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PubMed2002

Voltammetric investigation of beta-estradiol.

Electrooxidation of beta-estradiol was investigated using a glassy carbon electrode (GCE) by cyclic voltammetry (CV), and differential pulse voltammetry (DPV). The statistical analysis of the linear relationships between concentration and peak current permits the quantitation of beta-estradiol by both CV and DPV in the concentration range of 4 x 10(-5)-10(-3) M with enough precision and accuracy. A mechanism was proposed about the electrooxidation of this substance. The methods were applied to a tablet form and a transdermal therapeutic system (TTS) of this drug. The results were statistically compared with those of official high performance liquid chromatography (HPLC) method and the differences were found as insignificant.

Administration, Cutaneous↗
PubMed2004

Re-expression of estrogen receptor alpha using a tetracycline-regulated gene expression system induced estrogen-mediated growth inhibition of the MDA-MB-231 breast cancer cell line.

Estrogen receptor (ER)-negative breast carcinomas are often difficult to treat with antiestrogens. This work was performed to determine if the re-expression of the human ER alpha could restore the hormone response of these cells. We have transfected the human wild-type ER alpha to an ER-negative breast cancer cell line (MDA-MB-231) using a tetracycline-regulated gene expression system. We obtained a new cell line, MDA-A4-5/2. Cell count and flow cytometry "S" phase cell fraction showed that 17-beta-estradiol induced an inhibition on the proliferation of these cells; on the contrary, the antiestrogens ICI 182 780, and tamoxifen blocked this effect. Finally, we demonstrated an induction of the endogenous progesterone receptor gene when ER alpha was present. These results suggest that the re-expression of ER alpha in ER-negative breast cancer cells recreate, at least partially, a hormone-responsive phenotype and may be useful as a therapeutic approach to control this pathology.

Breast Neoplasms↗
PubMed2002

Selective estrogen receptor modulators inhibit the effects of insulin-like growth factors in hyperparathyroidism.

BACKGROUND: Primary hyperparathyroidism (HPT) predominantly affects perimenopausal women, leading to speculations that an estrogen imbalance may be liable. We have previously demonstrated the importance of the insulin-like growth factor (IGF) axis in HPT. Because the antiestrogen tamoxifen has been shown to modulate the IGF axis, we examined the interactions of selective estrogen receptor modulators (SERMs) and IGF in HPT. METHODS; Estrogen receptors were evaluated by Western immunoligand blotting. Sixteen parathyroid glands from 19 patients were included. After adhesion, the cells were treated with IGF (I or II) +/- estrogen +/- SERMs (tamoxifen, ICI 182,780) for 96 hours in serum-free media. Proliferation was assessed by measuring tritiated thymidine incorporation. RESULTS: Both primary and secondary HPT express estrogen receptors alpha and beta. Primary and secondary HPT had comparable responses to SERMs, they were analyzed together. Compared with control (100%), IGFs (I and II) induced a significant increase in DNA synthesis. Estradiol at 10(-8) and 10(-7) mol/L (physiologic range) had no significant effects on IGF (I and II, P >.05). Both tamoxifen and ICI 182,780 inhibited basal DNA synthesis (P <.05) and abolished the effects of both IGF I and II (P <.05). CONCLUSIONS: SERMs are capable of reducing basal and IGF-stimulated DNA synthesis. This reduction in proliferation has implications for cancer biology and therapeutic potential for SERMs in HPT.

Adenoma↗
PubMed1990

Clinical efficacy of current transdermal drug delivery systems: a retrospective evaluation.

In spite of intensive research on transdermal drug delivery systems (TDDSs), only four--nitroglycerin, clonidine, estradiol, and scopolamine--have reached the market, and the clinical effectiveness of these systems has yet to be clearly demonstrated. Ideally, a candidate for transdermal drug delivery should demonstrate clinical significance within a wide therapeutic range for a well-documented indication for use. Continuous administration of a drug should result in better control of the disease with fewer side effects and a marked increase in patient compliance than when traditional dosage forms are used. It appears that nitroglycerin is a poor candidate for transdermal drug delivery by virtue of the ambiguity associated with its clinical pharmacology, substantial interpatient variation in dose-response relationship, and development of tolerance with potential toxicity risks in chronic administration. Clonidine's well-defined indication for use coupled with its high potency and low molecular weight with high lipid solubility is well suited to transdermal therapy. Because estradiol is unsuitable for use in people who smoke and has dermatotoxic potential, it is a marginal candidate for use in TDDSs. Transdermal scopolamine was not reviewed because it is a unique entity (no conventional dosage forms of this product are available) intended for short-term use. Its use is dictated more by the patient's unique circumstances, such as travel requirements, than by physiological condition. Although TDDSs provide a convenient and effective means of administering medications, the aforementioned clinical constraints need to be evaluated in depth before more widespread application of TDDSs can be recommended. In particular; conclusive demonstration of biocompatibility of a TDDS is warranted.

