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T H Lippert

Publications and source records attributed to T H Lippert.

At least 19 recordsLinked to original sources
PubMed2001

A sensitive homologous radioimmunoassay for human relaxin-2 (h-RLX-2) based on antibodies characterized by epitope mapping studies.

We present a sensitive homologous radioimmunoassay (RIA) for the quantitative determination of human relaxin (hRLX) in human serum, plasma, seminal plasma, and urine. This assay is based on a rabbit antiserum which was generated using recombinant hRLX-2 as immunogen. Using 125I-hRLX-2 as tracer and a total incubation time of 20 - 24 hours the radioimmunoassay showed linearity in a range of 60 - 4000 ng/l, a lower detection limit of 38 ng/l and a mean recovery rate of 98.5%. Intraassay variation was 4.0% (mean = 526 ng/l) and 11.9% (mean = 2368 ng/l), and interassay variation 10.7% (mean = 256 ng/l) and 13.1% (mean = 2368 ng/l). Using hRLX-2 hexapeptides on polystyrene pins, epitopes recognized by the hRLX-2 specific rabbit antiserum were determined experimentally, and compared to predicted epitopes. Both methods led to comparable results. The antiserum, recognizing different epitopes, showed no cross-reactivity with human insulin, hZn-insulin, hIGF-I, hIGF-II, human inhibin alpha-subunit, two different forms of seminal plasma inhibin like peptide, spermolaxin, ubiquitin, prolactin, LH, FSH and hCG.

Amino Acid Sequence↗
PubMed2001

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↗
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

Continuous-combined treatment of the menopause with combinations of oestradiol valerate and dienogest - a dose-ranging study.

OBJECTIVES: To determine the progestational efficacy of continuous treatment with various doses of dienogest, combined with oestradiol valerate, on the basis of endometrial histology, effect on climacteric symptoms and bleeding profile in postmenopausal women. METHODS: Patients were randomised to one of five fixed-combination treatments, oestradiol valerate 2.0 mg plus dienogest 0.5, 1.0, 2.0, 3.0 or 4.0 mg. Efficacy was assessed by endometrial biopsy, menstrual charts and change in climacteric symptoms. RESULTS: The endometrium was classified as atrophic in 20.0, 31.3, 25.0, 55.6 and 57.1% of patients in the 0.5, 1.0, 2.0, 3.0 and 4.0 mg dienogest groups, respectively. The frequency of uterine bleeding was dose-dependent. The most favourable bleeding profile was seen in the 3.0 mg dienogest group, whereas the lower doses of dienogest had advantages with respect to the efficacy of the combined preparation. CONCLUSIONS: Dienogest 2.0 and 3.0 mg are the optimal doses for combination with 2.0 mg oestradiol valerate for continuous-combined hormone replacement therapy.

Adult↗
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 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

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

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↗
PubMed1999

Probing Premarin.

Explore the source record for details and available documents.

Estrogens, Conjugated (USP)↗
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↗
PubMed1999

[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↗
PubMed1999

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↗
PubMed1999

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↗