The antiovulatory effect of ethinyl oestradiol in sequential therapy.
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Abortion, Therapeutic↗
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A comparative multicenter study of two transdermal estradiol replacement therapies in the treatment of postmenopausal symptoms.
OBJECTIVE: Comparison of the effects of treatment of two transdermal therapeutic systems for estrogen replacement therapy with regard to efficacy, tolerability, and acceptance. DESIGN: Open randomized. SETTING: Multicenter. PATIENTS AND INTERVENTIONS: A study population of 104 postmenopausal women was randomized on a 1:1 basis to treatment with one of two estradiol patches, System (Cilag) and Estraderm (Ciba-Geigy). OUTCOME MEASURES: Systolic and diastolic BP, hot flushes, night sweating, fatigue, insomnia, depression, nervousness, headache, vaginal discomfort (efficacy variables); bleeding, dermatological symptoms, comfort and adhesiveness of patch, and other possible causes of discontinuation (tolerability); general evaluation by patient (acceptance). RESULTS: Considering all efficacy variables, 53% of Systen and 46% of Estraderm patients found the therapy satisfactory. Tolerability was somewhat higher in the Systen group. Adhesiveness of the patch was significantly better for Systen. Overall, 79% of Systen patients and 62% of Estraderm patients evaluated treatment as "good" or "very good." The majority of patients in both groups found the patch very comfortable or only slightly obtrusive.
Administration, Cutaneous↗
Combined effects of lutenizing hormone-releasing hormone analogue with antiestrogen on rat mammary tumors.
The efficacy of luteining hormone-releasing hormone (LH-RH) analogue, buserelin, combind with tamoxifen (TAM) on 7,12-dimethylbenz(a)anthracene (DMBA)-induced rat mammary tumors was investigated. Low-dose of TAM (L-TAM), 1 mg/kg daily, significantly suppressed the growth of tumors compared with no treatment group. High-dose of TAM (H-TAM), 10 mg/kg daily, suppressed growth considerably, and there was a significant difference in the antitumor effect between the L-TAM group and the H-TAM group. The combined treatment using buserelin and L-TAM significantly suppressed the tumor growth compared with the treatment using each single agent. LH-RH analogue actually reduced serum estradiol (E2) levels and enhanced the antitumor effect brought by a therapeutical dose of TAM. The reduction of serum cholesterol levels as a beneficial effect of TAM was reserved when combined with buserelin. Insulin-like growth factor 1 (IGF-1) expressions in tumors were significantly decreased in the buserelin and L-TAM group. These results support the usefulness of this combination in clinical use.
9,10-Dimethyl-1,2-benzanthracene↗
Digoxin does not alter plasma steroid levels in health men.
Digoxin has been reported to induce feminizing effects in man. It does not compete for estradiol cytosol receptors in human breast carcinoma cells, however, and has no uterotrophic effect. We therefore investigated whether feminization might be due to digoxin action on plasma concentrations of sex steroids. Six healthy men (31.5 +/- 4 yr old) received therapeutic doses of digoxin for 43 days. We measured plasma concentrations of testosterone, androstenedione, dehydroepiandrosterone, estrone, estradiol, progesterone, 17-hydroxyprogesterone, cortisol, and aldosterone. During 35 days on digoxin levels of these steroids remained in the normal range and there was no change from before-drug values. Digoxin was in the therapeutic range of 1.9 +/- 3 nmol/l throughout. After stimulation by adrenocorticotropic hormone or human choriongonadotropin, the rise in plasma steroids was in the same range as when digoxin was given, as well as 16 wk after it had been discontinued. A normal rise in luteinizing hormone after luteinizing hormone-releasing hormone showed that the hypothalamogonadal feedback was not altered by digoxin. Free testosterone, estradiol, and cortisol concentrations under basal conditions and after stimulation were also the same before and after drug. It is concluded that the estrogen-like activity of digoxin cannot be explained by altered steroid availability from plasma. Feminizing effects attributed to digoxin may be caused by other conditions known to influence sex steroid hormones that are common in patients with heart disease. Our data suggest that digoxin may be the preferred digitalis therapy to avoid feminizing effects.
Adrenal Cortex Hormones↗
Lipid and carbohydrate effects of a new triphasic oral contraceptive containing norgestimate.
