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At least 487 records · Page 27Linked to original sources
PubMed1986

Human mammary cancer cell mutants with altered hormone receptor activity.

We have recently isolated retinoic acid-resistant clones U-2 and U-3 from human breast cancer cell line MCF-7 (Ueda et al. (1985) Cancer Res. 45, 3332-3338). Growth of MCF-7 cells was found to be stimulated by estradiol but that of U-2 or U-3 was not. Cytosol from U-2 or U-3 cells contained no detectable estradiol receptor activity, whereas that from the parental MCF-7 cells showed estradiol receptor activity of 32 fmol/mg cytosol protein with a Kd of 2.6 X 10(-10) M by Scatchard analysis. Sucrose gradient centrifugation analysis of the cytosol fraction confirmed the presence of estradiol receptor activity in MCF-7 but not in U-2. Cytosol from MCF-7 and U-2 cells showed progesterone receptor activities of 106 fmol/mg protein with a Kd of 7.4 X 10(-10) M and 13 fmol/mg protein with a Kd of 9.9 X 10(-10) M, respectively. Addition of estradiol to the culture medium of the cells increased the level of progesterone receptor about 2-fold in MCF-7, but not in U-2. U-2 or U-3 cells showed about 5-fold higher resistance to an antiestrogen, tamoxifen, than MCF-7, and they were also 300- to 1,000-fold more resistant to other antiestrogens, epitiostanol and medroxyprogesterone, than MCF-7. The altered cellular sensitivity of U-2 or U-3 to the hormone antagonists is discussed in relation to the absence or presence of hormone receptors.

Androstanols↗
PubMed1980

Occurrence of common binding sites for progestin and glucocorticoid in the lactating mammary gland of the rat.

Previous reports have shown that in the cytosol from rat mammary gland, the high affinity binding of glucocorticoid is strongly inhibited by unlabeled progestin and that of progestin is strongly inhibited by glucocorticoid. Experiments were carried out with [3H]dexamethasone and [3H]R5020 to determine whether the binding sites for glucocorticoid and progestin are the same. Thermal inactivation experiments showed that the molecular properties of the [3H]-dexamethasone-binding sites closely resemble those of the [3H]R5020-binding sites. The dissociation constant of the [3H]R5020-receptor complex was almost exactly the same as the inhibition constant of unlabeled R5020 for [3H]dexamethasone-binding sites. The same correlation was observed between the dissociation constant and the inhibition constant of dexamethasone. In addition, no [3H]R5020-binding was observed after saturating the [3H]-dexamethasone-binding sites. These results led us to conclude that common binding sites for [3H]dexamethasone and [3H]R5020 exist in the cytosol from the rat mammary gland. The results of further experiments, including Scatchard analyses and dEAE-cellulose chromatography, strongly suggest that there are at least two classes of [3H]dexamethasone-binding sites, and that one of them binds both glucocorticoid and progestin stably.

Animals↗
PubMed1981

Androgen receptor in human placental villi.

In studies with a synthetic androgen, R 1881, an androgen-binding component was found in the cytosol of human placental villi. Kinetic analysis indicated that the Kd value of this component was 1.4 nM at 0-4 degrees C and that binding of R 1881 amounted to 277 +/- 73 fmol/mg protein. glycerol density gradient ultracentrifugation showed a peak of binding activity in the 8S region in a medium of low ionic strength, but in the 4.5S region in a medium containing 9.5 M KCl. The R 1881-binding component was inactivated by mild heat- or trypsin-treatment, but not by treatment with DNase or RNase. Most of the R 1881-binding activity was sedimented at 20 to 40% saturation of ammonium sulfate. These findings indicate that the R 1881-binding component in human placental cytosol is quite similar in its characteristics to androgen receptors, which are present in various androgen-responsive organs. Testosterone was a more potent competitor of R 1881-binding than DHT or cyproterone acetate. Scatchard plots indicated that the binding site of testosterone was identical with that of R 1881. These findings suggest that the androgen receptor in placental cytosol is specific for testosterone. The Kd value for testosterone was calculated to be 3.2 nM.

Cell Membrane↗
PubMed2003

Stimulatory effect of progesterone on the expression of steroidogenic acute regulatory protein in MA-10 Leydig cells.

