Lack of hepatic metabolism of C-telopeptides of type I collagen.

BACKGROUND: Bone biochemical markers have been used in dynamic studies of bone metabolism, and, for accurate interpretation of measured marker levels, it is essential to have information of extra-skeletal metabolism. Therefore, the objective of the present study was to investigate if the circulating C-telopeptides of type I collagen (CTX) was subject to hepatic extraction. METHODS: Splanchnic plasma flow, total plasma volume and the plasma concentration of CTX was determined in an artery and the liver vein of eight healthy female volunteers. For comparison, the concentration of N-terminal propeptide of type I collagen, PINP, was measured. RESULTS: No change in plasma level of CTX could be detected over the liver. In contrast, PINP decreased from an average of 52.9 ng/ml in the artery to 42.4 ng/ml in the vein, corresponding to a 19.8% reduction. CONCLUSIONS: The C-telopeptides of type I collagen (CTX) are not subject to hepatic metabolism.

Splanchnic extraction and clearance of tissue plasminogen activator (t-PA) after injection of recombinant t-PA (Actilyse) in resting healthy subjects is proportional to the arterial concentration.

The purpose of the study was to evaluate the splanchnic extraction of tissue plasminogen activator (t-PA) in normal healthy fasting subjects after the injection of recombinant t-PA (rt-PA; Actilyse). In nine healthy volunteers (five male, four female), 21-29 years of age, the concentration of t-PA was determined in plasma samples taken simultaneously from a femoral artery and a large liver vein after a bolus injection (5, 10 or 20 mg) of rt-PA. The splanchnic plasma flow rate, the plasma volume, and the splanchnic extraction fraction of t-PA were determined. After the rt-PA injection, the measured arterial concentration of t-PA decreased from 36 750 to 45 pmol/l for t-PA antigen and from 50 700 to 17 pmol/l for active t-PA. The splanchnic extraction fraction decreased from 0.95 to 0.02 for t-PA antigen and from 0.78 to 0.08 (n = 3) for active t-PA. The extraction fraction was proportional to the arterial concentration of t-PA when the arterial concentration of t-PA was above about 300 pmol/l (both t-PA antigen and active t-PA). The median splanchnic plasma flow rate was 911 ml/min (range, 651-1149 ml/min). In the individual subject, the splanchnic plasma flow rate remained constant during the experimental period. The main conclusion of the study is that the splanchnic clearance and extraction fraction of t-PA, following an injection of rt-PA in the resting fasting steady state, depends on the arterial concentration of t-PA. The higher the arterial concentration of t-PA, the higher the extraction fraction of t-PA.

Mean transit times and the sites of synthesis and catabolism of tissue plasminogen activator and plasminogen activator inhibitor type 1 in young subjects.

Using an invasive technique, we studied the mean transit time, the net quantitative turnover rate, and the sites of synthesis and catabolism of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) in healthy young volunteers in the fasting, steady state. Blood was sampled simultaneously from a large hepatic vein, an artery and the inferior caval vein, while measuring the splanchnic plasma flow rate and the plasma volume. We found that the catabolism of active t-PA and t-PA antigen took place in the splanchnic circulation with net rates of 7.2 and 6.3 pmol/min, respectively. The extraction fraction and the mean transit time in the splanchnic circulation were, respectively, 0.63 and 5.6 min for active t-PA and 0.17 and 21 min for t-PA antigen. Active PAI-1 was synthesized in the splanchnic circulation at a rate of 890 IU/min and had a mean transit time of about 9.8 min. No net extraction of PAI-1 antigen took place in the splanchnic circulation. In conclusion, we demonstrated that active t-PA and t-PA antigen are catabolized and active PAI-1 produced in the splanchnic circulation in young healthy subjects during steady state. Furthermore, our data show that active t-PA was also eliminated outside the splanchnic region with a catabolism rate of about 8.4 pmol/min. No net complex formation could be demonstrated in the peripheral circulation. We therefore suggest that active t-PA is eliminated by a re-uptake in the endothelium in the peripheral vessels or in the lung circulation.