Data are reported from the combined results of two studies assessing the lipid and carbohydrate effects of a triphasic preparation of norgestimate and ethinyl estradiol (Ortho TriCyclen, Tri-Cilest) over a 2-year period in 1,783 healthy women. Mean values for serum levels of high-density lipoprotein cholesterol (HDL-C) were increased significantly, with a percent change at 24 months of 13.2. Values for the ratio of low-density lipoprotein cholesterol to HDL-C were reduced throughout the study period (mean change of -6.4% at cycle 24). There were no clinically significant changes in fasting blood glucose levels or insulin levels or in values for glycosylated hemoglobin. These results are consistent with those of previous studies and indicate that the triphasic preparation of norgestimate and etinyl estradiol is a selective and minimally androgenic oral contraceptive agent. Long-term therapeutic benefit may accrue from the favorable influences on the lipid profile.
Adolescent↗
Inhibition of estradiol-induced early osteoarthritic changes by tamoxifen.
Previous studies on osteoarthritic changes induced by intraarticular injections of estradiol benzoate (EB) suggest estrogen as a risk factor in the development of knee osteoarthritis (OA). The present study observed the anti-arthritic effects of tamoxifen (TMX). Oophorectomized rabbits were subjected to intraarticular injections of vehicle control, EB, TMX, or EB/TMX for 3 weeks. The cartilage changes were assessed by light and scanning electron microscopic examination, enzyme histochemical analysis, and the amount of alcian blue stain binding to glycosaminoglycans. EB injections resulted in cell necrosis, chondrocyte clonings, and pittings, whereas the vehicle control, TMX, and EB/TMX-injected groups showed no histologic abnormalities. Histochemical analysis showed that the numbers of lactate dehydrogenase (LDH)-reactive chondrocytes in the EB-injected group were significantly reduced when compared to other groups (p less than 0.001). The injections of EB/TMX significantly reduced the chondrocyte numbers in the lateral superficial layer (p less than 0.05), compared with the vehicle injection. TMX-injected group revealed slight although insignificant decreases in chondrocyte numbers. The amount of alcian blue stains, representing the relative amount of proteoglycans, significantly decreased only in the superficial layer of the EB- and EB/TMX-injected groups (p less than 0.05). TMX, when concurrently injected with EB, antagonized the chondrodestructive effects of estradiol at the early stage of knee OA in rabbits. The results suggest the potential therapeutic use of TMX at the early stage of OA.
Alcian Blue↗
Inhibitory effects of bestrabucil, a conjugate of chlorambucil and estradiol, on the production of androgen-induced growth factor(s) by Shionogi carcinoma 115 cells.
It is known that diffusible trophic factors play an important role in both the normal and cancerous growth regulatory processes of hormone-responsive cells such as are found in the prostate and mammary glands. Consequently, it is important to identify whether the production of such growth factors is affected by administration of therapeutic agents. We examined the effect of bestrabucil, a benzoate of an estradiol-chlorambucil conjugate, on the production of growth factor(s) by Shionogi carcinoma 115 (SC-115) cells, an androgen-responsive cultured cancer cell line. We then investigated whether the inhibitory effect found was specific to bestrabucil, or if it was also produced by a mixture of the 2 compounds, estradiol and chlorambucil. Bioassay employing BALB/3T3 cells demonstrated the presence of two kinds of growth factor in the conditioned medium obtained by culturing SC-115 cells in medium containing 10(-8) M testosterone; these factors could be separated by heparin-sepharose column chromatography using 0.5 M NaCl and 1.1 M NaCl. When the SC-115 cells were cultured in medium containing bestrabucil, at a concentration of 10(-5) M, no growth factor activity was detected in the fraction eluted from the heparin-sepharose column by 1.1 M NaCl. At bestrabucil concentrations of 10(-5)-10(-7) M, concentration-dependent inhibition of growth factor production by SC-115 cells could be demonstrated by 3H-thymidine uptake assay. However, this inhibitory effect could not be demonstrated using only a mixture of estradiol and chlorambucil.(ABSTRACT TRUNCATED AT 250 WORDS)
Androgens↗
Potentiation of human alpha4beta2 neuronal nicotinic acetylcholine receptor by estradiol.
