Luann Sieve-Smith

Continuing metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce first-trimester spontaneous abortion: a pilot study

OBJECTIVE To determine whether metformin would safely reduce the rate of first-trimester spontaneous abortion without teratogenicity in 19 women with the polycystic ovary syndrome (PCOS). DESIGN Prospective pilot study. SETTING Outpatient. PATIENT(S) Twenty-two previously oligoamenorrheic, nondiabetic women with PCOS; 125 women with PCOS who were not currently pregnant and who had > or = 1 previous pregnancy while they were not receiving metformin. INTERVENTION(S) Metformin, 1.5-2.55 g/day, throughout pregnancy. MAIN OUTCOME MEASURE(S) Rates of first-trimester spontaneous abortion and teratogenicity. RESULT(S) Before metformin, 10 women had 22 previous pregnancies with 16 first-trimester spontaneous abortions (73%). While receiving metformin, these 10 women had 6 normal live births (60%), 1 spontaneous abortion (10%), and 3 normal ongoing pregnancies (30%) (all > or = 13 weeks; median gestation, 23 weeks). Among women receiving metformin, including those with live births and normal pregnancy for at least the first trimester, 1 of 10 (10%) had first-trimester spontaneous abortion compared with 73% in 22 previous pregnancies without metformin (P<.002). To date, the 19 women receiving metformin have had no adverse maternal side effects, and no birth defects have occurred; 9 (47%) had normal term live births, 2 (11%) had normal and appropriate for gestational age births (one at 33 and one at 35 weeks), 6 (32%) have ongoing normal pregnancies lasting longer than the first trimester, and 2 (10.5%) had first-trimester spontaneous abortions. Sonography showed normal fetal development without congenital defects in the 6 ongoing pregnancies (median gestation, 23 weeks). Among women who received metformin before conception, reductions in insulin and plasminogen activator inhibitor activity were correlated (r=0.65, P=.04). CONCLUSION(S) Metformin therapy throughout pregnancy in women with PCOS reduces the otherwise high rate of first-trimester spontaneous abortion seen among women not receiving metformin and does not appear to be teratogenic.

Incidence and treatment of metabolic syndrome in newly referred women with confirmed polycystic ovarian syndrome

In 138 oligo-amenorrheic white women with polycystic ovary syndrome (PCOS) (31+/-9-years-old), our first specific aim was to assess the incidence of the metabolic syndrome and to compare metabolic syndrome abnormalities in women with PCOS to those in the National Health and Nutrition Examination Survey (NHANES) III cohort of 1,887 white women. Our second aim was to determine whether metformin (2.55 g/d) and a diet of 1,500 calories, 26% protein, 44% carbohydrate (42% of carbohydrate complex), 30% fat (polyunsaturate/saturate ratio [P/S]=2/1), would ameliorate metabolic syndrome abnormalities in women with both PCOS and metabolic syndrome. The metabolic syndrome was present in 64 (46%) of the women with PCOS. In these 64 women, there were abnormalities in waist circumference (98%), high-density lipoprotein cholesterol (HDL-C) (95%), blood pressure (70%), triglycerides (56%), and glucose (11%). In these 64 women, mean +/- SD waist circumference was 116+/-15 cm, triglyceride 192+/-152 mg/dL, HDL-C 39+/-7 mg/dL, systolic blood pressure 131+/-13 mm Hg, diastolic blood pressure 83+/-7 mm Hg, and serum glucose 94+/-22 mg/dL. Serum insulin was high (>17 microU/mL) in 42 of the 64 women (66%). After age adjustment, 46.4%+/-4.2% of women with PCOS had the metabolic syndrome (> or =3 abnormalities) versus 22.8%+/-1.1% of NHANES III women, P<.0001 versus 6% of 20 to 29-year-old and 15% of 30 to 39-year-old NHANES III women. Of the 64 women with both PCOS and the metabolic syndrome, 50 had follow-up studies after an average of 6 months on metformin and diet. At 6 months follow-up, mean percent reductions were as follows: body weight 4.7% (111 to 106 kg, P<.0001), triglycerides 14% (197 to 136 mg/dL, P=.0001), systolic blood pressure 5.2% (131 to 124 mm Hg, P=.0002), diastolic blood pressure 6% (83 to 77 mm Hg, P=.0007), and insulin 31% (25 to 17 microU/mL, P<.0001); mean percent HDL-C increased 6% (39 to 41 mg/dL, P=.013). Of these 50 women, 29 had pretreatment baseline abnormal triglycerides (> or =150 mg/dL), 47 had low HDL-C (<50 mg/dL), 26 had high systolic blood pressure (> or =130 mm Hg), 16 had high diastolic blood pressure (> or =85 mm Hg), and 5 had glucose > or = 110 mg/dL. On metformin plus diet at 6 months, triglycerides moved within guidelines in 10 of 29 (34%) women, HDL-C in 6 of 47 (13%), systolic blood pressure in 16 of 26 (62%), diastolic blood pressure in 10 of 16 (63%), and glucose in 3 of 5 (60%). Metformin and diet ameliorate many of the features of the metabolic syndrome, present in 46% of women with PCOS in the current study, and should reduce risk for atherothrombosis and type 2 diabetes mellitus (DM) in PCOS.