Administration, Cutaneous↗
PubMed2006

Age-related differences in hormonal and nutritional impact on lean anorexia nervosa bone turnover uncoupling.

INTRODUCTION: In anorexia nervosa (AN) patients osteoporosis occurs within a framework of multiple hormonal abnormalities as a result of bone turnover uncoupling, with decreased bone formation and increased bone resorption. The aim of study was to evaluate the hormonal and nutritional relationships with both of these bone remodeling compartments and their eventual modifications with age. PATIENTS AND MEASUREMENTS: In a cohort of 115 AN patients (mean BMI:14.6 kg/m2) that included 60 mature adolescents (age: 15.5-20 years) and 55 adult women (age: 20-37 years) and in 28 age-matched controls (12 mature adolescents and 16 adults) we assessed: bone markers [serum osteocalcin, skeletal alkaline phosphatase (sALP), C-telopeptide of type I collagen (sCTX) and tartrate-resistant acid phosphatase type 5b (TRAP 5b)], nutritional markers [ body mass index (BMI, fat and lean mass), hormones (free tri-iodothyronine (T3), free T4, thyroid stimulating hormone (TSH), luteinizing hormone (LH), follicle stimulating hormone (FSH), 17 beta estradiol, free testosterone index (FTI), dehydroepiandrosterone (DHEAS), insulin-like growth factor 1 (IGF-1), growth hormone (GH) and cortisol], plasma methoxyamines (metanephrine and normetanephrine) and calcium metabolism parameters [parathyroid hormone (PTH), Ca, vitamin D3]. RESULTS: Osteocalcin reached similar low levels in both AN age subgroups. sCTX levels were found to be elevated in all AN subjects and higher in mature adolescents than in adult AN (11,567+/-895 vs. 8976+/-805 pmol/l, p<0.05). sALP was significantly lower only in mature adolescent AN patients, while there were no significant differences in the levels of TRAP 5b between AN patients and age-matched control groups. Osteocalcin correlated with sCTX in the control subjects (r=0.65) but not in the AN patients, suggesting the independent regulation of these markers in AN patients. Osteocalcin levels strongly correlated with freeT3, IGF-I, 17 beta estradiol and cortisol, while sCTX correlated with IGF-I, GH and cortisol in both age subgroups of the AN patients. Other hormones or nutritional parameters displayed age-related correlations with bone markers, leading to different stepwise regression models for each age interval. In mature adolescent AN patients, up to 54% of the osteocalcin variance was due to BMI, cortisol and 17 beta estradiol, while 54% of the sCTX variance was determined by GH. In adult subjects, freeT3 and IGF-I accounted for 64% of osteocalcin variance, while 65% of the sCTX variance was due to GH, FTI and methoxyamines. CONCLUSIONS: We suggest a more complex mechanism of AN bone uncoupling that includes not only "classical" influence elements like cortisol, IGF-I, GH or 17 beta estradiol but also freeT3, catecholamines and a "direct" hormone-independent impact of denutrition. Continuous changes of these influences with age should be considered within the therapeutic approach to AN bone loss.

Adolescent↗
PubMed1981

Mutagenicity assays of estrogenic hormones in mammalian cells.

In view of the extensive use of estrogenic hormones by the human population, either as therapeutic agents, or in the composition of contraceptive pills, it is important to investigate more thoroughly the adverse biological effects of synthetic hormones. Diethylstilbestrol, ethynylestradiol, estradiol-17beta and estrone were chosen for our experiments. Evidence of carcinogenicity in rodents has been reported for each of these compounds, but so far only few studies have been carried out in vitro. Because it has been shown that isolated liver cells in suspension are able efficiently to metabolize steroid hormones, we have tested these chemicals in V79 cells with a cell-mediated system using primary hepatocytes from male and female rats as the metabolic layer. The incubation in the presence of the chemical to be tested was carried out at concentrations ranging from 25 to 100 microM, for 48 h before plating the V79 cells to score for mutagenicity or toxicity. In the absence of hepatocytes, the 4 estrogenic hormones were very toxic, but not mutagenic. The co-cultivation of V79 cells with primary hepatocytes decreased the toxic effect induced by the sex hormones, except in the case of ethynylestradiol. However, no mutation, determined as 8-azaguanine- or ouabain-resistance, was induced under these conditions by any of the hormones tested. The lack of mutagenic activity of these hormones in our assay had been confirmed by the use of primary liver cells that originated from a rat treated with Aroclor, an inducer of drug-metabolizing enzymes.

