Effects of different progestin regimens in hormone replacement therapy on blood coagulation factor VII and tissue factor pathway inhibitor

BACKGROUND: Long-term hormone replacement therapy (HRT) reduces cardiovascular risk, but an early increased risk was reported in women with coronary heart disease. In such women the arterial intima can express tissue factor, and changes in coagulation factor VII (factor VII) and tissue factor pathway inhibitor (TFPI) may be deleterious. METHODS: We measured factor VII clotting activity, activated factor VII, and concentrations of factor VII and TFPI during 12 months in healthy post-menopausal women randomized to: (i). cyclic oral estrogen/progestin (n = 25); (ii). long-cycle oral estrogen/quarterly progestin (n = 32); (iii). continuous oral estrogen/progestin (n = 21); (iv). continuous oral estrogen/intrauterine progestin (n = 22); (v). no HRT (n = 26). Blood was collected at baseline, 3, 6 and 12 months. Additional sampling was done before progestin intake in the long cycle group. RESULTS: No variations were observed in the reference group. There was a substantial decrease in TFPI concentrations in the HRT groups irrespective of the type of progestin. In women receiving long-cycle treatment, all factor VII measures increased during the unopposed estrogen periods, and the increase was reversed after progestin intake. The integrated response, AUC, for TFPI was significantly lower in the HRT groups compared with the reference group. CONCLUSION: The observed changes may increase the early thrombotic risk associated with HRT use.     

Modulation of Thrombophilia Genes by Environmental Factors

Hormone replacement therapy (HRT) is associated with reduced risk of coronary heart disease (CHD) and stroke in observational studies; however the possibility of confounding by other risk factors requires prospective assessment of its risks and benefits in randomised controlled trials. The HERS trial of oral HRT in secondary CHD prevention observed an early increased risk of myocardial infarction (MI) and venous thromboembolism (VTE) with HRT: the latter risk has been confirmed by other prospective and case-control studies, and a past history of VTE or MI is now a contraindication to oral HRT. Other prospective randomised trials of HRT, CHD and stroke are in progress. Potential prothrombotic effects of oral HRT (but probably not transdermal HRT) include increased plasma factors VII and IX, activated protein C resistance and C-reactive protein; and decreased antithrombin, protein C and S, and tissue factor pathway inhibitor. Potential protective effects of HRT include decreased blood pressure, lipids, glucose intolerance, fibrinogen, viscosity and plasminogen activator inhibitor; and increased endothelial function. The overall balance of prothrombotic and protective effects varies with HRT preparations and individual women: and may be clarified by ongoing large randomised trials and case-control studies (and substudies of trials).     

The metabolic syndrome in postmenopausal women. Clinical implications

Cardiovascular diseases (CVD) remain the major cause of death in postmenopausal women. Before menopause, women are relatively protected from ischemic heart disease and thromboembolism by their circulating estrogens, but this protection is lost after menopause. Following menopause, adverse lipid changes occur and the levels of several coagulation factor increase. One of the major predisposing factors for CVD is the metabolic syndrome, including myriad risk biomarkers: abdominal girth, blood pressure, fasting glucose, triglycerides, lipids. In many ways, the metabolic syndrome is a precursor to the development of abnormalities of insulin action and diabetes. In parallel, there are effects upon blood coagulation and fibrinolysis. Common preventive therapies require rigorous evaluation. Hormone replacement therapy (HRT) has not produced the expected reduction in CVD and the ideal HRT is probably unobtainable. For long-term HRT users, the risk of thromboembolism needs to be weighed against probable benefits. With respect to the effects of HRT, oral estrogen is associated with elevation in C-reactive protein and varied effects on IL-6, but transdermal estradiol has no significant effect on these parameters. Despite the varied effects of HRT on inflammatory biomarkers, there is no definitive evidence that change in these markers results in modification of cardiovascular risk.     

