Stefan Störk

Effect of oral postmenopausal hormone replacement on progression of atherosclerosis : A randomized, controlled trial

Abstract —Postmenopausal hormone replacement therapy (HRT) is associated with low cardiovascular morbidity and mortality in epidemiological studies. Yet, no randomized trial has examined whether HRT is effective for prevention of coronary heart disease (CHD) in women with increased risk. The objective of this study was to determine whether HRT can slow progression of atherosclerosis, measured as intima-media thickness (IMT) in carotid arteries. Carotid IMT is an appropriate intermediate end point to investigate clinically relevant effects on atherogenesis. This randomized, controlled, observer-blind, clinical, single-center trial enrolled 321 healthy postmenopausal women with increased IMT in ≥1 segment of the carotid arteries. For a period of 48 weeks, subjects received either 1 mg/d 17&bgr;-estradiol continuously plus 0.025 mg gestodene for 12 days every month (standard-progestin group), or 1 mg 17&bgr;-estradiol plus 0.025 mg gestodene for 12 days every third month (low-progestin group), or no HRT. Maximum IMT in 6 carotid artery segments (common, bifurcation, and internal, both sides) was measured by B-mode ultrasound before and after intervention. HRT did not slow IMT progression in carotid arteries. Mean maximum IMT in the carotid arteries increased by 0.02±0.05 mm in the no HRT group and by 0.03±0.05 and 0.03±0.05 mm, respectively, in the HRT groups (P >0.2). HRT significantly decreased LDL cholesterol, fibrinogen, and follicle-stimulating hormone. In conclusion, 1 year of HRT was not effective in slowing progression of subclinical atherosclerosis in postmenopausal women at increased risk.

The effect of 17β-estradiol on endothelial and inflammatory markers in postmenopausal women: a randomized, controlled trial

Abstract Background: Intervention trials in postmenopausal women with coronary artery disease have failed to demonstrate beneficial effects of hormone replacement therapy (HRT) on the course of disease, potentially due to pro-inflammatory effects of conjugated equine estrogens. We characterized the effects of 48 weeks treatment with two estradiol-based HRT regimens on nonspecific (high sensitivity C-reactive protein [hs-CRP], blood sedimentation rate [BSR], fibrinogen) and specific endothelial markers (cell adhesion molecules: ICAM-1, VCAM-1, E-selectin). Method and Results: Postmenopausal women randomly received either 1 mg 17β-estradiol daily plus 25 μg gestodene for the last 12 days of each 28 day cycle (=standard dose progestin; n =65), or gestodene added each third cycle only (=low dose progestin; n =65), or no HRT ( n =73). Both HRT regimens reduced levels of ICAM-1 (−9%), VCAM-1 (−9%), E-selectin (−11%), fibrinogen (−12%), BSR (−5%). No effect was observed on hs-CRP levels in any group. In smokers, E-selectin remained unchanged whereas ICAM-1 and VCAM-1 were lowered. Subjects on antihypertensive or lipid lowering medication showed effects comparable to the whole cohort. Effects of low and standard dose progestin were not different. Conclusion: We conclude that a combination therapy with 1 mg 17β-estradiol favourably affects the vascular inflammation processes as indicated by a neutral effect on hs-CRP and reduction of cell adhesion molecules.

