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Query: UMLS:C0432222 (SEM)
 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The estrogen receptor (ER)-positive human breast cancer cell line T 47D exhibited genetic instability under cell culture conditions which maintained almost continuous exponential growth. This resulted in the spontaneous generation of three ER-positive sublines with a range of DNA ploidies and distinctive phenotypes. One of these sublines, T 47D-5, exhibited resistance to the growth-inhibitory effects of the synthetic nonsteroidal antiestrogen tamoxifen and the synthetic progestin ORG 2058, in marked contrast to "wild type" T 47D cells (designated T 47D-7 in this study). T 47D-5 cells were cloned by limiting dilution and 11 clonal cell lines were tested for sensitivity to tamoxifen. Although all clones of T 47D-5 were significantly less sensitive than T 47D-7 cells, a spectrum of sensitivities was observed. Three clones, T 47D-5-13, T 47D-5-21, and T 47D-5-23, were further characterized by measuring the concentrations of receptors for estrogen, progesterone, growth hormone, and epidermal growth factor and responses to estradiol, tamoxifen, and progestin, in terms of both induction of specific proteins and effects on cellular proliferation. Although the T 47D-5 subline and clone T 47D-5-23 were insensitive to both the growth-stimulatory effects of estradiol and the inhibitory effects of tamoxifen, this was not related to the concentration of ER or its ability to induce progesterone receptor. Estrogen receptor levels were similar in resistant and sensitive clones of T 47D-5 [70,000-81,000 sites/cell] and were 2.5-fold greater than in the sensitive T 47D-7 line [32,600 +/- 5,000 (SEM) sites/cell]. Northern blots showed no difference in the size of ER mRNA transcripts between sensitive and resistant clones. Estradiol treatment increased progesterone receptor (PR) levels in all cell lines but the magnitude and sensitivity of this response were unrelated to growth responses indicating a divergence in estrogenic control of cellular proliferation and specific protein synthesis within these clones. T 47D-5, T 47D-5-13, T 47D-5-21, and T 47D-5-23 were all insensitive to the growth-inhibitory effects of ORG 2058. The progestin was also unable to increase lactogenic and epidermal growth factor receptor concentrations in these four lines in contrast to the response in T 47D-7 cells. The insensitivity to progestin in the T 47D-5 subline and its three clonal cell lines could be accounted for, in part, by a 75-80% reduction in PR levels when compared with T 47D-7 cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Genetic instability and the development of steroid hormone insensitivity in cultured T 47D human breast cancer cells. 339 Aug 30

The binding affinities of a series of steroidal compounds for the hamster uterine progesterone receptor were determined using two sets of incubation conditions. These competitive binding conditions were designed to deduce the relative rates of ligand dissociation from the progesterone receptor. The progestin activity of these compounds was also determined in a bioassay employing the measurement of diamine oxidase in the traumatized hamster uterus. Steroids could be classified into two categories based on either an increase or decrease in relative binding affinity (RBA) with increasing time of competitive incubation. The mean (+/- SEM) progestin biopotency for the compounds having an increase in RBA was 120 +/- 18 (progesterone = 100), while the biopotency for compounds having a decrease in RBA was only 44 +/- 17. This difference was significant (P less than 0.01). Linear regression analyses revealed significant correlations between the RBAs and progestin biopotencies. Compounds showing a decrease in RBA with increasing time of incubation did not have antiprogestin activity. Kinetic studies of this type should be useful for selecting compounds with potent agonistic activity, but cannot unequivocally predict antihormonal activity.
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PMID:Relationship between progesterone receptor binding and progestin biological activity. 392 67

