[Pro- and antiprolactin agents. Diagnostic and therapeutic values].
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Breast Neoplasms↗
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Results for “ESTRADIOL, THERAPEUTIC”
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Neuroprotection by estradiol: a role of aromatase against spine synapse loss after blockade of GABA(A) receptors.
Estrogen has been suggested to be pro-epileptic by reducing GABA synthesis, resulting in increased spine density and a decreased threshold for seizures in the hippocampus, which, once they occur, are characterized by a dramatic spine loss in the affected brain areas. As considerable amounts of estradiol are synthesized in the hippocampus, in this study we focused on aromatase, the rate-limiting enzyme in estrogen synthesis in order to examine the role of locally synthesized estrogens in epilepsy. To this end, we first examined the effects of letrozole, a potent aromatase inhibitor, on GABA metabolism in single interneurons of hippocampal dispersion cultures. Letrozole downregulated estradiol release into the medium, as well as glutamate decarboxylase (GAD) expression and GABA synthesis, and decreased the number of GAD positive cells in the cultures. Next, we counted spine synapses and measured estradiol release of hippocampal slice cultures, in which GABA(A) receptors had been blocked by bicuculline, in order to mimic epileptic activity. Treatment of slice cultures with bicuculline resulted in a dramatic decrease in the number of spine synapses and in a significant suppression of estrogen synthesis. The decrease in synapse number in response to bicuculline was restored by combined application of estradiol and bicuculline. Surprisingly, estradiol alone had no effect on either spine synapse number or on GAD expression and GABA synthesis. "Rescue" of synapse number in "epileptic slices" by estradiol and maintenance of GABA metabolism by hippocampus-derived estradiol points to a neuroprotective role of aromatase in epilepsy. Re-filling of estradiol stores after their depletion due to overexcitation may therefore add to therapeutical strategies in epilepsy.
Animals↗
Ethinyl estradiol: its interaction on blood-lipid.
Lipophilicity (log P) of the drug plays an important role when drug reaches in the critical reaction site, i.e., active site cum receptors where the major constituent is lipid moieties. The drug molecule may be responsible for altering the lipid constituents, which is measured in terms of phosphorus content and can be explained by their fatty acid changes that are linked with biological effect of the drug. Having considered the lipophilicity of ethinyl estradiol (log P = 3.67), its interactions with the whole lipid of goat blood have been investigated along with fatty acid changes and lipid peroxidation phenomena. There was significant loss of phosphorus content of phospholipid and change of fatty acid constituents of whole lipid. This may be ascribed to binding affinity of ethinyl estradiol with lipid constituents in blood. Lipid binding potential of the drug may have role in its therapeutic effect. The peroxidation induced by drug has been quantitatively measured along with its suppression by using antioxidant. The results reveal that ethinyl estradiol caused significant extent of lipid peroxidation. Ascorbic acid, a promising antioxidant could significantly reduce drug induced lipid peroxidation.
Animals↗
Inhibition of human CYP19 by azoles used as antifungal agents and aromatase inhibitors, using a new LC-MS/MS method for the analysis of estradiol product formation.
Azoles are used as fungicides in agriculture or antifungal drugs in medicine. Their therapeutic activity is based on the inhibition of fungal lanosterol-14alpha-demethylase (CYP51). Azoles are also used for the treatment of estrogen-dependent diseases, e.g. in breast cancer therapy. Inhibition of CYP19 (aromatase) is the working principle for tumor therapy, but is an unwanted side effect of azoles used as fungicides or antifungal drugs. The inhibition of recombinant human CYP19 by 21 azoles in use for the three different purposes was investigated using the natural substrate testosterone. Estradiol product formation was measured by a newly developed and fully validated analytical method based on liquid chromatography-tandem mass spectrometry utilizing photospray ionization (APPI). Potency of enzyme inhibition was expressed in terms of IC50 concentrations. The two cytostatic drugs fadrozole and letrozole were the most potent inhibitors. However, azoles used as fungicides, e.g. prochloraz, or as antifungal drugs, e.g. bifonazole, were almost as potent inhibitors of aromatase as the drugs used in tumor therapy. Comparison of plasma concentrations that may be reached in antifungal therapy do not allow for large safety factors for bifonazole and miconazole. The IC50 values were compared to data obtained with other substrates, such as the pseudo-substrate dibenzylfluorescein (DBF). A high correlation was found, indicating that the fluorescence assay with DBF can well be used for potency ranking and screening of chemicals for aromatase inhibition. The data for antifungal drugs show that side effects on steroid hormone synthesis in humans due to inhibition of aromatase should be considered.
