An observational study of reduction of insulin resistance and prevention of development of type 2 diabetes mellitus in women with polycystic ovary syndrome treated with metformin and diet.

Our first specific aim in an observational study of 431 nondiabetic women with polycystic ovary syndrome (PCOS), aged >or=20 years and with >or=11 months follow-up on metformin diet, was to prospectively assess relationships between pretreatment glucose and insulin resistance (IR) and the development of type 2 diabetes mellitus (T2DM) or gestational diabetes (GD). Our second specific aim was to determine whether development of T2DM and GD was independently associated with lesser reduction of IR on metformin diet when compared with women who remained free of T2DM and GD. Women with body mass index <25 kg/m(2) and those with body mass index >or=25 kg/m(2) were, respectively, instructed in a 2000- or 1500-cal/d, high-protein (26% of calories), low-carbohydrate (44%) diet, with 30% of calories as fat and a polyunsaturate-saturate ratio of 2:1. Three groups of women with PCOS were categorized: (a) 17 with no previous GD, who developed T2DM on metformin diet (mean +/- SD follow-up, 49 +/- 33 months), (b) 401 with no previous GD and free of T2DM on metformin diet (follow-up, 38 +/- 25 months), and (c) 13 with either previous GD or GD on metformin diet (follow-up, 38 +/- 25 months). On metformin diet, women who developed T2DM vs those who remained free of T2DM had higher pretreatment glucose (odds ratio [OR], 1.09; 95% confidence interval [CI], 1.03-1.16; P = .003) and homeostasis model assessment of insulin resistance (HOMA-IR) (OR, 1.22; 95% CI, 1.04-1.42; P = .01), and less reduction of HOMA-IR (OR, 0.82; 95% CI, 0.72-0.92; P = .0008). On metformin diet, women either with previous GD or who developed GD vs those who remained free of T2DM had less reduction of HOMA-IR (OR, 0.88; 95% CI, 0.78-0.99; P = .03). By repeated-measures analysis, on metformin diet, women who did not develop T2DM had reduction in HOMA-IR (P < .0001), with the slope of this curve different (P = .002) from the unchanged IR exhibited by women who developed T2DM and different (P = .017) from an increased IR slope (P = .049) in women who had GD. In women with PCOS, pretreatment glucose and IR, and lesser reduction in IR on metformin diet were associated with T2DM and GD.

Sustainability of 8% weight loss, reduction of insulin resistance, and amelioration of atherogenic-metabolic risk factors over 4 years by metformin-diet in women with polycystic ovary syndrome.

In 74 women with polycystic ovary syndrome, treated for 4 years with metformin (MET) and diet, we prospectively assessed whether, and to what degree, weight loss, reduction of insulin resistance, and amelioration of coronary heart disease risk factors could be sustained. We hypothesized that response to MET-diet would not differ by pretreatment body mass index (BMI) classes <25 (normal), > or =25 to <30 (overweight), > or =30 to <40 (obese), and > or =40 (extremely obese). [table: see text] Metformin-diet was successful in producing stable approximately 8% weight reduction for all 4 years (trend P < .0001). Percentage of reductions in weight on MET-diet was significant (P < .05) and did not differ among the 3 highest BMI categories (> or =40, > or =30 to <40, > or =25 to <30), but were not significant in the normal-weight category (BMI, <25). On MET-diet, median homeostasis model assessment of insulin resistance (HOMA-IR) was 33% lower than entry at 1 year, 50% at 2 years, 51% at 3 years, and 50% at 4 years (trend, P < .0001). On MET-diet, median low-density lipoprotein cholesterol (LDL-C) was 6% lower than entry at year 1, 6% at year 2, 7% at year 3, and 11% at year 4 (trend P < .0001). On MET-diet, median high-density lipoprotein cholesterol (HDL-C) was 3% higher than entry at year 2, 8% higher at year 3, and 11% higher at year 4 (trend P < .0001). Percentage of reductions in HOMA-IR, LDL-C, triglyceride, and systolic blood pressure, and increments in HDL-C did not differ (P > .1) in the 4 BMI categories. By stepwise regression, weight loss was a significant (P < or = .01) positive explanatory variable for reduction in HOMA-IR for all 4 follow-up years. Metformin-diet in women with polycystic ovary syndrome effectively and safely reduces weight and LDL-C while raising HDL-C, and maintains these outcomes stable over 4 years.

