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PubMed1989

The influence of a combined oral contraceptive on uterine activity and reactivity to agonists in primary dysmenorrhea.

The mechanisms underlying the therapeutic effect of an oral contraceptive (150 micrograms levonorgestrel and 30 micrograms ethinyl estradiol daily for 21 days) in primary dysmenorrhea were studied by recordings of uterine activity and reactivity to lysine (L) vasopressin (VP) and prostaglandin (PG) F2 alpha on the first day of menstruation in 14 women before and after one period of oral contraceptive treatment. During the first session, when all women had moderate to severe dysmenorrhea, intra-uterine pressure recording showed an intensive uterine activity, and bolus injections of LVP (6 pmol/kg body weight; 6 subjects) or PGF2 alpha (6 or 12 nmol/kg body weight; 4 subjects in each group) increased contractile activity and discomfort. After oral contraceptive treatment, spontaneous uterine activity, measured as total pressure area, decreased significantly (p = 0.02 and p = 0.03 in the VP and PG groups, respectively). The mean uterine responses to LVP and PGF2 alpha were on average smaller after oral contraceptive treatment and the women experienced minimal discomfort after this injection. It is suggested that inhibition of uterine activity could be an important mechanism for the therapeutic effect of gestagen-dominated oral contraceptives in primary dysmenorrhea and that reduced uterine reactivity to agonists might contribute to this effect.

Adolescent↗

PubMedDate not supplied

Synthesis and biological behavior of a boronated analogue of the antiestrogen U 23,469-M.

A boronated analogue of the antiestrogen U 23,469-M (D. Lednicer, D. W. Emmert, S. C. Lyster, and G. W. Duncan, J. Med. Chem. 12, 881 (1969] was prepared, for possible use in neutron capture therapy of estrogen receptor-positive tumors. In this analogue, the terminal OH group was replaced by a B-decachloro-o-carboranyl residue. This compound showed a large, non-specific uptake in ZR 75-1 breast cancer-derived cells. It could partially inhibit the uptake of estradiol in these cells. Accumulation in the cells at physiologically obtainable concentrations was, however, too low to envisage a therapeutic effect following thermal neutron irradiation.

Boron↗

PubMed2004

Short-term transdermal estradiol therapy, cognition and depressive symptoms in healthy older women. A randomised placebo controlled pilot cross-over study.

The potential role of estrogen in protecting women from cognitive decline and reducing depressive symptoms is of great therapeutic interest. In a pilot randomised placebo controlled cross-over study, we aimed to determine the short-term effects of transdermal estradiol therapy on cognition and depressive symptoms in healthy cognitively normal post-menopausal women over 60 years of age. Nineteen cognitively normal women, without clinical depression whom had undergone a hysterectomy in the past were recruited. Women were randomised to receive either transdermal estradiol 50 microg/24 h (Femseven) or transdermal placebo for 12 weeks before crossing over to the other medication for a further 12 weeks. Cognition was assessed every 6 weeks by the cognitive drug research (CDR) computerised assessment which recorded both accuracy and speed in the following cognitive tests; simple reaction time, choice reaction time, digit vigilance, visual tracking, spatial working memory, immediate and delayed word recall and delayed face and picture recall. Depressive symptoms were measured using the brief assessment scale depression card (BASDEC) depression rating scale at baseline, 12 and 24 weeks. Participants had a mean age of 71, IQ of 115 and MMSE of 29. Simple reaction time and the BASDEC depression rating scale improved after 12 weeks of estradiol use. All other tests were unaltered by estradiol. Twelve weeks of transdermal estradiol therapy did not consistently improve the speed or accuracy of older women in various cognitive tests. However, the results do support the concept that depressive symptoms may be reduced by estradiol, and not simply due to the relief of climacteric symptoms.

Administration, Cutaneous↗

PubMed1987

Isolated angiitis of the brain in a young female on the contraceptive pill.

