[The value of hormone replacement therapy for prevention of coronary heart disease in women].
Explore the source record for details and available documents.
Aged↗
Biomedical subjects
A O Mueck
Publications and source records attributed to A O Mueck.
[Are the acute effects of transdermal estradiol in postmenopausal women with coronary disease related to changes of the autonomic tone?].
The single application of estradiol in postmenopausal women with symptomatic coronary heart disease has an antiischemic effect, which seems to be mainly related to the relaxation of the vascular smooth muscle. Longterm replacement with estrogen in postmenopausal women reduces their increased sympathetic activity. The aim of the double-blinded study was to assess whether a single transdermal estradiol administration also has an effect on the sympathovagal balance and may additionally explain the acute effects of estradiol. Methods Fifteen women with symptomatic and angiographically proven coronary artery disease were cross-over randomized to two 100-microgram patches of estradiol or identical placebo. After one week the women received the opposite treatment. One day after patch application a 24-hour Holter-ECG recording was performed to assess the mean heart rate over 24 hours as well as time domain and frequency domain indices of the heart rate variability. Results The estradiol plasma concentration rose significantly from 354 +/- 176 pmol/l after placebo to 800 +/- 260 pmol/l after estradiol application. Heart rate during placebo was 74 +/- 15 bpm and during therapy 74 +/- 15 bpm. Heart rate variability was not different for time domain indices such as SDNN (estradiol: 64 +/- 31 ms; placebo: 65 +/- 33 ms) or for frequency domain indices such as LF (estradiol: 15.8 +/- 8.0 ms; placebo: 15.3 +/- 9.4 ms) and HF (estradiol: 12.1 +/- 8.5 ms; placebo: 12.9 +/- 9.9 ms). Conclusion A single transdermal application of estradiol did not modify heart rate or heart rate variability of women with coronary artery disease. The modulation of the autonomic tone does not seem to be a relevant mechanism of short-term estradiol effects.
Administration, Cutaneous↗
Effect of two oral contraceptives containing ethinylestradiol and levonorgestrel on serum and urinary surrogate markers of endothelial function.
OBJECTIVE: To investigate the effect of two oral contraceptives containing 0.02 mg ethinylestradiol and 0.1 mg levonorgestrel (Formulation A, Leios), and the other containing 0.03 mg ethinylestradiol and 0.15 mg levonorgestrel (Formulation B, Stediril 30) on the serum and urinary concentrations of various markers reflecting the status of vascular tone and development of atherosclerosis. The adhesion molecules E-selectin, inter-cellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and homocysteine were included as serum markers and cGMP, prostacyclin and its antagonist thromboxane as urinary markers. METHODS: In a comparative, double-blind, randomized, parallel group study, 34 women received formulation A and 33 women formulation B. Serum samples were collected before treatment and after 3, 6 and 12 cycles. Nocturnal urine was collected before treatment and during cyclic treatment after 3 and 12 cycles. Serum and urinary markers were measured by enzyme immunoassays. RESULTS: E-selectin levels were significantly reduced by both contraceptives after 3, 6 and 12 months compared to pretreatment levels. A slight increase in ICAM concentrations was observed for both contraceptives after 6 cycles, but this fell to pretreatment levels after 12 cycles. VCAM values were significantly lowered after 3, 6 and 12 months by both contraceptives. No significant changes were found in serum levels of homocysteine. No significant differences were found between treatment groups for the serum markers. Both contraceptives significantly enhanced urinary cGMP excretion after 12 cycles. The prostacyclin metabolite remained unchanged in the case of both formulations, but the excretion of the thromboxane metabolite was significantly decreased after 12 cycles. Thus, the ratio of prostacyclin to thromboxane, decisive for the resulting effect on vascular tone, increased significantly. CONCLUSION: These results indicate that the low-dose oral contraceptives can reduce the production of adhesion molecules which play a crucial role in the early stages of atherosclerosis. In addition, these contraceptives can shift the balance of vascular tone towards dominance of vasodilatory substances after 12 cycles of treatment. Thus, the positive influence of these contraceptives on the various markers investigated may improve vascular tone and impede development of atherosclerosis.
