Reduced androgen levels in adult Turner syndrome: influence of female sex steroids and growth hormone status

BACKGROUND AND OBJECTIVES: In girls with Turner syndrome androgen levels are reduced. In order to assess androgen status in women with Turner syndrome, we compared untreated adult women with Turner syndrome with a group of normal women. In addition, the effects of female sex hormone replacement therapy and GH status on the levels of circulating androgens in Turner syndrome was examined. DESIGN: All patients were receiving female hormone replacement therapy (HRT), which was discontinued four months prior to the initial examination. Patients were studied before and during HRT. Following the initial evaluation, patients were given cyclical HRT for six months consisting of either oral substitution (17beta-oestradiol with norethisterone from day 13-22), or transdermal oestrogen substitution (17beta-oestradiol) with 1 mg norethisterone administered orally from day 13-22. Control subjects were studied once in the early follicular stage of the menstrual cycle. SUBJECTS: The study group consisted of 27 (33.2 +/- 7.9 years) patients with Turner syndrome and an age matched control group of 24 (32.7 +/- 7.6 years) normal women. MEASUREMENTS: Body composition measures, SHBG, testosterone (T), free testosterone (FT), dihydrotestosterone (DHT), alpha-4-androstendione (A), dehydroepiandrosterone sulphate (DHEAS), 17beta-oestradiol (E2), oestrone (E1), oestrone sulphate (ES), 24 h integrated GH concentration (ICGH), insulin-like growth factor I (IGF-I), insulin-like growth factor binding protein (IGFBP-3) were determined at baseline and after six months in women with Turner syndrome, and at baseline in control women. RESULTS: Circulating levels of A, T, FT, DHT, and SHBG were reduced by 25-40% in comparison with age matched normal women. The level of DHEAS was normal. The level of E2 was undetectable and levels of E1 and ES were very low in untreated Turner women. Treatment with 17beta-oestradiol and norethisterone increased oestrogen to levels comparable to those of normal women, while further decreasing FT (P = 0.02), DHT (P = 0.04), and T (P = 0.1). In untreated women with Turner syndrome IGF-I correlated significantly with DHEAS (R = 0.503, P < 0.01), while in normal women IGF-I correlated with A (R = 0.637, P < 0.01), T (R = 0.536, P < 0.01), and FT (R = 0.700, P < 0.01). During hormonal replacement in women with Turner syndrome IGF-I correlated significantly with DHEAS (R = 0.547, P < 0.01). Employing multiple regression analysis IGFBP-3, ICGH, DHEAS and fat free mass explained 85% (adjusted R = 0.92, P < 0.0005) of the variation in the level of IGF-I in untreated Turner syndrome. In treated Turners IGFBP-3, ICGH, SHBG, T, and FT explained 78% (adjusted R = 0.88, P < 0.0005). In controls IGFBP-3, SHBG, BMI and age explained 74% (adjusted R = 0.86, P < 0.0005) of the variation in IGF-I, while GH status did not contribute at all. CONCLUSION: The present study shows that many adults with Turner syndrome have reduced levels of circulating androgens, compared with an age-matched group of normal women. Conditions associated with Turner syndrome such as increased prevalence of sexual problems, reduced bone mineral content, osteoporosis, and an increased incidence of fractures and alterations in body composition could perhaps be alleviated or abolished by substitution with a low dose of androgens. Treatment with female hormonal replacement therapy is associated with a decrease in testosterone, free testosterone and dihydrotestosterone, possibly mediated by the androgenic effect of norethisterone. Furthermore significant differences in sex steroid levels, GH status and indices of body composition can be compatible with comparable levels of IGF-I in two very different groups of individuals.     

A placebo-controlled trial of long-term oral combined continuous hormone replacement therapy in postmenopausal women: effects on arterial compliance and endothelial function

OBJECTIVE: To study the effects of long-term combined continuous oral hormone replacement therapy (HRT) on vascular function in healthy postmenopausal women. BACKGROUND: The cardiovascular effects of HRT are controversial. Improvement in vascular function is a proposed mechanism of oestrogen action but there are no long-term controlled human trials in this area. In this study, we examined the effects of HRT on lipid profiles and vascular function, encompassing both biomechanical arterial properties [systemic arterial compliance (SAC) and pulse wave velocity (PWV)] and endothelial function [flow-mediated vasodilation (FMD)]. METHODS: In this 2-year, double-blind, placebo-controlled study, 59 healthy postmenopausal women were randomized to oral combined continuous oestrogen and progesterone [Kliogest, oestradiol (2 mg), norethisterone (1 mg)] or placebo, with end-points measured at baseline, 6 weeks and after 6,12 and 24 months of treatment. RESULTS: Oral combined HRT reduced lipoprotein a [Lp(a)], although other lipid benefits were not observed. There were no significant changes in SAC, PWV or FMD with oral combined HRT, compared to placebo. CONCLUSION: In this long-term, randomized placebo-controlled trial, oral continuous HRT with combined oestradiol and norethisterone in healthy postmenopausal women did not improve a spectrum of indices of arterial function compared to placebo. These results suggest that HRT might not be of cardiovascular benefit in postmenopausal women.     