The case of a 15 year old girl with a rapidly progressing right sided hemiparesis is reported. The history and clinical manifestations were suggestive of either herpes simplex encephalitis or occlusion of the left middle cerebral artery. At necropsy an occlusive thrombosis of the left middle cerebral artery due to a segmental necrotizing granulomatous panarteritis was found. The cause was obscure. A plausible incriminating factor was the contraceptive pill.

Adolescent↗

PubMed2006

Tamoxifen and estradiol interact with the flavin mononucleotide site of complex I leading to mitochondrial failure.

This study evaluated the action of tamoxifen and estradiol on the function of isolated liver mitochondria. We observed that although tamoxifen and estradiol per se did not affect mitochondrial complexes II, III, or IV, complex I is affected, this effect being more drastic (except for state 4 of respiration) when mitochondria were coincubated with both drugs. Furthermore, using two respiratory chain inhibitors, rotenone and diphenyliodonium chloride, we identified the flavin mononucleotide site of complex I as the target of tamoxifen and/or estradiol action(s). Tamoxifen (25 microm) per se induced a significant increase in hydrogen peroxide production and state 4 of respiration. Additionally, a significant decrease in respiratory control ratio, transmembrane, and depolarization potentials were observed. Estradiol per se decreased carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP)-stimulated respiration, state 3 of respiration, and respiratory control ratio and increased lag phase of repolarization. With the exception of state 4 of respiration whose increase induced by tamoxifen was reversed by the presence of estradiol, the effects of tamoxifen were highly exacerbated when estradiol was present. We observed that 10 microm tamoxifen in the presence of estradiol affected mitochondria significantly by decreasing FCCP-stimulated respiration, state 3 of respiration, respiratory control ratio, and ADP depolarization and increasing the lag phase of repolarization. All of the deleterious effects induced by 25 microm tamoxifen were highly exacerbated in the presence of estradiol. Furthermore, we observed that the effects of both compounds were independent of estrogen receptors because the pure estrogen antagonist ICI 182,780 did not interfere with tamoxifen and/or estradiol detrimental effects. Altogether, our data provide a mechanistic explanation for the multiple cytotoxic effects of tamoxifen including its capacity to destroy tamoxifen-resistant breast cancer cells in the presence of estradiol. This new piece of information provides a basis for the development of new and promising anticancer therapeutic strategies.

Adenosine Diphosphate↗

PubMed1983

Estradiol fatty acid esters occur naturally in human blood.

Treatment of nonpolar ether extracts of human female blood with mild alkali produced more immunoassayable estradiol than the unhydrolyzed extract. Analysis of the serum extracts showed that the substance which released immunoreactive estradiol after hydrolysis has chromatographic properties identical to those of fatty acid esters of estradiol esterified at carbon 17. The physiological role of these previously unknown endogenous esters might be inferred from their structural similarity to synthetic drugs used therapeutically for their prolonged estrogenic action.

Chromatography, High Pressure Liquid↗

PubMed2004

Development of novel steroid sulfatase inhibitors; II. TZS-8478 potently inhibits the growth of breast tumors in postmenopausal breast cancer model rats.

