Inhibition of the protective effect of estrogen by progesterone in experimental atherosclerosis.

The aim of the present study was to determine the effect of progesterone on the action of estrogen in the development of atherosclerosis. A total of 48 female New Zealand white (NZW) rabbits were ovariectomized. The animals were separated into 6 groups of 8 animals each and received subsequently a 0.5% cholesterol diet for 12 weeks. During this cholesterol feeding period, either estradiol (1 mg/kg body weight (BW)/week), progesterone (25 mg/kg BW/week), or combined estradiol/progesterone (in above dosages) was administered intramuscularly in each group (n = 8 each) of ovariectomized rabbits. One additional group of 8 animals received a combined estrogen/ progesterone regimen, but with progesterone at one third of the above mentioned dosage. In another 8 rabbits, progesterone was reduced to one ninth of the maximum dosage above, whereas estrogen was kept the same, at 1 mg/kg BW/week. Eight ovariectomized animals served as the control group and received no hormone treatment. After 12 weeks, the animals were sacrificed and the proximal aortic arch was removed for further histological examination. An inhibitory effect of estrogen of intimal thickening was found, in comparison to the control group (intimal area: 0.7 +/- 0.5 mm2 vs. 3.7 +/- 2.5 mm2, P < 0.01), whereas progesterone alone did not show a significant effect on intimal plaque size (intimal area: 4.0 +/- 2.3 mm2). In combination with progesterone (high dose), estrogen was not able to reduce intimal atherosclerosis (intimal area: 3.4 +/- 2.4 mm2). However, the beneficial effect of estrogen was not affected by progesterone, when this was reduced respectively to one third (intimal area: 0.8 +/- 0.7 mm2), or to one ninth of the highest dosage (intimal area: 0.6 +/- 0.4 mm2). Interestingly, these differences in atherosclerotic plaque development were observed without significant changes in plasma cholesterol concentrations by the administered hormones. In conclusion, progesterone was dose-dependently able to completely inhibit the beneficial effect of estrogen in experimental atherosclerosis, suggesting that progesterone exerts a direct inhibitory effect on the athero-protective action of estrogen. In the context of recently published data, the present work confirms the importance of the 'non-lipid-mediated', anti-atherosclerotic effect of estrogen, probably due to an interaction with six hormone receptors in vascular smooth muscle cells (VSMC).

The effect of zearalenone and 17 beta-estradiol on prostacyclin and thromboxane production in cell cultures from human umbilical cord veins.

The effect of zearalenone, a nonsteroidal mycotoxin with estrogenic activity, and of 17 beta-estradiol on prostacyclin and thromboxane production in human endothelial cells was investigated. Zearalenone stimulated prostacyclin production in low concentrations (10(-7) and 10(-8)M) and inhibited it at a higher concentration (10(-5)M). Estradiol alone in the concentration range 10(-5)-10(-8)M had no clear-cut effect on the prostacyclin production. The combination of both substances effected changes in prostacyclin production similar to that from zearalenone alone; with the exception of estradiol at a concentration of 10(-6)M which enhanced the effect of zearalenone. No distinct changes in the thromboxane production from the two substances could be found, either alone or in combination.

Acute improvement of peripheral endothelial function in postmenopausal women with coronary artery disease after single oral intake of 17beta-estradiol valerate.

Chronic estrogen supplementation is known to improve endothelial function in postmenopausal women. We studied the acute effect of a single dose of orally administered 17beta-estradiol valerate (E2) on the peripheral endothelial dependent and independent vasodilatation in postmenopausal women with coronary artery disease (CAD). 20 postmenopausal women (age: 64.9 (7.2) y, height: 1.61 (0.04) m. weight: 68.6 (10.6) kg) with angiographically confirmed CAD were randomly examined for flow-associated vasodilatation (= FAD%, a marker for endothelial dependent vasodilatation) and for glyceryltrinitrate (400 microg, p.o.) induced vasodilatation (= GTN%, representing endothelial independent vasodilatation) two hours after placebo controlled, randomized crossover intake of 4 mg E2 p.o. After placebo FAD% was impaired (3.5 (1.7)%) compared to historic controls. After the oral intake of 4 mg E2, FAD% improved to 5.0 (2.8)% (P=0.02). GTN% was not significantly influenced by the oral E2 (E2: 12.6 (5.7) v placebo: 11.2 (6.9)%, P=0.14). Endothelial dysfunction can partially be restored by a single oral dose of 4 mg E2. This indicates an acute vasoprotective effect of E2 beyond its genomic and lipid modifying actions. It remains to be investigated if estrogen might play a beneficial role in the acute treatment of symptomatic coronary artery disease such as angina pectoris or preinfarct syndrome.