The effect of 17β-estradiol on MCP-1 serum levels in postmenopausal women

Objective: Monocyte chemoattractant protein-1 (MCP-1) is considered a propagator of atherosclerosis and a key modulator of monocyte activity. Hormone replacement therapy (HRT) is currently being investigated as a means towards prevention of atherosclerosis. We aimed to assess (1) the range of circulating MCP-1 levels in postmenopausal women, (2) the correlation between MCP-1 and atherosclerotic burden, and (3) the effects of commencement and discontinuation of HRT on MCP-1 serum levels. Methods: This clinical prospective trial investigated 51 postmenopausal women at increased risk for cardiovascular events who were randomized to receive either no HRT or 1 mg 17β-estradiol continuously plus sequential progestagen over 1 year. Intima-media thickness (IMT) of carotid and femoral arteries was measured by ultrasound. Serum levels of MCP-1 and cellular adhesion molecules were measured by ELISA. Results: At baseline, MCP-1 levels and overall mean maximum IMT correlated ( r =0.589; P <0.0001, Pearsons coefficient). MCP-1 levels in serum gradually decreased after 3, 6, and 12 months of HRT by 16.8±15.7% at 12 months ( P <0.0001, MANOVA). Similarly, all cellular adhesion molecules decreased significantly by 6–12%. After 12 months, women decided whether to continue or discontinue treatment. At 18 months, in women discontinuing HRT ( n =17), MCP-1 levels rose by 21±20% ( P =0.003), but remained lowered in women continuing HRT. Conclusion: Our observations indicate that 17β-estradiol may have an antiatherosclerotic effect by reducing MCP-1 serum levels and cell adhesion molecules.

Effect of dietary supplementation with ω-3 fatty acids on progression of atherosclerosis in carotid arteries

OBJECTIVEnOmega-3 polyunsaturated fatty acids (omega-3 PUFA) from fish oil slow atherosclerosis progression in coronary arteries, as we showed in a randomized double-blind placebo-controlled clinical trial. Embedded in this trial, the present study examined the influence of 2 years of dietary supplementation with 1.65 g omega-3 PUFA per day on progression of carotid atherosclerosis in 223 patients with coronary artery disease.nnnMETHODSnCoronary angiography, a comprehensive clinical examination, and intima-media thickness measurement by B-mode ultrasound of the carotid arteries (common, internal and bifurcation), were performed at the study start and study end. An expert panel visually evaluated the global change of carotid atherosclerosis on a semiquantitative scale. A second outcome measure was the change of overall mean maximum intima-media thickness.nnnRESULTSnOne hundred and seventy-one patients completed the study. In the global change score, 38% of the patients in the fish oil group and 35% in the placebo group showed progression. Global change was not different between intervention groups. Mean maximum intima-media thickness increased by 0.07+/-0.13 mm and 0.05+/-0.11 mm in the fish oil and placebo group, respectively (mean+/-S.D., P=0.24). No correlation was found between the change in carotid and coronary arteries.nnnCONCLUSIONSnIn this group of selected patients with documented coronary artery disease omega-3 PUFA given for 2 years did not demonstrate an effect on slowing progression of atherosclerosis in carotid arteries as measured by ultrasound.

Hormone replacement therapy and distensibility of carotid arteries in postmenopausal women: a randomized, controlled trial.

OBJECTIVESnThe study objective was to clarify in a randomized, controlled, observer-blind trial whether hormone replacement therapy (HRT) improves elastic properties of the common carotid artery in women with signs of subclinical atherosclerosis, especially in subgroups with increased risk, and whether less progestin enhances the effect.nnnBACKGROUNDnPrevious observational studies have yielded conflicting results on the influence of HRT on central arteries. Some studies reported improvement of distensibility by estrogen alone or in the subgroup of smokers.nnnMETHODSnA total of 321 postmenopausal women were randomized to 1 mg 17beta-estradiol plus 0.025 mg gestodene for 12 days every month (HRT 1), or 1 mg 17beta-estradiol plus 0.025 mg gestodene for 12 days every third month (HRT 2), or no-HRT, during 48 weeks. In 173 women, distensibility of the common carotid artery was determined before and after therapy by M-mode ultrasound and brachial blood pressure measurement.nnnRESULTSnChange of distensibility was small and similar in the three treatment groups. In the subgroup of current smokers, HRT 2 (low progestin) increased distensibility by 32% (HRT 2: 8.2+/-11.7; HRT 1:0.6+/-6.0; no HRT: -1.8+/-6.8 x 10(-3)/kPa, p = 0.025 for no-HRT vs. HRT 2). In the subgroups with elevated blood pressure, high low density lipoprotein (LDL) cholesterol, or high age, no effect of HRT was detected.nnnCONCLUSIONSnThis randomized intervention study demonstrates that long-term HRT with estrogen and progestin does not substantially influence distensibility of central arteries. Yet, in currently smoking postmenopausal women, HRT with low progestin seems to improve distensibility; this merits further study in a specifically designed trial.

