Impact of isotype selective estrogen receptor agonists on ovarian function

Novel isotype selective receptor (ER) agonists, the selective ERalpha agonist 16-alpha-LE2 and the selective ERbeta agonist 8beta-VE2, were used in several studies in hypophysectomized rats or GnRH treated immature mice as well as in mature rats to elucidate the effect of subtype selective estrogens on the physiology of folliculogenesis and ovulation. In immature hypophysectomized animals, the ERbeta agonist and the reference compound 17beta-estradiol caused stimulation of early folliculogenesis, a decrease in follicular atresia, induction of ovarian gene expression and stimulation of late follicular growth accompanied by an increase in the number of ovulated oocytes. The ERbeta agonsit exhibited the same efficiency and a similar high potency as 17beta-estradiol in the respective studies. In contrast, the ERalpha agonist had little or no effect on these parameters implying that direct estrogen effects on ovarian follicular development are mediated by ERbeta. In adult rats, 17beta-estradiol and the ERalpha agonist caused a dose dependent inhibition of ovulation in contrast to the ERbeta agonist which affected ovulation only at very high doses. In contrast to 17beta-estradiol and the ERalpha agonist, the ERbeta agonist did not cause a detectable effect on uterine weight in intact female rats. This is in line with the assumption that the inhibitory effect of estrogens on ovulation and the stimulatory effect on the uterus are mediated by ERalpha but not by ERbeta. If future studies provide evidence that the selective follicle stimulating effect of the ERbeta agonist leads to improvement of oocyte and embryo quality, ERbeta agonists may provide clinicans the unique new option for tailoring classical ovarian stimulation protocols by the use of ERbeta agonists.