In postmenopausal breast cancer tissue, steroid sulfatase (STS) activity is high and much estrone sulfate also exists; these facts reveal that estrone sulfate may be involved in the growth of breast cancer as an estrogen source. Steroid sulfatase is an enzyme, which catalyzes hydrolysis from estrone sulfate to estrone, and the development of steroid sulfatase inhibitors is expected as novel therapeutic drugs for postmenopausal breast cancer. We have developed a novel compound 2',4'-dicyanobiphenyl-4-O-sulfamate (TZS-8478), which has potent steroid sulfatase-inhibitory activity and exhibits no estrogenicity in vitro and in vivo. To elucidate its usefulness as a therapeutic drug for postmenopausal breast cancer, we examined the breast cancer cell proliferation- and breast tumor growth-inhibitory activity of TZS-8478 in postmenopausal breast cancer model rats. TZS-8478 dose-dependently suppressed the estrone sulfate-stimulated proliferation of MCF-7 cells. Regarding nitrosomethylurea (NMU)-induced postmenopausal breast cancer models, furthermore, TZS-8478 (0.5 mg/kg per day) markedly inhibited the estrone sulfate-stimulated growth of breast tumors similarly to estrone sulfate-depletion. TZS-8478 completely inhibited steroid sulfatase activity in tumor, uterus and liver, and also markedly lowered plasma concentrations of estrone and estradiol. The above mentioned results suggested that TZS-8478 may be useful as a therapeutic drug for estrogen-dependent postmenopausal breast cancer.

Animals↗

PubMed1980

Prolactin changes in maternal plasma following termination by vacuum curettage and the effect of bromocriptine treatment on these changes.

To study the prolactin secretion and its dependence on the sex steroid concentrations during pregnancy, we measured the circulating prolactin, oestradiol-17 beta, progesterone and testosterone levels following vacuum curettage for termination of early pregnancy in 10 normal women and in 10 other women whose prolactin levels had been lowered with bromocriptine treatment. In normal women, anaesthesia and vacuum curettage led to consistent and significant (p < 0.01) rises in prolactin levels between 0.5 to 5 hours after abortion. This increase was not seen in women treated with bromocriptine whose prolactin level of 8.6 +/- 1.4 ng/ml (mean +/- SE) before abortion was lower than that of 29.6 +/- 6.4 ng/ml found in normal women. The oestradiol and progesterone concentrations decreased rapidly but similarly in both groups of patients following the evacuation of the uterus, whereas the testosterone level did not change significantly. These results indicate: (i) vacuum curettage stimulates prolactin secretion, (ii) the prolactin-stimulating effect of stress appears to be stronger than the prolactin-suppressing effect of postabortal oestradiol and/or progesterone declines, and (iii) bromocriptine blocks the stress-induced prolactin rise.

Abortion, Legal↗

PubMed1995

Testosterone enhances estradiol's effects on postmenopausal bone density and sexuality.

To investigate the role of androgens in increasing bone density and improving low libido in postmenopausal women, we have studied the long-term effects of estradiol and testosterone implants on bone mineral density and sexuality in a prospective, 2 year, single-blind randomised trial. Thirty-four postmenopausal volunteers were randomised to treatment with either estradiol implants 50 mg alone (E) or estradiol 50 mg plus testosterone 50 mg (E&T), administered 3-monthly for 2 years. Cyclical oral progestins were taken by those women with an intact uterus. Thirty-two women completed the study. BMD (DEXA) of total body, lumbar vertebrae (L1-L4) and hip area increased significantly in both treatment groups. BMD increased more rapidly in the testosterone treated group at all sites. A substantially greater increase in BMD occurred in the E&T group for total body (P < 0.008), vertebral L1-L4 (P < 0.001) and trochanteric (P < 0.005) measurements. All sexual parameters (Sabbatsberg sexual self-rating scale) improved significantly in both groups. Addition of testosterone resulted in a significantly greater improvement compared to E for sexual activity (P < 0.03), satisfaction (P < 0.03), pleasure (P < 0.01), orgasm (P < 0.035) and relevancy (P < 0.05). Total cholesterol and LDL-cholesterol fell in both groups as did total body fat. Total body fat-free mass (DEXA, anthropometry, impedance) increased in the E&T group only. We concluded that in postmenopausal women, treatment with combined estradiol and testosterone implants was more effective in increasing bone mineral density in the hip and lumbar spine than estradiol implants alone. Significantly greater improvement in sexuality was observed with combined therapy, verifying the therapeutic value of testosterone implants for diminished libido in postmenopausal women. The favourable estrogenic effects on lipids were preserved in women treated with T, in association with beneficial changes in body composition.