Metformin therapy throughout pregnancy reduces the development of gestational diabetes in women with polycystic ovary syndrome

OBJECTIVE To assess whether metformin safely reduced development of gestational diabetes in women with the polycystic ovary syndrome (PCOS). DESIGN Prospective and retrospective study. SETTING Outpatient clinical research center. PATIENT(S) The prospective study included 33 nondiabetic women with PCOS who conceived while taking metformin and had live births; of these, 28 were taking metformin through delivery. The retrospective study included 39 nondiabetic women with PCOS who had live birth pregnancies without metformin therapy. INTERVENTION(S) Metformin, 2.55 g/d, throughout pregnancy in women with PCOS. MAIN OUTCOME MEASURE(S) Development of gestational diabetes in women with PCOS. RESULT(S) Before metformin therapy, after covariance adjustment for age, the two cohorts did not differ in height, weight, basal metabolic index, insulin, insulin resistance, or insulin secretion. Both cohorts had high fasting insulin, were insulin resistant, and had high insulin secretion. Among the 33 women who received metformin, gestational diabetes developed in 1 of 33 (3%) pregnancies versus 8 of 12 (67%) of their previous pregnancies without metformin. Among the 39 women who did not take metformin, gestational diabetes developed in 14 of 60 (23%) pregnancies. When all live births were combined, gestational diabetes occurred in 22 of 72 pregnancies (31%) in women who did not take metformin versus 1 of 33 pregnancies (3%) in those who took metformin. With gestational diabetes as the response variable and age at delivery and treatment group (metformin or no metformin) as explanatory variables, the odds ratio for gestational diabetes in women with metformin versus without metformin was 0.093 (95% CI: 0.011 to 0.795). With gestational diabetes in 93 pregnancies as the response variable and age at delivery and treatment group (metformin no metformin) as explanatory variables, the odds ratio of gestational diabetes in pregnancies in women taking metformin versus without metformin was 0.115 (95% CI: 0.014 to 0.938). CONCLUSION(S) In PCOS, use of metformin is associated with a 10-fold reduction in gestational diabetes (31% to 3%). It also reduces insulin resistance and insulin secretion, thus decreasing the secretory demands imposed on pancreatic beta-cells by insulin resistance and pregnancy.

Metformin-induced resumption of normal menses in 39 of 43 (91%) previously amenorrheic women with the polycystic ovary syndrome

