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Biomedical subjects

H Seeger

Publications and source records attributed to H Seeger.

At least 55 records · Page 3Linked to original sources
PubMed2001

Lipid-independent effects of an estrogen-statin combination: inhibition of expression of adhesion molecules and plasminogen activator inhibitor--I in human endothelial cell cultures.

OBJECTIVE: Estrogens have been shown to elicit beneficial effects on the cardiovascular system by modulating the lipid profile as well as by direct vascular actions. Since estrogenic cardioprotection has still been not confirmed by randomized interventional trials, the combination with statins, which have been proved to act in a cardioprotective fashion, is of special interest. Statins are lipid-lowering drugs, but direct vascular effects also seem to be of importance in this case. Apart from some clinical studies investigating the effect of such combination therapy on the lipid profile, no reports of a possible influence on biochemical markers of vascular function are yet available. The aim of the present study was to investigate, for the first time, lipid-independent effects of an estrogen-statin combination on markers of vascular endothelial function. METHODS: Experiments were conducted using endothelial cell cultures from human umbilical veins. Markers of endothelial function chosen were adhesion molecules, which are involved in the early stages of atherosclerosis, and plasminogen activator inhibitor-1 (PAI-1), which is an independent risk factor for the development of cardiovascular disease. The concentrations of soluble forms of the adhesion molecules E-selectin and intercellular adhesion molecule (ICAM) as well as concentrations of PAI-1 were measured after the addition of 17 beta-estradiol, fluvastatin and equimolar combinations of the two in concentrations of 0.01, 0.1 and 1 mumol/l. RESULTS: Both drugs significantly reduced concentrations of E-selectin and ICAM, and the effect of the combination was not superior to that of the monosubstances. In addition, both substances were able to inhibit the synthesis of PAI-1. In this case the effect of the combination was significantly greater than that of the monosubstances. CONCLUSION: In summary, an estrogen-statin therapy is able to elicit lipid-independent positive modulations on the expression of cell adhesion molecules and the synthesis of PAI-1. The estrogen-statin combination showed partially additive effects and no negative, antagonistic actions. Since the combination of statins with hormone replacement therapy may attain clinical significance in preventing cardiovascular disease, it seems worthwhile to elucidate further the direct vascular effects of this combination therapy, especially in postmenopausal women with pre-existing coronary disease.

Anticholesteremic Agents↗
PubMed2001

The effect of medroxyprogesterone acetate and norethisterone on the estradiol stimulated proliferation in MCF-7 cells: comparison of continuous combined versus sequential combined estradiol/progestin treatment.

OBJECTIVE: Little is known on the type of progestin and regimen type in relation to breast cancer risk. We have compared the effect of medroxyprogesterone acetate (MPA) and norethisterone (NET) on the estradiol stimulated proliferation in MCF-7 cells with respect to different regimens used in combined hormone replacement therapy (HRT). DESIGN: To approximate the in vivo conditions in HRT, MCF-7 cultures were pretreated with estradiol followed by estradiol/progestin treatment to represent the sequential combined model and compared with non pretreated cultures followed by estradiol/progestin treatment for the continuous combined model. RESULTS: When using progestins in the continuous combined form with estradiol (10(-10) M) both progestins showed a significant reduction in the estradiol stimulated proliferation of the MCF-7 cells. In the sequential combined model the addition of MPA led to a stronger significant reduction of MCF-7 proliferation but in a narrower concentration range (from 10(-8) to 10(-6) M) compared to the continuous treatment. NET did not show any significant effect on proliferation in the SC model. CONCLUSION: Different regimen types and different progestins do lead to significantly different effects on the proliferation of a breast cancer cell line. These findings might be useful in the elucidation of potential mechanisms involved in the clinical situation.

Antineoplastic Agents, Hormonal↗
PubMed2000

The effects of A-ring and D-ring metabolites of estradiol on the proliferation of vascular endothelial cells.

