Platelet dysfunction in lean women with polycystic ovary syndrome and association with insulin sensitivity

Platelet dysfunction and its association with insulin resistance and/or hyperandrogenemia were evaluated in 50 women with polycystic ovary syndrome (PCOS), 50 women with non-classic congenital adrenal hyperplasia (NC-CAH), and 30 women in the control group. Agonist-induced platelet aggregation was measured. Women with PCOS had significantly higher levels of platelet aggregations induced by ADP (77.4 +/- 3.3 vs. 67.3 +/- 2.8), collagen (79.7 +/- 1.8 vs. 69.1 +/- 3.9), and epinephrine (84.7 +/- 2.6 vs. 67.8 +/- 3.8), compared with controls. However platelet aggregations of women with NC-CAH because of ADP (68.2 +/- 4.22), collagen (69.5 +/- 5.4), or epinephrine (68.6 +/- 4.3) were similar to those in the control group. There were negative correlations between aggregations induced by agonists and the insulin sensitivity in women with PCOS. These correlations also appeared significant after androgen levels with covariance analysis were excluded. These covariance analyses were performed because serum androgen levels might affect platelet function. Any significant correlations were not found between androgen levels and agonist-induced platelet aggregation in women with NC-CAH. We conclude that platelet dysfunction may be an important reason for the possible cardiovascular heart diseases in women with PCOS.     

Oral challenge with a methionine load in patients with inflammatory bowel disease: a better test to identify hyperhomocysteinemia

BACKGROUND: Patients with inflammatory bowel disease have an increased risk of thrombosis. Hyperhomocysteinemia is one of the factors that have been related to thromboembolic complications. Patients with hyperhomocysteinemia and normal fasting homocysteine levels can be identified with an oral methionine load. We studied homocysteine levels in patients with IBD during fasting and after methionine load to determine the true prevalence of hyperhomocysteinemia and its relation with thrombotic events. METHODS: Prospective analysis of homocysteine levels in consecutive patients with IBD during fasting and 6-8 hours after an oral methionine load. Levels of folate and vitamin B12 were also determined. History of thrombotic events were recorded. RESULTS: Eighty-two patients with IBD, 56 with UC and 26 with CD were included. Eighteen patients (22%) had hyperhomocysteinemia during fasting. Mean levels of homocysteine after methionine load were 20.4 +/- 18.1 micromol/l (range, 1-79.7 micromol/l), and 43 patients (52%) had hyperhomocysteinemia (> or =20 micromol/l) after methionine load. Six patients (7.3%) had history of thrombosis. The homocysteine levels during fasting and after methionine load were significantly higher in patients with thrombotic events than in patients without thrombosis (15.5 +/- 3.7 micromol/l vs. 6.6 +/- 6.5 micromol/l; P = 0.002; 44.5 +/- 20.9 micromol/l vs. 18.4 +/- 16.5 micromol/l; P < 0.001, respectively). CONCLUSIONS: There is a higher prevalence of hyperhomocysteinemia in IBD patients than previously thought, this can be identified with an oral challenge of a methionine load. Hyperhomocysteinemia increases the risk of thromboembolic complications in patients with IBD.     

Unravelling the phenotypic map of polycystic ovary syndrome (PCOS): a prospective study of 634 women with PCOS

BACKGROUND: The phenotypic spectrum of PCOS has been broadened but the prevalence and clinical significance of PCOS phenotypes continue to challenge the scientific community. OBJECTIVE: Analysis of the phenotypic spectrum of PCOS and determination of the association between metabolic, hormonal and new ultrasonographic criteria. DESIGN: Clinical prospective study. PATIENTS: Six hundred and thirty-four women with PCOS (18-35 years) and comparable body mass index (BMI), diagnosed by ESHRE/ASRM criteria, were categorized into two major groups of phenotypes: classic (NIH) and nonclassic (ESHRE/ASRM), and then subdivided into phenotypes with all possible combinations of diagnostic characteristics. One hundred and eight healthy women of reproductive age, matched for BMI, were recruited as the control group. MEASUREMENTS: Ultrasonographic (ovarian follicle number and volume), hormonal and metabolic parameters. RESULTS: Classic PCOS phenotype was more frequent (85.96%) than the nonclassic phenotype (14.04%). The patients were also classified according to the presence of biochemical (80.60%) or clinical hyperandrogenaemia (12.62%), and, in the newly introduced group, to absence of evidence of hyperandrogenaemia (6.78%). Subjects with classic PCOS with biochemical hyperandrogenaemia (74.76%) were more insulin resistant than controls. In women with PCOS, follicle number was positively related to both insulin resistance and biochemical hyperandrogenaemia. Additionally, women with PCOS had a 6.58-fold increased relative risk (RR) of > 12 follicles on intravaginal ultrasound and a 2.94-fold increased RR of ovarian volume > 10 cm(3) compared to controls. CONCLUSION: The most frequent PCOS phenotype is the subgroup with biochemical hyperandrogenaemia only within the classic phenotype, which is more insulin resistant than the control group. The follicle number, a newly introduced ultrasonographic marker, is related to both metabolic and hormonal features of PCOS.     

