Naila Goldenberg

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.

Low serum 25 (OH) vitamin D levels (<32 ng/mL) are associated with reversible myositis-myalgia in statin-treated patients.

Our specific aims were to determine whether low serum 25 (OH) vitamin D (D2 + D3) (<32 ng/mL) was associated with myalgia in statin-treated patients and whether the myalgia could be reversed by vitamin D supplementation while continuing statins. After excluding subjects who took corticosteroids or supplemental vitamin D, serum 25 (OH) D was measured in 621 statin-treated patients, which consisted of 128 patients with myalgia at entry and 493 asymptomatic patients. The 128 myalgic patients had lower mean +/- standard deviation (SD) serum vitamin D than the 493 asymptomatic patients (28.6 +/- 13.2 vs 34.2 +/- 13.8 ng/mL, P < 0.0001), but they did not differ (p > 0.05) by age, body mass index (BMI), type 2 diabetes, or creatine kinase levels. By analysis of variance, which was adjusted for race, sex, and age, the least square mean (+/- standard error [SE]) serum vitamin D was lower in the 128 patients with myalgia than in the 493 asymptomatic patients (28.7 +/- 1.2 vs 34.3 +/- 0.6 ng/mL, P < 0.0001). Serum 25 (OH) D was low in 82 of 128 (64%) patients with myalgia versus 214 of 493 (43%) asymptomatic patients (chi(2) = 17.4, P < 0.0001). Of the 82 vitamin-D-deficient, myalgic patients, while continuing statins, 38 were given vitamin D (50,000 units/week for 12 weeks), with a resultant increase in serum vitamin D from 20.4 +/- 7.3 to 48.2 +/- 17.9 ng/mL (P < 0.0001) and resolution of myalgia in 35 (92%). We speculate that symptomatic myalgia in statin-treated patients with concurrent vitamin D deficiency may reflect a reversible interaction between vitamin D deficiency and statins on skeletal muscle.

Metformin, pre‐eclampsia, and pregnancy outcomes in women with polycystic ovary syndrome

Aims  Was metformin during pregnancy in women with polycystic ovary syndrome (PCOS) associated with pre‐eclampsia, and was it safe for mother and neonate?

Pregnancy Loss, Polycystic Ovary Syndrome, Thrombophilia, Hypofibrinolysis, Enoxaparin, Metformin

Thrombophilia, hypofibrinolysis, and polycystic ovary syndrome (PCOS) are associated with recurrent pregnancy loss (RPL) and spontaneous abortion (SAB) alone and concurrently. The efficacy and safety of combined enoxaparin-metformin was prospectively assessed in women with PCOS with one or more previous SAB, thrombophilia, and/or hypofibrinolysis. Twenty-four white women with PCOS were studied; 23 with previous pregnancies, seven with RPL of unknown etiology (≥ three consecutive pregnancy losses <20 weeks’ gestation), two with two consecutive SABs, 13 with one SAB, and one with one live birth (HELLP syndrome). Prospectively, metformin (1.5 to 2.55 g/day) was administered before and throughout gestation, with concurrent enoxaparin (60 mg/day) throughout gestation. The 24 cases differed from 93 normal white female controls for the factor V Leiden mutation, 17% vs. 2%, Fisher’s p [pf] = .016, and for the 4G4G mutation of the plasminogen activator inhibitor-1 (PAI-1) gene (46% vs. 24%, Chi-square 4.63, p =. 031). The patients also differed from 44 normal white female controls for high levels (> 21.1 U/mL) of the PAI-1 gene product, plasminogen activator inhibitor activity (PAI-Fx) (33% vs. 8%, pf =. 018), and for high factor VIII (>150%) (22% vs. 0%, pf = .037). Of the 24 women, 23 had 65 previous pregnancies without metformin or enoxaparin, with 18 live births, 46 SAB (71%), and one elective abortion. On metforminenoxaparin, the same 23 women had 26 current pregnancies (28 fetuses), with 20 live births, two normal pregnancies 13 weeks or longer, and six SAB (21%), 3.4-fold lower than previous gestations (McNemar’s S = 33.6, p <. 0001). There were no adverse maternal or fetal therapy effects. Enoxaparin-metformin reduces pregnancy loss in women with PCOS with one or more previous SAB, who also have thrombophilia and/or hypofibrinolysis.