阻塞性睡眠呼吸暂停低通气综合征患者动脉粥样硬化无创检测指标分析

目的检测血流介导的血管扩张(FMD)、脉搏波传导速度(PWV)和颈动脉内膜中层厚度(CIMT),探讨阻塞性睡眠呼吸暂停低通气综合征(OSAHS)与动脉粥样硬化之间的关系。方法对76例OSAHS患者(OSAHS组)及76例年龄、性别、体重指数与之相匹配患者(对照组)进行FMD、PWV和CIMT检测,对两组间FMD、PWV和CIMT值进行比较,对OSAHS组睡眠呼吸暂停低通气指数(AHI)与FMD、PWV和CIMT之间关系进行相关性分析。结果OSAHS组PWV[(1720±247)cm/s]、CIMT[(1.10±0.34)mm]显著高于对照组[(1469±172)cm/s、(0.80±0.18)mm],FMD[(5.8±1.7)%]显著低于对照组[(8.9±1.4)%,P均<0.01];比较两组中所有伴高血压者,OSAHS组PWV、CIMT[(1850±244)cm/s、(1.24±0.35)mm]仍显著高于对照组[(1655±161)cm/s、(0.99±0.18)mm,P=0.001、0.003],FMD[(5.2±1.7)%]显著低于对照组[(7.5±1.1)%,P<0.01];OSAHS组AHI值与PWV、CIMT值呈正相关(r=0.883、0.698,P均<0.01),与FMD值呈负相关(r=-0.711,P<0.01)。结论OSAHS患者存在更为明显的内皮功能障碍及动脉粥样硬化,且与OSAHS严重程度有关。     

Osteopenia in young hypogonadal women with systemic lupus erythematosus receiving chronic steroid therapy: a randomized controlled trial comparing calcitriol and hormonal replacement therapy

OBJECTIVE: To evaluate the efficacy of calcitriol and hormonal replacement therapy (HRT) in the treatment of steroid-induced osteoporosis in hypogonadal women. METHODS: We studied 28 young patients (aged 37 +/- 6 yr) with systemic lupus erythematosus (SLE) on chronic steroid therapy for 130 +/- 22 months and requiring more than 10 mg/day prednisone. They were amenorrhoeic for more than 2 yr with proven ovarian failure. All had osteopenia with a T score at L2-4 of less than -1. They were randomized to receive HRT (conjugated oestrogen 0.625 mg daily from day 1 to day 21 plus medroxyprogesterone acetate 5 mg daily days 10-21) or calcitriol 0.5 microg daily. All received calcium carbonate 1 g/day. RESULTS: There were no differences in the baseline demographic, bone mineral density (BMD) and biochemical data between the two groups. Lumbar spine BMD increased by 2.0 +/- 0.4% after 2 yr with HRT (P<0.05), but reduced by 1.74 +/- 0.4% (P<0.05) with calcitriol treatment. No change was seen at the distal one-third radius with HRT treatment but significant bone loss (2.3 +/- 1.4%, P<0.02) was observed with calcitriol therapy. BMD at the hip did not change in both groups. Comparing both treatment groups, significant differences in the BMD at the spine (P<0.03) and radius (P<0.05) were seen at the end of 2 yr. The changes in urinary n-telopeptide excretion but not serum osteocalcin at 6 months and 12 months were inversely correlated with the changes in lumbar spine BMD at 24 months. HRT did not cause an adverse effect on SLE disease activity. CONCLUSION: HRT but not calcitriol could prevent bone loss in young hypogonadal women on chronic steroid therapy.     

Effect of age and sex on carotid intima-media thickness, elasticity and brachial endothelial function in healthy adults: the cardiovascular risk in Young Finns Study.

