Homocysteine-lowering treatment: an overview

Elevated fasting plasma concentrations of homocysteine have a high prevalence in subjects with cardiovascular disease and have also been associated with an increased risk of atherothrombosis in most, but not all, prospective studies. The most frequent causes of hyperhomocysteinaemia are genetic defects, such as cystathionine-beta-synthase (CBS) deficiency, deficiencies of folic acid and/or vitamin B12, renal failure and interference in homocysteine metabolism by drugs or metabolic alterations. In most cases, no underlying cause can be established. Subjects with CBS deficiency are treated with pyridoxine with additional folic acid and betaine if necessary. Folic acid and vitamin B12 deficiencies should be corrected by supplementation. Increases in folate intake by dietary changes or fortification can also lower plasma homocysteine in vitamin-replete subjects with normal plasma homocysteine levels. In renal failure, folic acid treatment (1-5 mg/day) ameliorates the plasma homocysteine level in most cases but hyperhomocysteinaemia persists in the majority of patients. Primary (fasting) hyperhomocysteinaemia can be treated with folic acid (0.5-5 mg/day). An abnormal methionine-loading test identifies additional patients at risk and postmethionine-loading hyperhomocysteinaemia should be treated with a combination of pyridoxine and folic acid. In the absence of dose-effect studies, a combination of pyridoxine (50 mg) and folic acid (5 mg) is advised. Large clinical trials are currently underway to establish the role of homocysteine-lowering therapy in the secondary prevention of atherothrombotic disease. In view of the effective, cheap and safe character of therapy with folic acid and pyridoxine, a policy can be accepted to screen and treat high-risk patients until these trials have been concluded.     

Therapeutic potential of total homocysteine-lowering drugs on cardiovascular disease

An elevated total homocysteine (tHcy) plasma concentration is associated with increased morbidity and mortality due to cardiovascular disease in the general population and in patients with impaired renal function. The prevalence of hyperhomocysteinaemia (plasma levels above 15 micromol/l) in the general population is less than 5% and can be as high as 50% in patients with vascular disease. In patients with renal insufficiency, elevated tHcy plasma levels are detected in 50 - 100% of the patients. Total homocysteine plasma levels can be lowered or normalised by folic acid and/or vitamin B(6) and vitamin B(12) supplementation. In patients with advanced chronic renal insufficiency or end-stage renal disease, hyperhomocysteinaemia is partially resistant to folic acid or vitamin therapy. However, higher tHcy plasma levels may also reflect tissue damage and the increase in Hcy after an acute incident such as stroke or myocardial infarction may be necessary for tissue repair mechanisms. This implies, that lowering tHcy may even be harmful to some patients. Currently, prospective studies are underway to clarify whether folate supplementation, with or without additional other vitamins, improves cardiovascular disease morbidity and mortality in the general population, as well as in renal failure patients. While population-wide screening for and treatment of hyperhomocysteinaemia is generally not recommended, treatment of high risk patients may be considered.     

Pharmacotherapy of hyperhomocysteinaemia in patients with thrombophilia

Hyperhomocysteinaemia is often the result of inherited abnormalities of the enzymes involved in homocysteine metabolism or vitamin deficiencies (vitamins B12, B6 or folate) and is present in approximately 5% of the general population. High homocysteine levels in these individuals are associated with a significant increase in relative risk for both arterial and venous thromboembolic disease. Consequently, effective homocysteine-lowering therapeutic strategies have been extensively investigated. Folic acid represents the cornerstone of treatment. In daily doses of at least 0.4 mg, it effectively reduces homocysteine levels, even in non-folate-deficient patients. The addition of vitamins B12 and/or B6, to folic acid supplementation may provide a small further reduction in homocysteine levels in certain groups of patients. Renal impairment is an important cause of hyperhomocysteinaemia. Individuals with hyperhomocysteinaemia secondary to renal disease commonly require significantly higher doses of folic acid (5-40 mg) to achieve maximal therapeutic effect. The important question of whether effective homocysteine-lowering therapy translates into a reduction in vascular disease remains unknown but is being addressed in a series of ongoing prospective trials.     

