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At least 703 records · Page 39Linked to original sources
PubMed2005

Xenoestrogen action in breast cancer: impact on ER-dependent transcription and mitogenesis.

Several estrogen mimics (xenoestrogens) inappropriately activate the estrogen receptor (ER) in the absence of endogenous ligand. Given the importance of the ER in breast cancer growth and regulation, delineating the impact of these agents under conditions related to tumor treatment is of significant importance. We examined the effect of two prevalent xenoestrogens (bisphenol A and coumestrol) on ER activation and ER-dependent mitogenesis in breast cancer cells. We show that the ability of these agents to induce mitogenesis was restricted to conditions of estrogen depletion, and that these agents failed to cooperate with estradiol to induce MCF-7 breast cancer cell growth. These observations are consistent with the impact of each agent specifically on exogenous ER activation as monitored in HeLa cells, wherein the xenoestrogens activated the receptor in the absence of estradiol but failed to cooperate with estrogen. Tamoxifen blocked bisphenol A and coumestrol-mediated ER activation, indicating that exposure to these agents is unlikely to disrupt such therapeutic intervention. The response of tumor-derived ER alleles to these xenoestrogens was also examined. Although the xenoestrogens failed to alter ER-Y537S function, the ER-D351Y mutant demonstrated an enhanced response to bisphenol A. Moreover, tamoxifen enhanced the agonistic effects of xenoestrogens on ER-D351Y. Lastly, we examined the impact of ER co-activator overexpression on xenoestrogen response. Bisphenol A and coumestrol exhibited differential responses to co-activators with regard to ER activation. However, when using mitogenesis as an endpoint, these co-activators were insufficient to provide a significant growth advantage. Combined, these data demonstrate that bisphenol A and coumestrol can impact ER activity and ER-dependent proliferation in breast cancer cells, but the influence of these agents is restricted to conditions of estrogen depletion, selective mutation of the ER, and expression of specific co-activators.

Benzhydryl Compounds↗
PubMed1991

Medical treatment of endometriosis: a comparison of the suppressive effects of danazol and nafarelin on reproductive hormones.

OBJECTIVE: Patients with endometriosis were studied to investigate hormonal suppression by the gonadotropin-releasing hormone against nafarelin acetate compared with danazol. We hypothesized that the pattern, time course, and degree of gonadotropin and ovarian suppression would be different. DESIGN: The study included 16 patients who were randomized into one of three 6-month treatment protocols. SETTING: Patients were recruited from a university hospital setting. PATIENTS: Eligible candidates were 18 to 45 years of age, with regular menses and documented pelvic endometriosis. INTERVENTION: Six-month treatment protocols included nafarelin 800 or 400 micrograms/d, or danazol 800 mg/d. MAIN OUTCOME MEASURES: Serum estradiol (E2), progesterone (P), luteinizing hormone (LH), and follicle-stimulating hormone were determined before treatment and then monthly. Thirteen patients consented to a 12-hour hospital admission during the 5th and 6th month of treatment to determine LH pulse frequency and amplitude. RESULTS: Estradiol and P were suppressed in all groups, but E2 significantly more by nafarelin than danazol (P less than or equal to 0.01). Nafarelin, 800 micrograms, significantly depressed LH pulse amplitude compared with danazol (P less than or equal to 0.05). Two patients in the nafarelin group had the administration of their medication observed, and both demonstrated single, high-amplitude pulses immediately after administration. CONCLUSION: Nafarelin is a more potent LH and E2 suppressor than danazol, and the agonist effect of nafarelin may continue to provoke transient gonadotropin responses despite long-term therapeutic suppression.

Adult↗
PubMed1990

Synthesis and structure-affinity of a series of 7 alpha-undecylestradiol derivatives: a potential vector for therapy and imaging of estrogen-receptor-positive cancers.

A series of 7 alpha-undecylestradiol derivatives, featuring various substituents at the end of the undecyl spacer chain, were synthesized and evaluated for their interaction with the estrogen receptor and nonreceptor sites. Their relative binding affinities (RBA) for calf uterine estrogen receptors were measured by competitive binding assays and varied between 0.5 and 8.4% of that of unlabeled 17 beta-estradiol. Enhanced lipophilicity and steric hindrance of the substituent on the end of the spacer chain resulted in decreased binding affinity for the estrogen receptor, while interactions with nonreceptor sites increased. RBA values were not affected by prolonged incubation times, suggesting a stable ligand-receptor complex. The potential to use the 7 alpha-undecylestradiol as a vector for site-selective delivery of diagnostic and therapeutic moieties to estrogen-receptor-positive human cancers is discussed.

