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We sought to determine if micronized progesterone in estrogen-primed women has an effect on the available cycling pool of proliferating glandular cells by studying 107 postmenopausal women who participated in a double-blind cyclical HRT trial. Each received 0.625 mg/day of conjugated equine estrogen (Premarin) orally for 6 weeks (cycle 1), followed by a baseline endometrial biopsy. These women were randomized to one of four doses (100 through 400 mg/day) of progesterone taken the last 10 days of each cycle or to estrogen only. Cyclical HRT (25-day cycles) was continued for three more cycles. Endometrial biopsies were performed at the end of cycle 4 and 64 subjects demonstrated an adequate biopsy for immunohistochemical evaluation. The number of proliferating gland cells was determined by an immunohistochemical stain measuring positive MIB1 staining nuclei per thousand gland cells. The number of proliferating endometrial gland cells in the cycling pool of women receiving 300-and 400-mg daily doses of progesterone was low (mean 4.9 and 1.7, respectively) when compared with women receiving 100 mg progesterone (mean 27.0) or to unopposed estrogen (mean 30.3). Late secretory endometrium from 19 premenopausal women had a mean of 0.6. In the progesterone-treated subjects, biopsies showed that secretory maturation increased as the serum progesterone and doses of progesterone increased. We conclude that micronized progesterone given to estrogen-primed menopausal women results in a dose dependent decrease in endometrial gland proliferation. The use of an immunohistochemical stain and the diagnosis of histologic secretory maturation are complementary techniques in determining the inhibition of glandular proliferation.