This study shows that HRT, as given in this trial is associated with moderate increase of non-fatal conditions including coronary heart disease, strokes, breast cancer and thromboembolism, with a concomitant reduction of colorectal cancer, and of skeletal fractures. Importantly, the mortality of these individual conditions has not been affected. Longer follow up is required to document whether the previously observed reduction in the mortality of the conditions evaluated in this trial (including breast cancer) seen in most observational studies, will also materialize also in this study population.

1. Results of this study cannot support, at this short follow of duration, HRT use for the primary prevention of CHD without intractable menopausal symptoms. Rather, it is recommended that women not suffering intractable menopausal symptoms but who take HRT for prevention of degenerative disease, consider other manoeuvers known to be effective for a given condition (i.e. statins for CHD; biphosphonates / SERMs for osteoporosis, etc.). However, if future follow up of this study shows mortality reductions of the conditions targeted by this trial, then these recommendations should be reassessed.

2. This study has not addressed the issue of QOL in women suffering intractable menopausal symptoms, nor has it evaluated incidence or mortality of the above conditions restricted to population women with intractable menopausal symptomatology. These women may differ in many characteristics from the participants in this trial who were selected for primary prevention. Therefore, it is appropriate to exercise caution in applying conclusions of this study for the population for which HRT should be directly indicated (i.e. for the young postmenopausal women suffering with menopausal symptoms). In those, the decision criteria for accepting or rejecting HRT and its risks and benefits may be entirely different.

3. Women with intractable menopausal symptoms should be counselled about the risks and benefits of HRT use so that these women are not discouraged from starting or continuing HRT. The recommendations for HRT could be considered if other manoeuvers to reduce the symptoms of menopause have shown to be ineffective, particularly in women with low recognized risk factors for those conditions with excess risk.

4. All women who have already started on HRT should be vigilantly monitored for all conditions causing excess risk as identified in this study, with early HRT discontinuation at first symptoms.

5. It is also prudent to recommend, that if HRT use is considered, the dosage and duration of HRT be kept at a minimum to achieve symptom relief, and that other interventions (i.e. vaginal estrogen ring, exercise, diet, reduction of stress, etc.) are considered.

6. Further follow up of this study, and of other research initiatives assessing hormonal use in selected populations of women (including also breast cancer survivors suffering with intractable menopausal symptoms), are required to fully determine the long-term impact of hormones on overall health, quality of life, and all-cause mortality.