Effect of postmenopausal hormone replacement on atherosclerosis in femoral arteries

OBJECTIVESnOn the basis of epidemiological and experimental data, it has been supposed that hormone replacement therapy (HRT) inhibits atherosclerosis in postmenopausal women. This randomized controlled trial examined whether 1 mg 17beta-estradiol daily, combined cyclically with 0.025 mg gestodene in every month (HRT 1), or in every third month (HRT 2) slows the increase of intima-media thickness in femoral arteries compared with no HRT.nnnMETHODSnHealthy postmenopausal women (n=321) with an increased risk for future vascular disease as indicated by >1 mm of intima-media thickness in the carotid arteries were equally randomized to one of the three groups for 48 weeks. Ultrasound scans of femoral arteries were recorded at study start and study end, together with a thorough clinical examination and laboratory work-up.nnnRESULTSnComplete scans were obtained in 260 of the 264 subjects who participated until study end. Mean maximum intima-media thickness of four femoral artery segments (common and superficial, both sides) was 0.93+/-0.37 mm (mean+/-S.D.) at study start. It increased by 0.02+/-0.05, 0.02+/-0.05, and 0.03+/-0.05 mm in the HRT 1, HRT 2 and no HRT groups, respectively (HRT 1 versus no HRT, HRT 2 versus no HRT; both P>0.2). Compared with no HRT, HRT significantly lowered follicle stimulating hormone, low-density lipoprotein cholesterol, and fibrinogen.nnnCONCLUSIONSnIn this 1-year trial, irrespective of the progestogen dose used, HRT with 1 mg 17 beta-estradiol did not inhibit progression of femoral artery atheroslerosis in postmenopausal women with subclinical vascular disease.

Short term effects of ω-3 fatty acids on the radial artery of patients with coronary artery disease

Long-term dietary v-3 fatty acids improve coronary endothelial function in CAD patients, heart transplant recipients and diabetics. This study assessed whether short term v-3 fatty acids affect radial artery function in CAD patients. A high resolution A-mode echotracking device (NIUS 02) was used to measure continuously, radial artery internal diameter at rest, during flow mediated vasodilation (FMD), during cold pressure test (CPT), and after sublingual glyceryl trinitrate (GTN). We studied 18 male CAD patients in a randomized, double blind, placebo controlled design. Between pre- and post-intervention measurements 24 h apart, nine subjects received 18 g fish oil concentrate (6.4 g eicosapentaenoic acid and 3.9 g docosahexaenoic acid) and nine subjects 18 g placebo. In the placebo group correlation between both baseline diameters was 0.98; PB 0.001. Pre-intervention FMD was 7.595.6%, CPT mediated vasoconstriction was 3.89 2.5%, and GTN induced vasodilation was 15.79 9.8%. Vascular responses post-intervention showed no significant difference to pre intervention, there was no significant difference between both treatment groups. The radial artery does not seem to be an immediate target for vasodilatory actions of v-3 fatty acids.

Endothelial function of the popliteal artery in patients with coronary artery disease

Coronary artery disease (CAD) is associated more closely with atherosclerosis in the popliteal than in the brachial artery. This case-control study aimed at clarifying whether endothelial dysfunction of patients with CAD can be detected non-invasively in the popliteal artery by means of ischemia-induced flow-mediated dilation (FMD) and cold pressor reaction (CPR), and how it compares with the brachial artery. We further investigated a new mode of evaluation of the CPR. Eleven cases with CAD were compared with 16 matched healthy controls. Popliteal and brachial arterial diameter was monitored by ultrasound for 20 min following ischemia and cold pressor. For CPR, the difference between maximum and minimum diameter was defined as maximum vasomotion. In the popliteal artery, maximum vasomotion and FMD were significantly smaller in cases than in controls, the difference being more pronounced than in the brachial artery, where only maximum vasomotion was significantly smaller. After exclusion of current smokers, only the difference in maximum vasomotion of both arteries remained significant. We conclude that maximum vasomotion may be more sensitive for detection of endothelial dysfunction than FMD. Endothelial dysfunction in patients with CAD is more pronounced in the popliteal artery than in the brachial artery.