The modulation of neurotransmitter receptors by various substances can reflect important physiological mechanisms involved in the regulation of neural function. Furthermore, such substances, in particular specific allosteric modulators, can reveal promising therapeutic targets for diseases of the nervous system. From this perspective, we investigated the effects of the steroid hormone estradiol on human neuronal nicotinic acetylcholine receptors expressed either in Xenopus laevis oocytes or human embryonic kidney cells. Acetylcholine-evoked currents were potentiated both by pre- and coapplications of estradiol in alpha4beta2 and alpha4beta4 receptors, but not in alpha3beta2 or alpha3beta4 receptors. The reversible potentiation of alpha4-containing receptors could be induced within seconds in X. laevis oocytes and at micromolar concentrations of estradiol. The potentiation was greatest for responses evoked by low concentrations of acetylcholine, resulting in an apparent increase of receptor affinity. At the single channel level, estradiol potentiation resulted from an increase in opening probability. Finally, the use of functional chimeric or truncated alpha4 subunits demonstrated that a site at the C-terminal tail of the alpha4 subunit is required for estradiol potentiation. These results suggest the presence of a specific site at the human nicotinic acetylcholine receptor alpha4 subunit through which estradiol can cause an allosteric potentiation of acetylcholine-evoked responses.
Acetylcholine↗
In vivo evaluation of 7 alpha-[11-(4-[125I]iodophenoxy)undecyl]-17 beta-estradiol: a potential vector for therapy of adrenal and estrogen receptor-positive cancers.
7 alpha-[11-(4-[125I]Iodophenoxy)undecyl]-17 beta-estradiol ([125I]IPUE2) was synthesized and its tissue distribution studied in immature female Fischer rats. Upon intravenous administration, [125I]IPUE2 was shown to accumulate in the adrenals and, to some extent, in the uterus and the ovaries. Coinjection with estrogen receptor (ER)-saturating quantities of unlabeled 17 beta-estradiol did not significantly reduce the uptake of [125I]IPUE2 in these tissues. The high adrenal uptake of [125I]IPUE2 is most likely associated with the lipophilic nature of the 7 alpha-substituted estradiol. The potential to use the 7 alpha-undecylestradiol as a vector to direct therapeutic groups to adrenal and ER-positive cancers is discussed.
Adrenal Gland Neoplasms↗
Estrogen replacement does not potentiate gonadotropin-releasing hormone agonist-induced androgen suppression in treatment of hirsutism.
The therapies presently available for treating ovarian hirsutism are not uniformly effective, and therefore, much has been expected from GnRH agonists. These inhibit the secretion of gonadotropins and thereby suppress ovarian function, but at the same time cause hypoestrogenic side-effects. We, therefore, administered goserelin, a long-acting GnRH agonist, for treatment of 20 hirsute women (18 with polycystic ovaries) for 9 months; half of them were randomized to receive cyclic estradiol and medroxyprogesterone replacement from the fourth month onward. Seventeen patients completed the study. Goserelin suppressed ovarian function, as evidenced by a profound reduction in serum estradiol levels. The circulating levels of total testosterone, free testosterone, and androstenedione were lowered at 3 months by 29%, 31%, and 38%, respectively, but there was no effect on the levels of sex hormone-binding globulin (SHBG) or dehydroepiandrosterone sulfate. Ovarian suppression, maintained for the duration of the trial, alleviated hirsutism, as evidenced by a decrease in Ferriman-Gallwey hirsutism scores. Estrogen plus progestin replacement restored estradiol levels and increased SHBG levels, but did not potentiate the therapeutic effect of goserelin or reduce free testosterone levels. Replacement therapy abolished or alleviated hypoestrogenic vasomotor symptoms, but it also caused bleeding and premenstrual symptoms, which necessitated the withdrawal of 3 of 10 women from the treatment. Thus, goserelin is an effective treatment for ovarian hyperandrogenism. Simultaneous estrogen replacement abolishes the hypoestrogenic side-effects, but does not potentiate the effect of goserelin on hirsutism. Interestingly, the estrogen-induced increase in SHBG did not affect free testosterone. Thus, the suppression of gonadotropins, rather than the increase in SHBG, appears to be of primary significance in the alleviation of ovarian hyperandrogenism by estrogens.
Adolescent↗
[Mechanisms of action of estrogens physiological and pharmacological aspects of hormonal "receptivity". The anti-estrogens (author's transl)].