In 43 amenorrheic women with polycystic ovary syndrome (PCOS), 31 (74%) with fasting hyperinsulinemia (> or =20 microU/mL), our aim was to determine whether Metformin (Bristol-Myers Squibb, Princeton, NJ), which reduces hyperinsulinemia, would reverse the endocrinopathy of PCOS, allowing resumption of regular normal menses. A second aim was to assess the effects of weight loss versus other Metformin-induced effects on ovarian function, and to determine if there were different responses to Metformin between those who lost weight and those who did not. A third aim was to assess associations between PCOS, 4G/5G polymorphism in the promoter sequence of the plasminogen activator inhibitor-1 gene (PAI-1 gene), and PAI activity (PAI-Fx). Of the 43 women, 40 (93%) had normal fasting blood glucose and 37 had normal hemoglobin A1C (HgA1C); onlythree (7%) had type 2 diabetes mellitus. Metformin (1.5 to 2.25 g/d) was given for 6.1+/-5.1 months (range, 1.5 to 24), to 16 patients for less than 3 months, to 12 for 3 to 6 months, and to 15 for at least 6 months. On Metformin, 39 of 43 patients (91%) resumed normal menses. The percentage of women resuming normal menses did not differ among treatment duration groups (P<.1) or among dose groups (P>.1). The body mass index (BMI) decreased from 36.4 + 7 Kg/m2 at study entry to 35.1+/-6.7 on Metformin (P=.0008). Of 43 patients, 28 (67%) lost weight (1 to 69 pounds), with nine (21%) losing at least 12 pounds. On Metformin, the median fasting serum insulin decreased from 26 microU/mL to 22 (P=.019), testosterone decreased from 61 ng/dL to 47 (P=.003), and estradiol increased from 41 pg/mL to 71 (P=.0001). Metformin-induced improvements in ovarian function were independent of weight loss (testosterone decrease, P<.002; estradiol increase, P<.0004). The change in response variables on Metformin did not differ (P>.05) between those who lost weight and those who did not, excepting Lp(a), which increased 4 mg/dL in those who lost weight and decreased 9 mg/dL in those who did not (P = .003). The change in response variables on Metformin did not differ among the five quintiles of weight loss, excepting fasting glucose (P<.05), which increased 6 mg/dL in those who lost the least weight on Metformin versus those in the 60th to 80th percentile for weight loss, in whom glucose decreased 33 mg/dL. Although the pretreatment fasting serum insulin was not significantly correlated with testosterone (r=.24, P=.13) or androstenedione (r=.27, P=.09), on Metformin, the change in insulin correlated positively with the change in testosterone (r=.35, P=.047) and with the change in androstenedione (r=.48, P=.01). Patients were more likely than normal controls (83% v 64%, P=.016) to be heterozygous or homozygous for 4G polymorphism of the PAI-1 gene and were also more likely to have high PAI-Fx (> or =22 U/mL, 28% v3%, chi(2)=10.1, P=.001). Metformin reduces the endocrinopathy of PCOS, allowing resumption of normal menses in most (91%) previously amenorrheic women with PCOS.

Evidence that homocysteine is an independent risk factor for atherosclerosis in hyperlipidemic patients

In 482 patients sequentially referred for diagnosis and therapy of hyperlipidemia, our specific aim was to determine the prevalence of homocysteinemia, to assess whether it was independently associated with atherosclerotic vascular disease, and to determine how effectively high homocysteine could be treated with folic acid and pyridoxine. Of the 482 patients, 18 (3.7%) had high homocysteine (> or = 16.2 mumol/L, median = 19), 31 had high cystathionine (> or = 342 nmol/L) with normal homocysteine (median = 12), and 433 had normal cystathionine and homocysteine (median = 9). Of the 18 patients with high homocysteine, 13 (72%) had atherosclerotic vascular disease, much higher than the 44% (192 of 433 patients) with normal homocysteine (chi-square = 5.4, p = 0.02). In the 18 kindreds with a homocysteinemic proband, 14 (78%) had > or = 1 first-degree relatives with atherosclerotic vascular disease before age 65, compared with 50% (215 of 433) of the families where the proband had normal homocysteine (chi-square = 5.5, p = 0.02). In the 482 patients already at high risk for atherosclerotic vascular disease by virtue of hyperlipidemia, when assessed by logistic regression, homocysteine was an independent positive predictor of atherosclerotic vascular disease (p = 0.007); relative risk for atherosclerotic events was 2.8 times higher (p = 0.0004) in patients with top (> or = 11.4 mumol/L) than with bottom (< 6.9 mumol/L) quintile homocysteine. After 15 weeks of folic acid (5 mg/day) and pyridoxine (100 mg/day) therapy in 10 patients with high homocysteine, median homocysteine normalized, decreasing from 18 to 11 mumol/L (p = 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Metformin to restore normal menses in oligo-amenorrheic teenage girls with polycystic ovary syndrome (PCOS)

