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At least 595 records · Page 33Linked to original sources
PubMed2005

The selective estrogen receptor modulators, tamoxifen and raloxifene, impair dendritic cell differentiation and activation.

Most immune cells, including myeloid progenitors and terminally differentiated dendritic cells (DC), express estrogen receptors (ER) making these cells sensitive to estrogens. Our laboratory recently demonstrated that 17-beta-estradiol (E2) promotes the GM-CSF-mediated development of CD11c+ CD11b(int) DC from murine bone marrow precursors. We tested whether the therapeutic selective estrogen receptor modulators (SERM), raloxifene and tamoxifen, can perturb DC development and activation. SERM, used in treatment of breast cancer and osteoporosis, bind to ER and mediate tissue-specific agonistic or antagonistic effects. Raloxifene and tamoxifen inhibited the differentiation of estrogen-dependent DC from bone marrow precursors ex vivo in competition experiments with physiological levels of E2. DC differentiated in the presence of SERM were assessed for their capacity to internalize fluoresceinated Ags as well as respond to inflammatory stimuli by increasing surface expression of molecules important for APC function. Although SERM-exposed DC exhibited increased ability to internalize Ags, they were hyporesponsive to bacterial LPS: relative to control DC, they less efficiently up-regulated the expression of MHC class II, CD86, and to a lesser extent, CD80 and CD40. This phenotype indicates that these SERM act to maintain DC in an immature state by inhibiting DC responsiveness to inflammatory stimuli. Thus, raloxifene and tamoxifen impair E2-promoted DC differentiation and reduce the immunostimulatory capacity of DC. These observations suggest that SERM may depress immunity when given to healthy individuals for the prevention of osteoporosis and breast cancer and may interfere with immunotherapeutic strategies to improve antitumor immunity in breast cancer patients.

Adjuvants, Immunologic↗
PubMed1996

[Systemic sensitization to 17-beta estradiol induced by transcutaneous administration].

INTRODUCTION: Transdermal administration of drugs to obtain a systemic effect may lead to allergic sensitization and compromise subsequent use via another administration route. OBSERVATION: A 52-year-old woman presented contact eczema with the transdermal therapeutic system Estraderm TTS50. Generalized eczema developed later after oral administration of an oestrogen derivative. Skin tests demonstrated allergic sensitization to 17 beta-oestradiol. DISCUSSION: Contact eczema due to transdermal therapeutic systems are usually caused by agents other than the active drug. Sensitization to the active drug raises the risk of generalized eczema and subsequent systemic complications. This risk must be taken into account when prescribing substitution hormone therapy for menopause.

Administration, Cutaneous↗
PubMed1993

Development of children and adolescents: physiological, pathophysiological, and therapeutic aspects.

Luteinizing hormone (LH) secretion is pulsatile with nocturnal augmentation even in prepubertal children, though at very low concentrations. With puberty wake-time, LH concentration increases 100-fold. Rising estradiol levels transiently increase growth hormone (GH) concentrations, which in turn leads to increases in insulin-like growth factor (IGF)-I, insulin resistance, and physiological hyper-insulinemia. In addition to estrogens, GH-IGF are important in accretion of bone mineral density (BMD) in puberty, and hypofunction may cause permanent low bone density. Growth hormone treatment of girls with Turner syndrome increases final height.

Adolescent↗
PubMed2003

Modulation of the folate receptor alpha gene by the estrogen receptor: mechanism and implications in tumor targeting.

