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PubMed2001

[Effects of estradiol and isoflavoid on the expression of adhesion molecules on neutrophils].

OBJECTIVE: To elucidate the effects of estradiol and isoflavoid on the expression of adhesion molecules on neutrophils. METHODS: Neutrophils of healthy subjects and ischemic stroke patients were treated with tumor necrosis factor alpha (TNF alpha), in the presence or absence of different concentrations of isoflavoid (WZ1, WZ2) and estradiol (WZ3, WZ4). Flow cytometry was used to detect the expression of CD18 and CD62L on neutrophil surface. RESULTS: 1. 10 ng/ml TNF alpha could activate neutrophils of healthy subjects; it increased the expression of CD18 by 10% on neutrophil surface and shed CD62L from the surface as shown by a 15% decrease of the fluorescence intensity and a 30% decrease of the percentage of positive cell. 2. Isoflavoid (WZ1, WZ2) had no significant effect on the expression of CD18 and CD62L on neutrophils. 3. Pretreatment of neutrophils with estradiol (WZ3, WZ4) could inhibit the activation of neutrophils by TNF alpha, which decreased the fluorescence intensity of CD18 by 8%, increased the fluorescence intensity of CD62L by 15% and increased the percentage of CD62L positive cell by 20%. 4. TNF alpha could activate the neutrophils of ischemic stroke patients strikingly; it increased the fluorescence intensity of CD18 by 20% and decreased the fluorescence intensity and percentage of positive cell of CD62L by 30%, and there was a significant difference when the patients were compared with the healthy subjects. Estradiol had the same effect on the expression of CD18 and CD62L as on those of healthy subjects. CONCLUSION: 1. TNF alpha is a strong activator of neutrophils; it plays an important role in the occurrence and development of ischemic stroke. 2. Isoflavoid has no obvious effect on the expression of adhesion molecules on neutrophils, so its role in protecting the cardiovascular system may come into play not by the way of affecting adhesion molecules expression. 3. Pretreatment of neutrophils with estradiol could protect them from activation by TNF alpha, thus decreasing the expression of adhesion molecules, the adhesion of neutrophils -endothelial cells, and hence the risk of ischemic stroke. However, in case that the neutrophils have been activated by TNF alpha, estradiol has no effect on the expression of adhesion molecules; this implies that estradiol possibly has no valid anti-adhesion therapeutic effect on ischemic stroke.

Adult↗
PubMed1976

Response of the binding capacity of plasma testosterone-estradiol-binding globulin to norethindrone, 2 mg., and mestranol, 0.1 mg., in polycystic ovarian disease.

The binding capacity of plasma testosterone-estradiol-binding globulin (TeBG) and testosterone (T) levels were measured in four women with proved polycystic ovaries and three women with a clinical diagnosis of polycystic ovarian disease before, during, and after administration of norethindrone, 2 mg., and mestranol, 0.1 mg. (N + M)...

Carrier Proteins↗
PubMed2002

Endometrial thickness and uterine diameter not affected by ultralow doses of 17beta-estradiol in elderly women.

OBJECTIVE: Our purpose was to monitor changes in endometrial thickness and uterine diameter during treatment with ultralow doses of estradiol, which might improve the serum lipid profile in elderly women. STUDY DESIGN: Ultrasonographic changes were monitored in 60 women with an intact uterus in a group of 70 healthy women who were previously evaluated for changes in serum lipid levels. Subjects were 60 years and older and were randomly assigned to receive parenteral 17beta-estradiol (7.5 microg/24 h), delivered by a vaginal ring (Estring; Pharmacia-Upjohn, Malmö, Sweden), or no treatment for 12 months. RESULTS: Estring treatment yielded minor increases in serum estrone sulfate and 17beta-estradiol levels within the normal postmenopausal range. The maximal endometrial thickness was 2.8 mm at baseline and 2.6 mm at 12 months. No significant changes within or between the study groups were found in endometrial thickness or uterine diameter. There were no significant interactions between age and baseline serum estrone sulfate or 17beta-estradiol levels. CONCLUSIONS: Ultralow doses of 17beta-estradiol, which might improve serum lipid levels, did not significantly change endometrial thickness or uterine diameter. This might indicate that there is a "therapeutic window" for systemic effects of ultralow doses of estradiol in elderly women without any apparent increase in endometrial thickness.