Expression environment determines K+ current properties: Kv1 and Kv4 alpha-subunit-induced K+ currents in mammalian cell lines and cardiac myocytes.

Voltage-gated K+ channel (Kv) pore-forming (alpha) subunits of the Kv1 and Kv4 subfamilies have been cloned from heart cDNA libraries, and are thought to play roles in the generation of the transient outward K+ current, Ito. Heterologous expression of these subunits in Xenopus oocytes, however, reveals K+ currents that are quite distinct from Ito. In the experiments here, the detailed time- and voltage-dependent properties of the currents expressed in mammalian cell lines and in cardiac myocytes by Kv1.4 and Kv4.2 were examined and compared to previous findings in studies of oocytes, as well as to Ito characterized in various myocardial cells. As in oocytes, expression of Kv1.4 in HEK-293, Ltk- or neonatal rat ventricular cells reveals rapidly activating K+ currents. In contrast to the currents in oocytes, however, there are two components of inactivation of the Kv1.4-induced currents in mammalian cells, and both components are significantly slower in myocytes than in either HEK-293 or Ltk- cells. In addition, in all three cell types, recovery of Kv1.4 from steady-state inactivation is very slow, proceeding with mean time constants in the range of 6-8 s. The properties of Kv4.2-induced currents also vary with cell type and, importantly, the rates of activation, inactivation and recovery from inactivation are significantly faster in mammalian cells than in Xenopus oocytes. In HEK-293, Chinese hamster ovary (CHO) and neonatal rat ventricular cells, for example, the currents recover from steady-state inactivation with mean (+/-SD) time constants of 153+/-32 (n=12), 245+/-112 (n=10) and 86+/-38 (n=11) ms, respectively; therefore, recovery proceeds 5-10 times faster than observed for Kv4.2 in oocytes. These results emphasize the importance of the cellular expression environment in efforts to correlate endogenous K+ currents with heterologously expressed K+ channel subunits. In addition, the finding that Kv alpha subunits produce distinct K+ currents in different cells suggests that cell-type-specific associations with endogenous Kv alpha or accessory beta subunits and/or post-translational processing play roles in determining the properties of functional K+ channels.

Metabolic and fibrinolytic response to changed insulin sensitivity in users of oral contraceptives.

The fundamental role of insulin resistance for metabolic changes linked to cardiovascular disease and type 2 diabetes is increasingly recognized. Oral contraceptives (OC) may affect insulin sensitivity, and a detailed characterization hereof, as well as the secondary effects on related metabolic systems, are relevant in the evaluation of the risk of developing vascular disorders or diabetes in OC users. We studied insulin sensitivity index (S(I)), glucose effectiveness (S(g)), and insulin response in young, healthy women by frequently sampled intravenous glucose tolerance tests before and after randomization to 6 months of treatment with ethinyl estradiol in triphasic combination with norgestimate (n = 17) or gestodene (n = 20). Measurements of fasting triglycerides and antigen concentrations of tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) were also included. Both compounds increased fasting plasma insulin and reduced S(i) but did not affect S(g). The relationships between S(i) and insulin response were unchanged. No consistent correlation between insulin sensitivity and triglycerides, t-PA, or PAI-1 were demonstrated before or during treatment. We conclude that the treatments were followed by a compensated decrease in insulin sensitivity that was unrelated to changes in triglycerides, t-PA, or PAI-1 antigen.

No influence of proinsulin and insulin on plasma levels of plasminogen activator inhibitor type 1 and tissue plasminogen activator in young women before and during intake of contraceptive steroids.