Vitamin D deficiency, myositis–myalgia, and reversible statin intolerance

Abstract Objective: In 150 hypercholesterolemic patients, unable to tolerate ≥1 statin because of myositis-myalgia, selected by low (<32 ng/ml) serum 25 (OH) vitamin D, we prospectively assessed whether vitamin D supplementation with resolution of vitamin D deficiency would result in statin tolerance, free of myositis–myalgia. Research design and methods: We studied 74 men, 76 women, median age 60, 131 white, 17 black and 2 other. On no statins, 50,000 units of vitamin D was given twice a week for 3 weeks, and then continued once a week. After 3 weeks on vitamin D, statins were restarted. Patients were re-assessed on statins and vitamin D every 3 to 4 months, with serial measures of serum 25 (OH) vitamin D, creatine phosphokinase (CPK), LDL cholesterol (LDLC) and assessment of myositis–myalgia. Main outcome measures: Percentage of patients myalgia-free on vitamin D plus reinstituted statins, serum 25 (OH) vitamin D, CPK, and LDLC on reinstituted statins and concurrent vitamin D supplementation. Results: On vitamin D supplementation plus re-instituted statins for a median of 8.1 months, 131 of the 150 patients (87%) were free of myositis–myalgia and tolerated the statins well. Serum 25 (OH) vitamin D increased from median 21 to 40 ng/ml (p < 0.001), and normalized (≥32 ng/ml) in 117 (78%) of 150 previously vitamin D deficient, statin-intolerant patients. Median LDLC decreased from 146 mg/dl to 95 mg/dl, p < 0.001. Conclusion: Symptomatic myositis–myalgia in hypercholesterolemic statin-treated patients with concurrent serum 25 (OH) vitamin D deficiency may reflect a reversible interaction between vitamin D deficiency and statins on skeletal muscle causing myalgia.

An observational study of severe hypertriglyceridemia, hypertriglyceridemic acute pancreatitis, and failure of triglyceride-lowering therapy when estrogens are given to women with and without familial hypertriglyceridemia.

BACKGROUND We assessed severe hypertriglyceridemia, hypertriglyceridemic acute pancreatitis, and failure of triglyceride-lowering therapy when estrogens were given to 56 women with and without familial hypertriglyceridemia. The 56 women had been consecutively referred to our center over a 3-year period because of triglycerides >400 mg/dl despite diet-drug treatment and/or a history of hypertriglyceridemic acute pancreatitis (AP). Of the 56 women, 17 had received estrogen replacement therapy (ERT), hormone replacement (HRT, n=6), or selective estrogen receptor modulators (SERM, n=1). METHODS After study at entry, in 56 women (median age, 52 years), 36 with familial hypertriglyceridemia, to lower triglycerides, estrogens and SERMs (hormone treatment, HT) were stopped; a very low fat diet (<15% of calories), gemfibrozil (1.2-1.5 mg/day), and omega-3-fatty acid (4-12 g/day) were started, with restudy 2-4 weeks later. RESULTS Of the 56 women, 24 (43%) were taking HT at entry, with median fasting triglycerides 1270 mg/dl in the HT group and 1087 mg/dl in the no-HT group. Seventeen women (30%) had a history of AP, nine of whom (53%) were/had been on HT at the development of AP. Significant positive correlates of triglycerides at entry in a stepwise regression model were hemoglobin A(1C) (partial r(2)=10.7%, p<0.05) and an interaction between estrogen use and familial hypertriglyceridemia (partial r(2)=15%, p=0.017). After 2-4 weeks on therapy, median triglycerides in the previous-HT group fell from 1270 to 284 mg/dl (p<0.0001) and in the no-HT group from 1087 to 326 mg/dl (p<0.0001). CONCLUSIONS Before starting HT, to avoid HT induced hypertriglyceridemic AP and exacerbation of overt or covert familial hypertriglyceridemia, triglycerides must be measured. HT is contraindicated in women with preexisting hypertriglyceridemia (triglycerides> or =500 mg/dl). Triglyceride-lowering diets and drugs often fail in the presence of HT and/or poorly controlled diabetes mellitus, but commonly succeed when HT is stopped and diabetes mellitus is tightly controlled.