The effects of 14 estradiol metabolites on the proliferation of cultured endothelial cells of human umbilical cord veins were examined and compared with that of their parent substance estradiol. The relationship between dosage and effect was tested over the pharmacological concentration range of 10(-8) to 10(-5) M. Estradiol showed a biphasic behaviour, in the form of stimulation at low concentrations and inhibition at the highest concentration. All 10 A-ring metabolites tested stimulated the growth of the endothelial cells at the lower concentrations. At the highest concentration, the 5 A-ring metabolites: 2-hydroxyestrone, 2-hydroxyestradiol, 2-hydroxyestriol, 4-hydroxyestrone and 4-hydroxyestradiol caused significant inhibitions. Except for the 2-hydroxyestradiol, methylation of these metabolites resulted in the loss of the proliferation inhibiting effect. The D-ring metabolites showed no marked effects compared to the A-ring metabolites except for 16alpha-hydroxyestrone which had an inhibiting effect from 10(-7) to 10(-5) M. Our results show that estradiol metabolites can influence the growth of vascular endothelial cells in the concentration range tested. While the antiproliferative action of 2-methoxyestradiol has been known for some time this study is the first to show the potential capacity of non-methylated metabolites of the A-ring metabolism in inhibiting endothelial proliferation. This may open up new clinical pharmacological aspects in the anti-angiogenetic treatment of tumors.

Cell Division↗
PubMed2000

The impact of endogenous estradiol metabolites on carcinogenesis.

The available literature on estrogen metabolism and estrogen metabolites involved in carcinogenesis is reviewed. Endogenous estradiol metabolism leads to metabolic products that can have various, and, to some extent, contrary, biologic effects. Thus, there are numerous research findings on the stimulation and inhibition of cancer growth by estrogen metabolites. Furthermore, there are indications that, in certain types of cancer, the production of growth-stimulating estradiol metabolites is increased. There are also reports on substances that can influence estradiol metabolism. So far, only a few estradiol metabolites have been examined with respect to their influence on the development and growth of cancer. It is presumed that other metabolites can also intervene directly or indirectly in the cancer process, but there is a great lack of research in this area. An understanding of the actions of estradiol metabolites may open up new avenues for the therapy of malignant diseases. Although little is known about the biologic effects of most of the estradiol metabolites, the reported actions of certain estradiol metabolites already justify clinical investigations on their possible beneficial uses in tumor therapy.

Animals↗
PubMed2000

Effect of oral contraceptives on the urinary excretion of biochemical markers indicating vasoactive action.

OBJECTIVE: In the present study the effect of two contraceptive pills, i.e. Neorlest, containing ethinylestradiol and norethisterone acetate, and Valette, containing ethinylestradiol and the new progestin dienogest, was investigated on the urinary excretion of vasoactive markers. As markers prostacyclin and its antagonist thromboxane, cGMP, serotonin, and the vasorelaxing mediators relaxin and urodilatin were measured. METHOD: 30 women received Neorlest and 33 women Valette in a randomized, open, parallel-group study design. Nocturnal urine was collected before treatment and during cyclic treatment after 6 and 11 weeks. RESULTS: For prostacyclin, the ratio of prostacyclin to thromboxane, relaxin and urodilatin significant increases compared to the pretreatment values were observed with Valette within 11 weeks treatment. For the markers cGMP and serotonin both contraceptive pills showed a tendency to an increase of the renal excretion after 11 weeks treatment. No significant differences between the two pills were observed, except in the case of the ratio of prostacyclin to thromboxane, which showed a significant, clear-cut enhancement with Valette. CONCLUSION: These results indicate that contraceptive pills may stimulate the production of vasodilative markers, an effect which can be attributed most likely to the oestrogenic component of the pill. The progestogenic component of the pill may elicit an impact on this oestrogen-induced vasodilation, which, however, seems to be minimized in the case of the new compound dienogest, a C-19 progestin with antiandrogenic properties.

Adult↗
PubMed2000

Fluvastatin combined with 17beta-estradiol: effect on the oxidation of human low density lipoprotein.

