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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:201.)
© 2002 American Heart Association, Inc.

Brief Reviews

Female Hormones and Thrombosis

F.R. Rosendaal; F.M. Helmerhorst; J.P. Vandenbroucke

From the Departments of Clinical Epidemiology (F.R.R., J.P.V.), Hematology (F.R.R.), and Obstetrics, Gynecology and Reproductive Medicine (F.M.H.),. Leiden University Medical Center, Leiden, the Netherlands.

Correspondence to Prof Dr F.R. Rosendaal, Clinical Epidemiology, LUMC, PO Box 9600, NL-2300 RC Leiden, Netherlands. E-mail f.r.rosendaal{at}lumc.nl

	Abstract

Top Abstract Introduction Oral Contraceptives Hormone Replacement Therapy Other Hormones References

 
Exogenous hormones are used by more than a hundred million women worldwide as oral contraceptives or for postmenopausal hormone replacement. Oral contraceptives increase the risk of venous thrombosis, of myocardial infarction, and of stroke. The risk is highest during the first year of use. The venous thrombotic risk of oral contraceptives is high among women with coagulation abnormalities and with so-called third-generation contraceptives (containing desogestrel or gestodene). The risk of myocardial infarction does not appear to depend on coagulation abnormalities or the type of oral contraceptive. Hormone replacement therapy increases the risk of venous thrombosis. This risk is also highest in the first year of use and among women with coagulation abnormalities. The risk becomes very high in women with a previous venous thrombosis. Randomized trials have not confirmed a beneficial effect of postmenopausal hormones on the occurrence of myocardial infarction.

Key Words: venous thrombosis • myocardial infarction • stroke • oral contraceptives • hormone replacement therapy

	Introduction

Top Abstract Introduction Oral Contraceptives Hormone Replacement Therapy Other Hormones References

 
Oral contraceptive use was first associated with thrombosis in 1961, with a report of pulmonary embolism in a nurse, who had just begun taking an oral contraceptive containing 100 µg mestranol for the treatment of endometriosis.¹ In 1963, the first case of myocardial infarction in an oral contraceptive user was reported.² Estrogens increase the risk of venous thrombosis when used as oral contraceptives or as postmenopausal hormone replacement.^3–5 A similar effect was observed in men when estrogens were used as a treatment of coronary disease⁶ or in sex-change treatment.⁷ Recently, it has been demonstrated that the progestins in combination oral contraceptives also affect the risk of thrombosis.^8–10

Thrombosis is a serious disorder. Venous thrombosis, although rarely fatal, often leads to a disabling postthrombotic syndrome.¹¹ Arterial thrombosis may be fatal, as myocardial infarction, or lead to disabling sequelae in stroke.

The risk factors for thrombosis (Table 1) can be divided into 3 groups of causes, according to Virchow¹²: reduced blood flow, changes in the vessel wall, and changes in the composition of the blood. In venous thrombosis, causes related to stasis and blood coagulability are most important, whereas in arterial disease, vessel wall changes stand out. Genetic risk factors for venous thrombosis lead to hypercoagulability, whereas the acquired causes are either associated with decreased flow (as found in immobilization, paralysis, surgery, and plaster casts) or related to blood coagulation (associated with the lupus anticoagulant, pregnancy, oral contraception, and malignancies).

View this table: [in this window] [in a new window]   Table 1. Risk Factors for Venous Thrombosis

	Oral Contraceptives

Top Abstract Introduction Oral Contraceptives Hormone Replacement Therapy Other Hormones References

 
Content and Mode of Action
Oral contraceptives first became licensed for birth control in 1959. Most oral contraceptives contain an estrogen and a progestogen, with both contained in each pill (monophasic preparations). Over the years, the estrogen dose and the progestogen compound have changed. The first oral contraceptive in the United States contained 150 µg mestranol. Since then, the estrogen dose has been reduced, first to 50 µg and then to 30 and to 35 µg, and some currently available brands contain only 20 or 15 µg ethinyl estradiol. The change in progestogen concerned the chemical composition of the progestogen rather than the dose because the progestogen component prevents ovulation. Early oral contraceptives contained a first-generation progestogen; in the 1970s, the second generation was used; and third generation progestogens were used from the early 1980s in Europe and the 1990s in the Unites States.

Oral contraceptives act by preventing ovulation through the action of the progestogen, which suppresses luteinizing hormone. Estrogens are mainly needed to prevent breakthrough bleedings. With complete compliance, the failure rate is <1%.

Ethinyl estradiol is a synthetic slightly altered version of the naturally occurring estradiol, which is inactive when taken orally. In the absence of a formal classification system of progestogens, these are usually grouped into "generations" that are based on when they were first produced. First-generation progestogens include norethisterone, norethynodrel, lynestrenol, and ethynodiol acetate. The second generation includes norgestrel, levonorgestrel, and norgestrione. The third generation includes desogestrel, gestodene, and norgestimate. Norgestimate is often grouped among second-generation progestogens, because after uptake, it is partly converted to levonorgestrel. Cyproterone acetate (not available in the United States) and drospirenone are not yet categorized.

Oral Contraceptives and Venous Thrombosis
An early comparative study was based on information gathered by the Royal College of General Practioners.¹³ From a comparison of patients and healthy controls (case-control study), it was reported in 1967 that oral contraceptive users had a 3-fold increased risk of venous thrombosis compared with nonusers. This was confirmed by other studies from the United Kingdom and the United States, with relative risk estimates ranging between 4 and 11.^14–17 In the 1970s, large prospective follow-up studies again confirmed these findings.^18–20 When we combine all studies performed until the 1990s, a 3-fold increased risk results.²¹ These studies also showed that oral contraceptives conferred an immediate effect: the risk did not become larger with longer duration of use and disappeared when oral contraceptives were discontinued.

These early studies were performed when objective testing for venous thrombosis was not widely used. We now know that the clinical diagnosis of venous thrombosis suffers from a high rate of false positives^22,23; therefore, these studies probably had substantial misclassification. This is supported by studies that compared the risk by level of certainty of diagnosis and that usually found higher risk estimates.^{14–16,19,20,24} Therefore, the risk of oral contraceptives may have been underestimated in the older studies.

In recent studies, performed in the 1990s, a 2- to 6-fold increased risk for venous thrombosis was found in oral contraceptive users.^25–28 In a Dutch study, the absolute risk was estimated at 0.8 per 10 000 per year among nonusers and 3.0 per 10 000 per year among oral contraceptive users.²⁵ In a study in the United Kingdom, a similar annual risk, 2.0 per 10 000 users, was found.²⁹ These numbers indicate a low absolute risk; ie, several thousands of women would need to abstain from oral contraceptives to prevent 1 case of thrombosis per year (numbers needed to treat). Because oral contraceptives are the most reliable form of reversible contraception, it has even been argued that such a policy might lead to an increase in venous thrombotic events through an increase in unintended pregnancies.²¹ Nevertheless, because oral contraceptives are so widely used, they are responsible for a large share, if not the majority, of all venous thromboses in young women.

Diagnostic Suspicion and Referral Bias
The so-called referral or diagnostic suspicion bias is the hypothesis that has been brought forward to explain the absence of a reduction of the risk of thrombosis associated with the use of oral contraceptives since the 1960s. This bias involved women presenting with leg complaints being referred for thrombosis especially if they used oral contraceptives, because doctors were aware of this association. If, subsequently, women with thrombosis were compared with healthy women, there would be an excess of oral contraceptive users among patients, spuriously suggesting an increased risk.

Two studies compared women who were referred for diagnostic tests that were positive for thrombosis with women who were referred for the same tests, which proved negative for thrombosis.^30,31 In this setting, referral bias would have acted similarly for both groups. The relative risks for thrombosis associated with oral contraceptive use found in these 2 studies were 6.4³⁰ and 3.9³¹; ie, they were similar to those found in studies with population controls. This demonstrates that the risk of venous thrombosis is still present and cannot be explained by referral bias.

Effect of Lowering of the Estrogen Dose
The first oral contraceptives contained doses of 100 to 150 µg mestranol or ethinyl estradiol, which over time has been reduced to 50 µg and, subsequently, to 30 µg and, even in some of the newest brands, to 20 µg ethinyl estradiol. One of the aims of this dose reduction was to lower the risk of thrombosis. However, when we look at the risk estimates from studies published from the 1960s to the 1990s, such a risk reduction appears not to be present (Figure). In several direct comparisons, a lower risk with a lower estrogen dose has been found.^20,24,32 In the most recent of these studies, a 10-fold increased risk compared with that for nonusers was found for users of oral contraceptives containing >50 µg ethinyl estradiol, and there was a 4-fold increased risk for contraceptives containing <50 µg ethinyl estradiol.³² Several other studies have not confirmed a lowering of risk with lower estrogen doses: in the Leiden Thrombophilia Study, a direct comparison of oral contraceptives that contained either 50 µg or 30 µg ethinyl estradiol and the same progestin (levonorgestrel) found no difference.⁸ There are no data involving oral contraceptives containing 20 µg ethinyl estradiol.

