Polycystic ovary syndrome and the single nucleotide polymorphisms of methylenetetrahydrofolate reductase: a pilot observational study

Polycystic ovary syndrome (PCOS), insulin resistance and overall mortality due to diabetes and coronary artery disease are higher in South Asians than in Caucasians. Aims: We compared the prevalence of the C677T and A1298C single nucleotide polymorphisms in the methylenetetrahydrofolate reductase gene in South Asian and Caucasian women, its association with folate and homocysteine (Hcy) metabolism, and its relevance to future atherogenic events. Methods and results: 71 women were recruited for the study: South Asian PCOS (21) plus controls (9) and Caucasian PCOS (25) plus controls (16). Anthropometric and laboratory parameters were compared. South Asian PCOS women were significantly hyperandrogenic and exhibited a greater degree of insulin resistance. Caucasian PCOS women had higher plasma Hcy concentrations with a 1.9 times higher frequency of the T allele than the South Asian PCOS group. In the presence of this variant allele, plasma Hcy levels appear to be higher in both PCOS groups. The South Asians had a 1.8 times higher frequency of the C allele than the Caucasians; however, the overall frequency was comparable in the two PCOS groups. The frequency of homozygosity, i.e. TT677 and CC1298, was 7.2% and 4.9% in the Caucasians and 0% and 16.6% in the South Asian recruits, respectively. Dietary inadequacies in the South Asian women can influence their plasma folate and B12 concentrations resulting in hyperhomocysteinemia which, in combination with dyslipidaemia and insulin resistance, can lead to long-term atherogenic consequences. CONCLUSIONS: Current data suggests that the mechanisms of atherothrombosis have separate pathways in the two ethnic groups. Larger studies exploring the current theme need to be carried out in the PCOS groups to obtain adequate insight.     

Plasma homocysteine concentrations and the single nucleotide polymorphisms in the methionine synthase gene (MTR 2756A>G): Associations with the polycystic ovary syndrome An observational study

BACKGROUND: Elevated plasma homocysteine (Hcy) is a recognized risk factor for cardiovascular disease (CVD) and other defects. Biochemical and genetic studies have characterized molecular determinants contributing to alter Hcy metabolism. The vitamin B12 dependent enzyme methionine synthase (MTR) regulates de novo production of methionine from homocysteine. Defects in the activity of this enzyme may possibly predispose to higher plasma Hcy concentrations. STUDY DESIGN: We examined the associations between plasma Hcy concentrations and a single nucleotide polymorphism (SNP) in the MTR gene (MTR 2756A>G), and plasma folate concentrations, in 71 women (Caucasian and South Asian) attending a fertility clinic. We also determined the ethnic variations in the frequencies of the 3 genotypes of the MTR 2756 A>G gene. RESULTS: The frequency of the variant G allele was similar in the Caucasians and the South Asians (OR: 1.83; 95% CI: 0.79-4.23, p=0.2). The frequency was also similar in the PCOS and non-PCOS groups (OR: 0.88; 95% CI: 0.39-1.99). Plasma Hcy levels were significantly higher in women with PCOS compared with non-PCOS controls (p=0.05) and in Caucasian women with PCOS compared with Caucasian controls (p=0.04) in the presence of the MTR 2756 AA genotype (wild type). After adjusting for age, BMI, waist circumference and ethnicity, the significant predictors of plasma Hcy concentrations were plasma LDL, whole blood folate concentrations and a clinical diagnosis of PCOS. CONCLUSIONS: The important predictors of plasma Hcy concentration in women of reproductive age are whole blood folate concentrations, a background of PCOS and plasma LDL concentrations. The SNP 2756 A>G in the MTR gene does not appear to influence the plasma Hcy levels.     

