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Realization of program of sex formation in multicellular organisms is a complex multistage process. The role of the inductor in this process is assigned to sex hormones synthesized by cells of the emerging gonads. The action of androgens on the formation of the male is now well understood. However, little is known about the involvement of estrogen the female gonad formation and the formation of a female as a whole. Here we present the results of experimental sex inversion in female chickens produced by aromatase inhibition and by the action of tamoxifen on chicken embryos. We have shown various masculinizing effect depending on the dose of active substance and the number of injections. We have noted that inhibition of aromatase does not block meiotic prophase in oogoniums. We have suggested that there are differences in the mechanisms of action of retinoic acid and estrogens on oogenesis. We have first shown proteins and nucleoproteins that interact with the estrogen receptor 1 and provided maps of their gene localization in human and chicken genomes.

Cytestrole acetate (CA), in the structure of which the steroidal antiestrogen component is associated with bis-β-cloroethylamino group, exhibits a strong cytotoxic activity against hormone-dependent cancer cell lines (CaOV, HeLa, MCF-7). In doxorubicin-resistant MCF-7 cells, CA potentiates the cytotoxic effect of etoposide and doxorubicin, and the IC50 for CA in these cells is 40 times lower than that for tamoxifen (TAM). In transplantable mice breast adenocarcinoma Ca-755, the therapeutic CA dose is 25 mg/kg when administered subcutaneously in oil solution for 5 days. On the DMBA-induced mammary tumors in rats, CA injected subcutaneously led to partial regressions 4 weeks after treatment in 75% of test rats, whereas TAM produced this effect in 43% of rats. Among various drug forms of CA, the most active were oil solution of CA in gelatin capsules for oral use and liposomal emulsion for intravenous administration, since these forms exhibited the highest values of Ca-755 tumor growth inhibition index (TGI = 97 - 98%).

As we showed previously, administration of estradiol in different doses (5 and 15 mcg per day for 21 day) initiates the development of pulmonary arterial hypertension (PAH) in ovariectomised female Wistar rats. The aim of current study was to analyze the involvement of antagonist of estrogen receptors type a- and beta- ICI 182,780 (fulvestrant) in development of hypoxia-induced pulmonary arterial hypertension. Ovariectomised female rats were separated into 5 groups received subcutaneously for 1 month : 1. Estrogen 15 mcg per day. 2. Estrogen 60 mcg per day 3. Antagonist of estrogen receptors type alpha- and beta- fulvestrant 150 mcg per day. 4. Estrogen 15 mcg/d + fulvestrant 150 mcg/d. 5. Propylenglycol as a control group. PAH was induced by exposure to hypobaric hypoxia. Rats were housed in a hypobaric chamber at simulated altitude of 5000 m, 10 h a day, 2 wk (O2 concentration reduced to 10%). We suppose that the development of pulmonary hypertension in ovariectomised female Wistar rats caused by administration of estrogen (15 mcg and 60 mcg per day for 1 month) is mediated by estrogen receptors type alpha- and beta-.

The loss of hormonal dependency in breast tumor cells is often accompanied by epithelial-mesenchymal transition (EMT) features and an increase in cell metastasizing and invasiveness. Here we studied the role of transcription factors Snail1--the central mediator of EMT, in the progression of hormonal resistance of breast cancer cells. The experiments were performed on the estrogen receptor(ER)-positive estrogen-dependent MCF-7 breast cancer cells, ER-positive estrogen-resistant MCF-7/LS subline generated through long-term cultivation of the parental cells in steroid-free medium, and ER-negative estrogen-resistant HBL-100 breast cancer cells. We found that decrease in the estrogen dependency of breast cancer cells is accompanied by an increase in Snail1 expression and activity, and demonstrated the Snail1 involvement in the negative regulation of ER. NF-kappaB was found to serve as a positive regulator of Snail1 in breast cancer cells, and simultaneous inhibition of NF-kappaB and Snail1 by RNA interference resulted in marked increase of cell response to antiestrogen tamoxifen. In general, the results obtained demonstrate that direct inhibition of NF-kappaB and Snail1 partially restores the estrogen receptor machinery, and show that Snail1 and NF-kappaB may serve as an important targets in the treatment of breast cancer.