View larger version (11K): [in this window] [in a new window]   Relative risk (RR) for venous thrombosis in oral contraceptive use. The RRs (users vs nonusers) are shown from studies published between 1967 and 1989, with 95% CIs. A relative risk of 1 indicates equal risks, and a relative risk >1 indicates a higher risk for users than for nonusers. The studies include case-control studies,13,15–17,158–162 follow-up studies,18–20,163–165 and 1 randomized controlled trial.166 Some figures were estimated from data in the original articles (reprinted with permission from Thrombosis and Hemostasis).

Effect of Changes in the Progestogen Content
Although estrogens have been known to be associated with the risk of thrombosis for many decades, it has always been considered that the progestogens in these combination preparations did not affect risk at all. However, in 1995, 3 studies published simultaneously reported an increase of thrombosis in women using oral contraceptives containing the newest progestins, ie, desogestrel and gestodene (also known as third-generation progestins).^8–10 Most subsequent studies confirmed this finding,^{29,31,33–37} but some did not.^38–41 A recent meta-analysis combining the evidence from all studies found an overall 1.7-fold increased risk for users of third-generation oral contraceptives compared with second-generation users.⁴² Interestingly, the relative risk was >2-fold increased in studies funded through public agencies but only 1.3-fold in studies sponsored by pharmaceutical companies producing third-generation contraceptives.⁴² The risk for third-generation users was higher during the early phases of use but remained 2-fold increased compared with the risk for second-generation users of oral contraceptives during long-term use.

In the debate after the publication of the original studies, potential biases have been put forward as alternative explanations.^{39,40,43–52} Careful consideration, reanalyses of the original studies, new studies, and an extensive comprehensive look in the meta-analysis led to the conclusion that bias could not explain the observations of an increased risk.^42,53–56 An independent expert committee convened by the World Health Organization concluded that third-generation contraceptives carried an increased risk of venous thrombosis.⁵⁷

Strong support for the epidemiological findings came from a biochemical study in 1997 showing that the plasma of women using third-generation contraceptives was tilted toward a prothrombotic state, as measured with a newly developed assay.⁵⁸ This assay measures sensitivity to activated protein C (APC), but unlike the standard APC-resistance test, which is based on the activated partial thromboplastin time, it is based on clotting activation through the extrinsic pathway by tissue factor.^58–60 In this assay, the endogenous thrombin potential (ETP) is quantified; ETP is defined as the time integral of free thrombin concentration, usually derived from residual levels of amidolytic activity, determined in the presence and absence of added APC, yielding an APC-sensitivity ratio.⁵⁸ This APC-resistance test proved sensitive in detecting factor V Leiden but was far more sensitive to exogenous factors than was the activated partial thromboplastin time–based APC-resistance test.^61,62 In the ETP-based APC-resistance test, use of third-generation oral contraceptives led to prothrombotic abnormalities comparable to those found in heterozygous factor V Leiden.⁵⁸ This result was confirmed by a randomized crossover trial of second- and third-generation oral contraceptives.⁶³ Differential effects were observed on procoagulant, anticoagulant, and fibrinolytic factors.^63–66 The main effects were a more pronounced APC resistance in the ETP-APC test as shown before,⁶³ a large increase in factor VII levels,⁶⁴ and sharp decreases in free and total protein S,⁶⁶ which was subsequently confirmed in another study.⁶⁷ These are all changes that would be expected to lead to an increased risk of thrombosis.

Other Risk Factors and Oral Contraceptive Use
For clinical purposes, it is important to consider whether some women have a higher risk of thrombosis when using oral contraceptives than do others. For venous thrombosis, risk factors to be considered include a personal or family history of venous thrombosis and prothrombotic abnormalities, ie, factor V Leiden, prothrombin 20210A, and deficiencies of protein C, protein S, or antithrombin.

A previous thrombosis is, by far, the strongest predictor for venous thrombotic events. In most studies, the recurrence rate after 3 months of anticoagulation is between 2% and 5% per year.^68–73 It is currently unclear whether the recurrence rate is higher for individuals with coagulation abnormalities.^71,74–82 Oral contraceptives are often withheld after a first episode of thrombosis; therefore, there are no firm data on the recurrence risk with continued use.

In families with deficiencies of protein C, protein S, and antithrombin, the risk of first thrombosis appears to be increased in women who have 1 of these abnormalities and who use oral contraceptives, with a very high risk in antithrombin deficiency.⁸³ Among relatives of unselected patients with 1 of these deficiencies, oral contraceptive use further increased thrombotic risk 6- to 8-fold.⁸³ Although deficiencies of natural anticoagulants are rare (1:5000 to 1:250), factor V Leiden and prothrombin 20210A are found in 2% to 7% percent of most Caucasian populations.^84–86 Carriers of factor V Leiden who use oral contraceptives have a 20- to 30-fold increased risk of developing venous thrombosis,^17,38 and there is an even much higher risk for homozygous factor V Leiden carriers using oral contraceptives.^87,88 Prothrombin 20210A is a mild risk factor for thrombosis, increasing risk 2- to 3-fold. However, in combination with oral contraceptives, the risk appears to be higher, with a 16-fold increased risk compared with that for noncarrier nonusers.³⁸

High levels of factor VIII are a common, moderately strong risk factor for venous thrombosis.^89–91 In combination with oral contraceptives, no synergistic effect has been observed; ie, the combination of high levels of factor VIII and oral contraceptive use led to no higher risk than did the sum of the separate effects.⁹²

The risk of thrombosis in users of oral contraceptives is highest during the first year of use.^37,93 This is particularly the case among women with prothrombotic defects,⁹³ which are indicative of a high thrombosis potential⁹⁴ in these women, in whom a small further increase in risk is sufficient to bring about thrombosis. However, the risk is also higher in the first year than during prolonged use in women without known prothrombotic defects, suggesting the presence of as-yet-unidentified risk factors.⁹³

Oral Contraceptives and the Risk of Arterial Disease
The first report of an association between oral contraceptive use and myocardial infarction was published in 1963,² an association with ischemic stroke was first published in 1968,⁹⁵ and an association with hemorrhagic stroke was published in 1973.⁹⁶ The association with arterial disease was confirmed in a series of studies.^97–104 Recently, the multicenter study by the World Health Organization (WHO) showed a 5-fold increased risk of myocardial infarction with currently used oral contraceptives,¹⁰⁵ as well as a 3-fold increased risk of ischemic stroke¹⁰⁶ and a 1.5- to 2-fold increased risk of hemorrhagic stroke.¹⁰⁷ It has repeatedly been shown that the risk of myocardial infarction is particularly high among users of oral contraceptives who also smoke or have hypertension.^57,99 Among women without major cardiovascular risk factors, the risk of myocardial infarction seems very low,⁵⁵ and in some studies, no excess risk was observed at all.¹⁰⁸

Over the years, the dose of estrogen has been lowered, and the progestogen has been modified, mainly in an effort to reduce the risk of arterial disease among users of oral contraceptives. It is unclear whether the lower risk of myocardial infarction associated with the use of oral contraceptives in several of the newer studies is the result of the lowering of the estrogen dose or of selective prescription to women without cardiovascular risk factors. The WHO study, which showed a large effect of blood pressure screening, suggests that the latter played a major role.¹⁰⁵

Contraceptives containing third-generation progestins desogestrel and gestodene have a favorable effect on the lipid profile, with a slight increase in HDL. Several small studies had conflicting results regarding whether the risk of myocardial infarction would be lower with these contraceptives.^105,109,110 Two recent large studies on myocardial infarction in young women and the use of oral contraceptives failed to demonstrate a benefit for third-generation preparations.^111,112 Prothrombotic abnormalities, which play a major role in the etiology of venous thrombosis, at most mildly increase the risk of myocardial infarction,^113–115 and this risk is only in women with major cardiovascular risk factors, in particular, smoking. There does not seem to be an enhanced risk of myocardial infarction with contraceptive use in women with these mutations.¹¹²

	Hormone Replacement Therapy

Top Abstract Introduction Oral Contraceptives Hormone Replacement Therapy Other Hormones References

 
The use of postmenopausal hormone substitution has become widespread in recent decades.¹¹⁶ Besides relief from menopausal complaints, hormone replacement is prescribed to reduce the progression of osteoporosis and the development of cardiovascular disease. Several observational studies showed impressive cardiovascular benefits, ie, a halving of the risk of cardiovascular events and deaths.^117–123 Because women who used hormone replacement usually had a better cardiovascular risk profile than did nonusers, selection bias offered an alternative explanation for the apparent benefits.^124–126 Therefore, several randomized trials have been performed or are in progress.

