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PubMed1984

The effect of 2 mg estradiol-17 beta plus 1 mg estriol, sequentially combined with 1 mg norethisteroneacetate, on LH, FSH, estradiol-17 beta, progesterone, testosterone and prolactin after ovariectomy.

The object of the study was to see whether maintenance of serum estradiol levels corresponding to the early and mid-follicular phase can prevent the gonadotrophin increase following ovariectomy. We also wanted to study the effect on LH and FSH of an additional dose of 1 mg dose of 1 mg norethisterone acetate administered for 10 days during each month. In 22 women with normal cycles 1 mg of estradiol benzoate was injected i.m. at the time of ovariectomy. From the first post-operative day onwards they received daily doses of 2 mg estradiol and 1 mg estriol in the form of micronized tablets. From the 41st to the 50th day and again from the 69th to the 78th day the patients received additional daily doses of 1 mg norethisterone acetate. LH, FSH, estradiol-17 beta, (E2) progesterone (P), testosterone (T), and prolactin (PRL) were measured in intervals of 2-17 days. Even though the estradiol mean values remained constant in the range of 65-115 pg throughout the period under observation, the LH mean levels increased continuously from 8 to a maximum of 23.9 mU/ml, and the FSH mean level from a pre-operative value of 6-48.0 mU/ml on the 85th day. On the 7th day after the last administration of norethisterone acetate LH was slightly depressed while FSH continued to rise slightly. Both FSH and LH are negatively correlated with E2 and this inverse correlation becomes even more pronounced the more time has elapsed after surgery. These findings suggest that not only the estrogens inhibit FSH and LH but also other steroids and/or nonsteroidal ovarian inhibiting factors.

Adult↗
PubMed1984

Changes in plasma estradiol and effects of triiodothyronine on plasma estradiol during smoltification of coho salmon, Oncorhynchus kisutch.

Plasma estradiol-17 beta levels were measured by radioimmunoassay in untreated coho salmon of both sexes or in fish fed triiodo-L-thyronine during the smoltification period. Mean plasma estradiol increased between February 25 and April 1 from 94 to 142 pg/ml, and then by May 13, it had decreased to 80 pg/ml. This hormonal cycle was followed by a second significant increase to 219 pg/ml on June 22. Plasma thyroxine level covaried with that of estradiol. Treatment with triiodothyronine had no effect on plasma estradiol or thyroxine levels. Plasma estradiol surges during the smoltification period must be considered along with other significant endocrine changes for a possible role in the developmental phenomena that characterize this period.

Animals↗
PubMed1988

Estradiol-binding molecules in the hepatocytes of the female water frog, Rana esculenta, and plasma estradiol and vitellogenin levels during the reproductive cycle.

Estradiol-binding molecules have been found both in cytosol and nuclear extract of hepatocytes of the female green frog Rana esculenta. These molecules show the properties of an estradiol receptor (Re): high and specific affinity for estrogens (2.10-7.10 x 10(-10) M), stability of binding at 0 and 20 degrees, localization in the nucleus, and cytosolic versus nuclear binding shift in estradiol-treated frogs. In hepatocytes, both filled and unfilled Re is detectable in all stages of the R. esculenta annual cycle. It increases during the recovery phase (September to January) when vitellogenetic processes are active in the ovary. These changes are positively correlated with vitellogenin. Only nuclear filled Re, moreover, is positively correlated to level of circulating estradiol. This suggests a direct connection: plasma estradiol level versus nuclear filled Re versus plasma vitellogenin level.

Animals↗
PubMed1983

Active immunization of female rats against 17 beta-estradiol. Preliminary studies on 17 beta-estradiol binding in uterine and pituitary cytosols.

Female rats were immunized with 17 beta-estradiol-6-carboxymethyloxime-bovine serum albumin. They developed antibodies to estradiol and, to a very low extent, antibodies to BSA. Anti-estradiol antibodies possessed tight specificity to estradiol-17 beta, without cross-reactivities with other estrogens. It was demonstrated that the specific estradiol binding in uterine and pituitary cytosols gradually decreased when antiserum titres increased. In uterine cytosols, the presence of progesterone receptor was studied using promegestone (R50 20) as ligand. No significant variations in promegestone binding were observed. Competition experiments however, questioned the permanence in immunized rats of the actual progesterone receptor or of a promegestone binding protein.