Animals↗
PubMed1984

In vitro sperm capacitation and transcervical intrauterine insemination for the treatment of refractory infertility: phase I.

Fourteen couples with long-standing infertility, associated with cervical mucus insufficiency, male subfertility, or unexplained infertility, participated in a therapeutic trial. The female partners, who were all ovulatory, were given human menopausal gonadotropin from day 2 of the menstrual cycle (controlled ovarian hyperstimulation). When plasma estradiol concentrations reached 1000 to 2000 pg/ml, human chorionic gonadotropin was given. Approximately 32 hours and again 70 hours thereafter, a masturbation specimen of the husband's sperm was capacitated in vitro and inseminated transcervically into the uterine cavity. Five women (35%) conceived following a single cycle of treatment. Four of the pregnancies are currently progressing normally; one ended in a spontaneous miscarriage in the early first trimester. The potential role of in vitro sperm capacitation and transcervical intrauterine insemination in the treatment of refractory infertility unrelated to female organic pelvic disease is discussed.

Chorionic Gonadotropin↗
PubMed1989

A trial of superovulation in ovum donors undergoing uterine lavage.

In an attempt to increase the number of fertilized ova recoverable by uterine lavage, the authors superovulated ovum donors using a combination of clomiphene citrate and human menopausal gonadotropin. Six women underwent seven lavage cycles with uterine flushes performed 96, 120, 144, and 168 hours after ovulation and artificial insemination. Ova were recovered from three women between 96 and 144 hours after ovulation. However, no ova were recovered from the other three donors, two of whom were later noted to be pregnant. Retained pregnancies occurred despite postlavage administration of high-dose contraceptive pills, endometrial aspiration, and, in one case, RU 486. None of the infertile women became pregnant as a result of the trial. The authors conclude that, although superovulation may increase ovum production, without reliable contragestion, such practice is unsafe for ovum donors undergoing uterine lavage.

Adult↗
PubMed2002

Emergency contraception.

The last decade has seen a huge interest in emergency contraception (EC) because of the potential it has to reduce abortion rates. A variety of hormonal methods is available although mifepristone-arguably the best method-is only licensed in China. The intrauterine device is highly effective but its use is limited because of the technical skill required for successful insertion. The mechanism of action of both the Yuzpe regimen of EC and of levonorgestrel is poorly understood and for all methods there are serious methodological difficulties involved with calculating efficacy. Nevertheless the risks and side-effects of EC are negligible and the practicalities of prescribing it are extremely simple. Research and programmatic efforts should concentrate on improving availability if EC is to fulfil its promise as a public health intervention to reduce unwanted pregnancy.

Contraceptives, Oral, Combined↗
PubMed1990

The placental transfer of mifepristone (RU 486) during the second trimester and its influence upon maternal and fetal steroid concentrations.

A double-blind, placebo-controlled study has assessed the maternal and fetal endocrine effects of the maternal administration of the anti-progestin mifepristone in mid-pregnancy. There were six women in each group. Four hours after oral administration of 600 mg mifepristone, the drug was detected in both maternal and fetal circulations and in the amniotic fluid. No significant changes in progesterone, cortisol, oestradiol, or aldosterone concentrations were detected in the maternal circulation after treatment with mifepristone or placebo. In women treated with mifepristone, the mean fetal aldosterone level was 1699 (SD 217) pmol/l which was significantly higher than the mean level of 999 (SD 84) pmol/l in the control group but no significant changes occurred in the fetal progesterone, oestradiol or cortisol concentrations. The significance of these results is discussed in relation to the possible therapeutic uses of mifepristone for inducing labour.

Aldosterone↗
PubMed1992

The comparison of two gonadotropin-releasing hormone agonists in an in vitro fertilization program.