Aged↗
PubMed1991

Transdermal therapeutic systems--actual state and future developments.

Modern transdermal therapeutic systems have been marketed since the last decade only. Nitroglycerin, scopolamine, clonidine, estradiol and nicotine are the current prominent representatives that have matched expectations regarding therapeutical benefits based on TTS applications. Although different TTS constructions have been realized, it is nevertheless appropriate to consider the governing role of the skin permanent. As the upper skin barrier limits flux rates, drug uptake has to be improved by the TTS's own occlusion or by flux enhancers. Enhancers act either on the hydrophilic keratin matrix or on the lipophilic intercellular material in the stratum corneum. Improvements in drug diffusion must be balanced carefully with the risk of skin irritation. In the future we should expect, among others, pulsatile systems to avoid tolerance, or systems comprising fixed combinations of transdermal drugs within one TTS, possibly at first in the field of hormones. Other expectations will be discussed. Therapeutic benefits are expected by the administration of highly potent topical drugs by means of TTS-analogous therapeutic systems, enabling a time-controlled drug release for purposes of topical treatment only.

Administration, Cutaneous↗
PubMed1977

A syndrome of functional hypogonadotropic hypogonadism and sterility in a male with elevated serum estradiol.

A 36-year-old male complaining of impotence was examined. He was a genotypic male. Phenotypically, he exhibited signs of long-standing estrogen excess, such as feminine body build, gynecomastia, and varicose veins. His testes were soft and borderline small, and his prostate was small and soft. However, he had a normal-sized penis, normal male hair distribution, normal sense of smell, and normal intelligence. The laboratory data were compatible with mild hypogonadotropic hypogonadism. Serum estradiol (E2) levels were consistently elevated. The patient had azoospermia and a decreased semen volume. Inappropriately low levels of luteinizing hormone and follicle-stimulating hormone responded normally to gonadotropin-releasing hormone and clomiphene citrate. Levels of both testosterone (T) and E2 increased dramatically after prolonged clomiphene medication and in response to human chorionic gonadotropin. There was no change in either T or E2 levels in response to manipulations of the pituitary-adrenal axis. It is concluded that the elevated E2 level was responsible for suppression of gonadotropins which, in turn, caused mild hypogonadism and sterility in this patient. According to the stimulation tests, the source of the elevated E2 levels was testicular.

Adolescent↗
PubMed1993

Sustained-release subdermal estradiol implants: a new alternative in estrogen replacement therapy.

OBJECTIVE: This trial was a therapeutic and pharmacokinetic dose-finding study with subdermal implants that showed a constant in vitro daily release rate of estradiol. The aim was to find the daily release rate of estradiol that produces serum estradiol concentrations comparable with those obtained with transdermal estradiol at 0.05 mg/day. STUDY DESIGN: The study was an open crossover comparison of transdermal and subcutaneous delivery systems. Thirty-six postmenopausal (serum follicle-stimulating hormone concentration > 30 IU/L before commencing the study) were treated with transdermal estradiol for 4 weeks. Immediately after this transdermal estradiol delivery was replaced by either one or three estradiol implants. The serum concentrations of estrone, estradiol, follicle-stimulating hormone, and sex hormone-binding globulin were followed up for 8 weeks on implant therapy and compared with those during transdermal estrogen administration. To oppose the estrogen effect on the endometrium, each patient received an intrauterine device releasing a progestin, levonorgestrel. RESULTS: The serum estradiol concentrations achieved with three implants were comparable with those during transdermal administration of estradiol at 0.05 mg/day. Suppression of follicle-stimulating hormone was also better maintained with three implants compared with one. CONCLUSIONS: This study shows that constant release profiles can be achieved with nonbiodegradable estradiol implants. The results suggest that a single application should give sufficient estrogen substitution for more than a year.

Administration, Cutaneous↗
PubMed1997

Gonadal steroid regulation of hamster facial nerve regeneration: effects of dihydrotestosterone and estradiol.