Content and Types of Hormone Replacement Therapy
Most preparations nowadays contain an estrogen and a progestin; this combination was introduced after it was shown that unopposed estrogen therapy increases the risk of endometrial cancer (reviewed in Grady et al¹¹⁶). Estrogen-only hormone replacement is still used in women without a uterus. Conjugated estrogens in oral preparations are extracted from pregnant mare urine; the progestin compound is usually medroxyprogesterone acetate. Micronized estradiol is available in tablets or can be delivered transdermally (patches), percutaneously by gels, or subcutaneously by pellets.¹²⁷

Hormone Replacement Therapy and Risk of Venous Thrombosis
In an early study of adverse effects of estrogen replacement therapy, a slight risk increase of venous thrombosis was observed.¹²⁸ This was not confirmed in subsequent studies,^129–131 and the idea that estrogen replacement could cause venous thrombosis was dismissed as "‘medical superstition."¹³² However, from 1996 onward, a series of studies has demonstrated that hormone replacement users have a 2- to 4-fold increased risk of venous thrombosis.^{3–5,133–138}

Risk of thrombosis is highest in the first year of use,^{3,4,134,135,138} and in some studies,^134,135,138 but not in all,^3,137 the risk was limited to the first year. Oral use and transdermal patches increase the risk of thrombosis,^134,135 and an association with thrombosis has been found for conjugated estrogens as well as for estradiol.^134,138

Why did the early studies not detect the thrombosis risk associated with thrombosis? This may have been caused by less reliable diagnostic methods in the past, which may have been adequate to detect the risk of the then high-dosed oral contraceptives but not of the lower estrogen dose in hormonal replacement therapy. The less widespread use of hormone replacement may also have been a factor.

Hormone Replacement Therapy and Arterial Thrombosis
The beneficial effects of postmenopausal hormones noted in observational studies have not been confirmed in the 2 randomized trials conducted to date. One study, including women with prior coronary disease, found no benefit of hormone substitution over placebo during 5 years of follow-up,¹³⁹ whereas an increase in venous thrombosis was reported from this trial.^136,137 Post hoc analyses showed that the arterial events were clustered in the first year, with lower risks in the active group than in the placebo group in years 4 and 5.¹³⁹ The other placebo-controlled trial is an ongoing study of nearly 30 000 women without prior disease.¹⁴⁰ In the first 2 years of follow-up in that study, an excess of myocardial infarction and venous thrombosis occurred in the treatment group.

Effect of Other Risk Factors
One randomized trial of hormone replacement therapy has been conducted among women with a previous deep vein thombosis.¹²⁷ The study was terminated prematurely and showed a high rate of recurrence of 8.5% per year in the treatment group versus only 1.1% in the placebo group.¹²⁷

The higher risk of venous thrombosis in the first year suggests that for hormone replacement therapy, as for oral contraceptives, some women are at higher risk, probably because of prothrombotic abnormalities. In the Oxford case-control study, a high risk was observed in women who were APC resistant and used hormone replacement therapy.^3,141 In a subsequent genetic analysis, it was confirmed that the APC resistance in these women was based on carrying factor V Leiden. Whereas factor V Leiden alone increased the risk 4-fold and hormone replacement increased the risk only 3-fold, the combination led to a 15-fold increased risk.¹⁴² Table 2 shows the effect of factor V Leiden in combination with either oral contraceptives or hormone replacement therapy on the risk of venous thrombosis.

View this table: [in this window] [in a new window]   Table 2. Factor V Leiden, Exogenous Hormones, and the Risk of Venous Thrombosis

For the arterial side, the increased risk in the first year in the randomized trials suggests a similar genetic predisposition in some women. Further evidence has come from a study reporting that in women with prothrombin 20210A, the use of hormones increases the risk of myocardial infarction, in particular among hypertensive women, with an 11-fold increased risk.¹⁴³

Biological Mechanism of the Effect of Hormones on Thrombotic Risk
Estrogens have many different effects on the coagulation system.^62,144–147 These include increases in the levels of procoagulant factors VII, X, XII, and XIII and reductions in the anticoagulant factors protein S and antithrombin. These changes predict a change toward a more procoagulant state (which is confirmed in studies examining global tests, such as APC resistance or thrombin generation),^61–64,66 which is not counterbalanced by an increased fibrinolytic activity.⁶⁵ The estrogens in hormonal replacement therapy have hemostatic effects similar to those in oral contraceptives.^148,149

It is currently unclear how these effects are brought about at the molecular level of the estrogen receptor. It is likely that these effects at the cellular level are also under genetic control, because the hemostatic system of some women appears to be more sensitive to the effect of estrogens than that of other women.¹⁵⁰ It is also unclear how estrogens and progestins interact in their effect on thrombosis, for instance, in the higher risk of oral contraceptives containing a third-generation progestin. It appears that estrogens are prothrombotic rather than proatherogenic, which explains the absence of an increased risk in former users.

	Other Hormones

Top Abstract Introduction Oral Contraceptives Hormone Replacement Therapy Other Hormones References

 
Selective estrogen receptor modulators, such as tamoxifen and raloxifene, have antiestrogenic effects on breast and endometrial tissue and are used in the treatment and prevention of breast cancer. However, these drugs have estrogenic effects on blood clotting. A placebo-controlled trial of tamoxifen in nearly 14 000 women with an increased risk of breast cancer showed increased risks of ischemic stroke (relative risk 1.6), of pulmonary embolism (relative risk 3.0), and of deep vein thrombosis (relative risk 1.6).¹⁵¹ Another placebo-controlled trial with tamoxifen in hysterectomized women also showed an increased risk of venous thrombosis, including superficial thrombophlebitis.¹⁵² In a randomized trial of breast cancer prevention, raloxifene increased the risk of venous thrombosis 3-fold.¹⁵³ In a case-control study of tamoxifen use for breast cancer treatment, it was shown to increase venous thrombotic risk 7-fold.¹⁵⁴ These studies convincingly show that currently used selective estrogen receptor modulators increase the risk of thrombosis.

Clinical Implications
Although many aspects of the thrombotic risks associated with female hormones are only just emerging, some clinical implications seem evident. First, in the choice of contraception, a personal history of thrombosis needs to be taken into account. The risk of thrombotic disease can be limited by considering other types of contraception in women with a personal history of thrombosis, a family history of thrombosis, gross obesity, and major cardiovascular risk factors. A contraceptive with 30 µg ethinyl estradiol should be the first choice, but there is little information that would favor the use of oral contraceptives with a lower dose of estrogen. Oral contraceptives containing third-generation progestogens, ie, desogestrel or gestodene, should be avoided because of the increased risk of venous thrombosis. Especially in smokers, oral contraceptives should not be continued beyond the 35th year of age because of the increased risk of arterial disease. Indiscriminate screening for prothrombotic mutations before the prescription of oral contraceptives is unlikely to be cost effective or even to have a positive risk-benefit balance.^155,156 It is currently unclear whether screening in the presence of a positive family history should be preferred over alternative contraception in all those women.

The best currently available data for postmenopausal hormone replacement do not support a cardiovascular benefit. The route of administration (oral or transdermal) does not materially affect the risk of side effects. Therefore, hormonal replacement therapy should not be prescribed for the prevention of cardiovascular disease, and short-term prescription for relief of menopausal symptoms should be the main indication. A recent statement from the American Heart Association also urges caution in the prescription of postmenopausal hormones.¹⁵⁷ Hormone replacement should be avoided in women with a personal or family history of venous thrombosis.

Received September 12, 2001; accepted October 29, 2001.

