The objective of the present study was to examine the zonal changes in endometrial proliferation that occur during the late secretory phase, menses, and postmenstrual endometrial regeneration. We used as our model ovariectomized rhesus monkey in which artificial menstrual cycles were simulated. Our marker of proliferation was the immunohistochemical detection of the Ki-67 antigen. On Day 26, as progesterone (P) levels are falling in the late secretory phase, proliferation in zone IV of the basalis decreased compared with Day 23 (peak P level). Proliferation in the upper regions of the endometrium remained suppressed. Three days after a single bolus injection of the potent antiprogestin RU-486 on Day 20, proliferation in zone IV was virtually absent compared with Day 23 of an artificial cycle. No distinct changes in the pattern of proliferation were observed in the upper regions of the endometrium. On Day 1 of menses (P levels undetectable, estradiol [E] levels of 70-100 pg/ml), there was little proliferation throughout the endometrium. On Day 3 or menses, proliferation returned to zones II-III of the basalis and the functionalis. This proliferation was primarily observed in the glandular epithelia whereas little or no proliferation was observed in zone IV of the basalis. By Day 5 proliferation continued in the glandular epithelia of zones I, II, and III, and was now clearly observable in the stromal cells. Only minimal proliferation was observed in glandular epithelia of zone IV. In the absence of basal E stimulation the return of proliferation to the glandular epithelia in zones I, II, and III was dramatically reduced. These data demonstrate a reciprocal pattern of proliferation in glandular epithelia that is dependent on the prevailing hormonal stimulation. Under P dominance, proliferation is inhibited in zones I, II, and III, and maintained in zone IV, whereas under E dominance (Day 3 or 5) proliferation is driven by E stimulation in zones I, II, and III with little or no proliferation present in zone IV. In addition, the inhibition of proliferation in zone IV by the antiprogestin RU-486 and the decline of zone IV proliferation associated with falling P levels provide further evidence that proliferation of glandular epithelia in zone IV is mediated in part by P.