Correlation of plasma insulin and insulin-like growth factor-I with indices of androgen transport and metabolism in women with polycystic ovary syndrome

OBJECTIVE: Polycystic ovary syndrome (PCOS) is said to be associated with hyperinsulinaemia. Insulin stimulates androgen production by ovarian tissue in vitro and previous studies have identified a positive correlation of insulin with androstenedione. The aim of the present study was to discover whether insulin levels correlate with clinical presentation and with markers of androgen transport and metabolism in women with PCOS. DESIGN: Within-group analysis of clinical and biochemical characteristics of a consecutive series of women with PCOS, focusing on correlations of plasma insulin with clinical presentation and androgens. Insulin levels were also compared with a control group of normal women. PATIENTS: Forty-seven women who presented with hirsutism, cycle abnormalities or both, with ultrasound proven PCOS, were recruited. Mean age was 26.6 +/- 0.7 years (mean +/- SEM), BMI 27.3 +/- 1.2 kg/m2. MEASUREMENTS: Plasma insulin levels were measured at 30-minute intervals for 3 hours following a 75 g glucose load. Blood was also taken for measurement of testosterone (T), androstenedione (A), free testosterone (fT), sex hormone binding globulin (SHBG) and insulin-like growth factor-I (IGF-I). Androsterone glucoronide (AG), a marker of peripheral androgen metabolism, was also measured. RESULTS: Neither basal insulin nor the sum of insulin measurements during the glucose tolerance test (sumINS) in women with PCOS were significantly different from a control group with normal ovaries. Within the PCOS group, basal insulin was greater in women with irregular cycles or amenorrhoea than in those with regular ovulatory menses (8.0 +/- 1.1 vs 3.1 +/- 1.5 mU/l, P less than 0.01) despite similarly raised androgen levels. Both basal insulin and sumINS correlated with BMI in women with PCO (r = 0.37, P less than 0.05 and r = 0.64, P less than 0.01 respectively) but not in controls. There was no significant correlation between insulin or IGF-I levels and T, A or AG despite a positive correlation of AG (but no other androgen) with BMI. SHBG showed an inverse correlation and fT correlated positively with sumINS (r = -0.51, P less than 0.01; r = 0.39, P less than 0.05). Regression analysis of each of the androgens on the other variables demonstrated no significant relationship between insulin and androgens. CONCLUSIONS: These data suggest that, in vivo, the major effect of insulin on androgen secretion is mediated by changes in SHBG rather than by direct stimulation of ovarian androgen production. Higher insulin concentrations in anovulatory compared with ovulatory women with hyperandrogenaemia may indicate that insulin resistance in the ovary contributes to the mechanism of anovulation in PCOS.     

在育龄期不孕的高雄激素血症女性中筛查先天性肾上腺皮质增生症

目的致不孕的原因复杂多样,在不孕原因的筛查中,先天性肾上腺皮质增生症(CAH)常被忽视。本研究在育龄期不孕的高雄激素血症女性中筛查CAH,并探讨拟妊娠女性CAH的诊治。方法纳入2016年12月至2019年4月因"不孕"就诊于南京医科大学第一附属医院生殖医学中心后转诊至内分泌科的育龄期高雄激素血症女性20例。完善血激素水平、糖脂代谢指标的检测,并行ACTH兴奋试验、子宫及双侧卵巢B超、肾上腺计算机断层扫描(CT)等检查,必要时行基因测序。结果20例不孕的高雄激素血症女性中CAH 7例(35.0%),其中基因测序确诊21-羟化酶缺陷症(21-OHD)6例、多囊卵巢综合征(PCOS)10例、特发性高雄激素血症(IHA)3例。性激素结果显示,CAH组睾酮水平显著高于PCOS组、IHA组[(4.4±2.0对2.9±0.4,2.8±0.8)nmol/L,P<0.05];ACTH兴奋试验结果显示,CAH组基础17-羟孕酮(17-OHP)显著高于PCOS组[(101.0±100.8对1.4±0.8)ng/ml,P<0.05],而与IHA组相比差异无统计学意义[(101.0±100.8对3.0±1.8)ng/ml,P>0.05];CAH组60 min 17-OHP显著高于PCOS组、IHA组[(200.1±80.8对3.1±1.2,3.4±0.2)ng/ml,P<0.05]。给予CAH患者糖皮质激素治疗后,4例成功妊娠并分娩。随访已分娩患者的后代,均未发现CAH临床症状及外生殖器畸形。结论ACTH兴奋试验在CAH特别是21-OHD的鉴别诊断中具有重要意义,基因检测有助于进一步明确CAH的突变类型。糖皮质激素治疗可提高CAH患者的妊娠率,也有助于降低母体高雄激素状态、避免女性后代出现男性化表现。     