Thrombotic events after starting exogenous testosterone in men with previously undiagnosed familial thrombophilia

Our specific aim was to describe thrombosis (osteonecrosis of the hips, pulmonary embolism, and amaurosis fugax) after exogenous testosterone was given to men with no antecedent thrombosis and previously undiagnosed familial thrombophilia. After starting testosterone patch or gel, 50 mg/day or intramuscular testosterone 400 mg IM/month, 2 men developed bilateral hip osteonecrosis 5 and 6 months later, and 3 developed pulmonary embolism 3, 7, and 17 months later. One man developed amaurosis fugax 18 months after starting testosterone gel 50 mg/day. Of these 6 men, 5 were found to have previously undiagnosed factor V Leiden heterozygosity, 1 of whom had ancillary MTHFR C677T homozygosity, and 2 with ancillary MTHFR C677T-A1298C compound heterozygosity. One man had high factor VIII (195%), factor XI (179%), and homocysteine (29.3 umol/L). Thrombotic events after starting testosterone therapy are associated with familial thrombophilia. We speculate that when exogenous testosterone is aromatized to E2, and E2-induced thrombophilia is superimposed on familial thrombophilia, thrombosis occurs. Men sustaining thrombotic events on testosterone therapy should be screened for the factor V Leiden mutation and other familial and acquired thrombophilias.

Metformin-diet ameliorates coronary heart disease risk factors and facilitates resumption of regular menses in adolescents with polycystic ovary syndrome.

BACKGROUND In 35 adolescent females (17 +/- 2 years) with polycystic ovary syndrome (PCOS), median body mass index (BMI) 30.8 kg/m2, we assessed effeicacy of metformin-diet for 1 year for reduction of weight, insulin, HOMA insulin resistance (IR), cholesterol, triglycerides, and resumption of regular menses. METHODS Calories (26% protein, 44% carbohydrate) were targeted to 1,500-1,800/day if BMI was <25 or to 1,200-1,500/day if BMI was > or = 25, along with 2,550 mg metformin. RESULTS Median weight fell from 82.7 to 79.1 kg (p = 0.009), insulin 16.7 to 13.3 microU/ml (p <0.0001), HOMA IR 3.41 to 2.74 (p = 0.0004), total cholesterol 164 to 151 mg/dl (p = 0.002), and triglyceride 103 to 85 mg/dl (p = 0.006). The percentage of cycles with normal menses rose from a pre-treatment mean of 22% to 74%, p < 0.0001. CONCLUSIONS In adolescents with PCOS, metformin-diet reduces weight, insulin, IR, cholesterol, and triglycerides, and facilitates resumption of regular menses.

