ABSTRACT
The justification for stopping the WHI study, and the validity of a global index as a measure for the risk/benefit ratio, have been discussed ever since. The discussion was further fueled by publication of the Million Women Study, indicating an even larger risk of breast cancer in HRT users than reported in the WHI study13. The regulatory authorities and medical associations reacted promptly. The US Preventive Services Task Force (USPSTF) concluded that the harmful effects of combined estrogen-and-progestin HRT were likely to exceed the chronic disease prevention benefits in most women14, and most organizations with guidelines on postmenopausal HRT have followed and revised their recommendations. Following the premature stop of the WHI study and the Million Women Study, HRT is now generally considered an acceptable treatment option for menopausal symptoms, but most organizations recommend against the longterm use of HRT for prevention. Also, the European Medicines Evaluation Agency (EMEA) no longer consider HRT as a first-line treatment for the long-term prevention of osteoporosis. HRT remains an option for postmenopausal women who are at high risk of future fractures, and who are intolerant of, or contraindicated for, other
Although hormone replacement therapy (HRT) is mainly prescribed for relief of vasomotor symptoms and urogenital atrophy, HRT has also been indicated for the prevention of postmenopausal osteoporosis. As shown by cohort studies and randomized controlled trials, HRT increases bone mineral density (BMD) and reduces the risk for fractures1-4. In addition, there is evidence that HRT reduces the risk for colorectal cancer5,6. HRT may also possibly reduce the risk of cognitive decline and dementia7. Until 2002, there was also fair evidence – mostly from large, prospective cohort studies – that HRT could protect women against cardiovascular disease8-10. However, the results from a secondary prevention trial (Heart and Estrogen/progestin Replacement Study (HERS) I and HERS II) did not demonstrate any benefit in terms of cardiovascular protection11,12, and the results from the Women’s Health Initiative (WHI)1 study published in 2002 showed that HRT was also not effective for primary prevention of cardiovascular disease. This latter outcome has considerably changed the perceived balance of benefits and harms of HRT. For the Data and Safety Monitoring Board (DSMB), a ‘global index’ was devised for the WHI studies to estimate the risk/benefit ratio. The index included the two primary outcomes coronary heart disease and invasive breast cancer, plus stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture and death due to other causes. It excluded menopausal symptoms and other osteoporotic fractures. Based on the ‘global index’, indicating
medicinal products approved for the prevention of osteoporosis15.
