Review ArticleEstrogen and thrombosis: A bench to bedside review
Introduction
Worldwide, hundreds of millions of women use exogenous estrogens either as contraceptives or as post-menopausal hormonal replacement. There is significant evidence that estrogen use in both these situations is associated with an increased risk of thrombosis, both arterial and venous. The increased risk is dependent both on the dose and well as the mode of delivery of the hormone, and studies identify alterations in numerous aspects of the hemostatic and fibrinolytic pathways that contribute to the generation of a prothrombotic milieu. This review summarizes the mechanisms identified, the various clinical situations predisposing to the increased risk of estrogen-associated thrombosis and the management thereof.
Section snippets
Discovery of estrogens
In 1896, a young Austrian researcher excised the ovaries of adult rabbits, re-implanted pieces of the ovaries in different locations and noted that unlike oophorectomized rabbits, there was an absence of uterine atrophy. Based on this, he postulated that the ovaries must likely send some substance via the blood stream to the uterus.[1] By 1924, the estrus cycle and its effects on the uterus was well established. [2] In 1929, pure oestrone crystals called “theelin”, were purified by Doisy from
Physiology of estrogen
The term estrogen is coined from the Greek word “Oistros” meaning “mad desire” and “andgennan” meaning “to produce”. It is a generic term for a family of hormones that affect the female reproductive system[7]. The female body naturally produces three forms of endogenous estrogen, which have many physiologic functions. 17β estradiol (E2) is a steroid hormone synthesized from cholesterol. E2 is the most potent form of estrogen produced by the ovary and has the highest affinity for the estrogen
Mechanisms
Although estrogen is known to affect multiple hemostatic variables, the exact molecular mechanism of estrogen-induced thrombosis remains unclear. Given the delicate balance between hemostasis and thrombosis, it is possible that small changes induced by hormonal therapy may increase the overall risk of thrombosis [50]. In the paragraphs below, we summarize the animal and human studies that identify pathways/factors altered with estrogen treatment and that are likely to affect the risk for
Venous thrombosis
The most common sites of thrombosis related to high estrogen states are the deep veins of the legs and the pulmonary veins. Consistently, approximately 80% of thromboses occurring in pregnancy are venous [90]. CHC use has also been associated with “unusual” sites of thrombosis. Multiple studies show an increase in the risk of cerebral venous sinus thrombosis, with an OR of 5.59 (95% CI 3.95–7.91) and 7.59 (95% CI 3.82—15.09) in two separate meta-analyses [91,92]. However, the absolute risk
Contraceptive management in women with high risk of thrombosis
Determining the thrombotic risk in women takes into consideration several factors, such as age, comorbidities, smoking history, family history, and history of thrombosis. Furthermore, while routine screening for hereditary thrombophilias remains controversial due to the rarity of these conditions, their presence can increase the risk of thrombosis.
The Medical Eligibility Criteria for contraceptive use by the World Health Organization lists history of VTE, surgery with prolonged immobilization,
Antiphospholipid antibodies
Women with anti-phospholipid syndrome (APS) on anticoagulation are continued on therapeutic anticoagulation with LMWH during pregnancy. There is a lack of robust data to guide the management of pregnancy or contraception in women with positive anti-phospholipid (aPL) antibodies without a history of thrombosis. A study by Lynch et al. measured aPL antibody levels in 451 low-risk nulliparous women during early pregnancy, and found that 24.4% had positive aPL antibodies. The rate of fetal loss in
Conclusion
CHCs are widely used and are safe and effective for regulation of fertility in the majority of women. Although thrombotic complications are the most important side effect, some clinical implications appear to be evident. The choice of a contraceptive method depends on a personal and family history of thrombosis, and those with a risk of thrombotic disease should be recommended alternatives to CHCs. Screening for prothrombotic mutations before initiating CHCs is not cost effective, and it is not
Author contributions
MAI and DS wrote manuscript and contributed the figures and tables; LN edited all versions of the manuscript.
Acknowledgements
LN's work is supported by National Heart, Lung and Blood Institute grants HL142647-01, HL121131-01, and U01 HL143402.
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