Estradiol concentrations in premenopausal women with coronary heart disease.

BACKGROUND: Because of the beneficial effects of estrogen, premenopausal women are normally protected against coronary heart disease (CHD) and are at lower risk for myocardial infarction; consequently, CHD occurs very rarely in menstrually active women. Given this background, the aim of the present study was to test the hypothesis that decreased concentrations of estrogen are associated with CHD in premenopausal women. METHODS: Fourteen premenopausal women with CHD were investigated and compared with a healthy control group comparable for age and cardiovascular risk factors. Relevant characteristics of patients and controls were assessed: age, blood pressure, body mass index, total cholesterol and high-density lipoprotein cholesterol, triglycerides, former pregnancies, ovariectomy and related surgical interventions, smoking history and former use of oral contraceptives. To ensure the premenopausal status of the participants, the regularity of the menstrual cycle and the follicle-stimulating hormone concentrations were also assessed. Plasma estradiol and progesterone and urine estrone concentrations (24 h urine collection) were measured at day 6 after estimated ovulation to assess the relative increase in plasma estradiol and progesterone during the second half of the menstrual cycle. RESULTS: Compared with the control group, premenopausal women with CHD had significantly lower concentrations of plasma estradiol (408.9 +/- 141 pmol/l and 287.8 +/- 109 pmol/l respectively; P = 0.0228) and total estrogen (2061 +/- 693 pg/mumol creatinine and 1607 +/- 448 pg/mumol creatinine respectively; P = 0.025) in the urine. However, the progesterone concentrations were not significantly different between the groups. These findings might be explained by a partial ovarian dysfunction, as the patient group had a significantly higher number of tubal sterilizations (eight compared with one). CONCLUSION: Our data provide support for the hypothesis that decreased concentrations of estradiol might be an additional pathogenetic factor for the development of CHD in menstrually active premenopausal women.

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.

Serotonin metabolite excretion after postmenopausal estradiol therapy.

Serotonin, known for its beneficial action on mood and well-being, is also involved in cardiovascular functions. Thus the current work was undertaken to study the effect of hormone replacement therapy on serotonin turnover in postmenopausal women. Eighteen women received estradiol transdermally and 17 women estradiol valerate orally for 4 weeks. The serotonin metabolite 5-hydroxyindole acetic acid (5-HIAA) was determined in the urine before, and after 2 and 4 weeks' estradiol treatment. With both administration routes estradiol produced a significant increase in urinary 5-HIAA excretion, greatest with transdermal estradiol after 28 days of treatment. The enhancement of serotonin turnover may contribute not only to an improvement of mood and well-being but also to a cardioprotective effect of estradiol observed after hormone substitution in postmenopausal women.

Effect of 17 alpha-ethinylestradiol, levonorgestrel, 3-keto-desogestrel, and gestodene on calcium influx via voltage-gated calcium channels in human aortic smooth muscles.

The effect of the synthetic estradiol, 17 alpha-ethinylestradiol, and three progestogens on calcium influx was investigated in cell cultures of human aortic smooth muscle. Neither the synthetic estrogen nor the progestogens levonorgestrel, 3-keto-desogestrel, and gestodene showed, in the concentration range of 10(-9) to 10(-6) M, a significant effect on calcium influx both alone or in equimolar estrogen-gestagen combinations. The results indicate that these substances, commonly used in contraceptive pills, do not change vasotonus interfering with calcium homeostasis.

Inhibitory effect of statins on the proliferation of human breast cancer cells.

OBJECTIVE: Long-term hormone therapy in the postmenopause is associated with a moderate increase in cardiovascular and breast cancer risk. Of great concern, therefore, is the question of how women with menopausal symptoms and enhanced cardiovascular risk can be treated. Evidence is growing that an estrogen/statin combination may be a good choice, since this combination seems to elicit additive beneficial effects on the lipid profile and on the vasculature. METHODS: In the present study, the effect of two statins on the proliferation of breast cancer cells in the presence and absence of estradiol was investigated. RESULTS: Atorvastatin and fluvastatin were able to inhibit the proliferation of MCF-7 cells in the absence of estradiol. This effect seems to depend on an apoptotic statin effect which may be mediated by the down-regulation of the anti-apoptotic protein Bcl-2 rather than up-regulation of Fas-L or p53. However, in the presence of estradiol the inhibitory effect of the statins was less pronounced. CONCLUSIONS: The present data indicate that statins may possess anticancerogenic properties concerning the development of breast cancer in postmenopausal women. Clinical trials are necessary to prove a beneficial statin effect on breast cancer risk when combined with long-term hormone therapy.