AIMS: The objective was to produce reference values and to analyse the associations of age and sex with carotid intima-media thickness (IMT), carotid compliance (CAC), and brachial flow-mediated dilatation (FMD) in young healthy adults. METHODS AND RESULTS: We measured IMT, CAC, and FMD with ultrasound in 2265 subjects aged 24-39 years. The mean values (mean +/- SD) in men and women were 0.592 +/- 0.10 vs. 0.572 +/- 0.08 mm (P < 0.0001) for IMT, 2.00 +/- 0.66 vs. 2.31 +/- 0.77%/10 mmHg (P < 0.0001) for CAC, and 6.95 +/- 4.00 vs. 8.83 +/- 4.56% (P < 0.0001) for FMD. The sex differences in IMT [95% confidence interval (CI) for sex difference -0.013 to 0.004 mm, P = 0.37] and CAC (-0.01 to 0.18%/10 mmHg, P = 0.09) became non-significant after adjustments with risk factors and carotid diameter. In FMD, the sex difference was unaltered after adjustments for risk factors, but was reversed after adjustment with brachial diameter (95% CI 0.18-1.32%, P < 0.01). With aging, IMT increased 5.7 +/- 0.4 microm/year and CAC decreased 0.042 +/- 0.003%/10 mmHg/year. The association of age with IMT and CAC was slightly attenuated (12 and 22%, respectively) after adjustments with risk factors, but remained significant (both P < 0.0001). Aging was not significantly related to brachial FMD (P = 0.16). CONCLUSION: Reference values produced in the present study can be utilized in the cardiovascular risk stratification among young people. Sex differences in the markers of subclinical atherosclerosis were mostly explained by differences in risk factors and vessel size. This emphasizes the importance of risk factor control in the prevention of atherosclerosis in young adults.     

Effects of low-dose prednisolone on endothelial function, atherosclerosis, and traditional risk factors for atherosclerosis in patients with rheumatoid arthritis--a randomized study

OBJECTIVE: To determine the influence of low-dose prednisolone on atherosclerosis, endothelial function, and risk factors for atherosclerosis in patients with early rheumatoid arthritis (RA). METHODS: At start of the first disease modifying antirheumatic drug, 67 patients with early, active RA were randomized to either 7.5 mg prednisolone daily (n = 34) or no prednisolone (n = 33). In the prednisolone group, 21 were treated for 2 years and 13 continuously. After a mean of 5 years intima-media thickness (IMT) and calculated intima-media area (cIMa) of the carotid arteries were determined by B-mode ultrasound. Endothelial function was determined by flow-mediated dilatation (FMD) of the brachial artery. RESULTS: IMT [median (interquartile range) 0.675 mm (0.58-0.82) vs 0.673 mm (0.0.62-0.80)], cIMa [13.7 mm2 (11.45-20.37) vs 14.1 mm2 (12.34-17.38)], prevalence of atherosclerotic plaques (82.3% vs 81.9%), and endothelial function [FMD% (mean +/- SD) 3.88% +/- 2.8 vs 3.74% +/- 2.9] did not differ between patients treated with and those not treated with prednisolone. There were no differences in lumen diameter of carotid arteries, or levels of lipoproteins, glucose, and blood pressure. Patients treated for at least 4 years (and currently treated) with prednisolone had a trend to higher systolic blood pressure (157 +/- 29 mm Hg) compared with untreated patients (141 +/- 28 mm Hg; p = 0.06) and had higher cholesterol levels (5.6 mmol/L +/- 1.39 vs 4.9 +/- 28; p = 0.03). In the whole cohort, age and HDL were independently associated with IMT; age, HDL, and blood pressure with cIMa; and age and serum creatinine with presence of atherosclerotic plaques. CONCLUSION: Low-dose prednisolone did not influence endothelial function and atherosclerosis in patients with RA. However, total cholesterol was higher in patients treated with prednisolone.     

Metabolic syndrome and vascular alterations in normotensive subjects at risk of diabetes mellitus

We evaluated the possible association between early vascular abnormalities and the metabolic syndrome (MS) in 77 normotensive subjects (mean age: 50 years) at risk of developing diabetes for family history of diabetes, obesity, or impaired fasting glucose. Fifty healthy subjects were recruited as controls. MS was defined according to the ATP III criteria. Brachial artery endothelium-dependent and -independent vasodilation were assessed as flow-mediated dilation (FMD) and response to glyceryl trinitrate (GTN, 25 microg sublingual), respectively, by automatic computerized edge detection system. Carotid-femoral pulse wave velocity (PWV) and radial augmentation index (AIx) were assessed by applanation tonometry. PWV was significantly (P<0.01) higher in subjects with MS (n=29, 9.0+/-1.9 m/s) as compared with those without MS (n=48, 7.7+/-1.2 m/s) and controls (7.2+/-1.5 m/s). FMD was significantly (P<0.05) reduced in both subjects with (5.8+/-2.7%) and without MS (6.1+/-3.7%) as compared with controls (6.9+/-2.5%). No significant differences were found for response to GTN and AIx. PWV and FMD were significantly (P<0.05) affected by increasing number of MS components. Among the components of the MS, only blood pressure significantly affected PWV, whereas blood pressure and fasting glucose influenced FMD. Logistic regression analysis showed that MS was associated with increased risk of altered PVW (odd ratio: 7.95, confidence limits: 1.06 to 69.11), whereas only blood pressure component was significantly related with increased risk of impaired FMD (odd ratio: 3.60, confidence limits: 1.01 to 12.78). In conclusion, in normotensive subjects at risk of developing diabetes mellitus, the presence of MS is associated with a selective alteration of central PWV.     