South Asian women with polycystic ovary syndrome exhibit greater sensitivity to gonadotropin stimulation with reduced fertilization and ongoing pregnancy rates than their Caucasian counterparts

Polycystic ovary syndrome (PCOS) is a heterogeneous syndrome. In vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) is required for PCOS cases that are refractory to standard ovulation induction or have co-existing infertility factors in women with PCOS and Tubal factor subfertility. OBJECTIVES: Assess ethnic variations in response to IVF/ICSI treatment. STUDY DESIGN: Observational Comparative study in a University hospital fertility clinic in women with PCOS and Tubal factor subfertility. Women with PCOS (Asians: AP=104; Caucasians: CP=220) and those with tubal factor infertility seeking fertility treatment were assessed (Asians: AC=84; Caucasians: CC=200). Six hundred and eight fresh IVF or ICSI cycles using long protocol of GnRHa suppression and resulting in a fresh embryo transfer were compared. The primary endpoint was to assess the dose of gonadotropins used in the cycles. The secondary outcomes were: total number of oocytes retrieved, fertilization and ongoing clinical pregnancy rates. RESULTS: We found that the South Asian women presented at a younger age for the management of sub-fertility. An extended stimulation phase and Caucasian ethnicity showed an inverse correlation with the number of oocytes retrieved in the PCOS subgroup. Caucasian ethnicity was associated with a higher fertilization rate however increase in body mass index (BMI) and the laboratory technique of IVF appeared to have a negative impact on fertilization rates in the PCOS subgroup. Commencing down regulation on day 1 of the cycles was negatively associated with fertilization rates in the tubal group. In terms of clinical pregnancy rates, the Caucasian PCOS had a 2.5 times (95% CI: 1.25-5) higher chance of an ongoing clinical pregnancy as compared with their Asian counterpart. Also, a unit increase in the basal FSH concentration reduced the odds of pregnancy by 18.6% (95% CI: 1.8-32.6%) in the PCOS group. CONCLUSIONS: The Asian PCOS have a greater sensitivity to gonadotropin stimulation with lower fertilization and ongoing clinical pregnancy rates as compared with their Caucasian counterparts.     

Levels of lipoprotein and homocysteine in non-obese and obese patients with polycystic ovary syndrome

Aim.?This study was designed to examine the relationship between homocysteine (Hcy), lipoprotein levels and insulin resistance in obese and non-obese patients with polycystic ovary syndrome (PCOS).

Materials and methods.?Eighty-five patients (38 obese, 47 non-obese) with PCOS and 50 healthy subjects (25 obese, 25 non-obese) were included in the study. PCOS was defined according to the Homburg criterion. Serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), dehydroepiandrosterone sulfate (DHEA-S), insulin, 17-hydroxyprogesterone, free testosterone, androstenedione, vitamin B₁₂ and folate were measured. Also, serum concentrations of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), lipoprotein (a) (Lp(a)), apoprotein B (Apo B) and apoprotein A (Apo A) were determined. Plasma Hcy levels were measured. Insulin resistance was evaluated by homeostasis model assessment (HOMA).

Results.?Plasma Hcy levels were significantly higher in women with PCOS than in healthy women. HOMA-R (insulin resistance) was significantly higher in women with PCOS compared with healthy women. Serum fasting TC, LDL-C, TG, Apo B, vitamin B₁₂ and folate levels were similar between PCOS and control groups. Lp(a) levels were higher in PCOS patients than in control subjects, whereas HDL-C and Apo A levels were lower. Compared with obese PCOS subjects, non-obese PCOS subjects had low HOMA-R, TC, LDL-C, TG, Apo B, Lp(a) and androgen levels. Plasma Hcy levels, serum HDL-C and Apo A levels were similar between obese and non-obese women with PCOS. Levels of HDL-C and Apo A were lower in both obese and non-obese PCOS patients than in obese and non-obese control subjects, whereas Lp(a) levels were higher. No correlation was observed between plasma Hcy, body mass index, HOMA-R, serum androgen levels, TC, LDL-C, HDL-C, Apo A, Apo B and Lp(a) levels.

Conclusion.?These results showed that elevated insulin resistance and plasma Hcy levels, and changes in serum lipid profile, which are possible risk factors for cardiovascular disorders, play important roles in the development of cardiovascular disease in both obese and non-obese patients with PCOS.     

