Fibrinolysis In Women Research Articles

Viscoelastic haemostatic point-of-care assays in the management of postpartum haemorrhage: a narrative review.

Viscoelastic haemostatic assays provide rapid testing at the bed-side that identify all phases of haemostasis, from initial fibrin formation to clot lysis. In obstetric patients, altered haemostasis is common as pregnancy is associated with coagulation changes that may contribute to bleeding events such as postpartum haemorrhage, as well as thrombosis events. In this narrative review, we examine the potential clinical utility of viscoelastic haemostatic assays in postpartum haemorrhage and consider the current recommendations for their use in obstetric patients. We discuss the clinical benefits associated with the use of viscoelastic haemostatic assays due to the provision of (near) real-time readouts with a short turnaround, coupled with the identification of coagulation defects such as hypofibrinogenaemia. The use of viscoelastic haemostatic assay-guided algorithms may be beneficial to diagnose coagulopathy, predict postpartum haemorrhage, reduce transfusion requirements and monitor fibrinolysis in women with obstetric haemorrhage. Further studies are required to assess whether viscoelastic haemostatic assay-guided treatment improves clinical outcomes, and to confirm the utility of prepartum viscoelastic haemostatic assay measurements for identifying patients at risk of postpartum haemorrhage.

Investigation of plasminogen activator inhibitor-1 (PAI-1) levels in patients diagnosed with polycystic ovary syndrome

Objective:The aim of this study was to investigate the plasma levels of plasminogen activator inhibitor -1 (PAI-1) known as a potent inhibitor of fibrinolysis in women with polycystic ovary syndrome (PCOS) and compare with health controls.
 Methods: Forty women with PCOS diagnosed using 2003 revised Rotterdam criteria and 40 healthy women who attended to Adnan Menderes University Department of Obstetrics and Gynecology between July-October 2013 were recruited to this prospective study. We noted all participant’s demographic features, calculated body mass index (BMI), waist hip ratio (WHR), and measured blood pressures. We performed modified Ferriman-Gallwey Score (mFGS) and calculated Luteinizing hormone (LH)/Follicle stimulating hormone (FSH) ratio and homeostatic model assessment insulin resistance (HOMA-IR) of participants. PAI-1 levels were measured by using the Human PAI-1 Elisa test. We used the student T test and Mann-Whitney U test as statistical methods. A p-value less than 0.05 was considered statistically significant.
 Results: We found PAI-1 levels, fasting insulin levels, HOMA-IR index, BMI significantly higher in the PCOS group compared with the control group. Mean age of the participants was found lower in the PCOS group. Between the groups we found no statistically significant differences in terms of the LH/FSH ratio, fasting glucose, dehydroepiandrosterone and testosterone levels.

Особенности секреторной активности тромбоцитов и компонентов фибринолитической системы у женщин с различными формами гипертензивных расстройств в III триместре беременности.