C-reactive protein and markers for thrombophilia in patients with chronic plaque psoriasis

Chronic plaque psoriasis is associated to an increased risk of cardiovascular events. The aim of our study is to test patients with psoriasis for common markers of acquired and inherited thrombophilia. A cross-sectional study on 172 patients with psoriasis and 198 controls was carried out. The plasma levels of coagulation protein C, coagulation protein S, homocysteine, folic acid, C-reactive protein (CRP) and fibrinogen as well as activated protein C resistance and antithrombin III activity, were measured. CRP and homocysteine levels were higher in patients with psoriasis than in controls (5.9 ± 7.1 vs 3.1 ± 2.4 mg/L, p=0.0003 and 16.3 ± 12.8 vs 10.4 ± 4.6 umol/L, p=0.0001; mean ± SD) whereas folic acid was lower in psoriatic patients compared to controls (4.3 ± 7.2 vs 12.6 ± 7.9 p=0.006). Levels of coagulation protein C, coagulation protein S, fibrinogen as well as activated protein C resistance, antithrombin III activity were within normal ranges both in cases and controls. In a multivariate regression analysis, psoriasis severity was an independent predictor of higher CRP. In conclusion, high levels of serum CRP and homocysteine were found in patients with psoriasis, related to the severity of the disease. These data suggest that the increased risk of thrombotic cardiovascular events observed in psoriasis patients should be ascribed to an acquired rather than inherited thrombophilic status.     

Therapeutic potential of total homocysteine-lowering drugs on cardiovascular disease

An elevated total homocysteine (tHcy) plasma concentration is associated with increased morbidity and mortality due to cardiovascular disease in the general population and in patients with impaired renal function. The prevalence of hyperhomocysteinaemia (plasma levels above 15 μmol/l) in the general population is less than 5% and can be as high as 50% in patients with vascular disease. In patients with renal insufficiency, elevated tHcy plasma levels are detected in 50 - 100% of the patients. Total homocysteine plasma levels can be lowered or normalised by folic acid and/or vitamin B₆ and vitamin B₁₂ supplementation. In patients with advanced chronic renal insufficiency or end-stage renal disease, hyperhomocysteinaemia is partially resistant to folic acid or vitamin therapy. However, higher tHcy plasma levels may also reflect tissue damage and the increase in Hcy after an acute incident such as stroke or myocardial infarction may be necessary for tissue repair mechanisms. This implies, that lowering tHcy may even be harmful to some patients. Currently, prospective studies are underway to clarify whether folate supplementation, with or without additional other vitamins, improves cardiovascular disease morbidity and mortality in the general population, as well as in renal failure patients. While population-wide screening for and treatment of hyperhomocysteinaemia is generally not recommended, treatment of high risk patients may be considered.     

冠心病患者血浆同型半胱氨酸与叶酸维生素B_(12)水平的相关性研究

目的　探讨冠心病 (CHD)患者血浆同型半胱氨酸 (Hcy)与叶酸、维生素 B1 2 浓度的变化及其相关性。方法　选择 76例经冠状动脉造影术证实为冠心病的患者 ,应用荧光偏振免疫分析法 (FPIA)测定血浆 Hcy浓度 ,离子捕获免疫分析法 (ICIA)测定血清叶酸浓度 ,非均相微粒子酶免疫分析法 (MEIA)测定血清维生素 B1 2 浓度。结果　冠心病患者血浆 Hcy浓度与正常对照组比较显著增高 (P<0 .0 0 1) ,而叶酸、维生素 B1 2 浓度则显著降低 (P<0 .0 0 1) ,以上两种变化呈负相关 (P<0 .0 0 1)。结论　高同型半胱氨酸血症是冠心病的新的独立危险因素 ,叶酸、维生素 B1 2 缺乏可能是诱发高 Hcy的重要因素。     

Fenofibrate-induced hyperhomocysteinaemia: clinical implications and management.

Fenofibrate is among the drugs of choice for treatment of hypertriglyceridaemia and low levels of high-density lipoprotein (HDL)-cholesterol, both recognised as risk factors for cardiovascular disease. Recently, a number of studies have shown an elevation of homocysteine levels with fenofibrate or bezafibrate therapy. Homocysteine is an atherogenic amino acid derived from the methionine cycle. At present, the underlying mechanism for this elevation has not been elucidated. While deterioration of vitamin status does not seem to be involved, impairment of renal function or changes in creatine metabolism are regarded as probable mechanisms. In patients not receiving lipid-lowering drugs, vitamin supplementation with folic acid and vitamin B12 effectively reduces the plasma homocysteine level. Two studies have shown that addition of folic acid or a vitamin combination to fenofibrate prevented most of the homocysteine increase associated with fenofibrate. Although the consequence of increasing homocysteine levels for cardiovascular risk has not been proven at present, it has to be considered that fenofibrate will be given for long-term treatment. Therefore, addition of folic acid and vitamin B12 to fenofibrate can be recommended to prevent the increase of homocysteine associated with fenofibrate, or treatment could be changed to gemfibrozil, which does not increase plasma homocysteine levels.     