Recombinant GH replacement in hypopituitary adults improves endothelial cell function and reduces calculated absolute and relative coronary risk

OBJECTIVE: Adult GH deficiency (GHD) is linked to endothelial dysfunction and vascular disease. We examined the effect of 12 months of GH therapy on endothelial function, C-reactive protein (CRP) and coronary risk. DESIGN: Open-design intervention study. PATIENTS: Fourteen GH-deficient patients (nonsmokers, without diabetes, hypertension or vascular disease) studied before, 6 months and 12 months after GH therapy. MEASUREMENTS: Flow-mediated dilatation (FMD), carotid intima-media thickness (IMT) thrombomodulin (TM), E-selectin, CRP, lipid profile, blood pressure and anthropometric data were recorded. We used the Framingham equation to calculate coronary risk. RESULTS: FMD improved (7.5 +/- 1.62 vs. 11.93 +/- 1.52, P = 0.038). Overall there was no change in IMT, TM, E-selectin or CRP. The correlation between TM and FMD showed a trend for statistical significance (r = -0.54, P = 0.056). Changes in CRP correlated with change in IGF-1 (r = -0.67, P = 0.012); E-selectin correlated with high density lipoprotein (HDL)-cholesterol (r = -0.60, P = 0.028), triglycerides (r = 0.68, P = 0.01) and waist-to-hip ratio (WHR) (r = 0.71, P = 0.006). Systolic (127.36 +/- 4.47 vs. 120.36 +/- 3.50, P = 0.017) and diastolic (84.71 +/- 2.73 vs. 76.93 +/- 2.03, P = 0.005) blood pressure decreased. HDL-cholesterol increased (0.70 +/- 0.05 vs. 0.93 +/- 0.06, P = 0.001). WHR decreased (0.90 +/- 0.02 to 0.88 +/- 0.02, P = 0.043) without changes in weight or body mass index (BMI). Ten-year absolute (P = 0.009) and relative (P = 0.002) cardiac risk decreased. CONCLUSION: Biophysical test of endothelial function (FMD) improved after 12 months of GH therapy but there was no significant change in biochemical endothelial or inflammatory markers. Calculated coronary risk decreased mainly due to reduction in systolic and diastolic blood pressure and increase in HDL-cholesterol.     

Hormone replacement therapy in postmenopausal women protects against smoking-induced changes in vascular structure and function.

OBJECTIVES: The purpose of this study was to investigate the role of hormone replacement therapy (HRT) in postmenopausal women who smoke. BACKGROUND: Hormone replacement therapy appears to afford cardiovascular protection in postmenopausal women; however, in high risk individuals, specifically smokers, this has not been adequately studied. This question was addressed in a cross-sectional study of arterial structure, function and plasma lipids in postmenopausal smokers and nonsmokers. METHODS: Vascular ultrasound was performed in two age-matched groups of postmenopausal women, 70 on HRT (35 smokers) and 70 control subjects not on HRT (35 smokers). Indexes of arterial structure (carotid intima-media thickness [IMT]) and vascular function (systemic arterial compliance [SAC]) and lipid profiles were measured. RESULTS: Participant characteristics were similar in the two groups. Smokers on HRT, compared with smoking control subjects, had lower cholesterol (6.0+/-0.2 vs. 6.8+/-0.3 mmol/liter, p = 0.03) and more favorable mean values for IMT (0.64+/-0.02 vs. 0.74+/-0.03 mm, p = 0.007) and SAC (0.41+/-0.03 vs. 0.32+/-0.03 U/mm Hg, p = 0.03). Nonsmokers on HRT compared with nonsmoking control subjects had lower total cholesterol (5.7+/-0.2 vs. 6.5+/-0.2 mmol/liter, p = 0.02) and low density lipoprotein cholesterol (3.4+/-0.2 vs. 4.4+/-0.3 mmol/liter, p = 0.01). Mean IMT and SAC values in nonsmokers on HRT and control subjects were not significantly different. Multiple regression demonstrated significant correlation between HRT status and both IMT and SAC, in smokers and in those with increased cholesterol. In nonsmokers and those with lower cholesterol, HRT status was not significantly correlated with vascular parameters. CONCLUSIONS: In postmenopausal women who smoke there may be a beneficial effect of long-term estrogen therapy on indexes of arterial structure and function as surrogate markers of cardiovascular disease. Long-term controlled studies are needed to confirm these findings.     