Changes in weight, papilledema, headache, visual field, and life status in response to diet and metformin in women with idiopathic intracranial hypertension with and without concurrent polycystic ovary syndrome or hyperinsulinemia.

The authors hypothesized that a metformin (MET)-diet would improve symptoms of idiopathic intracranial hypertension (IIH) in women who also had polycystic ovary syndrome (PCOS) or hyperinsulinemia without PCOS. Changes in weight, papilledema, headache, visual fields, and overall life status were prospectively assessed in response to 6 to 14 months on 2.25 g/day MET-diet or diet alone in 36 women with IIH, 23 with PCOS, selected by baseline body mass index (BMI) > or = 25, and no previous surgery for IIH. Overall life status was graded using a self-reported 1-5 scale (1 = well, normal activities; 2 = unwell, usual activities; 3 = poor, usual activities; 4 = poor, no usual activities; 5 = totally disabled). Conventional treatment for IIH was maintained unchanged during MET-diet intervention. The diet was hypocaloric (1500 calories/day), high protein (26% of calories), and low carbohydrate (44%). Of the 23 women with PCOS, 20 received MET-diet and 3 diet only (could not tolerate MET). Of the 13 women without PCOS, 7 were hyperinsulinemic and received MET-diet and 6 received diet alone. The 3 treatment groups (diet only [n = 9], PCOS-MET-diet [n = 20], and hyperinsulinemia-MET-diet [n = 7]) did not differ by median entry BMI (33.3, 37.6, and 35.7 kg/m(2)) or by duration of treatment (10.2, 11.4, and 10.9 months). Median percent weight loss was greatest in the PCOS-MET group (7.7%, P = 0.0015), was 3.3% in the diet only group, and 2.4% (P = 0.04) in the hyperinsulinemia-MET group. Papilledema significantly improved in the diet-alone group from 100% at baseline to 13% (P = 0.03), and in the PCOS-MET group from 95% to 30% (P = 0.002). If headache persisted on therapy, it was less intense-less frequent (P = 0.03) in the diet-only group and in the PCOS-MET group (P = 0.04). As many women with IIH have PCOS, and because weight loss is central to IIH treatment, diet-MET is a novel approach to treat IIH in women with concurrent PCOS or hyperinsulinemia without PCOS.

Growth, motor, and social development in breast- and formula-fed infants of metformin-treated women with polycystic ovary syndrome.

OBJECTIVES: To test the hypothesis that metformin during lactation versus formula feeding would have no adverse effects on infants' growth, motor-social development, or intercurrent illness. STUDY DESIGN: Growth, motor-social development, and illness requiring a pediatrician visit were assessed in 61 nursing infants (21 male, 40 female) and 50 formula-fed infants (19 male, 31 female) born to 92 mothers with polycystic ovary syndrome (PCOS) taking a median of 2.55 g metformin per day throughout pregnancy and lactation. RESULTS: Within sex, at 3 and 6 months of age, weight, height, and motor-social development did not differ (p > or = .06) between breast- and formula-fed infants. No infants had retardation of growth, motor, or social development. Intercurrent illnesses did not differ. CONCLUSIONS: Metformin during lactation appears to be safe and effective in the first 6 months of infancy.

Plasminogen activator inhibitor activity, 4G5G polymorphism of the plasminogen activator inhibitor 1 gene, and first-trimester miscarriage in women with polycystic ovary syndrome.