Adult↗
Tibolone versus 17beta-estradiol/norethisterone: effects on the proliferation of human breast cancer cells.
Tibolone is a synthetic progestin with estrogenic and progestogenic properties, widely used for alleviation of menopausal syndromes and for osteoporosis prophylaxis in postmenopausal women. Since only little data are available on tibolone and breast cancer risk the present study investigates the effect of tibolone on the growth of the human breast cancer cell line, MCF-7. Tibolone is clinically comparable to an estradiol/norethisterone combination, therefore we included this hormone combination in our experiments. Tibolone was examined alone and in the presence of 0.1 nM estradiol in the concentration range from 0.001 microM to 1 microM. Norethisterone was studied using the same concentration range in combination with 0.1 nM estradiol. Tibolone led to significant cell growth in the concentration range of 0.01 to 1 microM and was able to significantly stimulate estradiol-induced proliferation at the concentrations 0.01 and 0.1 microM. In contrast, the estradiol/norethisterone combination elicited significant inhibition of cell growth at the concentrations 0.001 and 0.01 microM. These data suggest that tibolone does have tumor cell-growth promoting effects in vitro whereas the estradiol/norethisterone combination partially inhibits cell growth. Therefore no differences in risk profile are to be expected between conventional hormone substitution using estradiol and norethisterone acetate and tibolone. Drawing a clinical consequence from our experiments would result in not recommending the use of tibolone in postmenopausal women at high risk for breast cancer development until long-term controlled clinical studies have been performed on the effect of tibolone administration and breast cancer risk.
Antineoplastic Agents, Hormonal↗
Comparison of the effects of 17alpha-ethinylestradiol and 17beta-estradiol on the proliferation of human breast cancer cells and human umbilical vein endothelial cells.
OBJECTIVE: Little is known about the direct comparison between 17alpha-ethinylestradiol (EE2) and 17beta-estradiol (E2) on pre-existing breast cancer cells and on their angiogenetic effects. In this study we investigated the effect of both estrogens on the proliferation of MCF-7 cells, a human breast cancer cell model, and on human umbilical vascular endothelial cells (HUVECs). METHODS: The steroids were tested in the concentration range of 10(-10) to 10(-5) M. The proliferation of MCF-7 and HUVEC cells was measured after five and six days by the crystal violet staining technique. RESULTS: In the concentration range from 10(-10) to 10(-5) M both estrogens showed a proliferative effect in the MCF-7 cells, E2 having a gradually declining effect on proliferation with increasing concentration while EE2 showed a constant proliferative effect over a large concentration range. At the highest concentration tested E2 had no effect on proliferation while EE2 even inhibited growth. In the HUVEC cells both estrogens showed a slightly significant stimulatory effect at the lowest concentration, and no significant effect at the remaining concentrations. EE2 again inhibited cell growth at the highest concentration. CONCLUSIONS: At the serum concentrations seen in hormone replacement therapy, EE2 appears to have less proliferative effect on breast cancer cells compared with E2, while both estrogens appear to have similar effects on endothelial cells.
Breast↗
Effect on biochemical vasoactive markers during postmenopausal hormone replacement therapy: estradiol versus estradiol/dienogest.
OBJECTIVES: Aim was to compare the effects of estradiol-only therapy with combined estradiol/progestin treatment on the excretion of vasoactive mediators surrogating on possible effects in the vascular system. The progestin used was dienogest, a new C19-progestin with antiandrogenic properties. METHODS: Prospective, randomized trial, 25 healthy postmenopausal women treated for 3 months with estradiol valerate (2 mg/day) and 27 women with estradiol valerate (2 mg/day) continuously combined with dienogest (2 mg/day). Assessment of the following markers or their stable metabolites in nocturnal urine: cGMP, serotonin, prostacyclin and thromboxane, and urodilatin. RESULTS: Estradiol alone increased the excretion of cGMP and serotonin significantly suggesting vasodilating effects. The prostacyclin/thromboxane ratio known to be crucial for the relation of vasorelaxation to vasoconstriction significantly increased. No significant changes were found for urodilatin, which is known to elicit different effects in the cardiovascular and renal system, respectively. Combined estradiol/dienogest therapy also led to significant increases in cGMP and serotonin excretion suggesting that progestin addition for three months does not affect these markers. However, in contrast to estrogen-only treatment, there was no significant increase for the prostacyclin/thromboxane ratio, which can be explained by antagonistic action of the progestin. The excretion of urodilatin was increased significantly, which might be due to counterbalancing progestin effects in the renal vascular system. CONCLUSIONS: The changes in vasoactive markers suggest an estrogen effect that is vasorelaxant. Since there were no significant differences between the two groups, possible vascular effects of the progestin dienogest, for the first time evaluated, might not be of clinical relevance, at least not in women without cardiovascular diseases.