Clinical observations in patients predisposed to cardiovascular disorders and recent experimental observations suggest that proinsulin and insulin participate in the regulation of fibrinolysis in vivo. In the present study, we examined if proinsulin and insulin affect the constitutive (fasting) secretion of plasminogen activator inhibitor type 1 (PAI-1) and tissue plasminogen activator (t-PA) in young healthy women (N = 17). We also measured the antigen concentrations of PAI-1 and t-PA during slow and fast changes in proinsulin and insulin levels induced by oral (OGTT) and intravenous (IVGTT) glucose tolerance tests. The assessments were performed before and after 6 months of treatment with contraceptive steroids, which have a well-defined influence on the fibrinolytic variables. We observed no consistent correlations between fasting values of proinsulin, insulin, PAI-1, and t-PA either before or during hormonal treatment. Before hormonal treatment, PAI-1 and t-PA antigen levels decreased (P < .05) during the hyperproinsulinemia and hyperinsulinemia induced by the OGTT and IVGTT. After hormonal intake for 6 months, a decrease only in t-PA concentrations during the OGTT was observed despite similar proinsulin and insulin responses to the glucose loads. Our findings suggest that proinsulin and insulin have no influence on the regulation of plasma levels of PAI-1 and t-PA in young healthy women, irrespective of intake of contraceptive steroids.

PIP: In Denmark, clinicians conducted clinical and metabolic evaluations on 17 healthy women, 21-26 years old, within the last 10 days of their menstrual cycle preceding intake with a triphasic oral contraceptive (OC) (ethinyl estradiol + norgestimate) and during the last 7 days of the sixth period of OC treatment. They aimed to examine the effect of proinsulin and insulin on fasting secretion of plasminogen activator inhibitor type 1 (PAI-1) and tissue plasminogen activator (t-PA). OCs have a well-defined effect on plasma levels of PAI-1 and t-PA. The clinical researchers also studied the antigen concentrations of PAI-1 and t-PA during slow and fast changes in proinsulin and insulin levels induced by oral and intravenous glucose tolerance tests. They did not find consistent correlations between fasting values of proinsulin, insulin, PAI-1, and t-PA either before or during OC treatment. During the glucose tolerance test induced hyperproinsulinemia and hyperinsulinemia and before OC treatment, PAI-1 and t-PA antigen levels fell (p 0.05). After 6 months of OC treatment, t-PA levels fell only during the oral glucose tolerance test (p 0.05) even though proinsulin and insulin responded similarly to the glucose loads. These findings suggest that neither proinsulin nor insulin regulate plasma levels of PAI-1 and t-PA in young healthy women regardless of OC use status.

[Diabetes regulation and oral contraceptives. Lipoporotein metabolism in women with insulin dependent diabetes mellitus using oral contraceptives]. / Diabetesregulering og p-piller. Lipoproteinomsaetning hos kvinder med insulinkraevende diabetes mellitus i p-pillebehandling.

In an open prospective study we evaluated the glycaemic control and lipoprotein metabolism in 22 women with uncomplicated insulin dependent diabetes mellitus during one year of oral contraception with ethinyl oestradiol and gestodene. Twenty women of comparable diabetic status using non hormonal contraception served as controls. No changes in glycaemic control were observed in any of the groups. In the oral contraceptive group decreased serum levels of low-density lipoprotein cholesterol and increased levels of triglycerides and lipoprotein A were noted whereas total cholesterol and high-density lipoprotein cholesterol levels were unchanged. In the control group a decrease of low-density lipoprotein cholesterol was observed. No effect of tobacco smoking on glycometabolic control or lipoprotein metabolism could be demonstrated during hormonal intake. In conclusion, we found no evidence of impaired glycometabolic control or adverse changes in serum levels of lipoproteins known to be associated to atherosclerosis in diabetic women during one year of oral contraception with ethinyl oestradiol and gestodene.

Contraception guidance in women with pre-existing disturbances in carbohydrate metabolism.