Aging↗
PubMed1997

Effect of sustained estradiol release in the intact male rat: correlation of estradiol serum levels with actions on body weight, serum testosterone, and peripheral androgen-dependent tissues.

The differential effect of increasing serum estradiol on various parameters in the intact male rat was assessed through the use of subcutaneously implanted, hormone-laden pellets. The delivery systems were designed to release drug through bioerosion at a zero-order rate over a 12-day time-course. Male Sprague-Dawley rats (190 to 220 g) were given estrogen pellets at increasing labeled strenghts (0, 0.001, 0.01, 0.1, 1.0, 10, 50, and 100 mg). Animals were weighed at various intervals before and after implantation. At Day 6, 12, and 26 after drug administration, rats were examined for 4 additional parameters, including serum estradiol and testoterone concentrations and accessory organ weights (i.e., ventral prostate and seminal vesicles). Serum estradiol levels were consistent with pellet potency and lifetime. Increases in body weight were suppressed 50% by circulating estradiol levels of approximately 200 pg/mL at Day 6,250 pg/mL at Day 12, and 285 pg/mL at Day 26. On the other hand, suppression of serum testosterone was more sensitive and was decreased 50% by peripheral estrogen levels of 36, 43, and 51 pg/mL at Days 6, 12, and 26, respectively. Accessory organ weights essentially reflected serum testosterone levels as indicated by their similar ED50 values: 50.5, 50.5, and 44.3 pg/mL for the ventral prostate at Day 6, 12, and 26, respectively, and 48, 56, and 51.5 pg/mL for the seminal vesicle regression at Day 6, 12, and 26, respectively. The data indicate the pellet used provided sustained plasma levels of hormone and these constant peripheral levels exerted potent pharmacological action. Initial body weight changes seemed to be less sensitive to the action of estradiol than serum testosterone or derivative properties, such as accessory organ weight.

Animals↗
PubMed2002

Positive effects on cardiovascular and breast metabolic markers of oral estradiol and dydrogesterone in comparison with transdermal estradiol and norethisterone acetate.

OBJECTIVES: To assess differences in two sequential combined hormone replacement therapy (HRT) products on selected cardiovascular and breast metabolic markers. The products were different concerning the route of administration of estradiol and its combined progestin, either oral or transdermal, and the androgenic properties of progestogens, respectively, dydrogesterone and norethisterone acetate. METHODS: One hundred and nineteen healthy non-hysterectomized postmenopausal women were included in this open, multi-center, two parallel group trial. They were randomized to a treatment of six 28-day cycles with oral estradiol sequentially combined with dydrogesterone (oE2/D10) or a sequential combination patch of estradiol plus norethisterone acetate (tdE/NETA). At baseline and after six cycles the high-density lipoprotein cholesterol (HDL-C), the sex hormone binding globulin (SHBG) and the total insulin-like growth factor-I (IGF-I) blood levels were determined by a central laboratory. A total of 89 women were compliant to the protocol. RESULTS: After six cycles, a statistically significant difference (P<0.001) concerning HDL-C, SHBG and IGF-I levels was found between the two treatment groups. The HDL-C levels were increased in the oE2/D10 group and decreased in the tdE/NETA group, with a final difference of about 0.3 mmol/l. The oE2/D10 treatment induced a sharp increase (about 57 mmol/l) in SHBG levels. IGF-I levels decreased with both the products, but the difference in favor of the oE2/D10 treatment was of about 30 ng/ml. Moreover, patients on tdE/NETA with an IGF-I baseline value below the median showed an increase. CONCLUSION: Oral estradiol sequentially combined with dydrogesterone, a non-androgenic progestogen, induced positive changes of some cardiovascular (HDL-C) and breast (SHBG and IGF-I) metabolic markers. These effects were significantly different from those obtained with a transdermal estradiol associated to an androgenic progestogen.

Administration, Cutaneous↗
PubMed2003

Genotoxic metabolites of estradiol in breast: potential mechanism of estradiol induced carcinogenesis.