PURPOSE To describe our clinical experience in using Metformin combined with a high protein-low carbohydrate diet to restore normal menstrual cycles in teenaged females with polycystic ovary syndrome (PCOS). METHODS To enter the study, patients had to have well-documented PCOS, be oligo- (six cycles or less in the preceding year) or amenorrheic (absence of menstrual cycles for 1 year), and not have exclusionary diseases or drugs. Accompanying a high protein-low carbohydrate diet, Metformin (1.5-2.55 g/day) was given for 10.5 +/- 6.4 months (range, 4.5-26.5 months). Follow-up every 8-10 weeks for > or =6 months was scheduled with interval history, review of menstrual status, assessment of any Metformin-related side effects, brief physical examination, and determination of weight and blood pressure. RESULTS All 11 girls had normal fasting blood glucose and glycohemoglobin. Pre-Metformin, five girls were amenorrheic, three had only one menstrual cycle in the previous year, and three had > or =6 cycles/year. With Metformin, 10 of 11 girls (91%) resumed regular normal menses; 39% of 38 follow-up visits with regular normal menstrual cycles were ovulatory with normal luteal-phase serum progesterone (> or =2.3 ng/mL). Of the 11 girls, nine (82%) lost weight; five girls lost > or =11 lb and seven lost > or =5 lb. After adjusting for weight reduction, with Metformin, estradiol and progesterone rose (p =.0014,.027, respectively) (changes consistent with resumption of regular normal menses), total plasma cholesterol fell (p =.026), and there was a downward trend in testosterone (p =.068). CONCLUSION Metformin safely ameliorates the endocrinopathy of PCOS in previously oligo-amenorrheic teenage females with PCOS, facilitating resumption of normal menses in most girls.

The plasminogen activator inhibitor-1 gene, hypofibrinolysis, and osteonecrosis.

In 59 patients with osteonecrosis of the hip, four genes associated with thrombophilia or hypofibrinolysis along with coagulation tests were studied to determine the pathoetiologic associations of heritable coagulation disorders with osteonecrosis. Patients did not differ from healthy control subjects for the thrombophilic Factor V Leiden, prothrombin, or methylenetetrahydrofolate reductase mutations. The plasminogen activator inhibitor-1 gene was shifted toward homozygosity for the 4G polymorphism; 41% of patients with osteonecrosis were homozygous for the 4G/4G polymorphism versus 20% of 40 healthy control subjects. The gene product of the 4G polymorphism, hypofibrinolytic plasminogen activator inhibitor activity, was higher in patients than in control subjects (median 19.2 versus 6.3 U/mL); 61% of patients had high plasminogen activator inhibitor activity (> or = 16.4 U/mL) versus 5% of control subjects. Stimulated tissue plasminogen activator activity (inhibited by plasminogen activator inhibitor activity) was lower in patients than in control subjects (3.10 versus 5.98 IU/mL); 31% of patients had low stimulated tissue plasminogen activator activity (< 2.28 IU/mL) versus 3% of control subjects. Heritable hypofibrinolysis conferred by the 4G/4G mutation of the plasminogen activator inhibitor-1 gene seems to be a major pathoetiology of primary osteonecrosis.

Effect of Exogenous Estrogen on Atherothrombotic Vascular Disease Risk Related to the Presence or Absence of the Factor V Leiden Mutation (Resistance to Activated Protein C)

Estrogen replacement therapy (ERT), which produces acquired resistance to activated protein C when superimposed on heritable resistance to activated protein C (the mutant Factor V Leiden trait), may promote venous and arterial thrombosis. In a cross-sectional study of 423 women referred for hyperlipidemic therapy (93 of whom [22%] were on ERT), our specific aim was to determine whether ERT and heterozygosity for the Factor V Leiden mutation and/or resistance to activated protein C interacted as risk factors for atherothrombosis. Of the 423 women, 168 (40%) had atherothrombosis, 19 (4%) were heterozygous for Factor V Leiden mutation or had resistance to activated protein C <2 (Factor V Leiden mutation+), and 404 were wild-type normal for the Factor V gene and/or had resistance to activated protein C > or =2 (Factor V Leiden mutation-). By stepwise logistic regression, positive explanatory variables for atherothrombosis included hypertension (p = 0.002), age (p = 0.003), relatives with atherothrombosis (p = 0.002), anticardiolipin antibody immunoglobulin-M (p = 0.02), and a Factor V Leiden mutation*ERT interaction term where atherothrombosis events were more likely in 2 subgroups of women (ERT- and Factor V Leiden mutation-) or (ERT+ and Factor V Leiden mutation+) (p = 0.02). High-density lipoprotein cholesterol was inversely associated with atherothrombosis (p = 0.004). In a separate logistic regression model for the 213 women with a polymerase chain reaction measurement of the Factor V gene, ERT was protective (p = 0.008); the Factor V Leiden mutation was positively associated with atherothrombosis (p = 0.05). The atherothrombosis odds ratio risk for ERT (yes vs no) was 0.36 (95% confidence intervals [CI] 0.16 to 0.74, p = 0.007). The atherothrombosis risk odds ratio in women heterozygous for the Factor V Leiden mutation (vs normal) was 2.00 (95% CI 1.02 to 4.22, p = 0.05). ERT may be protective against atherothrombosis when the Factor V Leiden mutation is absent, whereas the Factor V Leiden mutation may increase risk for atherothrombosis, particularly in the presence of ERT. We suggest that the Factor V Leiden mutation be measured in all women on ERT or before beginning ERT to identify those heterozygous for the Factor V Leiden mutation (4%), in whom ERT is relatively or absolutely contraindicated because of increased risk for atherothrombosis and thromboembolism. A second, much larger group of women will also be identified without the factor V Leiden mutation (96%), in whom ERT may reduce the risk for atherothrombosis.

