Impact of soy supplementation on sex steroids and vascular inflammation markers in postmenopausal women using tibolone: role of equol production capability.

OBJECTIVES: Tibolone is often taken concurrently with soy. Tibolone, soy and equol-producing capacity each affect vascular health, whereas their concomitant effects are unknown. We studied the effects of soy on sex steroids and vascular inflammation markers in long-term tibolone users. METHODS: Postmenopausal women (n = 110) on tibolone were screened with a soy challenge to find 20 equol producers and 20 non-producers. All women were treated for 8 weeks in a cross-over trial with soy (52 g of soy protein containing 112 mg of isoflavones) or placebo. Serum estrone, 17beta-estradiol, testosterone, androstenedione, dehydroepiandrosterone sulfate (DHEAS), sex hormone binding globulin (SHBG), C-reactive protein (CRP), vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and platelet-selectin (P-selectin) were assessed. RESULTS: Soy decreased (7.1%) the estrone level, significantly (12.5%) only in equol producers (from 80.2 +/- 10.8 to 70.3 +/- 7.0 pmol/l; p = 0.04). Testosterone was reduced (15.5%; from 586 +/- 62.6 to 495 +/- 50.1 pmol/l, p = 0.02) during soy treatment, and more markedly in equol producers than non-producers (22.1% vs. 10.0%). No changes appeared in SHBG, CRP or ICAM-1, but VCAM-1 increased (9.2%) and P-selectin decreased (10.3%) during soy treatment. CONCLUSIONS: Soy modified the concentrations of estrone, testosterone and some endothelial markers. Equol production enforced these effects. Soy supplementation may be clinically significant in tibolone users.

Urinary phytoestrogen excretion of rats bearing methylnitrosourea-induced mammary carcinoma in response to treatment with 2-methoxyestradiol.

The effect of treating mammary tumor-bearing rats with 2-methoxyestradiol (2-MeE2) on the urinary excretion of 12 phytoestrogens was investigated and compared with the changes in urinary excretion of estradiol metabolites. Alterations of excretion were registered for isoflavonoids, lignans and coumestans. However, due to large variations statistical significant differences were found only for two lignans, i.e. significant increases of enterodiol and matairesinol. Since the single components of phytoestrogens showed diverse alterations, excretions were expressed also by the ratio of total isoflavonoids to total lignans and compared with the estrogen ratios 2-hydroxyestrone to 16alpha-hydroxyestrone and A-ring to D-ring metabolites. The ratio of isoflavonoids to lignans was consistently decreased, whereas both ratios of estradiol metabolites were highly increased. The latter effect is probably due to demethylation of 2-methoxyestrone resulting in high catechol estrogen levels in urine. These results suggest that the high levels of catechol estrogens, produced by 2-MeE2 treatment, may have influenced the urinary excretion pattern of phytoestrogens.

Class-specific pro-apoptotic effect of statins on human vascular endothelial cells.

Neonangiogenesis represents an important step in tumor development and propagation. Statins may have anticancerogenic potential by blocking vascular endothelial cell growth. The antiproliferative effect of four statins on human endothelial cells was compared, concomitantly delineating a possible pro-apoptotic process. All four statins tested, i. e. atorvastatin, fluvastatin, lovastatin, and simvastatin inhibited cell proliferation. Nearly complete blocking of cell proliferation was achieved at a concentration of 10 microM. We were able to demonstrate that the antiproliferative effect of the statins is not due to cytotoxicity but rather to an apoptotic effect as demonstrated by comparison of cytotoxicity assay and apoptosis assay. The apoptotic mechanism seems to involve caspases, since the statins significantly enhanced caspase activity at dosages of 10 and 20 microM. Further experiments revealed a downregulation of the pro-apoptotic protein Bcl-2. Our data indicate that statins may class-specific inhibit angiogenesis at high dosages which can contribute to prevention of tumor development and progression.

Additive antioxidative effect of hormone replacement therapy combined with a statin.

