectal neoplasms remains to be defined.

Aged↗
PubMed1983

Assessment of structural similarities in chick oviduct progesterone receptor subunits by partial proteolysis of photoaffinity-labeled proteins.

Partial proteolytic fragmentation of the two chick oviduct progesterone receptor subunits was used to identify structural features shared by the two proteins. Both subunits can be photoaffinity labeled at their hormone-binding sites (Birnbaumer, M., Schrader, W. T., and O'Malley, B. W. (1983) J. Biol. Chem. 258, 1637-1644) using the radioactive steroid [methyl-3H] 17 alpha, 21-dimethyl-19-nor-pregn-4,9-diene-3,20-dione. Native subunits A (Mr = 79,000) and B (Mr = 108,000) were partially purified, photoaffinity-labeled, and then subjected to various mild proteolytic digestions. Labeled fragments were analyzed by fluorography after electrophoresis of the digests under denaturing conditions. Digestion patterns were characteristic for each protease tested. However, fragments from both A and B were indistinguishable for all peptides of less than Mr = 60,000. Time course studies demonstrated the sequential production of progressively smaller discrete fragments in a manner consistent with a precursor-product relationship among them and established the existence of similar structural domains resistant to proteolysis in both proteins. Autoradiographic peptide maps were obtained by 125I-labeling of pure A and B protein isolated by two-dimensional gel electrophoresis followed by exhaustive tryptic digestion and two-dimensional separation. These studies revealed that a significant proportion of the smaller A protein differs in its primary sequence from that of the B protein which excludes the possibility of their sharing a precursor-product relationship. We conclude that B and A subunits are separate proteins with common structural features in the native state, but with considerable amino acid sequence differences. The simplest hypothesis consistent with these findings is that B and A are the products of two separate genes which have diverged to give rise to two different but related proteins that fold in such a manner as to be almost indistinguishable by proteolytic attack of their native conformation.

Affinity Labels↗
PubMed1984

The rabbit progesterone receptor. Evidence for a single steroid-binding subunit and characterization of receptor mRNA.

Monoclonal antibodies were used to study the structure and the biosynthesis of the rabbit progesterone receptor. Proteins in nonfractionated uterine cytosol were submitted to gel electrophoresis in denaturing conditions, transferred onto nitrocellulose, and reacted with monoclonal antireceptor antibodies and 125I-protein A. A single 110,000-dalton protein was observed when precautions were taken during homogenization of the uteri and protease inhibitors used. Smaller forms of receptor (essentially of 79,000 daltons but also of 72,000 and in some experiments of 64,000 daltons) were present when these precautions were not observed and thus probably arose from artifactual proteolysis of receptor. When poly(A)+ RNA from rabbit uterus was translated in a reticulocyte lysate and the radioactive proteins precipitated by the antireceptor monoclonal antibodies, a radioactive protein of 110,000 daltons was also observed. Further evidence that this protein was the product of the translation of progesterone receptor mRNA was obtained by precipitation and immunoaffinity purification with several antireceptor monoclonal and polyclonal antibodies, inhibition of immunoprecipitation by purified receptor and its absence in a receptor-poor tissue (liver). Estrogen treatment is known to increase the concentration of progesterone receptor. RNA translation experiments showed that this effect is due to an increase in the concentration of receptor mRNA. The size of this messenger RNA was studied by sucrose gradient ultracentrifugation, followed by mRNA translation, and specific immunoprecipitation: progesterone receptor mRNA was found by this method to sediment at 20 S.

Animals↗