Effects of bezafibrate and simvastatin on plasma lipoproteins in hypercholesterolemia resistant to hormone replacement therapy

Objectives: Estrogen replacement therapy has favorable effects on serum lipoprotein levels in postmenopausal women with hypercholesterolemia. However, there are some patients who fail to respond to hormone replacement therapy (HRT) to lower the serum cholesterol level. In these cases, a conventional lipid-lowering therapy will be applied in addition to HRT, while the effects of these drugs are not well understood. In this study, we studied the effects of simvastatin and bezafibrate administered in addition to HRT. Methods: Patients who were hypercholesterolemic even after HRT were randomly assigned to three treatment groups: HRT only (control group, n=10), HRT+simvastatin (10 mg/day, n=10), or HRT+bezafibrate (400 mg/day, n=10). Serum lipids and lipoprotein levels were measured throughout 12 weeks. Results: The serum triglyceride levels were decreased by 24±28 and 38±13% in the HRT+simvastatin and HRT+bezafibrate groups, respectively. HRT+simvastatin decreased the total cholesterol (21±10%) and low-density lipoprotein cholesterol (28±12%) levels without affecting the high-density lipoprotein cholesterol (HDL-C) level, while HRT+bezafibrate increased the HDL-C level (12±11%). Conclusions: Treatment with simvastatin or bezafibrate in addition to HRT should be considered in cases of postmenopausal hypercholesterolemia in which HRT alone fails to lower the serum lipoprotein levels.     

Physical activity,body fat,and serum c‐reactive protein in postmenopausal women with and without hormone replacement

The objective was to determine whether higher physical activity is associated with lower serum C‐reactive protein (CRP), independent of oral hormone replacement therapy (HRT) status and body fatness, in 133 postmenopausal women using a cross‐sectional exploratory design at a university research laboratory. The subjects were 133 postmenopausal women, age 50–73 years, with no evidence of coronary artery disease or diabetes. The main outcome measures were: serum CRP, physical activity as measured by Stanford 7‐day activity recall, body fat (both total and regional) as measured by dual energy X‐ray absorptiometry (DXA), and anthropometry (waist and hip circumference). Secondary outcome measures included fasting plasma glucose and insulin as well as fasting serum triglycerides, total cholesterol, high‐density lipoprotein cholesterol, and low‐density lipoprotein cholesterol. Higher physical activity energy expenditures were significantly associated with lower serum CRP levels (r = ?0.18, P = 0.041), independent of oral HRT use, age, smoking behavior, alcohol consumption, aspirin use, and statin use. However, in the complete multivariate model, which included body fat, older ages (P = 0.047), greater trunk fat masses (P < 0.001), any oral HRT use (P < 0.001), and unopposed oral estrogen use (P = 0.012) were the sole independent predictors of higher serum CRP levels. The complete multivariate model accounted for 58% of the variance in serum CRP. We conclude that the association between higher physical activity and lower serum CRP levels is dependent on the lower body fat of the more active women, yet independent of oral HRT use. Future intervention trials should determine whether diet‐ and exercise‐related reductions in body fat may be effective ways to diminish the proinflammatory effects of oral HRT in postmenopausal women. Am. J. Hum. Biol. 15:91–100, 2003. © 2002 Wiley‐Liss, Inc.     

Differential effects of oral conjugated equine estrogen and transdermal estrogen on atherosclerotic vascular disease risk markers and endothelial function in healthy postmenopausal women

BACKGROUND: Recent studies have revealed that HRT may increase the risk for atherosclerotic vascular disease (ASVD). METHODS: We investigated the effects of HRT via different administration routes on the markers for ASVD and endothelial function in healthy postmenopausal women. The oral HRT group (n=18) received conjugated equine estrogen 0.625 mg/day; the transdermal HRT group (n=18) received 17beta-estradiol (E2) gel 0.6 mg/day for 6 months. The control group (n=30) had no treatment for 6 months. RESULTS: The C-reactive protein (CRP) rose from 0.129+/-0.116 to 0.752+/-0.794 mg/dl (P<0.01) in the oral HRT group but remained unchanged in the transdermal HRT and control groups. The flow-mediated vasodilation (FMD) in the brachial artery was increased significantly by HRT from 6.0% before oral HRT to 14.7% after oral HRT (P<0.001) and from 5.9% before transdermal HRT to 13.9% after transdermal HRT (P=0.001). CONCLUSIONS: These data suggest that oral estrogen induces ASVD risk by increasing acute inflammation; however, transdermal estrogen avoids this untoward effect. Additionally, transdermal estrogen exerts a positive effect on endothelial function similar to that of oral estrogen. Therefore, the transdermal route might be favourable in terms of ASVD risks.     