Levels of lipoprotein and homocysteine in non-obese and obese patients with polycystic ovary syndrome.

AIM: This study was designed to examine the relationship between homocysteine (Hcy), lipoprotein levels and insulin resistance in obese and non-obese patients with polycystic ovary syndrome (PCOS). MATERIALS AND METHODS: Eighty-five patients (38 obese, 47 non-obese) with PCOS and 50 healthy subjects (25 obese, 25 non-obese) were included in the study. PCOS was defined according to the Homburg criterion. Serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), dehydroepiandrosterone sulfate (DHEA-S), insulin, 17-hydroxyprogesterone, free testosterone, androstenedione, vitamin B12 and folate were measured. Also, serum concentrations of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), lipoprotein (a) (Lp(a)), apoprotein B (Apo B) and apoprotein A (Apo A) were determined. Plasma Hcy levels were measured. Insulin resistance was evaluated by homeostasis model assessment (HOMA). RESULTS: Plasma Hcy levels were significantly higher in women with PCOS than in healthy women. HOMA-R (insulin resistance) was significantly higher in women with PCOS compared with healthy women. Serum fasting TC, LDL-C, TG, Apo B, vitamin B12 and folate levels were similar between PCOS and control groups. Lp(a) levels were higher in PCOS patients than in control subjects, whereas HDL-C and Apo A levels were lower. Compared with obese PCOS subjects, non-obese PCOS subjects had low HOMA-R, TC, LDL-C, TG, Apo B, Lp(a) and androgen levels. Plasma Hcy levels, serum HDL-C and Apo A levels were similar between obese and non-obese women with PCOS. Levels of HDL-C and Apo A were lower in both obese and non-obese PCOS patients than in obese and non-obese control subjects, whereas Lp(a) levels were higher. No correlation was observed between plasma Hcy, body mass index, HOMA-R, serum androgen levels, TC, LDL-C, HDL-C, Apo A, Apo B and Lp(a) levels. CONCLUSION: These results showed that elevated insulin resistance and plasma Hcy levels, and changes in serum lipid profile, which are possible risk factors for cardiovascular disorders, play important roles in the development of cardiovascular disease in both obese and non-obese patients with PCOS.     

亚甲基四氢叶酸还原酶基因677位多态性、高同型半胱氨酸血症与复发性流产

目的:探讨亚甲基四氢叶酸还原酶基因(MTHFR)多态性(C677T)与高同型半胱氨酸(Hcy)血症以及复发性流产之间的关系。方法:采用前瞻性病例对照研究方法,收集71例复发性自然流产患者为病例组,另征集同期58例有正常妊娠史者为对照组,利用PCR-RFLP方法研究MTHFR基因多态性(C677T);同时应用酶法测定血清同型半胱氨酸水平;并随访病例组的妊娠结局。结果:①MTHFR基因677位点的3种基因型在病例组和对照组分布分别为CC:14.1%vs 43.1%、CT:49.3%vs 25.9%、TT:36.6%vs 31.0%,组间比较有极显著统计学差异(χ2=14.7,df=2,P=0.001);其中CC基因型在病例组显著降低(P=0.000,OR=0.216,95%CI:0.093-0.505);T等位基因分布在病例组显著升高(61.3%vs 38.7%,P=0.006)。②129例研究对象中TT基因型血同型半胱氨酸水平显著升高(P=0.000):TT为19.0±9.5 nmol/L、CC为13.1±6.2 nmol/L、CT为11.7±4.0 nmol/L,病例组和对照组高Hcy水平组间无统计学差异(P>0.05)。③病例组中有38.0%(27/71)为高Hcy血症,叶酸治疗有效。结论:MTHFR基因多态性(C677T)与复发性流产有关;MTHFR基因TT型与高Hcy血症有关;叶酸可用于治疗高Hcy血症且有助于改善下次妊娠结局。     