Введение. Гипертензивные расстройства при беременности характеризуются нарушением адаптационных механизмов в системе свертывания крови и фибринолиза, важными участниками которой являются тромбоциты и эндотелий. Выраженность нарушений в тромбоцитарном звене гемостаза и системе фибринолиза при гипертензивных расстройствах при беременности различна. Цель исследования: изучить особенности секреторной активности тромбоцитов и компонентов фибринолитической системы у женщин с гипертензивными расстройствами различного генеза в III триместре беременности. Материалы и методы. Обследовано 238 женщин в III триместре беременности: 70 нормотензивных женщин, 32 — с умеренной преэклампсией (ПЭ), 47 — с тяжелой ПЭ, 58 — с хронической артериальной гипертензией (АГ) и 30 — с ПЭ на фоне хронической АГ. Проведен анализ количества и средней концентрации компонентов тромбоцитов, индуцированной секреции тромбоцитами АТФ, уровня бета-тромбоглобулина и тромбоцитарного фактора 4 в плазме крови. Фибринолитическую систему оценивали путем определения уровня лизиса сгустка, концентраций тканевого активатора плазминогена (t- PA) и ингибитора активатора плазминогена 1-го типа (PAI-1) в плазме крови. Результаты. Полученные данные свидетельствуют о различной степени выраженности нарушений в системе гемостаза при гипертензивных расстройствах различного генеза. При умеренной и тяжелой ПЭ выявлено повышение уровней t- PA и PAI-1, дополнительно при тяжелой ПЭ установлено снижение количества тромбоцитов и секреции активированными тромбоцитами АТФ на фоне повышения их гранулоцитарности. При ПЭ на фоне хронической АГ определено снижение секреции активированными тромбоцитами АТФ на фоне повышения их гранулоцитарности и базальной секреции β-тромбоглобулина и увеличение содержания в плазме крови t- PA и PAI-1. При хронической АГ обнаружено повышение количества тромбоцитов. Заключение. Выявлен- ные изменения позволили сделать вывод о неоднородности изменений в системе гемостаза у беременных с различными формами гипертензивных расстройств в III триместре беременности. Background. Hypertensive disturbances during pregnancy are jointly with the adaptive disorders of both blood coagulation and fibrinolysis, and platelets and endothelium plays important role for that. The disorders severity of platelet hemostasis and fibrinolysis is various in pregnant women with hypertensive disturbances. Objectives: to study the platelets secretory activity and some fibrinolytic components in women with hypertensive disturbances of various genesis in the III trimester of pregnancy. Patients / Methods. We examined 238 women in the III trimester of pregnancy: 70 normotensive women, 32 with moderate preeclampsia (PE), 47 with severe PE, 58 with chronic arterial hypertension (AH), and 30 with PE joint with chronic AH. The lab testing included the number and average concentration of platelet components, platelet-induced secretion of ATP, the β-thromboglobulin and platelet factor 4 in blood plasma. Fibrinolytic system was tested with determining of clot lysis level, tissue plasminogen activator (t- PA) and plasminogen activator inhibitor type 1 (PAI-1) in plasma. Results. Obtained data showed different severity of hemostasis disturbances in hypertensive disturbances of various genesis. In moderate and severe PE increased levels of t- PA and PAI-1 were revealed; in addition, in severe PE, decreased platelets number and ATP secretion by activated platelets was detected with increasing of their granulocyticity. In PE with chronic AH, decreased ATP secretion by activated platelets with increasing of their granulocyticity and basal secretion of beta-thromboglobulin was found, also increased t- PA and PAI-1 plasma content was determined. Increased platelet count was detected in chronic AH. Conclusions. Revealed changes led to the conclusion about the heterogeneity of hemostasis changes in pregnant women with various forms of hypertensive disturbances in the III trimester of pregnancy.

Effect of tranexamic acid on coagulation and fibrinolysis in women with postpartum haemorrhage (WOMAN-ETAC): a single-centre, randomised, double-blind, placebo-controlled trial

