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Polycystic Ovary Syndrome
2003 Scientific Updates:
Coagulation disorders and polycystic ovary syndrome, associations with both recurrent pregnancy loss and with very early pregnancy loss (4/5/03).
WHOM CAN WE HELP?: 1. We are interested in working with women who have had recurrent pregnancy loss (RPL), defined by 3 or more consecutive pregnancy losses before 20 weeks gestation. 12. We are also interested in women who, despite normal ovulatory menstrual cycles, no anatomical abnormalities in the reproductive anatomy, with normal husbands' sperm count and motility, have been unable to conceive and those with pregnancy loss before 6 weeks gestation. 3. Women with polycystic ovary syndrome with RPL. In women with very early pregnancy loss , there is evidence that although the egg is fertilized and matures to the blastocyst stage, that it cannot implant, and is lost so quickly that the pregnancy-on signal does not get to the pituitary, and the next menstrual cycle appears on schedule without knowledge of the very early pregnancy loss (VEPL). Both RPL and VEPL appear to be caused, in part, by an increased tendency to form blood clots (thrombophilia), by a reduced ability to dissolve blood clots (hypofibrinolysis), by both, and by a common endocrine syndrome, polycystic ovary syndrome (PCOS). Without treatment with metformin (1.55-2.55 g/day) women with PCOS commonly have RPL, in part due to high levels of plasminogen activator inhibitor activity (PAI-Fx), the major determinant of fibrinolysis. We are interested in working with women and their physicians who have sustained RPL or VEPL, suggesting which coagulation tests to do, interpreting them, and suggesting therapy for subsequent pregnancies (commonly with Lovenox thromboprophylaxis). We are also interested in working with women and their physicians who may have PCOS as a cause of RPL. Background: Recurrent pregnancy loss (RPL) has traditionally been defined by 3 or more consecutive pregnancy losses before 20 weeks gestation. 1 RPL has been estimated to occur in approximately 0.3%2 to 1%1 of all couples. Multiple potential etiologies for RPL have been described1-6 including antiphospholipid antibody syndrome, thrombophilia, 7-15 parental karyotype abnormalities, uterine malformations, cervical incompetence, poorly controlled diabetes mellitus, hypothyroidism, and antithyroid antibodies. In most7-15 but not all16-22 studies, the thrombophilic G1691A Factor V Leiden mutation has been identified as an etiology for both RPL and for 2nd and 3rd trimester pregnancy complications.19,23-28 Fetal carriers of the Factor V Leiden mutation are prone to miscarriage and placental infarction.29 Pre-conception identification of maternal Factor V Leiden heterozygosity predicts increased fetal loss.6,30The presence of the maternal G1691A Factor V Leiden mutation may be a double-edged sword. 22 Dilley et al 22 postulated that the Factor V Leiden mutation may protect against bleeding in early pregnancy. However, two thrombophilic mutations, G1691A Factor V Leiden and the G20210A prothrombin gene, have been implicated in very early pregnancy loss.15 Acquired activated protein C resistance, independent of the Factor V Leiden mutation, is also a risk factor for RPL.31 The G20210A prothrombin gene mutation has been associated with both RPL and 2nd and 3rd trimester pregnancy complications in most 12,19,25,26,32 but not all 33 studies. The thrombophilic C677T mutation of the methylenetetrahydrofolate reductase gene (MTHFR) has also been associated with RPL and 2nd and 3rd trimester pregnancy complications in most 10,25,26,34,35 but not all 12 studies. The thrombophilic antiphospholipid antibody syndrome has been associated with RPL.36-38 Familial and acquired hypofibrinolytic disorders have also been implicated as etiologies for RPL including the 4G/5G mutation of the plasminogen activator inhibitor gene25,39 and its gene product, plasminogen activator inhibitor activity (PAI-Fx).40-43Women with polycystic ovary syndrome (PCOS) have a high frequency of first trimester spontaneous abortion (SAB), 42-48 ranging from 73%43 to 62%,44 42%,46 35%,47 and 25%48 of pregnancies. Metformin lowers the rate of first trimester SAB in PCOS.43-46 In the largest PCOS-pregnancy study to date (72 women, 84 fetuses),44 metformin during pregnancy safely reduced 1st trimester SAB from 62% to 26%, p<. 