Secondhand smoke, hypofibrinolysis, and Legg-Perthes disease

In 39 children with Legg-Perthes disease who were nonsmokers, the specific aim was to assess relationships among parental cigarette smoking during pregnancy, household smoking before diagnosis of Legg-Perthes disease, hypofibrinolysis, and thrombophilia. Fifteen (38%) children had no secondhand smoke exposure; 24 (62%) had secondhand smoke exposure before their diagnosis. Seventeen (71%) of these 24 children were exposed while in utero to smoking by a parent or live in relative and also had exposure to household smoke during childhood; seven (29%) had only household smoke exposure in childhood. In the full cohort of 39 children, secondhand smoke exposure correlated inversely with the major stimulator of fibrinolysis, stimulated tissue plasminogen activator activity. Of the children exposed to smoking, 48% had low stimulated tissue plasminogen activator activity (< 2.19 IU/ml) compared with 7% of the children without secondhand smoke exposure and 14% of 22 healthy control children. Secondhand smoke exposure had no significant effects on other measures of coagulation. Secondhand smoke exposure while in utero and during childhood appears to lower stimulated tissue plasminogen activator activity and additionally may depress heritable low stimulated tissue plasminogen activator activity, leading to hypofibrinolysis. Hypofibrinolysis may facilitate thrombotic venous occlusion in the head of the femur, leading to venous hypertension and hypoxic bone death, Legg-Perthes disease.

Risk factors for pulmonary emboli after total hip or knee arthroplasty

Because it is difficult to predict which patients may sustain a pulmonary embolism after total hip or knee arthroplasty, we assessed multiple thrombophilic and hypofibrinolytic parameters to identify risk factors. Twenty-nine patients who survived a known pulmonary embolism after total knee or total hip arthroplasty were matched by age, gender, race, arthritic diagnosis, procedure, and surgery date with 29 patient-controls who had a total hip or knee arthroplasty but who did not have a symptomatic known pulmonary embolism or deep vein thrombosis. Twenty-one serologic measures and five genes associated with thrombophilia, hypofibrinolysis, or both were assessed without knowledge of group assignment. All patients with pulmonary embolism had at least one abnormality of plasminogen activator inhibitor activity, dilute Russell’s viper venom time, prothrombin time, or total cholesterol versus 13 of 27 (48%) control patients. Forty-seven percent of patients who experienced pulmonary embolism had at least two abnormalities of plasminogen activator inhibitor activity, dilute Russell’s viper venom time, prothrombin time, or total cholesterol, versus 7% of control patients. Preoperatively, to identify patients at high risk of pulmonary embolism, plasminogen activator inhibitor activity, dilute Russell’s viper venom time, prothrombin time, and cholesterol levels were most predictive. Using at least one abnormality of these four measures as a screening test to detect risk of pulmonary embolism, the test is sensitive (100%), and the predictive value of a negative test is high (100%). After additional prospective study, this may allow identification of patients at low risk (the majority of patients) in whom anticoagulation may not be required and a small group of patients at high risk for pulmonary embolism in whom prophylactic anticoagulation should be provided.