Hormone replacement therapy in the post-Women's Health Initiative era. Report a a meeting held in Funchal, Madeira, February 24-25, 2003.

Over 24-25 February 2003 in Funchal, Madeira, Novo Nordisk gathered together 25 of the top international hormone replacement therapy (HRT) experts, in order to debate the results of the Women's Health Initiative (WHI) and interpret its possible implications for the future use of HRT. The meeting covered many interesting and controversial areas, addressing the complex and multifaceted issues with insight and realism. Some of the areas covered at the meeting were the use of HRT as a short- or long-term therapy for hot flushes, for general menopausal symptom relief and in osteoporosis prevention; the overall risk-benefit profile and specific breast cancer concerns were also discussed. The WHI data were reviewed and summarized, and, although it was generally agreed that the study was well designed and executed, its relevance to standard hormone therapy for clinical practice must be seriously called into question. The target population used in the WHI is not representative of the target population for whom menopausal HRT is normally considered. It is important to note that randomized controlled trials such as the WHI are really scientific tools for a group of research participants, not a form of individualized medical management. Since their publication, the relevance of the WHI study results for everyday clinical practice has been the subject of controversy. The WHI targeted a group of women who were much older than those normally treated and who had numerous other risk factors. These were not women for whom a practicing clinician would think about initiating hormone therapy with the regimen that was used. Putting a high-risk 70-year-old woman on 0.625 mg conjugated equine estrogens (CEE) plus 2.5 mg medroxyprogesterone acetate would not seem appropriate for any indication. With this in mind, we reviewed statements and guidance that followed the release of the WHI to the media, putting them in context with the actual results. Focusing on data taken out of context and without reference to subject profiles, the media created an emotive wave of uncertainty for patients and physicians, which needs to be addressed through realistic, factual communication. It is clear that hormone therapy is effective for postmenopausal symptoms and osteoporosis prevention. Timing is critical for the initiation of therapy and length of treatment. The individual's unique personal profile must be assessed. This leads to the paradox of osteoporosis prevention: therapy should be long-term, but it is long-term therapy that may increase breast cancer risk. The meeting reviewed the uncertain nature of the risks for breast cancer, although the evidence is becoming stronger that combinations of estrogen and progestogen cause a modest increase in risk after 5 years, while this seems not to be true for estrogen alone. Cardiovascular disease issues were also reviewed and discussed. This is perhaps the most misinterpreted result that came out of the WHI, given the population of women studied. Considering the vascular biology and effects of early interventions, the WHI finding that hormone therapy has no place in primary cardiovascular protection is an unwarranted conclusion. Other issues regarding the risk-benefit profile of HRT for the individual patient were also discussed. Additionally, presenters explored the possibility of class effects against the potential risk factors associated with particular estrogen and progestogen types. It is quite clear that CEE and 17beta-estradiol differ with respect to their source and composition; pharmacokinetic and metabolic data indicate that they differ in their total estrogenic potency, with CEE possessing greater estrogenic potency. Using 17beta-estradiol at the lowest dosage level can provide safe and effective therapy for most indications. The evidence for progestogen differences is even more clear. Medroxyprogesterone acetate and norethisterone acetate have different pharmacokinetic profiles and different activities on steroid receptors. Evidence from preclinical and clinical studies supports the conclusion that these differences result in different pharmacological and clinical effects in favor of norethisterone acetate. Having comprehensively discussed and reviewed all available evidence, a consensus was achieved with regard to appropriate therapy: HRT should be given to women with menopausal complaints to meet their individual needs, taking into account their individual risk profile and the overall therapeutic objectives.