血浆同型半胱氨酸与子(癎)前期发病的关系

目的 研究孕妇血浆同型半胱氨酸(homocysteine,Hcy)水平和亚甲基四氢叶酸还原酶(methylenetetrahydrofolate reductase,MTHFR)基因C677T的多态性,以探讨其在子癎前期发病中的作用.方法 选取子癎前期孕妇50例(子痴前期轻度14例,子癎前期重度36例),正常孕妇40例为研究对象.采用荧光偏振免疫法测定血浆Hcy水平,PCR法检测MTHFR基因C677T的多态性.结果 研究组Hcy水平显著高于对照组[(12.00±4.59)μmol/L和(7.85±1.51)μmol/L,P<0.05];轻度子癎前期组Hcy水平[(8.63±3.94)μmol/L高于对照组,但差异无统计学意义(P>0.05),重度子癎前期组Hcy水平(13.30±2.06)μmol/L]明显高于对照组(P<0.01);子痢前期组MTHFR基因677位点CT、TT基因型频率分布(C/T:42.0%;T/T:14.0%)和子癎前期组总的突变T等位基因频率(T:35.0%)均显著高于对照组(P<0.05).结论 血浆Hey水平升高可能是子瘸前期发病机制中的重要因素,而MTHFR基因C677T多态性影响了Hcy的代谢途径.可能是子癎前期的病因学机理之一.     

叶酸代谢相关基因的多态性与唐氏综合征的关系

目的 研究叶酸代谢中亚甲基四氢叶酸还原酶(methylenetetrahydrofolate reductase,MTHFR)基因的的遗传多态性是否与唐氏综合征(down syndrome,DS)的发生相关. 方法选择100例生育过DS患儿的汉族母亲为研究组和100例相匹配的汉族母亲为对照组,使用PCR-RFLP和MGB-Taqman实时PCR方法检测MTHFR 677和MTHFR 1298的基因型,化学发光法检测血浆同型半胱氨酸(homocysteine,HCY)的水平. 结果 MTHFR 677和MTHFR 1298一个和/或两个等位基因的变异可使生育DS患儿的风险率分别增加2.37倍(95%CI:1.32～4.27)和1.97倍(95%CI:1.04～3.75).同时合并MTHFR 677CT和1298AC/CC可使DS的发病风险率显著增高,OR=5.62(95%CI:1.86～17.03),而MTHFR 677TT合并1298AC/CC的基因型组合使OR=11.84(95%CI:1.39～100.62).研究组血浆HCY水平显著高于对照组[(9.04±3.85)μmol/L和(6.53±2.06)μmol/L,P<0.01].MTHFR 677一个和/或两个等位基因C→T的变异,使研究组和对照组HCY水平均显著增加(P<0.05).单纯存在MTHFR 1298A/C时两组血浆HCY水平无统计学差异(P>0.05).同时存在MTHFR 677CT/TT和1298AC/CC基因组合可使血浆HCY水平增高(P<0.05).结论 HCY/叶酸代谢相关基因的多态与汉族妇女生育DS患儿的风险相关,且可能存在基因的协同作用.     

Chronic inflammation and elevated homocysteine levels are associated with increased body mass index in women with polycystic ovary syndrome

Background. Women with polycystic ovary syndrome (PCOS) are insulin-resistant and have increased risk for type 2 diabetes mellitus (T2DM) and coronary heart disease (CHD). But it is controversial whether the increased risk of CHD and T2DM is associated with endocrine abnormalities occurring as a consequence of PCOS or whether it is related to obesity or metabolic changes frequently seen in women with PCOS.

Objective. Since both homocysteine (Hcy) and C-reactive protein (CRP) are supposed to predict T2DM and CHD, we investigated their possible relationship with insulin resistance, obesity, hyperandrogenemia and metabolic alterations in 44 PCOS women and 26 healthy controls matched by age and body mass index (BMI).