The effect of estradiol on the production of melatonin in postmenopausal women.

The influence of two routes of estradiol administration on pineal melatonin production in postmenopausal women was investigated. Both transdermal and oral estradiol treatment led to an increase as well as decrease of melatonin production in different patients. The reason why individuals respond either in a stimulatory or inhibitory manner is unknown and requires to be evaluated in further more extensive studies.

Cardiovascular protection by postmenopausal estrogen replacement therapy: possible mechanisms of the estrogen action.

Estrogen replacement therapy reduces the cardiovascular risk in postmenopausal women, but the mechanism has yet to be evaluated. There is growing evidence that estradiol administration results in direct vasodilatory effects on vessel walls. The biochemical mechanisms have been investigated in human arteries and veins with respect to different mediators and cell systems. Whereas estradiol had no direct effect on the prostaglandin system we found a endothelin-mediated stimulation of prostacyclin production in endothelial cell cultures. In experiments with the NO/cGMP-system estradiol activity could be demonstrated. In addition estradiol provoked an increase in the intracellular Ca2+ concentration. These results indicate that several mechanisms may be involved in the vasodilating effect of estradiol.

Eicosanoid production in human umbilical cord vessels: effect of 17 beta-estradiol.

This study was designed to investigate the effects of 17 beta-estradiol on prostanoid formation from exogenous arachidonic acid in homogenates of human umbilical cord vessels. The veins produced more prostanoids than the arteries and predominantly 6-keto-PGF1 alpha. 17 beta-estradiol had no effect on the rate of production of prostanoids in either vessels. Thus, at least in our in vitro system, the regulation of the vascular tone by prostanoids seems not to be altered by the addition of 17 beta-estradiol.

The effect of 17 beta-estradiol and endothelin 1 on prostacyclin and thromboxane production in human endothelial cell cultures.

The effect was investigated of endothelin 1 and 17 beta-estradiol on prostacyclin and thromboxane A2 production (determined as the stable metabolites 6-keto-PGF1 alpha and thromboxane B2, respectively) in endothelial cell cultures obtained from veins of human umbilical cord. There was a statistically significant increase of 6-keto-PGF1 alpha production with endothelin 1 at concentrations of 10(-8) and 10(-9) M [9.5 +/- 1.1% and 7.2 +/- 0.9%, (mean +/- SD, n = 5), respectively] compared to basal production. In contrast, 17 beta-estradiol alone (10(-6) and 10(-8) M) had no effect. In the presence of 17 beta-estradiol (10(-8) M) the stimulating effect of endothelin 1 (10(-8) and 10(-9) M) on 6-keto-PGF1 alpha production was further enhanced to 60.0 +/- 22.5% and 39.5 +/- 22.1%, respectively, compared to basal values. With respect to thromboxane B2, no change in its production was observed by the addition of endothelin 1 and 17 beta-estradiol, alone or in combination in the concentrations mentioned above. These results indicate that 17 beta-estradiol potentiates the effects of endothelin 1 on prostacyclin production in human endothelial cells.

[Treatment of estrogen deficiency-induced sex disorders]. / Die Behandlung östrogenmangelinduzierter Sexualstörungen.

OBJECTIVE: Is it possible to successfully treat sexual disturbances related to an estrogen deficiency syndrome with estrogens? METHODS: For 4 months, sexual dysfunctions (loss of libido, dyspareunia, difficulties in experiencing orgasm) were treated with a transdermal system-the estrogen patch-in one group cyclically and in a second continually. Women with uterus got 1 mg/day norethisterone acetate for 12 days a month. RESULTS: By estrogen therapy alone, success was seen in 40/41% for loss of libido, in 75/56% for dyspareunia and in 47/25% for difficulties of orgasm. CONCLUSIONS: In spite of the complexity of the biopsychosocial causes of the sexual disturbances in relation with an estrogen deficiency syndrome, the replacement therapy is successful in many cases.

-Is prevention of pre-eclampsia with low dosage aspirin possible? Critical assessment of available studies-. / Ist mit niedrigdosierter Aspirinbehandlung eine Prophylaxe der Pr-aeklampsie m"oglich? Kritische Betrachtung der vorliegenden Studien.