Antifungal Agents↗
[Clinical study on effect of Tripterygium wilfordii Hook. f. on uterin leiomyoma].
OBJECTIVE: To observe the therapeutic effect of Tripterygium wilfordii Hook. f. on patients with uterine leiomyoma. METHODS: Baseline ultrasound examinations of myomas and uterine were obtained and repeated three months, six months after treatment. Blood samples were collected in the mid-follicular or mid-luteal phase of the menstrual cycle before initiation of Tripterygium wilfordii Hook. f. therapy and after treatment 3-4 months and 5-6 months, for determination of estradiol, progesteron, testosterone, follicle-stimulating hormone, luteinizing hormone and prolactin by radioimmunoassay. RESULTS: Significant decrease in leiomyoma volume was detected in 39 of 65 (60.0%) patients after 3-4 months of Tripterygium wilfordii Hook. f. treatment and 28 of 40 (70.0%) patients after 5-6 months of treatment. The decrease in leiomyoma volume with Tripterygium wilfordii Hook. f. treatment was time-dependent while 27.84% in 3-4 months, 51.6% in 5-6 months. 25 of 65 patients were amenorrheic during the course of treatment. Compared with pretreatment values, Tripterygium wilfordii Hook. f. treatment induced an increase in mean luteinizing hormone, fdlicle-stimulating hormone levels and a decrease in mean estradiol, progesterone levels. CONCLUSIONS: Tripterygium wilfordii Hook. f. may be an effective therapeutic agent for leiomyomas with fewer side effects. Tripterygium wilfordii Hook. f. treatment showed a reversibly inhibitory effect on the ovary. It may be one of the mechanisms of Tripterygium wilfordii Hook. f. in decreasing leiomyoma volume.
Estradiol↗
Modulation of protein expression in endometrial adenocarcinoma cells by in vitro exposure to estradiol and progesterone.
Protein maps of in vitro hormone-modulated adenocarcinoma cells from an endometrial tumor are described. It is noted that mapping of tumor tissues by means of the two-dimensional analysis described by O'Farrell and associates of 35S-methionine-labeled proteins can provide a characteristic map for each tumor and that the methionine-containing proteins of tumor cells can be independently modulated by the in vitro additions of estradiol and progesterone. Such protein modulation could be indicative of hormonal therapeutic responsiveness of individual endometrial adenocarcinomas and other hormone receptor-positive tumors. Tumor maps may further provide data for the identification and isolation of new tumor markers which might be correlated with the radiotherapeutic and chemotherapeutic sensitivity of the malignancy.
Adenocarcinoma↗
The nongenomic protective effects of estrogen on the male cardiovascular system: clinical and therapeutic implications in aging men.
Although the preponderance of studies investigating the effects of estrogen on vasomotor tone and function have focused on women, a number of recent studies have intriguingly shown that estrogen's rapid vasodilatory properties is also preserved in men. Unlike classical steroid transcription mediated pathways, estrogen's acute vasodilatory effect is mediated by calcium dependent cell surface estrogen receptors that stimulate constitutive endothelial nitric oxide synthase (eNOS) activity. The transient release of eNOS derived nitric oxide exerts profound physiological effects on the vasculature exerting a state of cellular inhibition (i.e. vasodilation). Thus, the partial or complete attenuation of this rapid signaling system can promote endothelial dysfunction, an early pathophysiological event in atherosclerotic development. Consequently, human males experiencing age-related declines in testosterone and aromatase derived estradiol plasma levels may lose a vital cardioprotective mechanism that preserves proper endothelial function. Therapeutic strategies to preserve basal nitric oxide levels through the maintenance of normal physiological estradiol levels may confer cardiovascular benefits to aging males.