Plasma homocysteine concentrations in young individuals at increased risk of type 2 diabetes are associated with subtle differences in glomerular filtration rate but not with insulin resistance.

Plasma homocysteine levels are elevated in individuals with type 2 diabetes contributing to the increased cardiovascular risk of these patients. As insulin resistance is a key feature in type 2 diabetic patients, hyperhomocysteinemia might be a consequence of insulin resistance. We studied this hypothesis in 839 individuals(male: 302, female: 537, mean age: 37.5 years) with a higher prevalence of insulin resistance (positive family history of type 2 diabetes, history of gestational diabetes, overweight). Subjects with overt type 2 diabetes or known kidney disease were excluded from the study. Mean plasma homocysteine concentration was 8.9 micromol/l (95% RCI 4.8-14.9). Adjusted for age and sex we could not find a significant correlation between homocysteine levels and BMI, insulin levels, or the insulin sensitivity-index (r = 0.35; p = 0.48). Furthermore, after a successful lifestyle intervention resulting in a significant decrease in BMI, body fat content and improved insulin sensitivity (p < 0.0001 each) no differences in homocysteine concentrations could be achieved. However,in the cross-sectional analysis we found a significant and independent, negative correlation between glomerular filtration rate (GFR) and homocysteine levels (r = -0.37; p < 0.0001). In conclusion, our study did not reveal a significant association between levels of homocysteine and insulin resistance in a population with an increased risk for type 2 diabetes. However, plasma homocysteine levels were related to subtle differences in kidney function at this early stage.     

A comparison between the effects of low dose (1 microg) and standard dose (250 microg) ACTH stimulation tests on adrenal P450c17alpha enzyme activity in women with polycystic ovary syndrome

OBJECTIVE: Numerous studies have found elevated androgen production by the adrenal glands in patients with polycystic ovary syndrome (PCOS). However, the role and the mechanisms responsible for the adrenal androgen excess in women with PCOS are not well understood. DESIGN: Our aim was to compare 17-hydroxyprogesterone (17-OHP), androstenedione, dehydroepiandrosterone sulfate (DHEAS) and cortisol responses to a low dose (1 microg) ACTH stimulation test (LDT) with the responses to a standard dose (250 microg) ACTH stimulation test (SDT) in patients with PCOS. METHODS: Fifty women with PCOS (mean age 25.4+/-0.7 years) and 20 healthy women (mean age 27.3+/-2.2 years) were included in the study. The patients and controls underwent ACTH stimulation tests with 1 microg and 250 microg synthetic ACTH in the follicular phase of their cycles. Venous blood was drawn at 0, 30 and 60 min for determination of serum cortisol, 17-OHP, androstenedione and DHEAS levels. RESULTS: In PCOS subjects, peak and area under the curve (AUC) 17-OHP (9.3+/-0.3 nmol/l, 378.4+/-61 nmol/lx60 min), androstenedione (15.6+/-0.6 nmol/l, 806.4+/-52 nmol/lx60 min) and DHEAS (7.5+/-0.4 micromol/l, 385.6+/-25.5 micromol/lx60 min) responses to SDT were significantly higher than the levels in healthy women (respectively 5.7+/-0.3 nmol/l and 249.4+/-52.2 nmol/lx60 min for 17-OHP; 9.1+/-0.3 nmol/l and 413.7+/-31.6 nmol/lx60 min for androstenedione; 4.3+/-0.4 micromol/l and 224.9+/-24.5 micromol/lx60 min for DHEAS) (P<0.05). Peak and AUC cortisol responses to SDT were similar in PCOS and control subjects. Peak and AUC cortisol and 17-OHP responses to LDT in women with PCOS were similar to the values obtained in healthy women. Peak androstenedione (12.5+/-0.6 nmol/l) and peak (6.5+/-0.5 nmol/l) and AUC (336.3+/-22.4 micromol/lx60 min) DHEAS responses to LDT were significantly higher in women with PCOS. CONCLUSIONS: These results show that LDT is capable of revealing the adrenal hyperactivity in women with PCOS. Adrenal P450c17alpha enzyme dysregulation in PCOS is revealed by ACTH stimulation at a pharmacological dose (250 microg) but not by a physiological dose (1 microg). LDT is able to demonstrate adrenal hyperactivity characterized by an increase in DHEAS levels.     