OBJECTIVES: To review our studies on the clinical and metabolic impact of contraceptive methods in women with insulin dependent diabetes mellitus (IDDM) and women with previous gestational diabetes mellitus (GDM) in order to provide suggestions for the contraceptive counselling of these women. METHODS: The clinical events following first insertions of copper IUDs were studied in 103 women with IDDM and in 119 non-diabetic women. Moreover we studied the effects on glycometabolic control and lipid metabolism in women with well-controlled IDDM using low-dose oral contraceptives (OCs) containing ethinylestradiol combined with norethisterone (n = 10), levonorgestrel (n = 9) or gestodene (n = 11). Hemostatic and endothelial function was also studied in the women using the gestodene-containing preparation. Finally, we studied the impact of oral contraceptives on the insulin sensitivity in women with previous GDM. RESULTS: The continuation rates and indications for medical removal of the IUDs were similar in the diabetic and the non-diabetic women. There was no increased pregnancy rate or increased frequency of pelvic inflammatory disease in the diabetic women. The glycemic control was not changed by the OCs and none of the treatment regimens were associated with changes in plasma lipids linked to increased risk of atherosclerosis. Indications of increased fibrin formation, which seemed to be compensated by increased fibrinolytic activity, were noted with the gestodene-containing preparation. None of the women developed microalbuminuria during the study. Compared to normal women, we found reduced insulin sensitivity in the women with previous GDM using the pill. CONCLUSION: Intrauterine devices and barrier methods can be used by diabetic women with the same reservations as in the general population. Low-dose OCs do not influence the glycemic control and have no adverse impact on plasma lipids. The balance between fibrin formation and resolution was maintained during intake of the gestodene-containing pill. Our findings suggest that combined oral contraceptives can be used in women with uncomplicated IDDM and in women with previous GDM if clinical and metabolic monitoring can be ensured.

Hormonal contraception in women with IDDM. Influence on glycometabolic control and lipoprotein metabolism.

OBJECTIVE: Safe and effective contraceptive methods are essential for women with insulin-dependent diabetes mellitus (IDDM), but opinions on the use of hormonal oral contraceptives by these women are conflicting. We evaluated the effects on glycometabolic control and lipoprotein metabolism in women with IDDM treated with an oral contraceptive not previously studied in a diabetic population. RESEARCH DESIGN AND METHODS: A total of 22 women with IDDM received a monophasic combination of ethinyl estradiol and gestodene for 1 year; 20 women of comparable diabetic status using nonhormonal contraception were selected as control subjects. Evaluation was performed before and after 1, 3, 6, and 12 months of hormonal intake using nonparametric statistical methods. RESULTS: Except for a higher median age of the control group, the baseline values for all clinical and metabolic variables were similar in the two groups, and in neither of the groups were changes in blood pressure, body mass index, or glycemic control observed. In the oral contraceptive group, decreased serum levels of low-density lipoprotein (LDL) cholesterol and increased levels of triglycerides and lipoprotein A were noted, whereas total cholesterol and high-density lipoprotein cholesterol levels were unchanged. In the control group, a decrease of LDL cholesterol was observed. No effect of tobacco smoking on glycometabolic control or lipoprotein metabolism could be demonstrated during hormonal intake. CONCLUSIONS: No evidence of impaired glycometabolic control or adverse changes in serum levels of lipoproteins known to be associated with atherosclerosis was observed in women with well-controlled IDDM during 1 year of oral contraception with ethinyl estradiol and gestodene.

Balance of coagulation activity with fibrinolysis during use of oral contraceptives in women with insulin-dependent diabetes mellitus.

In healthy nondiabetic women, oral contraceptives (OCs) affect hemostatic function. In diabetic women, there is concern that they may also increase the risk of diabetic vascular complications. This study was designed to examine the balance between coagulation activity and fibrinolytic activity--an indirect measure of endothelial cell function--in women with insulin-dependent diabetes mellitus (IDDM) during long-term use of OCs. The study group included 11 young women with uncomplicated IDDM who were prescribed ethinyl estradiol 30 micrograms and gestodene 75 micrograms. Twelve other diabetic women not taking OCs constituted the control group. Hemostatic function was evaluated at entry and after 1,3,6, and 12 months. In women taking OCs, plasma levels of factor VII(c) increased, while fibrinogen levels did not change. Inhibition of coagulation was affected by increased levels of protein C, although plasma levels of antithrombin III and protein S remained stable. The antigen concentrations of tissue-type plasminogen activator and plasminogen activator levels themselves were unchanged. There was a proportionate increase in the concentrations of thrombin-antithrombin III complexes and D-dimer. None of the hemostatic variables changed significantly in the control group. We conclude that the balance between coagulation activity and fibrnolysis does not change during use of this OC. Our findings suggest that low-dose OCs induce a procoagulatory state that is compensated for by enhanced fibrinolytic activity.