We have studied the effects of estradiol injections on cytosolic estrogen, androgen and progesterone receptor levels in order to understand the role of this steroid in the induction of prostatic hyperplasia in the dog. Adult mongrel dogs were castrated and were then given injections of estradiol (0.25, 0.8 or 2.5 mg) dissolved in olive oil containing 5% benzyl alcohol on days 0, 2, 5 and 7 after castration. Steroid receptor levels were determined by Scatchard analysis using charcoal assay one day after the last injection. All three receptors were increased maximally with the 0.8 mg dosage when compared with castrated controls. Estradiol binding increased from 89 +/- 10 (mean +/- SEM) to 361 +/- 37 fmol per mg prot., androgen binding from 47 +/- 5 to 123 +/- 11 fmol per mg prot. and progesterone binding from 26 +/- 3 to 211 +/- 36 fmol per mg prot. The small dose of estradiol. (0.25 mg) produced a significant (P less than 0.05) increase of the progesterone receptor levels from 25 +/- 3 to 48 +/- 14 fmol/mg prot. Substitution of estradiol by 5 alpha-androstan-3 beta,17 beta-diol (2.5 or 25 mg) resulted in receptor levels similar to castrated animals. However treatment with 5 alpha-androstan-3 alpha,17 beta-diol (25 mg) alone or in combination with estradiol (0.25 mg) increased significantly the androgen receptor while it decreased the estrogen receptor. These results show that the administration of estradiol at doses used to induce experimental prostate hyperplasia produce measurable effects in the prostate and suggest that the estradiol receptor may be implicated in this phenomenon.
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PMID:Effect of hormone injections on levels of cytosolic receptors for estrogen, androgen and progesterone in dog prostate. 629 Jul 86

The affinity of danazol for oestrogen, androgen and progesterone receptors in human endometrium and myometrium was determined, to study the mechanism of action of this drug in the treatment of endometriosis. The ability of danazol to combine with each of the three types of receptor was similar in both endometrium and myometrium. The capacity of danazol to compete with oestradiol-17 beta for the oestrogen receptor was very low (1.72 +/- 0.48 X 10(-3%) cross reaction, mean +/- SEM) and danazol, at the maximum concentration used, was unable to saturate the receptor; but danazol's ability to compete with progesterone for its receptor was considerably higher (8.41 +/- 1.65% using progesterone, 1.95 +/- 0.41% using R5020) and was saturable. Danazol was also able to displace dihydrotestosterone from the cytosol androgen receptor (6.29 +/- 1.82% cross reaction). The association constant of oestradiol for the endometrial and myometrial oestrogen receptors was 2.19 X 10(9)M-1 and 7.45 X 10(9)M-1 respectively, while that of progesterone and dihydrotestosterone for their receptors was similar in endometrium and myometrium (mean 0.25 +/- 0.06 X 10(9) M-1 and 3.62 +/- 1.67 X 10(9) M-1 respectively). Using R5020, the association constant for the myometrial progesterone receptor was 2.50 +/- 0.73 X 10(9) M-1. We conclude that, in view of the high circulating levels of danazol present in patients being treated for endometriosis, it is possible that danazol may bind to, and partly saturate, endometrial and myometrial oestrogen, progesterone and androgen receptors during treatment. An explanation may thus be provided for some of the diverse actions of this drug.
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PMID:The interaction of human endometrial and myometrial steroid receptors with danazol. 662 94

Human breast carcinomas contain aromatase, the enzyme necessary for the conversion of androgens to estrogens. If present in sufficient amounts, aromatase could catalyze the synthesis of estrogens from plasma steroid precursors and produce high breast cancer tissue concentrations. To determine the biological importance of tumor aromatase, we validated a specific and highly sensitive 3H-labeled water release assay for aromatase and used this to quantitate the amount of estrogen synthesized in vitro in breast tumors. As proof of assay validity, the [3H] water release assay detected 22.7 +/- 0.09 (+/- SEM) pmol/g . h estrogen formed vs. 24.7 pmol/g . h with the direct product isolation assay. Of 61 human breast tumors studied, 48 contained measurable aromatase activity, ranging from 5-70.5 pmol estrone formed/g . h. Three aromatase inhibitors (aminoglutethimide, testololactone, and 4-hydroxyandrostenedione) blocked this activity at concentrations similar to those affecting aromatase activity in other tissues. If biologically important, the estrogen formed locally from aromatase would be expected to stimulate production of the progesterone receptor. Under these circumstances, a positive correlation of progesterone receptor and local estrogen production should be found. In contrast, no significant correlation between aromatase activity and progesterone receptor level was observed (r = -0.27; P = NS). In addition, no correlation between estrogen receptor content and aromatase activity was detected. Finally, the amount of aromatase activity present in most tumors was insufficient to produce biologically meaningful saturation of estrogen receptors. These observations suggested that aromatase, while present in the majority of breast cancer tissues, may only be biologically important in those few tumors with very high aromatase activity.
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PMID:Biological significance of aromatase activity in human breast tumors. 663 Apr 10