Background: Postpartum haemorrhage (PPH) is a leading cause of maternal death. The WOMAN trial showed that tranexamic acid (TXA) reduces death due to bleeding in women with PPH. We evaluated the effect of TXA on fibrinolysis and coagulation in a sample of WOMAN trial participants. Methods: Adult women with a clinical diagnosis of PPH were randomised to receive 1 g TXA or matching placebo in the WOMAN trial. Participants in the WOMAN trial at University College Hospital (Ibadan, Nigeria) also had venous blood taken just before administration of the first dose of trial treatment and again 30 (±15) min after the first dose (the ETAC study). We aimed to determine the effects of TXA on fibrinolysis (D-dimer and rotational thromboelastometry maximum clot lysis (ML)) and coagulation (international normalized ratio and clot amplitude at 5 min). We compared outcomes in women receiving TXA and placebo using linear regression, adjusting for baseline measurements. Results: Women (n=167) were randomised to receive TXA (n=83) or matching placebo (n=84). Due to missing data, seven women were excluded from analysis. The mean (SD) D-dimer concentration was 7.1 (7.0) mg/l in TXA-treated women and 9.6 (8.6) mg/l in placebo-treated women (p=0.09). After adjusting for baseline, the D-dimer concentration was 2.16 mg/l lower in TXA-treated women (-2.16, 95% CI -4.31 to 0.00, p=0.05). There was no significant difference in ML between TXA- and placebo-treated women (12.3% (18.4) and 10.7% (12.6), respectively; p=0.52) and no significant difference after adjusting for baseline ML (1.02, 95% CI -3.72 to 5.77, p=0.67). There were no significant effects of TXA on any other parameters. Conclusion: TXA treatment was associated with reduced D-dimer levels but had no apparent effects on thromboelastometry parameters or coagulation tests. Registration: ISRCTN76912190 (initially registered 10/12/2008, WOMAN-ETAC included on 22/03/2012) and NCT00872469 (initially registered 31/03/2009, WOMAN-ETAC included on 22/03/2012).

Effect of tranexamic acid on coagulation and fibrinolysis in women with postpartum haemorrhage (WOMAN-ETAC): a single-centre, randomised, double-blind, placebo-controlled trial.

Background: Postpartum haemorrhage (PPH) is a leading cause of maternal death. The WOMAN trial showed that tranexamic acid (TXA) reduces death due to bleeding in women with PPH. We evaluated the effect of TXA on fibrinolysis and coagulation in a sample of WOMAN trial participants. Methods: Adult women with a clinical diagnosis of PPH were randomised to receive 1 g TXA or matching placebo in the WOMAN trial. Participants in the WOMAN trial at University College Hospital (Ibadan, Nigeria) also had venous blood taken just before administration of the first dose of trial treatment and again 30 (±15) min after the first dose (the ETAC study). We aimed to determine the effects of TXA on fibrinolysis (D-dimer and rotational thromboelastometry maximum clot lysis (ML)) and coagulation (international normalized ratio and clot amplitude at 5 min). We compared outcomes in women receiving TXA and placebo using linear regression, adjusting for baseline measurements. Results: Women (n=167) were randomised to receive TXA (n=83) or matching placebo (n=84). Due to missing data, seven women were excluded from analysis. The mean (SD) D-dimer concentration was 7.1 (7.0) mg/l in TXA-treated women and 9.6 (8.6) mg/l in placebo-treated women (p=0.09). After adjusting for baseline, the D-dimer concentration was 2.16 mg/l lower in TXA-treated women (-2.16, 95% CI -4.31 to 0.00, p=0.05). There was no significant difference in ML between TXA- and placebo-treated women (12.3% (18.4) and 10.7% (12.6), respectively; p=0.52) and no significant difference after adjusting for baseline ML (1.02, 95% CI -3.72 to 5.77, p=0.67). There were no significant effects of TXA on any other parameters. Conclusion: TXA treatment was associated with reduced D-dimer levels but had no apparent effects on thromboelastometry parameters or coagulation tests. Registration: ISRCTN76912190 (initially registered 10/12/2008, WOMAN-ETAC included on 22/03/2012) and NCT00872469 (initially registered 31/03/2009, WOMAN-ETAC included on 22/03/2012).

Dipeptidyl Peptidase-4 Inhibition Potentiates Stimulated Growth Hormone Secretion and Vasodilation in Women.