Animals↗
PubMed2001

A reproductive phase-dependent effect of dietary L-tryptophan on pineal gland and gonad of a nocturnal bird, Indian spotted owlet Athene brama.

Unlike other temperate owls, Indian spotted owlet Athene brama possesses a well-developed pineal gland that secrets moderate amount of hydroxy- (serotonin) and methoxy- (melatonin) indoles in circulation. However, in this study, we have reported the response of this endocrine gland to exogenous L-Tryptophan (precursor of the above indoles), and also its effect on gonads of this nocturnal bird. During breeding phase or pineal inactive phase (March), oral treatment of L-Trp (0.5 mg/100 g Bwt/day) significantly increased the pineal gland wt and plasma melatonin (MEL) level, while decreased the gonadal wt and plasma sex steroids levels (estradiol and progesterone in female and testosterone in male). Interestingly, during reproductively quiescent phase or pineal active phase (August), similar amount of L-Trp significantly decreased the plasma MEL level, while increased the above sex steroid levels in plasma. Finally, the results show a clear reproductive phase-dependent inverse effect of L-Trp on pineal gland and gonads for both sexes of the spotted owlets, and suggest that the therapeutic use of this amino acid would be a great advantage for controlling the reproduction of these economically important birds.

Animals↗
PubMed1991

Spontaneous anovulation causing disappearance of cyclical symptoms in women with the premenstrual syndrome.

In the premenstrual syndrome the negative symptoms appear during the luteal phase of the menstrual cycle. Ovulation and the formation of a corpus luteum seem to be of great importance in precipitating the syndrome. In a large group of women with premenstrual syndrome investigated daily with symptom ratings and weekly plasma estradiol and progesterone assays, 8 were found to have one ovulatory and one spontaneously occurring anovulatory menstrual cycle. In both these cycles, the post- and premenstrual phases were compared by testing for recurrence of symptoms. All patients showed a highly significant cyclical worsening of negative premenstrual symptoms during the ovulatory cycles, whereas in the anovulatory cycles the cyclical symptoms disappeared, resulting in relief of the premenstrual syndrome. These results support earlier hypotheses, suggesting that the premenstrual syndrome appears as a result of provoking factors produced by the corpus luteum. This view is in line with earlier therapeutic findings showing that induced anovulation can relieve the premenstrual syndrome.

Adult↗
PubMed1991

Testicular function in active ankylosing spondylitis. Therapeutic response to human chorionic gonadotrophin.

Testicular function was studied in 22 patients with ankylosing spondylitis (AS) with serum measurements of hormone levels, seminal fluid analysis and testicular reserve test. Results were correlated with disease activity. The abnormal findings were elevated luteinizing hormone (LH), inversion of estradiol/testosterone ratio (E2:T) and diminished testicular reserve for testosterone (T) and slightly increased for estradiol (E2). Nine patients with severe active AS received biweekly 2,500 IU of human chorionic gonadotrophin injections with a resulting increase in E2 serum levels. When the values of E2 reached 40 pg/ml or higher, there was a decrease of the sedimentation rate (p less than 0.05) and a reversal to normal of the E2:T ratio. This was accompanied by an improvement in AS at the 10th week that lasted up to 9 weeks after discontinuation of treatment. Our findings suggest a possible role of sex hormones in the physiopathogenesis of AS and offers a possible therapeutic alternative.

20-alpha-Dihydroprogesterone↗
PubMed1988

Endocrinologic and clinical evaluation following a single administration of a gonadotrophin-releasing hormone agonist (Zoladex), in a depot formulation, to premenopausal women.

A single 3.6-mg Zoladex subcutaneous depot injection was effective in suppressing the pituitary-ovarian function for about 5 weeks in nine regularly menstruating, premenopausal volunteers. Menses returned approximately 9 weeks after the injection. Zoladex depot is a novel approach in the administration of GnRH agonists and offers great therapeutic potential.

Adult↗
PubMed1993

[Gestagen-estrogen combinations in gynecology. On the history, dosage and use of a hormone principle].