Although the in vivo effect of estrogen on myometrial differentiation is well documented, estrogen effects on primary myocytes in vitro have been difficult to demonstrate. To construct a stable uterine myocyte system, capable of direct estrogen responsiveness, we used a transformed hamster myometrial cell line. Since these cells expressed a low level of estrogen receptors (ERs), we have stably transfected them with a vector for the human ER. After transfection, ER concentration increased from less than 300 sites per cell to 17,000 +/- 2,000 sites per cell (mean +/- SEM). To test the functional integrity of the transfected receptors, a chloramphenicol acetyltransferase gene linked to an estrogen response element upstream of thymidine kinase promoter was transiently transfected, and the amount of chloramphenicol acetyltransferase activity, an indicator of estrogen responsiveness, was found to increase 20-fold in response to 17 beta-estradiol (1 nM for 48 h). Furthermore, we tested the ability of estrogen to activate endogenous genes by measuring progesterone receptor (PR) induction. PR concentration in the transfected cells was 3,700 +/- 800 and increased 9-fold to 33,000 +/- 6,000 with 17 beta-estradiol (2 nM). This receptor density increase was confirmed by immunoblotting. PR induction was maximal at 16 h, was concentration dependent, and was not elicited by tamoxifen or ICI 164,384. We conclude that transformed hamster myocytes transfected with an ER gene are capable of estrogen-dependent PR expression in vitro and may serve as a useful system to study estrogen effect on myocytes.
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PMID:Restoration of estrogen-dependent progesterone receptor expression in a uterine myocyte cell line. 846 59

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.
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PMID:Ligand specificity of uterine oestrogen and progesterone receptors in the subadult African elephant, Loxodonta africana. 915 28

The effects of the short-term pre-operative administration of tamoxifen (TAM, 20 mg once daily) on the tumor levels of steroid receptors and the nuclear proliferation Ki-67 antigen, were investigated in 32 elderly patients with hormone-sensitive, operable primary breast cancer by means of fine-needle aspiration biopsy (FNAB). The FNAB smears before (pre-TAM) and after six weeks of treatment (post-TAM) were stained immunocytochemically in order to obtain an H-score for steroid receptors, and the percentage of cellular nuclei containing Ki-67. The mean oestrogen receptor (ER) score between the pre- and post-TAM specimens fell from 181.2 9.7 ( SEM) to 148.1 7.9 (Wilcoxon's matched-pairs signed-rank test, p=0. 01) and there was also a significant decrease in both the mean progesterone receptor (PgR) score (178.4 10.6 vs 148.5 10.6; p=0.01) and mean Ki-67 index (8.2% 1.2 vs 4.9% 0.9; p=0.0002). The reliability of FNAB as a sampling method was checked by comparing the results of the immunocytochemical assay (ICA) of the post-TAM biopsies with those of the immunohistochemical assay (IHA) of the corresponding excised tumors. There was a positive correlation between the ICA and IHA scores: ER (Spearman's correlation coefficient, rho=0.66, p<0.001), PgR (rho=0.84, p<0.001) and Ki-67 (rho=0.96, p<0.001). We conclude that the sequential use of FNAB is a reliable means of assessing the behaviour of within-tumor biomarkers during endocrine therapy.
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PMID:Effects of short-term pre-operative tamoxifen on steroid receptor and Ki-67 expression in primary breast cancer: an immunocytochemical study. 949 46