Endothelial dysfunction in young women with polycystic ovary syndrome: relationship with insulin resistance and low-grade chronic inflammation

Women with polycystic ovary syndrome (PCOS) carry a number of cardiovascular risk factors. Cardiovascular morbidity is elevated even in young women with PCOS. Low-grade chronic inflammation, reflected in elevated levels of serum C-reactive protein (CRP) and endothelial dysfunction have recently been linked to development of atherosclerosis. We compared high-sensitivity (hs)CRP concentrations and endothelium dysfunction in 37 women with PCOS and 25 control subjects matched as a group for age and body mass index (BMI). Arterial endothelium and smooth muscle function was measured by examining brachial artery responses to endothelium-dependent and endothelium-independent stimuli.Serum LH, testosterone, androstenedione, and fasting insulin levels were significantly higher in the PCOS group than the control group. The PCOS group was more insulin resistant than age- and BMI-matched control women. CRP concentrations were higher in PCOS women than the healthy control group (0.25 vs. 0.09 mg/dl). hsCRP concentrations were correlated with BMI, insulin sensitivity indices (homeostasis model assessment and quantitative insulin sensitivity check index), and endothelium-dependent vasodilation. The groups were well matched for baseline brachial artery diameter. There was a significant difference in endothelium-dependent (flow- mediated dilation) and endothelium-independent (sublingual nitroglycerin) vascular responses between the women with PCOS and the normal healthy control group (P = 0.002 and P = 0.01, respectively). Endothelium-dependent vasodilation was correlated with hsCRP concentrations and insulin resistance.In conclusion, this study is the first to demonstrate increased levels of hsCRP, endothelial dysfunction, and the relation with insulin resistance in young and normal-weight women with PCOS. Clinical strategies aimed at reducing insulin resistance may prevent early atherosclerosis in women with PCOS.     

Insulin resistance and endothelial function are improved after folate and vitamin B12 therapy in patients with metabolic syndrome: relationship between homocysteine levels and hyperinsulinemia

OBJECTIVE: The purpose of this study was (a) to study whether a folate and vitamin B12 treatment, aimed at decreasing homocysteine levels, might ameliorate insulin resistance and endothelial dysfunction in patients with metabolic syndrome according to the National Cholesterol Education Program-Adult Treatment Panel-III criteria and (b) to evaluate whether, under these metabolic conditions, there is a relationship between hyperhomocysteinemia and insulin resistance. DESIGN AND METHODS: A double-blind, parallel, identical placebo-drug, randomized study was performed for 2 months in 50 patients. Patients were randomly allocated to two groups. In group 1, patients were treated with diet plus placebo for 2 months. In group 2, patients were treated with diet plus placebo for 1 month, followed by diet plus folic acid (5 mg/day) plus vitamin B12 (500 microg/day) for another month. RESULTS: In group 2, folate treatment significantly decreased homocysteine levels by 27.8% (12.2+/-1.2 vs 8.8+/-0.7 micromol/l; P<0.01). A significant decrement was observed for insulin levels (19.9+/-1.7 vs 14.8+/-1.6 microU/ml; P<0.01) accompanied by a 27% reduction in the homeostasis model assessment levels. A positive relationship was found between the decrement of homocysteine and insulin levels (r=0.60; P<0.002). In parallel, endothelial dysfunction significantly improved in the treated group, since post-ischemic maximal hyperemic vasodilation increased by 29.8% and cGMP by 13.6% while asymmetrical dimethylarginine levels decreased by 21.7%. On the contrary, in group 1 patients, treated with placebo, no changes were shown in any of the variables. CONCLUSIONS: Folate and vitamin B12 treatment improved insulin resistance and endothelial dysfunction, along with decreasing homocysteine levels, in patients with metabolic syndrome, suggesting that folic acid has several beneficial effects on cardiovascular disease risk factors.     

