Pituitary, ovarian and endometrial effects of progesterone released prematurely during the proliferative phase

The pituitary, ovarian and endometrial effects of premature exposure to progesterone during the proliferative phase were investigated in 18 normally menstruating women. Daily blood samples were drawn during a control cycle and an endometrial biopsy was obtained on cycle day 6 (in 9 subjects) and on cycle day 11 (in 9 subjects), respectively. Daily blood samples were drawn again throughout a treatment cycle, in which a vaginal delivery system releasing progesterone at a constant rate of 1.4 mg/24 h was inserted and left in situ for 96 hours during cycle days 2-6 (9 subjects) and cycle days 7-11 (9 subjects), respectively. On the 6th and 11th cycle day, respectively, the devices were removed and another biopsy specimen was obtained. In all blood samples the levels of immunoreactive lutropin (LH), estradiol (E2), 17-hydroxyprogesterone (17-HO-P), progesterone (P) and 20 alpha-dihydroprogesterone (20 alpha-HO-P) were estimated by radioimmunoassay. Insertion of the devices resulted in a rapid, approximately six-fold increase (from 0.5 to 3.0 nmol/l) in P levels and an approximately three-fold (from 0.5-0.6 to 1.5-2.0 nmol/l) increase in 20 alpha-HO-P levels. A high degree of correlation was found between P and 20 alpha-HO-P levels. No major changes were observed in the profiles and levels of the other hormonal indices studied. However, premature exposure to small amounts of P during cycle days 2-6 resulted in a significant decrease in the ratio of the E2 to LH peaks and exposure during cycle days 7-11 gave rise to a significant increase in the ratio of the length of follicular to luteal phases. Progesterone released during the early proliferative phase (days 2-6) exerted little, if any, effect on the appearance of the endometrium. However, the same dose of P released during the late proliferative phase (days 7-11) significantly diminished the number of glandular mitoses, the height of the glandular epithelium, reduced pseudostratification and the number of plasmolemmal vesicles, but did not induce any subnuclear vacuolation, predecidual reaction or leucocytic infiltration. It is suggested that systematic studies involving the exposure to progestogens in normally menstruating women during cycle days 7 to 11 will provide a reliable and practical method for the comparative assessment of the potency profile of individual progestogens in women.