We assessed whether hypofibrinolytic plasminogen activator inhibitor 1 (PAI-1 activity) showed an independent association with first-trimester miscarriage in the 430 women with polycystic ovary syndrome (PCOS) who had previous pregnancies (from a cohort of 967 women with PCOS). Prospectively, we hypothesized that Glucophage (Bristol-Myers Squibb, Princeton, NJ) promotes successful live births in women with PCOS by lowering PAI-1 activity before conception and maintaining further reductions of PAI-1 activity during the first trimester of pregnancy. We also assessed whether PAI-1 activity levels were independently related to PAI-1 genotype and to modifiable risk factors body mass index (BMI), insulin, and triglyceride. By stepwise logistic regression, with the dependent variable being previous pregnancy outcomes at 3 levels (live birth pregnancies only [n = 208]; both > or =1 live birth and > or =1 first-trimester miscarriage [n = 111]; or first-trimester miscarriages only [n = 71]) and explanatory variables PAI-1 genotype, PAI-1 activity, insulin, homeostasis model assessment of insulin resistance, BMI, and triglyceride, PAI-1 activity was positively associated with first-trimester miscarriage (P = .004). For each 5 IU/mL increment in PAI-1 activity, the risk being in an adverse first-trimester miscarriage category increased (odds ratio, 1.12; 95% confidence interval, 1.04-1.20). Prospectively, from pretreatment to the last preconception visit on Glucophage, in 30 women who subsequently had live births, PAI-1 activity fell 44%, but rose 19% in 23 women with first-trimester miscarriage (P = .03). In the 30 women with live birth pregnancies, median PAI-1 activity fell continuously from pretreatment through the first trimester (from 16.8 to 6.7 IU/mL), whereas PAI-1 activity was either unchanged or rose in women with first-trimester miscarriage. Of the 921 women with PCOS who had 4G5G data, 718 (78%) had 4G4G-4G5G genotypes vs 87 (69%) of 126 normal female controls (chi(2) = 4.95, P = .026). The 4G allele frequency was 53% in women with PCOS vs 46% in controls (chi(2) = 4.3, P = .04). Of the 866 women with PCOS who had PAI-1 activity data, by stepwise regression, positive independent determinants of PAI-1 activity included BMI (partial R(2) = 10.6%, P < .0001), insulin (partial R(2) = 2.8%, P < .0001), triglyceride (partial R(2) = 1.1%, P = .0009), and the 4G4G-4G5G genotype (partial R(2) = 1%, P = .0011). The PAI-1 gene 4G polymorphism is more common in women with PCOS than in normal women and, in concert with obesity, hyperinsulinemia, and hypertriglyceridemia, contributes to treatable, hypofibrinolytic, miscarriage-promoting, high PAI-1 activity. Preconception and first-trimester decrements in PAI-1 activity on Glucophage are associated with live births, whereas increments or no change in PAI-1 activity despite Glucophage appears to be associated with first-trimester miscarriage.

Obesity and extreme obesity, manifest by ages 20-24 years, continuing through 32-41 years in women, should alert physicians to the diagnostic likelihood of polycystic ovary syndrome as a reversible underlying endocrinopathy.

OBJECTIVES: Document obesity-extreme obesity in most 20-24, 25-29, and 32-41 years old women with PCOS as a stimulus for physicians to consider the diagnosis of PCOS, an underlying reversible endocrinopathy. STUDY DESIGN: In matched age groups 20-24, 25-29, and 32-41 years, we compared BMI in 84, 129, and 188 Caucasian women with PCOS versus 956, 815, and 815 women in NHANES I (general population), and 25, 36, and 45 non-pregnant women (community obstetrics practice). RESULTS: At ages 20-24, 25-29, and 32-41 years, mean+/-S.D. BMIs in women with PCOS (35.3+/-7.7, 36.0+/-9.4, 36.7+/-8.2) were much greater than NHANES I (22.8+/-4.6, 23.3+/-5.0, 24.5+/-5.6; p < .0001), and community (26.1+/-6.8, 26.9+/-6.6, 25.2+/-5.2; p < .0001). Classifying BMI <25 (normal), > or =25-30 (overweight), > or =30-40 (obese), > or =40 (extremely obese), at ages 20-24, 25-29, and 32-41 years: 76, 73, and 78% of PCOS women were obese-extremely obese, versus 7, 11, and 14% of NHANES I, and 20, 28, and 15% of community women. At ages 20-24, 25-29, and 32-41 years, only 10, 12, and 7% PCOS women had BMIs <25, versus 78, 74, and 66% NHANES I, and 48, 47, and 58% of community women. CONCLUSIONS: Obesity-extreme obesity in women, manifest by ages 20-24 years, continuing through 32-41 years, should alert physicians to the likelihood of PCOS, an underlying, heritable, potentially reversible, insulin resistant endocrinopathy that promotes obesity.

