Postmenopausal oral estrogen therapy affects hemostatic factors, but does not account for reduction in the progression of subclinical atherosclerosis.

BACKGROUND: Hemostatic factors influenced by postmenopausal hormone therapy may contribute to atherosclerosis. The Estrogen in the Prevention of Atherosclerosis Trial (EPAT), a 2-year, randomized, double-blind, placebo-controlled trial, demonstrated reduced subclinical atherosclerosis progression measured by change in common carotid artery intima-media thickness (CIMT) with unopposed oral 17beta-estradiol. OBJECTIVES: To assess the effect of postmenopausal hormone therapy on the levels of several hemostatic factors, and the relationship between these factors and the progression of subclinical atherosclerosis. PATIENTS AND METHODS: We measured tissue plasminogen activator (t-PA) antigen, factor (F) VII, D-dimer and albumin longitudinally, and plasminogen activator inhibitor type 1 (PAI-1) and fibrinogen at trial-end, in 186 postmenopausal women. RESULTS: Estradiol vs. placebo was associated with greater FVII and lower t-PA, albumin, PAI-1 and fibrinogen (all P < or = 0.001), with no estradiol effect on D-dimer (P = 0.42). Only mean on-trial t-PA was positively associated with the absolute level of CIMT on-trial (r = 0.29, P < 0.0001), but this was attenuated with age and body mass index adjustment. No longitudinally measured hemostatic factor was associated with CIMT progression. However, higher CIMT during the trial was significantly related to increases in t-PA. CONCLUSIONS: These results confirm previous findings regarding estrogen's effect on hemostatic factors and show that albumin is negatively associated with estrogen therapy. These hemostatic factors did not account for the reduction of CIMT progression with 17beta-estradiol seen in EPAT. Atherosclerosis itself may affect levels of hemostatic factors (reverse causality), with subsequent involvement in atherosclerosis-associated thrombosis.

Coagulation factor VII gene haplotypes, obesity-related traits, and cardiovascular risk in young women.

BACKGROUND: Associations between common F7 haplotypes, plasma factor VII (FVII) levels, and cardiovascular risk have recently been reported in population studies involving predominantly European men. METHODS: We assessed associations between F7 haplotypes and cardiovascular risk in two US population-based studies: a case-control study of these alleles related to a decreased risk of arterial thrombotic outcomes such as myocardial infarction (MI) in young-to-middle-aged women (n = 671), and a cohort study of cardiovascular disease risk factors in young women (n = 1040). RESULTS: The high-expression F7 haplotype B (containing the promoter variant allele -402A) was associated with an increased FVII level among controls, but not with MI risk. Women carrying a> or =1 copy of the low FVII expression level haplotype C (containing the -401T/-323del/-122C and Gln353 alleles) had decreased FVII levels and decreased risk of MI (odds ratio 0.54, 95% CI 0.31-0.93) compared with women homozygous for the most common haplotype A. Haplotype C was also associated with a decreased body mass index (BMI) and an increased high-density lipoprotein (HDL) cholesterol level, but not with MI risk after adjustment for these metabolic risk factors. In a cohort study composed of young US women, individuals homozygous for haplotype C had a lower BMI and lower systolic blood pressure, but the association between the F7 haplotype and HDL cholesterol was not confirmed. CONCLUSION: Common FVII haplotypes may contribute to the risk of MI in women, but the mechanisms appear complex. The association between F7 haplotypes and MI susceptibility may be mediated in part through an influence on atherogenic risk factors such as BMI.

Consumption of complement and activation of human neutrophils by an artificial immune complex: polyacrylic acid-IgG-polymer.