The folate receptor (FR) type alpha is a promising target for diagnostic imaging agents and therapeutic intervention in major subtypes of gynecological malignancies; however, the receptor levels in the tumors are variable and are generally relatively low in estrogen receptor (ER)-positive tumors. Here we report that the FR-alpha gene promoter is repressed in the presence of 17beta-estradiol and derepressed by the antiestrogens tamoxifen and ICI 182780 in a promoter-specific and ER-alpha-dependent manner in carcinoma cell lines including HeLa (cervical carcinoma), BG-1 (ovarian carcinoma), and IGROV-1 (ovarian carcinoma). The ligand and ER dose response of the FR-alpha promoter and its time course paralleled those of a classical estrogen response element-mediated effect. Antiestrogens produced an ER-dependent increase of up to 36-fold in the expression of the endogenous FR-alpha gene. Deletion analysis and FR-alpha/SV40 promoter chimeras showed that the ER effect is mediated exclusively within the G/C-rich region in the TATA-less P4 promoter of FR-alpha; electrophoretic mobility shift analysis demonstrated interaction of ER at only one of three G/C-rich elements. ER-beta only modestly affected FR-alpha promoter activity but did not diminish the ER-alpha-mediated effects. The ER corepressor, SMRT, enhanced the repression by 17beta-estradiol/ER, but ER coactivators, including SRC family members, did not appreciably impact the ER ligand response. The results suggest that in ER+ tumors, FR-alpha expression is directly and actively suppressed and predict that a brief treatment with antiestrogens will boost FR-alpha expression by passive derepression, enhancing the efficacy of FR-targeted diagnostic and therapeutic applications. They also reveal novel aspects of gene repression by ER.

Carrier Proteins↗
PubMed2006

Glutamate-induced apoptosis in neuronal cells is mediated via caspase-dependent and independent mechanisms involving calpain and caspase-3 proteases as well as apoptosis inducing factor (AIF) and this process is inhibited by equine estrogens.

BACKGROUND: Glutamate, a major excitatory amino acid neurotransmitter, causes apoptotic neuronal cell death at high concentrations. Our previous studies have shown that depending on the neuronal cell type, glutamate-induced apoptotic cell death was associated with regulation of genes such as Bcl-2, Bax, and/or caspase-3 and mitochondrial cytochrome c. To further delineate the intracellular mechanisms, we have investigated the role of calpain, an important calcium-dependent protease thought to be involved in apoptosis along with mitochondrial apoptosis inducing factor (AIF) and caspase-3 in primary cortical cells and a mouse hippocampal cell line HT22. RESULTS: Glutamate-induced apoptotic cell death in neuronal cells was associated with characteristic DNA fragmentation, morphological changes, activation of calpain and caspase-3 as well as the upregulation and/or translocation of AIF from mitochondria into cytosol and nuclei. Our results reveal that primary cortical cells and HT22 cells display different patterns of regulation of these genes/proteins. In primary cortical cells, glutamate induces activation of calpain, caspase-3 and translocation of AIF from mitochondria to cytosol and nuclei. In contrast, in HT22 cells, only the activation of calpain and upregulation and translocation of AIF occurred. In both cell types, these processes were inhibited/reversed by 17beta-estradiol and Delta8,17beta-estradiol with the latter being more potent. CONCLUSION: Depending upon the neuronal cell type, at least two mechanisms are involved in glutamate-induced apoptosis: a caspase-3-dependent pathway and a caspase-independent pathway involving calpain and AIF. Since HT22 cells lack caspase-3, glutamate-induced apoptosis is mediated via the caspase-independent pathway in this cell line. Kinetics of this apoptotic pathway further indicate that calpain rather than caspase-3, plays a critical role in the glutamate-induced apoptosis. Our studies further indicate that glutamate- induced changes of these proteins can be inhibited by estrogens, with Delta8,17beta-estradiol, a novel equine estrogen being more potent than 17beta-estradiol. To our knowledge, this is the first demonstration that glutamate-induced apoptosis involves regulation of multiple apoptotic effectors that can be inhibited by estrogens. Whether these observations can help in the development of novel therapeutic approaches for the prevention of neurodegenerative diseases with estrogens and calpain inhibitors remains to be investigated.

Animals↗
PubMed1990

Ovulation inhibitors containing cyproterone acetate or desogestrel in the treatment of hyperandrogenic symptoms.