0001. On metformin, reductions in serum insulin and PAI-Fx, an independent significant determinant of SAB,42 are correlated.43 To date, however, no placebo-controlled, blinded trials of metformin in prevention of SAB in PCOS have been published.Hyperinsulinemia is an independent, significant risk factor for RPL in PCOS. 44 In 72 women with PCOS, pre-treatment fasting serum insulin was a significant explanatory variable for total (previous and current) first trimester SAB, odds ratio 1.32 (for each 5 uU/ml rise in insulin), 95% CI 1.09-1.60, p=.0005.44 Craig et al49 have reported that women with RPL have a significantly increased prevalence of insulin resistance when compared with matched fertile controls. They speculated49 that the insulin-RPL association was mediated42 through hypofibrinolytic high PAI-Fx, an independent determinant of SAB. PAI-Fx rises with increasing levels of serum insulin and falls when insulin is reduced by metformin.42,43,50,51In women with recurrent miscarriage, screening reveals a higher than normal incidence of polycystic ovaries. 52 Hence, a high level of fetal loss is characteristic not only of women with RPL with thrombophilia,7-15,19,23-28,31,32,34-39 and/or hypofibrinolysis, 25,39-43 but also of women with PCOS.42-48Blumenfeld and Brenner 53 have proposed that placental thrombosis may be the final common pathophysiologic pathway for RPL. Prophylactic therapy with low molecular weight heparin54-59 or unfractionated heparin60 in women with heritable and acquired thrombophilia reduces pregnancy wastage compared to their previous pregnancies without thromboprophylaxis. To date, however, no placebo-controlled, blinded trials of low molecular weight heparin in prevention of RPL have been published. The only controlled clinical trials involving heparin and RPL have been carried out in women with antiphospholipid antibody syndrome.17,61How we can help you If you meet the criteria, as above for RPL, for VEPL, or have been diagnosed as having polycystic ovary syndrome, then work through your local physicians to get blood drawn for the following blood coagulation tests: PCR-cDNA: G1691A Factor V Leiden, G20210A Prothrombin, C677T and A 1298C MTHFR, and 4G/5G mutations of the plasminogen activator inhibitor-1 gene. These can be done in a 5 cc purple top tube of blood, and if these cannot easily be done in your locale, they can be done at MDL laboratory in Cincinnati, with the blood sent by overnight courier unrefrigerated. You can call them at 513-475-6631 to set up arrangements to have these assays done. Be sure to arrange for a copy of the laboratory results to be sent to Dr CJ Glueck at the Cholesterol Center and to have these marked RPL-VEPL so that Dr Glueck will know what study group they represent. Serologic tests (in the liquid blood): Resistance to activated protein C, Proteins C, S, antithrombin III, homocysteine, lupus anticoagulant, APTT, Factors VIII and XI, Lp(a), plasminogen activator inhibitor activity.. When the results are available, either email them to us ( glueckch@healthall.com) or fax them to us (513-585-7950), and we will interpret them, free of charge, and then send you suggestions as to how to deal with any problems that are found. All information will be entirely confidential.Should you wish to make a 1.5 hour outpatient visit to our Cholesterol Center in Cincinnati for a direct personal evaluation by Dr CJ Glueck and staff, that visit will not be free, but is usually covered by third party insurance. You can check on the mechanics of the third party insurance by calling 513-585-7800 and asking to speak to the receptionist.