Menopause and ischaemic stroke: basic,clinical and epidemiological considerations. The role of hormone replacement

Stroke is a leading cause of disability and death in women, despite progress in its prevention and treatment. As with coronary artery disease, the incidence of stroke rises after the menopause, in parallel with metabolic changes that add up to create an unfavourable risk factor profile for cardiovascular disease. The menopause metabolic syndrome, which includes weight gain and changes in lipids, insulin resistance, endothelial dysfunction, increased levels of homocysteine, lipoprotein (a) and several coagulation factors, may in part be attributable to estrogen deficiency, and may be reversible with hormone replacement therapy (HRT). As for blood pressure, a major detrimental risk factor for stroke, it is probably not affected by either the menopause per se or by HRT. Abundant experimental data exist indicating that estrogens have both anti-atherosclerotic and neuroprotective effects. The width or thickness of the carotid wall is a good indicator of carotid atherosclerosis; it increases after the menopause transition, and decreases with HRT. Estrogens may enhance cerebral blood flow and reduce vascular resistance. In animal models of stroke, estrogen induced anti-ischaemic effects. Several large-scale epidemiological studies have verified the concept of primary protection of stroke by HRT, though others have failed to do so. In light of these contradictory data, several recent reports were highly significant (Nurses' Health Study, HERS Study, Cancer Prevention II Trial, WEST Trial). Despite the known neural and vascular benefits of estrogen, it is uncertain whether HRT is associated with stroke protection. At present, prevention of stroke should involve proven risk reduction strategies.     

Positive correlation between circulating leptin levels and lipid lipoproteins in postmenopausal women administered hormone replacement therapy

Beneficial effects of hormone replacement therapy are reported on plasma concentrations of lipids and lipoproteins. Plasma leptin levels are reported to reflect lipid metabolism. We treated 40 healthy postmenopausal women with continuous combined HRT (0.625 mg conjugated equine estrogen and 2.5 mg medroxyprogesterone acetate orally) daily for 6 months and then investigated total cholesterol, triglyceride, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol, which are considered to be factors inducing cardiovascular disease (CVD). We measured the plasma levels of lipids and leptin, which are considered to be altered with HRT. Plasma leptin and lipid levels were measured at baseline and after 3 and 6 months of HRT. The plasma levels of leptin in PMW were not significantly reduced by HRT. Although the plasma levels of total cholesterol and LDL-cholesterol did not change by HRT, the administration of HRT significantly increased plasma levels of triglycerides and HDL-cholesterol in PMW. The correlation between leptin and total cholesterol or triglycerides was positive after HRT while these relations were not correlated at baseline. The correlation between lipid levels and leptin may explain the new role of leptin in plasma lipid levels in HRT.     

Current perspectives on the benefits of HRT in menopausal women

AIMS: Women in the West can now expect to live one third of their life in a postmenopausal state, and consequently in a state of estrogen deficiency. This can have a number of consequences, and many women suffer vasomotor symptoms during the climacteric. Estrogen deficiency can also result in changes to the skin, hair, urogenital, cardiovascular and skeletal systems. This article reviews some of the main actions of replacement estrogen in postmenopausal women, and discusses the major benefits of estrogen replacement therapy (ERT) and hormone replacement therapy (HRT). REVIEW: HRT is well documented to reduce vasomotor symptoms in women suffering from estrogen deficiency, and can have beneficial effects on the skin and the prevention of skin aging. HRT has beneficial effects on urogenitary function including reductions in urinary incontinence and vaginal atrophy. HRT is used as a first-line treatment to prevent or reverse the development of postmenopausal osteoporosis and can reduce the risk of fractures if taken for 5-10 years from the menopause. In epidemiological studies, ERT was associated with a reduction in the risk of coronary heart disease. Estrogens seem to affect the cardiovascular system directly and indirectly such as reducing some of the coronary risk factors. In recent years, estrogen has been linked to beneficial effects in the CNS including an association with a reduction in the risk of developing Alzheimer's Disease. Despite these benefits, HRT compliance remains low, and physicians need to address this if patients are to gain the benefits.     