Results. Hcy and CRP levels were significantly elevated in PCOS women compared with controls (13.30 ± 4.81 vs. 9.02 ± 3.36 μmol/l, p < 0.05 and 4.22 ± 2.95 vs. 2.66 ± 2.49 mg/l, p < 0.05). There was no correlation between Hcy and CRP (r = 0.171, p = 0.05) as two risk markers. While plasma Hcy levels were correlated with BMI, ratio of luteinizing hormone (LH) to follicle-stimulating hormone (FSH), total testosterone, free testosterone, triglyceride and insulin levels and homeostatic model assessment–insulin resistance index (HOMA-IR) (p < 0.05), CRP was correlated with BMI, total cholesterol, triglyceride, low-density lipoprotein cholesterol and insulin levels and HOMA-IR (p < 0.05). There was no correlation of CRP with parameters of PCOS such as testosterone and LH/FSH ratio (p > 0.05). Multiple regression analysis revealed BMI as the major factor examined that influenced both Hcy and CRP levels.

Conclusions. In PCOS women, plasma levels of Hcy and CRP were significantly elevated compared with age- and BMI-matched controls. Although most of the PCOS-related endocrine and metabolic changes are related to elevated plasma Hcy and CRP levels in PCOS women, BMI seems to be the major factor determining CHD and T2DM in women with PCOS.     

Racial and ethnic differences in assisted reproduction treatment outcomes: the benefit of racial admixture

The goal of the present study was to determine whether racial and ethnic differences affect the outcomes of assisted reproductive technology in the Brazilian population. 1497 patients undergoing intracytoplasmic sperm injection (ICSI) cycles were split into groups according to the patient's ethnicity: Caucasian (n = 2131), Mestizo (n = 358), Asian (n = 174), Black (n = 115) and Indian (n = 260). ICSI outcomes were compared among the groups. Body mass index was highest in the Black group, followed by the Mestizo, Indian, Caucasian and Asian groups (p > 0.001). The FSH dose (p > 0.001) was highest among Indians, followed by Asians and Caucasians, and the dose was lowest among Blacks and Mestizos. In contrast, the oocyte yield was highest among Mestizos, followed by Indians, Blacks and Caucasians, and lowest among Asians (p = 0.005). The fertilisation rate was highest among Mestizos, followed by Blacks, Indians and Caucasians, whereas Asians had the lowest fertilisation rate (p = 0.004). Pregnancy and implantation rates were also highest among Mestizos, followed by Blacks, Indians and Caucasians, whereas the Asian patients had the lowest rates (p = 0.008 and p > 0.001, respectively). In conclusion, our evidence suggests a possible beneficial effect of racial admixture on ICSI outcomes.     

Neural tube defects and a disturbed folate dependent homocysteine metabolism

Folate administration substantially reduces the risk on neural tube defects (NTD). The interest for a disturbed homocysteine (Hcy) metabolism in relation to NTD was raised by the observation of elevated blood Hcy levels in mothers of a NTD child. This observation resulted in the examination of enzymes involved in the folate dependent Hcy metabolism. This leads to the identification of the first and likely a second genetic risk factor for NTD. The C677T and A1298C mutations in the methylenetetrahydrofolate reductase (MTHFR) gene are associated with an increased risk of NTD and cause elevated Hcy concentrations. These levels can be normalized by an additional folate intake. Thus, a dysfunctional MTHFR partly explains the observed elevated Hcy levels in women with NTD pregnancies, and also in part the protective effect of folate on NTD. Although, the MTHFR polymorphisms are only moderate risk factors, population wide they may account for an important part of the observed NTD prevalence.     

Polymorphisms of the methylenetetrahydrofolate reductase gene (C677T and A1298C) in nulliparous women complicated with preeclampsia

Objective: To determine the prevalence of C677T and A1298C Single-nucleotide polymorphisms (SNPs) of the MTHFR gene in nulliparous women complicated with preeclampsia (PE).

Methods: One hundred fifty gestations complicated with PE and their corresponding controls without the disease were recruited for the genotyping of C677T and A1298C polymorphisms of the MTHFR gene using restriction fragment length polymorphism polymerase chain reaction. Secondarily, homocysteine (HCy) plasma levels were measured in preeclamptic women displaying the CC genotype of the A1298C polymorphism (homozygous) and compared to HCy levels determined among controls with the normal AA genotype for the A1298C variant.