Long term exposure to estradiol increases the risk of breast cancer in a variety of animal species, as well as in women. The mechanisms responsible for this effect have not been firmly established. The prevailing theory proposes that estrogens increase the rate of cell proliferation by stimulating estrogen receptor-mediated transcription and thereby the number of errors occurring during DNA replication. An alternative hypothesis proposes that estradiol can be metabolized to quinone derivatives which can react with DNA and then remove bases from DNA through a process called depurination. Error prone DNA repair then results in point mutations. We postulate that these two processes, increased cell proliferation and genotoxic metabolite formation, act in an additive or synergistic fashion to induce cancer. If correct, aromatase inhibitors would block both processes whereas anti-estrogens would only inhibit receptor-mediated effects. Accordingly, aromatase inhibitors would be more effective in preventing breast cancer than use of anti-estrogens. Our studies initially demonstrated that catechol estrogen (CE) quinone metabolites are formed in MCF-7 human breast cancer cells in culture. Measurement of estrogen metabolites and conjugates involved utilization of an HPLC separation coupled with an electrochemical detector. We then utilized an animal model that allows dissociation of estrogen receptor-mediated function from that of the effects of estradiol metabolites. Wnt-1 transgenic mice harboring a knock-out of ERalpha provides a means of examining the effect of estrogen deprivation in the absence of the ER in animals with a high incidence of breast tumors. ERbeta was shown to be absent in the breast tissue of these animals by RNase protection assay. In the breast tissue of these estrogen receptor alpha knock-out (ERKO)/Wnt-1 transgenic mice, we demonstrated formation of genotoxic estradiol metabolites. The ERKO/Wnt-1 breast extracts contained picomole amounts of the 4-catechol estrogens, but not their methoxy conjugates nor the 2-CE or their methoxy conjugates. The 4-CE conjugates with glutathione or its hydrolytic products (cysteine and N-acetylcysteine) were detected in picomole amounts in both tumors and hyperplastic mammary tissue, demonstrating the formation of CE-3,4-quinones. These results are consistent with the hypothesis that mammary tumor development is primarily initiated by metabolism of estrogens to 4-CE and, then, to CE-3,4-quinones, which may react with DNA to induce oncogenic mutations. The next set of experiments examined the incidence of tumors formed in Wnt-1 transgenic mice bearing wild type ERalpha (ER+/+), the heterozygous combination of genes (ER+/ER-) or ERalpha knock-out (ER-/-). To assess the effect of estrogens in the absence of ER, half of the animals were oophorectomized on day 15 and the other half were sham operated. Castration reduced the incidence of breast tumors in all animal groups and demonstrated the dependence of tumor formation upon estrogens. A trend toward reduction in tumor number (not statistically significant at this interim analysis) occurred in the absence of functional ER since the number of tumors was markedly reduced in ERKO animals which were castrated early in life. In aggregate, our results support the concept that metabolites of estradiol may act in concert with ER mediated mechanisms to induce breast cancer.

Animals↗
PubMedDate not supplied

Synthesis of 6beta-[(2'-Aminoethyl)carboxamidomethyl]estradiol and preparation of estradiol probes.

Reformatsky reaction of 3, 17beta-bis[(2-trimethylsilyl)ethoxymethyl]-1,3, 5(10)-estratrien-6-one (2) with bromoethyl acetate and zinc gave the ester (3) in 60% yield which upon treatment with methanesulfonyl chloride in pyridine afforded the olefinic esters (4 and 5) as an endo and exo mixture (67:33 ratio) in 81% yield. Hydrolysis of the SEM protective groups in compounds 4 and 5 followed by hydrogenation of the resulting hydroxy compounds 6 and 7 using 10% Pd/C afforded an epimeric mixture (beta:alpha = 79:21) of 6-[(ethoxycarbonyl)methyl]estradiol (8a and 8b) in 95% yield. Hydrolysis of the ethyl esters (8a and 8b) using sodium hydroxide gave the acid (9a and 9b) in 81% yield. The epimeric mixture of acids (9a and 9b) was activated, treated with tert-butyl-N-(2-aminoethyl)carbamate (10), and purified by HPLC to afford 6beta-[[[(2-tert-butoxycarbonyl)amino]ethyl]carboxamidomethyl] estradiol (11) in 39% yield as the major isomer. Hydrolysis of the BOC group in compound 11 using TFA afforded the desired 6beta-[(2-aminoethyl)carboxamidomethyl]estradiol 12 in 50% yield. The biotinylated estradiol probe 14, fluorescent probe 16, and chemiluminescent probe 18 were prepared from 6beta-[(2'-aminoethyl)carboxamidomethyl]estradiol (12) and the corresponding biotin, 5-carboxyfluorescein, and 10-(3-sulfopropyl)-N-tosyl-N-(3-carboxypropyl)acridinium-9-carboxamide N-succinimidyl esters (13, 15, and 17) in 65-74% yield and 99% purity.

