In postmenopausal women with lower levels of estrogen, HRT should pose a lesser risk than in premenopausal women. There have been a number of papers on clotting factors in postmenopausal women receiving estrogens. Stangel et al. (1977) reported low antithrombin III activity in 57 percent of postmenopausal women receiving estrogen, as compared with 15 percent of those not using estrogen. The dose of estrogen (1.25 mg conjugated estrogens) was, however, high by current standards. In a review paper, Wren (1992) noted that although several groups reported an increase in various clotting factors with 1.25 mg conjugated estrogens, other studies reported no differences in various clotting factors between estrogen users (0.625 mg to 1.25 mg conjugated estrogens) and nonusers. This was postulated to be due to a spontaneous increase in antithrombin III and other anticlotting factors with increasing age, thus negating any possible adverse effect of estrogens. In a case-control study of women between ages 48 and 87 (mean 65) who experienced venous thrombosis, Devor et al. (1992) reported a similar incidence of current estrogen use in cases (5 percent) and in controls (6 percent). The study had the power to detect only a twofold or greater risk.

Some women appear to be very sensitive to the clotting effects of estrogen. In addition, some older women appear to have a surprisingly ample degree of estrogenic activity. It is possible that, in these women—particularly if they are obese, smokers, sedentary, diabetic, hypertensive, or hyperlipidemic—administrationof estrogens may sufficiently increase the risk of thrombotic events to counteract the salubrious effect of estrogens on HDL- and LDL-cholesterol and vascular endothelium. (The same caveat applies to younger postmenopausal women as well; the same dosage is typically dispensed by physicians and will be administered in the WHI regardless of age and body size.)

Finally, elderly women experience a higher incidence of unacceptable breast tenderness and breakthrough bleeding when estrogens are administered than do younger postmenopausal women. These side effects may cause women to drop out of the CT; clinical staff should be aware of these issues and respond to participants' concerns appropriately. It may be that elderly women require lower doses to produce a given estrogenic effect than do younger postmenopausal women.

Studies conclusively demonstrate that estrogen therapy has a positive effect on bone mineral density in younger postmenopausal women, and that this effect continues with continued use into the elderly age range. Data also strongly suggest a positive effect on cardiovascular disease in younger and older postmenopausal women. Some elderly women may experience a benefit on osteoporosis from introduction of estrogens if they have sufficient estrogen-dependent bone remaining. It is, however, unknown whether introduction of estrogens in the elderly will result in a positive or negative effect on cardiovascular events and mortality. Also, the relative magnitude and timing of these effects remain fairly uncertain. Thus, the CT will serve an especially important role in helping to elucidate the benefits and/or risks of HRT in women over the age of 70.