The efficacy of low-dose aspirin treatment to prevent preeclampsia was assessed by reviewing studies of the available literature. 9 studies were performed examining nearly 13,000 pregnant women. Aspirin treatment compared with untreated control groups led to a significant reduction of preeclampsia in 5 small-scale studies. However, no prophylaxis could be achieved in 4 studies comprising more than 12,000 pregnant women. A assessment of low-dose aspirin treatment is difficult, since no dose-response study was performed to determine the optimal dose; the duration of treatment--beginning and end--was not defined and the drug risk for mother and child was not documented in accordance with GCP guidelines. The major problem of all studies, however, consisted in the recruitment of the patients since there are no easily performable and well-recognised screening tests available to estimate the risk of preeclampsia. In conclusion, at present no statement is possible if and under which conditions low-dose aspirin treatment will be able to prevent preeclampsia.

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.

[Does estradiol modify the NO/cGMP system of blood vessels? Studies of the mechanism of cardiovascular protection by estrogen substitution in the postmenopausal period]. / Beeinflusst Ostradiol das NO/cGMP-System der Gefässe? Untersuchungen zum Mechanismus der kardiovaskulären Protektion durch Ostrogensubstitution in der Postmenopause.

The effect of estradiol on the vasodilating NO/cGMP-system has been investigated in vitro and in vivo. Measurements of cGMP were carried out, cGMP values reflecting NO production. The incubation of human leg vein homogenates (n = 15) for 15 min. with estradiol in the concentrations 10(-6) M, 10(-7) M and 10(-8) M showed at 10(-8) a slight increase of the cGMP-concentrations. Due to high variation compass the difference to the control value was not statistically significant. The clinical part of the study included postmenopausal women, 20 were treated with transdermal estradiol patches (TTS, 0.05 mg/die) and 20 with estradiolvalerate orally (2 mg/die). There were 3 drop outs, 1 in the transdermal estrogen group, 2 in the oral estrogen group. In both groups there were no considerable differences in urinary cGMP concentrations. Thus, these results didn't clearly indicate an involvement of the NO/cGMP-system in the cardioprotective effect of an estrogen substitution therapy in postmenopausal women. Since former investigations are indicative of complex interactions of different vasoactive systems and of the requirement of longer treatment periods for an action of estradiol, an effect on the NO/cGMP-system cannot be ruled out.

Natural and synthetic estrogens and prostacyclin production in human endothelial cells from umbilical cord and leg veins.

We have evaluated the effects of 17 beta-estradiol and 17 alpha-ethinylestradiol on prostacyclin production (measured as prostaglandin-6-keto-F1 alpha) in human endothelial cell cultures that had been obtained from umbilical cord and from leg veins. Endothelial cultures were treated with the estrogens at 3 different concentrations (10(-6), 10(-7), 10(-8) M) for up to 72h. 17 beta-estradiol did not affect basal 6-keto-PGF1 alpha production in these cell cultures. With 17 alpha-ethinylestradiol the synthesis of 6-keto-PGF1 alpha was not statistically significant changed. At least in our in vitro system we could not find an effect of natural and synthetic estrogens on 6-keto-PGF1 alpha production. This does, of course not rule out an effect in the more complex in vivo-situation.

[Production of prostacyclin in human umbilical cord blood vessels. Effect of natural and synthetic estrogen]. / Produktion von Prostacyclin in menschlichen Nabelschnur-Gefässen. Einfluss von natürlichem und synthetischem Estrogen.

This investigation was conducted to evaluate the effects of 17 beta-estradiol and 17 alpha-ethinylestradiol on prostacyclin PGI2-production in homogenates of human umbilical cord arteries and veins in the presence of exogenous arachidonic acid. The incubation of 17 beta-estradiol at 2 different concentrations (10(-8) and 10(-6) M) in the presence of arachidonic acid for various times (5 min up to 24 h) effected an increase in the production of PGI2 (measured as 6-keto-prostaglandin F1 alpha) of 36-47% in the artery and 16-21% in the vein over basal values (100%). Under the same experimental conditions with 17 alpha-ethinylestradiol we observed an increases of 30-40% in the artery and 1-18% in the vein compared with basal values. For both estrogens this was not significantly different compared with untreated samples. In our in vitro system, natural and synthetic estrogens had no clear effect on PGI2 production in homogenates of human umbilical vessels.