Administration, Oral↗
Effect of two oral contraceptives with different ethinyl estradiol and levonorgestrel concentrations on the urinary excretion of biochemical vasoactive markers.
In the present study the effect on the urinary excretion of vasoactive markers of two oral contraceptives (OCs), i.e., Leios, containing 0.02 mg ethinyl estradiol and 0.1 mg levonorgestrel, and Stediril 30, containing 0.03 mg ethinyl estradiol and 0.15 mg levonorgestrel, was investigated. cGMP, prostacyclin and its antagonist thromboxane, serotonin, and urodilatin, a natriuretic and diuretic peptide formed in the kidney, were measured as markers. In a comparative, double-blind, randomized, parallel group study, 34 women received Leios and 33 women Stediril 30. Nocturnal urine was collected before treatment and during cyclic treatment after 3 and 12 cycles. Both contraceptives significantly enhanced cGMP excretion after 12 cycles. The prostacyclin metabolite remained unchanged for both formulations, but the excretion of the thromboxane metabolite was significantly decreased after 12 cycles. Thus, the ratio of prostacyclin to thromboxane, crucial for the resulting effect on vascular tone, increased significantly. For the serotonin metabolite, no changes were observed for both contraceptives. The excretion of urodilatin significantly increased for both preparations after 12 cycles compared to the pretreatment values. These results indicate that the low-dose OCs Leios and Stediril 30 may stimulate the production of some vasoactive markers, at least after 12 cycles of treatment. The positive influence of these contraceptives on the various markers investigated may improve vascular tone, impede development of atherosclerosis and arterial thrombosis, and improve water and electrolyte homeostasis. These effects most likely can be attributed to the estrogenic component. Levonorgestrel may elicit no impact on these estrogen-induced changes that, however, seem only to be manifested after a longer treatment period.
Adult↗
Further evidence for direct vascular actions of statins: effect on endothelial nitric oxide synthase and adhesion molecules.
The effect of the synthetic statin fluvastatin was investigated on the concentrations of endothelial nitric oxide synthase (eNOS) and of soluble adhesion molecules in human vascular endothelial cell cultures. Fluvastatin was able to increase dose-dependently eNOS concentration. In addition, fluvastatin reduced concentrations of E-Selectin and ICAM-1. These results further support the evidence that statins elicit important effects on the vascular endothelium which may contribute to the reduction of morbidity and mortality of cardiovascular diseases.
Cells, Cultured↗
The effects of postmenopausal hormone replacement therapy and oral contraceptives on the endogenous estradiol metabolism.
The estradiol metabolism may be of clinical relevance in the pathophysiology of various diseases; the increase in D-ring metabolites over A-ring metabolites in breast cancer patients is of special interest. Since estrogen therapy has been blamed for increasing the risk of breast cancer, the effects of hormonal replacement therapy (HRT) and oral contraception were investigated on the ratio of the main D-ring metabolite, 16alpha-hydroxyestrone (16-OHE1), to the main A-ring metabolite, 2-hydroxyestrone (2-OHE1). In our study, hormone replacement therapy (HRT) in postmenopausal women consisted of administration of estradiol valerate either with or without addition of the progestin dienogest. In the second part of the study, women of reproductive age received ethinylestradiol plus dienogest or ethinylestradiol plus norethisterone acetate as oral contraceptives (OC). 2-OHE1 and 16-OHE1 were measured by enzyme immunoassay in 8 h night-urine collected before and after 3 months of hormone administration. With HRT, that is, estradiol valerate or estradiol valerate plus dienogest, the ratios before treatment were 0.47 and 0.60; after 3 months, they were 0.54 and 0.52, respectively. There were no significant differences. With oral contraception, that is, ethinylestradiol plus dienogest or norethisterone acetate, the ratios before administration were 0.62 and 0.68, vs. 0.31 and 0.54 after 3 months, respectively. The ratio after ethinylestradiol and dienogest was significantly lower after treatment. HRT and OC in the estrogen-progestin combinations tested did not impose any negative effects on estradiol metabolism--they did not elicit a higher D-ring metabolism, which is considered to increase breast cancer risk.