The steroidogenic acute regulatory protein (StAR), by virtue of its ability to facilitate the intramitochondrial transport of cholesterol, plays an important role in regulating steroid hormone biosynthesis in steroidogenic cells. In agreement with published data, both StAR expression and progesterone production in MA-10 mouse Leydig tumor cells could be stimulated with hCG and 8Br-cAMP. Addition of aminoglutethimide, an inhibitor of cholesterol side chain cleavage (P450(scc)) enzyme, not only resulted in a drastic inhibition of progesterone production but also in an attenuation of StAR expression in response to either hCG or 8-Br-cAMP. Therefore, we addressed the question of whether progesterone, the end product of the steroidogenic cascade in these cells, could be in a position to regulate the StAR gene expression. In MA-10 cells, we report here that progesterone in microgram amounts can induce StAR gene expression in a time- and dose-dependent manner. StAR expression in response to a maximally effective concentration of progesterone of 10 microg/ml was highest at 6 h and started decreasing thereafter. The effect of progesterone on StAR protein and StAR mRNA induction was mimicked by its synthetic analog, progestin R5020, but not by other steroids, including dexamethasone, estradiol, testosterone, and dihydrotestosterone. Dexamethasone, in contrast, was able to inhibit StAR expression in MA-10 cells. Surprisingly, RU486, a potent antagonist of progesterone and glucocorticoid action, had a stimulatory effect on StAR mRNA levels. Reverse transcription-polymerase chain reaction analysis demonstrated the absence of the classical form of progesterone receptor in MA-10 cells. Thus, for the first time, a direct stimulatory effect of a steroid on StAR gene expression has been demonstrated. Furthermore, these results provide a new insight, indicating that progesterone mediates the activation of StAR expression exerted presumably through a novel, nonclassical progesterone receptor in mouse Leydig cells.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2003

Gonadotropin and steroid regulation of matrix metalloproteinases and their endogenous tissue inhibitors in the developed corpus luteum of the rhesus monkey during the menstrual cycle.

The factors regulating the dynamic expression of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in the primate corpus luteum (CL) during the menstrual cycle are unknown. We hypothesized that LH or progesterone (P) regulate interstitial-collagenase (MMP-1), the gelatinases (MMP-2 and -9), TIMP-1, and TIMP-2 in the CL. Hormone ablation/replacement was performed in rhesus monkeys on Days 9-11 of the luteal phase in five treatment groups (n = 4/group): control (no treatment), antide (GnRH antagonist), antide + LH; antide + LH + trilostane (TRL; 3beta-hydroxysteroid dehydrogenase inhibitor), and antide + LH + TRL + R5020 (nonmetabolizable progestin). On Day 12, the CL was removed and the RNA and protein isolated for real-time polymerase chain reaction and immunoassays, respectively. The MMP-1 mRNA increased 20-fold with antide, whereas LH replacement maintained MMP-1 mRNA at control levels. Likewise, TRL increased MMP-1 mRNA 54-fold, and R5020 prevented this effect. Immunodetectable MMP-1 protein also increased with antide or TRL; these increases were abated with LH or R5020. Gelatinase mRNA and/or protein levels increased with antide (e.g., 3-fold, MMP-2 mRNA), and LH replacement reduced protein levels (e.g., 11-fold, MMP-2). The TRL increased MMP-9, but not MMP-2, expression; however, R5020 replacement had no effect on mRNA or protein levels. The LH treatment increased TIMP-1 and -2 mRNA and TIMP-1 protein expression compared to controls and antide groups, whereas R5020 enhanced only immunodetectable TIMP-1. These data strongly suggest that LH suppresses MMP-1 in the primate CL via P and that it also suppresses gelatinases, either at the mRNA (MMP-2) or protein (MMP-2 and -9) levels, perhaps in part via steroids, including P. In contrast, LH promotes TIMP expression, perhaps via steroids, including P.

Animals↗
PubMed2004

Progesterone promotes oocyte maturation, but not ovulation, in nonhuman primate follicles without a gonadotropin surge.