Adult↗
Pharmacokinetics of three bioequivalent norethindrone/mestranol-50 micrograms and three norethindrone/ethinyl estradiol-35 micrograms OC formulations: are "low-dose" pills really lower?
We have examined the pharmacokinetic parameters derived from the analysis of plasma ethinyl estradiol (EE) and norethindrone levels after administration of a single dose of three bioequivalent norethindrone-1mg/mestranol (ME)-50 micrograms formulations (Ortho-NovumR 1/50, NorinylR 1/50 and Norcept-MR 1/50) and three norethindrone-1mg/ethinyl estradiol-35 micrograms formulations (Ortho-Novum 1/35R, NorinylR 1/35, Norcept-ER 1/35) in a randomized crossover design involving 24 women for the 35 micrograms and 27 women for the 50 micrograms agents. Differences between the AUC-EE of pairs from the same manufacturer (1 + 35 and 1 + 50) were not significantly different, indicating that 50 micrograms of mestranol was equivalent to 35 micrograms ethinyl estradiol with respect to this pharmacokinetic parameter. The Cmax values were also similar. Inter-individual coefficients of variation (C.V.) for the AUC-EE were 47% and 57% for the 1 + 35 and 1 + 50 agents, respectively. Intra-individual C.V.s were 41% and 42%, respectively. For norethindrone, the AUC was larger with the 1 + 50 formulations than with the 1 + 35 group (87.9 vs. 72.8 pg hr/ml). Additionally, the Cmax values were larger for the 1/50 group (17.7 vs. 14.0). Since the amount of norethindrone in the two dosage groups was the same, this difference in the pharmacokinetics between the 35 micrograms EE and the 50 micrograms ME formulations remains unexplained. The inter-individual C.V. averaged 56% for both dosage groups. The intra-individual C.V.s were 17% and 46% for the 1 + 35 and 1 + 50 groups, respectively. The large variation in blood levels of ethinyl estradiol and norethindrone between and within individuals may overshadow clinical differences attributable to differences in dosage.
Adult↗
[Estrogen therapy in carcinoma of the breast (author's transl)].
The controvery about the increase of carcinoma of the endometrium following estrogen therapy led to an investigation of the correlation between estrogen and cancer of the breast because of the close link between carcinoma of the endometrium and carcinoma of the breast. In the statistical matched pair comparison 120 cases of carcinoma of the breast were compared with thoroughly selected controls. To each patient with carcinoma of the breast a control person with essentially the same risk factors was assigned. It was found that: 1) Estrogen therapy in general does not lead to an increased risk for carcinoma of the breast. 2) The separate evaluation of different estrogen preparations showed no increase of the risk. 3) The risk was not increased by prolonged treatment with estrogen. 4) The number of patients taking conjugated estrogens was higher in the control group than in the carcinoma group. 5) The coincidence of estrogen treatment with the other risk factors of nulligravity, hypertension and obesity did not result in an increased risk for carcinoma of the breast.
Adult↗
Body weight gain induced by antipsychotic drugs: mechanisms and management.
