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Results for “Progesterone Congeners”

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At least 145 records · Page 8Linked to original sources
PubMed1985

Endometrial and pituitary responses to the steroidal antiprogestin RU 486 in postmenopausal women.

The effects of the antiprogestin RU 486 on the human endometrium were investigated. Seventeen postmenopausal women were injected with estradiol (E2) benzoate (0.625 mg/day) for 15 days. Progesterone (P) (25 mg/day) and/or RU 486 (100 or 200 mg/day) were given to groups of 2-3 women during the last 6 days of E2 benzoate treatment. Serial blood samples were drawn for the measurement of plasma E2, P, and LH and FSH. An endometrial biopsy was performed on the last day of treatment, and processed for histology or for assays of DNA polymerase alpha, E2-dehydrogenase (E2DH), and P receptor (PR). Treatment with E2 benzoate alone resulted in a marked decrease of plasma gonadotropins; in those patients who received either P, RU 486, or both, in addition to E2 benzoate, the concentrations of plasma LH and FSH were further decreased to premenopausal levels. In absence of glycerol, the affinity of RU 486 for the endometrial PR (Kd = 0.8 nM) was higher than that of P (Kd = 1.2 nM). Glycerol decreased markedly the affinity of RU 486, whereas the affinity of P for the PR was unchanged. RU 486 had negligible affinity for plasma transcortin. Either P or RU 486, but not both together, induced secretory changes in the endometrium as determined from histologic sections of tissue biopsies. Either P or RU 486 decreased DNA polymerase alpha and increased E2-DH activities in the endometrium. Unexpectedly, when P and RU 486 were given together. E2-DH activity remained at the level found in E2-treated women. In vitro cultures of proliferative endometrium treated with the synthetic progestagen R 5020 or with RU 486 also had increased E2-DH activity; RU 486 counteracted R 5020 effects. We conclude that, contrary to previous results with experimental animals, the anti-P RU 486 has some progestomimetic activity in humans under specific conditions. Paradoxically, when given together with P, RU 486 lost most of its progestomimetic activity in the endometrium and behaved as a pure antagonist.

Adult↗
PubMed1989

Progestin inhibition of progesterone receptor gene expression in human breast cancer cells.

The present study was designed to investigate whether inhibition of progesterone receptor (PR) gene transcription and/or regulation of PR mRNA half-life were involved in the progestin-mediated decrease of PR in T-47D human breast cancer cells. Cells were treated with the progestin ORG 2058 and PR mRNA measured by Northern blot analysis of total RNA. A major PR mRNA around 13.5 kilobases and minor species around the 28S ribosomal RNA subunit were decreased upon ORG 2058 treatment. The decrease was not detectable until 2-3 h after treatment and was the same at all ORG 2058 concentrations (1-100 nM) tested. The decrease in PR mRNA was unaffected by actinomycin D in the first 3 h but was inhibited thereafter. There was a partial recovery of PR mRNA levels 24 h after ORG 2058 exposure. Immunoblot analysis showed that immunoreactive PR decreased in parallel with PR mRNA. The rate of protein loss in the first 12 h after progestin treatment was related to the ORG 2058 concentration used. Nuclear run-on experiments showed that ORG 2058 caused a decrease of up to 70% in the transcription rate of the PR gene. The half-life of PR mRNA was shown to be 2-2.5 h by [3H]uridine incorporation, which was much shorter than estimates obtained using actinomycin D, and was unaffected by ORG 2058. In summary, these data have shown that the mechanism by which progestins decrease the concentration of PR includes inhibition of transcription of the PR gene.

Blotting, Northern↗
PubMed2001

Cystic endometrial hyperplasia/pyometra in dogs: a review of the causes and pathogenesis.

In this review the roles of endogenous and exogenous steroid hormones, steroid receptors, spontaneously occurring and experimentally induced genital tract infection, and endometrial trauma in the cause and pathogenesis of cystic endometrial hyperplasia/pyometra in bitches are considered. It is postulated that intrauterine bacteria, which ascend from the vagina during pro-oestrus and oestrus, induce the disease during metoestrus by acting on the progesterone-primed endometrium directly via toxin production, or indirectly by the release of inflammatory mediators. The lesion can be produced by endometrial trauma in a sterile uterus without the systemic effects associated with the disease. There is no association with premature or increased progesterone concentrations at the time that the disease is normally diagnosed in mid- to late metoestrus; however, such aberrant endocrine changes cannot be excluded from involvement in the pathogenesis of this disease, as there are no data from bitches preceding the onset of clinical signs. Expression of oestrogen and progesterone receptors are modified by endogenous steroid hormones but there is no clear evidence that changes in these receptors are involved in the pathogenesis of the disease; receptor expression can be modified by exogenous hormones.

Animals↗
PubMed1992

Experience in management of diminished growth in adolescent Turner's syndrome patients.

The aim in the management of patients with Turner's syndrome, besides substitution of sexual steroids, is the attempt to improve their final height. The data allow therapeutic recommendations, which, however, realize only the first intention. The final height, indeed, cannot be improved by traditional methods. Further two alternatives remain to be tested: long time low dose estrogen therapy, and high dosed HGH application.