Idiopathic intracranial hypertension: associations with thrombophilia and hypofibrinolysis in men.

The existence of an association between idiopathic intracranial hypertension (IIH) and coagulation disorders in men was assessed prospectively. Microthrombi, associated with thrombophilia-hypofibrinolysis, occlude arachnoid sinus villi, thus reducing resorption of cerebrospinal fluid, leading to IIH. Ten consecutively referred men with IIH, nine whites, one African American, median age 36 years, were 2 to 1 matched by age and race by healthy male controls. Polymerase chain reaction assays were done for four thrombophilic and one hypofibrinolytic gene mutations: G1691A factor V Leiden, G20210A prothrombin, C677T MTHFR, platelet glycoprotein IIb/IIIa (PL A1/A2), and 4G/5G polymorphism of the plasminogen activator inhibitor (PAI-1) gene promoter. Coagulation measures in plasma included dilute Russel's viper venom time (dRVVT), activated partial thromboplastin time (aPTT), the lupus anticoagulant, factor VIII, factor XI, plasminogen activator inhibitor activity (PAI-Fx), protein C antigenic, protein S total (antigenic), protein S free (antigenic), antithrombin III (functional), and resistance to activated protein C (RAPC). Tests performed on serum included anticardiolipin antibodies, homocysteine, and Lp(a). The body mass index was 40 kg/m(2) or greater (extremely obese) in two men, 30 to 40 kg/m(2) (obese) in three, and was 25 to 30 kg/m(2) in five (overweight). Cases differed from controls for inherited 4G4G homozygosity of the PAI-1 gene, four of 10 (40%) vs. one of 20 (5%), Fisher's p [p(f)]= .031, and for high levels (>21.1 U/mL) of the hypofibrinolytic PAI-1 gene product, PAI-Fx, 5 of 10 (50%) vs. one of 18 (6%), p(f) = .013. Thrombophilic factor VIII was high (> or = 150%) in three of 10 (30%) cases vs. zero of 16 (0%) controls, p(f)=. 046. The thrombophilic lupus anticoagulant was present in two of 10 (20%) cases vs. zero of 32 (0%) controls, p(f) = .052. Heritable hypofibrinolysis and heritable and acquired thrombophilia appear, speculatively, to be treatable etiologies of IIH in men. Understanding contributions of hypofibrinolysis and thrombophilia to the development of IIH should facilitate development of novel new approaches to treat this often-disabling neurologic disorder.

Enoxaparin prevents progression of stages I and II osteonecrosis of the hip.

UNLABELLED: In a prospective pilot study, we hypothesized that enoxaparin (60 mg/day for 12 weeks) would prevent progression of Stages I and II osteonecrosis of the hip associated with thrombophilia or hypofibrinolysis or both over > or = 108 weeks of followup versus untreated historic controls, with different treatment responses in primary versus corticosteroid-associated secondary osteonecrosis. Patients with one or more thrombophilic-hypofibrinolytic disorder and Ficat Stages I or II osteonecrosis of at least one hip were included. A blinded committee interpreted anteroposterior and frog-leg lateral radiographs at entry in the study and every 36 weeks to > or = 108 weeks. Maintenance of the disease at Stages I and II versus progression of the osteonecrosis to Stages III and IV requiring total hip replacement was the major end point. Sixteen patients had primary osteonecrosis (25 hips; 13 Stage I, 12 Stage II), and 12 had secondary osteonecrosis (15 hips; five Stage I, 10 Stage II). With no Enoxaparin-related complications, 19 of 20 hips (95%) with primary osteonecrosis were unchanged from Stages I and II osteonecrosis at > or = 108 weeks; 12 of 15 hips (80%) with secondary osteonecrosis progressed to Stages III and IV osteonecrosis. In primary osteonecrosis at > or = 108 weeks, survival of 95% hips, or 76% (19/25 hips, based on intent to treat), compared favorably with untreated historical controls (approximately 20% 2-year survival), comparable to 20% survival in secondary hip osteonecrosis. Enoxaparin may prevent progression of primary hip osteonecrosis, decreasing the incidence of total hip replacement. LEVEL OF EVIDENCE: Therapeutic study, II-1 (prospective cohort study).