National differences in lipid response to postmenopausal hormone replacement therapy

Objective: To compare the response of serum lipids and lipoproteins to the transdermal hormone replacement therapy (HRT) in five European countries. Methods: Five-hundred and sixty-seven healthy postmenopausal women from Belgium, Finland, the Netherlands, Sweden, and the UK received transdermal estradiol 50 μg daily for 12 months. In addition, two groups received transdermally norethisterone acetate (NETA) continuously, two groups sequentially (170 or 350 μg/day); one group received sequentially oral NETA (1 mg/day), and one group dydrogestrone (20 mg/day). Serum total cholesterol, HDL-, HDL2-, LDL-cholesterol, lipoprotein(a) (Lp(a)), and triglycerides were assessed before and at the end of treatment. Results: No significant national differences existed in the pretreatment levels of lipids and lipoproteins. Mean cholesterol, LDL, Lp(a), and triglycerides decreased during HRT, and HDL and HDL2 increased. Individual changes in responses to HRT were strongly dependent on pretreatment values. In this regard, British women differed from the others: their cholesterol, HDL, HDL2, and Lp(a) responses, when related to the pretreatment levels, were smaller than those of the others. Conclusion: A national difference discovered in response of serum lipids to HRT calls for caution in generalization of lipid data from one nation to another during HRT.     

The effects of hormone replacement therapy on plasma lipids in type II diabetes

Objectives: The effects of hormone replacement therapy on cardiovascular risk factors in postmenopausal women with non-insulin dependent diabetes mellitus (type II diabetes) is uncertain. Methods: The effects of estrogen replacement therapy (ERT, conjugated equine estrogen 0.625 mg orally daily), combined estrogen and continuous progestogen therapy (HRT, 0.625 mg of conjugated equine estrogens plus medroxyprogesterone acetate 5 mg daily) or placebo was compared in 20 postmenopausal type II diabetic women and 20 normal postmenopausal women in a double blind, randomised, crossover study. Patients receiving insulin were excluded from the study and all lipid modifying drugs were ceased at least 4 weeks prior to randomisation. Other medication including oral hypoglycaemics was kept constant for the duration of the study. Results: Women with type II diabetes were a similar age (58.7±1.3 years) to the non-diabetic women (59.6±1.6 years) but they had a significantly greater body mass index, a higher incidence of treated hypertension, higher fasting plasma glucose levels, higher triglycerides and lower HDL cholesterol levels than non-diabetic women. ERT reduced total cholesterol and LDL cholesterol by a similar extent (8.9–12.3%) in normal and type II diabetic women and increased HDL cholesterol to a similar extent in both groups (11.0 and 8.9% respectively). ERT did not significantly alter fasting triglyceride levels in either group. The addition of medroxyprogesterone acetate 5 mg daily abolished the increase in HDL cholesterol associated with ERT in both groups but did not significantly affect any of the other lipid measurements. ERT and HRT did not significantly alter fasting insulin levels nor alter fasting glucose levels in either non-diabetic women or women with type II diabetes. Conclusions: ERT and HRT have similar effects on lipids in women with type II diabetes and non-diabetic women after 1 month of therapy.     

