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At least 685 records · Page 38Linked to original sources
PubMed2002

[Pharma-Clinics. Medication of the month. Totelle Cycle: new sequential estrogen/progesterone regimen for hormone replacement therapy in menopause].

Totelle Cycle is a sequential regimen containing 2 mg of oestradiol for 28 days associated with a new progestogen, trimegestone, from day 15 to 28. It is indicated for the treatment of climacteric symptoms and the prevention of post-menopausal bone loss. Trimegestone is a new 19-NOR progesterone derivative with an original activity profile, near to--but much more powerful than--progesterone itself, and devoid of androgenic, glucocorticoïd and oestrogenic activity. This particular profile confers to trimegestone its metabolic neutrality and concurs to the high degree of safety and tolerance observed in studies related to Totelle Cycle.

Aged↗
PubMed2003

Distinct functional differences of human progesterone receptors A and B on gene expression and growth regulation in two endometrial carcinoma cell lines.

To study the functional differences between the two progesterone receptor isoforms (hPRA and hPRB) in human endometrial cancer, two new endometrial carcinoma cell lines were created-one expressing hPRA and one expressing hPRB.A well-differentiated, hPR-negative Ishikawa cell line was stably transfected with either hPRA or hPRB cDNA. Transfected cells were selected, and two cell lines expressing approximately equal amounts of receptor were isolated-one expressing hPRA (PRA-14) and one expressing hPRB (PRB-59). Cell growth experiments revealed a growth-inhibitory response to progestins (MPA and R5020) in the PRB-59 cells but not in the PRA-14 cells. Differences in expression of genes targeted by the two isoforms were studied using a cDNA expression array technique. A different set of genes appeared to be progesterone regulated in the PRA-14 cells than in the PRB-59 cells. None of the genes were regulated by both hPRA and hPRB. Insulin-like growth factor binding protein 3 expression was studied in more detail as an example of a gene regulated in PRB-59 cells but not in PRA-14 cells. We established a new model to study functional differences between the two hPR isoforms in human endometrial carcinoma cells. This model revealed distinctive differences in target gene regulation between the two hPR isoforms. Moreover, antiproliferative actions of progesterone on human endometrial cancer cells could be observed only in the PRB-expressing cell line.

Cell Division↗
PubMedDate not supplied

Characterization and inhibition of fatty acid synthase in pediatric tumor cell lines.

The current study characterizes the lipogenic enzyme fatty acid synthase (FAS; EC 2.3.1.85) in pediatric tumor cell lines of neural or neural crest origin [medulloblastoma (Daoy), malignant rhabdoid tumor of kidney (SM II), retinoblastoma (Y79), and neuroblastoma (SK-N-SH)]. Constitutive FAS content and activity in these lines were compared to human fibroblast cell line Hs27. Hs27 exhibits low levels of FAS and recapitulates enzyme status in normal human tissues under most physiological conditions. Western analysis detected significantly larger amounts of FAS protein in Y79 and SK-N-SH than Daoy, SM II and Hs27. Incorporation of radiolabeled malonyl-CoA into total cellular lipid revealed that enzyme activity correlated with amount. Increased FAS content and activity in Y79 and SK-N-SH relative to the other cell lines and Hs27, in particular, implied enzyme activation in retinoblastoma and neuroblastoma lineages. The enzyme also showed evidence of hormonal regulation, as dexamethasone induced FAS protein in Daoy and SK-N-SH. However, hormonal induction of FAS protein levels did not correlate with activity levels, which led us to speculate phosphorylation as a means of regulating the enzyme's activity. Finally, the FAS inhibitor cerulenin was investigated for its ability to suppress tumor cell growth. After four days of propagation, short-term treatment of cell lines with drug produced mean IC50s less than 10.5 micrograms/ml (i.e., 5.6 +/- 1.9 for SM II; 9.3 +/- 1.5 for Daoy; 10.2 +/- 0.2 for SK-N-SH; and 10.4 +/- 2.6 for Y79). Annexin V assays revealed that cerulenin initiated apoptosis. The antineoplastic properties of cerulenin documented here are consistent with prior studies showing its cytotoxic effects upon other types of cancer cells and illustrate the potential utility of FAS inhibition as a novel chemotherapeutic approach.

Apoptosis↗
PubMed1992

R5020 enhances PGE2 stimulated steroidogenesis in cultured rat granulosa cells.

