Pulsed estradiol exposure has a limited ability to induce uterine proliferation in ovariectomised female Wistar rats

All post-menopausal hormone replacement therapies (HRT) aim to provide a steady mid-follicular serum concentration of estrogen, with the exception of pulsed estrogen therapy, which concentrates estradiol (E2) exposure in the few hours following administration. This study was carried out to identify and characterise cellular and molecular mechanisms specifically involved in the response of the uterus to pulsed E2. Ovariectomised Wistar rats were treated with E2 for 10 days via IV route to mimic pulsed therapy (1, 4, 10 and 250 μg/kg) or with a subcutaneous pump to mimic standard HRT (10 and 250 μg/kg). Pulsed estrogen therapy effects on uterus was revealed by general E2 sensitivity markers (C3 mRNA, progesterone receptor (PR)) from the lower dose with no over stimulation even at the highest dose conversely to what observed with continuous exposure. Uterotrophic effect of pulsed E2 (uterine weight and epithelium thickness) was observed at all dose administered but with a limited maximal effect comparable to the ranges measurable in sham animals. This data corroborates with proliferating cell nuclear antigen (PCNA) expression in the uterine epithelium used as a marker of proliferation. PCNA was significantly induced after continuous administration but only slightly after pulsed E2 (250 μg/kg). In summary, pulsed E2 leads to a more limited proliferative effect than with continuous E2 in the uterus.