Bone Density↗

PubMed1990

[GnRH analogs in gynecology. Possibilities for therapeutic use].

Gonadotropin releasing hormone (GnRH) agonists are synthetic peptide analogues of the natural gonadotropin releasing hormone with a stronger and more prolonged effect than the natural GnRH. Repeated administration of GnRH agonists induces pituitary desensitization followed by a decrease in gonadotropin secretion and estradiol synthesis. Thus reversible hypogonadotropic hypogonadism is produced. Consequently, estrogen-dependent diseases can be treated successfully with GnRH analogues. The therapeutic results obtained in patients with endometriosis, leiomyoma, pubertas praecox, and metastatic breast cancer are discussed. Furthermore the contraceptive properties of GnRH analogues, and combination treatment with HMG to induce ovulation is reviewed.

Female↗

PubMed1991

[Therapeutic efficacy of testolactone (aromatase inhibitor) to oligozoospermia with high estradiol/testosterone ratio].

To our knowledge, the action of estradiol which is produced from testosterone by aromatase on human spermatogenesis has not been fully clarified. In oligozoospermia, with high values of E2/T ratio, it is considered that the role of estradiol is suppressive to spermatogenesis. In this study, alteration of spermatogenesis was evaluated when serum estradiol levels were decreased by suppression of aromatase activity. Nine male infertile patients were treated with testolactone (Teslac: 1.0 g/day, for 3 months), one of the aromatase inhibitors. Four of them had an increase in sperm count (more than 10 x 10(6)/ml relative to base line). In endocrinological findings, serum estradiol levels and E2/free T ratio were significantly decreased after treatment. Serum free testosterone levels were significantly increased in all cases, presumably from decreased sex hormone binding globulin (SHBG) levels. These findings suggested the effectiveness of the administrated aromatase inhibitor. In particular four patients whose sperm counts were improved after testolactone treatment had high values of basal serum estradiol levels and E2/free T ratio before treatment, and these values were normalized after treatment. In conclusion we suggest that an aromatase inhibitor may be effective to male infertile patients with high serum estradiol levels.

Adult↗

PubMed1978

[Therapeutic studies on two different models of experimental pyelonephritis (author's transl)].

By transurethral instillation of a suspension of a serum resistant E. coli strain (serotype O25:19:12), chronic pyelonephritis is induced in rats, if systemic and local defense mechanisms are impaired by estradiol application. Without hormonal treatment a similar infection can be achieved with a more virulent E. coli strain (serotype O2:1:4). Due to the chronic course of the renal infection in either model, beginning of therapy may be delayed (e.g., 10 days after infection) thus imposing difficult therapeutic conditions on the efficacy of antibiotics to be tested. Evaluation of antibiotics in both models produced differential therapeutic results. In spite of equal MIC's for the applied E. coli strains, gentamicin and particularly cefazolin treatment was less effective in the estradiol treated rats than in those without hormone application. Cefuroxime therapy produced favourable results in either model. The different therapeutic efficacy in both models is to be explained by differences in host resistance to infection. It is suggested that by simultaneans testing of antibiotics in either model, it will be possible to estimate to what extent the therapeutic efficacy of antibiotics depends on the support of intact host defense mechanisms.

Animals↗

PubMed2006

High-dose 17beta-estradiol treatment prevents development of heart failure post-myocardial infarction in the rat.