Adolescent↗
PubMed2005

The estrogenic activity of synthetic progestins used in oral contraceptives enhances fatty acid synthase-dependent breast cancer cell proliferation and survival.

Overexpression of the lipogenic enzyme fatty acid synthase (FAS) is a common molecular feature in subsets of sex-steroid-related tumors including breast carcinomas that is associated with poor prognosis. In this study, we explored whether breast-cancer associated FAS (oncogenic antigen-519) is regulated by the progestin component in oral contraceptives. In addition, we examined the role of FAS hyperactivity on progestin-regulated breast cancer cell proliferation, survival and metastatic properties. We found that in estrogen receptor (ER)- and progesterone receptor (PR)-positive MCF-7 human breast cancer cells, synthetic progestins used in oral contraceptives including norethynodrel (NOR) and norethindrone, induced a dose-dependent increase of FAS enzymatic activity, with a maximum response (> or = 4-fold) occurring at a concentration of 10(-8) M. FAS activity was only slightly stimulated after exposure to two other progestins, medroxy-progesterone acetate (MPA) and megestrol acetate (MGA), which are used in postmenopausal hormone replacement therapy and high-dose progestin treatment therapy. Western blot analyses showed that NOR-induced stimulation of FAS activity correlated closely with NOR-induced up-regulation of FAS protein expression. To determine the role of FAS accumulation following NOR exposure, we pharmacologically examined the requirement for FAS activity in NOR-stimulated breast cancer cell proliferation and survival. The novel small compound C75 (a slow-binding FAS inhibitor) blocked NOR-induced breast cancer cell proliferation in anchorage-dependent assays. More importantly, pharmacological inhibition of FAS activity completely abolished NOR-stimulated soft-agar colony formation of MCF-7 cells. To evaluate the involvement of PR and ER signalings in NOR-induced up-regulation of FAS expression and activity, NOR was used in combination with either the anti-progestin RU486 (mifepristone) or the pure antiestrogen ICI 182,780 (Faslodex). RU486 and ICI 182,780 similarly abolished NOR-induced FAS activation, supporting the notion that PR- and ER-mediated FAS up-regulation might play different roles in NOR-stimulated breast cancer cells. Interestingly, when we evaluated the involvement of PR and ER signalings on NOR-induced breast cancer cell proliferation, the anti-estrogen ICI 182,780, but not the anti-progestin RU486, was found to inhibit NOR-stimulated proliferation and survival of MCF-7 cells in anchorage-dependent and -independent assays. To further determine whether NOR produced their effects via the ER, we evaluated its effects on endogenous ER transcriptional activity by using transient transfection assays with an estrogen-response element reporter construct (ERE-Luciferase). In the absence of E2 stimulation, treatment with NOR dramatically increased the levels of ERE-dependent transcriptional activity. This estrogenic like-effect of NOR was blocked by the addition of ICI 182,780, whereas RU486 failed to inhibit NOR-induced ERE activity. In summary, this study provides direct evidence that: a) a number of synthetic progestins used in oral contraceptives significantly activates breast cancer-associated FAS (OA-519) activity and expression in hormone-dependent breast cancer cells; b) FAS activity is necessary for progestin-induced anchorage-independent growth and survival of human breast cancer cells, and c) activation of ER, but not PR signaling, is the stimulatory mechanism through which synthetic progestins enhance a FAS-dependent proliferative and pro-survival signaling. These findings should be helpful to explain the conflicting evidence linking oral contraceptives and breast cancer risk through the estrogenic activation of tumor-associated FAS (OA-519), a molecular marker associated with poor clinical outcome of breast cancer disease.

Breast Neoplasms↗
PubMedDate not supplied

A rational approach to the use of hormonal replacement therapy in postmenopausal and older women.

This report reviews the use of hormonal therapy in postmenopausal women and gives specific attention to its benefits in the older patients. Concomitant use of progestin is recommended for all but the very old who are being treated for urogenital problems. Strategies for minimizing withdrawal bleeding and the adverse impacts of progestins on lipoprotein subfractions are discussed.

Adult↗
PubMed1989

Epidemiology of cardiovascular disease in women and the role of sex steroid hormone use.

Women in the United States are at significant risk for CVD. After a 10- to 12-year delay in onset, the rate of increase in CAD with age in women is the same as that in men. Cardiovascular risk correlates positively with total serum cholesterol, LDL and triglyceride levels and inversely with HDL cholesterol. Triglycerides are an independent risk factor in women. The close correlation between cholesterol levels and myocardial infarction has been documented in population-based studies in men and women and in dietary and drug intervention trials in men. For every 1% decrease in cholesterol, there is a corresponding 2% decrease in cardiovascular risk in both sexes. For adults it is recommended that total cholesterol levels be less than 200 mg/dL. Fifty percent of women in the United States have cholesterol levels that exceed that number. Cholesterol screening, identification of high-risk individuals and early institution of overall risk management strategies are keys to reducing morbidity and mortality. Ideal therapeutic interventions are those that are lipid neutral or have a beneficial effect on the lipid profile.

