ERAAs for menopause treatment: Welcome the ‘designer estrogens’
ABSTRACT
Estrogen receptor agonist-antagonists (ERAAs) selectively inhibit or stimulate estrogen-like action in targeted tissues. This review summarizes how ERAAs can be used in combination with an estrogen or alone to treat menopausal symptoms (vasomotor symptoms, genitourinary syndrome of menopause), breast cancer or the risk of breast cancer, osteopenia, osteoporosis, and other female midlife concerns.
KEY POINTS
- Tamoxifen is approved to prevent and treat breast cancer. It may also have beneficial effects on bone and on cardiovascular risk factors, but these are not approved uses.
- Raloxifene, a second-generation ERAA, was initially approved for preventing and treating osteoporosis and later received approval to reduce the risk of invasive estrogen receptor-positive breast cancer in postmenopausal women.
- Ospemifene is approved for treatment of genitourinary syndrome of menopause.
- The combination of conjugated estrogen and bazedoxifene is approved for treating moderate to severe vasomotor symptoms associated with menopause and also for preventing postmenopausal osteoporosis in women with an intact uterus.
TAMOXIFEN: CANCER TREATMENT AND PREVENTION
After clomiphene, tamoxifen was the second ERAA on the market. Although researchers were looking for a new contraceptive drug, they found tamoxifen to be useful as a chemotherapeutic agent for breast cancer. First used in 1971, tamoxifen continues to be one of the most commonly prescribed chemotherapeutic medications today.
The FDA has approved tamoxifen to treat breast cancer as well as to prevent breast cancer in pre- and postmenopausal women at risk. It may also have beneficial effects on bone and on cardiovascular risk factors, but these are not approved uses for it.
Trials of tamoxifen for cancer treatment
The Early Breast Cancer Trialists’ Collaborative Group9 performed a meta-analysis and found that 5 years of adjuvant treatment with tamoxifen is associated with a 26% reduction in mortality and a 47% reduction in breast cancer recurrence at 10 years. In absolute terms, we estimate that 21 women would need to be treated to prevent 1 death and 8 would need to be treated to prevent 1 recurrence.
The ATLAS Trial (Adjuvant Tamoxifen Longer Against Shorter)10 and later the UK ATTOM (Adjuvant Tamoxifen Treatment to Offer More)11 trial confirmed an even greater reduction in recurrence and mortality after a total of 10 years of treatment.
Trials of tamoxifen for cancer prevention
Cuzik et al12 performed a meta-analysis of 4 trials of tamoxifen’s effectiveness in preventing breast cancer for women at elevated risk. The incidence of estrogen receptor-positive breast cancer was 48% lower with tamoxifen use, but there was no effect on estrogen-negative breast cancer. From their data, we estimate that 77 women would need to be treated to prevent 1 case of breast cancer.
The IBIS-I trial (International Breast Cancer Intervention Study I)13 found that, in healthy women at high risk of breast cancer, the benefit of taking tamoxifen for 5 years as preventive treatment persisted long afterward. The investigators estimated that at 20 years of follow-up the risk of breast cancer would be 12.3% in placebo recipients and 7.8% in tamoxifen recipients, a 4.5% absolute risk reduction; number needed to treat (NNT) 22.
Data on tamoxifen and osteoporosis
The Breast Cancer Prevention Trial revealed a 19% reduction in the incidence of osteoporotic fractures with tamoxifen, but the difference was not statistically significant.14 The 1-year rates of fracture in women age 50 and older were 0.727% with placebo and 0.567% with tamoxifen, an absolute difference of 0.151%; therefore, if the effect is real, 662 women age 50 or older would need to be treated for 1 year to prevent 1 fracture. Tamoxifen is not FDA-approved to treat osteoporosis.
Data on tamoxifen and cardiovascular risk reduction
Chang et al,15 in a study in women at risk of breast cancer, incidentally found that tamoxifen was associated with a 13% reduction in total cholesterol compared with placebo.
Herrington and Klein,16 in a systematic review, noted similar findings in multiple studies of tamoxifen, with decreases in total cholesterol ranging from 7% to 17% and decreases in low-density lipoprotein cholesterol ranging from 10% to 28%. However, they found no change in high-density lipoprotein cholesterol concentrations or in the cardiovascular mortality rate.
The ATLAS trial10 revealed a relative risk reduction of 0.76 (95% confidence interval [CI] 0.60–0.95, P = .02) in ischemic heart disease for women who took tamoxifen for 10 years compared with 5 years. We calculate that ischemic heart disease occurred in 163 (2.5%) of 6,440 women who took tamoxifen for 5 years compared with 127 (1.9%) of 6,454 women who took it for 10 years, a 0.6% absolute risk reduction, NNT = 167.
Adverse effects of tamoxifen
Uterine neoplasia. Women taking tamoxifen have a 2.5-fold increased risk of endometrial cancer.14 Tamoxifen also increases the risk of benign uterine disease such as endometrial hyperplasia and polyps. As many as 39% of women taking tamoxifen will have evidence of benign uterine changes on pathology.17 Other adverse effects:
Venous thromboembolism (the risk of pulmonary embolism is increased approximately threefold14)
Cataracts (there is a slight increase in cataract diagnosis in tamoxifen users)
Vasomotor symptoms, which limit the use of tamoxifen in many women.
Ideal candidate for tamoxifen
The ideal candidate for tamoxifen is a woman with breast cancer that is estrogen receptor-positive and who has a history of osteopenia or osteoporosis and no risk factors for venous thromboembolism.