Pharmacotherapy of hyperhomocysteinaemia in patients with thrombophilia

Hyperhomocysteinaemia is often the result of inherited abnormalities of the enzymes involved in homocysteine metabolism or vitamin deficiencies (vitamins B₁₂, B₆ or folate) and is present in ～ 5% of the general population. High homocysteine levels in these individuals are associated with a significant increase in relative risk for both arterial and venous thromboembolic disease. Consequently, effective homocysteine-lowering therapeutic strategies have been extensively investigated. Folic acid represents the cornerstone of treatment. In daily doses of at least 0.4 mg, it effectively reduces homocysteine levels, even in non-folate-deficient patients. The addition of vitamins B₁₂ and/or B₆, to folic acid supplementation may provide a small further reduction in homocysteine levels in certain groups of patients. Renal impairment is an important cause of hyperhomocysteinaemia. Individuals with hyperhomocysteinaemia secondary to renal disease commonly require significantly higher doses of folic acid (5 – 40 mg) to achieve maximal therapeutic effect. The important question of whether effective homocysteine-lowering therapy translates into a reduction in vascular disease remains unknown but is being addressed in a series of ongoing prospective trials.     

急性脑梗死与血浆同型半胱氨的关系研究

目的探讨急性脑梗死与血浆同型半胱氨酸（Hey）关系及其临床意义。方法选取120例急性脑梗死住院患者和80例同年龄段健康体格检查人群进行血浆Hey、叶酸和维生素B12的测定,并进行比较。结果急性脑梗死组患者血浆Hey水平明显升高（P〈0．01）,叶酸、维生素B12水平明显低于对照组（P〈0．01）。结论急性脑梗死组患者血浆Hcy升高,而叶酸、维生素B12下降,可以认为同型半胱氨酸血症是急性脑梗死的独立危险因素。     

脑梗死患者血清同型半胱氨酸水平及叶酸 甲钴胺的干预研究

目的研究脑梗死患者血清同型半胱氨酸(H cy)水平及叶酸、甲钴铵干预的影响作用。方法收集230例脑梗死患者、180名健康对照者血液标本,采用荧光偏振免疫法测定H cy、叶酸和维生素B12,酶法常规测定血脂水平。对高H cy的脑梗死患者给予叶酸、甲钴胺干预。结果脑梗死组患者血清H cy水平显著高于对照组(P<0.05),血清H cy与叶酸、维生素B12呈明显负相关(P<0.05),高H cy者药物干预3～4周后血H cy显著降低(P<0.01)。结论高H cy血症是脑梗死的独立危险因素,给予叶酸、甲钴胺干预可有效降低血清H cy水平,可能有助于减轻高H cy对血管的毒性作用。     

测定急性冠状动脉综合征患者血浆同型半胱氨酸的意义

目的探讨冠心病(CHD)尤其是急性冠状动脉综合征(ACS)患者血浆同型半胱氨酸(Hcy)及影响因素叶酸、维生素B12等水平变化与冠状动脉病变严重性之间的关系。方法采用荧光偏振免疫分析法、离子捕获免疫分析法及非均相微粒子酶免疫分析法等测定302例CHD患者,包括ACS组202例(急性心肌梗死组132例和不稳定型心绞痛组70例),稳定型心绞痛(SAP)组100例和正常对照组120例的血浆Hcy、叶酸及维生素B12等水平。对冠心病患者的冠状动脉损害行Gensini评分,并比较各组间的差异。结果①ACS组、SAP组Hcy浓度显著高于对照组[(19±12)μmol/L vs (10±6)μmol/L(P<0.01)、(15±5)μmol/L vs (10±6)μmol/L(P<0.01)],而叶酸,维生素B12浓度显著低于对照组[(3.2±0.7)μg/L vs (7.1±1.8)μg/L(P<0.01),(5.3±0.6)μg/L vs (7.1±1.8)μg/L(P<0.01);(184±32)ng/L vs (283±56)ng/L(P<0.01),(228±45)ng/L vs (283±56)ng/L(P<0.01)。并且ACS组和SAP组的血浆同型半胱氨酸和血清叶酸、维生素B12浓度差异也有统计学意义。②血浆Hcy浓度与血浆叶酸、维生素B12浓度呈线性负相关。③随着冠状动脉病变Gensini评分的增加,Hcy浓度明显升高。结论冠心病尤其是ACS患者血浆Hcy显著升高,其升高严重程度与CHD的发生、病情严重性和冠状动脉病变程度有密切关系,检测CHD患者血浆Hcy水平可以预测冠状动脉病变程度,对于高Hcy者应用叶酸,维生素B12治疗,对于延缓CHD尤其是ACS病变发展可能有十分重要的临床意义。     