The first experimental and clinical investigations with gestagen-oestrogen combinations were undertaken in the late 'forties and the early' fifties of this century. In the course of further research and development, the dosage and mixture ratio of this hormonal principle were adjusted, according to the physiological status of the corpus luteum phase and its imitation by means of administration of hormonal doses. Considering the relatively large individual variations, an average daily production of 0.05 mg oestradiol/oestrone and 25 mg progesterone can be assumed, the mixture ratio being 1:50. Further indicators for the dosage were obtained by studying the biological valency of the semi-synthetic substances on the basis of the following parameters: transformation dose, menstruation delay test, anti-oestrogenic effectiveness and ovulation inhibition dose. Finally, dosage was also determined by the relevant indications; in this respect, depending on the intended use, preparations with the emphasis either on the oestrogen component or the gestagen component were deliberately produced. Up to the end of the 'fifties', parenteral gestagen-oestrogen combinations were the only preparations available for gynaecological hormonal therapy. Oral medication was predominant from 1957 onwards. The high ranking achieved by the combination preparations was due to their properties with respect to regulating menstrual haemorrhage and inhibiting proliferation and ovulation, as well as to their antiandrogenic properties. As far as methods of application were concerned, cyclical administration was most frequently employed (including phase variants), therapeutic amenorrhoea being second, whereas high-dosage application in the sense of hormonal pseudopregnancy was less often used. The gestagen-oestrogen combinations have become the most important hormonal principle in gynaecology as therapeutic agents and hormonal contraceptives.

Contraceptives, Oral, Combined↗
PubMedDate not supplied

Chronic phospholipid liposomes administration and ovarian function.

In the past years, hypothalamic phospholipids (H-PL) have been used therapeutically for their behavioral effects. The major pharmacological effect of H-PLs is that they increase the turnover rate of biogenic amines in the brain. Previous studies have also shown that a single i.v. dose of H-PL may influence tha plasma levels of gonadotropins, prolactin (PRL) and growth hormone (GH). Since data have not yet been published concerning the effects, if any, of chronic i.m. administration of H-PL on the ovarian function, the present study was undertaken to gain insight into this issue. Four women were studied. Each subject was given H-PLs by i.m. injection from the 5th to the 20th day of the cycle at the dose of 100 mg/day. Blood samples were repeatedly taken over this period to measure the plasma concentrations of FSH, LH, E2, PRL, and progesterone. GH administration, no side-effects were noted in any of the subjects studied. All subjects presented normal plasma levels of FSH, LH, E2, PRL, and progesterone. GH demonstrated some upward fluctuations, which always regressed rapidly. Our findings demonstrate that chronic H-PL administration at therapeutic doses does not influence the ovarian cycle in women. In the light of our data, it appears that different hormonal effects are elicited by a single i.v. high-dose administration of H-PLs as compared with those produced by chronic i.m. treatment at therapeutic doses.

Adult↗
PubMed2000

Is estradiol a genotoxic mutagenic carcinogen?

The natural hormone 17 beta-estradiol (E2) induces tumors in various organs of rats, mice, and hamsters. In humans, slightly elevated circulating estrogen levels caused either by increased endogenous hormone production or by therapeutic doses of estrogen medications increase breast or uterine cancer risk. Several epigenetic mechanisms of tumor induction by this hormone have been proposed based on its lack of mutagenic activity in bacterial and mammalian cell test systems. More recent evidence supports a dual role of estrogen in carcinogenesis as a hormone stimulating cell proliferation and as a procarcinogen inducing genetic damage. Tumors may be initiated by metabolic conversion of E2 to 4-hydroxyestradiol catalyzed by a specific 4-hydroxylase (CYP1B1) and by further activation of this catechol to reactive semiquinone/quinone intermediates. Several types of direct and indirect free radical-mediated DNA damage are induced by E2, 4-hydroxyestradiol, or its corresponding quinone in cell-free systems, in cells in culture, and/or in vivo. E2 also induces various chromosomal and genetic lesions including aneuploidy, chromosomal aberrations, gene amplification, and microsatellite instability in cells in culture and/or in vivo and gene mutations in several cell test systems. These data suggest that E2 is a weak carcinogen and weak mutagen capable of inducing genetic lesions with low frequency. Tumors may develop by hormone receptor-mediated proliferation of such damaged cells.

Animals↗
PubMed2000

[Effect of kidney-replenishing herbs on ovarian function of dexamethasone-induced osteoporosis in rats].

