In this prospective clinical study, gene expression analysis of healthy post-menopausal women indicated that the genes which encode Ki-67, a cellular marker for proliferation, and progesterone receptor B mRNA are differentially expressed in women taking bio-identical or natural estrogen HRT. Two 28-day cycles of daily estradiol gel (1.5mg) and oral micronized progesterone (200mg) on days 14-28 did not significantly increase breast epithelial proliferation at the cellular level nor the mRNA level. However, daily oral conjugated equine estrogens (CEE) (0.625mg) and oral medroxyprogesterone acetate (MPA) (5mg on days 14-28) significantly increased proliferation at both the cellular and mRNA level. Furthermore, CEE + MPA was found to significantly enhance mammographic breast density, an important risk factor for breast cancer. This finding suggests that hormone therapy using natural estrogens effects a smaller number of genes and has less adverse effects on the normal breast in vivo than synthetic hormone therapy.