Idiopathic intracranial hypertension, polycystic-ovary syndrome, and thrombophilia.

We studied thrombophilia, hypofibrinolysis, and polycystic-ovary syndrome (PCOS) in 65 women consecutively referred because of idiopathic intracranial hypertension (IIH) as a means of better understanding the origin of IIH, with the ultimate goal of developing novel medical therapies for IIH. Our hypothesis: IIH results in part from inadequate drainage of cerebrospinal fluid (CSF) resulting from thrombotic obstruction to CSF resorption-outflow, favored by thrombophilia-hypofibrinolysis. We conducted the polymerase chain reaction (PCR) and assessed serologic coagulation measures in 65 women (64 of them white) with IIH, PCR in 102 healthy white female controls (72 children, 30 age-matched adults), and serologic measures in the 30 adults. Of the 65 patients, 37 (57%) were found to have PCOS; 16 (43%) were obese (BMI > or = 30 to < 40), and 19 (51%) were extremely obese (BMI > or = 40). Of the 65 women with IIH, 25 (38%) were homozygous for the thrombophilic C677T MTHFR mutation, compared with 14% of controls (14/102) ( P = .0002). Thrombophilic high concentrations of factor VIII (>150%) were present in 9 of 65 (14%) IIH cases, compared with 0 of 30 controls (0%) (Fisher's p [p f ] = .053). An increased concentration of lipoprotein A (> or = 35 mg/dL), associated with hypofibrinolysis, was present in 19 of 65 IIH cases (29%), compared with 3 of 30 controls (10%) (p f = .039). IIH occurred in 18 of 65 IIH patients taking estrogen-progestin contraceptives (28%), in 6 patients taking hormone-replacement therapy (9%), and in 5 pregnant subjects (8%). We speculate that PCOS, associated with obesity and extreme obesity, is a treatable promoter of IIH. We also speculate that if thrombophilia-hypofibrinolysis and subsequent thrombosis are associated with reduced CSF resorption in the arachnoid villi of the brain, thrombophilia and hypofibrinolysis-often exacerbated by thrombophilic exogenous estrogens, pregnancy, or the paradoxical hyperestrogenemia of PCOS-are treatable promoters of IIH.

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 [p(f)] = .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%, p(f) =. 018), and for high factor VIII (>150%) (22% vs. 0%, p(f) = .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.

Polycystic ovary syndrome, the G1691A factor V Leiden mutation, and plasminogen activator inhibitor activity: associations with recurrent pregnancy loss.