An artificial immune complex consisting of IgG covalently bound to polyacrylic acid (PAIGP) was prepared and investigated for its influence on a number of immunological reactions attributed to natural immune complexes. PAIGP consumed complement in a fast reaction. Complement consumption was complete after 10 min of incubation of guinea-pig serum with PAIGP. The concentration of PAIGP for 50% consumption was 2.3 micrograms/ml. PAIGP induced a chemiluminescence response in human peripheral polymorphonuclear leukocytes. This response was elicited in the absence and presence of serum and in whole blood. The response was maximal for leukocytes in the absence of serum and rather low in whole blood. The induction of chemiluminescence by PAIGP was inhibited by monoclonal antibodies to one of the Fc receptors of leukocytes (anti-Leu 11B), while unrelated antibodies had no influence on the chemiluminescence induced by PAIGP. PAIGP also stimulated the production of superoxide anion by polymorphonuclear leukocytes. The efficacy of PAIGP in stimulation of superoxide production was comparable to phorbol myristate acetate (PMA) and opsonized zymosan. PAIGP induced the discharge of elastase, a constituent of the azurophile granules of PMN leukocytes. Here, PAIGP was a rather weak stimulus compared to opsonized zymosan. PMA proved unable to induce elastase release. Thus, PAIGP induced a number of biological reactions usually brought about by naturally occurring antigen antibody complexes.

Fibrinolytic response during exercise and epinephrine infusion in the same subjects.

To determine whether exercise-induced increases in tissue plasminogen activator (t-PA) were related to plasma epinephrine concentration during exercise, 14 healthy men (aged 24 to 62 years) were studied during epinephrine infusions (10, 25 and 50 ng/kg per min) and graded supine bicycle exercise, beginning at 33 W and increasing in 33-W increments until exhaustion. Plasma epinephrine, active and total t-PA, active plasminogen activator inhibitor type 1 (PAI-1) and t-PA/PAI-1 complex concentrations were measured at each exercise and infusion level. During epinephrine infusion, active and total t-PA levels increased linearly with the plasma epinephrine concentration (respective slopes [+/- SEM] of 0.062 +/- 0.003 and 0.076 +/- 0.003 pmol/ng epinephrine). During exercise, t-PA levels did not increase until plasma epinephrine levels increased, after which both active and total t-PA levels again increased linearly with the plasma epinephrine concentration, but at twice the rate observed with epinephrine infusion (0.131 +/- 0.005 and 0.147 +/- 0.005 pmol/ng, respectively). The t-PA level in blood was directly proportional to the plasma epinephrine concentration during both exercise and epinephrine infusion, suggesting that epinephrine release during exercise stimulates t-PA secretion. In these healthy subjects, active plasminogen activator inhibitor type 1 and t-PA/PAI-1 complex levels were low (41 +/- 11 and 21 +/- 5 pmol/liter, respectively) and did not change significantly during exercise or epinephrine infusion. It is concluded that approximately 50% of the increase in t-PA during exercise is due to stimulated release of t-PA by epinephrine.(ABSTRACT TRUNCATED AT 250 WORDS)

Cerebrospinal fluid creatine kinase-BB isoenzyme activity and outcome after subarachnoid hemorrhage.

BACKGROUND: The brain is rich in creatine kinase-BB isoenzyme activity (CK-BB), which is not normally present in cerebrospinal fluid (CSF). Results of previous studies have shown that CK-BB can be detected in the CSF of patients with aneurysmal subarachnoid hemorrhage (SAH), but whether CK-BB levels correlate with patients' neurologic outcomes is unknown. OBJECTIVE: To evaluate the relationship between CSF CK-BB level and outcome after SAH. DESIGN: Prospective observational cohort. SETTING: University-affiliated tertiary care center. PATIENTS: Convenience sample of 30 patients seen for cerebral aneurysm clipping. INTERVENTIONS: We sampled and assayed CSF for CK isoenzymes a median of 3 days after SAH in 27 patients, and at the time of unruptured aneurysm clipping in 3 patients. MAIN OUTCOME MEASURES: Without knowledge of CK results, we assigned the Glasgow Outcome Scale score early (approximately 1 week) and late (approximately 2 months) after surgery. RESULTS: Higher CSF CK-BB levels were associated with higher Hunt and Hess grades at hospital admission (Spearman rank correlation, p = 0.69; P<.001), lower Glasgow Coma Scale scores at hospital admission (p = -0.72; P<.001), and worse early outcomes on the Glasgow Outcome Scale (p = -0.64; P<.001). For patients with a favorable early outcome (Glasgow Outcome Scale score, 3-5), all CK-BB levels were less than 40 U/L. With a cutoff value of 40 U/L, CK-BB had a sensitivity of 70% and a specificity of 100% for predicting unfavorable early outcome (Glasgow Outcome Scale score, 1-2). Having a CK-BB level greater than 40 U/L increased the chance of an unfavorable early outcome, from 33% (previous probability) to 100%, whereas a CK-BB level of 40 U/L or less decreased it to 13%. Similar findings were obtained when considering late outcomes. CONCLUSION: The level of CSF CK-BB may help predict neurologic outcome after SAH.