We have demonstrated, in a series of experiments, the therapeutic potential of androgens in facial motoneuron regeneration in the adult hamster. Initial work utilized testosterone propionate (TP) as the form of androgen given to adult hamster at the time of facial nerve crush axotomy at its exit from the stylomastoid foramen. TP is capable of being enzymatically converted to estrogen. Thus, the effects of TP on the regenerative properties of facial motoneurons could be due to androgens, estrogens, or both. Recent studies of androgen receptor (AR) mRNA levels suggest that androgens and estrogens work synergistically to regulate AR expression in these motoneurons. In this study, we examined the ability of dihydrotestosterone propionate (DHTP), a nonaromatizable androgen which cannot be converted to estrogen, and estradiol (E2) to alter facial nerve regeneration, using fast axonal transport of radioactively labeled proteins to assess facial nerve regeneration. Adult gonadectomized male hamsters were subjected to right facial nerve crush axotomy, with the left side serving as control, and divided into three groups. One-third of the animals received 1 subcutaneous implant of DHTP, one-third received 1 subcutaneous implant of E2, and the remaining third was sham implanted. Postoperative survival times were 4 and 7 days. As expected, DHTP treatment resulted in an approximately 40% increase in the rate of regeneration, with an associated prolongation in the delay time before sprouting occurred. These effects were slightly greater than previously observed with TP, as might be predicted given the more potent physiological effects observed with DHTP compared to TP. Surprisingly, E2 treatment also resulted in an increase in the rate of regeneration (30%), with minimal effects on the delay time before sprout formation occurred. The results argue for a synergistic role for androgens and estrogens in augmenting peripheral nerve regeneration in the model system used in this study.

Animals↗
PubMed2000

Regulation of dosage of conjugated equine estrogen is useful for add-back therapy.

In the hormonal treatment of uterine myomas, which are estrogen dependent, GnRH agonist (GnRHa) therapy has become widespread. However, the severe hypo-estrogenic state induced by the GnRHa gives rise to annoying side effects. Although the risk of these side effects may be reportedly modified when GnRHa is combined with estrogen (add-back therapy), it is difficult to target serum estradiol (E2) concentration to stay within the therapeutic window (20 approximately 50 pg/mL) by administering 0.625 mg conjugated equine estrogen (CEE)/day. Also, there is great individual variation in the circulating E2 concentration by administering the same dosage of CEE. Therefore, the use of smaller quantities of CEE in different dosages may approximate more closely to the clinical situation. This article focuses on the methods of administration of CEE combined with GnRHa for women with symptomatic uterine myomas.

Animals↗
PubMed2002

17Alpha-estradiol and 17beta-estradiol treatments are effective in lowering cerebral amyloid-beta levels in AbetaPPSWE transgenic mice.

Post-menopausal estrogen therapy is associated with a decreased incidence of Alzheimer disease and in vitro models have shown that 17beta-estradiol is effective in lowering amyloidogenic processing. To examine the effects of estrogen withdrawal and replacement on amyloid beta (Abeta) levels and amyloid beta-protein precursor (AbetaPP) processing in vivo, Swedish mutant AbetaPP transgenic mice were ovariectomized or sham ovariectomized at four weeks of age and treated with placebo or 17beta- or 17alpha-estradiol pellets, the latter being a weak estrogen receptor agonist. Compared to sham ovariectomized mice, ovariectomy with placebo did not alter Abeta levels; however, the levels of Abeta were decreased by 27% and 38% in mice treated with 17beta- and 17alpha- estradiol, respectively, with no change in AbetaPP holoprotein. Endogenous and exogenous estrogen both significantly increased the levels of sAbetaPPalpha, the secreted form of AbetaPP. The ratio of Abeta/sAbetaPPalpha, a measure of amyloidogenic processing, was reduced in all estrogen-containing groups. The Abeta lowering effect of 17beta- and 17alpha-estradiol was replicated when estrogens were administered at a more physiological dose in the drinking water, or when mice were ovariectomized at three months of age. The increased efficacy of 17alpha-estradiol versus 17beta-estradiol may help to develop safe and effective therapeutics.

Alzheimer Disease↗
PubMed1999

Estradiol receptor and prognostic parameters of human breast cancer.