Long-term administration of typical and atypical antipsychotic drugs (AP) induces excessive weight gain which afflicts up to 50% of patients, impairs health and interferes with treatment compliance. Basic and clinical research has shown that AP may affect body weight through diverse mechanisms. Increased appetite is probably related to the interaction of AP with neuronal receptors to dopamine, serotonin and histamine. Additional metabolic-endocrine disruption of weight regulation may be related to the effects of AP-induced hyperprolactinaemia on gonadal-adrenal steroids and insulin sensitivity. In humans, programmed physical activity, dietary restriction, anorectic agents, and drugs that counteract hyperprolactinaemia have been shown to be successful in a limited number of studies. Two novel strategies could expand the available therapeutic options. First, in preclinical experiments in female rats the estradiol antagonist/agonist drug tamoxifen or estradiol itself have been shown to completely prevent the obesity provoked by the AP sulpiride, and to induce an endocrine-metabolic milieu that seems to counteract AP-induced obesity. Secondly, it has also been shown that oral antihyperglycaemic agents such as metformin may decrease body weight and counteract insulin resistance and hyperinsulinaemia which is correlated with several metabolic abnormalities in obese subjects. Lastly, estradiol replacement, tamoxifen and/or antihyperglycaemic agents are not devoid of significant side-effects, and these drugs have not been tested in obese psychiatric patients. Therefore, further research is needed before their clinical use may be recommended.
Animals↗
Steroid sex hormones and prolactin in postmenopausal women with generalized mammary carcinoma during prolonged dexamethasone treatment.
The endocrine response to prolonged dexamethasone treatment was investigated in six postmenopausal women with generalized mammary carcinoma. Plasma cortisol levels decreased rapidly and became undetectable whereas significant concentrations of plasma dehydroepiandrosterone and androstenedione persisted throughout the study, even in two ovariectomized patients, indicating a certain degree of autonomy or a greater resistance of adrenal 'androgens' to the inhibition of ACTH secretion. Except in the ovariectomized patients, plasma testosterone did not fall significantly whereas the plasma oestrogens tended progressively towards undetectable concentrations. A similar response was found in six normal postmenopausal women although the disappearance of their oestrogens was relatively rapid. This indicates that much of the testosterone present after the menopause could still be produced by the ovaries whereas the ovarian production of oestrogens becomes negligible. The delayed disappearance of oestrogens in the patients with mammary carcinoma indicates that the persisting adrenal 'androgens' remained efficient precursors of oestrogen synthesis within the peripheral tissues and presumably within the mammary tumour itself. Plasma dihydrotestosterone behaved like the plasma oestrogens. Despite the fall in plasma oestrogens, plasma gonadotrophins did not increase further but plasma prolactin rose progressively. The persistance of steroid sex hormones and the rise of plasma prolactin might explain the poor response to dexamethasone treatment in mammary carcinoma.
Aged↗
[One-year follow-up of women treated with transdermal administration of estrogen for post-castration and climacteric syndromes].
Having gained preliminary knowledge in a selected group of 64 patients treated for three months by a transcutaneous form of estrogen therapy (Estraderm TTS) for postcastration and climacteric syndromes, the authors report in this paper on the results of a one-year follow-up of a series of 42 patients treated by ETTS 25 and 50 for the same diagnoses. Administration of ETTS makes it possible to take advantage of the therapeutic transdermal system for the transfer of 17 beta-estradiol directly into the blood stream. Estradiol in a daily dose of 25, 50 or 100 microgrammes is deposited in ethanol gel as a reservoir in a special sticking tape. From there it is absorbed across a microsporous membrane by molecular diffusion into the subcapillary plexus at a constant speed till an equilibration of the diffusion gradient between skin and the system is attained. For the aim of this study is to evaluate both the recession of the subjective as well as objective complaints in patients suffering from postcastration and climacteric syndromes and the reflection of the treatment in the blood levels of gonadotropins, estrogens, gestagens and cortisol and likewise the vaginal hormonal cytology. Both the systemic and local side-effects of treatment are subject to a careful study. On the basis of a comprehensive statistical study of these changes in every patient as well as in the whole series in the course of one year the authors reach the conclusion that the ETTS administration strikingly improves the subjective as well as objective complaints of the patients, and, in agreement with the literary data, objectively influences the laboratory results concerning especially the circulating levels of gonadotropins and of estradiol. In conclusion, the authors comment on the favourable contribution of this form of treatment to gynaecological practice in the therapy of postcastration, climacteric and estrogen-losing syndromes. A special modification of the record was prepared for this study when the running subjective evaluations of the effect of the treatment by the patient, as obtained in the course of directed interviews, as well as objective results of somatic and laboratory changes including the aggregate yearly evaluation of the effect of the treatment in every individual woman of the series are clearly arranged.