Microalbuminuria, pulse wave velocity and common carotid artery intima-media thickness in type 2 diabetes

The aim of the study was to evaluate pulse wave velocity (PWV) and carotid intima-media thickness (IMT) in type 2 diabetics with microalbuminuria (mualb). The study concerned 37 patients type 2 diabetics, age: 53.4 +/- 6.6, years free of cardiovascular complications. HbA1C was 7.73 +/- 1.39%, waist circumference 104.2 +/- 11.7 cm. 19 patients with BP > 130/85 mmHg were identified as mild hypertensives (17/19 under treatment). All patients underwent ABPM, PWV and IMT measurements. The study population was separated into 2 subgroups according to median of mualb (mg/24 h): 18.9. [table: see text] In patients with mualb > 18.9 mg/24, IMT and PWV were significantly increased (p = 0.06; p < 0.01). After adjustment to BP and age, there was no significant difference in IMT and PWV in the subgroups. In this selected population of type 2 diabetics, microalbuminuria appears associated to a pressure-dependant vascular remodeling.     

Evidence that parenteral testosterone therapy may improve endothelium-dependent and -independent vasodilation in postmenopausal women already receiving estrogen

The gender difference in cardiovascular disease has been partly attributed to higher androgenic hormone levels. Although testosterone in women may not affect lipids, it remains unknown whether it negates favorable estrogenic effects on endothelial function. We have investigated the effects of testosterone implant therapy on arterial reactivity encompassing endothelial-dependent and -independent vasodilation in women using hormone replacement therapy (HRT). B-mode ultrasound measurements of resting brachial artery diameter, following reactive hyperemia [endothelium-dependent flow- mediated dilation (FMD)] and following glyceryl trinitrate (GTN) (endothelium-independent dilation), were recorded in 33 postmenopausal women stabilized on HRT (>6 months), at baseline, and 6 weeks after a testosterone implant (50 mg), with 15 postmenopausal nonusers of HRT serving as controls. In the brachial artery, baseline resting diameter was similar (0.40 +/- 0.01 vs. 0.41 +/- 0.01 cm, P = 0.5). In the treated group, testosterone levels increased (0.99 +/- 0.08 to 4.99 +/- 0.3 nmol/L, P < 0.001), associated with a mean 42% increase in FMD (6.4% +/- 0.7 to 9.1% +/- 1.1, P = 0.03). The control group did not change (8.1% +/- 1.4 to 5.6% +/- 1.0, P = 0.4). ANOVA of repeated measures (P = 0.04) and mean change (P = 0.02) in FMD both demonstrated significantly greater improvement with testosterone compared with controls. GTN induced vasodilation increased with testosterone treatment (14.9% +/- 0.9 to 17.8% +/- 1.2, P = 0.03). Our preliminary data indicate that parenteral testosterone therapy improves both endothelial-dependent (flow-mediated) and endothelium-independent (GTN-mediated) brachial artery vasodilation in postmenopausal women using long-term estrogen therapy. The mechanisms underlying these potentially beneficial cardiovascular effects require further investigation.     

Cardiovascular risk markers in hypothalamic amenorrhoea

OBJECTIVE: To determine whether women with oestrogen deficiency due to hypothalamic amenorrhoea (HA) would demonstrate a lipid and lipoprotein pattern similar to that seen in menopause with higher total cholesterol (TC), LDL, triglyceride and Lp(a) and lower HDL levels than women with regular menstrual cycles. DESIGN: Cross-sectional. PATIENTS: Fifty subjects: 21 women with HA and 30 eumenorrhoeic controls (NL) matched for age, BMI and fat-free mass. MEASUREMENTS: Lipid and lipoprotein levels. RESULTS: There was a significant difference in Lp(a) levels in the HA group between women with >19% fat intake and those <19% fat intake (352+/-231 vs. 116+/-62 mg/l, P = 0.006). Percent fat intake was the most significant determinant of Lp(a) levels in HA, accounting for 51% of the variation in Lp(a) levels. Mean HDL levels were higher in the women with HA compared with the controls (1.3+/- 0.3 vs. 1.1+/-0.2 mmol/l, P = 0.002). There was no significant difference between the groups in TC [4.4+/-0.9 (HA) vs. 4.1+/-0.8 mmol/l (NL), P>0.05], LDL [2.8+/-0.6 (HA) vs. 2.7+/-0.7 mmol/l (NL), P>0.05], triglycerides [1.8+/-0.5 (HA) vs. 1.7+/-0.5 mmol/l (NL), P>0.05] or Lp(a) [234+/-199 (HA) vs. 247+/-222 (NL) mg/l, P>0.05] levels. CONCLUSION: Reduced Lp(a) levels were associated with low dietary fat in women with HA. Moreover, in contrast to menopausal oestrogen deficiency, young women with HA and oestrogen deficiency have increased levels of HDL and no increases in TC, LDL and triglycerides. These data suggest that the negative effects of oestrogen deficiency on cardiovascular risk factors may be modified in women with hypothalamic amenorrhoea.     

