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Stroke consititutes a large burden of illness for aging women, an observation that is often overlooked in our popularized view of cancer as the major killer of women.  Recent data from large, randomized, clinical trials question the use of hormone replacement therapy for either the primary or secondary prevention of coronary heart disease and stroke. In the British ESPRIT placebo-controlled trial, oral estradiol valerate, was ineffective as secondary prevention of myocardial infarction.[8] Follow-up of a very large British cohort (the Million Women Study) showed a significantly increased risk of breast cancer with all types of hormone replacement therapy, including estrogen-progestin combinations (relative risk 2.00; 95% confidence interval 1.88-2.12) and estrogen monotherapy.[5][8]

Estrogen appears to be neuroprotective in animal stroke models. However, recent results from the WHI Memory Study (WHIMS) show a lack of global cognitive benefits with combined estrogen-progestin therapy, and even the suggestion of some harm, as the rate of developing dementia doubled in the treatment arm of the study [4].

Although oral contraceptives (OC) are an efficient method of birth control, early use (in 1959) was related with increased risk of vascular disease. This has largely been attributed to the estrogen composition of the early formulation. The first generation of oral contraceptives contained up to 150 ug of estrogen, a high estrogen component associated with a five-fold increase in the risk of stroke. However, the present formulations of OC (second and third generation tablets) contain much lower doses of estrogen (20-30 ug) and are associated with a lower risk of arterial stroke.

Lidegaard et a.l (2002) found that "the use of OCs was associated significantly with the risk of venous thromboembolism. The risk among current users was reduced by more than 50% during the first years of use. The risk increased more than 100% with increasing estrogen dose, and the difference in risk between users of third- and second-generation OCs, after correction for length of use and estrogen dose, was 33%."[6]

Women over 35 who smoke are discouraged from using OCs, the combination is not a good idea for anyone.

Other factors in addition to OC use increase the risk of stroke. Congenital thrombophilia such as mutations of factor V Leiden and the prothrombin gene increase the risk of stroke in OC users[8]. It is recommended that patients with a family history of venous thrombosis be screened for these abnormalities before starting OC. In addition to age, the presence of other risks factors such as hypertension, smoking and migraine seem to increase the risk of stroke among OC users. At present there is no role for the use of aspirin for primary stroke prevention in this group of patients.

According to Wassertheil-Smoller et al (2003) estrogen plus progestin increases the risk of ischemic stroke in generally healthy postmenopausal women. Excess risk for all strokes attributed to estrogen plus progestin appeared to be present in all subgroups of women examined[2].

While the use of hormone replacement therapy (HRT) for prophylactic indications such as cardiovascular disease, osteoporosis, and Alzheimer’s disease was increasingly propagated during the 1990s, recent studies have reported no risk reduction for women after myocardial infarction (HERS - Heart and Estrogen/Progestin Replacement Study) or women from a mixed population with an average age of 63 years (Women’s Health Initiative [7] Study). The results of the latter study even suggest an increased risk for cardiovascular events and breast cancer with previous or ongoing combined oral estrogen plus progestin[3].

Recently, the Women’s Health Initiative (WHI) study demonstrated an increased incidence of breast cancer, MI, stroke, dementia and blood clots with hormone replacement therapy.

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2. Wassertheil-Smoller S, Hendrix SL, Limacher M, Heiss G, Kooperberg C, Baird A, Kotchen T, Curb JD, Black H, Rossouw JE, Aragaki A, Safford M, Stein E, Laowattana S, Mysiw WJ, Effect of estrogen plus progestin on stroke in postmenopausal women: the Women's Health Initiative: a randomized trial. JAMA. 2003 May 28;289(20):2673-84.

3. Seifert-Klauss V, Schumm-Draeger PM, Hormone therapy in menopause. A current update, Internist (Berl). 2003 Dec;44(12):1500-7.

4. Espeland, MA, Rapp, SR, Shumaker, SA, et al. Conjugated equine estrogens and global cognitive function in postmenopausal women: Women's Health Initiative Memory Study. JAMA 2004; 291:2959.

5. Million Women Study Collaborators. Lancet 2003; 362:419-427 abstract: http://www.millionwomenstudy.org/absbreast.html accessed February 13, 2006

6. Lidegaard O, Edstrom B, Kreiner S. Contraception. 2002 Mar;65(3):187-96.

7. Women's Health Initiative accessed March 28, 2006 http://www.nhlbi.nih.gov/whi/index.html

8. Post-menopausal hormone replacement therapy: risk-benefit balance in the hot seat. Prescrire Int. 2004;13(71):106-9.

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