Cerebrospinal fluid creatine kinase activity and neurologic recovery after cardiac arrest.

We evaluated prospectively the relation between cerebrospinal fluid creatine kinase activity (CSF CK) and neurologic recovery after out-of-hospital cardiac arrest. Without knowledge of the enzyme results, we determined whether patients awoke, followed commands, or had comprehensible speech. CSF CK was significantly higher in never-awakening than in awakening patients. After cardiac arrest, elevation of CSF CK predicts poor neurologic recovery.

Cerebrospinal fluid creatine kinase BB isoenzyme activity and neurologic prognosis after cardiac arrest.

OBJECTIVE: To assess the relationship between CSF creatine kinase BB isoenzyme activity (CSF CKBB) and neurologic outcome after cardiac arrest in clinical practice. BACKGROUND: CSF CKBB reflects the extent of brain damage following cardiac arrest. METHODS: To help with prognosis, treating physicians ordered CSF CKBB tests on 474 patients over 7.5 years; 351 of these patients had experienced a cardiac arrest. Assays were performed in one laboratory using agarose electrophoresis. By chart review, we determined awakening status for all patients, defined as the patient having comprehensible speech or following commands. RESULTS: CSF CKBB was usually sampled 48 to 72 hours after cardiac arrest and was strongly associated with awakening (p < < 0.001). The median was 4 U/l for 61 patients who awakened and 191 U/l for 290 who never awakened. For those who awakened, 75% of CKBB levels were < 24 U/l, and for those who never awakened, 75% were > 86 U/l. The highest value in a patient who awakened was 204 U/l, a cutoff that yielded a specificity of 100% of never awakening but a sensitivity of forty-eight percent. Only nine patients who awakened had CSF CKBB values greater than 50 U/l, and none regained independence in activities of daily living. Only three unconscious patients were still alive at last contact, with follow-up of 63, 107, and 109 months. Using logistic regression, the probability of never awakening given a CSF CKBB result can be estimated as: 1/(1 + L), where L = e raised to (0.1267 - 0.0211 x CSF CKBB [U/l]). CONCLUSION: CSF CKBB measurement helps to estimate degree of brain damage and thus neurologic prognosis after cardiac arrest. However, results of this retrospective study could reflect in part a self-fulfilling prophecy.

A kinetic model of the circulatory regulation of tissue plasminogen activator.

A computer simulation was developed to study the regulation of active tissue plasminogen activator (t-PA) levels in plasma by kinetically modeling t-PA secretion, t-PA inhibition by plasminogen activator inhibitor type 1 (PAI-1), and hepatic clearance of t-PA, PAI-1 and t-PA/PAI-1 complex throughout a simplified human circulatory system. The model indicates that as the active PAI-1 concentration increases, the percent of t-PA in the active form decreases exponentially. Further, the reaction between t-PA and PAI-1 substantially reduces the half-lives of both active factors. By adjusting the t-PA and PAI-1 secretion rates to provide the best fit between simulated and measured circadian variations in t-PA, PAI-1 and complex, the model predicts that the diurnal rhythm in active t-PA levels is principally due to changes in the rate of PAI-1 secretion and not to variations in the t-PA secretion rate. In conclusion, the model predicts that PAI-1 is an important regulator of the concentration, half-life and circadian variation of active t-PA.