Vasculopathy in Turner syndrome: arterial dilatation and intimal thickening without endothelial dysfunction

CONTEXT: Women with Turner syndrome (TS) have an increased cardiovascular mortality rate from both structural and ischemic heart disease, especially aortic dissection. OBJECTIVE: We hypothesized that TS women have a fundamental arterial wall defect that may be due to genetic factors or estrogen deficiency. DESIGN, SETTING, AND PATIENTS: TS women (n = 93) were compared with normal controls (n = 25) and women with 46,XX primary amenorrhea (PA) (n = 11) with a similar history of estrogen deficiency. Clinical parameters, aortic root diameter, extraaortic arterial structure [common carotid (CD), brachial artery diameter, and carotid intima-media thickness (IMT)], arterial stiffness (pulse-wave velocity, augmentation index), and endothelial function (flow-mediated dilatation) were assessed. MAIN OUTCOME MEASURES: These included arterial diameters and vascular physiology parameters. RESULTS: Differences in arterial structure were observed among TS, normal controls, and 46,XX PA women: IMT (0.61 +/- 0.07 vs. 0.55 +/- 0.06 vs. 0.60 +/- 0.05 mm, respectively; P < 0.001), CD (5.71 +/- 0.64 vs. 5.27 +/- 0.34 vs. 5.22 +/- 0.38 mm; P < 0.001), and brachial artery diameter (3.29 +/- 0.44 vs. 3.06 +/- 0.36 vs. 2.97 +/- 0.30 mm; P = 0.006). Aortic root diameter was greater in TS than normal control women. TS status, height, weight, and IMT were independently associated with increased CD after multivariate adjustment (P < 0.05). TS status, age, diastolic blood pressure, and CD remained independently associated with increased IMT after multivariate adjustment (P < 0.05). Pulse-wave velocity and flow-mediated dilatation were similar among the three groups. CONCLUSION: Women with TS have greater IMT and conduit artery diameters than normal controls. Similarly, increased IMT in TS and 46,XX PA women suggests that estrogen deficiency contributes to intimal thickening. Interventional studies are required to determine the extent to which blood pressure and estrogen deficiency may be appropriate therapeutic targets to reduce cardiovascular risk in TS.     

Effects of inhibition of basal nitric oxide synthesis on carotid-femoral pulse wave velocity and augmentation index in humans

Aortic stiffness, as measured by carotid-femoral pulse wave velocity (PWV), is a powerful, independent predictor of vascular risk. PWV in muscular arteries is influenced by basal nitric oxide (NO) release. It is not known whether NO also influences carotid-femoral PWV. We examined the effects of an NO synthase inhibitor, NG-monomethyl-l-arginine (L-NMMA), on carotid-femoral PWV and aortic augmentation index (AIx, an indirect measure of arterial stiffness). To control for effects of L-NMMA on distending pressure, we used doses of norepinephrine and dobutamine that caused similar changes in mean arterial blood pressure (MAP). Healthy men (32 to 48 years old, n=8) were studied on 4 occasions and received, in random order, vehicle, L-NMMA (3 mg x kg(-1) by intravenous bolus followed by 3 mg x kg(-1) x h(-1)), norepinephrine (50 ng x kg(-1) x min(-1)), and dobutamine (2.5 to 10 microg x kg(-1) x min(-1)), each for 30 minutes. PWV and AIx were measured by carotid-femoral PWV and radial tonometry, respectively. L-NMMA and norepinephrine increased MAP by 7.8+/-1.7 and 9.7+/-2.1 mm Hg, respectively (each P<0.05 vs vehicle) and increased PWV by 0.7+/-0.2 and 1.0+/-0.3 m x s(-1) (each P<0.01 vs vehicle). Dobutamine, at doses that produced a similar increase in MAP (9.6+/-2.9 mm Hg), increased PWV by 0.8+/-0.2 m x s(-1) (P<0.01 vs vehicle). Changes in PWV caused by the 3 pressor agents were closely correlated with changes in MAP (R>0.99, P<0.0001). L-NMMA and norepinephrine increased AIx, but dobutamine decreased AIx (P<0.01 vs norepinephrine and L-NMMA). Effects of inhibition of basal NO release on carotid-femoral PWV can be explained by the change in MAP that this causes rather than any specific effect of NO inhibition within the aorta.     

Functional and structural markers of atherosclerosis in human immunodeficiency virus-infected patients.

