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.

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.

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.

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.

Desogestrel and gestodene in oral contraceptives: 12 months' assessment of carbohydrate and lipoprotein metabolism.

We examined the influence on carbohydrate and lipoprotein metabolism of oral contraceptives (OCs) containing two new third-generation progestogens, desogestrel and gestodene. This was a prospective randomized study in which monophasic combinations of 20 micrograms ethinyl estradiol (E2) and 150 micrograms desogestrel or 30 micrograms ethinyl E2 plus 75 micrograms gestodene were administered to 15 and 19 healthy women, respectively. An oral glucose tolerance test including measurement of insulin response was performed before treatment and after 3, 6, and 12 months of treatment. We also determined fasting plasma concentrations of total cholesterol; high-density lipoprotein cholesterol, including the subfractions high-density lipoprotein2 cholesterol and high-density lipoprotein3 cholesterol; low-density lipoprotein cholesterol; very low-density lipoprotein cholesterol; and triglycerides. A transient deterioration of glucose tolerance was observed despite unchanged levels of insulin after treatment with both compounds for 3 months. In both groups plasma levels of triglycerides, very low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol increased significantly after 3 months. After 12 months, a significant increase in the high-density lipoprotein cholesterol/total cholesterol ratio was observed in the ethinyl E2-desogestrel group, and no persistent changes in low-density lipoprotein cholesterol could be demonstrated in any of the groups. Our results indicate that treatment with either compound for 12 months has no effect on carbohydrate or lipoprotein metabolism known to increase the risk of cardiovascular disease.

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.

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.

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.

Outcome of neonates with birth weights of less than 801 grams.

The follow-up results of intensive care for 68 infants with birth weights less than 801 g treated at Stanford University Hospital were reviewed. The overall survival rate for these infants was 35%, but was 50% for those infants who had been successfully resuscitated in the delivery room and were admitted to the Intensive Care Nursery. Infants under 601 g in weight or less than 25 weeks gestation were more likely to die in the delivery room, but survival among those admitted to the Intensive Care Nursery did not depend on birth weight or gestational age. One-minute and 5-minute Apgar scores less than 5 and interstitial emphysema were associated with increased risk of neonatal death. Only two of 22 survivors (9%) were severely handicapped and another eight (36%) had remediable disabilities at 2 years of age. No infant developed hydrocephalus and only one infant had spasticity. We suggest that the low incidence of major handicaps among survivors encourages the vigorous resuscitation of infants weighing less than 801 g at birth, yet strategies must be developed that will minimize both prolonged dying and the cost of intensive care for nonviable infants.

[Hormonal contraception with ethinylestradiol and gestoden. The effects on glucose tolerance and lipid metabolism]. / Hormonal kontraception med etinyløstradiol og gestoden. Effekt på glukosetolerans og lipidmetabolisme.

PIP: Only a few years following the introduction of combination oral contraceptives, it was determined that these hormonal preparations led to changes in the glucose and lipid metabolisms, which must be considered as potentially harmful. For example, women with no known disposition to diabetes mellitus may acquire diabetic glucose-overloading with use of oral contraceptives. In addition, the increased occurrence of cardiovascular complications among oral contraceptive users is thought to be directly associated with the effect of lipoprotein displacement. To reduce these effects, a new triphasic combination oral contraceptive, consisting of ethinyl-estradiol and gestodene (15-levonorgestrel), has been introduced. This study specifically investigated the effects of glucose tolerance and lipid metabolism from using this new preparation. 10 women between ages 21-32 (average age 25) participated. All had normal weights and were without known disposition to diabetes mellitus or heart disease. After receiving a medical examination, the women were given the 3-phase pill for 6 months. The pills were administered cyclically according to the usual schedule for oral contraceptives. In each cycle, the dosage consisted of 0.030 mg ethinyl-estradiol (EE) and 0.050 mg gestodene from day 1-6, then 0.400 mg EE and 0.070mg GD from days 7-11, and finally 0.030 mg EE and 0.100 mg GD in the last 10 days. Laboratory tests were done in the luteal phase before the trial's start, and before the final 10 days of the trial in the 2nd and 6th cycle. Fasting levels of plasma glucose and insulin were monitored. Though there are as yet no publications which deal with the influence of gestodene on glucose tolerance, the results from the present study indicate that gestodene in this 3-phase pill does not alter glucose tolerance in women with normal health. The raised AVC value for insulin, which was observed 6 months after treatment, may however indicate that he glucose homeostasis during treatment was maintained due to raised endogenous insulin secretion. It is therefore possible that individuals with latent insulin deficiency might acquire diabetic glucose tolerance because of an inability to show adequate insulin response.^ieng

[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.

[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.

[Self-reported pattern of illness and hospitalization during pregnancy. Results from a nation-wide questionnaire study]. / Selvrapporteret sygdoms- og indlaeggelsesmønster under graviditet. Resultater fra en landsdaekkende spørgeskemaundersøgelse.

In a representative questionnaire investigation covering all of Denmark, 3,152 women provided information about their health during a recent pregnancy. Of these, 1,411 (45%) had been ill or had experienced severe complaints related to the pregnancy and 625 (20%) had been hospitalized during pregnancy. The average duration of hospitalization was two weeks with great variations in the various conditions. Women with multiple pregnancies were hospitalized for an average of six weeks. Increased incidence of hypertension and placental insufficiency were found among women over the age of 35 years whereas preeclampsia was most common among primigravidae. Women who had previously had a spontaneous abortion had an increased frequency of haemorrhage, threatened abortion and threatened premature delivery. Previous infertility was not associated with increased occurrence of complications of pregnancy-related morbidity were observed between women who had work outside the home and women who worked in their homes. Women with work outside the home who reported illness or severe pregnancy-related symptoms had an average period of sick-leave of six weeks for health reasons. The most prolonged periods of sick-leave were in cases of threatened abortion, threatened premature delivery and multiple pregnancies. The right to take leave with pay or maintenance allowance prior to the expected date of delivery is not utilized to any great extent more by women with illness during pregnancy. On the other hand, women with long educations utilized this right to a greater extent than unskilled women, who had, on the other hand increased leave on account of health reasons.

[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.