Biotinylation↗
PubMed1998

Estradiol metabolism during oral and transdermal estradiol replacement therapy in postmenopausal women.

The metabolism of estradiol was investigated in postmenopausal women after 4 weeks' treatment with oral or transdermal unopposed estradiol. The urinary excretion of the metabolites was examined. With both administration routes, 2-hydroxyestrone, the main A-ring metabolite, and 16alpha-hydroxyestrone, the main D-ring metabolite, were excreted in higher amounts than estradiol and estrone. The ratio of 2-hydroxyestrone to 16alpha-hydroxyestrone remained the same for both administration routes. It has been suggested that dominance of D-ring metabolism, i.e. increase of 16alpha-hydroxyestrone production, is associated with an increased risk of breast cancer. The present study indicates that neither oral nor transdermal estradiol substitution shift this ratio to a higher level of possible risk. Oral estradiol substitution, however, in our study leads to higher metabolite concentrations which may be regarded as hazardous for women with diseases favoring D-ring metabolism.

Administration, Cutaneous↗
PubMed2003

Placement of the vaginal 17beta-estradiol tablets in the inner or outer one third of the vagina affects the preferential delivery of 17beta-estradiol toward the uterus or periurethral areas, thereby modifying efficacy and endometrial safety.

OBJECTIVE: The purpose of this study was to investigate whether the effects of 17beta-estradiol tablets that are designed for the treatment of postmenopausal urovaginal atrophy are influenced by the site of placement into the vagina. STUDY DESIGN: In this controlled crossover trial, 10 postmenopausal women received a single 17beta-estradiol tablet in the outer or inner one third of the vagina. Before and 3 hours after treatment, the pulsatility index, resistance index, and blood flow were evaluated in the uterine and periurethral vessels by Doppler examination. Parallel 17beta-estradiol serum evaluations were performed. RESULTS: Comparable and significant increases in 17beta-estradiol were observed. After inner administration, the pulsatility index and resistance index of both uterine arteries decreased; uterine artery blood flow increased significantly (P <.0001) but decreased in periurethral vessels (P <.02). After outer administration, the uterine artery pulsatility index, resistance index, and blood flow did not change, and the periurethral blood flow significantly increased (P <.0001). CONCLUSION: For optimizing the efficacy while minimizing the risk of endometrial hyperplasia, 17beta-estradiol tablets must be placed in the outer one third of the vagina.

Administration, Intravaginal↗
PubMed1987

Actions of estradiol on discrete attributes of the luteinizing hormone pulse signal in man. Studies in postmenopausal women treated with pure estradiol.

We assessed the time-dependent impact of estradiol on properties of the luteinizing hormone (LH) pulse signal in 12 hypoestrogenemic postmenopausal volunteers studied basally and after 1, 5, 10, and 30 d of estradiol delivery via an intravaginal Silastic ring. Computerized analysis of the plasma LH time series revealed a significant decrease in LH pulse frequency within 24 h of estrogen treatment, followed by a secondary increase (days 5 and 10), and then a sustained decline (day 30) in LH pulsatility. Estradiol also significantly suppressed incremental and maximal (but not fractional) LH pulse amplitudes in a biphasic manner. In contrast, LH peak duration was invariant until day 30 of estradiol replacement. These observations indicate that the well recognized biphasic actions of estradiol on mean serum LH concentrations can be modeled in relation to specific and time-dependent alterations in LH pulse frequency and amplitude.