Progesterone biosynthesis and metabolization to 20 alpha-hydroxyprogesterone was stimulated in granulosa cells cultured in the presence of 20 ng/ml of follicle stimulating hormone (FSH) or increasing concentrations of PGE2 (10(-9)-10(-7)M). Concurrent treatment with the synthetic progestin R5020 (10(-6) M) enhanced the FSH or PGE2 stimulated progesterone and 20 alpha-hydroxyprogesterone accumulation in culture media, as well as delta 5-3 beta-hydroxysteroid dehydrogenase activity in granulosa cell homogenates. These findings may represent another example of an autocrine control mechanism in which the steroidogenic product of the granulosa cell exerts an ultra-short loop regulation of its own production.

20-alpha-Dihydroprogesterone↗
PubMed1992

[Female contraception by a normal dose progestogen after 40 years of age. Possible association of nomegestrol--17-beta-estradiol acetate by percutaneous route].

Although fertility declines with age, the use of an effective contraceptive remains necessary in women over 40. Endocrine disorders, which are common in this age group, may also often require control. Conventional estroprogestogens, even those of the latest generation, cannot be used in women with a high cardiovascular risk, since age cannot be totally excluded as a possible risk factor. The contraceptive use of derivatives of 17-hydroxyprogesterone and 19-norprogesterone offer a promising alternative, despite the absence of any exhaustive investigation particularly in situations in which the blood level of estradiol has to be reduced. There are, however, some women who respond to this type of contraception by menstrual cycle irregularities, and sometimes by low blood levels of estradiol, regardless of the drug used. A preliminary study is described in which 5 mg of nomegestrol acetate was combined with 17-beta-estradiol by transcutaneous route and which has so-far demonstrated sustained contraceptive efficacy as well as excellent clinical and metabolic safety.

Administration, Cutaneous↗
PubMed1992

[Postmenopausal bone loss. Role of progesterone and androgens].

Oestrogen deficiency is the main physiopathological factor of postmenopausal osteoporosis. The repercussions on bone metabolism of decrease in other sex steroid levels (progesterone, androgens) remains imperfectly known. Several studies on both animals and man have demonstrated that androgens and progestogens derived from testosterone have an anabolic effect on bone tissue. The latest data from studies conducted in non-menopausal women treated with progesterone suggest that this hormone might prevent bone loss. The mechanism of action of this effect on cells remain to be determined, even though progesterone has been shown to exert a mitogenic activity in vitro. Altogether, these data suggest that side by side with oestrogen deficiency the decrease of other sex steroid levels might also play a role in the physiopathology of postmenopausal bone loss.

Adult↗
PubMed2003

Cutaneous microvascular effects of mid-term hormone replacement therapy in healthy postmenopausal women: a prospective placebo controlled trial.

OBJECTIVE: To study the mid-term effects of Hormone Replacement Therapy (HRT) on cutaneous microcirculatory blood flow and reactivity in healthy postmenopausal women. DESIGN: In a double-blind placebo controlled randomized study, 16 healthy postmenopausal women received either placebo or HRT (micronized estradiol: 1 mg/day, day 1-28, promegestrone: 0.25 mg/day, day 14-28). This regimen was completed 6 times. Cutaneous microcirculatory blood flow was recorded by laser-Doppler velocimetry on the foot dorsum, in the supine and then dependent positions, and after post-ischemic hyperemia. RESULTS: At day 0, the two groups were similar and none of the following data differed significantly between treated and placebo group: (supine flux: 11.8 +/- 1.8 u vs. 13.2 +/- 3.9, venoarteriolar reflex: 5.6 +/- 1.3 vs. 6 +/- 3.3, and post-ischemic hyperemia: 35.2 +/- 3.9 vs.48.3+/-11). At the end of the study (day 26-28 of 6th cycle), the supine flux was 9.8 +/- 2.1 in the HRT group vs.12.9 +/- 6 in the placebo group (NS), the venoarteriolar reflex, 1.2 +/- 2 vs. 7+/-1.7 (p=0.04), and post ischemic hyperemia, 31.8 +/- 5.4 vs. 39.5 +/- 4.6 (NS). Intragroup values did not change significantly for any of the microcirculatory parameters measured, which remained stable throughout the 6 months of the study. Intergroup values for these parameters did not change either, except for the venoarteriolar reflex, which was lower at the end of the study in the HRT (EP period, cycle 6 day 26-28) than placebo group (p=0.04). CONCLUSIONS: HRT does not impair the resting supine cutaneous microcirculation blood flow or post-ischemic hyperemia.

Double-Blind Method↗
PubMed2006

[Functional study of progesterone receptor isoforms in endometrial cancer cell lines].