Assessment of endothelial function during oral contraception in women with insulin-dependent diabetes mellitus.

The effects of contraceptive steroids on the expression of endothelial homeostasis were examined by direct and indirect measures in women with insulin-dependent diabetes mellitus (IDDM) in a prospective nonrandomized controlled study. Study subjects were 13 women with uncomplicated IDDM treated with a monophasic combination of 30 micrograms ethinyl estradiol and 75 micrograms gestodene for 12 consecutive cycles and 13 women of comparable diabetic status as control. During the study period, none of the participants developed increased renal albumin excretion, which was used as a direct measure of endothelial function. In the indirect assessment of endothelial function, we found a proportionate increase in plasma levels of thrombin-antithrombin III (TAT) complexes and D-dimer during treatment. Hormonal intake was followed by decreased antigen concentrations of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor (type 1 [PAI-1]), whereas the activities of t-PA and PAI-1 were unchanged. Plasma levels of plasminogen and histidine-rich glycoprotein (HRG) increased and decreased, respectively, whereas an increase in von Willebrand factor was observed in the treatment group. No significant changes in direct or indirect measures were observed in the control group during the observation period of 12 months. In conclusion, no adverse effect on endothelial function was demonstrated by direct measures, but our findings suggest that a procoagulant state, compensated by enhanced activity of the fibrinolytic system, is induced by hormonal treatment. Clinical and metabolic monitoring is recommended if the use of oral contraceptives in women with IDDM is extended.

Effects of contraceptive steroids on cardiovascular risk factors in women with insulin-dependent diabetes mellitus.

OBJECTIVE: We evaluated established cardiovascular risk factors within lipoprotein metabolism, hemostasis, and endothelial function in women with insulin-dependent diabetes mellitus who were using oral contraceptives. STUDY DESIGN: Twenty-five women with uncomplicated insulin-dependent diabetes mellitus, allocated to treatment with a monophasic combination of 30 micrograms ethinyl estradiol and 75 micrograms gestodene (treatment group, n = 12) or with nonhormonal contraception (control group, n = 13), were prospectively followed up for 12 months. Nonparametric methods were used for statistical evaluation. RESULTS: No statistical differences in the biochemical risk markers were noted between the two groups at the start of the study. In the treatment group serum levels of low-density lipoprotein cholesterol decreased, whereas the concentrations of total cholesterol, high-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol, and triglycerides were unchanged. Within the coagulation system factor VII coagulant activity increased, while fibrinogen levels were unchanged. In the fibrinolytic system we found unchanged activities but decreased antigen concentrations of tissue plasminogen activator and plasminogen activator inhibitor. The concentration of von Willebrand factor increased, but no change in albumin excretion rates were found. In the control group no changes in any of the variables were observed. CONCLUSION: Intake of modern oral contraceptives does not deteriorate the cardiovascular risk profile in women with insulin-dependent diabetes mellitus, but our study indicates a risk of disturbances of the endothelial integrity, which needs further investigation.

[Hemostatic balance during treatment with the newest contraceptives]. / Den haemostatiske balance under behandling med nyere p-pillepraeparater.

Thirty-four healthy young women were allocated to 12 consecutive cycles of treatment with monophasic combinations of: 20 micrograms ethinyl estradiol and 150 micrograms desogestrel (n = 15) or 30 micrograms ethinyl estradiol and 75 micrograms gestodene (n = 19). In both groups plasma levels of fibrinogen and factor VII increased while the capacity of coagulation inhibition was affected by increased protein C and decreased protein S levels. Increased fibrinolytic capacity was indicated by elevated activity and reduced antigen levels of tissue plasminogen activator and reduced activity and concentration of tissue plasminogen activator inhibitor. The ratio between thrombin-antithrombin-III-complexes and fibrin degradation products were unchanged signifying no effect of hormonal intake on the balance between thrombin formation and fibrin resolution. In conclusion, the dynamic balance between generation and resolution of fibrin was undisturbed during treatment with both hormonal compounds and our findings do not provide evidence for increased risk of thrombosis in normal women.