The in vitro effect of a statin and an estrogen on oxidation of human LDL was investigated for the first time, comparing the monosubstances fluvastatin and 17beta-estradiol as well as the effect of the combination. Fluvastatin significantly delayed the onset of LDL oxidation (controls = 90 min) by 23 min at 1 microM, by 110 min and by 221 min at 5 and 10 microM, respectively. 17Beta-estradiol significantly impeded the onset by 70 min at 1 microM and by more than 300 min at 5 and 10 microM. The combination of 1 microM 17beta-estradiol with 1, 5 and 10 microM fluvastatin showed an additive antioxidative effect; the onset was delayed by 100 min, by 167 min and by more than 300 min, respectively. It can be concluded that treatment of postmenopausal women with fluvastatin and 17beta-estradiol may have not only beneficial effects on lipid disorders but may also elicit a direct potent anti-atherosclerotic action on the vasculature.

Copper↗
PubMed2000

Effect of norethisterone acetate on estrogen metabolism in postmenopausal women.

Dominance of estradiol metabolism at the D-ring over the A-ring metabolism may play a role in the pathophysiology of human breast carcinogenesis. Currently, the influence of progestins on breast cancer risk is debated when added to postmenopausal estradiol replacement therapy. However, nothing is known about the action of progestins on estradiol metabolism. Therefore, the effect of oral and transdermal estradiol/norethisterone acetate (NETA) was investigated on the ratio of the main D-ring metabolite 16alpha-hydroxyestrone (16-OHE1) to the main Aring metabolite 2-hydroxyestrone (2-OHE1). The ratio of 16-OHE1 to 2-OHE1 after transdermal hormone replacement therapy (HRT) was 0.43 before treatment, 0.35 after estradiol and 0.52 after estradiol + NETA. The ratio after oral HRTwas 0.94 before treatment, 0.86 after estradiol and 2.30 after estradiol + NETA. Because of the high variations, no statistical significance could be calculated. Since there was a tendency to an increase after oral estradiol + NETA treatment, the individual patient profiles were examined. Here, three patients in the oral treatment group showed a significant increase of the ratio after the estradiol/NETA phase. In conclusion, transdermal NETA in HRT did not elicit any change in estrogen metabolism after 2 weeks' treatment. However, oral NETA may in some cases have an impact on estradiol metabolism which should be further evaluated.

Anticarcinogenic Agents↗
PubMed2000

Comparison of the effects of continuous combined and sequential combined medroxyprogesterone acetate-estradiol treatment on the proliferation of MCF-7 cells.

OBJECTIVE: The aim of the study was to examine the effects of two different, clinically relevant, hormone replacement therapy (HRT) regimen types, continuous combined and sequential combined, on breast cancer cells by means of an in vitro model. The study was carried out using the C21-progestin medroxyprogesterone acetate (MPA) in combination with estradiol, and with the proliferation of MCF-7, a human breast cancer cell-line, as end-point. METHODS: Proliferation of MCF-7 cells was measured by means of a crystal violet staining technique. Growth was triggered using a constant estradiol concentration of 10(-10) mol/l, while varying the MPA concentration from 10(-11) to 10(-6) mol/l. RESULTS: The continuous combined model of treatment led to the inhibition of estradiol-induced growth of MCF-7 with MPA concentrations of 10(-10) mol/l and upwards, compared with estradiol-alone-induced growth. The sequential combined model showed a greater inhibition at the higher MPA concentrations of 10(-8)-10(-6) mol/l, with reduced sensitivity to inhibition at the lower MPA concentrations tested, of 10(-11)-10(-9) mol/l. The different treatment types resulted in significantly different sensitivities of the MCF-7 cells to inhibition of estradiol-induced proliferation at the higher MPA concentrations of 10(-8)-10(-6) mol/l. CONCLUSIONS: The results demonstrate the importance of considering in vivo factors in an in vitro model with regard to improving the cell culture techniques used, to obtain a clearer picture of the possible mechanisms involved in the potential breast cancer risk with different HRT regimens.

Breast Neoplasms↗
PubMed2000

Effects of valsartan and 17 beta-estradiol on the oxidation of low-density lipoprotein in vitro.