Intimal hyperplasia following carotid endarterectomy in an insulin-resistant rat model

Hyperhomocysteinemia, a known risk factor for cardiovascular disease, results in an elevation of intimal hyperplasia (IH) following a carotid endarterectomy (CEA) in a rat model. An exaggerated IH response following CEA has been observed in rats with dietary induced hyperhomocysteinemia. Type 2 diabetics often present with hyperhomocysteinemia and are at higher risk for developing vascular blockage following surgical procedures. To determine if insulin resistance increases IH risks following endarterectomy, the 3 goals of this study were: (1) to establish plasma homocysteine concentrations in dietary induced insulin-resistant rats and their controls, (2) to investigate whether a positive correlation of IH and plasma homocysteine response occurs following CEA in the insulin-resistant rat model, and (3) if so, to attempt to decrease IH by supplementation with folic acid, a known enzymatic cofactor in the homocysteine metabolic pathway. To achieve these aims, male rats (275 to 300 g) were fed 1 of 4 diets for a 4-month period: (1) high-fat sucrose (HFS), (2) low-fat complex carbohydrate (LFCC), (3) HFS + 25 mg/kg folic acid (HFS+F), or (4) LFCC + 25 mg/kg folic acid (LFCC+F). At the end of the 4-month period the rats underwent an open (non-balloon) unilateral CEA. Two weeks post-endarterectomy, blood, liver and carotid tissue were removed to measure plasma insulin, folic acid, and homocysteine, 2 key enzymes of homocysteine metabolism-methylenetetrahydrofolate reductase (MTHFR) and cystathionine beta-synthase (CBS)-and percent lumenal stenosis (IH%). Computer-assisted morphometric analysis was used to measure the percentage of IH in the carotid artery. Plasma homocysteine was significantly higher in the HFS group when compared with the LFCC group (11.3+/-1.3 micromol/L v 7.4+/-0.6 mircomol/L, P=.008) as was post-endarterectomy IH producing lumenal stenosis (30.7%+/-4.2% v 14.0%+/-4.3%, P=.008). Plasma insulin in the HFS group was higher than the LFCC (control) group and was significant (36.3+/-3.0 microU/mL v 21.1+/-0.8 microU/mL, P=.0004). Folic acid supplementation in the HFS group resulted in reductions of plasma homocysteine (HFS v HFS+F, 11.3+/-1.3 micromol/L v 7.95+/-1.0 micromol/L, P=.02) and post-endarterectomy IH (HFS v HFS+F, 30.7%+/-4.2 % v 10.4%+/-1.6%, P=.0001). The control or LFCC group was not statistically different from the HFS+F group in homocysteine or IH. Folate supplementation did not decrease insulin concentrations in the HFS+F group compared to the LFCC group. We conclude that the HFS diet produced an insulin-resistant state with an elevated plasma homocysteine and an exaggerated IH response following carotid endarterectomy in this rat model. Dietary folate supplementation reduced plasma homocysteine concentrations in the HFS diet, which implicates hyperhomocysteinemia as an etiologic factor in the development of post-CEA IH in this insulin-resistant rat model.     

Relative impact of insulin resistance and obesity on cardiovascular risk factors in polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) affects 5% to 7% of women of reproductive age. Insulin resistance and obesity are components of this important syndrome that may contribute to excess cardiovascular risk. We analyzed data from 69 patients with PCOS who had undergone quantitative assessment of insulin sensitivity, blood pressure, lipid profiles, and androgen levels to determine the impact of insulin resistance and obesity on parameters of cardiovascular risk. Homeostasis model assessment (HOMA) was used to stratify patients in terms of insulin resistance. To obtain a reference population, we used data from the National Health and Nutrition Examination Study (NHANES III, 1988 to 1994). The most insulin-resistant tertile of patients exhibited higher body mass index (BMI), androgen levels, systolic and diastolic blood pressure (DBP), triglyceride (TG) levels, and decreased high-density lipoprotein cholesterol (HDL-C) levels. Insulin resistance, not BMI, was the main determinant of HDL-C and TG levels and systolic blood pressure (SBP) in PCOS. Among normal women, both BMI and insulin resistance influenced cardiovascular risk factors. Insulin resistance was a more significant predictor of TGs in women with PCOS than in normal women (P =.008). In contrast to normal women, insulin resistance in PCOS appears to be the prime determinant of abnormal lipids, blood pressure, and androgens. Thus, early detection of insulin resistance, as well as weight reduction, should be emphasized for all patients with PCOS.     

