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At least 433 records · Page 24Linked to original sources
PubMed2006

Glutamate-mediated excitotoxicity in neonatal hippocampal neurons is mediated by mGluR-induced release of Ca++ from intracellular stores and is prevented by estradiol.

Hypoxic/ischemic (HI) brain injury in newborn full-term and premature infants is a common and pervasive source of life time disabilities in cognitive and locomotor function. In the adult, HI induces glutamate release and excitotoxic cell death dependent on NMDA receptor activation. In animal models of the premature human infant, glutamate is also released following HI, but neurons are largely insensitive to NMDA or AMPA/kainic acid (KA) receptor-mediated damage. Using primary cultured hippocampal neurons we have determined that glutamate increases intracellular calcium much more than kainic acid. Moreover, glutamate induces cell death by activating Type I metabotropic glutamate receptors (mGluRs). Pretreatment of neurons with the gonadal steroid estradiol reduces the level of the Type I metabotropic glutamate receptors and completely prevents cell death, suggesting a novel therapeutic approach to excitotoxic brain damage in the neonate.

Animals↗
PubMed2001

Effect of therapeutic ultrasound on partition and diffusion coefficients in human stratum corneum.

Application of various enhancers including ultrasound and chemicals has been shown to enhance transdermal drug transport. Most of these enhancers increase transdermal transport by increasing either partition or diffusion coefficients in lipid bilayers. Although the effect of such enhancers on skin permeability has been measured in many cases, the effect of the same enhancers on solute partition and diffusion coefficients has not been measured since such measurements are difficult. In this paper, we describe application of a new method that can be used to determine the effect of enhancers on partition and diffusion coefficients. This method is based on two independent measurements of the transport properties of the SC and a theoretical model. This method was tested for five solutes including estradiol, napthol, aldosterone, lidocaine, and testosterone. Measurements based on our method showed that the primary effect of therapeutic ultrasound (1 MHz) is on diffusion coefficient and not partition coefficient. Specifically, ultrasound enhanced diffusion coefficients of these solutes by up to 15-fold. However, it did not significantly enhance partition coefficients. The method described in this paper is quite general and can be used to measure the effect of various enhancers on partition and diffusion coefficients.

Algorithms↗
PubMed2006

Potential of the FES-hERL PET reporter gene system -- basic evaluation for gene therapy monitoring.

PURPOSE: In vivo reporter genes can be powerful tools in supporting and ensuring the success of gene therapy. A careful and rational design of a reporter system is essential to realize a noninvasive in vivo reporter gene imaging system applicable for humans. We designed a new in vivo reporter gene imaging system that uses F-18-labeled estradiol (FES) and human estrogen receptor ligand (hERL) binding domain, taking advantage that FES is a radiopharmaceutical already being used for human studies with access to a wide range of tissues, including the brain, and that hERL lacking DNA binding domain can no longer work as a transcription factor, and carried out basic studies to evaluate its potential for gene therapy monitoring. METHODS: We constructed a plasmid (pTIER) to coexpress a model therapeutic gene and the reporter gene hERL and transfected Cos7 cells and examined their uptake of [(3)H]estradiol and FES in culture media. The uptake of FES by mouse calf muscle electroporated with pTIER was also tested. RESULTS: The cells transfected with pTIER took up the radioligands efficiently and specifically in culture media. Also, the mouse calf muscle electroporated with pTIER accumulated a higher amount of FES than did the control. CONCLUSION: The data indicate that our new reporter gene system seems promising for in vivo imaging of gene expression and gene therapy monitoring.

Animals↗
PubMed1998

[Endometriosis: clinical, histological and morphometric findings before and after Gn-RH agonist therapy].