Estradiol receptors are regarded to predict a likely success of hormonal therapeutic efforts and the prognosis of breast cancer patients. But today its prognostic importance is controversial, discussed as either reflecting intrinsic property of the tumor tissue or better therapeutic accessibility of receptor positive tumors. Moreover, the most important clinical prognosticators--tumor size and axillary lymph node involvement do not seem to be related to the estradiol receptor status. In our investigation, the length of disease free interval is similar in estradiol receptor positive and negative patients and in all sites of distant metastases, but it is significantly reduced if more than 4 axillary lymph nodes are involved. Post recurrence survival is significantly longer in estradiol receptor positive than negative patients and also in patients treated by tamoxifen containing therapies. Its length is independent of the number of axillary lymph node metastases and the type of distant metastases, with a tendency to be longer in estradiol receptor positive than negative patients. In addition, the overall survival is longer for estradiol receptor positive than negative patients and becomes reduced with more than 4 axillary lymph node metastases. Frequency of deaths in estradiol receptor positive patients is half that of negative subjects. Furthermore, the length of overall survival is independent on the type of distant metastases, with tendency to be longer in estradiol receptor positive than negative patients. Longest overall survival could be observed for estradiol receptor positive patients who got therapy regimens containing tamoxifen. The weak prognostic advantages of estradiol receptor positive patients are interpreted by estradiol receptors as intrinsic parameters of breast cancer tissue characterizing more its biological behavior than therapeutic accessibility.

Adult↗
PubMed2003

Repeated estradiol treatment prevents MPTP-induced dopamine depletion in male mice.

Epidemiological data suggest that the steroid hormone 17beta-estradiol plays an important role in protecting the brain from neurodegenerative processes, including that causing the loss of dopamine (DA) neurons in Parkinson's disease. Determining the mechanisms of neuroprotection in experimental systems may facilitate the development of estrogenic therapies for these diseases. The present study sought to further investigate the mechanism of the neuroprotective effect of 17beta-estradiol in a murine model of Parkinson's disease, i.e. 1-methyl- 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced striatal DA depletion. Consistent with previous findings, 17beta-estradiol was found to inhibit MPTP-induced DA depletion under a dosing regimen (repeated daily administration) that mimicked physiological levels of the steroid. However, high doses of the steroid administered repeatedly or acutely failed to inhibit toxicity, as did 17alpha-estradiol. These data suggest that the neuroprotective effect of 17beta-estradiol was mediated through an interaction with one of the nuclear estrogen receptors, and is not the result of an antioxidant action. In order to realize the therapeutic potential of the neuroprotective effect of 17beta-estradiol for Parkinson's disease, it will be necessary to identify synthetic estrogen receptor modulators that lack the activity of the steroid on peripheral tissue. In this study, raloxifene failed to mimic the neuroprotective effect of 17beta-estradiol against MPTP toxicity. Thus, exploration of new compounds with different pharmacological and/or physiochemical properties is warranted.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1991

Prolonged clearance of intraperitoneal 16 alpha-[125I]iodo-17 beta-estradiol in presence of ascites.

Radioestrogens have potential as adjunct therapeutic agents against ovarian carcinoma, because selected radionuclides can deposit lethal doses of radiation to tumor cells and many ovarian carcinomas and their metastases express estrogen receptors. Because intraperitoneal administration is a possible approach, we investigated absorption from the peritoneal cavity of a radioiodoestradiol after intraperitoneal application in rats with and without ovarian tumors and ascites and compared the distribution of the radioactivity with that obtained after intravenous injection. In the absence of ascites, 70% of the intraperitoneal dose was cleared into the intestine within 2 hours after injection, indicating fast absorption from the peritoneal cavity. In the presence of ascites, clearance of intraperitoneal radioiodoestradiol was considerably slower; at 2 hours after injection, 50% of the injected dose remained in the ascites, mostly as radioiodoestradiol. Uptake of radioactivity in estrogen receptor-rich tissues, e.g., uterus, after intraperitoneal injection was high (about 20:1 over blood), regardless of the presence of ascites, but moderately lower than that observed after intravenous injection of radioiodoestradiol.

Animals↗
PubMed1983

Guide-lines in the design of new antiestrogens and cytotoxic-linked estrogens for the treatment of breast cancer.

