Previous studies of the role of estrogen in primate luteolysis, designed to investigate the effects of estrogen antagonism or selective inhibition of luteal phase estrogen production on luteal function, have ignored the impact of such treatments on secretory endometrial development. We examined the effect of luteal phase estrogen antagonism on endometrial maturation and luteal function in six women. In each of two menstrual cycles in each woman, blood samples were obtained on alternate days from cycle days 3-9, daily until 1 day after the urinary LH surge (day 0), and again on alternate days until the onset of menses. In the second of each pair of cycles, clomiphene citrate (100 mg) was administered daily from 2 days after the LH surge until menses. Endometrial biopsy was performed 13 days after the LH surge in each cycle. Serum FSH, LH, estradiol, and progesterone (P) were measured by RIA. The endometrial histological date and concentration of cytosolic (C) and nuclear (N) estrogen (ER) and P (PR) receptors were determined. We found significant (P less than 0.05) increases in luteal phase serum FSH, LH, estradiol, and P levels in the clomiphene cycle compared to those in the control cycle. Endometrial histology was significantly (P less than 0.002) different during estrogen antagonism; a maturation delay of more than 2 days was found in all six women during the clomiphene cycle. Luteal phase duration was unchanged by clomiphene (P = 0.29). Endometrial ER-C [7.38 +/- 2.52 (+/- SEM) vs. 38.75 +/- 10.17 fmol/mg protein], ER-N (248 +/- 84 vs. 685 +/- 80 fmol/mg DNA), and PR-C (97 +/- 38 vs. 189 +/- 38 fmol/mg protein) were significantly lower (P less than 0.03) in the clomiphene cycle than in the control cycle, whereas PR-N was not different (P greater than 0.10). These data suggest that luteal phase estrogen 1) modulates endometrial PR and 2) plays an important role in secretory endometrial development.