Association of serum complement (C3, C4) and immunoglobulin (IgG,IgM) levels with hormone replacement therapy in healthy post-menopausal women

BACKGROUND: Recently published data suggest that hormone replacement therapy (HRT) may increase cardiovascular risk during the early months of therapy. Activation of the immune system is known to be involved in several types of cardiovascular disease. In this cross-sectional study, serum C3, C4, IgG and IgM levels were evaluated in healthy post-menopausal women receiving two different short-term HRT regimens, and in untreated women. METHODS: Serum C3, C4, IgM and IgG levels were assessed in 18 women receiving transdermal 17beta-estradiol (50 micro g/day) + continuous oral medroxyprogesterone acetate (MPA; 2.5 mg/day), in 56 women taking oral conjugated equine estrogen (CEE; 0.625 mg/day) + continuous MPA, and in 80 control women not receiving HRT. RESULTS: The mean serum C3 level was significantly higher in women using oral CEE + MPA than in women receiving transdermal 17beta-estradiol + MPA, and those not on HRT (P = 0.02 and P < 0.001 respectively). Furthermore, women taking oral CEE + MPA had significantly higher mean levels of C4 compared with untreated women (P < 0.01). IgG and IgM levels were similar among women either of the two HRT regimens and between women not on HRT. CONCLUSIONS: Oral HRT may be involved in the development of cardiovascular disease through inflammatory mechanisms, as suggested by increased serum levels of C3 and C4.     

The effects of oral and transdermal hormone replacement therapy on C-reactive protein levels and other inflammatory markers in women with high risk of thrombosis

INTRODUCTION: In the estrogen in venous thromboembolism (EVTET) study of 140 women with a history of venous thromboembolism (VTE), oral hormone replacement therapy (HRT) was associated with strong activation of coagulation markers and increased risk of recurrent VTE. No such associations were observed in the estrogen women atherosclerosis (EWA) study of 118 women with established coronary artery disease who were given transdermal HRT. OBJECTIVES AND METHODS: The aim of the present study was to evaluate the effects of oral and transdermal HRT on levels of C-reactive protein (CRP), which was assayed with a highly sensitive method. We also evaluated the effects on other inflammatory markers and the influence of possible confounding factors. RESULTS: Oral HRT was associated with a significant increase in CRP after 3 months as compared with placebo (median 79% [95% confidence interval 36-119%] versus -4% [-13 to 10%], p = 0.001). These changes sustained after 12 months. Among those allocated HRT, the median increase in CRP was higher in women who subsequently developed recurrent thrombosis (median 328%, n = 5, versus 54%, n = 60). TNF-alpha levels decreased significantly by mean -10% [-15 to -5%] versus 3% [-4 to 10%], p=0.004. Soluble VCAM-1 decreased in the HRT group compared to the placebo group (mean -13% [-18 to -8%] versus 1%, [-3 to 5%], p < 0.001). There were no significant changes in levels of IL-6, TGF-beta or P-selectin. On transdermal HRT no significant changes in CRP were observed after 3 and 12 months of treatment. CONCLUSIONS: Our findings substantiate that oral HRT containing estradiol is associated with a marked and rapid increase in CRP, whereas transdermal treatment is not. However, this increase on oral treatment was associated with no increases of other inflammatory markers.     

Inhibitory effects of estrogen on antithrombin III (author's transl)]

Derivatives of estrogen used in oral contraceptives have been reported in connection with occasional intravascular thrombosis. Hypothetically this can be attibuted to hypercoagulability with decreased antithrombin 3. An experiment was conducted to elucidate the hemostatic relationship between estrogen and antithrombin 3. Using Biggs' method and singleradial immunodifusion method with antithrombin 3 serum, by the addition of conjugated estrogen to plasma and purified antithrombin 3, the anticoagulant and antigenic activity of antithrombin 3 are decreased in proportion to the amount of estrogen added. The effects of estrogen added to the normal plasma is observed almost only in alpha globulin fraction allowing decreased amount of antithrombin 3 in immunoelectrophoresis and immunodiffusion method experiments. In the experiment of SDS electrophoresis of purified antithrombin 3 with or without conjugated estrogen any change of electrophoretic mobilities and concentration of antithrombin 3 are not observed. According to the results, it is assumed that decreased anticoagulability of antithrombin 3 in plasma due to the administration of remedies containing extrogen might have an effect on hemostatic action of the drug. It might cause thrombogenic tendencies in oral contraceptives. (Author's Modified)     