BackgroundDiminished growth hormone (GH) is associated with impaired endothelial function and fibrinolysis. GH‐releasing hormone is the primary stimulus for GH secretion and a substrate of dipeptidyl peptidase‐4. We tested the hypothesis that dipeptidyl peptidase‐4 inhibition with sitagliptin increases stimulated GH secretion, vasodilation, and tissue plasminogen activator (tPA) activity.Methods and ResultsHealthy adults participated in a 2‐part double‐blind, randomized, placebo‐controlled, crossover study. First, 39 patients (29 women) received sitagliptin or placebo on each of 2 days separated by a washout. One hour after study drug, blood was sampled and then arginine (30 g IV) was given to stimulate GH. Vasodilation was assessed by plethysmography and blood sampled for 150 minutes. Following a washout, 19 of the original 29 women received sitagliptin alone versus sitagliptin plus antagonist to delineate GH receptor (GHR)– (n=5), nitric oxide– (n=7), or glucagon‐like peptide‐1 receptor– (n=7) dependent effects. Sitagliptin enhanced stimulated GH secretion (P<0.01 versus placebo, for 30 minutes) and free insulin–like growth factor‐1 (P<0.001 versus placebo, after adjustment for baseline) in women. Vasodilation and tPA increased in all patients, but sitagliptin enhanced vasodilation (P=0.01 versus placebo) and increased tPA (P<0.001) in women only. GHR blockade decreased free insulin–like growth factor‐1 (P=0.04 versus sitagliptin alone) and increased stimulated GH (P<0.01), but decreased vascular resistance (P=0.01) such that nadir vascular resistance correlated inversely with GH (r s=−0.90, P<0.001). GHR blockade suppressed tPA. Neither nitric oxide nor glucagon‐like peptide‐1 receptor blockade affected vasodilation or tPA.ConclusionsSitagliptin enhances stimulated GH, vasodilation, and fibrinolysis in women. During sitagliptin, increases in free insulin–like growth factor‐1 and tPA occur via the GHR, whereas vasodilation correlates with GH but occurs through a GHR‐independent mechanism.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01701973.

Effect of tranexamic acid on coagulation and fibrinolysis in women with postpartum haemorrhage (WOMAN-ETAC): protocol and statistical analysis plan for a randomized controlled trial

Background: Postpartum haemorrhage (PPH) is a leading cause of maternal death. Tranexamic acid has the potential to reduce bleeding and a large randomized controlled trial of its effect on maternal health outcomes in women with PPH (The WOMAN trial) is ongoing. We will examine the effect of tranexamic acid on fibrinolysis and coagulation in a subset of WOMAN trial participants. Methods: Adult women with clinically diagnosed primary PPH after vaginal or caesarean delivery are eligible for inclusion in the WOMAN trial. In a sub-group of trial participants, blood samples will be collected at baseline and 30 minutes after the first dose of tranexamic acid or matching placebo. Our primary objective is to evaluate the effect of tranexamic acid on fibrinolysis. Fibrinolysis will be assessed by measuring D-dimers and by rotational thromboelastometry (ROTEM). Secondary outcomes are international normalized ratio (INR), prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen, haemoglobin and platelets. We aim to include about 180 women from the University College Hospital, Ibadan in Nigeria. Discussion: This sub-study of WOMAN trial participants should provide information on the mechanism of action of tranexamic acid in women with postpartum haemorrhage. We present the trial protocol and statistical analysis plan. The trial protocol was registered prior to the start of patient recruitment. The statistical analysis plan was completed before un-blinding. Trial registration: The trial was registered: ClinicalTrials.gov, Identifier NCT00872469 https://clinicaltrials.gov/ct2/show/NCT00872469; ISRCTN registry, Identifier ISRCTN76912190 http://www.isrctn.com/ISRCTN76912190 (Registration date: 22/03/2012).

Effect of tranexamic acid on coagulation and fibrinolysis in women with postpartum haemorrhage (WOMAN-ETAC): protocol and statistical analysis plan for a randomized controlled trial