PIP: 34 healthy women aged 21-30 years were assigned to 12 consecutive menstrual cycles of treatment with monophasic combinations. 15 women with a median age of 24 years received 20 mcg ethinyl estradiol (EE) and 150 mcg desogestrel (DSG) and 19 women with a median age of 23 years were treated with 30 mcg EE and 75 mcg gestodene (GST). Three women from the EE+DSG group and four women from the EE+GST group quit after six months because of personal reasons. Two more women from the EE+GST group quit after six months because of mammary tension and weight gain. Two women in each group smoked between one and ten cigarettes daily, the rest were nonsmokers. The evaluation of the hemostatic system was carried out in the luteal phase before the treatment began and within the last ten days in the third, sixth, and twelfth treatment cycle. In both groups plasma levels of fibrinogen (7.2 mcmol/l pretreatment to 8.7 mcmol/l posttreatment) and factor VIIc (80% pretreatment to 126% posttreatment) increased significantly under treatment, while the capacity of coagulation inhibition was affected after three months by increased protein C concentrations (15% in the EE+DSG group and 14% in the EE+GST group) and significantly decreased levels of protein C's cofactor, protein S levels by 11% and 15%, respectively. Increased fibrinolytic capacity was indicated by elevated activity and reduced antigen levels of tissue plasminogen activator and reduced activity and concentration of tissue plasminogen activator inhibitor. The ratio between thrombin antithrombin-III-complexes (TAT) and fibrin degradation products were unchanged, signifying no effect of hormonal intake on the balance between thrombin formation and fibrinolysis. The dynamic balance between coagulation and fibrinolysis was undisturbed during treatment with both hormonal compounds, and findings do not provide evidence for increased risk of thrombosis in normal women.

[Postoperative morbidity among alcohol abusers]. / Postoperativ morbiditet blandt alkoholmisbrugere.

Retrospective studies suggest increased postoperative morbidity among alcohol misusers. We have prospectively studied the risk associated with alcohol intake among patients undergoing surgery. We investigated 15 persons who required colorectal surgery and who were drinking at least five Danish drinks per day. These patients were matched for sex, nutrition, age, weight, cardio-pulmonary disease, diagnosis anesthesia, and surgery to 15 control persons who were consuming no more than two drinks daily. None of the patients showed signs of liver disease. The alcohol group developed more postoperative complications than controls (67 vs 20%, p < 0.05) and hospital stay was prolonged (20 vs 12 days, p < 0.05). Preoperatively, alcohol misusers had reduced left ventricular ejection fraction (54 vs 68%, p < 0.01). Delayed-type hypersensitivity responses were reduced in the alcohol group before (53 mm2 vs 78, p < 0.05) and after (18 mm2 vs 55, p < 0.01) surgery. Alcohol misusers had significantly longer bleeding times. Surgical stress responses, as assessed by changes in plasma cortisol and catecholamines, were higher among alcohol misusers (p < 0.05). Postoperative morbidity was increased in alcohol misusers without signs of liver damage. The mechanisms may include subclinical cardiac insufficiency, immunosuppression, and decreased haemostatic function. Preoperative alcohol consumption may be a more important risk factor for postoperative morbidity than previously thought.

Effects of monophasic low-dose oral contraceptives on fibrin formation and resolution in young women.