Administration, Cutaneous↗
[The position of drospirenone in premenstrual syndrome teratment].
OBJECTIVE: To evaluate influence of hormonal contraceptive drospirenone on premenstrual syndrome (PMS). DESIGN: Overall summary of literature. AUTHOR AFFILIATION: ADC Sanatorium, Praha. METHODS: Review of scientific studies and publications. CONCLUSIONS: The author submitted current opinions on premenstrual syndrome, its classification, and treatment. The role of renin--aldosterone system in the genesis of PMS was described. Basic pharmacological characteristics of the remedy containing in one pill 30 mg of Ethinyl Estradiol (EE) and 3 mg of drospirenone are presented. Its therapeutic effects on somatic and psychological PMS symptoms are discussed.
Androstenes↗
[Preventive and therapeutic effect of estrogen administration in adjuvant arthritis].
Using adjuvant arthritis as a model for human rheumatoid arthritis, we examined prophylactic and therapeutic effects for different doses of estrogen (0.5-5.0 mg estradiol 3x/week) in 40 male Long Evans rats compared to 16 control animals. More than 2.5 mg estradiol resulted in significantly reduced inflammatory activity, both in animals treated before or after induction of arthritis (Mann Whitney U-test, p less than 0.05).
Animals↗
Hormonal factors in the regulation of myometrial activity. An in vivo study.
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Abortion, Therapeutic↗
[Ovarian stimulation by a new therapeutic principle for the treatment of complications of the climacteric. Results of a double-blind crossover study with a defined spleen dialysate].
In a placebo-controlled double-blind cross-over study (test period 8 weeks) the spleen dialysate Solcosplen is tested for effectiveness and tolerance in 40 women, i.e. 14 pre- resp. 26 postmenopausal women in two consecutive periods (test periods I and II). The treatment begins in the first week of each test period with 2 ampoules i.m. t.i.d. and is to be continued for the following 7 weeks with 2 dragees b.i.d. Besides the incidence of clinical symptoms there intensity is summarized in a graded form to the Kupperman index. For further objectifying the therapeutic results vaginal-cytological examinations and radioimmunological analyses of estradiol (E2), LH, FSH and DHEA-S are carried out. The courses of therapy are frequented on a balanced basis. The progress of clinical symptoms shows in respect of incidence of appearance and intensity measured in Kupperman index in Phase I as well as in the cross-over statistically clear reciprocity, which demonstrates - with homogeneous prefindings - significantly differing results of treatment in favour of the dialysate. In the intraindividual comparison of judging the effectiveness by the physician and patient yields significant preferences for the verum. Side-effects were not observed. The proven effectiveness of the spleen dialysate within this study is explained by the stimulation of the ovarian residual function during menopause. It is discussed and compared to the presently applied monotherapeutic E2-substitution.
Adult↗
[Hormones in depressive illness. The role of cortisol and sexual steroids (author's transl)].
It is actually highly probable than depression is linked to a decrease in noradrenergic activity in brain, at least in some areas including hypothalamus. The complexity of relations between dopaminergic and serotoninergic systems lead to multiple possibilities in hypothetical etiologic factors and in therapeutic interventions. A plasmatic drop in testosterone in men and estradiol in women is one of the situation able to induce a decrease in noradrenergic activity. It seems to be of primordial influence on depression at least in patients with predominant clinical hypogonadic symptoms. We still don't know the frequency on hypogonadism in peoples with predominant depressive symptoms. However this incidence may be fairly high because it is now demonstrated than environmental stress could impaired testicular and ovarian function by the means of anxiety hormones, catecholamines and cortisol, and also by a direct effect on hypothalamus. In no case this hormonal reactions are adaptative by means of anti-anxiety or anti-depressive effects. In contrary, they contribute to maintain the psycho-endocrine syndrome.
Aggression↗