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In Reply: We agree with Dr Smith and colleagues that there are a variety of direct and indirect mechanisms by which estrogen and estrogen-containing hormone therapy could affect brain function or be associated with neurologic disease. The pathogenic relevance of modest elevations in plasma gonadotropin concentrations observed in women (but not men) with AD¹ is open to speculation and, of course, to experimental investigation and empirical validation.

Dr Rosenberg makes the point that recent randomized trials document increased risk of coronary heart disease for users of estrogen/progestin therapy, a finding that contrasts with benefit anticipated on the basis of several earlier observational studies. As Rosenberg notes, different results likely reflect the healthy user bias in observational studies, ie, the tendency for women who choose to take hormone therapy to be healthier and more highly educated. We discussed possible biases, confounders, and other limitations of the study by Zandi et al.² . . . [Full Text of this Article]

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