An open, randomized, multicenter study was carried out to compare two oral contraceptives as regards their therapeutic efficacy in androgenization symptoms such as acne, seborrhea and hirsutism in women. The preparations used were the combination of 2 mg cyproterone acetate (CPA) with 0.035 mg ethinyl estradiol (EE) (Diane 35, Schering AG, Berlin-West) and 0.150 mg desogestrel (DG) with 0.03 mg ethinyl estradiol (Marvelon, Organon, Oss, The Netherlands). The duration of therapy was 9 months. The combination of CPA-EE was used by 83 patients for 658 cycles and the combination of DG-EE by 79 women for 618 cycles. No pregnancy occurred under either therapy. Both preparations are well tolerated. However, some side-effects, such as reduced libido, nervousness and breast tenderness, were observed more frequently (p less than 0.05) in the DG-EE group than among the users of the CPA-EE combination. The therapeutic outcome was better in the CPA-EE group, especially in cases of facial acne (p less than 0.05). Seborrheic symptoms also responded better to the CPA-EE therapy. The results show that the CPA-EE combination is superior to the DG-EE combination in the treatment of acne and seborrhoea.

Acne Vulgaris↗
PubMed2005

The pharmacognosy of Humulus lupulus L. (hops) with an emphasis on estrogenic properties.

As the population ages, there is an ever-increasing need for therapeutic agents that can be used safely and efficaciously to manage symptoms related to postmenopausal estrogen deficiency. Endogenous estrogens, e.g., 17beta-estradiol, of exogenous mammalian origin, e.g., horses, have long been used to manage such symptoms. There are more than 20 different classes of phytochemicals that have demonstrated affinity for human estrogen receptors in vitro. Some studies on exogenous estrogenic substances of botanical origin (phytoestrogens), such as standardized formulations of plant extracts with in vitro and in vivo estrogenic activity from soy (Glycine max Merill.) and red clover (Trifolium pratense L.), suggest clinical efficacy. Few clinical data for phytoestrogens other than isoflavonoids are available. In an exhaustive review of the literature through 2003, only two clinical trials were identified that were designed to evaluate the effect of hops (Humulus lupulus L.) on symptoms related to menopause. Folkloric, chemical, and biological literature relating primarily to the use of hops for their estrogenic activity, and two human clinical trials, are reviewed.

Estrogens↗
PubMed2000

Clinical equivalence of intranasal and oral 17beta-estradiol for postmenopausal symptoms.

OBJECTIVE: The aim of this study was to demonstrate clinical equivalence between a novel intranasal estradiol formulation and a reference oral drug. STUDY DESIGN: In this multinational, double-blind, parallel-group study 659 postmenopausal women with moderate to severe postmenopausal symptoms were randomly assigned to receive either 300 microg/d intranasal 17beta-estradiol (S21400) or 2 mg/d oral micronized estradiol, plus the appropriate placebo, for 24 weeks. All patients also received 10 mg/d dydrogesterone for 14 days per 28-day cycle. Adjustment of intranasal dosage was permitted from week 14 on. The primary efficacy criterion was the Kupperman index at week 14, with a predefined limit of equivalence of 4. RESULTS: Kupperman index scores improved similarly in the 2 groups, from 28.4 +/- 6.2 to 10.0 +/- 8.6 (mean +/- SD) for S21400 and from 28.1 +/- 6.0 to 8.9 +/- 8.0 for oral therapy, with a difference between groups at week 14 of 1.1 +/- 0.6 (90% confidence interval, 0. 0 to 2.2). This was below the predefined equivalence limit of +4 for statistical noninferiority (P <.001). The daily number and intensity of hot flushes decreased similarly in the two treatment groups. Withdrawal bleeding was 20% less frequent with intranasal therapy (90% confidence interval, 12.5 to 27.6). Severe mastalgia was less frequent in the S21400 group (1.0%) than in the group with oral therapy (5.2%; P <.01). Triglyceride and angiotensinogen levels increased significantly with oral therapy but not with S21400. The same number of patients required dose adaptation in the 2 groups (approximately 20%). CONCLUSION: Intranasal administration of 300 microg/d estradiol was at least as effective as oral administration of 2 mg/d estradiol in alleviating postmenopausal symptoms, with less frequent mastalgia and uterine bleeding and without the metabolic consequences of the first-pass effect.