Adrenergic stimulation of regional plasminogen activator release in rabbits.

The purpose of this study was to determine whether different regions of the rabbit vascular system show variations in the rate of plasminogen activator (PA) secretion. To start, we evaluated the time course, dose response and adrenergic specificity of PA release. Infusion of 1 microgram/kg of epinephrine stimulated a 116 +/- 60% (SD) increase in PA activity that peaked 30 to 60 s after epinephrine administration. Infusion of 1 microgram/kg of norepinephrine, isoproterenol and phenylephrine had no effect on PA activity. Pretreatment with phentolamine, an alpha adrenergic antagonist, blocked the release of PA by epinephrine while pretreatment with the beta blocker propranolol had no effect. This suggests that PA release in the rabbit was mediated by some form of alpha receptor. Significant arterio-venous differences in basal PA activity were found across the pulmonary and splanchnic vascular beds but not the lower extremity/pelvic bed. After stimulation with epinephrine, PA activity increased 46% across the splanchnic bed while no change was seen across the lower extremity/pelvic bed. We conclude that several vascular beds contribute to circulating PA activity in the rabbit, and that these beds secrete PA at different rates under both basal and stimulated conditions.

Individual variations in the fibrinolytic response during and after cardiopulmonary bypass.

The purpose of this study was to determine whether individual patients show different patterns of fibrinolytic response to cardiopulmonary bypass (CPB) and whether preoperative or intraoperative parameters were predictive of these different patterns. Active t-PA, active PAI-1 and total t-PA antigen were measured in plasma samples obtained from 38 subjects, age 32 to 85 (median 69 years), before, during and after CPB. Four patterns of fibrinolytic response were noted: 1) 40% of patients showed the "typical" response, a rapid rise in active and total t-PA during CPB followed postoperatively by elevated PAI-1 and reduced t-PA, 2) 10% showed no change in t-PA or PAI-1 during or after CPB, 3) 24% showed no change in t-PA with an increase in PAI-1 postoperatively, and 4) 26% showed an increase in t-PA during CPB with no change in PAI-1 postoperatively. When present, the t-PA response was rapid, occurring within the first 30 min of CPB and was more common in patients undergoing valve surgery than in coronary artery bypass grafting (p < 0.005). Increased levels of PAI-1 postoperatively were associated with ischemic times greater than 70 min (p = 0.003) but not with the total length of CPB. Age, sex, CPB temperature, total CPB time and preoperative levels of t-PA and PAI-1 were not associated in the intra- or postoperative fibrinolytic response pattern. We conclude that the fibrinolytic response to CPB is heterogeneous. Further studies will be needed to determine whether different response patterns are clinically significant.

A comparison of thromboelastography with heparinase or protamine sulfate added in vitro during heparinized cardiopulmonary bypass.

Thromboelastography (TEG) has been used after cardiopulmonary bypass (CPB) to diagnose excessive postoperative hemorrhage. Conventional TEG during CPB is not possible due to the sensitivity of the TEG to even small amounts of heparin, which produces a nondiagnostic tracing. The purpose of this study was to compare heparin neutralization using heparinase or protamine in TEG blood samples obtained during CPB. TEG testing was performed on 48 patients before, during and after CPB. Tissue plasminogen activator activity and antigen were measured on a subset of 32 patients. We found: 1) heparinase neutralized at least 10 IU/ml heparin while 1.6 ug/ml protamine neutralized up to 7 IU/ml heparin, 2) in samples with complete heparin neutralization by both methods, there was no significant difference in the R values, 3) while there was good correlation for other TEG parameters between heparinase and protamine treated samples, heparinase treatment produced shorter K values and higher angle, MA and A60, 4) while fibrinolysis was detected using both methods, heparinase treatment suppressed fibrinolysis in the TEG in both samples from patients and after in vitro addition of tissue plasminogen activator, 5) TEG was not a sensitive indicator of t-PA activity, detecting only 21% of samples with increased t-PA activity during bypass, and 5) heparinase was at least 100 times more expensive than protamine. We conclude that while both heparinase and protamine can be used to neutralize heparin in TEG samples obtained during CPB, protamine neutralization is more sensitive to fibrinolysis and less expensive, but the protamine dose must be carefully selected to match the heparin level used at individual institutions.

