Eksp Klin Farmakol. 2002 May-Jun;65(3):25-7.
[Comparative evaluation of the antiradical and antioxidant activity of estrogens and their nitro derivatives]

[Article in Russian]

Matiushin AI, Gukasov VM, Rzheznikov VM, Balaban'ian VIu, Boiko MA.

Molecular Pharmacology and Radiobiology Department, State Medical University, ul. Ostrovityanova 1, Moscow, 117437 Russia.

Estradiol, ethynylestradiol, and estradiol acetate possess antiradical activity (K7 = (1.8-2.0) x 10(-4) liter/mole sec). Nistranol exhibits antiradical properties only upon acid hydrolysis. The results of experiments with egg yolk liposomes showed evidence of a pronounced antioxidant activity of estradiol, ethynylestradiol, and estradiol nitrate, and the absence of such activity in nistranol. In the experiments on rat heart homogenates, nitroestrogens in a concentration of about 10(-4) M reduced the level of TBA-active products.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12227090&dopt=Abstract estradiol




J Biol Chem. 2002 Nov 22;277(47):45219-25. Epub 2002 Sep 11.
Crystal structure of human sex hormone-binding globulin in complex with 2-methoxyestradiol reveals the molecular basis for high affinity interactions with C-2 derivatives of estradiol.

Avvakumov GV, Grishkovskaya I, Muller YA, Hammond GL.

Department of Obstetrics & Gynecology and Pharmacology, the Canadian Institutes of Health Research Group in Fetal and Neonatal Health and Development, the University of Western Ontario, London, Ontario N6A 4L6, Canada.

In a crystal structure of the amino-terminal laminin G-like domain of human sex hormone-binding globulin (SHBG), the biologically active estrogen metabolite, 2-methoxyestradiol (2-MeOE2), binds in the same orientation as estradiol. The high affinity of SHBG for 2-MeOE2 relies primarily on hydrogen bonding between the hydroxyl at C-3 of 2-MeOE2 and Asp(65) and an interaction between the methoxy group at C-2 and the amido group of Asn(82). Accommodation of the 2-MeOE2 methoxy group causes an outward displacement of residues Ser(128)-Pro(130), which appears to disorder and displace the loop region (Leu(131)-His(136)) that covers the steroid-binding site. This could influence the binding kinetics of 2-MeOE2 and/or facilitate ligand-dependent interactions between SHBG and other proteins. Occupancy of a zinc-binding site reduces the affinity of SHBG for 2-MeOE2 and estradiol in the same way. The higher affinity of SHBG for estradiol derivatives with a halogen atom at C-2 is due to either enhanced hydrogen bonding between the hydroxyl at C-3 and Asp(65) (2-fluoroestradiol) or accommodation of the functional group at C-2 (2-bromoestradiol), rather than an interaction with Asn(82). By contrast, the low affinity of SHBG for 2-hydroxyestradiol can be attributed to intra-molecular hydrogen bonding between the hydroxyls in the aromatic steroid ring A, which generates a steric clash with the amido group of Asn(82). Understanding how C-2 derivatives of estradiol interact with SHBG could facilitate the design of b




Physiol Res. 2002;51(3):267-76.
Sensitivity and specificity of the bioassay of estrogenicity in mammary gland and seminal vesicles of male mice.

Skarda J.

Institute of Animal Physiology and Genetics, Academy of Sciences of the Czech Republic, Prague.

Young intact (18 days old) and adult castrated males of CBA and C3H/Di mice were used for measuring the estrogenicity on the basis of growth response of mammary epithelial structures and the weight of seminal vesicles. It was demonstrated that heavier young males had disproportionally heavier seminal vesicles (sex steroid-responsive organs) than small animals at day 33 of age (that is on the day when experimental animals were killed and organs dissected). However, the weight of the spleen (sex steroid-nonresponsive organ) was proportionally related to body weight. To minimize variability in hormone responsiveness, all animals were weighed at the age of 18 days and only males weighing 8+/-1 g were used for hormone treatment. The percentage area of mammary fat pad occupiedby mammary epithelial structures was progressively increased by 17beta estradiol from dose 0.01 microg x d(-1). The maximum effective dose of estradiol was 0.1 microg x d(-1) and dose 10 microg x d(-1) of estradiol decreased mammary size to control level (inverted-U-shaped dose-response curve). Progesterone alone stimulated mammary growth only in high doses (500 microg x d(-1) and higher) in young intact males, but had no effect on mammary growth in adult castrated animals. In young intact males, estradiol alone, or progesterone alone decreased the weight of seminal vesicles. No such inhibitory effect of these hormones was noted in adult castrated males. Progesterone acted synergistically with estradiol to produce higher mammary growth compared to that in males treated with estradiol alone. In the presence of progesterone seminal vesicles weight was decreased by estradiol given in such low doses as 0.001 microg x d(-1) of estradiol, which is 10 times lower than that effe




Bull Exp Biol Med. 2002 Dec;134(6):544-7.
Binding of bis-beta-chloroethylamine derivatives of synthetic estrogens to proteins: dependence on the chemical structure.