OBJECTIVE: To study the functional differences between the two progestrone receptor isoforms(PR-A and PR-B) in human endometrial cancer,using antisense oligodeoxynucleotide(AS-ODN) to downregulate isoform B of progestrone receptor in endometrial carcinoma cell lines, After transfection of the oligodeoxynucleotide, several kinds of hormones were added in the cells to observe the different response, where to study the functional differences between the two isoforms. METHODS: The well-differentiated endometrial cancer cell line Ishikawa and moderate-differentiated endometrial cancer cell line Hec-1B were cultured in vitro. The cells were transfected with antisense, sense, and scramble-ODN. After 48 hours, the expressions of two progesterone receptor isoforms were detected by Western blot using specific antibody. Then the cells were planted in 96-well plates, transfected with antisense, sense, scramble-ODN and added in several hormones to search for the response in distinct hormones and oligodeoxynucleotides. RESULTS: After transfecting antisense-ODN, two cell lines were down-regulated in progesterone receptor isoform B,but progesterone receptor isoform A was not down-regulated,and the progesterone receptor isoform B of cells transfected with sense and scramble-ODN was not changed. When stimulated by 17beta-estradiol(E2)for 72 hours,the growth of Ishikawa cells was significantly higher than that of the control, Hec-1B cells only grew higher than control,but it was to significant in statistics.R5020 inhibited Ishikawa cells significantly after stimulating for 72 hours. There was the same effect in Hec-1B cells after stimulating for 96 hours. On the bases of E2 and R5020, we added mifepristone (RU486) . The cells developed after 96 hours in Ishikawa cells and developed after 48 hours in Hec-1B cells. When PR-B was down-regulated,the stimulating effect of E2 was enhanced, but the inhibitory effect of R5020 was decreased, RU486 antagonized R5020 weaklier than the control. CONCLUSION: AS-ODN directed against the human PR-B can inhibit the expression of PR-B effectively,through which the PR-A expresses predominantly. E2 can cause endometrial carcinoma cell growth, PR-B is associated with the stimulating effect of E2 in endometrial carcinoma cells. Progestin (R5020) inhibits the hyperplasia induced by E2,PR-B is involved in the inhibitory effect of R5020. RU486 antagonizes the effect of R5020,inhibiting cell growth, PR-B is involved in the antagonizing effect of RU486.

Adenocarcinoma↗
PubMed1991

Ionic and ligand-specific effects on the DNA binding of progesterone receptor bound to the synthetic progestin R5020 and the antiprogestin RU486.

Antiprogestin and other antihormones are valuable therapeutic agents in hormone-responsive cancers. A fundamental mechanism in the action of antiprogestin is its binding to PR,3 an intracellular protein that mediates the action of progesterone by direct interaction at the regulatory sites of responsive genes. To elucidate the mechanism of action of PR bound to agonistic and antagonistic ligands, we determined the binding affinity of rabbit uterine PR bound to R5020 and RU486, respectively, with different DNA sequences. We used 2 recombinant plasmid DNAs, pDHf14 and pDHf2, with 60- and 23-base pair inserts of potential Z-DNA-forming (dA-dC)n.(dG-dT)n sequences, respectively, parental plasmid pDPL6 with no insert, calf thymus DNA, and several synthetic polynucleotides in this study. The concentration of DNA required to elute 50% of the receptor bound to DNA-cellulose (EC50) was used as a measure of the relative binding affinity of the receptor for DNA. EC50 values of plasmids pDHf14 and pDHf2 were 1.2 +/- 0.5 (SD) and 2.5 +/- 0.6 micrograms/ml, respectively, for PR bound to R5020. In contrast, EC50 for control plasmid was 350 micrograms/ml. PR.R5020 had lower affinity for calf thymus DNA and polynucleotides compared with pDHf2 and pDHf14. Receptors complexed with the antiprogestin RU486 had lower affinity for the plasmids; EC50 values were 2.4 +/- 0.4 and 10 +/- 1 microgram/ml, respectively, for pDHf14 and pDHf2. This ligand-specific difference in DNA binding was amplified by the presence of 5 mM Mg2+ or Ca2+. The relative binding affinity of PR.R5020 to pDHf14 was 6- and 7-fold higher than that of PR.RU486, in the presence of 5 mM Mg2+ and Ca2+, respectively. These results show that PR.RU486 has lower binding affinity for specific DNA sequences than PR.R5020, but the binding affinity of both receptors is in a range that cannot preclude competitive interactions at the DNA recognition site. The effects of Mg2+ and Ca2+ on PR binding to DNA further suggest that these cations could affect PR recognition of DNA in a ligand-specific manner.

Animals↗
PubMed1991

Progestin regulation of alkaline phosphatase in the human breast cancer cell line T47D.