Results: Only the mutant CC genotype of the A1298C polymorphism was associated to higher risk of presenting PE, as frequency of this genotype was significantly higher among cases than controls (15.3% versus 0.7%, p?p?=?0.0001). Women with the mutant CC A1298C SNP displayed higher plasma HCy levels as compared to controls with normal AA A1298C genotype (8.4?±?2.6 versus 7.5?±?2.7?mmoL/L p?=?0.04).

Conclusion: Prevalence of the CC mutant genotype of the A1298C polymorphism was higher among PE women. This mutation among PE women was related to increased neck circumference and higher HCy levels. Future research should aim at linking these gestational findings with obesity and cardiovascular risk.     

Lack of association between C-850T polymorphism of the gene encoding tumor necrosis factor-α and polycystic ovary syndrome

In the present study, we determined whether genetic variability in the gene encoding tumor necrosis factor-α (TNF-α) contributes to individual differences in susceptibility to the development of polycystic ovary syndrome (PCOS). The study involved 87 Caucasian Finnish women with PCOS and 115 healthy control women who were genotyped for the C-850T polymorphism in the TNF-α gene promoter. Analysis by χ² was used to assess genotype and allele frequency differences between PCOS women and controls. A similar genotype distribution for the C-850T polymorphism was observed in the two groups, with the frequency of the variant T allele being 8.6% in the PCOS group and 9.6% in the control group (p = 0.862). Accordingly, the profile of genotype frequencies was similar in the groups. The observed profiles of allele and genotype frequencies confirm an equilibrium state between C-850T polymorphism and PCOS and suggest that polymorphism of the TNF-α gene is unlikely to contribute to the risk of PCOS.     

Methylenetetrahydrofolate reductase polymorphisms are not a risk factor for pre-eclampsia/eclampsia in Australian women

In European and Japanese but not in Australian, American, and South African women, the C677T methylenetetrahydrofolate reductase (MTHFR) polymorphism has been reported to be a genetic risk factor pre-eclampsia/eclampsia (PE/E). The recently described A1298C MTHFR gene polymorphism also results in reduced MTHFR enzyme activity, although to a lesser extent than the previously described C677T polymorphism. Heterozygotes for both polymorphisms are reported to have an even lower MTHFR enzymatic activity than seen in homozygotes for the C677T genotype. In this current study we determined the allele frequency of the A1298C MTHFR gene polymorphism in an Australian population and examined this polymorphism alone and in combination with the C677T MTHFR polymorphism for an association with PE/E. Neither the A1298C polymorphism alone nor a combination of both polymorphisms showed an association with PE/E in our population of Australian women.     

Atherogenic metabolic profile in PCOS patients: role of obesity and hyperandrogenism

Objective. To investigate glyco-lipidic metabolism and androgenic profile in a cohort of women with polycystic ovary syndrome (PCOS) divided according to Rotterdam phenotypes and body mass index (BMI).

Design. A prospective case–control study.

Setting. Gynecology department in a teaching hospital.

Patients. A total of 223 PCOS women and 25 healthy control women were studied.

Methods. Patients and controls were subdivided into three groups according to their BMI: normal weight (18.5?≤?[BMI]?≤24.9?kg/m²), overweight (25.0?≤?BMI?≤29.9?kg/m²), or obese (BMI?≥30.0?kg/m²) and according to Rotterdam criteria of PCOS.

Main outcome measures. Pituitary-gonadal axis assessment including follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, PRL, testosterone, androstenedione, DHEA-S, 17-hydroxyprogesterone and inhibin B. Metabolic parameters included cholesterol (Chol), high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides (TG) and apolipoproteins (APO) AII and B as well as serum fasting insulin, glucose and HOMA-IR.

Results. Serum fasting insulin, glucose, HOMA-IR, TG and HDL were significantly higher in women with PCOS compared to controls. Additionally, serum levels of Chol, LDL and TG were significantly higher and HDL levels were significantly lower in obese PCOS women compared with overweight/normal PCOS irrespective of Rotterdam phenotypes. Free testosterone index but not androstenedione or total testosterone significantly correlated with TG, HDL and APO B. No significant correlations were detected between gonadotropins, inhibin B or estradiol with metabolic parameters studied.

