Estrogen and Cardiac Events with all-cause Mortality. A Critical Review

As seen in the first part of this review, the primary objective of the WHI HRT trials was to evaluate the impact of HRT on cardiac and degenerative conditions among elderly women, where these outcomes are most frequent, and not necessarily to study the impact of HRT on menopause-related outcomes, or on primary prevention of heart and vascular diseases, which would require a much younger female population. The differential age impact of HRT on cardiovascular outcomes is singled out in this second chapter of our HRT review of particular importance, as the “harm versus benefit” ratio seen among older women may not necessarily be applicable to younger age groups. Specifically, as discussed below, cardiac gains have been restricted to young women and have not been identified in the elderly female population, as seen from most past trials, and now more lately also from the WHI HRT trials. The other issue requiring clarification is the agent specificity, within the HRT combination, and in particular, it is the HRT based on estrogen-alone which would render significant cardiac protection [i.e., evidence from WHI HRT trial 2], while HRT based on estrogen plus Provera combination [E + P] as seen in the WHI trial 1, would not materialize these benefits. As seen in Table 1, the rate of myocardial infarction among the younger women aged 50–59 was reduced in estrogen alone trial by 40–45 %, compared, to an actual rate increase of 25–27 % among women of similar age 50–59 in the combined estrogen plus progestin trial. So we have at least two HRT issues requiring clarification: First, can one today, in 2016, endorse more fully the “HRT cardiac timing hypothesis” where HRT cardiac benefits are restricted to young women only; and second, whether Progestin Provera would attenuate estrogen cardiac benefits, as there is some evidence at least from the overview of the WHI HRT trials that adding the Medroxyprogesterone Provera in the E + P combination would basically abolish benefits seen with estrogen alone.