Administration, Intravaginal↗
PubMed1977

Direction of estradiol metabolism as a control of its hormonal action--uterotrophic activity of estradiol metabolites.

The uterotrophic activities of the catechol metabolites of estradiol 2-hydroxyestrone, 2-methoxyestrone and 2-hydroxyestradiol were measured under conditions of continuous administration of sc implanted paraffin pellets. The activity of these estrogens was compared to that of estradiol-17beta and its other principal metabolites estrone, estriol and 15alpha-hydroxyestriol (estetrol). The major catechol estrogens, 2-hydroxyestrone and 2-methoxyestrone, and the pregnancy metabolite, 15alpha-hydroxyestriol, exhibited no uterotrophic activity. The minor catecholestrogen, 2-hydroxyestradiol, showed some activity whose character was different from that exhibited by implants of estradiol, estrone and estriol all of which were equipotent uterotrophic agents. Implants of 2-hydroxyestrone in the presence of estradiol or estriol pellets did not diminish the response to the latter indicating that the 2-hydroxyestrone is not antiestrogenic under these conditions. It is concluded that the direction of estradiol metabolism can have a profound influence on the expression of peripheral hormonal activity with hydroxylation at C-2 terminating and hydroxylation at C-16 extending it.

Animals↗
PubMed1984

Estradiol, estrone, and gonadotropin levels after use of vaginal estradiol.

The vaginal absorption of 0.5-mg tablets of micronized estradiol was evaluated in postmenopausal women. In a single-dose study, one hour after insertion, a 5.3-fold rise in mean serum estradiol levels and 1.5-fold rise in mean serum estrone levels were observed. Mean levels of luteinizing hormone and follicle-stimulating hormone were significantly depressed. In a three-week alternate-day regimen, mean serum levels of estradiol were consistently two to three times greater than those of estrone 12 hours after insertion. Vaginal absorption of micronized estradiol tablets into the systemic circulation was found to be rapid and efficient. The vaginal route was acceptable and well tolerated by patients. In addition, the major conversion of estradiol to estrone that follows oral or sublingual administration was reduced. The vagina may be a preferred alternate route for estrogen replacement therapy in selected patients.

Drug Administration Schedule↗
PubMedDate not supplied

[A new view of estradiol biotransformation in the body. Estradiol metabolism in the erythrocytes via the peroxidase reaction].

The study has established that in the presence of horseradish peroxidase, estradiol was subject to oxidative destruction under the action of hydrogen peroxide via the peroxidase reaction. The stoichiometric ratio of the hydrogen peroxide consumption to estradiol oxidation is 1:1 in this peroxidase reaction. Estradiol peroxidation was found to be catalyzed by methemoglobin by the same order as in case of horseradish peroxidase. Based on these results and the fact that estradiol is bound to erythrocytes and penetrates inside, it is concluded that erythrocytic estradiol is metabolically converted via its peroxidation.

Animals↗
PubMed1977

Fluorescein-labeled estradiol: a probe for anti-estradiol antibody.

A fluorescent estradiol derivative binds strongly to antiestradiol antibody. The binding, measured by fluorescence polarization, is inhibited by estradiol and by diethylstilbestrol. Tentatively characterized as N-(estradiol-6-iminooxyacetyl) fluorescein amine, the derivative was prepared from estradiol-6-iminooxyacetic acid, dicyclohexylcarbodiimide, and fluorescein amine, and isolated by TLC. It has a fluorescence emission similar to that of fluorescein and an absorption spectrum consistent with a fluorescein: estradiol molar ratio of 1:1.

Antibodies↗
PubMed1986

Estradiol membrane binding sites on human breast cancer cell lines. Use of a fluorescent estradiol conjugate to demonstrate plasma membrane binding systems.