Conclusions. Obesity but not overweight in PCOS is associated with dyslipidemia. Hyperandrogenic women showed the most atherogenic lipid profiles.     

反复妊娠丢失患者的亚甲基四氢叶酸还原酶的多态性

目的检测反复妊娠丢失(recurrent pregnancy loss,RPL)妇女亚甲基四氢叶酸还原酶(methylenetetrahydrofolate reductase,MTHFR)的多态性。方法选择不明原因的反复妊娠丢失二次以上的妇女71例,正常对照93例,无妊娠丢失及血栓病史,除外口服避孕药妇女。MALDI-TOF质谱检测技术检测MTHFR的多态性C677T、A1298C、T1317C和G1793A。结果RPL妇女MTHFR C677T、G1793A的杂合子和纯合子的突变率均明显高于对照组,差异有显著性(P<0.05)。MTHFR的A1298C在RPL组和正常对照组无明显差别。T1317C在两组中均未发现。RPL组连锁基因频率677CT/1793GA明显高于正常对照组(RR=4.92)。结论RPL与MTHFR多态性密切相关,MTHFR C677T、G1793A突变是RPL的危险因素。其连锁基因突变可使妊娠丢失的发生率增加4.92倍。     

Effect of folic acid in women with and without insulin resistance who have hyperhomocysteinemic polycystic ovary syndrome.

OBJECTIVE: To study the effect of folic acid on homocysteine (Hcy) levels in women with insulin resistance and polycystic ovary syndrome (PCOS) in a prospective clinical trial. METHOD: Of 210 women with PCOS, 70 were hyperhomocysteinemic; and of these, 32 were insulin resistant and 38 were not. The 70 women were treated with folic acid for 3 months. Baseline and serum levels of Hcy and insulin were measured in both groups. RESULTS: In both groups Hcy concentrations were significantly decreased following folic acid supplementation. The mean+/-SD levels before and after treatment were 14.03+/-1.5 micromol/L and 12.53+/-1.72 micromol/L in group 1 (P<0.001), and they were 12.07+/-0.87 micromol/L and 8.83+/-0.78 micromol/L in group 2 (P<0.001). CONCLUSION: The Hcy levels of hyperhomocysteinemic women with PCOS were reduced after 3 months of folic acid supplementation, and the rate of reduction was higher among women without insulin resistance. No change was found in fasting insulin levels.     

Dehydroepiandrosterone sulfate/free androgen index ratio predicts a favorable metabolic profile in patients with polycystic ovary syndrome

Potential effect of hyperandrogenemia on metabolic disturbances in polycystic ovary syndrome (PCOS) has always been a matter of interest. We analyzed the records of 125 patients with PCOS and 54 age-matched healthy women. All participants underwent biochemical and hormonal assessment and a 75?g oral glucose tolerance test was performed. PCOS and control groups were comparable in terms of age. Dehydroepiandrosterone sulfate/free androgen index (DHEAS/FAI) ratio was negatively correlated with body mass index (BMI) (p?<?.001), fasting glucose (p?=?.02), area under the curve (AUC) of glucose (p?=?.03), AUC of insulin (p?=?.001), homeostasis model assessment-estimated insulin resistance (HOMA-IR) (p?<?.001), and triglycerides (TG) (p?=?.009), and positively correlated with insulin sensitivity index (ISI) (p?<?.001) and high-density lipoprotein cholesterol (HDL-C) (p?<?.001) among PCOS patients. In logistic regression analysis, higher DHEAS/FAI ratio levels were associated with lower risk of low HDL-C [RR(95%CI); 0.97(0.95–0.98); p?<?.001] as well as atherogenic dyslipidemia (TG/HDL-C) [RR(95%CI); 0.97(0.94–0.99); p?=?.035] even after adjustment for BMI in the PCOS group. Androgens, DHEAS and FAI act differently on metabolic parameters. Our results demonstrate that high DHEA-S/FAI ratio levels are associated with a more favorable metabolic profile.     