	References

Top Abstract Introduction Oral Contraceptives Hormone Replacement Therapy Other Hormones References

 
1. Jordan WM. Pulmonary embolism. Lancet. 1961; 2: 1146–1147.

2. Boyce J, Fawcett JW, Noall EWP. Coronary thrombosis and Conovid. Lancet. 1963; 1: 111.[Medline] [Order article via Infotrieve]

3. Daly E, Vessey MP, Hawkins MM, Carson JL, Gough P, Marsh S. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet. 1996; 348: 977–980.[CrossRef][Medline] [Order article via Infotrieve]

4. Jick H, Derby LE, Wald Myers M, Vasilakis C, Newton KM. Risk of hospital admission for idiopathic venous thromboembolism among users of postmenopausal oestrogens. Lancet. 1996; 348: 981–983.[CrossRef][Medline] [Order article via Infotrieve]

5. Grodstein F, Stampfer MJ, Goldhaber SZ, Manson JE, Colditz GA, Speizer FE, Willett WC, Hennekens CH. Prospective study of exogenous hormones and risk of pulmonary embolism in women. Lancet. 1996; 348: 983–987.[CrossRef][Medline] [Order article via Infotrieve]

6. The Coronary Drug Project Research Group. The Coronary Drug Project: findings leading to discontinuation of the 2.5-mg day estrogen group. JAMA. 1973; 226: 652–657.[Abstract/Free Full Text]

7. van Kesteren PJ, Asscheman H, Megens JA, Gooren LJ. Mortality and morbidity in transsexual subjects treated with cross-sex hormones. Clin Endocrinol (Oxf). 1997; 47: 337–342.[CrossRef][Medline] [Order article via Infotrieve]

8. Bloemenkamp KWM, Rosendaal FR, Helmerhorst FM, Büller HR, Vandenbroucke JP. Enhancement by factor V Leiden mutation of risk of deep-vein thrombosis associated with oral contraceptives containing a third-generation progestagen. Lancet. 1995; 346: 1593–1596.[CrossRef][Medline] [Order article via Infotrieve]

9. World Health Organization. Effect of different progestagens in low oestrogen oral contraceptives on venous thromboembolic disease. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Lancet. 1995; 346: 1582–1588.[CrossRef][Medline] [Order article via Infotrieve]

10. Jick H, Jick SS, Gurewich V, Myers MW, Vasilakis C. Risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptives with differing progestagen components. Lancet. 1995; 346: 1589–1593.[CrossRef][Medline] [Order article via Infotrieve]

11. Brandjes DP, Büller HR, Heijboer H, Huisman MV, de Rijk M, Jagt H, Ten Cate JW. Randomised trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis. Lancet. 1997; 349: 759–762.[CrossRef][Medline] [Order article via Infotrieve]

12. Virchow R. Phlogose und Thrombose im Gefäßsystem.In: Gesammelte Abhandlungen zur Wissenschaftlichen Medizin. Frankfurt, Germany: Staatsdruckerei; 1856.

13. Records Unit and Research Advisory Service of the Royal College of General Practitioners. Oral contraception and thrombo-embolic disease. J R Coll Gen Pract. 1967; 13: 267–279.[Medline] [Order article via Infotrieve]

14. Vessey MP, Doll R. Investigation of relation between use of oral contraceptives and thromboembolic disease. BMJ. 1968; 1: 199–205.[Free Full Text]

15. Vessey MP, Doll R. Investigation of relation between use of oral contraceptives and thromboembolic disease: a further report. BMJ. 1969; 2: 651–657.[Abstract/Free Full Text]

16. Sartwell PE, Masi AT, Arthes FG, Greene GR, Smith HE. Thromboembolism and oral contraceptives: an epidemiological case-control study. Am J Epidemiol. 1969; 90: 365–380.[Abstract/Free Full Text]

17. Boston Collaborative Drug Surveillance Program. Oral contraceptives and venous thromboembolic disease, surgically confirmed gall bladder disease and breast tumours. Lancet. 1973; 1: 1399–1404.[CrossRef][Medline] [Order article via Infotrieve]

18. Porter JB. Oral contraceptives and nonfatal vascular disease: recent experience. Obstet Gynecol. 1982; 59: 299–302.[Medline] [Order article via Infotrieve]

19. Royal College of General Practitioners’ Oral Contraception Study. Oral contraceptives, venous thrombosis, and varicose veins. J R Coll Gen Pract. 1978; 28: 393–399.[Medline] [Order article via Infotrieve]

20. Vessey M, Mant D, Smith A, Yeates D. Oral contraceptives and venous thromboembolism: findings in a large prospective study. BMJ. 1986; 292: 526.[Free Full Text]

21. Koster T, Small RA, Rosendaal FR, Helmerhorst FM. Oral contraceptives and venous thromboembolism: a quantitative discussion of the uncertainties. J Intern Med. 1995; 238: 31–37.[Medline] [Order article via Infotrieve]

22. Lensing AW, Prandoni P, Brandjes D, Huisman PM, Vigo M, Tomasella G, Krekt J, Wouter TC, Huisman MV, Buller HR. Detection of deep-vein thrombosis by real-time B-mode ultrasonography. N Engl J Med. 1989; 320: 342–345.[Abstract]

23. Huisman MV, Buller HR, Ten Cate JW, Vreeken J. Serial impedance plethysmography for suspected deep venous thrombosis in outpatients: the Amsterdam General Practitioner Study. N Engl J Med. 1986; 314: 823–828.[Abstract]

24. Stolley PD, Tonascia JA, Tockman MS, Sartwell PE, Rutledge AH, Jacobs MP. Thrombosis with low-estrogen oral contraceptives. Am J Epidemiol. 1975; 102: 197–208.[Abstract/Free Full Text]

25. Vandenbroucke JP, Koster T, Briët E, Reitsma PH, Bertina RM, Rosendaal FR. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet. 1994; 344: 1453–1457.[CrossRef][Medline] [Order article via Infotrieve]

26. Thorogood M, Mann J, Murphy M, Vessey M. Risk factors for fatal venous thromboembolism in young women: a case-control study. Int J Epidemiol. 1992; 21: 48–52.[Abstract/Free Full Text]

27. World Health Organization. Venous thromboembolic disease and combined oral contraceptives: results of international multicentre case-control study: World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Lancet. 1995; 346: 1575–1582.[Medline] [Order article via Infotrieve]

28. Farmer RDT, Preston TD. The risk of venous thromboembolism associated with low-oestrogen oral contraceptives. J Obstet Gynecol. 1995; 15: 195–200.

29. Jick H, Kaye JA, Vasilakis-Scaramozza C, Jick SS. Risk of venous thromboembolism among users of third generation oral contraceptives compared with users of oral contraceptives with levonorgestrel before and after 1995: cohort and case-control analysis. BMJ. 2000; 321: 1190–1195.[Abstract/Free Full Text]

30. Realini JP, Encarnacion CE, Chintapalli KN, Rees CR. Oral contraceptives and venous thromboembolism: a case-control study designed to minimize detection bias. J Am Board Fam Pract. 1997; 10: 315–321.[Medline] [Order article via Infotrieve]

31. Bloemenkamp KWM, Rosendaal FR, Büller HR, Helmerhorst FM, Colly LP, Vandenbroucke JP. Risk of venous thrombosis with use of current low-dose oral contraceptives is not explained by diagnostic suspicion and referral bias. Arch Intern Med. 1999; 159: 65–70.[Abstract/Free Full Text]

32. Gerstman BB, Piper JM, Tomita DK, Ferguson WJ, Stadel BV, Lundin FE. Oral contraceptive estrogen dose and the risk of deep venous thromboembolic disease. Am J Epidemiol. 1991; 133: 32–37.[Abstract/Free Full Text]

33. Spitzer WO, Lewis MA, Heinemann LA, Thorogood M, MacRae KD. Third generation oral contraceptives and risk of venous thromboembolic disorders: an international case-control study: Transnational Research Group on Oral Contraceptives and the Health of Young Women. BMJ. 1996; 312: 83–88.[Abstract/Free Full Text]

34. Bennet L, Odeberg H. Resistance to activated protein C, highly prevalent amongst users of oral contraceptives with venous thromboembolism. J Intern Med. 1998; 244: 27–32.[CrossRef][Medline] [Order article via Infotrieve]

35. Andersen BS, Olsen J, Nielsen GL, Steffensen FH, Sørensen HT, Baech J, Gregersen H. Third generation oral contraceptives and heritable thrombophilia as risk factors for non-fatal venous thromboembolism. Thromb Haemost. 1998; 79: 28–31.[Medline] [Order article via Infotrieve]

36. Vasilakis C, Jick SS, Jick H. The risk of venous thromboembolism in users of postcoital contraceptive pills. Contraception. 1999; 59: 79–83.[CrossRef][Medline] [Order article via Infotrieve]

37. Herings RMC, Urquhart J, Leufkens HGM. Venous thromboembolism among new users of different oral contraceptives. Lancet. 1999; 354: 127–128.[CrossRef][Medline] [Order article via Infotrieve]

38. Martinelli I, Taioli E, Bucciarelli P, Akhavan S, Mannucci PM. Interaction between the G20210A mutation of the prothrombin gene and oral contraceptive use in deep vein thrombosis. Arterioscler Thromb Vasc Biol. 1999; 19: 700–703.[Abstract/Free Full Text]