Laboratory evaluation of fibrinolysis in patients with a history of myocardial infarction.

The aims of this study were to determine whether elevated plasminogen activator inhibitor type 1 (PAI-1) activity after myocardial infarction reflects baseline PAI-1 or represents an acute-phase response secondary to the infarction, and to determine how tissue plasminogen activator (t-PA) activity and total t-PA antigen levels in healthy control subjects differ from those in patients after myocardial infarction. Compared with healthy control subjects, patients studied 1-3 months after infarction had elevated levels of PAI-1 activity and fibrinogen but normal levels of C-reactive protein and von Willebrand factor antigen, whereas patients with a noncardiac acute-phase response showed elevation of all four proteins. Elevated PAI-1 activity in the absence of elevations in other acute-phase proteins suggests an intrinsic increase in PAI-1 secretion in the post-myocardial infarction group. In addition, when compared with healthy control subjects, post-myocardial infarction patients had higher levels of total t-PA antigen (bound and free t-PA) but lower t-PA activity and a lower percentage of active t-PA. Overall, survivors of myocardial infarction have reduced t-PA activity and increased PAI-1 activity that is not due to a prolonged acute-phase response.

Mitochondrial and MB isoenzymes of creatine kinase in cerebrospinal fluid from patients with hypoxic-ischemic brain damage.

Measurements of cerebrospinal fluid (CSF) creatine kinase (CK, EC 2.7.3.2) isoenzyme activity have been used to predict outcome in patients with acute brain injury following cardiac arrest. We identified two CK isoenzymes previously unreported in CSF from 16 patients with hypoxic-ischemic brain damage. Prior to analysis, the CK in the CSF samples was reactivated with dithiothreitol. CK isoenzymes were identified using electrophoretic and immunologic methods. Total CK activity ranged from 23 to 924 U/L (mean 452). CSF-CK-BB was the predominant isoenzyme present in all cases. In addition to CSF-CK-BB, the authors identified CSF-CK-MM in 6 cases, CSF-CK-MB in 8 cases, and CSF-mitochondrial-CK in 14 cases. The presence of CSF-CK-MM was significantly related to blood contaminating the CSF (P less than 0.02). It is proposed that CSF-CK-MB results from recombination of CK-MM and CK-BB in CSF and that mitochondrial CK is released with CK-BB into the CSF from the damaged brain tissue.

Adenocarcinoma of rete testis. Role of inguinal orchiectomy plus retroperitoneal lymph node dissection.

Adenocarcinoma of the rete testis is diagnosed rarely. We describe the clinical and pathologic findings in a forty-seven-year-old man with this unusual tumor. Treatment modalities are reviewed emphasizing the role of radical orchiectomy and retroperitoneal lymph node dissection.

Insulin, cortisol and catecholamines do not regulate circadian variations in fibrinolytic activity.