Influence of 17β-oestradiol on blood pressure of postmenopausal women at high vascular risk

Objectives It remains an unsolved issue whether hormone replacement therapy (HRT) lowers blood pressure. This randomized trial examined the effect of 17β-oestradiol combined cyclically with gestodene on blood pressure of postmenopausal women who were not on antihypertensive medication. All subjects had an increased risk for adverse vascular events as indicated by intima–media thickness of carotid arteries and standard risk factors. Design and setting Two hundred and twenty-six postmenopausal women were randomized to oral treatment for 48 weeks with 1 mg of 17β-oestradiol per day continuously, plus 0.025 mg gestodene on days 17–28 of each 4-week cycle (HRT 1), or plus gestodene in each third cycle only (HRT 2), or no HRT. According to predefined criteria, four subjects in HRT 1, 12 in HRT 2 and 13 in no HRT who were started on antihypertensive medication were excluded from the analysis. Thirty subjects ended participation prematurely for other reasons. Resting blood pressure was measured at baseline and after 12, 22 and 48 weeks. Results During treatment diastolic blood pressure changed significantly in both HRT groups compared to no HRT, by −3.7 ± 9.8 mmHg, −3.0 ± 8.8 mmHg and 1.0 ± 9.9 mmHg at week 48 in groups HRT 2, HRT 1 and no HRT, respectively (P = 0.008 for HRT 2 versus no HRT, P = 0.027 for HRT 1 versus no HRT). The higher the diastolic blood pressure was at beginning the greater was the decrease. The decrease of systolic blood pressure was not significantly different between groups. Conclusions For postmenopausal women with high cardiovascular risk but without antihypertensive medication, long-term treatment with 17β-oestradiol combined with gestodene lowers diastolic blood pressure.

Bone sialoprotein is a specific biochemical marker of bone metabolism in postmenopausal women: A randomized 1-year study

Abstract: Accelerated bone remodeling after the menopause is associated with increased bone loss that can be abolished using hormone replacement therapy (HRT). Biochemical markers of bone metabolism are known to correlate closely with changes in bone histomorphometry and osteodensitometry. Bone sialoprotein (BSP), a major constituent of bone matrix, is almost exclusively found in mineralized tissues and therefore considered a potential marker of bone metabolism. In 82 postmenopausal women, randomly allocated to either low-dose sequential HRT or no HRT, serum BSP was measured and compared with established specific biochemical markers of bone resorption [urinary deoxypyridinoline (DPD), pyridinoline (PYD) and amino-terminal telopeptide (NTx)] and markers of bone formation [serum osteocalcin (Oc) and bone-specific alkaline phosphatase (bALP)]. Longitudinal analysis showed a marked response of BSP levels following commencement of HRT, resulting in a 52% reduction after 12 months compared with initial values. The changes of BSP levels over time were at least as strong as in conventional markers of bone formation and resorption and paralleled their changes. A moderate to close correlation was found between BSP and both markers of bone resorption (r= 0.57 for NTx; r= 0.38 for DPD) and formation (r= 0.55 for Oc; r= 0.39 for bALP; p<0.0001, respectively). Our data demonstrate a cause and effect relationship between commencement of HRT and a change in serum BSP. In conclusion, serum BSP circumvents some of the limitations of urinary measurements and appears valuable for the quantitative monitoring of the skeletal response to HRT in healthy postmenopausal women.