Cardiovascular Diseases↗
PubMed1989

Subcellular distribution of estrogen receptor and progesterone receptor with and without specific ligand.

The estrogen receptor (ER) and progesterone receptor (PR) content of cultured human breast carcinoma cells (MCF-7) was determined by biochemical assay, immunoblot analysis, and immunohistochemical assay under varying conditions of hormonal stimulation. The ER and PR content in cytosolic and nuclear extracts varied with steroid treatment. However, both the amount and distribution of each receptor in these extracts was virtually the same when determined by steroid binding and immunoblot analyses. Two immunocytochemical parameters (staining intensity and proportion of cells stained) correlated with the quantitative analyses of ER and PR, but not with the subcellular distribution. When MCF-7 cells were grown for 4 days in charcoal-stripped serum without phenol red, 93% of total ER was found in the cytosol (10 mM KCl), whereas short-term treatment with 5 nM estradiol resulted in the appearance of 82% of total ER in the nuclear extract (400 mM KCl). With either cell treatment only nuclear staining for ER was observed. Progesterone receptor was virtually undetectable in the same cells by any method. After 4 days of treatment by 5 nM estradiol, PR was strongly induced (50-fold) in MCF-7 cells as determined by all three methods. As observed for ER, 95% of total induced PR was found in the cytosol in the absence of a progestin. Short-term treatment with 5 nM ORG 2058, a synthetic progestin, resulted in the appearance of 42% of total PR in the nuclear extract. However, only strong nuclear staining for PR was observed in either the presence or absence of a progestin. These findings are consistent with the current view of ER and PR as nuclear receptors present in at least two forms. One of these, the unoccupied form of the receptor, is easily removed from the nucleus by hypotonic buffers during the cell homogenization process and appears in the cytosolic extract. The other form of the receptor, the steroid-occupied form, is more tightly bound to nuclear components and is removed from nuclei only under more vigorous extraction conditions.

Blotting, Western↗
PubMed1989

Relationship of cytosolic estrogen and progesterone receptor content and the growth fraction in human mammary carcinomas.

In this study of breast cancer specimens, the relationship between cytosolic estrogen (ER) and progesterone receptor (PR) content to the size of the respective growth fraction (GF) (expressed as percentage of proliferating tumor cells) was investigated. We applied the recently developed ligand-binding assay for extracts of frozen sections and Ki-67 immunocytochemistry for the assessment of the GF to adjoining serial sections of a single tissue block. If the receptor content is plotted against the percentage of Ki-67 labeled cells, an inverse relationship between receptor content and proliferation becomes obvious, meaning that a high receptor content is associated with a small GF and vice versa. If tumor specimens are grouped according to the evaluated receptor status, the mean percentage of Ki-67-positive cells is 12% for ER-positive/PR-positive (ER+/PR+), 26% for ER-positive/PR-negative (ER+/PR-), 55% for ER-negative/PR-positive (ER-/PR+), and 57% for ER-negative/PR-negative (ER-/PR-) specimens. A significant population of tumors exists, however, which exhibit a high receptor content and a high GF. The percentages of ER+/PR+ samples with a high proliferation index are 16 and 26% if the total ER+ population is considered.

Biomarkers, Tumor↗
PubMed1989

[The effect of hydroxyprogesterone caproate and its combination with tamoxifen on steroid hormone receptors in the tumor and on the basic parameters of reproductive homeostasis in patients with cancer of the corpus uteri].

Oxyprogesterone capronate (OPC) was administered preoperatively to 46 patients with endometrial tumors and tamoxifen (T) + OPC--to 72 patients. Complex treatment was followed by more pronounced pathomorphosis in tumor. Both schedules inhibited gonadotropin secretion and lowered colpocytoscopic indexes. Dual effect of complex treatment (T + OPC) on the level of cytoplasmic receptors to progesterone was observed. Initially low levels rose while high ones dropped by the end of a 20-day course. Progestin treatment in endometrial carcinoma patients with relatively low estrogen levels should be complemented with tamoxifen to stimulate tumor sensitivity to progestagens.

17 alpha-Hydroxyprogesterone Caproate↗
PubMed1986

Measurements of androgenicity. The spectrum of progestogen activity.

The problem with applying information on progestogen potency obtained from biologic testing to clinical prescribing practices is that the changes in potency relate to more than progestogen dosage. The spectrum of progestogen activity is discussed, with an emphasis on the effects of the progestogens used in oral contraceptive therapy.

Acne Vulgaris↗
PubMed1988

Genetic instability and the development of steroid hormone insensitivity in cultured T 47D human breast cancer cells.

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)

Breast Neoplasms↗
PubMed1987

Dysfunctional uterine bleeding in adolescents.

Between 1970 and 1984 89 patients under 18 years of age were treated for dysfunctional premenarchal or postmenarchal bleeding. Patients' age varied from 8 to 18 years (average age 12.2 years). 12 cases were of dysfunctional bleeding in menarche and 68 were of menorrhagic or menometorrhagic menstruation after a period of 2 months to 6 years after menarche. Medical therapy was successful in all cases.

Adolescent↗