OBJECTIVES: We investigated functional and structural markers of atherosclerosis in human immunodeficiency virus (HIV)-infected patients in relation to the presence of the metabolic syndrome (MS). BACKGROUND: Antiretroviral combination therapy in HIV has been associated with cardiovascular risk factors that cluster in the MS. METHODS: Thirty-seven HIV-infected patients underwent assessment of flow-mediated vasodilation (FMD), aortic pulse-wave velocity (PWV), and carotid intima-media thickness (IMT). Age-matched type 2 diabetic patients (n = 13) and healthy controls (n = 14) served as reference groups. RESULTS: Fifteen HIV-infected patients (41%) fulfilled the National Cholesterol Education Program criteria of the MS. The FMD was similarly impaired in HIV-infected patients without the MS (MS- group) and the diabetic patients (5.1 +/- 0.4% and 4.9 +/- 0.6%, respectively) compared with controls (8.8 +/- 0.7%). The HIV-infected patients with the MS (MS+ group) had even more impaired FMD (2.5 +/- 0.3%). Carotid IMT was similarly increased in the MS+ group and the diabetic patients compared with the other groups. Aortic PWV was increased in the diabetic patients only. In HIV-infected patients, FMD was related to metabolic parameters, whereas aortic PWV and IMT were related to parameters of HIV infection, time on antiretroviral combination therapy, inflammatory (C-reactive protein and leukocytes) and metabolic parameters. CONCLUSIONS: The data of the present study suggest an increased cardiovascular risk in HIV-infected patients, even in the absence of clustering of metabolic risk variables. The presence of the MS in HIV is associated with even more advanced atherosclerotic changes. Presumably, both HIV infection and antiretroviral therapy may promote atherosclerosis through mechanisms involving endothelial cells, either directly or indirectly via metabolic risk factors.     

Influence of 17beta-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 17beta-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 17beta-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 17beta-oestradiol combined with gestodene lowers diastolic blood pressure.     

Oestrogen has no short-term effect on intestinal strontium absorption in healthy postmenopausal women

OBJECTIVE: Impaired intestinal calcium absorption in postmenopausal women is often indirectly linked to decreased serum 1,25(OH)2D or to intestinal resistance to its action rather than directly to low circulating oestrogen levels following the menopause. The purpose of this clinical study was to investigate the short-term effect of oral 17 beta-oestradiol on intestinal calcium absorption, with strontium as a marker. DESIGN AND PATIENTS: Twenty-five healthy postmenopausal women participated in this randomised double blind placebo controlled clinical trial. Twelve women received oestradiol therapy (2 mg/day) and thirteen placebo for 2 months. Fractional strontium absorption (Fc240) was assessed at baseline and after 2 months of oestradiol/placebo therapy. RESULTS: Intestinal strontium absorption (Fc240) was unchanged after treatment with 17 beta-oestradiol (10.1 +/- 5.0 vs. 10.2 +/- 3.8(%)). Serum total calcitriol (1,25(OH)2D) was unchanged after treatment with placebo (88 +/- 22 vs. 79 +/- 21 (pmol/l)) but increased after treatment with oestradiol (88 +/- 30 vs. 116 +/- 33 (pmol/l); P < 0.005). Serum vitamin D binding protein (DBP) increased after oestradiol but not after placebo treatment. The free serum 1,25(OH)2D index was calculated. This index did not change after oestrogen therapy (1.6 +/- 0.5 vs. 1.8 +/- 0.5). CONCLUSION: In healthy postmenopausal women, short-term suppletion with exogenous oral oestrogen did not influence intestinal calcium absorption as measured by the strontium absorption test.     

Flow-mediated vasodilatation of the brachial artery and intima-media thickness of carotid artery in never-treated subjects.

AIM: Data on the association between brachial artery flow-mediated dilatation (FMD) and common carotid intima-media thickness (IMT) are contrasting. The present study investigated the relationship between FMD and IMT and carotid atherosclerosis in never treated subjects. METHODS: Seventy-seven subjects were investigated: 46 had no coronary heart disease (CHD) risk factors, 21 had only one, and 10 had more than one risk factor. IMT of the common carotid was measured by ultrasonography and FMD was evaluated according to standardized methods. RESULTS: IMT increased with increasing number of risk factors (0.66+/-0.12, 0.69+/-0.12 and 0.8+/-0.17 mm, respectively, ANOVA P<0.05). FMD decreased with increasing number of risk factors (10.44+/-5.2, 6.52+/-7.11 and 7.35+/-4.42%, respectively, P<0.05). Endothelium-independent vasodilatation was similar in the 3 groups. IMT and FMD did not correlate neither in subjects without risk factors (r=-0.151, P=0.3), nor in those with 1 (r=-0.196, P=0.4) or with 2 or more risk factors (r=-0.387, P=0.2), while in the group as a whole the correlation was borderline significant (r=-0.217, P=0.058). Eleven subjects had carotid atherosclerosis and higher values of IMT, but not reduced FMD. In multiple regression analysis, diabetes and IMT, but not FMD, were associated with carotid atherosclerosis. CONCLUSIONS: The present findings indicate that, in never treated subjects, FMD is not strictly associated with IMT or atherosclerosis of the carotid arteries.     