E-mail: glueckch@healthall.com Metformin continued through pregnancy in women with polycystic ovary syndrome is not
associated with an increased prevalence of pre-eclampsia. E-mail: glueckch@healthall.com or cglueck@fuse.net Fax: 513-585-7950 cr2oo3_173). Presented, National Clinical Research Meetings, Baltimore, 3/14-16,2003 To prospectively assess the safety of metformin (2.55 g/day) during pregnancy, the development of pre-eclampsia was studied in 83 women with polycystic ovary syndrome (PCOS), 80 with singleton live births, 3 sets of twins (3.6%), compared to 252 normal, non-PCOS, consecutively delivered women in a community practice of obstetrics, 241 with singleton live births, 11 sets of twins (4.4%). Of the 83 women with PCOS, 2.4% were African-American vs 10% of controls, p= .034. Reflecting their predominant infertility before metformin therapy, the women with PCOS were older than the 252 control women (30.6 ± 4.7 vs 28.8 ± 5.9 years, p=0.023), and reflecting their hyperinsulinemia-driven morbid obesity, much heavier (205 ± 53 vs 159 ± 39 pounds, p<.0001). Of the 83 women with PCOS, 2 (2.4%) had pre-conception type 2 diabetes mellitus, not different (p>0.1) than controls (1/250 [0.4%]). Of 106 previous pregnancies without metformin, the 83 women with PCOS had 72 spontaneous abortions (68%) vs 51 of 289 (18%) previous pregnancies in the 252 controls, p< .0001. The percent of women with PCOS > age 35 at conception on metformin (14%) did not differ from controls (13%), p>0.7. In 83 pregnancies on metformin, 5 women with PCOS developed pre-eclampsia (6.0%) not different (p =.35) than 9 of 252 controls (3.6%). Pre-eclampsia did not differ (p>0.15) in PCOS vs controls after covariance adjusting for age, race, and body weight. In those 41 women with PCOS who were primigravidas, 2 (4.9%) sustained pre-eclampsia, not different (Fisher's p=1.0) from 4 of 91 (4.4%) control primigravidas. In a second analysis, the 83 women with PCOS were matched by age, race, and weight with 83 controls. In 83 pregnancies on metformin, 5 women with PCOS developed pre-eclampsia (6.0%) not different (p >0.7) than 3 of 83 (3.6%) age-race-weight-matched controls. Of the 86 live births to the 83 women with PCOS there were no major birth defects, birth weight and length did not differ from CDC national population controls, and there was no neonatal hypoglycemia. When continued throughout pregnancy in women with PCOS, metformin appears to be safe, and is not associated with pre-eclampsia. Recurrent pregnancy loss, thrombophilia, hypofibrinolysis, and polycystic ovary
syndrome. E-mail: glueckch@healthall.com or cglueck@fuse.net Fax: 513-585-7950 CR2003) Presented, National Clinical Research Meetings, Baltimore, 3/14-16,2003 Since thrombophilia, hypofibrinolysis, and polycystic ovary syndrome (PCOS) are all associated with recurrent pregnancy loss (RPL) (>3 consecutive pregnancy losses < 20 weeks gestation), our specific aim was to evaluate associations of thrombophilia and hypofibrinolysis and their interactions with RPL in 44 women referred with RPL, 28 of whom were subsequently found to have PCOS. For comparisons of gene mutations associated with thrombophilia (Arg506Glu leiden mutation in the Factor V gene, G20210 prothrombin gene, C677T MTHFR gene, glycoprotein Iib/IIIa [PL A1/A2] gene) or hypofibrinolysis (4G4G mutation of the plasminogen activator inhibitor gene [PAI-1]), the 44 women with RPL were compared to 238 healthy normal controls. For comparisons of non-PCR coagulation measures, the 44 women with RPL were compared to 23 normal parous women, matched for age and race. Main outcome measures included the presence of and interaction between coagulation disorders in women with RPL, as well as relationships of PCOS to coagulation disorders and to RPL. The 44 women with RPL differed from 238 normal controls for the Factor V Leiden mutation, 11% vs 3%, p=. 