Associations of thrombophilia, hypofibrinolysis, and retinal vein occlusion

We prospectively assessed whether thrombophilia and hypofibrinolysis, amplified by thrombophilic hormone replacement therapy (HRT), were associated with retinal vein occlusion (RVO). We studied 44 cases (18 men, 26 women), ≥ 3 months after RVO, 42 with central RVO, 2 with branch RVO, in the consecutive order of their referral by 2 community-based ophthalmologists. PCR and serologic coagulation assays were compared to 83 and 40 healthy adult normal controls, respectively. The 4G allele frequency of the plasminogen activator inhibitor-1 (PAI-1) gene, associated with hypofibrinolysis, was 56 of 88 (64%) in cases vs 79 of 166 (48%) in controls, X2 = 5.95, p = .015. The PAI-1 gene product, plasminogen activator inhibitor activity (PAI-Fx), was higher in cases than controls (age-race-sex-adjusted mean 12.2 U/mL vs 6.3, p = .013). By stepwise logistic regression, the PAI-1 gene 4G allele was associated with RVO, odds ratio 1.94, 95% CI 1.12-3.34, p = .018. Thrombophilic resistance to activated protein C (RAPC) was present in 6 of 32 (19%) of cases vs 0 of 40 (0%) controls, Fisher’s p [pf] = .006. Thrombophilic high factor VIII (>150%) was present in 3 of 30 (10%) cases vs 0 of 40 (0%) controls, p = .041, pf = .07. Comparing 23 RVO cases ≤ age 55 and controls ≤ age 55 (n = 44 for PCR, n = 40 for serologic measures), RAPC was present in 17% of cases vs 0% controls (pf = .026), high Factor VIII in 17% vs 0% (pf = .026), heterozygosity for the G1691A Factor V Leiden mutation in 13% vs 2% (pf = 0.11), and the 4G allele frequency of the PAI-1 gene 74% vs 39% (p = .0001). PAIFx was higher in cases than controls (age-race-sex adjusted mean 12.7 U/mL vs 6.7, p = .016). The case-control odds ratio for the PAI-1 4G allele was 5.54, 95% CI = 1.86-16.7, p = .002. Of the 26 women, 9 (35%) took HRT; 4 of the 9 had PAI-1 gene 4G4G homozygosity, 2 had thrombophilic high anticardiolipin antibody (IgG), 1 was heterozygous for the G1691A Factor V Leiden mutation, and 2 were heterozygous for the thrombophilic PL A1/A2 mutation of the platelet glycoprotein IIb/IIIa gene. Associations between heritable coagulation disorders and RVO, most marked in cases ≤ age 55, and often amplified in women by thrombophilic HRT, are, speculatively, causal.

Coronary heart disease risk factors in adult premenopausal white women with polycystic ovary syndrome compared with a healthy female population

Our specific aim was to determine whether coronary heart disease (CHD) risk factors in polycystic ovary syndrome (PCOS) patients were independent of their higher body mass index (BMI) and centripetal obesity. In adult, premenopausal, white women, CHD risk factors were compared between 488 patients with well-defined PCOS and 351 healthy free-living population controls from the Princeton Follow-up Study (PFS). After excluding women with irregular menses (putative PCOS phenotypes), comparisons were also made between the 261 PFS women with a history of regular menses and the 488 women with PCOS. Fasting lipids, insulin, glucose, homeostasis model assessment of insulin resistance (HOMA-IR), HOMA insulin secretion, blood pressure, BMI, and waist circumference were measured. Compared with both the full cohort of 351 PFS women and the subgroup of 261 PFS women with regular menses, women with PCOS had higher BMI, waist circumference, total and low-density lipoprotein cholesterol, triglyceride, systolic blood pressure, diastolic blood pressure, insulin, glucose, and HOMA-IR (all Ps < or = .005). After adjusting for age and BMI, women with PCOS, compared with the 351 and 261 PFS women, had lower high-density lipoprotein cholesterol (P < .0001, .0008) and higher systolic blood pressure (P = .0002, < .0001), insulin (P = .017, .039), HOMA-IR (P = .013, .032), and HOMA insulin secretion (P = .022, .037). The small subgroup of PCOS women with normal BMI (<25 kg/m(2)) (36/488, 7%) also had higher age-adjusted insulin, glucose, and HOMA-IR (all Ps < .005) than the subgroup of PFS women with BMI less than 25 kg/m(2) (123/261, 47%). Increased CHD risk factors and high HOMA-IR in PCOS cannot be exclusively attributed to their preponderant centripetal obesity. Identification of women with clinical features of PCOS should alert the clinician to potentially increased risk for CHD and prompt CHD risk factor testing.