Further data favoring the hypothesis of the uterine first-pass effect of vaginally administered micronized progesterone

Ten infertile women, 28 to 36 years of age, with regular menstrual cycles were treated with oral estradiol valerate and intravaginally administered micronized progesterone under pituitary suppression with leuprolide acetate. Patients underwent endometrial biopsies on cycle days 17 and 28 (luteal phase days 3 and 14) and blood sampling for plasma progesterone and estradiol determinations on cycle days 17, 21 and 26 (luteal phase days 3, 7 and 12). All ten endometrial biopsies on cycle day 17 were in-phase and only two out of ten (20%) were out-of-phase on cycle day 28. This produced an incidence of endometrial luteal phase deficiency that was not different from the 14% found among an infertile general population of 300 women. Midluteal estradiol plasma levels in the study group were similar to those found in a control group of fertile women, but progesterone levels were significantly lower on cycle day 21 in the treatment group. As much as 75% (six of eight patients) of treated women having in-phase late luteal endometrial biopsies had low midluteal plasma progesterone levels, a situation that is found in only 3% of infertile patients (9/300) of 3.5% (9/258) of those infertile women with normal endometria (p=0.03). Thus, the present study adds further evidence favoring the current postulate that vaginal micronized progesterone enhances hormone delivery to the uterus and this explains the marked discrepancy between the strong uterine effect and the relatively low plasma progesterone levels.