BACKGROUND: The 'sartans' are antagonists of the angiotensin type 1 (AT1) receptor that are mainly used for treatment of hypertension. Little is known about AT1-independent effects of these substances and interactions with other drugs used for prevention of cardiovascular diseases. Postmenopausal estradiol-replacement therapy has been shown to exert beneficial antiathero-sclerotic properties by inhibiting oxidation of low-density lipoprotein (LDL). OBJECTIVE: In the present study, the effects of valsartan alone and in combination with 17 beta-estradiol on the oxidation of isolated human LDL were investigated. METHODS: Oxidation of LDL, which was triggered by copper (II) chloride, was monitored spectrometrically at 234 nm. The test substances were added in vitro. RESULTS: Valsartan alone increased the duration of resistance of LDL to oxidation by 75.3 +/- 5.7 min at 5 mumol/l and by 138.2 +/- 8.1 min at 10 mumol/l. 17 beta-estradiol alone delayed the onset of oxidation of LDL by 75.7 +/- 5.1 min at 1 mumol/l. With the combination of 5 and 10 mumol/l valsartan with 1 mumol/l estradiol the time to onset of oxidation of LDL was increased by 142.8 +/- 4.9 and 215.3 +/- 6.9 min, respectively. CONCLUSIONS: There has been demonstrated an antioxidative effect of valsartan that was additive to that of 17 beta-estradiol. Thus this combination has the potential to be useful in the treatment of postmenopausal women with hypertension.

Antihypertensive Agents↗
PubMed2000

[Effect of transdermal versus oral estradiol administration on the excretion of vasoactive markers in postmenopausal women].

OBJECTIVES: Can transdermal (n=20) and oral (n=20) estradiol substitution influence the urinary excretion of vasoactive substances in postmenopausal women? METHOD: The vasoactive substances prostacyclin and thromboxane, cyclic guanosine monophosphate, which can reflect the systemic NO production, serotonin, relaxin, insulin and melatonin were measured in nocturnal 8-hour urine before and after 2 and 4 weeks' estradiol treatment. RESULTS: The excretion ot prostacyclin and thromboxane, calculated as a prostacyclin/thromboxane quotient, was shifted towards higher prostacyclin production. Only minor changes could be registered for the cyclic guanosine monophosphate excretion. The production of serotonin, relaxin and insulin was increased only after transdermal treatment with estradiol. For melatonin no changes could be observed. CONCLUSIONS: Hormone substitution therapy with estradiol in postmenopausal women is able to increase the urinary excretion of various vasoactive substances, both after transdermal and oral application, indicating a vasodilatory estrogenic action. Transdermal administration was more effective, although lower dosages were applied. An explanation may be that transdermal estradiol elicits continuous and constant effects on estrogenic target organs.

Administration, Cutaneous↗
PubMed2000

Fluvastatin increases prostacyclin and decreases endothelin production by human umbilical vein endothelial cells.

Fluvastatin, an agent of a class of lipid-lowering drugs, the "statins", significantly enhanced prostacyclin synthesis at the concentrations of 0.1 microM and 1 microM and significantly reduced endothelin production at the concentrations 0.01, 0.1 and 1 microM in cell cultures of human umbilical endothelial veins. Since prostacyclin is a vasodilator and endothelin a vasoconstrictor, fluvastatin may have a significant effect on hemodynamics by favoring the balance towards vasodilation. This mechanism may contribute to the prevention of cardiovascular diseases.

Anticholesteremic Agents↗
PubMed2000

Urinary excretion of vasoactive markers following estrogen replacement therapy in postmenopausal women.

OBJECTIVE: The effect of estradiol on the renal excretion of vasoactive substances was studied in postmenopausal women. The following markers surrogating an estrogenic effect on the cardiovascular system were measured: prostacyclin and thromboxane, cGMP, which reflects systemic nitric monoxide production, serotonin and relaxin. METHODS: The effect of estradiol was compared using two clinical forms of administration, transdermal and oral, in two groups of 20 postmenopausal women each. The treatment was carried out for two and four weeks, respectively. Nocturnal urine was collected over 8 hours before and after estradiol treatment. The quantity of markers excreted during the experiment was determined. RESULTS: Excretion of prostacyclin and thromboxane, calculated as prostacyclin/thromboxane ratio, was increased using both forms of administration. Both forms of treatment brought about only slight non-significant changes in renal cGMP excretion compared with values before treatment. The production of serotonin and relaxin was only increased using transdermal treatment. CONCLUSION: The resulting data show that estradiol replacement in postmenopausal women is able to increase renal excretion of various vasoactive substances implying a vasodilative effect of estrogen. This was seen, both in transdermal and oral administration, transdermal application having a more pronounced effect on the markers than oral administration.