During the periovulatory interval, intrafollicular progesterone (P) prevents follicular atresia and promotes ovulation. Whether P influences oocyte quality or maturation and follicle rupture independent of the midcycle gonadotropin surge was examined. Rhesus monkeys underwent controlled ovarian stimulation with recombinant human gonadotropins followed by a) experiment 1: an ovulatory bolus of hCG alone or with a steroid synthesis inhibitor (trilostane, TRL), or TRL + the progestin R5020; or b) no hCG, but rather sesame oil (vehicle), R5020, or dihydrotestosterone (DHT). In experiment 1, the majority of oocytes remained immature (65% +/- 20%) by 12 h post-hCG. However, the percentage of degenerating oocytes increased (P < 0.05) with TRL (42% +/- 22% vs. 0% controls), but was reduced (P < 0.05) by progestin replacement (15% +/- 7%). By 36 h post-hCG, the majority of oocytes in all three groups reached metaphase II (MI). In experiment 2, no evidence of follicle rupture was observed in the vehicle, R5020, or DHT groups. Despite the absence of hCG, a significant (P < 0.05) percentage of oocytes resumed meiosis to metaphase I in R5020- (41 +/- 9) and DHT- (36 +/- 15) but not vehicle- (4 +/- 4) treated animals. Only oocytes from R5020-treated animals continued meiosis in vivo to MII. More (P < 0.05) oocytes fertilized in vitro with R5020 (40%) than with vehicle (20%) or DHT (22%). Thus, P is unable to elicit ovulation in the absence of an ovulatory gonadotropin surge; however, P and/or androgens may prevent oocyte atresia and promote oocyte nuclear maturation in primate follicles.

Animals↗
PubMed1986

Synergism between granulosa and theca-interstitial cells in estrogen biosynthesis by gonadotropin-treated rat ovaries: studies on the two-cell, two-gonadotropin hypothesis using steroid antisera.

In mammalian ovaries, luteinizing hormone (LH) induces androgen biosynthesis by theca interna cells, whereas both follicle-stimulating hormone (FSH) and LH stimulate aromatase activity by granulosa cells. The joint action of these two types of cell and pituitary hormones forms the basis of a 2-cell, 2-gonadotropin hypothesis for biosynthesis of estrogen. We tested the synergism between these cell types using antisera against the estrogen precursors progesterone and testosterone. Ovaries were obtained from immature rats two days after a single injection of pregnant mare serum gonadotropin (PMSG). Granulosa cells were obtained by puncturing the follicles, and ovarian remnants were dissociated with collagenase to derive cells from the theca interstitium. Granulosa and theca interstitial cells were cultured alone or in combination for 20 h. Granulosa cells secreted negligible amounts of estrogen and testosterone, but contained high aromatase activity. Treatment with both FSH and human chorionic gonadotropin (hCG) increased production of progesterone in granulosa cells. In contrast, theca interstitial cells had negligible aromatase activity. Treatment with hCG, but not FSH, increased androgen production by theca interstitium; the hCG action was further augmented by the inclusion of exogenous progesterone. Furthermore, co-culture of gonadotropin-treated granulosa and theca interstitial cells resulted in substantial increases in estrogen production, indicating synergism between the two types of cell. The increases in estrogen production in the co-cultures were accompanied by decreases in progesterone content. To test the possibility that progesterone released by granulosa cells may serve as a substrate for production of androgen in theca cells, specific antiserum was used to adsorb progesterone present in the medium. Addition of the progesterone antibody inhibited gonadotropin-stimulated production of testosterone (39% decrease) and estrogen (64% decrease) by the combined cell cultures. The inhibitory effect on estrogen production could be reversed by the addition of progesterone (10(-6) M) or testosterone (10(-6) M) but not by the addition of a synthetic progestin, R5020. Since testosterone released from theca cells may serve as the substrate for aromatases in granulosa cells, specific testosterone antiserum was also used. Production of estrogens by the combined cell cultures was inhibited (78%) by the testosterone antiserum, but the inhibitory effect was completely reversed by exogenous testosterone or progesterone. Thus, synergistic interactions between granulosa and theca interstitial cells are important in effecting maximal estrogen biosynthesis.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

Regulation of uterine progesterone receptors by the nonsteroidal anti-androgen hydroxyflutamide.