In treating postmenopausal women both statins and estrogens have been shown to elicit favourable effects on lipids and lipoproteins. In addition direct beneficial effects of these substances on the vascular wall are discussed. However, progestin addition to estrogen replacement therapy, which is mandatory in women with an intact uterus. is thought to deteriorate at least partly estradiol-induced direct effects on the vasculature. Oxidation of LDL, which mainly takes place in the vessel wall, seems to be a crucial step in the development of atherosclerosis. Therefore, for the first time, the effect of a statin and an estrogen/progestin combination on the in vitro oxidation of human LDL was investigated comparing the monosubstances fluvastatin. 17beta-estradiol and norethisterone acetate (NETA) as well as the effect of the combination. LDL was isolated from human female serum and oxidation was initiated by copper(II)-chloride. The progression of LDL oxidation was monitored spectrometrically at 234 nm for 300 min. Fluvastatin significantly delayed the onset of LDL oxidation (controls = 85 min) by 21 min at 1 microM, by 99 min and by 210 min at 5 and 10 microM. respectively. 17beta-estradiol significantly reduced the onset by 73 min at 1 microM and by more than 300 min at 5 and 10 microM. NETA had no significant effect. The combination of I microM 17beta-estradiol and 1 microM fluvastatin with 1, 5 and 10 microM NETA showed an additive antioxidative effect of estradiol and fluvastatin and no deterioration by the addition of NETA even at high dosages. It can be concluded that treatment of postmenopausal women with fluvastatin and a combination of 17beta-estradiol with NETA may have not only beneficial effects on lipid disorders but may also elicit a direct potent antiatherosclerotic action on the vasculature.

Experimental and clinical results in shock lung treatment with vitamin E.

The adult respiratory distress syndrome (ARDS) is not confined only to late shock states but is a typical finding in intoxications with such oxidizing agents as O3, NO2, chlorate, or paraquat. Under experimental conditions, alpha-tocopherol in a high enteric dosage (2 x 50 mg/kg) was able to prevent alterations of pulmonary surface tension parameters (p less than 10(-5)) induced by microembolization of pulmonary vessels in awake rabbits. Parameters of gas exchange (PaO2' A-aDO2) were significantly less impaired (p less than 0.01) in the tocopherol group. Since there was no additional oxidative stress, the protective effect of tocopherol suggests an involvement of pathophysiologically occurring peroxidation mechanisms. Arachidonic acid (AA) metabolism is known to be a physiological oxygenation process yielding products with utmost biological efficacy. In a model of isolated, ventilated, and continuously perfused rabbit lungs, release or addition of AA resulted in an increase of pulmonary vascular resistance and permeability. The former could be ascribed to cyclooxygenase products, the latter to lipoxygenase products, of AA. The alpha-tocopherol effect in this model was a complex one: the antioxidative chromane structure (Trolox) as well as superoxide dismutase (SOD) decreased both pulmonary vascular resistance and permeability induced by AA metabolism dose dependently to a large degree, whereas the phytyl side chain augmented both effects. Pharmacological efficacy of high-dose alpha-tocopherol is not yet completely understood. Since 1977, we have applied all-rac-alpha-tocopheryl acetate (6-8 x 300-500 mg/day by gastric tube) to patients with manifest or threatening ARDS in addition to the required conventional complex therapy. Out of 176 patients being artificially ventilated for at least four days in the Internal Intensive Care Unit, Giessen University, 87 received tocopherol and 89 did not. There was no statistically valid stratification or randomization of the patients. In general, the tocopherol-treated patients were considered to have the worse prognosis, as is confirmed by higher maximum FIO2 and PEEP values. Thirty-four tocopherol patients (39%) and 15 nontocopherol patients (17%) survived. Surviving tocopherol patients were ventilated for a mean of 10.0 +/- 7.7 days (with maxima of 25, 28, and 41 days), whereas surviving nontocopherol patients were ventilated only for 5.5 +/- 1.1 days (none of these for more than 8 days). Absorption of alpha-tocopherol by these severely ill patients was shown by gas chromatography. A well-prepared clinical trial for tocopherol therapy of ARDS is suggested.