Receptivity to estrogens may indeed depend on the concentration of the corresponding receptor in the target cells. This concentration varies physiologically, and would possibly explain, at least in part, certain hormonal interactions and receptivity changes during the physiological cycles. The modifications of receptor concentrations could perhaps be of significance in explaining the effects of "priming" and the negative influence of one steroid on another. The simultaneous presence of different receptors for the same hormone or the competition of different hormones for the same receptor offer interesting pharmacological possibilities. It has already been shown that the characteristics of receptors can explain the differences between a natural hormone like estradiol and diethylstilbestrol, the hormone with the most common synthesis. A series of synthetic derivatives (triphenylethylene) seem to offer the possibility of an antagonist effect without pollution by significant estrogenic activity, and the potential therapeutic consequences are immense. Regulatory proteins, the steroid hormone receptors, provide some of the most advanced models for rational physico-chemical and physiological approaches to pharmacological and therapeutical problems.
Binding, Competitive↗
STUDIES ON THE AROMATISATION OF NEUTRAL STEROIDS IN PREGNANT WOMEN. 2. AROMATISATION OF DEHYDROEPIANDROSTERONE AND OF ITS SULPHATE ADMINISTERED SIMULTANEOUSLY INTO A UTERINE ARTERY.
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Abortion, Therapeutic↗
Differential lipemic and proteinemic response to oral ethinyl estradiol and parenteral estradiol cypionate.
Oral synthetic estrogen administration to normal women has been shown to result in both a lipemic and a proteinemic response. To determine whether parenteral estrogen administration would have similar results, the effects of intramuscular depo-estradiol cypionate on serum lipids and ceruloplasmin were examined. The oral and parenteral estrogens chosen for this study are frequently used therapeutically and varying doses in the range of those commonly employed clinically were given to the experimental subjects. Following oral ethinyl estradiol (20, 50, and 100 micrograms every 12 hr) comparable and significant increases in triglyceride (73 +/- 6 to 128 +/- 10 mg/dl, p < .001), ceruloplasmin (87 +/- 4 to 188 +/- 11 mg/dl, p < .001), and HDL-cholesterol (60 +/- 2 to 74 +/- 3 mg/dl, p < .001) were observed. In contrast, despite substantial increases in serum estrogens, parenteral estrogen administration (depo-estradiol cypionate, 5 and 10 mg) failed to result in alterations in any of the measured parameters. Thus, the route and/or type of estrogen administered may determine the proteinemic and lipemic effects of estrogen in man.
Administration, Oral↗
Xenobiotic interaction with and alteration of channel catfish estrogen receptor.
In teleostean in vivo studies, the vitellogenin response to environmental estrogens is not completely predicted by mammalian literature. One possible explanation for differences is heterogeneity of the estrogen receptor (ER) structure between species. Therefore, ER from channel catfish (Ictalurus punctatus) hepatic tissue was characterized by binding affinity for several compounds. Affinity was indirectly measured as potency of the chemical for inhibiting binding of radiolabeled estradiol (E2) to specific binding sites. The order of potency among therapeutic chemicals was ethinylestradiol > unlabeled E2 = diethylstilbestrol > mestranol > tamoxifen >> testosterone. Unlabeled E2 had an IC50 of 2.2 nM. Several environmentally relevant chemicals were evaluated in a similar manner and the order of potency established was the o-demethylated metabolite of methoxychlor (MXC) > nonylphenol (NP) > chlordecone > MXC > o,p'-DDT > o,p'-DDE > beta-hexachlorocyclohexane. Demethylated MXC had an IC50 1000-fold greater than that of E2. Of the most potent inhibitors, NP appeared to be a competitive inhibitor for the same binding site as E2, while o-demethylated MXC had a more complex interaction with the receptor protein. ER from nonvitellogenic females was determined to have a Kd value of 1.0 to 1.3 nM. Because E2 has been reported to up-regulate teleostean ER, the hepatic ER population following in vivo xenobiotic exposure was assessed. NP significantly increased ER per milligram hepatic protein almost to the same extent as E2, but did not increase Kd to the same extent as E2.
Animals↗
Ethinyl estradiol and medroxyprogesterone acetate in patients with epithelial ovarian carcinoma: a phase II study.