After bioptical diagnosis of endometriosis, 81 patients were treated with GnRH-agonists buserelin or leuprolide for six months. Biopsies before and after treatment were used to test a semiquantitative score-system, regarding atrophy of glands and stroma cells. Furthermore glandular diameter, circumference and area of nuclei were examined morphometrically using a microscopic semiautomatical measuring system. Morphometrical and histological alterations during therapy were evaluated. Additionally, data suitable for predicting a possible therapeutic success were described. After therapy 40 patients still showed endometriotic implants (partial responder) in contrast to 41 cases without foci (total responder). Therapeutic effect of GnRH-agonists was proved in every respect: clinical complaints decreased markedly during GnRH-agonists therapy. Both buserelin and leuprolide treated groups revealed increase of atrophy and reduction of extension of stroma. Correspondingly morphometrical analysed parameters such as diameter, circumference and area of glands decreased during therapy as well as area of cytoplasm and nuclei. Except the diameter of glands, the leuprolide treated partial responder group (residual foci after GnRH-therapy) revealed a stronger therapeutic effect than the buserelin treated partial responder group. Obviously this effect seems to be produced by the stronger estradiol suppression of leuprolide. Pretherapeutic comparison of measured values pointed out a minor distinct endometriosis in the total responder group. Success or failure of therapy seems to depend more on the pretherapeutic degree of expression of endometriosis. Obviously the kind of applicated GnRH-agonist plays a minor distinct role. Morphometrical data of endometriotic foci appear to be appropriate to predict a possible therapeutic success of GnRH-agonist therapy. But because of many exceptions only a roughly estimated prediction is possible.

Adult↗
PubMed2006

17beta-estradiol, genistein, and 4-hydroxytamoxifen induce the proliferation of thyroid cancer cells through the g protein-coupled receptor GPR30.

The higher incidence of thyroid carcinoma (TC) in women during reproductive years compared with men and the increased risk associated with the therapeutic use of estrogens have suggested a pathogenetic role exerted by these steroids in the development of TC. In the present study, we evaluated the potential of 17beta-estradiol (E2), genistein (G), and 4-hydroxyta-moxifen (OHT) to regulate the expression of diverse estrogen target genes and the proliferation of human WRO, FRO, and ARO thyroid carcinoma cells, which were used as a model system. We have ascertained that ARO cells are devoid of estrogen receptors (ERs), whereas both WRO and FRO cells express a single variant of ERalpha that was neither transactivated, modulated, nor translocated into the nucleus upon treatment with ligands. However, E2, G, and OHT were able either to induce the transcriptional activity of c-fos promoter constructs, including those lacking the estrogen-responsive elements, or to increase c-fos, cyclin A, and D1 expression. It is noteworthy that we have demonstrated that the G protein-coupled receptor 30 (GPR30) and the mitogen-activated protein kinase (MAPK) pathway mediate both the up-regulation of c-fos and the growth response to E2, G, and OHT in TC cells studied, because these stimulatory effects were prevented by silencing GPR30 and using the MEK inhibitor 2'-amino-3'-methoxyflavone (PD 98059). Our findings provide new insight into the molecular mechanisms through which estrogens may induce the progression of TC.

Antineoplastic Agents↗
PubMed1984

[Pharmacology and metabolism of a new therapeutic drug for prostatic cancer "Estracyt"].

Estracyt is a new drug for treatment of prostatic cancer, which is a molecule combining estradiol and nornitrogen mustard by a carbamate link. Estracyt is completely dephosphorylated prior to reaching the peripheral circulation after oral administration of the drug to men. Estramustine, i. e. dephosphorylated Estracyt, appears to be metabolized in liver as follows: Estramustine leads to estromustine leads to nitrogen mustard + estrone. There is a large amount of estramustine binding protein (EMBP) in the cytosol 3.5 S fraction of human prostatic cancer tissue, which is involved with the selective uptake and long term retention of both estramustine and estromustine in prostate. The anticancer action of Estracyt appears to be the sum of the direct prostatic action of estramustine and estromustine and the indirect prostatic action of free estradiol-17 beta and estrone via the inhibition of hypothalamo-pituitary axis. Estracyt Research Group in Japan concluded that Estracyt was effective in 38% of reactivated prostatic cancer patients (15% (I-C, I-B), 23% (I-A, O-B, O-C]. Side effects of this drug at the time of 3 months treatment is as follows: gastrointestinal disturbance in 36%, edema in 15%, and hepatic disorder in 7%.