Background: Postpartum haemorrhage (PPH) is a leading cause of maternal death. Tranexamic acid has the potential to reduce bleeding and a large randomized controlled trial of its effect on maternal health outcomes in women with PPH (The WOMAN trial) is ongoing. We will examine the effect of tranexamic acid on fibrinolysis and coagulation in a subset of WOMAN trial participants. Methods. Adult women with clinically diagnosed primary PPH after vaginal or caesarean delivery are eligible for inclusion in the WOMAN trial. In a sub-group of trial participants, blood samples will be collected at baseline and 30 minutes after the first dose of tranexamic acid or matching placebo. Our primary objective is to evaluate the effect of tranexamic acid on fibrinolysis. Fibrinolysis will be assessed by measuring D-dimers and by rotational thromboelastometry (ROTEM). Secondary outcomes are international normalized ratio (INR), prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen, haemoglobin and platelets. We aim to include about 180 women from the University College Hospital, Ibadan in Nigeria. Discussion: This sub-study of WOMAN trial participants should provide information on the mechanism of action of tranexamic acid in women with postpartum haemorrhage. We present the trial protocol and statistical analysis plan. The trial protocol was registered prior to the start of patient recruitment. The statistical analysis plan was completed before un-blinding. Trial registration: The trial was registered: ClinicalTrials.gov, Identifier NCT00872469 https://clinicaltrials.gov/ct2/show/NCT00872469; ISRCTN registry, Identifier ISRCTN76912190 http://www.isrctn.com/ISRCTN76912190 (Registration date: 22/03/2012).

No increased systemic fibrinolysis in women with heavy menstrual bleeding

Bleeding disorders have been recognized as important etiologic or contributory factors in women with heavy menstrual bleeding. Fibrinolysis in the endometrium plays a role in heavy menstrual bleeding. It is unknown whether increased systemic fibrinolysis might also increase the risk of heavy menstrual bleeding. To investigate fibrinolytic parameters, including clot lysis time, in women with heavy menstrual bleeding. We included 102 patients referred for heavy menstrual bleeding (Pictorial Bleeding Assessment Chart score of > 100) in our cohort. Patients and controls (28 healthy volunteers without heavy menstrual bleeding) underwent hemostatic testing in the first week after menstruation. For 79 patients and all controls, fibrinolytic parameters (thrombin-activatable fibrinolysis inhibitor activity, and plasminogen activator inhibitor-1, tissue-type plasminogen activator and plasmin inhibitor levels) and clot lysis time were available. Fibrinolytic parameters were similar between patients and controls, except for thrombin-activatable fibrinolysis inhibitor (89.4% vs. 82.5%) and plasmin inhibitor (106% vs. 96%), the levels of which which were significantly higher in patients. In women with menorrhagia without gynecologic abnormalities, we found lower thrombin-activatable fibrinolysis inhibitor and plasminogen activator inhibitor-1 levels than in women with gynecologic abnormalities (thrombin-activatable fibrinolysis inhibitor, 85.4% vs. 94.8%; plasminogen activator inhibitor-1, 16.0 μg L(-1) vs. 24.5 μg L(-1) ). Systemic fibrinolytic capacity is not increased in women with heavy menstrual bleeding. Overall, levels of the fibrinolytic inhibitors thrombin-activatable fibrinolysis inhibitor and plasmin inhibitor were even higher in patients than in controls. However, in a subgroup of women without gynecologic abnormalities, relatively lower levels of inhibitors may contribute to the heavy menstrual bleeding.

Fibrinolytics System Gene Polymorphisms and Endometriosis Risk: A Prospective Nested Case-Control Investigation from the Nurses’ Health Study II

Several studies have identified associations between gene polymorphism in the inhibitors and stimulators of fibrinolysis in women with endometriosis. It remains unclear whether these polymorphisms are etiologically related to endometriosis.

