use of combined oral contraceptives (containing estrogen and progesterone) is
common across the world. Unfortunately, their use has resulted in
considerable adverse drug events that have caused much debate about their
safety in the general population. One such adverse drug event that dates
back to the early 1960's is the development of venous thromboembolism (VTE),
which includes both deep vein thrombosis (DVT) and pulmonary embolism (PE).1-7
It has been estimated that the annual incidence of venous thromboembolism (VTE)
in women of child bearing age who are not taking oral contraceptives is 1 in
10,000.8 The incidence is increased 3-5 fold when women of child bearing
age use estrogen containing oral contraceptives.9 This risk is even
greater in patients taking higher doses of estrogen, those with an underlying
hypercoaguable disorder, such as factor V Leiden, and in patients taking third
generation oral contraceptives containing desogestrel, gestodene, or
do estrogen containing oral contraceptives increase the risk for VTE?
Estrogen containing oral contraceptives increase the plasma concentrations of
clotting factors II, VII, X, XII, factor VIII, fibrinogen, and thrombin
activatable fibrinolysis inhibitor (TAFI) (see figure 1).13,17-19
However, not all of the increases in clotting factors are of the same
magnitude. Factor VII appears to have the greatest magnitude of increase
and factor VIII the least magnitude of increase, comparatively.13,17 As
it relates to the magnitude of increase in factor VII concentrations, it
appears that desogestrel containing oral contraceptives confer the greatest
impact (26-32% increase) when compared to a second generation oral contraceptive
containing levonorgestrel (9-12% increase).13,17 All of these effects
shift the balance towards thrombus formation and prevention of clot
breakdown. There is also an effect that favors reduced clot
formation. There is a small decrease in factor V, which is necessary for
the activation of prothrombin (II) to thrombin (IIa).13,17 While a
decrease in factor V may appear to be beneficial, factor V actually works
synergistically with protein S to inhibit factor VIII; thus, the potential
reduction in risk of thrombus that may have been realized by a reduction in
factor V levels is effectively negated.20,21 Therefore, the overall
effect on the coagulation system is a shift in favor of clot formation and
prevention of clot dissolution.
does estrogen increase clotting factors and other components that result in a
net increase in the risk for clot formation?
Estrogen, like many lipophilic hormones, affects the gene transcription of
various proteins. Thus, estrogen increases plasma concentrations of these
clotting factors by increasing gene transcription. While the exact
mechanism is complicated and not entirely known, estrogen crosses the cell
membrane for a particular target tissue, which there are many that estrogen
influence, and once inside the cytoplasm binds to nuclear receptors (i.e.,
estrogen receptors).20-22 The estrogen/nuclear receptor complex then
travels into the nucleus where it recognizes and binds to specific recognition
sites, called hormone response elements or in this case, "estrogen
response elements".22-24 This binding then turns on gene
transcription by allowing RNA polymerase II to transcribe the protein in that
region of the DNA.22-24 In this case, these new proteins are the clotting
factors and proteins described above. However, just as the
estrogen/nuclear receptor complex can turn on gene transcription, they can also
have the opposite effect and repress gene transcription, which may be the
reason for the reductions in factor V concentrations. The degree of
influence that estrogen has on gene transcription is unfortunately more complex
and not limited to nuclear receptor binding to DNA. Estrogen bound to
nuclear receptors (estrogen receptors) also regulates gene expression through
protein-protein interaction with other transcription factors. Again, this
effect on gene expression can result in increased or decreased gene
expression. Also, estrogen receptors influence intracellular signaling
pathways, such as MAPK and IP3 kinase pathways, that may also influence overall
gene expression.22 As stated earlier, higher doses of estrogen appear to
confer a greater risk of venous thrombus formation. This can be explained
by a greater degree of nuclear receptor binding and overall activation of gene
transcription for these clotting factors.
are patients taking third generation oral contraceptives, containing
desogestrel and gestodene in particular, at a greater risk for developing VTE
as compared to patients taking first and second generation progestin containing
To our knowledge this has not been fully determined, but there are data
supporting the hypothesis that desogestrel containing oral contraceptives cause
a greater increase in plasma concentrations of factor VII when compared to a
second generation contraceptive that contains levonorgestrel.17 This
would further tip the balance of the coagulation cascade in the direction of
enhanced clot formation. Therefore, it is likely that a combination of
all of these intracellular reactions brought about by estrogen and the type of
progesterone used influence gene expression and excess production of clotting factors.