Animals↗
PubMed1994

Estrogen receptor-associated proteins: possible mediators of hormone-induced transcription.

The estrogen receptor is a transcription factor which, when bound to estradiol, binds DNA and regulates expression of estrogen-responsive genes. A 160-kilodalton estrogen receptor-associated protein, ERAP160, was identified that exhibits estradiol-dependent binding to the receptor. Mutational analysis of the receptor shows that its ability to activate transcription parallels its ability to bind ERAP160. Antiestrogens are unable to promote ERAP160 binding and can block the estrogen-dependent interaction of the receptor and ERAP160 in a dose-dependent manner. This evidence suggests that ERAP160 may mediate estradiol-dependent transcriptional activation by the estrogen receptor. Furthermore, the ability of antiestrogens to block estrogen receptor-ERAP160 complex formation could account for their therapeutic effects in breast cancer.

Base Sequence↗
PubMed2000

Low-dose oral contraceptives: health consequences of discontinuation.

Presently, the lowest effective estrogen dose available as a combination oral contraceptive (OC) in the United States is 20 microg of ethinyl estradiol (EE) with different progestins. Twenty micrograms of EE coupled with levonorgestrel results in fewer side effects and cycle control comparable with higher-dose pills. Differences between therapeutically equivalent and brand-name, low-dose oral contraceptives, with respect to the bioavailability of hormones, may interfere with contraceptive efficacy and increase breakthrough bleeding. One of the most common reasons why women discontinue OCs is increased breakthrough bleeding. Because after OC discontinuation most women switch to a less-effective method, or no method, of contraception, an increase in breakthrough bleeding could ultimately result in an increase in unintended pregnancy. Thus, substituting a therapeutically equivalent for a brand-name low-dose oral contraceptive may have significant clinical and economic effects on individual and public health.

Adolescent↗
PubMed1983

Differential response of an ovarian-responsive mouse mammary tumor to androgenic and estrogenic agents.

An ovarian-responsive mammary tumor subline, T4-OR26, was isolated from an outgrowth of a progressed TPDMT-4 pregnancy-dependent mammary tumor in a virgin DDD mouse. T4-OR26 tumors were characterized by significantly faster growth in virgin mice than in ovariectomized mice. Both estrogen and progesterone were important for growth of the subline, as they were for that of the parent. Tamoxifen (TAM), with estrogenic activity, and epithiostanol (EPI) and testosterone propionate, with androgenic activity, which all caused TPDMT-4 tumors to regress, were compared for antitumor potency against the new subline by 3 s.c. injections weekly in virgins. EPI at 300 micrograms and testosterone propionate at 1000 micrograms elicited immediate tumor growth suppression with subsequent slight regression as did ovariectomy. TAM at 1000 micrograms caused tumor growth suppression after 2 weeks without subsequent regression. At 600 micrograms, EPI but not TAM significantly inhibited 17 beta-estradiol plus progesterone-induced tumor growth; at 400 micrograms, neither had any significant effect on the tumor growth induced by 17 beta-estradiol alone. With regard to their effect on hormone receptors, it was noted that EPI and testosterone propionate treatments with tumor regression caused significant reduction in cytoplasmic progesterone receptor, but TAM treatment, which does not influence tumor growth, did not cause such reduction. The results provide evidence that hormone-dependent mammary tumors may acquire greater resistance to estrogenic than to androgenic therapeutics with progression.

Androstanols↗
PubMed1988

Iliac crest biopsy in longitudinal therapeutic trials of osteoporosis.

