Endothelial function and insulin resistance in early postmenopausal women with cardiovascular risk factors: importance of ESR1 and NOS3 polymorphisms.

Cardiovascular benefits from estradiol activation of nitric oxide endothelial production may depend on vascular wall and on estrogen receptor alpha (ESR1) and nitric oxide synthase (NOS3) polymorphisms. We have evaluated the microcirculation in vivo through nailfold videocapillaroscopy, before and after acute nasal estradiol administration at baseline and after increased sheer stress (postocclusive reactive hyperemia response) in 100 postmenopausal women, being 70 controls (healthy) and 30 simultaneously hypertensive and diabetic (HD), correlating their responses to PvuII and XbaI ESR1 polymorphisms and to VNTR, T-786C and G894T NOS3 variants. In HD women, C variant allele of ESR1 Pvull was associated to higher vasodilatation after estradiol (1.72 vs 1.64 mm/s, p = 0.01 compared to TT homozygotes) while G894T and T-786C NOS3 polymorphisms were connected to lower increment after shear stress (15% among wild type and 10% among variant alleles, p = 0.02 and 0.04). The G variant allele of ESR1 XbaI polymorphism was associated to higher HOMA-IR (3.54 vs. 1.64, p = 0.01) in HD and higher glucose levels in healthy women (91.8 vs. 87.1 mg/dl, p = 0.01), in which increased waist and HOMA-IR were also related to the G allele in NOS3 G894T (waist 93.5 vs 88.2 cm, p = 0.02; HOMA-IR 2.89 vs 1.48, p = 0.05). ESR1 Pvull, NOS3 G894T and T-786C polymorphism analysis may be considered in HD postmenopausal women for endothelial response prediction following estrogen therapy but were not discriminatory for endothelial response in healthy women. ESR1 XbaI and G894T NOS3 polymorphisms may be useful in accessing insulin resistance and type 2 diabetes risks in all women, even before menopause and occurrence of metabolic disease.

Early postmenopausal women with cardiovascular risk factors improve microvascular dysfunction after acute estradiol administration.

OBJECTIVE: This study aimed to compare endothelial microcirculatory function in hypertensive and diabetic (HD) and healthy postmenopausal women before and after nasal application of 17ß-estradiol. METHODS: Seventy-one women aged 42 to 59 years within 10 years of menopause, divided into HD (n = 31) and similar-age healthy (n = 40) women were evaluated noninvasively through nailfold videocapillaroscopy before and 1 hour after estradiol, measuring basal (RBCV) and maximum (RBCVmax) red blood cell velocity after 1 minute of arterial occlusion, representing baseline and endothelial-mediated vasodilation, and time to reach RBCVmax (TRBCVmax), representing microvascular compliance/stiffness. RESULTS: Hot flashes did not differ from or affect microvascular results. Before estradiol, HD showed lower RBCV (1.495 ± 0.20 vs 1.52 ± 0.10 mm/s, P = 0.019), borderline lower RBCVmax (1.655 ± 0.09 vs 1.706 ± 0.10 mm/s, P = 0.054), and shorter TRBCVmax (7.94 ± 1.44 vs 8.8 ± 2.03 s, P = 0.011) compared with healthy women. After estradiol, RBCV and RBCVmax increased, and TRBCVmax decreased in both groups (P = 0.0001 for all). HD women showed a higher RBCV increment (14.6% ± 2% vs 11.1 ± 1.4%, P = 0.021) associated with a smaller TRBCVmax reduction (23.6% ± 2% vs 31% ± 2%, P = 0.045). Changes in RBCVmax did not differ between HD (11.6% ± 1%) and healthy (8.3% ± 1.3%, P = 0.1) women. RBCV, RBCVmax, and TRBCVmax absolute values after estradiol were similar between groups. Past oral contraceptive exposure (P = 0.035) and cigarette smoking (P = 0.047) influenced healthy women's microvascular responses to estradiol, whereas triglyceride levels impaired HD vasodilation (P = 0.028). CONCLUSIONS: Before estradiol, HD presented impaired microvascular dilation and compliance compared with control women of similar age. After estradiol, HD recovered microvascular endothelial-mediated dilation, reaching similar absolute values, but the smaller reduction in TRBCVmax suggests irreversible microvascular stiffness.