- Jordan WM. Pulmonary embolism. Lancet 1961;278:1146-7.
PE, Masi AT, Arthes FG et al. Thromboembolism and oral contraceptives:
an epidemiologic case-control study. Am J Epidemiol 1969;90:365-80.
MP, Doll R. Investigation of relation between use of oral
contraceptives and thromboembolic disease. A further report. Br Med J
- Drill VA. Oral contraceptives and thromboembolic disease. I. prospective and retrospective studies. JAMA 1972;219:583-92.
M, Mant D, Smith A et al. Oral contraceptives and venous
thromboembolism: findings in a large prospective study. Br Med J (Clin
Red Ed) 1986;292:526.
BB, Piper JM, Tomita DK et al. Oral contraceptive estrogen dose and
the risk of deep vein thromboembolic disease. Am J Epidemiol
I, Battaglioli T, Mannucci PM. Pharmacogenetic aspects of the use of
oral contraceptives and the risk of thrombosis. Pharamcogenetics
- Martinelli I. Risk factors in venous thromboembolism. Thromb Haemost 2001;86:395-403.
- Hannaford P. Health consequences of combined oral contraceptives. Br Med Bull 2000;56:749-60.
JP, Koster T, Briet E et al. Increased risk of venous thrombosis in
oral-contraceptive users who are carriers of factor V Leiden mutation.
M, Heinemann LA, Schramm W. Are factor V Leiden carriers who use oral
contraceptives at extreme risk for venous thromboembolism? Eur J
Contracept Reprod Health Care 2000;5:105-12.
P. Cardiovascular events associated with different combined oral
contraceptives: a review of current data. Drug Saf 2000;22:361-71.
JM, Algra A, Meijers JC et al. Effects of second and third generation
oral contraceptives and their respective progestagens on the coagulation
system in the absence or presence of the factor V Leiden mutation.
Thromb Haemost 2002;87:199-205.
Scientific Group on Cardiovascular Disease and Steroid Hormone
Contraception. Cardiovascular Disease and Steroid Hormone
Contraception: Report of a WHO Scientific Group. WHO Technical Report
Series, 877. Geneva, Switzerland: WHO, 1998.
- Jick H, Jick SS,
Gurewich V et al. Risk of idiopathic death and nonfatal venous
thromboembolism in women using oral contraceptives with differing
progestagen components. Lancet 1995;346:1589-93.
MA, Spitzer WO, Heinemann LA et al. Third generation oral
contraception and risk of myocardial infarction: an international
case-control study. Transnational Research Group on Oral Contraceptives
and the Health of Young Women. BMJ 1996;312:88-90.
S, Meijers JC, van den Ende AE et al. Effects on coagulation of
levonorgestrel- and desogestrel-containing low dose oral contraceptives:
a cross over-study. Thromb Haemost 2000;84:4-8.
EM, Johnson TR, Ramos LP et al. Enhanced expression of factor XII
(Hageman factor) in isolated livers of estrogen- and prolactin-treated
rats. J Lab Clin Med 1991;117:353-8.
JC, Middeldrop S, Tekelenburg W et al. Increased fibrinolytic activity
during use of oral contraceptives is counteracted by an enhanced factor
XI-independent down regulation of fibrinolysis: a randomized cross-over
study of two low-dose oral contraceptives. Thromb Haemost
L, Dahlback B. Factor V and protein S as synergistic cofactors to
activated protein C in degradation of factor VIIIa. J Biol Chem
L, He X, Dahlback B. Synergistic cofactor function of factor V and
protein S to activated protein C in the inactivation of the cofactor
VIIIa-factor IXa complex - species specific interactions of components
of the protein C anticoagulant system. Thromb Haemost
- Nilsson S, Makela S, Treuter E et al. Mechanisms of estrogen action. Physiol Rev 2001;81:1535-65.
- Robinson-Rechavi M, Escriva Garcia H, Laudet V. The nuclear receptor superfamily. J Cell Sci 2003;116:585-6.
M, Fujiki R, Takezawa S et al. Nuclear receptor mediated gene
regulation through chromatin remodeling and histone modifications.
Endocr J 2006;53:157-72.