In T47D breast cancer cell line, progestin (R5020) induces de novo synthesis of an alkaline phosphatase enzyme. Based on inhibitor profiles and antigenic specificity, it is apparent that this enzyme belongs to the class of membrane-associated tissue-unspecific alkaline phosphatases. Enzyme induction was uniquely specific to progestins and not altered by other steroid hormones or synthetic analogues. The progestin induction of the tissue-unspecific alkaline phosphatase was time and dose dependent. The protein synthesis inhibitor cycloheximide blocks the enzyme synthesis and tunicamycin blocks the enzyme activity, showing that the induction was new synthesis of protein in its complete glycosylated form and not activation of a preexisting enzyme. To our knowledge this is the first report of progesterone-induced expression of a tissue-unspecific alkaline phosphatase gene of such magnitude (about 30- to 100-fold) in a progesterone-responsive tissue.

Acid Phosphatase↗
PubMed1990

Hormonal modulation of HER-2/neu protooncogene messenger ribonucleic acid and p185 protein expression in human breast cancer cell lines.

Recent work has suggested that overexpression of the HER-2/neu protooncogene may play a role in the aggressive clinical behavior of some breast tumors. Since hormones are also known to change the proliferation rate and invasiveness of these cells, we have studied the effect of sex steroid hormones and antihormones on levels of the HER-2/neu mRNA and protein in human breast cancer cell lines using complementary DNA and antibody probes. In MCF-7 cells, which contain high levels of estrogen receptor and an estradiol (E2)-inducible progesterone receptor (PR), 1 nM E2 caused a rapid drop in HER-2/neu mRNA (4.8 kilobases), to 40% of control values by 6 h, and a more gradual decrease in HER-2/neu protein, to 50% by 24 h. HER-2/neu protein and mRNA levels remained reduced throughout 1 week of E2 treatment. The effect of E2 was dose dependent, with the maximal effect seen with concentrations of 10(-10) M E2 and above, and antiestrogen partly reversed the E2-induced decrease in HER-2/neu expression. These characteristics suggest that the observed modulation of HER-2/neu is an estrogen receptor-mediated process. In contrast, progestins did not change HER-2/neu mRNA or protein levels in E2-primed MCF-7 cells that contain high levels of PR; in T47D cells, which contain low levels of ER and high levels of PR, addition of E2 or the progestin R5020 or the antiprogestin RU38,486 had no significant effect on HER-2/neu mRNA or protein levels over 6 days of treatment. These results indicate that estrogen but not progestin modulates HER-2/neu protooncogene expression in these breast cancer cell lines and suggest that aggressiveness associated with high levels of HER-2/neu mRNA and protein may be uncoupled from estrogen-stimulated proliferation in these cells.

Breast Neoplasms↗
PubMed1990

Regulation of fatty acid synthetase by progesterone in normal and tumoral human mammary glands.

Progesterone and estrogens play an important role in the control of growth, differentiation and function of mammary epithelial cells. Their mechanism of action can be studied in human metastatic breast cancer cell lines (MCF7, T47D, ZR75-1...) that contain progesterone and estrogen receptors. We used this system to try to define progestin-regulated human genes which would permit to study progestin-regulation of gene expression in cell culture and to develop clinical markers of progestin-responsiveness. This paper summarizes our investigation of the progestin-regulated 250K protein, recently identified as human fatty acid synthetase (FAS).

Breast↗
PubMed1990

Hormone regulated enzyme activities of plasma membrane of decidual endometrium of the rat.

Plasma membranes were purified from deciduoma of pseudopregnant rats and rat liver. Preparations contained 80% plasma membrane-derived material as based on electron microscope morphometry and analysis of enzyme markers. Several plasma membrane enzymes were tested for direct response to hormones. NADH-ferricyanide reductase of plasma membranes from both tissues was stimulated by glucagon and inhibited by insulin but was unresponsive to steroids. For steroids, responsiveness was limited to a reduction in NaF-stimulated adenylate cyclase activity by the steroid R5020. Thus, interaction of steroid hormones with plasma membranes, unlike that of glucagon and insulin, is not reflected in an altered activity of plasma membrane-bound dehydrogenases but may be exerted directly on adenylate cyclase.

Adenylyl Cyclases↗
PubMed1990

The progesterone receptor can regulate transcription in the absence of a functional TATA box element.

We have investigated the importance of the TATA box element in the induction of transcription by the progesterone receptor. Transcription was analyzed from promoters containing a steroid response element upstream of a wild-type or mutated TATA box. Mutation of the TATA box resulted in a loss of correctly initiated transcripts and abolished binding of TATA factor to the TATA box in vitro but did not inhibit transcriptional activation by the progesterone receptor. Thus we conclude that the receptor is able to stimulate the rate of transcription in the absence of a functional TATA box.