OBJECTIVE: The purpose of this study was to examine key variables in the regulation of coagulation and fibrinolysis during intake of low-dose oral contraceptives containing newly developed progestogens. STUDY DESIGN: Thirty-four healthy young women were allocated to 12 consecutive cycles of treatment with monophasic combinations of 20 micrograms ethinyl estradiol and 150 micrograms desogestrel (n = 15) or 30 micrograms ethinyl estradiol and 75 micrograms gestodene (n = 19). Nonparametric analysis of variance was used for statistical evaluation. RESULTS: In both groups plasma levels of fibrinogen and Factor VIIc increased, and the capacity of coagulation inhibition was affected by increased protein C and decreased protein S levels. Increased fibrinolytic capacity was indicated by elevated activity and reduced antigen levels of tissue plasminogen activator and by reduced activity and concentration of plasminogen activator inhibitor. Thrombin-antithrombin III complexes and fibrin degradation products were unchanged, signifying no effect of hormonal intake on the degree of activation of the coagulation system or the efficacy of fibrinolysis. CONCLUSION: The overall dynamic balance between generation and resolution of fibrin was maintained during treatment with both hormonal compounds. Our findings suggest that the risk of thrombosis in normal women should not be increased.

PIP: Cardiovascular disorders observed in women using combined oral contraceptives have been linked to alterations in hemostatic function and in lipoprotein and carbohydrate metabolism. In the coagulation system, concentrations of vitamin-K-dependent coagulation factors tend to increase with decreased, increased, or unchanged concentrations of the inhibitors of coagulation. Some changes have also been seen in the fibrinolytic system; particularly with regard to increased capacity. The influence of oral contraceptives upon the two systems depends mainly upon estrogen dose. The possibility therefore exists that the changes in hemostatic variables and the occurrence of thromboembolism may be associated as suggested by the reported decrease in vascular morbidity with reduced estrogen dose. The authors report findings from their evaluation of the influence on coagulation and fibrinolysis of two combined oral contraceptives containing ethinyl estradiol in monophasic combination with the newly developed progestogens desogestrel and gestodene with respect to the capacity within the two systems and their dynamic balance by means of intermediate reaction products over a 12-month period. 34 healthy young women aged 21-30 years with no evidence of current or past liver disease or thromboembolic disorders were allocated to 12 consecutive cycles of treatment with the combinations. All participants had normal blood pressure and were within 10% of their ideal body weight. 15 women received a combination of 20 mcg ethinyl estradiol and 150 mcg desogestrel, while 19 women received 30 mcg ethinyl estradiol and 75 mcg gestodene. The overall dynamic balance between generation and resolution of fibrin was maintained during treatment with both hormonal compounds. These findings suggest that the risk of thrombosis in normal women should not be increased as a result of such treatment regimes.

Postoperative morbidity among symptom-free alcohol misusers.

Retrospective studies suggest that there is an increased postoperative morbidity among alcohol misusers. We have prospectively studied the risk of alcohol intake among patients undergoing surgery. We investigated 15 symptom-free subjects who required colorectal surgery and who were drinking at least 60 g of alcohol per day. These patients were matched for sex, nutrition, age, weight, cardiovascular and pulmonary disease, diagnosis, anaesthesia, and surgery to 15 control subjects who were consuming below 25 g of alcohol daily. Those drinking at least 60 g of alcohol per day developed more postoperative complications than controls (67% vs 20%, p less than 0.05) and hospital stay was prolonged (20 vs 12 days, p less than 0.05). Preoperatively, alcohol misusers had reduced left ventricular ejection fraction (median, 54% vs 68%, p less than 0.01). Delayed hypersensitivity responses were smaller in the alcohol group before (53 mm2 vs 78 mm2, p less than 0.05) and after (18 mm2 vs 55 mm2, p less than 0.01) surgery. Alcohol misusers had longer bleeding times during the first postoperative week (p less than 0.01). Surgical stress responses, as assessed by changes in plasma cortisol and catecholamines, were higher among alcoholics (p less than 0.05). Postoperative morbidity is increased in symptom-free alcohol misusers. The mechanism is probably subclinical cardiac insufficiency, immunosuppression, and decreased haemostatic function. Preoperative alcohol consumption may be a more important risk factor than previously thought.