We have recently reported that the anti-androgen hydroxyflutamide causes delayed implantation and exhibits antideciduogenic activity in the rat. The present experiments were conducted to examine whether hydroxyflutamide binds to the uterine progesterone receptors and/or alters the progesterone binding sites in the uterus. Cytosol and nuclear fractions from decidualized rat uterus were incubated with [3H]-R5020 without or with increasing concentrations of radioinert R5020, RU486, dihydrotestosterone, or hydroxyflutamide. From the log-dose inhibition curves, the relative binding affinity of both hydroxyflutamide and dihydrotestosterone was less than 0.1% and 2%, compared with R5020 (100%) for displacing [3H]-R5020 bound to uterine cytosol and nuclear fractions, respectively. Injection of estradiol-17 beta (1 microgram/rat) to ovariectomized prepubertal rats induced a 1.85-fold increase in uterine weight by 24 h. Hydroxyflutamide at 2.5 or 5.0 mg did not significantly alter the estrogen-induced increase in uterine weight. Compared to vehicle alone, estrogen induced an approximately 5-fold increase in uterine cytosolic progesterone binding sites. Hydroxyflutamide at both 2.5- and 5.0-mg doses significantly attenuated the estrogen-induced elevation in uterine progesterone binding sites. These studies demonstrate that hydroxyflutamide does not bind with high affinity to progesterone receptors, but suppresses the estrogen-induced elevation in progesterone receptor levels in the uterus.

Androgen Antagonists↗
PubMed1989

Estrogen and anti-estrogen effects on the growth of human epithelial ovarian cancer in vitro.

An epithelial ovarian cancer cell line, PE04, has been shown to contain high levels of cytosolic estrogen receptor-like binding. Analysis of PE04 cytosol on low-salt sucrose density gradients demonstrated 7-9S binding of [3H]17 beta-estradiol, with specificity consistent with that of an estrogen receptor. When compared with the proliferation of cells grown in monolayer without steroids, a 50% increase in growth rate of the cell line was observed by treatment with 17 beta-estradiol (E2). Growth stimulation was dose-dependent and maximal at 10(-10) M. The E2 effect on substrate-independent growth was more striking; 3 x 10(-9) M produced a 30-fold increase in cloning efficiency. Treatment with 4-hydroxytamoxifen resulted in a dose-dependent inhibition (maximal at 3 x 10(-9) M) of cell growth, which was reversible by E2. Although treatment with estrogen in systems containing functional estrogen receptor commonly results in progesterone receptor synthesis, E2 induction of progesterone receptor could not be demonstrated in this cell line. The endocrine characteristics of PE04 contrast with those of another ovarian cancer cell line, NIH:OVCAR-3, in which E2 induces progesterone receptor but does not stimulate cell proliferation. This is the first report of an ovarian cancer cell line in which the clinically important end-effect of estrogen, cell growth, has been observed. Furthermore, retention of a mitogenic response to estrogen in the apparent absence of progesterone receptor induction has not been described previously in model systems.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenocarcinoma, Mucinous↗
PubMedDate not supplied

Trimegestone in a low-dose, continuous-combined hormone therapy regimen prevents bone loss in osteopenic postmenopausal women.

OBJECTIVE: To determine the efficacy of estrogen + progestogen therapy with 1 mg 17beta-estradiol and 0.125 mg trimegestone in the prevention of postmenopausal osteoporosis. DESIGN: For this study, 360 healthy, postmenopausal women with osteopenia [lumbar spine bone mineral density (BMD) between -1.0 and -2.5 SD of the premenopausal mean value] were enrolled in a 2-year prospective, randomized study, and 70% completed. Treatments were 1 mg 17beta-estradiol + 0.125 mg trimegestone (n = 179) or placebo (n = 181), given as daily oral therapy. All received a daily supplement of 500 mg calcium and 400 IU vitamin D. BMD measurements at the lumbar spine, total hip, and femoral neck as well as blood and urinary biochemical markers of bone turnover (serum osteocalcin), serum bone-specific alkaline phosphatase, serum CrossLaps, and urinary CrossLaps took place regularly. RESULTS: BMD increases relative to placebo were 6.3%, 3.9%, and 3.8% at the lumbar spine, total hip, and femoral neck, respectively (all P < 0.001). The biochemical markers of bone turnover were suppressed accordingly. Serum CrossLaps and urinary CrossLaps decreased rapidly, by 52% and 54%, respectively, whereas serum osteocalcin and serum bone-specific alkaline phosphatase revealed a more retarded decrease of 40% and 33%, respectively. Of the women receiving hormone therapy, 75% had amenorrhea from the first cycle, and 5% withdrew prematurely due to metrorrhagia or mastalgia. CONCLUSION: This new estrogen + progestogen therapy is efficient in increasing BMD in an osteopenic postmenopausal population. Furthermore, it is well tolerated, with few adverse events and an early bleeding control, which is likely to improve compliance to the treatment over the long term.