Animals↗
PubMed1990

Progestins increase insulin receptor content and insulin stimulation of growth in human breast carcinoma cells.

The effects of progesterone on the growth of breast carcinoma cells are undefined. In the present study we investigated the effect of progestins on insulin receptor gene expression and insulin action in human breast cancer cells. Treatment of T47D cells with the synthetic progestin R5020 induced a time- and dose-dependent increase in insulin receptor content as measured by both ligand-binding studies and radioimmunoassay. Binding was half-maximally stimulated at 300 pM R5020 and maximal levels were reached after 4 days of treatment. Progesterone was 10-fold less potent than R5020. Cortisol had no effect on insulin receptor levels, while 17 beta-estradiol and dihydrotestosterone had minimal effects. Progestin treatment both increased insulin receptor mRNA levels and altered the relative distribution of the multiple insulin receptor mRNA transcripts. In order to study the functional significance of the increased insulin receptor levels, we incubated T47D cells with progesterone and then treated them with insulin. Insulin alone had a small effect on cell growth; however, the effect of insulin was markedly potentiated by progesterone treatment. These studies in breast cancer cells demonstrate, therefore, that insulin receptor gene expression is under the regulation of progestins and raise the possibility that progestin-insulin interactions may regulate breast cancer cell growth in vivo.

Antibodies, Monoclonal↗
PubMed1990

Nuclear progestin receptors in rat thymic tissue.

The thymus and its associated endothelial cells and lymphocytes act as an important immunological tissue. The endothelial cells of the thymus have been reported to synthesize cytoplasmic progestin receptor in response to estrogen priming. To measure nuclear progestin receptor, female rats were castrated and primed for 3 days with estradiol benzoate (30 micrograms/0.1 ml/d) and immediately before sacrifice injected subcutaneously with 0.2 mg of progesterone. By Scatchard plot analysis we found that specific progestin receptor (KA = 0.89 +/- 0.10 x 10(9) M-1) was present in the KCl-nuclear extract. The concentration of nuclear progestin receptor was found to be in the range of 312.6 +/- 49 fmole/g tissue (n = 9, 1 hour after progesterone injection) while the nuclear receptor was significantly reduced (approximately 44 fmol/g tissue) in the oil treated controls. This level verges on the limits of sensitivity for this assay. For cytoplasmic progestin receptor the concentration was 3.46 +/- 0.20 pmole/g tissue in oil treated controls (n = 14) and 3.36 +/- 0.20 pmole/g tissue in progesterone treated animals (n = 24). The KA of this thymic cytoplasmic progestin receptor was 1.35 +/- 0.06 x 10(9) M-1. By competition assay, the relative binding affinity of nuclear progestin receptor was: R5020 (a potent synthetic progestin) (100%), progesterone (9%), testosterone (0.56%), corticosterone (0.53%), estradiol-17 beta (0%). It is concluded that thymic reticuloepitheleal cells contain nuclear progestin receptor and this finding supports the hypothesis that progesterone, like other sex steroids may play a regulatory role in thymic cell function.

Animals↗
PubMed1990

Regulation of progesterone receptor gene expression.

The levels of progesterone receptor (PR) mRNA, PR protein, and [3H]R5020 binding activity were measured in parallel experiments conducted on a T47D subline expressing the estrogen receptor. A significant increase of PR mRNA levels could be detected within 6 h of exposure of the cells to estradiol (10(-8) M). The changes in mRNA, however, did not lead to any variation of PR protein levels of [3H]R5020 binding activity. A parallel analysis of PR mRNA and [3H]R5020 binding was then performed in a series of tumor biopsies. In estrogen receptor-positive and PR-positive tissues a correlation among the two values was found. It is postulated that the above mentioned data could reflect the existence of a difference in the mechanisms controlling the numerous steps of the PR synthesis in the various hormone-responsive tissues. This variability could allow an organ-specific response to the cyclic changes of circulating hormone.

Blotting, Northern↗
PubMed1990

Steroid interactions with plasma membrane of decidual endometrium of the rat.

Plasma membranes were purified from deciduoma of pseudopregnant rats, rat liver and intestine, and calf uterus. Steroid binding evaluated with deciduoma plasma membranes showed competitive progestin binding, in contrast with estradiol binding which was nondisplaceable as measured by competition binding assay. When the photosensitive steroid [3H]-R5020 was photocrosslinked to plasma membrane, binding was reduced competitively by either progesterone or R5020. These results indicate that the decidual cell plasma membrane contains specific sites for interactions with progestins.

Animals↗