Antiestrogens (Tamoxifen) are used for the treatment of breast cancer. However these compounds are also weak estrogens that may stimulate tumor growth. Cytotoxic-linked estrogens (Estradiol Mustard, Estracyt) are devoid of major therapeutic activity. This led to search for new antiestrogens devoid of estrogenicity and for active cytotoxic-estrogens. Hydroxylation of C-4 of triphenylethylene antiestrogens (tamoxifen, CI 628 and U 23,469) largely increases their binding affinity for the estrogen receptor (ER). Hydroxylation also increases the in vitro antitumor activity of the drugs as shown by their higher ability to inhibit the growth of the ER-positive cell line MCF-7. Triphenylethylene antiestrogens contain an aminoethoxy side chain which appears essential for their physiological activity. Removal of the chain of tamoxifen suppresses its antiestrogenicity and antitumor activity. The grafting of side chains on a weak estrogen of the gem-diphenylethylene category produces "symmetrical" antiestrogens devoid of estrogenic activity. This observation raises the question of the role played by the third phenyl ring of the triphenylethylenes since the trans-isomers of the latter display antiestrogenicity and the cis-isomers estrogenicity. Comparison of the binding affinity for ER and antitumor activity of di- and triphenylethylene antiestrogens suggests that this third phenyl ring increases the interaction with ER of the 4-phenolic group of the drugs and/or their aminoethoxy side chain. An analogue of this chain is without any biological activity suggesting that the di-(tri)pheny-lalkene structure is required for promoting the interaction of the chain with ER. New chemical structures yielding antiestrogens with antitumor activity are also reviewed. New cytotoxic estrogens designed for producing lethal damage of DNA show a low binding affinity for ER. Moreover, there is no evidence suggesting specific antitumor activity. Such activity may be more easily obtained with estrogens bearing reagents for proteins rather than DNA. The biological properties of a 2-mesylate derivative of estrone irreversibly interacting with ER supports the concept. On MCF-7 cells, the drug displays a strong antitumor activity which can only be suppressed by high, equimolar, concentrations of estradiol. It is devoid of cytotoxic activity on the ER-negative cell line Evsa-T suggesting that ER is involved in its action.

Antineoplastic Agents↗
PubMed2005

Idiopathic stuttering priapism treated successfully with low-dose ethinyl estradiol: a single case report.

INTRODUCTION: Chronic priapism represents a challenging therapeutic dilemma. Inadequate or deferred treatment can result in impaired quality of life and permanent erectile dysfunction. The etiology of stuttering priapism is speculated to be initially an ischemic injury that damages the neurologic and/or endothelial-mediated mechanisms that normally regulate detumescence and maintain penile flaccidity. AIM: We report a case of stuttering priapism successfully treated with low-dose ethinyl estradiol. METHODS: A 51-year-old man presented with idiopathic stuttering priapism. Treatment was given in the form of low-dose ethinyl estradiol for six consecutive weeks. RESULTS: Moderate lowering of testosterone level and effective prevention of priapism for at least 6 months with retaining of erectile function. CONCLUSION: The use of low-dose estrogen shows a potential to be an effective and relatively rapid treatment option for some cases of idiopathic stuttering priapism.

Drug Administration Schedule↗
PubMed1987

Use of the aromatase inhibitor 4-hydroxyandrostenedione in postmenopausal breast cancer: optimization of therapeutic dose and route.

4-Hydroxyandrostenedione (4-OHA) is a potent inhibitor of estrogen production by aromatase and causes suppression of plasma estradiol levels and disease regression in postmenopausal breast cancer patients. Groups of patients were given p.o. or parenteral 4-OHA, and plasma estradiol and 4-OHA levels were measured to enable the delineation of the minimal effective dose and optimal therapeutic regimen. A single injection of 500 mg i.m. suppressed estradiol levels to a mean 36.3 +/- 3.3% (SE) (n = 14) of base line after 4 to 7 days and maintained this suppression in six of seven patients for greater than 14 days. The half-life of 4-OHA was approximately 8 days, and when the level had fallen to less than 3 ng/ml, estradiol levels began to rise. Similar suppression was achieved by a single i.m. injection of 125 mg of 4-OHA and by 500 mg of 4-OHA p.o. daily after 1 wk, but escape from suppression was more rapid.

Administration, Oral↗