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 microg/kg) or with a subcutaneous pump to mimic standard HRT (10 and 250 microg/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 microg/kg). In summary, pulsed E2 leads to a more limited proliferative effect than with continuous E2 in the uterus.

The differential ability of the phytoestrogen genistein and of estradiol to induce uterine weight and proliferation in the rat is associated with a substance specific modulation of uterine gene expression.

In this study the ability of the phytoestrogen genistein (GEN) to regulate proliferation in the rat uterine tissue and the associated molecular mechanisms were investigated in a dose and time dependent manner. A single administration of GEN induced a rapid increase of the uterine weight during the first 24 h. In contrast to E2, treatment with GEN for 3 days did not result in a further increase of the uterine weight. GEN only marginally effected the thickness of the uterine epithelium and the expression of epithelial proliferating cell nuclear antigen (PCNA). Whereas, estrogen sensitive genes were modulated significantly, the expression of key genes involved in the regulation of proliferation (PCNA, ERalpha /ERbeta ratio) remained unaffected by GEN. Our results indicate that GEN has only a limited ability to activate molecular mechanisms involved in the induction of proliferation whereas estrogen sensitive genes are induced in a estrogen like manner.