[Postmenopausal estrogen therapy: pharmacological treatment or replacement of the lacking hormone?].
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Cardiovascular Diseases↗
Biomedical subjects
T H Lippert
Publications and source records attributed to T H Lippert.
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↗
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↗
[The significance of estrogen metabolism for hormone-dependent neoplasms from the clinical-pharmacological viewpoint].
The present review summarizes existing data regarding estrogen metabolism and hormone-responsive cancers. Endogenous estradiol breakdown takes place by oxidation at the A-ring and the D-ring; the resulting metabolites, however, are not inactive substances, as assumed formerly, but elicit different biological effects, with A- and D-ring metabolites to some extent developing opposite actions. Multiple results are available showing stimulating and inhibiting properties of some metabolites on the growth of cancer. Among the D-ring metabolites are substances with proliferation-stimulating properties, e.g. 16 alpha-hydroxyestrone, and among the A-ring metabolites, the catechol estrogens, compounds with inhibiting properties. There are indications that endogenous production of proliferation-stimulating metabolites, especially 16 alpha-hydroxyestrone, which has been shown to be mutagenic, is increased in some cancers. In these cases the ratio of A- to D-ring metabolism is shifted in favour of the D-ring metabolites. This ratio can be influenced by various substances e.g. by indole-3-carbinol, an ingredient of cruciferous vegetables, which can increase the body's own production of catechol estrogens. However, as yet only a few metabolites have been investigated with respect to their influence on cancer development and growth. Presumably other metabolites may also be able to interfere directly or indirectly with cancer progression. Thus a great deficit in research work remains in this field. The existing findings on the pathophysiology of estradiol metabolism on the development and progression of cancer offer promising opportunities for clinical-pharmacological intervention in the treatment of human cancer. 2-Methoxyestradiol, physiologically present at low concentrations, seems to be of special interest. Several investigations were able to demonstrate that 2-methoxyestradiol inhibits proliferating tumoric tissues. Inhibition of neoangiogenesis and inhibition of tubulin polymerization have been revealed as mechanisms. Specific studies on the clinical use of this estradiol metabolite seem to be justified.
Animals↗
Calcium antagonistic effect of 17 alpha-estradiol derivatives: in vitro examinations.
The calcium antagonistic effect of 17 alpha-estradiol derivatives was investigated in vitro in human aortic smooth muscle cells. The substances tested were 17 alpha-estradiol, 17 alpha-ethinylestradiol, the scavestrogens J811 and J861, and 17 beta-estradiol. Examinations were carried out by measuring 45Ca influx into the cells. All compounds showed a significant inhibition of calcium influx at the concentration of 10(-6) M. The strongest effect could be registered for the scavestrogens. Since these substances are virtually devoid of estrogenic activity, they may offer advantages over 17 beta-estradiol in the therapy and prevention of cardiovascular disease.
Antioxidants↗
Valsartan inhibits angiotensin II-stimulated proliferation of smooth muscle cells from human coronary artery.
OBJECTIVES: Angiotensin II is involved in the pathogenesis of atherosclerosis by inducing hyperproliferation of vascular smooth muscle cells. Little is known whether the sartans can inhibit the angiotensin-stimulated proliferation of smooth muscle cells. METHOD: The effect of valsartan on the angiotensin II-stimulated proliferation of smooth muscle cells from human coronary artery was investigated. RESULTS: Angiotensin II significantly increased cell proliferation by about 30% at a concentration of 10(-6) M without significant changes at the lower concentrations 10(-7) and 10(-8) M. Valsartan at the dosages 10(-8) to 10(-6) M had no effect on serum-stimulated proliferation. Valsartan at the dosages 10(-6) and 10(-7) M inhibited the cell proliferation induced by 10(-6) M angiotensin. CONCLUSION: Valsartan may prevent atherosclerosis by inhibiting angiotensin-induced vascular smooth muscle cell proliferation.
Angiotensin II↗
[The role of estradiol metabolites in prevention of cardiovascular diseases by hormone substitution in postmenopause].
Postmenopausal estrogen replacement therapy has shown to reduce cardiovascular disease by direct and indirect estradiol-mediated effects on the cardiovascular system. Recently, evidence is growing that estradiol metabolites may also have beneficial actions. In the present review the existing experimental data for vascular effects of estradiol metabolites are summarized. The results of our own experiments in addition to those of other groups indicate that estradiol metabolites, especially catechol estrogens, exert beneficial effects on the vascular system and perhaps may play a physiologic role in the cardiovascular system. Reference to clinical-pharmacological aspects for the use of estradiol metabolites for prevention and treatment of cardiovascular diseases is presented.