Beta blocker effects on plasma homocysteine levels in patients with hypertension

Recent studies have shown that hyperhomocysteinemia might play a role in the pathogenesis of hypertension. The effects of antihypertensive agents on plasma homocysteine levels have not been tested extensively. We investigated the effects of beta-blocker therapy on homocysteine levels in patients with hypertension. In the study, 120 patients with newly diagnosed hypertension were enrolled. All patients received metoprolol succinate 100 mg/day initially. If blood pressure was above normal on the 15th day of follow-up, the metoprolol dosage was doubled. Before initiation of the antihypertensive medication and after the fourth month of treatment, homocysteine levels were measured. Of the 120 patients enrolled, 39 could not complete the study. Homocysteine levels decreased significantly by the end of the fourth month when compared with basal values (13.5+/-4.5 micromol/l versus 12.4+/-4.9 micromol/l; P = 0.001). There was no relation between homocysteine level and blood pressure control. There was a significant decrease in homocysteine levels in the women treated in this study (P = 0.001); however, this effect was absent in men (P = 0.185). We demonstrate that metoprolol succinate treatment significantly decreases plasma homocysteine levels in patients with hypertension, especially in women.     

Phenotypic characteristics according to insulin sensitivity in non-obese Korean women with polycystic ovary syndrome

Over 50% of women with polycystic ovary syndrome (PCOS) have been reported to have varying degree of insulin resistance and it may contribute to hyperandrogenism. The aim of the study is to identify whether the insulin resistance is present in non-obese Korean women with PCOS and whether the phenotype is different according to insulin sensitivity. Seventy-three non-obese (BMI<23 kg/m(2)) women with PCOS and 34 age and BMI comparable control women with regular menstrual cycles were examined. Standard 75 g OGTT was performed to determine the status of glucose tolerance. Insulin sensitivity was measured by euglycemic hyperinsulinemic clamp technique. The fasting plasma glucose (p<0.01) and post-glucose load plasma insulin (p<0.01) of women with PCOS were higher than those of controls. Glucose disposal rate (M-value) was lower in women with PCOS compared to controls (p<0.05). Insulin resistant (IR) and insulin sensitive (IS) PCOS were divided by the M-value of 25-percentile (5.5mg/kg min) in controls. Between IR and IS groups, DHEAS (p<0.01), post-glucose load plasma insulin (p<0.05) showed differences after the adjustment for BMI. Our non-obese women with PCOS showed significant insulin resistance compared to their age and BMI comparable control subjects and their insulin resistance may contribute to hyperandrogenism especially via adrenal androgen overproduction.     

Hyperhomocysteinemia in patients with heart failure referred for cardiac transplantation: preliminary observations

BACKGROUND: Hyperhomocysteinemia is becoming recognized as a risk factor for cardiovascular disease, yet there are limited data on the prevalence of hyperhomocysteinemia in patients with heart failure. HYPOTHESIS: The purpose of this study was to examine the prevalence of hyperhomocysteinemia in patients with severe heart failure and to correlate serum homocysteine levels with factors that may affect homocysteine metabolism. METHODS: Serum homocysteine levels were measured at the time of cardiac transplant evaluation in 89 consecutive patients with severe heart failure. Homocysteine levels for patients with ischemic cardiomyopathy (ICM) were compared with levels obtained in patients with nonischemic cardiomyopathy (NICM), and homocysteine levels were correlated with demographic and hemodynamic parameters as well as functional status. RESULTS: The mean plasma homocysteine level was increased (14.3 +/- 5.3 micromol/l, normal <9.0 micromol/l) and was equivalent between patients with ICM versus NICM (14.7 +/- 5.8 micromol/l vs. 13.8 +/- 4.5 micromol/l, p = 0.44). Elevated homocysteine levels were seen in a large proportion (89%) of patients and were equally common to patients with NICM (94%) and ICM (85%). Serum homocysteine levels correlated with serum creatinine (r = 0.51, p < 0.001), with a history of diabetes (p = 0.028), and with a history of peripheral vascular disease (p = 0.045). Only 6% of patients were receiving folic acid therapy at the time of transplant referral. CONCLUSION: Hyperhomocysteinemia is common in patients with severe heart failure, and plasma homocysteine levels are uniformly elevated regardless of the etiology of heart failure. Elevated plasma homocysteine levels are likely a consequence of heart failure-related renal insufficiency.     