Administration, Intranasal↗
PubMed1987

Preliminary results of treatment and endocrinology of chronic endometritis in the dairy cow.

Cows with chronic endometritis were treated by using uterine irrigation, prostaglandin or oestradiol benzoate. An attempt was made to relate the success of treatment to the nature of the discharge. No statistically significant differences were demonstrated between the different treatments, nor did the severity of the disease as judged by the amount of pus in the discharge affect the success of treatment. Progesterone and in some cases a metabolite of prostaglandin were measured in a milk sample taken at the time of treatment. Increased prostaglandin concentrations were found in 69 of 71 samples examined but they were not correlated with the progesterone concentrations. These measurements from cases of endometritis were higher than those from normal cows in the immediate post partum period and during established oestrous cycles. Treatment with prostaglandin when the concentration of progesterone was high was not more effective than when progesterone concentrations were low. Treatment had less influence on the subsequent fertility of the cow than other factors investigated; in particular, the sooner after calving the cow was treated the greater was the chance of success. This was thought to be due, at least in part, to the high rate of spontaneous recovery. Before treatment can be evaluated effectively a method must be found to identify persistent cases.

Animals↗
PubMed1989

Influence of the size of the area of treatment on percutaneous absorption of estradiol in the rat.

The influence of the dose, as well as the application area of topically applied 3H-estradiol in a volatile solution on its systemic bioavailability was investigated in hairless rats in vivo. The bioavailability was determined by comparing the urinary and fecal excretion of radioactivity after intravenous injection and after topical application. Whatever the size of the surface of application (1, 4 or 16 cm2), the bioavailability was similar (47-65%) 4 days after the application of a single low dose (50 nmol). When the surface of application was washed 24 h after dosing, the absorption was the same for the areas of 3 and 9 cm2. In all cases average fluxes on the first day were higher for the larger area. When applied doses were increased (1,000 and 10,000 nmol), the percentage of percutaneous absorption decreased with the reduction in the areas of application. Thus, with a dose of 1,000 nmol applied on a surface of 1, 4 and 16 cm2, absorption was equal to 18.7, 21 and 37%, respectively, of the dose. There was a linear relationship between the log of the dose applied per unit of skin area and the percentage of absorption after 4 days (r = 0.99 with washing; r = 0.98 without washing).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Topical↗
PubMed1999

Ribozyme-mediated cleavage of the estrogen receptor messenger RNA and inhibition of receptor function in target cells.

Estrogen receptor (ER) functions as a ligand-activated transcription factor for estrogen-regulated genes. Because of the critical role of the ER in the proliferation of certain estrogen-dependent cancer cell types such as the mammary tumor, inhibitors of estrogen action at the level of receptor function are of major clinical interest. Here we describe developments of two ribozymes that can selectively degrade the human ER mRNA and inhibit trans-activation of an artificial promoter containing the estrogen response element. Two ribozymes, designated RZ-1 and RZ-2, cleave the human ER alpha mRNA at nucleotide positions +956 and +889, respectively. These cleavage sites lie within the coding sequence for the DNA-binding domain of the receptor protein. Both RZ-1 and RZ-2 were also effective in inhibiting the progression of quiescent MCF-7 breast cancer cells to the S phase of the cell cycle after their exposure to 17beta-estradiol (10(-9) M). These results provide a new avenue for inhibition of estrogen action by selective mRNA degradation with its potential therapeutic application through targeted gene delivery vectors.

Animals↗