OBJECTIVE: To investigate the effect of Kidney-replenishing herbs (KRH) on ovarian function of experimental rats with dexamethasone-induced osteoporosis (OP). METHODS: Radioimmunoassay was used to analyse blood level of growth hormone (GH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E2), progesterone (P), testosterone (T) and prolactin (PRL) of animals and data of three groups, the normal control group, the pathologic control group (non-treated OP model) and the treated group (model rats treated with KRH) were compared. Weight and histomorphological features of ovary and uterus of the rats were also observed. RESULTS: As compared with the normal control group, levels of GH, LH, FSH, E2 and P in the pathologic control group were significantly lowered (P < 0.05), and the weight of ovary and uterus decreased (P < 0.05). In comparison of the treated group and the pathologic group, GH, LH, FSH, E2 and P levels were significantly higher and weight of ovary and uterus heavier in the treated group (P < 0.05). No obvious changes occurred in T and PRL levels. KRH showed markedly improving effect on the ovarian and uterine morphological construction of rats. CONCLUSIONS: KRH could elevate the level of GH, LH, FSH, E2 and P, increase the weight and improve the histomorphologic features of ovary and uterus in OP rats, it demonstrated that KRH has therapeutic effect in treating dexamethasone-induced OP rats.

Animals↗
PubMed1982

Reduction of proline transport in R3230AC mammary carcinomas by estrogens in vitro.

The effects of estrogens on proline and leucine transport into enzymatically dissociated cells from the R3230AC mammary adenocarcinoma were studied. Estradiol-17beta demonstrated a time- and dose-dependent reduction of proline transport; at 10-6M, transport of proline was decreased by 50 percent. Kinetic analysis of these effects indicate that estradiol displayed characteristics of a non-competitive inhibitor, with a Ki of 1.79 microM. Other estrogens, and the anti-estrogen tamoxifen, gave somewhat higher estimated Ki values and could be ranked as inhibitors as follows estradiol 17beta greater than diethylstilbestrol greater than tamoxifen greater than estriol congruent to estrone greater than estradiol-17alpha. No effects of these estrogens on leucine transport were observed, indicating their selectiveness for the A system. The synthetic glucocorticoid, dexamethasone, was comparable to diethylstilbestrol as an inhibitors of proline transport, but dexamethasone also decreased transport of leucine, Testosterone and progesterone were approximately comparable to estrone in their actions. It is proposed that these actions of estrogens represent one potential mechanism whereby pharmacological levels exert therapeutic benefit in the treatment of advanced breast cancer.

Adenocarcinoma↗
PubMed1997

Biochemical effects of estrogen on articular cartilage in ovariectomized sheep.

Cartilage is a sex-hormone-sensitive tissue but the role of estrogen in the pathogenesis of osteoarthritis (OA) remains controversial. In this study, intrinsic material properties and thickness of articular cartilage of the knee joint of ovariectomized (OVX) and estrogen-treated sheep were measured. Skeletally mature ewes (N = 36, same breed, same housing 4-5 years old) were divided into; sham treated (n = 9), OVX (N = 13), OVX plus one estradiol implant (OVXE; N = 10) and OVX plus two estradiol implants (OVX2E; N = 4). Twelve months following sham procedure or OVX, sheep were euthanized and articular cartilage from a total of 216 points in the left femorotibial (knee) joints was tested for aggregate modulus, Poisson's ratio, permeability, thickness and shear modulus (six sites per sheep). When all of the sites in each knee were grouped together, OVX had a significant effect on articular cartilage. The sham cartilage of all sites grouped together had a larger aggregate modulus (P = 0.001) and a larger shear modulus (P = 0.054) than the OVX tissue. No statistically significant differences were seen for permeability and thickness between OVX, sham, OVXE and OVX2E. Differences existed in biomechanical properties at the different sites that were tested. Overall, no one location tended to be lowest or highest for all variables. This biomechanical study suggests that OVX may have a detrimental effect on the intrinsic material properties of the articular cartilage of the knee, even though the cartilage of the OVX animals appeared normal. Treatment with estradiol implants ameliorated these deleterious effects and may have helped maintain the tissue's structural integrity. Our study supports epidemiological studies of OA in women after menopause. The protective effect of estrogen and it's therapeutic effect remain to be further defined. This model may allow the relationship of estrogen and estrogen antagonists to be studied in greater detail, and may be valuable for the study of the pathogenesis and therapies of OA of postmenopausal women, particularly in its early stages.

Animals↗