S Shapiro1. 1. Emeritus Professor of Epidemiology, Boston University, USA.
Abstract
BACKGROUND: Soon after combined estrogen/progestogen oral contraceptives (COCs) were introduced in the 1950s, it was established that they cause venous thromboembolism (VTE), that the risk is related to estrogen dose, and that COCs also increase the risk of myocardial infarction among female smokers over age 35. Stroke risk is also increased. early studies of supplemental hormone therapy were inconclusive. OBJECTIVE: To consider new findings. NEW FINDINGS ON ORAL CONTRACEPTIVES: Genetic predisposition to VTE has been established with the discovery of Leiden factor V mutation. Based on an irrational classification of low-estrogen-dose (<or= 30 microg ethinylestradiol) COCs as 'second generation' (containing 'older' progestogens, mainly norethisterone), or 'third generation' (containing the 'newer' progestogens, desogestrel or gestodene), it was claimed that the latter cause more VTE than the former. That claim has been rebutted, and it has been shown that VTE is a class effect, also shared by the newest progestogen, drosperinone. VTE risk is now known to be greatest during the initial year of COC use, after which the risk remains elevated, but somewhat less so. NEW FINDINGS ON HORMONE THERAPY: It is now established that hormone therapy increases the risk of VTE, and perhaps of stroke. The pattern is much the same as for oral contraceptives. Based on data from the Women's Health Initiative (WHI), a purportedly controlled trial, it was first claimed that estrogen plus progestogen therapy increases the overall risk of myocardial infarction. Then that claim was modified to suggest that therapy increases the risk mainly during the first year, and that the overall risk may possibly be reduced among recently menopausal women. Recently, based on the WHI data, and on data from an observational follow-up component of the WHI, the risks of myocardial infarction, VTE and stroke appeared to be increased maximally after therapy commenced, and then to decline to levels of little or no increased risk. CONCLUSIONS: It is likely that the WHI studies were biased and that they overestimated the overall and time- and duration-specific risks of VTE, myocardial infarction and stroke. Particularly for myocardial infarction, a protective effect, perhaps strongest among the youngest women, but present at all ages, may correctly have been identified in earlier observational studies, and have been missed in the WHI studies. This paper was presented by Professor Shapiro as a Plenary Lecture at the 12th World Congress on Menopause, Madrid, May 2008.
BACKGROUND: Soon after combined estrogen/progestogen oral contraceptives (COCs) were introduced in the 1950s, it was established that they cause venous thromboembolism (VTE), that the risk is related to estrogen dose, and that COCs also increase the risk of myocardial infarction among female smokers over age 35. Stroke risk is also increased. early studies of supplemental hormone therapy were inconclusive. OBJECTIVE: To consider new findings. NEW FINDINGS ON ORAL CONTRACEPTIVES: Genetic predisposition to VTE has been established with the discovery of Leiden factor V mutation. Based on an irrational classification of low-estrogen-dose (<or= 30 microg ethinylestradiol) COCs as 'second generation' (containing 'older' progestogens, mainly norethisterone), or 'third generation' (containing the 'newer' progestogens, desogestrel or gestodene), it was claimed that the latter cause more VTE than the former. That claim has been rebutted, and it has been shown that VTE is a class effect, also shared by the newest progestogen, drosperinone. VTE risk is now known to be greatest during the initial year of COC use, after which the risk remains elevated, but somewhat less so. NEW FINDINGS ON HORMONE THERAPY: It is now established that hormone therapy increases the risk of VTE, and perhaps of stroke. The pattern is much the same as for oral contraceptives. Based on data from the Women's Health Initiative (WHI), a purportedly controlled trial, it was first claimed that estrogen plus progestogen therapy increases the overall risk of myocardial infarction. Then that claim was modified to suggest that therapy increases the risk mainly during the first year, and that the overall risk may possibly be reduced among recently menopausal women. Recently, based on the WHI data, and on data from an observational follow-up component of the WHI, the risks of myocardial infarction, VTE and stroke appeared to be increased maximally after therapy commenced, and then to decline to levels of little or no increased risk. CONCLUSIONS: It is likely that the WHI studies were biased and that they overestimated the overall and time- and duration-specific risks of VTE, myocardial infarction and stroke. Particularly for myocardial infarction, a protective effect, perhaps strongest among the youngest women, but present at all ages, may correctly have been identified in earlier observational studies, and have been missed in the WHI studies. This paper was presented by Professor Shapiro as a Plenary Lecture at the 12th World Congress on Menopause, Madrid, May 2008.