Gender difference in age-related changes in vascular function

PURPOSE: We investigated whether, in a randomly selected population of 55-year-old men and women, there is a relationship between vascular function measured as flow-mediated (endothelium-dependent) and nitroglycerine-mediated (nonendothelium-dependent) dilatation of the brachial artery and conventional risk factors for cardiovascular disease such as gender, smoking, elevated blood-lipids and high blood pressure. The results are compared with those in a young healthy population of 35-year-olds. SUBJECTS: A total of 57 men (73% of the invited males) living in the community and 47 women (62% of the invited females) participated and were compared with a previously studied 35-year-old population (52 men and 56 women). METHODS: Basal brachial artery diameter was measured by high-frequency ultrasound methods. Endothelial function was measured as flow-mediated dilatation (FMD) in response to reactive hyperaemia. The nonendothelium-dependent vasodilatation was measured after administering sublingual nitroglycerine (NTG). RESULTS: Flow-mediated endothelium-dependent dilatation was similar in men and women being 3.1 +/- 2.5% (mean +/- SD) in men vs. 2.6 +/- 2.3% in women. FMD of the brachial artery was negatively correlated with vessel size in both men and women (P < 0.001). Men had larger brachial artery diameter than women (4.6 +/- 0.7 vs. 3.6 +/- 0.4 mm, P < 0.001). There was no difference in FMD or in NTG-induced dilatation in the women receiving oral oestrogen replacement therapy compared with those that did not. The women taking oral oestrogen had lower cholesterol than those not taking oral oestrogen (P=0.04). FMD was not correlated with any of the risk factors. NTG-induced vasodilatation was correlated with the body mass index (BMI) in men (P=0.01) and a combined risk factor score in women (P=0.04). There was a large increase in the number of subjects with cardiovascular risk factors in the 55-year-old men and women compared with the 35-year-olds. The distribution of risk factors was fairly equal amongst men and women. CONCLUSION: There are no correlations between any of the conventional cardiovascular risk factors and FMD in a population of 55-year-olds, but there is a high prevalence of risk factors in the 55-year-old age group. NTG-induced vasodilatation correlated with the BMI in men and a combined risk-factor score in women. FMD-induced vasodilatation is smaller in women at 55 years of age than at 35 years of age. FMD was similar in men at 35 and 55 years of age and in men and women at 55 years of age. The smaller FMD in women at 55 years of age, compared with at 35, could be due to postmenopausal hormonal changes.     

Effect of a six-month treatment with lanreotide on cardiovascular risk factors and arterial intima-media thickness in patients with acromegaly

OBJECTIVE: To evaluate the effect of a 6-month treatment with slow-release lanreotide (LAN) on cardiovascular risk and atherosclerosis in 24 normotensive patients with active acromegaly (GH=67.4 +/- 12.6 mU/l, IGF--I=866.0 +/- 55.8 microg/l) and 24 healthy subjects sex-, age- and body mass index-matched with the patients (as controls). DESIGN: Open, prospective, multicenter. METHODS: The following were measured before and after 6 months of LAN treatment (dose 60-90 mg/month): fasting GH, IGF-I, LDL, HDL and total cholesterol, triglyceride, glucose, glycosylated hemoglobin, insulin and fibrinogen levels, intima-media thickness (IMT) and blood systolic and diastolic peak velocity (SPV and DPV respectively) in both common carotids. RESULTS: At study entry, insulin, total and LDL cholesterol, triglyceride and fibrinogen levels were higher while HDL cholesterol levels were lower in patients than in controls. At the right (0.88 +/- 0.04 vs 0.77 +/- 0.03 mm, P=0.05) and left (0.93 +/- 0.03 vs 0.78 +/- 0.02 mm, P=0.01) common carotid IMT was significantly higher in patients than in controls; 12 patients and two controls showed an IMT of > or = 1 mm (chi(2)=8.2, P=0.004). After 6 months of LAN treatment, disease control was achieved in 15 patients (62.5%). Insulin, triglyceride and fibrinogen levels were significantly decreased, and a trend toward a decrease of IMT in the right (from 0.90 +/- 0.05 to 0.78 +/- 0.04 mm, P=0.06) and left (from 0.95 +/- 0.04 to 0.84 +/- 0.04 mm, P=0.06) common carotid arteries was observed only in patients with disease control, while SPV and DPV did not change. CONCLUSIONS: LAN treatment for 6 months significantly lowered GH, IGF-I, insulin and fibrinogen levels and reduced IMT of both common carotid arteries in normotensive patients with acromegaly.