Administration, Cutaneous↗
PubMed2000

Effect of sequential estrogen/progestin treatment on biochemical vasoactive markers in postmenopausal women comparing oral and transdermal application.

PURPOSE: Estrogen replacement in postmenopause can elicit vasodilatory effects which may be important for cardiovascular protection. Progestin addition can antagonise this beneficial effect, but until now, only a few studies have been performed on this issue. In the present study the effect of estradiol as well as of added norethisterone acetate (NETA), a C19-progestin, on the renal excretion of various biochemical markers which can reflect vasoactive actions was investigated. METHODS: 37 postmenopausal women were treated for one sequential estrogen/progestin treatment cycle, i.e. two weeks with estradiol alone followed by two weeks with an estradiol/progestin combination. Both oral (n = 20) as well as 'complete' transdermal (n = 17) hormone substitution was applied, and the excretion of the following vasoactive substances or the stable metabolites, respectively, were measured in nocturnal urine prior to treatment, after 14 and 28 days: cGMP, which can reflect the production of nitric oxide, prostacyclin, thromboxane and serotonin. RESULTS: The excretion of cGMP was increased with both forms of administration during the estrogen phase as well as during the consecutive estrogen/progestin treatment. The prostacyclin-thromboxane quotient increased during estrogen phases, but decreased significantly by the addition of oral, but not with transdermal NETA, reflecting possible vasoconstrictory effects. Serotonin excretion increased, but this only was significant after the oral estrogen-only phase (2 weeks treatment), and after one cycle of complete transdermal treatment (4 weeks treatment), respectively. CONCLUSION: The observed effects can be explained by vasodilatory actions during the estrogen phases which can be maintained or even increased during the consecutive estrogen/progestin treatment suggesting a time-dependent beneficial estrogen effect. However, oral progestin addition may antagonise this effect already within two weeks of treatment whereby the prostacyclin-thromboxane quotient seems to be the most sensitive marker surrogating on vasoconstrictory progestin action.

Administration, Cutaneous↗
PubMed2000

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.

Anticholesteremic Agents↗
PubMed1999

Fluvastatin reduces endothelin secretion of cultured human umbilical vein endothelial cells.

OBJECTIVE: Fluvastatin is an agent of a new lipid lowering drug class, the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, which seems to elicit direct effects on the vasculature. METHODS: The effect of fluvastatin on endothelin secretion in endothelial cell cultures from human umbilical veins was investigated. RESULTS: Fluvastatin significantly reduced endothelin secretion by 13% at a concentration of 10(-8) M, by 41% at 10(-7) M and by 62% at 10(-6) M. CONCLUSION: Since endothelin is a potent vasoconstrictor which may be associated with the aetiology of cardiovascular diseases, the reduction of its synthesis by fluvastatin may contribute to the beneficial effects of this substance on the cardiovascular system.

Anticholesteremic Agents↗
PubMed1999

Effect of estradiol metabolites on prostacyclin synthesis in human endothelial cell cultures.

Estradiol can stimulate prostacyclin production in the vessel wall, thereby eliciting vasodilatation. In the present work the effect of the estradiol metabolites estrone, 2-methoxyestrone, 2-methoxyestradiol, and 16alpha-hydroxyestrone were investigated to find out if they are also able to stimulate prostacyclin synthesis. All metabolites triggered an increase of prostacyclin synthesis in human endothelial cells starting at a concentration of 10(-9) M. The parent substance, 17beta-estradiol, accomplished this effect only starting at a concentration of 10(-8) M. These results indicate that estradiol metabolites may take part in the estradiol-induced vasodilatation in vivo.

2-Methoxyestradiol↗