Animals↗
The effect of estradiol on urodilatin production in postmenopausal women.
Urodilatin, which is structurally homologous to atrial natriuretic peptide, is most probably synthesized in the kidney. It inhibits water and sodium reabsorption and causes renal vasodilatation. However, little is known about the regulation of its synthesis, especially with regard to the influence of hormones. Transdermal administration of estradiol with low dosage producing physiologic conditions, and oral administration of estradiol with high pharmacologic dosage were investigated for their effect on urodilatin production in postmenopausal women measuring urinary excretion. Both routes of administration of estradiol increased urodilatin excretion after 28 days of treatment, the increment being statistically significant only for the transdermal route. The increased urodilatin production registered after transdermal estradiol replacement therapy may suggest that estradiol has a vasodilatory effect on the kidney.
Administration, Cutaneous↗
Estradiol metabolism during oral and transdermal estradiol replacement therapy in postmenopausal women.
The metabolism of estradiol was investigated in postmenopausal women after 4 weeks' treatment with oral or transdermal unopposed estradiol. The urinary excretion of the metabolites was examined. With both administration routes, 2-hydroxyestrone, the main A-ring metabolite, and 16alpha-hydroxyestrone, the main D-ring metabolite, were excreted in higher amounts than estradiol and estrone. The ratio of 2-hydroxyestrone to 16alpha-hydroxyestrone remained the same for both administration routes. It has been suggested that dominance of D-ring metabolism, i.e. increase of 16alpha-hydroxyestrone production, is associated with an increased risk of breast cancer. The present study indicates that neither oral nor transdermal estradiol substitution shift this ratio to a higher level of possible risk. Oral estradiol substitution, however, in our study leads to higher metabolite concentrations which may be regarded as hazardous for women with diseases favoring D-ring metabolism.
Administration, Cutaneous↗
Estrogens and the cardiovascular system: role of estradiol metabolites in hormone replacement therapy.
Estrogen substitution in the postmenopause reduces cardiovascular disease by means of direct and indirect effects of estradiol on the cardiovascular system. Recently, there have been increased indications that estradiol metabolites can also have beneficial effects. In the present short review, the existing experimental data for effects of estradiol metabolites on the blood vessels have been compiled. Results of our own studies, together with those of other research groups, indicate that particularly the catechol estrogens are able to exert a positive influence on the cardiovascular system, and may perhaps play a physiological role there. Attention is drawn to clinical-pharmacological aspects for use of estradiol metabolites for the prevention and treatment of cardiovascular disease.
Animals↗
The inhibitory effect of endogenous estrogen metabolites on copper-mediated in vitro oxidation of LDL.
The antioxidant effects of 17beta-estradiol, its main A- and D-ring metabolites, and of vitamin E were compared in vitro. Low density lipoprotein (LDL) was isolated from fresh human blood, and LDL oxidation was evaluated spectrometrically by monitoring diene formation of fatty acids. All substances tested exhibited antioxidant potential. The A-ring metabolites (catecholestrogens) emerged as more potent inhibitors of LDL oxidation than the parent substance estradiol, its D-ring metabolites, and vitamin E. Since oxidized LDL seems to play a crucial role in the development of atherosclerosis, its inhibition may be of preventive value. In summary, A-ring metabolites of estradiol (catecholestrogens), substances that occur naturally in the body, may be involved in the physiologic inhibition of LDL oxidation.
Antioxidants↗
Estradiol inhibits LDL oxidation: do the progestins medroxyprogesterone acetate and norethisterone acetate influence this effect?
Estrogen replacement therapy in postmenopausal women must be combined with progestin to avoid endometrial cancer. However, progestin addition could antagonize cardioprotective effects of estradiol. Therefore we investigated the effect of the two most commonly used progestins--medroxyprogesterone acetate (progesterone-derivative) and norethisterone acetate (nortestosterone-derivate)--alone and in combination with 17 beta-estradiol on copper-mediated oxidation of low density lipoprotein (LDL). Whereas 17 beta-estradiol alone inhibited the onset of LDL oxidation at the concentrations 0.5, 1.0, 5 and 10 microM, the progestins alone did not demonstrate any significant effect. In the estrogen-progestin combinations of 0.5 microM 17 beta-estradiol with 0.5, 1.0, 5 and 10 microM progestin, respectively, the estradiol effect was not changed. These results suggest that medroxyprogesterone acetate as well as norethisterone acetate do not counteract the beneficial effect of 17 beta-estradiol on LDL oxidation when used in hormone replacement therapy.