Changes in tetracycline-labelled iliac crest biopsies taken before and after 1 year of treatment with nandrolone decanoate + calcium, 17 beta-estradiol + norethisterone acetate + calcium or placebo were compared with changes in plasma bone Gla protein (pBGP), serum alkaline phosphatase (sAP), whole body retention (WBR) of Technetium-99m-diphosphonate [( 99mTc]DP) and bone mineral content (BMC) of the forearm. Based on a comparison between biopsy and noninvasive results, as well as on evaluation of the variation in the groups, certain guidelines for the use of bone histomorphometry in longitudinal therapeutic trials are suggested. It is proposed that bone biopsy is not used to monitor changes in amount of bone and that evaluation of changes in biopsy evaluated bone turnover is only attempted when the groups are large.

Aged↗
PubMed1978

Therapy of androgenetic sympatomatology with cyproterone acetate and ethinyl estradiol.

The effectiveness of therapy with cyproterone acetate and ethinyl estradiol was studied in 103 women. Acne and seborrhea responded best with 91.7 and 93.3% respectively, including complete and partial therapeutic success. For hirsutism complete remission and partial improvement were found in 75.3% of the treated women. Under therapy, body weight did not change in 51.9%, while 24.7% of the patients gained weight and 23.4% lost weight. The cycle length remained normal after therapy in 35.8%. Normalization or improvement was found in 54.7%. In 6.3% no improvement was noted after therapy and in 3.2% cycle irregularity developed in women with previous undisturbed pattern. According to BBT, improvement of the functional capacity of the reproductive system was found in 32.9% of the patients. Only 3% of the women studied demonstrated a deterioration. The 17-ketosteroid excretion was diminished in 35.3% after therapy and remained unchanged in 64.7%. The therapeutic regimen used for the study was well tolerated and good cycle control was obtained.

17-Ketosteroids↗
PubMed2002

Barriers to remember: brain-targeting chemical delivery systems and Alzheimer's disease.

Brain-targeted chemical delivery systems (CDSs) represent rational drug design attempts not only to deliver but also to target drugs to their site of action. Using a sequential metabolism approach, the special bidirectional properties of the blood-brain barrier can be exploited to smuggle the precursors of therapeutic compounds across the barrier and lock them inside the brain ready for sustained release of the active drugs. Many potential therapeutic applications can be envisioned for such CDSs; here, the potential of brain-targeted estradiol for the prevention and treatment of Alzheimer's disease is reviewed in detail.

Alzheimer Disease↗
PubMed1979

Serum sex hormone binding globulin and testosterone binding after estradiol administration, castration, and their combination in men with prostatic carcinoma.

We measured serum sex hormone binding globulin (SHBG) binding capacity, the index of testosterone binding to SHRG, and the serum concentrations of testosterone, 5 alpha-dihydrotestosterone, and estradiol in 16 patients treated for advanced prostatic carcinoma in order to evaluate the effectiveness of various therapeutic regimes in reducing total and biologically active androgen in blood. Polyestradiol phosphate (Estradurin, 80 mg im as a monthly injection) treatment alone is not as efficient as castration in reducing serum testosterone and 5 alpha-dihydrotestosterone. There was no clear difference between the castration and combination treatment (castration followed by polyestradiol phosphate administration) groups in this respect. It is apparent that Estradurin treatment alone and in combination with castration results in small but significant increases in SHBG binding capacity, whereas this parameter did not alter after castration alone. All three forms of treatment resulted in relatively similar significant increases in the index of testosterone binding to SHBG. The rather mild effect of Estradurin on the parameters measured may be attributable to the binding of the exogenous estradiol to SHBG, which thus greatly reduces its biologic activity. We concluded that castration is clearly more effective in reducing the amount of biologically active testosterone than Estradurin and the combination of these treatments has little influence on further reducing total or biologically active circulating testosterone.

Aged↗