Drugs affecting homocysteine metabolism: impact on cardiovascular risk

Elevated total plasma homocysteine has been established as an independent risk factor for thrombosis and cardiovascular disease. A strong relationship between plasma homocysteine levels and mortality has been reported in patients with angiographically confirmed coronary artery disease. Homocysteine is a thiol containing amino acid. It can be metabolised by different pathways, requiring various enzymes such as cystathionine beta-synthase and methylenetetrahydrofolate reductase. These reactions also require several co-factors such as vitamin B6 and folate. Medications may interfere with these pathways leading to an alteration of plasma homocysteine levels. Several drugs have been shown to effect homocysteine levels. Some drugs frequently used in patients at risk of cardiovascular disease, such as the fibric acid derivatives used in certain dyslipidaemias and metformin in type 2 (non-insulin-dependent) diabetes mellitus, also raise plasma homocysteine levels. This elevation poses a theoretical risk of negating some of the benefits of these drugs. The mechanisms by which drugs alter plasma homocysteine levels vary. Drugs such as cholestyramine and metformin interfere with vitamin absorption from the gut. Interference with folate and homocysteine metabolism by methotrexate, nicotinic acid (niacin) and fibric acid derivatives, may lead to increased plasma homocysteine levels. Treatment with folate or vitamins B6 and B12 lowers plasma homocysteine levels effectively and is relatively inexpensive. Although it still remains to be demonstrated that lowering plasma homocysteine levels reduces cardiovascular morbidity, surrogate markers for cardiovascular disease have been shown to improve with treatment of hyperhomocystenaemia. Would drugs like metformin, fibric acid derivatives and nicotinic acid be more effective in lowering cardiovascular morbidity and mortality, if the accompanying hyperhomocysteinaemia is treated? The purpose of this review is to highlight the importance of homocysteine as a risk factor, and examine the role and implications of drug induced modulation of homocysteine metabolism.     

帕金森病患者血浆同型半胱氨酸水平与认知功能障碍相关性研究

目的：探讨帕金森病（Parkinson’s disease,PD）患者血浆同型半胱氨酸（Homocysteine,Hcy）水平与认知功能障碍的相关性。方法选取106例PD患者（包含认知障碍者55例,认知正常者51例）及50例健康对照者,收集临床资料、认知功能评估,应用高效液相色谱法测定血浆Hcy浓度,放射免疫法测定血浆叶酸、维生素B12浓度,分析血浆Hcy含量与认知功能的相关性。结果认知障碍组血浆Hcy值显著高于认知正常组,差异具有统计学意义（P＜0.05）,两组血浆叶酸、维生素B12浓度无统计学差别。PD认知障碍组简易智能状态量表评分及蒙特利尔认知评估量表评分均与血浆Hcy值存在显著负相关。结论血浆Hcy升高与PD认知功能障碍存在显著相关性,血浆Hcy升高可能是PD认知损害的一个风险因子。     

糖尿病合并脑梗死认知功能障碍的治疗研究

目的探讨应用叶酸、维生素B12治疗糖尿病合并脑梗死（DCI）患者,对其血浆同型半胱氨酸（Hcy）水平的影响,及其对认知功能恢复的疗效。方法将60例DCI患者,按双盲方法分成两组,DCI-A组予补充叶酸、维生素,DCI-B组则否,两组患者同时接受缺血性卒中常规治疗。于入院24h内及治疗后第3个月的最后1d,分别测定各组血浆Hcy水平,并用MMSE量表了解患者治疗前后认知功能的改变。结果叶酸、维生素B12治疗3个月后患者的血浆Hcy水平降低。DCI-A组MMSE评分的提高明显高于DCI-B组（P〈0.05）。结论应用叶酸、维生素B12治疗3个月,可显著降低患者的Hcy水平,而且较常规治疗对改善患者的认知功能有更好的疗效。     