OBJECTIVE: To compare two gonadotropin-releasing hormone agonists (GnRH-a), buserelin acetate and leuprolide acetate [LA], used in combination with gonadotropins in ovarian stimulation for in vitro fertilization (IVF). DESIGN: Randomized prospective study. SETTING: Assisted Reproduction Unit of the Hospital Clínic i Provincial in Barcelona. PATIENTS: Thirty-five pairs of IVF patients who were matched on age, indication, and number of attempts. These women were randomized to receive either buserelin acetate plus gonadotropins (group B) or LA plus gonadotropins (group L). MAIN OUTCOME MEASURES: Luteolysis, ovarian response, and IVF outcome. RESULTS: The mean time for total ovarian arrest and the total dose of gonadotropins and estradiol levels on the day of human chorionic gonadotropin administration were similar in the two groups of patients. The number of follicles punctured, the number of oocytes retrieved, and the percentage of mature oocytes in group L were significantly higher. The number of embryos suitable for replacement and cryopreservation was higher in group L compared with group B approaching statistical significance. CONCLUSION: Our results warrant further studies to compare different GnRH-a as therapeutic tools in IVF.

Adult↗
PubMedDate not supplied

Alzheimer's disease and estrogen.

The preventive effect of estrogen on Alzheimer's disease (AD) has become clear with epidemiological data. Therapeutic effects of estrogen have not yet been established. In this presentation, we report our new basic and clinical data. The estrogen receptor, (ER)alpha, and ERbeta mRNA were investigated in rat brain. Estradiol-17beta (E(2)) treatment following OVX reduced the levels of ERalpha mRNA in the hypothalamus. In the substantia innominata (SI), the number of choline acetyltransferase immunoreacive cells increased significantly in the estrogen treatment rat. The neurons in SI projecting to the forebrain cortex contained ERalpha. Increasing amounts of intracellular calcium, peroxidation, and apoptosis with amyloid beta were suppressed in neuronal cells from rat pheochromocytoma (PC12) cells with E(2). ERalpha cDNA transfected PC 12 cells elaborated more neurite-like processes with E(2). In clinics, we are currently preparing vaginal progesterone tablets, which essentially may concentrate in the endometrium to prevent endometrial cancer, with few general circulation of progesterone inviting less depression. The therapeutic effects of cyclic estrogen, such as its preventive effect, are suggested in these studies, at least on mild AD.

Alzheimer Disease↗
PubMed2001

Brain aromatase is neuroprotective.

The expression of aromatase, the enzyme that catalyzes the biosynthesis of estrogens from precursor androgens, is increased in the brain after injury, suggesting that aromatase may be involved in neuroprotection. In the present study, the effect of inactivating aromatase has been assessed in a model of neurodegeneration induced by the systemic administration of neurotoxins. Domoic acid, at a dose that is not neurotoxic in intact male mice, induced significant neuronal loss in the hilus of the hippocampal formation of mice with reduced levels of aromatase substrates as a result of gonadectomy. Furthermore, the aromatase substrate testosterone, as well as its metabolite estradiol, the product of aromatase, were able to protect hilar neurons from domoic acid. In contrast, dihydrotestosterone, the 5 alpha-reduced metabolite of testosterone and a nonaromatizable androgen, was not. These findings suggest that aromatization of testosterone to estradiol may be involved in the neuroprotective action of testosterone in this experimental model. In addition, aromatase knock-out mice showed significant neuronal loss after injection of a low dose of domoic acid, while control littermates did not, indicating that aromatase deficiency increases the vulnerability of hilar neurons to neurotoxic degeneration. The effect of aromatase on neuroprotection was also tested in male rats treated systemically with the specific aromatase inhibitor fadrozole and injected with kainic acid, a well characterized neurotoxin for hilar neurons in the rat. Fadrozole enhanced the neurodegenerative effect of kainic acid in intact male rats and this effect was counterbalanced by the administration of estradiol. Furthermore, the neuroprotective effect of testosterone against kainic acid in castrated male rats was blocked by fadrozole. These findings suggest that neuroprotection by aromatase is due to the formation of estradiol from its precursor testosterone. Finally, a role for local cerebral aromatase in neuroprotection is indicated by the fact that intracerebral administration of fadrozole enhanced kainic acid induced neurodegeneration in the hippocampus of intact male rats. These findings indicate that aromatase deficiency decreases the threshold for neurodegeneration and that local cerebral aromatase is neuroprotective. Brain aromatase may therefore represent a new target for therapeutic approaches to neurodegenerative diseases.

Animals↗