Drug Interactions↗
The influence of norethisterone acetate on urinary urodilatin excretion in postmenopausal women.
We have previously found that transdermal estradiol application significantly stimulated the urinary excretion of urodilatin, a newly discovered renal peptide with diuretic properties. It is well established that the addition of progestogen is necessary in hormone replacement therapy in women with an intact uterus. This study was designed specifically to examine the effect of progestogen norethisterone acetate (NETA) in postmenopausal women. NETA given alone orally in dosages of 1 mg/d and 2 mg/d for 10 days, as used for the progestogen-challenge test, did not increase urodilatin excretion. NETA in combination with estradiol, administered orally and transdermally in the second half of a 4-week estradiol treatment cycle, did not significantly change urodilatin excretion. The results of the present study indicate that NETA addition to estrogen replacement therapy may antagonize the stimulating estradiol effect on urodilatin production as registered in our earlier study.
Atrial Natriuretic Factor↗
[The breast cancer risk in postmenopausal estrogen substitution. The dilemma of risk assessment].
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Breast Neoplasms↗
Effect of estradiol metabolites on the susceptibility of low density lipoprotein to oxidation.
The main estradiol metabolites 2-hydroxyestrone, 2-methoxyestrone and 16alpha-hydroxyestrone were investigated in vitro for the susceptibility of low density lipoprotein to oxidation and the effects compared with those of estradiol and vitamin E. 2-hydroxyestrone and 2-methoxyestrone had a greater inhibitory effect than estradiol and vitamin E whereas 16alpha-hydroxyestrone approximates the inhibition of estradiol. These results indicate that 2-hydroxyestrone and 2-methoxyestrone possess non-genomic actions which may play a role in the lipid metabolism.
Estradiol↗
Effect of melatonin and metabolites on copper-mediated oxidation of flow density lipoprotein.
AIMS: A prophylactic use of melatonin as an anti-ageing drug has recently gained public interest due to its radical scavenging property in vitro. The present study was designed to investigate a possible antiatherogenic effect of melatonin and its physiological metabolites by examining their action on the radical-initiated formation of oxidized LDL, which is known to possess a high atherogenic potency. The metabolites investigated were the precursors serotonin and N-acetyl-serotonin and the main breakdown product 6-hydroxymelatonin. METHODS: The effect of the test substances on the in vitro oxidation of LDL (increase in conjugated diene formation) was investigated at concentrations of 1, 5, and 10 microM. RESULTS: Melatonin increased the lag time of formation of oxidized LDL only at a concentration of 10 microM. In contrast, 6-hydroxymelatonin, serotonin and N-acetylserotonin as well as vitamin E showed inhibitory effects starting at 1 microM. Thus the antioxidative action of melatonin was negligible compared with the effect of its main metabolite, its precursors and of vitamin E. CONCLUSIONS: The present results indicate that the pineal hormone melatonin appears to have little antiatherogenic property as regards the oxidation of LDL. Its main breakdown product 6-hydroxymelatonin, however, inhibits LDL-oxidation comparable to vitamin E. The precursors of melatonin, N-acetyl-serotonin and serotonin may also play a role in the inhibition of LDL oxidation in vivo.
Adult↗
Influence of norethisterone acetate and estradiol on the serotonin metabolism of postmenopausal women.
Previous studies have shown that estradiol increases urinary excretion of the main stable metabolite of serotonin, 5-hydroxyindole acetic acid (5-HIAA), reflecting an increase in serotonin production. In the present study, the effect of the progestin norethisterone acetate (NETA) on serotonin metabolism was investigated, both alone and in addition to estradiol replacement in 20 postmenopausal women. Urinary excretion of 5-HIAA was measured after treatment with NETA orally for 8 days, estradiol valerate orally for 9 days and a combination of both hormones for 12 days. 5-HIAA values, expressed as percentages of the pretreatment values, were significantly increased only after the estrogen treatment phase. NETA alone did not significantly alter the serotonin metabolite excretion; in combination with estradiol, the estradiol effect on serotonin metabolism was abolished. This indicates that adding norethisterone acetate to estradiol replacement therapy may have a negative impact on the effect of estradiol on serotonin metabolism.
Estradiol↗
Urinary excretion of insulin after estradiol treatment of postmenopausal women.
The influence of estradiol treatment on the urinary excretion of insulin was investigated in postmenopausal women. Thirteen women were treated with transdermal estradiol and 12 with oral estradiol for 4 weeks. With transdermal, but not with oral administration, a significant increase of urinary insulin excretion was registered.
Administration, Cutaneous↗