OBJECTIVE: To examine the endometrial effects of three different doses of progesterone administered vaginally. METHODS: Forty women 25-41 years old deprived of ovarian function received estradiol (E2) for 28 days. From days 15 to 27, a new mucus-like vaginal gel of progesterone was administered every other day, randomly, dosed at 45 mg (group A, n = 14), 90 mg (group B, n = 13), or 180 mg (group C, n = 13). Plasma gonadotropins, estrone, E2, and progesterone were measured. An endometrial biopsy was performed on day 20 (n = 20) or 24 (n = 20) for endometrial dating and for estrogen and progesterone receptor determinations. RESULTS: Plasma estrogen levels were in the menstrual cycle range. Mean progesterone levels were lower in group A (2.4 +/- 0.2 ng/mL) than in group B (3.6 +/- 0.2 ng/mL) or C (3.4 +/- 0.4 ng/mL) (P < .005). Plasma FSH and LH decreased significantly during progesterone treatment. In all groups, we observed secretory transformation in the glands (day 20) and stroma (day 24) and the distribution of estrogen and progesterone receptors seen in normal menstrual cycles. CONCLUSION: Transvaginal administration of progesterone induced normal secretory transformation of the endometrium despite low plasma levels, suggesting a direct transit into the uterus or "first uterine pass effect."