To evaluate possible hormonal regulators of the diurnal rhythm in fibrinolytic activity, we measured tissue plasminogen activator (t-PA) activity, plasminogen activator inhibitor activity (PAI-1), t-PA antigen, insulin, cortisol, and catecholamines in 6 healthy males (age 34 +/- 5) every 2 hours for 24 hours. Fibrinolysis was characterized by a peak in PAI-1 activity and a trough in t-PA activity at 0600 h. PAI-1 activity increased 92% and t-PA activity decreased 56% between 2400 h and 0600 h. t-PA antigen (principally a measure of t-PA/PAI-1 complex), peaked at 0800 h. In comparison, insulin levels were lowest at night when PAI-1 activity was rising. The weak inverse correlation between insulin and PAI-1 activity (r = -0.28, p less than 0.02), was not sufficient to explain the diurnal change in fibrinolysis. While cortisol demonstrated the expected circadian change, the increase in cortisol did not occur until 0400 h, 4-6 hours after the rise in PAI-1 and decrease in t-PA activity started. Supine resting plasma epinephrine and norepinephrine showed no circadian rhythm. From this data, we hypothesize that the increased level of PAI-1 in the morning consumes t-PA, leading to decreased t-PA activity and increased t-PA/PAI-1 complex. Further, we conclude that insulin, cortisol, and catecholamines are not responsible for the circadian rhythm of fibrinolysis.

Effects of endurance training on the circadian rhythm of fibrinolysis in men and women.

This randomized study compared the fibrinolytic circadian rhythm of healthy older men and older women (average age 66 +/- 5), before and after 6 months of endurance training versus stretching controls. Compared with men, women at baseline had similar rhythms for tissue plasminogen activator (t-PA) activity and plasminogen activator inhibitor 1 (PAI-1) activity, but lower levels of total t-PA antigen. In men (N = 16), endurance training increased VO2max 15% (P < 0.001), while decreasing PAI-1 activity 37% (P = 0.034) and total t-PA antigen 18% (P = 0.0003) between midnight and 6 a.m., but did not affect t-PA activity. In women (N = 9), endurance training increased VO2max 18% (P = 0.003), and increased t-PA activity 20% (P = 0.027) and total t-PA antigen 55% (P = 0.007) between 10 p.m. and 4 a.m., but had no effect on PAI-1 activity. After endurance training there were no significant differences in the fibrinolytic circadian rhythm of men versus women. Six months of nonaerobic stretching had no effect on VO2max or fibrinolysis in men (N = 11) or women (N = 8). This study indicates that potentially favorable changes occur in fibrinolytic factors after endurance training in older men and older women.

A kinetic model of the circulatory regulation of tissue plasminogen activator during orthotopic liver transplantation.

To better understand the regulation of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) during liver transplantation, we used a computer model of the human circulatory system to simultaneously evaluate the effect of t-PA secretion, t-PA inhibition by PAI-1, hepatic clearance of t-PA, blood loss, transfusion and hemodynamics on t-PA and PAI-1 levels during liver transplantation in three patients that differed in severity of liver disease, blood loss and anhepatic changes in t-PA. Higher preoperative t-PA levels were primarily related to underlying liver disease and reduced hepatic clearance. During the anhepatic stage, when hepatic t-PA clearance was eliminated: (1) the expected rise in t-PA was modulated by the extent of bleeding, which acted as an alternate t-PA clearance mechanism; and (2) the ratio of t-PA:PAI-1 was increased due both to lower t-PA clearance and reduced PAI-1 secretion. Recirculation of the new liver was associated with renewed clearance of t-PA, an acute phase increase in PAI-1 and a drop in the t-PA:PAI-1 ratio. Understanding fibrinolytic regulation required simultaneous analysis of t-PA secretion, inhibition and clearance. Anhepatic t-PA levels could be predicted based on preoperative liver function and surgical blood loss, which acted as an alternate t-PA clearance mechanism.

Factor XIIIA and clot strength after cardiopulmonary bypass.