Estrogens belong to more or less frequently prescribed preparations. Main fields of application of these preparations (as in monotherapy as well as in combination) are contraception and hormone replacement therapy during menopause. More uncommon indications of estrogens are growth inhibition and hypogonadism (in this case they are prescribed along with gonadotropic hormones). Synthesis and metabolism of estrogens, as well as their intracellular receptors are well studied these days, which allow us to understand physiology and pharmacology of these hormones. In pharmacology the main stage is detection of estrogen receptors inside of cells of targets. There are two types of estrogen receptors alpha- and beta- coded by different genes. A number of steroid and non-steroid compounds have characteristics of estrogens. Likely in the future their popularity will increase, as by the aging of population number of those women, who receive replacement therapy, will increase. Investigations to find an ideal elective modulator of estrogen receptors, that will possess anti-estrogenic activity in connection with mammal gland and develop indifference in connection with endometrium and at the same time will display ability to reduce hot flushes, bone resorption, atrophy of mucous membranes of vagina and urinary bladder, as well as it will favorably effect on metabolism of lipoproteins are carried out.

Tamoxifen did not influence the human platelet aggregation in vitro, while estradiol at a concentration of 10(-6) M inhibited the aggregation of human thrombocytes induced by ADP, serotonin + adrenaline, and adrenaline (epinephrine) by 14.7, 12.5, and 16.6%, respectively. Estradiol introduced in the range of effective concentrations from 10(-8) to 10(-4) M inhibited lipid peroxidation, while tamoxifen produced this effect only at a concentration of 10(-4) M. There was a correlation between the antiaggregant activity and antioxidant properties of estradiol.

A study was made of the influence of a long-term exposure of 1,25-dihydroxyvitamin D3 and 17 beta-estradiol on deactivation of MAP kinases in correlation with proliferation of cancer cells. The obtained results illustrate inhibition of cell growth after vitamin D treatment. Mechanisms of such an inhibition are discussed.

Protracted per os introduction of "Anaster" preparation, the derivative of carbon acids causes inhibitory effect to sexual activity of female rodents (rats, mice, hamsters) in particular, to the dynamics of sexual cycles and as a result sharp decrease of reproductive function. "Anaster" has no remote after-effects and the stop of its taking leads to quick and complete restoration of sexual cycles.

Influence of antiestrogen and antiandrogen derivatives of acylhydrazine, potentiating the antitumoral effect of cytostatics, on properties of nucleoside triphosphatases (NTPases), adenylate content in nuclea of normal and tumoral cells was studied. It was shown that acylhydrazines activated specifically the intranuclear NTPase of normal and tumoral cells. Activity of nuclear membrane-linked NTPases from liver cells was also increased after administration of acylhydrazines, sex hormones or phenobarbital. The increase in activity of intranuclear NTPase (namely ATPase) correlated with decrease of adenylates (ADP, ATP) in nuclea isolated from tumors after simultaneous treatment with acylhydrazines and thiophosphamide. Distinct increase in sensitivity of tumoral cell DNA to the effect of these alkylating preparations appear to be due to noncompensated decrease in content of ATP.

Specificity of interaction between estrogen-receptor systems of guinea pig uterus and oviducts and six estrogens was studied. The obtained datas suggest existence of tissue specificity in estrogen-receptor interaction in uterus and oviducts. Modifications of the steroid molecule led to decrease in extent of estrogen affinity. Introduction of an ethyl group into 17 alpha-position resulted in the effect, by the rate of estrogen-receptor binding equal to reduction of 17 beta-hydroxyl. Low but distinct affinity of 17 alpha-estradiol, its structure and stability, enabled to select this substance as a preparation with anticipated anti-estrogenic activity.

The effects of estradiol (E2) and some other endocrine factors on rat plasma angiotensinogen (AG) have been studied. AG was determined by RIA. Both single and multiple injections of E2 to female rats were shown to cause a dose-dependent increase in AG in the blood. The effect of E2 was inhibited by cycloheximide. Multiple injections of E2 to male rats caused the same hepatic AG synthesis induction as those to female rats. Unlike E2, long-term treatment with large doses of testosterone propionate did not affect AG synthesis. AG levels in blood plasma of ovariectomized and immature female rats did not differ from those seen in mature intact rats. However, immature females were insensitive to the stimulant effect of the pharmacological doses of E2. Drastic reduction in hepatocyte sensitivity of the stimulant effect of E2 was seen in hypophysectomized female rats as well. Treatment of hypophysectomized animals with human GH, which did not affect AG levels per se, caused an almost complete recovery of hepatocyte ability to react by increasing AG synthesis in response to E2 injection. The possible role of different hormonal and genetic hepatotrophic factors in hepatocyte reactivity to the stimulant effect of E2 on AG synthesis is discussed.