Androgen response to endogenous insulin secretion during the frequently sampled intravenous glucose tolerance test in normal and hyperandrogenic women

Women with ovarian hyperandrogenism frequently have insulin resistance, whose underlying mechanism remains to be determined. In the present study we have investigated the relationship between insulin sensitivity and the acute effect of endogenous insulin secretion on circulating androgen levels. Insulin sensitivity, glucose-mediated insulin release, and glucose/insulin-stimulated androgen responses were determined during a frequently sampled iv glucose tolerance test in a group of 19 women with clinical evidence of polycystic ovary syndrome (PCOS) and 9 age- and weight-matched controls. Insulin (I), glucose, androstenedione, testosterone (T), free T, and dehydroepiandrosterone (DHEA) levels were measured before and during the 3 h following iv administration of glucose (300 mg/kg). Intravenous tolbutamide (300-500 mg) was injected 20 min after the glucose injection. Insulin sensitivity (SI) was calculated by application of the minimal model of glucose kinetics. Fasting androstenedione, T, free T, and I concentrations were significantly higher in the women with PCOS than in controls (P less than 0.02). In PCOS subjects, fasting I was correlated with both T (r = 0.51; P less than 0.05) and DHEA (r = 0.706; P less than 0.01). SI was significantly lower in PCOS subjects [SI, 68.35 +/- 8.34 min-1/(nmol/mL] than in control subjects (SI, 133.36 +/- 21.7 min-1/(nmol/mL)]. A significant decline in DHEA levels was observed in control subjects 3 h after glucose administration (from 28.4 +/- 3.0; final, 16.2 +/- 2.4; P less than 0.02). PCOS women with normal insulin sensitivity [SI, greater than 75.0 min-1/(nmol/mL)] showed a similar fall in DHEA (from 20.3 +/- 2.5 to 12.8 +/- 1.8 nmol/L; P less than 0.02). No significant change occurred in insulin-resistant PCOS subjects [SI, less than 75.0 min-1/(nmol/mL)]. Other androgen levels showed a modest nonsignificant decline during the study in PCOS and control groups. These findings confirm the weight-independent insulin resistance of some hyperandrogenic women. The failure of glucose-stimulated endogenous insulin secretion to significantly depress DHEA levels in insulin-resistant women with PCOS may account in part for their androgen excess.     

Is hyperprolactinemia associated with insulin resistance in non-obese patients with polycystic ovary syndrome?

Insulin resistance is common in polycystic ovary syndrome (PCOS). Moderate elevations in serum PRL concentration may contribute to insulin resistance in PCOS. The aim of this study was to determine PRL on development of insulin resistance in non-obese hyperprolactinemic patients with PCOS. Ninety-eight non-obese subjects with PCOS and 100 non-obese healthy control were accepted in the study. Serum glucose, lipids, androgens, free androgen index (FAI), gonadotropins, fat mass and percentage, SHBG, and insulin levels were measured. Homeostasis model assessment (HOMA) was used as index of pancreatic beta-cell function and tissue insulin sensitivity. Independent t-test was used in comparison of results. In patients with PCOS, FAI and mean HOMA-(%B) level were higher than in the control group (p<0.0001), whereas mean HOMA-(%S) in subjects with PCOS was lower than in the control group (p<0.0001). Patients with PCOS were divided into subgroups according to their serum prolactin level (< 24 or > or = 24 ng/ml). Although FAI was not different, mean insulin and HOMA-(%B) levels in hyperprolactinemic patients were higher than in normoprolactinemic subjects (p<0.001). HOMA-(%S) in hyperprolactinemic patients with PCOS was lower than in normoprolactinemic patients (p<0.002). In conclusion, PCOS is associated with insulin resistance; non-obese hyperprolactinemic PCOS patients may be more insulin-resistant than normoprolactinemics and there may be an association between hyperprolactinemia and insulin resistance in PCOS.     

Hyperhomocysteinemia in women with advanced breast cancer

Patients with malignancy have an increased risk of venous thromboembolic disease but the pathophysiology of this association has not been precisely defined. Hyperhomocysteinemia has become established as one of the commonest conditions associated with venous and arterial thrombosis. We examined the prevalence of hyperhomocysteinemia in women with early (group A, n = 31), metastatic breast cancer (group B, n = 41) and in a group of healthy females (group C, n = 29). Blood samples were collected at diagnosis or prior to treatment. We measured both total plasma homocysteine (tHcy) and red cell folate (RCF). The Mean (SD) tHcy were group A - 9.43 micromol/l (5.6), group B - 11.34 micromol/l (5.1) and group C - 7.9 micromol/l (1.5). A total of 39% of patients with metastatic and 22.6% with early breast cancer had tHcy concentrations above the upper limit of normal. Women with metastatic disease had significantly higher tHcy compared with controls (P < 0.01) but not when compared with women with early breast cancer. Also, no difference was observed when women with early disease were compared with controls. We found no correlation between age and tHcy. Lower RCF levels were identified in group B compared with group A, but this does not fully explain the increased tHcy levels seen within the same group. We conclude that hyperhomocysteinemia is common in women with advanced breast cancer. This observation could explain the high rate of venous thrombosis in women with metastatic breast malignancy.     

