27 - 30 May 2005

NOVEL SELECTIVE AGONISTS AS TOOLS TO DISSECT BIOLOGICAL FUNCTIONS OF ER ALPHA AND ER BETA Fritzemeier KH*, Prelle K*, Hegele-Hartung C**, Hillisch A°,Kosemund D+, Kaufmann U*, Mueller G+, Muhn P*, Peters O+ *Schering AG Female Health Care Research **Schering AG Safety Pharmacology +Jenapharm GmbH+Co.KG Medical Chemistry °EnTec GmbH Structural Bioinformatics and Drug Design

Estrogens exhibit physiological effects mainly through two different nuclear estrogen receptors (ERs). Erbeta is predominantly expressed in ovarian granulosa cells, prostate, vascular tissue, immune cells, intestine and specific brain regions, whereas pituitary, uterus and liver express Eralpha at high levels.

Data from various lines of Erbeta knockout mice showing different degrees of female subfertility or infertility due to reduced follicular maturation and ovulation rate imply that Erbeta plays an important role in the control of ovarian function and folliculogenesis. The stimulatory activity of estrogens on granulosa cell growth was demonstrated in diverse studies in rodents. Less information is available on direct effects of oestrogen on the human ovary. However, a number of primate studies indicate that oestrogen-free or reduced intraovarian oestrogen levels are associated with reduced rates of meiotic maturation and fertilisation.

Additional information on the function of Eralpha and Erbeta will be provided by the application of subtype-selective ER-agonists. Based on the crystal structure of the Eralpha ligand-binding domain steroidal ligands were designed to bind preferentially to either Eralpha or Erbeta and were tested in vitro using transactivation assays. This approach directly led to highly ER isotype-selective (~200 fold) and potent ligands (50% of E2). To unravel physiological effects, in vivo experiments were performed using the Eralpha- and Erbeta-selective ligands. In ovariectomised rats the Eralpha ligand induced uterine growth and caused bone-protective effects, while the Erbeta ligand exhibited estrogen-like effects on these parameters only at high doses.

Therefore, oestrogen effects on the uterus, pituitary, bone and liver may be primarily mediated via Eralpha. In hypophysectomised animals, the Erbeta agonist caused stimulation of early folliculogenesis and a decrease in follicular atresia, accompanied by an increase in the number of ovulated oocytes. In contrast, the Eralpha agonist had little or no effect on these parameters implying that direct oestrogen effects on follicular development are mediated primarily by Erbeta.

List of abstracts from the 3rd International Conference on the Female Reproductive Tract