Changes in serum lipids, plasma fibrinogen and other haemostatic parameters induced by ciprofibrate action in hyperlipidemic patients with and without coronary artery disease

The effects of drugs with hypolipidemic properties in the prevention of the atherothrombotic vascular disease, go further than reducing serum lipids, suggesting that there are other nonlipid-related mechanisms involved; the maintenance of appropriate haemostatic balance being one of them. The objective of this investigation was a drug intervention with ciprofibrat in hyperlipidemic people with high level of plasmatic fibrinogen with the purpose of knowing the effects of the drug over these risk factors and other haemostatic parameters. Forty people, both sexes, 20 of them apparently healthy and the other 20 with clinical and angiographic evidence of coronary artery disease, were randomized to receive 100 mg of ciprofibrat or placebo during an average of 56 weeks. All of them had a clinical exam, EKG and stress test. Laboratory exams included lipid profile, plasma fibrinogen (Fg), VII factor, vonWillebrand factor, protein C (PC) and the tissue plasminogen activator with samples taken every 8 weeks. The Ciprofibrat group showed significant changes of lipids: cholesterol -23%, triglycerides -31%, high-density lipoprotein (HDLc) +24% and very low-density lipoprotein -23%, except low-density lipoprotein -24%. The haemostatic parameters in 40 weeks showed that Fg decreased 21% (p = 0.001), decreasing to 9% at the end of the follow-up. In the placebo group the HDLc showed a 10% increase (p = 0.02), PC reduced to 20% (p = 0.01) and Fg kept blood levels close to basal line, descending 10% at the end of the follow-up. In this study, the use of ciprofibrat in patients with high risk of developing atherothrombotic events, showed efficiency and security in handling hyperlipidemia, such as keeping and appropriate haemostatic balance.     

Plasma lipids, lipoprotein Lp(a), apolipoproteins, and hemostatic risk factors distributions in postmenopausal women

In the present study, the effect of hormone replacement therapy on lipid metabolism, apolipoproteins and hemostatic risk factors for cardiovascular disease was assessed in 216 Croatian postmenopausal women. There were 156 current users divided in to two groups according to the duration of therapy. The short-term study of < 10 months (X +/- SD 5.31 +/- 2.69) included 49 users, and long-term study of > 11 months (X +/- SD 22.06 +/- 10.95) included 107 users of hormone replacement therapy. Sixty nonusers served as a control group. In the short-term study, current users had a significant increase in serum HDL cholesterol, apolipoprotein A-I, A-II and a decrease in total/HDL cholesterol ratio, apoB and antithrombin III (p < 0.05). No significant differences were recorded for total cholesterol, triglycerides, LDL cholesterol, lipoprotein Lp(a) and plasminogen. In the long-term study, a significant increase in HDL cholesterol, apo A-I and total/HDL cholesterol ratio, and a decrease in AT III were observed. Results of the study showed favorable effects of hormone replacement therapy on serum lipid profile and apolipoproteins as a protective regimen from cardiovascular disease in both treatment groups of postmenopausal women. There are conflicting reports regarding increased fibrinolytic activity. The clinical relevance of the observed changes in antithrombin III concentrations as an important coagulation inhibitor is doubtful and should be considered in a more extensive evaluation of the potential hemostatic risk factors for cardiovascular risk and thromboembolism.     

Tibolone: a review

Tibolone appears to be at least as efficacious as other forms of hormonal replacement therapy (HRT) on climacteric symptoms. It does not cause withdrawal bleeding when used in women with at least 1 year of amenorrhea. It is, therefore, not indicated in perimenopause because it may cause irregular bleeding. The androgenic action of tibolone may have a two-fold benefit: on the one hand, it may help depression and libido more than other forms of HRT, while, on the other hand, it may improve some lipid parameters such as Lp(a), and triglycerides. However, this androgenic action, may also be responsible for the reduction of HDL cholesterol, that may thus reduce the beneficial effect of tibolone on lipids. It is estimated that only 30% of cardiovascular risk protection of HRT is due to improvement of classical lipids parameters while a great role is played by the direct effect of estrogen on vessels. Tibolone, as well as estrogen, has been shown to induce peripheral vasodilatation and also has a direct effect on vascular reactivity thus increasing peripheral blood flow with no changes in blood pressure or cardiac output. Tibolone seems to exert a similar effect as other forms of HRT on markers of bone metabolism and bone mass, but no data is yet available on fracture prevention.     