01, and for the 4G4G genotype of PAI-1 gene, 34% vs 20%, p=. 042. Of the 238 normals, 84 (35.3%) had both wild type normal V Leiden and PAI-1 genes, vs 3 of 28 cases (6.8%); cases were more likely to have ³ 1 gene mutation or 2 gene mutations (2.3% vs 0.8%), X2 = 15, df =3. p =. 002. By stepwise logistic regression, the V Leiden mutation (p =. 014) and the 4G4G PAI-1 genotype (p=. 003) were associated with RPL. The odds ratio of cases versus controls for a V Leiden*PAI-1 gene mutation interaction was 2.02, 95% CI 1.41-3.43, p = .0005. RPL cases also differed from 23 normal female controls for high plasminogen activator inhibitor activity (PAI-Fx), 29% vs 4%, p=. 024. Of 44 RPL cases, 28 (64%) were found to have PCOS. Heritable thrombophilia (the Factor V Leiden mutation), heritable hypofibrinolysis (4G4G PAI-1 genotype, high PAI-Fx), their interactions, and PCOS are treatable disorders associated with RPL. Actos and metformin in women with polycystic ovary sydrome not optimally responsive
to metformin. E-mail: glueckch@healthall.com or cglueck@fuse.net Fax: 513-585-7950 CR 2003_4) ) Presented, National Clinical Research Meetings, Baltimore, 3/14-16,2003 Our specific aim in a prospective open label study in an outpatient clinical research center was to assess the efficacy and safety of Actos (45 mg/d, median 7 months) when added to antecedent Metformin (2.55 g/d, median 12 months) and diet (1500 calorie, 26% protein, 44% carbohydrate), in 15 women with polycystic ovary syndrome (PCOS) not optimally responsive to Metformin and diet. Fifteen oligo-amenorrheic women with PCOS, mean ± SD BMI 38.4 ± 8.8, age 29 ± 10, were studied. All subjects followed a 1500 calorie, 26% protein, 44% carbohydrate diet. Metformin alone was given to 15 women for a median of 12 months; Actos (45 mg/d) was then added to the Metformin for a median of 7 months in 13 women. Main outcome variables were menstrual status, changes in sex hormones, insulin, HOMA insulin resistance (IR), insulin secretion, and HDL cholesterol. On Metformin, median fasting serum insulin fell (21 to 16 uU/ml, p=. 02), DHEAS, HOMA IR, and insulin secretion were unchanged (p ³ 0.1); sex hormone binding globulin (SHBG) fell (40 to 31 nmol/l, p =. 025). On Metformin, 54 of 134 (40%) expected menses occurred. Menstrual status on Metformin included none (36%), irregular (>6 weeks apart) (37%), and regular (27%), versus pre-Metformin baseline (54% none, 46% irregular, X2 = 4.7, p = .098). Compared to Metformin, on Actos + Metformin, DHEAS fell (178 to 154 ug/dl, p =. 017), SHBG rose (31 to 42 nmol/l, p=. 0015), insulin fell (16 to 11 uU/ml, p =. 0002), IR fell (3.58 to 2.04, p =. 006), insulin secretion fell (224 to 144, p=.0002), and HDL cholesterol rose (39 to 41 mg/dl, p=.008). On Actos + Metformin, 51 of 83 (61%) expected menses occurred, better than on Metformin alone (X2 = 9.2, p = .0024). Menstrual status on Actos + Metformin included none (11%), irregular (57%), and regular (32%), X2 = 7.5, p =. 023 vs Metformin alone, X2 =12.5, p =. 0019 vs pre-Metformin baseline. In women with PCOS who failed to respond optimally to Metformin, when Actos was added as a second insulin-sensitizing drug, insulin, IR, insulin secretion, and DHEAS fell, SHBG and HDL cholesterol rose, and menstrual regularity improved, without adverse side effects on the Metformin-Actos combination. Metformin during pregnancy in women with
polycystic ovary syndrome reduces development of gestational diabetes and protects against fetal macrosomia. E-mail: glueckch@healthall.com or cglueck@fuse.net Fax: 513-585-7950
E-mail: glueckch@healthall.com |