Endothelial-mediated microcirculatory responses to an acute estradiol test are influenced by time since menopause, cumulative hormone exposure, and vasomotor symptoms.

OBJECTIVE: The aim of this study was to determine which factors could influence microcirculatory responses to an acute estradiol test during postmenopause. METHODS: Dynamic nailfold videocapillaroscopy was performed in 68 healthy 34- to 70-year-old postmenopausal women before and 1 hour after administration of 300 mug nasal estradiol. Red blood cell velocity (RBCV; mm/s) at rest and after the release of 60-second arterial occlusion (RBCVmax; mm/s) and time to reach it (TRBCVmax; s) were correlated to clinical and laboratory data. RESULTS: After estradiol administration, RBCV and RBCVmax increased by 13.4% and 9.4%, respectively, and TRBCVmax decreased by 29.1% (P = 0.0001 for all). These changes were not associated to the women's age but rather to time since menopause (P = 0.04; r = 0.245) and previous duration of hormone therapy (P = 0.03; r = 0.324). Past users of oral contraceptives presented higher velocities but smaller increases compared with never users (12.4% vs 17.7%, P = 0.022, for RBCV and 8.4% vs 13.7%, P = 0.028, for RBCVmax), and triglyceride levels were negatively associated to velocity increases (P = 0.05 and r = -0.243 for RBCV and P = 0.03 and r = -0.261 for RBCVmax) after estradiol administration. Previous smokers showed a smaller reduction in TRBCVmax, associated directly to total estimated number of smoked cigarettes (P = 0.03; r = -0.468). The reduction in TRBCVmax was also inversely related to the intensity of current vasomotor symptoms (P = 0.04; r = -0.252). CONCLUSIONS: Changes in RBCVs and TRBCVmax after estradiol administration indicate an increase in endothelial-dependent vasodilatation and vascular elasticity, respectively. Moreover, maintenance of endothelial responsiveness depends on cumulative exposure to sex steroids, duration of hormone deprivation, and triglyceride levels. Past smoking and current vasomotor symptoms could be associated to microvascular wall stiffness/elasticity.

Microcirculatory function in postmenopausal women: role of aging, hormonal exposure and metabolic syndrome.

Menopausal hormone therapy (HT) has shown conflicting cardiovascular endpoints, depending on the women studied. The endothelium is the main site for sex steroids cardiovascular action. To assess the influence of age, previous hormonal exposure and of metabolic syndrome (MS) on microcirculatory function, we studied 68 normotensive non-diabetic postmenopausal women, 34-70 years old, by dynamic nailfold videocapillaroscopy evaluating red blood cell velocity (RBCV) at baseline and during the reactive hyperemia response after 1 min ischemia (RBCV(max)) and time taken to reach it (TRBCV(max)). There was an inverse correlation between RBCV and RBCV(max), versus age (p=0.02 for both) and time since menopause (TSM, p=0.01 and p=0.03, respectively). Women who used oral contraceptives in the past showed higher RBCV (1.51+/-0.10 vs. 1.43+/-0.09 mm/s, p=0.01) and RBCV(max) (1.70+/-0.11 vs. 1.63+/-0.07 mm/s, p=0.03) compared to never user ones. A longer time after menopause without HT was associated to lower RBCV(max) (p=0.05). Women with MS had longer TRBCV(max) (9.85+/-1.77 vs. 8.47+/-1.71 s, p=0.02), as well as those with higher hematocrit, hemoglobin and leukocyte counts (p=0.03, p=0.01 and p=0.03, respectively) and lower HDL (p=0.03). In conclusion, in postmenopausal women of low cardiovascular risk, advanced age, longer TSM, longer time after menopause without HT and MS were associated to microcirculatory function impairment, whereas past use of oral contraceptives seemed to have a protective effect.