Does ovarian stimulation for in-vitro fertilization induce a hypercoagulable state?

Effects on blood coagulation and fibrinolytic activity during ovarian stimulation for in-vitro fertilization (IVF) were examined in 12 women. Blood samples were taken prior to hormonal stimulation (days 2-3 of the menstrual cycle, mean serum oestradiol concentration 0.16 nmol/l) and the day after ovulation induction with human chorionic gonadotrophin (HCG) (days 10-12, mean serum oestradiol concentration 5.35 nmol/l). We measured whole blood clotting time, whole blood clot lysis time, plasma fibrinogen, factor VII and antithrombin III. The whole blood clotting time was slightly, but not significantly shortened after ovarian stimulation. A significant rise in plasma fibrinogen (P less than 0.001) and reduction in antithrombin III (P less than 0.001) were observed, whereas no change in factor VII was found. The blood fibrinolytic activity was significantly reduced as evaluated by an increase in the clot lysis time (P less than 0.02). These results indicate that ovarian stimulation for IVF may create a state of hypercoagulability.     

Antithrombin 3 changes in women using oral contraceptives

Antithrombin III was determined by the van Kaulla method in 19 women taking combined oral contraceptives containing 75-150 mcg estrogen, 60 women taking pills containing 50 mcg ethinyl estradiol and .5 mg norgestrel, and in 79 controls. Subjects were aged 20-45, had been taking pills from 3 months to 5 years, and were sampled on Day 23 of the menstrual cycle. The antithrombin assay measured, by fibrometer, neutralization of a given amount of thrombin in the presence of fibrinogen, by serum stored frozen in plastic tubes: controls with Michaelis buffer took 7 seconds. The women on 75-150 mcg estrogen pills had mean antithrombin values of 33 seconds with 12 (63%) blow normal limits (30 seconds). This was signifigantly lower than the values for the controls. (p.001) Those on 50 mcg ethinyl estradiol averaged 60 seconds, with 7 (12%) abnormal. The controls' mean antithrombin values were 79 seconds, with 4 (5%) abnormal.     

Differential effects of progestins on hemostasis

Recently large, prospective, randomized studies on hormone replacement therapy (HRT) have indicated that the progestin use might interfere with hemostasis and thus increase venous thrombotic events. Therefore, available publications were evaluated to determine whether progestins interfere with hemostasis, either when given alone via oral or parenteral routes or in combination with ethinylestradiol as synthetic estrogen or natural estrogens. There are indications that such interference is dependent upon the type and dose of the progestin, the route of application, the length of treatment and the type and dose of the estrogen with which it is combined. For natural progesterone, no negative effects on the hemostatic system were seen with either oral or parenteral application, in cyclic or continuous regimens, for the doses investigated. Similarly, no unwanted effects were seen with progestin only pills (POP), independent of the type and dose of progestin, or parenteral progestins. With the high-dose progestins used in gynaecological oncology, the increased activation of the hemostatic system resulting from the disease itself has to be taken into account when looking at any increased incidence of thromboembolic events in these patients. For estrogen/progestin combinations, the risk of venous thromboembolism is attributed to the estrogen used. Recent studies showed an increased rate of thromboembolic events in association with desogestrel-and gestodene-containing oral contraceptives, compared with those containing levonorgestrel. With HRT, a decrease in antithrombin factors could explain the increased rate of venous thrombotic events. In conclusion, progestins seems to have different effects on the hemostatic system due to their different pattern of biological activities. This was also shown in the arterial vascular system, where some progestins may reduce the endothelium-dependent vasodilating action of estrogens and stimulate intima proliferation and upregulate thrombin receptor expression while other progestins did not.