Effects of pulsed or continuous estradiol exposure on uterine growth, histology, gene expression and proliferation in ovariectomised female wistar rats

Abstract

A wide variety of routes of administration and formulations are employed in estrogen replacement therapy. Recently, an intranasal 17ß-estradiol (E2) spray S21400 (AERODIOL) has been developed. This study was set out to investigate the effects of pulsed estrogen administration compared to continuous therapy, with regard to uterine proliferation. Ovariectomised wistar rats were either treated pulsed or continuously with 1, 4, 10 and 250mg/kg/BW E2 for 10 days. Control groups consisted of ovariectomised and Sham-operated rats. Uterine weight, the height of the uterine epithelium, the expression of Complement 3 gene (C3) and PCNA was determined. Continuous administration of E2 resulted in a dose dependent increase of uterine dry and wet weight and an increase of the height of the uterine epithelium. A dose of 10mg/kg/BW/day resulted in a uterine wet weight comparable to Sham animals but in a thickness of the uterine epithelium of 42mm, compared to 25mm of the Sham animals. Pulsed administration of E2 resulted even in the highest dose administrated in a uterine wet weight of 50% of the Sham animals. The height of the uterine epithelium was stimulated to a maximum of 30mm, even in the highest dose administrated. Pulsed administration of 10 and 250mg/kg/BW/day E2 resulted in a 5-fold induction of C3 mRNA expression compared to Sham animals, whereas the C3 expression in continuously treated animals was induced 10 respectively 15-fold compared to Sham animals. Proliferation in the uterine epithelium, indicated by immunohistochemical analysis of PCNA expression, was stimulated dramatically after continuous administration of 10mg/mg/BW day E2. In contrast, only a faint stimulation of proliferation could be detected in pulsed treated animals. In conclusion our data demonstrate that pulsed administration of E2 resulted in a significantly lower activity on the uterine epithelium compared to continuous administration. Our results strengthen data of clinical studies demonstrating a good endometrial safety of pulsed estrogen therapy