39. Lidegaard O, Edstrom B, Kreiner S. Oral contraceptives and venous thromboembolism: a case-control study. Contraception. 1998; 57: 291–301.[CrossRef][Medline] [Order article via Infotrieve]

40. Farmer RD, Lawrenson RA, Thompson CR, Kennedy JG, Hambleton IR. Population-based study of risk of venous thromboembolism associated with various oral contraceptives. Lancet. 1997; 349: 83–88.[CrossRef][Medline] [Order article via Infotrieve]

41. Farmer RD, Todd JC, MacRae KD, Williams TJ, Lewis MA. Oral contraception was not associated with venous thromboembolic disease in recent study. BMJ. 1998; 316: 1090–1091.[Free Full Text]

42. Kemmeren JM, Algra A, Grobbee DE. Third generation oral contraceptives and risk of venous thrombosis: meta-analysis. BMJ. 2001; 323: 131–134.[Abstract/Free Full Text]

43. Spitzer WO. Thromboembolism and the pill: the saga must end. Hum Reprod. 1998; 13: 1117–1118.[Medline] [Order article via Infotrieve]

44. Helmerhorst FM, Rosendaal FR, Vandenbroucke JP. The pill and venous thromboembolism: a disarray of several layers of debate. Hum Reprod. 1998; 13: 1119–1120.[Medline] [Order article via Infotrieve]

45. Spitzer WO. Balanced view of risks of oral contraceptive. Lancet. 1997; 350: 1566–1567.[CrossRef][Medline] [Order article via Infotrieve]

46. Meirik O. Risks of oral contraceptives. Lancet. 1998; 351: 521.

47. Lidegaard O. Oral contraceptives and venous thromboembolism: an epidemiological review. Eur J Contracept Reprod Health Care. 1996; 1: 13–20.[Medline] [Order article via Infotrieve]

48. Cramer DW. Safety of combined oral contraceptive pills. Lancet. 1996; 347: 546–548.[CrossRef][Medline] [Order article via Infotrieve]

49. Suissa S, Blais L, Spitzer WO, Cusson J, Lewis M, Heinemann L. First-time use of newer oral contraceptives and the risk of venous thromboembolism. Contraception. 1997; 56: 141–146.[CrossRef][Medline] [Order article via Infotrieve]

50. Lewis MA, Heinemann LA, MacRae KD, Bruppacher R, Spitzer WO. The increased risk of venous thromboembolism and the use of third generation progestagens: role of bias in observational research: the Transnational Research Group on Oral Contraceptives and the Health of Young Women. Contraception. 1996; 54: 5–13.[CrossRef][Medline] [Order article via Infotrieve]

51. Farmer RD, Williams TJ, Simpson EL, Nightingale AL. Effect of 1995 pill scare on rates of venous thromboembolism among women taking combined oral contraceptives: analysis of general practice research database. BMJ. 2000; 321: 477–479.[Abstract/Free Full Text]

52. Todd J, Lawrenson R, Farmer RD, Williams TJ, Leydon GM. Venous thromboembolic disease and combined oral contraceptives: a re-analysis of the MediPlus database. Hum Reprod. 1999; 14: 1500–1505.[Abstract/Free Full Text]

53. Vandenbroucke JP, Helmerhorst FM, Bloemenkamp KWM, Rosendaal FR. Third-generation oral contraceptive and deep venous thrombosis: from epidemiologic controversy to new insight in coagulation. Am J Obstet Gynecol. 1997; 177: 887–891.[CrossRef][Medline] [Order article via Infotrieve]

54. Walker AM. Newer oral contraceptives and the risk of venous thromboembolism. Contraception. 1998; 57: 169–181.[CrossRef][Medline] [Order article via Infotrieve]

55. Farley TMM, Meirik O, Collins J. Cardiovascular disease and combined oral contraceptives: reviewing the evidence and balancing the risks. Hum Reprod Update. 1999; 5: 721–735.[Abstract/Free Full Text]

56. Vandenbroucke JP, Rosing J, Bloemenkamp KW, Middeldorp S, Helmerhorst FM, Bouma BN, Rosendaal FR. Oral contraceptives and the risk of venous thrombosis. N Engl J Med. 2001; 344: 1527–1535.[Free Full Text]

57. World Health Organization. Cardiovascular Disease and Steroid Hormone Contraception: Report of a WHO Scientific Group. Geneva, Switzerland: World Health Organization; 1998. WHO Technical Report Series, No. 877.

58. Rosing J, Tans G, Nicolaes GA, Thomassen MC, Van Oerle R, Van der Ploeg PM, Heijen P, Hamulyak K, Hemker HC. Oral contraceptives and venous thrombosis: different sensitivities to activated protein C in women using second- and third-generation oral contraceptives. Br J Haematol. 1997; 97: 233–238.[CrossRef][Medline] [Order article via Infotrieve]

59. Dahlbäck B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognised mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. Proc Natl Acad Sci U S A. 1993; 90: 1004–1008.[Abstract/Free Full Text]

60. de Ronde H, Bertina RM. Laboratory diagnosis of APC-resistance: a critical evaluation of the test and the development of diagnostic criteria. Thromb Haemost. 1994; 72: 880–886.[Medline] [Order article via Infotrieve]

61. Henkens CM, Bom VJ, Seinen AJ, van der MJ. Sensitivity to activated protein C; influence of oral contraceptives and sex. Thromb Haemost. 1995; 73: 402–404.[Medline] [Order article via Infotrieve]

62. Olivieri O, Friso S, Manzato F, Guella A, Bernardi F, Lunghi B, Girelli D, Azzini M, Brocco G, Russo C. Resistance to activated protein C in healthy women taking oral contraceptives. Br J Haematol. 1995; 91: 465–470.[Medline] [Order article via Infotrieve]

63. Rosing J, Middeldorp S, Curvers J, Christella M, Thomassen LG, Nicolaes GA, Meijers JC, Bouma BN, Buller HR, Prins MH, et al. Low-dose oral contraceptives and acquired resistance to activated protein C: a randomised cross-over study. Lancet. 1999; 354: 2036–2040.[CrossRef][Medline] [Order article via Infotrieve]

64. Middeldorp S, Meijers JCM, van den Ende AE, van Enk A, Bouma BN, Tans G, Rosing J, Prins MH, Büller HR. Effects on coagulation of levonorgestrel- and desogestrel-containing low dose oral contraceptives: a cross-over study. Thromb Haemost. 2000; 84: 4–8.[Medline] [Order article via Infotrieve]

65. Meijers JCM, Middeldorp S, Tekelenburg W, van den Ende AE, Tans G, Prins MH, Rosing J, Büller HR, Bouma BN. Increased fibrinolytic activity during use of oral contraceptives is counteracted by an enhanced factor XI-independent downregulation of fibrinolysis: a randomized cross-over study of two low-dose oral contraceptives. Thromb Haemost. 2000; 84: 9–14.[Medline] [Order article via Infotrieve]

66. Tans G, Curvers J, Middeldorp S, Thomassen MCLGD, Meijers JCM, Prins MH, Bouma BN, Büller HR, Rosing J. A randomized cross-over study on the effects of levonorgestrel- and desogestrel-containing oral contraceptives on the anticoagulant pathways. Thromb Haemost. 2000; 84: 15–21.[Medline] [Order article via Infotrieve]

67. Mackie IJ, Piegsa K, Furs SA, Johnson J, Bounds W, Machin SJ, Guillebaud J. Protein S levels are lower in women receiving desogestrel-containing combined oral contraceptives (COCs) than in women receiving levonorgestrel-containing COCs at steady state and on cross-over. Br J Haematol. 2001; 113: 898–904.[CrossRef][Medline] [Order article via Infotrieve]

68. Heit JA, Mohr DN, Silverstein MD, Petterson TM, O’Fallon WM, Melton LJ III. Predictors of recurrence after deep vein thrombosis and pulmonary embolism: a population-based cohort study. Arch Intern Med. 2000; 160: 761–768.[Abstract/Free Full Text]

69. Schulman S, Granqvist S, Holmstrom M, Carlsson A, Lindmarker P, Nicol P, Eklund SG, Nordlander S, Larfars G, Leijd B, et al. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism: the Duration of Anticoagulation Trial Study Group. N Engl J Med. 1997; 336: 393–398.[Abstract/Free Full Text]