Reduced factor XIIIA levels and decreased clot strength have been associated with increased bleeding after cardiopulmonary bypass (CPB). The purpose of this study was to evaluate the relationship between hemostatic factors, including factor XIIIA, and clot strength before, during and after CPB. Factor XIIIA antigen, platelet counts, fibrinogen, factor V activity, tissue plasminogen activator and clot strength (by thromboelastograph) were measured at baseline, after 45 min of CPB, at the end of CPB and 4 h post-operatively in 34 patients. Baseline factor XIIIA antigen was 5.2 +/- 1.4 mg/l. On average, factor XIIIA levels dropped to 64% and clot strength to 77% of baseline values after 45 min on CPB and remained below baseline during the immediate post-operative period. Clot strength was significantly correlated (r = 0.81) with platelet count and fibrinogen but not plasma factor XIIIA levels. Addition of 10 mg/l recombinant factor XIII[a2] significantly increased clot strength. Postoperative bleeding at 2 h was inversely correlated with platelet count, factor XIIIA antigen and clot strength measured at the end of CPB. Maintenance of adequate platelet counts and factor XIIIA levels at the end of CPB may play a role in maintaining clot strength and reducing blood loss.

Thrombogenic alleles, Escherichia coli O157:H7 infections, and hemolytic uremic syndrome.

Hemolytic uremic syndrome (HUS) of childhood most commonly follows gastrointestinal infection with Escherichia coli O157:H7. This pathogen elaborates Shiga toxins that are believed to cause microvascular injury and to trigger a thrombogenic response. The exact mechanisms leading to variable disease manifestations are unknown. Allelic variation in genes encoding selected coagulation factors and inhibitors of fibrinolysis were examined to determine whether or not a causal relationship exists between hypercoagulability and the development of HUS. No correlation between the thrombogenic factor V (G1691A), factor II (G20210A), methylenetetrahydrofolate reductase (C677T), or the plasminogen activator inhibitor (PAI)-1 promotor (4G/5G) genotypes and the risk of infection with E. coli O157:H7, or the risk of development of HUS among infected patients, was found. Serum PAI-1 levels did not correlate with the PAI-1 genotype. We conclude that the alleles studied are not major risk factors for the acquisition of E. coli O157:H7 infection, or of E. coli O157:H7-related HUS.

Comparison of the lipoprotein, carbohydrate, and hemostatic effects of phasic oral contraceptives containing desogestrel or levonorgestrel.

Desogestrel (DSG) is a less-androgenic progestogen than levonorgestrel (LNG). This difference in androgenicity may be responsible for observed differences in metabolic effects between oral contraceptive (OC) formulations containing almost equivalent estrogen doses but with either DSG or LNG as a progestogen. To test the hypothesis, a prospective 9-month randomized comparison of plasma lipids, glucose, insulin, hemostasis, and sex hormone binding globulin (SHBG) was conducted in 66 healthy women using phasic formulations of OCs containing either DSG (DSG-OC) or LNG (LNG-OC). The study results showed that SHBG increased 3-fold with DSG-OC and 2-fold with LNG-OC. DSG-OC increased HDL-C, HDL(2)-C and HDL(3)-C; LDL-C decreased transiently. LNG-OC decreased HDL(2)-C and increased HDL(3)-C; HDL-C was unchanged and LDL-C decreased transiently. Both formulations increased VLDL-C and triglycerides, more with DSG-OC, but apolipoprotein B levels increased equally. Apo A-I and A-II increased more with DSG-OC than with LNG-OC. Neither formulation altered Lp(a) or fasting glucose and insulin levels. Postprandially, both formulations decreased glucose and increased insulin responses, but to an equivalent degree. Both OCs slightly enhanced procoagulant and profibrinolytic parameters to the same extent except for internally compensating decreases in Factor V and protein S with DSG-OC. In summary, at almost equivalent estrogen doses, a phasic OC containing DSG compared with LNG has a less androgenic effect on lipoproteins and SHBG, similar effects on hemostatic parameters with lower protein S and factor V activity and equivalent effects on carbohydrate metabolism. The lipoprotein, SHBG, and protein S and factor V differences are likely due to the lesser androgenicity of DSG allowing for a greater expression of the dose of estrogen.