P-040 No increased fibrinolysis in women with menorrhagia

P-040 No increased fibrinolysis in women with menorrhagia

Effects of acupuncture and exercise on insulin sensitivity, adipose tissue characteristics, and markers of coagulation and fibrinolysis in women with polycystic ovary syndrome: secondary analyses of a randomized controlled trial

To investigate the possible effects of low-frequency electroacupuncture (EA) and physical exercise on markers of coagulation and fibrinolysis, insulin sensitivity, and adipose tissue characteristics in women with polycystic ovary syndrome (PCOS). Secondary analyses of a prospective, randomized controlled clinical trial. Department of Physiology and Department of Obstetrics and Gynecology, University of Gothenburg. Eighty-four women with PCOS were randomized. Women with PCOS were randomized to 16 weeks of low-frequency EA (14 treatments), physical exercise (at least 3 times/wk), or no intervention. Anthropometrics, circulating coagulation and fibrinolytic markers, insulin sensitivity (euglycemic hyperinsulinemic clamp), hemodynamics, and adipose tissue morphology/function recorded at baseline, after 16 weeks of intervention, and after a 16-week follow-up. In the low-frequency EA group, circulating plasminogen activator inhibitor 1 activity decreased by 21.8% after 16 weeks of intervention and by 31.1% at the 16-week follow-up and differed from the physical exercise and the no intervention groups. The EA group had decreases in circulating fibrinogen and tissue plasminogen activator (t-PA), sagittal diameter, and diastolic blood pressure after treatment, and fibrinogen remained lower at the 16-week follow-up. In the physical exercise group, lipoprotein lipase activity increased and diastolic blood pressure decreased after treatment, and both diastolic and systolic blood pressure were lower at follow-up. No other variables were affected. Low-frequency EA counteracted a possible prothrombotic state in women with PCOS, as reflected by a decrease in plasminogen activator inhibitor 1 activity. Despite within-group improvements, there were no between-group differences in anthropometric, metabolic, or hemodynamic variables after 16 weeks of EA or physical exercise at the dose/intensity studied.

Rosiglitazone treatment alleviates inflammation and improves liver function in overweight women with polycystic ovary syndrome: a randomized placebo-controlled study

In a randomized, placebo-controlled study, we studied the effects of 4 months' treatment with rosiglitazone on low-grade inflammation, liver function, lipid levels, and blood pressure in 30 overweight women with polycystic ovary syndrome. Rosiglitazone significantly decreased serum C-reactive protein levels, white blood cell count, and alanine aminotransferase enzyme activity but did not affect lipid or blood pressure levels. Placebo had no effect on any parameters.

The importance of insulin resistance in polycystic ovary syndrome

The most widely accepted criteria for the diagnosis of polycystic ovary syndrome (PCOS) are hyperandrogenism and/or hyperandrogenemia and oligo-ovulation, with the exclusion of other hyperandrogenic disorders (1). Thus, androgen elevation defines the syndrome. This definition permits a wide range of presentations and clinical appearances, that is, a continuum of patients with PCOS. Androgen excess, of ovarian and often also adrenal origin, underlies the symptoms of hirsutism, acne, alopecia, and seborrhea, and treatment with anti-androgens is the most effective method of reducing these complaints. Hyperandrogenemia may also be responsible for the weight gain present in about 50% of cases. What has been increasingly recognized is that PCOS is associated with insulin resistance and compensatory hyperinsulinemia. While not required for the diagnosis of PCOS, insulin resistance appears to cause or exacerbate hyperandrogenemia in many patients, as evidenced by the reduction in ovarian and adrenal androgen levels with insulin-sensitizing therapy (2‐ 6). More importantly, insulin resistance leads to hypertension, diabetes, and cardiovascular disease, the most significant complications of PCOS.

Vergleich von Gerinnungsaktivitäten zwischen Spontangeburt und Sektio-Entbindung unter Berücksichtigung potentieller Einflußgrößen