70. Agnelli G, Prandoni P, Santamaria MG, Bagatella P, Iorio A, Bazzan M, Moia M, Guazzaloca G, Bertoldi A, Tomasi C, et al. Three months versus one year of oral anticoagulant therapy for idiopathic deep venous thrombosis: Warfarin Optimal Duration Italian Trial Investigators. N Engl J Med. 2001; 345: 165–169.[Abstract/Free Full Text]

71. Kyrle PA, Minar E, Hirschl M, Bialonczyk C, Stain M, Schneider B, Weltermann A, Speiser W, Lechner K, Eichinger S. High plasma levels of factor VIII and the risk of recurrent venous thromboembolism. N Engl J Med. 2000; 343: 457–462.[Abstract/Free Full Text]

72. Hansson PO, Sorbo J, Eriksson H. Recurrent venous thromboembolism after deep vein thrombosis: incidence and risk factors. Arch Intern Med. 2000; 160: 769–774.[Abstract/Free Full Text]

73. Grau E, Real E, Medrano J, Pastor E, Selfa S. Recurrent venous thromboembolism in a Spanish population: incidence, risk factors, and management in a hospital setting. Thromb Res. 1999; 96: 335–341.[CrossRef][Medline] [Order article via Infotrieve]

74. Simioni P, Prandoni P, Lensing AW, Scudeller A, Sardella C, Prins MH, Villalta S, Dazzi F, Girolami A. The risk of recurrent venous thromboembolism in patients with an Arg506Gln mutation in the gene for factor V (factor V Leiden). N Engl J Med. 1997; 336: 399–403.[Abstract/Free Full Text]

75. Simioni P, Prandoni P, Lensing AW, Manfrin D, Tormene D, Gavasso S, Girolami B, Sardella C, Prins M, Girolami A. Risk for subsequent venous thromboembolic complications in carriers of the prothrombin or the factor V gene mutation with a first episode of deep-vein thrombosis. Blood. 2000; 96: 3329–3333.[Abstract/Free Full Text]

76. Den Heijer M, Blom HJ, Gerrits WB, Rosendaal FR, Wijermans PW, Bos GM. Is hyperhomocysteinemia a risk factor for recurrent venous thrombosis? Lancet. 1995; 345: 882–885.[CrossRef][Medline] [Order article via Infotrieve]

77. Eichinger S, Stumpflen A, Hirschl M, Bialonczyk C, Herkner K, Stain M, Schneider B, Pabinger I, Lechner K, Kyrle PA. Hyperhomocysteinemia is a risk factor of recurrent venous thromboembolism. Thromb Haemost. 1998; 80: 566–569.[Medline] [Order article via Infotrieve]

78. De Stefano V, Martinelli I, Mannucci PM, Paciaroni K, Chiusolo P, Casorelli I, Rossi E, Leone G. The risk of recurrent deep venous thrombosis among heterozygous carriers of both factor V Leiden and the G20210A prothrombin mutation. N Engl J Med. 1999; 341: 801–806.[Abstract/Free Full Text]

79. Lindmarker P, Schulman S, Sten-Linder M, Wiman B, Egberg N, Johnsson H. The risk of recurrent venous thromboembolism in carriers and non-carriers of the G1691A allele in the coagulation factor V gene and the G20210A allele in the prothrombin gene: DURAC Trial Study Group Duration of Anticoagulation. Thromb Haemost. 1999; 81: 684–689.[Medline] [Order article via Infotrieve]

80. Eichinger S, Pabinger I, Stumpflen A, Hirschl M, Bialonczyk C, Schneider B, Mannhalter C, Minar E, Lechner K, Kyrle PA. The risk of recurrent venous thromboembolism in patients with and without factor V Leiden. Thromb Haemost. 1997; 77: 624–628.[Medline] [Order article via Infotrieve]

81. Eichinger S, Minar E, Hirschl M, Bialonczyk C, Stain M, Mannhalter C, Stumpflen A, Schneider B, Lechner K, Kyrle PA. The risk of early recurrent venous thromboembolism after oral anticoagulant therapy in patients with the G20210A transition in the prothrombin gene. Thromb Haemost. 1999; 81: 14–17.[Medline] [Order article via Infotrieve]

82. Rintelen C, Pabinger I, Knobl P, Lechner K, Mannhalter C. Probability of recurrence of thrombosis in patients with and without factor V Leiden. Thromb Haemost. 1996; 75: 229–232.[Medline] [Order article via Infotrieve]

83. Simioni P, Sanson BJ, Prandoni P, Tormene D, Friederich PW, Girolami B, Gavasso S, Huisman MV, Buller HR, Wouter TC, et al. Incidence of venous thromboembolism in families with inherited thrombophilia. Thromb Haemost. 1999; 81: 198–202.[Medline] [Order article via Infotrieve]

84. Rees DC, Cox M, Clegg JB. World distribution of factor V Leiden. Lancet. 1995; 346: 1133–1134.[CrossRef][Medline] [Order article via Infotrieve]

85. Rosendaal FR, Doggen CJM, Zivelin A, Arruda VR, Aiach M, Siscovick DS, Hillarp A, Watzke HH, Bernardi F, Cumming AM, et al. Geographic distribution of the 20210 G to A prothrombin variant. Thromb Haemost. 1998; 79: 706–708.[Medline] [Order article via Infotrieve]

86. Ridker PM, Miletich JP, Hennekens CH, Buring JE. Ethnic distribution of factor V Leiden in 4047 men and women. JAMA. 1997; 277: 1305–1307.[Abstract/Free Full Text]

87. Rosendaal FR, Koster T, Vandenbroucke JP, Reitsma PH. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance). Blood. 1995; 85: 1504–1508.[Abstract/Free Full Text]

88. Rintelen C, Mannhalter C, Ireland H, Lane DA, Knobl P, Lechner K, Pabinger I. Oral contraceptives enhance the risk of clinical manifestation of venous thrombosis at a young age in females homozygous for factor V Leiden. Br J Haematol. 1996; 93: 487–490.[CrossRef][Medline] [Order article via Infotrieve]

89. Koster T, Blann AD, Briët E, Vandenbroucke JP, Rosendaal FR. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet. 1995; 345: 152–155.[CrossRef][Medline] [Order article via Infotrieve]

90. O’Donnell J, Tuddenham EGD, Manning R, Kemball-Cook G, Johnson D, Laffan M. High prevalence of elevated FVIII levels in patients referred for thrombophilia screening: role of increased synthesis and relationship to the acute phase reaction. Thromb Haemost. 1997; 77: 825–828.[Medline] [Order article via Infotrieve]

91. Kraaijenhagen RA, in’t Anker PS, Koopman MM, Reitsma PH, Prins MH, van den EA, Buller HR. High plasma concentration of factor VIIIc is a major risk factor for venous thromboembolism. Thromb Haemost. 2000; 83: 5–9.[Medline] [Order article via Infotrieve]

92. Bloemenkamp KWM, Helmerhorst FM, Rosendaal FR, Vandenbroucke JP. Venous thrombosis, oral contraceptives and high factor VIII levels. Thromb Haemost. 1999; 82: 1024–1027.[Medline] [Order article via Infotrieve]

93. Bloemenkamp KWM, Rosendaal FR, Helmerhorst FM, Vandenbroucke JP. Higher risk of venous thrombosis during early use of oral contraceptives in women with inherited clotting defects. Arch Intern Med. 2000; 160: 49–52.[Abstract/Free Full Text]

94. Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet. 1999; 353: 1167–1173.[CrossRef][Medline] [Order article via Infotrieve]

95. Inman WHW, Vessey MP. Investigation of death from pulmonary, coronary, and cerebral thrombosis and embolism in women of child-bearing age. BMJ. 1968; 2: 193–199.[Free Full Text]

96. Collaborative Group for the Study of Stroke in Young Women. Oral contraception and increased risk of cerebral ischemia or thrombosis. N Engl J Med. 1973; 288: 871–878.[Medline] [Order article via Infotrieve]

97. Mann JI, Vessey MP, Thorogood M, Doll R. Myocardial infarction in young women with special reference to oral contraceptive practice. BMJ. 1975; 2: 241–245.[Abstract/Free Full Text]

98. Rosenberg L, Hennekens CH, Rosner B, Belanger C, Rothman KJ, Speizer FE. Oral contraceptive use in relation to nonfatal myocardial infarction. Am J Epidemiol. 1980; 111: 59–66.[Abstract/Free Full Text]

99. Shapiro S, Slone D, Rosenberg L, Kaufman DW, Stolley PD, Miettinen OS. Oral-contraceptive use in relation to myocardial infarction. Lancet. 1979; 1: 743–747.[Medline] [Order article via Infotrieve]

100. Jick H, Dinan B, Herman R, Rothman KJ. Myocardial infarction and other vascular diseases in young women: role of estrogens and other factors. JAMA. 1978; 240: 2548–2552.[Abstract/Free Full Text]