OBJECTIVES: Prognosis of heart failure remains poor despite therapeutic advances, such as angiotensin converting enzyme inhibition or beta-receptor blockade. Thus, more effective forms of treatment are urgently needed. Since estrogens have been shown to modulate migration and proliferation of cardiac fibroblasts and to modulate the expression of estrogen receptors of cardiomyocytes we examined whether high-dose estrogen treatment can affect post-myocardial infarction left ventricular remodeling. METHODS: Female rats were treated with 17beta-estradiol (7.5 mg/90 d) or placebo for ten weeks, starting two weeks prior to experimental myocardial infarction. Eight weeks after infarction, in vivo echocardiographic and hemodynamic measurements as well as isolated heart perfusion were performed. RESULTS: In vivo, chronic estrogen treatment almost completely prevented the development of all signs of heart failure that occur in untreated infarcted hearts, such as increased left ventricular diameters (dilatation), reduced fractional shortening (systolic dysfunction) or increased left ventricular end-diastolic pressure (diastolic dysfunction). In vitro, the right- (indicating structural dilatation) and downward (indicating left ventricular dysfunction) shift of left ventricular pressure-volume curves occurring in untreated infarcted hearts was completely prevented by estrogen. CONCLUSIONS: High dose estradiol treatment prevented development of post-MI remodeling, as assessed by in vivo and in vitro parameters of LV dysfunction. Estrogen may hold the potential of becoming a new form of heart failure treatment.However, the mechanisms responsible for this striking and unexpected beneficial action of estrogen in heart failure remain to be elucidated.

Animals↗

PubMedDate not supplied

Enhanced sister-chromatid exchange rate in human lymphocytes exposed to 17beta estradiol in vitro.

BACKGROUND: Epidemiologic data and animal experiments strongly implicate that steroid hormones are involved in the process of malignant transformation due to their capability to stimulate mitotic division and/or elevate the level of mutations in susceptible cells. METHODS: The objectives of this investigation were to evaluate the effects of 17beta estradiol in sister-chromatid exchange (SCE) test on cultured human peripheral blood lymphocytes. The lowest concentration of 17beta estradiol used in this experiment (10(-10) M) was calculated as comparable with the physiologic blood level of 17beta estradiol in women. Three experimental concentrations corresponded to minimal (7 x 10(-8) M), average (3.5 x 10(-6) M), and maximal (7 x 10(-6) M) therapeutic doses in human medicine. In addition, the highest concentrations exceed maximal therapeutic dose 10-fold (7 x 10(-5) M) and 30-fold (2.1 x 10(-4) M), respectively. RESULTS: The obtained results indicate that estradiol significantly elevates SCE per cell frequency at all concentrations applied except at the lowest one. However, estradiol has not influenced mitotic activity of cultured human lymphocytes significantly. CONCLUSIONS: It can be concluded that 17beta estradiol expressed genotoxic effects and therefore might represent a human health risk.

Adult↗

PubMed1985

The role of immunoassay in the analysis of microcontaminants in water samples.

Concentrations of natural and synthetic steroids and an anticancer drug (methotrexate) have been determined in water by adapting established immunoassay procedures. The limits of detection for the assays used were 10 ng/liter for norethisterone, 5 ng/liter for ethinyl estradiol and progesterone, and 6.25 ng/liter for methotrexate. Results below the level of detection were obtained in all the samples examined (8 river samples and 6 potable supply samples) except for 2 river samples (17 ng/liter) for norethisterone, and 1 river sample and 1 potable water sample for progesterone (6 ng/liter). A concentration of 1 microgram/liter of methotrexate was found in a sample of hospital effluent. There appears to be no evidence of adverse effects from reused water resources which may be contaminated from the normal use of such highly active therapeutic agents.

Ethinyl Estradiol↗

PubMed2002

Uterine bleeding pattern during low dosage Noretisterone acetate and 17-b-Estradiol treatment in postmenopausal patients.