A case-control study of methylenetetrahydrofolate reductase polymorphisms in cervical carcinogenesis

OBJECTIVES: Polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene are thought to be associated with a varying risk of cervical dysplasia. The purpose of this trial was to study the role of the two common functional MHTFR polymorphisms in a large multiracial population at risk for cervical dysplasia and cancer. METHODS: This is a nested case-control study of 376 subjects obtained from cohorts enrolled in an ongoing prospective cervical carcinogenesis protocol. Cases included invasive cancers (n = 51), and high (n = 50) and low (n = 50) grade dysplasia. There were 225 normal controls. Functional MTHFR 677C-->T and 1298A-->C genotypes were identified. Follow-up cytology data were reviewed for the control subjects from the time of study entry until August 2004. RESULTS: There is a significant racial difference in allele frequency of the 677C-->T polymorphism (P < 0.005). African-American women had an extremely low prevalence of the 677T allele (8%). There was no significant difference in the frequency of the 677T allele between cases and controls. There is no racial difference in allele frequency of the 1298A-->C polymorphism. Also, no significant difference was found between cases and controls. Of the 51 cancers, no case was homozygous for both aberrant polymorphisms (677T, 1298C), and only 3 cases were heterozygous for both. Follow-up data were available for 129 of 225 control subjects (57%). Only 15 (12%) have had a subsequent abnormal pap, and there was no association with the 677C-->T polymorphism. CONCLUSIONS: We confirm a significant difference in the 677T allele frequencies among racial groups. However, there is no association of either the 677C-->T or 1298A-->C polymorphisms in cervical carcinogenesis. There is no role of the combined polymorphism effect in cervical cancer or evidence of prediction for future Pap abnormalities.     

Chronic inflammation and elevated homocysteine levels are associated with increased body mass index in women with polycystic ovary syndrome.

BACKGROUND: Women with polycystic ovary syndrome (PCOS) are insulin-resistant and have increased risk for type 2 diabetes mellitus (T2DM) and coronary heart disease (CHD). But it is controversial whether the increased risk of CHD and T2DM is associated with endocrine abnormalities occurring as a consequence of PCOS or whether it is related to obesity or metabolic changes frequently seen in women with PCOS. OBJECTIVE: Since both homocysteine (Hcy) and C-reactive protein (CRP) are supposed to predict T2DM and CHD, we investigated their possible relationship with insulin resistance, obesity, hyperandrogenemia and metabolic alterations in 44 PCOS women and 26 healthy controls matched by age and body mass index (BMI). RESULTS: Hcy and CRP levels were significantly elevated in PCOS women compared with controls (13.30 +/- 4.81 vs. 9.02 +/- 3.36 micromol/l, p < 0.05 and 4.22 +/- 2.95 vs. 2.66 +/- 2.49 mg/l, p < 0.05). There was no correlation between Hcy and CRP (r = 0.171, p = 0.05) as two risk markers. While plasma Hcy levels were correlated with BMI, ratio of luteinizing hormone (LH) to follicle-stimulating hormone (FSH), total testosterone, free testosterone, triglyceride and insulin levels and homeostatic model assessment-insulin resistance index (HOMA-IR) (p < 0.05), CRP was correlated with BMI, total cholesterol, triglyceride, low-density lipoprotein cholesterol and insulin levels and HOMA-IR (p < 0.05). There was no correlation of CRP with parameters of PCOS such as testosterone and LH/FSH ratio (p > 0.05). Multiple regression analysis revealed BMI as the major factor examined that influenced both Hcy and CRP levels. CONCLUSIONS: In PCOS women, plasma levels of Hcy and CRP were significantly elevated compared with age- and BMI-matched controls. Although most of the PCOS-related endocrine and metabolic changes are related to elevated plasma Hcy and CRP levels in PCOS women, BMI seems to be the major factor determining CHD and T2DM in women with PCOS.