C.D.A. Stehouwer

Postmenopausal hormone replacement, risk estimators for coronary artery disease and cardiovascular protection

Menopause, regardless of age at onset, is associated with a marked increase in coronary artery disease (CAD) risk. A large body of observational clinical studies repeatedly demonstrated favorable associations between postmenopausal hormone replacement therapy (HRT) and cardiovascular morbidity, mortality, and risk factors. Estrogens may act in a gender-specific way on vascular endothelial cells and other components of the vessel wall, enhancing the synthesis and release of nitric oxide (NO) and other vasodilators, and by inhibiting the synthesis and release of vasoconstricting agents, thus favoring vasodilation. Menopause-related changes in metabolic cardiovascular risk factors are identifiable, as are HRT-related changes in these factors. The metabolic effects include changes in lipoprotein (a), coagulation and fibrinolysis as well as homocysteine metabolism. The various actions of estrogen alone and combined with progestogen on the vascular system are reviewed. Furthermore, the outcome of the recently published Heart and estrogen/progestin replacement study (HERS) data are put in perspective. In addition, we outline the present data on the effects of raloxifene, a new second generation selective estrogen receptor modulator (SERM), which has been shown to favorably alter several markers of cardiovascular risk in postmenopausal women.

Effects of hormone replacement therapy on blood platelets.

Background Hormone replacement therapy (HRT) increases the risk of cardiovascular morbidity in postmenopausal women under certain circumstances. Part of this effect may be the result of the influence of HRT on blood platelets. We studied the effect of short‐term oral hormone replacement therapy (unopposed oestradiol or sequentially combined oestradiol and trimegestone or dydrogesterone) on platelet activation parameters in healthy postmenopausal women.

Plasma adiponectin concentration has an inverse and a non linear association with estimated glomerular filtration rate in patients with K/DOQI 3 ― 5 chronic kidney disease

BACKGROUND Chronic kidney disease (CKD) is associated with an increased incidence of cardiovascular disease (CVD). A few studies have demonstrated elevated plasma adiponectin and leptin levels in CKD. The aims of this study were to assess whether 1) estimated glomerular filtration rate (eGFR) is associated with plasma leptin and adiponectin; and 2) adiponectin and leptin (partly) explain associations of CKD with endothelial dysfunction, insulin resistance, and low-grade inflammation in patients with K/DOQI Stage 3 - 5 CKD. METHODS Baseline data from 91 patients with Stage 3 - 4 CKD in the anti-oxidant therapy in chronic renal insufficiency study, a randomized, double-blind, placebo-controlled trial, in which the effects of oxidative stress-lowering treatment on vascular function and structure were studied, and from 50 dialysis naïve patients, who took part in an open-label, randomized study that compared two peritoneal dialysis regimens, used in the analysis. All subjects for both the studies were recruited in the same centres. RESULTS The association between eGFR and adiponectin was non-linear. In multivariate analysis, log-eGFR (unstandardized beta = 8.303 microg/ml, p < 0.0001) was the strongest determinant of adiponectin, and body mass index the strongest determinant of leptin (beta = 2.477 ng/ml, p < 0.0001). Plasma adiponectin and leptin did not modify the associations between eGFR and plasma von Willebrand factor or soluble vascular adhesion molecule-1. Plasma leptin had the strongest association with the homeostatic model assessment (HOMA-IR) index. Plasma C-reactive protein had no association with adiponectin or leptin. CONCLUSIONS In patients with K/DOQI Stage 3 - 5 CKD, renal function had a significant non-linear inverse association with and was the strongest predictor of adiponectin. BMI was the strongest predictor of plasma leptin. Plasma adiponectin and leptin did not explain, and thus presumably are not involved in, the association between eGFR and some markers of endothelial dysfunction.

Postmenopausal oestradiol-dydrogesterone therapy favourably affects fibrinolysis and Lp(a) in healthy women

Background: Impaired fibrinolysis and increased lipoprotein (a) [Lp(a)] are major elements in the pathogenesis of atherothrombotic events. This study was undertaken to investigate the long-term effects of oestradioldydrogesterone therapy on fibrinolysis and lipoprotein (a) in healthy postmenopausal women. Methods: 27 women were randomized into a hormone-replacement therapy (HRT) group (n=14) and a control group (n=1313). During the first 12 months, the HRT group was treated with oral 17β-oestradiol (E2), 1 mg daily, sequentially combined with dydrogesterone 5 or 10 mg daily (14 days per 28-day treatment cycle). Thereafter these women received oral E2, 2 mg daily, sequentially combined with dydrogesterone, 10 mg daily (14 days per 28-day treatment cycle) for a period of 3 months. The control group received no treatment. Results: At baseline no significant differences were noted between the two groups. As compared to the control group (ANOVA for repeated measures with the baseline value as covariate), 15 months of HRT was associated with lower levels of plasma plasminogen activator inhibitor-1 (−26%; P=0.02) and serum Lp(a) (−46%; P<0.01), as well as with higher levels of plasma plasmin-antiplasmin (PAP) complexes (+8%; P=0.02). After 12 months of treatment with the 1 mg E2 regimen, similar significant results were found, except for PAP complexes. When compared to no treatment, HRT was not associated with differences in plasma levels of tissue plasminogen activator, thrombin-antithrombin complexes, prothrombin fragment 1+2, factor Vllc or factor Vlla. Conclusions: Long-term sequentially combined E2-dydrogesterone increases fibrinolytic potential and decreases serum Lp(a) levels without deterioration of the coagulation markers measured.

WS17: Newcomers WS17‐01Hormone replacement therapy reduces impedance to flow in different vascular beds

An HRT‐associated reduction of the pulsatility index (PI) has been reported in the literature, although cross‐sectional studies have shown conflicting data. In a prospective, controlled study we randomized 30 healthy postmenopausal women (mean age 52 ± 3 years) into two groups. Women in the HRT group (N = 15) received 1 mg micronized 17β‐estradiol daily (E2) sequentially combined with 5 or 10 mg dydrogesterone for 14 days of each 28‐day cycle during 12 months, and, thereafter, 2 mg E2 combined with 10 mg dydrogesterone for a period of 3 months. The control group (N = 15) received no treatment. Color Doppler ultrasound was used to measure the impedance to flow (pulsatility index [PI]) within the uterine, central retinal and ophthalmic arteries in the E2‐phase at baseline and after 3, 12 and 15 months. Compared to controls, 12 months of HRT was associated with a significant decrease in the mean PI of the uterine artery of −39% (HRT −25%, controls +14%) and in that of the central retinal artery of −29% (HRT −9%, controls +20%). After 3 months this effect was already evident. During HRT, the reductions in mean PI of the uterine and central retinal arteries vs. baseline were larger (both P = 0.002) in the women with high pretreatment PI values when compared to those with low pretreatment values. The baseline PI of the uterine artery correlated positively with age and with duration of amenorrhoea (r = 0.42, P = 0.01 and r = 0.48, P = 0.008, respectively). Our 12‐month study expanded on earlier reports of a reduced PI of the uterine artery. We used a combined regimen containing a low‐dose of oestrogens. These results are important because the recent trend is to recommend combined HRT that contain lower dosages of oestrogens than before. Furthermore, a 29% reduction of the PI of the central retinal artery was observed, which suggests that HRT has a positive influence on the impedance of the cerebral circulation. From the point of view of atherothrombotic risk these observations are beneficial and possibly helpful in understanding the decreased risk of cardiovascular disease, and of the impairment of cognitive functions associated with oestrogens in epidemiological data.