The effects of metformin on metabolic and cardiovascular risk factors in nonobese women with polycystic ovary syndrome

Objective There are conflicting data regarding the effects of metformin in lean women with polycystic ovary syndrome (PCOS). Thus, our aim was to evaluate the effects of 6 months of metformin therapy on various metabolic and cardiovascular risk factors in lean women with PCOS. Design This was a prospective clinical study performed in a University hospital. Patients Twenty nonobese PCOS women and 20 age‐ and BMI‐matched healthy women were included in the study. Metformin (2550 mg/day) was administered for 6 months in women with PCOS. The hormonal and metabolic parameters were evaluated before and after metformin treatment. Measurements The main outcome measures were serum androgens, FSH, LH, oestradiol, 17‐hydroxyprogesterone, glucose, insulin, lipid profile, lipoprotein(a) [Lp(a)] and homocysteine levels. In addition 24‐h ambulatory blood pressure monitoring (ABPM) and carotid intima‐media thickness (IMT) were taken. Results After 6 months of metformin therapy, women with PCOS had decreased LH, total testosterone, free androgen index and slightly increased SHBG levels. Metformin treatment resulted in resumption of regular menses in 12 (60%) patients, and in 8 (40%) of them serum progesterone level was compatible with ovulation. Glucose and insulin responses to oral glucose tolerance test (OGTT) and homeostasis model assessment of insulin resistance (HOMA‐IR) did not improve after the metformin therapy. There were no significant changes in terms of cardiovascular risk factors such as lipids and homocysteine, IMT and ABPM. Conclusion Metformin may have beneficial effects in lean PCOS women in terms of resumption of menses without any remarkable effect on metabolic and cardiovascular risk factors.     

Role of homocysteine for thromboembolic complication in patients with non-valvular atrial fibrilation.

Thromboembolism is the most important complication in patients with atrial fibrilation (AF). Homocysteine is a toxic amino acid that has been recently accepted as a risk factor for atherosclerosis and stroke. The aim of the present study is to show whether there is a relation between hyperhomocysteinemia and thromboembolic complications in patients with non-valvular AF. We admitted 38 patients with non-valvular AF. The patients were divided into two groups: group A (n = 20; mean age, 75.7 +/- 10.4 years; three males/17 females), and group B (n = 18; mean age, 68.0 +/- 10.6 years; 11 males/seven females). While group A consisted of the patients with AF and stroke, group B was composed of the patients with AF but without stroke. The patients having sinus rhythm (15 subjects) were used as the reference group to obtain the cut-off value. Homocysteine was measured by the immunoassay method. The means of the homocysteine levels were 12.4 +/- 3.3 micromol/l in group A, 8.3 +/- 2.3 micromol/l in group B and 9.3 +/- 1.8 micromol/l in the reference group. The cut-off value was 10.6 micromol/l. Group A had a statistically higher homocysteine level than not only group B, but also the reference group (P < 0.05). While 60% of group A (n = 12) had the elevated homocysteine level, the rate was only 22% for group B (n = 4). In conclusion, hyperhomocysteinemia may be one of the explanations for the increased rate of thromboembolic complications in older patients with AF.     

Relationship between homocysteine and insulin resistance in women with polycystic ovary syndrome

Hyperhomocysteinemia is a risk factor for atherosclerotic vascular diseases. It is known that plasma homocysteine levels are higher in polycystic ovary syndrome (PCOS) patients than in healthy subjects. The aim of our study was to determine the relationship between plasma homocysteine level and insulin resistance in women with PCOS. Twenty-nine patients (age, 23.90 +/- 5.86 years) and twenty-five healthy subjects (age, 25.24 +/- 4.28 years) were involved in the study. Plasma levels of fasting insulin, glucose, homocysteine, FSH, and LH levels were measured. A statistically significant difference in plasma concentrations of HOMA index, homocysteine, basal insulin levels and LH/FSH ratios was observed between groups (P = 0.001, P = 0.001, P = 0.001, and P = 0.01, respectively). There was no relationship between Hcy and the other variables. In multiple logistic regression analysis, age, BMI and insulin resistance were not predictors of Hcy.