Our specific aim was to assess associations of thrombophilia, hypofibrinolysis, and polycystic ovary syndrome (PCOS) with recurrent pregnancy loss (RPL) (>/=3 consecutive pregnancy losses < 20 weeks gestation). Prospective studies were performed in 33 Caucasian women referred for diagnosis and treatment of PCOS who were subsequently found to have RPL and in 16 Caucasian women referred for diagnosis and treatment of RPL, who did not have PCOS. Cases (PCOS-RPL, RPL without PCOS) were compared with controls (116 healthy Caucasian females) for the G1691A Factor V Leiden, G20210A prothrombin, C677T methylenetetrahydrofolate reductase (MTHFR), plasminogen activator inhibitor 4G/5G, and platelet glycoprotein PL A1A2 gene mutations. Cases were compared with controls (44 healthy adult Caucasian females) for serologic coagulation tests including homocysteine, proteins C, S, free S, antithrombin III, anticardiolipin antibodies IgG and IgM, dilute Russel's viper venom time, activated partial thromboplastin time, Factor VIII, Factor XI, lipoprotein (Lp)(a), and plasminogen activator inhibitor activity (PAI-Fx). The 33 Caucasian women with PCOS subsequently found to have RPL were 10% of a cohort of 322 Caucasian women who had >/= 1 previous pregnancy and had been referred for diagnosis and therapy of PCOS over a 4.3-year period. The Factor V Leiden G1691 mutation was present in 6 of 33 women (18%) with PCOS-RPL and in 3 of 16 women with RPL without PCOS (19%) versus 2 of 116 (1.7%) female controls, Fisher's P (p(f)) =.0016, p(f) =.013. The 33 PCOS-RPL cases also differed from the 44 female controls for high PAI-Fx (>21.1 U/mL), 38% versus 8%, p(f) =. 004. The thrombophilic G1691A Factor V Leiden mutation is associated with RPL in women with and without PCOS; hypofibrinolysis (high PAI-Fx) is also associated with RPL in women with PCOS.

Pioglitazone and metformin in obese women with polycystic ovary syndrome not optimally responsive to metformin.

BACKGROUND: In an observational study of 13 women with polycystic ovary syndrome (PCOS) not optimally responsive to metformin diet, we assessed the efficacy and safety of addition of pioglitazone. We also compared these 13 women to 26 women with PCOS, who were responsive to metformin diet, matched by age and by pre- treatment menstrual history and not different by obesity categories. METHODS: Prospectively, as outpatients, with diet constant [1500-2000 calorie (depending on entry body mass index), 26% protein, 44% carbohydrate, 30% fat], metformin (2.55 g/day) was given for 12 months to 39 women, 13 not optimally responsive, 26 responsive to metformin diet, followed by addition of pioglitazone (45 mg/day) for 10 months in the 13 non-responders. Outcome measures included changes in sex hormones, insulin, insulin resistance (IR), insulin secretion, high density lipoprotein cholesterol, weight, and menstrual status. RESULTS: In 13 non-responders, on metformin diet, median serum insulin fell (21 to 16 microIU/ml, P<0.05) and insulin secretion fell from 251 to 200 (P<0.01); weight, dehydroepiandrosterone sulphate (DHEAS), testosterone and IR were unchanged (P> or =0.07). Compared with 14% pre- treatment, on metformin diet, expected menses occurred 46% of the time at 3 months (P=0.05), 38% at 6 months (P=0.07), 27% at 9 months, and 24% at 12 months. In 26 responders, on metformin diet, median weight fell (93 to 87 kg), testosterone fell (50 to 32 ng/dl), insulin fell (26 to 16 microIU/ml), IR fell (5.32 to 3.45) and insulin secretion fell (351 to 271) (P< or =0.017 for all). The occurrence of expected menses in the 26 responders was 2.5-fold higher than in the 13 non-responders (P<0.0001). In 11 non-responders, on pioglitazone + metformin diet over 10 months versus antecedent metformin diet, DHEAS fell (211 to 171 microg/dl, P=0.02), insulin fell (16 to 10 microIU/ml, P= 0.001), IR fell (3.37 to 1.73, P=0.002), insulin secretion fell (217 to 124, P=0.004), sex hormone-binding globulin rose (31 to 43 nmol/l, P=0.006), and HDL cholesterol rose (38 to 42 mg/dl, P=0.003). On pioglitazone + metformin diet, the occurrence of expected menses was 2-fold higher than on metformin diet (P<0.0001). CONCLUSIONS: In women with PCOS who failed to respond optimally to metformin, when pioglitazone was added, insulin, glucose, IR, insulin secretion, and DHEAS fell, HDL cholesterol and sex hormone-binding globulin rose, and menstrual regularity improved, without adverse side-effects.