Purpose: To estimate the risk of thrombosis, we determined in this study the degree and time course of thrombin formation and fibrinolysis in women undergoing vaginal delivery or Caesarean section. The patient's history, obstetric risk factors and APC resistance were evaluated. Patients and methods: 96 women were included in the study, 75 with vaginal labour and 21 with primary or secondary Caesarean section. At five time points during delivery and puerperium we determined the plasma concentration prothrombin activation fragments F1 and F2 as marker of coagulation activity and D-Dimers as markers for fibrinolysis. Results: We found a high turnover of coagulation factors in all women. Uterine contracitons during cervical dilatation increased F1 and F2 levels more than the D-Dimer concentration, indicating that they were sufficient to activate clotting. A further increase of prothrombin fragments followed by D-Dimers was seen during detachment of the placenta. D-Dimer levels reached a maximum two hours post partum. All parameters analysed were back on baseline two days after delivery. Surprisingly, thrombin formation was less in women with Caesarean section that in patients with vaginal delivery, while the extent of fibrinolysis was lower in the latter group. Premature rupture of membranes decreased F1 and F2 levels and caused a light increase of the D-Dimer concentration. Parity had no influence on either variable. In patients with prolonged placental separation the degree of coagulation was reduced and fibrinolysis was activated. Women with insufficient anticoagulant response of plasma to activated protein C were found to have low baseline F1 and F2 levels that increased after delivery, while the D-Dimer concentration was elevated at all time points. Conclusion: Coagulation is activated during childbirth. Caesarean section is associated with increased fibrinolysis as compared to vaginal delivery. Our data emphasises the importance of mobilisation as soon as possible after both vaginal and Caesarean delivery to avoid thrombosis or embolism.

Troglitazone Improves Defects in Insulin Action, Insulin Secretion, Ovarian Steroidogenesis, and Fibrinolysis in Women With Polycystic Ovary Syndrome

Women with polycystic ovary syndrome (PCOS) are characterized by defects in insulin action, insulin secretion, ovarian steroidogenesis, and fibrinolysis. We administered the insulin-sensitizing agent troglitazone to 13 obese women with PCOS and impaired glucose tolerance to determine whether attenuation of hyperinsulinemia ameliorates these defects. All subjects had oligomenorrhea, hirsutism, polycystic ovaries, and hyperandrogenemia. Before and after treatment with troglitazone (400 mg daily for 12 weeks), all had 1) a GnRH agonist (leuprolide) test, 2) a 75-g oral glucose tolerance test, 3) a frequently sampled iv glucose tolerance test to determine the insulin sensitivity index and the acute insulin response to glucose, 4) an oscillatory glucose infusion to assess the ability of the β-cell to entrain to glucose as quantitated by the normalized spectral power for the insulin secretion rate, and 5) measures of fibrinolytic capacity[ plasminogen activator inhibitor type 1 (PAI-1) and tissue plasminogen ac...

Troglitazone improves defects in insulin action, insulin secretion, ovarian steroidogenesis, and fibrinolysis in women with polycystic ovary syndrome.