Adult↗
[Effect of tibolone on vascular markers of human female coronary arteries - comparison with estradiol/norethisterone].
OBJECTIVES: Tibolone, a synthetic norethynodrel derivative, is effective at alleviating climacteric complaints and for osteoporosis prophylaxis. Concerning the cardiovascular system little data are available on possible direct effects on the vasculature compared with hormone replacement therapy. Since tibolone is pharmacologically best comparable to an estradiol/norethisterone combination (E2/NET), the aim of the present study was to compare these treatment regimens with respect to their effects on human vascular cells, this being the first study to investigate this question. - MATERIAL AND METHODS: Human female coronary arteries were used, the most appropriate vessels for our issue in question. The experiments were conducted with endothelial cells as well as smooth muscle cells. Tibolone and E2/NET were tested at the concentrations 0.1, 1 und 10 microM. Incubation time was 24 h for endothelial cell cultures and 7 days for smooth muscle cell cultures. The effects on markers of pathophysiologically different problems were studied in a comparable manner: Markers of endothelial function such as prostacyclin, endothelin and plasminogen-activator-inhibitor-1 (PAI-1), markers of plaque initiation such as the adhesion molecules E-Selectin, ICAM-1 and the monocyte attraction protein-1 (MCP-1) and markers of plaque stability such as the precursor of the matrix-metalloproteinase-1 (pro-MMP-1). - RESULTS: Tibolone reduced the synthesis of endothelin as well as the concentrations of E-Selectin, PAI-1 and pro-MMP-1. The magnitude of the effects on these markers varied and was in the range of 11-42 %. similar inhibitions were seen for E2/NET; yet a significantly stronger inhibitory effect was found for pro-MMP-1. Moreover, E2/NET also reduced concentrations of ICAM-1 and MCP-1. Concerning smooth muscle cells only E2/NET was able to elicit an anti-proliferative effect. - CONCLUSIONS: Tibolone can positively influence the synthesis of markers in cell cultures of human female coronary artery which modulate vascular tone and which play a decisive role in the various stages of atherosclerosis. In this respect estradiol combined with norethisterone is as potent as tibolone, in addition this combination is partially more effective and able to influence a wider range of markers which are important in the early stages of atherogenesis or for the stability of atherosclerotic plaques. Experimental studies such as the present one are useful to explore mechanisms, but clearly cannot replace clinical studies.
Cell Division↗
Valsartan and candesartan can inhibit deteriorating effects of angiotensin II on coronary endothelial function.
The angiotensin II (Ang II) AT1-receptor antagonists, valsartan and candesartan, were compared with regard to their effect on Ang II-mediated changes in parameters of coronary endothelial function. Ang II (10 microM) induced increased concentrations of the vasoconstrictor endothelin, the procoagulatory substance plasminogen-activator-inhibitor-1 (PAI-1) and the precursor of the matrix-metalloproteinase 1 (MMP-1) in endothelial cell cultures from human coronary arteries. These increases were completely prevented by the addition of 10 microM valsartan or candesartan and partially by the addition of lower concentrations of these drugs, i.e. 1 microM and 0.1 microM. No significant difference between the effect of the two AT1-receptor antagonists was observed. These results suggest that AT1-receptor antagonists not only can reduce blood pressure by blocking the action of Ang II, but might also contribute to the prevention of atherogenesis and plaque instability.
Angiotensin II↗
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↗
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↗
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↗
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↗
Is the use of conjugated equine oestrogens in hormone replacement therapy still appropriate?
Explore the source record for details and available documents.
Animals↗
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↗
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↗