101. Jick H, Porter J, Rothman KJ. Oral contraceptives and nonfatal stroke in healthy young women. Ann Intern Med. 1978; 89: 58–60.[Abstract/Free Full Text]

102. Jick H, Dinan B, Rothman KJ. Oral contraceptives and nonfatal myocardial infarction. JAMA. 1978; 239: 1403–1406.[Abstract/Free Full Text]

103. Stadel BV. Oral contraceptives and cardiovascular disease (first of two parts). N Engl J Med. 1981; 305: 612–618.[Medline] [Order article via Infotrieve]

104. Stadel BV. Oral contraceptives and cardiovascular disease (second of two parts). N Engl J Med. 1981; 305: 672–677.[Medline] [Order article via Infotrieve]

105. World Health Organization. Acute myocardial infarction and combined oral contraceptives: results of an international multicentre case-control study: WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Lancet. 1997; 349: 1202–1209.[CrossRef][Medline] [Order article via Infotrieve]

106. World Health Organization. Ischaemic stroke and combined oral contraceptives: results of an international, multicentre, case-control study. WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Lancet. 1996; 348: 498–505.[CrossRef][Medline] [Order article via Infotrieve]

107. World Health Organization. Haemorrhagic stroke, overall stroke risk, and combined oral contraceptives: results of an international, multicentre, case-control study: WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Lancet. 1996; 348: 505–510.[CrossRef][Medline] [Order article via Infotrieve]

108. Sidney S, Siscovick DS, Petitti DB, Schwartz SM, Quesenberry CP, Psaty BM, Raghunathan TE, Kelaghan J, Koepsell TD. Myocardial infarction and use of low-dose oral contraceptives: a pooled analysis of 2 US studies. Circulation. 1998; 98: 1058–1063.[Abstract/Free Full Text]

109. Lewis MA, Heinemann LA, Spitzer WO, MacRae KD, Bruppacher R. The use of oral contraceptives and the occurrence of acute myocardial infarction in young women: results from the Transnational Study on Oral Contraceptives and the Health of Young Women. Contraception. 1997; 56: 129–140.[CrossRef][Medline] [Order article via Infotrieve]

110. Jick H, Jick S, Myers MW, Vasilakis C. Risk of acute myocardial infarction and low-dose combined oral contraceptives. Lancet. 1996; 347: 627–628.[Medline] [Order article via Infotrieve]

111. Dunn N, Thorogood M, Faragher B, de Caestecker L, MacDonald TM, McCollum C, Thomas S, Mann R. Oral contraceptives and myocardial infarction: results of the MICA case-control study. BMJ. 1999; 318: 1579–1584.[Abstract/Free Full Text]

112. Tanis BC, van den Bosch MAAJ, Kemmeren JM, Manger Cats V, Helmerhorst FM, Algra A, van der Graaf Y, Rosendaal FR. Oral contraceptives and the risk of myocardial infarction. N Engl J Med. In press.

113. Rosendaal FR, Siscovick DS, Schwartz SM, Beverly RK, Psaty BM, Longstreth WT Jr, Raghunathan TE, Koepsell TD, Reitsma PH. Factor V Leiden (resistance to activated protein C) increases the risk of myocardial infarction in young women. Blood. 1997; 89: 2750–2754.

114. Rosendaal FR, Siscovick DS, Schwartz SM, Psaty BM, Raghunathan TE, Vos HL. A common prothrombin variant (20210 G to A) increases the risk of myocardial infarction in young women. Blood. 1997; 90: 1747–1750.[Abstract/Free Full Text]

115. Doggen CJM, Manger Cats V, Bertina RM, Rosendaal FR. Interaction of coagulation defects and cardiovascular risk factors: increased risk of myocardial infarction associated with factor V Leiden or prothrombin 20210A. Circulation. 1998; 97: 1037–1041.[Abstract/Free Full Text]

116. Grady D, Rubin SM, Petitti DB, Fox CS, Black D, Ettinger B, Ernster VL, Cummings SR. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med. 1992; 117: 1016–1037.[Abstract/Free Full Text]

117. Hutchinson TA, Polansky SM, Feinstein AR. Post-menopausal oestrogens protect against fractures of hip and distal radius: a case-control study. Lancet. 1979; 2: 705–709.[Medline] [Order article via Infotrieve]

118. Weiss NS, Ure CL, Ballard JH, Williams AR, Daling JR. Decreased risk of fractures of the hip and lower forearm with postmenopausal use of estrogen. N Engl J Med. 1980; 303: 1195–1198.[Abstract]

119. Stampfer MJ, Willett WC, Colditz GA, Rosner B, Speizer FE, Hennekens CH. A prospective study of postmenopausal estrogen therapy and coronary heart disease. N Engl J Med. 1985; 313: 1044–1049.[Abstract]

120. Psaty BM, Heckbert SR, Atkins D, Siscovick DS, Koepsell TD, Wahl PW, Longstreth WT Jr, Weiss NS, Wagner EH, Prentice R. A review of the association of estrogens and progestins with cardiovascular disease in postmenopausal women. Arch Intern Med. 1993; 153: 1421–1427.[Abstract/Free Full Text]

121. Bush TL, Cowan LD, Barrett-Connor E, Criqui MH, Karon JM, Wallace RB, Tyroler HA, Rifkind BM. Estrogen use and all-cause mortality: preliminary results from the Lipid Research Clinics Program Follow-Up Study. JAMA. 1983; 249: 903–906.[Abstract/Free Full Text]

122. Ross RK, Paganini-Hill A, Mack TM, Arthur M, Henderson BE. Menopausal oestrogen therapy and protection from death from ischaemic heart disease. Lancet. 1981; 1: 858–860.[CrossRef][Medline] [Order article via Infotrieve]

123. Nachtigall LE, Nachtigall RH, Nachtigall RD, Beckman EM. Estrogen replacement therapy I: a 10-year prospective study in the relationship to osteoporosis. Obstet Gynecol. 1979; 53: 277–281.[Medline] [Order article via Infotrieve]

124. Hemminki E, Sihvo S. A review of postmenopausal hormone therapy recommendations: potential for selection bias. Obstet Gynecol. 1993; 82: 1021–1028.[Medline] [Order article via Infotrieve]

125. Hemminki E, Malin M, Topo P. Selection to postmenopausal therapy by women’s characteristics. J Clin Epidemiol. 1993; 46: 211–219.[CrossRef][Medline] [Order article via Infotrieve]

126. Posthuma WF, Westendorp RG, Vandenbroucke JP. Cardioprotective effect of hormone replacement therapy in postmenopausal women: is the evidence biased? BMJ. 1994; 308: 1268–1269.[Abstract/Free Full Text]

127. Hoibraaten E, Qvigstad E, Arnesen H, Larsen S, Wickstrom E, Sandset PM. Increased risk of recurrent venous thromboembolism during hormone replacement therapy: results of the randomized, double-blind, placebo-controlled estrogen in venous thromboembolism trial (EVTET). Thromb Haemost. 2000; 84: 961–967.[Medline] [Order article via Infotrieve]

128. Boston Collaborative Drug Surveillance program. Surgically confirmed gallbladder disease, venous thromboembolism and breast tumors in relation to postmenopausal estrogen therapy. N Engl J Med. 1974; 290: 15–19.[Medline] [Order article via Infotrieve]

129. Nachtigall LE, Nachtigall RH, Nachtigall RD, Beckman EM. Estrogen replacement therapy II: a prospective study in the relationship to carcinoma and cardiovascular and metabolic problems. Obstet Gynecol. 1979; 54: 74–79.[Medline] [Order article via Infotrieve]

130. Devor M, Barrett-Connor E, Renvall M, Feigal D Jr, Ramsdell J. Estrogen replacement therapy and the risk of venous thrombosis. Am J Med. 1992; 92: 275–282.[CrossRef][Medline] [Order article via Infotrieve]

131. Petitti DB, Wingerd J, Pellegrin F, Ramcharan S. Risk of vascular disease in women: smoking, oral contraceptives, noncontraceptive estrogens, and other factors. JAMA. 1979; 242: 1150–1154.[Abstract/Free Full Text]

132. Young RL, Goepfert AR, Goldzieher HW. Estrogen replacement therapy is not conducive of venous thromboembolism. Maturitas. 1991; 13: 189–192.[CrossRef][Medline] [Order article via Infotrieve]

133. Daly E, Vessey MP, Painter R, Hawkins MM. Case-control study of venous thromboembolism risk in users of hormone replacement therapy. Lancet. 1996; 348: 1027.[CrossRef]