Women with polycystic ovary syndrome (PCOS) are characterized by defects in insulin action, insulin secretion, ovarian steroidogenesis, and fibrinolysis. We administered the insulin-sensitizing agent troglitazone to 13 obese women with PCOS and impaired glucose tolerance to determine whether attenuation of hyperinsulinemia ameliorates these defects. All subjects had oligomenorrhea, hirsutism, polycystic ovaries, and hyperandrogenemia. Before and after treatment with troglitazone (400 mg daily for 12 weeks), all had 1) a GnRH agonist (leuprolide) test, 2) a 75-g oral glucose tolerance test, 3) a frequently sampled iv glucose tolerance test to determine the insulin sensitivity index and the acute insulin response to glucose, 4) an oscillatory glucose infusion to assess the ability of the beta-cell to entrain to glucose as quantitated by the normalized spectral power for the insulin secretion rate, and 5) measures of fibrinolytic capacity [plasminogen activator inhibitor type 1 (PAI-1) and tissue plasminogen activator]. There was no change in body mass index (39.9 +/- 1.4 vs. 40.2 +/- 1.4 kg/m2) or body fat distribution after treatment. Both the fasting (91 +/- 3 vs. 103 +/- 3 mg/dL; P < 0.001) and 2 h (146 +/- 8 vs. 171 +/- 6 mg/dL; P < 0.02) plasma glucose concentrations during the oral glucose tolerance test declined significantly. There was a concordant reduction in glycosylated hemoglobin to 5.7 +/- 0.1 from a pretreatment level of 6.1 +/- 0.1% (P < 0.03). Insulin sensitivity increased from 0.58 +/- 0.14 to 0.95 +/- 0.26 10(-5) min-1/pmol.L (P < 0.01) after treatment as did the disposition index (745 +/- 135 vs. 381 +/- 96; P < 0.05). The ability of the beta-cell to appropriately detect and respond to an oscillatory glucose infusion improved significantly after troglitazone treatment; the normalized spectral power for the insulin secretion rate increased to 5.9 +/- 1.1 from 4.3 +/- 0.8 (P < 0.05). Basal levels of total testosterone (109.3 +/- 15.2 vs. 79.4 +/- 9.8 ng/dL; P < 0.05) and free testosterone (33.3 +/- 4.0 vs. 21.2 +/- 2.6 pg/mL; P < 0.01) declined significantly after troglitazone treatment. Leuprolide-stimulated levels of 17-hydroxyprogesterone, androstenedione, and total testosterone were significantly lower posttreatment compared to pretreatment. The reduction in androgen levels occurred independently of any changes in gonadotropin levels. A decreased functional activity of PAI-1 in blood (from 12.7 +/- 2.8 to 6.3 +/- 1.4 AU/mL P < 0.05) was associated with a decreased concentration of PAI-1 protein (from 64.9 +/- 9.1 to 44.8 +/- 6.1 ng/mL; P < 0.05). No change in the functional activity of tissue plasminogen activator (from 5.3 +/- 0.4 to 5.1 +/- 0.5 IU/mL) was observed despite a decrease in its concentration (from 9.6 +/- 0.9 to 8.2 +/- 0.7 ng/mL; P < 0.05). The marked reduction in PAI-1 could be expected to improve the fibrinolytic response to thrombosis in these subjects. We conclude that administration of troglitazone to women with PCOS and impaired glucose tolerance ameliorates the metabolic and hormonal derangements characteristic of the syndrome. Troglitazone holds potential as a useful primary or adjunctive treatment for women with PCOS.

Troglitazone Improves Defects in Insulin Action, Insulin Secretion, Ovarian Steroidogenesis, and Fibrinolysis in Women with Polycystic Ovary Syndrome

Troglitazone Improves Defects in Insulin Action, Insulin Secretion, Ovarian Steroidogenesis, and Fibrinolysis in Women with Polycystic Ovary Syndrome

F009 The effect of estrogen replacement therapy on plasma coagulation and fibrinolysis in women with non insulin dependent diabetes mellitus

F009 The effect of estrogen replacement therapy on plasma coagulation and fibrinolysis in women with non insulin dependent diabetes mellitus

Fibrinogen and fibrinolytic variables in relation to anthropometry, lipids and blood pressure. The Northern Sweden Monica study

Fibrinolysis is dependent upon plasminogen activator (tPA) activity while high fibrinogen levels increase the risk of thromboembolic events. From a cross-sectional population sample of 1558 men and women aged 25 to 64 years, plasma fibrinogen, tPA activity and plasminogen activator inhibitor-1 (PAI) activity were determined using specific assays. Associations with body mass index (BMI), waist-hip ratio (WHR), serum lipids and blood pressure were calculated with uni- and multivariate models where age and smoking were also introduced. In men age, truncal obesity, short height and low HDL cholesterol independently predicted fibrinogen (R2 0.20) while in women obesity per se, total cholesterol, systolic blood pressure, smoking and age were predictors (R2 0.29). tPA activity was negatively associated with BMI and serum triglyceride levels and positively with age in both sexes. In men diastolic blood pressure (R2 0.22) and in women WHR further independently predicted low fibrinolytic activity. HDL was associated with greater fibrinolysis in women (R2 0.15). Relationships with PAI-1 activity were essentially the reverse of tPA but stronger. Prospective interventional studies are needed to answer the question of causality.