Administration, Oral↗
PubMed2005

Sleep apnea and hormone replacement therapy: a pilot study and a literature review.

BACKGROUND: Sleep apnea syndrome (SAS) is a common condition and a risk factor of cardiovascular and cerebrovascular diseases. The purpose of this pilot study was to investigate the effect of a gestagen (trimegeston) and estradiol hormone combination on perimenopausal and postmenopausal women with SAS. METHODS: Four postmenopausal and one perimenopausal women were studied by polysomnography before and after treatment with hormone replacement therapy (HRT). RESULTS: The subjects had a mean reduction of the severity of their sleep apnea by 75% measured by apnea/hypopnea index. CONCLUSIONS: HRT might be an alternative in the treatment of SAS.

Estradiol↗
PubMed1984

Progesterone receptors in breast cancer.

Sixty-six women who had received hormonal therapy for advanced disease were assessed for objective response to treatment. Another 51 patients who had received chemotherapy were similarly studied. Progesterone receptor was of no value as a predictor of patients unlikely to respond to hormone therapy, though it may have a role in predicting patients likely to respond favourably. The addition of progesterone receptor data to oestrogen receptor data may increase prediction of response in the ER+ range but clinicians should be cautious in their interpretation of progesterone receptor results in the ER- range. Progesterone receptor was of no value in predicting response to chemotherapy in this series. Analysis of survival data of 1731 women with primary breast cancer showed a highly significant trend toward longer survival in patients with progesterone receptor positive tumours than in those with receptor negative tumours (P less than 0.001). This trend was evident in both pre- and post-menopausal women. Even though the prognostic discrimination provided by progesterone receptor was correlated with that of oestrogen receptor, the addition of progesterone receptor data to oestrogen receptor data significantly improved prediction of survival (P less than 0.05).

Adult↗
PubMed2000

The effect of submucous fibroids on the dose-dependent modulation of uterine bleeding by trimegestone in postmenopausal women treated with hormone replacement therapy.

OBJECTIVE: To assess the value of identifying endometrial structural abnormalities at baseline hysteroscopy in predicting the pattern of bleeding in postmenopausal women treated with hormone replacement therapy. DESIGN: A randomised, double-blind, dose-ranging study. SETTING: A teaching hospital in the UK. POPULATION: One hundred and seventy-six healthy postmenopausal women. METHODS: Women were randomised to receive one of four doses of oral trimegestone (0.05, 0.1, 0.25 and 0.5 mg per day), from day 15-28, and a daily dose of 2 mg oral micronised oestradiol for six treatment cycles. Women completed diaries in which the bleeding episodes were recorded. Hysteroscopy under local anaesthesia and endometrial biopsy were performed at baseline and on day 24 of the last treatment cycle. RESULTS: Women with submucous fibroids had more prolonged (P = 0.026) and heavier (P = 0.002) progestogen-associated bleeding (odds ratio 4.54). The incidence of intermenstrual bleeding, but not its duration or severity, was higher in women with submucous fibroids (P = 0.017). There was a clear dose-dependent effect of trimegestone, with a consistently later onset of progestogen-associated bleeding occurring with increasing doses of trimegestone (P < 0.001), and such episodes became progressively lighter and of shorter duration over time (P < 0.001). CONCLUSION: Hysteroscopic evaluation of the endometrial cavity in women treated with hormone replacement therapy, predicts the occurrence of heavy and unscheduled bleeding.

Dose-Response Relationship, Drug↗
PubMed1983

Increased androgen binding in keloids: a preliminary communication.

Sex hormone binding protein analyses were performed on six keloids, the adjacent skin, and on six simple scars. A high level of androgen binding (510 to 1149 Fm/mg of cytosol protein) was found in the keloids. The estrogen and progesterone binding activities were low. Para-keloid tissues were found to have androgen binding of 177 to 476 Fm/mg of cytosol protein. Once again, estrogen and progesterone binding activities were low. In six simple scars, androgen binding was less than 1/10 of that found in the keloids (37 to 60 Fm/mg of cytosol protein); estrogen and progesterone binding was so low that it was almost undetectable. We believe this data suggests that localized hyperandrogen metabolism may play a causal or at least contributory role in the pathogenesis of keloids.

Adult↗