134. Varas Lorenzo C, Garcia Rodriguez LA, Cattaruzzi C, Troncon MG, Agostinis L, Perez Gutthann S. Hormone replacement therapy and the risk of hospitalization for venous thromboembolism: a population-based study in southern Europe. Am J Epidemiol. 1998; 147: 387–390.[Abstract/Free Full Text]

135. Perez Gutthann S, Garcia Rodriguez LA, Castellsague J, Duque Oliart A. Hormone replacement therapy and risk of venous thromboembolism: population based case-control study. BMJ. 1997; 314: 796–800.[Abstract/Free Full Text]

136. Grady D, Furberg C. Venous thromboembolic events associated with hormone replacement therapy. JAMA. 1997; 278: 477[Abstract/Free Full Text]

137. Grady D, Wenger NK, Herrington D, Khan S, Furberg C, Hunninghoke D, Vittinghoff E, Hulley S. Postmenopausal hormone therapy increases risk for venous thromboembolic disease. Ann Intern Med. 2000; 132: 689–696.[Abstract/Free Full Text]

138. Hoibraaten E, Abdelnoor M, Sandset PM. Hormone replacement therapy with estradiol and risk of venous thromboembolism: a population-based case-control study. Thromb Haemost. 1999; 82: 1218–1221.[Medline] [Order article via Infotrieve]

139. Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E, for the Heart and Estrogen/Progestin Replacement Study (HERS) Research Group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA. 1998; 280: 605–613.[Abstract/Free Full Text]

140. Larkin M. Ups and downs for HRT and heart disease. Lancet. 2000; 355: 1338.

141. Lowe G, Woodward M, Vessey M, Rumley A, Gough P, Daly E. Thrombotic variables and risk of idiopathic venous thromboembolism in women aged 45–64 years: relationships to hormone replacement therapy. Thromb Haemost. 2000; 83: 530–535.[Medline] [Order article via Infotrieve]

142. Rosendaal FR, Vessey M, Rumley A, Daly E, Woodward M, Helmerhorst FM, Lowe GDO. Hormonal replacement therapy, prothrombotic mutations and the risk of venous thrombosis. Br J Haematol In press.

143. Psaty BM, Smith NL, Lemaitre RN, Vos HL, Heckbert SR, Lacroix AZ, Rosendaal FR. Hormone replacement therapy, prothrombotic mutations, and the risk of incident non-fatal myocardial infarction. JAMA. 2001; 285: 906–913.[Abstract/Free Full Text]

144. Scarabin PY, Plu-Bureau G, Zitoun D, Bara L, Guize L, Samama MM. Changes in haemostatic variables induced by oral contraceptives containing 50 micrograms or 30 micrograms oestrogen: absence of dose-dependent effect on PAI-1 activity. Thromb Haemost. 1995; 74: 928–932.[Medline] [Order article via Infotrieve]

145. Quehenberger P, Loner U, Kapiotis S, Handler S, Schneider B, Huber J, Speiser W. Increased levels of activated factor VII and decreased plasma protein S activity and circulating thrombomodulin during use of oral contraceptives. Thromb Haemost. 1996; 76: 729–734.[Medline] [Order article via Infotrieve]

146. A multicentre study of coagulation and haemostatic variables during oral contraception: variations with four formulations: Task Force on Oral Contraceptives: WHO Special Programme of Research, Development and Research Training in Human Reproduction, World Health Organization, Geneva, Switzerland. Br J Obstet Gynaecol. 1991; 98: 1117–1128.[Medline] [Order article via Infotrieve]

147. Meade TW, Haines AP, North WR, Chakrabarti R, Howarth DJ, Stirling Y. Haemostatic, lipid, and blood-pressure profiles of women on oral contraceptives containing 50 microgram or 30 microgram oestrogen. Lancet. 1977; 2: 948–951.[Medline] [Order article via Infotrieve]

148. Teede HJ, McGrath BP, Smolich JJ, Malan E, Kotsopoulos D, Liang YL, Peverill RE. Postmenopausal hormone replacement therapy increases coagulation activity and fibrinolysis. Arterioscler Thromb Vasc Biol. 2000; 20: 1404–1409.[Abstract/Free Full Text]

149. Koh KK, Horne MKIII, Cannon ROIII. Effects of hormone replacement therapy on coagulation, fibrinolysis, and thrombosis risk in postmenopausal women. Thromb Haemost. 1999; 82: 626–633.[Medline] [Order article via Infotrieve]

150. Bloemenkamp KWM, Rosendaal FR, Helmerhorst FM, Koster T, Bertina RM, Vandenbroucke JP. Hemostatic effects of oral contraceptives in women who developed deep-vein thrombosis while using oral contraceptives. Thromb Haemost. 1998; 80: 382–387.[Medline] [Order article via Infotrieve]

151. Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, Vogel V, Robidoux A, Dimitrov N, Atkins J, et al, and other National Surgical Adjuvant Breast, and Bowel Project Investigators. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project p-1 study. J Natl Cancer Inst. 1998; 90: 1371–1388.[Abstract/Free Full Text]

152. Veronesi U, Maisonneuve P, Costa A, Sacchini V, Maltoni C, Robertson C, Rotmensz N, Boyle P, on behalf of the Italian Tamoxifen Prevention Study. Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomised trial among hysterectomised women. Lancet. 1998; 352: 93–97.[Medline] [Order article via Infotrieve]

153. Cummings SR, Eckert S, Krueger KA, Grady D, Powles TJ, Cauley JA, Norton L, Nickelsen T, Bjarnason NH, Morrow M, et al. The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial: Multiple Outcomes of Raloxifene Evaluation. JAMA. 1999; 281: 2189–2197.[Abstract/Free Full Text]

154. Meier CR, Jick H. Tamoxifen and risk of idiopathic venous thromboembolism. Br J Clin Pharmacol. 1998; 45: 608–612.[CrossRef][Medline] [Order article via Infotrieve]

155. Rosendaal FR. Oral contraceptives and screening for factor V Leiden. Thromb Haemost. 1996; 75: 524–525.[Medline] [Order article via Infotrieve]

156. Vandenbroucke JP, van der Meer FJ, Helmerhorst FM, Rosendaal FR. Factor V Leiden: should we screen oral contraceptive users and pregnant women? BMJ. 1996; 313: 1127–1130.[Free Full Text]

157. Mosca L, Collins P, Herrington DM, Mendelsohn ME, Pasternak RC, Robertson RM, Schenck-Gustafsson K, Smith SC, Taubert KA, Wenger NK. Hormone replacement therapy and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation. 2001; 104: 499–503.[Free Full Text]

158. Greenblatt DJ. A retrospective case-control study of diseases associated with oral contraceptive use. Am Heart J. 1975; 89: 677–678.[CrossRef][Medline] [Order article via Infotrieve]

159. Petitti DB, Wingerd J, Pellegrin F, Ramcharan S. Oral contraceptives, smoking, and other factors in relation to risk of venous thromboembolic disease. Am J Epidemiol. 1978; 108: 480–485.[Abstract/Free Full Text]

160. Maguire MG, Tonascia JA, Sartwell PE, Stolley PD, Tockman MS. Increased risk of thrombosis due to oral contraceptives: a further report. Am J Epidemiol. 1979; 110: 188–195.[Abstract/Free Full Text]

161. Helmrich SP, Rosenberg L, Kaufman DW, Strom B, Shapiro S. Venous thromboembolism in relation to oral contraceptive use. Obstet Gynecol. 1987; 69: 91–95.[Medline] [Order article via Infotrieve]

162. Cardiovascular disease and use of oral contraceptives: WHO Collaborative Study. Bull World Health Organ. 1989; 67: 417–423.[Medline] [Order article via Infotrieve]

163. Grounds M. Anovulants: thrombosis and other associated changes. Med J Aust. 1974; 2: 440–446.[Medline] [Order article via Infotrieve]

164. Diddle AW, Gardner WMH, Williamson PH, Johnson JR, Hemphill JL, Godwin CW. Oral contraceptives steroids and thrombophlebitis. J Tenn Med Assoc. 1978; 71: 22–26.[Medline] [Order article via Infotrieve]

165. Porter JB, Hunter JR, Jick H, Stergachis A. Oral contraceptives and nonfatal vascular disease. Obstet Gynecol. 1985; 66: 1–4.[Medline] [Order article via Infotrieve]

166. Fuertes de la Haba A, Curet JO, Pelegrina I, Bangdiwala I. Thrombophlebitis among oral and nonoral contraceptive users. Obstet Gynecol. 1971; 38: 259–263.[Medline] [Order article via Infotrieve]

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