Mayatskaya EE, Semeikin AV, Rzheznikov VM, Shimanovskii NL.

Department of Molecular Pharmacology and Radiobiology, Russian State Medical University, Moscow, Russia.

We studied binding of 10 new bis-beta-chloroethylamine derivatives of synthetic estrogens of different chemical structure to estradiol receptors in cytosolic fraction of breast carcinoma tissue and to blood plasma proteins. 11alpha-derivatives of estrone and ethynylestradiol with bis-beta-chloroethylamine radical at the 3-position were most potent, while 11beta-substances with the cytostatic residue in this position less effectively competed with labeled estradiol for estradiol receptors. Estrone derivatives with cytostatic residue at the 3-position bound primarily to serum albumin. Ethynylestradiol derivatives with cytostatic residue at the 3-position of the steroid nucleus bound to plasma globulins. Cytostatic radical at the 11-position changed spatial conformation of estrogen cytostatics and they lost their ability to interact with estradiol receptors and blood plasma proteins.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12660833&dopt=Abstract estradiol




Steroids. 2002 Oct;67(11):883-93.
Some new aspects of 17alpha-estradiol metabolism in man.

Hobe G, Schon R, Goncharov N, Katsiya G, Koryakin M, Gesson-Cholat I, Oettel M, Zimmermann H.

Hans-Knoll-Institute for Natural Products Research, Beutenberg-Str 11, 07745 Jena, Germany. ghobmail.hki-jeena.de

17Alpha-estradiol (1,3,5(10)-estratriene-3,17alpha-diol) together with a tracer dose of the tritium-labeled compound was administered orally and sublingually to male volunteers. The serum concentrations of 17alpha-estradiol (free and liberated by enzymatic hydrolysis) were quantified by GC/MS, and the serum total radioactivity and urinary radioactivity excretion were determined. After oral administration, 17alpha-estradiol was rapidly and intensively conjugated; only tiny quantities of the free steroid (<1% of total) appeared in serum. Sublingual administration resulted in temporary (up to 3 h p.a.) higher serum levels of the free compound. The metabolite patterns obtained by TLC of extracts from serum and urine demonstrated that 17alpha-estradiol is the subject of a poor phase I metabolism in man. A great discrepancy was found in the serum concentrations of 17alpha-estradiol (free + conjugated) determined by GC/MS and the serum radioactivity expressed in 17alpha-estradiol equivalents. By TLC analysis of the steroid conjugates extracted from serum, various 17alpha-estradiol conjugate peaks were found. By enzymatic hydrolysis with beta-glucuronidase/aryl sulfatase from Helix pomatia they were only partially cleaved. Thus, the difference between the serum radioactivity and the 17alpha-estradiol levels determined by GC/MS had to be attributed to an incomplete conjugate hydrolysis. It has been shown with the synthesized 17alpha-estradiol sulfate conjugates that only the 3-sulfate is cleaved by enzymatic hydrolysis, whereas the 17-sulfate group resists enzymatic hydrolysis. The methanolysis procedure (acetyl chloride in MeOH) has proved to be an efficient method for cleaving both the 3-sulf




J Neurosci Res. 2002 Oct 1;70(1):90-6.
Neuroprotective effect of estradiol and phytoestrogens on MPP+-induced cytotoxicity in neuronal PC12 cells.

Gelinas S, Martinoli MG.

Department of Biochemistry, Universite du Quebec a Trois-Rivieres, Trois-Rivieres, Quebec, Canada.

A large body of experimental evidence supports a role for oxidative stress as a mediator of nerve cell death in Parkinson's disease. To better understand the cellular insult of oxidative stress on dopaminergic neurons, we studied the cytotoxic effect of the 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) metabolite, 1-methyl-4-phenyl pyridium (MPP(+)), on several parameters of cell distress using neuronal PC12 cells. We also measured the level of protein expression for the dopamine transporter and the estrogen receptors alpha and beta. Since estrogens have been reported to prevent neuronal degeneration caused by increased oxidative burden, we investigated the ability of 17beta-estradiol, the stereoisomer 17alpha-estradiol, and several phytoestrogens to rescue neuronal PC12 cells submitted to MPP(+)-induced cytotoxicity. Our results consistently show a protective effect of 17alpha-estradiol, 17beta-estradiol and certain phytoestrogens such as quercetin and resveratrol, in neuronal PC12 cells treated with MPP(+). In our cellular paradigm, phytoestrogens coumestrol, genistein, and kaempferol did not revert MPP(+)-induced cellular death. By Western blot, we demonstrated that administration of MPP(+) alone decrease dopamine transporter expression, while treatments with MPP(+) together with 17alpha-estradiol, 17beta-estradiol, quercetin, or resveratrol could restore dopamine transporter protein expression to control levels. Moreover, the same treatments did not modulate alpha estrogen receptor or beta estrogen receptor expression. By these studies, we aim to provide more evidence for the involvement of phytoestrogens in the process of neuroprotection and to test our hypothesis that some of these compounds may act as neuroprot




Ann Thorac Surg. 2002 Sep;74(3):695-9.
Acute effects of 17beta-estradiol on left internal mammary graft after coronary artery bypass grafting.