Treatment of depression: time to consider folic acid and vitamin B12

We review the findings in major depression of a low plasma and particularly red cell folate, but also of low vitamin B12 status. Both low folate and low vitamin B12 status have been found in studies of depressive patients, and an association between depression and low levels of the two vitamins is found in studies of the general population. Low plasma or serum folate has also been found in patients with recurrent mood disorders treated by lithium. A link between depression and low folate has similarly been found in patients with alcoholism. It is interesting to note that Hong Kong and Taiwan populations with traditional Chinese diets (rich in folate), including patients with major depression, have high serum folate concentrations. However, these countries have very low life time rates of major depression. Low folate levels are furthermore linked to a poor response to antidepressants, and treatment with folic acid is shown to improve response to antidepressants. A recent study also suggests that high vitamin B12 status may be associated with better treatment outcome. Folate and vitamin B12 are major determinants of one-carbon metabolism, in which S-adenosylmethionine (SAM) is formed. SAM donates methyl groups that are crucial for neurological function. Increased plasma homocysteine is a functional marker of both folate and vitamin B12 deficiency. Increased homocysteine levels are found in depressive patients. In a large population study from Norway increased plasma homocysteine was associated with increased risk of depression but not anxiety. There is now substantial evidence of a common decrease in serum/red blood cell folate, serum vitamin B12 and an increase in plasma homocysteine in depression. Furthermore, the MTHFR C677T polymorphism that impairs the homocysteine metabolism is shown to be overrepresented among depressive patients, which strengthens the association. On the basis of current data, we suggest that oral doses of both folic acid (800 microg daily) and vitamin B12 (1 mg daily) should be tried to improve treatment outcome in depression.     

血清同型半胱氨酸水平与冠心病的相关性探讨

目的：探讨血清同型半胱氨酸（Hcy）、叶酸及维生素（Vit)B12水平与冠心病（CHD）的相关性。方法：应用荧光微粒子发光法（测定Hcy及VitB12）及离子捕捉法（测定叶酸）检测CHD组（A组）、其它心血管疾病组（B组）和健康对照组（C组）各30例受检查血清Hcy、叶酸、VitB12水平。结果：A组血清Hcy含量明显高于B组（P＜0．01）及C组（P＜0．01）；A组血清叶酸含量明显低于B组（P＜0．01）及C组（P＜0．01）；A组血清VitB12含量明显低于B组（P＜0．05）及C组（P＜0．05）。结论：血清Hcy水平的升高与CHD可能有明显的关系。叶酸和VitB12水平的下降与Hcy水平的升高在CHD的发生中可能起着相似的作用。     

Association between plasma homocysteine levels and coronary artery disease: a population-based study in northern Greece

OBJECTIVE: Elevated plasma total homocysteine (tHcy) levels constitute a risk factor for coronary artery disease (CAD). We prospectively examined the association of fasting tHcy levels in patients in Northern Greece who had established CAD. PATIENTS AND METHODS: Plasma fasting tHcy levels were measured in 42 patients with angiographically documented CAD and compared to 42 age-, sex-, BMI- and smoking habit-matched control subjects. We also determined the plasma vitamin B(12), folic acid and lipoprotein levels in all patients and controls. Conventional risk factors for CAD were also estimated. RESULTS: In a univariate analysis, tHcy (micromol/l) levels were higher in patients compared to controls almost reaching statistical significance (13 (7-41) vs 11.3 (4-39); p= 0.07). Multivariate analysis of conventional risk factors showed that tHcy levels were not an independent risk factor for CAD. However, tHcy levels were significantly higher in patients with a previous history of myocardial infarction compared to patients without such a history and to controls (15 (8.8-29) vs 11.7 (7-41); p = 0.007 and 15 (8.8-29) vs 11.3 (4-39); p = 0.002, respectively). Hyperhomocysteinaemia (> 15 micromol/l) was detected in 35.7% of patients and 11.9% of controls (p < 0.05). CONCLUSIONS: In Northern Greece, plasma tHcy levels may not be an independent risk factor for CAD in patients with angiographically documented CAD. However, patients with CAD have a trend towards higher tHcy levels. Additionally, plasma tHcy levels may be associated with the development of myocardial infarction.     

