The WHI trials examined treatment only with conjugated equine estrogens and medroxyprogesterone acetate. The effects of other oral estrogen agents, transdermal estradiol, therapy with other progestins, or cyclic hormone therapy may be different. In observational studies, transdermal estrogen therapy is not associated with an increased risk of venous thromboembolic disease (54). The average age of women participating in these trials was more than 15 years beyond the age at which women typically initiate hormone therapy for the treatment of vasomotor symptoms. It is possible that early initiation of hormone therapy may result in a more favorable risk–benefit profile.
The effects of the estrogen agonist-antagonist raloxifene on CHD was studied in a multicenter, randomized trial of approximately 10,000 older postmenopausal women with heart disease or multiple risk factors. Compared with placebo, raloxifene had no significant effect on death from any cause, coronary events, or total stroke, though risk of fatal stroke and venous thromboembolic disease was increased (55). The risks of clinical vertebral fractures and invasive breast cancer were significantly reduced.
Breast Cancer Breast cancer is a major health concern for menopausal women, as it is the most common cancer in women and the second leading cause of cancer death (56). The lifetime risk of invasive breast cancer for US women is 12%; therefore, any therapies that increase or reduce this risk will have a major impact on women’s health. Risk factors for breast cancer include age, family history, early menarche, late menopause, and prior breast disease, including epithelial atypia and cancer. Risk is reduced in women who had bilateral oophorectomy or a term pregnancy before the age of 30. Many of these risk factors are consistent with the hypothesis that prolonged estrogen exposure increases breast cancer risk.
Long-term use of hormone therapy, generally defined as greater than 5 years, is associated with an increased risk of breast cancer (relative risk [RR] = 1.3) in observational studies (57). There is no increased risk of breast cancer in past users of hormone therapy. The results of several studies suggest that the risk of breast cancer associated with the use of estrogen alone may be lower, with a higher risk in users of estrogen plus progestin (58). The WHI randomized controlled trial demonstrated a significant (26%) increase in the risk of invasive breast cancer after approximately 5 years of use of hormone therapy (51). In women with a prior hysterectomy, there was no increased risk of breast cancer after an average of 7 years of use of estrogen alone (52).
Hormone therapy should not be prescribed to women with a history of breast cancer and should be used by women at high risk only after a very careful assessment of potential benefits and risks. A randomized trial of hormone therapy use in women with a history of breast cancer and bothersome hot ﬂashes was stopped after only 2 years, as more new breast cancers were diagnosed in woman randomized to hormone therapy (59).
The estrogen agonist-antagonist tamoxifen (Nolvadex, 20 mg per day orally) is used in the treatment of estrogen-receptor positive breast cancer. Both tamoxifen and raloxifene reduce the risk of breast cancer in high-risk women by approximately 50% and are approved for this indication (60). The risk of venous thromboembolism is increased approximately threefold with the use of tamoxifen and raloxifene, similar to the increase seen with hormone therapy. Tamoxifen acts as an estrogen agonist in the endometrium, increasing the risk of endometrial polyps, hyperplasia, and cancer, whereas no endometrial stimulation is seen with raloxifene. Performing a screening mammography examination annually for women older than age 50 years reduces breast cancer mortality. Monthly breast self-examination is advised.