BACKGROUND: Recent years have been characterized by progressive optimization of postmenopausal hormonal replacement therapy. More physiological therapeutic protocols have been, in fact, proposed to control the possible symptomatology and to prevent the associated risks, with estro-progestinic compounds characterized by lower effective dosages and suitable for the single patient need. However this therapy is not widely accepted by the women from our country for the fears and the inconvenience raised around such side effects as abnormal uterine bleeding and spotting. AIM: to obtain a good compliance and clinical benefits a continuous administration protocol of the hormonal replacement therapy, alternatively to the sequential one has been proposed. METHODS: Our research group has been observing a sample of 42 patients for 12 months, taking oral 17-b-estradiol 1 mg/noretisterone 0.5 mg in continuous administration. All of them were aged from 42 to 63 years and had been in symptomatic menopause for at least 3 months. The characteristics, the onset and the trend of vaginal bleeding were registered in appropriate monthly diaries. Endometrial thickness was evaluated by transvaginal sonography before starting the administration, not exceeding 4 mm in all the women considered. RESULTS: The incidence of bleeding (calculated as a percent of women who experienced a vaginal bleeding for al least a day during a menstrual cycle) was from 26% to 32% in the 1st trimester, reducing during the following months. At 6 months of therapy only 5% of women reported evident vaginal bleeding; at 12 months 90% of women complained with absence of bleeding or spotting. At 12 months no women showed an endometrial thickness over 6 mm. CONCLUSIONS: This observational study suggests that the majority of treated patients proved to be positively responsive to the treatment and that the 17-b-estradiol 1 mg/noretisterone 0.5 mg association reduces the incidence of bleeding and spotting with a sufficient endometrial protection from hyperplasia.

Adult↗

PubMedDate not supplied

Effects of chronic valproate treatment on reproductive endocrine hormones in female and male Wistar rats.

Valproate (VPA) has been claimed to induce endocrine disorders in both sexes in humans. There is sparse information regarding the mechanisms behind these disturbances. By using an animal model, we wanted to study the effect of valproate on hormonal function in non-epileptic rats. Female rats were given 0 (vehicle control, n=15), 200mg/kg (n=15), or 300 mg/kg (n=20) valproate twice daily by gavage for 90 days, resulting in mean valproate concentrations within the therapeutic range 4-6h after the last dose given. Serum testosterone concentrations remained unchanged, while estradiol levels were significantly reduced in both treatment groups, leading to significantly increased testosterone/estradiol ratios. Follicle stimulating hormone (FSH) levels remained unaltered in valproate treated rats, whereas the luteinizing hormone (LH) concentrations were reduced at the lowest valproate dose. Male rats received 0 (vehicle control, n=15), 200mg/kg (n=15), or 400mg/kg (n=20) valproate twice daily by gavage for 90 days, resulting in mean valproate concentrations within the therapeutic range 4-6h after the last dose. Serum testosterone levels were not significantly changed, but there was a highly significant increase in FSH and LH concentrations at the high dose. In conclusion, the study demonstrates a drug-induced effect of valproate on endocrine function in both male and female rats. The results indicate that the drug exerts its effect primarily at the gonadal level, although a centrally mediated effect cannot be ruled out.

Administration, Oral↗

PubMed2000

Absolute structure determination of the highly biologically active bisdehydrodoisynolic acids.

In a project designed to relate the unexpected in vivo and in vitro properties exhibited by (+)- and (-)-bisdehydrodoisynolic acid with their absolute stereochemical structure, an X-ray crystal-structure analysis was undertaken of the highly estrogenic, poorly binding (-) enantiomer. (1) and (13)C NMR spectra are also reported for the first time. The crystal structure shows the cis juxtaposition of the carboxyl and ethyl groups, which are separated by a large torsion angle, and that only the carbon atom holding the carboxyl group is out of the plane in which the remainder of the fused three-ring moiety lies. The crystal structure, which unequivocally characterizes the (-) enantiomer as cis-13(S),14(R) and, implicitly, the (+) enantiomer as cis-13(R),14(S), will be useful in continued studies aimed at explaining the selective estrogen receptor modulation (SERM) of these enantiomers which, in some cases, produces significantly different end-organ effects compared to those of estradiol, in both males and females, affording the promise of a variety of therapeutic and pharmacologic applications.

Crystallography, X-Ray↗