Polvani G, Marino MR, Roberto M, Dainese L, Parolari A, Pompilio G, Di Matteo S, Fumero A, Cannata A, Barili F, Biglioli P.

Department of Cardiac Surgery, University of Milan, Centro Cardiologico Monzino IRCCS, Italy. luca.polvanardiologicomonzino.it

BACKGROUND: Vasospasm of arterial conduits used for coronary surgical procedures is an important cause of postoperative graft failure. Mounting experimental evidence suggests that estrogen reverses acetylcholine-induced vasospasm of the coronary arteries in animals and humans. Estrogen also affects endothelium-derived constrictor factors. We therefore investigated the in vivo vasomotor responses to transdermal 17beta-estradiol of the left internal mammary artery (LIMA) grafted on the anterior descending coronary artery. METHODS: We studied 20 women, mean age of 62 +/- 7.2 years (range, 48 to 73 years), who had undergone cardiopulmonary bypass for coronary artery bypass grafting. They received transdermal 17beta-estradiol on the fifth day after operation. The diameter, cross-sectional area, and blood flow of the LIMA graft were measured by transthoracic color Doppler echography before (basal values) and after the transdermal administration of 50 microg of 17beta-estradiol (control). RESULTS: LIMA graft vasodilation after the administration of 17beta-estradiol was observed. A significant increase in diameter (2.06 +/- 0.4 mm versus 2.37 +/- 0.28 mm; p = 0.035) and cross-sectional area (3.45 +/- 1. 2 mm2 versus 4.24 +/- 1 mm2; p = 0.039) was registered. The LIMA graft mean flow increased by 49% (44.76 +/- 27.19 mL/min versus 56.62 +/- 27.69 mL/min), but this increase was not statistically significant (p = 0.06). CONCLUSIONS: The acute postoperative transdermal administration of 17beta-estradiol induced a significant increase of LIMA graft diameter and cross-sectional area in postmenopausal women who und




Proc Int Congr Endocrinol. 1960;7A(266):529-30.
The effect of testosterone propionate and estradiol given separately and in combination upon the reproductive organs and the gonadotrophin content of the pituitary in the rat.

Patanelli DJ, Nelson WO.

PIP: Groups of 30-day-old male rats were treated for 1, 2, 3, and 4 weeks with .05 mg estradiol, 1 mg testosterone propionate, or a combination of the 2 hormones in order to determine whether duration of treatment might account for previous divergent observations on the effect of these hormones on the reproductive organs and the gonadotropin content of the pituitary in the rat. At each of the weekly intervals, administration of estradiol markedly reduced the weight of the testes, prostate, and seminal vesicles. Testosterone propionate alone, or in combination with estradiol, at each of the weekly intervals maintained the testicular weight to about 85% of the controls. The finding relates very well to observations that have been made in hypophysectomized animals injected with testosterone propionate and is explained by the fact that, in the rat, androgenic hormone alone is sufficient to maintain spermatogenesis. The pituitaries of untreated males reached a peak of gonadotropin content at 44 days of age, following which no appreciable change occurred. After 1 week of treatment, estradiol reduced the gonad otropin value by about 40% and thereafter to zero. Testosterone propionate alone, or in combination with estradiol, reduced the gonadotropin content to essentially the same modest extent when administered for 1 or 2 weeks. During the following 2 weeks of treatment, progressive decrease in gonadotropin levels occurred in animals which received testosterone propionate or testosterone propionate antagonizes the gonadotropin-suppressing effect of estradiol but that this inhibitory action is lost progressively after 2 weeks of treatment.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12255446&dopt=Abstract estradiol




J Popul Res. 1974 July-December;1(1):44-50.
Effect of estradiol-17-beta on spermatozoa of castrated rats.

Bandopadhyaha GP, Das RP, Roy S.

PIP: The effect of estradiol-17-beta on spermatozoa of castrated rats was investigated. Rats received daily im injections of .02 mcg estradiol-17-beta/100 gm body weight, 2 mcg testosterone/100 (gm body weight, or estradiol plus testosterone for 1, 2, 3, 4, or 5 weeks from the day after castration. Administration of estradiol maintained the normal motility pattern of spermatozoa of some parts of the epididymis and vas deferens for 7 days but by 21 days spermatozoa were absent in the whole tract. Testosterone restored the normal pattern of motility which was maintained for 14 days. The combined treatment also maintained the normal motility pattern up to 14 days. Estradiol accelerated and testosterone retarded sperm transport in the epididymis and vas deferens. Vas deferens and seminal vesicle weight increased after estradiol. Only epididymis weight increased after testosterone and only the seminal vesicle weight increased after combined treatment. These results indicate that estrogen may play a major role in the maintenance of the normal motility pattern of spermatozoa in the epididymis and vas deferens and in sperm transport in combination with androgen.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12257820&dopt=Abstract estradiol