Clinical studies have suggested that hormone replacement therapy (HRT) may reduce the risk of coronary heart disease in postmenopausal women. Although progestins are commonly added to HRT preparations for uteroprotection, the perceived beneficial cardiovascular effects of HRT are thought to be mediated predominantly by the estrogen component. Platelets play a critical role in the pathogenesis of atherosclerosis and cardiovascular disease and, hence, it is possible that the cardiovascular effects of estrogens are mediated, at least in part, through inhibition of illicit platelet activation. The aim of this study was to examine the effects of sex steroids on adenosine diphosphate (ADP)-induced platelet aggregation and adenosine triphosphate (ATP) release in vitro in postmenopausal women. In addition, the effects of antiestrogens 14-hydroxy tamoxifen (4-OHT) and ICI 182780] and antiprogestins (RU 486 and ZK 98299) were also investigated. Preincubation of platelet-rich plasma (PRP) with antiestrogens or antiprogestins did not alter subsequent platelet aggregation or ATP release in response to ADP. However, preincubation with 17beta-estradiol (E2) significantly inhibited ADP-mediated platelet aggregation by a mean (+/-SEM) of 37%+/-6% (p = 0.02) and ATP release by 82%+/-6% (p = 0.03), an effect that was reversed by the addition of ICI 182780 or 4-OHT but not RU 486 and ZK 98299. Although the progestin medroxyprogesterone acetate (MPA) also significantly inhibited platelet aggregation (by 28%+/-5%, p = 0.02) and ATP release (by 63%+/-9%, p = 0.02), this inhibition was not reversed by the addition of antiprogestins or antiestrogens. These data show that sex steroids can modulate platelet function in vitro. Furthermore, as platelets are devoid of nuclear components, these findings indicate that estrogens may regulate platelet function through binding to a non-nuclear receptor with ligand-binding properties similar or identical to the wild-type receptor. By contrast, MPA appears to exert its effect through a mechanism that does not involve binding to the "classical" progesterone receptor.
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PMID:Regulation of platelet aggregation and adenosine triphosphate release in vitro by 17beta-estradiol and medroxyprogesterone acetate in postmenopausal women. 1105 72

The purpose of the present study was to determine whether Octopus vulgaris spermatozoa are activated by progesterone stimulation. Spermatozoa were collected from the spermatophores in the Needham's sac of the male (MS) and from the spermathecae of oviducal glands of the female (FS). We used transmission (TEM) and scanning (SEM) electron microscopy to study the morphology of untreated, Ca2+ ionophore A23187 and progesterone-treated MS spermatozoa, and untreated FS spermatozoa. We showed that ionophore and progesterone stimulation of MS spermatozoa induce breakdown of the membranes overlapping the acrosomal region, exposing the spiralized acrosome. These modifications resemble the acrosome reaction observed in other species. FS stored in the spermathecae did not show the membranes covering the acrosomal region present in the MS spermatozoa. When ionophore and progesterone treatments were performed in Ca2+-free artificial sea water, no changes were observed, suggesting the role of external calcium in modifying membrane morphology. Lectin studies showed a different fluorescence distribution and membrane arrangement of FS-untreated spermatozoa with respect to the MS, suggesting that spermatozoa transferred in the female genital tract after mating, are stored in a pre-activated state. The plasma membrane of the untreated MS and FS spermatozoa was labelled with Progesterone-BSA-FITC, indicating the presence of plasma membrane progesterone receptor. Taken together these data suggest that progesterone induces an acrosome- like reaction in MS spermatozoa similar to that induced by calcium elevation. In addition progesterone may play a role in the pre-activation of spermatozoa stored in the female tract, further supporting the hypothesized parallelism between cephalopods and vertebrates.
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PMID:Progesterone induces activation in Octopus vulgaris spermatozoa. 1133 51


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