A fluorescent estradiol macromolecular complex was used to study and to characterize steroid binding to membranes of living target cells. Ligand binding to plasma membranes was quantitated with a sensitivity of 0.1 nM. In this way, we found two types of estradiol-binding sites on hormone sensitive MCF-7 cells. Type A sites (8000-16000 sites per cell) were rapidly saturated at low concentrations of the estradiol-bovine serum albumin-fluorescein isothiocyanate macromolecular complex (E2-BSA-FITC). They had a greater affinity for the complex than did the type B sites for which a phenomenon of cooperative fixation was shown. The complex binding was displaced by estrogenic molecules, but not by non-estrogenic compounds, such as cortisol or progesterone. We also studied complex binding on another breast cancer cell line, MDA-MB-231 (MDA), without intracellular estrogen receptors. These cells showed a specific plasma membrane binding system for estrogen, but lacked the high affinity type A binding site. Then, we report the effects of enzyme treatments (trypsin, phospholipase A2 and neuraminidase) on E2-BSA-FITC binding to MCF-7 cell membranes. The quantity of complex bound to membranes decreased after phospholipase and neuraminidase treatments and increased after trypsin. But, in the three cases, the binding was no longer specific because it could not be displaced by E2-BSA or by estradiol. The enzymatic effects were reversible and specific binding was totally restored within 24 h. However, in the presence of the protein synthesis inhibitor, cycloheximide, no restoration of specific binding occurred on trypsin-treated cells. Estrogen binding to MCF-7 and MDA cell plasma membranes thus possesses the three characteristics of all mediated transport processes across biological membranes: saturability, substrate specificity, and specific inhibition. However, the high affinity type A binding site was found only on the estrogen-sensitive cell line, MCF-7.

Binding Sites↗
PubMed1986

Estradiol regulation of uterine nucleolar estradiol binding sites.

Rat uterine nuclei contain two types of estrogen binding sites (I and II). Type I is the classical high-affinity, low-capacity binding component, while Type II has lower affinity and higher capacity. Investigation of the presence and number of estrogen-binding proteins in isolated uterine nucleoli, and the possible role of the estrogen-binding protein(s) in the stimulation of nucleolar RNA synthesis was undertaken. Isolated uterine nucleoli contain a large number of lower-affinity binding sites (Type II) but are devoid of a significant number of high-affinity binding protein(s) (Type I). Following in vivo treatment with estradiol the number of detectable Type II estradiol-binding sites in isolated uterine nucleoli increased with time of estrogen treatment, peaking between 16 and 24 h after hormone administration and gradually decreasing to control levels between 48 and 72 h. The estrogen-activated binding activity but not the basal activity is sensitive to dithiothreitol and insensitive to beta-mercaptoethanol during the in vitro assay, suggesting that important disulfide bonds may be involved in the estrogen-induced nucleolar binding sites. The in vivo activation of nucleolar estradiol-binding sites exhibits steroid specificity. Data indicate that a strong correlation exists between activation of uterine nucleolar transcriptional and estradiol-binding activities.

Animals↗
PubMed1975

Catalytic competence, a new criterion for affinity labeling. Demonstration of the reversible enzymatic interconversion of estrone and estradiol-17 beta covalently bound to human placental estradiol-17 beta dehydrogenase.

Human placental estradiol-17beta dehydrogenase is rapidly inactivated upon treatment with 3-bromoacetoxyestrone. Pseudo-first order kinetic data are obtained and inactivation is accompanied by incorporation of 1 mol of 3-acetoxyestrone/mol of subunit (Mr =34,000). Treatment of the inactivated enzyme with (4S)-[4-2H]DPNH results in the formation of covalently bound [17alpha-2H]estradiol-17beta, which can be released by hydrolysis and identified by gas chromatography-mass sepctrometry. When (4R)-[4-2H]DPNH was used, deuterium was not transferred. Thus, the normal stereochemistry of hydridetransfer is preserved for both partners. After treatment with p-mercuribenzoate, affinity-labeled estradiol-17beta dehyrogenase is no longer able to caralyze reduction its covalently bound estrone; in the presence of DPNH and native enzyme, however, reduction occurs, demonstrating that affinity-labeled enzyme can itself serve as subtrate for native estradiol-17beta dehydrogenase. The reversible enzymatic interconversion of covalently bound estrone was demonstrated using a transhydrogenase assay. The ability of an enzyme to catalyze its normal reaction with a covalently bound substrate is termed catalytic competence, and is considered to be a new criterion for affinity labeling.

Affinity Labels↗