Homocysteine lowering with folic acid and vitamin B supplements: effects on cardiovascular disease in older adults

Cardiovascular disease (CVD) is the leading cause of death in older men and women and contributes significantly to morbidity in later life. Folic acid and other vitamin B deficiencies and elevated total plasma homocysteine levels are associated with increased cardiovascular risk in geriatric patients, but recent studies have questioned the importance of these risk factors in older people. Data on the effects of homocysteine-lowering therapy (e.g. folic acid and vitamin B supplements) on surrogate CVD endpoints, such as atherosclerotic progression, endothelial function, inflammation and hypercoagulation, are conflicting. Findings from randomised clinical trials using clinical CVD outcomes show that folic acid and vitamin B supplements may not provide cardiovascular protection. Furthermore, these findings raise questions about whether the combination of folic acid and B vitamins may actually be harmful. Other large randomised clinical trials are underway to help clarify the role of folic acid and vitamin B supplements in CVD prevention in older people. Data to date do not support use of homocysteine-lowering therapies in either middle-aged or older adults.     

The effect of fibrates and other lipid-lowering drugs on plasma homocysteine levels

Hyperlipidaemia is a major risk factor for cardiovascular disease. The drugs of choice for the treatment of hyperlipidaemia are either fibrates, in the case of hypertriglyceridaemia, or statins, in the case of hypercholesterolaemia. Recently, it has been shown that some of the most prescribed fibrates cause hyperhomocysteinaemia, which itself has been recognised as a cardiovascular risk factor. In particular, fenofibrate and bezafibrate lead to a 20 – 40% elevation of plasma levels of the atherogenic amino acid homocysteine, thereby possibly counteracting the desired cardiovascular protection. The most likely mechanism for this increase is an alteration of creatine–creatinine metabolism and changes in methyl transfer. Gemfibrozil does not increase homocysteine. Statins have no effect on the plasma homocysteine concentration. The increase of plasma homocysteine after fenofibrate can be lowered by the concurrent administration of folic acid and vitamins B₁₂ and B₆. Thus, patients with hypertriglyceridaemia can either be concurrently treated with fenofibrate and vitamins or with gemfibrozil.     

Hyperhomocysteinaemia and cardiovascular risk in female ovariectomized rats: role of folic acid and hormone replacement therapy

Hyperhomocysteinaemia is an independent risk factor for arteriosclerosis, recurrent thromboembolic complications and osteoporosis. After menopause, a high level of total homocysteine seems to be secondary to the altered hormonal status. Hormone replacement therapy (HRT) limits the development of coronary artery disease through a variety of mechanisms. One such mechanism is through affecting homocysteine metabolism. Folate and vitamin B12 deficiencies are considered to be major risks for hyperhomocysteinaemia. This study, therefore, was undertaken to examine whether lowering homocysteine with HRT or folic acid in ovariectomized rats could attenuate cardiovascular complications. Sixty sexually mature female Wistar rats were ovariectomized. Three weeks later, they were treated with estradiol (15 microg kg(-1), every two weeks, i.m.) or folic acid (90 microg daily, orally), either alone or in a combined form for four weeks. In addition, groups of ovariectomized rats (positive control) and healthy rats (negative control) were given cottonseed oil. Blood samples were then collected for serum and plasma separation. Serum total homocysteine, folate, estradiol, plasma nitric oxide (NO), lipid profile, and susceptibility of non-high-density-lipoprotein cholesterol (non HDLC) content to oxidation were determined. In ovariectomized rats, hyperhomocysteinaemia was established and associated with significant increments of both atherogenic indexes (total cholesterol/HDLC, low-density-lipoprotein cholesterol (LDLC)/HDLC) and susceptibility of their non HDLC to oxidation. However, plasma NO, serum folate, and estradiol levels significantly decreased. HRT and folic acid significantly reduced total homocysteine and susceptibility of non HDLC to oxidation and increased plasma NO content. Moreover, a significant negative correlation was found between total homocysteine versus folate and estradiol (r = -0.5, P < 0.01; r = -0.25, P < 0.05, respectively). Meanwhile, a positive correlation with the susceptibility of lipoprotein to oxidation was observed (r = 0.85, P < 0.001). In conclusion, a low folate level is found to be associated with elevated total homocysteine. Folic acid supplementation, either individually or in a combined form with HRT, has a beneficial effect in low estrogen status subsequent to ovariectomy.