According to the Women's Health Initiative (WHI) study, the most important risks during combined hormone replacement therapy (HRT) are breast cancer, stroke and venous thromboembolism. To date, combinations of estradiol with natural progesterone or its retroisomer dydrogesterone are the only combined HRT regimens for which large case-control or cohort studies show no increase in any of these three risks. Moreover, due to the neutral effect of dydrogesterone on the vascular and metabolic systems, the preventive effect of the estradiol component with respect to myocardial infarction and metabolic syndrome can be maintained if HRT is started early after the menopause. Although a study with the same design as the WHI has not been performed, these results appear to be plausible considering the positive experimental evidence, particularly in the context of breast cancer and cardiovascular risks/benefits. Combination with dydrogesterone avoids endometrial hyperproliferation, maintains the beneficial effects of estradiol (i.e. efficacy against climacteric symptoms and prevention of osteoporotic fractures) and minimizes the most important risks known to be associated with the progestogen components of HRT regimens.
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