Patients with ovarian carcinoma refractory to chemotherapy received a sequential combination of ethinyl estradiol and medroxyprogesterone acetate in two dose regimens. There was no difference in therapeutic activity of the two dose regimens. Of 65 patients, nine (14%) responded to treatment and 13 (20%) had stable disease. Vascular complications occurred in three patients; hemiplegia developed in one of those. Nine patients had significant nausea and vomiting, and one experienced severe depression that required treatment withdrawal. The sequential and combined use of ethinyl estradiol and medroxyprogesterone acetate may provide an alternative treatment for certain patients with ovarian carcinoma that does not respond to optimum chemotherapy. Additional studies are required to determine if synergism exists between this treatment and other modalities of therapy. Further investigation is required into the vascular disorders that complicate therapy to determine whether appropriate preventive measures are possible.
Adult↗
Antioxidants J811 and 17beta-estradiol protect cerebellar granule cells from methylmercury-induced apoptotic cell death.
Cerebellar granule cells (CGC) have provided a reliable model for studying the toxicity of methylmercury (MeHg), a well-known neurotoxicant contaminating the environment. In the present study we report that doses of MeHg ranging from 0.1 microM to 1.5 microM activated apoptosis, as shown by cell shrinkage, nuclear condensation, and formation of high-molecular-weight DNA fragments. Nevertheless, caspase-3-like activity was not significantly induced, and the broad caspase inhibitor Z-VAD-FMK was not capable of protecting the cells. This argues for a minor role of caspases in the intracellular pathways leading to MeHg-induced cell death in CGC. Instead, proteolytic fragments obtained by specific calpain cleavage of procaspase-3 and alpha-fodrin were increased consistently in samples exposed to MeHg, pointing to a substantial activation of calpain. Notably, two antioxidants, 17beta-estradiol (10 microM) and the Delta(8,9)-dehydro derivative of 17alpha-estradiol J811 (10 microM), protected from MeHg damage, preventing morphological alterations, chromatin fragmentation, and activation of calpain. These findings underscore the key role of oxidative stress in MeHg toxicity, placing it upstream of calpain activation. The shielding effect of the 17beta-estradiol and the radical scavenger J811 is potentially relevant for the development of therapeutic strategies for MeHg intoxication.
Amino Acid Chloromethyl Ketones↗
Influence of hormono- and/or chemotherapy on the MXT mouse mammary tumor as monitored by 31P MRS.
We describe the early in vivo modifications that occurred in the MXT mouse hormone sensitive mammary tumor following various treatments which were monitored by 31P NMR spectroscopy. The MXT mouse mammary tumor was subjected to clinically relevant low-dose chemotherapy, i.e. seven cycles of 20 mg/kg cyclophosphamide (CPA) with or without an attempt at estrogenic cell recruitment prior to the CPA treatment. NMR measurements were begun at the end of the CPA treatment in order to evaluate the remaining 'long-term' chemotherapy-induced modifications within the MXT tumors. Statistical analyses performed on the 31P NMR parameters revealed that treatment had induced significant effects on bATP/PCr, Pi/PCr and PME/PDE only, with PCr being the most discriminating index. Its presence within MXT tumors was verified by means of an analysis of perchloric extracts. The results indicate a relative decrease of PME/PDE and a better conservation of PCr within the CPA-treated group as compared to the control one. This feature appeared even prior to any macroscopic modifications, as was the case within the group which contained tumors smaller than 120 mm2, and where no significant differences appeared between the mean sizes of the MXT cancers. In contrast, within the G2 group, which contained tumors equal to or larger than 120 mm2, CPA significantly slowed down tumor growth, while the administration of estradiol (E2) prior to CPA treatment antagonized the positive CPA-induced therapeutic effect. In conclusion, the non-invasive follow-up of the chemotherapeutic treatment of a clinically relevant mammary tumor model by 31P NMR spectroscopy backed up by statistical analyses revealed metabolic changes that appeared well before any modifications in histopathology or growth.
Animals↗
Receptor-mediated oligodeoxynucleotides delivery by estradiol and folic acid polylysine conjugates.
The lack of efficient and specific delivery to target cells still limits the potential application of antisense oligodeoxynucleotides as therapeutic agents in cancer disease. We have covalently linked a polylysine chain (10,000-20,000 mw) to compounds as folic acid, retinoic acid, transferrin, insulin and estradiol, to deliver c-myb antisense oligonucleotide into tumor cells. Using these complexes as carriers for the oligodeoxynucleotides can be achieved an increase in their uptake into target cells through a natural endocytosis pathway.
Biological Transport, Active↗