Hormone Replacement Therapy : The New Debate Susan T. Hingle, M.D.
Background Hormone replacement therapy (HRT) is extensively used in the United States, especially for: *treatment of menopausal symptoms *prevention of heart disease *prevention and treatment of osteoporosis
Background Continued There is some evidence (but NOT conclusive) for using HRT for: prevention of colon cancer prevention of dementia
What Do We Know? HRT relieves symptoms of menopause Increases bone mineral density, decreases fracture risk Decreases LDL, increases HDL, decreases lipoprotein(a), but increases TG s New evidence shows no cardiac benefit in women with known CAD
Recent clinical trials have raised new questions about the risks and benefits of HRT There are now other options, such as the specialized estrogen receptor modulators and bisphosphonates
Some of the Remaining Questions Is HRT effective in primary prevention of coronary disease? Does HRT increase the risk of breast cancer? BOTTOM LINE: Are the benefits worth the risks?
Clinical Trials
PEPI (Postmenopausal Estrogen and Progesterone Interventions) Started in 1995 Subjects: 875 postmenopausal women Design: 3 year randomized, double-blind, placebo-controlled clinical trial Objective: To determine effects of HRT on cholesterol Results: Increase in HDL, increase in TG s
HERS (Heart and Estrogen Replacement Started in 1998 Study) Subjects: 2763 postmenopausal women with known CAD Design: Large, randomized, double-blinded, placebo-controlled secondary prevention trial Objective: To determine if HRT alters risk for cardiac events in women with known CAD (followed for ~4 years) Results: Decrease LDL, increase HDL, increase TG s, no change in cardiac events
ERA (Estrogen Replacement and Atherosclerosis) Started in 1999, recently completed Subjects: 309 postmenopausal women with known CAD Design: Randomized, double-blind, placebocontrol trial (3 year follow-up) Objective: To determine effects of HRT vs. placebo on progression of atherosclerosis (using angiography) Results: Improved lipid profile, but did NOT alter progression of atherosclerosis
CAD (Estrogen Replacement and Coronary Artery Disease) Study published in 1990 10 year randomized angiographic study of 2268 women with CAD Showed a statistically significant ( p < 0.007) improvement in survival for women on HRT
ACAPS (Asymptomatic Carotid Atherosclerotic Progression Study) Study of postmenopausal women with asymptomatic carotid disease Published in 1995 Showed cessation of progression and some regression of carotid artery atherosclerosis as assessed by ultrasound
WHI (Women s Health Initiative) Started in 1992 Subjects: >160,000 multi-ethnic women aged 50-79yo; >27,000 on HRT for 6-11 years Design: Long-term (15 year), double-blind clinical trial (64,500 women) and observational study (100,000 women) Objective: To evaluate strategies for preventing CAD, breast cancer, colon cancer, and osteoporosis Ongoing study, preliminary data not promising
WISDOM (Women s International Study of Long Duration Oestrogen After Menopause) On-going International randomized controlled study designed to help clarify if HRT is effective in primary prevention of CHD events
Breast Cancer
Background Link between hormones and breast cancer dates back to 1896 when George Basten described a partial response in three premenopausal women with breast cancer in response to bilateral oophorectomy Rebbeck et al recently found decrease in breast cancer in women with BRCA 1 mutations who underwent oophorectomies
Anti-estrogens decrease the incidence of breast cancer In vitro, estrogens have been shown to modulate human breast cancer cells Risk factors for breast cancer include nulliparity, early menarche and late menopause
Nachtigall et al Published in 1992 The only placebo-controlled randomized trial to date with breast cancer as the primary end point Matched 84 pairs of postmenopausal women to HRT vs. placebo for 10 years Incidence in placebo was 11.5% Incidence in HRT group was 0%
Recent Retrospective Studies
Meta-Analyses STUDY # OF STUDIES EVER USED -- RR Armstrong 23 1.01 (0.95-1.08) Steinberg 16 1.01 (0.99-1.02) Dupont & 31 1.07 (1.01- Page 1.10) Silero-Arenas 27 1.06 (1.00-1.12) Grady 35 1.01 (0.97-1.05) Colditz 34 1.02 (0.93-1.12) LONG TERM USE - 1.30 (1.20-1.60) 1.09 (0.89-1.50) 1.23 (1.07-1.42) 1.25 (1.04-1.51) 1.23 (1.08-1.40)
Collaborative Group on Hormonal Factors in Breast Cancer (CGHFBC) Meta-analysis from 51 epidemiological studies 52,705 women with breast cancer and 108, 411 women without breast cancer RR increases with duration of use (~7 years) Increased risk dissipates within 4 years of stopping estrogen therapy
ERT vs. HRT STUDY CASES RR w/ RR w/ ERT HRT Schairer 2082 1.2 1.4 Ross 1897 0.93 1.79 Colditz 2035 1.1 1.58 Magnussen 3345 2.7 2.95 Newcomb 3130 0.81 1.06
Yearly Incremental Relative Risk Study ERT HRT Schairer 1% 8% Ross 1.2% 7.6% Colditz 3.3% 9% Magnussen 3% 7%
WHI (Women s Health Initiative) Started in 1992 Subjects: >160,000 multi-ethnic women aged 50-79yo; >27,000 on HRT for 6-11 years Design: Long-term (15 year), double-blind clinical trial (64,500 women) and observational study (100,000 women) Objective: To evaluate strategies for preventing CAD, breast cancer, colon cancer, and osteoporosis Ongoing study
WISDOM (Women s International Study of Long Duration Oestrogen After Menopause) On-going International randomized controlled study designed to help clarify if HRT increases risk of breast cancer
So what should we do?
HRT and Menopause
HRT and Heart Disease
HRT and Osteoporosis